Complications and Patient-Reported Outcomes after Abdominally Based Breast Reconstruction: Results of the Mastectomy Reconstruction Outcomes Consortium Study.

Background: Abdominal flap reconstruction is the most popular form of autologous breast reconstruction. The current study compared complications and patient-reported outcomes after pedicled transverse rectus abdominis myocutaneous (TRAM), free TRAM, deep inferior epigastric perforator (DIEP), and superficial inferior epigastric artery (SIEA) flaps.

Methods: Patients undergoing abdominally based breast reconstruction at 11 centers were prospectively evaluated for abdominal donor-site and breast complications.

ASCO Value Framework Highlights the Relative Value of Treatment Options in Ovarian Cancer.

Purpose: The ASCO value framework allows physicians and patients to compare the relative value of novel treatments. Our aim was to assess the value of three frontline ovarian cancer therapies by using this framework.

Methods: From phase III, randomized controlled clinical trial (RCT) data, the net health benefits (NHBs) for three frontline ovarian cancer treatment options-dose-dense paclitaxel (Japanese Gynecologic Oncology Group study JGOG 3016), intraperitoneal (IP)/intravenous (IV) chemotherapy (Gynecologic Oncology Group [GOG] study GOG 172), and concurrent plus maintenance bevacizumab (GOG 218 and the Seventh International Collaborative Ovarian Neoplasm study [ICON7])-were calculated.

Molecular Analyses Reveal Inflammatory Mediators in the Solid Component and Cyst Fluid of Human Adamantinomatous Craniopharyngioma.

Pediatric adamantinomatous craniopharyngioma (ACP) is a highly solid and cystic tumor, often causing substantial damage to critical neuroendocrine structures such as the hypothalamus, pituitary gland, and optic apparatus. Paracrine signaling mechanisms driving tumor behavior have been hypothesized, with IL-6R overexpression identified as a potential therapeutic target. To identify potential novel therapies, we characterized inflammatory and immunomodulatory factors in ACP cyst fluid and solid tumor components.

High Sensitivity Quantitative Proteomics Using Automated Multidimensional Nano-flow Chromatography and Accumulated Ion Monitoring on Quadrupole-Orbitrap-Linear Ion Trap Mass Spectrometer.

Quantitative proteomics using high-resolution and accuracy mass spectrometry promises to transform our understanding of biological systems and disease. Recent development of parallel reaction monitoring (PRM) using hybrid instruments substantially improved the specificity of targeted mass spectrometry. Combined with high-efficiency ion trapping, this approach also provided significant improvements in sensitivity.

Adult T-Cell Leukemia/Lymphoma.

Adult T-cell lymphoma/leukemia (ATL) is a rare T-cell lymphoproliferative neoplasm caused by human T-lymphotrophic virus 1. In its more common, aggressive forms, ATL carries one of the poorest prognoses of the non-Hodgkin lymphomas. The disease has clinical subtypes (ie, acute, lymphoma, chronic, and smoldering forms) defined by the presenting features, and therefore, the clinical course can vary.

Prediction of potent shRNAs with a sequential classification algorithm.

We present SplashRNA, a sequential classifier to predict potent microRNA-based short hairpin RNAs (shRNAs). Trained on published and novel data sets, SplashRNA outperforms previous algorithms and reliably predicts the most efficient shRNAs for a given gene. Combined with an optimized miR-E backbone, >90% of high-scoring SplashRNA predictions trigger >85% protein knockdown when expressed from a single genomic integration.

ProteoModlR for functional proteomic analysis.

Background: High-accuracy mass spectrometry enables near comprehensive quantification of the components of the cellular proteomes, increasingly including their chemically modified variants. Likewise, large-scale libraries of quantified synthetic peptides are becoming available, enabling absolute quantification of chemically modified proteoforms, and therefore systems-level analyses of changes of their absolute abundance and stoichiometry. Existing computational methods provide advanced tools for mass spectral analysis and statistical inference, but lack integrated functions for quantitative analysis of post-translationally modified proteins and their modification stoichiometry.

Pembrolizumab as Second-Line Therapy for Advanced Urothelial Carcinoma.

Background: Patients with advanced urothelial carcinoma that progresses after platinum-based chemotherapy have a poor prognosis and limited treatment options.

Methods: In this open-label, international, phase 3 trial, we randomly assigned 542 patients with advanced urothelial cancer that recurred or progressed after platinum-based chemotherapy to receive pembrolizumab (a highly selective, humanized monoclonal IgG4κ isotype antibody against programmed death 1 [PD-1]) at a dose of 200 mg every 3 weeks or the investigator's choice of chemotherapy with paclitaxel, docetaxel, or vinflunine. The coprimary end points were overall survival and progression-free survival, which were assessed among all patients and among patients who had a tumor PD-1 ligand (PD-L1) combined positive score (the percentage of PD-L1-expressing tumor and infiltrating immune cells relative to the total number of tumor cells) of 10% or more.

Role of STARD4 in sterol transport between the endocytic recycling compartment and the plasma membrane.

Cholesterol is an essential constituent of membranes in mammalian cells. The plasma membrane and the endocytic recycling compartment (ERC) are both highly enriched in cholesterol. The abundance and distribution of cholesterol among organelles are tightly controlled by a combination of mechanisms involving vesicular and nonvesicular sterol transport processes.

Clinical outcomes and survival surrogacy studies of prostate-specific antigen declines following enzalutamide in men with metastatic castration-resistant prostate cancer previously treated with docetaxel.

Background: In the AFFIRM trial, enzalutamide significantly increased overall survival (OS) for men with metastatic castration-resistant prostate cancer (mCRPC) after chemotherapy versus placebo and significantly decreased prostate-specific antigen (PSA) levels. The goal of this post hoc analysis was to associate levels of PSA decline from baseline after enzalutamide with clinical outcomes in the postchemotherapy mCRPC setting.

Methods: Men in the AFFIRM trial (n = 1199) were grouped by maximal PSA decline in the first 90 days of treatment.

The cell cycle restricts activation-induced cytidine deaminase activity to early G1.

Activation-induced cytidine deaminase (AID) converts cytosine into uracil to initiate somatic hypermutation (SHM) and class switch recombination (CSR) of antibody genes. In addition, this enzyme produces DNA lesions at off-target sites that lead to mutations and chromosome translocations. However, AID is mostly cytoplasmic, and how and exactly when it accesses nuclear DNA remains enigmatic.

Basophils Promote Tumor Rejection via Chemotaxis and Infiltration of CD8+ T Cells.

Elevated numbers of regulatory T cells (Treg) in patient tumors are known to inhibit efficient antitumor T-cell responses. To study the mechanisms controlling tumor rejection, we assessed different mouse models for Treg depletion. In Foxp3DTR knock-in mice, about 99% Treg depletion was achieved, resulting in complete rejection of transplanted HCmel12 melanomas in a CD8 T-cell-dependent way.

Cotranscriptional folding of a riboswitch at nucleotide resolution.

RNAs can begin to fold immediately as they emerge from RNA polymerase. During cotranscriptional folding, interactions between nascent RNAs and ligands are able to direct the formation of alternative RNA structures, a feature exploited by noncoding RNAs called riboswitches to make gene-regulatory decisions. Despite their importance, cotranscriptional folding pathways have yet to be uncovered with sufficient resolution to reveal how cotranscriptional folding governs RNA structure and function.

Towards comprehensive and quantitative proteomics for diagnosis and therapy of human disease.

Given superior analytical features, MS proteomics is well suited for the basic investigation and clinical diagnosis of human disease. Modern MS enables detailed functional characterization of the pathogenic biochemical processes, as achieved by accurate and comprehensive quantification of proteins and their regulatory chemical modifications. Here, we describe how high-accuracy MS in combination with high-resolution chromatographic separations can be leveraged to meet these analytical requirements in a mechanism-focused manner.

A Data-Driven Approach to Predicting Successes and Failures of Clinical Trials.

Over the past decade, the rate of drug attrition due to clinical trial failures has risen substantially. Unfortunately it is difficult to identify compounds that have unfavorable toxicity properties before conducting clinical trials. Inspired by the effective use of sabermetrics in predicting successful baseball players, we sought to use a similar "moneyball" approach that analyzes overlooked features to predict clinical toxicity.

Cross-Sectional and Longitudinal Associations of Diffuse Idiopathic Skeletal Hyperostosis and Thoracic Kyphosis in Older Men and Women.

Objective: To investigate cross-sectional and longitudinal associations of diffuse idiopathic skeletal hyperostosis (DISH) and thoracic kyphosis in older persons.

Methods: DISH and kyphosis were assessed in 1,500 men from the Osteoporotic Fractures in Men (MrOS) study and in 1,267 women from the Study of Osteoporotic Fractures (SOF). DISH was assessed using baseline lateral spine radiographs, and Cobb angle of kyphosis was measured from baseline and followup radiographs, a mean 4.

Should EGFR tyrosine kinase inhibitors be used in non-small cell lung cancer in the absence of EGFR mutations? No, EGFR TKIs should be reserved for patients with EGFR mutations.

Tyrosine kinase inhibitors (TKIs) that block epidermal growth factor receptor (EGFR) clearly work best in patients who have non-small cell lung cancer (NSCLC) with EGFR mutations, but are they worth using in patients without these mutations? In this month's Counterpoints, Dr Frances A. Shepherd says that there is a role for EGFR TKIs in patients with wild-type EGFR disease. Dr Gregory J.

T cell receptor signalling in the control of regulatory T cell differentiation and function.

Regulatory T cells (TReg cells), a specialized T cell lineage, have a pivotal function in the control of self tolerance and inflammatory responses. Recent studies have revealed a discrete mode of T cell receptor (TCR) signalling that regulates TReg cell differentiation, maintenance and function and that affects gene expression, metabolism, cell adhesion and migration of these cells. Here, we discuss the emerging understanding of TCR-guided differentiation of TReg cells in the context of their function in health and disease.

Recommendations for Health Monitoring and Reporting for Zebrafish Research Facilities.

The presence of subclinical infection or clinical disease in laboratory zebrafish may have a significant impact on research results, animal health and welfare, and transfer of animals between institutions. As use of zebrafish as a model of disease increases, a harmonized method for monitoring and reporting the health status of animals will facilitate the transfer of animals, allow institutions to exclude diseases that may negatively impact their research programs, and improve animal health and welfare. All zebrafish facilities should implement a health monitoring program.

Pharmacology in the Era of Targeted Therapies: The Case of PI3K Inhibitors.

The PI3K pathway is often aberrantly activated in estrogen receptor positive (ER(+)) breast cancer and therapies combining PI3K inhibitors and antiestrogens are under clinical development. Given that many PI3K inhibitors have substantial toxicities with continuous dosing and that alternate dosing schedules are equally active, further clinical exploration is warranted. Clin Cancer Res; 22(9); 2099-101.