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The incidences of both breast cancer and obesity are rising in the UK. Obesity increases the risk of developing breast cancer in the postmenopausal population and leads to worse outcomes in those of all ages treated for early-stage breast cancer. In this review we explore the multifactorial reasons behind this association and the clinical trial evidence for the benefits of physical activity and dietary interventions in the early and metastatic patient groups. As more people with breast cancer are cured, and those with metastatic disease are living longer, cancer survivorship is becoming increasingly important. Therefore, ensuring the long-term implications of cancer and cancer treatment are addressed is vital. Although there remains a lack of definitive evidence that deliberate weight loss after a diagnosis of breast cancer reduces disease recurrence, a number of studies have reported benefits of weight loss and of physical activity. However, the limited data currently available mean that clinicians remain unclear on the optimal lifestyle advice to give their patients. Further high-quality research is needed to provide this evidence base, which will be required to optimise clinical care and for the commissioning of lifestyle interventions in the UK in breast cancer survivors.

The authors identify 11 discrete genetic subsets of acute myeloid leukemia on the basis of the expression and coexpression of particular mutations. Prospective studies may elucidate distinct approaches to their management. Acute myeloid leukemia (AML) is characterized by clonal expansion of undifferentiated myeloid precursors, resulting in impaired hematopoiesis and bone marrow failure. Although many patients with AML have a response to induction chemotherapy, refractory disease is common, and relapse represents the major cause of treatment failure. 1 Cancer develops from somatically acquired driver mutations, which account for the myriad biologic and clinical complexities of the disease. A classification of cancers that is based on causality is likely to be durable, reproducible, and clinically relevant. This is already evident in the case of AML, for which there has been a progressive shift from . . .

The most common causes of chronic liver disease are excess alcohol intake, viral hepatitis and non-alcoholic fatty liver disease, with the clinical spectrum ranging in severity from hepatic inflammation to cirrhosis, liver failure or hepatocellular carcinoma (HCC). The genome of HCC exhibits diverse mutational signatures, resulting in recurrent mutations across more than 30 cancer genes 1 – 7 . Stem cells from normal livers have a low mutational burden and limited diversity of signatures 8 , which suggests that the complexity of HCC arises during the progression to chronic liver disease and subsequent malignant transformation. Here, by sequencing whole genomes of 482 microdissections of 100–500 hepatocytes from 5 normal and 9 cirrhotic livers, we show that cirrhotic liver has a higher mutational burden than normal liver. Although rare in normal hepatocytes, structural variants, including chromothripsis, were prominent in cirrhosis. Driver mutations, such as point mutations and structural variants, affected 1–5% of clones. Clonal expansions of millimetres in diameter occurred in cirrhosis, with clones sequestered by the bands of fibrosis that surround regenerative nodules. Some mutational signatures were universal and equally active in both non-malignant hepatocytes and HCCs; some were substantially more active in HCCs than chronic liver disease; and others—arising from exogenous exposures—were present in a subset of patients. The activity of exogenous signatures between adjacent cirrhotic nodules varied by up to tenfold within each patient, as a result of clone-specific and microenvironmental forces. Synchronous HCCs exhibited the same mutational signatures as background cirrhotic liver, but with higher burden. Somatic mutations chronicle the exposures, toxicity, regeneration and clonal structure of liver tissue as it progresses from health to disease. Whole-genome sequencing of liver microdissections from five healthy individuals and nine with cirrhosis demonstrates the effects of liver disease on the genome, including increased rates of mutation, complex structural variation and different mutational signatures.

Only a third of patients with depression respond fully to antidepressant medication but little evidence exists regarding the best next-step treatment for those whose symptoms are treatment resistant. The CoBalT trial aimed to examine the effectiveness of cognitive behavioural therapy (CBT) as an adjunct to usual care (including pharmacotherapy) for primary care patients with treatment resistant depression compared with usual care alone. This two parallel-group multicentre randomised controlled trial recruited 469 patients aged 18–75 years with treatment resistant depression (on antidepressants for ≥6 weeks, Beck depression inventory [BDI] score ≥14 and international classification of diseases [ICD]-10 criteria for depression) from 73 UK general practices. Participants were randomised, with a computer generated code (stratified by centre and minimised according to baseline BDI score, whether the general practice had a counsellor, previous treatment with antidepressants, and duration of present episode of depression) to one of two groups: usual care or CBT in addition to usual care, and were followed up for 12 months. Because of the nature of the intervention it was not possible to mask participants, general practitioners, CBT therapists, or researchers to the treatment allocation. Analyses were by intention to treat. The primary outcome was response, defined as at least 50% reduction in depressive symptoms (BDI score) at 6 months compared with baseline. This trial is registered, ISRCTN38231611. Between Nov 4, 2008, and Sept 30, 2010, we assigned 235 patients to usual care, and 234 to CBT plus usual care. 422 participants (90%) were followed up at 6 months and 396 (84%) at 12 months, finishing on Oct 31, 2011. 95 participants (46%) in the intervention group met criteria for response at 6 months compared with 46 (22%) in the usual care group (odds ratio 3·26, 95% CI 2·10–5·06, p<0·001). Before this study, no evidence from large-scale randomised controlled trials was available for the effectiveness of augmentation of antidepressant medication with CBT as a next-step for patients whose depression has not responded to pharmacotherapy. Our study has provided robust evidence that CBT as an adjunct to usual care that includes antidepressants is an effective treatment, reducing depressive symptoms in this population. National Institute for Health Research Health Technology Assessment.

During April-July 2022, outbreaks of severe acute hepatitis of unknown etiology (SAHUE) were reported in 35 countries. Five percent of cases required liver transplantation, and 22 patients died. Viral metagenomic studies of clinical samples from SAHUE cases showed a correlation with human adenovirus F type 41 (HAdV-F41) and adeno-associated virus type 2 (AAV2). To explore the association between those DNA viruses and SAHUE in children in Ireland, we quantified HAdV-F41 and AAV2 in samples collected from a wastewater treatment plant serving 40% of Ireland's population. We noted a high correlation between HAdV-F41 and AAV2 circulation in the community and SAHUE clinical cases. Next-generation sequencing of the adenovirus hexon in wastewater demonstrated HAdV-F41 was the predominant HAdV type circulating. Our environmental analysis showed increased HAdV-F41 and AAV2 prevalence in the community during the SAHUE outbreak. Our findings highlight how wastewater sampling could aid in surveillance for respiratory adenovirus species.

Analysis of publicly available genomic and gene expression data demonstrates that MCL1 expression is frequently elevated in breast cancer. Distinct from other pro-survival Bcl-2 family members, the short half-life of MCL-1 protein led us to investigate MCL-1 protein expression in a breast cancer tissue microarray and correlate this with clinical data. Here, we report associations between high MCL-1 and poor prognosis in specific subtypes of breast cancer including triple-negative breast cancer, an aggressive form that lacks targeted treatment options. Deletion of MCL-1 in the mammary epithelium of genetically engineered mice revealed an absolute requirement for MCL-1 in breast tumorigenesis. The clinical applicability of these findings was tested through a combination of approaches including knock-down or inhibition of MCL-1 to show triple-negative breast cancer cell line dependence on MCL-1 in vitro and in vivo . Our data demonstrate that high MCL-1 protein expression is associated with poor outcome in breast cancer and support the therapeutic targeting of MCL-1 in this disease.

[...]public deposition of omics data is on the increase. In 2016, a group of researchers, publishers and research funders published the first guidelines to make data “findable, accessible, interoperable and re-usable” (FAIR; https://www.force11.org/group/fairgroup/fairprinciples)3. [See PDF for image] Figure 2 Distributions of OmicsDI data sets. (a) Distribution of data sets per omics type and organism category including model organisms, non-model organisms (excluding human) and human. (b) The data set view showing the other related omics data sets, including the ontology-highlighting option to extract the most relevant terms in the metadata. (c) Pearson-correlation plot of the metadata similarity score and the biological similarity score, across transcriptomics (T), proteomics (P) and metabolomics (M) data sets. (d) The shared molecules box shows all data sets with a biological similarity score of more than 0.5, with a slider allowing a user to increase the cutoff value (here set to 0.81). [...]the publication associated with a data set can be used to link data sets that are deposited in different repositories.

Peter Campbell, Mel Greaves and colleagues use exome and whole-genome sequencing to characterize somatic mutations in childhood acute lymphoblastic leukemias with the ETV6 - RUNX1 fusion gene. They find that RAG-mediated deletions are the dominant mutational process. The ETV6 - RUNX1 fusion gene, found in 25% of childhood acute lymphoblastic leukemia (ALL) cases, is acquired in utero but requires additional somatic mutations for overt leukemia. We used exome and low-coverage whole-genome sequencing to characterize secondary events associated with leukemic transformation. RAG-mediated deletions emerge as the dominant mutational process, characterized by recombination signal sequence motifs near breakpoints, incorporation of non-templated sequence at junctions, ∼30-fold enrichment at promoters and enhancers of genes actively transcribed in B cell development and an unexpectedly high ratio of recurrent to non-recurrent structural variants. Single-cell tracking shows that this mechanism is active throughout leukemic evolution, with evidence of localized clustering and reiterated deletions. Integration of data on point mutations and rearrangements identifies ATF7IP and MGA as two new tumor-suppressor genes in ALL. Thus, a remarkably parsimonious mutational process transforms ETV6 - RUNX1 –positive lymphoblasts, targeting the promoters, enhancers and first exons of genes that normally regulate B cell differentiation.

Ischemic stroke, brain tissue infarction following obstructed cerebral blood flow, leads to long-term neurological deficits and death. While neocortex is a commonly affected region with established preclinical models, less is known about deeper brain strokes, despite having unique neurological outcomes. We induced focal ischemic stroke while simultaneously monitoring neuronal activity in awake behaving Thy1-GCaMP6f mice by delivering and collecting light through bilateral fiberoptic implants. Unilateral hippocampal stroke resulted in atypical wandering behavior coincident with ipsilesional terminal spreading depolarization (sustained increase in GCaMP6f fluorescence). Ischemia induced seizures that propagated to the contralesional hippocampus triggering a transient spreading depolarization, predominantly in females. Hippocampal stroke impaired contextual fear conditioning acquired pre-stroke. Yet, 7 days post-stroke, contextual fear conditioning was only improved in mice with contralesional spreading depolarization. Blunting peri-stroke contralesional spreading depolarization prevented recovery of hippocampus-dependent learning. Together, we show that regionally isolated deleterious and beneficial spreading depolarizations can occur concurrently in the murine brain during acute stroke. Neural mechanisms underlying deep brain strokes are not fully understood. Here authors demonstrate that spreading depolarizations occur in the intact contralesional hippocampus during unilateral stroke. These spreading depolarizations are more common in female mice and allow preservation of hippocampus-dependent learning.