Thursday, September 30, 2010

Ingredient (Triclosan) in soap points toward new drugs for Toxoplasmosis !

We know that, Triclosan (see structure)  is an antibacterial ingredient in some soaps, toothpastes, odor-fighting socks, and even computer keyboards. Now researchers lead by Dr. Rima McLeod from The University of Chicago, have come up with interesting findings about this drug, i.e., triclosan's molecular structure can be used as  the model for developing other potential medications for toxoplasmosis. 

In the study, Rima McLeod and colleagues point out that toxoplasmosis is one of the world's most common parasitic infections (spread by the parasite Toxoplasma gondiiT. gondii), from contact with feces from infected cats, eating raw or undercooked meat, and in other ways. Many have no symptoms because their immune systems keep the infection under control and the parasite remains inactive. But it can cause eye damage and other problems, even becoming life threatening in individuals with immune systems weakened by certain medications and diseases like HIV infection, which allow the parasite to become active again, and in some persons without immune compromise. Most current treatments have some potentially harmful side effects and none of them attack the parasite in its inactive stage.

The scientists knew from past research that triclosan has a powerful effect in blocking the action of a key enzyme that T. gondii uses to live. As per the claim by the researchers, Triclosan, however, cannot be used as a medication because it does not dissolve in the blood, how ever  one can use triclosan's molecular structure as the model for developing other potential medications, including some that show promise as more effective treatments for the disease.  Hope this research will lead to a better drug than Triclosan without any carcinogenecity and many other side effects associated with this drug..

Ref : http://pubs.acs.org/stoken/presspac/presspac/abs/10.1021/jm9017724

Thursday, September 16, 2010

Enzyme telomerase activating compound discovered....

In continuation of telomerase and its importance...

Sierra Sciences, in collaboration with TA Sciences, Geron Corporation, PhysioAge, and the Spanish National Cancer Research Center (CNIO), has announced the first compound ever discovered that activates the enzyme telomerase in the human body - a critical prerequisite for technology that could arrest or reverse the aging process in humans. This compound is a natural product derived nutraceutical known as TA-65.

TA-65, exclusively licensed to TA Sciences from Geron Corporation, is a >95% pure single chemical entity isolated from a proprietary extract of the dried root of Astragalus membranaceus and formulated into 5- to 10-mg capsules with inert excipients. Starting doses of 5–10 mg/day were considered safe on the basis of historical usage of extracts. Some subjects increased their dosage after several months on the product to 25–50 mg/day. Cumulative dose consumed during the year was recorded for each subject and used for preliminary dose–response analysis.

Researchers discovered that TA-65 was associated with a statistically significant "age-reversal" effect in the immune system, in that it led to declines in the percentage of senescent cytotoxic T cells and natural killer cells after six to twelve months of use. In addition, further analysis with automated high-throughput confocal microscopy (HT-qFISH) revealed a decline in the percentage of white blood cells with critically short telomeres after twelve to eighteen months of use.

Telomere shortening is thought to be the "clock of aging" contained within the human body. It has been repeatedly demonstrated that a human cell that does not undergo telomere shortening will divide indefinitely and is, by all available measurements, immortal.

Researchers reports that TA-65 can cause telomerase, an enzyme that lengthens telomeres, to become active in human cells.  Telomerase activation by TA-65 was shown to lengthen the shortest telomeres in humans, potentially extending human lifespan and healthspan. Telomerase activation is thought to be a keystone of future regenerative medicine and a necessary condition for clinical immortality. Although TA-65 is probably too weak to completely arrest the aging process, it is the first telomerase activator recognized as safe for human use.

"We are on the cusp of curing aging," said William Andrews, Ph.D., co-author of this study and President and CEO of Sierra Sciences, LLC. "TA-65 is going to go down in history as the first supplement you can take that doesn't merely extend your life a few years by improving your health, but actually affects the underlying mechanisms of aging. Better telomerase inducers will be developed in the coming years, but TA-65 is the first of a whole new family of telomerase-activating therapies that could eventually keep us young and healthy forever."


Telomerase activation has potential medical applications beyond extending human lifespan.  Epidemiological studies have shown that short telomeres in humans are a risk factor for diseases including, among others, atherosclerosis, diabetes, Alzheimer's, and cancer. The present study also reports encouraging news on the effect of TA-65 on the body's immune system. Infectious diseases lead to telomere shortening in the immune system, as immune cells divide to fight infections. Telomerase activation should prevent this telomere shortening and allow the body's immune system to fight a chronic infection indefinitely.

The present study on TA-65 lends support to this hypothesis. In individuals infected with CMV, a virus which prematurely ages the immune system and significantly reduces life expectancy, TA-65 caused an apparent "age reversal" of approximately 5 to 20 years based on one biomarker of immune aging. For the same reason, telomerase activation is a potential treatment for AIDS.

"We tend to see HIV turning into AIDS when the cells of the immune system develop critically short telomeres," said Andrews...

HIV can essentially cause the immune system to die of old age while the majority of the body is still young and therefore the researchers are hopeful that a telomerase activator could theoretically prevent an HIV-positive individual from ever developing AIDS....

Tuesday, September 14, 2010

Method developed to reduce acrylamide (carcinogen) formation during production of potatoes and coffee...



A small research-based Norwegian company has developed a method to reduce the formation of the carcinogenic compound acrylamide during industrial production of potatoes and coffee. International food giants are paying attention. In 2002 Swedish researchers found that the carcinogenic compound acrylamide was present in many foods - a discovery that grabbed international headlines and frightened consumers and food safety authorities around the world. What these production foods had in common was high-temperature cooking which formed a crust or browning reaction. The acrylamide issue has had dramatic consequences for the manufacturers involved.

Since then a great deal of research has been focused on acrylamide. The compound has been found in bread, some types of crackers and sweet biscuits, deep-fried potato products and coffee. Research has also been carried out on the compound's effects on humans and on production methods that can reduce or remove acrylamide from our foods.

Norwegian Hans Blom  and his research team found a method that limits the formation of acrylamide during the production of potato products and coffee. It was the patent for this method that provided the springboard for the company Zeracryl.
"Our method is based on lactic acid fermentation," explains Dr Blom. "Acrylamide is formed as a reaction between the amino acid asparagine and simple sugars such as glucose and fructose. Put simply, the lactic acid bacteria remove these compounds and inhibit the formation of acrylamide."

The team's ongoing experiments show that 10 to 15 minutes' immersion in lactic acid bacteria culture before cooking reduces acrylamide formation in the final product by roughly 90 per cent.
Zeracryl will continue its work in the research project Lactic acid fermentation as a tool to reduce formation of acrylamide in fried potato products and roasted coffee in cooperation with the international food conglomerate Nestlé, the Norwegian producers of potato products Hoff AS and Maarud, and the research institute Nofima. The project is supported by the Research Council of Norway's Food Programme and is scheduled to run until 2012...

Ref 1. http://www.angelfire.com/az/sthurston/acrylamides_cancer_causing.html
      2. Zeracryl 

Monday, September 13, 2010

Synthetic derivative of Retinoic acid can induce cell death

Retinoic acid (RA), a natural derivative of vitamin A, is the basis of a number of treatments against cancer. Nevertheless, it has certain disadvantages, such as the possibility of the appearance of retinoic acid syndrome, present in 25 % of cases and which can lead to death. The development of 4-HPR (see structure -Fenretinide 4-hydroxy(phenyl)retinamide) a synthetic derivative of RA, has meant a considerable advance due to its greater efficacy compared to its predecessor. It is able to induce the death of tumour cells as the method for reducing their proliferation, in a precise manner and without serious damage to surrounding tissue. Moreover, it halts the referred-to retinoic acid syndrome and even functions with cells that resist RA. In vitro studies corroborate its effectiveness as a chemopreventive agent and also as a chemotherapeutic agent, both with leukaemias and with ovary, breast or brain tumour cells.

Biologist Ms Aintzane Apraiz studied the 4-HPR in depth, focusing on the causes that, according to previous research, give rise to this ability to induce cell death. To this end, she applied this synthetic derivative to acute lymphoblastic leukaemia T cells (LLA-T). Her PhD thesis, defended at the University of the Basque Country (UPV/EHU), is entitled Role of sphingolipids and oxidative stress in the antineoplasic activity of 4-HPR: study in a leucemia model.

Amongst the various processes that can induce cell death, in the case of 4-HPR, apoptosis is outstanding; a precise mechanism and without inflammatory processes or serious damage to surrounding tissue. According to Ms Apraiz, previous research on LLA-T undertaken by the team of which she is a member, showed that 4-HPR induced a massive accumulation of ceramides (lipids of the cell membrane) and of reactive oxygen species (ROS), both of which can cause cell death. 

More...

Thursday, September 9, 2010

Methylphenidate facilitates recovery from drug addiction...



A brain-scanning study at the U.S. Department of Energy's (DOE) Brookhaven National Laboratory, conducted with collaborators from Stony Brook University, reveals that an oral dose of methylphenidate, commonly known as Ritalin, improves impaired brain function and enhances cognitive performance in people who are addicted to cocaine.

Researchers were encouraged by the fact that, methylphenidate does decrease behaviors such as risk taking and impulsivity and improves brain function and cognitive performance in a range of other conditions that also affect the brain's prefrontal cortex, including attention deficit hyperactivity disorder (ADHD), some forms of dementia, and certain kinds of brain injury. To begin with Goldstein's (lead researcher)  group performed functional magnetic resonance imaging (fMRI) on 13 cocaine users and 14 healthy control subjects who were asked to perform a cognitive task after being given either a low oral dose of methylphenidate (20 milligrams) or a placebo. The task involved pushing a button to correctly identify the color of a printed word; some words had to do with drug use, others were "neutral." Subjects received monetary rewards for correct answers. The scientists were particularly interested in two parts of the prefrontal cortex previously shown to be impaired during this cognitive activity in cocaine-addicted individuals.

"These regions help to regulate emotion, cognition, and behavior in response to salient stimuli - the things we find particularly interesting or relevant," Goldstein said. "Because drug users have deficits in these regions, they may have less ability to regulate their emotions and exert cognitive control over certain behaviors."

Researchers found that,  compared  with cocaine users given placebos - who (compared to healthy controls) exhibited reduced function in these prefrontal cortex regions - cocaine users given a low dose of methylphenidate had improved brain function such that they were more like the healthy control subjects. The subjects given methylphenidate were also less likely to make "errors of commission" (pressing a button incorrectly or prematurely), a measure of impulsivity, while performing the cognitive task than subjects given a placebo. Furthermore, the greater the improvement in task accuracy with methylphenidate, the larger the increase in fMRI signal in the prefrontal cortex regions of interest, showing that the improvements in brain function were directly related to improved cognitive performance.

Though future studies need to evaluate whether these results can be generalized to other tasks or activities that involve these specific brain regions, but these results do suggest that by enhancing prefrontal cortex function and associated cognitive performance - particularly the decrease in impulsivity - methylphenidate could help to improve clinical outcomes in people seeking to overcome drug addiction…
  
 Ref : http://www.pnas.org/content/early/2010/08/30/1011455107.full.pdf+html?sid=be34425f-b8cc-4a90-8929-03aca9f8bbe4

Wednesday, September 8, 2010

ESPAC-3 trial (Fluorouracil and Folinic Acid) shows promising results to prevent pancreatic cancer

In continuation of my update on  drug discovery and 5-fluorouracil

A major international trial has shown a commonly used chemotherapy drug, 5-fluorouracil, and  Folinic Acid  is as effective at helping prevent pancreatic cancer returning after surgery as the more expensive standard chemotherapy treatment.

The results of the Cancer Research UK- funded study mean the cheaper drug - called 5-fluorouracil (5-FU) - could be prescribed in cases when the standard chemotherapy - gemcitabine - has failed, providing an extra lifeline for patients whose cancer comes back after surgery.

They also raise hopes that a new trial currently underway, looking at combining an oral version of 5-FU with the standard treatment of gemcitabine, could lead to a more effective treatment for pancreatic cancer patients who are eligible for surgery.

The trial, called European Study Group for Pancreatic Cancer (ESPAC)-3, is the largest of its kind and involved 159 centres in Europe, Australasia, Japan and Canada which between them recruited 1088 patients who had undergone surgery for pancreatic cancer.

One group had the standard chemotherapy treatment - gemcitabine. The second group had a cheaper widely available drug called 5-fluorouralcil (5-FU) that is commonly used in cancer treatment already.
The results mean that 5-FU should now also be considered one of the standard options for the treatment of patients with this disease.

They build on earlier trial results suggesting patients who had surgery and chemotherapy had better a chance of survival than patients who only had surgery. 

Finding out these two drugs are as effective as each other at preventing pancreatic cancer returning after surgery is important. It raises hopes that a new trial currently looking at giving two similar drugs together could be successful at preventing or at least delaying pancreatic cancer returning after surgery.

"Previous trial results involving advanced pancreatic cancer patients have shown this drug combination can give precious extra months or even years of life, so there is reason to be hopeful the survival benefit could be even more marked for patients who are eligible for surgery."
 Ref : http://jama.ama-assn.org/cgi/content/full/304/10/1073

Saturday, September 4, 2010

Scientists discover how omega-3 fatty acids shut down inflammation and reverse diabetes

(Picture, courtsey : Cell) Omega-3 fatty acids (-3 FAs), DHA and EPA, exert anti-inflammatory effects, but the mechanisms are poorly understood. Now the  researchers  show that the G protein-coupled receptor 120 (GPR120) functions as an -3 FA receptor/sensor. As per the claim by the researchers, stimulation of GPR120 with -3 FAs or a chemical agonist causes broad anti-inflammatory effects in monocytic RAW 264.7 cells and in primary intraperitoneal macrophages. All of these effects are abrogated by GPR120 knockdown. Since chronic macrophage-mediated tissue inflammation is a key mechanism for insulin resistance in obesity, researchers fed obese WT and GPR120 knockout mice a high-fat diet with or without -3 FA supplementation.

The -3 FA treatment inhibited inflammation and enhanced systemic insulin sensitivity in WT mice, but was without effect in GPR120 knockout mice. In conclusion, GPR120 is a functional -3 FA receptor/sensor and mediates potent insulin sensitizing and antidiabetic effects in vivo by repressing macrophage-induced tissue inflammation. ….....

Thursday, September 2, 2010

Study on current insect repellants confirms need for better insect repellants...

In continuation of update on  mosquito repellents developments and DEET

Now, Johns Hopkins scientists have discovered what it is in the bugs' molecular makeup that enables citronellal (the aromatic liquid used in lotions, sprays and candles) and DEET, to deter insects from landing and feeding on you. A better understanding of these molecular-behavioral links already is aiding the team's search for more effective repellants.

Researchers claim that, three taste receptors on the insects' tongue and elsewhere are needed to detect DEET. Citronellal detection is enabled by pore-like proteins known as TRP (pronounced "trip") channels. When these molecular receptors are activated by exposure to DEET or citronellal, they send chemical messages to the insect brain, resulting in an aversion response.

"DEET has low potency and is not as long-lasting as desired, so finding the molecules in insects that detect repellents opens the door to identifying more effective repellents for combating insect-borne disease," says Craig Montell, Ph.D., a professor of biological chemistry and member of Johns Hopkins' Center for Sensory Biology.

As per the lead researcher, when a mosquito lands, it tastes your skin with its gustatory receptors, before it bites. Researchers suggests that,  one of the reasons DEET is relatively effective is that it causes avoidance responses not only through the sense of smell but also through the sense of taste.

The team filled feeding plates with high and low concentrations of color-coded sugar water (red and blue dyes added to the sugar), allowing the flies to feed at will and taking note of what they ate by the color of their stomachs: red, blue or purple (a combination of red and blue). Wild-type (normal) flies preferred the more sugary water to the less sugary water in the absence of DEET. When various concentrations of DEET were mixed in with the more sugary water, the flies preferred the less sugary water, almost always avoiding the DEET-laced sugar water.Flies that were genetically engineered to have abnormalities in three different taste receptors showed no aversion to the DEET-infused sugar water, indicating the receptors were necessary to detect DEET. 

"We found that the insects were exquisitely sensitive to even tiny concentrations of DEET through the sense of taste," Montell reports. "Levels of DEET as low as five hundredths of a percent reduced feeding behavior."

To add to the evidence that three taste receptors (Gr66a, Gr33a and Gr32a) are required for DEET detection, the team attached recording electrodes to tiny taste hairs (sensilla) on the fly tongue and measured the taste-induced spikes of electrical activity resulting from nerve cells responding to DEET. Consistent with the feeding studies, DEET-induced activity was profoundly reduced in flies with abnormal or mutated versions of Gr66a, Gr33a, and Gr32a. 

In the second study, Montell and colleagues focused on the repellent citronellal. To measure repulsion to the vapors it emits, they applied the botanical compound to the inside bottom of one of the two connected test tubes, and introduced about 100 flies into the tubes. After a while, the team counted the flies in the two tubes. As expected, the flies avoided citronellal. 

The researchers identified two distinct types of cell surface channels that are required in olfactory neurons for avoiding citronellal vapor. The channels let calcium and other small, charged molecules into cells in response to citronellal. One type of channel, called Or83b, was known to be required for avoiding DEET. The second type is a TRP channel. 

The team tested flies with mutated versions of 11 different insect TRP channels. The responses of 10 were indistinguishable from wild-type flies. However, the repellent reaction to citronellal was reduced greatly in flies lacking TRPA1. Loss of either Or83b or TRPA1 resulted in avoidance of citronellal vapor.

The team then "mosquito-ized" the fruit flies by putting into them the gene that makes the mosquito TRP channel (TRPA1) and found that the mosquito TRPA1 substituted for the fly TRPA1. Researchers found that the mosquito-version of TRPA1 was directly activated by citronellal. Montell's lab and others have tallied 28 TRP channels in mammals and 13 in flies, broadening understanding about how animals detect a broad range of sensory stimuli, including smells and tastes.

Hop this discovery now raises the possibility of using TRP channels to find better insect repellents.

Ref 1: http://www.cell.com/current-biology/abstract/S0960-9822%2810%2901006-7
      2 : http://download.cell.com/neuron/pdf/PIIS0896627310005441.pdf?intermediate=true

Wednesday, September 1, 2010

Naringenin (grape fruits) initiates increased fatty acid oxidation, inhibits vLDL production...

Naringenin is a flavonoid that is considered to have a bioactive effect on human health as antioxidant, free radical scavenger, anti-inflammatory, carbohydrate metabolism promoter, and immune system modulator. It is the predominant flavanone in grapefruit. It  has been shown to have an inhibitory effect on the human cytochrome P450 isoform CYP1A2, which can change pharmacokinetics in a human (or orthologous) host of several popular drugs in an adverse manner, even resulting in carcinogens of otherwise harmless substances. Naringenin has also been shown to reduce hepatitis C virus production by infected hepatocytes (liver cells) in cell culture. This seem to be secondary to Naringenin ability to inhibit the secretion of very-low-density lipoprotein by the cells.It has been reported that Naringenin,  lowers the plasma and hepatic cholesterol concentrations by suppressing HMG-CoA reductase and ACAT in rats fed a high-cholesterol diet. 

Now interestingly, researchers from Hebrew University of Jerusalem and Massachusetts General Hospital (MGH) report that naringenin activates a family of small proteins, called nuclear receptors, causing the liver to break down fatty acids. In fact, the compound seems to mimic the actions of other drugs, such as the lipid-lowering Fenofibrate and the anti-diabetic Rosiglitazone, offering the advantages of both. If the results of this study extend to human patients, this dietary supplement could become a staple in the treatment of hyperlipidemia, type-2 diabetes, and perhaps metabolic syndrome.

The researchers demonstrated that the compound activates PPARα and PPARγ by dramatically increasing the levels of a co-activator peptide of both, called PGC1α. At the same time, naringenin bound directly to LXRα, blocking its activation. These effects culminated with increased fatty acid oxidation and the inhibition of vLDL ('bad cholesterol') production.  

"It is a fascinating find," says Yaakov Nahmias, PhD, of the Hebrew University of Jerusalem the paper's senior author. "We show the mechanism by which naringenin increases two important pharmaceutical targets, PPARα and PPARγ, while blocking a third, LXRα. The results are similar to those induced by long periods of fasting".
Authors claim that, it is a process which is similar to the Atkins diet, without many of the side effects and the liver behaves as if fasting, breaking down fatty acids instead of carbohydrates. 

"Dual PPARα and PPARγ agonists, like naringenin, were long sought after by the pharmaceutical industry," says Nahmias, "but their development was plagued by safety concerns. Remarkably, naringenin is a dietary supplement with a clear safety record. Evidence suggests it might actually protect the liver from damage."....
 Ref : http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0012399

Monday, August 30, 2010

Plantain and broccoli fiber help in Crohn’s disease........















In continuation of my update on dietary benefits of broccoli....

New research from University School of Clinical Sciences in Liverpool, lead by Prof. Jonathan Rhodes,  suggests that plant fibers in plantains and broccoli can help prevent relapses of Crohn's disease. This disease is a long term disease of the gut that is characterized by inflammation of the lining of the digestive system, with symptoms including diarrhea and abdominal pain. Scientists believe that rise in processed food and decrease in fibers in diet could be a reason for rise of incidence of this disease.

For this study the scientists tested a range of soluble plant fiber to judge their effect on Crohn's disease. Soluble plant fiber is the kind which comes out of vegetables when they are boiled in water. The results of the study showed that soluble fiber from plantain and broccoli specifically stopped 45% to 82% of the bacteria E.coli from crossing into cells in the intestine. Fiber from leek and apple had no effect.

The sticky E. coli are capable of penetrating the gut wall via special cells, called M-cells that act as 'gatekeepers' to the lymphatic system. Studies have shown that patients with Crohn's disease this leak leads to chronic inflammation in the gut. This study shed that plantain soluble fibers prevented the uptake and transport of E. coli across M.cells. They compared these results with tests on polysorbate-80 - a fat emulsifier used in processed food to bind ingredients together. The tests revealed that polysorbate had the opposite effect to plantain fibers, and encouraged the movement of bacteria through the cells.

The research shows that different dietary components can have powerful effects on the movement of bacteria through the bowel. We  know  the general health benefits of eating plantain and broccoli, which are both high in vitamins and minerals, but until now we have not understood how they can boost the body's natural defences against infection common in Crohn's patients. This work, suggests that it might be important for patients with this condition to eat healthily and limit their intake of processed foods.

Experimental drug PLX4032 holds promise against cancers with faulty BRAF gene....

Plexxikon  recently announced the publication of data from the Phase 1 clinical trial of PLX4032 (RG7204), confirming that treatment of metastatic melanoma patients with the BRAF V600E (mutation resulted in significant tumor shrinkage in the majority of patients). The company claims that, in the melanoma extension cohort of the study, nearly all patients showed some response; 81 percent of patients had tumor shrinkage of at least 30 percent and the company concludes that these results further support the current PLX4032 development strategy, which includes parallel and ongoing Phase 2 (BRIM2) and Phase 3 (BRIM3) studies to support registration. PLX4032 is a novel, orally administered, targeted agent that is selective for a key oncogenic driver in melanoma and other cancers. 
Primary objectives of the melanoma extension cohort were to establish further safety and pharmacokinetics (PK) data beyond the dose-escalation phase, as well as demonstrate proof-of-concept in the target patient population at the MTD of 960 mg twice daily.

Results Demonstrate Significant Anti-tumor Activity with PLX4032 . In the melanoma extension cohort, in which 32 patients with metastatic melanoma harboring the BRAF mutation were enrolled, data showed an 81 percent response rate by RECIST criteria, including:  2 complete responses (no evidence of disease) and 24 partial responses (tumor shrinkage of at least 30 percent)
As per the claim by the company, all patients except two showed some tumor regression. The estimated median progression-free survival (PFS) among these patients was at least seven months as of January 31, 2010, compared to historical PFS of less than two months. Sixteen patients were still on study as of January 31, 2010.
Company also claims that, drug-related adverse events were predominantly mild in severity and included rash, joint pain, photosensitivity and fatigue. Among the 48 patients treated in the dose-escalation and extension cohorts, 18 patients developed cutaneous squamous cell carcinoma in sun exposed areas of the skin (primarily keratoacanthoma subtype) that were treated by excision, while treatment with PLX4032 was continued.

This PLX4032 trial represents the first evidence that a treatment that targets activating BRAF mutations can induce significant tumor regressions in patients," said Dr. K. Peter Hirth, CEO  of  Plexxikon. He adds that "these data are particularly encouraging, with responses observed at all sites of disease, including challenging visceral lesions in the bone, liver and small bowel and  they are  hopeful that PLX4032 will provide similar benefit to these patients so urgently in need of effective therapies."..


PLX4032 is currently being tested in a randomized, controlled Phase 3 (BRIM3) trial in previously untreated metastatic melanoma patients who test positive for the BRAF mutation. Enrollment for the trial is currently under way. The primary endpoint for the BRIM3 trial is overall survival....

Ref : http://www.nejm.org/doi/full/10.1056/NEJMoa1002011