Background and Aim Familial adenomatous polyposis (FAP) is the most common adenomatous polyposis syndrome. Patients with FAP are screened for germline mutations of two genes, APC and MUTYH. However, limited data exist on the clinical characterization and genotypic spectrum of FAP in China. This study was aimed to determine APC and MUTYH mutational status in a small cohort of FAP probands in China and to characterize the genotype–phenotype correlation in mutated patients. Methods Mutation screening of 46 unrelated probands was performed using multigene panels by next‐generation sequencing. Clinical data of the index were used to assess genotype–phenotype correlations. Results Overall, 42 out of 46 (91.30%) unrelated probands found mutations, including 35 (76.09%) with APC mutations, 3 (6.52%) with MUTYH mutations, and 4 (8.70%) with both APC and MUTYH mutations. Ten APC genetic alterations variants were novel. The hereditary pattern of the family with both APC and MUTYH mutations was autosomal dominant inheritance. Upper gastrointestinal polyp was the most common extracolonic manifestations. The onset time for patients with both APC and MUTYH mutations was earlier than MUTYH mutation carriers and similar to APC mutation carriers. But the age of carcinogenesis for patients with both APC and MUTYH mutations was later than APC mutation carriers and similar to MUTYH mutation carriers. Conclusion In this study, we show the importance of using multigene panels that allow for a parallel comprehensive screening. We suggest that genetic testing of patients with suspected adenomatous polyposis syndromes should include APC and MUTYH gene mutation analyses simultaneously.
Background: Pazopanib is an approved multitarget anticancer agent for soft tissue sarcoma (STS) and renal cell carcinoma (RCC), which is also under clinical investigation for other malignancies, including small cell lung cancer (SCLC). However, the potential anti-SCLC mechanisms of pazopanib remain unclear. Methods: Cell viability was evaluated by CCK-8, apoptotic cell detection was conducted using annexin V/PI staining followed by flow cytometry, and Western blot analysis was used to detect the apoptotic-related molecules and ER-stress pathway effectors. The intracellular reactive oxygen species (ROS) level was determined by DCFH-HA staining followed by flow cytometry. An NCI-H446 xenograft model was established to evaluate pazopanib on tumor suppression in vivo. Immunohistochemistry (IHC) was used to assess the proliferative activity of xenograft in NCI-H446 cell-bearing NOD-SCID mice. Results: Pazopanib dose-and time-dependently inhibited SCLC cell proliferation induced significant apoptosis in SCLC cell lines, increased cleaved-caspase3 and Bax, and decreased Bcl-2. Moreover, the PERK-related ER-stress pathway was potently activated by pazopanib treatment, inhibiting ER-stress by salubrinal significantly reversing pazopanibmediated apoptosis in SCLC cell lines. Furthermore, pazopanib-induced intracellular ROS levels increased, while inhibiting ROS by NAC significantly reversed pazopanib-induced apoptosis in SCLC cells. In addition, pazopanib significantly suppressed NCI-H446 xenograft growth and decreased Ki67 positive cells in the tumor. Conclusion: Our findings indicate that pazopanib induces SCLC cell apoptosis through the ER-stress process via upregulation of ROS levels. Further investigation of relevant biomarkers to accurately select patients for benefit from pazopanib should be further investigated. K E Y W O R D S apoptosis, endoplasmic reticulum stress (ER-stress), Pazopanib, reactive oxygen species (ROS), small cell lung cancer (SCLC)
Aims This study aimed to investigate the prognostic implications of increased postprocedural cardiac troponin levels in patients undergoing elective percutaneous coronary intervention (PCI) and to define the threshold of prognostically relevant periprocedural myocardial injury (PMI). Methods and Reasults A total of 3,249 patients with normal baseline troponin levels referred for elective PCI were enrolled and followed up for a median period of 20 months. The primary endpoint was major adverse cardiovascular events (MACEs) comprising all-cause death, myocardial injury (MI) and ischemic stroke. Post-PCI high-sensitivity cardiac troponin T (hs-cTnT) > 99% upper reference limit (URL) occurred in 78.3% of patients and did not increase the risk of MACEs (adjusted hazard ratio (adHR), 1.00, 95% confidence interval (CI), 0.58-1.74, p = 0.990). Nor did ‘major PMI’ defined as post-PCI hs-cTnT above 5 × URL (adHR, 1.30, 95% CI, 0.76-2.23, p = 0.340). Post-PCI troponin > 8 × URL, with an incidence of 15.2%, started to show an association with a higher risk of MACEs (adHR, 1.89, 95% CI, 1.06-3.37, p = 0.032), mainly driven by myocardial infarction (adHR, 2.38, 95% CI, 1.05-5.38, p = 0.037) and ischemic stroke (adHR 3.35, 95% CI, 1.17-9.64, p = 0.025). Conclusions In patients with normal baseline troponin values undergoing elective PCI, PMI defined as hs-cTnT > 8 × URL after PCI was more appropriate for identifying patients with an increased risk of MACEs, which may help guide clinical practice in this population.
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