With the Big Red going to the Big Apple Paulie Pi


first_imgWith the Big Red going to the Big Apple, Paulie Pigskin would like to acknowledge the best known New York Jet player of ’em all. That’s right, in honor of Broadway Joe Namath’s (in)famous sound bite on Monday Night – “team strugggling” – we’ve been thinnnking. But first, let’s hit ‘zoom out’ on our hand held devices because this is a big picture question that we’ve been chewing on since, well…before the Thanksgiving leftovers. Actually, ever since the ribs of Kevin Kolb were torn asunder like a wishbone. Former Cardinals kicker Phil Dawson retires Top Stories 0 Comments   Share   Grace expects Greinke trade to have emotional impact The 5: Takeaways from the Coyotes’ introduction of Alex Meruelo No, we’re talking about a “winning” QB. How does Paulie Pigskin Inc. define that? Simple. A quarterback that doesn’t lose football games, capisce?! (All apologies…a pair of interceptions returned for touchdowns in a game lost by exactly 14 points still has us a rootin’ & a tootin’.) In fact, following Sunday, did you happen to catch this Holy Cannoli Stat? In 33 drives since the injury, they’ve “punted 17 times, lost seven fumbles, thrown four interceptions and had one possession end on downs. It scored two touchdowns and two field goals.” What’s more, the QB rating was “38.7…thanks, largely, to three second-half interceptions” in a loss to a 3-8 team. The above stats come from the Cards loss to the Rams, right? #Buzzer. That’s a blurb lifted from the Pittsburgh Post-Gazette this week, detailing the Steelers offensive woes since the rib injury to Ben Roethlisberger, including the Steelers heinous loss to the Browns (3-8). And something tells us that if you examined the Bears minus Jay Cutler, the numbers would not be flattering. In other words, NFL teams are best served to remember: don’t throw the entire roster out with the QB bath water. Are the Arizona Cardinals a team that is struggling? Or are the Cards an NFL team that is struggling at quarterback?Team struggling? Or a team struggling at the QB position? Either way, you wind up in the same landing spot – below sea level in the standings. Both scenarios are akin to driving on bald tires in a rainstorm. Eventually, you’ll find yourself in a full-blown power slide and looking at the road ahead through your side windows. The difference comes when the skid (seven games) grinds to a halt. How do you put that car back on the road? Do you ever get behind the wheel of that car again? Because if your entire team is struggling, then you’re rebuilding (“Fire in the Hole!”) However, if it’s the QB position that’s struggling, then you’re either recruiting (“Hey, uh, Peyton, can we buy you dinner?”) or commencing with research and reconnaissance (Matt Barkley?) Wait, hit ‘zoom out’ again. New question — how many franchises succeed without a winning QB? We’re not saying a Pro Bowl or Hall of Fame QB. We’re not even saying a bona fide franchise signal caller. Derrick Hall satisfied with D-backs’ buying and sellinglast_img read more

Scientists identify melanoma biomarkers that could help tailor immunotherapy treatments


first_img Source:http://www.dana-farber.org Jul 19 2018Scientists at Dana-Farber/Brigham and Women’s Cancer Center (DF/BWCC) have identified biomarkers in melanoma that could help tailor immunotherapy treatments to maximize the benefits for patients while reducing the likelihood of severe side effects.While the utility of these biomarkers needs to be validated in future clinical trials, the findings reported in Science Translational Medicine suggest that the current practice of combining two different types of immune checkpoint blocker drugs in advanced melanoma patients may be the best course in some instances, but not in others, because the immune makeup of some melanoma tumors may cause them to be resistant to one class of checkpoint inhibitors.”By looking at how melanoma is avoiding immune detection, we may be able to identify patients who may do just as well with a single agent, with no loss of efficacy, but improved tolerability,” said Scott Rodig, MD, PhD, an oncologic pathologist at DF/BWCC and first author on the report. The study revealed that some patients, whose tumors are deficient in a protein needed for the immune system to recognize cancer cells, are unlikely to benefit from ipilimumab, an immunotherapy drug that blocks the CTLA-4 checkpoint, but which has potentially severe side effects. Therefore, identifying such patients with a biomarker test prior to treatment could spare them the adverse effects.The outlook for patients with advanced melanoma has dramatically improved in recent years because of drugs known as immune checkpoint inhibitors, which mobilize the immune system to attack cancer. These drugs block checkpoint molecules that act as brakes on the immune system; by removing these brakes, checkpoint inhibitors unleash immune defenders such as T cells to recognize and attack cancer.Typically, patients with advanced melanoma receive a combination of two different checkpoint inhibitor types: one, such as ipilimumab, targets the CTLA-4 checkpoint, while the other, including nivolumab and pembrolizumab, targets the PD-1 checkpoint.In general, patients with advanced melanoma have better outcomes when they receive drugs that block both the CTLA-4 checkpoint and the PD-1 or PD-L1 checkpoints, said F. Stephen Hodi, MD, director of the Melanoma Disease Center at Dana-Farber and senior author of the report. Treated with the combination, more than 50 percent of patients will have tumor shrinkage and some of the responses will be quite prolonged, he said. But this benefit can come at a steep cost – around 50 percent of patients will have severe side effects, such as inflammation of the gut causing diarrhea; rash, or inflammation of the liver and pancreas.The new study was inspired by recent research by Margaret Shipp, MD, at Dana-Farber showing that Hodgkin lymphomas frequently avoid immune detection by eliminating their MHC class I proteins. MHC class I proteins are found on the surface of most cells in the body. Their function is to bind fragments of foreign proteins, including those stemming from cancer cells, and present them to T cells, which then mount a mass attack on the invader. But if cancer manages to somehow dial down the abundance of MHC class I proteins, the immune system won’t recognize the cancer as foreign and respond against it. In Hodgkin lymphoma, the tumor cells accomplish this feat by deleting a key gene required for expression of the MHC class I proteins.Related StoriesUAMS-developed noninvasive device detects melanoma in earliest stagesNuclear medicine imaging assesses melanoma patients’ response to immunotherapyStudy identifies possible way to predict which melanomas are hot and coldSpeculating that something similar might occur in melanoma, the authors of the new study used data from two clinical trials of immunotherapy for advanced melanoma that included measurements of MHC class I proteins and other immune cells and immune regulators. The investigators found that partial or complete loss of MHC class I proteins was common in untreated melanoma patients, and those patients had poor responses to treatment with ipilimumab – the drug that blocks the CTLA-4 checkpoint. “CTLA-4 is exquisitely sensitive to even partial loss of these MHC class I proteins,” said Rodig. The result was the melanoma was highly resistant to ipilimumab treatment and the cancer continued to grow, because even though the immunotherapy drug was releasing the CTLA-4 brake on the immune system, the melanoma cells weren’t recognized due to the lack of MHC class I proteins to “present” the cancer fragments to the T cells. These findings may explain why most melanoma patients don’t respond to single-agent ipilimumab.However, the researchers also observed that the deficiency of MHC class 1 proteins did not make melanoma tumors resistant to the other type of checkpoint inhibitor, drugs like nivolumab, a PD-1 inhibitor. That is because responses to those drugs activate an immune substance known as interferon-gamma, which in turn activates both MHC class I-dependent and MHC class I-independent immune pathways and thereby promotes anti-tumor activity when MHC class I levels are reduced by the tumor. Indeed, the data from the clinical trials showed that patients whose tumors had higher pre-treatment levels of interferon-gamma had better outcomes when treated with nivolumab or a combination of nivolumab and ipilimumab but not ipilimumab alone.These results, the authors conclude, reveal that the clinical efficacy of anti-CTLA-4 drugs like ipilimumab is “dependent on robust, pre-existing expression of MHC class I proteins by tumor cells.” By contrast, efficacy of anti-PD1 checkpoint blockers like nivolumab depends on “pre-existing interferon-gamma-mediated inflammation within the tumor microenvironment.” Combining the two types of checkpoint blockers “provides a further immune stimulus over individual therapies alone and, in addition, overcomes the limitations of each,” they said.Going forward, the researchers said, it would be ideal to have clinical trials in which treatment options are determined in accordance with the results of tissue-based biomarker studies.”last_img read more