Decisive role of mDia-family formins in cell cortex function of highly adherent cells.

Cortical formins, pivotal for the assembly of linear actin filaments beneath the membrane, exert only minor effects on unconfined cell migration of weakly and moderately adherent cells. However, their impact on migration and mechanostability of highly adherent cells remains poorly understood. Here, we demonstrate that loss of cortical actin filaments generated by the formins mDia1 and mDia3 drastically compromises cell migration and mechanics in highly adherent fibroblasts.

Clinical utility analysis of the Hoxb8 mast cell activation test for the diagnosis of peanut allergy.

Background: Peanut allergy is among the most severe and common food allergies. The diagnosis has a significant impact on the quality of life for patients and their families. An effective management approach depends on accurate, safe, and easily implementable diagnostic methods.

HSPA8 Chaperone Complex Drives Chaperone-Mediated Autophagy Regulation in Acute Promyelocytic Leukemia Cell Differentiation.

Introduction: Acute myeloid leukemia (AML) is a cancer of the hematopoietic system characterized by hyperproliferation of undifferentiated cells of the myeloid lineage. While most of AML therapies are focused toward tumor debulking, all-trans retinoic acid (ATRA) induces neutrophil differentiation in the AML subtype acute promyelocytic leukemia (APL). Macroautophagy has been extensively investigated in the context of various cancers and is often dysregulated in AML where it can have context-dependent pro- or anti-leukemogenic effects.

Operating under the influence: the effect of alcohol on operative performance using a virtual robotic training platform-an experimental comparative cohort study.

An elevated percentage of medical personnel reports using alcohol to relieve stress. Levels of alcohol addiction are almost double that of the general population. Robotic surgery is becoming more widespread.

Can perioperative pCO gaps predict complications in patients undergoing major elective abdominal surgery randomized to goal-directed therapy or standard care? A secondary analysis.

The difference between venous and arterial carbon dioxide pressure (pCO gap), has been used as a diagnostic and prognostic tool. We aimed to assess whether perioperative pCO gaps can predict postoperative complications. This was a secondary analysis of a multicenter RCT comparing goal-directed therapy (GDT) to standard care in which 464 patients undergoing high-risk elective abdominal surgery were included.

Non-canonical BIM-regulated energy metabolism determines drug-induced liver necrosis.

Paracetamol (acetaminophen, APAP) overdose severely damages mitochondria and triggers several apoptotic processes in hepatocytes, but the final outcome is fulminant necrotic cell death, resulting in acute liver failure and mortality. Here, we studied this switch of cell death modes and demonstrate a non-canonical role of the apoptosis-regulating BCL-2 homolog BIM/Bcl2l11 in promoting necrosis by regulating cellular bioenergetics. BIM deficiency enhanced total ATP production and shifted the bioenergetic profile towards glycolysis, resulting in persistent protection from APAP-induced liver injury.

Glucose measurements with accu check inform II versus hexokinase plasma method during surgery under general anesthesia, an observational cohort study.

Purpose: Limited research exists on translation of in-vitro glucose measurement interfering compounds to the in-vivo situation. We investigated whether Point-of-Care glucose measurements by Accu Chek Inform II (ACI II) were accurate to monitor glucose concentrations during surgery with general anesthesia by comparing with the reference laboratory hexokinase plasma glucose test.

Method: Patients undergoing surgery with general anesthesia were included.

Apoptotic cell death in disease-Current understanding of the NCCD 2023.

Apoptosis is a form of regulated cell death (RCD) that involves proteases of the caspase family. Pharmacological and genetic strategies that experimentally inhibit or delay apoptosis in mammalian systems have elucidated the key contribution of this process not only to (post-)embryonic development and adult tissue homeostasis, but also to the etiology of multiple human disorders. Consistent with this notion, while defects in the molecular machinery for apoptotic cell death impair organismal development and promote oncogenesis, the unwarranted activation of apoptosis promotes cell loss and tissue damage in the context of various neurological, cardiovascular, renal, hepatic, infectious, neoplastic and inflammatory conditions.

Unleashed Actin Assembly in Capping Protein-Deficient B16-F1 Cells Enables Identification of Multiple Factors Contributing to Filopodium Formation.

Background: Filopodia are dynamic, finger-like actin-filament bundles that overcome membrane tension by forces generated through actin polymerization at their tips to allow extension of these structures a few microns beyond the cell periphery. Actin assembly of these protrusions is regulated by accessory proteins including heterodimeric capping protein (CP) or Ena/VASP actin polymerases to either terminate or promote filament growth. Accordingly, the depletion of CP in B16-F1 melanoma cells was previously shown to cause an explosive formation of filopodia.

External Validation of Mortality Prediction Models for Critical Illness Reveals Preserved Discrimination but Poor Calibration.

Objectives: In a recent scoping review, we identified 43 mortality prediction models for critically ill patients. We aimed to assess the performances of these models through external validation.

Design: Multicenter study.

Pharmacological Induction of Granulocyte Cell Death as Therapeutic Strategy.

Apoptosis is central for the maintenance of health. In the immune system, apoptosis guarantees proper development of immune cells and shutdown of immune reactions by the coordinated elimination of activated immune cells. Limitation of the life span of granulocytes is important, as overactivation of these cells is associated with chronic inflammation and collateral tissue damage.

Hexokinase 3 enhances myeloid cell survival via non-glycolytic functions.

The family of hexokinases (HKs) catalyzes the first step of glycolysis, the ATP-dependent phosphorylation of glucose to glucose-6-phosphate. While HK1 and HK2 are ubiquitously expressed, the less well-studied HK3 is primarily expressed in hematopoietic cells and tissues and is highly upregulated during terminal differentiation of some acute myeloid leukemia (AML) cell line models. Here we show that expression of HK3 is predominantly originating from myeloid cells and that the upregulation of this glycolytic enzyme is not restricted to differentiation of leukemic cells but also occurs during ex vivo myeloid differentiation of healthy CD34 hematopoietic stem and progenitor cells.

The BCL-2 family member BOK promotes KRAS-driven lung cancer progression in a p53-dependent manner.

A variety of cancer entities are driven by KRAS mutations, which remain difficult to target clinically. Survival pathways, such as resistance to cell death, may represent a promising treatment approach in KRAS mutated cancers. Based on the frequently observed genomic deletions of BCL-2-related ovarian killer (BOK) in cancer patients, we explored the function of BOK in a mutant Kras-driven murine model of lung cancer.

Perioperative goal-directed therapy in high-risk abdominal surgery. A multicenter randomized controlled superiority trial.

Study Objective: The potential of perioperative goal-directed therapy (PGDT) to improve outcome after high-risk abdominal surgery remains subject of debate. In particular, there is a need for large, multicenter trials focusing on relevant patient outcomes to confirm the evidence found in small, single center studies including minor complications in their composite endpoints. The present study therefore aims to investigate the effect of an arterial waveform analysis based PGDT algorithm on the incidence of major complications including mortality after high-risk abdominal surgery.

A novel functional mast cell assay for the detection of allergies.

Background: Clinical management of allergic diseases has been hampered by the lack of safe and convenient tests to reliably identify culprit allergens and to closely follow changes in disease activity over time. Because allergy diagnosis is a complex and laborious multistep procedure, there is an urgent need for simpler but still functionally accurate ex vivo assays allowing objective diagnosis, substantiating treatment choices, and quantifying therapeutic responses.

Objective: In this study, we sought to develop a novel functional cell-based assay that relies on passive sensitization of allergic effector cells with patient serum, circumventing current limitations in allergy diagnosis.

Identifying and characterizing high-risk clusters in a heterogeneous ICU population with deep embedded clustering.

Critically ill patients constitute a highly heterogeneous population, with seemingly distinct patients having similar outcomes, and patients with the same admission diagnosis having opposite clinical trajectories. We aimed to develop a machine learning methodology that identifies and provides better characterization of patient clusters at high risk of mortality and kidney injury. We analysed prospectively collected data including co-morbidities, clinical examination, and laboratory parameters from a minimally-selected population of 743 patients admitted to the ICU of a Dutch hospital between 2015 and 2017.

Cognitive biases, environmental, patient and personal factors associated with critical care decision making: A scoping review.

Purpose: Cognitive biases and factors affecting decision making in critical care can potentially lead to life-threatening errors. We aimed to examine the existing evidence on the influence of cognitive biases and factors on decision making in critical care.

Materials And Methods: We conducted a scoping review by searching MEDLINE for articles from 2004 to November 2020.

Loss of BOK Has a Minor Impact on Acetaminophen Overdose-Induced Liver Damage in Mice.

Acetaminophen (APAP) is one of the most commonly used analgesic and anti-pyretic drugs, and APAP intoxication is one of the main reasons for liver transplantation following liver failure in the Western world. While APAP poisoning ultimately leads to liver necrosis, various programmed cell death modalities have been implicated, including ER stress-triggered apoptosis. The BCL-2 family member BOK (BCL-2-related ovarian killer) has been described to modulate the unfolded protein response and to promote chemical-induced liver injury.

Sialic Acids and Their Influence on Human NK Cell Function.

Sialic acids are sugars with a nine-carbon backbone, present on the surface of all cells in humans, including immune cells and their target cells, with various functions. Natural Killer (NK) cells are cells of the innate immune system, capable of killing virus-infected and tumor cells. Sialic acids can influence the interaction of NK cells with potential targets in several ways.

Current use of inotropes in circulatory shock.

Background: Treatment decisions on critically ill patients with circulatory shock lack consensus. In an international survey, we aimed to evaluate the indications, current practice, and therapeutic goals of inotrope therapy in the treatment of patients with circulatory shock.

Methods: From November 2016 to April 2017, an anonymous web-based survey on the use of cardiovascular drugs was accessible to members of the European Society of Intensive Care Medicine (ESICM).