Genome-wide in vivo CRISPR screens identify GATOR1 complex as a tumor suppressor in Myc-driven lymphoma.

Identifying tumor suppressor genes is predicted to inform on the development of novel strategies for cancer therapy. To identify new lymphoma driving processes that cooperate with oncogenic MYC, which is abnormally highly expressed in ~70% of human cancers, we use a genome-wide CRISPR gene knockout screen in Eµ-Myc;Cas9 transgenic hematopoietic stem and progenitor cells in vivo. We discover that loss of any of the GATOR1 complex components - NPRL3, DEPDC5, NPRL2 - significantly accelerates c-MYC-driven lymphoma development in mice.

IgG4-Related Disease: Emerging Roles of Novel Genetic Variants, Immune Cell Subsets and Therapeutic Targets.

IgG4, the least abundant IgG subclass in humans, is increasingly recognised for its involvement in allergic and autoimmune pathologies. Its unique properties, such as the tendency to form half-molecules (one heavy chain and one light chain) and its generally non-inflammatory nature, distinguish it from other IgG subclasses. Its role in immune dysregulation is further underscored by a distinct disease entity called IgG4-related disease (IgG4-RD), a systemic fibroinflammatory disorder characterised by IgG4 plasma cell tissue infiltration, storiform fibrosis and obliterative phlebitis, reflecting a dysregulated immune response affecting multiple organs.

A brain-penetrant CDK4/6 inhibitor - AU3-14 shows robust anti-tumor efficacy against glioblastoma.

The cyclin D-CDK4/6-INK4-Rb pathway is frequently dysregulated in glioblastoma (GBM), the most aggressive and poorly prognosed brain malignancy. Despite extensive research, advances in GBM treatment have seen limited progress, with current therapy largely reliant on temozolomide (TMZ), underscoring the need for novel therapeutic strategies. This study explores the therapeutic potential of AU3-14, a potent and selective CDK4/6 inhibitor, for GBM.

Nedd4-2 ablation in kidney improves glycaemic control in diabetic mice.

NEDD4-2, a ubiquitin ligase, regulates a number of ion channels and transporters by promoting their ubiquitination, internalisation and degradation, thereby affecting many signalling and physiological outcomes. Loss of this gene in mice results in tubular cell death and a chronic kidney disease (CKD)-like phenotype due to aberrant Na transport, caused by elevated expression of NEDD4-2 substrates including the epithelial sodium channel (ENaC). One of the biggest risk factors for CKD is diabetes, as up to 50% of diabetic patients develop diabetic kidney disease (DKD).

NEDD4 Promotes Sertoli Cell Proliferation and Adult Leydig Cell Differentiation in the Murine Testis.

Successful testis development relies on the coordinated differentiation and assembly of various cell types to establish both endocrine and reproductive functions. The ubiquitin ligase NEDD4 has emerged as a key player in murine testis development, with this enzyme being implicated in gonadal sex determination and spermatogonial stem cell differentiation. Here, we report hitherto uncharacterized roles of NEDD4 in postnatal testis development.

IsomiR stoichiometry changes as disease biomarkers.

Despite substantial research interest over the past decade, microRNAs (miRNAs) have not yet succeeded in reaching their potential as non-invasive diagnostic biomarkers. One key hindrance to their use is the lack of disease specificity of single miRNAs, combined with variable baseline expression between individuals. In the current work, we sought to leverage variations of the stoichiometry of miRNA isoform variants, or isomiRs, to expand the pool of potential miRNA biomarkers and facilitate normalization of their expression, using one isoform to normalize expression of another from the same miRNA.

Macrophages downregulate NEDD9 to counteract S. Typhimurium- mediated FAK-AKT activation and lysosome inhibition.

The scaffolding protein NEDD9 coordinates signaling downstream of integrins by interacting with focal adhesion kinase (FAK) and thereby promotes cell migration. NEDD9 expression is altered in a number of clinical conditions such as cancer, but its role in innate immunity against infections remains elusive. Transcriptome analysis of Salmonella Typhimurium (ST)-infected murine macrophages showed downregulation of NEDD9 and genes belonging to its signaling network.

ER stress and/or ER-phagy in drug resistance? Three coincidences are proof.

Cancer is influenced by the tumor microenvironment (TME), which includes factors such as pH, hypoxia, immune cells, and blood vessels. These factors affect cancer cell growth and behavior. The tumor microenvironment triggers adaptive responses such as endoplasmic reticulum (ER) stress, unfolded protein response (UPR), and autophagy, posing a challenge to cancer treatment.

Identification of Sphingosine Kinase 1 as a Novel Protein Regulated by High Molecular Weight Hyaluronan in Ovarian Cancer.

The effects of hyaluronan (HA) in cancer are widely studied; however, the role of different molecular weight HA is poorly understood. Identifying novel proteins regulated by different molecular weight HA may highlight novel therapeutic targets. Proteomics analysis was performed to identify novel proteins regulated by different molecular weight HA (27, 183 and 1000 kDa) in ES-2 ovarian cancer cells over-expressing Notch3 intra-cellular domain.

Molecular and histological evidence for the biocompatibility of PEDOT-coated microneedles in human skin.

The increasing demand for real-time, continuous health monitoring has driven improvements in wearable and skin-attachable devices, particularly in sensing vital body signs and biomarkers. Research on conducting polymers (CPs) in these devices is also growing due to their low cost, flexibility, and versatile fabrication. However, despite their widespread use and claims of biocompatibility, there are limited studies on the biocompatibility of CPs in human skin, and those that exist have only been conducted using cell cytotoxicity or animal testing, lacking proper and comprehensive assessments.

Comprehensive αβ T-Cell Receptor Repertoire Analysis Reveals a Unique CD8+ TCR Landscape in DOCK8-Deficient Patients.

Background: Dedicator of cytokinesis protein 8 (DOCK8) is a guanine nucleotide exchange factor highly expressed in, and critical for, the function of various innate and adaptive immune cells. DOCK8 deficiency leads to combined immunodeficiency characterized by susceptibility to infections, autoimmunity, and a severe Th2-type immune response. While dysfunction in various T cell subsets has been implicated in these phenotypes, a comprehensive analysis of the T-cell receptor (TCR) repertoire in these patients has not yet been documented.

Validation of the 5th edition of the World Health Organization and International Consensus Classification guidelines for TP53-mutated myeloid neoplasm in an independent international cohort.

The World Health Organization (WHO-5) and International Consensus Classification (ICC) acknowledge the poor prognosis of TP53-mutated (TP53) myeloid neoplasm (MN). However, there are substantial differences between the two classifications that may lead to under- or overestimation of the prognostic risk. We retrospectively applied WHO-5 and ICC to 603 MN cases harboring TP53 (variant allele frequency, VAF ≥ 2%).

Microfluidic Optimization of PEI-Lipid Hybrid Nanoparticles for Efficient DNA Delivery and Transgene Expression.

: Lipid nanoparticles (LNPs) and polyethyleneimine (PEI) have independently been used for DNA complexation and delivery. However, non-ideal gene delivery efficiency and toxicity have hindered their clinical translation. We developed DNA-PEI-LNPs as a strategy to overcome these limitations and enhance DNA delivery and transgene expression.

P62 inhibits IL-1β release during Typhimurium infection of macrophages.

Macrophages are critical for the innate immune defense against the facultative intracellular Gram-negative bacterium serovar Typhimurium. Following phagocytosis by macrophages, . Typhimurium activates cytoplasmic NLRC3 and NLRP4 inflammasomes, which share the adaptor ASC, resulting in the secretion of the pro-inflammatory cytokine IL-1β.

TRanscriptome ANalysis of StratifiEd CohorTs (TRANSECT) enables automated assessment of global gene regulation linked to disparate expression in user defined genes and gene sets.

Publicly accessible expression data produced by large consortium projects like TCGA and GTEx are increasing in number and size at an unprecedented rate. Their utility cannot be underestimated given the diversity of valuable tools widely used to interrogate these data and the many discoveries of biological and clinical significance already garnered from these datasets. However, there remain undiscovered ways to mine these rich resources and a continuing need to provide researchers with easily accessible and user-friendly applications for complex or bespoke analyses.

Inhibitor of DNA binding-1 is a key regulator of cancer cell vasculogenic mimicry.

Solid tumours routinely access the blood supply by promoting endothelium-dependent angiogenesis; but tumour vasculature can also be formed by cancer cells themselves via vasculogenic mimicry (VM). Investigation of the gene expression profile during the early stages of VM formation by MDA-MB-231-LM2 breast cancer cells identified the transcriptional regulator inhibitor of DNA binding 1 (ID1) to be elevated ~ 10-fold within the first 2 hours. This role for ID1 in promoting VM was supported by ID1 genetic knockdown or chemical inhibition interrupting VM formation by MDA-MB-231-LM2 (breast) and BxPC-3 (pancreatic) cancer cells.

Evidence-based risk stratification of myeloid neoplasms harboring TP53 mutations.

This retrospective analysis aimed to provide evidence-based risk stratification of TP53-mutated (TP53mut) myeloid neoplasms (MNs). Of 580 MNs harboring TP53mut with variant allele frequency (VAF) ≥2%, 219 (37.8%), 194 (33.

Personalising glioblastoma medicine: explant organoid applications, challenges and future perspectives.

Glioblastoma (GBM) is a highly aggressive adult brain cancer, characterised by poor prognosis and a dismal five-year survival rate. Despite significant knowledge gains in tumour biology, meaningful advances in patient survival remain elusive. The field of neuro-oncology faces many disease obstacles, one being the paucity of faithful models to advance preclinical research and guide personalised medicine approaches.

Defective kinase activity of IKKα leads to combined immunodeficiency and disruption of immune tolerance in humans.

IKKα is a multifunctional serine/threonine kinase that controls various biological processes, either dependent on or independent of its kinase activity. However, the importance of the kinase function of IKKα in human physiology remains unknown since no biallelic variants disrupting its kinase activity have been reported. In this study, we present a homozygous germline missense variant in the kinase domain of IKKα, which is present in three children from two Turkish families.

Decoding secret role of mesenchymal stem cells in regulating cancer stem cells and drug resistance.

Drug resistance caused by the efflux of chemotherapeutic drugs is one of the most challenging obstacles to successful cancer therapy. Several efflux transporters have been identified since the discovery of the P-gp/ABCB1 transporter in 1976. Over the last four decades, researchers have focused on developing efflux transporter inhibitors to overcome drug resistance.