Targeting DOT1L and EZH2 synergizes in breaking the germinal center identity of Diffuse Large B-cell Lymphoma.

Differentiation of antigen-activated B cells into pro-proliferative germinal center (GC) B cells depends on the activity of the transcription factors MYC and BCL6, and the epigenetic writers DOT1L and EZH2. GCB-like Diffuse Large B Cell Lymphomas (GCB-DLBCLs) arise from GCB cells and closely resemble their cell of origin. Given the dependency of GCB cells on DOT1L and EZH2, we investigated the role of these epigenetic regulators in GCB-DLBCLs and observed that GCB-DLBCLs synergistically depend on the combined activity of DOT1L and EZH2.

Deintensification of Radiotherapy Use in Treatment of Ductal Carcinoma In Situ in the Netherlands-A Nationwide Overview From 2008 Until 2022.

Aims: Ductal Carcinoma In Situ (DCIS) treated by breast-conserving surgery followed by radiotherapy aims to decrease the probability of locally recurrent disease. The role of whole breast irradiation, specifically in DCIS having low recurrence risk and low risk of becoming invasive, is increasingly debated. Also, the added value of applying boost irradiation in DCIS has been questioned.

Generation of effective and specific human TCRs against tumor/testis antigen NY-ESO-1 in mice with humanized T cell recognition system.

Generation of high avidity T cell receptors (TCRs) reactive to tumor-associated antigens (TAA) is impaired by tolerance mechanisms, which is an obstacle to effective T cell therapies for cancer treatment. NY-ESO-1, a human cancer-testis antigen, represents an attractive target for such therapies due to its broad expression in different cancer types and the restricted expression in normal tissues. Utilizing transgenic mice with a diverse human TCR repertoire, we isolated effective TCRs against NY-ESO-1 restricted to HLA-A*02:01.

Endocrine dysfunction in long-term survivors of pediatric head and neck rhabdomyosarcoma.

Objective: Survivors of pediatric head and neck rhabdomyosarcoma (HNRMS) are at risk of developing endocrinopathies following local treatment, resulting from radiation damage to the pituitary gland, hypothalamus, or thyroid gland, often at a young age. Our aim was to determine the prevalence of endocrine dysfunction in long-term HNRMS survivors and compare the prevalence of anterior pituitary insufficiency (API) among different local treatment strategies: external beam radiation with photons, external beam radiation with protons, microscopically radical surgery combined with external irradiation, and macroscopic radical surgery combined with brachytherapy.

Design And Methods: Head and neck rhabdomyosarcoma survivors treated between 1993 and 2017, with ≥2 years of follow-up, without recurrent disease or secondary malignancy were eligible for this study.

MRI of the Rectum: A Decade into DISTANCE, Moving to DISTANCED.

Over the past decade, advancements in rectal cancer research have reshaped treatment paradigms. Historically, treatment for locally advanced rectal cancer has focused on neoadjuvant long-course chemoradiotherapy, followed by total mesorectal excision. Interest in organ preservation strategies has been strengthened by the introduction of total neoadjuvant therapy with improved rates of complete clinical response.

A Repurposed Drug Selection Pipeline to Identify CNS-Penetrant Drug Candidates for Glioblastoma.

Background: Glioblastoma is an aggressive and incurable type of brain cancer. Little progress has been made in the development of effective new therapies in the past decades. The blood-brain barrier (BBB) and drug efflux pumps, which together hamper drug delivery to these tumors, play a pivotal role in the gap between promising preclinical findings and failure in clinical trials.

Adoptive T cell therapy targeting an inducible and broadly shared product of aberrant mRNA translation.

Prolonged exposure to interferon-gamma (IFNγ) and the associated increased expression of the enzyme indoleamine 2,3-dioxygenase 1 (IDO1) create an intracellular shortage of tryptophan in the cancer cells, which stimulates ribosomal frameshifting and tryptophan to phenylalanine (W>F) codon reassignments during protein synthesis. Here, we investigated whether such neoepitopes can be useful targets of adoptive T cell therapy. Immunopeptidomic analyses uncovered hundreds of W>F neoepitopes mainly presented by the HLA-A24:02 allele.

Molecular dependencies and genomic consequences of a global DNA damage tolerance defect.

Background: DNA damage tolerance (DDT) enables replication to continue in the presence of fork stalling lesions. In mammalian cells, DDT is regulated by two independent pathways, controlled by the polymerase REV1 and ubiquitinated PCNA, respectively.

Results: To determine the molecular and genomic impact of a global DDT defect, we studied Pcna;Rev1 compound mutants in mouse cells.

Deciphering the role of the MALT1-RC3H1 axis in regulating GPX4 protein stability.

Ferroptosis, a unique form of iron-dependent cell death triggered by lipid peroxidation accumulation, holds great promise for cancer therapy. Despite the crucial role of GPX4 in regulating ferroptosis, our understanding of GPX4 protein regulation remains limited. Through FACS-based genome-wide CRISPR screening, we identified MALT1 as a regulator of GPX4 protein.

Generalizability, robustness, and correction bias of segmentations of thoracic organs at risk in CT images.

Objective: This study aims to assess and compare two state-of-the-art deep learning approaches for segmenting four thoracic organs at risk (OAR)-the esophagus, trachea, heart, and aorta-in CT images in the context of radiotherapy planning.

Materials And Methods: We compare a multi-organ segmentation approach and the fusion of multiple single-organ models, each dedicated to one OAR. All were trained using nnU-Net with the default parameters and the full-resolution configuration.

Cytosolic-enhanced dark Epac-based FRET sensors allow for intracellular cAMP detection in live cells via FLIM.

Fluorescence resonance energy transfer (FRET)-based biosensors are powerful tools for studying second messengers with high temporal and spatial resolution. FRET is commonly detected by ratio imaging, but fluorescence lifetime imaging microscopy (FLIM), which measures the donor fluorophore's lifetime, offers a robust and more quantitative alternative. We have introduced and optimized four generations of FRET sensors for cAMP, based on the effector molecule Epac1, including variants for either ratio imaging or FLIM detection.

Surgical navigation for targeted retroperitoneal lymph-node removal: a randomised, controlled, phase 3 trial.

Background: Metastatic retroperitoneal lymph node dissection (LND) for nodal recurrence is applied for a variety of cancers, such as urological, gynaecological and rectal cancer. Precise localisation and resection of these lymph nodes (LNs) during surgery can be challenging, especially after previous radiotherapy or surgery. The objective of this study was to assess the added value of surgical navigation for targeted LND in the retroperitoneum.

Polygenic score distribution differences across European ancestry populations: implications for breast cancer risk prediction.

Background: The 313-variant polygenic risk score (PRS) provides a promising tool for clinical breast cancer risk prediction. However, evaluation of the PRS across different European populations which could influence risk estimation has not been performed.

Methods: We explored the distribution of PRS across European populations using genotype data from 94,072 females without breast cancer diagnosis, of European-ancestry from 21 countries participating in the Breast Cancer Association Consortium (BCAC) and 223,316 females without breast cancer diagnosis from the UK Biobank.

An update on access to novel treatment for metastatic melanoma in Europe - A 2024 survey of the European melanoma registry and the European association of dermato-oncology.

Advances in cancer treatments have significantly improved their effectiveness, yet access to first-line therapies remains limited. A 2017 survey revealed that over 25 % of metastatic melanoma patients in Europe lacked access to recommended therapies. To address this, the European Association of Dermato-Oncology and the European Melanoma Registry conducted a follow-up study on the registration and reimbursement of first-line treatments.

Hippocampal avoidance prophylactic cranial irradiation (HA-PCI) for small cell lung cancer better preserves white matter networks compared to conventional PCI.

Background: Hippocampal avoidance during prophylactic cranial irradiation (HA-PCI) is proposed to reduce neurocognitive decline, while preserving the benefits of PCI. We evaluated whether (HA-)PCI induces changes in white matter (WM) microstructure and whether sparing the hippocampus has an impact on preserving brain network topology. Additionally, we evaluated associations between topological metrics with hippocampal volume and neuropsychological outcomes.

ZNF143 is a transcriptional regulator of nuclear-encoded mitochondrial genes that acts independently of looping and CTCF.

Gene expression is orchestrated by transcription factors, which function within the context of a three-dimensional genome. Zinc-finger protein 143 (ZNF143/ZFP143) is a transcription factor that has been implicated in both gene activation and chromatin looping. To study the direct consequences of ZNF143/ZFP143 loss, we generated a ZNF143/ZFP143 depletion system in mouse embryonic stem cells.

Associations of intraoperative end-tidal CO levels with postoperative outcome-secondary analysis of a worldwide observational study.

Background: Patients receiving intraoperative ventilation during general anesthesia often have low end-tidal CO (etCO). We examined the association of intraoperative etCO levels with the occurrence of postoperative pulmonary complications (PPCs) in a conveniently-sized international, prospective study named 'Local ASsessment of Ventilatory management during General Anesthesia for Surgery' (LAS VEGAS).

Methods: Patients at high risk of PPCs were categorized as 'low etCO' or 'normal to high etCO' patients, using a cut-off of 35 mmHg.

Muscle atrophy and organ enlargement associated with quality of life during systemic therapy for melanoma: findings from an AI-based body composition analysis.

Introduction: Health-related quality of life (HRQoL) is emerging as an endpoint, adjunct to survival, in cancer treatment. For this reason, the European Organization for Research and Treatment of Cancer (EORTC) has developed standardized quality-of-life questionnaires to collect patient-reported outcome measurement (PROM), which so far have been widely used in clinical trials to evaluate the impact of new drugs on cancer patients. However, while these questionnaires comprehensively describe patient functions, little is known about their association with patient characteristics.

Win Ratio approach for the composite outcome of postoperative pulmonary complications: Secondary analysis of a harmonised and pooled database of three randomised clinical trials.

Background: The win ratio analysis method might provide new insight on the impact of positive end-expiratory pressure (PEEP) on clinical outcomes.

Objective: The aim is to re-analyse the results of the 'Re-evaluation of the effects of high PEEP with recruitment manoeuvres vs. low PEEP without recruitment manoeuvres during general anaesthesia for surgery' (REPEAT) study using the win ratio analysis.

An antibiotic that mediates immune destruction of senescent cancer cells.

Drugs that eliminate senescent cells, senolytics, can be powerful when combined with prosenescence cancer therapies. Using a CRISPR/Cas9-based genetic screen, we identify here SLC25A23 as a vulnerability of senescent cancer cells. Suppressing SLC25A23 disrupts cellular calcium homeostasis, impairs oxidative phosphorylation, and interferes with redox signaling, leading to death of senescent cells.

Identification of a sorting motif for Tspan3 to MHCII compartments in human B cells.

Tetraspanins are four-transmembrane proteins that play fundamental roles in the immune system by enabling processes like migration, proliferation, signaling and protein trafficking. While the importance of cell surface tetraspanins has been established, the function of intracellular tetraspanins is less well understood. Here, we investigated the role of tetraspanin 3 (Tspan3) in lymphocytes.