Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and fibromyalgia (FM) are debilitating disorders with overlapping symptoms such as chronic pain and fatigue. Dysregulation of the endogenous Show more
Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and fibromyalgia (FM) are debilitating disorders with overlapping symptoms such as chronic pain and fatigue. Dysregulation of the endogenous opioid system, particularly µ-opioid receptor function, may contribute to their pathophysiology. This study examined whether epigenetic modifications, specifically µ-opioid receptor 1 gene ( Show less
Cancer-associated fibroblasts (CAFs) exhibit phenotypic heterogeneity with each functional state playing critical roles in tumor progression. Notably, subtypes like inflammatory CAFs (iCAFs), characte Show more
Cancer-associated fibroblasts (CAFs) exhibit phenotypic heterogeneity with each functional state playing critical roles in tumor progression. Notably, subtypes like inflammatory CAFs (iCAFs), characterized by increased chemokine/cytokine secretion, and myofibroblast-like CAFs (myCAFs), characterized by enhanced extracellular matrix (ECM) deposition and increased actomyosin contractility, can undergo phenotypic switching in response to cues from the tumor microenvironment (TME) and therapeutic interventions. Elucidation of the signaling pathways associated with the diverse phenotypes could enable development of strategies to therapeutically reprogram CAFs. Through the analysis of single-cell RNA sequencing data from colorectal cancer (CRC) patients, we identified that the PI3K/mTOR and MAPK/ERK signaling pathways, among other pathways, are linked to the formation of myCAF and iCAF subtypes, respectively. Unbiased pharmacological interference of 12 distinct signaling pathways using three-dimensional (3D) human CRC-derived CAF cultures, ex vivo patient-derived tumor fragments, and mouse models further revealed the significance of PI3K/mTOR and MAPK/ERK signaling in CAF plasticity and functional behavior. PI3K/mTOR inhibition drove iCAF formation through compensatory FGF-2 release and FGFR1-JAK2-STAT3 activation, leading to chemokine/cytokine secretion that promoted tumor spheroid growth and neutrophil infiltration. Conversely, MEK inhibition induced a myCAF phenotype via interferon-dependent ROCK and JAK1 signaling, resulting in ECM production that enhanced tumor colony formation. In summary, these findings reveal a functional significance of PI3K/mTOR and MAPK/ERK signaling pathways in CAF plasticity and underscore how standard-of-care targeted therapies can directly influence CAF phenotypes in CRC. Show less
Familial hypertrophic cardiomyopathy (HCM) is a primary myocardial disease with a prevalence of 1 in 500 in human beings. Causative mutations have been identified in several sarcomeric genes, includin Show more
Familial hypertrophic cardiomyopathy (HCM) is a primary myocardial disease with a prevalence of 1 in 500 in human beings. Causative mutations have been identified in several sarcomeric genes, including the cardiac myosin binding protein C (MYBPC3) gene. Heritable HCM also exists in a large-animal model, the cat, and we have previously reported a mutation in the MYBPC3 gene in the Maine coon breed. We now report a separate mutation in the MYBPC3 gene in ragdoll cats with HCM. The mutation changes a conserved arginine to tryptophan and appears to alter the protein structure. The ragdoll is not related to the Maine coon and the mutation identified is in a domain different from that of the previously identified feline mutation. The identification of two separate mutations within this gene in unrelated breeds suggests that these mutations occurred independently rather than being passed on from a common founder. Show less