Differential Effects of Dietary versus Exercise Intervention on Intrahepatic MAIT Cells and Histological Features of NAFLD

Background: Mucosal-associated invariant T (MAIT) cells promote inflammation in obesity and are implicated in the progression of non-alcoholic fatty liver disease (NAFLD). However, as the intrahepatic MAIT cell response to lifestyle intervention in NAFLD has not been investigated, this work aimed to examine circulating and intrahepatic MAIT cell populations in patients with NAFLD, after either 12 weeks of dietary intervention (DI) or aerobic exercise intervention (EI). Methods: Multicolour flow cytometry was used to immunophenotype circulating and intrahepatic MAIT cells and measure MAIT cell expression (median fluorescence intensity, MFI) of the activation marker CD69 and apoptotic marker CD95. Liver histology, clinical parameters, and MAIT cell populations were assessed at baseline (T0) and following completion (T1) of DI or EI. Results: Forty-five patients completed the study. DI participants showed decreased median (interquartile range) expression of the activation marker CD69 on circulating MAIT cells (T0: 104 (134) versus T1 27 (114) MFI; p = 0.0353) and improvements in histological steatosis grade post-intervention. EI participants showed increased expression of the apoptotic marker CD95, both in circulating (T0: 1549 (888) versus T1: 2563 (1371) MFI; p = 0.0043) and intrahepatic MAIT cells (T0: 2724 (862) versus T1: 3117 (1622) MFI; p = 0.0269). Moreover, the percentage of intrahepatic MAIT cells significantly decreased after EI (T0: 11.1 (14.4) versus T1: 5.3 (9.3)%; p = 0.0029), in conjunction with significant improvements in fibrosis stage and hepatocyte ballooning. Conclusions: These data demonstrate independent benefits from dietary and exercise intervention and suggest a role for intrahepatic MAIT cells in the observed histological improvements in NAFLD.     

Gaps and opportunities in the treatment of relapsed-refractory multiple myeloma: Consensus recommendations of the NCI Multiple Myeloma Steering Committee

A wide variety of new therapeutic options for Multiple Myeloma (MM) have recently become available, extending progression-free and overall survival for patients in meaningful ways. However, these treatments are not curative, and patients eventually relapse, necessitating decisions on the appropriate choice of treatment(s) for the next phase of the disease. Additionally, an important subset of MM patients will prove to be refractory to the majority of the available treatments, requiring selection of effective therapies from the remaining options. Immunomodulatory agents (IMiDs), proteasome inhibitors, monoclonal antibodies, and alkylating agents are the major classes of MM therapies, with several options in each class. Patients who are refractory to one agent in a class may be responsive to a related compound or to a drug from a different class. However, rules for selection of alternative treatments in these situations are somewhat empirical and later phase clinical trials to inform those choices are ongoing. To address these issues the NCI Multiple Myeloma Steering Committee formed a relapsed/refractory working group to review optimal treatment choices, timing, and sequencing and provide recommendations. Additional issues considered include the role of salvage autologous stem cell transplantation, risk stratification, targeted approaches for genetic subsets of MM, appropriate clinical trial endpoints, and promising investigational agents. This report summarizes the deliberations of the working group and suggests potential avenues of research to improve the precision, timing, and durability of treatments for Myeloma.Subject terms: Combination drug therapy, Cancer therapeutic resistance, Targeted therapies     

Yield of chest computed tomography angiogram in cystic fibrosis patients with suspected pulmonary embolism

IntroductionIndividuals with cystic fibrosis (CF) may be at increased risk of pulmonary embolism (PE). Symptoms of PE overlap substantially with those of CF respiratory exacerbations. CF patients commonly undergo chest computed tomography (CT) angiograms (CTPA) to evaluate for PE, but little is known about the clinical presentation and diagnosis of PE in this population.ObjectivesThe objectives of this study are to determine the diagnostic yield of CTPA for PE in adult patients with CF and assess the utility of the Revised Geneva Score (RGS) in this population.MethodsRetrospective review of all CTPA results was performed on CF patients with suspected PE at a large CF center from 1 January 2011 through 31 March 2017. Patient demographics, medical history, and presenting signs and symptoms were abstracted by chart review.ResultsA total of 103 unique CTPA studies were performed in 68 patients. Most were hospitalized at the time of CTPA, predominantly for respiratory manifestations of CF. CTPA identified four patients with PE. The small number of positive studies precluded analysis of predictors of PE. Fewer PE were diagnosed than predicted by the Revised Geneva Score, which was intermediate probability in 77/103 (75%) patients.ConclusionThe prevalence of PE in CF patients undergoing CTPA for suspected PE was 4%, which is lower than predicted by the Revised Geneva Score. This may be due to a large overlap in the signs and symptoms of PE and exacerbations of CF lung disease.