August 3, 2010

Feature: Hunting for a hepatitis vaccine

Understanding how the immune system responds to hepatitis C is crucial in developing a vaccine. An ongoing study by Andrew Lloyd and his team is hoping to shed light on this virus and its weaknesses.

Fiona Wylie (Australian Life Scientist)
04 August, 2010 10:35
 
This feature appeared in the May/June 2010 issue of Australian Life Scientist. To subscribe to the magazine, go here.
 
Professor Andrew Lloyd of the University of New South Wales is one of the central figures in the HITS study (Hepatitis C Incidence and Transmission Study) is a long-term prospective cohort study of eligible prison inmates in NSW. Lloyd’s cohort comprises high-risk, uninfected injecting drug users, who are followed at regular intervals longitudinally.

“Sadly we are identifying a significant number becoming infected,” he says. And this is despite significant education on preventative behaviours. “In terms of a hepatitis C vaccine, prisons are, for better or worse, a typical venue that might be targeted as a population in terms of vaccine preparation in the first instance, and ultimately for application of a effective vaccine.”

According to Lloyd, the ideal target population for a candidate hepatitis C vaccine must be well characterised, with well-understood risk behaviours, and a high documented incidence as well as a good follow-up likelihood, so that the effects of the vaccine on incidence are easier to interpret and more significant.

“These criteria are reasonably readily available in our prison population, but not so easy to find within the general population, particularly as injecting drug users, who are the main sufferers of hepatitis C in Australia, tend to be fairly socially chaotic (as a broad statement) outside the prison venue. We recently reported that, sadly, the prison population has an annual incidence of infection of about 30-40 per cent, which is very high.”

The success of hepatitis C vaccine development also requires some knowledge of the protective immunity strategies used by the body against the virus. “What we know already about hepatitis C infection is quite interesting,” says Lloyd.

“For a start, about one in every three people will successfully clear the virus after infection. This is good, because it means that there is something that the host immune response can do to get rid of the virus. The bad news is that most of those people apparently remain susceptible and so can get reinfected.

“Although, it also seems that re-exposure has a better outcome the second time around, meaning that your likelihood of clearing the virus on round two, three, four or five appears better than on the first round. So the evidence suggests that, yes, there probably is such a thing as protective immunity.”

Developing a hepatitis vaccine
 
The final part of Lloyd’s discussion at the ASM meeting will focus on recent work by the group regarding cellular immunity against hepatitis C infection. As part of the HITS study, Lloyd has been looking at high-risk cohort members who remain uninfected.

“These individuals have been using drugs, sharing needles and doing all the other high-risk behaviours for many years, but have no evidence whatsoever of the virus, by antibody testing and by PCR. And that is really a bit of a surprise,” he says.

“We know that the key element of the immune response that confers successful clearance is cellular immunity – that is, T cells reactive against the virus – and we have found that a significant minority of these high-risk, hard-core, long-standing injectors that were not infected actually have cellular immunity against hepatitis C infection.”

Analyses of T cells within this prison sub-group revealed a population of T cells with the right markers of defence against the virus and which are reactive against the virus when challenged in vitro, suggesting that these individuals have a degree of naturally occurring protective immunity.

“From the vaccine aspect, this means that for some individuals you don’t need to induce de novo primary immunity, but rather to simply boost pre-existing immunity, and the characteristics of that naturally occurring immunity might provide a facsimile of what you might try to generate with a vaccine.”

Current efforts are now focused on better characterising this immunity and in doing so, guiding the strategies for vaccine development and other prevention strategies in both the prison setting and the general community.

The HITS prison study being undertaken under the guidance of Lloyd, together with a more recently established community-based HITS cohort, is providing vital information for the global efforts to develop an effective hepatitis C vaccine.

As Lloyd explains: “It is such an important, time-consuming and challenging task to develop the right vaccine in the research lab, but in the hep C business, it is equally tough to find and manage the right populations to test candidate vaccines.”

Source

Hepatitis B linked to lymphoma in study

WASHINGTON
Tue Aug 3, 2010 6:37pm EDT

WASHINGTON (Reuters) - People infected with hepatitis B virus are around twice as likely to develop non-Hodgkin lymphoma, researchers reported on Tuesday.

Hepatitis B was already known to cause liver cancer and some scientists had suspected it might cause lymphoma, too. The study, published in Lancet Oncology, confirms this. Hepatitis C is also linked to lymphoma.

The blood cancer is not common and widespread vaccination against the viruses is unlikely to affect non-Hodgkin lymphoma rates much, the researchers noted. But it may be possible to treat the virus and help non-Hodgkin lymphoma patients, they said.

Dr. Eric Engels of the U.S. National Cancer Institute and Sun Ha Jee of Yonsei University in Seoul studied the records of more than 600,000 people in South Korea, where hepatitis B was extremely common before a vaccination campaign began in 1995.

Of these, 53,000 or about 9 percent had evidence of hepatitis B infection. After 14 years, rates of non-Hodgkin lymphoma were more common among the infected people -- 19.4 cases per 100,000 people compared to 12.3 per 100,000 who did not have hepatitis B.

Viral hepatitis is the leading cause of liver cancer and the most common reason for liver transplantation, according to the U.S. Centers for Disease Control and Prevention. The various hepatitis viruses are not closely related -- the word hepatitis means inflammation of the liver.

An estimated 350 million people worldwide are infected with hepatitis B virus, which causes 340,000 cases of liver cancer a year and kills between 500,000 and 1.2 million people a year.

Researchers think both hepatitis B and C may cause lymphoma by overstimulating the immune system as it tries to fight off the liver infection.

(Reporting by Maggie Fox, editing by Alan Elsner)

Source
Gut doi:10.1136/gut.2009.205971

Paper

Janine Rohrbach 1, Nicola Robinson 2, Gillian Harcourt 2, Emma Hammond 3, Silvana Gaudieri 3,4, Meri Gorgievski 5, Amalio Telenti 6, Olivia Keiser 7, Huldrych F Günthard 8, Bernhard Hirschel 9, Matthias Hoffmann 10, Enos Bernasconi  11, Manuel Battegay 12, Hansjakob Furrer 1, Paul Klenerman 2, Andri Rauch 1,3, the Swiss HIV Cohort Study

1 Division of Infectious Diseases, University Hospital Berne and University of Berne, Switzerland
2 Nuffield Department of Clinical Medicine, Oxford University, UK
3 Centre for Clinical Immunology and Biomedical Statistics, Royal Perth Hospital and Murdoch University, Perth, Australia
4 Centre for Forensic Sciences and School of Anatomy and Human Biology, University of Western Australia, Perth, Australia
5 Institute for Infectious Diseases, University of Berne, Switzerland
6 Institute of Microbiology, University Hospital Centre and University of Lausanne, Switzerland
7 Institute of Social and Preventive Medicine, University of Berne, Switzerland
8 Division of Infectious Diseases and Hospital Epidemiology, University Hospital Zurich, University of Zurich, Switzerland
9 Department of Infectious Diseases, Geneva University Hospital, Switzerland
10 Division of Infectious Diseases, Kantonsspital St Gallen, Switzerland
11 Division of Infectious Diseases, Ospedale Regionale di Lugano, Switzerland
12 Division of Infectious Diseases and Hospital Epidemiology, University Hospital Basel, Switzerland

Correspondence to
Andri Rauch, Klinik und Poliklinik für Infektiologie, University Hospital Berne and University of Berne, Inselspital PKT2B, 3010 Bern, Switzerland; andri.rauch@insel.ch

Revised 31 March 2010
Accepted 13 April 2010
Published Online First 26 July 2010

Abstract

Background Hepatitis C virus (HCV) infection is a major cause of morbidity in HIV infected individuals. Coinfection with HIV is associated with diminished HCV-specific immune responses and higher HCV RNA levels.

Aims To investigate whether long-term combination antiretroviral therapy (cART) restores HCV-specific T cell responses and improves the control of HCV replication.

Methods T cell responses were evaluated longitudinally in 80 HIV/HCV coinfected individuals by ex vivo interferon-γ-ELISpot responses to HCV core peptides, that predominantly stimulate CD4+ T cells. HCV RNA levels were assessed by real-time PCR in 114 individuals.

Results The proportion of individuals with detectable T cell responses to HCV core peptides was 19% before starting cART, 24% in the first year on cART and increased significantly to 45% and 49% after 33 and 70 months on cART (p=0.001). HCV-specific immune responses increased in individuals with chronic (+31%) and spontaneously cleared HCV infection (+30%). Median HCV RNA levels before starting cART were 6.5 log10 IU/ml. During long-term cART, median HCV-RNA levels slightly decreased compared to pre-cART levels (−0.3 log10 IU/ml, p=0.02).

Conclusions Successful cART is associated with increasing cellular immune responses to HCV core peptides and with a slight long-term decrease in HCV RNA levels. These findings are in line with the favourable clinical effects of cART on the natural history of hepatitis C and with the current recommendation to start cART earlier in HCV/HIV coinfected individuals.

Source

Rare Organ Transplant Gives Single Mom New Lease on Life

 
A single mom from North Carolina recently received an extremely rare triple transplant. She received a new heart, lungs and a liver and is enjoying her new lease on life.

Shereyse Joyner from Ahoskie, NC, is believed to be only the twelfth patient in the U.S. since 1988 to receive the triple organ transplant.
2:06 (mm:ss)

Transcript of Video
 
Source
Celsion Corporation announced today that the consensus recommendations of the National Cancer Institute (NCI) Clinical Trials Planning Meeting (CTPM) for Hepatocellular Carcinoma have been released and published in the August 2010 issue of Journal of Clinical Oncology, the official publication of American Society of Clinical Oncology (ASCO). In addition to evaluating the current standard of care, the NCI panel also recommended Celsion's Phase III ThermoDox ® HEAT Study as a Priority Clinical Trial for HCC.

"We are pleased this prominent panel of experts at the NCI Clinical Trials Planning Meeting have recognized the importance of our Phase III HEAT Study," stated Michael H. Tardugno, President and Chief Executive Officer of Celsion. "Upon completion of the trial and eventual marketing approval, ThermoDox plus RFA will provide an additional therapeutic option for patients afflicted with HCC, a dreadful disease with high unmet medical need." Dr. Nicholas Borys, Chief Medical Officer of Celsion Corporation commented, "This JCO article also reinforces the global importance of new therapies for HCC, and highlights the prominence of the ThermoDox program, which is now over 2/3rds enrolled in 75 global sites and 11 countries."

Celsion's global Phase III ThermoDox study for primary liver cancer plans to enroll 600 patients and is being conducted under a FDA Special Protocol Assessment (SPA). The study is designed to evaluate the efficacy of ThermoDox in combination with radiofrequency ablation (RFA) when compared to patients who receive RFA alone as the control. The primary endpoint for the study is progression-free survival. Additional information on the Phase III ThermoDox clinical study may be found at http://www.clinicaltrials.gov/.

About ThermoDox®

ThermoDox® is a proprietary heat-activated liposomal encapsulation of doxorubicin, an approved and frequently used oncology drug for the treatment of a wide range of cancers including breast cancer. ThermoDox® is administered intravenously and in combination with hyperthermia has the potential to provide local tumor control and improve quality of life. Localized mild hyperthermia (39.5-42 degrees Celsius) releases the entrapped doxorubicin from the liposome. This delivery technology enables high concentrations of doxorubicin to be deposited preferentially in a targeted tumor.

ThermoDox has already demonstrated remarkable evidence of clinical activity in Phase I studies for primary liver cancer and recurrent chest wall breast cancer. For the primary liver cancer indication, Celsion has been granted FDA Orphan Drug designation. For recurrent chest wall breast cancer, ThermoDox® is being evaluated in a pivotal Phase I/II open-label, dose-escalating trial that is designed to measure durable local complete response at the tumor site.

ThermoDox® is a registered trademark of Celsion Corporation


About ThermoDox Global Phase III HEAT Study

Celsion's global ThermoDox Phase III study for HCC, the most common form of primary liver cancer, is being conducted under a Special Protocol Assessment with the U.S. Food and Drug Administration (FDA). The 600 patient study, is designed to evaluate the efficacy of ThermoDox in combination with RFA when compared to patients who receive RFA alone as the control. The primary endpoint is progression free survival with a secondary confirmatory endpoint of overall survival. A pre-planned, un-blinded interim efficacy analysis will be performed by an independent Data Management Committee when 50% of the progression-free survival endpoint events are realized in the study population. Based on an historical review of RFA cases, Celsion expects the study could be completed by the middle of 2011, and pending positive data, a New Drug Application would be submitted to the FDA before the end of 2011. Additional information on the ThermoDox Phase III clinical study may be found at http://www.clinicaltrials.gov/.

About Primary Liver Cancer

Primary liver cancer is one of the most deadly forms of cancer and ranks as the fifth most common solid tumor cancer. The incidence of primary liver cancer is approximately 20,000 cases per year in the United States and is rapidly growing worldwide at approximately 1,000,000 cases per year, due to the high prevalence of Hepatitis B and C in developing countries. Among the standard treatment options for liver cancer is surgical resection of the tumor; however 70% to 80% of patients are ineligible for surgery. Radio frequency ablation (RFA) has increasingly become the standard of care for non-resectable liver tumors, but the treatment becomes less effective for larger tumors.

About Celsion

Celsion is dedicated to the development and commercialization of innovative oncology drugs including tumor-targeting treatments using focused heat energy in combination with heat-activated drug delivery systems. Celsion has licensed ThermoDox(R) to Yakult-Honsha for the Japanese market and has a partnership agreement with Phillips Medical to jointly develop its heat activated liposomal technology in combination with high intensity focused ultrasound to treat difficult cancers. Celsion has research, license, or commercialization agreements with leading institutions such as the National Institutes of Health, Duke University Medical Center, University of Hong Kong, Cleveland Clinic, and the North Shore Long Island Jewish Health System.

For more information on Celsion, visit our website: http://www.celsion.com/

Celsion wishes to inform readers that forward-looking statements in this release are made pursuant to the "safe harbor" provisions of the Private Securities Litigation Reform Act of 1995. Readers are cautioned that such forward-looking statements involve risks and uncertainties including, without limitation, unforeseen changes in the course of research and development activities and in clinical trials by others; possible acquisitions of other technologies, assets or businesses; possible actions by customers, suppliers, competitors, regulatory authorities; and other risks detailed from time to time in the Company's periodic reports filed with the Securities and Exchange Commission.

Source
Pockros PJ, Hamzeh FM, Martin P, Lentz E, Zhou X, Govindarajan S, Lok AS.
Scripps Clinic, La Jolla, CA.

Abstract

Patients with chronic hepatitis C with partial virologic response or nonresponse to interferon-based therapies can experience treatment-related improvements in liver histology. This retrospective analysis assessed the histologic response to treatment in patients with varying degrees of virologic response (sustained virologic response [SVR], breakthrough, relapse, or nonresponse), time to hepatitis C virus (HCV) RNA undetectability, and duration of viral suppression. Patients (HCV genotypes 1-6) with baseline and follow-up liver biopsies from eight phase 2 to phase 4 interferon-based trials were analyzed. Blinded biopsies were evaluated by a single pathologist. Improvements or worsening of METAVIR necroinflammatory activity and fibrosis were defined as increase or decrease of >/=1 grading category from baseline to 24 weeks after end of treatment. A majority of the 1571 patients with paired biopsy data were white, male, with HCV genotype 1/4, baseline HCV RNA levels >800,000 IU/mL, and baseline alanine aminotransferase levels HEPATOLOGY 2010;).

Source

Diagnosis of occult hepatitis C without the need for a liver biopsy

Journal of Medical Virology
Volume 82 Issue 9, Pages 1554 - 1559
Published Online: 15 Jul 2010
Copyright © 2010 Wiley-Liss, Inc., A Wiley Company

Inmaculada Castillo 1, Javier Bartolomé 1, Juan Antonio Quiroga 1, Guillermina Barril 1 2, Vicente Carreño 1 *

1 Foundation for the Study of Viral Hepatitis, Madrid, Spain
2 Department of Nephrology, Hospital Universitario de la Princesa, Madrid, Spain
email: Vicente Carreño (fehvhpa@fehv.org)

* Correspondence to Vicente Carreño, Fundación para el Estudio de las Hepatitis Virales, Guzmán el Bueno 72, 28015 Madrid, Spain.

Funded by:
-Fundación Investigaciones Biomédicas, Madrid, Spain
-Fundación Caja Navarrra, Pamplona, Spain

Keywords
occult HCV • PBMCs • HCV-RNA • anti-core HCV

Abstract

The diagnosis of occult hepatitis C virus (HCV) infection is based on the presence of HCV-RNA in the liver. This study aimed to evaluate the use of combining non-invasive assays to diagnose occult HCV. A total of 122 patients with occult HCV (HCV-RNA in the liver without detectable anti-HCV and serum HCV-RNA) and 45 patients with cryptogenic chronic hepatitis (without HCV-RNA in the liver and negative for anti-HCV and serum HCV-RNA) were included. HCV-RNA was tested in peripheral blood mononuclear cells (PBMCs) and in 2 ml of ultracentrifuged serum. Anti-core HCV was examined by a non-commercial enzyme-linked immunosorbent assay. All controls were negative for the three HCV markers studied. Among patients with occult HCV, 36% were anti-core HCV positive, 57% had serum HCV-RNA after ultracentrifugation, and 61% had HCV-RNA in PBMCs. Combining the results of the assays, 91% of the patients were positive for at least one marker. Intrahepatic HCV-RNA load was significantly higher in patients who were positive simultaneously for the three HCV markers than in patients who were negative for all markers (P = 0.006) and than in those with one or two HCV markers (P = 0.039). Replication of HCV in liver was detected more frequently in patients with three (93%, P = 0.002), two (82%, P = 0.001), and one HCV marker (73%, P = 0.011) than in those without markers (27%). In conclusion, testing for all these markers allows diagnosis of occult HCV without the need for a liver biopsy and these assays may help to elucidate the clinical significance of occult HCV infection. J. Med. Virol. 82:1554-1559, 2010. © 2010 Wiley-Liss, Inc.

Accepted: 17 May 2010

Digital Object Identifier (DOI)
10.1002/jmv.21866 About DOI

Source
Journal of Medical Virology
Volume 82 Issue 9, Pages 1537 - 1544
Published Online: 15 Jul 2010
Copyright © 2010 Wiley-Liss, Inc., A Wiley Company

Hidenori Toyoda *, Takashi Kumada, Seiki Kiriyama, Makoto Tanikawa, Yasuhiro Hisanaga, Akira Kanamori, Toshifumi Tada, Makiko Takagi, Takeshi Hiramatsu, Takanori Hosokawa, Takahiro Arakawa, Masashi Fujimori

Department of Gastroenterology, Ogaki Municipal Hospital, Ogaki, Japan
email: Hidenori Toyoda (hmtoyoda@spice.och.ne.jp)

*Correspondence to Hidenori Toyoda, Department of Gastroenterology, Ogaki Municipal Hospital, 4-86 Minaminokawa, Ogaki, Gifu 503-8502, Japan.

Keywords
chronic hepatitis C • standard interferon • peginterferon and ribavirin • non-response • resistance to interferon

Abstract

As combination therapy with peginterferon (PEG-IFN) and ribavirin has a high morbidity, identifying individuals with hepatitis C virus (HCV) who will not respond to the treatment would be beneficial. The early responses of serum HCV RNA levels to standard interferon (IFN) and PEG-IFN were examined to determine if it was possible to identify resistance to combination therapy. One hundred thirty-one patients infected with HCV genotype 1b were enrolled. Patients were given 6 MU of standard IFN alpha-2b at least 2 weeks before initiating combination therapy. Serum HCV RNA levels were measured before, 24 hr after the administration of standard IFN, and 24 hr after the administration of PEG-IFN (at the start of the combination therapy). The association between reductions in HCV RNA levels at 24 hr after the administration of standard IFN and PEG-IFN and the outcome of combination therapy were analyzed. Reductions in HCV RNA levels were poorer in patients who did not respond than in those with a sustained virologic responses or relapses (P < 0.0001), both 24 hr after the administration of standard IFN and 24 hr after the administration of PEG-IFN. Reductions in HCV RNA levels 24 hr after the administration of standard IFN were an independent factor associated with non-response by multivariate analysis. An early reduction in viral load to a single administration of standard IFN is a useful predictor of non-response in patients with HCV genotype 1, allowing for pretreatment identification of patients who will not benefit from combination therapy. J. Med. Virol. 82:1537-1544, 2010. © 2010 Wiley-Liss, Inc.

Accepted: 20 April 2010

Digital Object Identifier (DOI)
10.1002/jmv.21858 About DOI

Source
Journal of Gastroenterology and Hepatology

Published Online: 28 Jun 2010
Journal compilation © 2010 Blackwell Publishing Asia Pty Ltd and Journal of Gastroenterology and Hepatology Foundation

Hye Jin Cho, 1 Yeon Seok Seo, 1 Kwang Gyun Lee, 1 Jong Jin Hyun, 1 Hyonggin An, 2 Bora Keum, 1 Ji Hoon Kim, 1 Hyung Joon Yim, 1 Yoon Tae Jeen, 1 Hong Sik Lee, 1 Hoon Jai Chun, 1 Soon Ho Um, 1 Chang Duck Kim, 1 Ho Sang Ryu 1

Department of Internal Medicine 1 and Department of Biostatistics, 2 Korea University College of Medicine, Seoul, Korea

Correspondence to Yeon Seok Seo
Department of Internal Medicine, Korea University College of Medicine, 126-1, 5-Ga, Anam-Dong, Seongbuk-Gu, Seoul, Korea (136-705)
Tel: 82-2-920-6608 / FAX: 82-2-953-1943
e-mail: drseo@korea.ac.kr

This is an Accepted Article that has been peer-reviewed and approved for publication in the Journal of Gastroenterology and Hepatology, but has yet to undergo copy-editing and proof correction. Please cite this article as an "Accepted Article"; doi: 10.1111/j.1440-1746.2010.06419.x

KEYWORDS
FibroScan • liver stiffness • alanine aminotransferase • necroinflammation

ABSTRACT

Background: It is still uncertain whether the accuracy of transient elastography (TE) in predicting the fibrosis stage is similar in chronic hepatitis B (CHB) and chronic hepatitis C (CHC). This study was performed to evaluate whether the underlying cause of chronic viral hepatitis affects the predictive accuracy of TE. Methods: Patients with CHB or CHC who were admitted for a liver biopsy were enrolled. Patients underwent TE and laboratory tests on the same day as the liver biopsy. The predictive accuracy was analyzed by comparing the areas under the receiver-operating characteristic curves (AUCs). Results: Two-hundred seven patients were enrolled, comprising 121 CHB patients and 86 CHC patients). The patients were aged 44 ± 14 years, and 121 (58.5%) of them were men. AUCs for predicting significant fibrosis were significantly lower in CHB patients than in CHC patients (P = 0.043). The serum alanine aminotransferase (ALT) level was associated with overestimation and underestimation of the fibrosis stage, while the cause of chronic hepatitis was not. AUCs for predicting significant fibrosis were significantly lower in patients with ALT levels >70 IU/L (AUC, 0.830; 95% CI, 0.742-0.898) than in patients with ALT levels ≤70 IU/L (0.944; 0.882-0.979; P= 0.015). Conclusions: Although the predictive accuracy of TE in predicting significant fibrosis differed significantly with the cause of chronic hepatitis, this difference was due to the degree of serum ALT levels rather than to the cause of hepatitis itself. Avoiding performing TE in patients with elevated ALT levels is recommended to guarantee the predictive accuracy of TE.

Received date: 06-Apr-2010
Accepted date: 07-Jun-2010

DIGITAL OBJECT IDENTIFIER (DOI)
10.1111/j.1440-1746.2010.06419.x About DOI
 
Source

Vaccine Shows Some Promise Against Advanced Cancers


But only a minority of patients benefited and more work may need to be done, experts say

Monday, August 2, 2010
 
MONDAY, Aug. 2 (HealthDay News) -- Scientists have genetically tweaked a virus to fashion a therapeutic vaccine that appears to attack a variety of advanced cancers.
 
The vaccine has provoked the required tumor-fighting immune response in early human trials, but only in a minority of patients tested.

And one expert urged caution. "They were able to generate an immune response [with the vaccine]. That's a good thing but we need a little more information," said Dr. Adam Cohen, assistant professor in medical oncology at Fox Chase Cancer Center in Philadelphia. He was not involved in the study.

"This is the first study in cancer patients with this type of vaccine, with a relatively small number of patients treated so far," Cohen noted. "So while the immune response data are promising, further study in a larger number of patients will be required to assess the clinical benefit of the vaccine."

One vaccine to treat prostate cancer, Provenge, was recently approved by the U.S. Food and Drug Administration. However, Cohen noted that many other cancer vaccines have shown early promise and not panned out.

The theory behind therapeutic cancer vaccines is that people with cancer tend to have defects in their immune system that compromise their ability to respond to malignancy, explained study lead author Dr. Michael Morse, associate professor of medicine at Duke University Medical Center.

"A vaccine has to work by activating immune cells that are capable of killing tumors and those immune cells have to survive long enough [to] get to the tumor and destroy it," he explained.

For this vaccine, the authors used the Venezuelan equine encephalitis virus, an "alphavirus" that affects the nervous systems of equines, including horses and donkeys.

Alphaviruses provide an attractive vector for vaccines because they naturally seek out dendritic cells, which stimulate the body's immune system.

In their work, the authors removed the innards of the virus and substituted instead a gene for the carcinoembryonic antigen (CEA). This immune system biomarker is overproduced in many different types of cancer.

The vaccine was then administered multiple times over a period of three months to 28 patients with advanced, recurrent forms of lung, colon, breast, appendix or pancreatic cancer. The participants had already failed several rounds of standard chemotherapy.

Five patients displayed a response to the therapy: Two who had already been in remission stayed in remission; two patients saw their cancers stabilize; and a liver lesion in one patient with pancreatic cancer was no longer evident.

The responses tended to occur in patients with smaller tumors and in those receiving higher doses of the vaccine.

The alphavirus-based vaccine also managed to evade the immune system's regulatory T cells, which could have shut down the body's immune response, the researchers said.

Although T cell levels were elevated in some patients, the vaccine was able to get around them.

Co-authors included employees from Alphavax, which develops new vaccine technology. The study was partially supported by the U.S. National Cancer Institute.

SOURCES: Michael Morse, M.D., associate professor, medicine, Duke University Medical Center; Adam Cohen, M.D., assistant professor, medical oncology, Fox Chase Cancer Center, Philadelphia; Aug. 2, 2010, Journal of Clinical Investigation, online

Source

Boomers May Be Last Boom of Hepatitis C

U.S. Centers for Disease Control and Prevention • U.S. News

August 2, 2010

A new study of U.S. blood donors shows a "strikingly lower prevalence" of hepatitis C virus (HCV) compared with 1992-93, according to lead researcher Dr. Edward Murphy of the University of California-San Francisco.

HCV is a blood-borne infection that is primarily contracted from dirty syringes, but a small number of cases are sexually transmitted or passed from mother to infant during childbirth. The body can clear hepatitis C, though infections become chronic 75 percent to 85 percent of the time. CDC estimates that 1 percent to 5 percent of people with chronic HCV eventually die of cirrhosis or liver cancer.

In the early 1990s, about a half a percent of blood donors were positive for HCV antibodies, indicating either a chronic infection or past infection that cleared. From 2006 to 2007, the study analyzed samples from nearly 960,000 blood donors at six U.S. blood banks, finding less than a tenth of a percent were positive for HCV antibodies.

Murphy said the decrease probably reflects an overall decline of hepatitis C, especially among younger Americans. The baby boom generation, which had higher rates of injection drug use than subsequent generations, has more carriers of the infection and is at higher risk for HCV-related liver disease.

Two other factors for higher risk of hepatitis C among blood donors were found. Among women, the odds of having HCV antibodies increased with the number of children they had given birth to -- from 1 infection in 3,300 among women who had never given birth to 1 in 1,000 among women with five or more children.

Obese adults were less likely than their normal-weight peers to have HCV antibodies. And among those with antibodies, obese persons were less likely to have the genetic material that signals the ongoing presence of HCV.

The study, "Hepatitis C Virus Prevalence and Clearance Among U.S. Blood Donors, 2006-2007: Associations with Birth Cohort, Multiple Pregnancies, and Body Mass Index," was published in the Journal of Infectious Diseases (2010;202:576-584).
 
Source
David E Jones a, Ahmad Al-Rifai a, James Frith a, Imran Patanwala a, Julia L Newton b

Received 14 January 2010; received in revised form 7 May 2010; accepted 8 May 2010. published online 02 August 2010.
Accepted Manuscript

Abstract

Background & Aims
Long-term outcome in Primary Biliary Cirrhosis (PBC) remains unclear. Whilst response to Ursodeoxycholic Acid (UDCA) is associated with good outcome, this effect is not universal. Early data from our group have suggested that one factor associated with a poorer outcome in PBC is fatigue. The aim of this study was to explore the inter-relationship between UDCA use, response, and fatigue in determining outcome over 9 years in a unique, comprehensive patient cohort.

Methods
Longitudinal prospective study of a geographically-defined complete cohort of PBC patients in North- East England and matched community controls.

Results
Survival to death or transplant was significantly lower in PBC patients than in the case-control population (88/136 (65%) v 114/136 84% (p <0.001 by log-rank test), with better survival in UDCA responders (defined using the Paris criteria) than in patients not treated with UDCA at study outset. Compared to the whole control group survival was reduced in PBC patients fatigued at study outset but not in those without fatigue (p <0.0001); an effect independent of the beneficial effect of UDCA response and of conventional parameters of liver disease severity. UDCA responders without fatigue at the study outset had a 9 year survival which was identical to controls. Patients without fatigue at the study outset who developed fatigue during follow-up had significantly worse survival than patients who remained without fatigue throughout (p <0.05). Fatigued controls had worse survival than non-fatigued controls (p = 0.05).

Conclusions
Survival in a comprehensive cohort of PBC patients is substantially reduced compared with case-matched community controls. Development of fatigue and non-treatment with UDCA were specifically (and independently) associated with increased risk of death in PBC.

Keywords: Fatigue, outcomes research, quality of life, liver cirrhosis, biliary

No full text is available. To read the body of this article, please view the PDF online.

a Institute of Cellular Medicine, Newcastle University, Newcastle-upon-Tyne, UK

b Institute for Ageing and Health, Newcastle University, Newcastle-upon-Tyne, UK

PII: S0168-8278(10)00679-3
doi:10.1016/j.jhep.2010.05.026
© 2010 Published by Elsevier Inc

Source
Dominique Thabut a b, Vijay Shah a

Received 21 April 2010; received in revised form 7 July 2010; accepted 12 July 2010. published online 02 August 2010.
Accepted Manuscript

Abstract

Portal hypertension accounts for the majority of morbidity and mortality that is encountered in patients with cirrhosis. Portal hypertension is initiated in large part through increases in intrahepatic vascular resistance. Fibrosis, regenerative nodule formation, and intrahepatic vasoconstriction are classical mechanisms that account for increased intrahepatic vascular resistance in cirrhosis. Recent data suggests that intrahepatic angiogenesis and sinusoidal remodeling could also be involved in sinusoidal resistance, fibrosis, and portal hypertension. While angiogenesis is defined as the formation of new vessels deriving from existing ones, sinusoidal remodeling in its pathological form associated with cirrhosis is characterized by increased mural coverage of vessels by contractile HSC. Most attention on the mechanisms of these processes has focused on the liver sinusoidal endothelial cell (SEC), the hepatic stellate cell (HSC), and the paracrine signaling pathways between these two cell types. Interventions that target these vascular structural changes have beneficial effects on portal hypertension and fibrosis in some animal studies which has stimulated interest for pursuing parallel studies in humans with portal hypertension.

Keywords: Portal hypertension, cirrhosis, angiogenesis, vascular remodeling, receptor tyrosine kinase

No full text is available. To read the body of this article, please view the PDF online.

a Gastroenterology Research Unit, Advanced Liver Disease Study Group, Fiterman Center for Digestive Diseases, Mayo Clinic, Rochester, MN, USA.

b Université Pierre et Marie Curie, AP-HP, Service d’Hépato-Gastroentérologie, Groupe Hospitalier Pitié-Salpêtrière, Paris, FRANCE.

PII: S0168-8278(10)00632-X
doi:10.1016/j.jhep.2010.07.004
© 2010 Published by Elsevier Inc.

Source
Annette von dem Bussche a, Raiki Machida a, Ke Li a, Gideon Loevinsohn a b, Amrin Khander a b, Jianguo Wanga b, Takaji Wakita b, Jack R. Wands a, Jisu Li a

Received 28 December 2009; received in revised form 22 April 2010; accepted 6 May 2010. published online 02 August 2010.
Accepted Manuscript

Abstract

Background & Aims
We previously reported that the NS2 protein of hepatitis C virus (HCV) inhibits the expression of reporter genes driven by a variety of cellular and viral promoters. The aim of the study was to determine whether the broad transcriptional repression is caused by endoplasmic reticulum (ER) stress.

Methods
Phosphorylation of the translation initiation factor eIF2α and HCV replication were detected by Western and Northern blot, respectively. De novo protein synthesis was measured by metabolic labeling. Activation of ER stress responsive genes was determined by promoter reporter assay, as well as mRNA and protein measurement by real time PCR and Western blot.

Results
Transient or inducible NS2 protein expression increased eIF2α phosphorylation and reduced de novo protein synthesis. It up-regulated promoter activities and transcript levels of ER stress inducible genes including GRP78, ATF6, and GADD153, as well as GRP78 protein level. The same effect was observed when NS2 was synthesized as part of the core-E1-E2-p7-NS2 polypeptide. NS2 protein also inhibited reporter gene expression from the HCV internal ribosome entry site and consequently reduced HCV replication. The full-length HCV replicon activated GRP78, ATF6, and GADD153 promoters more efficiently than the subgenomic replicon lacking the coding sequence for both the structural proteins and NS2. Abrogation of HCV infection/replication, by an inhibitor of the NS3 protease, relieved ER stress.

Conclusions
HCV infection can induce ER stress, with NS2 protein being a major mediator. The stress can be relieved by a feedback mechanism.

Abbreviations: HCV, hepatitis C virus, NS2, no-structural protein 2, ER, endoplasmic reticulum, eIF2α, eukaryotic translation initiation factor 2, GRP78, glucose regulated protein 78, ATF6, activating transcription factor 6, GADD153, growth arrest and DNA damage induced gene-153, CMV, cytomegalovirus, SV40, simian virus 40, TNFα, tumor necrosis factor alpha, NFκB, nuclear factor kappa-light-chain-enhancer of activated B cells, HBV, hepatitis B virus, FL, full-length, SG, subgenomic, SEAP, secreted alkaline phosphatase, ECL, enhanced chemiluminescence, PERK, PKR-like ER kinase, IRE1, inositol-requiring enzyme 1, IRES, internal ribosomal entry site, DGD, glycine decarboxylase, p.t., post transfection

Keywords: HCV infection, ER stress, viral pathogenesis, NS2 protein

No full text is available. To read the body of this article, please view the PDF online.

a Liver Research Center, Rhode Island Hospital and Warren Alpert Medical School of Brown University, Providence, Rhode Island 02903, USA

b Department of Virology II, National Institute of Infectious Diseases, 1-23-1 Toyama, Shinjuku, Tokyo 162-8640, Japan

PII: S0168-8278(10)00622-7
doi:10.1016/j.jhep.2010.05.022
© 2010 Published by Elsevier Inc.

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U.S. dietary supplements often contaminated: report

By Maggie Fox, Health and Science Editor
WASHINGTON
Tue Aug 3, 2010 6:14am EDT

(Reuters) - Many popular dietary supplements contain ingredients that may cause cancer, heart problems, liver or kidney damage, but U.S. stores sell them anyway and Americans spend millions on them, according to Consumer Reports.

The consumer magazine published a report on Tuesday highlighting the U.S. Food and Drug Administration's lack of power to regulate such supplements, and said the agency rarely uses what little power it does have.

The report from the influential group urged Congress to speed up small moves toward giving the agency more clout, especially in regulating supplements.

Despite the "natural" labels carried by many of the supplements, many are contaminated.

Yet Americans flock to take them, according to the magazine, citing the Nutrition Business Journal as saying the market was worth $26.7 billion in 2009.

"Of the more than 54,000 dietary supplement products in the Natural Medicines Comprehensive Database, only about a third have some level of safety and effectiveness that is supported by scientific evidence," the report reads.

In addition, the FDA has not inspected any supplement factories in China, even though the agency set up field offices there starting in 2008, Consumer Reports said.

The organization pointed to 12 supplement ingredients in particular that it said could be dangerous: aconite, bitter orange, chaparral, colloidal silver, coltsfoot, comfrey, country mallow, germanium, greater celandine, kava, lobelia, and yohimbe.

Potential dangers include liver and kidney damage, heart rhythm disorders and unhealthy blood pressure levels, it said.

INDUSTRY FRIENDLY LAWS

The group is critical of the 1994 Dietary Supplement Health and Education Act or DSHEA, which it describes as industry friendly and which prevents the FDA from regulating supplements in the same way as it regulates prescription medications.

The Federal Trade Commission regulates the marketing of herbal supplements, whose makers are not allowed to claim they treat medical conditions.

The FDA has banned only one supplement ingredient -- ephedrine alkaloids -- although it has persuaded many companies to pull their products off the market.

"Supplements are marketed with very seductive and sometimes overblown sales pitches for increasing your performance in the bedroom, slimming down, or boosting your athletic prowess," said Nancy Metcalf, senior program editor for the magazine.

"And consumers are easily lulled into believing that supplements can do no harm because they're 'natural'," Metcalf said in a statement.

"However, some natural ingredients can be hazardous, and on top of that the FDA has repeatedly found hazardous ingredients, including synthetic prescription drugs, in supplements."

In May, the Government Accountability Office found that sellers of ginseng, Echinacea and other herbal and dietary supplements often tell consumers the pills can cure cancer or replace prescription medications.

Experts at the Institute of Medicine said earlier this year the FDA needs to use the same strict standards to regulate supplements as it uses for drugs, and the GAO said the FDA should ask Congress for more power to regulate supplements.

(Editing by Todd Eastham)

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Medical Marijuana: At Work, a Drug Dilemma

LIFE & STYLE
AUGUST 3, 2010

By STEPHANIE SIMON

An employee recently approached Josh Ward, an executive at a Denver plumbing company, with a question he never thought he'd hear.

Her husband, the employee said, is a state-registered medical marijuana patient. Could she buy his marijuana with her company-provided flexible spending account?

"We were like, 'Whoa!'" Mr. Ward said.

Mr. Ward did a bit of research and quickly told the employee no. Her account, funded with pretax dollars, is regulated by the Internal Revenue Service and cannot be used to purchase a drug that's illegal under federal statutes, even if Colorado treats it as a legitimate medication.

The employee, whom the firm would not make available for comment, didn't press it, Mr. Ward said. Still, the issue made him uneasy. "It's a big can of worms," said Mr. Ward, vice president of Applewood Plumbing, Heating & Electric.

Employers from coast to coast are facing similar dilemmas. Many are closely watching a pending lawsuit against Wal-Mart Stores Inc. in Michigan. An employee who used medical marijuana was fired by the retailer after a positive drug test on the job.

Fourteen states and the District of Columbia have laws or constitutional amendments that allow patients with certain medical conditions such as cancer, glaucoma or chronic pain, to use marijuana without fear of prosecution. The Obama administration has directed federal prosecutors not to bring criminal charges against marijuana users who follow their states' laws.

But that can put employers in a difficult position, trying to accommodate state laws on medical marijuana use while at times having to enforce federal rules or company drug-use policies that are based on federal law.

"It's certainly an issue that's coming up regularly," said Danielle Urban, an attorney with Fisher & Phillips, a national labor and employment law firm. "Employers are between a rock and a hard place."

The federal government lists marijuana as a Schedule I drug on par with LSD or synthetic heroin. Employers can fire, or refuse to hire, employees for using the drug without running afoul of the Americans with Disabilities Act or any other federal anti-discrimination statute, said Christopher Kuczynski, assistant legal counsel with the U.S. Equal Employment Opportunity Commission.

State laws vary considerably. The state Supreme Courts in Oregon, California and Montana and the Washington Court of Appeals have all ruled that employers have a right to fire medical-marijuana patients for using the drug. The medical-marijuana laws in Rhode Island and Maine state that most employers may not penalize individuals solely because of their status as marijuana patients.

In Michigan, the law states that registered patients shall not be "denied any right or privilege" or face disciplinary action at work because they use pot. The only exception: Employers do have the right to terminate workers who use marijuana on site or come to work high.

But determining if a worker is impaired on the job can be difficult.

Sean Short, a 25-year-old college student, was injured last fall while taking pictures of skiers in Breckenridge, Colo., for his employer, an event photographer. Mr. Short says that, at the time, he was using marijuana in compliance with Colorado law to ease pain from a back injury.

He sayshe was not high when a skier smashed into him on the job, fracturing his shoulder. Mr. Short says he was required by his employer to take a urine drug screen after the accident. He flunked. He then gave managers his medical-marijuana card. "They said, 'Sorry, we're terminating you,"' Mr. Short said.

His employer did not return calls seeking comment.

Mr. Short says he's now reluctant to apply for any job requiring a drug test. "I can have a college degree. I can be well-spoken and intelligent," he said. "But as long as I'm a 'druggie,' I'm going to be discriminated against."

Sophisticated tests can measure the amount of THC, the active ingredient in marijuana, in blood samples taken within four to six hours of ingestion. Users are generally considered high at a level of five nanograms of THC per milliliter of blood, said Robert Lantz, director of Rocky Mountain Instrumental Laboratories, a drug-testing facility in Fort Collins, Colo.

Such precise tests require expensive instruments. Dr. Lantz's lab charges $450 for a single blood test; his bulk discount rate is $200 per test. Many employers use far cheaper, less sensitive urine screens. At OnSite Medical Testing, a lab in Greenwood Village, Colo., a basic urine test costs $35, or $25 for bulk clients.

The typical urine screen can detect the presence of metabolized THC compounds, but can't determine when the marijuana was ingested or in what quantities, Dr. Lantz said.

Advocates of legalized marijuana say they would never insist that workers be allowed to use the drug on duty. "No one thinks you should be able to get stoned and go to work, obviously," said Keith Stroup, legal counsel for the national advocacy group NORML. Still, Mr. Stroup argues that, absent clear signs of impairment, employers should trust workers who have valid medical-marijuana-registration cards to take the drug responsibly.

Too dangerous, some employers say. At Hoffman Construction Co. in Portland, Ore., cannabis has been implicated more than any other drug in workplace accidents resulting in injury or property damage, said Dan Harmon, a vice president.

Any move to permit off-duty drug use raises "real safety concerns," Mr. Harmon said. His firm doesn't accept medical-marijuana cards, he said. To do so would be "disastrous."

Employers and medical-marijuana patients are hoping the Michigan lawsuit can bring some clarity to the situation.

Joseph Casias, who says he uses medical marijuana to ease pain from an inoperable brain tumor, sued Wal-Mart in a state court in June, saying the retailer was wrong to fire him from his job as an inventory manager in Battle Creek, Mich., after he tested positive for marijuana.

Mr. Casias, who is represented by the American Civil Liberties Union, says he uses cannabis on his oncologist's advice and in compliance with Michigan law. The 30-year-old father of two says he takes the drug at night and has never come to work high. But last November, he failed a drug test that was administered as a matter of company policy after he twisted his knee on the job.

A Wal-Mart spokesman called the case "unfortunate" and the decision to fire Mr. Casias "difficult." But, he said: "As more states allow this treatment, employers are left without any guidelines except the federal standard. In these cases, until further guidance is available, we will always default to what we believe is the safest environment for our associates and customers."

Write to Stephanie Simon at stephanie.simon@wsj.com

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CDC Launches New Campaign Targeting Unsafe Injections

Media reports of outbreaks and infections caused by unsafe injection practices in healthcare facilities—especially in outpatient settings—seem to confirm the Centers for Disease Control and Prevention (CDC) statistics that since 1999, more than 125,000 U.S. patients have received letters alerting them of potential exposure to infection with hepatitis viruses or human immunodeficiency virus (HIV) due to unsafe injection practices such as the reuse of syringes.

And in a little more than a decade, the lack of adherence to safe injection practices by healthcare professionals has resulted in more than 30 outbreaks of viral hepatitis and other healthcare-acquired infections (HAIs) in the U.S. For example, a patient notification resulting from unsafe injection practices at an endoscopy clinic in Las Vegas in 2008 required health officials to alert more than 50,000 patients who had been potentially exposed to bloodborne pathogens. This patient notification, response and testing is estimated to have cost between $16 million and $21 million.

To address these alarming trends, the CDC and the Safe Injection Practices Coalition (SIPC) has launched the "One & Only Campaign," a public health initiative to help raise awareness among patients and healthcare providers about safe injection practices, and to eradicate outbreaks resulting from unsafe practices, including reusing single-use medical devices. According to organizers, the goal of the One & Only Campaign is to ensure patients are protected every time they receive a medical injection, and that this can be attained by empowering patients and re-educating healthcare professionals about safe injection practices. Creating and strengthening a culture of patient safety is critical, and campaign organizers emphasize that focus on the message behind the slogan, "One Needle, One Syringe, Only One Time" can be an important driver for proper clinical behavior during injections.

The campaign is currently being piloted in Nevada and New York, states that have experienced significant outbreaks linked to unsafe injection practices in recent years. Upon completion of these state pilot campaigns, the One & Only Campaign will expand to additional states and eventually nationwide, according to organizers. This effort is complimented by the launch of a new educational video from the SIPC for healthcare providers that imparts a 10-minute lesson on safe injection practices.

The video targets the educational needs of individuals who regularly administer or supervise injections; it addresses their responsibility to protect patients from HAIs and promotes evidence-based, common-sense safe injection practices from the CDC. The video demonstrates situations where injections are administered, and also dispels common misperceptions, such as the belief that it is safe to administer medication from single-dose vials to multiple patients. "One infection due to unsafe injection practices is unacceptable," says Michael Bell, MD, deputy director for infection control at CDC and narrator of the video. "Every healthcare provider has the responsibility to ensure that all injections given to patients are safe, and we hope that this video will help make that happen."

Helping to drive the campaign and appearing in the video is SIPC member Evelyn McKnight, AuD, president and co-founder of the Hepatitis Outbreaks National Organization for Reform (HONOReform) Foundation. McKnight was battling a recurrence of breast cancer when she became one of 99 Nebraska cancer patients to be infected with hepatitis C virus because healthcare professionals reused syringes to access a shared bag of saline.

"By addressing the urgent need for education and heightened awareness about safe injection practices, we hope to avoid further tragedies," says McKnight. "Through this and other Coalition-led educational activities, we hope to make outbreaks due to syringe reuse 'never' events. No patient should ever have to worry about contracting a disease while seeking medical care or treatment."

McKnight says that the most important message about safe injection practices that she wants healthcare providers to understand is that "It is never acceptable to reuse disposable medical equipment intended for one-time use (e.g., syringes, IV tubing, needles), even on the same patient," she says. The question is, do healthcare providers lack safe injection-practice knowledge or do they simple ignore protocol? "I believe that medical professionals were taught proper injection practices when they were in training but for a number of reasons (workload pressure, improper instruction by supervisors, etc) adopt shortcuts such as reusing syringes that endanger patients," McKnight says. "Healthcare professionals who reuse syringes may believe that because they have changed the needle, the injection is safe. They have not thought through the likelihood of contamination of the syringe."

McKnight says that key stakeholders can play an important role in promoting safe injection practices. "I encourage manufacturers to design injection systems that utilize safety design to eliminate human error from injection practices. And I encourage hospitals’ infection preventionists to provide proactive training to clinical staff on safe injection practices on a regular basis."

The SIPC points to recent investigations undertaken by state and local health departments and the CDC that have identified improper use of syringes, needles and medication vials during routine procedures such as administering injections. These practices have resulted in transmission of bloodborne viruses, including hepatitis C virus, to patients; notification of thousands of patients of possible exposure to bloodborne pathogens and recommendation that they be tested for hepatitis C virus (HCV), hepatitis B virus (HBV) and HIV; referral of providers to licensing boards for disciplinary action; and malpractice suits filed by patients.

The SIPC says these unfortunate events "serve as a reminder of the serious consequences of failure to maintain strict adherence to safe injection practices during patient care." The organization urges healthcare professionals to carefully review their infection control practices and should ensure that staff:

-- Never administer medications from the same syringe to more than one patient, even if the needle is changed

-- Do not enter a vial with a used syringe or needle

HCV, HBV and HIV can be spread from patient to patient when these simple precautions are not followed. Additional protection is offered when medication vials can be dedicated to a single patient. The SIPC reminds healthcare professionals it is critical that:

-- Medications packaged as single-use vials never be used for more than one patient

-- Medications packaged as multi-use vials be assigned to a single patient whenever possible

-- Bags or bottles of intravenous solution not be used as a common source of supply for more than one patient

-- Absolute adherence to proper infection control practices be maintained during the preparation and administration of injected medications

The SIPC has created free posters and brochures for use in healthcare institutions; visit www.oneandonlycampaign.org/.

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Continuing Battle Against HIV-AIDS

08-02-2010

The 18th International AIDS Conference saw a renewed global commitment to the HIV/AIDS response.

Opening session of the International AIDS Conference in Vienna Austria.
(Photo: AP)

The 18th International AIDS Conference convened in Vienna, Austria in late July, with 20,000 delegates meeting to discuss new ways to combat this scourge. Medical breakthroughs were discussed, such as a promising microbicide gel, which offers women a means to protect themselves even without the cooperation of their male partners. Women who used this gel in a trial reduced their risk of infection by up to 40 percent.

The delegates also found that the criminalization of drug abuse and persecution of homosexuals in many parts of the world, as well as the stigmatization of HIV/AIDS patients in general, are seriously undermining medical developments in the treatment and prevention of HIV/AIDS. These laws exclude high-risk groups from services and fuel further spread of the disease.

The discussion also focused on the global commitment to the HIV/AIDS response. The United States is the largest contributor to global AIDS programs through the President's Emergency Plan for AIDS Relief, or PEPFAR. And through the Global Health Initiative, which builds on PEPFAR, the United States is investing 63 billion $ over 6 years to help partner countries improve the health of their people through strengthened health systems.

U.S. President Barack Obama stated in a video message for the International AIDS Conference that he has "asked for increases to PEPFAR in both his budgets; 2011 being the largest PEPFAR budget to date. We’ve also embedded it in a comprehensive Global Health Initiative to help other countries improve health care, save lives and increase life expectancy."

"The Global Health Initiative has set clear goals to get this done. We’re going to double the number of babies born HIV-free, and work to prevent more than 12 million new infections. We’ll provide direct support to more than 4 million people on treatment. And we’ll help more than 12 million people – including 5 million children and orphans – get the care they need."

"Ending this pandemic won’t be easy, and it won’t happen overnight," said President Obama. "But thanks to you, we’ve come a long way – and the United States is committed to continuing that progress."

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Some Stem Cells Find it Hard to Forget

Induced pluripotent stem cells derived from blood cells.
Image courtesy of Kim et al., Nature.

August 2, 2010

Scientists have discovered why induced pluripotent stem cells—which many hope will replace the need for embryonic stem cells one day—don’t always function as well as the embryonic variety. The researchers also developed ways to get around the problem.

Embryonic stem cells have the ability to form virtually any cell type in the body and can grow indefinitely in the laboratory. Many scientists hope to learn how to harness the potential of these cells to repair tissues and organs. However, the cells have been controversial because isolating them entails destroying an early human embryo.

In recent years, researchers have developed 2 different ways of reprogramming adult cells to give them the properties of embryonic stem cells. One technique involves adding just 4 genes that convert adult cells into multipurpose stem cells called induced pluripotent stem (iPS) cells. The other technique entails transferring the nucleus—the compartment that contains the DNA—from an adult cell into an egg from which the original nucleus has been removed. The egg then reprograms the adult nucleus, enabling the isolation of pluripotent stem cells with the genetic makeup of the adult cell.

Learning how to guide any of these cells to different fates is a significant challenge for scientists. Reprogramming iPS cells into cells other than the type they were originally derived from is particularly inefficient. Two research teams—one led by Dr. George Q. Daley at Children's Hospital Boston, the other by Dr. Konrad Hochedlinger at Harvard University—worked independently to explore why iPS cells seem to retain a "memory" of their former states. Both teams were supported by NIH, the Howard Hughes Medical Institute and others. They coordinated joint publications on July 19, 2010, in the advance online editions of Nature (Daley) and Nature Biotechnology (Hochedlinger).

The teams looked for differences in methylation—a chemical modification to DNA that can affect gene expression. They discovered that genetically reprogrammed mouse iPS cells still have some residual DNA methylation reflecting their tissue of origin. The methylation patterns affect gene expression and restrict the ultimate fates of the cells.

Daley's team also discovered that, compared to genetically reprogrammed iPS cells, stem cells derived through nuclear transfer were more similar to embryonic stem cells in their methylation patterns and their ability to differentiate. Methylation, they concluded, is more effectively erased and reset by nuclear transfer.

The encouraging news is that the researchers discovered the memories of iPS cells could be reset—at least in part—either by growing the cell lines for long periods or by treating them with drugs that affect DNA methylation.

"The backdrop to this research is that a lot of people have the impression that iPS cells are the equivalent of embryonic stem cells," Daley says. "That has been used as an argument that we do not need to keep studying embryonic stem cells. But iPS cells often don’t function as well as embryonic cells, and our new research offers an explanation as to why that is the case."

The finding has other implications as well. Patient-specific iPS cells are a potentially valuable tool for studying diseases and developing therapies. "Any subtle differences you see in your patient-derived iPS cells could in fact be the result of not only the disease abnormality, but also the memory retained in the iPS cells," Hochedlinger explains. Researchers will need to learn how iPS cells derived from different cell types vary on a molecular level before they draw conclusions about the molecular mechanisms of disease.

—by Harrison Wein, Ph.D.

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What It Takes to Become a Living Donor

HEALTH JOURNAL
AUGUST 3, 2010

More than 3,000 people have signed up to be potential bone-marrow donors since word spread that 11-year-old Shannon Tavarez, one of the child stars of "The Lion King" on Broadway, needed a transplant to combat her acute myelogenous leukemia.


Hundreds more have joined bone-marrow registries in hopes of helping 22-year-old Mandi Schwartz, a Yale hockey player, 12-year-old Esther Persaud or 6-month-old Sophia Lopez, all of whom are battling leukemia.

If you're considering joining them, here's what you should know: signing up is simple, but a serious commitment. Donating is relatively painless, contrary to popular belief. And if the transplant succeeds, the results are astonishing.

A small amount of donated bone marrow—about 5% of the donor's total—can not only replenish a leukemia patient's diseased supply. The donated cells also seek out and destroy any remaining cancer cells and then keep growing, converting the recipient's blood type into the donor's type for the rest of his or her life.

The donor and the recipient must be a close genetic match, based on human leukocyte antigens (HLAs), which reflect parts of the immune system passed down from ancestors. Each of a patient's siblings has a 25% chance of being a compatible donor. In about 70% of cases, there is no one in the family who is a match, so patients and their doctors must turn to big international registries in hopes of finding someone who is. The Be the Match registry is the largest in the U.S., with more than 8 million samples. It links to other registries in the U.S. and overseas for a total of nearly 15 million possibilities.

For patients whose ancestors are Caucasians from northern Europe, Japanese and other areas that stayed homogenous for millennia, the chance of finding a close genetic match is more than 90%. It's only about 60% for patients with African, Hispanic or South Asian ancestors, since those groups are far more varied.

The odds are longer still for people of mixed racial backgrounds, like Broadway's Shannon Tavarese, who is half African-American and half Hispanic.

"That's why we need people of every race and mixture to join the registry," says Jeffrey Chell, chief executive officer of the National Marrow Donor Program, the nonprofit organization that runs the Be the Match Registry.


Signing Up

Joining a registry requires only a cheek swab and a health questionnaire. You must be between 18 to 55 years old and free of cancer, heart disease, hepatitis, epilepsy, HIV and other diseases. You can sign up at a local donor center or bone-marrow drive—many organizations sponsor them—or request a kit at www.marrow.org.

Once you join a registry, you are on it until you reach age 61, or ask to be removed.

If your cells are a match for a patient, you'll be asked to undergo tests to further assess your health and compatibility. There's no cost to the donor and travel expenses are reimbursed; but the tests and donation can be time-consuming.

These days, about 75% of bone-marrow transplants don't require actual bone-marrow. The donor's blood is circulated through a machine that filters out marrow-making cells called peripheral blood stem cells (PBSC), then the remaining blood is returned to the donor.

"It couldn't have been easier. I sat in a hospital bed for seven hours with a needle in one arm, and another needle in the other arm, and I could see the bag filling up with stem cells," says Caitlin Emma, 21, who joined a registry as a student at the University of Connecticut, and matched with a young leukemia patient last fall. "I felt a little light headed afterwards, but I went back to school the next day," she says.

Like all PBSC donors, she did have to get injections of a protein that stimulates marrow-growth daily for five days before the extraction, which causes flu-like symptoms.

So far, she only knows that the transplant was successful. There's a one-year confidentiality period in which donors and recipients are told very little about each other. After that, getting in touch is optional on both sides.

If a recipient requires traditional bone marrow, the donor is given either general or local anesthesia. Needles are inserted into the donor's pelvic bone in several spots to extract the liquid-like marrow inside. The procedure takes about two hours. The donor goes home the same day, and may feel like he's had a bad fall on the tailbone for several days.

"I was definitely sore. I spent a few days lying on the couch," says Stefanie Kienstra, who signed up at a campus blood drive at the University of Missouri in 2007, and matched a few months later with a 31-year-old man who had leukemia.

Meeting the Recipient

Once the one-year confidentiality period ended, the two started corresponding. They met for the first time in April at a gala hosted by DKMS, the New York-based donor center where Ms. Kienstra registered.

"I wouldn't be speaking to you today if Stefanie hadn't said, 'Sure, swab my cheek'," says the recipient, David Jolley of Seattle, who finished law school and took the bar exam last week.

The first potential donor for Mr. Jolley decided not to go through with the procedure at the last minute, something that happens occasionally. That's why donor registries ask that anyone who joins keep the registry informed of any changes in their health status, availability or address so they can be located quickly.

"Understand that when we call, the need might be urgent. The patient may have just a few weeks to live," Dr. Chell says.

In recent years, an additional source of bone-marrow transplants has emerged: the umbilical cords of newborn babies, typically discarded as medical waste.

Just two tablespoons of umbilical cord blood contains about one billion stem cells, which are so versatile they can be used to create bone marrow, as well as treating a variety of cancers and diseases. And they don't require as close a match between donor and recipient. Be the Match registry includes about 160,000 searchable cord blood units; patients often turn to those when no adult match can be found.

Donating a newborn's umbilical cord does not affect the mother, the baby or the delivery, but it does require some advance planning, since the cord must be preserved immediately after it is clamped and cut.

If the delivering hospital belongs to a public cord-blood program, the procedure is free. (For a list, see http://www.marrow.org/). If not, parents may still be able to donate, but may have to bear some costs themselves. Some obstetricians charge $150 for the procedure.

Donations to a public bank are anonymous. You'll never know when or if your baby's cord blood is used.

Parents can preserve their newborn's cord blood in a private bank in case the baby or another family member someday needs the cells for a bone-marrow transplant or other life-saving treatment. Researchers hope to one day use stem cells to treat Parkinson's, Alzheimer's and other devastating diseases. The initial cost to preserve cord blood is about $2,000, with about $200 a year for storage.

Write to Melinda Beck at HealthJournal@wsj.com

Source

New Role For Glypican-3 In Hepatocellular Carcinoma

Article Date: 03 Aug 2010 - 2:00 PDT

GPC3 is a member of the glypican family of glycosylphosphatidylinositol-anchored cell-surface heparan sulfate proteoglycans. GPC3 is highly expressed in HCC cells and tissues. It is thought that GPC3 joins a multiprotein complex, which is composed of the ligand, receptor, GPC3, and probably other proteins. However, little is known about the association of GPC3 expression with Wnt and other growth signaling molecules. Characterization of the association is necessary to better understand the potential role of GPC3 in HCC. This is the first study to report that GPC3, in conjunction with MMPs and growth signaling molecules, might play an important role in the progression of HCC.

The potential role of GPC3 in human HCC is receiving increasing attention. However, the association of GPC3 with growth signal molecules has not been systematically analyzed in HCC.

A research article published in the World Journal of Gastroenterology addresses this problem. The research team led by Dr. Hiroyuki Yamamoto of Sapporo Medical University revealed an association of GPC3 expression with MMPs and growth signaling molecules in HCC. Using real-time RT-PCR, immunoblotting, immunostaining, and siRNA-transfection, the research team analyzed the association of GPC3 expression with Wnt and other growth signaling molecules in HCC. GPC3 was overexpressed in most HCCs at mRNA and protein levels and its serum levels were significantly higher in patients with HCC than in non-HCC subjects. Altered expressions of various MMPs and growth signaling molecules, some of which were correlated with GPC3 expression, were observed in HCCs. Down-regulation of GPC3 expression by siRNA in GPC3-overexpressing HCC cell lines resulted in a significant decrease in expressions of MMP2, MMP14, FGFR1, IGF1R. GPC3 expression was significantly correlated with nuclear/cytoplasmic localization of β-catenin.

In the view of the authors, further studies are necessary to clarify the direct and/or indirect interactions between GPC3 and growth signaling molecules in HCC.

Considering the tumor specific expression pattern of GPC3 together with its oncogenic function, GPC3 could be an attractive target for molecular diagnosis and/or therapy in clinical settings.

Reference:
Akutsu N, Yamamoto H, Sasaki S, Taniguchi H, Arimura Y, Imai K, Shinomura Y. Association of glypican-3 expression with growth signaling molecules in hepatocellular carcinoma. World J Gastroenterol 2010; 16(28): 3521-3528

Source:
Lin Tian
World Journal of Gastroenterology

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