| COFFEE INTERFERES WITH HCV REPLICATION IN VITRO BY INHIBITION OF WNT SIGNALING | |
| Speaker: | Amelie Keller |
| Author: | A.D. Keller1*, K. Singethan2, A. Wuestenberg1, V. Lohmann3, R. Bartenschlager3, M. Dandri4, U. Protzer2, G. Tiegs1, G. Sass1 |
| Affiliation: | 1Institute of Experimental Immunology and Hepatology, University Medical Center Hamburg Eppendorf, Hamburg, 2Institute of Virology, Technische Universität München (TUM), Munich, 3Department of Molecular Virology, University of Heidelberg, Heidelberg, 4Department of Medicine I, University Medical Center Hamburg-Eppendorf, Hamburg, Germany. *amelie_keller@web.de |
Background and aims: Coffee is the worldwide most frequently used legal psychoactive substance. On the other hand its consumption has been shown to decrease the risk of fibrosis formation and to improve anti-viral effects of interferon alpha/ribavirin treatment of HCV patients. We investigated effects of regular and decaffeinated coffee and coffee ingredients on HCV replication and infection in vitro. Methods: To investigate effects of coffee on HCV replication, infectious as well as subgenomic replicon cell culture systems were used. Cells were incubated in the presence of regular or decaffeinated coffee or the coffee ingredients caffeine or chlorogenic acid. Effects on HCV replication and wnt pathway activity were measured by luciferase reporter assay or real time RT-PCR. Results: Coffee reduced HCV replication with regular coffee having a more pronounced effect. Coffee significantly reduced HCV replication at concentrations achievable by coffee consumption, while caffeine as well as caffeine degradation products interfered with HCV replication at high concentrations (about 100 µM or more). Chlorogenic acid did not reduce HCV replication up to concentrations of 200 µM. Wnt pathway activity was found to be markedly increased in HCV replicating cells in comparison to the background cell line Huh7. Inhibition of wnt pathway activity, e.g. by use of siRNA directed against beta-catenin, interfered with HCV replication. Likewise, coffee-but not caffeine-incubation reduced wnt pathway activity, as detected by reporter assays or real time RT-PCR for beta-catenin, conductin or the wnt pathway promoter kinase CK2. In addition to its inhibitory effects on HCV replication, two hours of pre-incubation with coffee decreases subsequent HCV infection and modulated HCV receptor expression on primary human hepatocytes. Conclusions: Coffee interferes with HCV replication by inhibition of the wnt signaling pathway which might represent a novel target for HCV therapy. Coffee also interferes with HCV infection in vitro which might reduce virus spreading within the infected liver. http://mobile.ilcapp.eu/EASL_161/poster_24038/program.aspx | |
Sunday, April 29, 2012
EASL- COFFEE INTERFERES WITH HCV REPLICATION IN VITRO BY INHIBITION OF WNT SIGNALING
Friday, April 27, 2012
EASL 2012 - Weekend Reading
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'Reading', a painting by Kuroda Seiki
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Most weekends this blog offers up a few substantial links to relevant HCV information, click here for previous "Weekend Reading" articles.
The 47th European Association for the Study of the Liver - EASL
As the annual meeting ends educational sites related to liver disease and hepatitis begin the process of putting together key data on hepatitis C and treatment.
Viral Ed offers continuing medical education-CME and will bring us an Internet symposium discussing important highlights of the meeting. The program -"The 47th Annual EASL: Advances in Chronic Hepatitis C Management and Treatment" will soon be ready to view, make sure you register for the upcoming 1.5-hour program by clicking here.
As a side note - The 19th Conference on Retroviruses and Opportunistic Infections (CROI) Internet Symposium is also on the site.
Clinical Options is still in the process of putting up slides but 20 capsule summaries are ready to view, click here to register.
Clinical Options is still in the process of putting up slides but 20 capsule summaries are ready to view, click here to register.
Additional coverage on the meeting is available at NATAP, HIV and Hepatitis C, hepmag and articles can be read at Medpage Today, aidsmap, Medscape Medical News and Hepatitis C New Drugs and Liver Health.
New online; Advances in HCV Treatment Volume 20 Issue 1 April/May 2012 - Perspective Advances in the Treatment of Hepatitis C Virus Infection, download PDF here.
Summary
The current era in HCV treatment is reminiscent of the transformation of HIV treatment that occurred in the mid-1990s. With the new HCV treatments, cure and complications occur more frequently. We can make smart applications of the treatments available to us right now in some patients, and we await tomorrow’s treatments for other patients. As with the first wave of HIV medications in the potent antiretroviral era, the new HCV drugs offer huge advantages but also present substantial challenges.
Sadly, as most of you know the experimental hepatitis C drug combination of daclatasvir and GS-7977 we read so much about during the meeting may not be entering into phase III clinical trials. The drug companies Bristol-Myers Squibb-daclatasvir and Gilead-GS-7977 may forgo working together on further development of the two drug combo. This is such a disservice to the 170 million individuals worldwide - 3.2 million people in the US- suffering with hepatitis C. According to the CDC in the US there are an estimated 30,000 new acute infections a year, and 8000-10,000 deaths. This disease has rapidly surpassed HIV as a cause of death in the United States.
Please sign the online petition urging Gilead and BMS to collaborate on the promising experimental treatment for hepatitis C.
This April podcast comes to you from the nationally syndicated public radio program The Health Show on WAMC with host Bob Barrett and guest physician discussing both hepatitis C, treatment and Sjogren’s Syndrome, a disease - although rarely - seen in hepatitis C patients.
New online; Advances in HCV Treatment Volume 20 Issue 1 April/May 2012 - Perspective Advances in the Treatment of Hepatitis C Virus Infection, download PDF here.
Summary
The current era in HCV treatment is reminiscent of the transformation of HIV treatment that occurred in the mid-1990s. With the new HCV treatments, cure and complications occur more frequently. We can make smart applications of the treatments available to us right now in some patients, and we await tomorrow’s treatments for other patients. As with the first wave of HIV medications in the potent antiretroviral era, the new HCV drugs offer huge advantages but also present substantial challenges.
Sadly, as most of you know the experimental hepatitis C drug combination of daclatasvir and GS-7977 we read so much about during the meeting may not be entering into phase III clinical trials. The drug companies Bristol-Myers Squibb-daclatasvir and Gilead-GS-7977 may forgo working together on further development of the two drug combo. This is such a disservice to the 170 million individuals worldwide - 3.2 million people in the US- suffering with hepatitis C. According to the CDC in the US there are an estimated 30,000 new acute infections a year, and 8000-10,000 deaths. This disease has rapidly surpassed HIV as a cause of death in the United States.
Please sign the online petition urging Gilead and BMS to collaborate on the promising experimental treatment for hepatitis C.
This April podcast comes to you from the nationally syndicated public radio program The Health Show on WAMC with host Bob Barrett and guest physician discussing both hepatitis C, treatment and Sjogren’s Syndrome, a disease - although rarely - seen in hepatitis C patients.
Enjoy Your Weekend !
EASL-Interferon Lambda Beats Alfa in Clearing HCV Genotype 2 or 3
From Medscape Medical News
Interferon Lambda Beats Alfa in Clearing HCV Genotype 2 or 3
Daniel M. Keller, PhD
April 27, 2012 (Barcelona, Spain) — In a phase 2b study of treatment-naive adults with chronic hepatitis C virus (HCV) infection, pegylated interferon-lambda was more effective and safer than interferon-alfa in eliminating the virus in patients infected with HCV genotypes 2 or 3. The study is the first report of sustained virologic response with lambda.
Stefan Zeuzem, MD, professor of medicine and chief of the Department of Medicine I at the J.W. Goethe University Hospital in Frankfurt, Germany, who presented the results here at the International Liver Congress 2012, showed data demonstrating that 180 μg of lambda, compared with alfa, produced a more rapid virologic response and a greater sustained virologic response at 24 weeks (SVR24), and was associated with fewer adverse events and less need for a dose reduction of lambda and of the accompanying ribavirin.
Treatment of chronic HCV with alfa interferons and ribavirin is limited by hematologic toxicity and other adverse effects. Lambda has marked activity against HCV and a restricted distribution of receptors in the body, which could make organ systems outside the liver less susceptible to its effects.
Dr. Zeuzem and colleagues performed a blinded randomized study of 526 noncirrhotic treatment-naive HCV-infected adults, 18 to 70 years of age, 118 of whom were chronically infected with genotype 2 or 3 and had HCV RNA levels of at least 100,000 IU/mL. The genotype 2/3 patients received daily ribavirin and weekly doses of lambda 120 μg (n = 29), 180 μg (n = 29), or 240 μg (n = 30) for 24 weeks. Other patients (n = 30) received daily ribavirin plus alfa 180 μg weekly for 24 weeks.
At baseline, the 4 groups were similar in age (range, 48.1 to 50.6 years), sex (range, 52% to 70% male), body mass index (range, 27.8 to 29.0 kg/m²), and viral load (range, 6.42 to 6.66 log10 IU/mL). Most participants were white (range, 76.7% to 89.7%). The proportion of genotype 2 patients was 41.4% in the 120 μg group, 58.6% in the 180 μg group, 53.3% in the 240 μg group, and 50% in the alfa group. A large majority of patients in each group had low liver fibrosis scores.
Lambda Effective With Fewer Adverse Events
Lambda/ribavirin treatment was associated with an early and rapid drop in HCV RNA in a dose-dependent manner. After 2 weeks of treatment, the greatest reductions were seen with the 180 μg and 240 μg doses. All 3 doses of lambda produced more rapid decreases in virus level than alfa/ribavirin. The 180 μg dose will be used going forward in phase 3 trials.
HCV RNA was undetectable at week 4 in 75.9% of patients in the 180 μg group and in 30.0% in the alfa group (P < .05). Complete early virologic response (meaning HVC RNA was detectable at week 4 but not at week 12) and SVR24 were somewhat better with lambda than with alfa, but the difference was not statistically significance. In the lambda groups, 96.6% of patients achieved a complete early virologic response and 75.9% achieved SVR24.
With lambda 180 μg, 70.6% of genotype 2 patients achieved SVR24, as did 83.3% of genotype 3 patients.
Relapse rates, defined as an HCV RNA level of 25 IU/mL or greater during the follow-up period, were low, at about 21% in the lambda 180 μg group and about 25% in the alfa group.
Although all groups experienced a high level of adverse events (in the range of about 95%), some long associated with alfa therapy — "in particular, flu-like symptoms...such as myalgia, arthralgia, pyrexia, and chills" — were significantly lower in the lambda groups (7% to 17% in the 180 μg group) than in the alfa group (20% to 33%). Flu-like symptoms were definitely lower in all 3 lambda groups (20.7% for 180 μg) than in the alfa group (40%), Dr. Zeuzem said, as were musculoskeletal symptoms (20.7% vs 63.3%).
However, the prevalence of psychiatric adverse events (e.g., depression, irritability, or insomnia) was greater in the lambda groups than in the alfa group (41.4% vs 33.3%).
There were no discontinuations because of adverse events in the 180 μg group, but 6.7% dropped out of the alfa group. In the lambda groups, there were dose reductions in lambda or ribavirin at a rate of 6.9% for each; in the alfa group, there were dose reductions at rates of 26.7% for alfa and 43.3% for ribavirin.
Serious adverse events affected less than 4% of patients in the 180 μg and alfa groups. There were no serious adverse events directly related to treatment in the lambda groups.
It has been reported that lambda causes elevations in serum bilirubin, but in this trial at the 180 μg dose, there was only 1 patient (3.4%) with bilirubin elevation (in the range of 1.6 to 2.5 times the upper limit of normal).
There were no reductions in neutrophil or platelet counts associated with any dose of lambda. There were drops in both in the alfa group as long as therapy continued. Low hemoglobin (below 10 g/dL, or a drop of at least 3.4 g/dL), often associated with alfa/ribavirin, occurred in 44.8% of the alfa group and necessitated a ribavirin dose reduction in 23.3% of patients. Hemoglobin levels did not drop as much in the 180 μg group; only 6.9% were classified as having low hemoglobin, and none required a ribavirin dose reduction.
Session moderator George Papatheodoridis, MD, associate professor of medicine and gastroenterology at the Medical School of Athens University and Hippokration General Hospital in Greece, and a member of the Governing Board Scientific Committee of the European Association for the Study of the Liver (EASL), summarized the findings for Medscape Medical News.
"It seems that the efficacy of interferon lambda might be slightly higher [than alfa], but definitely we can say that the safety profile is better.... The only side effect that was higher, and we cannot explain that, is the psychiatric side effects," he said.
In light of a robust pipeline of oral drugs now in development, Dr. Papatheodoridis said the use of interferons could be fairly limited in the treatment of HCV in the future. "I don't know what role interferon lambda may find when and if it gets licensed. After 2 or 3 years, it is possible that most of the patients will be treated with interferon-free regimens," he explained.
Mark Thursz, MD, professor of hepatology in the Department of Medicine at Imperial College, London, United Kingdom, and secretary general of the EASL, alluded to this point during a news conference, drawing attention to the safety profile of lambda. Patients receiving ribavirin typically show a drop in hemoglobin, "but there's a smaller drop...in the lambda- than in the alfa-treated patients," he said. "More important are these data on neutrophils and platelets.... You can see no drop in patients who were treated with the lambda interferon.... For patients who still need an interferon and in whom problems with cell counts are going to be an issue, this is a solution."
Dr. Papatheodoridis noted that the bilirubin increase seen with lambda probably does not indicate any damage to the liver, but is perhaps the effect of "this interferon on the enzymes that are involved in the metabolism of bilirubin, which is not very dangerous; it's a lab finding without major clinical significance."
Dr. Zeuzem reports being a consultant for Abbott, Achillion, AstraZeneca, Bristol-Myers Squibb, Boehringer Ingelheim, Gilead, Idenix, Inhibitex, iTherX, Janssen, Merck, Novartis, Presidio Pharmaceuticals, Roche, Santaris, and Vertx Pharmaceuticals. Dr. Papatheodoridis and Dr. Thursz have disclosed no relevant financial relationships.
The International Liver Congress 2012: Abstract 10. Presented April 19, 2012.
Interferon Lambda Beats Alfa in Clearing HCV Genotype 2 or 3
Daniel M. Keller, PhD
April 27, 2012 (Barcelona, Spain) — In a phase 2b study of treatment-naive adults with chronic hepatitis C virus (HCV) infection, pegylated interferon-lambda was more effective and safer than interferon-alfa in eliminating the virus in patients infected with HCV genotypes 2 or 3. The study is the first report of sustained virologic response with lambda.
Stefan Zeuzem, MD, professor of medicine and chief of the Department of Medicine I at the J.W. Goethe University Hospital in Frankfurt, Germany, who presented the results here at the International Liver Congress 2012, showed data demonstrating that 180 μg of lambda, compared with alfa, produced a more rapid virologic response and a greater sustained virologic response at 24 weeks (SVR24), and was associated with fewer adverse events and less need for a dose reduction of lambda and of the accompanying ribavirin.
Treatment of chronic HCV with alfa interferons and ribavirin is limited by hematologic toxicity and other adverse effects. Lambda has marked activity against HCV and a restricted distribution of receptors in the body, which could make organ systems outside the liver less susceptible to its effects.
Dr. Zeuzem and colleagues performed a blinded randomized study of 526 noncirrhotic treatment-naive HCV-infected adults, 18 to 70 years of age, 118 of whom were chronically infected with genotype 2 or 3 and had HCV RNA levels of at least 100,000 IU/mL. The genotype 2/3 patients received daily ribavirin and weekly doses of lambda 120 μg (n = 29), 180 μg (n = 29), or 240 μg (n = 30) for 24 weeks. Other patients (n = 30) received daily ribavirin plus alfa 180 μg weekly for 24 weeks.
At baseline, the 4 groups were similar in age (range, 48.1 to 50.6 years), sex (range, 52% to 70% male), body mass index (range, 27.8 to 29.0 kg/m²), and viral load (range, 6.42 to 6.66 log10 IU/mL). Most participants were white (range, 76.7% to 89.7%). The proportion of genotype 2 patients was 41.4% in the 120 μg group, 58.6% in the 180 μg group, 53.3% in the 240 μg group, and 50% in the alfa group. A large majority of patients in each group had low liver fibrosis scores.
Lambda Effective With Fewer Adverse Events
Lambda/ribavirin treatment was associated with an early and rapid drop in HCV RNA in a dose-dependent manner. After 2 weeks of treatment, the greatest reductions were seen with the 180 μg and 240 μg doses. All 3 doses of lambda produced more rapid decreases in virus level than alfa/ribavirin. The 180 μg dose will be used going forward in phase 3 trials.
HCV RNA was undetectable at week 4 in 75.9% of patients in the 180 μg group and in 30.0% in the alfa group (P < .05). Complete early virologic response (meaning HVC RNA was detectable at week 4 but not at week 12) and SVR24 were somewhat better with lambda than with alfa, but the difference was not statistically significance. In the lambda groups, 96.6% of patients achieved a complete early virologic response and 75.9% achieved SVR24.
With lambda 180 μg, 70.6% of genotype 2 patients achieved SVR24, as did 83.3% of genotype 3 patients.
Relapse rates, defined as an HCV RNA level of 25 IU/mL or greater during the follow-up period, were low, at about 21% in the lambda 180 μg group and about 25% in the alfa group.
Although all groups experienced a high level of adverse events (in the range of about 95%), some long associated with alfa therapy — "in particular, flu-like symptoms...such as myalgia, arthralgia, pyrexia, and chills" — were significantly lower in the lambda groups (7% to 17% in the 180 μg group) than in the alfa group (20% to 33%). Flu-like symptoms were definitely lower in all 3 lambda groups (20.7% for 180 μg) than in the alfa group (40%), Dr. Zeuzem said, as were musculoskeletal symptoms (20.7% vs 63.3%).
However, the prevalence of psychiatric adverse events (e.g., depression, irritability, or insomnia) was greater in the lambda groups than in the alfa group (41.4% vs 33.3%).
There were no discontinuations because of adverse events in the 180 μg group, but 6.7% dropped out of the alfa group. In the lambda groups, there were dose reductions in lambda or ribavirin at a rate of 6.9% for each; in the alfa group, there were dose reductions at rates of 26.7% for alfa and 43.3% for ribavirin.
Serious adverse events affected less than 4% of patients in the 180 μg and alfa groups. There were no serious adverse events directly related to treatment in the lambda groups.
It has been reported that lambda causes elevations in serum bilirubin, but in this trial at the 180 μg dose, there was only 1 patient (3.4%) with bilirubin elevation (in the range of 1.6 to 2.5 times the upper limit of normal).
There were no reductions in neutrophil or platelet counts associated with any dose of lambda. There were drops in both in the alfa group as long as therapy continued. Low hemoglobin (below 10 g/dL, or a drop of at least 3.4 g/dL), often associated with alfa/ribavirin, occurred in 44.8% of the alfa group and necessitated a ribavirin dose reduction in 23.3% of patients. Hemoglobin levels did not drop as much in the 180 μg group; only 6.9% were classified as having low hemoglobin, and none required a ribavirin dose reduction.
Session moderator George Papatheodoridis, MD, associate professor of medicine and gastroenterology at the Medical School of Athens University and Hippokration General Hospital in Greece, and a member of the Governing Board Scientific Committee of the European Association for the Study of the Liver (EASL), summarized the findings for Medscape Medical News.
"It seems that the efficacy of interferon lambda might be slightly higher [than alfa], but definitely we can say that the safety profile is better.... The only side effect that was higher, and we cannot explain that, is the psychiatric side effects," he said.
In light of a robust pipeline of oral drugs now in development, Dr. Papatheodoridis said the use of interferons could be fairly limited in the treatment of HCV in the future. "I don't know what role interferon lambda may find when and if it gets licensed. After 2 or 3 years, it is possible that most of the patients will be treated with interferon-free regimens," he explained.
Mark Thursz, MD, professor of hepatology in the Department of Medicine at Imperial College, London, United Kingdom, and secretary general of the EASL, alluded to this point during a news conference, drawing attention to the safety profile of lambda. Patients receiving ribavirin typically show a drop in hemoglobin, "but there's a smaller drop...in the lambda- than in the alfa-treated patients," he said. "More important are these data on neutrophils and platelets.... You can see no drop in patients who were treated with the lambda interferon.... For patients who still need an interferon and in whom problems with cell counts are going to be an issue, this is a solution."
Dr. Papatheodoridis noted that the bilirubin increase seen with lambda probably does not indicate any damage to the liver, but is perhaps the effect of "this interferon on the enzymes that are involved in the metabolism of bilirubin, which is not very dangerous; it's a lab finding without major clinical significance."
Dr. Zeuzem reports being a consultant for Abbott, Achillion, AstraZeneca, Bristol-Myers Squibb, Boehringer Ingelheim, Gilead, Idenix, Inhibitex, iTherX, Janssen, Merck, Novartis, Presidio Pharmaceuticals, Roche, Santaris, and Vertx Pharmaceuticals. Dr. Papatheodoridis and Dr. Thursz have disclosed no relevant financial relationships.
The International Liver Congress 2012: Abstract 10. Presented April 19, 2012.
Genotype 1-Risk of Atherosclerosis Increases in Hepatitis C Patients With Fibrosis
In the first study, researchers led by Dr. Salvatore Petta from the Di.Bi.M.I.S. University of Palermo in Italy evaluated 174 patients with chronic HCV (genotype 1) along with 174 controls from an outpatient cardiology unit for signs of atherosclerosis. Ultrasonography was used to measure thickening of the carotid artery. Severity of fibrosis was determined for all HCV patients.
The team found carotid plaques in 42% of HCV patients compared to 23% of patients in the control group. Older age and severe liver fibrosis were independently associated with the presence of carotid plaque according to the authors. In patients 55 years or younger who had less sever fibrosis (stage F0-F2) only 22% had plaques in their artery compared to 52% with more sever fibrosis (stage F3-F4). Patients older the 55 years of age had similar prevalence of carotid lesions for those with or without severe fibrosis at 58% and 51% respectively.
"Our findings suggest that severe liver fibrosis places chronic HCV patients at higher risk of early atherosclerosis," said Dr. Petta. "This patient group should be carefully monitored to prevent progression of cardiovascular disease that is independent of their metabolic profile." The authors also caution that a majority of the European study participants were overweight, which should be considered in applying results to other patient populations.
A second study by Dr. Michaela Kozakova and colleagues from the University of Pisa further explored whether the association between fatty liver disease and early atherosclerosis is a consequence of shared conventional risk factors or is it determined by a specific circulating factor originating from liver or adipose tissue. For this purpose the researches investigated the association between the presence of early carotid plaques and the fatty liver index (FLI), which is an established surrogate marker for fatty liver disease based on body mass index (BMI), waist circumference, triglycerides and gamma glutamyltransferase (GGT), in subjects who were part of the multicenter European RISC (Relationship between Insulin Sensitivity and Cardiovascular risk) study group. For the present study, a subgroup of 1.012 RISC subjects who were free of hypertension, diabetes, cardiovascular diseases, chronic hepatic, inflammatory and neoplastic diseases, abnormal lipid levels, and metabolic syndrome were included.
In such a healthy population, only about 5% of subjects had small carotid plaques, and these subjects were older, had a FLI of 60 or more, and had higher blood pressure, LDL cholesterol, glucose, GGT and C-reactive protein than participants without plaques. In logistic regression model, after adjustment for conventional cardiovascular risk factors, family history, liver transaminase and alcohol consumption, the independent predictors of plaque presence were age, FLI of 60 or more and smoking habit. However, when FLI in the model was replaced by variables used in its equation the predictors of early atherosclerosis were age, GGT and smoking.
"Our cross-sectional study indicates that GGT may represent a link between fatty liver disease and development of early atherosclerosis," concludes Dr. Kozakova. On the basis of these results the authors suggest the GGT levels in the blood could be used as a biomarker of atherosclerosis.
Source
Bioengineered organs may hold the future for transplants
Bioengineered organs may hold the future for transplants
by Erin M. Massey
April 26, 2012
April 26, 2012
.jpg) |
Erin Massey/MEDILL A mouse recovering from a new model of transplant surgery. |
Once engineered, Zhang said her team will be able to test the functionality of such organs as transplants in the rodents. For now, Zhang and fellow researchers are using a biodegradable scaffold, a kind-of-skeleton of an organ with all living cells removed, to test the model.
By developing a successful animal model, the stage is set for future testing on primates and eventually humans. Zhang said bioengineered organs would significantly reduce waiting times for people needing transplants and prevent rejection of healthy organs.
Researchers also want to gain a better understanding of the cytomegalovirus (CMV), a particular threat to transplant recipients.
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Erin Massey/MEDILL A researcher performing micro-surgery in rodents to test a new model for transplants. |
CMV is a common virus found in 50-90% of all people, but has a greater chance of being activated after transplantation due to immunosuppression (reduction or complete absence of a healthy immune response or immune system).
The immune systems of healthy individuals are able to fight off the virus or put it in a latent state. Compromised immune systems have a much harder time fighting the virus that can cause respiratory and other health problems.
Zhang talks about her research of ongoing projects and current successful models already established.
The immune systems of healthy individuals are able to fight off the virus or put it in a latent state. Compromised immune systems have a much harder time fighting the virus that can cause respiratory and other health problems.
Zhang talks about her research of ongoing projects and current successful models already established.
Q. You mentioned that the core is working on 10 ongoing projects. What are these?
A. One of the projects is tissue engineering. For example, an idea in the transplant field is regenerative medicine. If you have a damaged organ, you would want it to regenerate, such as in the case of acute kidney failure. Also, a lot of people are on the waiting list for transplants. There is an organ shortage. We are trying to grow tissues and organs in the lab using stem cells from bone marrow or a particular organ of adult mice. In the future, we hope to take cells from something living and grow them. Normally, you can only grow embryonic stem cells. Now, we can use any cells to become pluripotent, meaning any cell.
Another project deals with the CMV virus. We want to study why this virus is activated after transplant surgery so that we can prevent it. It is one of a couple of viruses that suddenly wake up with immunosuppression. CMV can be transferred via saliva, bodily fluids or through the placenta. Only an active CMV agent can be transferred and is a threat only when activated. A great percentage of the population carry the virus in their bodies but it is latent until activated. Immunosuppression in a transplant recipient can greatly affect a person’s ability to fight off the virus.
Q. What organs have you successfully worked with so far?
A. So far, we have had success with the kidney, liver, and heart in these animals. Normally, the mouse or rat can survive two surgeries.
Q. Have you been successful in taking the cells out of an organ, infusing new cells, and transplanting a completely functional organ into a mouse or rat yet?
A. We are in the early stages. What we have been successful doing is removing all the cells from an organ, such as a kidney or liver and injecting new cells, called endothelial cells, on the surface of the organ. We are in the process of testing these organs to see if they can hold blood and function normally.
Q. What have you been able to accomplish thus far with the stem cells?
A. Our research entails using real organs in whole or part from mice and rats. We use a machine to diffuse the organ and take out all of the cells, leaving a scaffold, skeleton-like structure that looks like a honeycomb. Then we infuse new cells that are grown in a bioreactor. The intention of infusing cells is for them to grow into the desired organ or tissue.
The bioreactor is able to simulate a natural environment where these cells would normally be grown. We are able to monitor the environment and determine the best condition for use. Usually the time the organ spends in the machine can range from 10 days or even longer depending on the type and size of the organ.
Q. What is the significance behind choosing to conduct this research on rodents?
A. If we can equate an animal model, we can use it for testing a bioengineered organ and see if it is functional, how long the cells with survive, and if it will form a normal structure. In a mouse we can do all sorts of things we can’t do in humans.
Q. Why do you test both mice and rats?
A. We will test this model on rodents, then primates, and eventually humans. The difference between a rat and a mouse is the size. Rats are 10 times bigger than mice and are easier to work on. We use only inbred rodents. These animals have been studied for years so we know the genetic make-up and can precisely test the type of rejection they will experience.
Q. In how many of the cases will an animal or human experience rejection of an organ?
A. In all cases, animals and humans experience some type of rejection. In the case of humans, regardless if two people are a complete match, some molecules are bound to be different. Each cell has a molecule on the surface and what is called a major histocompatibility complex, or antigens. Humans are more complicated than animals and with the mice it is much easier to control the immunosuppression response.
Q. How are humans treated when they experience rejection of an organ?
A. All people are treated and will take medicine for the rest of their lives. The rejection is variable as is the dosage of medicine a person will take. Examples of medicine prescribed include Tacrolimus or Thymoglobulin. For kidney and liver transplants, there is a current success rate of about 90 percent.
Q. How do you infect the rodents with the CMV virus?
A. We inject the mouse with the virus and let it survive for a couple of months. Initially, it will suffer respiratory problems. Sometimes, it will not happen, because the mouse has cleared the virus from its system. A healthy individual can sometimes clear out the virus, but someone whose immune system is compromised won’t be able to clear it out.
Q. What is the goal of studying rejection?
A. One of the projects is tissue engineering. For example, an idea in the transplant field is regenerative medicine. If you have a damaged organ, you would want it to regenerate, such as in the case of acute kidney failure. Also, a lot of people are on the waiting list for transplants. There is an organ shortage. We are trying to grow tissues and organs in the lab using stem cells from bone marrow or a particular organ of adult mice. In the future, we hope to take cells from something living and grow them. Normally, you can only grow embryonic stem cells. Now, we can use any cells to become pluripotent, meaning any cell.
Another project deals with the CMV virus. We want to study why this virus is activated after transplant surgery so that we can prevent it. It is one of a couple of viruses that suddenly wake up with immunosuppression. CMV can be transferred via saliva, bodily fluids or through the placenta. Only an active CMV agent can be transferred and is a threat only when activated. A great percentage of the population carry the virus in their bodies but it is latent until activated. Immunosuppression in a transplant recipient can greatly affect a person’s ability to fight off the virus.
Q. What organs have you successfully worked with so far?
A. So far, we have had success with the kidney, liver, and heart in these animals. Normally, the mouse or rat can survive two surgeries.
Q. Have you been successful in taking the cells out of an organ, infusing new cells, and transplanting a completely functional organ into a mouse or rat yet?
A. We are in the early stages. What we have been successful doing is removing all the cells from an organ, such as a kidney or liver and injecting new cells, called endothelial cells, on the surface of the organ. We are in the process of testing these organs to see if they can hold blood and function normally.
Q. What have you been able to accomplish thus far with the stem cells?
A. Our research entails using real organs in whole or part from mice and rats. We use a machine to diffuse the organ and take out all of the cells, leaving a scaffold, skeleton-like structure that looks like a honeycomb. Then we infuse new cells that are grown in a bioreactor. The intention of infusing cells is for them to grow into the desired organ or tissue.
The bioreactor is able to simulate a natural environment where these cells would normally be grown. We are able to monitor the environment and determine the best condition for use. Usually the time the organ spends in the machine can range from 10 days or even longer depending on the type and size of the organ.
Q. What is the significance behind choosing to conduct this research on rodents?
A. If we can equate an animal model, we can use it for testing a bioengineered organ and see if it is functional, how long the cells with survive, and if it will form a normal structure. In a mouse we can do all sorts of things we can’t do in humans.
Q. Why do you test both mice and rats?
A. We will test this model on rodents, then primates, and eventually humans. The difference between a rat and a mouse is the size. Rats are 10 times bigger than mice and are easier to work on. We use only inbred rodents. These animals have been studied for years so we know the genetic make-up and can precisely test the type of rejection they will experience.
Q. In how many of the cases will an animal or human experience rejection of an organ?
A. In all cases, animals and humans experience some type of rejection. In the case of humans, regardless if two people are a complete match, some molecules are bound to be different. Each cell has a molecule on the surface and what is called a major histocompatibility complex, or antigens. Humans are more complicated than animals and with the mice it is much easier to control the immunosuppression response.
Q. How are humans treated when they experience rejection of an organ?
A. All people are treated and will take medicine for the rest of their lives. The rejection is variable as is the dosage of medicine a person will take. Examples of medicine prescribed include Tacrolimus or Thymoglobulin. For kidney and liver transplants, there is a current success rate of about 90 percent.
Q. How do you infect the rodents with the CMV virus?
A. We inject the mouse with the virus and let it survive for a couple of months. Initially, it will suffer respiratory problems. Sometimes, it will not happen, because the mouse has cleared the virus from its system. A healthy individual can sometimes clear out the virus, but someone whose immune system is compromised won’t be able to clear it out.
Q. What is the goal of studying rejection?
Heart Surgery Safe for Compensated Cirrhosis Patients
Patients with compensated cirrhosis, defined by a Child-Pugh score of <8, have no significant increase in postoperative mortality and morbidity following cardiac surgery with cardiopulmonary bypass, according to a study published in the May issue of Clinical Gastroenterology and Hepatology.THURSDAY, April 26 (HealthDay News) --
Patients with compensated cirrhosis, defined by a Child-Pugh (CP) score of <8, have no significant increase in postoperative mortality and morbidity following cardiac surgery with cardiopulmonary bypass, according to a study published in the May issue of Clinical Gastroenterology and Hepatology.
To investigate the effect of cirrhosis on mortality and morbidity after cardiac surgery, Carole Macaron, M.D., of the Cleveland Clinic, and colleagues conducted a retrospective study of 54 patients with cirrhosis and 216 matched controls without cirrhosis. All participants underwent cardiac surgery with cardiopulmonary bypass at the same institution between 1992 and 2009. For patients with cirrhosis, the CP class and score were calculated.
The researchers found that, within 90 days of surgery, the mortality rate was 4.6 percent for those with a CP score <8, similar to that observed in control patients without cirrhosis, and significantly lower than the mortality rate for patients with a CP score of ≥8 (70 percent). Hospital stays were significantly shorter for patients with CP scores <8, (15.6 days, versus 26 days for those with CP scores ≥8). Renal failure and the need for dialysis were significantly less likely in those with CP scores <8. These values were similar to those of matched controls.
"Among the patients with liver cirrhosis, patients with CP score <8 might safely undergo cardiac surgery with cardiopulmonary bypass," the authors write. "Our study shows that such patients had similar outcomes in terms of mortality and morbidity compared with their matched controls."
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Thursday, April 26, 2012
Four in ten hepatitis C patients who drank alcohol refrained from it as part of a Duke pilot program that integrates alcohol and hepatitis C treatments.
Integrated Health Care Model Shows Promise for Hepatitis C Patients in DurhamReported by the Duke Global Health Institute:
Four in ten hepatitis C patients who drank alcohol refrained from it as part of a Duke pilot program that integrates alcohol and hepatitis C treatments. Led by DGHI researcher Rae Jean Proeschold-Bell and Duke physician Andrew Muir, the dual model of care may be a viable option for steering these patients away from alcohol, who may otherwise develop serious health complications that lead to liver failure or death.
The Duke study, featured in the April issue of Digestive Diseases and Sciences, involved hepatitis C patients from the Duke Liver Clinic who received both alcohol treatment and medical care over a six-month period. Of the 53 alcohol-drinking patients in the study, 44 percent had stopped drinking alcohol by the end of the six months. Patients who did not become abstinent by six months still reported a 30 percent drop in alcohol consumption, spending on alcohol and urges to drink.
“We were able to show that integrated hepatitis C-alcohol care is feasible,” said Proeschold-Bell, a DGHI faculty member at the Center for Health Policy and Inequalities Research. “More than that, the study shows that such integrated care results in alcohol reductions that benefit patient health.”
Researchers say the intervention worked in part because it focused on liver health, rather than simply reducing alcohol use. It involved weekly group therapy and bi-weekly individual sessions customized to each patient that address alcohol use, nutrition, stress and family support. Because knowledge alone does not change behavior, the addictions specialist taught patients practical ways to improve other aspects of their lives based on their individual circumstances. Study participants were also evaluated for mental illness and had access to a psychiatrist for care, if needed.
The research team also found ways to increase communication and collaboration between the patient’s hepatologist and addictions specialist, a critical part of the study.
“We didn’t know the extent to which we could get busy medical providers and addictions specialists to collaborate. We had to find ways to fit the collaboration into the clinic flow,” said Proeschold-Bell. “In some instances, we had the addictions specialist use a laptop outside the patient exam rooms so medical providers could easily access her and her knowledge about the patient’s alcohol use and behavior changes.”
To date, studies have shown that adults with hepatitis C are three times more likely to have at least one alcoholic drink a day and almost eight times more likely to have at least three drinks a day, compared to adults without hepatitis C. The combination of alcohol use and hepatitis C speeds the time to liver failure and increases rates of liver fibrosis and cancer.
As strong proponents of clinic-based alcohol treatment, Proeschold-Bell and Muir hope to pursue a larger study that recruits patients from the Duke Liver Clinic, the UNC Liver Clinic and the Durham Veterans Affairs Medical Center.
“Alcohol treatment needs to occur in a trusted and known setting,” said Muir. “This study shows that patients will attend alcohol treatment offered in the liver clinic setting and try to change their behaviors in the context of their lives beyond alcohol use.”
More information on this CHPIR project on the HEP ART page
What do you tell hepatitis C patients who are drinking?
Gilead profit narrowly misses Street view
(Reuters) - Gilead Sciences Inc's (GILD.O) reported quarterly earnings that fell slightly short of Wall Street estimates as sales of its flagship HIV drugs rose nearly 20 percent but expenses also moved higher.
Gilead is the world's largest maker of branded drugs to treat the human immunodeficiency virus, but its near-term future is tightly linked to progress with the experimental hepatitis C drug acquired with its recent $11 billion buyout of Pharmasset.
"With sales strength reaffirming their HIV franchise and continued progress towards becoming an HCV (hepatitis C virus) leader, we believe Gilead shares are poised for appreciation," Wells Fargo analyst Brian Abrahams said in a research note.
Excluding $194 million in costs related to the Pharmasset deal, Gilead earned 91 cents a share in the first quarter, 2 cents short of the average Wall Street forecast, according to ISI Group.
"I think it was a fine, solid quarter," said Cowen & Co analyst Phil Nadeau. "The top line beat our estimates and the bottom line was a little light, but that seems to be due to a writedown of Greek debt.
Speaking on a conference call with investors and analysts, Gilead Chief Scientific Officer Norbert Bischofberger said the company could file for regulatory approval of the hepatitis C drug, called 7977, in certain patient populations as early as mid-2013.
He declined to comment on whether Gilead would consider further studies of 7977 in combination with another experimental oral drug from Bristol-Myers Squibb Co (BMY.N). The two-drug regimen was shown to be effective in a mid-stage trial earlier this month.
Gilead's first-quarter sales of HIV drug Atripla rose 19 percent to $887.6 million, exceeding the $851 million expected by analysts, according to numbers published by BMO Capital Markets. Gilead attributed the large uptick to increased buying from certain drug assistance programs funded by U.S. states.
Sales of older HIV drug Truvada rose 13 percent to $758.3 million, also ahead of analysts' estimate of $744 million.
Overall revenue rose 18 percent to $2.28 billion. Analysts expected $2.2 billion, according to Thomson Reuters I/B/E/S.
Looking ahead, Gilead said it still expects full-year 2012 sales of $8.6 billion to $8.8 billion.
First-quarter research and development spending rose 80 percent to $458 million.
Including $194 million in acquisition-related expenses, Gilead's quarterly net profit fell to $442 million from $651.1 million a year earlier.
Shares of Gilead, which closed at $52.72 on the Nasdaq, were higher at $52.99 after hours.
(Reporting By Deena Beasley; Editing by Richard Chang, Gunna Dickson and Steve Orlofsky)
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