Conditional lethality profiling reveals anticancer mechanisms of action and drug-nutrient interactions.

Chemical screens across hundreds of cell lines have shown that the drug sensitivities of human cancers can vary by genotype or lineage. However, most drug discovery studies have relied on culture media that poorly reflect metabolite levels in human blood. Here, we perform drug screens in traditional and Human Plasma-Like Medium (HPLM).

Recharacterization of RSL3 reveals that the selenoproteome is a druggable target in colorectal cancer.

Ferroptosis is a non-apoptotic form of cell death resulting from the iron-dependent accumulation of lipid peroxides. Colorectal cancer (CRC) cells accumulate high levels of intracellular iron and reactive oxygen species (ROS) and are thus particularly sensitive to ferroptosis. The compound (S)-RSL3 ([1S,3R]-RSL3) is a commonly used ferroptosis inducing compound that is currently characterized as a selective inhibitor of the selenocysteine containing enzyme (selenoprotein) Gluathione Peroxidase 4 (GPx4), an enzyme that utilizes glutathione to directly detoxify lipid peroxides.

Targeting PIKfyve-driven lipid homeostasis as a metabolic vulnerability in pancreatic cancer.

Pancreatic ductal adenocarcinoma (PDAC) subsists in a nutrient-deregulated microenvironment, making it particularly susceptible to treatments that interfere with cancer metabolism. For example, PDAC utilizes and is dependent on high levels of autophagy and other lysosomal processes. Although targeting these pathways has shown potential in preclinical studies, progress has been hampered by the challenge of identifying and characterizing favorable targets for drug development.

BRD4-mediated epigenetic regulation of endoplasmic reticulum-mitochondria contact sites is governed by the mitochondrial complex III.

Inter-organellar communication is critical for cellular metabolic homeostasis. One of the most abundant inter-organellar interactions are those at the endoplasmic reticulum and mitochondria contact sites (ERMCS). However, a detailed understanding of the mechanisms governing ERMCS regulation and their roles in cellular metabolism are limited by a lack of tools that permit temporal induction and reversal.

Radiological outcomes following surgical fixation with wires versus moulded cast for patients with a dorsally displaced fracture of the distal radius: a radiographic analysis from the DRAFFT2 trial.

Aims: The primary aim of this study was to report the radiological outcomes of patients with a dorsally displaced distal radius fracture who were randomized to a moulded cast or surgical fixation with wires following manipulation and closed reduction of their fracture. The secondary aim was to correlate radiological outcomes with patient-reported outcome measures (PROMs) in the year following injury.

Methods: Participants were recruited as part of DRAFFT2, a UK multicentre clinical trial.

Conditional lethality profiling reveals anticancer mechanisms of action and drug-nutrient interactions.

Chemical screening studies have identified drug sensitivities across hundreds of cancer cell lines but most putative therapeutics fail to translate. Discovery and development of drug candidates in models that more accurately reflect nutrient availability in human biofluids may help in addressing this major challenge. Here we performed high-throughput screens in conventional versus Human Plasma-Like Medium (HPLM).

Levelling up: prioritisation of global health.

Trauma has been described as "The forgotten pandemic" (Rossiter in Int Orthop 46:3-11, 2022  https://doi.org/10.1007/s00264-021055213-z ) or "The hidden pandemic" (Graham SM, Laubscher M, Lalloo DG, Harrison WJ, Maqungo S in The Surg, 20, 231-236.

CRISPR/Cas9 Screening to Identify Conditionally Essential Genes in Human Cell Lines.

Forward genetic screens across hundreds of cancer cell lines have started to define the genetic dependencies of proliferating human cells. However, most such screens have been performed in vitro with little consideration into how medium composition might affect gene essentiality. This protocol describes a method to use CRISPR/Cas9-based loss-of-function screens to ask how gene essentiality in human cell lines varies with medium composition.

"Trauma-the forgotten pandemic?".

Global annual deaths from Trauma are greater than any other single cause in the global working population, and, more than all contagious diseases added together including COVID-19. The number of people injured, either temporarily or permanently, is greater than any other medical condition. This problem affects Low and Middle Income Countries (LMICs) disproportionately.

CRISPR screens in physiologic medium reveal conditionally essential genes in human cells.

Forward genetic screens across hundreds of cancer cell lines have started to define the genetic dependencies of proliferating human cells and how these vary by genotype and lineage. Most screens, however, have been carried out in culture media that poorly reflect metabolite availability in human blood. Here, we performed CRISPR-based screens in traditional versus human plasma-like medium (HPLM).

Mechanical prophylaxis, early mobilisation and risk stratification: as effective as drugs for low risk patients undergoing primary joint replacement. Results in 13,384 patients.

Introduction: Current NICE Guidelines state that all patients undergoing total hip and knee arthroplasty should be given both mechanical and chemical prophylaxis. At our institution, a targeted thromboprophylaxis policy has been in place since October 1999. The aim of this study was to calculate our venous thromboembolism rates and compare these to published rates in the literature.

Venous thromboembolism prophylaxis strategies for people undergoing elective total knee replacement: a systematic review and network meta-analysis.

Background: Hospital-associated venous thromboembolism is a major patient safety concern. Provision of prophylaxis to patients admitted for elective total knee replacement surgery has been proposed as an effective strategy to reduce the incidence of venous thromboembolism. We aimed to assess the relative efficacy and safety of all available prophylaxis strategies in this setting.

Cost-Utility Analysis of Venous Thromboembolism Prophylaxis Strategies for People Undergoing Elective Total Hip and Total Knee Replacement Surgeries in the English National Health Service.

Major orthopedic surgery, such as elective total hip replacement (eTHR) and elective total knee replacement (eTKR), are associated with a higher risk of venous thromboembolism (VTE) than other surgical procedures. Little is known, however, about the cost-effectiveness of VTE prophylaxis strategies in people undergoing these procedures. The aim of this work was to assess the cost-effectiveness of these strategies from the English National Health Service perspective to inform NICE guideline (NG89) recommendations.

A unified theory of bone healing and nonunion: BHN theory.

This article presents a unified clinical theory that links established facts about the physiology of bone and homeostasis, with those involved in the healing of fractures and the development of nonunion. The key to this theory is the concept that the tissue that forms in and around a fracture should be considered a specific functional entity. This 'bone-healing unit' produces a physiological response to its biological and mechanical environment, which leads to the normal healing of bone.

Understanding visualization: a formal approach using category theory and semiotics.

This paper combines the vocabulary of semiotics and category theory to provide a formal analysis of visualization. It shows how familiar processes of visualization fit the semiotic frameworks of both Saussure and Peirce, and extends these structures using the tools of category theory to provide a general framework for understanding visualization in practice, including: Relationships between systems, data collected from those systems, renderings of those data in the form of representations, the reading of those representations to create visualizations, and the use of those visualizations to create knowledge and understanding of the system under inspection. The resulting framework is validated by demonstrating how familiar information visualization concepts (such as literalness, sensitivity, redundancy, ambiguity, generalizability, and chart junk) arise naturally from it and can be defined formally and precisely.

Improved survival with inhibitory killer immunoglobulin receptor (KIR) gene mismatches and KIR haplotype B donors after nonmyeloablative, HLA-haploidentical bone marrow transplantation.

Natural killer (NK) cell alloreactivity, which may contribute to the graft-versus-leukemia (GVL) effect of allogeneic hematopoietic stem cell transplantation (HSCT), is influenced by the interaction of killer-cell immunoglobulin-like receptors (KIRs) on donor NK cells and their ligands, human leukocyte antigen (HLA) class I molecules on recipient antigen-presenting cells (APCs). Distinct models to predict NK cell alloreactivity differ in their incorporation of information from typing of recipient and donor KIR and HLA gene loci, which exist on different autosomes and are inherited independently as haplotypes. Individuals may differ in the inheritance of the 2 KIR haplotypes, A and B, or in the expression of individual KIR genes.

Nonmyeloablative HLA-haploidentical bone marrow transplantation with high-dose posttransplantation cyclophosphamide: effect of HLA disparity on outcome.

Although some reports have found an association between increasing HLA disparity between donor and recipient and fewer relapses after allogeneic blood or marrow transplantation (BMT), this potential benefit has been offset by more graft-versus-host disease (GVHD) and nonrelapse mortality (NRM). However, the type of GVHD prophylaxis might influence the balance between GVHD toxicity and relapse. The present study analyzed the impact of greater HLA disparity on outcomes of a specific platform for nonmyeloablative (NMA), HLA-haploidentical transplantation.

How big is a hand?

Use of the patient's hand to estimate percentage body surface area (BSA) of injury is well established in the management of burns. Exactly what constitutes "the palm of the hand' and how large an area this is, depends on whether you follow Advanced Trauma Life Support teaching. United Kingdom teaching, or use a "Lund and Browder chart'.