A Clearer Picture of Cloudy Eyes

A new study appearing in JBC provides more insight into cataracts, the leading cause of vision loss and blindness in the elderly, finding that small pieces of a perfectly normal protein become toxic during the aging process.

A cataract results from deterioration in the highly ordered assembly of crystallin proteins in the eye lens. Normally, the ordered structure keeps lenses clear and able to efficiently transmit light. However, crystallins gradually break down during aging, causing the lens to become opaque and scatter light instead. Besides age, other risk factors such as diabetes, ultraviolet radiation, or drugs like corticosteroids can also contribute to cataracts.

Like cataracts themselves, the exact mechanisms governing their formation are cloudy, but Krishna Sharma and colleagues found that tiny bits of crystallin greatly contribute to this process.

They compared a range of human donor lenses and found that aged and cataract lenses accumulated about four times as many short (~10-20 amino acids) crystallin fragments compared to young lenses. These fragments could readily bind full-length crystallins, which disrupted their natural shape and organization and caused them to become insoluble.

Ironically, these tiny fragments are a by-product of the eye’s efforts to stay healthy; when a crystallin becomes damaged, other proteins chew it up to remove it; but occasionally the process is incomplete, leaving tiny pieces that can cause greater damage. (Newswise)

Study Provides Clues to Prevent Spread of Ovarian Cancer

A drug that blocks production of an enzyme that enables ovarian cancer to gain a foothold in a new site can slow the spread of the disease and prolong survival in mice, according to a study by researchers from the University of Chicago Medical Center, but only if the drug is given early in the disease process.

In the April issue of the Journal of Clinical Investigation, the researchers show that an enzyme known as MMP-2 is necessary for ovarian cancer to attach itself to the sites where it tends to spread. Several drugs known as MMP inhibitors (for example, marimastat or prinomastat) inhibit the enzyme, dramatically reducing the tumor's ability to establish itself at sites beyond the ovary. But such MMP inhibitors, which were abandoned after they failed to extend survival in earlier clinical trials, have to be given before the cancer has spread.

"Our study suggests that MMP-2 inhibitors could have a significant impact on ovarian cancer but only if administered quite early, before the cancer has advanced beyond the ovary," said Ernst Lengyel, assistant professor of obstetrics and gynecology at the University of Chicago.

This approach could help women who receive surgical treatment while the disease is still limited to the ovary as well as those who have successful surgery to remove all evidence of local spread of the disease. In the earlier trial, marimastat was given to women with late-stage disease that had already spread.

The fifth leading cause of cancer death in women, ovarian cancer -- unlike breast, colon or lung cancer -- tends to spread within the abdominal cavity and not to distant organs. Carried by fluid, it most often spreads throughout the peritoneal cavity and to the omentum, a large fat pad draped over the small bowel.

Lengyel and colleagues wanted to understand the many steps required for ovarian cancer to dislodge from its original site and establish itself elsewhere in the peritoneal cavity. They found that one of the key steps was production of MMP-2 by cancer cells that came in contact with the cells that line the peritoneal cavity.

When ovarian cancer cells make contact with the cells that line this internal cavity, they produce MMP-2 (an acronym for matrix metalloproteinase-2). MMP-2 alters two proteins--vitronectin and fibronectin--found on the surface of the cells that line the cavity. These alterations change those proteins in a way that enables the cancer cells to latch on to them better. Once attached, the cancer cells can multiply rapidly and invade.

By inhibiting MMP-2 activity early in the disease course, Lengyel and colleagues were able to prevent injected ovarian cancer cells from attaching to their target tissues in the peritoneum and omentum. This reduced the growth of new tumors by 68 percent, when measured four weeks after treatment.

The inhibitor nearly doubled survival time in mice that were injected with ovarian cancer cells. Those who received it survived an average of 63 days, compared to untreated mice, who survived only 36 days.

Brief and early intraperitoneal treatment with an MMP inhibitor, the authors conclude, may reduce peritoneal attachment, reduce metastases and significantly prolong survival.

The treatment has much less impact, however, once cancerous cells have attached and formed colonies. In several earlier trials, marimastat, an oral MMP inhibitor, was given for a prolonged period of time to women with late-stage disease that had already spread.

"MMP-inhibitors were given at the wrong time for too long, causing side effects," Lengyel said. Attachment is the first step for metastatic spread. MMP-2, the target of MMP inhibitors, plays a role in early cancer spread.

"Our study examines the initial step of ovarian cancer metastasis," the authors note, when cancer cells meet unprepared target cells. Other steps in this process, they suggest, may also provide additional treatment targets.

The National Institutes of Health, the Department of Defense, the Ovarian Cancer Research Fund, the Gynecologic Cancer Foundation and the Illinois Department of Health funded the research. Additional authors include Hilary Kenny and Swayamjot Kaur of the University of Chicago and Lisa Coussens of the University of California San Francisco.


Tags - OVARIAN CANCER, METASTASIS, MMP-2, MARIMASTAT, OMENTUM

Parkinson’s Disease Drug Might Work in Cancer Patients

A study published in the March 13 online issue of The Journal of Clinical Investigation shows that dopamine, a drug currently used to treat Parkinson’s disease and other illnesses, also might work in cancer patients. The study, which was done in mouse and laboratory models, shows that dopamine could possibly prevent new blood vessels from growing and as a result, slow cancer progression.

Dopamine is a neurotransmitter in the brain that regulates movement and affects behavior. In its synthetic form, dopamine is used to treat heart attack victims, Parkinson’s disease and pituitary tumors. But it wasn’t known until now that dopamine worked by blocking the growth of new blood vessels (a process called angiogenesis).

“Researchers now can test this concept in solid tumors where angiogenesis plays a critical role in the growth and progression of these cancers,” says Sujit Basu, M.D., Ph.D., a Mayo Clinic scientist who conducted this study with Partha Sarathi Dasgupta, Ph.D., a scientist with the Chittaranjan National Cancer Institute (CNCI) in Calcutta, India.; and, Debanjan Chakroborty, Ph.D., a postdoctoral fellow in biochemistry at Mayo Clinic and CNCI.

“Sometimes new drugs may not be the answer. We looked instead at a novel use for an established product and have found very promising results,” Dr. Basu says.

The study has not been replicated in humans, but the results are encouraging, he says.

Dr. Basu has been studying the role of dopamine in cancer for years, and was credited with the initial discovery that dopamine can block new blood vessel growth. His current study is based on mouse and laboratory models of sarcoma -- a malignant tumor affecting soft tissues. The research is the first report that dopamine has a role in cancer’s use of endothelial progenitor cells to provide a supply line of nourishing blood, Dr. Basu says. These cells, a form of stem cells, are released by bone marrow into the blood system in response to the vascular endothelial growth factor-A (VEGF-A), which is a protein that is secreted by oxygen-deprived cancer cells. The endothelial progenitor cells then help form new blood vessels to feed the cancer.

Researchers discovered that dopamine stops the transfer of endothelial progenitor cells from the bone marrow into the circulatory system by binding to a specific receptor on the surface of the progenitor cells. This binding suppresses the activity of matrix metallopeptidase 9 (MMP-9), an enzyme that enables these cells to move out of bone marrow.

In their experiments, they found that treatment with dopamine significantly decreased mobilation of the progenitor cells from the bone marrow, and it also decreased MMP-9 expression.

“This is the first time it has been shown that an important neurotransmitter like dopamine is regulating the mobilization of these progenitor cells from the bone marrow. This is very important and represents why these findings are so unique,” Dr. Basu says.

Other authors include: Chandrani Sarkar, Ph.D., of both CNCI and Mayo Clinic; Uttio Roy Chowdhury, Ph.D., and Rathindranath Baral, Ph.D., both of CNCI.

This research was supported by grants from the Department of Biotechnology, the Government of India; the National Institutes of Health; and the U.S. Department of Defense.


Tags - DOPAMINE, CANCER PROGRESSION

Breast Cancer More Aggressive Among Obese Women

Women with breast cancer have more aggressive disease and lower survival rates if they are overweight or obese, according to findings published in the March 15 issue of Clinical Cancer Research, a journal of the American Association for Cancer Research.

“The more obese a patient is, the more aggressive the disease,” said Massimo Cristofanilli, MD, associate professor of medicine in the Department of Breast Medical Oncology at The University of Texas M.D. Anderson Cancer Center. “We are learning that the fat tissue may increase inflammation that leads to more aggressive disease.”

Cristofanilli and colleagues observed 606 women with locally advanced breast cancer. These women were classified by body mass index into the following three groups: normal/underweight (24.9 or below), overweight (at least 25 but less than 30) or obese (more than 30). Body mass index is calculated by dividing a person’s weight by their height.

At five years, overall survival was 56.8 percent among obese women, 56.3 percent among overweight women and 67.4 percent among normal weight women. The 10-year survival rate was 42.7 percent among obese women, 41.8 percent among overweight women and 56.5 percent among normal weight women.

The rate of inflammatory breast cancer, previously shown to have worse outcomes than non-inflammatory breast cancer, among obese women was 45 percent compared with 30 percent in overweight women and only 15 percent in women considered normal weight, researchers found.

Risk of breast cancer recurrence was also higher in obese or overweight women. By five years, 50.8 percent of obese women reported a recurrence compared with 38.5 percent of normal weight women. By 10 years, the rate of recurrence was 58 percent among obese women and 45.4 percent among normal weight women.

“Obesity goes far beyond just how a person looks or any physical strain from carrying around extra weight. Particular attention should be paid to our overweight patients,” Cristofanilli said.

Cristofanilli said physicians need to pay close attention to breast cancer patients because commonly used drugs, such as tamoxifen, tend to increase weight gain during treatment.

“We have actually become quite good at managing acute side effects such as nausea in our chemotherapy patients and it goes away within a couple of days,” Cristofanilli said.

“Following the nausea, our patients tend to overeat, which further increases their risk of weight gain. We need to implement lifestyle modifications interventions and develop better methods to follow these patients closely.”

The study was funded by the Susan G. Komen Foundation, the Nellie B. Connally Fund for Breast Cancer Research and the Inflammatory Breast Cancer Research Group.



The mission of the American Association for Cancer Research is to prevent and cure cancer. Founded in 1907, AACR is the world's oldest and largest professional organization dedicated to advancing cancer research. The membership includes nearly 27,000 basic, translational, and clinical researchers; health care professionals; and cancer survivors and advocates in the United States and more than 70 other countries. AACR marshals the full spectrum of expertise from the cancer community to accelerate progress in the prevention, diagnosis and treatment of cancer through high-quality scientific and educational programs. It funds innovative, meritorious research grants. The AACR Annual Meeting attracts more than 17,000 participants who share the latest discoveries and developments in the field. Special Conferences throughout the year present novel data across a wide variety of topics in cancer research, treatment, and patient care. AACR publishes five major peer-reviewed journals: Cancer Research; Clinical Cancer Research; Molecular Cancer Therapeutics; Molecular Cancer Research; and Cancer Epidemiology, Biomarkers & Prevention. Its most recent publication and its sixth major journal, Cancer Prevention Research, is the only journal worldwide dedicated exclusively to cancer prevention, from preclinical research to clinical trials. The AACR also publishes CR, a magazine for cancer survivors, patient advocates, their families, physicians, and scientists. CR provides a forum for sharing essential, evidence-based information and perspectives on progress in cancer research, survivorship, and advocacy.


Tags - BREAST CANCER, OBESITY, RESEARCH, CANCER

Snoring May Be Chronic Despite Surgery

Especially for African-American Children and Children with Rapid Weight Gain


Children who gain weight rapidly after having their tonsils and adenoids removed to treat sleep-disordered breathing (SDB) may improve in the short-term, but over time they may relapse or even worsen. African-American children also tend to relapse, according to new research from Cincinnati Children’s Hospital Medical Center.

Adenotonsillectomy is the most commonly performed surgery in children, ranging from about 19 per 10,000 in Canada to 115 per 10,000 in the Netherlands. In the U.S., the rate is about 50 per 10,000. It is the first line of treatment for SDB in children. For many kids, undergoing this major surgery provides only temporary relief.

“The high rate of recurrence we observed in both obese and non-obese children indicates that SDB is a chronic condition,” said Raouf Amin, M.D., director of pulmonary medicine at the hospital.

The results were published in the second issue for March of the American Journal of Respiratory and Critical Care Medicine, published by the American Thoracic Society.

The researchers recruited 40 healthy children between seven and 13 whose parents and otolaryngologists had jointly agreed upon adenotonsillectomy surgery to treat nightly snoring. The investigators also recruited 30 sex- and age-matched children who were not undergoing adenotonsillectomy as a control group. They performed polysomnographies on each child at time of recruitment, and again at six weeks, six months, and a year following surgery. Children in the control group had polysomnographies at the same intervals.

While the majority of children with SDB showed significant improvement in their AHI scores six weeks after surgery, the rate of relapse one year later had no correlation with the six-week score. Children who relapsed were more likely to be more obese, have worse SDB at baseline, have an accelerated body mass index (BMI) gain, and to be African-American.

“Most post-adenotonsillectomy outcome studies have focused on the assessment of SDB six to 16 weeks after surgery. Resolution of SDB during this window was usually interpreted as a cure for the disorder,” noted Dr. Amin. “We report[ed] for the first time the longitudinal outcome of adenotonsillectomy in healthy children, the important influence of BMI gain velocity and African-American race on recurrence of SDB.”

Half of the non-obese children, and two-thirds of the obese children had an AHI score of greater than 3 prior to surgery. A year later, 27 percent of the non-obese children and 79 percent of obese children had AHI score of greater than 3, indicating that the surgery was significantly more effective at a year in non-obese children.

While children who were obese at the baseline were more likely to relapse than their no-obese peers, accelerated BMI gain was also an independent risk factor for relapse.

“These results highlight the differential disease mechanisms between those due to obesity and those due to the rapid change in body composition associated with accelerated BMI gain,” explained Dr. Amin.

Furthermore, children who relapsed had significantly higher blood pressure at follow up than children who didn’t.

“SDB appears to be a chronic disorder that is clearly linked to other medical problems. Given the rate of relapse, we advocate long-term follow up of children with SDB, monitoring of BMI gain, and reevaluation of children who demonstrate rapid BMI gain, especially those who are African-American,” the researchers concluded.


TAGS - SLEEP DISORDERED BREATHING, PEDIATRICS, SNORING, ADENOTONSILLECTOMY, TONSILLECTOMY