This work demonstrates the clinical utility of multiplex dPCR to screen for multiple mutations simultaneously with a sensitivity sufficient to detect mutations in circulating DNA obtained by noninvasive blood collection.
Secondary degeneration in areas beyond ischemic foci can inhibit poststroke recovery. The cysteine protease Cathepsin B (CathB) regulates cell death and intracellular protein catabolism. To investigate the roles of CathB in the development of secondary degeneration in the ventroposterior nucleus (VPN) of the ipsilateral thalamus after focal cerebral infarction, infarct volumes, immunohistochemistry and immunofluorescence, and Western blotting analyses were conducted in a distal middle cerebral artery occlusion (dMCAO) stroke model in adult rats. We observed marked neuron loss and gliosis in the ipsilateral thalamus after dMCAO, and the expression of CathB and cleaved caspase-3 in the VPN was significantly upregulated; glial cells were the major source of CathB. Although it had no effect on infarct volume, delayed intracerebroventricular treatment with the membrane-permeable CathB inhibitor CA-074Me suppressed the expression of CathB and cleaved caspase-3 in ipsilateral VPN and accordingly alleviated the secondary degeneration. These data indicate that CathB mediates a novel mechanism of secondary degeneration in the VPN of the ipsilateral thalamus after focal cortical infarction and suggest that CathB might be a therapeutic target for the prevention of secondary degeneration in patients after stroke.
Objective: Hepatocellular carcinoma (HCC) is a genetically and phenotypically heterogeneous tumor, and the prediction of its prognosis remains a challenge. In the past decade, studies elucidating the mechanisms that induce tumor cell pyroptosis has rapidly increased. The elucidation of their mechanisms is essential for the clinical development optimal application of anti-hepatocellular carcinoma therapeutics.Methods: Based on the different expression profiles of pyroptosis-related genes in HCC, we constructed a LASSO Cox regression pyroptosis-related genes signature that could more accurately predict the prognosis of HCC patients.Results: We identified seven pyroptosis-related genes signature (BAK1, CHMP4B, GSDMC, NLRP6, NOD2, PLCG1, SCAF11) in predicting the prognosis of HCC patients. Kaplan Meier survival analysis showed that the pyroptosis-related high-risk gene signature was associated with poor prognosis HCC patients. Moreover, the pyroptosis-related genes signature performed well in the survival analysis and ICGC validation group. The hybrid nomogram and calibration curve further demonstrated their feasibility and accuracy for predicting the prognosis of HCC patients. Meanwhile, the evaluation revealed that our novel signature predicted the prognosis of HCC patients more accurately than traditional clinicopathological features. GSEA analysis further revealed the novel signature associated mechanisms of immunity response in high-risk groups. Moreover, analysis of immune cell subsets with relevant functions revealed significant differences in aDCs, APC co-stimulation, CCR, check-point, iDCs, Macrophages, MHC class-I, Treg, and type II INF response between high- and low-risk groups. Finally, the expression of Immune checkpoints was enhanced in high-risk group, and m6A-related modifications were expressed differently between low- and high-risk groups.Conclusion: The novel pyroptosis-related genes signature can predict the prognosis of patients with HCC and insight into new cell death targeted therapies.
ObjectiveTo investigate prognostic factors of more than 10 years of survival for liver cancer patients after liver transplantation.MethodsFrom May 2000 to May 2007, a total of 134 liver cancer patients who underwent liver transplantation in the Department of Hepatobiliary Surgery, Peking University People’s Hospital, were continuously and retrospectively enrolled. The patients included 120 males and 14 females. There were 124 cases (92.5%) of primary hepatocellular carcinoma, 9 cases (6.7%) of cholangiocarcinoma, and 1 case of mixed hepatocellular carcinoma and cholangiocarcinoma. Patients with perioperative death were excluded. Follow-up was performed until May 31st, 2017 or the time of death. According to the data on postoperative survival time, patients were divided into a < 10 years group (81 cases) and a ≥ 10 years group (53 cases). Patients’ clinical data were recorded and analyzed, including alpha-fetoprotein (AFP) level (≥ 400 µg/L or < 400 µg/L), number of tumor lesions (< 3 or ≥ 3), tumor size (≤ 5 cm or > 5 cm), vascular tumor thrombus (large blood vessel or non-large blood vessel), and histological differentiation degree. The Kaplan–Meier method was used to calculate survival rates. The log-rank method was used to compare the differences between survival curves. The Cox proportional hazards regression model was used to perform multivariate analyses of possibly influential factors.Results(1) Follow-up was conducted with all 134 liver cancer patients after liver transplantation. The follow-up periods were 1–201 months, with a median of 18 (8.75, 132.5) months. The Kaplan–Meier survival analysis results showed that the 1-year, 3-year, 5-year, and 10-year cumulative survival rates were 70.3%, 48.6%, 46.8%, and 46.8%, respectively. (2) The differences in the age of patients, the incidence rate of AFP ≥ 400 µg/L, tumor histological differentiation, vascular tumor thrombi, tumor lesion size, and number of tumor lesions between two groups were all statistically significant (all P < 0.01). (3) The cumulative survival rates were different in AFP (log-rank χ2 = 13.428), histopathologic differentiation (log-rank χ2 = 33.592), large blood vessel tumor thrombi (log-rank χ2 = 36.470), tumor lesion size (log-rank χ2 = 39.835), and number of tumor lesions (log-rank χ2 = 47.016), and there were statistically significant differences between groups (all P < 0.01). (4) Multivariate Cox proportional hazards regression analyses showed that ≥ 3 tumor lesions [hazard ratio (HR) = 2.879, 95% confidence interval (CI) 1.566–5.422], tumor lesion size > 5 cm (HR = 2.682, 95% CI 1.382–5.366), large blood vessel tumor thrombi (HR = 1.831, 95% CI 1.010–3.341), and poor histological differentiation (HR = 2.150, 95% CI 1.372–3.394), were risk factors affecting the 10-year survival of liver cancer patients after liver transplantation (all P < 0.05).ConclusionTumor size, tumor number, large blood vessel tumor thrombi, and low tumor differentiation were all found to be independent risk factors affecting the 10-year survival rate after li...
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