Discovery of Cis-Regulatory Mechanisms via Non-Coding Mutations in Acute Lymphoblastic Leukemia.

The non-coding genome, constituting 98% of human DNA, remains largely unexplored, yet holds potential for identifying new biomarkers and therapeutic targets in acute lymphoblastic leukemia (ALL). In this study, we conducted a systematic analysis of recurrent somatic non-coding single nucleotide variants (SNVs) in pediatric B-cell precursor (BCP) ALL. We leveraged whole genome sequencing (WGS) data from 345 pediatric BCP ALL cases, representing all major genetic subtypes and identified 346 mutational hotspots that harbored somatic SNVs in at least three cases.

Clinical and Genomic Predictors of Adverse Events in Newly Diagnosed Glioblastoma.

Purpose: Adverse clinical events cause significant morbidity in patients with GBM (GBM). We examined whether genomic alterations were associated with AE (AE) in patients with GBM.

Experimental Design: We identified adults with histologically confirmed IDH-wild-type GBM with targeted next-generation sequencing (OncoPanel) at Dana Farber Cancer Institute from 2013 to 2019.

Clonal origin and development of high hyperdiploidy in childhood acute lymphoblastic leukaemia.

High hyperdiploid acute lymphoblastic leukemia (HeH ALL), one of the most common childhood malignancies, is driven by nonrandom aneuploidy (abnormal chromosome numbers) mainly comprising chromosomal gains. In this study, we investigate how aneuploidy in HeH ALL arises. Single cell whole genome sequencing of 2847 cells from nine primary cases and one normal bone marrow reveals that HeH ALL generally display low chromosomal heterogeneity, indicating that they are not characterized by chromosomal instability and showing that aneuploidy-driven malignancies are not necessarily chromosomally heterogeneous.

Integrated molecular and clinical analysis of BRAF-mutant glioma in adults.

BRAF mutations are a significant driver of disease in pediatric low-grade glioma, but the implications of BRAF alterations on the clinical course and treatment response in adult glioma remain unclear. Here, we characterize a multi-institutional cohort of more than 300 patients (>200 adults) with BRAF-mutated glioma using clinical, pathological/molecular, and outcome data. We observed that adult and pediatric BRAF-mutant gliomas harbor distinct clinical and molecular features, with a higher prevalence of BRAF (Class I) and BRAF fusions in pediatric tumors.

Posttraumatic stress disorder symptoms associated with protective and risky behaviors for coronavirus disease 2019.

Objective: Psychiatric disorders increase risk for contracting coronavirus disease 2019 (COVID-19), but we know little about relationships between psychiatric symptoms and COVID-19 risky and protective behaviors. Posttraumatic stress disorder (PTSD) has been associated with increased propensity to engage in risky behaviors, but may also be associated with increased COVID-19 protective behaviors due to increased threat sensitivity and social isolation.

Method: We examined associations of PTSD symptoms with COVID-19-related protective and risky behaviors using data from a cross-sectional online United States study among 845 US adults in August through September 2020.

Clusters of COVID-19 protective and risky behaviors and their associations with pandemic, socio-demographic, and mental health factors in the United States.

Individual behaviors are critical for preventing the spread of coronavirus disease 2019 (COVID-19) infection. Given that both protective risky behaviors influence risk of infection, it is critical that we understand how such behaviors cluster together and in whom. Using a data-driven approach, we identified clusters of COVID-19-related protective and risky behaviors and examined associations with socio-demographic, pandemic, and mental health factors.

A molecularly integrated grade for meningioma.

Background: Meningiomas are the most common primary intracranial tumor in adults. Clinical care is currently guided by the World Health Organization (WHO) grade assigned to meningiomas, a 3-tiered grading system based on histopathology features, as well as extent of surgical resection. Clinical behavior, however, often fails to conform to the WHO grade.

Genomic landscape of gliosarcoma: distinguishing features and targetable alterations.

Gliosarcoma is an aggressive brain tumor with histologic features of glioblastoma (GBM) and soft tissue sarcoma. Despite its poor prognosis, its rarity has precluded analysis of its underlying biology. We used a multi-center database to characterize the genomic landscape of gliosarcoma.

The oncogene AAMDC links PI3K-AKT-mTOR signaling with metabolic reprograming in estrogen receptor-positive breast cancer.

Adipogenesis associated Mth938 domain containing (AAMDC) represents an uncharacterized oncogene amplified in aggressive estrogen receptor-positive breast cancers. We uncover that AAMDC regulates the expression of several metabolic enzymes involved in the one-carbon folate and methionine cycles, and lipid metabolism. We show that AAMDC controls PI3K-AKT-mTOR signaling, regulating the translation of ATF4 and MYC and modulating the transcriptional activity of AAMDC-dependent promoters.

Histone H3.3G34-Mutant Interneuron Progenitors Co-opt PDGFRA for Gliomagenesis.

Histone H3.3 glycine 34 to arginine/valine (G34R/V) mutations drive deadly gliomas and show exquisite regional and temporal specificity, suggesting a developmental context permissive to their effects. Here we show that 50% of G34R/V tumors (n = 95) bear activating PDGFRA mutations that display strong selection pressure at recurrence.

Honeybee venom and melittin suppress growth factor receptor activation in HER2-enriched and triple-negative breast cancer.

Despite decades of study, the molecular mechanisms and selectivity of the biomolecular components of honeybee () venom as anticancer agents remain largely unknown. Here, we demonstrate that honeybee venom and its major component melittin potently induce cell death, particularly in the aggressive triple-negative and HER2-enriched breast cancer subtypes. Honeybee venom and melittin suppress the activation of EGFR and HER2 by interfering with the phosphorylation of these receptors in the plasma membrane of breast carcinoma cells.

13q12.2 deletions in acute lymphoblastic leukemia lead to upregulation of FLT3 through enhancer hijacking.

Mutations in the FMS-like tyrosine kinase 3 (FLT3) gene in 13q12.2 are among the most common driver events in acute leukemia, leading to increased cell proliferation and survival through activation of the phosphatidylinositol 3-kinase/AKT-, RAS/MAPK-, and STAT5-signaling pathways. In this study, we examine the pathogenetic impact of somatic hemizygous 13q12.

Rab GTPases: Emerging Oncogenes and Tumor Suppressive Regulators for the Editing of Survival Pathways in Cancer.

The Rab GTPase family of proteins are mediators of membrane trafficking, conferring identity to the cell membranes. Recently, Rab and Rab-associated factors have been recognized as major regulators of the intracellular positioning and activity of signaling pathways regulating cell growth, survival and programmed cell death or apoptosis. Membrane trafficking mediated by Rab proteins is controlled by intracellular localization of Rab proteins, Rab-membrane interactions and GTP-activation processes.

Proteogenomics and Hi-C reveal transcriptional dysregulation in high hyperdiploid childhood acute lymphoblastic leukemia.

Hyperdiploidy, i.e. gain of whole chromosomes, is one of the most common genetic features of childhood acute lymphoblastic leukemia (ALL), but its pathogenetic impact is poorly understood.

Identification of Targetable Lesions in Anaplastic Thyroid Cancer by Genome Profiling.

Anaplastic thyroid cancer (ATC) is a rare and extremely malignant tumor with no available cure. The genetic landscape of this malignancy has not yet been fully explored. In this study, we performed whole exome sequencing and the RNA-sequencing of fourteen cases of ATC to delineate copy number changes, fusion gene events, and somatic mutations.

The uptake of transdermal fentanyl in a pregnant sheep model.

Objective: To evaluate the maternal and foetal uptake of transdermal fentanyl patch applied to the groin of pregnant sheep following surgery.

Study Design: Prospective series.

Animals: A group of 16 singleton pregnant sheep underwent anaesthesia for laparotomy, hysterotomy and instrumentation of the foetus.

Stable Control of Physiological Parameters, But Not Infection, in Preterm Lambs Maintained on Ex Vivo Uterine Environment Therapy.

Ex vivo uterine environment (EVE) therapy is an experimental neonatal intensive care strategy wherein gas exchange is performed by membranous oxygenators attached to the umbilical vessels. Our aim was to assess the ability of a newly refined EVE system to maintain key physiological parameters in preterm lambs within optimal ranges for 48 h. EVE group; n = 6: Preterm lambs were delivered under general anesthesia at 115 ± 2 days of gestational age.