Steve Connor: The promise of an unlimited supply for transfusions
By Steve Connor
Monday, 16 August 2010
More than two million units of blood – some 250,000 gallons – are handled by the transfusion service each year. Yet shortages can and do happen, especially around holiday periods and special events, such as the recent World Cup, when many donors stayed at home.
But one of the greatest problems facing the transfusion service is the growing menace of new infectious agents which can pass undetected into the blood supply. Hepatitis C, HIV and more recently the infectious "prion" behind Creutzfeldt-Jacob disease have all emerged in the population before there was a reliable blood test to screen donated blood.
The issue of emerging infections is likely to get worse with greater international travel and the continued encroachment of humans on the wild places where many of these animal-borne diseases lurk in their natural reservoirs. West Nile virus, for example, is passed on by mosquitoes, but in 2002 the first cases in the US occurred as a result of transmission from infected blood donors.
Developing safe, synthetic alternatives to blood is not, therefore, of simple academic interest. The central function of red blood cells is to carry oxygen around the body and for many decades scientists have laboured over potential alternatives to living red blood cells, from oxygen-carrying chemicals known as perfluorocarbons to the use of the natural oxygen-carrying pigment, haemoglobin.
None of these approaches has really proved a success. However, the manufacture of "synthetic" red blood cells derived from embryonic stem cells makes perfect logical sense. The red blood cell is the vehicle the body uses to oxygenate the tissues and everything we know of embryonic stem cells suggests they can be made to produce red cells. Stem cells from four-day-old spare IVF embryos are also likely to be free of infectious diseases.
Scientists have shown already that mature red blood cells can be made from the adult blood stem cells found in the bone marrow, although these stem cells have limited ability to replicate. Stem cells derived from embryos, however, can multiply ad infinitum, meaning that in theory just one "universal donor" of blood type "O-negative" could supply the country's entire needs.
Source
August 15, 2010
Liver Cancer - Related to Hepatitis B Carrier State?
August 15, 2010
Liver cancer refers to either primary liver cancer, that is cancer originating from the liver cells or supporting cells in the liver, or secondary liver cancer, that is cancer that has spread to the liver from the surrounding organs, usually via the blood that drains those organs and flow through the liver. In this article we shall confine ourselves to primary liver cancer, also referred to as hepatocellular carcinoma.
Liver cancer is one of the more commonly occurring cancers in the world, being the fifth most common cancer in men and the eighth most common cancer in women. The total number of new cases diagnosed is estimated to be about 500,000 every year. Men seem to be twice as likely as women to get liver cancer.
What could cause this problem?
The incidence of liver cancer seems to be higher in certain countries. Studies appear to indicate a positive relationship between the incidence of liver cancer and that of hepatitis B virus carrier states as well as hepatitis C virus infections. The risk of a hepatitis B carrier developing liver cancer is about 60 times higher than that of a non hepatitis B carrier. This risk appears to be even higher than the risk of a smoker developing lung cancer (about 20 to 25 times).
What countries have a higher incidence of hepatitis B carrier states? It is observed that certain countries seem to have a much higher incidence of hepatitis B carriers. One case in point is Taiwan, where it is noted that an abnormally high 20% of pregnant mothers were discovered to be carriers of hepatitis B. This compares significantly to the incidence of 1% in the United States. Similar studies show a higher incidence of hepatitis B carrier rates in South-East Asian countries, between 10% to 15%. This has led to the belief that Oriental persons are genetically less able to overcome the hepatitis B virus. This observation is supported by another observation, that the conversion rate to immunization with hepatitis B vaccine is lower in Chinese as compared with other races.
Studies also show that the incidence of new cases of primary liver cancer has decreased significantly in those countries where there has been a deliberate effort to immunize persons to hepatitis B with hepatitis B vaccine. This is one of the rare situations where there is a demonstrable cause/effect relationship, and where there is definite proof that a particular cancer can be prevented, by both vaccination and by screening of blood and blood products for hepatitis B and C viruses.
Other risk factors or suspected causes of liver cancer need to be mentioned here. They are:
Liver Cirrhosis. A situation of scarring of the liver due to chronic damage as a result commonly of heavy drinking. There is a slight increase of risk of liver cancer developing.
Inherited causes. Persons with hemochromatosis, a genetic problem of excess iron deposits in the body have a higher chance of developing liver cancer.
Aflatoxin. A mold found in bad peanuts and grain is a well known culprit in the causation of liver cancer.
Source
Liver cancer refers to either primary liver cancer, that is cancer originating from the liver cells or supporting cells in the liver, or secondary liver cancer, that is cancer that has spread to the liver from the surrounding organs, usually via the blood that drains those organs and flow through the liver. In this article we shall confine ourselves to primary liver cancer, also referred to as hepatocellular carcinoma.
Liver cancer is one of the more commonly occurring cancers in the world, being the fifth most common cancer in men and the eighth most common cancer in women. The total number of new cases diagnosed is estimated to be about 500,000 every year. Men seem to be twice as likely as women to get liver cancer.
What could cause this problem?
The incidence of liver cancer seems to be higher in certain countries. Studies appear to indicate a positive relationship between the incidence of liver cancer and that of hepatitis B virus carrier states as well as hepatitis C virus infections. The risk of a hepatitis B carrier developing liver cancer is about 60 times higher than that of a non hepatitis B carrier. This risk appears to be even higher than the risk of a smoker developing lung cancer (about 20 to 25 times).
What countries have a higher incidence of hepatitis B carrier states? It is observed that certain countries seem to have a much higher incidence of hepatitis B carriers. One case in point is Taiwan, where it is noted that an abnormally high 20% of pregnant mothers were discovered to be carriers of hepatitis B. This compares significantly to the incidence of 1% in the United States. Similar studies show a higher incidence of hepatitis B carrier rates in South-East Asian countries, between 10% to 15%. This has led to the belief that Oriental persons are genetically less able to overcome the hepatitis B virus. This observation is supported by another observation, that the conversion rate to immunization with hepatitis B vaccine is lower in Chinese as compared with other races.
Studies also show that the incidence of new cases of primary liver cancer has decreased significantly in those countries where there has been a deliberate effort to immunize persons to hepatitis B with hepatitis B vaccine. This is one of the rare situations where there is a demonstrable cause/effect relationship, and where there is definite proof that a particular cancer can be prevented, by both vaccination and by screening of blood and blood products for hepatitis B and C viruses.
Other risk factors or suspected causes of liver cancer need to be mentioned here. They are:
Liver Cirrhosis. A situation of scarring of the liver due to chronic damage as a result commonly of heavy drinking. There is a slight increase of risk of liver cancer developing.
Inherited causes. Persons with hemochromatosis, a genetic problem of excess iron deposits in the body have a higher chance of developing liver cancer.
Aflatoxin. A mold found in bad peanuts and grain is a well known culprit in the causation of liver cancer.
Source
Peginterferon Plus Ribavirin and Sustained Virological Response in HCV-Related Cirrhosis: Outcomes and Factors Predicting Response
Am J Gastroenterol advance online publication 10 August 2010; doi: 10.1038/ajg.2010.294
Conrado M Fernández-Rodríguez MD 1, Sonia Alonso MD 1, Stella M Martinez MD 2, Xavier Forns MD 2, Jose M Sanchez-Tapias MD 2, Diego Rincón MD 3, Gil Rodriguez-Caravaca MD 1, Rafael Bárcena MD 4, Miguel A Serra MD 5, Manuel Romero-Gómez MD 6, Inmaculada Fernandez MD 7, Javier Garcia-Samaniego MD 8, Javier Fuente MD 9, Ricard Solá MD 10, Ricardo Moreno-Otero MD 11 and Ramón Planas MD 12 on behalf of the Group for the Assessment of Prevention of Cirrhosis Complications and Virological Response (APREVIR)
1 Hospital Universitario Fundación Alcorcón, Madrid, Spain
2 Hospital Clinic I Provincial, Badalona and IDIBAPS, Ciberehd, Badalona, Spain
3 Hospital Universitario Gregorio Marañón Ciberehd, Madrid, Spain
4 Hospital Ramón y Cajal, Madrid, Spain
5 Hospital Clínico Universitario, Valencia, Spain
6 Hospital de Valme Ciberehd, Sevilla, Spain
7 Hospital Universitario 12 de Octubre, Madrid, Spain
8 Hospital Carlos III Ciberehd, Madrid, Spain
9 Hospital Miguel Servet, Zaragoza, Spain
10 Hospital del Mar, Badalona, Spain
11 Hospital Universitario de La Princesa, Madrid, Spain
12 Hospital Germans Trias i Pujol, Ciberehd, Badalona, Spain
Correspondence: Conrado M. Fernández-Rodríguez, MD, Hospital Universitario Fundación Alcorcón, Av Budapest-1, 28922, Madrid, Spain. E-mail: cfernandez@fhalcorcon.es
Received 4 September 2010; Accepted 11 March 2010; Published online 10 August 2010.
OBJECTIVES: Patients with hepatitis C virus (HCV) cirrhosis are difficult to treat and have a high risk of liver decompensation or hepatocellular carcinoma. We sought to identify factors that could predict treatment response.
METHODS: Collaborating centers (n=26) provided data for patients (n=568) with HCV cirrhosis undergoing treatment with peginterferon-α plus ribavirin (RBV). Univariate and multivariate analyses were used to evaluate factors predicting treatment outcomes.
RESULTS: Sustained viral response (SVR) in naive patients was 30.7%, with no significant differences between centers. Median follow-up was 35 months (range: 1–81). Factors predicting SVR were: non-genotype 1 (odds ratio (OR)=4.183; 95% confidence interval (CI): 2.353–7.438) overall dose and ≥80% of the scheduled time of treatment (OR=3.177; 95% CI: 1.752–5.760); serum γ-glutamyl transpeptidase (GGT) <76 IU per ml (OR=4.092; 95% CI: 2.418–6.927); baseline viral load <6 × 105 (OR=2.597; 95% CI: 1.583–4.262); absence of ultrasound signs of portal hypertension (OR=2.067; 95% CI: 1.26–3.39). No patient with a HCV-RNA decline <1 log10 at week 4 achieved SVR. Event-free survival at 5 years was 91% in patients with SVR vs. 59% in non-responders (P<0.001). Overall survival in patients with SVR was 98% vs. 86% in non-responders (P=0.005). Independent factors predicting events were absence of SVR (hazard ratio (HR)=2.66; 95% CI: 1.32–5.54), baseline serum albumin <3.9 g per 100 ml (HR=3.06; 95% CI: 1.81–5.15), presence of esophageal varices on endoscopy (HR=2.489; 95% CI: 1.546–4). Improved outcome was more evident in responders with less advanced disease at baseline.
CONCLUSIONS: SVR can be achieved in approximately one-third of patients with HCV-related cirrhosis. SVR independently reduces the likelihood of clinical decompensation and improves survival.
Source
Conrado M Fernández-Rodríguez MD 1, Sonia Alonso MD 1, Stella M Martinez MD 2, Xavier Forns MD 2, Jose M Sanchez-Tapias MD 2, Diego Rincón MD 3, Gil Rodriguez-Caravaca MD 1, Rafael Bárcena MD 4, Miguel A Serra MD 5, Manuel Romero-Gómez MD 6, Inmaculada Fernandez MD 7, Javier Garcia-Samaniego MD 8, Javier Fuente MD 9, Ricard Solá MD 10, Ricardo Moreno-Otero MD 11 and Ramón Planas MD 12 on behalf of the Group for the Assessment of Prevention of Cirrhosis Complications and Virological Response (APREVIR)
1 Hospital Universitario Fundación Alcorcón, Madrid, Spain
2 Hospital Clinic I Provincial, Badalona and IDIBAPS, Ciberehd, Badalona, Spain
3 Hospital Universitario Gregorio Marañón Ciberehd, Madrid, Spain
4 Hospital Ramón y Cajal, Madrid, Spain
5 Hospital Clínico Universitario, Valencia, Spain
6 Hospital de Valme Ciberehd, Sevilla, Spain
7 Hospital Universitario 12 de Octubre, Madrid, Spain
8 Hospital Carlos III Ciberehd, Madrid, Spain
9 Hospital Miguel Servet, Zaragoza, Spain
10 Hospital del Mar, Badalona, Spain
11 Hospital Universitario de La Princesa, Madrid, Spain
12 Hospital Germans Trias i Pujol, Ciberehd, Badalona, Spain
Correspondence: Conrado M. Fernández-Rodríguez, MD, Hospital Universitario Fundación Alcorcón, Av Budapest-1, 28922, Madrid, Spain. E-mail: cfernandez@fhalcorcon.es
Received 4 September 2010; Accepted 11 March 2010; Published online 10 August 2010.
OBJECTIVES: Patients with hepatitis C virus (HCV) cirrhosis are difficult to treat and have a high risk of liver decompensation or hepatocellular carcinoma. We sought to identify factors that could predict treatment response.
METHODS: Collaborating centers (n=26) provided data for patients (n=568) with HCV cirrhosis undergoing treatment with peginterferon-α plus ribavirin (RBV). Univariate and multivariate analyses were used to evaluate factors predicting treatment outcomes.
RESULTS: Sustained viral response (SVR) in naive patients was 30.7%, with no significant differences between centers. Median follow-up was 35 months (range: 1–81). Factors predicting SVR were: non-genotype 1 (odds ratio (OR)=4.183; 95% confidence interval (CI): 2.353–7.438) overall dose and ≥80% of the scheduled time of treatment (OR=3.177; 95% CI: 1.752–5.760); serum γ-glutamyl transpeptidase (GGT) <76 IU per ml (OR=4.092; 95% CI: 2.418–6.927); baseline viral load <6 × 105 (OR=2.597; 95% CI: 1.583–4.262); absence of ultrasound signs of portal hypertension (OR=2.067; 95% CI: 1.26–3.39). No patient with a HCV-RNA decline <1 log10 at week 4 achieved SVR. Event-free survival at 5 years was 91% in patients with SVR vs. 59% in non-responders (P<0.001). Overall survival in patients with SVR was 98% vs. 86% in non-responders (P=0.005). Independent factors predicting events were absence of SVR (hazard ratio (HR)=2.66; 95% CI: 1.32–5.54), baseline serum albumin <3.9 g per 100 ml (HR=3.06; 95% CI: 1.81–5.15), presence of esophageal varices on endoscopy (HR=2.489; 95% CI: 1.546–4). Improved outcome was more evident in responders with less advanced disease at baseline.
CONCLUSIONS: SVR can be achieved in approximately one-third of patients with HCV-related cirrhosis. SVR independently reduces the likelihood of clinical decompensation and improves survival.
Source
Cancer’s little helpers
Home / August 28th, 2010; Vol.178 #5 / Feature
Tiny pieces of RNA may turn cells to the dark side
By Tina Hesman Saey
August 28th, 2010; Vol.178 #5 (p. 18)
When tiny hairpin-shaped molecules act up, they don’t rebel loner-style like James Dean. Instead they take on the persona of Darth Vader, crushing proteins under their command and turning acquaintances to the dark side as well. In this case, though, the fight is for control not of the universe, but of the body. And a dark-side victory could end in cancer.
No one would have predicted a decade ago that these microRNAs, as the hairpins are called, were involved in cancer, because no one even knew that they existed in people. Mere snippets of RNA — DNA’s underappreciated cousin — these micromolecules are about 22 chemical letters long. But their size belies their power.
When on their best behavior, the molecules are competent and capable managers of the protein-building process that keeps a cell humming in perfect harmony. But when microRNAs go rogue, the results can be disastrous.
New research is revealing just how important these newly discovered molecules are. An imbalance of microRNAs can cause cancer by encouraging runaway cell growth or by dampening a cell’s defenses, and can also make the disease more stubborn. But just as Darth Vader never completely lost the young Jedi Anakin Skywalker within him, even bad microRNAs may have good in them yet. Some scientists think that therapies aimed at soothing riled-up microRNAs may help cure the very cancers that the molecules help cause.
Most of the discoveries linking microRNAs and cancer have come in the past five years. “This is extremely rapid progression,” says Curtis Harris, chief of the human carcinogenesis lab at the National Cancer Institute, based in Bethesda, Md.
Micro middle managers
The realization that such small molecules could play a big role in disease was late in coming, says Carlo Croce of Ohio State University in Columbus. “In the beginning there was no interest in microRNAs at all,” he says.
The first microRNA was discovered in 1993 in roundworms. It took another seven years before the next microRNA was found in the same organism. Though both of those microRNAs help control worm development, most scientists regarded them as biological curiosities.
But then researchers found microRNAs at work in fruit flies, people and other organisms. Those discoveries suggested that microRNAs might be important regulatory molecules for all animals, not just flukes of worm biology.
MicroRNAs work in middle management in most plant and animal cells, scientists now know. The molecules help regulate the protein-manufacturing process by essentially issuing permits decreeing when and where proteins may be built. By riding piggyback on messenger RNAs, which are copies of the protein-building blueprints contained within DNA, microRNAs prevent the instructions from reaching protein-building machinery inside cells.
While it may sound nefarious, microRNAs’ interference with protein production helps a cell maintain balance. MicroRNAs ensure that cells save energy by not making unnecessary proteins and help prevent levels of potentially harmful proteins, such as those that initiate the self-destruct program known as apoptosis, from reaching critical mass.
Each type of microRNA in a cell may potentially pair with hundreds of different types of messenger RNA, says Isidore Rigoutsos, a computational and molecular biologist at Thomas Jefferson University in Philadelphia. And each messenger RNA may have many different microRNAs piling on its back.
“It’s safe to say that microRNAs are important,” Rigoutsos says. “The difficulty is saying what are the limits of importance, and they keep being expanded more and more and more.”
Cancer connection
Croce’s lab was among the first to illustrate just how big a role the little molecules could play in people. His group showed that genes encoding microRNAs frequently go missing in tumor cells. In particular, two microRNAs, miR-15 and miR-16, are missing or found at lower than normal levels in 68 percent of chronic lymphocytic leukemia cases.
Cancer biologists usually lump microRNAs into two groups: those that protect against cancer and those that promote it (though the distinction isn’t perfect). Cancer cells tend to have lower levels of most microRNAs but have an oversupply of a few others.
In the protective corner are microRNAs such as miR-15 and miR-16. One of the many proteins regulated by those two microRNAs is BCL2, which keeps cells from pushing the self-destruct button. Cells commit suicide when they become too damaged to operate properly — an important self-defense mechanism for an organism that doesn’t want to walk around with malfunctioning cells. So cells need just the right amount of BCL2 to keep from killing themselves unnecessarily, but not so much of it that they can never die.
The microRNAs pair with messenger RNA to strike the right balance of BCL2. But when miR-15 and miR-16 levels are knocked down — which can happen if a copy of a gene is lost or if something goes wrong during microRNA manufacturing — cells make far too much BCL2, essentially disabling the self-destruct mechanism and making cells immortal. Immortality is one hallmark of cancer.
At the opposite end of the spectrum is one of the baddest microRNA bad boys, miR-21. Elevated levels cause cancer in mice, researchers from Yale University reported online August 8 in Nature. And higher than normal levels have been linked to at least 13 major types of cancer in people and to poor prognoses for people with colon, lung, breast, pancreatic or head and neck cancers, Harris says (SN: 2/2/08, p. 70).
High levels of miR-21 can slow an important cellular security system involving a protein named p53, researchers from the University of California, Santa Barbara have found. This protein performs multiple protective services, including spurring repair of damaged DNA, halting growth until damage is repaired or ending it all if repair isn’t possible (SN: 12/6/08, p. 22). Last year researchers reported in Nature that p53 helps slice microRNAs into their mature form. Too much miR-21 can strip cells of their p53 defenses, leading to cancer.
Though miR-21 has stood out among the troublemakers, Croce’s team has shown that this microRNA and others don’t work alone. The molecular managers are master networkers. In 50 different normal human tissues, microRNAs collaborate to direct cellular activities, Croce and colleagues reported online May 3 in Genome Research. The networks consist of microRNAs that help direct production of proteins, some of which, in turn, control production of other microRNAs, and so on.
But time and again, in 51 different types of cancer, Croce’s team found that the microRNAs’ teamwork had broken down. The cohesive networks disintegrated into rogue hubs of activity. These anarchist factions throw a wrench into the well-oiled machinery that usually keeps a cell healthy.
It’s a rather small wrench, though. MicroRNAs wield their power subtly, tweaking and massaging protein levels up or down a wee bit here and there instead of stopping production altogether.
“A microRNA doesn’t function like an ‘off’ switch,” says cancer biologist Dihua Yu of the University of Texas MD Anderson Cancer Center in Houston.
Even a little bump or dip in protein levels, maybe by just 5 to 10 percent, is enough to send a cell careening down the path to cancer, Croce says.
One of the most delicately balanced cancer-associated proteins is PTEN. It reins in cell growth to prevent wild replication, as seen in cancer. In the parlance of cancer research, PTEN is known as a tumor suppressor, and it works best when there is just the right amount of it.
Losing one copy of the gene for PTEN — essentially cutting protein levels in half — is enough to turn a cell cancerous, previous studies have shown. Other research has demonstrated that microRNAs, including miR-21, help govern production of PTEN. And a study reported June 24 in Nature found that a messenger RNA doppelgänger of PTEN found in healthy cells distracts PTEN-stifling microRNAs, allowing more of the protein to be made. If the twin is missing, the weight of microRNAs on messenger RNA’s back can crush protein production.
New research from Yu’s lab also suggests that reducing the amount of PTEN protein in a tumor cell even slightly is not a good idea. Higher levels of miR-21 slow down PTEN production and make breast cancer cells resistant to an anticancer agent called Herceptin, Yu and colleague Sumaiyah Rehman reported in April in Washington, D.C., at the annual meeting of the American Association for Cancer Research.
Dicer danger
PTEN isn’t the only protein that can make cancer worse. A new study shows that small changes in the amount of a protein involved in producing microRNAs can determine whether tumors stay put or spread to the rest of the body.
That discovery grew from efforts to figure out why most microRNAs are at lower levels in cancer cells but some microRNAs are overproduced. “We were intrigued by this paradox,” says Stefano Piccolo, a cellular and molecular biologist at the University of Padua in Italy.
The resolution came from an unexpected source, a protein that helps slice larger RNAs into microRNAs. This protein, Dicer, is a key component of the microRNA manufacturing machinery. Cutting levels of Dicer in half spurs on cancer because less of it leads to less microRNA, which can mean increased production of proteins that drive rapid growth. Still, cancer cells need some Dicer to survive and reproduce, since Dicer helps make microRNAs that regulate production of proteins.
So cancer cells need to control Dicer levels the way a student sets the volume on an iPod to provide background study music. The volume shouldn’t be too quiet or too loud. “You need to find that perfect middle,” Piccolo says.
Cells dial in just the right amount of Dicer by using a family of microRNAs, miR-103.1, miR-103.2 and miR-107, Piccolo and his colleagues reported in the June 25 Cell. Those three microRNAs, which occur at high levels in some cancer cells, latch on to messenger RNAs encoding Dicer and ratchet down its production, meaning less of other microRNAs get made. But Dicer levels never drop to nothing, because the same microRNAs rely on the protein to snip them free from larger pieces of RNA.
Piccolo’s finding neatly solves the paradox of why most microRNA levels can be low in cancer cells while some are high, but his study didn’t stop there. The research also provides further evidence that low Dicer levels make cancer more dangerous.
In the study, Piccolo’s team discovered that some aggressive tumors had higher than normal levels of the microRNAs that regulate Dicer, and thus less of the protein. More of these microRNAs were also associated with breast cancer’s spread and poor prognosis in patients.
Additional experiments with tumor cells growing in lab dishes showed that the cells usually tend to cluster. But when Dicer levels are lowered to about 50 to 60 percent of normal, or levels of miR-107 are increased, cells begin migrating across the dish. Dips in Dicer levels make cells mobile, the team suggests. Less Dicer may mean less of other microRNAs that hold back production of proteins that are responsible for getting cells in gear. With fewer inhibitory microRNAs around, go-proteins can be made and cells get a move on.
Tumor cells may be taking advantage of one of Dicer’s jobs in normal cells — helping cells move around. “Cancer doesn’t invent anything,” Piccolo says.
Tiny treatment options
Getting a clue that a microRNA is involved in a problem also gives researchers a potential solution. In experiments with mice, inhibiting miR-21 made resistant tumor cells more susceptible to Herceptin, Rehman reported at the cancer research meeting.
Increasing susceptibility to anticancer drugs is just one way that microRNAs could be useful in the clinic, says oncologist Muller Fabbri of Ohio State.
Specific microRNA levels rise or fall in different tumor types, creating a signature for that type of cancer, studies have shown. Such signatures could help correctly diagnose cancer in people whose tumors have migrated. Often pathologists can examine a brain tumor and determine that it arose from breast cancer cells, but sometimes cancer cells conceal their real birthplace. Characteristic patterns of microRNA could help identify where tumor cells originated in the 8 to 10 percent of cases when “even the pathologist doesn’t have a clue,” Fabbri says. Examining the pattern of microRNA levels in a patient’s tumor may also help doctors identify aggressive forms (SN: 2/2/08, p. 70).
In diseases such as liver cancer, researchers may be able to replace missing microRNAs or boost levels to stop the cancer, a team reported last year in Cell. And in cancers in which levels of certain microRNAs are too high, researchers can deploy decoy molecules to pull microRNAs from their targets. A team reported in January in Science that the strategy appears to work for treating hepatitis C infection in monkeys (SN: 1/2/10, p. 14).
Croce thinks that targeting several microRNAs in anarchist networks may help treat cancer with little chance of resistance developing. But such therapies are still years away. “We have to show that it is really true,” he says, “not just in experiments with mice, but in clinical trials.”
For now, no microRNA therapies are available for cancer, but researchers are watching trials of the anti-microRNA therapy against hepatitis C in people.
“The rapidity of what’s going on is what gives some of us optimism that this could have value,” Harris says. “Relatively shortly, we’re going to know the degree of importance of microRNAs.”
Source
Tiny pieces of RNA may turn cells to the dark side
By Tina Hesman Saey
August 28th, 2010; Vol.178 #5 (p. 18)
When tiny hairpin-shaped molecules act up, they don’t rebel loner-style like James Dean. Instead they take on the persona of Darth Vader, crushing proteins under their command and turning acquaintances to the dark side as well. In this case, though, the fight is for control not of the universe, but of the body. And a dark-side victory could end in cancer.
No one would have predicted a decade ago that these microRNAs, as the hairpins are called, were involved in cancer, because no one even knew that they existed in people. Mere snippets of RNA — DNA’s underappreciated cousin — these micromolecules are about 22 chemical letters long. But their size belies their power.
When on their best behavior, the molecules are competent and capable managers of the protein-building process that keeps a cell humming in perfect harmony. But when microRNAs go rogue, the results can be disastrous.
New research is revealing just how important these newly discovered molecules are. An imbalance of microRNAs can cause cancer by encouraging runaway cell growth or by dampening a cell’s defenses, and can also make the disease more stubborn. But just as Darth Vader never completely lost the young Jedi Anakin Skywalker within him, even bad microRNAs may have good in them yet. Some scientists think that therapies aimed at soothing riled-up microRNAs may help cure the very cancers that the molecules help cause.
Most of the discoveries linking microRNAs and cancer have come in the past five years. “This is extremely rapid progression,” says Curtis Harris, chief of the human carcinogenesis lab at the National Cancer Institute, based in Bethesda, Md.
Micro middle managers
The realization that such small molecules could play a big role in disease was late in coming, says Carlo Croce of Ohio State University in Columbus. “In the beginning there was no interest in microRNAs at all,” he says.
The first microRNA was discovered in 1993 in roundworms. It took another seven years before the next microRNA was found in the same organism. Though both of those microRNAs help control worm development, most scientists regarded them as biological curiosities.
But then researchers found microRNAs at work in fruit flies, people and other organisms. Those discoveries suggested that microRNAs might be important regulatory molecules for all animals, not just flukes of worm biology.
MicroRNAs work in middle management in most plant and animal cells, scientists now know. The molecules help regulate the protein-manufacturing process by essentially issuing permits decreeing when and where proteins may be built. By riding piggyback on messenger RNAs, which are copies of the protein-building blueprints contained within DNA, microRNAs prevent the instructions from reaching protein-building machinery inside cells.
While it may sound nefarious, microRNAs’ interference with protein production helps a cell maintain balance. MicroRNAs ensure that cells save energy by not making unnecessary proteins and help prevent levels of potentially harmful proteins, such as those that initiate the self-destruct program known as apoptosis, from reaching critical mass.
Each type of microRNA in a cell may potentially pair with hundreds of different types of messenger RNA, says Isidore Rigoutsos, a computational and molecular biologist at Thomas Jefferson University in Philadelphia. And each messenger RNA may have many different microRNAs piling on its back.
“It’s safe to say that microRNAs are important,” Rigoutsos says. “The difficulty is saying what are the limits of importance, and they keep being expanded more and more and more.”
Cancer connection
Croce’s lab was among the first to illustrate just how big a role the little molecules could play in people. His group showed that genes encoding microRNAs frequently go missing in tumor cells. In particular, two microRNAs, miR-15 and miR-16, are missing or found at lower than normal levels in 68 percent of chronic lymphocytic leukemia cases.
Cancer biologists usually lump microRNAs into two groups: those that protect against cancer and those that promote it (though the distinction isn’t perfect). Cancer cells tend to have lower levels of most microRNAs but have an oversupply of a few others.
In the protective corner are microRNAs such as miR-15 and miR-16. One of the many proteins regulated by those two microRNAs is BCL2, which keeps cells from pushing the self-destruct button. Cells commit suicide when they become too damaged to operate properly — an important self-defense mechanism for an organism that doesn’t want to walk around with malfunctioning cells. So cells need just the right amount of BCL2 to keep from killing themselves unnecessarily, but not so much of it that they can never die.
The microRNAs pair with messenger RNA to strike the right balance of BCL2. But when miR-15 and miR-16 levels are knocked down — which can happen if a copy of a gene is lost or if something goes wrong during microRNA manufacturing — cells make far too much BCL2, essentially disabling the self-destruct mechanism and making cells immortal. Immortality is one hallmark of cancer.
At the opposite end of the spectrum is one of the baddest microRNA bad boys, miR-21. Elevated levels cause cancer in mice, researchers from Yale University reported online August 8 in Nature. And higher than normal levels have been linked to at least 13 major types of cancer in people and to poor prognoses for people with colon, lung, breast, pancreatic or head and neck cancers, Harris says (SN: 2/2/08, p. 70).
High levels of miR-21 can slow an important cellular security system involving a protein named p53, researchers from the University of California, Santa Barbara have found. This protein performs multiple protective services, including spurring repair of damaged DNA, halting growth until damage is repaired or ending it all if repair isn’t possible (SN: 12/6/08, p. 22). Last year researchers reported in Nature that p53 helps slice microRNAs into their mature form. Too much miR-21 can strip cells of their p53 defenses, leading to cancer.
Though miR-21 has stood out among the troublemakers, Croce’s team has shown that this microRNA and others don’t work alone. The molecular managers are master networkers. In 50 different normal human tissues, microRNAs collaborate to direct cellular activities, Croce and colleagues reported online May 3 in Genome Research. The networks consist of microRNAs that help direct production of proteins, some of which, in turn, control production of other microRNAs, and so on.
But time and again, in 51 different types of cancer, Croce’s team found that the microRNAs’ teamwork had broken down. The cohesive networks disintegrated into rogue hubs of activity. These anarchist factions throw a wrench into the well-oiled machinery that usually keeps a cell healthy.
It’s a rather small wrench, though. MicroRNAs wield their power subtly, tweaking and massaging protein levels up or down a wee bit here and there instead of stopping production altogether.
“A microRNA doesn’t function like an ‘off’ switch,” says cancer biologist Dihua Yu of the University of Texas MD Anderson Cancer Center in Houston.
Even a little bump or dip in protein levels, maybe by just 5 to 10 percent, is enough to send a cell careening down the path to cancer, Croce says.
One of the most delicately balanced cancer-associated proteins is PTEN. It reins in cell growth to prevent wild replication, as seen in cancer. In the parlance of cancer research, PTEN is known as a tumor suppressor, and it works best when there is just the right amount of it.
Losing one copy of the gene for PTEN — essentially cutting protein levels in half — is enough to turn a cell cancerous, previous studies have shown. Other research has demonstrated that microRNAs, including miR-21, help govern production of PTEN. And a study reported June 24 in Nature found that a messenger RNA doppelgänger of PTEN found in healthy cells distracts PTEN-stifling microRNAs, allowing more of the protein to be made. If the twin is missing, the weight of microRNAs on messenger RNA’s back can crush protein production.
New research from Yu’s lab also suggests that reducing the amount of PTEN protein in a tumor cell even slightly is not a good idea. Higher levels of miR-21 slow down PTEN production and make breast cancer cells resistant to an anticancer agent called Herceptin, Yu and colleague Sumaiyah Rehman reported in April in Washington, D.C., at the annual meeting of the American Association for Cancer Research.
Dicer danger
PTEN isn’t the only protein that can make cancer worse. A new study shows that small changes in the amount of a protein involved in producing microRNAs can determine whether tumors stay put or spread to the rest of the body.
That discovery grew from efforts to figure out why most microRNAs are at lower levels in cancer cells but some microRNAs are overproduced. “We were intrigued by this paradox,” says Stefano Piccolo, a cellular and molecular biologist at the University of Padua in Italy.
The resolution came from an unexpected source, a protein that helps slice larger RNAs into microRNAs. This protein, Dicer, is a key component of the microRNA manufacturing machinery. Cutting levels of Dicer in half spurs on cancer because less of it leads to less microRNA, which can mean increased production of proteins that drive rapid growth. Still, cancer cells need some Dicer to survive and reproduce, since Dicer helps make microRNAs that regulate production of proteins.
So cancer cells need to control Dicer levels the way a student sets the volume on an iPod to provide background study music. The volume shouldn’t be too quiet or too loud. “You need to find that perfect middle,” Piccolo says.
Cells dial in just the right amount of Dicer by using a family of microRNAs, miR-103.1, miR-103.2 and miR-107, Piccolo and his colleagues reported in the June 25 Cell. Those three microRNAs, which occur at high levels in some cancer cells, latch on to messenger RNAs encoding Dicer and ratchet down its production, meaning less of other microRNAs get made. But Dicer levels never drop to nothing, because the same microRNAs rely on the protein to snip them free from larger pieces of RNA.
Piccolo’s finding neatly solves the paradox of why most microRNA levels can be low in cancer cells while some are high, but his study didn’t stop there. The research also provides further evidence that low Dicer levels make cancer more dangerous.
In the study, Piccolo’s team discovered that some aggressive tumors had higher than normal levels of the microRNAs that regulate Dicer, and thus less of the protein. More of these microRNAs were also associated with breast cancer’s spread and poor prognosis in patients.
Additional experiments with tumor cells growing in lab dishes showed that the cells usually tend to cluster. But when Dicer levels are lowered to about 50 to 60 percent of normal, or levels of miR-107 are increased, cells begin migrating across the dish. Dips in Dicer levels make cells mobile, the team suggests. Less Dicer may mean less of other microRNAs that hold back production of proteins that are responsible for getting cells in gear. With fewer inhibitory microRNAs around, go-proteins can be made and cells get a move on.
Tumor cells may be taking advantage of one of Dicer’s jobs in normal cells — helping cells move around. “Cancer doesn’t invent anything,” Piccolo says.
Tiny treatment options
Getting a clue that a microRNA is involved in a problem also gives researchers a potential solution. In experiments with mice, inhibiting miR-21 made resistant tumor cells more susceptible to Herceptin, Rehman reported at the cancer research meeting.
Increasing susceptibility to anticancer drugs is just one way that microRNAs could be useful in the clinic, says oncologist Muller Fabbri of Ohio State.
Specific microRNA levels rise or fall in different tumor types, creating a signature for that type of cancer, studies have shown. Such signatures could help correctly diagnose cancer in people whose tumors have migrated. Often pathologists can examine a brain tumor and determine that it arose from breast cancer cells, but sometimes cancer cells conceal their real birthplace. Characteristic patterns of microRNA could help identify where tumor cells originated in the 8 to 10 percent of cases when “even the pathologist doesn’t have a clue,” Fabbri says. Examining the pattern of microRNA levels in a patient’s tumor may also help doctors identify aggressive forms (SN: 2/2/08, p. 70).
In diseases such as liver cancer, researchers may be able to replace missing microRNAs or boost levels to stop the cancer, a team reported last year in Cell. And in cancers in which levels of certain microRNAs are too high, researchers can deploy decoy molecules to pull microRNAs from their targets. A team reported in January in Science that the strategy appears to work for treating hepatitis C infection in monkeys (SN: 1/2/10, p. 14).
Croce thinks that targeting several microRNAs in anarchist networks may help treat cancer with little chance of resistance developing. But such therapies are still years away. “We have to show that it is really true,” he says, “not just in experiments with mice, but in clinical trials.”
For now, no microRNA therapies are available for cancer, but researchers are watching trials of the anti-microRNA therapy against hepatitis C in people.
“The rapidity of what’s going on is what gives some of us optimism that this could have value,” Harris says. “Relatively shortly, we’re going to know the degree of importance of microRNAs.”
Source
Alpha-fetoprotein above normal levels as a risk factor for the development of hepatocellular carcinoma in patients infected with hepatitis C virus
Journal of Gastroenterology
DOI: 10.1007/s00535-010-0293-6
Masakuni Tateyama, Hiroshi Yatsuhashi, Naota Taura, Yasuhide Motoyoshi, Shinya Nagaoka, Kenji Yanagi, Seigo Abiru, Koji Yano, Atsumasa Komori and Kiyoshi Migita, et al.
Abstract
Background
Noninvasive risk factors are required for predicting the development of hepatocellular carcinoma (HCC) not only in patients with cirrhosis but also in those with chronic hepatitis who are infected with hepatitis C virus (HCV).
Methods
A total of 707 patients with chronic HCV infection without other risks were evaluated for the predictive value of noninvasive risk factors for HCC, including age, sex, viral load, genotype, fibrosis stage, aspartate and alanine aminotransferase levels, bilirubin, albumin, platelet count, and alpha-fetoprotein (AFP) at entry to the study, as well as interferon (IFN) therapy they received.
Results
The ten-year cumulative incidence rates of HCC for patients with fibrosis stages F0/F1, F2, F3, and F4 were 2.5, 12.8, 19.3, and 55.9%, respectively. Multivariate analysis identified age ≥57 years [hazard ratio (HR) 2.026, P = 0.004], fibrosis stage F4 (HR 3.957, P < 0.001), and AFP 6–20 ng/mL (HR 1.942, P = 0.030) and ≥20 ng/mL (HR 3.884, P < 0.001), as well as the response to IFN [relative risk (RR) 0.099, P < 0.001], as independent risk factors for the development of HCC. The ten-year cumulative incidence rates of HCC in the patients with AFP levels of <6, 6–20, and ≥20 ng/mL at entry were 6.0, 24.6, and 47.3%, respectively.
Conclusions
Not only high (>20 ng/mL), but also even slightly elevated (6–20 ng/mL) AFP levels, could serve as a risk factor for HCC to complement the fibrosis stage. In contrast, AFP levels <6 ng/mL indicate a low risk of HCC development in patients infected with HCV, irrespective of the fibrosis stage.
Keywords Alpha-fetoprotein - Hepatitis C virus - Hepatocellular carcinoma
Source
DOI: 10.1007/s00535-010-0293-6
Masakuni Tateyama, Hiroshi Yatsuhashi, Naota Taura, Yasuhide Motoyoshi, Shinya Nagaoka, Kenji Yanagi, Seigo Abiru, Koji Yano, Atsumasa Komori and Kiyoshi Migita, et al.
Abstract
Background
Noninvasive risk factors are required for predicting the development of hepatocellular carcinoma (HCC) not only in patients with cirrhosis but also in those with chronic hepatitis who are infected with hepatitis C virus (HCV).
Methods
A total of 707 patients with chronic HCV infection without other risks were evaluated for the predictive value of noninvasive risk factors for HCC, including age, sex, viral load, genotype, fibrosis stage, aspartate and alanine aminotransferase levels, bilirubin, albumin, platelet count, and alpha-fetoprotein (AFP) at entry to the study, as well as interferon (IFN) therapy they received.
Results
The ten-year cumulative incidence rates of HCC for patients with fibrosis stages F0/F1, F2, F3, and F4 were 2.5, 12.8, 19.3, and 55.9%, respectively. Multivariate analysis identified age ≥57 years [hazard ratio (HR) 2.026, P = 0.004], fibrosis stage F4 (HR 3.957, P < 0.001), and AFP 6–20 ng/mL (HR 1.942, P = 0.030) and ≥20 ng/mL (HR 3.884, P < 0.001), as well as the response to IFN [relative risk (RR) 0.099, P < 0.001], as independent risk factors for the development of HCC. The ten-year cumulative incidence rates of HCC in the patients with AFP levels of <6, 6–20, and ≥20 ng/mL at entry were 6.0, 24.6, and 47.3%, respectively.
Conclusions
Not only high (>20 ng/mL), but also even slightly elevated (6–20 ng/mL) AFP levels, could serve as a risk factor for HCC to complement the fibrosis stage. In contrast, AFP levels <6 ng/mL indicate a low risk of HCC development in patients infected with HCV, irrespective of the fibrosis stage.
Keywords Alpha-fetoprotein - Hepatitis C virus - Hepatocellular carcinoma
Source
Hep C lawsuit asserts 1991 incident at Texas hospital should have increased caution
By Felisa Cardona
The Denver Post
Posted: 08/15/2010 01:00:00 AM MDT
Eighteen years before surgery scrub technician Kristen Parker infected 18 patients at Rose Medical Center with hepatitis C, another employee infected patients the same way at a Texas hospital later owned by one of the owners of Rose.
A lawsuit filed in Denver District Court states that Hospital Corporation of America, which partly owns Rose Medical Center, should have been more careful with the way drugs were stored and secured after its earlier lawsuit.
Parker, 27, is serving 30 years in federal prison after she injected herself with the painkiller fentanyl that was meant for surgery patients. She then filled the syringes with saline and placed them back on carts, resulting in the patients being injected with the infected needles during surgery.
The latest lawsuit, filed Aug. 3, claims anesthesiologists left the drugs in unlocked surgery rooms — in violation of hospital policy and state and federal statutes.
"Every single surgery room at Rose had controlled substances that were intended for vulnerable surgery patients lying around for drug addicts like Parker to divert, use and fill with saline," said patients' attorney Hollynd Hoskins.
Five lawsuits are pending against Rose Medical Center, and one has been settled, said Cara Harshberger, spokeswoman for the hospital.
The first case set for trial is in June before Denver District Judge Herbert Stern.
The latest suit was filed by Hoskins on behalf of a Denver mother of three who is using the initials L.K. because she does not want her medical condition made public.
For six minutes, a syringe filled with the painkiller fentanyl sat unsecured in a surgery room before L.K.'s procedure on Feb. 13, 2009. The lawsuit says that is when Parker stole the drug and left the infected needle behind.
The anesthesiologist, Dr. Herbert N. Chado, named as a defendant in the lawsuit, unknowingly injected L.K. with the contaminated needle, and months later, the woman learned that she was infected with hepatitis C.
L.K. underwent interferon treatment and, at first, responded to the medication, but the virus has since come back.
In 1994, the Colorado Board of Medical Examiners placed Chado on five years of probation for abusing the drug Sufenta, an opiate. Chado, who pursued treatment, did not practice medicine from 1993 to 2001, state records show.
Chado did not return a call seeking comment about the lawsuit.
Minutes before L.K. was infected, Chado failed to lock the surgery room and didn't have the fentanyl in his sight, the suit says.
"We have had and continue to have rigorous controls in place to ensure medication security," Harshberger said. "This includes having pass- code-protected computerized medication systems in each operating room, with methodical auditing of the usage of that equipment, providing ongoing education for staff and physicians regarding medication security, and exploring options for packaging of medication."
In 1991, scrub tech David Wayne Thomas stole fentanyl from the now-defunct Mid-Cities Surgi-Center in Bedford, Texas.
The hospital was owned by Medical Care America at the time of the incident but was acquired by Hospital Corporation of America in 1994, Harshberger said.
Thomas, who was infected with hepatitis C, pleaded guilty to stealing the drugs and served three years of an eight-year sentence, according to a 1995 Fort Worth Star-Telegram article. It is not clear whether Thomas knew he was infected with the virus, as Parker did, when he was contaminating the needles.
Civil lawsuits were brought by 48 patients against Hospital Corporation of America and the anesthesiologists who were responsible for securing the medication. The cases were settled.
Legal experts told the newspaper the settlements could have surpassed $100 million.
Harshberger said Rose remains committed to helping patients, including paying for the testing and treatment of those affected by Parker's actions.
"The criminal actions of this former employee put our patients at risk, and for that we were truly saddened and angered," she said.
Felisa Cardona: 303-954-1219 or fcardona@denverpost.com
Source
The Denver Post
Posted: 08/15/2010 01:00:00 AM MDT
Eighteen years before surgery scrub technician Kristen Parker infected 18 patients at Rose Medical Center with hepatitis C, another employee infected patients the same way at a Texas hospital later owned by one of the owners of Rose.
A lawsuit filed in Denver District Court states that Hospital Corporation of America, which partly owns Rose Medical Center, should have been more careful with the way drugs were stored and secured after its earlier lawsuit.
Parker, 27, is serving 30 years in federal prison after she injected herself with the painkiller fentanyl that was meant for surgery patients. She then filled the syringes with saline and placed them back on carts, resulting in the patients being injected with the infected needles during surgery.
The latest lawsuit, filed Aug. 3, claims anesthesiologists left the drugs in unlocked surgery rooms — in violation of hospital policy and state and federal statutes.
"Every single surgery room at Rose had controlled substances that were intended for vulnerable surgery patients lying around for drug addicts like Parker to divert, use and fill with saline," said patients' attorney Hollynd Hoskins.
Five lawsuits are pending against Rose Medical Center, and one has been settled, said Cara Harshberger, spokeswoman for the hospital.
The first case set for trial is in June before Denver District Judge Herbert Stern.
The latest suit was filed by Hoskins on behalf of a Denver mother of three who is using the initials L.K. because she does not want her medical condition made public.
For six minutes, a syringe filled with the painkiller fentanyl sat unsecured in a surgery room before L.K.'s procedure on Feb. 13, 2009. The lawsuit says that is when Parker stole the drug and left the infected needle behind.
The anesthesiologist, Dr. Herbert N. Chado, named as a defendant in the lawsuit, unknowingly injected L.K. with the contaminated needle, and months later, the woman learned that she was infected with hepatitis C.
L.K. underwent interferon treatment and, at first, responded to the medication, but the virus has since come back.
In 1994, the Colorado Board of Medical Examiners placed Chado on five years of probation for abusing the drug Sufenta, an opiate. Chado, who pursued treatment, did not practice medicine from 1993 to 2001, state records show.
Chado did not return a call seeking comment about the lawsuit.
Minutes before L.K. was infected, Chado failed to lock the surgery room and didn't have the fentanyl in his sight, the suit says.
"We have had and continue to have rigorous controls in place to ensure medication security," Harshberger said. "This includes having pass- code-protected computerized medication systems in each operating room, with methodical auditing of the usage of that equipment, providing ongoing education for staff and physicians regarding medication security, and exploring options for packaging of medication."
In 1991, scrub tech David Wayne Thomas stole fentanyl from the now-defunct Mid-Cities Surgi-Center in Bedford, Texas.
The hospital was owned by Medical Care America at the time of the incident but was acquired by Hospital Corporation of America in 1994, Harshberger said.
Thomas, who was infected with hepatitis C, pleaded guilty to stealing the drugs and served three years of an eight-year sentence, according to a 1995 Fort Worth Star-Telegram article. It is not clear whether Thomas knew he was infected with the virus, as Parker did, when he was contaminating the needles.
Civil lawsuits were brought by 48 patients against Hospital Corporation of America and the anesthesiologists who were responsible for securing the medication. The cases were settled.
Legal experts told the newspaper the settlements could have surpassed $100 million.
Harshberger said Rose remains committed to helping patients, including paying for the testing and treatment of those affected by Parker's actions.
"The criminal actions of this former employee put our patients at risk, and for that we were truly saddened and angered," she said.
Felisa Cardona: 303-954-1219 or fcardona@denverpost.com
Source
Death at his back
As his body succumbs to hepatitis C, inmate spends last days trying to warn others
11:33 PM CDT on Saturday, August 14, 2010
By Donna Fielder / Staff Writer
This is a cautionary tale from a dead man walking.
Michael Mabry doesn’t have a lot to be proud of.
He’s been in and out of prison all his adult life. He’s been a speed fiend and a cokehead most of that time. He’s been busted for drugs and burglarizing buildings and tried two jailbreaks, and he has a criminal record in three states. He has eight children “scattered around,” he says, but he’s mostly alone now.
He’s a dead man, he says.
He won’t leave the infirmary at the Denton County Jail alive. Hepatitis C attacked his liver before he knew anything was wrong. By the time it was diagnosed, he was in the final stages of cirrhosis of the liver, and there’s nothing anyone can do for him, in jail or not.
So the 49-year-old Denton man sits on his cot in a medical cell, with a commode in the open a couple of feet away and the only decoration a roll of toilet paper and some graffiti scratched on the wall, and he thinks about his life and what he’s done wrong. He wonders what he could do to maybe get one small mark on the right side of his sheet.
“I don’t think I’ve done anything to warrant going to hell,” he says. “But you never know. It sure wouldn’t hurt to get a few points in with the Man up there.”
He doesn’t have much time. He’s a con man, he admits. But he can’t con his way out of the trouble he’s in.
The only thing Mabry can offer is his life experience and its consequences as a warning to others. He got hepatitis C from jailhouse tattoos, he says. Everybody in prison gets tats; many contract hepatitis C from the methods they use.
But it’s the youngsters he’d like to help now, he said. Tattoos also are popular with the general population. Most adults go to tattoo parlors that are licensed by the state and have strict guidelines to hold down the chance of contracting a disease from infected implements. But those younger than 18 must have parental permission to legally obtain a tattoo. Many young people turn to more informal — and more dangerous — methods of inking up.
Gang wannabes use homemade devices to ink in their gang affiliations. Other kids get a friend to help them render forever their girlfriends’ names or symbols that have meaning to them. If they knew, Mabry says, if they understood that dirty needles, shared tattoo devices made of paper clips, safety pins — the myriad other unhealthy, sharp things — can kill them, maybe they wouldn’t get started down that road.
According to medical information provided by a website devoted to hepatitis, 4 million Americans now have hepatitis C.
It is more prevalent in Europe, but it emerged in the U.S. in the 1960s, related to blood transfusions and intravenous drug use. A reliable test for it was developed in the 1990s, and it was revealed to be a much larger problem than anyone knew. It causes cirrhosis of the liver and liver cancer.
When casual users share a needle to inject drugs or an instrument to inject ink under the skin, blood can be transmitted from one person to another. Hepatitis C is one of the diseases that can be transmitted in blood. It attacks the liver — and left untreated, destroys it.
The liver has many functions, including filtering harmful substances from the blood, breaking down fats, storing vitamins and producing urea. The body cannot survive without it. Cirrhosis inflames the liver and ultimately causes it to fail. Caught early, the symptoms can be treated. But it is incurable.
Jailhouse prevalence of hepatitis C
Doug Sanders supervises the medical staff at the jail. He believes that Mabry is within weeks of death. Since Mabry’s disease is only communicable by bodily fluid exchange, there’s no reason to isolate him, he said. The staff manages his medication to try to keep him comfortable.
Since Mabry also injected drugs, he could have contracted hepatitis from a dirty needle. But he is convinced it was a tattoo needle, and since he has so many tattoos, it is reasonable to think that he is right, Sanders said.
“It’s alarming. It’s extremely prevalent in jail populations. You might think the HIV virus would be more prevalent, but the greatest risk exposure in jails and prisons nationwide is hepatitis C.”
Jail administrators try hard to keep inmates from finding ways to make jailhouse tattoos, Sanders said. Guards seize anything that could be used to make them.
“We are absolutely discouraging it. We confiscate it. But they have so many ways of engineering a machine. They find ways around it,” he said.
Mabry’s isn’t the first advanced case that the jail medical staff have treated. They are preparing him as best they can for the suffering he’s about to endure, Sanders said. “He has some very difficult days ahead.”
A dim future
Death is becoming real for Mabry. He spends a lot of time talking to chaplain Bobby Ayers. He’s working on a bill he’d like to become a law. He knows he’s not going to finish it, so he offers advice.
“Kids are knuckleheaded, you know,” Mabry says. “If I could save one kid ...”
Perched on his cot, his longish black hair slicked down, his orange jumpsuit covering the numerous tats on his back, chest and legs, he thinks about that for a minute.
“It ain’t just the needle you get it from. It’s the ink they reuse,” he said. “You know, I studied the law and I beat it one time. I slicked out of a charge I did on a technicality. They wrote on my paperwork that I’m a master manipulator of the law. I studied this disease. I’m not stupid. I studied to find a way to beat it, but you can’t.”
He pulls up his shirt to display drug- and gang-related tattoos. He has a bandito tat on his chest, a large dagger with a snake wrapped around it — he says it’s related to Rex Cauble and the Cowboy Mafia — on one leg, and a fairly good rendering of the Grim Reaper on his back.
“He’s coming for me, by God,” he said. “It’s day by day now.”
Mabry demonstrates how a tattoo machine can be made with things not considered contraband in the jail and some that are. A decent jailhouse tattoo machine can be constructed with a ballpoint pen, a paper clip, some string and the tiny motor from a Walkman, he says. Ashes and shampoo can be combined to make ink.
Walkman tape players are no longer available at the county jail. Mabry said an inmate can always figure out another way.
“We say you can put one prisoner on one roof with a match and another one on another roof a mile away with a cigarette, and before you know it both of them have half a match and half a cigarette and they’re both smoking,” he said.
Mabry says his liver no longer functions. It swelled, he said, until it broke his ribs. He said he’s had eight heart attacks since he was diagnosed less than a year ago, and his aorta burst because his veins and arteries thinned out. He also has diabetes. He’s in pain, which the medical personnel in the infirmary try to lessen with drugs. He’s a poster boy for staying away from casual tattoos. If you have to get them, go to a licensed tattoo shop, he says. They have rules to keep things clean.
Mabry often loses his train of thought. He rambles and forgets.
“The worst part of this disease is your brain goes,” he said. “They tell me that when it gets that far, it’s the best thing for me. But I don’t want my brain to go and just be lying here.”
He thinks a minute and then laughs.
“I have a million dollars worth of medical bills right now. But they ain’t never gonna get it. Maybe somebody will read this story and it will save them. It’d be good if I could at least do that.”
DONNA FIELDER can be reached at 940-566-6885. Her e-mail address is dfielder@dentonrc.com.
Source
11:33 PM CDT on Saturday, August 14, 2010
By Donna Fielder / Staff Writer
This is a cautionary tale from a dead man walking.
Michael Mabry doesn’t have a lot to be proud of.
He’s been in and out of prison all his adult life. He’s been a speed fiend and a cokehead most of that time. He’s been busted for drugs and burglarizing buildings and tried two jailbreaks, and he has a criminal record in three states. He has eight children “scattered around,” he says, but he’s mostly alone now.
He’s a dead man, he says.
He won’t leave the infirmary at the Denton County Jail alive. Hepatitis C attacked his liver before he knew anything was wrong. By the time it was diagnosed, he was in the final stages of cirrhosis of the liver, and there’s nothing anyone can do for him, in jail or not.
So the 49-year-old Denton man sits on his cot in a medical cell, with a commode in the open a couple of feet away and the only decoration a roll of toilet paper and some graffiti scratched on the wall, and he thinks about his life and what he’s done wrong. He wonders what he could do to maybe get one small mark on the right side of his sheet.
“I don’t think I’ve done anything to warrant going to hell,” he says. “But you never know. It sure wouldn’t hurt to get a few points in with the Man up there.”
He doesn’t have much time. He’s a con man, he admits. But he can’t con his way out of the trouble he’s in.
The only thing Mabry can offer is his life experience and its consequences as a warning to others. He got hepatitis C from jailhouse tattoos, he says. Everybody in prison gets tats; many contract hepatitis C from the methods they use.
But it’s the youngsters he’d like to help now, he said. Tattoos also are popular with the general population. Most adults go to tattoo parlors that are licensed by the state and have strict guidelines to hold down the chance of contracting a disease from infected implements. But those younger than 18 must have parental permission to legally obtain a tattoo. Many young people turn to more informal — and more dangerous — methods of inking up.
Gang wannabes use homemade devices to ink in their gang affiliations. Other kids get a friend to help them render forever their girlfriends’ names or symbols that have meaning to them. If they knew, Mabry says, if they understood that dirty needles, shared tattoo devices made of paper clips, safety pins — the myriad other unhealthy, sharp things — can kill them, maybe they wouldn’t get started down that road.
According to medical information provided by a website devoted to hepatitis, 4 million Americans now have hepatitis C.
It is more prevalent in Europe, but it emerged in the U.S. in the 1960s, related to blood transfusions and intravenous drug use. A reliable test for it was developed in the 1990s, and it was revealed to be a much larger problem than anyone knew. It causes cirrhosis of the liver and liver cancer.
When casual users share a needle to inject drugs or an instrument to inject ink under the skin, blood can be transmitted from one person to another. Hepatitis C is one of the diseases that can be transmitted in blood. It attacks the liver — and left untreated, destroys it.
The liver has many functions, including filtering harmful substances from the blood, breaking down fats, storing vitamins and producing urea. The body cannot survive without it. Cirrhosis inflames the liver and ultimately causes it to fail. Caught early, the symptoms can be treated. But it is incurable.
Jailhouse prevalence of hepatitis C
Doug Sanders supervises the medical staff at the jail. He believes that Mabry is within weeks of death. Since Mabry’s disease is only communicable by bodily fluid exchange, there’s no reason to isolate him, he said. The staff manages his medication to try to keep him comfortable.
Since Mabry also injected drugs, he could have contracted hepatitis from a dirty needle. But he is convinced it was a tattoo needle, and since he has so many tattoos, it is reasonable to think that he is right, Sanders said.
“It’s alarming. It’s extremely prevalent in jail populations. You might think the HIV virus would be more prevalent, but the greatest risk exposure in jails and prisons nationwide is hepatitis C.”
Jail administrators try hard to keep inmates from finding ways to make jailhouse tattoos, Sanders said. Guards seize anything that could be used to make them.
“We are absolutely discouraging it. We confiscate it. But they have so many ways of engineering a machine. They find ways around it,” he said.
Mabry’s isn’t the first advanced case that the jail medical staff have treated. They are preparing him as best they can for the suffering he’s about to endure, Sanders said. “He has some very difficult days ahead.”
A dim future
Death is becoming real for Mabry. He spends a lot of time talking to chaplain Bobby Ayers. He’s working on a bill he’d like to become a law. He knows he’s not going to finish it, so he offers advice.
“Kids are knuckleheaded, you know,” Mabry says. “If I could save one kid ...”
Perched on his cot, his longish black hair slicked down, his orange jumpsuit covering the numerous tats on his back, chest and legs, he thinks about that for a minute.
“It ain’t just the needle you get it from. It’s the ink they reuse,” he said. “You know, I studied the law and I beat it one time. I slicked out of a charge I did on a technicality. They wrote on my paperwork that I’m a master manipulator of the law. I studied this disease. I’m not stupid. I studied to find a way to beat it, but you can’t.”
He pulls up his shirt to display drug- and gang-related tattoos. He has a bandito tat on his chest, a large dagger with a snake wrapped around it — he says it’s related to Rex Cauble and the Cowboy Mafia — on one leg, and a fairly good rendering of the Grim Reaper on his back.
“He’s coming for me, by God,” he said. “It’s day by day now.”
Mabry demonstrates how a tattoo machine can be made with things not considered contraband in the jail and some that are. A decent jailhouse tattoo machine can be constructed with a ballpoint pen, a paper clip, some string and the tiny motor from a Walkman, he says. Ashes and shampoo can be combined to make ink.
Walkman tape players are no longer available at the county jail. Mabry said an inmate can always figure out another way.
“We say you can put one prisoner on one roof with a match and another one on another roof a mile away with a cigarette, and before you know it both of them have half a match and half a cigarette and they’re both smoking,” he said.
Mabry says his liver no longer functions. It swelled, he said, until it broke his ribs. He said he’s had eight heart attacks since he was diagnosed less than a year ago, and his aorta burst because his veins and arteries thinned out. He also has diabetes. He’s in pain, which the medical personnel in the infirmary try to lessen with drugs. He’s a poster boy for staying away from casual tattoos. If you have to get them, go to a licensed tattoo shop, he says. They have rules to keep things clean.
Mabry often loses his train of thought. He rambles and forgets.
“The worst part of this disease is your brain goes,” he said. “They tell me that when it gets that far, it’s the best thing for me. But I don’t want my brain to go and just be lying here.”
He thinks a minute and then laughs.
“I have a million dollars worth of medical bills right now. But they ain’t never gonna get it. Maybe somebody will read this story and it will save them. It’d be good if I could at least do that.”
DONNA FIELDER can be reached at 940-566-6885. Her e-mail address is dfielder@dentonrc.com.
Source
Physicians Concerned About Nationwide Drug Shortages
Reported by: Kevin Reece - KHOU TV
HOUSTON - A watchdog group calls the current state of drug shortages in this country “alarming” and doctors in the Texas Medical Center agree the problem is more severe this summer than in years past.
Jonathan O’Malley, 18, is a leukemia patient at MD Anderson. Earlier this year he received a cord blood transplant and doctors are managing his recovery and the variety of health issues his fight includes. Among the litany of problems chemotherapy has already brought him, he's developed an infection. It’s called cytomegalovirus or CMV. The recommended treatment and final line of defense for Jonathan is an anti-viral drug called Foscarnet.
But on the blog kept by Jonathan's parents, we noticed this disturbing sentence from his mom: "There is a nationwide shortage of this drug and they have absolutely none available...this could be life or death for so many cancer patients," Melanie O’Malley wrote.
At Texas Children's Hospital we found a doctor who agreed.
“For these patients these drugs are life-saving and absolutely vital,” said Dr. Robert Krance, a stem cell and gene therapy expert. Two of his stem cell transplant patients also rely on Foscarnet to keep infections in check.
"And when you don't have suitable alternatives you really have patients at risk for having complications and even fatal complications if you can't work around that,” Krance said.
So why is Foscarnet suddenly in short supply? That's a difficult answer to get.
It was originally made by two companies: Astra Zeneca and Hospira. Astra Zeneca stopped making the drug last year. And now Hospira has temporarily halted production altogether.
The company, headquartered in Lake Forest, Illinois would only tell us by email that: “We expect to be back on the market in the fourth quarter (the quarter starting Oct. 1 and running through Dec. 31).” A report by the American Society of Health-Systems Pharmacists last month stated that “Hospira has Foscarnet presentations on hold due to product testing out of specification.”
"We really don't get a very clear reason why it happens so you're always left somewhat in the dark,” said Krance.
And it's not the only drug in short supply. The American Society of Health System Pharmacists currently lists shortages for more than 140 drugs and drug products including the likes of Hepatitis A Vaccine, morphine injections, and measles, mumps, and rubella vaccine.
The institute for Safe Medication Practices called the shortages "alarming," "unprecedented" and "grim."
"I think a lot of that is financial pressure,” said Wendy Smith RPH, PharmD, a pharmacist at MD Anderson. “There's not a lot of excess drugs sitting on the shelf at any one place."
Smith agrees the shortages are more severe this summer. But said managing sparse drug supplies are a daily part of doing business.
The Food and Drug Administration blames shortages on the business decisions of drug companies, occasional problems with manufacturing, or, in the case of Foscarnet, only one company finds it profitable to produce.
“We may not ever know why a particular product was shorted out,” added Smith.”So it's frustrating for a lot of people."
"We try to preserve product for patients who need it the most and try to withstand and wait until things on the production is able to be picked up,” said Smith.
As for Jonathan, we are told he has enough of the drugs he needs at least for now. Although Krance says he wishes it wasn’t an issue at all.
“When drugs are no longer available to a patient who needs it desperately, it's often too late,” said Krance
Source
The Race Is On For Hepatitis C Treatment
On Friday August 13, 2010, 6:57 pm EDT
How's this for a biopharmaceutical market opportunity? Prospective patients in need: 170 million. That's 3% of the world's population.
The disease is hepatitis C, a contagious, slow-developing, blood-borne disease that can make 80% of those infected vulnerable to severe liver problems, including cirrhosis and cancer.
Hepatitis C wasn't even identified until 1987. A blood test for it became available in 1992.
Now a score of companies are racing to bring new treatments on stream. Out front are Merck (NYSE:MRK - News) with boceprevir, and a partnership of Vertex Pharmaceuticals (NMS:VRTX) and Johnson & Johnson (NYSE:JNJ - News) with telaprevir.
The market will be pretty much evenly split between the two, says Damien Conover, a strategist and senior pharmaceutical analyst at rating firm Morningstar. Telaprevir may have a slight edge, he says.
Both drugs are protease inhibitors, which prevent a virus from replicating itself. While they treat the same disease, they are different in both results and side effects.
Used on patients who have had no previous treatment, boceprevir and telaprevir beat down the hepatitis C virus to undetectable levels in 66% and 75% of patients respectively, Conover says.
Both drugs are likely to go to the Food and Drug Administration for a verdict by the end of the year. That means both could reach the market next year.
"Right now it's hard to tell who's in the lead," Conover said.
Meanwhile, Merck and Vertex-J&J appear to be competing for headlines.
A week ago, the British-based Lancet medical journal carried a Merck-funded study showing that boceprevir brought the virus down to undetectable levels in 66% of patients over 48 weeks of treatment in combination with drugs in use now.
The next day, Aug. 10, Vertex reported study results showing that some patients did so well after a 24-week course of telaprevir (plus the current drugs in use) that they got no added benefit from a 48-week course of treatment. The message: Telaprevir does the job in half the time.
Merck acquired boceprevir with its $41 billion purchase of Schering-Plough in 2009. Vertex developed telaprevir with money from J&J in return for marketing rights.
Whether one or both of the drugs get FDA approval, the hepatitis market is about to undergo a "major paradigm shift," said Steven Silver, an analyst at Standard & Poor's.
"We've gone many years without a new drug on the landscape," he said.
It's hard to know which drug will do better in real life and in the market because they have not been tested head-to-head.
That's a long-standing problem in the drug-development industry. Prospective new products are tested either against a placebo (sugar pills) or, as in the cases of boceprevir and telaprevir, against the current standard of care.
For hepatitis C, that standard is a combination of interferon and ribavirin. It's a hit-or-miss treatment.
In simple terms, ribavirin is an antiviral medication that stops the virus that causes hepatitis C from spreading. Interferon prevents viral replication in surrounding cells.
According to the National Center for Biotechnology Information, it's not known if treatment with ribavirin and interferon actually cures hepatitis C infection, prevents liver damage caused by hepatitis C or keeps hepatitis C from spreading to other people.
The standard hepatitis C treatment results in a reduction of the virus to undetectable levels in fewer than half of cases, according to WebMD (NMS:WBMD).
Boceprevir and telaprevir are protease inhibitors. In brief, they attack the hepatitis C virus itself, WebMD says.
Without head-to-head tests, with the same dosing regimen and with the same kind of patient population, it's hard for investors to figure out whether boceprevir or telaprevir will be the greater success, assuming both get FDA approval, Conover says.
But head-to-head studies "are often not in the best interest of the company," he said.
They can show one drug so superior as to make the other unmarketable. "Head-to-head studies can backfire," Conover said.
According to Silver, the investment community "is trying to ballpark the information released to date."
He sees Vertex prevailing with telaprevir: "It's poised to be the market leader."
Data collected on real world use of these drugs are still some years off.
The market will be watching boceprevir and telaprevir for the next three or four years, Silver says.
An important factor will be the success rate of the drugs on people who have previously failed to respond to the standard of care.
That's not how clinical trials are run. They are usually conducted with patients who have not had therapy, the so-called treatment-naive. Using treatment-naive patients creates a baseline but does not approximate real-life conditions.
Most people with a disease have tried one or more drugs, ratcheting up from least to most powerful and expensive.
Another real-life issue will be the side effects. Newly diagnosed patients may find the side effects of either drug, plus interferon and ribavirin, intolerable.
The most common telaprevir side effect is a rash, Stevens says.
Boceprevir's predominant side effect is anemia. That raises the prospect that another drug will need to be added to the regimen, perhaps Epogen, the anemia-fighting biologic from Amgen (NMS:AMGN).
It's available as a generic in Europe, but remains branded in the U.S.
Another reason to think telaprevir has the inside track is the likelihood that it will require a shorter period of treatment, Silver says.
"At the end of the day, this race will be data-driven," he said.
While there's been no head-to-head trial, the existing data should become available for close comparison at a meeting of the American Association for the Study of Liver Diseases in Boston starting Oct. 28.
By most counts, the global market for hepatitis C products is now $4 billion a year. According to a report from the commercial analysis firm Research & Markets, that should rise to $8.5 billion by 2016.
The reasons for the growth: the increasing number of cases and the new drugs in the pipeline that will make treatment more accessible and tolerable.
Source
How's this for a biopharmaceutical market opportunity? Prospective patients in need: 170 million. That's 3% of the world's population.
The disease is hepatitis C, a contagious, slow-developing, blood-borne disease that can make 80% of those infected vulnerable to severe liver problems, including cirrhosis and cancer.
Hepatitis C wasn't even identified until 1987. A blood test for it became available in 1992.
Now a score of companies are racing to bring new treatments on stream. Out front are Merck (NYSE:MRK - News) with boceprevir, and a partnership of Vertex Pharmaceuticals (NMS:VRTX) and Johnson & Johnson (NYSE:JNJ - News) with telaprevir.
The market will be pretty much evenly split between the two, says Damien Conover, a strategist and senior pharmaceutical analyst at rating firm Morningstar. Telaprevir may have a slight edge, he says.
Both drugs are protease inhibitors, which prevent a virus from replicating itself. While they treat the same disease, they are different in both results and side effects.
Used on patients who have had no previous treatment, boceprevir and telaprevir beat down the hepatitis C virus to undetectable levels in 66% and 75% of patients respectively, Conover says.
Both drugs are likely to go to the Food and Drug Administration for a verdict by the end of the year. That means both could reach the market next year.
"Right now it's hard to tell who's in the lead," Conover said.
Meanwhile, Merck and Vertex-J&J appear to be competing for headlines.
A week ago, the British-based Lancet medical journal carried a Merck-funded study showing that boceprevir brought the virus down to undetectable levels in 66% of patients over 48 weeks of treatment in combination with drugs in use now.
The next day, Aug. 10, Vertex reported study results showing that some patients did so well after a 24-week course of telaprevir (plus the current drugs in use) that they got no added benefit from a 48-week course of treatment. The message: Telaprevir does the job in half the time.
Merck acquired boceprevir with its $41 billion purchase of Schering-Plough in 2009. Vertex developed telaprevir with money from J&J in return for marketing rights.
Whether one or both of the drugs get FDA approval, the hepatitis market is about to undergo a "major paradigm shift," said Steven Silver, an analyst at Standard & Poor's.
"We've gone many years without a new drug on the landscape," he said.
It's hard to know which drug will do better in real life and in the market because they have not been tested head-to-head.
That's a long-standing problem in the drug-development industry. Prospective new products are tested either against a placebo (sugar pills) or, as in the cases of boceprevir and telaprevir, against the current standard of care.
For hepatitis C, that standard is a combination of interferon and ribavirin. It's a hit-or-miss treatment.
In simple terms, ribavirin is an antiviral medication that stops the virus that causes hepatitis C from spreading. Interferon prevents viral replication in surrounding cells.
According to the National Center for Biotechnology Information, it's not known if treatment with ribavirin and interferon actually cures hepatitis C infection, prevents liver damage caused by hepatitis C or keeps hepatitis C from spreading to other people.
The standard hepatitis C treatment results in a reduction of the virus to undetectable levels in fewer than half of cases, according to WebMD (NMS:WBMD).
Boceprevir and telaprevir are protease inhibitors. In brief, they attack the hepatitis C virus itself, WebMD says.
Without head-to-head tests, with the same dosing regimen and with the same kind of patient population, it's hard for investors to figure out whether boceprevir or telaprevir will be the greater success, assuming both get FDA approval, Conover says.
But head-to-head studies "are often not in the best interest of the company," he said.
They can show one drug so superior as to make the other unmarketable. "Head-to-head studies can backfire," Conover said.
According to Silver, the investment community "is trying to ballpark the information released to date."
He sees Vertex prevailing with telaprevir: "It's poised to be the market leader."
Data collected on real world use of these drugs are still some years off.
The market will be watching boceprevir and telaprevir for the next three or four years, Silver says.
An important factor will be the success rate of the drugs on people who have previously failed to respond to the standard of care.
That's not how clinical trials are run. They are usually conducted with patients who have not had therapy, the so-called treatment-naive. Using treatment-naive patients creates a baseline but does not approximate real-life conditions.
Most people with a disease have tried one or more drugs, ratcheting up from least to most powerful and expensive.
Another real-life issue will be the side effects. Newly diagnosed patients may find the side effects of either drug, plus interferon and ribavirin, intolerable.
The most common telaprevir side effect is a rash, Stevens says.
Boceprevir's predominant side effect is anemia. That raises the prospect that another drug will need to be added to the regimen, perhaps Epogen, the anemia-fighting biologic from Amgen (NMS:AMGN).
It's available as a generic in Europe, but remains branded in the U.S.
Another reason to think telaprevir has the inside track is the likelihood that it will require a shorter period of treatment, Silver says.
"At the end of the day, this race will be data-driven," he said.
While there's been no head-to-head trial, the existing data should become available for close comparison at a meeting of the American Association for the Study of Liver Diseases in Boston starting Oct. 28.
By most counts, the global market for hepatitis C products is now $4 billion a year. According to a report from the commercial analysis firm Research & Markets, that should rise to $8.5 billion by 2016.
The reasons for the growth: the increasing number of cases and the new drugs in the pipeline that will make treatment more accessible and tolerable.
Source
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