The generation of stable microvessels in ischemia is mediated by endothelial cell derived TRAIL.

Reversal of ischemia is mediated by neo-angiogenesis requiring endothelial cell (EC) and pericyte interactions to form stable microvascular networks. We describe an unrecognized role for tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) in potentiating neo-angiogenesis and vessel stabilization. We show that the endothelium is a major source of TRAIL in the healthy circulation compromised in peripheral artery disease (PAD).

Publisher Correction: Novel immunotherapeutics against LGR5 to target multiple cancer types.

[Image: see text]

Novel immunotherapeutics against LGR5 to target multiple cancer types.

We have developed and validated a highly specific, versatile antibody to the extracellular domain of human LGR5 (α-LGR5). α-LGR5 detects LGR5 overexpression in >90% of colorectal cancer (CRC), hepatocellular carcinoma (HCC) and pre-B-ALL tumour cells and was used to generate an Antibody-Drug Conjugate (α-LGR5-ADC), Bispecific T-cell Engager (α-LGR5-BiTE) and Chimeric Antigen Receptor (α-LGR5-CAR). α-LGR5-ADC was the most effective modality for targeting LGR5 cancer cells in vitro and demonstrated potent anti-tumour efficacy in a murine model of human NALM6 pre-B-ALL driving tumour attrition to less than 1% of control treatment.

Titration of RAS alters senescent state and influences tumour initiation.

Oncogenic RAS-induced senescence (OIS) is an autonomous tumour suppressor mechanism associated with premalignancy. Achieving this phenotype typically requires a high level of oncogenic stress, yet the phenotype provoked by lower oncogenic dosage remains unclear. Here we develop oncogenic RAS dose-escalation models in vitro and in vivo, revealing a RAS dose-driven non-linear continuum of downstream phenotypes.

Strand-resolved mutagenicity of DNA damage and repair.

DNA base damage is a major source of oncogenic mutations. Such damage can produce strand-phased mutation patterns and multiallelic variation through the process of lesion segregation. Here we exploited these properties to reveal how strand-asymmetric processes, such as replication and transcription, shape DNA damage and repair.

DNA lesion bypass and the stochastic dynamics of transcription-coupled repair.

DNA base damage is a major source of oncogenic mutations and disruption to gene expression. The stalling of RNA polymerase II (RNAP) at sites of DNA damage and the subsequent triggering of repair processes have major roles in shaping the genome-wide distribution of mutations, clearing barriers to transcription, and minimizing the production of miscoded gene products. Despite its importance for genetic integrity, key mechanistic features of this transcription-coupled repair (TCR) process are controversial or unknown.

Single-mitosis dissection of acute and chronic DNA mutagenesis and repair.

How chronic mutational processes and punctuated bursts of DNA damage drive evolution of the cancer genome is poorly understood. Here, we demonstrate a strategy to disentangle and quantify distinct mechanisms underlying genome evolution in single cells, during single mitoses and at single-strand resolution. To distinguish between chronic (reactive oxygen species (ROS)) and acute (ultraviolet light (UV)) mutagenesis, we microfluidically separate pairs of sister cells from the first mitosis following burst UV damage.

Prescriber decision-making on antithrombotic therapy after endovascular intervention for peripheral artery disease: a protocol for a discrete choice experiment.

Introduction: Peripheral artery disease (PAD) is a major risk factor for cardiovascular morbidity and mortality, despite surgical and endovascular treatments. Emerging evidence supports the use of immediate antithrombotic medications after endovascular intervention for PAD, however, there is a lack of consensus regarding choice and duration of antithrombotic therapy. Prescriber decision-making is a complex process, with prior studies demonstrating patient factors can influence variability in antithrombotic therapy for PAD.

The prevalent causes of death in patients with peripheral artery disease undergoing revascularisation or amputation.

Objective: Preventing untimely death in patients with peripheral artery disease (PAD) requires a detailed understanding of the predominant causes of death (COD). This literature review aims to describe how short- and long-term COD are reported in patients who had surgery for PAD.

Methods: A literature review was conducted according to Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) guidelines for articles reporting specific causes of mortality in patients who had surgery for all stages of PAD.

The artificial intelligence-based model ANORAK improves histopathological grading of lung adenocarcinoma.

The introduction of the International Association for the Study of Lung Cancer grading system has furthered interest in histopathological grading for risk stratification in lung adenocarcinoma. Complex morphology and high intratumoral heterogeneity present challenges to pathologists, prompting the development of artificial intelligence (AI) methods. Here we developed ANORAK (pyrAmid pooliNg crOss stReam Attention networK), encoding multiresolution inputs with an attention mechanism, to delineate growth patterns from hematoxylin and eosin-stained slides.

Sex, Endothelial Cell Functions, and Peripheral Artery Disease.

Peripheral artery disease (PAD) is caused by blocked arteries due to atherosclerosis and/or thrombosis which reduce blood flow to the lower limbs. It results in major morbidity, including ischemic limb, claudication, and amputation, with patients also suffering a heightened risk of heart attack, stroke, and death. Recent studies suggest women have a higher prevalence of PAD than men, and with worse outcomes after intervention.

Cancer Evolution: A Multifaceted Affair.

Unlabelled: Cancer cells adapt and survive through the acquisition and selection of molecular modifications. This process defines cancer evolution. Building on a theoretical framework based on heritable genetic changes has provided insights into the mechanisms supporting cancer evolution.

Optimising Medications in Older Vascular Surgery Patients Through Geriatric Co-management.

Background: Prescribing of potentially inappropriate medications and under-prescribing of guideline-recommended medications for cardiovascular risk modification have both been associated with negative outcomes in older adults. Hospitalisation represents an important opportunity to optimise medication use and may be achieved through geriatrician-led interventions.

Objective: We aimed to evaluate whether implementation of a novel model of care called Geriatric Comanagement of older Vascular (GeriCO-V) surgery patients is associated with improvements in medication prescribing.

The experience of hospital care for older surgical patients and their carers: A mixed-methods study.

Objective: A growing proportion of older adults are undergoing surgery, but there is a paucity of patient and carer experience research in this group. This study investigated the experience of hospital care in an older vascular surgery population for patients and their carers.

Methods: This was a mixed-methods convergent design, including simultaneous collection of quantitative and qualitative research strands by combining open-ended questions with rating scales in a questionnaire.

Protocol for a qualitative study exploring haemodialysis dependent patients' arteriovenous fistula experience, values and concerns in Sydney, Australia.

Introduction: The experiences of patients from culturally and linguistically diverse backgrounds, with chronic mental illness, disabilities or who identify as sexual or religious minorities are under-represented in clinical research on arteriovenous fistula (AVF) for haemodialysis access. A greater understanding of the experiences, values and concerns of these diverse patient groups are needed to provide haemodialysis access care that addresses the needs of all haemodialysis-dependent patients. This study seeks to describe a broad range of patient experiences related to the creation, care and surveillance of AVFs, including interactions with healthcare teams.

Timing of minor and major amputation in patients with diabetes-related foot ulceration admitted to two public tertiary referral hospitals in Australia.

Background: There is limited information regarding the number of patients with diabetes-related foot ulceration (DFU) who receive minor or major amputation, and how quickly these amputations occur. This study aimed to identify the incidence of index minor and major amputation among inpatients with DFU over 4 years, and where amputation occurred during the patient's index DFU-related admission, investigate prognostic factors.

Methods: The incidence of index minor and major amputation, and the admission sequence during which amputation occurred were identified from DFU-related admissions to two public hospitals during 2014-2018.

Coagulation factor V is a T-cell inhibitor expressed by leukocytes in COVID-19.

Clotting Factor V (FV) is primarily synthesized in the liver and when cleaved by thrombin forms pro-coagulant Factor Va (FVa). Using whole blood RNAseq and scRNAseq of peripheral blood mononuclear cells, we find that FV mRNA is expressed in leukocytes, and identify neutrophils, monocytes, and T regulatory cells as sources of increased FV in hospitalized patients with COVID-19. Proteomic analysis confirms increased FV in circulating neutrophils in severe COVID-19, and immunofluorescence microscopy identifies FV in lung-infiltrating leukocytes in COVID-19 lung disease.

Geriatric Comanagement of Older Vascular Surgery Inpatients Reduces Hospital-Acquired Geriatric Syndromes.

Objective: This study evaluates the impact of a novel model of care called Geriatric Comanagement of Older Vascular surgery inpatients on clinical outcomes.

Design, Setting, And Participants: A pre-post study of geriatric comanagement, comparing prospectively recruited preintervention (February-October 2019) and prospectively recruited postintervention (January-December 2020) cohorts. Consecutively admitted vascular surgery patients age ≥65 years at a tertiary academic hospital in Concord and with an expected length of stay (LOS) greater than 2 days were recruited.