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Purpose: The clinical benefits of poly(ADP-ribose) polymerase (PARP) inhibitors are limited to triple-negative breast cancer (TNBC) with BRCA deficiency due to primary and acquired resistance. Thus, there is a pressing need to develop alternative treatment regimens to target BRCA-mutated TNBC tumors that are resistant to PARP inhibition. Similar to PARP, poly(ADP-ribose) glycohydrolase (PARG) plays a role in DNA replication and repair. However, there are conflicting reports on the vulnerability of BRCA1-deficient tumor cells to PARG inhibition. This study aims to investigate the synergistically lethal effect of the PARG inhibitor COH34 and the ubiquitin-specific protease (USP) 14 inhibitor IU1-248 and the underlying mechanisms in BRCA1-mutant, PARP inhibitor-resistant TNBC cells. Methods: The cytotoxicity of PARG inhibition alone or in combination with USP14 inhibition in the BRCA-mutant, PARP inhibitor-resistant TNBC cell lines, HCC1937 and SUM149PT, was analyzed using cell viability and proliferation assays and flow cytometry. The molecular mechanisms underlying the synergistic effects of IU1-248 and COH34 were evaluated by immunofluorescence staining, DNA repair reporter assays and Western blot analysis. Results: It was found that HCC1937 and SUM149PT cells exhibited moderate responsiveness to PARG inhibition alone. To the best of our knowledge, this research is the first to demonstrate that the combination of IU1-248 and COH34 produces synergistic effects against TNBC cells in the same setting. Mechanistically, the blockade of USP14 by IU1-248 was shown to increase DNA damage and promote error-prone non-homologous end joining (NHEJ), as evidenced by the accumulation of γH2AX and 53BP1 in the nucleus and the activation of a reporter assay. Additionally, it was demonstrated that the inhibition of NHEJ repair activity attenuates the synergistic effects of concomitant PARG and USP14 inhibition. IU1-248 promotes NHEJ repair through the downregulation of the expression of c-Myc. Conclusion: USP14 inhibition may be a plausible strategy for expanding the utility of PARG inhibitors in TNBC in BRCA-mutant, PARP inhibitor-resistant settings.

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INTRODUCTION: The efficacy of cilostazol administration to treat subarachnoid hemorrhage remains controversial. We conduct a systematic review and meta-analysis to explore the influence of cilostazol administration on treatment efficacy for subarachnoid hemorrhage. METHODS: We have searched PubMed, Embase, Web of science, EBSCO, and Cochrane Library databases through July 2020 for randomized controlled trials assessing the effect of cilostazol administration in patients with subarachnoid hemorrhage. This meta-analysis is performed using the random-effect model. RESULTS: Four randomized controlled trials involving 405 patients were included in the meta-analysis. Overall, compared with control group for subarachnoid hemorrhage, cilostazol intervention can significantly reduce symptomatic vasospasm (odds ratio [OR], 0.35; 95% confidence interval [CI], 0.21-0.60; P = 0.0001) and cerebral infarction (OR, 0.40; 95% CI, 0.22-0.73; P = 0.003) and improve no or mild angiographic vasospasm (OR, 2.01; 95% CI, 1.19-3.42; P = 0.01) and an mRS score of 2 or less (OR, 2.70; 95% CI, 1.09-6.71; P = 0.03), but revealed no obvious influence on severe angiographic vasospasm (OR, 0.53; 95% CI, 0.27-1.02; P = 0.06). There were no increase in adverse events (OR, 1.17; 95% CI, 0.54-2.52; P = 0.69), hemorrhagic events (OR, 0.62; 95% CI, 0.06-6.27; P = 0.69), and cardiac events (OR, 2.14; 95% CI, 0.44-10.27; P = 0.34) after the cilostazol intervention than control intervention. CONCLUSIONS: Cilostazol treatment may be effective to treat subarachnoid hemorrhage in the terms of symptomatic vasospasm, cerebral infarction, no or mild angiographic vasospasm, and an mRS score of 2 or less.

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MicroRNAs (miRNAs or miRs) are critical regulators in various diseases. In the current study, the role of miR­30c­5p in the formation of sodium oxalate­induced kidney stones was investigated. For this purpose, human renal tubular epithelial cells (HK­2 cells) were incubated with sodium oxalate at the concentrations of 100, 250, 500, 750 and 1,000 µM. Cell viability and the miR­30c­5p expression level were respectively measured by CCK­8 assay and RT­qPCR. After separately transfecting miR­30c­5p mimic and inhibitor into the HK­2 cells, the cell apoptotic rate, the levels of mitochondrial membrane potential (MMP) and ROS were determined by flow cytometry. The levels of oxidative stress indicators [lactate dehydrogenase (LDH), malondialdehyde (MDA), superoxide dismutase (SOD) and catalase (CAT)] were determined using commercial kits. Crystal­cell adhesion assay was performed to evaluate the crystal adhesion capacity in vitro. miR­30c­5p binding at autophagy related 5 (ATG5) was predicted by TargetScan7.2 and further verified by dual­luciferase reporter assay. Rescue experiments were performed to confirm the molecular mechanisms underlying sodium oxalate­induced kidney formation in HK­2 cells. The results revealed that sodium oxalate decreased the viability of HK­2 cells in a concentration­dependent manner, and that miR­30c­5p expression was significantly downregulated by exposure to 750 µM sodium oxalate. In addition, the increase in cell apoptosis and crystal number, and the upregulated levels of LDH, MDA and ROS were reversed by the overexpression of miR­30c­5p. Moreover, the overexpression of miR­30c­5p upregulated the levels of SOD, CAT and MMP induced by sodium oxalate. ATG5 was directly regulated by miR­30c­5p, and the inhibition of cell cytotoxicity and crystal­cell adhesion induced by miR­30c­5p mimic was blocked by ATG5. These data indicated that the overexpression of miR­30c­5p alleviated cell cytotoxicity and crystal­cell adhesion induced by sodium oxalate through ATG5. Thus, the current study provides a better understanding of the role of miR­30c­5p in sodium oxalate­induced kidney stones.

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BACKGROUND: Tranexamic acid shows some treatment efficacy for traumatic brain injury. This systematic review and meta-analysis is conducted to investigate the efficacy of tranexamic acid for traumatic brain injury. METHODS: The databases including PubMed, EMbase, Web of science, EBSCO, and Cochrane library databases are systematically searched for collecting the randomized controlled trials (RCTs) regarding the efficacy of tranexamic acid for traumatic brain injury. RESULTS: This meta-analysis has included six RCTs. Compared with placebo group in patients with traumatic brain injury, tranexamic acid results in remarkably reduced mortality (risk ratio (RR) = 0.91; 95% confidence interval (CI) = 0.85 to 0.97; P = 0.004) and growth of hemorrhagic mass (RR = 0.78; 95% CI = 0.61 to 0.99; P = 0.04), but has no important impact on neurosurgery (RR = 0.99; 95% CI = 0.85 to 1.15; P = 0.92), extracranial surgery (RR = 1.00; 95% CI = 0.97 to 1.04; P = 0.99), unfavorable outcome (Glasgow Outcome Scale, GOS) (RR = 0.72; 95% CI = 0.47-1.11; P = 0.14), pulmonary embolism (RR = 1.86; 95% CI = 0.42-8.29; P = 0.42), and deep venous thrombosis (RR = 0.97; 95% CI = 0.64-1.47; P = 0.88). CONCLUSIONS: Tranexamic acid is associated with substantially reduced mortality and growth of hemorrhagic mass in patients with traumatic brain injury, but the need of neurosurgery and extracranial surgery, as well as the risk of unfavorable outcome (GOS) are similar between tranexamic acid and placebo.

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BACKGROUND: The expression of p38 MAPK is high in breast cancer while its subunit p38γ had been rarely reported. We aimed to explain the effect of p38γ in breast cancer from the perspective of metabolomics. METHODS: In this study, we detected the expression of p38γ in 28 breast carcinoma and para-tumor samples. Following MDA-MB-231 cell transfection with p38γ siRNAs and pc-DNA-3.1, cell viability, apoptosis, metastasis were determined through CCK-8, the cytometry analysis, transwell assay and wound healing assay. Finally, gas chromatograph-mass spectrometer (GC-MS) was used for analysis the differential metabolites. RESULTS: The expression of p38γ was significantly up-regulated in breast cancer tissues. The transfection of si-p38γs could inhibit MDA-MB-231 cell propagation, metastasis, and induced cell apoptosis while overexpressed p38γ could promote the cell propagation, metastasis, and inhibit cell apoptosis. A total of 238 metabolites were identified and 72 of them differentially expressed in three groups (all P < 0.05, FDR < 0.05). Then the metabolites were enriched in the metabolism pathway, 85 pathways were included and 27 were significant (all P < 0.05, FDR < 0.05). CONCLUSIONS: p38γ was up-regulated in breast cancer, which exerts a great influence on the cell growth, cell mobility, invasiveness, and apoptosis of MDA-MB-231 cells and also affected the metabolism.

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p53 is the most highly mutated tumor suppressor in human malignancies. A wide array of p53 mutations has been revealed to play pivotal roles during cancer progression, which abolish anti-tumor functions of wild type p53 but also elicit tumorigenic effects by activating a diverse subset of downstream molecules. R273H mutation of p53 has been closely implicated in human cancer. Here we report miR-30a as a novel downstream target of p53 R273H mutant, which binds to the promoter region to repress miR-30a expression. Consequently, p53 R273H mutant enhances the migratory capabilities of tumor cells that are compromised by exogenous miR-30a over-expression. Our further investigation indicates that p53 R273H mutation unleashes the inhibition effect of miR-30a on IGF-1R expression, thus leading to elevated activation of IGF-1R-AKT signaling cascade in tumor cells.

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The electronic transport properties of monolayer graphene with extreme physical deformation are studied using ab initio calculations. The aim is to explore the influence of physical bending on transport properties and identify the most important geometrical parameter. The transmission spectra are relatively insensitive to the geometrical parameters in low-energy regions-even in the extreme case of uniaxial bending. The results suggest that graphene, with its superb electromechanical robustness, could serve as a viable nanoscale material platform in a wide spectrum of applications such as photovoltaics, flexible electronics, and 3D carbon chips.