Randomized Phase III Trial of Paclitaxel and Carboplatin Versus Paclitaxel and Ifosfamide in Patients With Carcinosarcoma of the Uterus or Ovary: An NRG Oncology Trial.

Purpose: This phase III randomized trial (NCT00954174) tested the null hypothesis that paclitaxel and carboplatin (PC) is inferior to paclitaxel and ifosfamide (PI) for treating uterine carcinosarcoma (UCS).

Patients And Methods: Adults with chemotherapy-naïve UCS or ovarian carcinosarcoma (OCS) were randomly assigned to PC or PI with 3-week cycles for 6-10 cycles. With 264 events in patients with UCS, the power for an overall survival (OS) hybrid noninferiority design was 80% for a null hazard ratio (HR) of 1.

Why does obesity cause diabetes?

The accumulation of an excessive amount of body fat can cause type 2 diabetes, and the risk of type 2 diabetes increases linearly with an increase in body mass index. Accordingly, the worldwide increase in the prevalence of obesity has led to a concomitant increase in the prevalence of type 2 diabetes. The cellular and physiological mechanisms responsible for the link between obesity and type 2 diabetes are complex and involve adiposity-induced alterations in β cell function, adipose tissue biology, and multi-organ insulin resistance, which are often ameliorated and can even be normalized with adequate weight loss.

The CD6/ALCAM pathway promotes lupus nephritis via T cell-mediated responses.

T cells are central to the pathogenesis of lupus nephritis (LN), a common complication of systemic lupus erythematosus (SLE). CD6 and its ligand, activated leukocyte cell adhesion molecule (ALCAM), are involved in T cell activation and trafficking. Previously, we showed that soluble ALCAM is increased in urine (uALCAM) of patients with LN, suggesting that this pathway contributes to disease.

The National Institute on Aging Late-Onset Alzheimer's Disease Family Based Study: A resource for genetic discovery.

Introduction: The National Institute on Aging Late-Onset Alzheimer's Disease Family Based Study (NIA-LOAD FBS) was established to study the genetic etiology of Alzheimer's disease (AD).

Methods: Recruitment focused on families with two living affected siblings and a third first-degree relative similar in age with or without dementia. Uniform assessments were completed, DNA was obtained, as was neuropathology, when possible.

Acid-Catalyzed Synthesis of Isatoic Anhydride-8-Secondary Amides Enables IASA Transformations for Medicinal Chemistry.

Quinazolin-dione--3-alklyl derivatives are the core scaffolds for several categories of bioactive small molecules, but current synthetic methods are costly, involve environmental hazards, and are not uniformly scalable. Here, we report an inexpensive, flexible, and scalable method for the one-pot synthesis of substituted quinazolin-dione--3-alkyls (isomers of isatoic-8-secondary amides (IASAs)) from isatin that take advantage of capture of imidic acid under acidic conditions. We further show that this method can be used for the synthesis of a wide variety of derivatives with medicinal uses.

International Bladder Cancer Group Consensus Statement on Clinical Trial Design for Patients with Bacillus Calmette-Guérin-exposed High-risk Non-muscle-invasive Bladder Cancer.

Context: A large proportion of patients with non-muscle-invasive bladder cancer (NMIBC) fall in the gap between bacillus Calmette-Guérin (BCG)-naïve and BCG-unresponsive disease. As multiple therapeutic agents move into this gray area, there is a critical need to define the disease state and establish recommendations for optimal trial design.

Objective: To develop a consensus on optimal trial design for patients with BCG-exposed NMIBC, defined as high-grade recurrence after BCG treatment that does not meet the criteria for BCG-unresponsive disease.

Conformational Models of APP Processing by Gamma Secretase Based on Analysis of Pathogenic Mutations.

Proteolytic processing of amyloid precursor protein (APP) plays a critical role in the pathogenesis of Alzheimer's disease (AD). Sequential cleavage of APP by β and γ secretases leads to the generation of Aβ40 (non-amyloidogenic) and Aβ42 (amyloidogenic) peptides. Presenilin-1 (PS1) or presenilin-2 (PS2) play the role of a catalytic subunit of γ-secretase.

Wnt5a Promotes Lysosomal Cholesterol Egress and Protects Against Atherosclerosis.

Background: Impairment of cellular cholesterol trafficking is at the heart of atherosclerotic lesions formation. This involves egress of cholesterol from the lysosomes and 2 lysosomal proteins, the NPC1 (Niemann-Pick C1) and NPC2 that promotes cholesterol trafficking. However, movement of cholesterol out the lysosome and how disrupted cholesterol trafficking leads to atherosclerosis is unclear.

Type 1 polyisoprenoid diphosphate phosphatase modulates geranylgeranyl-mediated control of HMG CoA reductase and UBIAD1.

UbiA prenyltransferase domain-containing protein-1 (UBIAD1) utilizes geranylgeranyl pyrophosphate (GGpp) to synthesize the vitamin K subtype menaquinone-4. The prenyltransferase has emerged as a key regulator of sterol-accelerated, endoplasmic reticulum (ER)-associated degradation (ERAD) of HMG CoA reductase, the rate-limiting enzyme in synthesis of cholesterol and nonsterol isoprenoids including GGpp. Sterols induce binding of UBIAD1 to reductase, inhibiting its ERAD.

An Open-Source Wireless Electrophysiological Complex for In Vivo Recording Neuronal Activity in the Rodent's Brain.

Multi-electrode arrays (MEAs) are a widely used tool for recording neuronal activity both in vitro/ex vivo and in vivo experiments. In the last decade, researchers have increasingly used MEAs on rodents in vivo. To increase the availability and usability of MEAs, we have created an open-source wireless electrophysiological complex.

A Hybrid Model Composed of Two Convolutional Neural Networks (CNNs) for Automatic Retinal Layer Segmentation of OCT Images in Retinitis Pigmentosa (RP).

Purpose: We propose and evaluate a hybrid model composed of two convolutional neural networks (CNNs) with different architectures for automatic segmentation of retina layers in spectral domain optical coherence tomography (SD-OCT) B-scans of retinitis pigmentosa (RP).

Methods: The hybrid model consisted of a U-Net for initial semantic segmentation and a sliding-window (SW) CNN for refinement by correcting the segmentation errors of U-Net. The U-Net construction followed Ronneberger et al.

Defining adverse events during trauma resuscitation: a modified RAND Delphi study.

Background: The majority of preventable adverse event (AEs) in trauma care occur during the initial phase of resuscitation, often within the trauma bay. However, there is significant heterogeneity in reporting these AEs that limits performance comparisons between hospitals and trauma systems. The objective of this study was to create a taxonomy of AEs that occur during trauma resuscitation and a corresponding classification system to assign a degree of harm.

Intrasinusoidal Hodgkin Lymphoma; A Mimic of Anaplastic Large Cell Lymphoma.

The distinction between classical Hodgkin lymphoma (HL) and anaplastic large cell lymphoma (ALCL) is not problematic in most instances. In rare situations, HL may present with a sinusoidal infiltrative pattern that may mimic ALCL. It is important to use a battery of immunohistochemical stains to differentiate between these two entities as therapy and clinical behavior are different.

ATYPICAL MRI FINDINGS IN CEREBRAL ADRENOLEUKODYSTROPHY: A CASE REPORT.

Adrenoleukodystrophy is a rare X-linked hereditary disease that results in accumulation of very-long-chain fatty acids in all body tissues, thus causing demyelination of the white matter. Magnetic resonance imaging (MRI) is a reliable radiological modality to demonstrate the extension of brain lesions and severity of the disease. In the classic form, the parieto-occipital white matter is affected.

Neurodevelopmental outcomes of preterm infants after randomisation to initial resuscitation with lower (FiO 0.3) or higher (FiO 0.6) initial oxygen levels. An individual patient meta-analysis.

Objective: To determine the effects of lower (≤0.3) versus higher (≥0.6) initial fractional inspired oxygen (FiO) for resuscitation on death and/or neurodevelopmental impairment (NDI) in infants <32 weeks' gestation.

Effects of Extracorporeal Membrane Oxygenation Initiation on Oxygenation and Pulmonary Opacities.

Introduction: There is limited data on the impact of extracorporeal membrane oxygenation (ECMO) on pulmonary physiology and imaging in adult patients. The current study sought to evaluate the serial changes in oxygenation and pulmonary opacities after ECMO initiation.

Methods: Records of patients started on veno-venous, or veno-arterial ECMO were reviewed (n=33; mean (SD): age 50(16) years; Male: Female 20:13).

LIFR inhibition enhances the therapeutic efficacy of HDAC inhibitors in triple negative breast cancer.

Histone deacetylase inhibitors (HDACi) are identified as novel therapeutic agents, however, recent clinical studies suggested that they are marginally effective in treating triple negative breast cancer (TNBC). Here, we show that first-in-class Leukemia Inhibitory Factor Receptor (LIFRα) inhibitor EC359 could enhance the therapeutic efficacy of HDACi against TNBC. We observed that both targeted knockdown of LIFR with CRISPR or treatment with EC359 enhanced the potency of four different HDACi in reducing cell viability, cell survival, and enhanced apoptosis compared to monotherapy in TNBC cells.

Time and metabolic state-dependent effects of GLP-1R agonists on NPY/AgRP and POMC neuronal activity in vivo.

Objective: Long-acting glucagon-like peptide-1 receptor agonists (GLP-1RAs), like liraglutide and semaglutide, are viable treatments for diabetes and obesity. Liraglutide directly activates hypothalamic proopiomelanocortin (POMC) neurons while indirectly inhibiting Neuropeptide Y/Agouti-related peptide (NPY/AgRP) neurons ex vivo. While temporal control of GLP-1R agonist concentration as well as accessibility to tissues/cells can be achieved with relative ease ex vivo, in vivo this is dependent upon the pharmacokinetics of these agonists and relative penetration into structures of interest.

Detection of G Protein-coupled Receptor Expression in Mouse Vagal Afferent Neurons using Multiplex In Situ Hybridization.

This study describes a protocol for the multiplex in situ hybridization (ISH) of the mouse jugular-nodose ganglia, with a particular emphasis on detecting the expression of G protein-coupled receptors (GPCRs). Formalin-fixed jugular-nodose ganglia were processed with the RNAscope technology to simultaneously detect the expression of two representative GPCRs (cholecystokinin and ghrelin receptors) in combination with one marker gene of either nodose (paired-like homeobox 2b, Phox2b) or jugular afferent neurons (PR domain zinc finger protein 12, Prdm12). Labeled ganglia were imaged using confocal microscopy to determine the distribution and expression patterns of the aforementioned transcripts.