TASK DEFINITION: In this task, you are given a passage which has a question and the context. You have to generate an answer to the question based on the information present in the context.
PROBLEM: Context: Enterovirus infections are major etiological factors in myocarditis and dilated cardiomyopathy. Using an experimental murine model of this disease, previous studies have shown that myocarditis susceptibility depends upon activation of T lymphocytes expressing the gamma delta T cell receptor (TcR), and that only mouse strains which accumulate gamma delta T cells in the myocardium show apoptosis of myocytes or evidence of dilated cardiomyopathy-like disease. The objective of the present studies is to demonstrate that gamma delta T cells directly induce greater Fas-dependent apoptosis of cultured myocytes than T cells expressing the alpha beta TcR.', 'Bl.Tg.E alpha mice were infected for 7 days with coxsackievirus B3 (CVB3). Hearts were removed and were either formalin-fixed, sectioned and stained with hematoxylin and eosin for inflammation, and using TdT-TUNEL for apoptosis, or were minced and collagenase digested for isolation of gamma delta+ and alpha beta+ T cells using immunomagnetic bead separation. Neonatal cultures of cardiac myocytes were isolated from mice less than 2 days old by collagenase and pancreatin digestion, and were either untreated or infected with virus. Levels of Fas (CD95) were measured using FITC-conjugated hamster anti-mouse Fas monoclonal antibody and flow cytometry. Susceptibility of myocytes to Fas-dependent killing was measured by 51Cr-release by labeled myocytes incubated for 4 h on either 3T3-mock or 3T3-FasL transfected cell monolayers. Killing by T cells was also measured in a 4 h 51Cr-release assay. Fas-dependent and perforin-dependent cytotoxicity was determined by specific blocking using either Fas-Fc or concanamycin A.', 'Virally infected myocyte cultures showed significantly enhanced Fas expression compared to uninfected cells, with maximal upregulation of Fas occurring 18-24 h after virus infection. Both infected and uninfected myocytes were selectively killed by FasL-transfected 3T3 cells but not by mock control cells. Approximately 38% of CD3+ lymphocytes isolated from the heart express the gamma delta TcR with the remainder expressing the alpha beta TcR. Both gamma delta+ and alpha beta+ T cells lysed myocyte targets. Blocking studies indicate that gamma delta+ T cells induced predominantly Fas-mediated killing, while alpha beta+ cell produced more perforin-mediated death, although these effectors were capable of Fas-dependent killing as well.\Question: Do t cells expressing the gamma delta T cell receptor induce apoptosis in cardiac myocytes?

SOLUTION: These studies demonstrate that T cells expressing the gamma delta TcR are more effective mediators of myocyte apoptosis than alpha beta+ T cells in vitro and suggests that these effectors may be primarily responsible for myocardial injury associated with dilated cardiomyopathy-like signs during coxsackievirus B3-induced myocarditis.

PROBLEM: Context: Dynamic pelvic magnetic resonance imaging (DP-MRI) offers a comprehensive evaluation of pelvic organ structure in addition to functional information regarding evacuation. Opportunity to apply this technology can be limited due to regional lack of availability. Ideally, clues from standard anorectal testing could predict abnormalities on DP-MRI, leading to its efficient use. The aim of this study is to determine whether high-resolution anorectal manometry (HR-ARM) correlates with findings on DP-MRI.', "This is a retrospective study of HR-ARM performed on patients with constipation who also underwent DP-MRI. Studies were reviewed for significant findings including posterior pelvic organ prolapse, rectocele\u2009>\u20093\u2009cm, rectal intussusception, and anorectal angle. Statistical analysis was performed using Pearson's correlation coefficient, Student's t-test, and Fisher's exact test.", 'Twenty-three patients undergoing HR-ARM (age range 25-78) also underwent DP-MRI. All were female; 76% were Caucasian. Twenty had significant structural findings: small pelvic prolapse (n\u2009=\u20092), moderate pelvic prolapse (n\u2009=\u200910), large pelvic prolapse (n\u2009=\u20099), rectocele (n\u2009=\u20098), or rectal intussusception (n\u2009=\u20093). Only intrarectal pressure on HR-ARM weakly correlated with size of rectocele (r\u2009=\u20090.46; P\u2009=\u20090.03) and degree of pelvic organ prolapse (r\u2009=\u20090.48; P\u2009=\u20090.02). The remainder of the HR-ARM parameters did not significantly correlate with DP-MRI findings. Patients with dyssynergy were not more likely to have rectoceles\u2009>\u20093\u2009cm (44.4% versus 35.7%; P\u2009=\u20090.5) or large prolapses (44.4% versus 50%, P\u2009=\u20091.0), compared with those without dyssynergy, on HR-ARM.\Question: Are high-resolution anorectal manometry and dynamic pelvic magnetic resonance imaging complementary technologies?

SOLUTION: We were unable to find a correlation between HR-ARM findings and structural pelvic defects on DP-MRI. Therefore, these two technologies provide complementary information in the evaluation of defecatory dysfunction.

PROBLEM: Context: BRAF mutations occur in 5% to 10% of metastatic colorectal cancers and are biomarkers associated with a poor prognosis. However, the outcomes with standard chemotherapy over sequential lines of therapy in a large cohort of patients with BRAF-mutant tumors have not been described.', 'We searched the M.D. Anderson Cancer Center databases for patients with colorectal cancer and identified BRAF mutations between December 2003 and May 2012. Patients were analyzed for clinical characteristics, PFS, overall survival, and chemotherapeutic agents used. Survival was estimated according to the Kaplan-Meier method.', 'Among the 1567 patients tested for BRAF mutations at our institution, 127 (8.1%) had tumors with BRAF mutations. The 71 patients who presented with metastatic disease received a median of 2 lines of chemotherapy. For the first 3 lines of chemotherapy, median PFS was 6.3 months (n\xa0= 69 patients; 95% confidence interval [CI], 4.9-7.7 months), 2.5 months (n\xa0= 58 patients; 95% CI, 1.8-3.0 months), and 2.6 months (n\xa0= 31 patients; 95% CI, 1.0-4.2 months), respectively. Median PFS was not affected by the backbone chemotherapeutic agent in the first-line setting, whether oxaliplatin-based or irinotecan-based (6.4 months vs. 5.4 months, respectively; P\xa0= .99).\Question: Does progression-free survival remain poor over sequential lines of systemic therapy in patients with BRAF-mutated colorectal cancer?

SOLUTION:
PFS is expectedly poor for patients with BRAF-mutated metastatic colorectal cancer. Despite the ascertainment bias present (with testing preferentially performed in patients suitable for clinical trials in refractory disease), these data provide historic controls suitable for future study design and support the idea that novel therapeutic options are essential in this population.