Water and chloride as allosteric inhibitors in WNK kinase osmosensing.

Osmotic stress and chloride regulate the autophosphorylation and activity of the WNK1 and WNK3 kinase domains. The kinase domain of unphosphorylated WNK1 (uWNK1) is an asymmetric dimer possessing water molecules conserved in multiple uWNK1 crystal structures. Conserved waters are present in two networks, referred to here as conserved water networks 1 and 2 (CWN1 and CWN2).

Magnetoactive elastomer-based dynamic urethral support device for stress urinary incontinence.

Stress urinary incontinence (SUI) is the involuntary leakage of urine in response to increased intra-abdominal pressure during episodes of exertion. A common treatment method for SUI is sling implantation underneath the urethra to provide support. Most current sling procedures, however, cannot adjust urethral tension postoperatively.

Trimodality Therapy Versus Radical Cystectomy for Muscle-invasive Bladder Cancer: A Systematic Review and Meta-analysis of Matched Cohort Studies.

Background And Objective: Radical cystectomy (RC) is the standard treatment for muscle-invasive bladder cancer (MIBC). It is highly invasive and associated with perioperative risks, while bladder-preserving trimodality therapy (TMT) offers a less invasive alternative with preferable quality of life for selected patients. We aimed to compare oncological outcomes of TMT and RC in MIBC patients, and evaluate TMT-specific outcomes.

Clinical and radiological implications of subpotent generic fingolimod in multiple sclerosis: a case series.

An expansion in the availability of generic specialty disease modifying therapies (DMTs) for treatment of multiple sclerosis (MS) has increased recently. Generic specialty medications aim to provide greater access to molecules that alter the disease trajectory at lower costs. The US Food and Drug Administration requires generic products to contain between 90% and 110% of the stated active ingredient and an 80%-125% bioequivalence range.

Impact of Lifestyle Modifications on the Prevention and Treatment of Pelvic Organ Prolapse.

Introduction And Hypothesis: This manuscript is a part of the International Urogynecology Consultation (IUC) on pelvic organ prolapse (POP) chapter three, committee three, on the impact of lifestyle modifications (i.e., weight loss, treatment of constipation, activity restriction, etc.

Predictors of Facial Synkinesis Severity.

Background: There is a lack of studies exploring factors influencing synkinesis severity. This study aims to identify factors that may contribute to variations in severity of facial synkinesis.

Methods: Patients with a diagnosis of facial synkinesis presenting between 2009 and 2024 were reviewed.

PKN2 is a dependency of the mesenchymal-like cancer cell state.

Cancer cells exploit a mesenchymal-like transcriptional state (MLS) to survive drug treatments. Although the MLS is well characterized, few therapeutic vulnerabilities targeting this program have been identified. Here, we systematically identify the dependency network of mesenchymal-like cancers through an analysis of gene essentiality scores in ~800 cancer cell lines, nominating a poorly studied kinase, PKN2, as a top therapeutic target of the MLS.

Behavioural economics to improve and motivate vaccination in primary care using nudges through the electronic health record: rationale and design of the BE IMMUNE randomised clinical trial.

Introduction: Annual influenza vaccination reduces disease burden but vaccination rates are suboptimal, with persistent disparities among subpopulations. The purpose of this trial is to evaluate multicomponent behavioural economic nudge interventions to clinicians and patients to increase influenza vaccination. This trial also includes an intensification nudge to reduce disparities in vaccination among older adult, primary care patients.

Rational Design of Enhanced Nme2Cas9 and Nme2Cas9 Nucleases and Base Editors.

CRISPR-Cas genome editing tools enable precise, RNA-guided modification of genomes within living cells. The most clinically advanced genome editors are Cas9 nucleases, but many nuclease technologies provide only limited control over genome editing outcomes. Adenine base editors (ABEs) and cytosine base editors (CBEs) enable precise and efficient nucleotide conversions of A:T-to-G:C and C:G-to-T:A base pairs, respectively.

PD-L1 (22C3) expression and prognostic implications in esophageal squamous cell carcinoma.

Programmed cell death-ligand 1 (PD-L1) clone 22C3 is the only Food and Drug Administration-approved companion diagnostic test for pembrolizumab for the treatment of esophageal squamous cell carcinoma (ESCC). However, prior studies conducted in Asia and Europe have used various PD-L1 antibody clones other than 22C3. We aimed to study the expression profile of PD-L1, specifically of clone 22C3, in ESCC and its significance with regards to histological features, clinical parameters, and overall survival in a case series from two large US hospital systems.

Financial Toxicity Among Patients With Traumatic Finger Amputation: A Retrospective Study.

Background: Patients face increasing financial toxicity (FT), defined as emotional distress due to the cost of medical treatment. However, little is known regarding FT in the context of upper extremity trauma.

Methods: We surveyed patients who sustained traumatic finger amputation (October 21, 2011-January 1, 2021).

Exam quality of ultrasound and dynamic contrast-enhanced abbreviated MRI and impact on early-stage HCC detection.

Purpose: MRI is a potential alternative to ultrasound for hepatocellular carcinoma (HCC) detection. We evaluated the impact of ultrasound and dynamic abbreviated MRI (AMRI) exam quality on early-stage HCC detection.

Methods: We conducted a multicenter case-control study among patients with cirrhosis (cases with early-stage HCC per Milan Criteria; controls without HCC) who underwent both a liver ultrasound and dynamic contrast-enhanced (DCE) AMRI within 6 months in 2012-2019.

ARF alters PAF1 complex integrity to selectively repress oncogenic transcription programs upon p53 loss.

The polymerase associated factor 1 (PAF1) complex (PAF1c) promotes RNA polymerase II (RNA Pol II) transcription at the elongation step; however, how PAF1c transcription activity is selectively regulated during cell fate transitions remains poorly understood. Here, we reveal that the alternative reading frame (ARF) tumor suppressor operates at two levels to restrain PAF1c-dependent oncogenic transcriptional programs upon p53 loss in mouse cells. First, ARF assembles into homo-oligomers to bind the PAF1 subunit to promote PAF1c disassembly, consequently dampening PAF1c interaction with RNA Pol II and PAF1c-dependent transcription.

Patient centered HCC surveillance - complementary roles of ultrasound and CT/MRI.

Hepatocellular carcinoma (HCC) is a leading cause of cancer-related mortality worldwide and is the fastest growing cause of cancer death in the United States (U.S.) In the U.

Creeping Fat-Derived Free Fatty Acids Induce Hyperplasia of Intestinal Muscularis Propria Muscle Cells: A Novel Link Between Fat and Intestinal Stricture Formation in Crohn's Disease.

Background & Aims: In Crohn's disease, wrapping of mesenteric fat around the bowel wall, so-called "creeping fat," is highly associated with strictures. The strongest contributor to luminal narrowing in strictures is a thickening of the human intestinal muscularis propria (MP). We investigated creeping fat-derived factors and their effect on mechanisms of human intestinal MP smooth muscle cell (HIMC) hyperplasia.

Atopic dermatitis treatment: A comprehensive review of conventional and novel bioengineered approaches.

Atopic dermatitis (AD) remains a challenging condition, with conventional treatments often leading to adverse effects and limited efficacy. This review explores the diverse landscape of AD treatments, encompassing conventional methods, novel topical and systemic therapies, and emerging bioengineered strategies. While conventional drug administration often requires high dosages or frequent administration, leading to adverse effects, targeted biologics have shown promise.

F2-Isoprostanes Are Associated With Increased Fracture Risk in Type 2 Diabetes.

Context: Fracture risk is higher in type 2 diabetes (T2D) for a given bone mineral density (BMD) level. Increased oxidative stress in T2D induces diabetic complications and may affect T2D bone fragility.

Objective: To investigate whether the levels of plasma F2-isoprostanes, a reliable oxidative stress marker, are associated with incident clinical fracture risk in older adults with diabetes.

NRG Oncology International Consensus Contouring Atlas on Target Volumes and Dosing Strategies for Dose-Escalated Pancreatic Cancer Radiation Therapy.

Purpose: Dose-escalated radiation therapy is increasingly used in the treatment of pancreatic cancer; however, approaches to target delineation vary widely. We present the first North American cooperative group consensus contouring atlas for dose-escalated pancreatic cancer radiation therapy.

Methods And Materials: An expert international panel comprising 15 radiation oncologists, 2 surgeons, and 1 radiologist was recruited.

Current Standards and Controversies in Multidisciplinary Management of Locoregional Gastroesophageal Junction Tumors.

Purpose Of Review: There has been controversy in the management of gastroesophageal (GE) junction cancers with pre-operative chemoradiation and peri-operative chemotherapy as accepted practices. We aim to assess and compare the defining trials establishing current standards of care and discuss future directions seeking to further improve patient-centered outcomes in GE junction cancers.

Recent Findings: Over the last two decades, several large Phase III randomized trials have been conducted including GE junction cancers, showing superiority of 1) pre-operative chemoradiation over surgery (CROSS) and 2) peri-operative chemotherapy with FLOT over CROSS without radiotherapy (FLOT 4).