DUSP6 inhibition overcomes neuregulin/HER3-driven therapy tolerance in HER2+ breast cancer.

Despite clinical benefits of tyrosine kinase inhibitors (TKIs) in cancer, most tumors can reactivate proliferation under TKI therapy. Here we present transcriptional profiling of HER2+ breast cancer cells transitioning from dormant drug tolerant cells to re-proliferating cells under continuous HER2 inhibitor (HER2i) therapy. Focusing on phosphatases, expression of dual-specificity phosphatase DUSP6 was found inhibited in dormant cells, but strongly induced upon regrowth.

In Vitro Investigation of Insulin Dynamics During 4 Hours of Simulated Cardiopulmonary Bypass.

Background: Hyperglycemia is common in patients undergoing cardiovascular surgery with cardiopulmonary bypass. We hypothesize that intraoperative hyperglycemia may be, at least partially, attributable to insulin loss due to adhesion on artificial surfaces and/or degradation by hemolysis. Thus, our primary aim was to investigate the loss of insulin in 2 different isolated extracorporeal circulation circuits (ECCs), that is, a conventional ECC (cECC) with a roller pump, and a mini-ECC (MiECC) system with a centrifugal pump.

YidC from Forms an Ion-Conducting Pore upon Activation by Ribosomes.

The universally conserved protein YidC aids in the insertion and folding of transmembrane polypeptides. Supposedly, a charged arginine faces its hydrophobic lipid core, facilitating polypeptide sliding along YidC's surface. How the membrane barrier to other molecules may be maintained is unclear.

Atelectasis in obese patients undergoing laparoscopic bariatric surgery are not increased upon discharge from Post Anesthesia Care Unit.

Background: Obese patients frequently develop pulmonary atelectasis upon general anesthesia. The risk is increased during laparoscopic surgery. This prospective, observational single-center study evaluated atelectasis dynamics using Electric Impedance Tomography (EIT) in patients undergoing laparoscopic bariatric surgery.

Causes of Hypoxemia in COVID-19 Acute Respiratory Distress Syndrome: A Combined Multiple Inert Gas Elimination Technique and Dual-energy Computed Tomography Study.

Background: Despite the fervent scientific effort, a state-of-the art assessment of the different causes of hypoxemia (shunt, ventilation-perfusion mismatch, and diffusion limitation) in COVID-19 acute respiratory distress syndrome (ARDS) is currently lacking. In this study, the authors hypothesized a multifactorial genesis of hypoxemia and aimed to measure the relative contribution of each of the different mechanism and their relationship with the distribution of tissue and blood within the lung.

Methods: In this cross-sectional study, the authors prospectively enrolled 10 patients with COVID-19 ARDS who had been intubated for less than 7 days.

Randomized, Double-Blind, Placebo-Controlled Crossover Trial of Once Daily Empagliflozin 25 mg for the Treatment of Postprandial Hypoglycemia After Roux-en-Y Gastric Bypass.

To investigate the effect of empagliflozin on glucose dynamics in individuals suffering from postbariatric hypoglycemia (PBH) after Roux-en-Y gastric bypass (RYGB). Twenty-two adults with PBH after RYGB were randomized to empagliflozin 25 mg or placebo once daily over 20 days in a randomized, double-blind, placebo-controlled, crossover trial. The primary efficacy outcome was the amplitude of plasma glucose excursion (peak to nadir) during a mixed-meal tolerance test (MMTT).

Time requirements for perioperative glucose management using fully closed-loop versus standard insulin therapy: A proof-of-concept time-motion study.

Aims: To compare the time required for perioperative glucose management using fully automated closed-loop versus standard insulin therapy.

Methods: We performed a time-motion study to quantify the time requirements for perioperative glucose management with fully closed-loop (FCL) and standard insulin therapy applied to theoretical scenarios. Following an analysis of workflows in different periods of perioperative care in elective surgery patients receiving FCL or standard insulin therapy upon hospital admission (pre- and intra-operatively, at the intermediate care unit and general wards), the time of process-specific tasks was measured by shadowing hospital staff.

Performance of the Dexcom G6 Continuous Glucose Monitoring System During Cardiac Surgery Using Hypothermic Extracorporeal Circulation.

Objective: Continuous glucose monitoring (CGM) may be challenged by extreme conditions during cardiac surgery using hypothermic extracorporeal circulation (ECC).

Research Design And Methods: We evaluated the Dexcom G6 sensor in 16 subjects undergoing cardiac surgery with hypothermic ECC, of whom 11 received deep hypothermic circulatory arrest (DHCA). Arterial blood glucose, quantified by the Accu-Chek Inform II meter, served as reference.

Fully Closed-Loop Insulin Delivery in Patients Undergoing Pancreatic Surgery.

The central role of pancreas in glucose regulation imposes high demands on perioperative glucose management in patients undergoing pancreatic surgery. In a post hoc subgroup analysis of a randomized controlled trial, we evaluated the perioperative use of subcutaneous (SC) fully closed-loop (FCL; CamAPS HX) versus usual care (UC) insulin therapy in patients undergoing partial or total pancreatic resection. Glucose control was compared using continuous glucose monitoring (CGM) metrics (% time with CGM values between 5.

Perioperative Fully Closed-Loop Insulin Delivery in Patients Undergoing Elective Surgery: An Open-Label, Randomized Controlled Trial.

Objective: Perioperative management of glucose levels remains challenging. We aimed to assess whether fully closed-loop subcutaneous insulin delivery would improve glycemic control compared with standard insulin therapy in insulin-requiring patients undergoing elective surgery.

Research Design And Methods: We performed a single-center, open-label, randomized controlled trial.

RGS3L allows for an M muscarinic receptor-mediated RhoA-dependent inotropy in cardiomyocytes.

The role and outcome of the muscarinic M acetylcholine receptor (MR) signaling in healthy and diseased cardiomyocytes is still a matter of debate. Here, we report that the long isoform of the regulator of G protein signaling 3 (RGS3L) functions as a switch in the muscarinic signaling, most likely of the MR, in primary cardiomyocytes. High levels of RGS3L, as found in heart failure, redirect the G-mediated Rac1 activation into a G-mediated RhoA/ROCK activation.

Validation of a high throughput screening assay to identify small molecules that target the eukaryotic replicative helicase.

Mcm2-7 is the catalytic core of the eukaryotic replicative helicase, which together with CDC45 and the GINS complex unwind parental DNA to generate templates for DNA polymerase. Being a highly regulated and complex enzyme that operates via an incompletely understood multi-step mechanism, molecular probes of Mcm2-7 that interrogate specific mechanistic steps would be useful tools for research and potential future chemotherapy. Based upon a synthetic lethal approach, we previously developed a budding yeast multivariate cell-based high throughput screening (HTS) assay to identify putative Mcm inhibitors by their ability to specifically cause a growth defect in an mcm mutant relative to a wild-type strain[1].

Resolution of Precapillary Pulmonary Hypertension After Liver Transplantation for Hereditary Hemorrhagic Telangiectasia: Systematic Review and Case Report.

Background: Pulmonary hypertension (PH) is a known complication of hereditary hemorrhagic telangiectasia (HHT) in patients with hepatic arteriovenous malformations (HAVM). Orthotopic liver transplantation (OLT) is a recognized treatment of HAVM in HHT, but its effect on PH has not been reported in detail before.

Methods: Systematic review on HHT patients with pre- or postcapillary PH who underwent OLT and report of a case.

Assessment of Myocardial Function During Blood Pressure Manipulations Using Feature Tracking Cardiovascular Magnetic Resonance.

Coronary autoregulation is a feedback system, which maintains near-constant myocardial blood flow over a range of mean arterial pressure (MAP). Yet in emergency or peri-operative situations, hypotensive or hypertensive episodes may quickly arise. It is not yet established how rapid blood pressure changes outside of the autoregulation zone (ARZ) impact left (LV) and right ventricular (RV) function.

A systems-level study reveals host-targeted repurposable drugs against SARS-CoV-2 infection.

Understanding the mechanism of SARS-CoV-2 infection and identifying potential therapeutics are global imperatives. Using a quantitative systems pharmacology approach, we identified a set of repurposable and investigational drugs as potential therapeutics against COVID-19. These were deduced from the gene expression signature of SARS-CoV-2-infected A549 cells screened against Connectivity Map and prioritized by network proximity analysis with respect to disease modules in the viral-host interactome.

A High-Content Screening Assay for Small Molecules That Stabilize Mutant Triose Phosphate Isomerase (TPI) as Treatments for TPI Deficiency.

Triose phosphate isomerase deficiency (TPI Df) is an untreatable, childhood-onset glycolytic enzymopathy. Patients typically present with frequent infections, anemia, and muscle weakness that quickly progresses with severe neuromusclar dysfunction requiring aided mobility and often respiratory support. Life expectancy after diagnosis is typically ~5 years.

Estimating cardiac output based on gas exchange during veno-arterial extracorporeal membrane oxygenation in a simulation study using paediatric oxygenators.

Veno-arterial extracorporeal membrane oxygenation (VA-ECMO) therapy is a rescue strategy for severe cardiopulmonary failure. The estimation of cardiac output during VA-ECMO is challenging. A lung circuit ([Formula: see text]) and an ECMO circuit ([Formula: see text]) with oxygenators for CO removal ([Formula: see text]CO) and O uptake ([Formula: see text]O) simulated the setting of VA-ECMO with varying ventilation/perfusion ([Formula: see text]/[Formula: see text]) ratios and shunt.

Day-to-day variability of insulin requirements in the inpatient setting: Observations during fully closed-loop insulin delivery.

The aim of this study was to characterize the variability of exogenous insulin requirements during fully closed-loop insulin delivery in hospitalized patients with type 2 diabetes or new-onset hyperglycaemia, and to determine patient-related characteristics associated with higher variability of insulin requirements. We retrospectively analysed data from two fully closed-loop inpatient studies involving adults with type 2 diabetes or new-onset hyperglycaemia requiring insulin therapy. The coefficient of variation quantified day-to-day variability of exogenous insulin requirements during up to 15 days using fully automated closed-loop insulin delivery.

Identification of protein quality control regulators using a Drosophila model of TPI deficiency.

Triosephosphate isomerase (TPI) deficiency (Df) is a rare recessive metabolic disorder that manifests as hemolytic anemia, locomotor impairment, and progressive neurodegeneration. Research suggests that TPI Df mutations, including the "common" TPImutation, result in reduced TPI protein stability that appears to underlie disease pathogenesis. Drosophila with the recessive TPI allele (a.

Point-of-care ultrasound in the preoperative setting.

Point-of-care ultrasound (POCUS) is a widely used diagnostic tool, especially in emergency and critical care medicine, and it is increasingly being used in the perioperative setting. Its specific role in preoperative assessment of patients, however, has not yet been defined. While some data show innovative use of the technique in the preoperative setting, higher-level evidence to underscore potential advantages is still limited.

Perioperative glucose management: Current status and future directions.

Hyperglycemia in surgical patients is common and associated with increased morbidity and mortality. Optimal perioperative care includes pre-surgery evaluation of glucose control, adequate preoperative management of glucose-lowering therapies, and repeated blood glucose monitoring on the day of surgery. There is consensus regarding the maintenance of intraoperative glucose levels below 10.