Variation of Glaucoma Discovered To Be an Inflammatory Disease

Researchers at the University of California, San Diego School of Medicine and Sun Yat-sen University in China have shown that acute glaucoma in mice is largely an inflammatory disease and that high pressure in the eye causes vision loss by setting in motion an inflammatory response similar to that evoked by bacterial infections.

University of California - San Diego - School of Medicine

The study, published in this week’s issue of the Proceedings of the National Academy of Sciences, has immediate clinical relevance in treating the tens of millions of people worldwide from what is known as acute closed-angle glaucoma.

“Our research is the first to show an inflammatory mechanism by which high ocular pressure causes vision loss in acute glaucoma patients,” said co-senior author Kang Zhang, MD, PhD and professor of ophthalmology.

The second leading cause of irreversible blindness globally, glaucoma refers to a group of eye diseases associated with elevated intraocular pressure broadly classified as either open-angle or closed-angle. Open-angle is sometimes called the silent thief of sight because of its slow, often overlooked progression. By contrast, acute closed-angle glaucoma often is a painful ophthalmologic emergency in which there is a sudden rise in eye pressure and immediate damage to eyesight.

Less than 10 percent of glaucoma patients in America have the closed-angle form, but in parts of Asia it accounts for almost half of all cases. The higher prevalence of closed-angle glaucoma in Asians and women is believed to be due to a shallower anterior (frontal) eye chamber.

In the study, researchers showed that a rapid, sustained large increase in eye pressure in mice turns on a gene (TLR4) that activates a protein known as caspase-8. This signaling protein in turn triggers the production of inflammatory proteins that normally help mammals fight microbial infections.

“This immune response is a double-edge sword because, while these proteins protect us from infection in a normal situation, they stimulate apoptosis (programmed cell death) in retinal cells in cases of acute glaucoma,” said Zhang, who is also a staff physician at the Veterans Affairs San Diego Healthcare System.

To further confirm the mechanism linking high eye pressure to retinal damage, researchers showed that they could slow retinal cell death in mice with acute glaucoma by suppressing either the TLR4 gene or caspace-8 protein.

The latter is particularly significant because caspace-8 inhibitors are currently in clinical trials for treating cancer and stroke. “By injecting these inhibitors into the eyes of acute glaucoma patients, it may be possible to evaluate and bring them vision-sparing treatments more quickly,” said co-author Robert N. Weinreb, MD, chairman and Distinguished Professor of Ophthalmology.

- MFP News Services
- 9/1/14

Researchers Discover New Route For the Spread of Ovarian Cancer

Circulating tumor cells spread ovarian cancer through the bloodstream, homing in on a sheath of abdominal fatty tissue where it can grow and metastasize to other organs, scientists at The University of Texas MD Anderson Cancer Center report in Cancer Cell.

University of Texas - M. D. Anderson Cancer Center

“This completely new way of thinking about ovarian cancer metastasis provides new potential avenues to predict and prevent recurrence or metastasis,” said senior author Anil Sood, M.D., professor of Gynecologic Oncology and Reproductive Medicine and Cancer Biology.

The researchers found the circulating tumor cells (CTCs) rely on HER3, a less-famous sibling of the HER2 receptor protein prominent in some breast cancers, to find their way to the omentum, a sheet of tissue that covers and supports abdominal organs.

HER3′s heavy presence on these cells makes it a biomarker candidate and suggests possible therapeutic options to thwart ovarian cancer progression, the researchers noted. “The CTCs are not just a correlation, they seem to have a functionally important role in metastasis,” Sood said.

High expression of HER3 in ovarian cancer tumors is associated with shorter survival, the team found.

Ovarian cancer has been thought mainly to spread via direct surface contact with neighboring organs in the abdominal cavity. “However, it also metastasizes to more distant organs such as the liver and spleen, which seems to indicate arrival through the bloodstream,” Sood said.

Ovarian tumor cells are found abundantly in the blood vessels of the omentum and CTCs are present in ovarian cancer patients. However the importance of CTCs was not well understood.

Two mice, one blood supply

The researchers used a parabiosis mouse model, in which two mice are joined at the skin from hip to shoulder. They share blood supply but not lymphatic vessels. “This was the most convincing way to prove that CTCs play a role in metastasis,” said first author Sunila Pradeep, Ph.D., instructor of Gynecologic Oncology and Reproductive Medicine.

When the host mouse of each pair was injected with ovarian cancer cells, a primary tumor developed and metastases were found in the omenta of all of the host mice. In the guest mice, metastatic cells and tumors appeared first in the omentum before spreading to other organs.

The team compared gene expression in tumors between the original ovarian cancer cell line and its metastatic version found in the omentum.

Expression of HER3, also known as ERBB3, was highly elevated and activated. The binding protein, or ligand, most likely to cause that activation is NRG1, which was found abundantly on the metastatic cells.

More than 95 percent of CTCs collected from mice with the metastatic version of ovarian cancer were HER3-positive. The more HER3-positive cells the mice had, the greater the tumor burden.

HER3 expression reduces human survival

In tumor samples from 11 ovarian cancer patients, 90 percent of cells were HER3-positive. Tumor cells found in the omental blood vessels of five patients analyzed also had strong HER3 expression.

In a cohort of 217 advanced-stage patients, lower HER3 expression correlated with improved overall survival of 4.9 years compared to 3.15 years for high-HER3 tumors.

Analyzed by itself, HER3 expression was significantly associated with advanced-stage disease at diagnosis. When other variables such as the patient’s age, disease stage and tumor grade were controlled for, HER3 expression remained an independent factor for patient survival. They also found:

HER3 expression to be significantly higher in human stage 3 and 4 tumors compared to stage 1 and 2 tumors.
Blocking HER3 with siRNA significantly lowered expression of the protein, decreased tumor growth and reduced metastasis in mice.
Plugging HER3 with the antibody MM-121 reduced the size and number of tumors and frequency of metastasis in treated mice to a tiny fraction of that found in control mice.
Results were repeated with additional high-grade serous ovarian cancer and colon cancer models.
NRG1 in omentum draws in circulating tumor cells
Experiments showed knocking down HER3 in cancer cell lines in the lab did not have the same effect as it did in the mice. This led the researchers to suspect something present in the omentum microenvironment caused the cancer’s dependency on HER3.

The binding ligand NRG1 is more abundant in the omentum than in other tissues. The team found:

Colonies of cancer cells treated with NRG1 were triple the size of untreated tumor cell colonies.
Analysis of 11 human tumors found NRG1 evident both in the tumors and the microenvironment.
Blocking NRG1 with siRNA in mice with ovarian cancer significantly reduced metastasis.
“The NRG1 ligand expressed in the omentum attracts HER3-positive CTCs,” Sood said.

The next steps for the team are to further flesh out the details and understand opportunities to intervene in this cancer-spreading process. The findings provide a rational route to develop new drugs, Sood noted.

Potential uses include using HER3-positive cells as a biomarker for recurrence for patients or for occurrence in women at high-risk for developing ovarian cancer. Maintenance anti-HER3 therapy after treatment could prevent metastasis to the omentum.

Clinical trials are under way for pertuzumab, an antibody that blocks HER2, to explore whether it might thwart both proteins in ovarian and breast cancer. HER2 and HER3 are members of the epidermal growth factor receptor family of receptor tyrosine kinase proteins.

- MFP News Services
- 8/27/14

The ‘Obesity Paradox’: Cardiovascular Mortality Lowest Among Overweight Patients

Is being overweight sometimes a good thing? Data suggest higher BMI protects against adverse cardiovascular outcomes, reports Mayo Clinic Proceedings

Rochester, MN, – High body mass index (BMI) is associated with multiple cardiovascular diseases. However, emerging data suggest that there is an “obesity paradox,” that being overweight may actually protect patients from cardiovascular mortality. Investigators have now confirmed that the risk of total mortality, cardiovascular mortality, and myocardial infarction is highest among underweight patients, while cardiovascular mortality is lowest among overweight patients, according to two reports published today in Mayo Clinic Proceedings.

Currently more than two-thirds of adult Americans are classified as overweight or obese. Because of the high prevalence of coronary heart disease (CAD), overweight and obese patients more frequently undergo revascularization procedures such as percutaneous coronary intervention (PCI) and coronary artery bypass graft (CABG). Obesity has been considered a risk factor for worst clinical outcomes following cardiovascular procedures like these, however, emerging data suggest that higher BMI protects against adverse outcomes in many acute and chronic disease states. This prompted experts to reexamine assumptions about body fat and explore the counterintuitive phenomenon known as the “obesity paradox.”

In a landmark meta-analysis of 36 studies, Abhishek Sharma, MD, Cardiology Fellow at the State University of New York Downstate Medical Center in Brooklyn, New York, and colleagues determined that low BMI (less than 20 kg/m2) in tens of thousands of patients with coronary artery disease who underwent coronary revascularization procedures was associated with a 1.8- to 2.7-fold higher risk of myocardial infarction and all-cause and cardiovascular mortality over a mean follow up period of 1.7 years. Conversely overweight and obese patients had more favorable outcomes. Cardiovascular mortality risk was lowest among overweight patients with a high BMI (25-30 kg/m2) compared to people with a normal BMI (20-25 kg/m2). Indeed, in obese and severely obese patients with a BMI in the 30-35 and over 35 kg/m2 range, all-cause mortality was 27% and 22% lower than people with normal BMI.

Dr. Sharma observes, “At this stage we can only speculate on the reasons for this paradox. One explanation may be that overweight patients are more likely to be prescribed cardioprotective medications such as beta blockers and statins and in higher doses than the normal weight population. Further, obese and overweight patients have been found to have large coronary vessel damage, which might contribute to more favorable outcomes. This population may have a higher metabolic reserve, which might act protectively in chronic conditions like CAD. Also, there could be a difference in the pathophysiology of cardiovascular disease in over- and underweight patients. A non-modifiable genetic predisposition may also play a role in underweight patients.”

He concludes, “However, this is still speculation. Further prospective studies are needed to investigate this association and explore potential underlying mechanisms.”

In a second study published in the same issue, investigators examined the “obesity paradox” from another perspective by evaluating the effects of body composition as a function of lean mass index (LMI) and body fat (BF) on the correlation between increasing BMI and decreasing mortality. They estimated BF and LMI in nearly 48,000 people with a preserved left ventricular ejection fraction of more than 50% and examined the survival advantages of obesity across strata of these body compositions.

This large observational study showed that higher lean body mass was associated with 29% lower mortality, and while higher fat mass also exhibited survival benefits, this advantage disappeared after adjustment for lean body mass, suggesting that non-fat tissue bears the primary role in conferring greater survival.

University of California - Irvine

“Body composition plays a critical role in the obesity paradox,” says senior investigator Carl Lavie, MD, FACC, FACP, FCCP, Medical Director of Cardiac Rehabilitation and Preventative Cardiology at the John Ochsner Heart & Vascular Institute, Ochsner Clinical School, the University of Queensland School of Medicine, New Orleans. “Whenever examining a potential protective effect of body fat, lean mass index – which likely represents larger skeletal muscle mass – should be considered. At higher BMI, body fat is associated with an increase in mortality.”

Noted expert Kamyar Kalantar-Zadeh, MD, MPH, PhD, of the Department of Medicine, University of California Irvine Medical Center, Orange, CA, observes that “although the underlying mechanisms of the obesity paradox and reverse epidemiology remain unclear, the consistency of the data is remarkable, leaving little doubt that these observational data are beyond statistical constellations and bear biologic plausibility.

“The findings in these studies should not be considered as an attempt to undermine the legitimacy of the anti-obesity campaign in the best interest of public health. Nonetheless, given the preponderance and consistency of epidemiologic data, there should be little doubt that in certain populations higher BMI, which is associated with higher risk of metabolic syndrome and poor cardiovascular outcomes in the long-term, confers short-term survival and cardiovascular advantages. Metaphorically we can liken cardiovascular risk factors to a friend who is a negative influence, causing you to misbehave and be sentenced to jail, but once imprisoned the friend remains loyal and protects you against poor prison conditions and other inmates.”

- MFP News Services
- 8/26/14