Extrachromosomal DNA-Driven Oncogene Spatial Heterogeneity and Evolution in Glioblastoma.

Unlabelled: Oncogenes amplified on extrachromosomal DNA (ecDNA) contribute to treatment resistance and poor survival across cancers. Currently, the spatiotemporal evolution of ecDNA remains poorly understood. In this study, we integrate computational modeling with samples from 94 treatment-naive human glioblastomas (GBM) to investigate the spatiotemporal evolution of ecDNA.

A pan-cancer, pan-treatment model for predicting drug responses from patient-derived xenografts.

The translatability of patient-derived xenograft (PDX)-generated clinical data into patient-specific outcomes for therapeutic guidance is limited by the challenges in generalizability of models across patients, treatments, and cancer types. Previously, machine learning (ML) models have been developed for the two most abundant cancer types, i.e.

Toxicity and efficacy of antibody-drug conjugates in advanced solid tumors: a retrospective single-center analysis of clinical trials.

Background: Antibody-drug conjugates (ADCs) combine targeted monoclonal antibodies with cytotoxic payloads and are an emerging modality in systemic cancer therapy. Thirteen ADCs are Food and Drug Administration approved, with many more in development. However, design and use remain challenging, with issues including on/off-target toxicity, resistance from prior exposure to payload classes, and optimal target/payload selection.

Conformational dynamics of the bacterial E3 ligase SspH1.

The SspH/IpaH family of novel E3 ligases (NELs) are found in a number of Gram-negative bacteria and are used to target host enzymes for degradation to support pathogenesis. These E3 enzymes are autoinhibited in the absence of substrate and different models for release of autoinhibition have been suggested. However, many of the molecular details of individual steps during the ubiquitin transfer reaction remain unknown.

Procollagen IIA mediates positive feedback control of the mouse cardiogenic transcriptional network.

Cardiogenesis relies on the integrated interplay between cardiac transcription factors and signaling pathways. Here, we uncover a role for type IIA procollagen (IIA), an extracellular matrix (ECM) protein encoded by an alternatively spliced transcript, encoding a N-terminal cysteine-rich domain, as a critical regulator in a cardiac gene regulatory feedback loop. The cysteine-rich domain of IIA protein was previously reported to interact with bone morphogenetic proteins (BMPs) and transforming growth factors-beta (TGFβ) in in vitro binding assays and acts as a BMP antagonist in amphibian embryo assays.

Protocol for rapid 5-plex 3D imaging and single-cell analysis of immune responses in whole murine lymph nodes.

Lymph nodes orchestrate adaptive immune responses, with germinal centers enabling affinity maturation and plasma cell formation. Here, we present a protocol for rapid, high-resolution, multicolor 3D imaging of whole immunized mouse lymph nodes. We describe steps for immunization, lymph node harvesting, fixation, permeabilization, staining, and clearing.

Investigating factors driving shifts in subtype dominance within H5Nx clade 2.3.4.4b high pathogenicity avian influenza viruses.

H5Nx clade 2.3.4.

Chemical proteomic approaches to investigate N-myristoylation.

The protein lipidation event N-myristoylation is catalyzed by the N-myristoyltransferase (NMT) enzymes and occurs on over 200 proteins with N-terminal glycines. The modification controls the localization, stability, function and interactions of its substrate proteins and has been implicated in the regulation of multiple biological processes and disease pathologies. Understanding how the N-myristoylated proteome is altered in these pathologies and in response to pharmacological NMT inhibition is therefore critical to understand how N-myristoylation regulates basic biology and how its pharmacological inhibition may be optimally leveraged in clinical settings.

Uveal Melanoma UK national guidelines: 2023 update.

UK Guidelines for the management of uveal melanoma (UM) were first published in 2015 using an evidence-based systematic approach. The primary aim of this guideline was to optimise patient care by providing recommendations based on the best available scientific evidence. The resulting guideline reflected the strengths and weaknesses of the available evidence, made recommendations that were clinically impactful around prognostication, surveillance, and treatment for patients with primary lesions and metastatic disease.

State of the art biology, progression, and clinical management of monoclonal B-cell lymphocytosis (MBL): consensus report from the Intercepting Blood Cancers Workshop Committee.

In March 2023 and 2024, a panel of international experts convened at the first and second Intercepting Blood Cancers (IBC) Workshops, with the aim of better appreciating the diagnostic challenges, pathophysiology, and potential therapeutic interventions for precursor malignant hematology conditions. Here, we report a summary of the proceedings from the sessions focused on monoclonal B-cell lymphocytosis (MBL)/chronic lymphocytic leukemia (CLL). We highlight four main content areas: biology of MBL, clinical implications of MBL, progression of MBL and transformation from indolent CLL to aggressive disease, and opportunities for therapeutic intervention in early CLL.

Third exposure to COVID-19 infection or vaccination differentially impacts T cell responses.

Background: In 2021, the rapid rollout of two doses of SARS-CoV-2 vaccines reduced COVID-19 severity and mortality. However, further vaccine doses as a prime-boost schedule were limited, and lifting of public health restrictions by late 2021 frequently led to infection, rather than vaccine, as a third exposure.

Objective: To compare how the third exposure through mRNA booster or SARS-CoV-2 infection shapes humoral and cellular immunity following two vaccine doses.

Phenoscaping Reveals Multimodal γδ T Cell Cytotoxicity as a Strategy to Overcome Cancer Cell-Mediated Immunomodulation.

γδ T cells can kill cancer cells via antibody-independent cytotoxicity (AIC) and antibody-dependent cellular cytotoxicity (ADCC). A better understanding of how these cytotoxic mechanisms are impacted by different cancer cells and different T cell donors could help identify improved immunotherapeutic strategies. To test the combinatorial interactions between T cell inter-donor heterogeneity (IDH), cancer cell inter-tumor heterogeneity (ITH), and multimodal γδ T cell killing, we performed a systematic single-cell phenoscaping analysis of >1,000 cultures of γδ T cells and colorectal cancer (CRC) patient-derived organoids (PDO).

Mesenchymal stromal cells from myeloproliferative neoplasms support healthy and malignant hematopoiesis in a humanized scaffold model in vivo.

Myeloproliferative Neoplasms (MPN) are malignancies of hematopoietic stem and progenitor cells (HSPCs) that lead to the overproduction of mature blood cells. These disorders include Essential Thrombocythemia (ET), Polycythemia Vera (PV), and Primary Myelofibrosis (PMF), primarily driven by somatic mutations such as . Research indicates that mesenchymal stromal cells (MSCs) support fibrosis in PMF, though their role in ET and PV remains less clear.

An alternative cytoplasmic SFPQ isoform with reduced phase separation potential is up-regulated in ALS.

Splicing factor proline- and glutamine-rich (SFPQ) is an RNA binding protein that broadly regulates RNA metabolism. Although its nuclear roles are well studied, evidence of SFPQ's cytoplasmic functionality is emerging. Altered expression and nuclear-to-cytoplasmic redistribution of SFPQ have been recognized in amyotrophic lateral sclerosis (ALS) pathology, yet the mechanistic bases for these phenomena remain undetermined.

MYC deregulation sensitizes cancer cells to N-myristoyltransferase inhibition.

Human N-myristoyltransferases (NMTs) catalyze N-terminal protein N-myristoylation and are promising targets in cancer, with an emerging mechanistic rationale for targeted therapy. Here, we screened 245 cancer cell lines against IMP-1320, a potent NMT inhibitor (NMTi), and conducted pathway-level analyses to identify that deregulated MYC increases cancer cell sensitivity to NMTis. Proteomics on detergent-enriched membrane fractions in MYC or MYCN-deregulated cancer cell models revealed that cell death is associated at least in part with loss of membrane association of mitochondrial respiratory complex I.

RARE-seq: an inflection point in cfRNA liquid biopsy.

Historically, the clinical application of cell-free RNA (cfRNA) liquid biopsies has been limited by background noise. In a recent study, Nesselbush et al. developed a method for denoising cfRNA analysis, resulting in RARE-seq, a versatile liquid biopsy platform that enables transcriptomic profiling, and cancer detection and monitoring, unlocking the potential of this exciting analyte.

Evaluation of Hepatitis B core-related antigen (HBcrAg) as a biomarker in cohorts from the United Kingdom and South Africa.

Objectives: We set out to evaluate Hepatitis B core-related antigen (HBcrAg) as a proxy for hepatitis B (HBV) viral load (VL) and liver disease in two different population settings.

Methods: We undertook a cross-sectional retrospective observational study using samples and data from adults living with chronic HBV infection from the United Kingdom (UK, n=142) and South Africa (SA, n=211). We assessed HBcrAg distribution, relationship with other biomarkers, and risk stratification performance, applying point of care test (POCT) thresholds.

A clinical practice guideline for tuberculous meningitis.

Tuberculous meningitis is the most severe form of tuberculosis, causing death or disability in around half of those affected. There are no up-to-date international guidelines defining its optimal management. Therefore, the Tuberculous Meningitis International Research Consortium conducted a systematic review of available evidence to address key management questions and to develop practice guidance.

Kif11-haploinsufficient oocytes reveal spatially differential requirements for chromosome biorientation.

Bipolar spindle assembly and chromosome biorientation are prerequisites for chromosome segregation during cell division. The kinesin motor KIF11 (also widely known as Eg5) drives spindle bipolarization by sliding antiparallel microtubules bidirectionally, elongating a spherical spindle into a bipolar-shaped structure in acentrosomal oocytes. During meiosis I, this process stretches homologous chromosome pairs, establishing chromosome biorientation at the spindle equator.

Targeted CRISPR screens reveal genes essential for Cryptosporidium survival in the host intestine.

The Cryptosporidium parasite is one of the leading causes of diarrheal morbidity and mortality in children, and adolescent infections are associated with chronic malnutrition. There are no vaccines available for protection and only one drug approved for treatment that has limited efficacy. A major barrier to developing new therapeutics is a lack of foundational knowledge of Cryptosporidium biology, including which parasite genes are essential for survival and virulence.

Visualizing Phosphatidic Acid and Diacylglycerol at the Nuclear Envelope in Fission Yeast.

Although the outer membrane of the nuclear envelope is continuous with the endoplasmic reticulum, temporally regulated and functionally significant differences in membrane lipid composition may exist between the two nuclear membranes and between the outer nuclear membrane and the endoplasmic reticulum. Biochemical approaches to probing lipid composition are challenged when lipid dynamics must be analyzed with fine spatiotemporal resolution, for instance, within the cell cycle of a single cell. Here we describe a method to probe the distribution of phosphatidic acid and diacylglycerol, two interconvertible biosynthetic precursors for other membrane glycerophospholipids, in living cells of the model fission yeast Schizosaccharomyces pombe.

Is health, growth and development impaired in children who are Hepatitis B-exposed but uninfected?

An estimated 254 million people are living with chronic hepatitis B virus (HBV) infection worldwide. Many infants are born to mothers with HBV but do not themselves acquire the infection. It is unclear whether this exposure to HBV in early life - without the development of active infection - may be associated with adverse outcomes.