Tuberculosis drug shows promise against latent bacteria
September 13, 2008 by Breakthrough digest
A new study has shown that an investigational drug (R207910, currently in clinical trials against multi-drug resistant tuberculosis strains) is quite effective at killing latent bacteria. This revelation suggests that R207910 may lead to improved and shortened treatments for this globally prevalent disease.
Despite numerous treatment advances, tuberculosis (TB) remains a serious disease –fueled by co-infection of HIV patients, the rise of drug-resistant strains, and the ability of Mycobacterium tuberculosis to become dormant and linger in the lungs. In fact, one third of the world population is infected, asymptomatically, with latent TB and is at risk of developing active TB disease during their life time.
Anil Koul and colleagues at Johnson & Johnson tested ? on dormant M. tuberculosis in three different laboratory models of latency. ? targets a protein (ATP synthase) essential for making cellular energy (ATP) in actively replicating TB. The researchers reasoned that even dormant bacteria, which are essentially physiologically “turned off”, still need to produce small quantities of ATP to survive. As such, a block in ATP synthesis might be an Achilles heel for killing dormant bacteria.
This reasoning proved to be correct and ? was able to kill dormant bacteria by greater than 95% whereas current drugs like isoniazid had no effect. Surprisingly, they found that ? is slightly more effective in killing dormant bacteria as compared to actively replicating ones, a unique spin as all known TB drugs are more effective on replicating bugs. Koul and colleagues hope to validate these results clinically, and note that ATP synthase should be looked at as a drug target for other persistent bacterial infections.
Sunday, September 14, 2008
Anti Tumor Therapy....
Anti-tumor therapy with endoscopic ultrasound may fight cancer more safely and effectively
September 12, 2008 by
Anti-tumor therapy guided by endoscopic ultrasound may allow doctors to fight cancer more safely and effectively
The chairman of EUS2008 today announced that investigational research on a therapeutic technique that will allow physicians to directly inject malignant tumors with cancer fighting agents from inside the body will be presented at the 16th International Symposium of
Endoscopic Ultrasonography (EUS2008) in San Francisco on September 12-13. This technique, which uses a flexible gastrointestinal endoscope with a miniature ultrasound transducer on the tip to guide a small needle directly into a tumor, could prove to be a safer and more effective approach to administering chemotherapy since it allows doctors to deliver therapy right to the tumor and avoid damaging normal surrounding tissues. Injecting drugs directly into the cancer using endoscopic ultrasound (EUS) in combination with systemic chemotherapy to kill cancer cells that have spread may prove to be a more effective approach to some cancers.
EUS combines endoscopy and ultrasound in order to obtain the most accurate, high resolution images and information about the digestive tract and the surrounding tissue and organs. A more advanced form of EUS, called curvilinear EUS, allows doctors to operate within the lumen of the gut while at the same time detect, biopsy and treat lesions and tumors that lie outside the intestinal wall. This technique is particularly useful in patients with pancreatic, esophageal and rectal cancer.
“Curvilinear endosonography will likely become the dominant technology within the field of EUS,” said co-chairman of EUS2008, Robert Hawes, M.D., Professor of Medicine and Peter Cotton Chair for Endoscopic Innovation at the Medical University of South Carolina. “The potential for accurate diagnosis using ultrasound-guided biopsy, precise staging with high resolution ultrasound images and then the enormous opportunity for new therapies with the curvilinear endoscope is why we are focusing this meeting on the use of this instrument alone.”
Used in conjunction with real time imaging, EUS can help physicians to detect blood flow in blood vessels in and around tumors as well as detect and biopsy tumors and lymph nodes as small as 3-5 mm. This allows doctors to avoid puncturing blood vessels when sampling tissue, get the most accurate view of the cancer and know exactly what stage a cancer is in for optimal therapy for treatment. This could save cancer patients with late stage disease from going through unnecessary surgery. EUS may also play a role in the future of minimally invasive surgery (MIS). A new paradigm in MIS is called natural orifice translumenal endoscopic surgery (NOTES®). This entails using the stomach as a window to the abdominal cavity rather than the skin. EUS could play an important role in helping surgeons gain safe access to the abdominal cavity as part of NOTES.
EUS 2008 will be devoted to teaching current applications of curvilinear endoscopic ultrasonography in order to encourage endosonographers and gastroenterologists to become proficient in these procedures, enhance their techniques and increase collaboration with oncology surgeons. This meeting has a rich tradition dating back to the first meeting held in Stockholm, Sweden in 1982. The meeting has evolved as technology has changed and improved along with the exponential growth of endosonographers around the world.
September 12, 2008 by
Anti-tumor therapy guided by endoscopic ultrasound may allow doctors to fight cancer more safely and effectively
The chairman of EUS2008 today announced that investigational research on a therapeutic technique that will allow physicians to directly inject malignant tumors with cancer fighting agents from inside the body will be presented at the 16th International Symposium of
Endoscopic Ultrasonography (EUS2008) in San Francisco on September 12-13. This technique, which uses a flexible gastrointestinal endoscope with a miniature ultrasound transducer on the tip to guide a small needle directly into a tumor, could prove to be a safer and more effective approach to administering chemotherapy since it allows doctors to deliver therapy right to the tumor and avoid damaging normal surrounding tissues. Injecting drugs directly into the cancer using endoscopic ultrasound (EUS) in combination with systemic chemotherapy to kill cancer cells that have spread may prove to be a more effective approach to some cancers.
EUS combines endoscopy and ultrasound in order to obtain the most accurate, high resolution images and information about the digestive tract and the surrounding tissue and organs. A more advanced form of EUS, called curvilinear EUS, allows doctors to operate within the lumen of the gut while at the same time detect, biopsy and treat lesions and tumors that lie outside the intestinal wall. This technique is particularly useful in patients with pancreatic, esophageal and rectal cancer.
“Curvilinear endosonography will likely become the dominant technology within the field of EUS,” said co-chairman of EUS2008, Robert Hawes, M.D., Professor of Medicine and Peter Cotton Chair for Endoscopic Innovation at the Medical University of South Carolina. “The potential for accurate diagnosis using ultrasound-guided biopsy, precise staging with high resolution ultrasound images and then the enormous opportunity for new therapies with the curvilinear endoscope is why we are focusing this meeting on the use of this instrument alone.”
Used in conjunction with real time imaging, EUS can help physicians to detect blood flow in blood vessels in and around tumors as well as detect and biopsy tumors and lymph nodes as small as 3-5 mm. This allows doctors to avoid puncturing blood vessels when sampling tissue, get the most accurate view of the cancer and know exactly what stage a cancer is in for optimal therapy for treatment. This could save cancer patients with late stage disease from going through unnecessary surgery. EUS may also play a role in the future of minimally invasive surgery (MIS). A new paradigm in MIS is called natural orifice translumenal endoscopic surgery (NOTES®). This entails using the stomach as a window to the abdominal cavity rather than the skin. EUS could play an important role in helping surgeons gain safe access to the abdominal cavity as part of NOTES.
EUS 2008 will be devoted to teaching current applications of curvilinear endoscopic ultrasonography in order to encourage endosonographers and gastroenterologists to become proficient in these procedures, enhance their techniques and increase collaboration with oncology surgeons. This meeting has a rich tradition dating back to the first meeting held in Stockholm, Sweden in 1982. The meeting has evolved as technology has changed and improved along with the exponential growth of endosonographers around the world.
Saturday, August 16, 2008
Arthritis, Gout and Joint Disease
One injection ‘vaccine’ cure for arthritis within five years
A single injection that could cure rheumatoid arthritis is being developed by British scientists. The treatment works like a vaccine and could be available within five years. Cells would be taken from the body, altered, and injected back into the affected joint.
A team at Newcastle University will now test the vaccine on volunteers with the disease.
Scientists in the field are extremely excited about the development.
There are 350,000 people in the UK with rheumatoid arthritis, which is a condition where the body’s immune system attacks the joints, unlike oestoarthritis which is more like wear and tear of the joints.
Rheumatoid arthritis is difficult to treat because it is caused by a malfunctioning immune system, causing inflammation in the wrong places.
Prof Alan Silman, medical director of the charity Arthritis Research Campaign, which funded the research, said: “This is an important potential cure. It is possible one injection could switch off the abnormal immune response.
“If it works it could reverse the disease and stop further episodes.”
The Newcastle team will test the effectiveness of the new vaccine in eight volunteers with rheumatoid arthritis from the Freeman Hospital as part of a pilot study, which could then lead to larger trials.
The vaccine works by reprogramming the body’s own immune cells.
Using chemicals, steroids and Vitamin D, the team has devised a way to manipulate a patient’s white blood cells so they surpress, rather than activate, the immune system.
It is thought the cells will then act as a brake on the over-reacting immune system and stop it attacking its own joints.
Although a similar technique has been used in cancer research, this is the first time it has been adapted to rheumatoid arthritis.
John Isaacs, Professor of Clinical Rheumatology at Newcastle University’s Musculoskeletal Research Group, who is leading the team, said that although the work was in a very early, experimental stage it was “hugely exciting”.
“Based on previous laboratory research we would expect that this will specifically suppress or down regulate the auto-immune response,” he said.
Samples will be taken two weeks after the injection to establish whether it has induced the expected response.
The team also hope to find out if the vaccine is effective only in the joints it is injected into, or whether the new cells spread throughout the body.
Prof Silman said the treatment may prove expensive as each patient would have to have their own cells taken and manipulated rather than a drug which can be made in bulk and prescribed to all people with a condition.
He said it would be unlikely that the vaccine could be offered in normal local hospitals because of the expertise necessary to manipulate the cells in the laboratory.
It raises fears the vaccine would have to go through the National Institute for health and Clinical Excellence cost effectiveness tests.
But if the vaccine did work with a one off injection and completely stop the disease it is likely to offer such a huge benefit to the patient that even a relatively large price may be deemed acceptable. Prof Silman said he expected the jab to cost less than £25,000.
The research is being funded by medical research charity the Arthritis Research Campaign, which is providing £216,000 over 18 months.
A single injection that could cure rheumatoid arthritis is being developed by British scientists. The treatment works like a vaccine and could be available within five years. Cells would be taken from the body, altered, and injected back into the affected joint.
A team at Newcastle University will now test the vaccine on volunteers with the disease.
Scientists in the field are extremely excited about the development.
There are 350,000 people in the UK with rheumatoid arthritis, which is a condition where the body’s immune system attacks the joints, unlike oestoarthritis which is more like wear and tear of the joints.
Rheumatoid arthritis is difficult to treat because it is caused by a malfunctioning immune system, causing inflammation in the wrong places.
Prof Alan Silman, medical director of the charity Arthritis Research Campaign, which funded the research, said: “This is an important potential cure. It is possible one injection could switch off the abnormal immune response.
“If it works it could reverse the disease and stop further episodes.”
The Newcastle team will test the effectiveness of the new vaccine in eight volunteers with rheumatoid arthritis from the Freeman Hospital as part of a pilot study, which could then lead to larger trials.
The vaccine works by reprogramming the body’s own immune cells.
Using chemicals, steroids and Vitamin D, the team has devised a way to manipulate a patient’s white blood cells so they surpress, rather than activate, the immune system.
It is thought the cells will then act as a brake on the over-reacting immune system and stop it attacking its own joints.
Although a similar technique has been used in cancer research, this is the first time it has been adapted to rheumatoid arthritis.
John Isaacs, Professor of Clinical Rheumatology at Newcastle University’s Musculoskeletal Research Group, who is leading the team, said that although the work was in a very early, experimental stage it was “hugely exciting”.
“Based on previous laboratory research we would expect that this will specifically suppress or down regulate the auto-immune response,” he said.
Samples will be taken two weeks after the injection to establish whether it has induced the expected response.
The team also hope to find out if the vaccine is effective only in the joints it is injected into, or whether the new cells spread throughout the body.
Prof Silman said the treatment may prove expensive as each patient would have to have their own cells taken and manipulated rather than a drug which can be made in bulk and prescribed to all people with a condition.
He said it would be unlikely that the vaccine could be offered in normal local hospitals because of the expertise necessary to manipulate the cells in the laboratory.
It raises fears the vaccine would have to go through the National Institute for health and Clinical Excellence cost effectiveness tests.
But if the vaccine did work with a one off injection and completely stop the disease it is likely to offer such a huge benefit to the patient that even a relatively large price may be deemed acceptable. Prof Silman said he expected the jab to cost less than £25,000.
The research is being funded by medical research charity the Arthritis Research Campaign, which is providing £216,000 over 18 months.
FDA : Some cholesterol and heart drugs dont mix
FDA: Some cholesterol and heart drugs don’t mix
Patients taking some common medications for high cholesterol and irregular heart beats can suffer severe muscle damage because of a problem in the way the drugs interact, the government warned on Friday.
The Food and Drug Administration said doctors should use extra care when prescribing Zocor, generic Zocor, or Vytorin to patients who are also taking amiodarone, a heart rhythm drug marketed as Cordarone or Pacerone. The danger is higher for patients taking more than 20 milligrams a day of the cholesterol drugs, the agency said.
The generic name for the cholesterol medications is simvastatin.
Muscle injury is a risk with any of the cholesterol drugs known as statins, including Lipitor, particularly for the elderly. Although the risk of such injuries is low overall, they can be serious because they can lead to kidney failure and even death.
The FDA urged doctors to consider switching patients who are taking the heart rhythm drug to other statins for controlling cholesterol. The heart medication is mainly used to treat irregular rhythms in the ventricles, the heart chambers that pump blood to the lungs and body.
A previous warning dating back to 2002 about the drug interaction apparently has not put an end to the problem. The FDA said since that time it has received 52 reports of serious muscle injury to patients taking the combination of medications, and almost all the patients had to be hospitalized.
Patients taking some common medications for high cholesterol and irregular heart beats can suffer severe muscle damage because of a problem in the way the drugs interact, the government warned on Friday.
The Food and Drug Administration said doctors should use extra care when prescribing Zocor, generic Zocor, or Vytorin to patients who are also taking amiodarone, a heart rhythm drug marketed as Cordarone or Pacerone. The danger is higher for patients taking more than 20 milligrams a day of the cholesterol drugs, the agency said.
The generic name for the cholesterol medications is simvastatin.
Muscle injury is a risk with any of the cholesterol drugs known as statins, including Lipitor, particularly for the elderly. Although the risk of such injuries is low overall, they can be serious because they can lead to kidney failure and even death.
The FDA urged doctors to consider switching patients who are taking the heart rhythm drug to other statins for controlling cholesterol. The heart medication is mainly used to treat irregular rhythms in the ventricles, the heart chambers that pump blood to the lungs and body.
A previous warning dating back to 2002 about the drug interaction apparently has not put an end to the problem. The FDA said since that time it has received 52 reports of serious muscle injury to patients taking the combination of medications, and almost all the patients had to be hospitalized.
Tuesday, June 10, 2008
Solid Tumor Cells....
As published on 11th june 2008 in Breakthrough digest.
Solid tumor cells not killed by radiation and chemotherapy become stronger
Because of the way solid tumors adapt the body’s machinery to bring themselves more oxygen, chemotherapy and radiation may actually make these tumors stronger.
“In a sense, these therapies can make the tumor healthier,” said Mark W. Dewhirst, D.V.M., Ph.D., professor of radiation oncology at Duke University Medical Center. “Unless the treatment is very effective in killing many if not most tumor cells, you are shooting yourself in the foot.”
Dewhirst and colleagues Yiting Cao, M.D., Ph.D., of Duke Pathology, and Benjamin Moeller, M.D., Ph.D. have introduced this counter-intuitive idea at recent conferences and in a review article featured in the June issue of Nature Reviews Cancer.
Radiation and chemotherapy do kill most solid tumor cells, but in the cells that survive, the therapies drive an increase in a regulatory factor called HIF1 (hypoxia-inducible factor 1), which cells use to get the oxygen they need by increasing blood vessel growth into the tumor. Solid tumors generally have low supplies of oxygen, Dewhirst explained and HIF1 helps them get the oxygen they need.
The review article concludes that blocking HIF1 would provide a clear mechanism for killing solid-tumor cells, particularly cells that are proving resistant to radiation or chemotherapy treatments.
As a part of this work, Dewhirst’s team has been studying the phenomenon of rising and falling oxygen levels in tumors, called cycling hypoxia. Oxygen levels have been found to naturally cycle up and down in individual blood vessels as well as large tumor regions. This instability in the tumor’s oxygen levels can increase HIF-1 production and cause radiation therapy to fail, Dewhirst said.
“It is my opinion that the whole tumor grows more aggressively because of this pulsation of oxygen at low levels,” Dewhirst said. “Most people thought cycling hypoxia was caused by temporary stoppage of blood flow in single blood vessel in tumors. In fact, however, oxygen levels cycle up and down virtually everywhere in the tumor, which is caused by fluctuations in blood flow rate. It has been a challenge to convince people of this.”
Dewhirst and colleagues have made movies of oxygen transport in a tumor of a living animal that show the oxygen levels cycle up and down significantly, pulsing in waves seen as color changes in the movies. (View these movies at the Nature Reviews Cancer site: http://www.nature.com/nrc/journal/v8/n6/suppinfo/nrc2397.html )
The Duke team argues that blocking HIF1 is the consistent answer to tumor growth problems. Blocking HIF1 activity interferes with the tumor’s ability to undergo glycolysis (energy production) in low-oxygen conditions, which blocks tumor growth, the authors wrote. Exactly how to accomplish chemotherapy or radiation treatment in the safest, most effective ways, in combination with HIF1 blockade, is still open for exploration, Dewhirst said.
For example, targeting HIF1 in the early stages of tumor growth, especially in very early cancer spread, may help, Dewhirst said. “For a woman who has had a primary breast tumor removed, and who is at high risk for cancer spread, this might be a situation in which you’d target HIF1,” he explained. “Blocking HIF1 makes sense during the early stages of angiogenesis, which is the accelerated phase of blood vessel formation. In this way, you could keep the early metastasis sites inactive and prevent them from growing.”
The Duke team has completed a phase I trial with a HIF1 inhibitor. “We are actively pursuing this clinically and will be moving this study into Phase 2,” Dewhirst said. “We are interested in other applications of HIF-1 inhibition in combination with radiation and chemotherapy for different diseases.”
Solid tumor cells not killed by radiation and chemotherapy become stronger
Because of the way solid tumors adapt the body’s machinery to bring themselves more oxygen, chemotherapy and radiation may actually make these tumors stronger.
“In a sense, these therapies can make the tumor healthier,” said Mark W. Dewhirst, D.V.M., Ph.D., professor of radiation oncology at Duke University Medical Center. “Unless the treatment is very effective in killing many if not most tumor cells, you are shooting yourself in the foot.”
Dewhirst and colleagues Yiting Cao, M.D., Ph.D., of Duke Pathology, and Benjamin Moeller, M.D., Ph.D. have introduced this counter-intuitive idea at recent conferences and in a review article featured in the June issue of Nature Reviews Cancer.
Radiation and chemotherapy do kill most solid tumor cells, but in the cells that survive, the therapies drive an increase in a regulatory factor called HIF1 (hypoxia-inducible factor 1), which cells use to get the oxygen they need by increasing blood vessel growth into the tumor. Solid tumors generally have low supplies of oxygen, Dewhirst explained and HIF1 helps them get the oxygen they need.
The review article concludes that blocking HIF1 would provide a clear mechanism for killing solid-tumor cells, particularly cells that are proving resistant to radiation or chemotherapy treatments.
As a part of this work, Dewhirst’s team has been studying the phenomenon of rising and falling oxygen levels in tumors, called cycling hypoxia. Oxygen levels have been found to naturally cycle up and down in individual blood vessels as well as large tumor regions. This instability in the tumor’s oxygen levels can increase HIF-1 production and cause radiation therapy to fail, Dewhirst said.
“It is my opinion that the whole tumor grows more aggressively because of this pulsation of oxygen at low levels,” Dewhirst said. “Most people thought cycling hypoxia was caused by temporary stoppage of blood flow in single blood vessel in tumors. In fact, however, oxygen levels cycle up and down virtually everywhere in the tumor, which is caused by fluctuations in blood flow rate. It has been a challenge to convince people of this.”
Dewhirst and colleagues have made movies of oxygen transport in a tumor of a living animal that show the oxygen levels cycle up and down significantly, pulsing in waves seen as color changes in the movies. (View these movies at the Nature Reviews Cancer site: http://www.nature.com/nrc/journal/v8/n6/suppinfo/nrc2397.html )
The Duke team argues that blocking HIF1 is the consistent answer to tumor growth problems. Blocking HIF1 activity interferes with the tumor’s ability to undergo glycolysis (energy production) in low-oxygen conditions, which blocks tumor growth, the authors wrote. Exactly how to accomplish chemotherapy or radiation treatment in the safest, most effective ways, in combination with HIF1 blockade, is still open for exploration, Dewhirst said.
For example, targeting HIF1 in the early stages of tumor growth, especially in very early cancer spread, may help, Dewhirst said. “For a woman who has had a primary breast tumor removed, and who is at high risk for cancer spread, this might be a situation in which you’d target HIF1,” he explained. “Blocking HIF1 makes sense during the early stages of angiogenesis, which is the accelerated phase of blood vessel formation. In this way, you could keep the early metastasis sites inactive and prevent them from growing.”
The Duke team has completed a phase I trial with a HIF1 inhibitor. “We are actively pursuing this clinically and will be moving this study into Phase 2,” Dewhirst said. “We are interested in other applications of HIF-1 inhibition in combination with radiation and chemotherapy for different diseases.”
Saturday, June 7, 2008
Cord Blood Stem Cells in Bone Marrow Transplants
New Technology Enhances and Expands “Homing”and Therapeutic Potential of Cord Blood Stem Cells in Bone Marrow Transplants
A CD26 Inhibitor increases the efficiency and responsiveness of umbilical cord blood for bone marrow transplants and may improve care for blood cancer patients according to research from Rush University Medical Center being presented at the 6th Annual International Umbilical Cord Blood
Transplantation Symposium, June 6-7 in Los Angeles.
Kent W. Christopherson II, PhD, assistant professor of medicine and researcher in the Sections of Hematology and Stem Cell Transplantation at Rush, is researching a CD26 Inhibitor, a small molecule enzyme inhibitor that enhances directional homing of stem cells to the bone marrow by increasing the responsiveness of donor stem cells to a natural homing signal. Homing is the process by which the donor stem cells find their way to the bone marrow. It is the first and essential step in stem cell transplantation.
Cord blood is increasingly being used by transplant centers as an alternative source of stem cells for the treatment of blood cancers, including myeloma, lymphoma and leukemia. The cells, which are collected from the umbilical cord after the baby is delivered and separated from the cord, are most commonly used for bone marrow transplantation when a donor from a patient’s family or an unrelated donor does not produce an appropriate bone marrow match.
The current drawback to the usage of cord blood cells is that due to the limited volume and cell number, there are generally only enough cells available from a single cord blood collection for children or very small adults. Cord blood cells also usually take longer to engraft, leaving the patient at a high risk
for infection longer than donor matched transplanted marrow or peripheral blood stem cells. The goal of Christopherson’s research is to increase the transplant efficiency of umbilical cord blood and ultimately make transplant safer and available to all patients who require this treatment.
In his discussion on “Strategies to Improve Homing,” Christopherson states that results from his and other laboratories suggest “the beneficial effects of the CD26 Inhibitor usage and the potential of this technology to change hematopoietic stem cell transplantation.”
Christopherson will co-chair the session and review some of his Leukemia & Lymphoma Society funded work at the symposium in a session entitled “Basic Science and Clinical Studies Addressing Obstacles to Successful Umbilical Cord Blood Transplants (UCBT)”. He will be joined by Dr. Patrick Zweidler-McKay of the University if Texas MD Anderson Cancer Center. Zweidler-McKay will discuss his team’s work in the same session on Engraftin™, a human recombinant enzyme technology that increases the efficiency of engraftment and reduces graft failure in transplantation of cord blood derived stem cells.
Research results in animal models by Christopherson and Zweider-McKay show that both Engraftin and CD26 Inhibitor can enhance homing and rate of engraftment, which will result in reduced patient morbidity and mortality in bone marrow transplants. American Stem Cell, Inc., the developer of both technologies, plans to begin human trials in the next few months.
There are over 250,000 new cancer patients per year who require or would benefit from stem cell transplantation and as many as 20% are unable to find a blood or marrow match.
A CD26 Inhibitor increases the efficiency and responsiveness of umbilical cord blood for bone marrow transplants and may improve care for blood cancer patients according to research from Rush University Medical Center being presented at the 6th Annual International Umbilical Cord Blood
Transplantation Symposium, June 6-7 in Los Angeles.
Kent W. Christopherson II, PhD, assistant professor of medicine and researcher in the Sections of Hematology and Stem Cell Transplantation at Rush, is researching a CD26 Inhibitor, a small molecule enzyme inhibitor that enhances directional homing of stem cells to the bone marrow by increasing the responsiveness of donor stem cells to a natural homing signal. Homing is the process by which the donor stem cells find their way to the bone marrow. It is the first and essential step in stem cell transplantation.
Cord blood is increasingly being used by transplant centers as an alternative source of stem cells for the treatment of blood cancers, including myeloma, lymphoma and leukemia. The cells, which are collected from the umbilical cord after the baby is delivered and separated from the cord, are most commonly used for bone marrow transplantation when a donor from a patient’s family or an unrelated donor does not produce an appropriate bone marrow match.
The current drawback to the usage of cord blood cells is that due to the limited volume and cell number, there are generally only enough cells available from a single cord blood collection for children or very small adults. Cord blood cells also usually take longer to engraft, leaving the patient at a high risk
for infection longer than donor matched transplanted marrow or peripheral blood stem cells. The goal of Christopherson’s research is to increase the transplant efficiency of umbilical cord blood and ultimately make transplant safer and available to all patients who require this treatment.
In his discussion on “Strategies to Improve Homing,” Christopherson states that results from his and other laboratories suggest “the beneficial effects of the CD26 Inhibitor usage and the potential of this technology to change hematopoietic stem cell transplantation.”
Christopherson will co-chair the session and review some of his Leukemia & Lymphoma Society funded work at the symposium in a session entitled “Basic Science and Clinical Studies Addressing Obstacles to Successful Umbilical Cord Blood Transplants (UCBT)”. He will be joined by Dr. Patrick Zweidler-McKay of the University if Texas MD Anderson Cancer Center. Zweidler-McKay will discuss his team’s work in the same session on Engraftin™, a human recombinant enzyme technology that increases the efficiency of engraftment and reduces graft failure in transplantation of cord blood derived stem cells.
Research results in animal models by Christopherson and Zweider-McKay show that both Engraftin and CD26 Inhibitor can enhance homing and rate of engraftment, which will result in reduced patient morbidity and mortality in bone marrow transplants. American Stem Cell, Inc., the developer of both technologies, plans to begin human trials in the next few months.
There are over 250,000 new cancer patients per year who require or would benefit from stem cell transplantation and as many as 20% are unable to find a blood or marrow match.
Brain stem cells...
Brain stem cells can be awakened?
Study findings promise to help in treatment of brain diseases
Boston, MA-Scientists at Schepens Eye Research Institute have identified specific molecules in the brain that are responsible for awakening and putting to sleep brain stem cells, which, when activated, can transform into neurons (nerve cells) and repair damaged brain tissue. Their findings are published online this week in the Proceedings of the National Academy of Science (PNAS).
An earlier paper (published in the May issue of Stem Cells) by the same scientists laid the foundation for the PNAS study findings by demonstrating that neural stem cells exist in every part of the brain, but are mostly kept silent by chemical signals from support cells known as astrocytes.
³The findings from both papers should have a far-reaching impact,² says principal investigator, Dr. Dong Feng Chen, who is an associate scientist at Schepens Eye Research Institute and an assistant professor of ophthalmology at Harvard Medical School. Chen believes that tapping the brain¹s dormant, but intrinsic, ability to regenerate itself is the best hope for people suffering from brain-ravaging diseases such as Parkinson¹s or Alzheimer¹s disease or traumatic brain or spinal cord injuries.
Until these studies, which were conducted in the adult brains of mice, scientists assumed that only two parts of the brain contained neural stem cells and could turn them on to regenerate brain tissue– the subgranular zone (SGZ) of the hippocampus and the subventricular zone (SVZ). The hippocampus is responsible for learning and memory, while the SVZ is a brain structure situated throughout the walls of lateral ventricles (part of the ventricular system in the brain) and is responsible for generating neurons reponsible for smell. So scientists believed that when neurons died in other areas of the brain, they were lost forever along with their functions.
In the first study, Chen¹s team learned that stem cells existed everywhere in the brain by testing tissue from different parts of adult mice brains in cultures containing support cells (known as astrocytes) from the hippocampus, where stem cells do regenerate.
In the cultures the stem cells from other brain regions came to life and turned into neurons.
When they compared the chemical makeup of the areas known to generate new neurons in the hippocampus with other parts of the brain, the team discovered that astrocytes in the hippocampus were sending one signal to the stem cells and that those from the rest of the brain were sending a different signal to stem cells.
In the second (PNAS) study, the team went on to discover the exact nature of those different chemical signals. They learned that in the areas where stem cells were sleeping, astrocytes were producing high levels of two related molecules–ephrin-A2 and ephrin-A3. They also found that removing these molecules (with a genetic tool) activated the sleeping stem cells.
The team also found that astrocytes in the hippocampus produce not only much lower levels of ephrin-A2 and ephrin-A3, but also release a protein named sonic hedghoc that, when added in culture or injected into the brain, stimulates neural stem cells to divide and become new neurons.
³These findings identify a key pathway that controls neural stem cell growth in the adult brain and suggest that it may be possible to reactivate the dormant regenerative potential by adding sonic hedgehoc, or blocking ephrin-A2 or ephrin-A3,² says Dr. Jianwei Jiao, the first author of the two papers.
The next step for the team will be to stimulate the sleeping stem cells in animals who are models of neurodegenerative disorders, such as Parkinson’s disease, to see if the brains can repair themselves and restore their damaged functions.
Study findings promise to help in treatment of brain diseases
Boston, MA-Scientists at Schepens Eye Research Institute have identified specific molecules in the brain that are responsible for awakening and putting to sleep brain stem cells, which, when activated, can transform into neurons (nerve cells) and repair damaged brain tissue. Their findings are published online this week in the Proceedings of the National Academy of Science (PNAS).
An earlier paper (published in the May issue of Stem Cells) by the same scientists laid the foundation for the PNAS study findings by demonstrating that neural stem cells exist in every part of the brain, but are mostly kept silent by chemical signals from support cells known as astrocytes.
³The findings from both papers should have a far-reaching impact,² says principal investigator, Dr. Dong Feng Chen, who is an associate scientist at Schepens Eye Research Institute and an assistant professor of ophthalmology at Harvard Medical School. Chen believes that tapping the brain¹s dormant, but intrinsic, ability to regenerate itself is the best hope for people suffering from brain-ravaging diseases such as Parkinson¹s or Alzheimer¹s disease or traumatic brain or spinal cord injuries.
Until these studies, which were conducted in the adult brains of mice, scientists assumed that only two parts of the brain contained neural stem cells and could turn them on to regenerate brain tissue– the subgranular zone (SGZ) of the hippocampus and the subventricular zone (SVZ). The hippocampus is responsible for learning and memory, while the SVZ is a brain structure situated throughout the walls of lateral ventricles (part of the ventricular system in the brain) and is responsible for generating neurons reponsible for smell. So scientists believed that when neurons died in other areas of the brain, they were lost forever along with their functions.
In the first study, Chen¹s team learned that stem cells existed everywhere in the brain by testing tissue from different parts of adult mice brains in cultures containing support cells (known as astrocytes) from the hippocampus, where stem cells do regenerate.
In the cultures the stem cells from other brain regions came to life and turned into neurons.
When they compared the chemical makeup of the areas known to generate new neurons in the hippocampus with other parts of the brain, the team discovered that astrocytes in the hippocampus were sending one signal to the stem cells and that those from the rest of the brain were sending a different signal to stem cells.
In the second (PNAS) study, the team went on to discover the exact nature of those different chemical signals. They learned that in the areas where stem cells were sleeping, astrocytes were producing high levels of two related molecules–ephrin-A2 and ephrin-A3. They also found that removing these molecules (with a genetic tool) activated the sleeping stem cells.
The team also found that astrocytes in the hippocampus produce not only much lower levels of ephrin-A2 and ephrin-A3, but also release a protein named sonic hedghoc that, when added in culture or injected into the brain, stimulates neural stem cells to divide and become new neurons.
³These findings identify a key pathway that controls neural stem cell growth in the adult brain and suggest that it may be possible to reactivate the dormant regenerative potential by adding sonic hedgehoc, or blocking ephrin-A2 or ephrin-A3,² says Dr. Jianwei Jiao, the first author of the two papers.
The next step for the team will be to stimulate the sleeping stem cells in animals who are models of neurodegenerative disorders, such as Parkinson’s disease, to see if the brains can repair themselves and restore their damaged functions.
Wednesday, June 4, 2008
Autoimmune Disease Treatment
A New Approach to Treating Autoimmune Disease
In autoimmune diseases, the immune system turns against the body’s own tissues and organs, wreaking havoc and destruction for no apparent reason. Partly because the origins of these diseases are so obscure, no effective treatment exists, and the suffering they inflict is enormous. Now Weizmann Institute scientists have developed a method that in the future may make it possible to treat autoimmune diseases effectively without necessarily knowing their exact cause. Their approach is equivalent to sending a police force to suppress a riot without seeking out the individuals who instigated the unrest.
In healthy people, a small but crucial group of immune cells called regulatory T cells, or T-regs, keeps autoimmunity in check, but in people with inflammatory bowel disease (IBD), one of the most common autoimmune disorders, too few of these cells appear in the diseased intestine, and the ones that do fail to function properly. The new Weizmann Institute approach consists of delivering highly selective, genetically engineered functioning T-regs to the intestine. The study was conducted by Dr. Eran Elinav, a physician from Tel Aviv Sourasky Medical Center’s gastroenterology institute who is working toward his Ph.D. at the Weizmann Institute, and lab assistant Tova Waks, in the laboratory of Prof. Zelig Eshhar of the Immunology Department.
Relying on Eshhar’s earlier work in which he equipped a different type of T cell to zero in on cancerous tumors, the team genetically engineered T-regs, outfitting these cells with a modular receptor consisting of three units. One of these units directed the cells to the intestine while the other two made sure they became duly activated. As reported in the journal Gastroenterology, the approach proved effective in laboratory mice with a disease that simulates human IBD: Most of the mice treated with the genetically-engineered T-regs developed only mild inflammation or no inflammation at all.
The cells produced what the scientists called a ‘bystander’ effect: They were directed to the diseased tissue using neighboring, or ‘bystander’ markers that identified the area as a site of inflammation, and suppressed the inflammatory cells in the vicinity by secreting soluble suppressive substances.
The scientists are currently experimenting with human T-regs for curing ulcerative colitis and believe that in addition to IBD, their ‘bystander’ approach could work in other autoimmune disorders, even if their causes remain unknown. They also think the method could be valuable in suppressing unwanted inflammation in diseases unrelated to autoimmunity, as well as in preventing graft rejection and certain complications in bone marrow and organ transplantation, in which inflammation is believed to play a major role.
Prof. Zelig Eshhar’s research is supported by the M.D. Moross Institute for Cancer Research; the Phyllis and Joseph Gurwin Fund for Scientific Advancement; and the Friends of Assaf Harofeh Medical Center. Prof. Eshhar is the incumbent of the Marshall and Renette Ezralow Professorial Chair of Chemical and Cellular Immunology.
The Weizmann Institute of Science in Rehovot, Israel, is one of the world’s top-ranking multidisciplinary research institutions. Noted for its wide-ranging exploration of the natural and exact sciences, the Institute is home to 2,600 scientists, students, technicians and supporting staff. Institute research efforts include the search for new ways of fighting disease and hunger, examining leading questions in mathematics and computer science, probing the physics of matter and the universe, creating novel materials and developing new strategies for protecting the environment.
In autoimmune diseases, the immune system turns against the body’s own tissues and organs, wreaking havoc and destruction for no apparent reason. Partly because the origins of these diseases are so obscure, no effective treatment exists, and the suffering they inflict is enormous. Now Weizmann Institute scientists have developed a method that in the future may make it possible to treat autoimmune diseases effectively without necessarily knowing their exact cause. Their approach is equivalent to sending a police force to suppress a riot without seeking out the individuals who instigated the unrest.
In healthy people, a small but crucial group of immune cells called regulatory T cells, or T-regs, keeps autoimmunity in check, but in people with inflammatory bowel disease (IBD), one of the most common autoimmune disorders, too few of these cells appear in the diseased intestine, and the ones that do fail to function properly. The new Weizmann Institute approach consists of delivering highly selective, genetically engineered functioning T-regs to the intestine. The study was conducted by Dr. Eran Elinav, a physician from Tel Aviv Sourasky Medical Center’s gastroenterology institute who is working toward his Ph.D. at the Weizmann Institute, and lab assistant Tova Waks, in the laboratory of Prof. Zelig Eshhar of the Immunology Department.
Relying on Eshhar’s earlier work in which he equipped a different type of T cell to zero in on cancerous tumors, the team genetically engineered T-regs, outfitting these cells with a modular receptor consisting of three units. One of these units directed the cells to the intestine while the other two made sure they became duly activated. As reported in the journal Gastroenterology, the approach proved effective in laboratory mice with a disease that simulates human IBD: Most of the mice treated with the genetically-engineered T-regs developed only mild inflammation or no inflammation at all.
The cells produced what the scientists called a ‘bystander’ effect: They were directed to the diseased tissue using neighboring, or ‘bystander’ markers that identified the area as a site of inflammation, and suppressed the inflammatory cells in the vicinity by secreting soluble suppressive substances.
The scientists are currently experimenting with human T-regs for curing ulcerative colitis and believe that in addition to IBD, their ‘bystander’ approach could work in other autoimmune disorders, even if their causes remain unknown. They also think the method could be valuable in suppressing unwanted inflammation in diseases unrelated to autoimmunity, as well as in preventing graft rejection and certain complications in bone marrow and organ transplantation, in which inflammation is believed to play a major role.
Prof. Zelig Eshhar’s research is supported by the M.D. Moross Institute for Cancer Research; the Phyllis and Joseph Gurwin Fund for Scientific Advancement; and the Friends of Assaf Harofeh Medical Center. Prof. Eshhar is the incumbent of the Marshall and Renette Ezralow Professorial Chair of Chemical and Cellular Immunology.
The Weizmann Institute of Science in Rehovot, Israel, is one of the world’s top-ranking multidisciplinary research institutions. Noted for its wide-ranging exploration of the natural and exact sciences, the Institute is home to 2,600 scientists, students, technicians and supporting staff. Institute research efforts include the search for new ways of fighting disease and hunger, examining leading questions in mathematics and computer science, probing the physics of matter and the universe, creating novel materials and developing new strategies for protecting the environment.
CFC propelled inhalers....
FDA Advises Patients to Switch to HFA-Propelled Albuterol Inhalers Now CFC-propelled inhalers no longer available as of Dec. 31, 2008
The U.S. Food and Drug Administration today issued a public health advisory to alert patients, caregivers and health care professionals to switch to hydrofluoroalkane (HFA)-propelled albuterol inhalers because chlorofluorocarbon (CFC)-propelled inhalers will not be available in the United States after Dec. 31, 2008.
CFC-propelled albuterol inhalers are being phased out because they are harmful to the environment by contributing to depletion of the ozone layer above the Earth's surface.
Three HFA-propelled albuterol inhalers have been approved by the FDA: Proair HFA Inhalation Aerosol, Proventil HFA Inhalation Aerosol, and Ventolin HFA Inhalation Aerosol. In addition, an HFA-propelled inhaler containing levalbuterol, a medicine similar to albuterol, is available as Xopenex HFA Inhalation Aerosol.
"Concern about the environment stimulated the need to phase out CFCs," said Janet Woodcock, M.D., director of the FDA's Center for Drug Evaluation and Research. "The FDA wants to emphasize that HFA-propelled albuterol inhalers are safe and effective replacements for CFC-propelled albuterol inhalers."
Albuterol inhalers are used to treat bronchospasm (wheezing) in patients with asthma and chronic obstructive pulmonary disease (COPD), which includes chronic bronchitis and emphysema. Patients use albuterol inhalers to deliver medicine directly into the lungs.
The FDA is urging patients to talk with their health care professionals now about switching to HFA-propelled albuterol inhalers. These products are safe and effective replacements for CFC-propelled albuterol inhalers.
Manufacturers have been increasing production of HFA albuterol inhalers, so an adequate supply is available now.
HFA-propelled albuterol inhalers may taste and feel different than the CFC-propelled albuterol inhalers. The spray of an HFA-propelled albuterol inhaler may feel softer than that of a CFC-propelled albuterol inhaler. Patients must also prime and clean HFA-propelled albuterol inhalers. Doing so prevents buildup of the drug in the inhalation device, and buildup can block the medicine from reaching the lungs. Each HFA-propelled albuterol inhaler has different priming, cleaning, and drying instructions, and patients should read and understand the instructions first before using the inhaler.
The phaseout of CFC-propelled inhalers is the result of the Clean Air Act and an international environmental treaty, the Montreal Protocol on Substances that Deplete the Ozone Layer. Under this treaty, the United States has agreed to phase out production and importation of ozone depleting substances including CFCs. No CFC-propelled albuterol inhalers may be produced, marketed or sold in the United States after Dec. 31, 2008.
The U.S. Food and Drug Administration today issued a public health advisory to alert patients, caregivers and health care professionals to switch to hydrofluoroalkane (HFA)-propelled albuterol inhalers because chlorofluorocarbon (CFC)-propelled inhalers will not be available in the United States after Dec. 31, 2008.
CFC-propelled albuterol inhalers are being phased out because they are harmful to the environment by contributing to depletion of the ozone layer above the Earth's surface.
Three HFA-propelled albuterol inhalers have been approved by the FDA: Proair HFA Inhalation Aerosol, Proventil HFA Inhalation Aerosol, and Ventolin HFA Inhalation Aerosol. In addition, an HFA-propelled inhaler containing levalbuterol, a medicine similar to albuterol, is available as Xopenex HFA Inhalation Aerosol.
"Concern about the environment stimulated the need to phase out CFCs," said Janet Woodcock, M.D., director of the FDA's Center for Drug Evaluation and Research. "The FDA wants to emphasize that HFA-propelled albuterol inhalers are safe and effective replacements for CFC-propelled albuterol inhalers."
Albuterol inhalers are used to treat bronchospasm (wheezing) in patients with asthma and chronic obstructive pulmonary disease (COPD), which includes chronic bronchitis and emphysema. Patients use albuterol inhalers to deliver medicine directly into the lungs.
The FDA is urging patients to talk with their health care professionals now about switching to HFA-propelled albuterol inhalers. These products are safe and effective replacements for CFC-propelled albuterol inhalers.
Manufacturers have been increasing production of HFA albuterol inhalers, so an adequate supply is available now.
HFA-propelled albuterol inhalers may taste and feel different than the CFC-propelled albuterol inhalers. The spray of an HFA-propelled albuterol inhaler may feel softer than that of a CFC-propelled albuterol inhaler. Patients must also prime and clean HFA-propelled albuterol inhalers. Doing so prevents buildup of the drug in the inhalation device, and buildup can block the medicine from reaching the lungs. Each HFA-propelled albuterol inhaler has different priming, cleaning, and drying instructions, and patients should read and understand the instructions first before using the inhaler.
The phaseout of CFC-propelled inhalers is the result of the Clean Air Act and an international environmental treaty, the Montreal Protocol on Substances that Deplete the Ozone Layer. Under this treaty, the United States has agreed to phase out production and importation of ozone depleting substances including CFCs. No CFC-propelled albuterol inhalers may be produced, marketed or sold in the United States after Dec. 31, 2008.
Rapid Wound Healing....
Rapid wound healing
A new type of wound dressing made of silica gel fibers will soon help to heal difficult wounds caused by burns or diabetes. The dressing forms a supporting matrix for newly growing skin cells and is fully absorbed by the body during the healing process.
In Germany alone, about three million – mostly elderly – patients suffer from poorly healing large-area wounds caused by complaints such as diabetes, burns or bedsores. The wounds can be treated with conventional collagen dressings or polylactic acid dressings, but the success rate is not as good as it should be. A new type of dressing made of silica gel fibers, developed by scientists at the Fraunhofer Institute for Silicate Research ISC in Würzburg, shall solve the problem. This novel dressing has many advantages: it is shape-stable, pH-neutral and 100 percent bioresorbable. Once applied it remains in the body, where it gradually degrades without leaving any residues. What’s more, the fibre fleece provides the healthy cells around the edges of the wound with the structure they additionally need for a proper supply of growth-supporting nutrients. To prevent any infection, treatment of the wound must be absolutely sterile. “As only the outer bandage needs to be changed, the risk of contaminating the wound is low,” explains Dr. Jörn Probst of the ISC. And thanks to the supporting
matrix for the cells, the chances of a scar-free natural closure of the wound are very good.
The fibers are produced by means of wet-chemical material synthesis, a sol-gel process in which a transparent, honey-like gel is produced from tetraethoxysilane (TEOS), ethanol and water in a multi-stage, acidically catalyzed synthesis process. The gel is processed in a spinning tower: “We press it through fine nozzles at constant temperatures and humidity levels,” explains Walther Glaubitt, the inventor of the silica gel fibers. “This produces fine endless threads which are collected on a traversing table and spun in a specific pattern to produce a roughly A4-sized multi-layer textile web.” The dressings are then cut, packed and sterilized. Dr. Jörn Probst and Dipl.-Ing. Walther Glaubitt will receive the Joseph von Fraunhofer Prize 2008 for developing the biocompatible dressing.
A partner to support the development and market the dressing has already been found: Bayer Innovation GmbH BIG, a wholly owned subsidiary of Bayer AG. “We anticipate that hospitals will start to use the silica gel wound dressing in 2011,” states Iwer Baecker, project manager at Bayer Innovation GmbH. And that is by no means the end of the story. The scientists plan to integrate active substances such as antibiotics or painkillers in the dressing to improve and accelerate the healing process.
A new type of wound dressing made of silica gel fibers will soon help to heal difficult wounds caused by burns or diabetes. The dressing forms a supporting matrix for newly growing skin cells and is fully absorbed by the body during the healing process.
In Germany alone, about three million – mostly elderly – patients suffer from poorly healing large-area wounds caused by complaints such as diabetes, burns or bedsores. The wounds can be treated with conventional collagen dressings or polylactic acid dressings, but the success rate is not as good as it should be. A new type of dressing made of silica gel fibers, developed by scientists at the Fraunhofer Institute for Silicate Research ISC in Würzburg, shall solve the problem. This novel dressing has many advantages: it is shape-stable, pH-neutral and 100 percent bioresorbable. Once applied it remains in the body, where it gradually degrades without leaving any residues. What’s more, the fibre fleece provides the healthy cells around the edges of the wound with the structure they additionally need for a proper supply of growth-supporting nutrients. To prevent any infection, treatment of the wound must be absolutely sterile. “As only the outer bandage needs to be changed, the risk of contaminating the wound is low,” explains Dr. Jörn Probst of the ISC. And thanks to the supporting
matrix for the cells, the chances of a scar-free natural closure of the wound are very good.
The fibers are produced by means of wet-chemical material synthesis, a sol-gel process in which a transparent, honey-like gel is produced from tetraethoxysilane (TEOS), ethanol and water in a multi-stage, acidically catalyzed synthesis process. The gel is processed in a spinning tower: “We press it through fine nozzles at constant temperatures and humidity levels,” explains Walther Glaubitt, the inventor of the silica gel fibers. “This produces fine endless threads which are collected on a traversing table and spun in a specific pattern to produce a roughly A4-sized multi-layer textile web.” The dressings are then cut, packed and sterilized. Dr. Jörn Probst and Dipl.-Ing. Walther Glaubitt will receive the Joseph von Fraunhofer Prize 2008 for developing the biocompatible dressing.
A partner to support the development and market the dressing has already been found: Bayer Innovation GmbH BIG, a wholly owned subsidiary of Bayer AG. “We anticipate that hospitals will start to use the silica gel wound dressing in 2011,” states Iwer Baecker, project manager at Bayer Innovation GmbH. And that is by no means the end of the story. The scientists plan to integrate active substances such as antibiotics or painkillers in the dressing to improve and accelerate the healing process.
Friday, May 23, 2008
Latent TB treatment - Rifampin
Rifampin: Latent TB treatment saves time money and lives
A new way to treat patients with latent tuberculosis (TB), who are infected with TB but without symptoms, can effectively treat it in less than half the time and at a lower cost than the current standard treatment, according to researchers who conducted a multi-center, randomized controlled trial. The results will be presented at the American Thoracic Society’s 2008 International Conference in Toronto on Tuesday, May 20.
“We found that using a therapy of four months of Rifampin instead of the current nine months of Isoniazid costs significantly less for the healthcare system,” said lead analyst, Anne Aspler, M.Sc., of the Respiratory Epidemiology & Clinical Research Unit at McGill University’s Montreal Chest Institute.
“Overall, Rifampin costs about $484 less per patient treated, which, if we assume that four months of Rifampin has at least equal efficacy to nine months of Isoniazid, represents an added savings to the health system of more than $10,000 per patient prevented from developing TB disease. And because of improvements in compliance, we are actually preventing more cases. This treatment can save money as well as lives.”
At present, two billion people are believed to have latent or dormant TB. Of those infected, eight to nine million will develop TB each year, of whom 1.6 million will die.
“This is one of the most pressing public health crises in our modern world,” said Ms. Aspler.
Rifampin is offered in developing countries, where TB presents the greatest burden, at a subsidized cost through the Global Drug Facility of the World Health Organization. In addition to the cost savings, therapy with Rifampin has the advantage of increased compliance.
“While Isoniazid therapy is 90 percent effective for those who complete it, in reality, fewer than 50 percent do,” Ms. Aspler explained. The high attrition rate can have serious public heath effects, not only for the patients who fail to complete therapy, but also for the individuals they may later infect.
According to previous research and program experience in Maryland and New Jersey, a four-month treatment has been shown to improve compliance by 20 to 25 percent. In addition to better completion rates, a four-month course of Rifampin offers the advantages of fewer adverse reactions (fewer serious side effects such as hepatotoxicity or liver damage), and lower costs.
“The next step in research is a major Phase III clinical trial of efficacy—ideally in HIV-infected and non-infected patients and in low-income settings where tuberculosis is the leading cause of death in people living with HIV,” said Ms. Aspler.
A new way to treat patients with latent tuberculosis (TB), who are infected with TB but without symptoms, can effectively treat it in less than half the time and at a lower cost than the current standard treatment, according to researchers who conducted a multi-center, randomized controlled trial. The results will be presented at the American Thoracic Society’s 2008 International Conference in Toronto on Tuesday, May 20.
“We found that using a therapy of four months of Rifampin instead of the current nine months of Isoniazid costs significantly less for the healthcare system,” said lead analyst, Anne Aspler, M.Sc., of the Respiratory Epidemiology & Clinical Research Unit at McGill University’s Montreal Chest Institute.
“Overall, Rifampin costs about $484 less per patient treated, which, if we assume that four months of Rifampin has at least equal efficacy to nine months of Isoniazid, represents an added savings to the health system of more than $10,000 per patient prevented from developing TB disease. And because of improvements in compliance, we are actually preventing more cases. This treatment can save money as well as lives.”
At present, two billion people are believed to have latent or dormant TB. Of those infected, eight to nine million will develop TB each year, of whom 1.6 million will die.
“This is one of the most pressing public health crises in our modern world,” said Ms. Aspler.
Rifampin is offered in developing countries, where TB presents the greatest burden, at a subsidized cost through the Global Drug Facility of the World Health Organization. In addition to the cost savings, therapy with Rifampin has the advantage of increased compliance.
“While Isoniazid therapy is 90 percent effective for those who complete it, in reality, fewer than 50 percent do,” Ms. Aspler explained. The high attrition rate can have serious public heath effects, not only for the patients who fail to complete therapy, but also for the individuals they may later infect.
According to previous research and program experience in Maryland and New Jersey, a four-month treatment has been shown to improve compliance by 20 to 25 percent. In addition to better completion rates, a four-month course of Rifampin offers the advantages of fewer adverse reactions (fewer serious side effects such as hepatotoxicity or liver damage), and lower costs.
“The next step in research is a major Phase III clinical trial of efficacy—ideally in HIV-infected and non-infected patients and in low-income settings where tuberculosis is the leading cause of death in people living with HIV,” said Ms. Aspler.
Saturday, May 17, 2008
Thyroid Cancer....
Thyroid cancer discovery points to new treatments, prevention
Molecular mechanisms of cancer-causing protein revealed
KINGSTON, Ont. — The actions of a mutated protein in cells linked to thyroid cancer have been uncovered by researchers at Queen’s University. The discovery paves the way for the future development of drugs to more effectively target, treat and possibly even prevent both inherited and non-inherited thyroid cancers.
“We now know why this gene causes these tumours and can start looking at how best to target the mutant proteins so that the cells expressing them can be killed or stopped from growing,” says Lois Mulligan, professor of pathology and molecular medicine with the Division of Cancer Biology and Genetics of the Queen’s Cancer Research Institute. She is senior author of a study to be published November 15 in the journal Cancer Research.
Taranjit S. Gujral, a Ph D student in Queen’s Department of Pathology and Molecular Medicine and lead author on the paper, developed three-dimensional models of the mutated RET protein implicated in a condition causing cancerous thyroid tumours. The model allowed him to predict and compare the protein’s molecular actions and to see that the protein was ten times more active than normal in cells associated with Multiple Endocrine Neoplasia 2B (MEN 2B) syndrome, an inherited cancer syndrome. Co-authors on the study include
Vinay K. Singh and Zongchao Jia of Queen’s Biochemistry Department.
“It’s like stepping on the gas in a car and getting way more gas than you bargained for,” says Mulligan. “The mutation may cause some new actions but it chiefly does some actions more efficiently than normal.”
MEN 2B is a dominantly inherited condition – the most severe of its kind – and is characterized by the early onset of thyroid tumours, sometimes even affecting infants, and can also cause developmental abnormalities including elongated bones, gastric problems and bumpy lips.
MEN 2B is currently treated with surgery, and other treatments, such as radiation and chemotherapy are not very effective. The study provides valuable tools for specific targeting of the actions of the protein that may aid in the development of anticancer therapies.
###The models created by Mr. Gujral, a Canadian Institutes of Health Research (CIHR) Trainee in Transdisciplinary Cancer Research and Protein Function Discovery, can be used further to help illuminate the actions of the protein with MEN 2B’s other mutations. The research team credits the transdisciplinary approach and its benefits for providing fresh perspectives in generating the new understanding of RET’s role in MEN 2B. Additional funding for the study came from the Canadian Cancer Society and the CIHR.
Molecular mechanisms of cancer-causing protein revealed
KINGSTON, Ont. — The actions of a mutated protein in cells linked to thyroid cancer have been uncovered by researchers at Queen’s University. The discovery paves the way for the future development of drugs to more effectively target, treat and possibly even prevent both inherited and non-inherited thyroid cancers.
“We now know why this gene causes these tumours and can start looking at how best to target the mutant proteins so that the cells expressing them can be killed or stopped from growing,” says Lois Mulligan, professor of pathology and molecular medicine with the Division of Cancer Biology and Genetics of the Queen’s Cancer Research Institute. She is senior author of a study to be published November 15 in the journal Cancer Research.
Taranjit S. Gujral, a Ph D student in Queen’s Department of Pathology and Molecular Medicine and lead author on the paper, developed three-dimensional models of the mutated RET protein implicated in a condition causing cancerous thyroid tumours. The model allowed him to predict and compare the protein’s molecular actions and to see that the protein was ten times more active than normal in cells associated with Multiple Endocrine Neoplasia 2B (MEN 2B) syndrome, an inherited cancer syndrome. Co-authors on the study include
Vinay K. Singh and Zongchao Jia of Queen’s Biochemistry Department.
“It’s like stepping on the gas in a car and getting way more gas than you bargained for,” says Mulligan. “The mutation may cause some new actions but it chiefly does some actions more efficiently than normal.”
MEN 2B is a dominantly inherited condition – the most severe of its kind – and is characterized by the early onset of thyroid tumours, sometimes even affecting infants, and can also cause developmental abnormalities including elongated bones, gastric problems and bumpy lips.
MEN 2B is currently treated with surgery, and other treatments, such as radiation and chemotherapy are not very effective. The study provides valuable tools for specific targeting of the actions of the protein that may aid in the development of anticancer therapies.
###The models created by Mr. Gujral, a Canadian Institutes of Health Research (CIHR) Trainee in Transdisciplinary Cancer Research and Protein Function Discovery, can be used further to help illuminate the actions of the protein with MEN 2B’s other mutations. The research team credits the transdisciplinary approach and its benefits for providing fresh perspectives in generating the new understanding of RET’s role in MEN 2B. Additional funding for the study came from the Canadian Cancer Society and the CIHR.
Thymic Cancer....
Treatment of Thymus Cancers by Stage and Type
Stage I thymoma:
Most patients with stage I thymic cancer have their cancer surgically removed through median sternotomy as described earlier. Long-term survival following complete removal of a stage I thymoma approaches 100%.
Radiation therapy is not used in treating stage I thymomas except for cases in which complete removal is not possible (for example, in patients with other serious medical conditions who are unable to undergo a major operation). For these patients, radiation after partial removal, or radiation instead of surgery are options. However, the best outlook for cure is provided by complete removal whenever possible.
Stages II, III, IV thymoma:
Patients with stage II and III thymic cancer are typically treated with surgical removal of the thymus and, when possible, removal of any other tissues to which the tumor has spread. Postoperative (after surgery) radiation is then given to reduce the risk of recurrence and spread of the tumor, especially for stage III and IV.
Some stage III and most stage IV thymomas have spread too widely to be completely removed. For example, sometimes the tumor is wrapped around the major artery (aorta) or vein (vena cava) in the middle of the chest. These tumors are usually treated by radiation therapy.
Many doctors feel it is important to remove as much of the tumor as is possible in people with stage III disease (where the tumor has not spread widely). This gives the post-operative radiation a better chance of getting rid of the remaining cancer. For stage IV disease (where the cancer has spread more widely), some studies suggest that debulking (removing as much tumor as possible) before radiation therapy improves survival rates, but the value of debulking has not yet been proven.
Other options for unresectable (unable to be completely
removed) thymomas include chemotherapy, or chemotherapy plus radiation therapy. In some cases, neoadjuvant chemotherapy, given before surgery, will shrink a tumor enough so that it can then be completely resected. Even if chemotherapy before surgery does not shrink the tumor enough to permit complete resection, some studies suggest that it may improve survival. After the surgery, radiation therapy alone or together with more chemotherapy will usually be given.
A drug called octreotide has been successful in treating some patients with advanced thymoma. The drug is effective because thymoma cells often bind a hormone called somatostatin. The octreotide replaces somatostatin at the binding sites and causes the thymoma cells to stop growing or die. Results of one study suggest that the combination of octreotide plus prednisone is better than either drug alone.
Recurrent thymoma:
Treatment for thymoma that has recurred after initial treatment depends on what the original treatment was. For example, if you were originally treated with radiation, use of more radiation after recurrence might cause severe damage to normal tissues. In most cases, options for recurrent thymoma include radiation or chemotherapy. The value of surgery in this situation is debated, but some studies suggest that if recurrences are not too widespread, surgical removal offers the best chance of long-term survival. Usually chemotherapy is given and can be very effective in controlling the cancer.
Treatment of thymic carcinoma:
The usual treatment is removal of as much of the thymic tumor as possible, followed by radiation and chemotherapy. Sometimes chemotherapy is given before surgery.
Treatment of thymic carcinoid:
Complete surgical removal, when possible, is the main strategy. If complete removal is not possible, radiation therapy is given after debulking. Radiation is also used in treating local recurrences. Chemotherapy is sometimes used in treating thymic carcinoids with distant spread.
Stage I thymoma:
Most patients with stage I thymic cancer have their cancer surgically removed through median sternotomy as described earlier. Long-term survival following complete removal of a stage I thymoma approaches 100%.
Radiation therapy is not used in treating stage I thymomas except for cases in which complete removal is not possible (for example, in patients with other serious medical conditions who are unable to undergo a major operation). For these patients, radiation after partial removal, or radiation instead of surgery are options. However, the best outlook for cure is provided by complete removal whenever possible.
Stages II, III, IV thymoma:
Patients with stage II and III thymic cancer are typically treated with surgical removal of the thymus and, when possible, removal of any other tissues to which the tumor has spread. Postoperative (after surgery) radiation is then given to reduce the risk of recurrence and spread of the tumor, especially for stage III and IV.
Some stage III and most stage IV thymomas have spread too widely to be completely removed. For example, sometimes the tumor is wrapped around the major artery (aorta) or vein (vena cava) in the middle of the chest. These tumors are usually treated by radiation therapy.
Many doctors feel it is important to remove as much of the tumor as is possible in people with stage III disease (where the tumor has not spread widely). This gives the post-operative radiation a better chance of getting rid of the remaining cancer. For stage IV disease (where the cancer has spread more widely), some studies suggest that debulking (removing as much tumor as possible) before radiation therapy improves survival rates, but the value of debulking has not yet been proven.
Other options for unresectable (unable to be completely
removed) thymomas include chemotherapy, or chemotherapy plus radiation therapy. In some cases, neoadjuvant chemotherapy, given before surgery, will shrink a tumor enough so that it can then be completely resected. Even if chemotherapy before surgery does not shrink the tumor enough to permit complete resection, some studies suggest that it may improve survival. After the surgery, radiation therapy alone or together with more chemotherapy will usually be given.
A drug called octreotide has been successful in treating some patients with advanced thymoma. The drug is effective because thymoma cells often bind a hormone called somatostatin. The octreotide replaces somatostatin at the binding sites and causes the thymoma cells to stop growing or die. Results of one study suggest that the combination of octreotide plus prednisone is better than either drug alone.
Recurrent thymoma:
Treatment for thymoma that has recurred after initial treatment depends on what the original treatment was. For example, if you were originally treated with radiation, use of more radiation after recurrence might cause severe damage to normal tissues. In most cases, options for recurrent thymoma include radiation or chemotherapy. The value of surgery in this situation is debated, but some studies suggest that if recurrences are not too widespread, surgical removal offers the best chance of long-term survival. Usually chemotherapy is given and can be very effective in controlling the cancer.
Treatment of thymic carcinoma:
The usual treatment is removal of as much of the thymic tumor as possible, followed by radiation and chemotherapy. Sometimes chemotherapy is given before surgery.
Treatment of thymic carcinoid:
Complete surgical removal, when possible, is the main strategy. If complete removal is not possible, radiation therapy is given after debulking. Radiation is also used in treating local recurrences. Chemotherapy is sometimes used in treating thymic carcinoids with distant spread.
New treatment for Hepatitis C
Researchers Find New Treatment for Hepatitis C
“New” drug is already approved for lowering cholesterol
Researchers at the OU Health Sciences Center have found a new use for an old drug. Their findings appear online Friday in the American Journal of Gastroenterology.
The drug, Fluvastatin, has been approved since 1993 by the U.S. Food and Drug Administration for the treatment of elevated cholesterol in adults. Millions of patients have taken Fluvastatin for cholesterol without difficulty.
In a study of 31 veterans at the Veteran’s Administration Medical Center in Oklahoma City, researchers found that Fluvastatin significantly lowered the viral load, or levels of hepatitis C virus, for up to six weeks when used alone.
Hepatitis C is the disease that claimed the life of Oklahoman Mickey Mantle.
“This research is the first to demonstrate the antiviral activity of Fluvastatin in human beings infected with hepatitis C, most of whom were non-responders to the standard of care treatment,” said Ted Bader, M.D., the principle investigator on the project and the director of liver diseases at the OU Health Sciences Center.
Since Fluvastatin will not completely clear the hepatitis C virus by itself, researchers have started a phase II randomized, controlled trial that combines Fluvastatin with the standard treatment of peg-interferon and ribavirin. They hope to use the combination of medicines to significantly improve the cure rate for hepatitis C. After further required testing and approval, the drug could be available as a new treatment for hepatitis C far sooner than any other anti-hepatitis C drug currently under research and development.
“We need additional drugs to add to this regimen to improve the cure rate,” Bader said. “When patients are cured, they feel dramatically better, their health care costs plummet, their risk of liver cancer drops dramatically, and if they do not have cirrhosis, they will not need a liver transplant. Moreover, they are no longer infectious.”
In the initial investigative study funded by the VA Research Foundation of Oklahoma City and Dr. Michael Bronze at the OU College of Medicine, veterans with chronic HCV were given oral doses of Fluvastatin daily for two to 12 weeks. Within a month, half of the patients showed a reduction of the virus. One patient’s viral load was about 50 times lower than before taking Fluvastatin.
Hepatitis C is a significant problem for Oklahoma. More than 80,000 Oklahomans have chronic hepatitis C (HCV), but less than 5 percent have been treated. HCV is the leading cause of liver-related deaths in our state and also is the cause for the majority of the 70 liver transplants performed in Oklahoma each year.
Nationwide, 2 percent of Americans (about 4 million) are infected with chronic hepatitis C, which is four times the number of patients infected with HIV. Chronic hepatitis C is often asymptomatic and can lead to progressive liver disease.
Most people with hepatitis C contracted the disease through blood transfusions before 1992 when a test was implemented to screen for the disease. You also can get the virus by injecting drugs with contaminated needles and, less commonly, from contaminated needles used in tattooing and body piercing.
“New” drug is already approved for lowering cholesterol
Researchers at the OU Health Sciences Center have found a new use for an old drug. Their findings appear online Friday in the American Journal of Gastroenterology.
The drug, Fluvastatin, has been approved since 1993 by the U.S. Food and Drug Administration for the treatment of elevated cholesterol in adults. Millions of patients have taken Fluvastatin for cholesterol without difficulty.
In a study of 31 veterans at the Veteran’s Administration Medical Center in Oklahoma City, researchers found that Fluvastatin significantly lowered the viral load, or levels of hepatitis C virus, for up to six weeks when used alone.
Hepatitis C is the disease that claimed the life of Oklahoman Mickey Mantle.
“This research is the first to demonstrate the antiviral activity of Fluvastatin in human beings infected with hepatitis C, most of whom were non-responders to the standard of care treatment,” said Ted Bader, M.D., the principle investigator on the project and the director of liver diseases at the OU Health Sciences Center.
Since Fluvastatin will not completely clear the hepatitis C virus by itself, researchers have started a phase II randomized, controlled trial that combines Fluvastatin with the standard treatment of peg-interferon and ribavirin. They hope to use the combination of medicines to significantly improve the cure rate for hepatitis C. After further required testing and approval, the drug could be available as a new treatment for hepatitis C far sooner than any other anti-hepatitis C drug currently under research and development.
“We need additional drugs to add to this regimen to improve the cure rate,” Bader said. “When patients are cured, they feel dramatically better, their health care costs plummet, their risk of liver cancer drops dramatically, and if they do not have cirrhosis, they will not need a liver transplant. Moreover, they are no longer infectious.”
In the initial investigative study funded by the VA Research Foundation of Oklahoma City and Dr. Michael Bronze at the OU College of Medicine, veterans with chronic HCV were given oral doses of Fluvastatin daily for two to 12 weeks. Within a month, half of the patients showed a reduction of the virus. One patient’s viral load was about 50 times lower than before taking Fluvastatin.
Hepatitis C is a significant problem for Oklahoma. More than 80,000 Oklahomans have chronic hepatitis C (HCV), but less than 5 percent have been treated. HCV is the leading cause of liver-related deaths in our state and also is the cause for the majority of the 70 liver transplants performed in Oklahoma each year.
Nationwide, 2 percent of Americans (about 4 million) are infected with chronic hepatitis C, which is four times the number of patients infected with HIV. Chronic hepatitis C is often asymptomatic and can lead to progressive liver disease.
Most people with hepatitis C contracted the disease through blood transfusions before 1992 when a test was implemented to screen for the disease. You also can get the virus by injecting drugs with contaminated needles and, less commonly, from contaminated needles used in tattooing and body piercing.
Sunday, May 11, 2008
Thalassemia Disorders
NIH Scientists Discover Novel Cause of Iron Overload in Thalassemia Disorders
Researchers at the National Institutes of Health (NIH) have discovered a novel cause of iron overload in patients with thalassemia, a genetic blood disorder that causes anemia. According to the study, thalassemia patients overproduce a protein called GDF15, which suppresses the production of a liver protein, hepcidin, which in turn leads to an increase in the uptake of dietary iron in the gut. This finding has implications for iron metabolism in other diseases, including cancer, and may contribute to the future development of therapies for thalassemia. The study, led by researchers at the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) at the NIH, appears online August 26, 2007, as an Advanced Online Publication in the journal, Nature Medicine.
Thalassemia is an inherited blood disease characterized by the under production of normal hemoglobin, the oxygen-carrying protein in red blood cells. People with severe forms of thalassemia often suffer from anemia, a condition in which the body tissues do not get enough oxygen from the blood, and often require blood transfusions. Blood transfusions contribute to iron overload in people with thalassemia, but these people also suffer from iron overload independent of blood transfusions. Excess iron causes damage to many organs including the heart and liver, and diabetes can develop in severe cases. Patients with thalassemia often require treatment to remove the excess iron to prevent tissue damage.
“The treatment of iron overload in patients with thalassemia is particularly difficult because of their anemia,” says Jeffery L. Miller, M.D., chief of the Molecular Genomics and Therapeutics Section of the Molecular Medicine Branch, Division of Intramural Research, NIDDK, and last author of the study. “So we have been searching for the mechanism responsible for iron overload in thalassemia in hopes of finding new therapies for those patients.”
Thalassemia patients absorb too much iron from food due to abnormally low levels of a small peptide, called hepcidin, which regulates iron uptake from the gut. People with thalassemia should produce hepcidin at high levels. Instead, these patients have reduced levels of hepcidin. This confounded the authors and led them to ask if the low levels of hepcidin were somehow caused by the underlying problem in thalassemia -abnormal development of red blood cells.
Red blood cells, also called erythrocytes, are filled with hemoglobin, which transports oxygen throughout the body. Erythrocytes circulate in the blood, but they originate in the bone marrow as erythroblasts and go through several stages of differentiation until they finally leave the bone marrow and enter the blood stream as fully-formed erythrocytes. Previous research has shown that people with thalassemia disorders have elevated numbers of erythroblasts in the bone marrow, but have reduced numbers of healthy erythrocytes circulating in the blood. Due to the problems with forming hemoglobin, many erythroblasts never make it into the blood stream as healthy erythrocytes.
“Since erythroblasts need iron to make hemoglobin, we reasoned that the increased number of erythroblasts in thalassemia may send stronger messages to the liver to suppress hepcidin and thereby absorb more iron even in the condition of iron overload,” says the study’s lead author, Toshihiko Tanno, Ph.D., an investigator in Miller’s laboratory in the NIDDK’s Division of Intramural Research.
With this hypothesis in mind, Dr. Tanno set out to identify all the messages that are produced by adult stem cells, as they become erythroblasts and red blood cells. For this work, the team was able to examine all the genes expressed in those cells because a catalogue of those genes now exists based upon the NIH’s Human Genome Project. The authors identified growth differentiation factor 15 (GDF15) protein as being unusually elevated in people with thalassemia compared to healthy volunteers. Further study showed that GDF15 does indeed signal reduced hepcidin production in liver cells, and the study revealed additional erythroblast proteins that may be involved.
“We are continuing the search for other factors that regulate expression of hepcidin,” says Miller. “We are also keenly interested in determining if the elevated levels of GDF15 cause other problems in thalassemia in addition to hepcidin suppression.”
The team is now developing strategies to apply and translate their discovery into new diagnostic and therapeutic tools for the clinic. Drs. Miller and Tanno both agreed that while their discovery is a good start, the project will not be complete until the patients have benefited.
The NIDDK, a component of the NIH, conducts and supports research in diabetes and other endocrine and metabolic diseases; digestive diseases, nutrition, and obesity; and kidney, urologic and hematologic diseases. Spanning the full spectrum of medicine and afflicting people of all ages and ethnic groups, these diseases encompass some of the most common, severe, and disabling conditions affecting Americans.
The National Institutes of Health (NIH) — The Nation’s Medical Research Agency — includes 27 Institutes and Centers and is a component of the U.S. Department of Health and Human Services. It is the primary federal agency for conducting and supporting basic, clinical and translational medical research, and it investigates the causes, treatments, and cures for both common and rare diseases.
Researchers at the National Institutes of Health (NIH) have discovered a novel cause of iron overload in patients with thalassemia, a genetic blood disorder that causes anemia. According to the study, thalassemia patients overproduce a protein called GDF15, which suppresses the production of a liver protein, hepcidin, which in turn leads to an increase in the uptake of dietary iron in the gut. This finding has implications for iron metabolism in other diseases, including cancer, and may contribute to the future development of therapies for thalassemia. The study, led by researchers at the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) at the NIH, appears online August 26, 2007, as an Advanced Online Publication in the journal, Nature Medicine.
Thalassemia is an inherited blood disease characterized by the under production of normal hemoglobin, the oxygen-carrying protein in red blood cells. People with severe forms of thalassemia often suffer from anemia, a condition in which the body tissues do not get enough oxygen from the blood, and often require blood transfusions. Blood transfusions contribute to iron overload in people with thalassemia, but these people also suffer from iron overload independent of blood transfusions. Excess iron causes damage to many organs including the heart and liver, and diabetes can develop in severe cases. Patients with thalassemia often require treatment to remove the excess iron to prevent tissue damage.
“The treatment of iron overload in patients with thalassemia is particularly difficult because of their anemia,” says Jeffery L. Miller, M.D., chief of the Molecular Genomics and Therapeutics Section of the Molecular Medicine Branch, Division of Intramural Research, NIDDK, and last author of the study. “So we have been searching for the mechanism responsible for iron overload in thalassemia in hopes of finding new therapies for those patients.”
Thalassemia patients absorb too much iron from food due to abnormally low levels of a small peptide, called hepcidin, which regulates iron uptake from the gut. People with thalassemia should produce hepcidin at high levels. Instead, these patients have reduced levels of hepcidin. This confounded the authors and led them to ask if the low levels of hepcidin were somehow caused by the underlying problem in thalassemia -abnormal development of red blood cells.
Red blood cells, also called erythrocytes, are filled with hemoglobin, which transports oxygen throughout the body. Erythrocytes circulate in the blood, but they originate in the bone marrow as erythroblasts and go through several stages of differentiation until they finally leave the bone marrow and enter the blood stream as fully-formed erythrocytes. Previous research has shown that people with thalassemia disorders have elevated numbers of erythroblasts in the bone marrow, but have reduced numbers of healthy erythrocytes circulating in the blood. Due to the problems with forming hemoglobin, many erythroblasts never make it into the blood stream as healthy erythrocytes.
“Since erythroblasts need iron to make hemoglobin, we reasoned that the increased number of erythroblasts in thalassemia may send stronger messages to the liver to suppress hepcidin and thereby absorb more iron even in the condition of iron overload,” says the study’s lead author, Toshihiko Tanno, Ph.D., an investigator in Miller’s laboratory in the NIDDK’s Division of Intramural Research.
With this hypothesis in mind, Dr. Tanno set out to identify all the messages that are produced by adult stem cells, as they become erythroblasts and red blood cells. For this work, the team was able to examine all the genes expressed in those cells because a catalogue of those genes now exists based upon the NIH’s Human Genome Project. The authors identified growth differentiation factor 15 (GDF15) protein as being unusually elevated in people with thalassemia compared to healthy volunteers. Further study showed that GDF15 does indeed signal reduced hepcidin production in liver cells, and the study revealed additional erythroblast proteins that may be involved.
“We are continuing the search for other factors that regulate expression of hepcidin,” says Miller. “We are also keenly interested in determining if the elevated levels of GDF15 cause other problems in thalassemia in addition to hepcidin suppression.”
The team is now developing strategies to apply and translate their discovery into new diagnostic and therapeutic tools for the clinic. Drs. Miller and Tanno both agreed that while their discovery is a good start, the project will not be complete until the patients have benefited.
The NIDDK, a component of the NIH, conducts and supports research in diabetes and other endocrine and metabolic diseases; digestive diseases, nutrition, and obesity; and kidney, urologic and hematologic diseases. Spanning the full spectrum of medicine and afflicting people of all ages and ethnic groups, these diseases encompass some of the most common, severe, and disabling conditions affecting Americans.
The National Institutes of Health (NIH) — The Nation’s Medical Research Agency — includes 27 Institutes and Centers and is a component of the U.S. Department of Health and Human Services. It is the primary federal agency for conducting and supporting basic, clinical and translational medical research, and it investigates the causes, treatments, and cures for both common and rare diseases.
Stroke Victims Benefit from stem cell transplants
Stroke victims may benefit from stem cell transplants
According to two studies published in the current issue of CELL TRANSPLANTATION (Vol.16 No.10), stroke victims may benefit from human mesenchymal stem cell (hMSC) or bone marrow stromal cell (BMSCs) transplantation. In both studies, the migration of chemically “tagged” transplanted stem cells were tracked to determine the degree to which the transplanted cells reached damaged areas of the brain and became therapeutically active.
Tracking transplanted hMSCs to infarcted areas In a study carried out by Korean researchers, labeled hMSCs (early precursor cells to musculoskeletal, blood, vascular and urogenital systems) were transplanted into animal stroke models with cerebral artery occlusion and tracked by magnetic resonance imaging (MRI) at two days, one week, two weeks, six weeks and ten weeks after transplant.
“Cells started showing indications of migration as early as one or two weeks following transplantation,” said lead author Jihwan, Song, DPhil, of the Pochon CHA University College of Medicine. “At 10 weeks, the majority of the cells were detected in the core of the infarcted area.”
The study concluded that there is a strong tendency for transplanted hMSCs to migrate toward the infarcted area regardless of injection site but that the degree of migration was likely based on differences in each animal’s ischemic condition.
“We speculate that the extensive migratory nature of stem cells and their utilization will provide an important tool for developing novel stroke therapies,” said Song.
BMSCs migrate to damaged brain tissue, improve neural function
In a joint Canadian, Chinese study, BMSCs - connective tissue cells - were
injected into animals 24 hours following middle cerebral artery occlusion. Using laser scanning confocal microscopy to track fluorescent signals and immuno markers attached to the cells, researchers found that within seven days of the injection the BMSCs had migrated through the region of the middle cerebral artery into the scar area and border zone of the ischemic region.
“We evaluated vascular density in the ischemic region in all animals seven days after cell transplantation,” said study lead author Ren-Ke Li, MD, PhD. “The animals exhibited significant reductions in scar size and cell death and improvements in neurological function when compared to controls that received no BMSCs.”
Researchers concluded that the intravenous delivery of bone marrow-derived cells may enhance tissue repair and, in turn, functional recovery after a stroke. While the potential mechanisms for this recovery are unclear, among the possibilities are that the brain microenvironment early on following a stroke may mimic brain development. Subsequent elevated levels of growth factors might enhance homing of BMSCs to the injured area and induce cell proliferation.
“Our results support the potential therapeutic use of BMSCs after a stroke,” concluded Li.
Editor’s comments:
“Both studies lend important support to a growing body of laboratory evidence that bone marrow is a remarkable adult stem cell source for transplant therapy following stroke,” says Cell Transplantation associate editor Cesar V. Borlongan, Ph.D. of the Medical College of Georgia. “The non-invasive MRI visualization of pre-labeled BMSCs could become a routine clinical marker for transplanted cells as well as for safety and efficacy.”
According to two studies published in the current issue of CELL TRANSPLANTATION (Vol.16 No.10), stroke victims may benefit from human mesenchymal stem cell (hMSC) or bone marrow stromal cell (BMSCs) transplantation. In both studies, the migration of chemically “tagged” transplanted stem cells were tracked to determine the degree to which the transplanted cells reached damaged areas of the brain and became therapeutically active.
Tracking transplanted hMSCs to infarcted areas In a study carried out by Korean researchers, labeled hMSCs (early precursor cells to musculoskeletal, blood, vascular and urogenital systems) were transplanted into animal stroke models with cerebral artery occlusion and tracked by magnetic resonance imaging (MRI) at two days, one week, two weeks, six weeks and ten weeks after transplant.
“Cells started showing indications of migration as early as one or two weeks following transplantation,” said lead author Jihwan, Song, DPhil, of the Pochon CHA University College of Medicine. “At 10 weeks, the majority of the cells were detected in the core of the infarcted area.”
The study concluded that there is a strong tendency for transplanted hMSCs to migrate toward the infarcted area regardless of injection site but that the degree of migration was likely based on differences in each animal’s ischemic condition.
“We speculate that the extensive migratory nature of stem cells and their utilization will provide an important tool for developing novel stroke therapies,” said Song.
BMSCs migrate to damaged brain tissue, improve neural function
In a joint Canadian, Chinese study, BMSCs - connective tissue cells - were
injected into animals 24 hours following middle cerebral artery occlusion. Using laser scanning confocal microscopy to track fluorescent signals and immuno markers attached to the cells, researchers found that within seven days of the injection the BMSCs had migrated through the region of the middle cerebral artery into the scar area and border zone of the ischemic region.
“We evaluated vascular density in the ischemic region in all animals seven days after cell transplantation,” said study lead author Ren-Ke Li, MD, PhD. “The animals exhibited significant reductions in scar size and cell death and improvements in neurological function when compared to controls that received no BMSCs.”
Researchers concluded that the intravenous delivery of bone marrow-derived cells may enhance tissue repair and, in turn, functional recovery after a stroke. While the potential mechanisms for this recovery are unclear, among the possibilities are that the brain microenvironment early on following a stroke may mimic brain development. Subsequent elevated levels of growth factors might enhance homing of BMSCs to the injured area and induce cell proliferation.
“Our results support the potential therapeutic use of BMSCs after a stroke,” concluded Li.
Editor’s comments:
“Both studies lend important support to a growing body of laboratory evidence that bone marrow is a remarkable adult stem cell source for transplant therapy following stroke,” says Cell Transplantation associate editor Cesar V. Borlongan, Ph.D. of the Medical College of Georgia. “The non-invasive MRI visualization of pre-labeled BMSCs could become a routine clinical marker for transplanted cells as well as for safety and efficacy.”
Stroke Risk - Latest Research
Metabolic genes tied to inflammatory predictor of heart disease and stroke risk
Two new studies provide evidence that differences in people’s blood levels of C reactive protein (CRP) stem in part from natural variation in known metabolic genes. The researchers report their findings in the May American Journal of Human Genetics, a publication of Cell Press.
“ Many years ago, we showed that CRP levels in healthy, middle aged men can predict—better than cholesterol—who would die from a cardiac event,” said Paul Ridker of Harvard Medical School, who led one of the two studies. “We’ve now confirmed that the CRP gene itself plays a role in setting CRP levels. And the most extraordinary finding is that some of the other genes involved relate to metabolic syndrome pathways.”
The findings come just weeks after the “JUPITER Trial,” designed to test whether cholesterol-lowering statins can prevent heart disease in people with normal cholesterol but increased CRP levels, was ended early. The drug company AstraZeneca announced that they were halting the trial of rosuvastatin calcium (trade name Crestor) because early results showed that the drug reduced death and risk of heart problems in patients compared to placebo.
“In light of the study being stopped early, a fundamental understanding of the genetics underlying CRP becomes even more important,” said Ridker, who also chaired the JUPITER trial.
CRP has long been considered a hallmark of low-grade, systemic inflammation. Although researchers have known for more than a decade that CRP levels can predict the risk of heart disease, stroke, metabolic syndrome and diabetes, it hasn’t been entirely clear why. Environmental factors, including obesity, smoking and stress, contribute to CRP, but studies have also shown that its levels have a strong genetic component.
In search of the genes responsible, Ridker’s team conducted a genome-wide association study among 6,345 apparently healthy women participating in the Women’s Genome Health Study. Specifically, the women were evaluated for hundreds of thousands of single nucleotide polymorphisms (sites in the genome that harbor lots of variation among individuals) that they thought might possibly determine plasma CRP level.
The study turned up seven sites that were significantly associated with CRP. Two of those, responsible for proteins known as glucokinase regulatory protein (GCKR) and hepatic nuclear factor-1A (HNF1A), are suspected or known to be associated with maturity-onset diabetes of the young, they noted. GCKR had earlier been linked to triglyceride and glucose levels, but not to CRP, Ridker said.
A second report of two additional genetic association studies (from the Pharmacogenomics and Risk of Cardiovascular Disease study and the Cardiovascular Health Study), each including thousands of participants, provided independent and confirmatory evidence for an association between common variants of HNF1A and CRP concentrations.
“ It all fits together nicely,” said Alexander Reiner of the University of Washington, Seattle, who led the second report. “In both studies, HNF1A came out as one of the strongest predictors of plasma CRP.”
HNF1A is produced in the liver and pancreas, where it regulates the activity of other genes, he explained. An earlier study also showed that the promoter region of the human CRP gene contains an HNF1A-binding site.
“ Our finding … that HNF1A polymorphism significantly impacts upon CRP levels would appear to have a strong functional basis,” Ridker said. His team also uncovered links between CRP levels and the inflammatory cytokine known as interleukin-6 as well as a site in or near the gene encoding leptin, a fat-produced hormone that regulates appetite and metabolism. Both studies also found links between blood CRP levels and the CRP gene itself in addition to the apolipoprotein E (APOE) gene, consistent with earlier reports.
“ The protein products of six of the seven loci [we’ve uncovered] are directly involved in metabolic syndrome, insulin resistance, [insulin-producing] beta-cell function, weight homeostasis, and/or premature atherothrombosis,” Ridker’s team concluded. “Thus, common variation in several genes involved in metabolic and inflammatory regulation have significant effects on CRP levels, consistent with CRP’s identification as a useful biomarker of risk for incident vascular disease and diabetes.”
“ Together, these observations suggest the possibility that CRP and metabolic phenotypes may, at least in part, be under coordinate genetic control,” Reiner and his colleagues said. “Given the association between plasma CRP concentration and various metabolic and cardiovascular diseases, larger studies assessing the potential association of HNF1A genotype with more complex, clinical disease-related endpoints may shed additional light on the role of genetic regulation of CRP in the occurrence of disorders such as myocardial infarction, stroke, diabetes, and metabolic syndrome.”
Two new studies provide evidence that differences in people’s blood levels of C reactive protein (CRP) stem in part from natural variation in known metabolic genes. The researchers report their findings in the May American Journal of Human Genetics, a publication of Cell Press.
“ Many years ago, we showed that CRP levels in healthy, middle aged men can predict—better than cholesterol—who would die from a cardiac event,” said Paul Ridker of Harvard Medical School, who led one of the two studies. “We’ve now confirmed that the CRP gene itself plays a role in setting CRP levels. And the most extraordinary finding is that some of the other genes involved relate to metabolic syndrome pathways.”
The findings come just weeks after the “JUPITER Trial,” designed to test whether cholesterol-lowering statins can prevent heart disease in people with normal cholesterol but increased CRP levels, was ended early. The drug company AstraZeneca announced that they were halting the trial of rosuvastatin calcium (trade name Crestor) because early results showed that the drug reduced death and risk of heart problems in patients compared to placebo.
“In light of the study being stopped early, a fundamental understanding of the genetics underlying CRP becomes even more important,” said Ridker, who also chaired the JUPITER trial.
CRP has long been considered a hallmark of low-grade, systemic inflammation. Although researchers have known for more than a decade that CRP levels can predict the risk of heart disease, stroke, metabolic syndrome and diabetes, it hasn’t been entirely clear why. Environmental factors, including obesity, smoking and stress, contribute to CRP, but studies have also shown that its levels have a strong genetic component.
In search of the genes responsible, Ridker’s team conducted a genome-wide association study among 6,345 apparently healthy women participating in the Women’s Genome Health Study. Specifically, the women were evaluated for hundreds of thousands of single nucleotide polymorphisms (sites in the genome that harbor lots of variation among individuals) that they thought might possibly determine plasma CRP level.
The study turned up seven sites that were significantly associated with CRP. Two of those, responsible for proteins known as glucokinase regulatory protein (GCKR) and hepatic nuclear factor-1A (HNF1A), are suspected or known to be associated with maturity-onset diabetes of the young, they noted. GCKR had earlier been linked to triglyceride and glucose levels, but not to CRP, Ridker said.
A second report of two additional genetic association studies (from the Pharmacogenomics and Risk of Cardiovascular Disease study and the Cardiovascular Health Study), each including thousands of participants, provided independent and confirmatory evidence for an association between common variants of HNF1A and CRP concentrations.
“ It all fits together nicely,” said Alexander Reiner of the University of Washington, Seattle, who led the second report. “In both studies, HNF1A came out as one of the strongest predictors of plasma CRP.”
HNF1A is produced in the liver and pancreas, where it regulates the activity of other genes, he explained. An earlier study also showed that the promoter region of the human CRP gene contains an HNF1A-binding site.
“ Our finding … that HNF1A polymorphism significantly impacts upon CRP levels would appear to have a strong functional basis,” Ridker said. His team also uncovered links between CRP levels and the inflammatory cytokine known as interleukin-6 as well as a site in or near the gene encoding leptin, a fat-produced hormone that regulates appetite and metabolism. Both studies also found links between blood CRP levels and the CRP gene itself in addition to the apolipoprotein E (APOE) gene, consistent with earlier reports.
“ The protein products of six of the seven loci [we’ve uncovered] are directly involved in metabolic syndrome, insulin resistance, [insulin-producing] beta-cell function, weight homeostasis, and/or premature atherothrombosis,” Ridker’s team concluded. “Thus, common variation in several genes involved in metabolic and inflammatory regulation have significant effects on CRP levels, consistent with CRP’s identification as a useful biomarker of risk for incident vascular disease and diabetes.”
“ Together, these observations suggest the possibility that CRP and metabolic phenotypes may, at least in part, be under coordinate genetic control,” Reiner and his colleagues said. “Given the association between plasma CRP concentration and various metabolic and cardiovascular diseases, larger studies assessing the potential association of HNF1A genotype with more complex, clinical disease-related endpoints may shed additional light on the role of genetic regulation of CRP in the occurrence of disorders such as myocardial infarction, stroke, diabetes, and metabolic syndrome.”
Stroke...
Blood Pressure Drug Telmisartan Shows Powerful Activity Against Stroke
Drug, Alone or in Combination, Eliminated Stroke Risk, Weill Cornell Team Reports
NEW YORK (Dec. 12, 2007) — Telmisartan, a drug widely used to help control blood pressure, may have uniquely potent activity in preventing stroke, according to a new study conducted in an animal model.
Whether they used the drug alone or in combination with a different type of antihypertensive medication, ramipril, Weill Cornell Medical College researchers found that rats fed a high-salt, stroke-inducing diet were completely protected from the brain attacks while on telmisartan.
“No other study has ever shown complete protection against stroke in this rat model using normal human drug doses” notes study senior author Dr. Daniel F. Catanzaro, professor of physiology and biophysics and professor of physiology in cardiothoracic surgery at Weill Cornell Medical College.
The study, which was funded by telmisartan’s German maker, Boehringer Ingelheim Pharma GmbH & Co., is published online in the Journal of the American Society of Hypertension.
Telmisartan (brand name Micardis) is one of a class of widely used antihypertensive drugs known as angiotensin receptor blockers (ARBs). “These drugs primarily act on the vasculature to relax the small blood vessels,” Dr. Catanzaro explains.
Telmisartan stands out from other ARBs in that its molecular structure allows it to more easily pass through the blood-brain barrier and enter the brain — something many drugs cannot do.
The new animal study was not constructed to specifically look at telmisartan’s effect on stroke. “Because blood pressure is closely related to stroke risk, we really just wanted to look and see if combinations of antihypertensive drugs were better at lowering blood pressure and stroke compared to the use of single agents,” Dr. Catanzaro explains.
In this case, his team tested two drugs — telmisartan and an ACE inhibitor, ramipril (Altace) — in a rat model long favored by stroke researchers. In this approach, rats are fed what’s known as a “stroke-prone diet,” meaning they get lots of salt in both their food and water.
“This rat model has been great at showing us the neuroprotective properties of different drugs in the past, and the results usually correlate with results in humans,” Dr. Catanzaro says.
In the study, 25 rats were fed the stroke-prone diet for 8 weeks and received either no medication, telmisartan alone, ramipril alone, or the two drugs together at either full- or half-doses.
“A main finding was that combination therapy did reduce blood pressure the best of any treatment, and it also was best at cutting damage to the rats’ hearts and kidneys,” Dr. Catanzaro says. “But what was really surprising to us was that any regimen involving telmisartan at doses that would normally be given to humans completely prevented stroke in this model. Most studies with other drugs have used much higher doses and have found only partial protection.”
Specifically, 83 percent of rats given no medication showed signs of stroke, as did 56 percent of rats given ramipril alone. However, no strokes were noted in the telmisartan-only or the telmisartan/ramipril combo groups.
Telmisartan’s ability to easily pass through the blood-brain barrier (something ramipril cannot do) is likely behind the neuroprotective effect noted in the study, the researchers say.
“Going forward, that’s something that we would really like to test out in head-to-head trials pitting telmisartan against other ARBs, for example,” Dr. Catanzaro said. “At the same time, we’d like to examine whether telmisartan is actually getting into the brain, or if more peripheral effects — a lowering of blood pressure, for instance — are behind the reduction in stroke.”
In the meantime, Boehringer Ingelheim is nearing the end of a major clinical trial looking at the effectiveness of combining telmisartan with ramipril to lower patients’ blood pressures and reduce their odds for heart attack and stroke. Dr. Catanzaro’s team is not involved in that study.
Co-authors on this study include lead researcher Dr. Ying Zhou, as well as Dr. Fangmin Yu and Dr. Ada R. Ene — all of Weill Cornell Medical College in New York City.
Weill Cornell Medical CollegeWeill Cornell Medical College — Cornell University’s Medical School located in New York City — is committed to excellence in research, teaching, patient care and the advancement of the art and science of medicine, locally, nationally and globally. Weill Cornell, which is a principal academic affiliate of NewYork-Presbyterian Hospital, offers an innovative curriculum that integrates the teaching of basic and clinical sciences, problem-based learning, office-based preceptorships, and primary care and doctoring courses. Physicians and scientists of Weill Cornell Medical College are engaged in cutting-edge research in such areas as stem cells, genetics and gene therapy, geriatrics, neuroscience, structural biology, cardiovascular medicine, infectious disease, obesity, cancer, psychiatry and public health — and continue to delve ever deeper into the molecular basis of disease in an effort to unlock the mysteries behind the human body and the malfunctions that result in serious medical disorders. The Medical College — in its commitment to global health and education — has a strong presence in such places as Qatar, Tanzania, Haiti, Brazil, Austria and Turkey. With the historic Weill Cornell Medical College in Qatar, the Medical School is the first in the U.S. to offer its M.D. degree overseas. Weill Cornell is the birthplace of many medical advances — from the development of the Pap test for cervical cancer to the synthesis of penicillin, the first successful embryo-biopsy pregnancy and birth in the U.S., the first clinical trial for gene therapy for Parkinson’s disease, the first indication of bone marrow’s critical role in tumor growth, and, most recently, the world’s first successful use of deep brain stimulation to treat a minimally-conscious brain-injured patient.
Drug, Alone or in Combination, Eliminated Stroke Risk, Weill Cornell Team Reports
NEW YORK (Dec. 12, 2007) — Telmisartan, a drug widely used to help control blood pressure, may have uniquely potent activity in preventing stroke, according to a new study conducted in an animal model.
Whether they used the drug alone or in combination with a different type of antihypertensive medication, ramipril, Weill Cornell Medical College researchers found that rats fed a high-salt, stroke-inducing diet were completely protected from the brain attacks while on telmisartan.
“No other study has ever shown complete protection against stroke in this rat model using normal human drug doses” notes study senior author Dr. Daniel F. Catanzaro, professor of physiology and biophysics and professor of physiology in cardiothoracic surgery at Weill Cornell Medical College.
The study, which was funded by telmisartan’s German maker, Boehringer Ingelheim Pharma GmbH & Co., is published online in the Journal of the American Society of Hypertension.
Telmisartan (brand name Micardis) is one of a class of widely used antihypertensive drugs known as angiotensin receptor blockers (ARBs). “These drugs primarily act on the vasculature to relax the small blood vessels,” Dr. Catanzaro explains.
Telmisartan stands out from other ARBs in that its molecular structure allows it to more easily pass through the blood-brain barrier and enter the brain — something many drugs cannot do.
The new animal study was not constructed to specifically look at telmisartan’s effect on stroke. “Because blood pressure is closely related to stroke risk, we really just wanted to look and see if combinations of antihypertensive drugs were better at lowering blood pressure and stroke compared to the use of single agents,” Dr. Catanzaro explains.
In this case, his team tested two drugs — telmisartan and an ACE inhibitor, ramipril (Altace) — in a rat model long favored by stroke researchers. In this approach, rats are fed what’s known as a “stroke-prone diet,” meaning they get lots of salt in both their food and water.
“This rat model has been great at showing us the neuroprotective properties of different drugs in the past, and the results usually correlate with results in humans,” Dr. Catanzaro says.
In the study, 25 rats were fed the stroke-prone diet for 8 weeks and received either no medication, telmisartan alone, ramipril alone, or the two drugs together at either full- or half-doses.
“A main finding was that combination therapy did reduce blood pressure the best of any treatment, and it also was best at cutting damage to the rats’ hearts and kidneys,” Dr. Catanzaro says. “But what was really surprising to us was that any regimen involving telmisartan at doses that would normally be given to humans completely prevented stroke in this model. Most studies with other drugs have used much higher doses and have found only partial protection.”
Specifically, 83 percent of rats given no medication showed signs of stroke, as did 56 percent of rats given ramipril alone. However, no strokes were noted in the telmisartan-only or the telmisartan/ramipril combo groups.
Telmisartan’s ability to easily pass through the blood-brain barrier (something ramipril cannot do) is likely behind the neuroprotective effect noted in the study, the researchers say.
“Going forward, that’s something that we would really like to test out in head-to-head trials pitting telmisartan against other ARBs, for example,” Dr. Catanzaro said. “At the same time, we’d like to examine whether telmisartan is actually getting into the brain, or if more peripheral effects — a lowering of blood pressure, for instance — are behind the reduction in stroke.”
In the meantime, Boehringer Ingelheim is nearing the end of a major clinical trial looking at the effectiveness of combining telmisartan with ramipril to lower patients’ blood pressures and reduce their odds for heart attack and stroke. Dr. Catanzaro’s team is not involved in that study.
Co-authors on this study include lead researcher Dr. Ying Zhou, as well as Dr. Fangmin Yu and Dr. Ada R. Ene — all of Weill Cornell Medical College in New York City.
Weill Cornell Medical CollegeWeill Cornell Medical College — Cornell University’s Medical School located in New York City — is committed to excellence in research, teaching, patient care and the advancement of the art and science of medicine, locally, nationally and globally. Weill Cornell, which is a principal academic affiliate of NewYork-Presbyterian Hospital, offers an innovative curriculum that integrates the teaching of basic and clinical sciences, problem-based learning, office-based preceptorships, and primary care and doctoring courses. Physicians and scientists of Weill Cornell Medical College are engaged in cutting-edge research in such areas as stem cells, genetics and gene therapy, geriatrics, neuroscience, structural biology, cardiovascular medicine, infectious disease, obesity, cancer, psychiatry and public health — and continue to delve ever deeper into the molecular basis of disease in an effort to unlock the mysteries behind the human body and the malfunctions that result in serious medical disorders. The Medical College — in its commitment to global health and education — has a strong presence in such places as Qatar, Tanzania, Haiti, Brazil, Austria and Turkey. With the historic Weill Cornell Medical College in Qatar, the Medical School is the first in the U.S. to offer its M.D. degree overseas. Weill Cornell is the birthplace of many medical advances — from the development of the Pap test for cervical cancer to the synthesis of penicillin, the first successful embryo-biopsy pregnancy and birth in the U.S., the first clinical trial for gene therapy for Parkinson’s disease, the first indication of bone marrow’s critical role in tumor growth, and, most recently, the world’s first successful use of deep brain stimulation to treat a minimally-conscious brain-injured patient.
Saturday, May 3, 2008
Stomach infection...
Early treatment of stomach infection may prevent cancer
Based on research using a new mouse model of gastritis and stomach cancer, researchers from the Massachusetts Institute of Technology (MIT) say that prompt treatment of Helicobacter pylori (H. pylori) infections reverses damage to the lining of the stomach that can lead to cancer.
In the May 1 issue of Cancer Research, a journal of the American Association for Cancer Research, researchers say their study results should lay to rest any question about whether – and when - antibiotic treatment of H. pylori can eliminate or reduce risk of developing gastric, or stomach cancer.
“We concluded that H. pylori eradication prevented gastric cancer to the greatest extent when antibiotics were given at an early point of infection, but that eradication therapy given at a later time point also delayed the development of severe lesions that can lead to cancer,” said the study’s lead author, James G. Fox, D.V.M., professor and director of the Division of Comparative Medicine at MIT.
The findings are important, Fox says, because stomach cancer is the second leading cause of cancer death worldwide, and approximately half of the world’s population is infected with H. pylori. Although H. pylori infection is now recognized as the major cause of both peptic ulcers and gastric cancer, and has been classified as a group I carcinogen by the World Health Organization, physicians are not sure whom to screen and treat with costly antibiotics, aside from first degree relatives of gastric cancer patients and those with peptic ulcer disease, he adds.
Since it typically takes several decades for gastric cancer to develop in those who are susceptible – which is estimated to be up to three percent of infected people – researchers also do not know when to treat the infection for maximum benefit. Human studies that tested treatment in patients who had already developed tumors had mixed results, but one previous study showed that giving antibiotics before premalignant lesions develop was successful in preventing cancer, Fox says.The current study examined the effects of treating and eliminating H. pylori at different stages of progression from gastritis, an inflammation of the mucous membrane layer of the stomach, to development of gastric cancer. To do this, Fox and colleagues from MIT and Columbia University developed transgenic “INS-GAS” mice that over-expressed gastrin, a hormone that controls secretion of gastric acid by the stomach’s parietal cells.
“If you lose these cells over time, they stop secreting gastric acid, and this is, in and of itself, a risk factor for development of cancer, but gastric acid also helps protect against commensal bacterial colonization of the stomach,” Fox said.
With increasing age, parietal cells in INS-GAS mice stopped producing gastric acid and underwent precancerous changes. By 20 months of age, the mice spontaneously developed invasive gastric cancer. Infection by H. pylori and progression to gastric cancer was accelerated in these mice, researchers discovered.
Researchers then treated the mice with antibiotics and looked for cellular changes. They found that, at every stage of advancing infection, mice that were treated with antibiotics had less severe disease. . Treating mice that were eight weeks post-infection reduced risk of developing cancer to the same level seen in uninfected mice. But using antibiotics at 12 and 22 weeks post-infection did not reverse the damaging changes, such as inflammation and development of precancerous lesions, to the levels seen in uninfected mice.
“Our mouse model mimics the progressive process we know occurs in development of human gastric cancer,” Fox said. “This shows early intervention provides the maximum benefit.”
Of added benefit, Fox says, is the associated finding that antibiotic treatment also reduces the level of other bacterial species that have invaded the stomach. “Gastric acid is a barrier to bacteria, and if there is no barrier, bacteria can move into the stomach from the lower bowel and colonize it, producing inflammation and progression to cancer,” he said. . “Findings in humans and mice now suggest that antibiotic treatment potentially changes gastric microbiota and may impact gastric carcinogenesis.”’
Based on research using a new mouse model of gastritis and stomach cancer, researchers from the Massachusetts Institute of Technology (MIT) say that prompt treatment of Helicobacter pylori (H. pylori) infections reverses damage to the lining of the stomach that can lead to cancer.
In the May 1 issue of Cancer Research, a journal of the American Association for Cancer Research, researchers say their study results should lay to rest any question about whether – and when - antibiotic treatment of H. pylori can eliminate or reduce risk of developing gastric, or stomach cancer.
“We concluded that H. pylori eradication prevented gastric cancer to the greatest extent when antibiotics were given at an early point of infection, but that eradication therapy given at a later time point also delayed the development of severe lesions that can lead to cancer,” said the study’s lead author, James G. Fox, D.V.M., professor and director of the Division of Comparative Medicine at MIT.
The findings are important, Fox says, because stomach cancer is the second leading cause of cancer death worldwide, and approximately half of the world’s population is infected with H. pylori. Although H. pylori infection is now recognized as the major cause of both peptic ulcers and gastric cancer, and has been classified as a group I carcinogen by the World Health Organization, physicians are not sure whom to screen and treat with costly antibiotics, aside from first degree relatives of gastric cancer patients and those with peptic ulcer disease, he adds.
Since it typically takes several decades for gastric cancer to develop in those who are susceptible – which is estimated to be up to three percent of infected people – researchers also do not know when to treat the infection for maximum benefit. Human studies that tested treatment in patients who had already developed tumors had mixed results, but one previous study showed that giving antibiotics before premalignant lesions develop was successful in preventing cancer, Fox says.The current study examined the effects of treating and eliminating H. pylori at different stages of progression from gastritis, an inflammation of the mucous membrane layer of the stomach, to development of gastric cancer. To do this, Fox and colleagues from MIT and Columbia University developed transgenic “INS-GAS” mice that over-expressed gastrin, a hormone that controls secretion of gastric acid by the stomach’s parietal cells.
“If you lose these cells over time, they stop secreting gastric acid, and this is, in and of itself, a risk factor for development of cancer, but gastric acid also helps protect against commensal bacterial colonization of the stomach,” Fox said.
With increasing age, parietal cells in INS-GAS mice stopped producing gastric acid and underwent precancerous changes. By 20 months of age, the mice spontaneously developed invasive gastric cancer. Infection by H. pylori and progression to gastric cancer was accelerated in these mice, researchers discovered.
Researchers then treated the mice with antibiotics and looked for cellular changes. They found that, at every stage of advancing infection, mice that were treated with antibiotics had less severe disease. . Treating mice that were eight weeks post-infection reduced risk of developing cancer to the same level seen in uninfected mice. But using antibiotics at 12 and 22 weeks post-infection did not reverse the damaging changes, such as inflammation and development of precancerous lesions, to the levels seen in uninfected mice.
“Our mouse model mimics the progressive process we know occurs in development of human gastric cancer,” Fox said. “This shows early intervention provides the maximum benefit.”
Of added benefit, Fox says, is the associated finding that antibiotic treatment also reduces the level of other bacterial species that have invaded the stomach. “Gastric acid is a barrier to bacteria, and if there is no barrier, bacteria can move into the stomach from the lower bowel and colonize it, producing inflammation and progression to cancer,” he said. . “Findings in humans and mice now suggest that antibiotic treatment potentially changes gastric microbiota and may impact gastric carcinogenesis.”’
Tuesday, April 29, 2008
Skin Disorders
Research suggests new options in treating skin pigment problems
Melanocytes are not the only cells responsible for differences in skin coloration. New research from the University of Cincinnati (UC) has shown that some of the most basic cells on the skin’s surface influence pigment production and help regulate skin coloration.
The finding offers hope for new approaches to the treatment of pigmentation disorders that leave the skin disfigured by light or dark blotches.
In a two-year, preclinical dermatological study, Raymond Boissy, PhD, and his team found that cells known as keratinocytes express certain characteristics that could control skin pigmentation.
Keratinocytes are surface skin cells that make up about 96 percent of the skin’s outer layer (epidermis). The cells give the skin structural integrity and protect the body from infection.
Melanocytes, the body’s melanin-producing cells, make up another 2 percent of the epidermis. Melanin is the chemical responsible for skin pigmentation or color.
Boissy says his team’s findings could help scientists develop new drugs that alter the physiological processes that cause pigmentation disorders such as vitiligo—white blotches that occur near the body’s orifices and joints—and melasma, a disorder characterized by dark pigmented lesions.
“We’ve isolated specific physiological properties that regulate the melanocytes’ functional abilities,” explains Boissy, UC professor of dermatology and principal investigator for the study. “This is an important discovery because many pigment diseases are the result of deregulation of the melanocyte.”
“Now we have a new set of molecules to investigate that may help create uniform skin color—both for patients with pigment disorders or serious burn wounds as well as those seeking improved cosmetic skin appearance,” he adds.
The UC-led study, published in the September issue of The FASEB Journal, is the first to identify a specific model for manipulating melanin production in the body by using keratinocytes.
Previous research has shown that keratinocytes receive “packages” of pigment granules (melanosomes) from melanocytes. In dark-skinned people, these packages are dispersed throughout the cell individually, creating a larger surface area that absorbs more light than skin cells of light-skinned people, which disperse pigment in clusters.
“This was the first clue that keratinocytes played a role in skin coloration outside of genetic factors regulating the melanocyte,” says Boissy. “Further study showed there was no informational difference between the melanosomes in keratinocytes for dark and light skin responsible for sorting within the keratinocyte. The cells sorted themselves based on ethnic background, so we wanted to learn more about the factors that influence skin pigmentation.”
For this study, Boissy and his team developed a human skin substitute model using a combination of keratinocytes and melanocytes derived from donated light and dark skin. These mixed cells were transplanted into a mouse model and allowed to grow into the skin substitute for about three months.
“We found that by transplanting keratinocytes from light-skinned individuals to bioengineered skin substitutes produced a lightening effect,” says Boissy. “The same effect resulted when keratinocytes from dark-skinned individuals were transplanted into the skin substitute, creating a darkening effect.
“Surprisingly,” he adds, “intermediate skin color was obtained when melanocytes and keratinocytes were combined from light and dark skin together.”
In addition, the researchers discovered that the keratinocytes also influenced how much pigment is actually produced. Boissy says the effect is subtle, but it shows that it’s not just genetics of the melanocyte that determines skin coloration.
Melanocytes are not the only cells responsible for differences in skin coloration. New research from the University of Cincinnati (UC) has shown that some of the most basic cells on the skin’s surface influence pigment production and help regulate skin coloration.
The finding offers hope for new approaches to the treatment of pigmentation disorders that leave the skin disfigured by light or dark blotches.
In a two-year, preclinical dermatological study, Raymond Boissy, PhD, and his team found that cells known as keratinocytes express certain characteristics that could control skin pigmentation.
Keratinocytes are surface skin cells that make up about 96 percent of the skin’s outer layer (epidermis). The cells give the skin structural integrity and protect the body from infection.
Melanocytes, the body’s melanin-producing cells, make up another 2 percent of the epidermis. Melanin is the chemical responsible for skin pigmentation or color.
Boissy says his team’s findings could help scientists develop new drugs that alter the physiological processes that cause pigmentation disorders such as vitiligo—white blotches that occur near the body’s orifices and joints—and melasma, a disorder characterized by dark pigmented lesions.
“We’ve isolated specific physiological properties that regulate the melanocytes’ functional abilities,” explains Boissy, UC professor of dermatology and principal investigator for the study. “This is an important discovery because many pigment diseases are the result of deregulation of the melanocyte.”
“Now we have a new set of molecules to investigate that may help create uniform skin color—both for patients with pigment disorders or serious burn wounds as well as those seeking improved cosmetic skin appearance,” he adds.
The UC-led study, published in the September issue of The FASEB Journal, is the first to identify a specific model for manipulating melanin production in the body by using keratinocytes.
Previous research has shown that keratinocytes receive “packages” of pigment granules (melanosomes) from melanocytes. In dark-skinned people, these packages are dispersed throughout the cell individually, creating a larger surface area that absorbs more light than skin cells of light-skinned people, which disperse pigment in clusters.
“This was the first clue that keratinocytes played a role in skin coloration outside of genetic factors regulating the melanocyte,” says Boissy. “Further study showed there was no informational difference between the melanosomes in keratinocytes for dark and light skin responsible for sorting within the keratinocyte. The cells sorted themselves based on ethnic background, so we wanted to learn more about the factors that influence skin pigmentation.”
For this study, Boissy and his team developed a human skin substitute model using a combination of keratinocytes and melanocytes derived from donated light and dark skin. These mixed cells were transplanted into a mouse model and allowed to grow into the skin substitute for about three months.
“We found that by transplanting keratinocytes from light-skinned individuals to bioengineered skin substitutes produced a lightening effect,” says Boissy. “The same effect resulted when keratinocytes from dark-skinned individuals were transplanted into the skin substitute, creating a darkening effect.
“Surprisingly,” he adds, “intermediate skin color was obtained when melanocytes and keratinocytes were combined from light and dark skin together.”
In addition, the researchers discovered that the keratinocytes also influenced how much pigment is actually produced. Boissy says the effect is subtle, but it shows that it’s not just genetics of the melanocyte that determines skin coloration.
Monday, March 24, 2008
24th March - World T.B Day
World TB Day, falling on 24 March each year, is designed to build public awareness that tuberculosis today remains an epidemic in much of the world, causing the deaths of several million people each year, mostly in the third world. 24 March commemorates the day in 1882 when Dr Robert Koch astounded the scientific community by announcing that he had discovered the cause of tuberculosis, the TB bacillus. At the time of Koch's announcement in Berlin, TB was raging through Europe and the Americas, causing the death of one out of every seven people. Koch's discovery opened the way toward diagnosing and curing tuberculosis.
I am stopping TB is more than slogan. It is the start of a two-year campaign that belongs to people everywhere who are doing their part to Stop TB.
This year's World TB Day is about celebrating the lives and stories of people affected by TB: women, men and children who have taken TB treatment; nurses; do
About
The Stop TB Partnership was established in 2000 to eliminate tuberculosis as a public health problem and ultimately to realize a world free of TB. It comprises a network of more then 500 international organizations, countries, donors from the public and private sectors, and nongovernmental and governmental organizations that have expressed an interest in working together to achieve this goal.ctors; researchers; community workers--anyone who has contributed towards the global fight against TB.
What is T.B (Tuberculosis)?
Tuberculosis, or TB, is an infectious bacterial disease caused by Mycobacterium tuberculosis, which most commonly affects the lungs. It is transmitted from person to person via droplets from the throat and lungs of people with the active respiratory disease.
In healthy people, infection with Mycobacterium tuberculosis often causes no symptoms, since the person's immune system acts to “wall off” the bacteria. The symptoms of active TB of the lung are coughing, sometimes with sputum or blood, chest pains, weakness, weight loss, fever and night sweats. Tuberculosis is treatable with a six-month course of antibiotics.
I am stopping TB is more than slogan. It is the start of a two-year campaign that belongs to people everywhere who are doing their part to Stop TB.
This year's World TB Day is about celebrating the lives and stories of people affected by TB: women, men and children who have taken TB treatment; nurses; do
About
The Stop TB Partnership was established in 2000 to eliminate tuberculosis as a public health problem and ultimately to realize a world free of TB. It comprises a network of more then 500 international organizations, countries, donors from the public and private sectors, and nongovernmental and governmental organizations that have expressed an interest in working together to achieve this goal.ctors; researchers; community workers--anyone who has contributed towards the global fight against TB.
What is T.B (Tuberculosis)?
Tuberculosis, or TB, is an infectious bacterial disease caused by Mycobacterium tuberculosis, which most commonly affects the lungs. It is transmitted from person to person via droplets from the throat and lungs of people with the active respiratory disease.
In healthy people, infection with Mycobacterium tuberculosis often causes no symptoms, since the person's immune system acts to “wall off” the bacteria. The symptoms of active TB of the lung are coughing, sometimes with sputum or blood, chest pains, weakness, weight loss, fever and night sweats. Tuberculosis is treatable with a six-month course of antibiotics.
Nanotechnology - Cancer News
Using nanotechnology, researchers discover cancer cells ‘feel’ much softer than normal cells
Method may provide a new diagnostic tool for cancerA multidisciplinary team of UCLA scientists were able to differentiate metastatic cancer cells from normal cells in patient samples using leading-edge nanotechnology that measures the softness of the cells.
The study, published Dec. 2, 2007 in the advance online edition of the journal Nature Nanotechnology, represents one of the first times researchers have been able to take living cells from cancer patients and apply nanotechnology to analyze them and determine which were cancerous and which were not. The nano science measurements may provide a potential new method for detecting cancer, especially in cells from body cavity fluids where diagnosis using current methods is typically very challenging. The method also may aid in personalizing treatments for patients.
When cancer is becoming metastatic, or invading other organs, the diseased cells must travel throughout the body. Because the cells need to enter the bloodstream and maneuver through tight anatomical spaces, cancer cells are much more flexible, or softer, than normal cells. These spreading, invading cancer cells can cause a build-up of fluids in body cavities such as the chest and abdomen. But fluid build-up in patients does not always mean cancer cells are present. If the fluid could be quickly and accurately tested for the presence of cancer, oncologists could make better decisions about how aggressive a treatment should be administered or if any treatment is necessary at all.
In this study, researchers collected fluid from the chest cavities of patients with lung, breast and pancreatic cancers, a relatively non-invasive procedure. One problem with diagnosing metastatic disease in this setting is that cancer cells and normal cells in body cavity fluids look very similar under an optical microscope, said Jianyu Rao, a researcher at UCLA’s Jonsson Cancer Center, an associate professor of pathology and laboratory medicine and one of the study’s senior authors. Conventional diagnostic methods detect about 70 percent of cases where cancer cells are present in the fluid, missing about 30 percent of cases.
“We detect cancer cells typically by looking at them under a microscope after the cells are fixed and stained with chemicals, which is really an antiquated method,” Rao said. “Usually the cancer cells have larger nuclei and other subtle features. However, the normal cells from body cavity fluids can look almost identical to cancer cells under an optical microscope. While staining for tumor protein markers could increase diagnostic accuracy, what we were missing was a way to determine if cancer cells have different mechanical properties than normal cells.”
Employing one of the most valuable tools in the nanotechnology arsenal, the research team used an Atomic Force Microscope (AFM) to measure cell softness. Since the cells being analyzed were less than half the diameter of a human hair, researchers needed a very precise and delicate instrument to measure resistance in the cell membrane, said James Gimzewski, professor of chemistry and biochemistry, a member of the California NanoSystems Institute and also one of the study’s senior authors.
“We had to measure the softness of the cell without bursting it,” Gimzewski said. “Otherwise, it’s like trying to measure the softness of a tomato using a hammer.”
The AFM uses a minute, sharp tip on a spring to push against the cell surface and determine the degree of softness. Think of it as an extension of a doctor’s hands performing a physical examination to determine disease, Gimzewski said.
“You look at two tomatoes in the supermarket and both are red. One is rotten, but it looks normal,” Gimzewski said. “If you pick up the tomatoes and feel them, it’s easy to figure out which one is rotten. We’re doing the same thing. We’re poking and quantitatively measuring the softness of the cells.”
After probing a cell, the AFM assigns a value that represents how soft a cell is based on the resistance encountered. What the team found was that the cancer cells were much softer than the normal cells and they were similarly soft with very little variation in gradation. The normal, healthy cells from the same specimen were much stiffer than the cancer cells and, in fact, the softness values assigned to each group did not overlap at all, making diagnosis using this nanomechanical measurement easier and more accurate.
“It was fascinating to find such striking characteristics between the metastatic cancer cells and normal cells,” said Sarah Cross, a graduate student in the chemistry and biochemistry department and a study author. “The metastatic cancer cells were extremely soft and easily distinguishable from the normal cells despite similarities in appearance. And we’re looking at live cells taken from human patients, so that makes this is a unique finding.”
Calvin Quate of Stanford University, the co-inventor of the Atomic Force Microscope, said the UCLA study breaks new ground.
“This manuscript is the first that directly shows a relationship between the nanomechanical properties and physiological function in clinical samples from patients with suspected cancer,” said Quate, 1992 Medal of Science recipient.
National breast cancer expert Susan Love said the study findings “open a new era for function-based tumor cell diagnostics.”
“With these findings, it is foreseeable that a combined biochemical, biophysical and morphological analysis for analyzing human cytological specimens using AFM may be finally realized,” said Love, president and medical director of the Susan Love Research Foundation and a clinical professor of surgery at UCLA.
Researchers next will explore whether the nanomechanical analysis can be used to personalize cancer treatment based on the characteristics of a patient’s cancer cells. There are standard chemotherapy drugs that are used to treat metastatic cancer, Rao said, but response varies from patient to patient. If researchers could test the cancer cells beforehand, they could potentially apply therapies that would make the cells stiffer, making it more difficult for the diseased cells to spread through the body.
###The study was a collaboration between the California NanoSystems Institute, the Jonsson Cancer Center and the Departments of Chemistry and Biochemistry and Pathology and Laboratory Medicine. In addition to Rao, Gimzewski and Cross, the research team included Yu-Sheng Jin.
UCLA’s Jonsson Comprehensive Cancer Center comprises about 235 researchers and clinicians engaged in disease research, prevention, detection, control, treatment and education. One of the nation’s largest comprehensive cancer centers, the Jonsson center is dedicated to promoting research and translating basic science into leading-edge clinical studies. In July 2007, the Jonsson Cancer Center was named the best cancer center in California by U.S. News & World Report, a ranking it has held for eight consecutive years. For more information on the Jonsson Cancer Center, visit our web site at
www.cancer.mednet.ucla.edu.
The California NanoSystems Institute is a multidisciplinary research center at UCLA whose mission is to encourage university–industry collaboration and to enable the rapid commercialization of discoveries in nanosystems. CNSI members include some of the world’s preeminent scientists, and the work conducted at the institute represents world-class expertise in five targeted areas of nanosystems-related research: renewable energy, environmental nanotechnology and nanotoxicology, nanobiotechnology and biomaterials, nanomechanical and nanofluidic systems, and nanoelectronics, photonics and architectonics.
Method may provide a new diagnostic tool for cancerA multidisciplinary team of UCLA scientists were able to differentiate metastatic cancer cells from normal cells in patient samples using leading-edge nanotechnology that measures the softness of the cells.
The study, published Dec. 2, 2007 in the advance online edition of the journal Nature Nanotechnology, represents one of the first times researchers have been able to take living cells from cancer patients and apply nanotechnology to analyze them and determine which were cancerous and which were not. The nano science measurements may provide a potential new method for detecting cancer, especially in cells from body cavity fluids where diagnosis using current methods is typically very challenging. The method also may aid in personalizing treatments for patients.
When cancer is becoming metastatic, or invading other organs, the diseased cells must travel throughout the body. Because the cells need to enter the bloodstream and maneuver through tight anatomical spaces, cancer cells are much more flexible, or softer, than normal cells. These spreading, invading cancer cells can cause a build-up of fluids in body cavities such as the chest and abdomen. But fluid build-up in patients does not always mean cancer cells are present. If the fluid could be quickly and accurately tested for the presence of cancer, oncologists could make better decisions about how aggressive a treatment should be administered or if any treatment is necessary at all.
In this study, researchers collected fluid from the chest cavities of patients with lung, breast and pancreatic cancers, a relatively non-invasive procedure. One problem with diagnosing metastatic disease in this setting is that cancer cells and normal cells in body cavity fluids look very similar under an optical microscope, said Jianyu Rao, a researcher at UCLA’s Jonsson Cancer Center, an associate professor of pathology and laboratory medicine and one of the study’s senior authors. Conventional diagnostic methods detect about 70 percent of cases where cancer cells are present in the fluid, missing about 30 percent of cases.
“We detect cancer cells typically by looking at them under a microscope after the cells are fixed and stained with chemicals, which is really an antiquated method,” Rao said. “Usually the cancer cells have larger nuclei and other subtle features. However, the normal cells from body cavity fluids can look almost identical to cancer cells under an optical microscope. While staining for tumor protein markers could increase diagnostic accuracy, what we were missing was a way to determine if cancer cells have different mechanical properties than normal cells.”
Employing one of the most valuable tools in the nanotechnology arsenal, the research team used an Atomic Force Microscope (AFM) to measure cell softness. Since the cells being analyzed were less than half the diameter of a human hair, researchers needed a very precise and delicate instrument to measure resistance in the cell membrane, said James Gimzewski, professor of chemistry and biochemistry, a member of the California NanoSystems Institute and also one of the study’s senior authors.
“We had to measure the softness of the cell without bursting it,” Gimzewski said. “Otherwise, it’s like trying to measure the softness of a tomato using a hammer.”
The AFM uses a minute, sharp tip on a spring to push against the cell surface and determine the degree of softness. Think of it as an extension of a doctor’s hands performing a physical examination to determine disease, Gimzewski said.
“You look at two tomatoes in the supermarket and both are red. One is rotten, but it looks normal,” Gimzewski said. “If you pick up the tomatoes and feel them, it’s easy to figure out which one is rotten. We’re doing the same thing. We’re poking and quantitatively measuring the softness of the cells.”
After probing a cell, the AFM assigns a value that represents how soft a cell is based on the resistance encountered. What the team found was that the cancer cells were much softer than the normal cells and they were similarly soft with very little variation in gradation. The normal, healthy cells from the same specimen were much stiffer than the cancer cells and, in fact, the softness values assigned to each group did not overlap at all, making diagnosis using this nanomechanical measurement easier and more accurate.
“It was fascinating to find such striking characteristics between the metastatic cancer cells and normal cells,” said Sarah Cross, a graduate student in the chemistry and biochemistry department and a study author. “The metastatic cancer cells were extremely soft and easily distinguishable from the normal cells despite similarities in appearance. And we’re looking at live cells taken from human patients, so that makes this is a unique finding.”
Calvin Quate of Stanford University, the co-inventor of the Atomic Force Microscope, said the UCLA study breaks new ground.
“This manuscript is the first that directly shows a relationship between the nanomechanical properties and physiological function in clinical samples from patients with suspected cancer,” said Quate, 1992 Medal of Science recipient.
National breast cancer expert Susan Love said the study findings “open a new era for function-based tumor cell diagnostics.”
“With these findings, it is foreseeable that a combined biochemical, biophysical and morphological analysis for analyzing human cytological specimens using AFM may be finally realized,” said Love, president and medical director of the Susan Love Research Foundation and a clinical professor of surgery at UCLA.
Researchers next will explore whether the nanomechanical analysis can be used to personalize cancer treatment based on the characteristics of a patient’s cancer cells. There are standard chemotherapy drugs that are used to treat metastatic cancer, Rao said, but response varies from patient to patient. If researchers could test the cancer cells beforehand, they could potentially apply therapies that would make the cells stiffer, making it more difficult for the diseased cells to spread through the body.
###The study was a collaboration between the California NanoSystems Institute, the Jonsson Cancer Center and the Departments of Chemistry and Biochemistry and Pathology and Laboratory Medicine. In addition to Rao, Gimzewski and Cross, the research team included Yu-Sheng Jin.
UCLA’s Jonsson Comprehensive Cancer Center comprises about 235 researchers and clinicians engaged in disease research, prevention, detection, control, treatment and education. One of the nation’s largest comprehensive cancer centers, the Jonsson center is dedicated to promoting research and translating basic science into leading-edge clinical studies. In July 2007, the Jonsson Cancer Center was named the best cancer center in California by U.S. News & World Report, a ranking it has held for eight consecutive years. For more information on the Jonsson Cancer Center, visit our web site at
www.cancer.mednet.ucla.edu.
The California NanoSystems Institute is a multidisciplinary research center at UCLA whose mission is to encourage university–industry collaboration and to enable the rapid commercialization of discoveries in nanosystems. CNSI members include some of the world’s preeminent scientists, and the work conducted at the institute represents world-class expertise in five targeted areas of nanosystems-related research: renewable energy, environmental nanotechnology and nanotoxicology, nanobiotechnology and biomaterials, nanomechanical and nanofluidic systems, and nanoelectronics, photonics and architectonics.
Friday, February 15, 2008
McGill researchers report breakthrough in rapid malaria detection
Optical laser technique could eliminate the need for slides, staining and microscopes
A research team led by Dr. Paul Wiseman of the Departments of Physics and Chemistry at McGill University has developed a radically new technique that uses lasers and non-linear optical effects to detect malaria infection in human blood, according to a study published in the Biophysical Journal. The researchers say the new technique holds the promise of simpler, faster and far less labour-intensive detection of the malaria parasite in blood samples.
Malaria is a vector-borne infectious disease spread by parasites of the genus Plasmodium. Most common in tropical and subtropical regions, it is a global scourge with 350 to 500 million new cases – and one to three million fatalities – reported annually. Most of the fatalities are concentrated in sub-Saharan Africa, where the resources and trained personnel currently required to accurately diagnose the disease are spread the thinnest.
Current detection techniques require trained technicians to stain slides, look for the parasite’s DNA signature under the microscope, and then manually count all the visible infected cells, a labourious process dependent on the skill and availability of trained analysts. By contrast, the proposed new technique relies on a known optical effect called third harmonic generation (THG), which causes hemozoin – a crystalline substance secreted by the parasite – to glow blue when irradiated by an infrared laser.
“People who are familiar with music know about acoustic harmonics,” said Dr. Wiseman. “You have a fundamental sound frequency and then multiples of that frequency. Non-linear optical effects are similar: if you shine an intense laser beam of a specific frequency on certain types of materials, you generate multiples of the frequency. Hemozoin has a huge, non-linear optical response for the third harmonic, which causes the blue glow.”
Dr. Wiseman and his colleagues now hope to adapt well-established existing technologies like fibre-optic communications lasers and fluorescent cell sorters to quickly move the technique out of the laboratory and into the field.
“We’re imagining a self-contained unit that could be used in clinics in endemic countries,” said Dr. Wiseman. “The operator could inject the cell sample directly into the device, and then it would come up with a count of the total number of existing infected cells without manual intervention.”
Optical laser technique could eliminate the need for slides, staining and microscopes
A research team led by Dr. Paul Wiseman of the Departments of Physics and Chemistry at McGill University has developed a radically new technique that uses lasers and non-linear optical effects to detect malaria infection in human blood, according to a study published in the Biophysical Journal. The researchers say the new technique holds the promise of simpler, faster and far less labour-intensive detection of the malaria parasite in blood samples.
Malaria is a vector-borne infectious disease spread by parasites of the genus Plasmodium. Most common in tropical and subtropical regions, it is a global scourge with 350 to 500 million new cases – and one to three million fatalities – reported annually. Most of the fatalities are concentrated in sub-Saharan Africa, where the resources and trained personnel currently required to accurately diagnose the disease are spread the thinnest.
Current detection techniques require trained technicians to stain slides, look for the parasite’s DNA signature under the microscope, and then manually count all the visible infected cells, a labourious process dependent on the skill and availability of trained analysts. By contrast, the proposed new technique relies on a known optical effect called third harmonic generation (THG), which causes hemozoin – a crystalline substance secreted by the parasite – to glow blue when irradiated by an infrared laser.
“People who are familiar with music know about acoustic harmonics,” said Dr. Wiseman. “You have a fundamental sound frequency and then multiples of that frequency. Non-linear optical effects are similar: if you shine an intense laser beam of a specific frequency on certain types of materials, you generate multiples of the frequency. Hemozoin has a huge, non-linear optical response for the third harmonic, which causes the blue glow.”
Dr. Wiseman and his colleagues now hope to adapt well-established existing technologies like fibre-optic communications lasers and fluorescent cell sorters to quickly move the technique out of the laboratory and into the field.
“We’re imagining a self-contained unit that could be used in clinics in endemic countries,” said Dr. Wiseman. “The operator could inject the cell sample directly into the device, and then it would come up with a count of the total number of existing infected cells without manual intervention.”
Thursday, February 7, 2008
LUNG CANCER
Preventing lung scarring may extend lives of lung cancer patients
Researchers have found that using a special type of drug called a pharmaceutical monoclonal antibody to block the integrin beta6-TGF-beta pathway prevents a serious side effect of radiation therapy for lung cancer patients – pulmonary fibrosis (scarring of the lungs), thereby extending patients’ lives and improving their quality of life, according to a study presented at the Plenary I session on October 29, 2007, at the American Society for Therapeutic Radiology and Oncology’s 49th Annual Meeting in Los Angeles.
“The toxicity of pulmonary fibrosis limits the amount of the radiation dose that can be safely given to patients,” said Simon Cheng, M.D., Ph.D., an author of the study and a radiation oncologist at New York University Medical Center in New York. “These study results may lead to more effective radiation therapies for advanced lung cancer, which is the leading cause of cancer deaths in the U.S.”
More than 50 percent of patients receiving radiation therapy for advanced lung cancer develop radiation-induced lung fibrosis, a painful side effect that can affect patients’ quality of life and, in some cases, can be fatal. Pulmonary (lung) fibrosis involves inflammation and scarring of the lungs causing patients to feel short of breath, have a chronic dry cough, feel fatigue and pain in the chest, and suffer loss of appetite and weight loss. Over time, fibrosis causes the air sacs of the lungs to be replaced by scar tissue, causing difficulty breathing and an irreversible loss of the tissue’s ability to transfer oxygen into the bloodstream.
This study involved mice treated with a 14 Gy single dose of radiation to the lungs. Researchers wanted to determine if using an antibody to block integrin beta6 (a specific activator of the transforming growth factor (TGF-beta) signaling pathway), could prevent the onset of radiation-induced pulmonary fibrosis. The study shows that mice that were given integrin beta6 monoclonal antibodies did not develop radiation-induced lung fibrosis, while the control group of mice developed the lung condition.
“Fibrosis is a very serious side effect that often keeps doctors from giving patients a full dose of radiation for fear that the serious problems caused by fibrosis will outweigh the good done by the radiation. If further studies conclude that this drug can indeed prevent fibrosis in lung cancer patients, I believe researchers are a huge step closer to curing this disease,” said Dr. Cheng.
Researchers have found that using a special type of drug called a pharmaceutical monoclonal antibody to block the integrin beta6-TGF-beta pathway prevents a serious side effect of radiation therapy for lung cancer patients – pulmonary fibrosis (scarring of the lungs), thereby extending patients’ lives and improving their quality of life, according to a study presented at the Plenary I session on October 29, 2007, at the American Society for Therapeutic Radiology and Oncology’s 49th Annual Meeting in Los Angeles.
“The toxicity of pulmonary fibrosis limits the amount of the radiation dose that can be safely given to patients,” said Simon Cheng, M.D., Ph.D., an author of the study and a radiation oncologist at New York University Medical Center in New York. “These study results may lead to more effective radiation therapies for advanced lung cancer, which is the leading cause of cancer deaths in the U.S.”
More than 50 percent of patients receiving radiation therapy for advanced lung cancer develop radiation-induced lung fibrosis, a painful side effect that can affect patients’ quality of life and, in some cases, can be fatal. Pulmonary (lung) fibrosis involves inflammation and scarring of the lungs causing patients to feel short of breath, have a chronic dry cough, feel fatigue and pain in the chest, and suffer loss of appetite and weight loss. Over time, fibrosis causes the air sacs of the lungs to be replaced by scar tissue, causing difficulty breathing and an irreversible loss of the tissue’s ability to transfer oxygen into the bloodstream.
This study involved mice treated with a 14 Gy single dose of radiation to the lungs. Researchers wanted to determine if using an antibody to block integrin beta6 (a specific activator of the transforming growth factor (TGF-beta) signaling pathway), could prevent the onset of radiation-induced pulmonary fibrosis. The study shows that mice that were given integrin beta6 monoclonal antibodies did not develop radiation-induced lung fibrosis, while the control group of mice developed the lung condition.
“Fibrosis is a very serious side effect that often keeps doctors from giving patients a full dose of radiation for fear that the serious problems caused by fibrosis will outweigh the good done by the radiation. If further studies conclude that this drug can indeed prevent fibrosis in lung cancer patients, I believe researchers are a huge step closer to curing this disease,” said Dr. Cheng.
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