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.

Clone copy number diversity is linked to survival in lung cancer.

Both single nucleotide variants (SNVs) and somatic copy number alterations (SCNAs) accumulate in cancer cells during tumour development, fuelling clonal evolution. However, accurate estimation of clone-specific copy numbers from bulk DNA-sequencing data is challenging. Here we present allele-specific phylogenetic analysis of copy number alterations (ALPACA), a method to infer SNV and SCNA coevolution by leveraging phylogenetic trees reconstructed from multi-sample bulk tumour sequencing data using SNV frequencies.

The National Health Service-Galleri multi-cancer screening trial: explanation and justification of unique and important design issues.

Despite there being a plethora of multi-cancer early-detection tests, NHS-Galleri (ISRCTN91431511) is the only randomized controlled trial (RCT) of a multi-cancer liquid biopsy in a screening setting thus far. The NHS-Galleri trial has generated much debate, and it has been criticized in the medical press. Some of these criticisms stem from differing opinions over the choice of primary endpoint, others from poor reporting in statements to journalists from those not directly involved in the trial.

Nivolumab and Ipilimumab for Metastatic Castration-Resistant Prostate Cancer With an Immunogenic Signature: The Multicenter, Two-Cohort, Phase II NEPTUNES Study.

Purpose: Efficacy of immune checkpoint inhibitors in unselected patients with metastatic castration-resistant prostate cancer (mCRPC) is limited. The NEPTUNES study evaluated combination nivolumab and ipilimumab in patients with immunogenic signature-positive (ImS+) mCRPC.

Materials And Methods: This open-label, 2-cohort, phase II trial enrolled patients with ImS+ mCRPC progressing on ≥1 previous line of treatment.

Functional liver genomics identifies hepatokines promoting wasting in cancer cachexia.

In cancer cachexia, the presence of a tumor triggers systemic metabolic disruption that leads to involuntary body weight loss and accelerated mortality in affected patients. Here, we conducted transcriptomic and epigenomic profiling of the liver in various weight-stable cancer and cancer cachexia models. An integrative multilevel analysis approach identified a distinct gene expression signature that included hepatocyte-secreted factors and the circadian clock component REV-ERBα as key modulator of hepatic transcriptional reprogramming in cancer cachexia.

Extrachromosomal DNA: shaping the evolutionary dynamics of cancer.

Cancers are complex, diverse, and elusive, with extrachromosomal DNA (ecDNA) recently emerging as a crucial player in driving the evolution of about 20% of all tumors. In this review we discuss open questions concerning the evolutionary role of ecDNA in tumor development, including tumorigenesis and metastatic seeding, the mutational landscape on ecDNA, the dynamic ecDNA genotype-phenotype map, the structural evolution of ecDNA, and how knowledge of tissue-specific ecDNA evolutionary paths can be leveraged to deliver more effective clinical treatment. Looking forward, evolutionary theoretical modeling will be instrumental in advancing new research in the field, and we explore how modeling has contributed to our understanding of the evolutionary principles governing ecDNA dynamics.

Subclonal immune evasion in non-small cell lung cancer.

Cancers rarely respond completely to immunotherapy. While tumors consist of multiple genetically distinct clones, whether this affects the potential for immune escape remains unclear due to an inability to isolate and propagate individual subclones from human cancers. Here, we leverage the multi-region TRACERx lung cancer evolution study to generate a patient-derived organoid - T cell co-culture platform that allows the functional analysis of subclonal immune escape at single clone resolution.

The mutagenic forces shaping the genomes of lung cancer in never smokers.

Lung cancer in never smokers (LCINS) accounts for around 25% of all lung cancers and has been associated with exposure to second-hand tobacco smoke and air pollution in observational studies. Here we use data from the Sherlock-Lung study to evaluate mutagenic exposures in LCINS by examining the cancer genomes of 871 treatment-naive individuals with lung cancer who had never smoked, from 28 geographical locations. KRAS mutations were 3.

A genome-wide in vivo CRISPR activation screen identifies BACE1 as a therapeutic vulnerability of lung cancer brain metastasis.

Brain metastasis occurs in up to 40% of patients with non-small cell lung cancer (NSCLC). Considerable genomic heterogeneity exists between the primary lung tumor and respective brain metastasis; however, the identity of the genes capable of driving brain metastasis is incompletely understood. Here, we carried out an in vivo genome-wide CRISPR activation screen to identify molecular drivers of brain metastasis from an orthotopic xenograft model derived from a patient with NSCLC.

Cancer gene identification from RNA variant allelic frequencies using RVdriver.

Existing approaches to identifying cancer genes rely overwhelmingly on DNA sequencing data. Here, we introduce RVdriver, a computational tool that leverages paired bulk genomic and transcriptomic data to classify RNA variant allele frequencies (VAFs) of non-synonymous mutations relative to a synonymous mutation background. We analyze 7882 paired exomes and transcriptomes from 31 cancer types and identify novel, as well as known, cancer genes, complementing other DNA-based approaches.

ctDNA Analysis in ERBB2-Amplified Colorectal Cancer: Biomarker Analysis of the MyPathway Trial.

Purpose: A combination of two HER2-directed antibodies, pertuzumab and trastuzumab (P + T), has antitumor activity in HER2-positive colorectal cancer. Although liquid biopsies are increasingly being used in clinical oncology, the association between tumor and ctDNA ERBB2 status and ctDNA monitoring for early response and resistance are unknown.

Patients And Methods: Eighty-five patients with ERBB2-amplified and/or -overexpressed colorectal cancer were treated with P + T in the MyPathway trial; 42 had ctDNA testing at cycle (C) 1 day (D) 1, and 38 had longitudinal plasma tested for ctDNA.

Investigation of Influenza A(H5N1) Virus Neutralization by Quadrivalent Seasonal Vaccines, United Kingdom, 2021-2024.

We tested cross-neutralization against highly pathogenic avian influenza A(H5N1) virus in adults vaccinated with 2021-2023 seasonal quadrivalent influenza vaccine in the United Kingdom. Seasonal quadrivalent influenza vaccines are unlikely to protect vulnerable persons against severe H5N1 disease during widespread transmission. Enhanced measures are needed to protect vulnerable people from H5N1 virus infection.

Circulating tumor DNA monitoring and blood tumor mutational burden in patients with metastatic solid tumors treated with atezolizumab.

Immune checkpoint inhibitors are important for treatment across tumor types but are not universally effective in controlling disease. Early understanding of tumor response, or lack thereof, can inform treatment decisions. This study evaluates changes in circulating tumor DNA (ctDNA) and blood tumor mutational burden (bTMB) for associations with response to programmed cell death 1 ligand 1 (PD-L1) blockade.

Clinical referral to the NHS following multi-cancer early detection test results from the NHS-Galleri trial.

Introduction: The large, randomised, controlled NHS-Galleri trial (NCT05611632) is assessing the clinical utility of a multi-cancer early detection (MCED) test for asymptomatic cancer screening in England. We describe how we enabled the efficient referral of trial participants into existing National Health Service (NHS) urgent suspected cancer pathways for diagnostic investigations.

Methods/results: Participants were enrolled across eight of the 21 Cancer Alliance regions in England, served by 56 Hospital Trusts.

FaceAge, a deep learning system to estimate biological age from face photographs to improve prognostication: a model development and validation study.

Background: As humans age at different rates, physical appearance can yield insights into biological age and physiological health more reliably than chronological age. In medicine, however, appearance is incorporated into medical judgements in a subjective and non-standardised way. In this study, we aimed to develop and validate FaceAge, a deep learning system to estimate biological age from easily obtainable and low-cost face photographs.

Tumor-Infiltrating Clonal Hematopoiesis.

Background: Clonal hematopoiesis of indeterminate potential (CHIP) is an age-related condition associated with increased mortality among patients with cancer. CHIP mutations with high variant-allele frequencies can be detected in tumors, a phenomenon we term tumor-infiltrating clonal hematopoiesis (TI-CH). The frequency of TI-CH and its effect on tumor evolution are unclear.

Safety and Activity of Fibroblast Growth Factor Receptor Inhibitors in Advanced Malignancies: A Pooled Analysis of Early-Phase Clinical Trials.

Purpose: Aberrant signaling through the fibroblast growth factor receptor () due to activating somatic alterations has been associated with multiple malignancies. FGFR inhibitors (FGFRi) with distinct profiles recently entered standard of care. This work summarizes the experience of a dedicated clinical trial unit with FGFRi developed in the last decade within the context of clinical trials.

A phase II trial of mTORC1/2 inhibition in STK11 deficient non small cell lung cancer.

There are no current stratified medicine options for STK11-deficient NSCLC. STK11 loss mediates mTORC activation, GLUT1 up-regulation and increased glycolysis. This metabolic reprogramming might represent a therapeutic vulnerability targetable with mTORC1/2 inhibition.

Integrating model systems and genomic insights to decipher mechanisms of cancer metastasis.

Deciphering metastatic processes is crucial for understanding cancer progression and potential treatment options. Genetic studies of model systems engineered to mimic metastatic disease, including organoids, genetically engineered mice and human cell lines, have had an important role in shaping our understanding of the metastatic cascade and how it can be manipulated. More recently, advances in high-throughput sequencing have enabled human metastases to be studied at single-cell and single-nucleotide resolution, providing insights into metastatic evolution and phenotypes of both cancer cells and immune cells.

Accurate evaluation of live-virus microneutralisation for SARS-CoV-2 variant JN.1 in the assessment of vaccination and therapeutics.

Emerging SARS-CoV-2 variants require rapid assessments of pathogenicity and evasion of existing immunity to inform policy. A crucial component of these assessments is accurate estimation of serum neutralising antibody titres using cultured live virus isolates. Here, we report a comparison of culture methods for Omicron sub-variant JN.