Healthy News for Healthy Nation

Arlin Rogers, principal research scientist in the MIT Division of Comparative Medicine, looks at slides of in his office. He and colleagues have figured out why men are more susceptible to liver cancer than women. (Credit: Photo / Donna Coveney)

A fundamental difference in the way males and females respond to chronic liver disease at the genetic level helps explain why men are more prone to liver cancer, according to MIT researchers.

“This is the first genome-wide study that helps explain why there is such a gender effect in a cancer of a nonreproductive organ, where you wouldn’t expect to see one,” said Arlin Rogers, an MIT experimental pathologist and lead author of a paper that appeared recently in the journal Cancer Research.

Men develop liver cancer at twice the rate of women in the United States. In other countries, especially in Asia, the rate for men can be eight or 10 times that for women.

Liver cancer is the fifth most common cancer in the world and the third-biggest killer. Rates in the United States are lower than those in other countries but are rising rapidly, in part due to high hepatitis C infection rates during the 1970s from blood transfusions and IV drug abuse. Obesity and type 2 diabetes are additional risk factors of current concern.

“It’s an epidemic waiting to happen,” said Rogers, a principal research scientist in MIT’s Division of Comparative Medicine.

Male and female livers are inherently different, with most of the differences arising during puberty when male livers are exposed to periodic bursts of growth hormone. This prompts male livers to express different genes than female livers, which explains why men and women can have different reactions to certain antibiotics and other medications.

The MIT team studied mice, which also have higher liver cancer rates among males. The mice were infected with Helicobacter hepaticus, which produces the same hepatitis symptoms characteristic of human hepatitis B and C.

In humans and mice, healthy males and females both can respond to acute toxins and other stresses. But the male liver is less well equipped to cope with the chronic inflammation induced by certain infectious agents.

When the male mice developed chronic hepatitis, some masculine liver genes were upregulated and others turned off. At the same time, some feminine genes were reactivated. This resulted in an unpredictable gene profile termed “liver-gender disruption.”

“There’s no rhyme or reason to it. There’s just a complete scrambling of masculine and feminine genes,” said Rogers.

When the researchers mapped the sex-specific genes, they found intimate associations with inflammatory pathways. In males with chronic hepatitis, some gender-specific genes were overexpressed and others underexpressed, the liver was unable to maintain normal metabolic function and cancer emerged in a significant number of the animals.

The authors propose that adult females are less vulnerable to liver-gender disruption because there is no requirement for the active signaling needed to maintain a masculine gene profile. Because the female liver follows the “default” developmental pathway, a greater disturbance is required to initiate the cancer process, said Rogers.

The researchers had expected that castrating male mice at one year of age when they had chronic hepatitis, but not cancer, would have a protective effect. They also gave some mice a powerful androgen to see if that would promote tumors. Neither treatment had any effect, demonstrating that male sex hormones such as testosterone do not directly promote liver cancer in adults.

These results could be relevant to cancers of other organs, such as the stomach and colon, which also are associated with chronic inflammation and are more common in men.

“This study was a collaboration between the Division of Comparative Medicine and Center for Environmental Health Sciences. It would not have been possible without the expertise and team-oriented philosophy of the wonderful scientists we have here,” said Rogers.

Authors of the paper are Elizabeth Theve, postdoctoral fellow in the Division of Comparative Medicine (DCM); Yan Feng, research scientist in DCM; Rebecca Fry, assistant scientific director for the Center for Environmental Health Sciences (CEHS); Koli Taghizadeh, research scientist in CEHS; Kristen Clapp, research technician in DCM; Chakib Boussahmain, technical assistant in DCM; Kathleen Cormier, supervisor of histology in DCM; and senior author James Fox, director of DCM and a professor in MIT’s Department of Biological Engineering.

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These three images of a mouse liver used by researchers at Stony Brook University Medical Center show: a normal liver; a diseased liver with Hepatocellular carcinoma (HCC), due to loss of the Iqgap2 gene; and another liver with HCC but with less severe disease, due to simultaneous inactivation of the Iqgap1 gene. (Credit: Image courtesy of Stony Brook University Medical Center)

An interdisciplinary team of researchers at Stony Brook University Medical Center has identified a family of genes linked to the development of liver cancer. Principal Investigator Wadie F. Bahou, M.D., Professor of Medicine and Genetics, and colleagues discovered in a mouse model that the loss of one specific gene (Iqgap2) in this family causes Hepatocellular carcinoma (HCC). They also found that when another member of the gene family (Iqgap1) is turned on, a more aggressive form of the disease occurs.

Dr. Bahou says that the findings regarding the two genes demonstrate that both genes could serve as a basis for developing important targets for early diagnosis and/or treatment of HCC. The disease accounts for more than 80 percent of all liver cancer in humans, which causes death in 500,000 to 1 million adults annually worldwide. Treatment for advanced HCC is often ineffective. A recently approved chemotherapy drug developed to treat metastatic liver cancer provides disease stabilization but not a cure.

“This is an exciting development in the field of cancer research, as there is a tremendous need for targeted therapies for liver cancer,” emphasizes Dr. Bahou. “The data resulting from our research provides important insights into genes that may predispose to HCC development,” he adds, further noting that the model is a valuable tool for testing therapeutic agents aimed at curing liver cancer.

Dr. Bahou explains that to date attempts to treat liver cancer have been difficult without appropriate animal models of disease. He says that the model generated by the Stony Brook team is the closest to human disease because:

1. The disease closely resembles human HCC microscopically;
2. does not require intervention from outside sources, such as chemically induced cancer models;
3. is associated with a reproducible and very high incidence of HCC, and
4. is strictly limited to HCC.

With expertise ranging from hematology/oncology, genetics, pharmacology and pathology, the team detailed their results in an article titled “Development of Hepatocellular Carcinoma in Iqgap2-Deficient Mice Is Iqgap1-dependent.” They collectively found that Iqgap1 and Iqgap2 have functionally divergent roles in hepatocellular carcinogenesis. When they removed the Iqgap2 gene using sophisticated genetic techniques, the mice developed HCC. This result confirmed that Iqgap2 has a fundamentally important protective role against the development of liver cancer.

When mice retained Iqgap1, the cousin gene of Iqgap2, the animals developed more advanced disease. Further experimentation showed that inactivation of Iqgap1 in the mouse liver limits the aggressiveness of HCC caused by Iqgap2 deficiency.

According to Dr. Bahou, the researchers are currently conducting similar genetic analyses in human liver cancer.

These findings are reported in the March issue of Molecular and Cellular Biology. Co-investigators of the mouse study include lead author Valentina A. Schmidt, Ph.D., Department of Medicine; Carmine S. Chiariello, Ph.D., Program in Genetics; Encarnación Capilla, Ph.D., Department of Pharmaological Sciences, and Frederick Miller, M.D., Department of Pathology. The research was supported by the National Institutes of Health.

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Taste tests were conducted at the Instituto de Investigación Nutricional in Lima, Peru, to gauge the acceptability of porridge to infants. (Credit: Photo by Maria Reyna Liria Dominguez)

Researchers with the Agricultural Research Service (ARS) and Cornell University have developed new techniques for boosting the amount of iron infants absorb from solid food.

Children who are five to six months old are growing rapidly and need sufficient iron to fuel their development. However, this is also the time when an infant’s first iron reserves start becoming depleted.

Physiologist Raymond Glahn at the ARS Plant, Soil and Nutrition Research Unit in Ithaca, N.Y., worked with Cornell nutritionist Rebecca Stoltzfus and graduate student Helena Pachón (who now works at Colombia’s International Center for Tropical Agriculture) to find ways to increase infants’ iron uptake.

The team processed freeze-dried samples of chicken liver and beef in a blender, which reduced the meat to small, uniform particles. They found that these particles–which become distributed evenly throughout cereals because of their size and consistency–can serve as a source of supplementary iron for infants.

In addition, in vitro tests indicated that iron uptake from cereal supplemented with the beef particles was greater when blending time was increased. Chicken liver particles processed in a blender for six minutes resulted in more than twice as much iron uptake than chicken liver blended for just 60 seconds.

This research can help address iron deficiency-induced anemia, a problem that affects as much as one-third of the global population. In developing countries, infants and children are especially susceptible to anemia because the solid foods they eat are often low in iron. In addition, they may not be able to absorb the iron efficiently.

Adding ingredients such as chicken thigh or chicken liver to infant meals can provide impoverished communities with more heme iron. This form of iron, which contains molecules of hemoglobin and myoglobin, is more easily absorbed and used by the body for nutritional health.

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Michael Pichichero, M.D., professor of Microbiology, Immunology and Pediatrics at the University of Rochester Medical Center. (Credit: Image courtesy of University of Rochester Medical Center)

Researchers have discovered a strain of bacteria resistant to all approved drugs used to fight ear infections in children, according to an article in the Journal of the American Medical Association. A pair of pediatricians discovered the strain because it is their standard practice to perform an uncommon procedure called tympanocentesis (ear tap) on children when several antibiotics fail to clear up their ear infections. The procedure involves puncturing the child’s eardrum and draining fluid to relieve pressure and pain. Analyzing the drained fluid is the only way to describe the bacterial strain causing the infection.

Even after the ear tap and additional rounds of antibiotics, infections persisted in a small group of children in a Rochester, New York, pediatric practice, leading to ear tube surgery and, in one case, to permanent hearing loss. The physicians realized they may be dealing with a “superbug” and tested the children’s ear tap fluid at the University of Rochester Medical Center. The tests showed that the superbug, called the 19A strain, could be killed only by an antibiotic (levofloxacin, Levaquin) approved for adults that had a warning in its label against use in children. With no other choice, they treated the children with crushed, adult-approved pills, and it worked.

The 19A strain was most likely created by a combination of the speed of bacterial evolution and the overprescribing of antibiotics, the authors said. They warn that, while it may very well never happen, the medical profession must now at least consider the prospect of a worse-case scenario: this multi-drug-resistant bacterial ear infection spreads to other communities, or invades the lungs and bloodstream, where it leads to cases of pneumonia or meningitis treatable only with unconventional antibiotics not approved for use in children.

Experts have been arguing for years that pediatricians need to determine the type of bacteria causing an ear infection before “throwing an antibiotic at it.” Most do not know, nor are the later generations of doctors required to learn, tympanocentesis, the technique that makes that determination possible, according to the authors. The decision is made to treat with antibiotics regardless of whether the strain will clear up by itself, or whether the strain in question is resistant to the antibiotic used.

“Children with the new strain of superbug represented a small subset of those in our practice, but the results are worrisome, especially since there are no new antibiotics in the pipeline for ear infections in children,” said Michael Pichichero, M.D., professor of Microbiology, Immunology and Pediatrics at the University of Rochester Medical Center, and a partner at Legacy Pediatrics, the private practice involved. “While we must be careful not to create undue alarm, the potential exists for newly evolved strains to spread to the ears of more children,” said Pichichero, an author of the JAMA article.

Using an antibiotic not approved by the U.S. Food and Drug Administration (FDA) in children is a concern because the FDA makes certain that the drug is safe and effective before granting approval, Pichichero said.

The ‘off-label’ use of drugs like levofloxacin, a fluoroquinolone antibiotic, has been an area of intense debate because of potential safety issues, and because its excessive use in children, if it came about, may create resistance to the only drug effective against the superbug.

In the age of daycare, 83 percent of U.S. children experience one or more ear infections by age three. Acute otitis media is a bacterial ear infection that causes pain, fluid buildup and hearing loss in the worst cases. Until 2000, one species of bacteria, S. pneumoniae, also called pneumoccous, was the leading cause of otitis media, as well as of pneumonia and meningitis. Thanks to technology developed in part at the University of Rochester Medical Center, Wyeth Pharmaceuticals in 2000 introduced Prevnar (pneumococcal 7-valent conjugate vaccine), which reduced the incidence of pneumonia and meningitis by at least 69 percent, and difficult to treat ear infections by 24 percent as well, researchers said.

While tetanus is caused by a single strain of bacteria, S pnemoniae seeks to evade the human immune system by coating itself in 90 variations of sugar capsule that mimic human cell coatings. Seven of these capsule variations, the most common in children and adults, were included in the 2000 version of Prevnar to create immunity against them. The 19A strain is named after its sugar capsule type, which is not among the seven in Prevnar. With the most common seven strains knocked down by Prevnar, the next several most common, including 19A, “filled the vacuum.” Physicians in the US then “barraged kids with antibiotics, often unnecessarily,” Pichichero said. That created evolutionary pressure in favor of the bacteria most able to resist antibiotics.

The 19A strain, for example, has developed resistance to every antibiotic approved by the FDA for use in children with ear infections (18 antibiotics). Having anticipated this problem, Wyeth began working on a vaccine that would also protect against the next six most common strains of S. pnemoniae, including 19A, almost as soon as it got approval for the original vaccine. Even if all goes well, however, the 13-strain vaccine is not expected before 2010.

In the current study, two pediatricians used tympanocentisis to identify S pneumoniae strains that caused ear infections in children between September 2003 and June 2005. All the children had received the Prevnar vaccine. Among 1815 children, aged 6 to 36 months, in whom otitis media was diagnosed, tympanocentesis was performed in 212, yielding 59 cases of S pneumoniae infection and 9 cases infected with a serotype 19A strain resistant to all FDA-approved antibiotics for use in children.
Of those nine, four required surgery to implant ear tubes after several attempts to treat with antibiotics failed. Levofloxacin was used in the next five cases, resolving the infection without surgery. Pichichero has published on the effectiveness and safety of quinolones in children with hard-to-treat ear infections, and the American Academy of Pediatrics endorsed their limited use where the benefits outweigh the risks, he said. Some past animal studies caused concern that the drug class may cause damage to weight-bearing joint cartilage in children, although such a side effect has not been observed in humans.

As expected, analyses of the ear tap samples over the three years revealed that those strains included in the original Prevnar vaccine were effectively prevented. But the study also found that strains not included in the vaccine have become more numerous in their place. In addition, the study showed that the strains not included in Prevnar at first were nearly all sensitive to most antibiotics, but over three years became dramatically more resistant to penicillin (from 25 to 93 percent of cases) (P<.001) and other antibiotics.

“The solutions to this problem are clear,” said Janet Casey. M.D., co-author of the study, associate professor of Pediatrics at the Medical Center and a partner in Legacy Pediatrics. “Many more physicians need to learn and use the ear tap technique and how to test for the strains once the sample is collected. They also need to resist pleas by parents to treat colds with antibiotics for comfort’s sake alone.”

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