Novel p53 reactivators that are synergistic with olaparib for the treatment of gynecologic cancers with mutant p53.

Ovarian and endometrial cancers frequently harbor a mutation in the tumor suppressor gene TP53, which occurs in over 90 % of ovarian cancers and in the most aggressive endometrial cancers. The normal tumor suppressive functions of p53 are disrupted, resulting in unregulated cell growth and therapeutic resistance to standard treatments including chemotherapy and PARP inhibitors. Hence, a novel therapeutic strategy is urgently needed for p53 mutant gynecologic cancers, and we propose that converting mutant p53 to a wild type conformation and restoring its tumor suppressive functions has the potential to greatly improve treatment.

Biomarkers for the Diagnosis of Perinatal Mood and Anxiety Disorders: Existing Landscapes and Emerging Frontiers.

Perinatal mood and anxiety disorders (PMADs) are a spectrum of mental health conditions that are the most common pregnancy-related complications in the United States. Despite great strides in developing appropriate pharmacological and psychological treatments, PMADs continue to lack biological measures for diagnosis and prediction. Such measures could be effectively utilized to subtype and mechanistically explore PMADs and appropriately leverage mental healthcare resources.

Genetically determined body mass index is associated with diffuse large B-cell lymphoma in polygenic and Mendelian randomization analyses.

Obesity has been associated with non-Hodgkin lymphoma (NHL), but the evidence is inconclusive. We examined the association between genetically determined adiposity and four common NHL subtypes: diffuse large B-cell lymphoma (DLBCL), follicular lymphoma, chronic lymphocytic leukemia, and marginal zone lymphoma, using eight genome-wide association studies of European ancestry (N = 10,629 cases, 9505 controls) and constructing polygenic scores for body mass index (BMI), waist-to-hip ratio (WHR), and waist-to-hip ratio adjusted for BMI (WHRadjBMI). Higher genetically determined BMI was associated with an increased risk of DLBCL [odds ratio (OR) per standard deviation (SD) = 1.

How Do Patient Outcomes in Mechanical Thrombectomy for Large-Core Stroke Vary Based on Neuroimaging Modalities Used for Patient Selection? A Multicenter Multinational Study.

The role of different imaging modalities-non-contrast CT (NCCT), CT perfusion (CTP), and diffusion-weighted imaging (DWI)-in selecting patients with large-core stroke for endovascular thrombectomy (EVT) is a subject of ongoing debate. This study aims to determine whether patients with large-core acute ischemic stroke (AIS) undergoing EVT triaged with CTP or DWI in addition to NCCT had different clinical outcomes compared to those only triaged with NCCT. We queried the Stroke Thrombectomy and Aneurysm Registry (STAR) for patients enrolled between 2014 and 2023 who presented with anterior-circulation AIS and large ischemic core (ASPECTS < 6) who underwent EVT in 41 stroke centers in the USA, Europe, Asia, and South America.

Cleavage of N-terminus of polycystin-1 increases calcium permeability of polycystin-1/2 receptor channel complexes.

Mutations on genes encoding polycystin-1 (PC1) and -2 (PC2) cause autosomal-dominant polycystic kidney disease. How these two proteins work together to exert anti-cystogenesis remains elusive. PC1 resembles adhesion G-protein coupled receptors and undergoes autocleavage in the extracellular N-terminus to expose a hidden "stalk" region, which is hypothesized to act as a "tethered agonist".

Sialoglycoconjugate profiling of human choroid, retinal pigment epithelium, and basal laminar deposits.

Age-related macular degeneration is a leading cause of central vision loss in the elderly. Early hallmarks of the disease include basal laminar deposit beneath the retinal pigment epithelium (RPE) and choriocapillaris degeneration. We utilized sialic acid binding lectins Sambucus nigra/Elderberry Bark Lectin (EBL) and Maackia amurensis lectin II (MAL-II), to assess the localization of ɑ-2,6 and ɑ-2,3 sialic acids, respectively, in human macular retina, RPE, basal laminar deposits, and choroid.

Tooth Grinding in Older Adults: A Retrospective Cross-Sectional Study.

Objectives: This study aims to determine the prevalence of self-reported tooth grinding among older adult patients at a dental school and to examine the associations between tooth grinding and various demographic and clinical factors.

Methods: Data were retrieved from the electronic patient database at the University of Iowa College of Dentistry. Descriptive statistics and bivariate analyses were used to explore associations between tooth grinding and various demographic and clinical factors.

Pulmonary Biomechanics in COPD: Imaging Techniques and Clinical Applications.

The respiratory system depends on complex biomechanical processes to enable gas exchange. The mechanical properties of the lung parenchyma, airways, vasculature, and surrounding structures play an essential role in overall ventilation efficacy. These complex biomechanical processes however are significantly altered in chronic obstructive pulmonary disease (COPD) due to emphysematous destruction of lung parenchyma, chronic airway inflammation, and small airway obstruction.

Weakly Supervised Deep Learning for Monitoring Sleep Apnea Severity Using Coarse-grained Labels.

Sleep apnea, a prevalent sleep-related breathing disorder, often remains undiagnosed and untreated in a large patient population due to the need of extensive manual annotations on various physiological signals for clinical diagnosis. Despite the surge of interest in applying machine learning to automate apnea detection, the effectiveness of existing techniques highly relies on strongly supervised learning that requires massive finely labeled training data for sufficiently short time intervals - a requirement often unmet due to the prohibitively high cost of manual labeling in clinical practice. In this article, we incorporate clinical knowledge to establish a weakly supervised deep learning framework for automatically estimating the latent fine-grained apnea severity when only coarse-grained labels indicating apnea presence are available in the training data.

Hearing Loss, Retinal Abnormality, and Seizures in People With Facioscapulohumeral Muscular Dystrophy.

Introduction/aims: Few studies describing comorbidities in individuals with facioscapulohumeral muscular dystrophy (FSHD) are available. We used data from the Muscular Dystrophy Surveillance, Tracking and Research Network (MD STARnet) to identify and describe the prevalence of three comorbidities-hearing loss, retinal abnormalities, and seizures-in individuals with FSHD.

Methods: We analyzed retrospective population-based data from 548 individuals diagnosed with FSHD who had at least one health visit during 2008-2019.

Evaluating the efficacy and safety of milrinone for prevention of post-patent ductus arteriosus closure syndrome (the MIDAS trial) in extremely preterm infants: a multicentre, double-masked, randomised, placebo-controlled trial.

Introduction: Post-ligation cardiac syndrome (PLCS) represents a state of severe post-intervention cardiopulmonary instability, seen in up to 50% of extremely premature infants after surgical closure of the patent ductus arteriosus (PDA); yet an evidence-based approach to treatment of this condition does not exist. The objective of this study is to determine the efficacy and safety of prophylactic milrinone in reducing incidence of PLCS and/or mortality within the first 7 days following PDA closure. The central hypothesis is that administration of intravenous milrinone will reduce the incidence of PLCS or death within 7 days of PDA closure either by percutaneous device (PCD) closure or surgical ligation (SL).

Search for a Neutral Gauge Boson with Nonuniversal Fermion Couplings in Vector Boson Fusion Processes in Proton-Proton Collisions at sqrt[s]=13 TeV.

The first search for a heavy neutral spin-1 gauge boson (Z^{'}) with nonuniversal fermion couplings produced via vector boson fusion processes and decaying to tau leptons or W bosons is presented. The analysis is performed using LHC data at sqrt[s]=13  TeV, collected from 2016 to 2018 with the CMS experiment and corresponding to an integrated luminosity of 138  fb^{-1}. The data are consistent with the standard model predictions.

Biomechanical Implications of Mass Loading in a Swine Model of Acute Hypoxemic Respiratory Failure.

In obesity, excess weight of the chest and abdomen (mass loading) decreases lung volume and can worsen acute hypoxemic respiratory failure (AHRF). We investigated whether positive end-expiratory pressure (PEEP) fully reverses the effects of mass loading on lung volume and respiratory mechanics in an AHRF swine model. Eighteen Yorkshire pigs were studied: six healthy, eight pre- and post-injury, and four post-injury only.

Social inference brain networks in autistic adults during movie-viewing: functional specialization and heterogeneity.

Background: Difficulty in social inferences is a core feature in autism spectrum disorders (ASD). On the behavioral level, it remains unclear whether reasoning about others' mental states (Theory of Mind, ToM) and empathic responses to others' physical states may be similarly or differentially affected in autism. On the neural level, these inferences typically engage distinct brain networks (ToM versus Pain networks), but their functional specialization remains not well understood in autism.

Bleaching with biocatalysts and violet LED: a randomized clinical trial using a hybrid design with parallel-group and split-mouth approaches : Violet LED and biocatalysts in in-office whitening: a split-mouth trial.

Objective: To compare conventional 35% hydrogen peroxide whitening for 45 min with test therapies lasting 15 min using a polymeric scaffold, peroxidase, and violet LED.

Materials And Methods: Sixty patients were randomized into three groups (n = 20): TC45 (35% HP for 45'), T15 (35% HP for 15'), and TT (polycaprolactone scaffold + 35% HP with peroxidase for 15'). One hemiarch was irradiated with violet LED (L) (8 cycles of 1 min, with 30-second intervals).

Kidney function and risk of heart failure in older adults: findings from a prospective cohort study.

Background: We examined whether impaired kidney function, identified through elevated levels of urine albumin to creatinine ratio (UACR) or reduced estimated glomerular filtration rate (eGFR), is associated with hospitalisation or death due to heart failure (HF) in a large community-based cohort of older adults.

Methods: We included 17 834 participants from the ASPirin in Reducing Events in the Elderly (ASPREE) clinical trial and follow-up ASPREE eXTension observational study with complete baseline data on albuminuria and eGFR. HRs for hospitalisation due to HF (HHF), HF death, a composite outcome of HHF and HF death, and HF re-admission were calculated using Cox models adjusting for potential confounders.

Primary Ewing Sarcoma Within an Autosomal Dominant Polycystic Kidney: A Case Report.

Ewing sarcoma, that originates from neuroectoderm, is typically encountered in the bone and soft tissue of children and young adults and rarely presents as a primary renal tumor. Autosomal dominant polycystic kidney disease, which is the most common type of inherited kidney disease, has been debated to be associated with an increased risk of kidney cancer. This report describes the first documented case of primary Ewing sarcoma arising within an autosomal dominant polycystic kidney.

Dexamethasone-eluting cochlear implants reduce inflammation and foreign body response in human and murine cochleae.

The inflammatory foreign body response (FBR) following cochlear implantation (CI) can negatively impact CI outcomes, including increased electrode impedances. This study aims to investigate the long-term efficacy of dexamethasone-eluting cochlear implant and locally delivered dexamethasone, a potent anti-inflammatory glucocorticoid, on the intracochlear FBR and electrical impedance post-implantation in a murine model. Preliminary impedance data in humans are also provided as a complement to the murine data to illustrate generalizability and reinforce implications related to clinical application.

cAMP-related second messenger pathways modulate hearing function in mosquitoes.

The powerful ears of male mosquitoes facilitate identification and localization of mating partners via detection of female flight tones. Male hearing function is modulated by the efferent release of neurotransmitters, though the secondary mechanisms underlying this modulation remain unclear. Here, we investigated these mechanisms using octopamine as a model, as octopamine modulates hearing function and the erection status of fibrillar hairs lining male ears.

Distinct cascades for secure and insecure infants from early anger dysregulation to mothers' and fathers' power-assertive control at toddler age to externalizing outcomes at preschool age: a replication.

Background: Bowlby's concept of attachment as a biobehavioral proximity-regulating system providing infants with confidence in protection and support for exploration has been expanded to include early security's legacy for socialization processes. We report a continued programmatic effort to replicate our model of security as a potent catalyst moderating common maladaptive longitudinal cascades from early child difficulty to increased parental power assertion to externalizing developmental outcomes. We elucidate the multifinality of sequelae that can unfold from early child difficulty.

Ionocyte CFTR Coordinates Chloride Absorption and Secretion to Balance Airway Fluid.

Rationale: The cystic fibrosis transmembrane conductance regulator (CFTR) channel contributes to the precise control of airway surface liquid (ASL) volume by regulating fluid absorption and secretion, both of which are disrupted in cystic fibrosis (CF). CFTR is highly expressed in pulmonary ionocytes, yet conflicting evidence has emerged regarding how pulmonary ionocytes regulate ion and fluid transport. Different groups have shown that pulmonary ionocytes mediate chloride and fluid absorption, but whether ionocytes and/or secretory cells mediate chloride secretion remains unclear.

Flash Communication: Boron K‑edge XAS and TDDFT Studies of Covalent Metal-Ligand Bonding in Ni(CBH).

Ligand K-edge X-ray absorption spectroscopy (XAS), a technique that can measure variations in covalent metal-ligand bonding, has rarely been used to assess covalency in complexes containing metal-boron bonds. Here we describe ligand K-edge XAS and TDDFT studies of the Ni dicarbollide complex Ni-(CBH) () and the Ni-free salt (HNMe)-(CBH) (). The XAS spectrum for reveals a pre-edge feature indicative of covalent Ni-B bonding, which is corroborated by time-dependent density functional theory (TDDFT) calculations and comparative analysis to and inner-shell electron energy loss spectroscopy (ISEELS) collected on the same Ni complex.

Expression in Rodent, Rhesus Monkey, and Human Brainstem.

Background: The gene encodes a transcription factor responsible for the development of neural structures involved in vocalization in vertebrates. Animal models have proven critical in the study of gene expression, although a comparative interspecies analysis of brainstem structures is understudied. This study evaluates the expression of protein within the brainstem of rats, rhesus monkeys, and humans.

Nationwide Danish Register Based Study Showed a Stable Prevalence of Congenital Diaphragmatic Hernias From 1994 to 2021 but a Decrease in Syndromic Cases.

Aim: Congenital diaphragmatic hernia (CDH) is a severe malformation with high morbidity and mortality. This Danish study evaluated the birth prevalence, co-occurring malformations, and temporal trends of CDH over nearly three decades.

Methods: Nationwide data from the Danish Biobank Register were used to identify liveborn infants diagnosed with CDH from 1994 to 2021.