July 15, 2010

Mayo Clinic Health Letter Highlights MicroRNA -- A Switch that Determines Cell Behavior and Holds Answers on Disease, Prevention, Treatment

Posted : Thu, 15 Jul 2010 21:19:45 GMT
Author : Mayo Clinic
Category : Press Release
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ROCHESTER, Minn. - (Business Wire) Thousands of research studies are under way to better understand microRNA -- short for micro ribonucleic acid. These tiny genetic strands may play a role in identifying, treating and possibly preventing many diseases, according to the July issue of Mayo Clinic Health Letter.

MicroRNA acts like a switch that changes cell behavior. Different microRNAs are in each tissue of the body. For instance, what makes liver cells unique is, in part, their expression of a particular microRNA that influences which protein is produced.

About 1,000 distinct human microRNAs have been identified. Each can influence and regulate expression of hundreds of genes that determine a major change for the cell, such as whether it lives or dies, multiplies rapidly or develops into bone, muscle or another type of cell.

MicroRNA is a relatively new discovery. Scientists have been aware of its role for about 20 years, and there is still much to be learned. Scientists hope that microRNA research might eventually lead to improved diagnosis, more accurate predictions of disease outcomes and new treatment and medication options with fewer side effects.

Diseases being studied include:

•Heart failure -- MicroRNAs associated with this disease process may eventually tie into innovative therapeutic approaches.

•Alzheimer’s disease -- Studies have linked survival of brain cells (neurons) to their ability to produce microRNAs. Neurons incapable of doing so slowly die.

•Hepatitis C virus -- This virus “hijacks” certain microRNA to make copies of the virus within liver cells. Work is under way to develop a treatment that might keep the microRNA away from the virus.

•Schizophrenia -- Researchers are looking at possible associations between microRNA and this severe psychiatric disorder.

•Cancer -- Scientists have used microRNA to destroy liver cancer cells without harming healthy liver cells. Researchers have discovered a correlation between certain microRNAs and aggressive prostate cancer.

Mayo Clinic Health Letter is an eight-page monthly newsletter of reliable, accurate and practical information on today’s health and medical news. To subscribe, please call 1-800-333-9037 (toll-free), extension 9771, or visit www.HealthLetter.MayoClinic.com.


A sustained virologic response is durable in patients with chronic hepatitis C treated with peginterferon alfa-2a and ribavirin

Mark G. Swain, Ming-Yang Lai, Mitchell L. Shiffman, William G.E. Cooksley, Stefan Zeuzem, Douglas T. Dieterich, Armand Abergel, Mário G. Pessôa, Amy Lin, Andreas Tietz, Edward V. Connell, Moisés Diago

Received 25 January 2010; received in revised form 11 June 2010; accepted 8 July 2010. published online 15 July 2010.

Accepted Manuscript


Background & Aims:
A sustained virologic response (SVR) to therapy for Hepatitis C virus (HCV) infection is defined as the inability to detect HCV RNA 24 weeks after treatment has been completed. Although small studies have reported that the SVR is durable and lasts for long time periods, it has not been conclusively demonstrated.

The durability of treatment responses were examined in patients who were originally enrolled in 1 of 9 randomized, multicenter trials (n=1343). The study included patients who received peginterferon alfa-2a alone (n=166) or in combination with ribavirin (n=1077, including 79 patients with normal levels of alanine aminotransferase and 100 patients that were co-infected with HIV and HCV) and whose serum samples were negative for HCV RNA (<50 IU/mL) at their final assessment. Patients were assessed annually, from the date of last treatment, for a mean of 3.9 years (range 0.8–7.1).

Most patients (99.1%) that achieved an SVR had undetectable levels of HCV RNA in serum samples throughout the follow-up period. Serum samples from 0.9% of the patients contained HCV RNA after a mean period of 1.8 years (range 1.1–2.9 years) after treatment ended. It is not clear if these patients were re-infected or relapsed.

In a large cohort of patients monitored for the durability of a SVR, the SVR was maintained for almost 4 years after treatment with peginterferon alfa-2a alone or in combination with ribavirin. In patients with chronic hepatitis C infection, the SVR is durable and these patients should be considered as cured.

Keywords: PEGASYS, cure, safety analysis, clinical outcome

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


The Best Hospitals in the U.S.

Thursday, July 15, 2010

U.S. News & World Report has released its annual list of the best hospitals in the U.S. for 2010-11. So which hospital received the most points and ranked the highest in this year’s list? Once again, it’s Johns Hopkins Hospital in Baltimore, which has held the No. 1 spot for the last 20 years.

Out of nearly 5,000 hospitals reviewed, only 152 made the cut. Each of these hospitals appears in the rankings for at least one of the 16 specialties, ranging from cancer to diabetes to heart surgery.

Scores were based on objective and subjective measures such as death rates, patient safety, and reputation. U.S. News says it publishes the Best Hospitals list each year to help patients who need high-stakes care because of the complexity of their condition.

These 14 hospitals, in order by most points overall, made the “honor roll” list for ranking near the top in at least six of the specialties:

1. Johns Hopkins Hospital, Baltimore
2. Mayo Clinic, Rochester, Minn.
3. Massachusetts General Hospital, Boston
4. Cleveland Clinic
5. Ronald Reagan UCLA Medical Center, Los Angeles
6. New York-Presbyterian University Hospital of Columbia and Cornell
7. University of California, San Francisco Medical Center
8. Barnes-Jewish Hospital/Washington University, St. Louis
9. Hospital of the University of Pennsylvania, Philadelphia
10. Duke University Medical Center, Durham, N.C.
11. Brigham and Women’s Hospital, Boston
12. University of Washington Medical Center, Seattle
13. UPMC-University of Pittsburgh Medical Center
14. University of Michigan Hospitals and Health Centers, Ann Arbor

And here are the No. 1 hospitals in each specialty category:

• Cancer: University of Texas M.D. Anderson Cancer Center, Houston
• Diabetes & Endocrinology: Mayo Clinic, Rochester
• Ear, Nose & Throat: Johns Hopkins Hospital, Baltimore
• Gastroenterology: Mayo Clinic, Rochester
• Geriatrics: Mount Sinai Medical Center, New York
• Gynecology: Johns Hopkins Hospital, Baltimore
• Heart & Heart Surgery: Cleveland Clinic
• Kidney Disorders: Mayo Clinic, Rochester
• Neurology & Neurosurgery: Johns Hopkins Hospital, Baltimore
• Ophthalmology: Bascom Palmer Eye Institute at the University of Miami
• Orthopedics: Hospital for Special Surgery, New York
• Psychiatry: Massachusetts General Hospital, Boston
• Pulmonology: National Jewish Health, Denver
• Rehabilitation: Rehabilitation Institute of Chicago
• Rheumatology: Johns Hopkins Hospital, Baltimore
• Urology: Johns Hopkins Hospital, Baltimore

To see the entire list and a detailed description of the analysis in the specialties, visit the U.S. News website.

- Courtney Ware, WebMD


BMS HCV Study in Null Responders: 2 oral HCV Drugs Alone vs quad with peg/rbv plus 2 orals

'Study to Determine the Effectiveness of Antiviral Combination Therapy to Treat Hepatitis C Virus (HCV) Infected Patients Who Have Previously Failed Standard of Care' - HCV-Infected Genotype 1 Null responders to current standard of care

This study is currently recruiting participants.

Verified by Bristol-Myers Squibb, June 2010
First Received: November 12, 2009 Last Updated: June 29, 2010

Estimated Enrollment: 50
Study Start Date: December 2009
Estimated Study Completion Date: August 2012
Estimated Primary Completion Date: October 2011 (Final data collection date for primary outcome measure)


Ages Eligible for Study: 18 Years to 70 Years
Genders Eligible for Study: Both
Accepts Healthy Volunteers: No


Inclusion Criteria:

* Male and female subjects ages 18 to 70 years
* HCV-Infected Genotype 1 Null responders to current standard of care

Exclusion Criteria:

* Evidence of a medical condition associate with chronic liver disease other than HCV
* History of variceal bleeding, hepatic encephalopathy, or ascites requiring management with diuretics or paracentesis
* History of Cancer within 5 years of enrollment
* History of gastrointestinal disease or surgical procedure (except Cholecystectomy)
* History of clinically significant cardiac disease
* History of G6PD deficiency
* Documented cirrhosis within 12 months prior to dosing
* Positive for HIV or HBV
* Pregnant

Contacts and Locations
Please refer to this study by its ClinicalTrials.gov identifier: NCT01012895

Contact: For participation information at a USA site use a phone number below. For site information outside the USA please email: Clinical.Trials@bms.com Contact: First line of email MUST contain NCT# & Site#. Only trial sites that are recruiting have contact information at this time.


United States, California

Advanced Clinical Res Inst Recruiting
Anaheim, California, United States, 92801
Contact: Michael Demicco, Site 004 714-774-7777

Local Institution Not yet recruiting
San Jose, California, United States, 95128
Contact: Site 018

United States, Colorado

University Of Colorado Denver & Hospital Recruiting
Aurora, Colorado, United States, 80045
Contact: Gregory Everson, Site 007 303-724-1877

United States, Maryland

Local Institution Not yet recruiting
Baltimore, Maryland, United States, 21202
Contact: Site 014

United States, Massachusetts

Llc Dba The Research Institute Recruiting
Springfield, Massachusetts, United States, 01107
Contact: Claudia Martorell, Site 002 413-747-5566
United States, Michigan

University Of Michigan Health System Recruiting
Ann Arbor, Michigan, United States, 48109
Contact: Anna S. F. Lok, Site 009

United States, North Carolina

Charlotte Gastroenterology & Hepatology, Pllc Recruiting
Charlotte, North Carolina, United States, 28207
Contact: John S. Hanson, Site 016 704-375-9485

Carolinas Center For Liver Disease Recruiting
Statesville, North Carolina, United States, 28677
Contact: Robert W. Reindollar, Site 013 704-978-1144

United States, Texas

The Liver Institute At Methodist Dallas Recruiting
Dallas, Texas, United States, 75208
Contact: Reem H Ghalib, Site 012
Alamo Medical Research Recruiting

San Antonio, Texas, United States, 78215
Contact: Eric J. Lawitz, Site 003 210-253-3426

United States, Virginia

Metropolitan Research Recruiting
Fairfax, Virginia, United States, 22031
Contact: Vinod K. Rustgi, Site 010 703-698-9254

Sponsors and Collaborators
Bristol-Myers Squibb


Hepatitis C: viral and host factors associated with non-response to pegylated interferon plus ribavirin

Liver International
Early View (Articles online in advance of print)
Published Online: 14 Jul 2010
© 2010 John Wiley & Sons A/S

Tarik Asselah 1,2 , Emilie Estrabaud 1 , Ivan Bieche 3,4 , Martine Lapalus 1 , Simon De Muynck 1 , Michel Vidaud 3,4 , David Saadoun 5 , Vassili Soumelis 6 and Patrick Marcellin 1,2

1 INSERM, U773, Centre de Recherche Bichat-Beaujon CRB3, Paris, France
2 Service d'hépatologie, Hôpital Beaujon, Clichy, France
3 INSERM, U745, Université René Descartes, Paris, France
4 Service de Biochimie, Hôpital Beaujon, Clichy, France
5 Service de Médecine Interne, Hôpital Pitié-Salpétrière, Paris, France
6 INSERM U653, Institut Curie, Paris, France

Dr Tarik Asselah, Service d'Hépatologie, Hôpital Beaujon, 100 Bd du Gl Leclerc, 92110 Clichy, France
Tel: +33 1 4087 5579
Fax: +33 1 4730 9440
e-mail: tarik.asselah@bjn.aphp.fr

Re-use of this article is permitted in accordance with the Terms and Conditions set out at http://www3.interscience.wiley.com/authorresources/onlineopen.html


antiviral • boceprevir • immunity • interferon-stimulated genes • pegylated-interferon • polymerase inhibitors • protease inhibitors • STAT-C • sustained virological response • telaprevir


Treatment for chronic hepatitis C virus (HCV) infection has evolved considerably in the last years. The standard of care (SOC) for HCV infection consists in the combination of pegylated interferon (PEG-IFN) plus ribavirin. However, it only induces a sustained virological response (SVR) in half of genotype 1-infected patients. Several viral and host factors have been associated with non-response: steatosis, obesity, insulin resistance, age, male sex, ethnicity and genotypes. Many studies have demonstrated that in non-responders, some interferon-stimulated genes were upregulated before treatment. Those findings associated to clinical, biochemical and histological data may help detect responders before starting any treatment. This is a very important issue because the standard treatment is physically and economically demanding. The future of HCV treatment would probably consist in the addition of specifically targeted antiviral therapy for HCV such as protease and/or polymerase inhibitors to the SOC. In genotype 1 patients, very promising results have been reported when the protease inhibitor telaprevir or boceprevir is added to the SOC. It increases the SVR rates from approximately 50% (PEG-IFN plus ribavirin) to 70% (for patients treated with a combination of PEG-IFN plus ribavirin plus telaprevir). Different elements are associated with non-response: (i) viral factors, (ii) host factors and (iii) molecular mechanisms induced by HCV proteins to inhibit the IFN signalling pathway. The goal of this review is to present the mechanisms of non-response, to overcome it and to identify factors that can help to predict the response to anti-HCV therapy.

Received 24 August 2009
Accepted 30 April 2010
10.1111/j.1478-3231.2010.02283.x About DOI

Murphy: Let's recognize true heroes

Posted: July 14, 2010 - 4:44pm
Updated: July 15, 2010 - 3:18am

By mark e. murphy

I got an e-mail today from some friends in Oregon - an update on the health status of a courageous former patient appropriately named Grace.

A brilliant violinist who once played with the Savannah Symphony, Grace acquired hepatitis C as a result of a blood transfusion that she received after an emergency appendectomy when she was a child. She's had three liver transplants and numerous infectious complications, and has spent the better part of this year in the hospital.

No one would blame Grace if she were bitter; her health has consumed much of her spare time over the last 15 years. But Grace has a strong and indelible faith, and her outlook has always been positive. Her husband Mike said in the e-mail that Grace was "so looking forward to vitality."

After reading that e-mail, I clicked through the news online. There were people in Cleveland burning NBA star LeBron "King" James's jersey for going to the Miami Heat for roughly $100 million over five years. Another article criticized teen singer Miley Cyrus's "changed image."

Both Mr. James and Ms. Cyrus were all over the news this month.

"Miley is my hero," said one quoted teen. "People need to leave her alone."

"King James needs to do what's right for him," said a Heat fan. "He's making a heroic move to come here."

And right there, in a nutshell, is what is wrong with America.

We glorify our entertainers. We buy their music and watch their movies and buy tickets to their games because they amuse us, because they distract us from the crushing repetition of everyday life. And they get paid millions for providing that entertainment. People call them heroes.

But these people are not heroes. They distract us from what true heroism is.

Heroism is taking a risk with no expectation of reward. Many of our soldiers meet this definition of heroism - people like Richmond Hill's Capt. Matthew Freeman, who sacrificed his life in Afghanistan to protect the freedoms we all enjoy.

There is also the quiet heroism of perseverance, the maintenance of a positive outlook in the face of enormous adversity. My former patient Grace would give anything for her illness to simply leave her alone.

The mundane details of everyday life that we all take for granted are a blessed indulgence to her. It would be easy for Grace to wallow in self-pity, but she refuses to do so. Grace is a dedicated wife and mother who will not let a life-threatening illness deplete her spirit. We could all learn something from her example.

Modern politics could use a few heroes. Many of our nation's most courageous men and women have been in politics. Our nation's founders fought for our country's independence with the knowledge that they would be hanged as traitors if they lost. But today's Washington, D.C., is a desert of heroism.

Congressmen send our young men and women into battle in the Middle East while they squabble over the petty vagaries of party politics. Jefferson, Washington, Franklin and Adams would be appalled at the nest of vipers that the District of Columbia has become. Honor, altruism and self-sacrifice have evaporated as virtues; money, power and influence now motivate most of our political figures.

That's a sad statement about the transformation of our national value system. Over the last few decades, the American Dream has mutated into a preoccupation with hedonistic excess. We glorify those who represent that excessive lifestyle and elect politicians who we think can help us get the things we want. And that's not right.

America has historically been a land of opportunity - a place where a person who is honest and hard-working can realize their dreams no matter what their socioeconomic background. But our selfish preoccupation with material gain has cast us adrift from those things that made our country great.

We no longer recognize the importance of the journey itself - the inherent value of honesty or the intrinsic worth of simply doing a job well. The most essential values in life have very little to do with getting the next i-whatever or with which movie superstar is vacationing with whom.

We need to re-order our national priorities. It's time we learned who our true heroes are. Let's recognize those people who serve others first. Let's elect politicians guided by right instead of by might, politicians who understand the meaning of the phrase "public servant."

And let's say a prayer or two for people like Grace, who manifest heroism in the most beautiful and unassuming of ways.

Mark E. Murphy, M.D, is a Savannah physician and writer.


Huffington Post Provides Latest Anti-gene Patenting Soapbox

July 14, 2010
By Kevin E. Noonan --

The Internet over the past decade has given rise to a wide variety of "alternative media" outlets, including for example Slate, The Drudge Report, The Huffington Post, and arguably blogs like this one. Even conventional news outlets like The New York Times, The Washington Post, and The Wall Street Journal have exclusively on-line content. Despite the differences between these disparate sources, including writing by some non-traditional "journalists," news outlets of all stripes have many things in common. Unfortunately one of these is an uninformed antipathy to biotechnology, particularly with regard to gene patenting.

This similarity is evidenced most recently in The Huffington Post, in a piece entitled "Gene Patenting Produces Profits, Not Cures." The author, Harriet A. Washington (who also authored Deadly Monopolies; more on that later) writes that Myriad Genetics "predictably" appealed Judge Robert Sweet's decision invalidating fifteen claims in seven patents challenged by several breast cancer patients, medical associations, and researchers (and supported by the ACLU and the Public Patent Foundation). The piece is replete with misstatements concerning the scope of rights conferred by gene patents, such as that Biogen controls "your kidney's essential KIM gene" as well as a list of other genes patented by the University of California and other patent holders. Ms. Washington boldly asserts that the "coalition" challenging gene patents in the Myriad case may have too narrow an agenda, and proposes (conveniently, since her argument provides a précis of her "forthcoming book") that all "life patents" should be banned. These include "the more than 500,000 genes that control the most basic processes of human life," a stunning statement in view of the reality that there are only about 30,000-40,000 genes in the human genome. Setting her sights even higher than genes, she believes that patents on "bacteria, viruses, biologicals such as 'artificial blood', cell lines, tissues, pharmaceuticals, and even on medically important plants and animals such as Harvard's patented cancer-prone 'oncomouse'" should be banned. Why? Because "[t]he $60 billion pharmaceutical industry became the most profitable industry on the planet by exploiting its plethora of patents."

She sets forth a generally correct history of the development of the biotechnology industry. She mentions the Diamond v. Chakrabarty decision, and passage of the Bayh-Dole Act that encouraged universities to protect their inventions (instead of letting them fall into the public domain where they could be exploited by corporations, including foreign corporations, with no compensation to the university or its researchers). She also discusses the rise in university patenting, from about 260 patents/year prior to Bayh-Dole to more than 3,000 patents/year today. She also notes that "by 1991 [universities] had gleaned $218 million in royalties" (an amount certainly much higher today).

Where she begins to show her naïveté about how technology its transferred between academia and pharmaceutical companies is when she says that "corporations receive valuable, ready-made patents on medications, biologicals, genes, devices, plants and animal hybrids," which suggests that the technology transferred is ready to be commercially exploited solely as the result of federal grant support and "university brainpower." While necessary, these factors are woefully insufficient, at least because the FDA requires extensive safety and efficacy studies before any pharmaceutical comes on the market (protection it is unlikely Ms. Washington opposes).

Her argument seems to be that with all the patents and all the research, the public has received less than they were promised. She cites in support of this proposition that "[b]y 2003, North American university researchers had started 374 companies and academic institutions had completed 4,516 licensing arrangements earning them more than $1.3 billion" and that "[b]y 2006, university technology transfer offices had generated at least $45 billion, largely from licensing fees." The result, she maintains, is that universities have become research "satellites" rather than independent entities. This charge is, ironically, belied by the statistics on licensing, which illustrate how universities, due to their patent rights, are in the position to grant licenses to those companies committed to commercializing their inventions. Indeed, most such licenses have commercialization milestones and other provisions that, for example, change an exclusive license to a non-exclusive one (that can be licensed to another company) should the performance milestones not be met.

She repeats some oft-told tales, such as the purported pernicious effects of Chiron's hepatitis C virus test, and the company's failure to produce better treatment despite patents on isolated viral genes. She uses Chiron's lawsuit against a commercial infringer to allege that there was a "chilling effect on researchers who wish to work on better HCV treatments," but provides no evidence that Chiron has sued any basic (non-commercial) researcher working on HCV biology. This is similar to allegations in the Myriad suit that the company was inhibiting basic research, despite the >8,000 basic research papers easily found in PubMed and other databases.

Ms. Washington raises some real limitations to the Western medical research model, including that diseases prevalent in the undeveloped world (such as trypanosmiasis) have not been adequately addressed, and the inefficiencies in business models that require "blockbuster" drug status to support the incredible costs ($800 million - $1.2 billion) of bringing a drug to market. And she mentions John Moore's hairy cell leukemia, Henrietta Lack's vulval adenocarcinoma (HeLa) cells, and Canavan's disease patient samples as examples of corporate exploitation. On the contrary, all of these incidents occurred in a university setting, and the HeLa example occurred in the same time period that saw Jonas Salk perform experiments on his polio vaccine with retarded children from a nearby sanitorium, with precious little informed (or parental) consent.

What Ms. Washington refuses to acknowledge (because it doesn't support her argument) is the real benefits (or "cures") that biotechnology has provided over the past 30 years. Nowhere in her piece is there anything about the thousands (millions?) of heart attack patients whose lives have been saved by recombinant tPA (Genentech), or the thousands (millions?) of kidney disease patients leading relatively normal lives due to recombinant EPO (Amgen), or the thousands (millions?) of breast cancer patients treated with Herceptin® (Genentech), or colon cancer patients treated with Avastin® (Genentech) or macular degeneration patients whose eyesight has improved using Lucentis® (Genentech), not to mention the hundreds of other biotechnological drugs on the market or in development. No, these triumphs don't exist in the world Ms. Washington describes, which must make it easier for her to say:

Some argue that gene patents are necessary to generate the profits essential to funding the medical cures. But as the cases of breast cancer, hepatitis C and hemochromatosis illustrate, genes are more commonly used for faster, easier routes to profit, such as marketing tests, selling licenses and suing those patent-infringers who step on the corporation's biomedical toes.

The biotechnology industry is not without its inefficiencies, but failing to acknowledge the benefits along with the deficiencies makes it easier to set forth the portrayal contained in Ms. Washington's article. But doing so fails to describe "the rest of the story," and does a disservice to anyone wanting to understand the role of both universities and patenting in the biotechnology industry.

Also See: Gene Patenting Produces Profits, Not Cures

EGYPT: Liver cancer risk greatest for men

Millions of Egyptians living in slum areas are unable to afford medical treatment. Photo: Ben Hubbard/IRIN

CAIRO, 15 July 2010 (IRIN) - Hanging around a hospital lobby has become a daily pastime for 50-year-old labourer Ahmed Ismail. Every morning for the past few weeks the liver cancer sufferer has been going to al-Demerdash Hospital in Cairo in the hope of having his malignant hepatic tumour surgically removed.

“The hospital administrators asked me to get ready for the operation a long time ago. But each time I come, they tell me that my turn hasn’t come yet,” he told IRIN.

Ismail is one of hundreds of thousands of poor liver cancer patients contributing to ever-growing waiting lists for operations in hospitals around the country.

Egypt has one of the highest incidences of hepatitis C, one of the main causes of liver cancer, in the world, according to the World Health Organization (WHO).

“Infection with hepatitis C virus (HCV) is a major global health care problem. WHO estimates that up to 3 percent of the world’s population has been infected with the virus. The infection rate ranges from as low as 0.1 percent in Canada to the extremely high rate of 18.1 percent in Egypt,” said a WHO study published in April 2010.

Lack of funds

While the government’s allocation of 650 million Egyptian pounds (US$114 million) to liver diseases makes up 40 percent of the 1.5 billion pounds ($263 million) of health subsidies it provides, it is simply not enough specialists say.

Ashraf Omar, president of Egypt’s Liver Cancer Association, last week said the number of deaths resulting from liver cancer in the country had risen from 4 percent in 1993 to 11 percent in 2009.

“Hepatitis C is just one main reason for liver cancer,” Mohamed Fathi, a liver specialist from Ain Shams University, said. “The terrible thing is that the disease is on the increase. Studies say liver cancer will hit even more Egyptians 10 years from now.”

Fathi said between 500,000 and a million Egyptians would die in the coming few years because they could not pay for treatment. Other specialists said the figure would be even higher as many poor people die of liver cancer without ever knowing what condition they had.

In labourer Ismail’s case, he said it all started with a “terrible and immobilizing” pain in his side. “It took my breath away and made me collapse onto the floor. My wife advised me to go to a clinic to get treatment, thinking it would be a temporary pain.”

His local clinic referred him to a hospital in Cairo where doctors discovered after a series of scans that he had a liver tumour. “I almost fell to the ground from shock,” Ismail said. “I didn’t expect it to be so serious.”

Food contamination

A study by Amal Samy Ibrahim, a professor of epidemiology at Egypt’s National Cancer Institute, said food contamination, which is a major cause of liver cancer, is rampant in Egypt.

The study said grain storage methods were not controlled and there was a lack of awareness of the dangers of improper storage.

The enormity of liver cancer as a health hazard in Egypt is even clearer when compared with other countries. Ibrahim said that in her study statistics provided by the Middle East Cancer Consortium (MECC) showed that the liver was not a common organ for cancer, except in Egypt.

“Liver cancer’s relative frequency was below 2.0 percent in the other MECC countries,” said the study. “In Egypt, however, liver cancer accounted for 12.7 percent of male cancers, 3.4 percent of female cancers, and 8.1 percent of both sexes together.”

The study said a male predisposition to liver cancer was more marked in Egyptians, with a 3.8:1 male-to-female ratio. Cypriots were second with a 3.1:1 ratio, followed by Israeli Arabs, Jordanians and Israeli Jews with respective ratios of 3:1, 1.6:1 and 1.4:1.

Ismail hopes and prays he does not become another statistic: “I know that waiting means that the tumour can spread to other areas in my body,” he said. “But I must wait because I don’t have other options.”

Researchers examine human immune response to virus at the atomic level

July 15, 2010

A team of biochemists has identified the molecular mechanism by which an immune response is triggered by the invading viruses, according to recent research.

The results could eventually lead to new therapies for many different kinds of viral infections, from the common cold to hepatitis and AIDS, according to Dr. Pingwei Li, Texas A&M University's department of biochemistry and biophysics.

"This work provided insight into how our immune system recognizes viral RNA at the atomic level," Li said.

The results of the team's research were published on July 15 by Structure of Cell Press, said Li, who is one of a 10-member team, four of who are with Li's department.

In the last few years, Li's group studied an enzyme called "RIG-I" that senses the presence of foreign RNA and triggers an innate immune response.

Unlike an adaptive immune response, innate immune response gives immediate protection against infection. Adaptive immune responses are learned by the body -- or "taught" as with inoculation, Li said. But innate immunity is built right into the cell's genetic structure and is ready to respond whenever a pathogen invades the host.

The innate immune system can rapidly respond to an entirely novel virus or bacteriological threat, while the adaptive immune system has to go through a kind of learning process that may take weeks to be effective sometimes. Just as important, the adaptive immune system is coupled to innate immunity, Li said.

Because of this connection to immune response, learning exactly how RIG-I senses foreign viruses promises great rewards in treating a host of diseases, he said.

"It is a very exciting and hot topic among researchers these days," Li said. "A couple of labs were racing to figure out how RIG-I works, but our team was the first to show how RIG-I recognizes the terminal triophosphate of viral RNA. We determined the structure almost a year ago and the result was presented at the Keystone Symposium for Structural Biology early this year."

Viruses contain RNA, which are molecules similar to DNA in many ways but which play different roles. The RNA molecules from virus often have structures that do not exist in human RNA. RIG-I specifically targets these unique structures and launches an immune response by triggering the secretion of interferon, Li said

Interferons are proteins produced and released by the infected cells to fight pathogens such as viruses or bacteria.

But exactly what was the mechanism by which RIG-I triggers the antiviral immune responses? Though there were some clues offered by previous research, it was not clear how it worked at the molecular level, Li said.

Researchers knew, for example, that the RIG-I enzyme specifically targets the structural unit called "5' triphosphate," which is unique to viral RNA. Furthermore, it was known what a particular part of the RIG-I binds to the viral RNA.

"This crucial part is its 'C-terminal domain,' a small RNA binding module capable of recognizing RNA from many different kinds of viruses," he said.

To examine the molecular mechanism of viral RNA sensing by RIG-I, the team used human RIG-I C-terminal domain, and examined the binding action through several different techniques. First, they used gel-filtration chromatography to figure out what kind of RNA binds to RIG-I. Then, using surface plasmon resonance, a biosensor-based technonolgy, they examined how tightly RIG-I binds viral RNA and how fast it "gets on and gets off the enzyme," Li said.

Surface plasmon resonance uses a laser beam to detect molecular bindings, he said.

Next, the team used a sophisticated analytical tool called "X-ray crystallography" to determine the three-dimensional structure of RIG-I bound to viral RNA.

Much like CAT scan used in hospitals, X-ray crystallography uses an X-ray beam diffracted through a crystal to image the atomic structure of molecules.

"Using a series of X-ray diffraction patterns, a crystallographer produces a 3D image of a molecule," Li said. "The image shows how a protein looks and how it recognizes the other molecules such as proteins or RNA."

Li noted the structure and mechanisms described in the article concerned only a fragment of the RIG-I protein that is responsible for binding to viral RNA. The team is currently working to analyze the full-length protein to gain further insight into how RNA binding activates signaling by RIG-I.

Li received a $1.5 million grant from the National Institutes of Health early this year to continue the research on RIG-I, he said.

"The ultimate goal of this research is to understand how our immune system fights viral infections. Findings from this research will facilitate the development of novel antiviral and anticancer reagents and more effective vaccines."

Provided by Texas A&M AgriLife Communications


Novel biomarkers predict liver fibrosis in hepatitis C patients: alpha 2 macroglobulin, vitamin D binding protein and apolipoprotein AI

The gold standard of assessing liver fibrosis is liver biopsy, which is invasive and not without risk. Therefore, searching for noninvasive serologic biomarkers for liver fibrosis is an importantly clinical issue.

Methods: A total of 16 healthy volunteers and 45 patients with chronic hepatitis C virus (HCV) were enrolled (F0: n=16, F1: n=7, F2: n=17, F3: n=8 and F4: n=13, according to the METAVIR classification).

Three serum samples of each fibrotic stage were analyzed by two-dimension difference gel electrophoresis (2D-DIGE). The differential proteins were identified by the cooperation of MALDI-TOF/TOF and MASCOT; then western blotting and Bio-Plex Suspension Array were used to quantify the protein levels.

Results: Three prominent candidate biomarkers were identified: alpha 2 macroglobulin (A2M) is up regulated; vitamin D binding protein (VDBP) and apolipoprotein AI (ApoAI) are down regulated.

The serum concentration of A2M was significantly different among normal, mild (F1/F2) and advanced fibrosis (F3/F4) (p <0.01). The protein levels of VDBP and ApoAI were significantly higher in normal/mild fibrosis, when compared to those in advanced fibrosis (both p <0.01).

Conclusions: This study not only reveals three putative biomarkers of liver fibrosis (A2M, VDBP and ApoAI) but also proves the differential expressions of those markers in different stages of fibrosis.

We expect that combination of these novel biomarkers could be applied clinically to predict the stage of liver fibrosis without the need of liver biopsy.

Author: Ai-Sheng HoChun-Chia ChengShui-Cheng LeeMeng-Lun LiuJing-Ying LeeWen-Ming WangChia-Chi Wang

Credits/Source: Journal of Biomedical Science 2010, 17:58
Published on: 2010-07-15

Daily Checkup: Alcohol still risk, but viral hepatitis, fatty liver disease main causes of cirrhosis

BY Katie Charles
Friday, July 16th 2010, 4:00 AM

The specialist: Dr. Scott Friedman on cirrhosis
As the chief of the division of liver diseases at Mount Sinai, Scott Friedman is a hepatologist who does research on how scar tissue forms in the liver.

Who’s at risk
“Fibrosis” is a term doctors use to describe the scarring of the liver that builds up over time as the result of liver damage. “Over many years, that scarring progresses and culminates in cirrhosis, which refers to an end-stage fibrosis,” says Friedman. “By then, the blood flow through the liver is impaired, and liver function may be compromised.”

A healthy liver has many vital functions, like detoxifying the blood, synthesizing critical proteins and hormones, fighting off infection and metabolizing sugars, fats and proteins.

Advanced fibrosis and cirrhosis are major public-health concerns that dramatically increase your chance of developing liver cancer.

“Liver cancer is the fastest-rising cancer in the U.S. and the third-leading cause of cancer mortality worldwide,” says Friedman. “The bulk of patients with cirrhosis in this country have it from hepatitis B or C − about 5.3 million Americans are living with chronic viral hepatitis.”

The second-leading cause of fibrosis is called “fatty liver disease,” in which fat accumulates in the liver and eventually leads to scarring. “Obese patients often overlook the risk of liver damage,” says Friedman. “Obesity often goes hand in hand with metabolic syndrome, which is associated with elevated blood lipids and blood pressure, insulin resistance and pro-thrombotic and an inflammatory state.” Fatty liver disease often improves after weight-loss regimens like bariatric surgery.

The underlying cause for fibrosis can also be alcohol abuse or rarer conditions like autoimmune diseases of the liver. “Alcohol abuse is definitely a risk factor, but the vast majority of patients with fibrosis and cirrhosis don’t abuse alcohol,” says Friedman. The old association linking cirrhosis solely with alcohol abuse no longer holds true now that viral hepatitis and fatty liver disease are the two primary causes of fibrosis and cirrhosis.

Signs and symptoms
One of the challenges of diagnosing and treating liver disease is that it most often develops stealthily.

“The liver is so resilient that it can compensate for years of disease, and the patient may have no symptoms until the disease is very progressed,” says Friedman. “In reality, many patients have advanced fibrosis but have no symptoms.”

The very late manifestation of symptoms means that it is even more important to identify if people are at risk and screen them to catch the disease early.

“People at high risk of liver disease include Asian immigrants, who are more prone to hepatitis B, and patients with evidence of metabolic syndrome, who are at high risk of fatty liver disease,” says Friedman. Other risk factors for hepatitis include people who got blood transfusions before 1990 and people who engage in high-risk behavior like needle-sharing. Alcohol abuse is still a risk factor, even if it is no longer the most common underlying cause.

New evidence shows that simple blood tests can do an excellent job of identifying a patient’s risk of liver disease. “We screen for ALT − alanine aminotransferase − an enzyme that enters the bloodstream if the liver is damaged,” says Friedman. “An elevated ALT level without explanation merits followup.”

Traditional treatment
“We have no treatments approved to attack the scarring in the liver yet,” says Friedman. “But we have some excellent treatments for the underlying diseases.”

There are effective medical therapies for hepatitis B and C. “For hepatitis B, the main drugs are molecules that block the multiplication of the virus,” says Friedman. “The hepatitis C treatments are a combination of the drugs interferon and an immunomodulatory drug called ribavarin, which together boost the immune system to fight the virus.”

New drugs that attack the hepatitis C virus directly are expected to be available next year. For patients with fatty liver disease, weight-loss regimens also reduce liver damage. “Anything from diet and exercise and medications to bariatric surgery can have great results,” says Friedman.

If alcohol abuse is the underlying cause, patients are usually required to enroll in a 12-step rehab program.

Once the liver disease progresses to the point of impairing liver function, doctors treat the resulting symptoms. “We try to treat all the liver problems and screen for liver cancer,” says Friedman. “For select patients, liver transplantation may be necessary.”

But doctors hope they can help more patients control their liver damage before it gets to that point. “There is now evidence that if we treat the underlying liver disease, even cirrhosis is reversible,” says Friedman.

Doctors are making liver disease an increasingly manageable illness through prevention, early detection and the treatment of fibrosis before it progresses too far.

Research breakthroughs
Some of the most exciting liver disease research is being done at the molecular level.

In 1985, Friedman identified the cell type that’s responsible for the formation of scarring tissue.

“Basically, we’ve gone from uncovering [what] causes scar formation to soon being able to treat and prevent fibrosis with medication,” says Friedman. “Our hope is that if we develop new treatments for fibrosis, we’ll be able to prevent the development of cirrhosis.”

Questions for your doctor
Hepatitis is a major public health risk, so be proactive about asking your doctor, “Am I at risk of hepatitis?”

Follow up with, “Should I be vaccinated for hepatitis A and B?” Another good question is, “Do I have any risk factors for liver disease?” and “Is my ALT elevated?”

What you can do
  • Know your risk level. That means knowing the risk factors of liver disease — especially hepatitis and fatty liver disease — and knowing your ALT level. “If your ALT level is abnormal on even one reading, you should have it followed up,” says Dr. Scott Friedman.
  • Get informed.The American Liver Foundation has great patient information on support services and advocacy. See http://www.liverfoundation.org/.
  • See a specialist. “If there’s evidence of chronic liver disease based on virus or blood tests, see a liver specialist,” says Friedman.
  •  Support liver disease research. “It’s a terribly underfunded research area,” says Friedman, who recommends giving to the American Association for the Study of Liver Disease at http://www.aasld.org/.

Can antioxidant supplements be used for liver diseases?

 The Cochrane Hepato-Biliary Group investigates antioxidant supplements for liver diseases, as reported in the most recent issue of Alimentary Pharmacology & Therapeutics.

Several liver diseases have been associated with oxidative stress. Accordingly, antioxidants have been suggested as potential therapeutics for various liver diseases.

The evidence supporting these suggestions is equivocal.

Professor Bjelakovic and colleagues from Serbia assessed the benefits and harms of antioxidant supplements for patients with liver diseases.

The research team identified trials through electronic and manual searches until 2009.

The researchers included randomized trials comparing antioxidant supplements vs. placebo or no intervention for autoimmune liver diseases, viral hepatitis, alcoholic liver disease and cirrhosis.

Random-effects and fixed-effect meta-analyses were conducted.

The team identified 20 randomized trials with 1225 participants.

The trials assessed beta-carotene, vitamin A, vitamin C, vitamin E and selenium.

The majority of the trials had high risk of bias and showed heterogeneity.

Overall, the assessed antioxidant supplements had no significant effect on all-cause mortality or liver-related mortality.

Stratification according to the type of liver disease assessed did not affect the conclusions.

The researchers found that antioxidant supplements significantly increased the activity of gamma glutamyl transpeptidase.

Professor Bjelakovic's team concludes, "We found no evidence to support or refute antioxidant supplements in patients with liver disease."

"Antioxidant supplements may increase liver enzymes."

Aliment Pharmacol Ther 2010: 32(3): 356-67

15 July 2010


Imminent Launch of Small-molecule Antiviral Drugs Poised to Enhance Treatment Success Rates for Hepatitis C Patients, Finds Frost & Sullivan

SINGAPORE, July 15 /PRNewswire/ -- Efforts to raise disease awareness in the Philippines have increased the number of cases and patient pool available for hepatitis C treatment. Screening and detection efforts by the Red Cross as well as growing awareness in the Philippines have been largely responsible for the rise in the number of diagnosed cases. These campaigns have encouraged people, mostly from the urban areas, to opt for physical examinations that enable the detection of hepatitis C.

(Logo: http://photos.prnewswire.com/prnh/20081117/FSLOGO)

(Logo: http://www.newscom.com/cgi-bin/prnh/20081117/FSLOGO)

Physicians and key opinion leaders (KOLs) believe that the diagnosis rate will increase gradually, after the Philippine Government officially implements its hepatitis C program to spread awareness of the disease in the country. In the future, refined versions of current hepatitis C virus (HCV) drugs, oral formulations of small molecule inhibitors, and the new drug class known as protease inhibitors are expected to improve treatment success rates for patients and take the market forward.

New analysis from Frost & Sullivan (http://www.pharma.frost.com/), Multi-Client Study: Opportunities Assessment for the Hepatitis C Therapeutics Market in the Philippines, finds that the market earned revenues of $2.3 billion in 2007 and is expected to increase to approximately $4.5 billion by 2017, due to new drug launches occurring after 2010.

"The highest patient group for Hepatitis C in the Philippines is injecting drug users who share needles both for narcotic and therapeutic purposes," says Rhenu Bhuller, Global Vice President of Pharmaceuticals and Biotechnology at Frost & Sullivan. "Another patient group at risk for Hepatitis C includes those who receive blood products that may not have been screened properly; the latter is more of a concern in rural rather than urban areas in the country."

Although diagnosis rates have improved, there are impediments that are deterring market progression. Treatment of hepatitis C is restrained by the high cost of medication for patients who do not have health insurance. Combined with the known side effects, which include flu-like symptoms, neuropsychiatric disorders, and autoimmune syndromes, has resulted in lowered patient compliance.

The Philippines does not reimburse treatment for hepatitis C, and medical insurance companies do not allow reimbursement for these costs. In the Philippines, the cost of medicines is notably higher compared to other Asian countries and patients struggle to shoulder the cost of treatment. It is challenging for both urban and rural patients to afford the costly treatment for hepatitis C. Additionally, the intravenous mode of administration is viewed as inconvenient by many patients, resulting in lower compliance.

"As far as treatment modes are concerned, small molecule antivirals are dominating the pipeline at present since they have met with success in the treatment of other viral infections, such as hepatitis B and HIV," says Bhuller. "Several strategies are being explored in clinical trials, including add-on therapy to the current standard of care, interferon replacement, and ribavirin replacement."

To circumvent the bottlenecks in this market, companies must offer treatment options that expedite efficiency, have fewer side effects, and be reasonably priced. Patients should be made aware of their disease status as early as possible and be encouraged to remain compliant to treatment. Additionally, incentives must be provided to ensure compliance to HCV treatment. This will amplify the likelihood of future compliance, especially for improved treatments.

To educate at-risk patients, public and private organizations, including pharmaceutical companies, must increase efforts to spread awareness. Greater information outreach will help patients obtain the right mode of treatment and ultimately stem the onslaught of the HCV virus in the Philippines.

If you are interested in more information on this study, please send an e-mail to Nicklaus Au, Corporate Communications, at nicklaus.au@frost.com, with your full name, company name, title, telephone number, company e-mail address, company website, city, state and country.

Multi-Client Study: Opportunities Assessment for the Hepatitis C Therapeutics Market in the Philippines is part of the Pharmaceuticals & Biotechnology Growth Partnership Services program, which also includes research in the following markets: Opportunities Assessment of Hepatitis C Market in Taiwan, Opportunities Assessment of Hepatitis C in China, Opportunities Assessment of Hepatitis C in Indonesia, Opportunities Assessment of Hepatitis C in Singapore, Opportunities Assessment of Hepatitis C in Australia, Opportunities Assessment of Hepatitis C in Thailand, Opportunities Assessment of Hepatitis C in Hong Kong, Opportunities Assessment of Hepatitis C in India, Opportunities Assessment of Hepatitis C in Korea, and Opportunities Assessment of Hepatitis C in Malaysia. All research services included in subscriptions provide detailed market opportunities and industry trends that have been evaluated following extensive interviews with market participants.

About Frost & Sullivan

Frost & Sullivan, the Growth Partnership Company, enables clients to accelerate growth and achieve best-in-class positions in growth, innovation and leadership. The company's Growth Partnership Service provides the CEO and the CEO's Growth Team with disciplined research and best-practice models to drive the generation, evaluation, and implementation of powerful growth strategies. Frost & Sullivan leverages over 45 years of experience in partnering with Global 1000 companies, emerging businesses and the investment community from 40 offices on six continents. To join our Growth Partnership, please visit http://www.frost.com/.

Multi-Client Study: Opportunities Assessment for the Hepatitis C Therapeutics Market in the Philippines


Nicklaus Au
Corporate Communications – Asia Pacific
P: +603 6204 5836


Are We on the Verge of Gene-Based Personalized Treatment for Hepatitis C Virus Infection?

William F. Balistreri, MD
Authors and Disclosures
Posted: 07/14/2010

I've heard that it is now possible to predict which patients with chronic hepatitis C virus infection will respond to treatment -- is this true?

Response from William F. Balistreri, MD
Dorothy M.M. Kersten Professor of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio; Medical Director, Liver Transplantation Program, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio

Yes -- to an extent. As we learn more about the genetic and molecular mechanisms of liver injury and repair, we will be better able to predict response to treatment and therefore tailor the therapeutic strategy. This will be especially relevant to chronic hepatitis C virus (HCV) infection; it will permit us to direct treatment resources to the patients who are most likely to benefit.

Identification of the determinants of clearance and response to treatment in HCV Infection has been a high research priority. Recovery from HCV infection and the response to standard antiviral treatment depends on host factors, viral factors, and treatment (adherence) factors. The viremia in about 30% of people who acquire HCV infection will spontaneously resolve without long-term consequences.

Differences (eg, polymorphisms) in genes encoding cytokines and other immunologic mediators partially explain spontaneous recovery from HCV.[1,2] Similarly, marked differences are possible in the degree to which individuals with chronic HCV infection respond to treatment.[3]

The currently recommended treatment for chronic HCV infection is a 48-week course of pegylated-interferon alpha α alpha-2b) or PegIFN α alpha-2a combined with ribavirin. Like spontaneous clearance, treatment-related resolution of chronic hepatitis C is associated with clearance of viremia and reduction in the risk for long-term consequences of infection.[4] Differences in candidate genes are also found in patients who respond to treatment compared with so-called nonresponders.[5-7] Patients of European ancestry have a significantly higher probability of being cured than patients of African ancestry.

Rauch and colleagues performed a genome-wide association study to screen for host genetic determinants of HCV persistence and response to therapy.[8] They compared the frequency of approximately 500,000 single nucleotide polymorphisms (SNPs) in DNA from patients with spontaneous HCV resolution and patients with persistent infection. The strongest association with spontaneous recovery was detected for rs8099917, a SNP located nearest to interleukin 28B (IL28B), the gene that encodes for IFN lambda-3. Patients who are homozygous for C at rs12979860 have a >2.5-fold increased likelihood of spontaneous resolution of HCV compared with control patients who have persistent HCV infection.[9] The frequency of the minor G allele is over-represented among patients with chronic hepatitis C compared with those with spontaneous recovery; it is also overrepresented in the subset of patients with chronic infection who do not respond to PegIFN and ribavirin compared with those who achieve a sustained virologic response. Other groups have confirmed and expanded these observations.[10-12] The association of the IL28B locus with natural and treatment-associated control of HCV suggests the importance of innate immunity and IFN lambda-3 in the pathogenesis of HCV infection.

Ge and colleagues compared the frequencies of approximately 600,000 SNPs in DNA from patients with persistent HCV infection according to their response to PegIFN and ribavirin.[12] They reported that a genetic polymorphism near the IL28B gene was associated with a 2-fold change in response to treatment, among patients of European ancestry and those of African-American ancestry.[12] The C/C genotype, associated with a better response, is more frequent in European than African populations. This genetic polymorphism also explains much of the difference in response rates between black patients and patients of European ancestry. Patients who were homozygous for the T/T genotype were less likely to respond to treatment. Thus, the global distribution of the protective C/C allele correlates strongly with ethnic differences in spontaneous resolution of HCV and in treatment-related response.[12,13]

What functional mechanism underlies the IL28B response? HCV RNA triggers production of type 1 interferons by hepatocytes; these molecules stimulate transcription of interferon-stimulated genes (ISGs). Exogenous (therapeutic) interferon alpha signals similarly. Given that the polymorphism 3-kb upstream of IL28B appears to be associated with natural clearance as well as treatment response, it seems likely that the gene product is involved in the innate control of HCV. Indeed, IFN lambda has antiviral activity against genotype 1 HCV in vitro and in vivo.

Data presented at Digestive Disease Week 2010 further indicated that we can predict sustained virologic response on the basis of emerging validation of the genetic variation in regulation of the immune response to HCV.[13] The specific IL28B polymorphism (C/C, which occurs in up to 33% of patients) is strongly associated with reduced expression of intrahepatic ISGs and the response rate to PegIFN and ribavirin. Genetic variation in IL28B regulates the innate immune response to HCV in the liver, priming patients for a stronger response to exogenous IFN alpha therapy.[13]

Thus, at least 5 independent studies provide overwhelming genetic evidence for the role of IL-28B in the pathogenesis of HCV infection and in spontaneous and treatment-related recovery from HCV infection. Future studies will link these findings to improved, and perhaps personalized, HCV treatment and prevention worldwide.