Effects of Neoadjuvant Radiation and Recipient Vessel Characteristics on Microvascular Complication Rates in Reconstruction of Lower Extremity Soft Tissue Sarcoma Defects.

Background:  The treatment approach for soft tissue sarcomas (STS) of the lower extremity has shifted toward the use of neoadjuvant radiation combined with limb-sparing surgery (LSS). The resulting defects often require reconstruction with free tissue transfer for adequate outcomes. Data have demonstrated a potentially increased risk of microvascular complications for free flaps performed using irradiated recipient vessels.

Time to treatment and disability attributed to index stroke in the POINT trial.

Background: In the Platelet-Oriented Inhibition in New TIA and Minor Ischemic Stroke (POINT) trial, dual antiplatelet therapy (DAPT) was associated with reduced disability attributable to the index stroke compared to antiplatelet monotherapy. However, it is unknown whether earlier treatment with DAPT versus aspirin is associated with greater benefit.

Methods: We analyzed patients enrolled in POINT with minor ischemic stroke who had available data recording the treatment initiation time and modified Rankin Scale (mRS) at 90 days.

SJPedPanel: A Pan-Cancer Gene Panel for Childhood Malignancies to Enhance Cancer Monitoring and Early Detection.

Purpose: The purpose of the study was to design a pan-cancer gene panel for childhood malignancies and validate it using clinically characterized patient samples.

Experimental Design: In addition to 5,275 coding exons, SJPedPanel also covers 297 introns for fusions/structural variations and 7,590 polymorphic sites for copy-number alterations. Capture uniformity and limit of detection are determined by targeted sequencing of cell lines using dilution experiment.

Race and Ethnicity, Socioeconomic Factors, and Epigenetic Age Acceleration in Survivors of Childhood Cancer.

Importance: Current research in epigenetic age acceleration (EAA) is limited to non-Hispanic White individuals. It is imperative to improve inclusivity by considering racial and ethnic minorities in EAA research.

Objective: To compare non-Hispanic Black with non-Hispanic White survivors of childhood cancer by examining the associations of EAA with cancer treatment exposures, potential racial and ethnic disparity in EAA, and mediating roles of social determinants of health (SDOH).

Colchicine in patients with acute ischaemic stroke or transient ischaemic attack (CHANCE-3): multicentre, double blind, randomised, placebo controlled trial.

Objectives: To assess the efficacy and safety of colchicine versus placebo on reducing the risk of subsequent stroke after high risk non-cardioembolic ischaemic stroke or transient ischaemic attack within the first three months of symptom onset (CHANCE-3).

Design: Multicentre, double blind, randomised, placebo controlled trial.

Setting: 244 hospitals in China between 11 August 2022 and 13 April 2023.

Bone morphogenetic protein (BMP) signaling determines neuroblastoma cell fate and sensitivity to retinoic acid.

Retinoic acid (RA) is a standard-of-care neuroblastoma drug thought to be effective by inducing differentiation. Curiously, RA has little effect on primary human tumors during upfront treatment but can eliminate neuroblastoma cells from the bone marrow during post-chemo consolidation therapy-a discrepancy that has never been explained. To investigate this, we treated a large cohort of neuroblastoma cell lines with RA and observed that the most RA-sensitive cells predominantly undergo apoptosis or senescence, rather than differentiation.

An integrated single-cell RNA-seq map of human neuroblastoma tumors and preclinical models uncovers divergent mesenchymal-like gene expression programs.

Neuroblastoma is a common pediatric cancer, where preclinical studies suggest that a mesenchymal-like gene expression program contributes to chemotherapy resistance. However, clinical outcomes remain poor, implying we need a better understanding of the relationship between patient tumor heterogeneity and preclinical models. Here, we generated single-cell RNA-seq maps of neuroblastoma cell lines, patient-derived xenograft models (PDX), and a genetically engineered mouse model (GEMM).

Associations between mitochondrial copy number, exercise capacity, physiologic cost of walking, and cardiac strain in young adult survivors of childhood cancer.

Purpose: Childhood cancer survivors are at risk for cardiac dysfunction and impaired physical performance, though underlying cellular mechanisms are not well studied. In this cross-sectional study, we examined the association between peripheral blood mitochondrial DNA copy number (mtDNA-CN, a proxy for mitochondrial function) and markers of performance impairment and cardiac dysfunction.

Methods: Whole-genome sequencing, validated by quantitative polymerase chain reaction, was used to estimate mtDNA-CN in 1720 adult survivors of childhood cancer (48.

Conditional c-MYC activation in catecholaminergic cells drives distinct neuroendocrine tumors: neuroblastoma vs somatostatinoma.

The MYC proto-oncogenes (c-MYC, , ) are among the most deregulated oncogenic drivers in human malignancies including high-risk neuroblastoma, 50% of which are -amplified. Genetically engineered mouse models (GEMMs) based on the transgene have greatly expanded the understanding of neuroblastoma biology and are powerful tools for testing new therapies. However, a lack of c-MYC-driven GEMMs has hampered the ability to better understand mechanisms of neuroblastoma oncogenesis and therapy development given that c-MYC is also an important driver of many high-risk neuroblastomas.

Identification and Development of Cyclic Peptide Inhibitors of Hypoxia Inducible Factors 1 and 2 That Disrupt Hypoxia-Response Signaling in Cancer Cells.

Hypoxia inducible factor (HIF) is a heterodimeric transcription factor composed of an oxygen-regulated α subunit and a constitutively expressed β subunit that serves as the master regulator of the cellular response to low oxygen concentrations. The HIF transcription factor senses and responds to hypoxia by significantly altering transcription and reprogramming cells to enable adaptation to a hypoxic microenvironment. Given the central role played by HIF in the survival and growth of tumors in hypoxia, inhibition of this transcription factor serves as a potential therapeutic approach for treating a variety of cancers.

Health-related quality of life and DNA methylation-based aging biomarkers among survivors of childhood cancer.

Background: Childhood cancer survivors are at high risk for morbidity and mortality and poor patient-reported outcomes, typically health-related quality of life (HRQOL). However, associations between DNA methylation-based aging biomarkers and HRQOL have not been evaluated.

Methods: DNA methylation was generated with Infinium EPIC BeadChip on blood-derived DNA (median for age at blood draw = 34.

Baseline Stroke Risk and Efficacy of Dual-Antiplatelet Therapy: A Post Hoc Analysis of the POINT Trial.

Background: High-risk transient ischemic attacks and minor ischemic strokes are followed by a variable risk of ischemic stroke. We aimed to determine how baseline stroke risk modified the efficacy of clopidogrel-aspirin (referred to here as dual-antiplatelet therapy [DAPT]) for transient ischemic attack and minor ischemic stroke.

Methods: We performed an unplanned secondary analysis of the POINT trial (Platelet-Oriented Inhibition in New Transient Ischemic Attack and Minor Ischemic Stroke).

SJPedPanel: A pan-cancer gene panel for childhood malignancies.

Background: Large scale genomics projects have identified driver alterations for most childhood cancers that provide reliable biomarkers for clinical diagnosis and disease monitoring using targeted sequencing. However, there is lack of a comprehensive panel that matches the list of known driver genes. Here we fill this gap by developing SJPedPanel for childhood cancers.

A CRISPR-drug perturbational map for identifying compounds to combine with commonly used chemotherapeutics.

Combination chemotherapy is crucial for successfully treating cancer. However, the enormous number of possible drug combinations means discovering safe and effective combinations remains a significant challenge. To improve this process, we conduct large-scale targeted CRISPR knockout screens in drug-treated cells, creating a genetic map of druggable genes that sensitize cells to commonly used chemotherapeutics.

Integrome signatures of lentiviral gene therapy for SCID-X1 patients.

Lentiviral vector (LV)-based gene therapy holds promise for a broad range of diseases. Analyzing more than 280,000 vector integration sites (VISs) in 273 samples from 10 patients with X-linked severe combined immunodeficiency (SCID-X1), we discovered shared LV integrome signatures in 9 of 10 patients in relation to the genomics, epigenomics, and 3D structure of the human genome. VISs were enriched in the nuclear subcompartment A1 and integrated into super-enhancers close to nuclear pore complexes.

Cancer germline predisposing variants and late mortality from subsequent malignant neoplasms among long-term childhood cancer survivors: a report from the St Jude Lifetime Cohort and the Childhood Cancer Survivor Study.

Background: Carriers of cancer predisposing variants are at an increased risk of developing subsequent malignant neoplasms among those who have survived childhood cancer. We aimed to investigate whether cancer predisposing variants contribute to the risk of subsequent malignant neoplasm-related late mortality (5 years or more after diagnosis).

Methods: In this analysis, data were included from two retrospective cohort studies, St Jude Lifetime Cohort (SJLIFE) and the Childhood Cancer Survivor Study (CCSS), with prospective follow-up of patients who were alive for at least 5 years after diagnosis with childhood cancer (ie, long-term childhood cancer survivors) with corresponding germline whole genome or whole exome sequencing data.

Autocrine IL-6 drives cell and extracellular matrix anisotropy in scar fibroblasts.

Fibrosis is associated with dramatic changes in extracellular matrix (ECM) architecture of unknown etiology. Here we exploit keloid scars as a paradigm to understand fibrotic ECM organization. We reveal that keloid patient fibroblasts uniquely produce a globally aligned ECM network in 2-D culture as observed in scar tissue.

Chitosan Sponges Are Associated With Higher Rates of Wound Complications Compared to Calcium Sulfate Beads.

Background In this study, we aimed to determine if there is a difference in the rates of wound dehiscence, delayed union, nonunion, and unanticipated surgery after the use of bioabsorbable local antibiotic-delivery systems (LADS), specifically comparing antibiotic-impregnated calcium sulfate pellets (Osteoset-T, Wright Medical Technology Inc., Arlington, TN, USA, hereafter referred to as beads) and chitosan sponge (Sentrex BioSponge, Bionova Medical, Germantown, TN, USA, hereafter referred to as sponges) in the management of acute and chronic extremity wounds. Methodology We conducted a retrospective comparative cohort study in the setting of a level 1 trauma center.

Epigenetic Age in Peripheral Blood Among Children, Adolescent, and Adult Survivors of Childhood Cancer.

Importance: Certain cancer therapies are risk factors for epigenetic age acceleration (EAA) among survivors of childhood cancer, and EAA is associated with chronic health conditions (CHCs). However, small numbers of younger survivors (aged <20 years) previously evaluated have limited the ability to calculate EAA among this age group.

Objective: To evaluate the change rate of epigenetic age (EA) and EAA in younger compared with older survivors and the possible association of EAA with early-onset obesity (aged <20 years), severity/burden of CHCs, and late mortality (>5 years from cancer diagnosis).