Pushing the boundaries of radiotherapy-immunotherapy combinations: highlights from the 7 immunorad conference.

Over the last decade, the annual Immunorad Conference, held under the joint auspicies of Gustave Roussy (Villejuif, France) and the Weill Cornell Medical College (New-York, USA) has aimed at exploring the latest advancements in the fields of tumor immunology and radiotherapy-immunotherapy combinations for the treatment of cancer. Gathering medical oncologists, radiation oncologists, physicians and researchers with esteemed expertise in these fields, the Immunorad Conference bridges the gap between preclinical outcomes and clinical opportunities. Thus, it paves a promising way toward optimizing radiotherapy-immunotherapy combinations and, from a broader perspective, improving therapeutic strategies for patients with cancer.

High-throughput discovery and deep characterization of cyclin-CDK docking motifs.

Cyclin-CDKs are master regulators of cell division. In addition to directly activating the CDK, the cyclin subunit regulates CDK specificity by binding short peptide "docking" motifs in CDK substrates. Here, we measure the relative binding strength of ~100,000 peptides to 11 human cyclins from five cyclin families (D, E, A, B and F).

Population-based germline testing of , and in breast cancer patients in the United Kingdom: Evidence to support extended testing, and definition of groups who may not require testing.

Purpose: To assess the contribution of germline pathogenic variants (PVs) in population-based series of breast cancers and the best strategy to improve detection rates.

Methods: Three cohort studies were utilized, including a hospital-based series identified from new UK mainstream testing criteria (group-1), offering testing to all women (group-2-BReast CAncer [BRCA]-DIRECT), and a Greater Manchester cohort study recruited from the mammography screening population (group-3-Predicting Risk of Cancer at Screening). DNA samples from women with breast cancer were sequenced for PVs in , , and Partner and Localiser of BRCA2 ().

Clinical performance of a simulated abbreviated liver magnetic resonance imaging in combination with contrast-enhanced computed tomography for the baseline evaluation of the liver in patients with colorectal cancer.

Aim: To assess the diagnostic accuracy and inter-reader agreement of a simulated abbreviated gadoxetate liver magnetic resonance imaging (MRI) protocol together with contrast-enhanced computed tomography (CE-CT) against a standard gadoxetate MRI for the detection of colorectal liver metastases at baseline.

Materials And Methods: Three readers independently evaluated two sets of images per patient, recording number and location of metastases and benign lesions. Set 1 comprised T1w, T2w, DWI, multiphase CE-T1w, and hepatobiliary phase (HBP) images (standard).

Identification of bioactive compounds with popular single-atom modifications: Comprehensive analysis and implications for compound design.

The extensive bioactivity data available in public databases, such as ChEMBL, has facilitated in-depth structure-activity relationship (SAR) analysis, which are essential for understanding the impact of molecular modifications on biological activity in a comprehensive manner. A central strategy in SAR analysis is the assessment of molecular similarity. Several approaches preferred by medicinal chemists have been developed to efficiently capture structurally related compounds on a large scale.

Plasma prolactin and postmenopausal breast cancer risk: a pooled analysis of four prospective cohort studies.

Background: Prolactin, a hormone produced by the pituitary gland, regulates breast development and may contribute to breast cancer etiology. However, most epidemiologic studies of prolactin and breast cancer have been restricted to single, often small, study samples with limited exploration of effect modification.

Methods: The Biomarkers in Breast Cancer Risk Prediction consortium includes 8,279 postmenopausal women sampled from four prospective cohort studies, of whom 3,441 were diagnosed with invasive breast cancer after enrollment.

Treatment planning for very high energy electrons: Studies that indicate the potential of the modality.

Background And Purpose: Radiotherapy using Very High Energy Electrons (VHEE) has the potential to reduce dose to organs at risk compared to photons. This article therefore reviews treatment planning for VHEE, to clarify the potential benefit of the modality.

Materials And Methods: Articles on VHEE were identified and those which focused on treatment planning were manually selected, particularly those which contained results on patient datasets.

Expert recommendations on treatment sequencing and challenging clinical scenarios in human epidermal growth factor receptor 2-positive (HER2-positive) metastatic breast cancer.

Human epidermal growth factor receptor 2 (HER2) overexpression and/or ERBB2 gene amplification occurs in approximately 15-20% of breast cancers and is associated with poor prognosis. While the introduction of HER2-targeted therapies has significantly improved survival in patients with HER2-positive metastatic breast cancer, the incidence of brain metastases has increased due to patients living longer. Current recommendations sequence treatments by line of therapy, as well as by the status of brain metastases in patients with HER2-positive breast cancer.

Lorlatinib-associated weight gain and dyslipidaemia: A retrospective analysis and implications for future care.

Objectives: The objective of our study was to benchmark the incidence and severity of lorlatinib-related weight gain and dyslipidaemia in a real-world context, to guide future therapeutic strategies to mitigate these toxicities.

Methods: We conducted a retrospective, observational analysis of patients with ALK and ROS1-positive NSCLC at a single institution in the UK who were commenced on lorlatinib from 11/2016 to 11/2022. Non-small cell lung cancer (NSCLC) patients prescribed lorlatinib were identified through institutional electronic pharmacy records.

Exposing 24-hour cycles in bile acids of male humans.

Bile acids are trans-genomic molecules arising from the concerted metabolism of the human host and the intestinal microbiota and are important for digestion, energy homeostasis and metabolic regulation. While diurnal variation has been demonstrated in the enterohepatic circulation and the gut microbiota, existing human data are poorly resolved, and the influence of the host circadian system has not been determined. Using entrained laboratory protocols, we demonstrate robust daily rhythms in the circulating bile acid pool in healthy male participants.

A quantitative intracellular peptide binding assay reveals recognition determinants and context dependence of short linear motifs.

Transient protein-protein interactions play key roles in controlling dynamic cellular responses. Many examples involve globular protein domains that bind to peptide sequences known as Short Linear Motifs (SLiMs), which are enriched in intrinsically disordered regions of proteins. Here we describe a novel functional assay for measuring SLiM binding, called Systematic Intracellular Motif Binding Analysis (SIMBA).

Generation of TWO iPSC lines (CRICKi009-A; CRICKi010-A) from patients with type 1 von Hippel-Lindau (VHL) and histopathologically confirmed renal cell carcinoma (RCC).

VHL disease is an inherited and autosomal dominant disorder affecting 1 in 36,0000 individuals worldwide. It is caused by von Hippel-Lindau (VHL) gene mutations and can affect both genders and all ethnic backgrounds (Nordstrom-O'Brien et al., 2009; Maher, 2004).

Germline sequencing in men with metastatic castration-resistant prostate cancer from the BARCODE2 study reveals a wide range of pathogenic variants in DNA repair genes.

Background: The presence of germline mutations plays an increasingly important role in risk assessment and treatment of prostate cancer (PrCa). Screening for high-risk mutations in subsets of patients is becoming routine. We explore the prevalence of germline genetic mutations in men with metastatic castration-resistant prostate cancer (mCRPC) recruited to the BARCODE2 trial.

Life history dynamics of evolving tumors: insights into task specialization, trade-offs, and tumor heterogeneity.

The evolution of cancer cells parallels species evolution in numerous ways. Variations arise and spread under the pressure of competition between cancer cells. Current investigations of tumor evolution echo earlier debates between biologists.

A PSA SNP associates with cellular function and clinical outcome in men with prostate cancer.

Genetic variation at the 19q13.3 KLK locus is linked with prostate cancer susceptibility in men. The non-synonymous KLK3 single nucleotide polymorphism (SNP), rs17632542 (c.

Inhibition of GPX4 enhances CDK4/6 inhibitor and endocrine therapy activity in breast cancer.

CDK4/6 inhibition in combination with endocrine therapy is the standard of care for estrogen receptor (ER+) breast cancer, and although cytostasis is frequently observed, new treatment strategies that enhance efficacy are required. Here, we perform two independent genome-wide CRISPR screens to identify genetic determinants of CDK4/6 and endocrine therapy sensitivity. Genes involved in oxidative stress and ferroptosis modulate sensitivity, with GPX4 as the top sensitiser in both screens.

Classification of variants of reduced penetrance in high-penetrance cancer susceptibility genes: Framework for genetics clinicians and clinical scientists by CanVIG-UK (Cancer Variant Interpretation Group-UK).

Purpose: Current practice is to report and manage likely pathogenic/pathogenic variants in a given cancer susceptibility gene as though having equivalent penetrance, despite increasing evidence of intervariant variability in risk associations. Using existing variant interpretation approaches, largely based on full-penetrance models, variants in which reduced penetrance is suspected may be classified inconsistently and/or as variants of uncertain significance. We aimed to develop a national consensus approach for such variants within the Cancer Variant Interpretation Group UK (CanVIG-UK) multidisciplinary network.

An Attribution of Value Framework for Combination Treatments.

Objectives: The use of cost-effectiveness methods to support policy decisions has become well established, but difficulties can arise when evaluating a new treatment that is indicated to be used in combination with an established backbone treatment. If the latter has been priced close to the decision maker's willingness-to-pay threshold, this may mean that there is no headroom for the new treatment to demonstrate value, at any price, even if the combination is clinically effective. Without a mechanism for attributing value to component treatments within a combination therapy, the health system risks generating negative funding decisions for combinations of proven clinical benefit to patients.

Molecular and cell phenotype programs in oral epithelial cells directed by co-exposure to arsenic and smokeless tobacco.

Chronic arsenic exposure can lead to various health issues, including cancer. Concerns have been mounting about the enhancement of arsenic toxicity through co-exposure to various prevalent lifestyle habits. Smokeless tobacco products are commonly consumed in South Asian countries, where their use frequently co-occurs with exposure to arsenic from contaminated groundwater.

Ultrasound-guided intra-tumoral administration of directly-injected therapies: a review of the technical and logistical considerations.

Background: Directly-injected therapies (DIT) include a broad range of agents within a developing research field in cancer immunotherapy, with encouraging clinical trial results in various tumour subtypes. Currently, the majority of such therapies are only available within clinical trials; however, more recently, talimogene laherparepvec (T-VEC, Imlygic) has been approved as the first oncolytic virus therapy in the USA and Europe. Our institution contributes to multiple different trials exploring the efficacy of DIT, the majority of which are performed by oncologists in clinic.

How to write an ending: Telomere replication as a multistep process.

Telomeres are protective nucleoprotein caps found at the natural ends of eukaryotic chromosomes and are crucial for the preservation of stable chromosomal structure. In cycling cells, telomeres are maintained by a multi-step process called telomere replication, which involves the eukaryotic replisome navigating a complex repetitive template tightly bound by specific proteins, before terminating at the chromosome end prior to a 5' resection step that generates a protective 3' overhang. In this review, we examine mechanistic aspects of the telomere replication process and consider how individual parts of this multistep event are integrated and coordinated with one-another.