Loss of Epigenetic Regulation Disrupts Lineage Integrity, Induces Aberrant Alveogenesis, and Promotes Breast Cancer.

Unlabelled: Systematically investigating the scores of genes mutated in cancer and discerning disease drivers from inconsequential bystanders is a prerequisite for precision medicine but remains challenging. Here, we developed a somatic CRISPR/Cas9 mutagenesis screen to study 215 recurrent "long-tail" breast cancer genes, which revealed epigenetic regulation as a major tumor-suppressive mechanism. We report that components of the BAP1 and COMPASS-like complexes, including KMT2C/D, KDM6A, BAP1, and ASXL1/2 ("EpiDrivers"), cooperate with PIK3CAH1047R to transform mouse and human breast epithelial cells.

Venting percutaneous radiologic gastrostomy in malignant bowel obstruction: safety and effectiveness in a comprehensive cancer centre.

Objective: Approximately 20% of established malignant bowel obstruction (MBO) patients do not respond to pharmacological treatment. In these cases, venting percutaneous radiologic gastrostomy (VPRG) may be useful. Existing evidence is based on retrospective studies with methodological limitations.

Generation of heterozygous SAMD9 CRISPR/Cas9-edited iPSC line (ESi086-A-3), carrying p.I1567M mutation.

Germline SAMD9 mutations are one of the most common alterations that predispose to pediatric myelodysplastic syndrome (MDS), a clonal disorder characterized by ineffective hematopoiesis, increasing the risk of developing acute myeloid leukemia (AML). Up to date, a disease model to study the role of SAMD9 mutation in MDS is still lacking. Here, we have generated a human induced pluripotent stem cell (hiPSC) line carrying SAMD9 (p.

Ovarian Signet-ring Stromal Tumor: A Morphologic, Immunohistochemical, and Molecular Study of 7 Cases With Discussion of the Differential Diagnosis.

Signet-ring stromal tumor (SRST) is a rare ovarian stromal neoplasm characterized by a population of bland signet-ring cells, devoid of mucin or lipid, in a generally cellular fibromatous stroma. Previous reports have described heterogenous immunohistochemical and molecular genetic findings, including occasional nuclear β-catenin expression and/or CTNNB1 mutations. We report 10 ovarian stromal neoplasms originally diagnosed as SRST.

Glycosylation defects, offset by PEPCK-M, drive entosis in breast carcinoma cells.

On glucose restriction, epithelial cells can undergo entosis, a cell-in-cell cannibalistic process, to allow considerable withstanding to this metabolic stress. Thus, we hypothesized that reduced protein glycosylation might participate in the activation of this cell survival pathway. Glucose deprivation promoted entosis in an MCF7 breast carcinoma model, as evaluated by direct inspection under the microscope, or revealed by a shift to apoptosis + necrosis in cells undergoing entosis treated with a Rho-GTPase kinase inhibitor (ROCKi).

Germline Missense Variants in CDC20 Result in Aberrant Mitotic Progression and Familial Cancer.

Unlabelled: CDC20 is a coactivator of the anaphase promoting complex/cyclosome (APC/C) and is essential for mitotic progression. APC/CCDC20 is inhibited by the spindle assembly checkpoint (SAC), which prevents premature separation of sister chromatids and aneuploidy in daughter cells. Although overexpression of CDC20 is common in many cancers, oncogenic mutations have never been identified in humans.

Inflammatory exposure drives long-lived impairment of hematopoietic stem cell self-renewal activity and accelerated aging.

Hematopoietic stem cells (HSCs) mediate regeneration of the hematopoietic system following injury, such as following infection or inflammation. These challenges impair HSC function, but whether this functional impairment extends beyond the duration of inflammatory exposure is unknown. Unexpectedly, we observed an irreversible depletion of functional HSCs following challenge with inflammation or bacterial infection, with no evidence of any recovery up to 1 year afterward.

The mGlu Receptor Protomer-Mediated Dopamine D Receptor Trans-Inhibition Is Dependent on the Adenosine A Receptor Protomer: Implications for Parkinson's Disease.

The adenosine A receptor (AR), dopamine D receptor (DR) and metabotropic glutamate receptor type 5 (mGluR) form AR-DR-mGluR heteroreceptor complexes in living cells and in rat striatal neurons. In the current study, we present experimental data supporting the view that the AR protomer plays a major role in the inhibitory modulation of the density and the allosteric receptor-receptor interaction within the DR-mGluR heteromeric component of the AR-DR-mGluR complex in vitro and in vivo. The AR and mGluR protomers interact and modulate DR protomer recognition and signalling upon forming a trimeric complex from these receptors.

Living a longer life: unique lessons from the naked mole-rat blood system.

Analysis of functional deterioration of the blood system during ageing has been largely confined to the mouse and human system. In this issue, Emmrich et al (2022) report the first comprehensive characterisation of the haematopoietic system of the naked mole-rat (NMR), an exceptionally long-lived rodent, highlighting its unique features and uncovering potential strategies to sustain haematopoiesis during an extended lifetime.

Fast and high-fidelity 3D imaging protocol for stem cells and niche components for mouse organs and tissues.

Quantitative 3D imaging of organ-wide cellular and subcellular components is central for revealing and understanding complex interactions between stem cells and their microenvironment. Here, we present a gentle but fast whole-mount immunofluorescence staining protocol for 3D confocal microscopy (iFAST3D) that preserves the 3D structure of the entire tissue and that of subcellular structures with high fidelity. The iFAST3D protocol enables reproducible and high-resolution 3D imaging of stem cells and various niche components for many mouse organs and tissues.

The Effectiveness of Combination Therapy for Treating Methicillin-Susceptible Bacteremia: A Systematic Literature Review and a Meta-Analysis.

Background: This meta-analysis aims to evaluate the effectiveness of combination therapy for treating MSSA bacteremia.

Methods: We searched Ovid MEDLINE, EMBASE, Cochrane CENTRAL, and clinicaltrials.gov for studies including adults with MSSA bacteremia.

The X-linked splicing regulator MBNL3 has been co-opted to restrict placental growth in eutherians.

Understanding the regulatory interactions that control gene expression during the development of novel tissues is a key goal of evolutionary developmental biology. Here, we show that Mbnl3 has undergone a striking process of evolutionary specialization in eutherian mammals resulting in the emergence of a novel placental function for the gene. Mbnl3 belongs to a family of RNA-binding proteins whose members regulate multiple aspects of RNA metabolism.

Pathogenic BRCA1 variants disrupt PLK1-regulation of mitotic spindle orientation.

Preneoplastic mammary tissues from human female BRCA1 mutation carriers, or Brca1-mutant mice, display unexplained abnormalities in luminal differentiation. We now study the division characteristics of human mammary cells purified from female BRCA1 mutation carriers or non-carrier donors. We show primary BRCA1 mutant/+ cells exhibit defective BRCA1 localization, high radiosensitivity and an accelerated entry into cell division, but fail to orient their cell division axis.

Facilitators and Barriers to Dementia Assessment and Diagnosis: Perspectives From Dementia Experts Within a Global Health Context.

Objectives: Dementia poses one of the greatest global health challenges, affecting 50 million people worldwide. With 10 million new cases each year, dementia is a growing burden, particularly in low- and middle-income countries (LMIC). This study aimed to identify the facilitators and barriers to providing quality dementia assessment and care in LMICs from a global health perspective.

Modification of BRCA1-associated breast cancer risk by HMMR overexpression.

Breast cancer risk for carriers of BRCA1 pathological variants is modified by genetic factors. Genetic variation in HMMR may contribute to this effect. However, the impact of risk modifiers on cancer biology remains undetermined and the biological basis of increased risk is poorly understood.

Cathepsin D interacts with adenosine A receptors in mouse macrophages to modulate cell surface localization and inflammatory signaling.

Adenosine A receptor (AR)-dependent signaling in macrophages plays a key role in the regulation of inflammation. However, the processes regulating AR targeting to the cell surface and degradation in macrophages are incompletely understood. For example, the C-terminal domain of the AR and proteins interacting with it are known to regulate receptor recycling, although it is unclear what role potential AR-interacting partners have in macrophages.

A Descriptive Analysis of Urinary ESBL-Producing- in Cerdanya Hospital.

Urinary tract infections caused by extended-spectrum β-lactamase (ESBL-EC) are increasing worldwide and are a current concern because treatment options are often limited. This study investigated antimicrobial susceptibility, antimicrobial resistance genes (ARGs), and the biological diversity of urinary ESBL-EC isolates at Cerdanya Hospital, a European cross-border hospital that combines French and Spanish healthcare models. Bacterial identification and susceptibility were determined using the Microscan WalkAway system and ESBL production was examined by the double-disk synergy method.

Modeling iPSC-derived human neurofibroma-like tumors in mice uncovers the heterogeneity of Schwann cells within plexiform neurofibromas.

Plexiform neurofibromas (pNFs) are developmental tumors that appear in neurofibromatosis type 1 individuals, constituting a major source of morbidity and potentially transforming into a highly metastatic sarcoma (MPNST). pNFs arise after NF1 inactivation in a cell of the neural crest (NC)-Schwann cell (SC) lineage. Here, we develop an iPSC-based NC-SC in vitro differentiation system and construct a lineage expression roadmap for the analysis of different 2D and 3D NF models.

Zebrafish patient-derived xenograft models predict lymph node involvement and treatment outcome in non-small cell lung cancer.

Background: Accurate predictions of tumor dissemination risks and medical treatment outcomes are critical to personalize therapy. Patient-derived xenograft (PDX) models in mice have demonstrated high accuracy in predicting therapeutic outcomes, but methods for predicting tumor invasiveness and early stages of vascular/lymphatic dissemination are still lacking. Here we show that a zebrafish tumor xenograft (ZTX) platform based on implantation of PDX tissue fragments recapitulate both treatment outcome and tumor invasiveness/dissemination in patients, within an assay time of only 3 days.

Evidence for shared genetic risk factors between lymphangioleiomyomatosis and pulmonary function.

Introduction: Lymphangioleiomyomatosis (LAM) is a rare low-grade metastasising disease characterised by cystic lung destruction. The genetic basis of LAM remains incompletely determined, and the disease cell-of-origin is uncertain. We analysed the possibility of a shared genetic basis between LAM and cancer, and LAM and pulmonary function.

CDK5RAP3, a New BRCA2 Partner That Regulates DNA Repair, Is Associated with Breast Cancer Survival.

BRCA2 is essential for homologous recombination DNA repair. mutations lead to genome instability and increased risk of breast and ovarian cancer. Similarly, mutations in BRCA2-interacting proteins are also known to modulate sensitivity to DNA damage agents and are established cancer risk factors.

Validation of Anticorrelated TGFβ Signaling and Alternative End-Joining DNA Repair Signatures that Predict Response to Genotoxic Cancer Therapy.

Purpose: Loss of TGFβ signaling increases error-prone alternative end-joining (alt-EJ) DNA repair. We previously translated this mechanistic relationship as TGFβ and alt-EJ gene expression signatures, which we showed are anticorrelated across cancer types. A score representing anticorrelation, βAlt, predicts patient outcome in response to genotoxic therapy.