Increased nuclear factor I-mediated chromatin access drives transition to androgen receptor splice variant dependence in prostate cancer.

Androgen receptor (AR) splice variants, of which ARv7 is the most common, are increased in castration-resistant prostate cancer, but the extent to which they drive AR activity is unclear. We generated a subline of VCaP cells (VCaP16) that is resistant to the AR inhibitor enzalutamide (ENZ). AR activity in VCaP16 is driven by ARv7, independently of full-length AR (ARfl), and its cistrome and transcriptome mirror those of ARfl in VCaP cells.

Efficacy and Safety of Filgotinib in Rheumatoid Arthritis Patients Aged over and under 65 Years (ENANTIA-65).

Background: According to recent data, the age of patients could represent an important risk factor for MACE (major cardiovascular events), cancer, and VTE (venous thromboembolism) during treatment with JAK inhibitors in rheumatoid arthritis. We decided to analyze the population involved in the ReLiFiRa study by identifying two groups of patients: 65 years or more and less than 65 years of age, evaluating the efficacy and tolerability of 200 mg of Filgotinib daily.

Methods: Of the 120 ReLiFiRa patients, 54 were younger than 65 years old and 66 patients were 65 years old or older.

Predictions of Colloidal Molecular Aggregation Using AI/ML Models.

To facilitate the triage of hits from small molecule screens, we have used various AI/ML techniques and experimentally observed data sets to build models aimed at predicting colloidal aggregation of small organic molecules in aqueous solution. We have found that Naïve Bayesian and deep neural networks outperform logistic regression, recursive partitioning tree, support vector machine, and random forest techniques by having the lowest balanced error rate (BER) for the test set. Derived predictive classification models consistently and successfully discriminated aggregator molecules from nonaggregator hits.

A noncoding regulatory variant in IKZF1 increases acute lymphoblastic leukemia risk in Hispanic/Latino children.

Hispanic/Latino children have the highest risk of acute lymphoblastic leukemia (ALL) in the US compared to other racial/ethnic groups, yet the basis of this remains incompletely understood. Through genetic fine-mapping analyses, we identified a new independent childhood ALL risk signal near IKZF1 in self-reported Hispanic/Latino individuals, but not in non-Hispanic White individuals, with an effect size of ∼1.44 (95% confidence interval = 1.

Thio-2 Inhibits Key Signaling Pathways Required for the Development and Progression of Castration-resistant Prostate Cancer.

Therapies that abrogate persistent androgen receptor (AR) signaling in castration-resistant prostate cancer (CRPC) remain an unmet clinical need. The N-terminal domain of the AR that drives transcriptional activity in CRPC remains a challenging therapeutic target. Herein we demonstrate that BCL-2-associated athanogene-1 (BAG-1) mRNA is highly expressed and associates with signaling pathways, including AR signaling, that are implicated in the development and progression of CRPC.

Unique Capabilities of Genome Sequencing for Rare Disease Diagnosis.

Background: Causal variants underlying rare disorders may remain elusive even after expansive gene panels or exome sequencing (ES). Clinicians and researchers may then turn to genome sequencing (GS), though the added value of this technique and its optimal use remain poorly defined. We therefore investigated the advantages of GS within a phenotypically diverse cohort.

Increased chromatin accessibility mediated by nuclear factor I drives transition to androgen receptor splice variant dependence in castration-resistant prostate cancer.

Androgen receptor (AR) splice variants, of which ARv7 is the most common, are increased in prostate cancer (PC) that develops resistance to androgen signaling inhibitor drugs, but the extent to which these variants drive AR activity, and whether they have novel functions or dependencies, remain to be determined. We generated a subline of VCaP PC cells (VCaP16) that is resistant to the AR inhibitor enzalutamide (ENZ) and found that AR activity was independent of the full-length AR (ARfl), despite its continued high-level expression, and was instead driven by ARv7. The ARv7 cistrome and transcriptome in VCaP16 cells mirrored that of the ARfl in VCaP cells, although ARv7 chromatin binding was weaker, and strong ARv7 binding sites correlated with higher affinity ARfl binding sites across multiple models and clinical samples.

Inherited blood cancer predisposition through altered transcription elongation.

Despite advances in defining diverse somatic mutations that cause myeloid malignancies, a significant heritable component for these cancers remains largely unexplained. Here, we perform rare variant association studies in a large population cohort to identify inherited predisposition genes for these blood cancers. CTR9, which encodes a key component of the PAF1 transcription elongation complex, is among the significant genes identified.

Low Carbohydrate, High Fat Diet Alters the Oral Microbiome without Negating the Nitrite Response to Beetroot Juice Supplementation.

A low carbohydrate, high fat (LCHF) diet in athletes increases fat oxidation but impairs sports performance, potentially due to impaired exercise economy. Dietary nitrate supplementation can improve exercise economy via an increase in nitric oxide production, which is initiated by the reduction of nitrate to nitrite within the oral cavity. This reaction is dependent on the presence of nitrate-reducing oral bacteria, which can potentially be altered by dietary changes, including a LCHF diet.

ReLiFiRa (Real Life Filgotinib in Rheumatoid Arthritis): Retrospective Study of Efficacy and Safety in Common Clinical Practice.

Background: Filgotinib (FIL) is a selective JAK1 inhibitor with an affinity 30-fold higher than JAK2, approved to treat moderate to severe active rheumatoid arthritis (RA), in adults with inadequate response or intolerance to one or more disease-modifying antirheumatic drugs (DMARDs).

Methods: We conducted a retrospective, multicentric study in order to evaluate efficacy and safety of FIL 200 mg daily therapy, after 3 and 6 months, in 120 patients affected by RA, managed in Tuscany and Umbria rheumatological centers. The following clinical records were analyzed: demographical data, smoking status, previous presence of comorbidities (Herpes zoster -HZ- infection, venous thromboembolism -VTE-, major adverse cardiovascular events -MACE-, cancer, diabetes, and hypertension), disease duration, presence of anti-citrullinated protein antibodies (ACPA), rheumatoid factor (RF), number of biological failures, and prior csDMARDs utilized.

Shared and distinct genetic etiologies for different types of clonal hematopoiesis.

Clonal hematopoiesis (CH)-age-related expansion of mutated hematopoietic clones-can differ in frequency and cellular fitness by CH type (e.g., mutations in driver genes (CHIP), gains/losses and copy-neutral loss of chromosomal segments (mCAs), and loss of sex chromosomes).

Identification of an Imidazopyridine-based Compound as an Oral Selective Estrogen Receptor Degrader for Breast Cancer Therapy.

Unlabelled: The pro-oncogenic activities of estrogen receptor alpha (ERα) drive breast cancer pathogenesis. Endocrine therapies that impair the production of estrogen or the action of the ERα are therefore used to prevent primary disease metastasis. Although recent successes with ERα degraders have been reported, there is still the need to develop further ERα antagonists with additional properties for breast cancer therapy.

A genetic disorder reveals a hematopoietic stem cell regulatory network co-opted in leukemia.

The molecular regulation of human hematopoietic stem cell (HSC) maintenance is therapeutically important, but limitations in experimental systems and interspecies variation have constrained our knowledge of this process. Here, we have studied a rare genetic disorder due to MECOM haploinsufficiency, characterized by an early-onset absence of HSCs in vivo. By generating a faithful model of this disorder in primary human HSCs and coupling functional studies with integrative single-cell genomic analyses, we uncover a key transcriptional network involving hundreds of genes that is required for HSC maintenance.

AR Structural Variants and Prostate Cancer.

Therapeutic interventions for advanced castration-resistant prostate cancer (CRPC) are focused on inhibiting the androgen receptor (AR) through targeting of its C-terminal ligand binding domain (LBD). However, a significant subset of CRPC patients demonstrate primary resistance to androgen deprivation and anti-androgen therapies, suggesting that other targets, outside of the AR, might be pertinent to the cancer progression. One explanation is the expression of androgen receptor splice variants (AR-Vs).

Variant to function mapping at single-cell resolution through network propagation.

Genome-wide association studies in combination with single-cell genomic atlases can provide insights into the mechanisms of disease-causal genetic variation. However, identification of disease-relevant or trait-relevant cell types, states and trajectories is often hampered by sparsity and noise, particularly in the analysis of single-cell epigenomic data. To overcome these challenges, we present SCAVENGE, a computational algorithm that uses network propagation to map causal variants to their relevant cellular context at single-cell resolution.

A chemical probe for BAG1 targets androgen receptor-positive prostate cancer through oxidative stress signaling pathway.

BAG1 is a family of polypeptides with a conserved C-terminal BAG domain that functions as a nucleotide exchange factor for the molecular chaperone HSP70. BAG1 proteins also control several signaling processes including proteostasis, apoptosis, and transcription. The largest isoform, BAG1L, controls the activity of the androgen receptor (AR) and is upregulated in prostate cancer.

Variant to function mapping at single-cell resolution through network propagation.

With burgeoning human disease genetic associations and single-cell genomic atlases covering a range of tissues, there are unprecedented opportunities to systematically gain insights into the mechanisms of disease-causal variation. However, sparsity and noise, particularly in the context of single-cell epigenomic data, hamper the identification of disease- or trait-relevant cell types, states, and trajectories. To overcome these challenges, we have developed the SCAVENGE method, which maps causal variants to their relevant cellular context at single-cell resolution by employing the strategy of network propagation.

Clonal hematopoiesis in sickle cell disease.

BACKGROUNDCurative gene therapies for sickle cell disease (SCD) are currently undergoing clinical evaluation. The occurrence of myeloid malignancies in these trials has prompted safety concerns. Individuals with SCD are predisposed to myeloid malignancies, but the underlying causes remain undefined.

Heparin resistance in severe thermal injury: A prospective cohort study.

Background: Low molecular-weight heparin (LMWH) is routinely administered to burn patients for thromboprophylaxis. Some studies have reported heparin resistance, yet the mechanism(s) and prevalence have not been systematically studied. We hypothesized that nucleosomes, composed of histone structures with associated DNA released from injured tissue and activated immune cells in the form of neutrophil extracellular traps (NETs or NETosis), neutralize LMWH resulting in suboptimal anticoagulation, assessed by reduction in anti-factor Xa activity.

Changes in Burn Wound Microbiology Profile Over 14 Years of an Adult Tertiary Burn Center.

Burn wound colonization can progress to invasive infection. During 14 years of this study, the burn center was relocated to a center with improved infrastructure. This study investigates the association that infrastructure, geography, and time may have on colonization.

A single-centre ten-year retrospective cohort study of malignant small bowel obstruction.

Introduction: Management of malignant small bowel obstruction (mSBO) is challenging. The decision to perform an operation evaluates the perceived chance of success against a patient's fitness for operation. The aim of this study was to characterise the mSBO patient population in a tertiary UK centre and assess the patient's treatment pathway including use and effects of palliative surgery, total parenteral nutrition (TPN), Gastrografin and dexamethasone as well as preoperative stratification.

Androgen receptor splice variant 7 functions independently of the full length receptor in prostate cancer cells.

One mechanism for reactivation of androgen receptor (AR) activity after androgen deprivation therapy in castration-resistant prostate cancer (CRPC) is expression of splice variants such as ARv7 that delete the ligand binding domain and have constitutive activity. Exogenous overexpressed ARv7 can function as a homodimer or heterodimer with full length AR (ARfl), which is highly expressed with ARv7 in CRPC. However, the extent to which endogenous ARv7 function is dependent on heterodimerization with ARfl remains to be determined.

Inpatient burden and mortality of heatstroke in the United States.

Background: This study aimed to assess inpatient prevalence, characteristics, outcomes, and resource utilisation of hospitalisation for heatstroke in the United States. Additionally, this study aimed to explore factors associated with in-hospital mortalities of heatstroke.

Methods: The 2003-2014 National Inpatient Sample database was used to identify hospitalised patients with a principal diagnosis of heatstroke.