Strategies to improve access to physical activity opportunities for people with physical disabilities.

Community-based physical activity opportunities have been shown to help adults with physical disabilities improve their participation in daily activities and reduce social isolation. Despite the known benefits, substantial barriers and challenges inhibit accessibility to these physical activity opportunities. To facilitate the co-construction of strategies to overcome accessibility issues pertaining to community-based physical activity opportunities.

MOZ and Menin-MLL Complexes Are Complementary Regulators of Chromatin Association and Transcriptional Output in Gastrointestinal Stromal Tumor.

Unlabelled: Gastrointestinal stromal tumor (GIST) is commonly characterized by activating mutations in the receptor tyrosine kinase KIT. Tyrosine kinase inhibitors are the only approved therapy for GIST, and complementary treatment strategies are urgently needed. As GIST lacks oncogene amplification and relies upon an established network of transcription factors, we hypothesized that unique chromatin-modifying enzymes are essential in orchestrating the GIST epigenome.

Preclinical Modeling of Leiomyosarcoma Identifies Susceptibility to Transcriptional CDK Inhibitors through Antagonism of E2F-Driven Oncogenic Gene Expression.

Purpose: Leiomyosarcoma (LMS) is a neoplasm characterized by smooth muscle differentiation, complex copy-number alterations, tumor suppressor loss, and the absence of recurrent driver mutations. Clinical management for advanced disease relies on the use of empiric cytotoxic chemotherapy with limited activity, and novel targeted therapies supported by preclinical research on LMS biology are urgently needed. A lack of fidelity of established LMS cell lines to their mesenchymal neoplasm of origin has limited translational understanding of this disease, and few other preclinical models have been established.

Identification and Therapeutic Targeting of GPR20, Selectively Expressed in Gastrointestinal Stromal Tumors, with DS-6157a, a First-in-Class Antibody-Drug Conjugate.

Currently, the only approved treatments for gastrointestinal stromal tumor (GIST) are tyrosine kinase inhibitors (TKI), which eventually lead to the development of secondary resistance mutations in KIT or PDGFRA and disease progression. Herein, we identified G protein-coupled receptor 20 (GPR20) as a novel non-tyrosine kinase target in GIST, developed new GPR20 IHC, and assessed GPR20 expression in cell lines, patient-derived xenografts, and clinical samples from two institutes (United States and Japan). We studied GPR20 expression stratified by treatment line, KIT expression, GIST molecular subtype, and primary tumor location.

HAND1 and BARX1 Act as Transcriptional and Anatomic Determinants of Malignancy in Gastrointestinal Stromal Tumor.

Purpose: Gastrointestinal stromal tumor (GIST) arises from interstitial cells of Cajal (ICC) or their precursors, which are present throughout the gastrointestinal tract. Although gastric GIST is commonly indolent and small intestine GIST more aggressive, a molecular understanding of disease behavior would inform therapy decisions in GIST. Although a core transcription factor (TF) network is conserved across GIST, accessory TFs HAND1 and BARX1 are expressed in a disease state-specific pattern.

Detection of Circulating Tumor DNA in Patients With Leiomyosarcoma With Progressive Disease.

Purpose: Leiomyosarcoma (LMS) is a soft tissue sarcoma characterized by multiple copy number alterations (CNAs) and without common recurrent single nucleotide variants. We evaluated the feasibility of detecting circulating tumor DNA (ctDNA) with next-generation sequencing in a cohort of patients with LMS whose tumor burden ranged from no evidence of disease to metastatic progressive disease.

Patients And Methods: Cell-free DNA in plasma samples and paired genomic DNA from resected tumors were evaluated from patients with LMS by ultra-low passage whole genome sequencing (ULP-WGS).

Enhancer Domains in Gastrointestinal Stromal Tumor Regulate KIT Expression and Are Targetable by BET Bromodomain Inhibition.

Gastrointestinal stromal tumor (GIST) is a mesenchymal neoplasm characterized by activating mutations in the related receptor tyrosine kinases KIT and PDGFRA. GIST relies on expression of these unamplified receptor tyrosine kinase (RTK) genes through a large enhancer domain, resulting in high expression levels of the oncogene required for tumor growth. Although kinase inhibition is an effective therapy for many patients with GIST, disease progression from kinase-resistant mutations is common and no other effective classes of systemic therapy exist.

Peptidomimetics Targeting Protein-Protein Interactions for Therapeutic Development.

Background: Interactions between proteins play a key role in nearly all cellular process, and therefore, its dysregulation may lead to many different types of cellular dysfunctions. Hence, pathologic Protein-Protein Interactions (PPIs) constitute highly attractive drug targets and hold great potential for developing novel therapeutic agents for the treatment of incurable human diseases. Unfortunately, the identification of PPI inhibitors is an extremely challenging task, since traditionally used small molecules ligands are mostly unable to cover and anchor on the extensive and flat surfaces that define those binary protein complexes.

Crystal structures of a manganese(I) and a rhenium(I) complex of a bi-pyridine ligand with a non-coordinating benzoic acid moiety.

The structures of two facially coordinated Group VII metal complexes are reported, namely: -bromido-[2-(2,2'-bipyridin-6-yl)benzoic acid-κ,']tricarbonyl-manganese(I) tetra-hydro-furan monosolvate, [MnBr(CHNO)(CO)]·CHO, , and -[2-(2,2'-bipyridin-6-yl)benzoic acid-κ,']tricarbonyl-chlorido-rhenium(I) tetra-hydro-furan monosolvate, [ReCl(CHNO)(CO)]·CHO, . In both complexes, the metal ion is coordinated by three carbonyl ligands, a halide ion, and a 2-(2,2'-bipyridin-6-yl)benzoic acid ligand, in a distorted octa-hedral geometry. In manganese complex , the tetra-hydro-furan (THF) solvent mol-ecule could not be refined due to disorder.