Activating Connexin43 gap junctions primes adipose tissue for therapeutic intervention.

Adipose tissue is a promising target for treating obesity and metabolic diseases. However, pharmacological agents usually fail to effectively engage adipocytes due to their extraordinarily large size and insufficient vascularization, especially in obese subjects. We have previously shown that during cold exposure, connexin43 (Cx43) gap junctions are induced and activated to connect neighboring adipocytes to share limited sympathetic neuronal input amongst multiple cells.

Clinical experience with the Bendit steerable microcatheter: a new paradigm for endovascular treatment.

Background: Vessel tortuosity poses a challenge during endovascular treatment of neurovascular lesions. Bendit Technologies (Petah Tikva, Israel) has developed flexible, steerable microcatheters designed with unique bending and torquing capabilities.

Objective: To describe our first-in-human trial of Bendit21.

Hepatic non-parenchymal S100A9-TLR4-mTORC1 axis normalizes diabetic ketogenesis.

Unrestrained ketogenesis leads to life-threatening ketoacidosis whose incidence is high in patients with diabetes. While insulin therapy reduces ketogenesis this approach is sub-optimal. Here, we report an insulin-independent pathway able to normalize diabetic ketogenesis.

Perinatal management: Lessons learned from the neonatal research network.

Recent contributions of the Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network (NRN) regarding obstetrical perinatal interventions and neonatal delivery room practices include the following: the impact of multiple antepartum factors including maternal diabetes, hypertension, obesity and mode of delivery on outcomes of extremely preterm newborns, effects of delayed delivery interval for extremely preterm multiples, effects of antenatal steroids on preterm newborn outcomes and the impact of antenatal magnesium sulfate therapy on neurodevelopmental outcomes for extremely preterm infants. NRN studies also contribute important evidence for neonatal delivery room resuscitation guidelines including umbilical cord management and maintenance of euthermia immediately after birth. The updated NRN outcome calculator helps better counsel families regarding possible outcomes for the most immature newborns if resuscitation is attempted at birth.

Thermal Shift Assay for Small GTPase Stability Screening: Evaluation and Suitability.

Thermal unfolding methods are commonly used as a predictive technique by tracking the protein's physical properties. Inherent protein thermal stability and unfolding profiles of biotherapeutics can help to screen or study potential drugs and to find stabilizing or destabilizing conditions. Differential scanning calorimetry (DSC) is a 'Gold Standard' for thermal stability assays (TSA), but there are also a multitude of other methodologies, such as differential scanning fluorimetry (DSF).

The diagnosis and management of nonalcoholic fatty liver disease: A patient-friendly summary of the 2018 AASLD guidelines.

Content available: Author Interview and Audio Recording.

Biodegradable and Inherently Fluorescent pH-Responsive Nanoparticles for Cancer Drug Delivery.

Purpose: The development of two novel pH-only and pH- and thermo-responsive theranostic nanoparticle (NP) formulations to deliver an anticancer drug and track the accumulation and therapeutic efficacy of the formulations through inherent fluorescence.

Methods: A pH-responsive formulation was synthesized from biodegradable photoluminescent polymer (BPLP) and sodium bicarbonate (SBC) via an emulsion technique, while a thermoresponsive BPLP copolymer (TFP) and SBC were used to synthesize a dual-stimuli responsive formulation via free radical co-polymerization. Cisplatin was employed as a model drug and encapsulated during synthesis.

Chest compressions and medications during neonatal resuscitation.

Prolonged resuscitation in neonates, although quite rare, may occur in response to profound intractable bradycardia as a result of asphyxia. In these instances, chest compressions and medications may be necessary to facilitate return of spontaneous circulation. While performing chest compressions, the two thumb method is preferred over the two finger technique, although several newer approaches are under investigation.

Brown adipose tissue activation with ginsenoside compound K ameliorates polycystic ovary syndrome.

Background And Purpose: Polycystic ovary syndrome (PCOS) is a common metabolic and endocrine disease affecting women of reproductive age. Due to its complex aetiology, there is no currently effective cure for PCOS. Brown adipose tissue (BAT) activity is significantly decreased in PCOS patients, and BAT activation has beneficial effects in animal models of PCOS.

Mortality after multivessel revascularisation involving the proximal left anterior descending artery.

Objective: We sought to investigate whether long-term clinical outcomes differ following percutaneous coronary intervention (PCI) or coronary artery bypass grafting (CABG) in patients with three-vessel disease (3VD) and lesions in the proximal left anterior descending artery (P-LAD).

Methods: This post-hoc analysis of the Synergy between PCI with Taxus and Cardiac Surgery (SYNTAX) Extended Survival study included patients with 3VD who were classified according to the presence or absence of lesions located in the P-LAD. Ten-year all-cause death and 5-year major adverse cardiac or cerebrovascular events (MACCE) were assessed.

Persistent Pain After Hindfoot Fusion.

One of the most challenging problems facing orthopedic surgeons is persistent pain after surgery and certainly is just as frustrating following hindfoot fusion. The hindfoot joints consist of the subtalar, talonavicular, and calcaneocuboid (CC) joints. These joints are commonly fused for degenerative changes, deformity correction, inflammatory or neuropathic arthropathy, tarsal coalition, or primarily after trauma.

Targeting LIPA independent of its lipase activity is a therapeutic strategy in solid tumors via induction of endoplasmic reticulum stress.

Triple-negative breast cancer (TNBC) has a poor clinical outcome, due to a lack of actionable therapeutic targets. Herein we define lysosomal acid lipase A (LIPA) as a viable molecular target in TNBC and identify a stereospecific small molecule (ERX-41) that binds LIPA. ERX-41 induces endoplasmic reticulum (ER) stress resulting in cell death, and this effect is on target as evidenced by specific LIPA mutations providing resistance.

Intratumoral Resolution of Driver Gene Mutation Heterogeneity in Renal Cancer Using Deep Learning.

Unlabelled: Intratumoral heterogeneity arising from tumor evolution poses significant challenges biologically and clinically. Dissecting this complexity may benefit from deep learning (DL) algorithms, which can infer molecular features from ubiquitous hematoxylin and eosin (H&E)-stained tissue sections. Although DL algorithms have been developed to predict some driver mutations from H&E images, the ability of these DL algorithms to resolve intratumoral mutation heterogeneity at subclonal spatial resolution is unexplored.

Safety and efficacy of elsubrutinib or upadacitinib alone or in combination (ABBV-599) in patients with rheumatoid arthritis and inadequate response or intolerance to biological therapies: a multicentre, double-blind, randomised, controlled, phase 2 trial.

Background: ABBV-599 is a novel fixed-dose combination of the Bruton's tyrosine kinase (BTK) inhibitor elsubrutinib and the Janus kinase (JAK) inhibitor upadacitinib under investigation for the treatment of autoimmune diseases. We aimed to determine whether ABBV-599 could increase the treatment response for patients with active rheumatoid arthritis compared with inhibiting either pathway alone, while maintaining an acceptable safety profile.

Methods: We conducted a multicentre, double-blind, parallel-group, dose-exploratory, randomised, controlled, phase 2 trial at 75 community sites in eight countries in Europe and North America.

Statin therapy for primary prevention in women: What is the role for coronary artery calcium?

By current guidelines, statin treatment decisions depend on multiple risk factor algorithms (e.g., pooled cohort equations [PCEs]).

Synthesis and Structure-Activity relationships of cyclin-dependent kinase 11 inhibitors based on a diaminothiazole scaffold.

Cyclin-dependent kinases (CDK) are attractive targets for drug discovery due to their wide range of cellular functions. CDK11 is an understudied CDK with roles in transcription and splicing, cell cycle regulation, neuronal function, and apoptosis. In this study, we describe a medicinal chemistry campaign to identify a CDK11 inhibitor.

Therapeutic Targeting the Allosteric Cysteinome of RAS and Kinase Families.

Allosteric mechanisms are pervasive in nature, but human-designed allosteric perturbagens are rare. The history of KRAS inhibitor development suggests that covalent chemistry may be a key to expanding the armamentarium of allosteric inhibitors. In that effort, irreversible targeting of a cysteine converted a non-deal allosteric binding pocket and low affinity ligands into a tractable drugging strategy.

A sound-driven cortical phase-locking change in the Fmr1 KO mouse requires Fmr1 deletion in a subpopulation of brainstem neurons.

Background: Sensory impairments commonly occur in patients with autism or intellectual disability. Fragile X syndrome (FXS) is one form of intellectual disability that is often comorbid with autism. In electroencephalographic (EEG) recordings obtained from humans with FXS, the ability of cortical regions to consistently synchronize, or "phase-lock", to modulated auditory stimuli is reduced compared to that of typically developing individuals.

T618I mutated chronic myelomonocytic leukemia: A proliferative subtype with a distinct mutational profile.

Chronic myelomonocytic leukemia (CMML) is a clonal myeloid neoplasm characterized by sustained monocytosis and mutations in , and . We describe a rare case of T618I mutated CMML that has a proliferative phenotype, myelodysplasia, and additional mutations in and . Comparing the clinicopathologic features of this case to previously reported cases of T618I mutated CMML and non-T618I mutated CMML, T618I seems to define a unique proliferative subtype of CMML with a distinct mutational profile.

Youth Aware of Mental Health (YAM) Program With Texas Adolescents: Depression, Anxiety, and Substance Use Outcomes.

To determine the state of mental health problems among a general youth population and assess whether the Youth Aware of Mental Health (YAM) intervention can improve symptoms of depression and anxiety. We implemented YAM with a cluster quasi-experimental study design from August 2017 through June 2019 in 29 middle schools and high schools in North Texas. Students completed the Quick Inventory of Depressive Symptomatology, Adolescent version; the Generalized Anxiety Disorder Screener; and additional substance use questionnaires before YAM delivery and 3-6 months after implementation.

CSF-1R inhibitor, pexidartinib, sensitizes esophageal adenocarcinoma to PD-1 immune checkpoint blockade in a rat model.

Esophageal adenocarcinoma (EAC) is a leading cause of cancer deaths. Pexidartinib, a multi-gene tyrosine kinase inhibitor, through targeting colony-stimulating factor 1 (CSF-1) receptor (CSF-1R), down modulates macrophage-mediated pro-survival tumor signaling. Previously, CSF-1R inhibitors have successfully shown to enhance antitumor activity of PD-1/PD-L1 inhibitors by suppressing tumor immune evasion, in solid tumors.

Role of Hepatitis C Infection in Acute Liver Injury/Acute Liver Failure in North America.

Background: While hepatitis A and B are well-known causes of acute liver failure (ALF), few well-documented cases of hepatitis C virus (HCV) infection (absent preexisting liver disease or other liver insults) have been described that result in ALF. We reviewed the Acute Liver Failure Study Group registry for evidence of HCV as a primary or contributing cause to ALF.

Methods: From January 1998 to January 2017, 2,332 patients with ALF (INR ≥ 1.

Pilot Study of Neurologic Pupil Index as A Predictor of External Ventricular Drain Clamp Trial Failure After Subarachnoid Hemorrhage.

Background: External ventricular drains (EVDs) provide a temporary egress for cerebrospinal fluid (CSF) in patients with symptomatic hydrocephalus following aneurysmal subarachnoid hemorrhage. Before EVD removal, a wean trial, which involves clamping the EVD, is typically attempted to ensure that CSF self-regulation is achieved. Automated infrared pupillometry (AIP) has been shown to detect early neurologic decline.