Translational research : the journal of laboratory and clinical medicine
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Review
Risk Factors for Clonal Hematopoiesis of Indeterminate Potential and Mosaic Chromosomal Alterations.
Clonal hematopoiesis of indeterminate potential (CHIP) and mosaic chromosomal alterations (mCAs) of the autosomes, X, and Y chromosomes are aging-related somatic mutations detectable in peripheral blood. The presence of these acquired mutations predisposes otherwise healthy adults to increased risk of several chronic aging-related conditions including hematologic cancers, atherosclerotic cardiovascular diseases, other inflammatory conditions, and mortality. While the public health impact and disease associations of these blood-derived somatic mutations continue to expand, the inherited, behavioral/lifestyle, environmental risk factors and comorbid conditions that influence their occurrence and progression have been less well characterized. ⋯ Some loci, such as TERT, ATM, TP53, CHEK2, and TCL1A, have overlapping associations with different types of CHIP, mCAs, and cancer predisposition. Various environmental or co-morbid contexts associated with presence or expansion of specific CHIP or mCA mutations are beginning to be elucidated, such as cigarette smoking, diet, cancer chemotherapy, particulate matter, and premature menopause. Further characterization of the germline genetic and environmental correlates of CHIP/mCAs may inform our ability to modify their progression and ultimately reduce the risk and burden of chronic diseases associated with these clonal somatic phenomena.
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Genetic diagnosis of familial hypercholesterolemia (FH) remains unexplained in 30 to 70% of patients after exclusion of monogenic disease. There is now a growing evidence that a polygenic burden significantly modulates LDL-cholesterol (LDL-c) concentrations. Several LDL-c polygenic risk scores (PRS) have been set up. ⋯ These results were replicated using the UK biobank. This new 165-SNP PRS, usable in routine diagnosis, exhibits better diagnosis abilities for a polygenic hypercholesterolemia diagnosis. It would be a valuable tool to optimize referral for whole genome sequencing.
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Gemcitabine (GEM) is the first-line medication for pancreatic ductal adenocarcinoma (PDAC). However, over some treatment cycles, GEM sensitivity declines and chemotherapeutic resistance develops, resulting in tumor recurrence and metastasis. Therefore, it is critical to elucidate the mechanism of GEM chemoresistance. ⋯ In vitro and in vivo, ATO combined with GEM has a collaborative anticancer effect, inhibiting cancer cell proliferation, migration, invasion, and suppressing tumor growth both in PDAC parental and GEM-resistant cells. Overall, the TIMP1/PI3K/AKT/mTOR pathway is present in PDAC and linked to GEM resistance. ATO suppresses the axis to sensitize GEM and reverse GEM resistance, suggesting a promising treatment for the disease.
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Dendritic cells (DCs) are key regulators of the adaptive immune response. Tolerogenic dendritic cells play a crucial role in inducing and maintaining immune tolerance in autoimmune diseases such as type 1 diabetes in humans as well as in the NOD mouse model. We previously reported that bone marrow-derived DCs (BM. ⋯ Furthermore, analysis of C/EBPβ-/- GM/DCs demonstrated that C/EBPβ is required for IL-23 production. Of physiological relevance, the level of protection from diabetes following transfusion of GM/DCs into young NOD mice was significantly reduced when NOD mice were transfused with GM/DCs pretreated with a PI3K inhibitor. Our data suggest that PI3K/C/EBPβ signaling is important in controlling tolerogenic function of GM/DCs by limiting their Th17-promoting cytokines.
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Tyrosine kinase inhibitor (TKI) is a standard treatment for patients with NSCLC harboring constitutively active epidermal growth factor receptor (EGFR) mutations. However, most rare EGFR mutations lack treatment regimens except for the well-studied ones. We constructed two EGFR variant libraries containing substitutions, deletions, or insertions using the saturation mutagenesis method. ⋯ Moreover, the top 5% of the enriched insertion variants included a glycine or serine insertion at high frequency. We present a comprehensive reference for the sensitivity of EGFR variants to five commonly used TKIs. The approach used here should be applicable to other genes and targeted drugs.