Cancer journal: A happy birthday despite grim news

I don't usually post things like this, but after reading the strength and courage that this man has, I just had to share it. God Bless you Mike Celizic!

A day that begins with a fateful choice ends with a celebration

 
By Mike Celizic

TODAYshow.com contributor
updated 8/19/2010 12:45:22 PM ET

Journal

Editor's note: Mike Celizic is TODAYshow.com’s ace morning news reporter as well as a sports columnist for msnbc.com. He is renowned for his ability to write compelling, accurate stories at lightning speed, as well as for his trademark hat, which he never removes, even when appearing as a guest commentator on MSNBC.

Last year Mike was diagnosed with T-cell lymphoma. As a dyed-in-the-wool journalist, his first instinct was: Report on it. Thus he is sharing this cancer journal with TODAYshow.com and msnbc.com readers as he turns his reporting skills to his most difficult subject: his own mortality.

I’m dying.

The lymphoma we’d thought we’d beaten into remission back in May came roaring back last month. We threw some really nasty chemo at it. The cancer ate it up and came back for more.

And so I’m going to die, and not in four or five months. I’ve got probably a couple of halfway decent weeks left. Then the lymphoma will take over my bloodstream and kill me.

I don’t have to die that quickly. I could undergo months of brutal and debilitating chemo that will leave me racked by pain and barely in control of what few senses I have.

The chemo itself could kill me. And even if it didn’t, I wouldn’t have a single day when I’d feel even vaguely normal. I would then have to get a bone marrow transplant — if a match could be found. There’s about a 10 percent chance that I’d survive, and a smaller chance that I’d be cured.

Taking that chance might be worth it to some, but not to me.

The object isn’t to live as long as you can, but as well as you can. I’ve lived very well; had a grand and glorious life. I’ve done everything I’ve ever wanted to do except meet Al Roker. I’m not afraid to die. But I don’t want to die, and there’s the problem. I love life, love this glorious planet, love simple pleasures, love living.

The choice

I learned my situation Wednesday. I’ve spent a lot of the time since crying like Glenn Beck, only for real.

But there’s no other choice for me. It’s about controlling what life I have left. Enter treatment, and you surrender all control for a tiny chance of survival at a diminished capacity.

I already tried that. I’m not going to do it again.

So I’ve made the most personal decision I ever will make. It’s taken every ounce of my courage and 40 years of philosophizing and thinking and reading and traveling and learning to make. The easy choice would have been to go into chemo. For me, it would also be the wrong choice.

I’m writing this because I owe it to all the wonderful people who started reading the blog I started when I began treatment for lymphoma last year. It was called “Adventures in Cancerland.” I wrote two really swell entries, I say with no modesty at all, full of insight and humor and perspective.

Related: Adventures in Cancerland, Part 1 — The diagnosis

Related: Adventures in Cancerland, Part 2 — Lust for life

Then I quit.

Sorry about that. It wasn’t that I didn’t want to write; it was just that I was waiting for an adventure, and one never presented itself. Getting treated for lymphoma turned out to be as tedious as picking cat hairs off a cashmere coat. It was not exciting. The painful parts weren’t that painful. Nothing gruesome happened.

I left the hospital in December, spent three months in isolation at home, and was cleared to return to real life. Sometime in May, I was officially in remission.\

But it didn’t last long. The cancer came back in July, and this time it’s not messing around.

My oncologist, Dr. Ariela Noy, came into my room early Wednesday here at Memorial Sloan-Kettering Cancer Center in New York City. She’s an extraordinary doctor and person; tenacious, dedicated, talented, caring — name a quality you want in a doctor, and she’s got it.

It was my birthday, and she fidgeted as she told me the situation. We’d talked about this scenario, and she wasn’t surprised at my choice. I did promise to sleep on it, and then we had a good hug and cry. (I’m not usually given to crying, but this has opened the floodgates.)

I called my wife and told her. I promised to sleep on it, and she promised to come in today to collect me and my belongings.

Birthday contraband

I sent some e-mails to some close friends. One, Joe, e-mailed telling me to hide the nurses and be ready for an 11:30 a.m. visit. He showed up with major contraband: a huge bacon cheeseburger with wedge fries, an ice-cold Corona and cups and plates. My nurse, who should probably remain nameless, thought it was pretty funny.

I could only manage about four sips of beer, but the first one was the most perfect beer experience of my life. After six weeks without one, the hops exploded on my palate. There was barley, a perfect, cold crispness; it was the best beer I’d ever tasted.

It was the same for the burger. Juicy goodness with bacon and tomato and lettuce, salt and pepper. I only managed about five bites, but after three weeks of pudding cups, I was in heaven.

We went up to the 15th-floor terrace to sit in the sun. I smelled cigarette smoke — a good smell for me — and it was coming from a cancer patient in the farthest corner. I had given up smoking when I was first diagnosed a year ago, but there’s no point to that now, so I bummed a smoke.

For a day that started out with “You’re going to die,” this was turning out all right.

I went back to my room, Joe went back to work, my nurse grinned at her naughty boy. About an hour later, she came back in carrying a birthday cake, leading all the nurses and aides on the floor as they sang “Happy Birthday” to me.

I totally lost it. When she came back later with a bunch of birthday balloons, I was reduced to a soggy mess.

When I could talk, I told my nurse friends, “This is one of the best days of my life.”

I never thought I’d say that about the day I learned I would die, but it’s the absolute truth. The big things are great and memorable, but it’s the little, unexpected pleasures that make life so wonderful.

I’m going to miss it. Terribly.

© 2010 MSNBC Interactive

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Continuing Our Commitment to Prioritizing HIV/AIDS

Policy
August 20, 2010

By Jeffrey S. Crowley, M.P.H., Director, Office of National AIDS Policy (Cross-posted from the Office of National AIDS Policy Blog)

Today, the Obama Administration is taking new action to prioritize support for Federal HIV/AIDS prevention and care programs. We are sending to the Congress an amendment to the President’s FY 2011 budget request to increase HIV/AIDS funding by $65 million. This is comprised of a requested $35 million increase for HIV prevention in order to continue exciting new HIV prevention activities described below to support the National HIV/AIDS Strategy and a $30 million increase for State AIDS drug assistance programs to respond to the ongoing crisis States are facing in operating these essential programs. These resources come on top of proposed increases for HIV prevention and care at the Centers for Disease Control and Prevention (CDC) and the Health Resources and Services Administration (HRSA) that were included in the original budget submission. Ultimately, the Congress will enact a budget that will establish Federal funding levels for the fiscal year that begins on October 1st.

Last month, the Obama Administration released the National HIV/AIDS Strategy. This was the product of a robust dialogue with the HIV community and other members of the public and identifies a small set of priority action steps for moving the Nation forward in responding to the domestic HIV epidemic. On the evening of July 13th, the President hosted a reception for the HIV community at the White House where he spoke about the Strategy and his commitment to fighting HIV/AIDS. He said the following,

Now, I know that this strategy comes at a difficult time for Americans living with HIV/AIDS, because we’ve got cash-strapped States who are being forced to cut back on essentials, including assistance for AIDS drugs. I know the need is great. And that’s why we’ve increased Federal assistance each year that I’ve been in office, providing an emergency supplement this year to help people get the drugs they need, even as we pursue a national strategy that focuses on three central goals.

We recognize that times are tough and there are significant challenges faced by people living with HIV/AIDS and other Americans that must be addressed. The Federal government cannot tackle these problems alone, but we can do our part.

In the current fiscal year, FY2010, Congress appropriated funding of $835 million for the AIDS Drug Assistance Program (ADAP). In July, due to the serious shortfalls in State ADAPs resulting largely from State cutbacks, HHS Secretary Sebelius took an emergency step by re-allocating $25 million for ADAPs for a total of $860 million. Our FY 2011 budget request had included increased ADAP funding, but today’s proposed $30 million increase would continue funding in FY 2011 for the emergency supplemental funds announced last month. If the Congress follows our recommendation, Federal funding for ADAPs would rise to $885 million next year—a $50 million increase from the level appropriated by Congress for this year. This action, alone, will not resolve the challenges faced by ADAPs. We need States to continue to prioritize their funding for ADAPs even in these difficult times, and we need our pharmaceutical company partners, businesses, foundations, and community-based organizations to do their part as well.

On the issue of HIV prevention, Secretary Sebelius announced new investments in HIV prevention when we released the National HIV/AIDS Strategy. To ensure that these initiatives continue, we are requesting $35 million in additional funds for next year. In FY 2010, these resources are supporting:

• Comprehensive HIV prevention ($11.6 million): This will fund the implementation and evaluation of effective combinations of behavioral and biomedical prevention interventions in the highest prevalence jurisdictions. These jurisdictions will compete to scale-up effective comprehensive approaches in subsequent years. The funding opportunity announcement (FOA) for this initiative is available on Grants.gov. Be sure to type “CDC-RFA-PS10-10181” as the Funding Opportunity Number to download the FOA.

• Increased testing and linkage to care ($4.4 million): Building on CDC’s new Expanded Testing Initiative, these funds will ensure that resources are provided to support targeted testing and linkage services for high prevalence communities, including Black, Latino, injection drug using (IDU), and gay male communities.

• Expanded HIV surveillance ($5.5 million): This will support work with jurisdictions to ensure that all jurisdictions report CD4 cell counts and viral loads to the public health surveillance system, enable jurisdictions to estimate community viral load, and take other steps to improve the surveillance system.

• Consultation, evaluation, technical support and annual MSM survey ($6.5 million): These resources will support evaluation and monitoring, assisting with developing and implementing new activities and conducting an annual internet survey for men who have sex with men (MSM) to collect behavioral, HIV testing, and other information.

• HIV, viral hepatitis, STD prevention and sexual health promotion with Tribal Communities ($1 million): CDC will partner with the Indian Health Service (IHS) to work with Tribal communities on prevention and health promotion.

These activities reflect a new direction that we believe will have a greater impact at lowering the number of new HIV infections in the United States.

Today’s announcement demonstrates that we are committed to implementing the National HIV/AIDS Strategy and ensuring that necessary investments in prevention and care services for people living with HIV continue.

Source

Drug addicts: criminals or patients?

Lynda Moyo reports on the pipe dream of decriminalising drugs

Date Published: 20/08/2010 12:32:12

In the same week Phil Mitchell went from meat-head to crack-head in Eastenders, British Medical Journal (BMJ) writer Stephen Rolles - along with the backing of distinguished outing physician, Professor Sir Ian Gilmore - has suggested we’re fighting a losing battle against the war on drugs in the UK.

Rolles clams we need to end the criminalisation of drugs and instead set up regulatory models that will control drug markets and reduce the health and social harms caused by current policy.

He said: ‘Evidence is mounting that this policy has not only exacerbated many public health problems, such as adulterated drugs and the spread of HIV and hepatitis B and C infection among injecting drug users, but has created a much larger set of secondary harms associated with the criminal market.’

Professor Gilmore is the president of the Royal College of Physicians (RCP). He seconded Rolles’ article by sending a scathing email to the RCP’s 25,000 members. Deemed as controversial to some, the email not only detailed the war on drugs from a health perspective, but also outlined how changes to drug laws could reduce crime. Speaking to the BBC, Gilmore said the present policy of prohibition ‘is not a success', citing his experience working as a liver specialist as a major cause for concern.

"Every day in our hospital wards we see drug addicts with infections from dirty needles; we see heroin addicts with complications from contaminated drugs," he said. He argued that many of the problems health staff encountered were the consequences of prohibition, not drugs, endorsing a BMJ article titled An alternative to the war on drugs.

Phil Mitchell's story is part of a bigger picture

The Home Office has restated its position on drugs, following the BMJ report and Gilmore’s call for a review of the law. A spokesperson said: “Drugs such as heroin, cocaine and cannabis are extremely harmful and can cause misery to communities across the country.

“The government does not believe that decriminalisation is the right approach. Our priorities are clear; we want to reduce drug use, crack down on drug-related crime and disorder and help addicts come off drugs for good.”

Opinion is clearly mixed on the issue. Those against decriminalisation believe legalising drugs would simply result in a lot more people taking them, whilst those in favour often refer to the success of decriminalisation in other European countries. In Portugal, changes to the law in 2001 led to a cut in overdoses and a fall in the number of young users.

It’s certainly provided a talking point over what appear to be a growing problem in the UK. Police revealed this week that more than 6,800 cannabis farms and factories were discovered in the UK last year alone. They also reported that cannabis growers are often involved in other crimes, ranging from counterfeiting currency and money laundering to firearms, prostitution, and people trafficking.

Whilst it may be unpleasant to think of drug users and the associated health and crime implications, the problem isn’t going away.

As Eastenders actress Tanya Franks said, in response to viewer complaints about the Phil Mitchell storyline: "I wasn't surprised that people complained because it's pushed a boundary. But in my opinion, the good that comes from storylines like this far outweighs whatever concerns people might have. We shouldn't shy away from it."

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A new opportunity for hepatitis C research

The hepatitis C virus is highly specialised. We humans are its natural hosts. The only other living organisms that could be infected with the hepatitis C virus in the lab are chimpanzees. Nevertheless it is – from the viewpoint of the virus – highly successful: around 170 million people are chronically infected with the virus. And with the chronic infection the risk of developing liver cancer also increases.
Researchers worldwide are working to develop vaccines and medication to combat the virus. The problem is that although they are able to research in liver cell cultures, when they want to find out how the immune system controls an infection or whether possible vaccines are effective research comes up against a brick wall: tests at such an early stage are unthinkable for humans or chimpanzees.

At TWINCORE researchers are now adapting the HCV to mice, thus enabling immunologists and vaccine researchers to take the next steps against this illness in the future. Because the immune system of mice is very similar to that of humans and it is only when vaccines are successful and safe in animal experiments that researchers can take the risk of transferring them to humans.

The fact that HCV can only infect humans and chimpanzees is partly down to the highly complicated mechanism with which it accesses the cell. The virus has to first bind four different molecules on the surface of our liver cells. This triggers a mechanism in our cells that transports the virus into the liver cells. “Mice also have these receptors on their liver cells in principle,” says scientist Julia Bitzegeio of the Department of Experimental Virology at TWINCORE, “however, they do not fit those on the surface of the virus.”

The two molecules that cause particular difficulty are called CD81 and occludin – these need to be human, otherwise the virus has no chance of infecting the cell. To make the HCV “mouse-capable” the researchers resorted to a trick: they have removed the CD81 receptor from human liver cells and replaced it with mouse CD81. In an electrical field they then tore tiny holes in the cell membrane before inserting the HC virus artificially through these holes. “The virus reproduced inside the cells and we repeatedly inserted the virus into the altered liver cells,” explains Julia Bitzegeio. This led to the highly transformable virus gradually changing until it was able to penetrate the cells with mouse CD81 receptor even without assistance.

“In this selection process the surface of the virus altered so much that it continued to infect human cells very quickly, but also simple mouse cells containing the four mouse variants of the HCV receptors,” says Research Group Leader Professor Thomas Pietschmann. The mouse-adapted virus is able to penetrate the mouse cells; however, the human specialisation of the HC virus is so high that it is unable to reproduce in the cells. “Successful infiltration is the first step towards a new small animal model, one that is urgently required for immunological investigations and the development of vaccines against HCV.”

Source : Helmholtz Association of German Research Centres

Source: BiologyNews – Microbiology

Source

AIDS virus changes in semen make it different than in blood

Scanning electron micrograph of HIV-1 budding from cultured lymphocyte. Image source: Centers for Disease Control & Prevention.

The new findings are significant because the nature of the virus in the male genital tract is of central importance to understanding the transmission process and the selective pressures that may impact the transmitted virus.

Media contacts: Leslie Lang (919) 966-9366, llang@med.unc.edu or Tom Hughes (919) 966-6047 or tahughes@unch.unc.edu

Embargoed until 5 p.m. EDT Thursday, August 19, 2010

CHAPEL HILL – The virus that causes AIDS may undergo changes in the genital tract that make HIV-1 in semen different than what it is in the blood, according to a study led by researchers from the University of North Carolina at Chapel Hill.

Worldwide much of the transmission of HIV-1 is through sexual contact, men being the transmitting partner in a majority of cases. The new findings are significant because the nature of the virus in the male genital tract is of central importance to understanding the transmission process and the selective pressures that may impact the transmitted virus. Ultimately it is the transmitted virus that must be blocked by a vaccine or microbicide.

“If everything we know about HIV is based on the virus that is in the blood, when in fact the virus in the semen can evolve to be different, it may be that we have an incomplete view of what is going on in the transmission of the virus,” said senior study author Ronald Swanstrom, PhD, professor of biochemistry and biophysics and of microbiology and immunology at the UNC School of Medicine.

The results of his research appear August 19, 2010 in the online journal PLoS Pathogens.

In the study, Swanstrom and his colleagues compared viral populations in blood and semen samples collected from 16 men with chronic HIV-1 infection. Using an expensive and labor-intensive laboratory technique called single genome sequencing, they analyzed the gene coding for the major surface protein of the virus -- called envelope or Env – in the samples. The differences between the viruses from the two sources were striking.

“The sequence differences between the blood and the semen were like a flashing red light, it was a big hint about the biology of virus in the seminal tract” said Swanstrom. “When we looked at sequences in the blood, we hardly found any that were the same, it was a very complex and diverse population. But when we looked in the semen, suddenly we were getting the same sequence over and over again.”

They found two mechanisms that significantly altered the viral population in the semen, which they called clonal amplification and compartmentalization. In the first, one to several viruses are rapidly expanded over a short period of time such that the viral population is relatively homogeneous (compared to the complex population in the blood). In the second, the virus replicates in T cells in the seminal tract over a long period of time, creating a separate population of virus that is both complex and distinct from the virus in the blood.

To begin to answer why these mechanisms are at play, the researchers measured the levels of 19 cytokines and chemokines in the blood and semen samples. They discovered a significant concentration of these immune system modulators in the semen relative to the blood, which could boost viral replication by creating an environment where target cells are kept in an activated state.

Swanstrom’s laboratory is now exploring whether evolutionary selection for some special property of the virus is occurring in the seminal tract that does not happen in the blood. Knowing how the virus in the semen is different is an important part of understanding the HIV transmission puzzle.

The UNC research was funded by the National Institutes of Health in the context of the Center for HIV/AIDS Immunology (CHAVI). Study co-authors include Jeffrey A. Anderson, Li-Hua Ping, Oliver Dibben, Cassandra Jibara, Leslie Arney, Laura Kinser, Yuyang Tang, Marcia Hobbs, Irving Hoffman, Peter Kazembe, Corbin D. Jones, Persephone Borrow, Susan Fiscus and Myron S. Cohen. Volunteers participating in this study were attending the Kamuzu Central Hospital and the UNC Project in Lilongwe, Malawi.
 
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Researchers Identify Two FDA Approved Drugs That May Fight HIV

ScienceDaily (Aug. 20, 2010) — Researchers at the University of Minnesota Academic Health Center have identified two drugs that, when combined, may serve as an effective treatment for HIV.

The two drugs, decitabine and gemcitabine -- both FDA approved and currently used in pre-cancer and cancer therapy -- were found to eliminate HIV infection in the mouse model by causing the virus to mutate itself to death -- an outcome researchers dubbed "lethal mutagenesis."

This is a landmark finding in HIV research because it is the first time this novel approach has been used to attack the deadly virus without causing toxic side effects. Because decitabine and gemcitabine are already FDA approved, researchers believe that if their research is effective in large animal models, it will be much easier to expedite the development of the drugs for human use.

The study is a collaboration between molecular virologists Louis Mansky, Ph.D., and Christine Clouser, Ph.D., of the Institute for Molecular Virology and School of Dentistry, as well as medicinal chemist Steven Patterson, Ph.D., from the Center for Drug Design. The findings were recently published online in the Journal of Virology.

"The findings provide hope that such an approach will someday help the 33 million people worldwide who currently live with HIV," Mansky said.

Lethal mutagenesis

HIV mutates and evolves quickly. Rather than inhibiting virus growth and replication like current HIV drugs, this new drug combination forces the virus to do just the opposite -- evolve beyond control, to the point of extinction.

"HIV's ability to mutate makes it difficult to target and treat," Mansky said. "We wanted to take advantage of this behavior by stimulating HIV's mutation rate, essentially using the virus as a weapon against itself."

Drug repositioning

One way to decrease cost and expedite the development of novel drugs is by the use of drug repositioning, the process of taking a drug that is used to treat one medical condition, and using it to treat a different illness.

By examining drugs that are already approved by the Food and Drug Administration, the researchers hope to expedite the development of this drug combination because the safety profiles of the two drugs are known.

U of M researchers found that the drug concentrations needed to eliminate HIV infection cause no measureable cell toxicity and were effective against HIV cultures at concentrations well below the current levels used for cancer treatment.

The path ahead

Gemcitabine and decitabine have been administered in pre-clinical trials with mice. Initial findings confirm that the drugs are an effective antiviral therapy for HIV.

The researchers are now in the process of modifying the drugs to forms that can be absorbed by the human body when taken orally.

The study was funded by the Center for Drug Design, Academic Health Center and the National Institutes of Health.

Source

Cells' demise provides clues about cancer

Derek Parker From: The Australian
August 21, 2010

APOPTOSIS may sound like an unfortunate malady.

In fact, it may be the secret to understanding the development of cancer and devising better cancer therapies.

Ultimately, it may provide an alternative to invasive surgery or debilitating chemotherapy.

Research into apoptosis is taking place worldwide, with several large drug companies pouring money into the area, but critical work is being undertaken in Australia.

"The key is to look at how cancer cells differ from healthy cells," says Andreas Strasser, of the molecular genetics of cancer division at Melbourne's Walter and Eliza Hall Institute.

"We need to understand how cells function and, even more importantly, how they die.

"Apoptosis is the study of programmed cell death and it is taking us into very promising areas of research, including towards a whole new generation of anti-cancer drugs."

All healthy cells in the body have genes that can cause or program them to die. Cell suicide and replenishment are crucial to all living organisms and play critical roles in the body's development even before birth.

But many cancer cells can override or ignore their programmed death machinery. They grow, mutate and multiply at a rate enabling them to take over and eventually destroy their host.

There's also good evidence that subversion of the cell death machinery is necessary for the transformation of normal cells into cancer cells.

Although the principle of apoptosis was recognised in the 19th century, much of the fundamental work in translating the idea into possible therapies can be traced to a 1988 paper published by WEHI researchers David Vaux, Suzanne Cory and Jerry Adams.

They showed that a cancer-causing gene, Bcl-2, inhibits apoptosis. The finding was the critical breakthrough in the field.

Little wonder that as a postdoctoral researcher Strasser was excited by the opportunity to continue the work. And followed up the research in a 1990 paper he co-authored with Alan Harris and Cory. It demonstrated that blocking apoptosis in mice could cause cancer. It also revealed that combined abnormalities in cell death and the control of cell division co-operated in tumour development.

"The field of cancer biology has come to the realisation that a cancer is caused by a string of abnormalities, maybe five or six, in critical cellular processes, including a lack of cell death," he says. "If we can reliably overcome or restore one or even several of the processes in that string, it would be a major advance for cancer therapy."

Strasser's WEHI team recently announced findings that could lead to a new class of anti-cancer drugs.

"Until now, everybody believed that a failure of damaged cells to undergo suicide allowed mutated cells to proliferate, which contributes to tumour development," he says. "That's certainly true, but we discovered that, in certain settings, the opposite can also hold, that the body's natural cell-suicide program can fuel tumour development."

Specifically, their experiments with mice showed this could happen if cellular DNA was damaged, say, by repeated exposure to low doses of radiation. When the body attempts to replace the damaged tissue it drives tumour development because the damaged cells will divide quickly, promoting tumour development.

The critical issue, Strasser notes, is whether a gene called Puma is present. His group found that if mice with the Puma gene were given a low dose of radiation it destroyed about 80 per cent of the mature white blood cells.

This means stem cells in the bone marrow must work extra hard to replace the white cells, many of which may themselves be damaged. The result: leukaemia, cancer of the blood or bone marrow.

"The surprise was that mice that don't carry the Puma gene are fully protected from this type of tumour development," says Strasser. "Puma is essential for the death of cells that have damaged DNA. If mice don't have the Puma gene when they receive low doses of radiation the white blood cells aren't destroyed, so they don't force stem cells to become activated to replenish the blood system."

This suggests the risk of cancer is increased in people who experience cycles of tissue destruction followed by tissue repopulation by stem cells. Such a process may account for the liver cancers frequently associated with viral infections, such as hepatitis C, or alcohol-related liver damage.

The finding also helps explain why secondary cancers sometimes arise in patients who were cured of their primary cancer. The secondary cancer was triggered by the DNA damaged from the original life-saving chemotherapy.

To transform its research into therapeutic products, WEHI has entered into a collaborative agreement with US medical giants Genentech and Abbott. The agreement involves funding support for WEHI, as well as data sharing between the parties.

The present focus of research is to develop drugs targeted at a specific protein that would activate the suicide process in existing cancer cells or in other cells likely to become cancerous if genetic activity overrode their programmed cell death.

Early phase clinical trials with people are under way in several places across the world using a compound called ABT-263, which is showing promising signs.

Apoptosis is also revealing other strategies for dealing with cancer, according to Paul Ekert of the Children's Cancer Centre at the Murdoch Childrens Research Institute in Melbourne.

"Building on the basic work from WEHI, we've been looking at how the apoptosis pathways are activated, or how activation fails in response to signals that originate from outside the cell," he explains. "We want to understand the biochemical processes [that] underpin how signals originate and are transmitted."

In particular, this research is examining the role of a family of genes called the Hox genes, which appears to regulate critical aspects of the apoptosis pathway.

"Originally we were simply using the Hox gene to create large numbers of cells for experimentation purposes," Ekert says. "But then we began to think about how it could be manipulated for possible therapeutic purposes."

According to Ekert, the idea is to inhibit the division of some cells while not affecting others.

This could be especially relevant to treating leukaemia-type cancers, although the applications could be broad.

"The way signals from the outside of the cells regulate apoptosis pathways is still something of a black box, where you can see things going in and things coming out, but you don't know much about what happens inside," Ekert says. "We are starting to lift the lid."

He is collecting proof-of-principle data as the basis for early-stage testing.

Another area of apoptosis research focuses on the nature of the suicide trigger.

"There are cells [that] require constant signals to stay alive and they die when those signals cease," says John Silke of the biology department at La Trobe University, where he heads a team looking at apoptosis-related proteins.

"There are others [that] require a particular signal to activate the suicide trigger," says Silke.

"Understanding those processes would go a long way to understanding not just cancer but a whole gamut of cell-related diseases."

This research has already led to a drug, at present in phase one trials in the US, he says. The drug mimics a natural protein that activates apoptosis, amplifying the signal so cells commit suicide.

"There's still a long way to go, but there is the potential to focus on specific types of cells, avoiding the system damage generated by approaches like chemotherapy," Silke says.

"It would be like using a sniper rifle rather than a hand grenade."

For his part, Strasser underlines the importance of fighting cancer at the fundamental level: "It's a matter of understanding your enemy."

As he notes, cancer cells are an excellent example of so-called generational evolution.

"Our medium-term goal is to be able to disrupt that process, to give the body of a person with cancer a good fighting chance."

His long-term goal?

"To fight cancer at the time in the early stages of its development, hopefully preventing it from becoming a danger in the first place."

Source

HBV DNA Decline at 24 Weeks Predicts Sustained Response to Pegylated Interferon for Chronic Hepatitis B

SUMMARY: Patients who experience a significant decrease in hepatitis B virus (HBV) DNA, or viral load, during the first 24 weeks of treatment with pegylated interferon were more likely to achieve a long-term response, according to a study described in the July 2010 Journal of Medical Virology. If HBV DNA does not decline by at least 100-fold during this period, however, treatment is unlikely to be successful and should be discontinued, the researchers recommended.
By Liz Highleyman

Bettina Hansen from Erasmus University Medical Center in Rotterdam and colleagues aimed to develop a model that could better predict at baseline which chronic hepatitis B patients would respond to pegylated interferon, and to establish an early indicator for when treatment should be halted.

Pegylated interferon leads to virological response (undetectable HBV DNA) and hepatitis B "e" antigen (HBeAg) loss in only a minority of patients with HBeAg positive chronic hepatitis B. The treatment is expensive and can cause difficult side effects, so clinicians want to know when to stop therapy that is unlikely to produce a favorable outcome.

Known baseline predictors of response to pegylated interferon include HBV genotype (B responds better than D), pre-treatment HBV viral load, and alanine aminotransferase (ALT) level. The investigators looked at whether viral load reduction early in treatment also has predictive value.

This analysis included 136 chronic hepatitis B patients treated with pegylated interferon. Response was defined as HBV DNA < 10,000 copies/mL and HBeAg loss 26 weeks after completion of treatment. The researchers used logistic regression analysis to develop a dynamic prediction model using HBV DNA during the first 32 weeks of therapy.

Results

• The researchers identified an early clinically useful rule for continuation or discontinuation of treatment, with a grid of cut-off values for HBV DNA decline during treatment.
• Adding HBV DNA decline at weeks 4, 12, and 24 to baseline factors improved predictions of sustained response.
• HBV DNA decline of at least 2?log(10), or 100-fold, within 24 weeks of starting therapy was strongly associated with response when added to baseline predictors. 

These findings led the study authors to conclude, "A dynamic model including HBV DNA decline during treatment provides more accurate predictions of response to pegylated interferon."

"The model strongly supports individual decision making on treatment (dis)continuation in patients with HBeAg positive chronic hepatitis B," they continued. "It is recommended that pegylated interferon treatment is stopped by 24 weeks if HBV DNA declined < 2?log(10)."

Investigator affiliations: Departments of Gastroenterology & Hepatology, Biostatistics, and Public Health, Erasmus MC, University Medical Center Rotterdam, Rotterdam, Netherlands; Department of L-Biostat, Catholic University of Leuven, Leuven, Belgium.

8/20/10

Reference
BE Hansen, EHCJ Buster, EW Steyerberg, and others. Prediction of the response to peg-interferon-alfa in patients with HBeAg positive chronic hepatitis B using decline of HBV DNA during treatment. Journal of Medical Virology 82(7): 1135-1142 (Abstract). July 2010.

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Silymarin Milk Thistle Extract May Inhibit Hepatitis C Virus Entry into Cells

SUMMARY: Silymarin, an extract from the milk thistle plant, has an inhibitory effect on the hepatitis C virus (HCV) polymerase in laboratory studies, but its anti-HCV action also appears to include blocking HCV from entering cells and preventing cell-to-cell transmission, according to research described in the June 2010 issue of Hepatology.

Milk thistle (Silybum marianum) has an extensive history of use as a remedy for liver problems in both Eastern and Western traditional medicine. Silymarin is a flavonoid comprised of a mix of milk thistle components including silibinin. Most silymarin studies have looked at its effect on liver fibrosis, but in recent years researchers have studied its direct activity against HCV in the laboratory and in vivo.

A survey of participants in the HALT-C trial -- which evaluated the benefits of long-term pegylated interferon for patients who did not respond to standard treatment with pegylated interferon plus ribavirin -- found that participants who said they used silymarin did not have lower HCV viral load on average than non-users. Another recent study, however, showed that silymarin inhibited activity of the HCV polymerase, which copies viral genetic material as part of replication.

In the present study, Jessica Wagoner from the University of Washington in Seattle and colleagues further characterized the antiviral action of silymarin in the laboratory.

Results

• Silymarin had antiviral effects against HCV in cell cultures, including inhibition of virus entry into cells, HCV RNA and protein expression, and production of infectious virus particles.
• Silymarin did not block HCV binding to cells, but did inhibit entry of viral pseudoparticles and fusion of HCV pseudoparticles with liposomes, or fat bubbles.
• Silymarin -- but not silibinin -- inhibited activity of the HCV genotype 2a NS5B RNA-dependent RNA polymerase at concentrations 5-10 times higher than required for an anti-HCV effect in cell culture.
• Silymarin had only minimal activity against genotype 1b isolate BK and 4 genotype 1b polymerases derived from HCV-infected patients, however.
• Silymarin did not inhibit HCV replication in 5 independent genotype 1a, 1b, and 2a replicon model cell lines that did not produce infectious virus.
• Silymarin inhibited microsomal triglyceride transfer protein activity, apolipoprotein B secretion, and infectious virion production in cell culture medium.
• Silymarin also blocked cell-to-cell spread of HCV. 

Based on these findings, the study authors concluded, "Although inhibition of in vitro NS5B polymerase activity is demonstrable, the mechanisms of silymarin's antiviral action appear to include blocking of virus entry and transmission, possibly by targeting the host cell."

Investigator affiliations: Departments of Laboratory Medicine, Microbiology, and Global Health, University of Washington, Seattle, WA; Center for Engineering in Medicine, Massachusetts General Hospital, Boston, MA; Department of Pediatrics, University of Texas Medical Branch, Galveston, TX; School of Medicine, University of Texas Southwestern Medical Center, Dallas, TX; Hepatitis C Virus Research Group, Institute of Biomedical Research, University of Birmingham, Birmingham, UK; Institut de Biologie et Chimie des Protéines, Université Lyon 1, IFR128 Lyon Biosciences Gerland, CNRS-Universite Claude Bernard, Lyon, France; Department of Chemistry and Biochemistry, University of North Carolina at Greensboro, Greensboro, NC; Department of Molecular Virology, University of Heidelberg, Heidelberg, Germany; Department of Molecular Microbiology and Immunology, Saint Louis University School of Medicine, St. Louis, MO.

8/20/10

Reference
J Wagoner, A Negash, OJ Kane, and others. Multiple effects of silymarin on the hepatitis C virus lifecycle. Hepatology 51(6): 1912-1921 (Abstract). June 2010.

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Acute Hepatitis C as a Sexually Transmitted Infection in HIV Positive Men

SUMMARY: Sexual transmission of hepatitis C virus (HCV) among HIV positive men who have sex with men has now been recognized for a decade, occurring in cities in Europe, North America, and Australia. Since acute HCV outbreaks occur almost exclusively among men with HIV, being HIV positive probably plays a critical role, according to the authors of a review article in the July 31, 2010 issue of AIDS.
By Liz Highleyman

Thijs van de Laar from the Amsterdam Public Health Service and colleagues presented an overview of acute HCV infection among gay/bisexual men with HIV, including epidemiology, risk factors, natural history, disease progression, and challenges of management. The review was based on published studies identified through a MEDLINE search and relevant conference abstracts.

HCV Transmission

HCV is usually transmitted through direct blood contact, for example, via shared needles for injection drug use (IDU) or blood transfusions before donated blood was screened. Due to common transmission routes, an estimated 4-5 million people -- or approximately one-third of people with HIV -- are HIV/HCV coinfected.

Sexual transmission of HCV was traditionally thought to be uncommon (less than 1%) based on studies of monogamous heterosexual couples. Early cross-sectional studies found a relatively high HCV prevalence rate among men who have sex with men (MSM), but these often did not take into account injection drug use.

Since 2000, however, several outbreaks of acute hepatitis C among HIV positive gay and bisexual men who denied injection drug use have been reported, first in the U.K., then in other large cities in France, Germany, and the Netherlands, followed by Australia, the U.S., and Canada.

ACUTE HEPATITIS C

"Given the burden of liver disease, in particular HCV, on the morbidity and mortality in HIV patients in the era of combination antiretroviral therapy, the rapid and significant rise in the incidence of HCV in the HIV-infected MSM population in high-income countries is alarming," the review authors wrote. "This relates to a significant change in the epidemiology of HCV that has occurred, with HCV emerging as a sexually transmitted infection within this population."

In the Netherlands, for example, a biannual survey among sexually transmitted infection (STI) clinic attendees showed an increase in HCV prevalence among HIV positive MSM from 1%-4% before 2000 to 15% in 2007 and 21% in 2008. HCV prevalence among HIV negative gay/bisexual men, however, remains comparable to that of the general population.

Most cases of acute hepatitis C among MSM in Europe involve hard-to-treat HCV genotypes 1a and 4d, the latter of which is otherwise uncommon in Europe and the U.S. Genetic sequencing has revealed closely related virus strains coinciding with sexual networks.

Evolutionary analysis "suggests multiple independent introductions of HCV into the MSM community, some as early as the 1980s," the authors surmised. "Most likely, these strains were introduced from the IDU population." They noted that the recent increase in HCV sexual transmission coincides with a rise in sexual risk behavior and increased STI rates in the era of effective combination ART, some of which is due to serosorting, or HIV positive men have unprotected sex with other positive men.

Research to date indicates that HCV transmission is associated with a variety of sexual practices -- including fisting, unprotected anal intercourse, use of shared sex toys, group sex, and sex while on drugs -- though specific activities vary from study to study. Other risk factors include non-injection drug use and presence of other sexually transmitted diseases.

These studies show that "most MSM with HCV report a combination of various, potentially high-risk, sexual and drug practices," the authors wrote. "The interaction between sex and drugs is complex, and many of these factors are highly correlated and difficult to disentangle."

"Given this occurs almost exclusively in HIV-infected MSM, HIV probably has a critical role mediated either through behavioral and/or biological factors," they stated. "It is not yet known whether lower CD4 cell count increases the risk of acquiring HCV, but the fact that many MSM with acute HCV have relatively preserved CD4 cell counts suggests this may not be a critical factor."

Disease Progression and Treatment

Turning to hepatitis C disease progression in this population, they wrote, "The natural history of HCV is determined by host-viral interactions, which are perturbed in HIV coinfection, resulting in accelerated liver fibrosis, higher HCV loads, and poorer responses to interferon-based therapy when compared with HCV monoinfection."

While about 25% of HIV negative individuals spontaneously clear HCV without treatment, this is less likely among people with HIV -- as low as 5% in one study -- perhaps due to reduced T-cell responses. HIV/HCV coinfection is associated with more rapid liver fibrosis. Some studies indicate that progression is especially fast among people who already have HIV at the time of HCV infection, but other data are conflicting.

Hepatitis C treatment using pegylated interferon (with or without ribavirin) is quite successful during acute HCV infection. Because they receive regular liver function tests to monitor drug toxicity, people with HIV are more likely to have HCV infection diagnosed during the acute stage. Acute hepatitis C cure rates among HIV positive people are around 60%-80% in most studies.

Optimal timing and duration of therapy for acute HCV infection is not well defined, but most experts recommend waiting 12 weeks to see if spontaneous clearance will occur. Most favor combination therapy over pegylated interferon monotherapy and a treatment duration of 24 weeks for coinfected patients.

"Targeted prevention such as raising awareness, regular screening and treatment of acute and chronic infections are needed to stop the further spread among MSM," the review authors concluded. "It is clear that a message of 'safe sex' through condom use during anal intercourse could be provided, but given the practice of negotiated unprotected sex among HIV-infected MSM might not be accepted. In addition, it may not cover practices that increase risk of blood-to-blood contact (e.g. fisting). Furthermore, MSM population needs to be informed that reinfection is an ongoing risk, given the recent reports of HCV reinfection following successful treatment and documented clearance of HCV."

Cluster of Infectious Diseases, Public Health Service, Amsterdam, Netherlands; Viral Hepatitis Clinical Research Program, National Centre for HIV Epidemiology and Clinical Research, University of New South Wales, Sydney, Australia; Department of Internal Medicine, Centre for Infection and Immunity Amsterdam, Academic Medical Centre, University of Amsterdam, Amsterdam, Netherlands; St. Vincent's Clinical School, Faculty of Medicine, University of New South Wales, Sydney, Australia.

8/20/10

Reference
TJ van de Laar, GV Matthews, M Prins, and M Danta. Acute hepatitis C in HIV-infected men who have sex with men: an emerging sexually transmitted infection. AIDS 24(12): 1799-1812 (Abstract). July 31, 2010.

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Adoptive transfer of splenocytes to study cell-mediated immune responses in hepatitis C infection using HCV transgenic mice

Hepatitis C virus (HCV) is a major cause of chronic hepatitis and a health problem affecting over 170 million people around the world. We previously studied transgenic mice that express HCV Core, Envelope 1 and Envelope 2 proteins predominantly in the liver, resulting in steatosis, liver and lymphoid tumors, and hepatocellular carcinoma.

Herein, the immune-mediated cell response to hepatitis C antigens was evaluated by adoptive transfers of carboxyfluorescein succinimidyl ester (CFSE) labelled splenocytes from HCV immunized mice into HCV transgenic mice.

Results: In comparison to non-transgenic mice, there was a significant decrease in the percentage of CFSE-labeled CD4+ and CD8+ T cells in transgenic mouse peripheral blood receiving adoptive transfers from immunized donors. Moreover, the percentage of CFSE-labeled CD4+ and CD8+ T cells were significantly higher in the spleen of transgenic and non-transgenic mice when they received splenocytes from non-immunized than from immunized mice.

On the other hand, the percentages of CD4+ and CD8+ T cells in the non-transgenic recipient mouse lymph nodes were significantly higher than the transgenic mice when they received the adoptive transfer from immunized donors. Interestingly, livers of transgenic mice that received transfers from immunized mice had a significantly higher percentage of CFSE labeled T cells than livers of non-transgenic mice receiving non-immunized transfers.

Conclusions: These results suggest that the T cells from HCV immunized mice recognize the HCV proteins in the liver of the transgenic mouse model and homed to the HCV antigen expression sites.

We propose using this model system to study active T cell responses in HCV infection.

Author: Turaya NaasMasoud GhorbaniCatalina SoareNicole SherlingRudy MullerPeyman GhorbaniFrancisco Diaz-Mitoma

Credits/Source: Comparative Hepatology 2010, 9:7

Published on: 2010-08-20

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Achillion to Raise $50M in Stock Offering for HCV Studies

By Catherine Hollingsworth
Staff Writer

Achillion Pharmaceuticals Inc. plans to raise about $50 million through the sale of stock and warrants to a select group of investors, money that would be used to advance the company's early stage pipeline of drug candidates for hepatitis C virus (HCV).

At the end of June, the New Haven, Conn.-based company had $20 million in cash resources. With the added funds from the financing, which is expected to close Aug. 20, Achillion hopes to extend its cash through most of 2012.

The financing is intended to take the company's ACH-1625 protease inhibitor to the completion of Phase IIa testing, explained Mary Kay Fenton, Achillion's vice president and chief financial officer.

The Phase II study, which is expected to get under way next month, will have a 28-day segment that is targeted to report data in March 2011 and a 12-week segment that is slated to report results at the end of next year.

"We believe this financing will get us through both of those milestones," Fenton told BioWorld Today.

In addition, Achillion hopes to move its preclinical candidates, ACH-2684, a pan-genotypic protease inhibitor, and ACH 2928, an NS5A inhibitor, through Phase I testing in 2011. The company also plans to put those candidates in combination studies in 2012 with other HCV assets in development, Fenton said.

ACH-1625, while it has shown promising data in Phase Ib studies, is far behind the front runners in the crowded HCV space. Both Vertex Pharmaceuticals Inc. and Merck & Co. Inc. have their own HCV candidates in Phase III, protease inhibitors telaprevir and boceprevir, respectively. Analysts view both drugs as approvable.

The current standard therapy for HCV is a combination of ribavirin and a pegylated interferon. There are no protease inhibitors currently approved for the infection.

Achillion believes its protease inhibitor, though still in early testing, may stand apart from the others because of its safety and tolerability and sustained viral suppression.

"Based on the early Phase Ib data, we view ACH-1625 as a very promising HCV protease inhibitor in early development," Cowen & Co. analyst Phil Nadeau stated in a research note. He added, "We believe the risk/reward of owning ACHN shares at current levels is highly favorable."

In several dosing cohorts, study patients infected with HCV were dosed for five days and showed a mean maximum drop in viral load of between 3.63 and 4.25 logs. All dosing cohorts also showed a sustained viral suppression in HCV-infected subjects, even after dosing was completed.

"This observation could be an important distinguishing feature and competitive advantage for our compound in comparison to other HCV therapies," Elizabeth Olek, vice president and chief medical officer, said in a Thursday conference call.

A select group of investors, namely venture firms Domain Associates, Clarus ventures, Quaker BioVentures and Pappas Ventures, have agreed to purchase Achillion's stock and warrants in the private placement offering.

While the company's focus is HCV, it also has an HIV candidate elvucitabine, an L-cytosine nucleoside analogue reverse transcriptase inhibitor. Earlier this year, Achillion reported 96-week data showing that the drug had a substantial antiviral effect similar to 3TC (lamivudine, GlaxoSmithKline plc), with 95 percent of patients in the elvucitabine-treated group achieving undetectable viral load compared with 93 percent in the 3TC group.

Achillion is offering 19,755, 101 shares of common stock at a price of $2.49 per share, its consolidated closing bid price reported by NASDAQ Aug. 17.

The warrants to purchase 0.35 shares of common stock for each share of common stock are priced at $0. 125 per warrant share. The warrants, which have a seven-year term from the date of issuance, represent the right to acquire an aggregate of 6,921,285 shares of common stock and will be exercisable at a price of $3. 1125 per share.

Shares in Achillion (NASDAQ:ACHN) lost 1 cent, closing at $2.60 Thursday.

In other financing news:

• Complete Genomics Inc., of Mountain View, Calif., which recently filed to take the company public, raised $39 million in its Series E financing. New investor Sands Capital led the round and was joined by existing investors Essex Woodlands, OVP Venture Partners, Prospect Venture Partners, OrbiMed Advisors, Highland Capital Management and Enterprise Partners. Complete Genomics also reported that it is evaluating a lawsuit alleging patent infringement filed against it by Illumina Inc., of San Diego, and Solexa Inc. (acquired by Illumina), in the U.S. District Court in Delaware. The lawsuit claims that the Complete Genomics Analysis Platform infringes three patents owned by the plaintiffs. The company said it believes it has "substantial and meritorious defenses to the claims."
• Corcept Therapeutics Inc., of Menlo Park, Calif., has filed a shelf registration statement to sell, from time to time, up to $100 million in equity, debt and other offerings. Specific terms will be disclosed at the time of any financing. Proceeds will be used for research, development and commercial activities, working capital and other general purposes. The company is developing drugs to treat severe metabolic and psychiatric disorders that are associated with steroid hormone cortisol. Lead product Corlux is a Phase III drug candidate for Cushing's syndrome and psychotic depression.

• Jennerex Inc., of San Francisco, completed a fully subscribed private placement financing with aggregate gross proceeds of about $8.6 million. The money will allow the company to complete the ongoing Phase II trials of JX-594 in patients with liver cancer and colorectal cancer. Existing stockholders as well as a number of new investors participated in the financing.

• MannKind Corp., of Valencia, Calif., said that it has entered a previously announced stock lending agreement in which it will lend 9 million shares of its common stock to Bank of America NA. It also entered an underwriting agreement with Bank of America affiliate Merrill Lynch, Pierce, Fenner & Smith Inc., in which Merrill Lynch will sell the shares at an offering price of $5.55 per share. MannKind will not receive any proceeds from the common stock offering but will receive a nominal one-time lending fee. And Bank of America will be required to return the borrowed shares under the terms of the share lending agreement. Bank of America will use the short position resulting from the loan and sale of the shares of MannKind's common stock to facilitate the establishment of hedge positions by investors in a concurrent private offering of $100 million aggregate principal amount of MannKind's senior convertible notes due 2015. The notes, which will mature on Aug. 15, carry an approximate conversion price of $6.80 per share. An additional $10 million aggregate principal amount of the notes could be purchased to cover any overallotments. The closing of the common stock offering is expected to take place Aug. 24.

• Silence Therapeutics Plc, of London, a company focused on RNAi therapeutics, said that it anticipates future milestones of more than $65 million stemming from a siRNA deal that partner Quark Pharmaceuticals Inc., of Fremont Calif., recently entered with Novartis AG, of Basel Switzerland. Privately held Quark would receive a potential $680 million, including $10 million up front, under the deal, which grants the Swiss drugmaker an option to obtain an exclusive worldwide license to develop and commercialize QPI-1002. The investigational p53 temporary inhibitor which incorporates Silence Therapeutics' AtuRNAi technology. (See BioWorld Today, Aug. 19, 2010.)

Published August 20, 2010

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