Necroptosis-related signatures identify two distinct hepatocellular carcinoma subtypes: Implications for predicting drug sensitivity and prognosis.

Background: Necroptosis is associated with oncogenesis, tumor immunity and progression. This research aims to investigate the association of necroptosis-related genes with drug sensitivity and prognosis in hepatocellular carcinoma (HCC). Methods: Based on necroptosis-related signatures, HCC patients retrieved from the TCGA database were categorized. Survival outcomes, mutation profile, immune microenvironment, and drug sensitivity between HCC subtypes were further compared. Then, LASSO analysis was performed to construct a necroptosis-related prognostic signature, which was further evaluated using another independent cohort. Results: A total of 371 patients with HCC could be categorized into two necroptosis-related subtypes. About 36% of patients were allocated to subtype A, with worse survival, more mutant TP53, and a lower likelihood of immunotherapy response. In contrast, patients in subtype B had a favorable prognosis, with lower expression of immunosuppressive signatures but a lower abundance of B and CD8+ T-cell infiltration. The prognostic risk score calculated using the expression levels of nine genes involved in the necroptosis pathway (MLKL, FADD, XIAP, USP22, UHRF1, CASP8, RIPK3, ZBP1, and FAS) showed a significant association with tumor stage, histologic grade, and Child‒Pugh score. Additionally, the risk score model was proven to be accurate in both the training and independent external validation cohorts and performed better than the TNM staging system and three well-recognized risk score models. Conclusions: Based on necroptosis-related signatures, we identified two HCC subtypes with distinctive immune microenvironments, mutation profiles, drug sensitivities, and survival outcomes. A novel well-performing prognostic model was further constructed.

Inhibition of miR-141-3p attenuates apoptosis of neural stem cells via targeting PBX1 to regulate PROK2 transcription in MCAO mice.

MicroRNA-141-3p (miR-141-3p) has been found to be altered in the brain following a stroke. Herein, we investigate the impact of miR-141-3p on the apoptosis of neural stem cells (NSCs) in mice with middle cerebral artery occlusion (MCAO) and the potential mechanisms involved. Eight-week-old mice were injected intracerebroventricularly with miR-141-3p, antagomir-141-3p, or agomir negative control 2 h before MCAO, and animal behavior tests and infraction volume measurements were performed 24 h later. MCAO-mediated brain injury and NSCs apoptosis were observed by H&E, TTC, and TUNEL staining. The expression of cleaved caspase-3 and Ki67 was detected by western blotting. The luciferase reporter assay proved that miR-141-3p in combination with its target gene PBX homeobox 1 (PBX1). Exogenous miR-141-3p (agomir-141-3p) treatment increased infraction volume and brain edema and damaged neurological functions compared to control mice. Agomir-141-3p increased miR-141-3p expression in brain tissue of mice with MCAO and suppressed PBX1 expression. The effects of the agomir-141-3p-induced apoptosis in NSCs treated with oxygen-glucose deprivation (OGD)/reoxygenation (R) were abolished by PBX1 overexpression. The results from UCSC and JASPAR database showed that prokineticin 2 (PROK2) was a transcription factor of PBX1. The expression of PROK2 was transcriptionally regulated by PBX1 using RT-PCR and western blot assays. The effects of the apoptosis-promoting caused by PBX1 inhibition in NSCs treated with OGD/R were reversed by PROK2 inhibition. In conclusion, the miR-141-3p/PBX1/PROK2 axis might be a novel therapeutic target for the apoptosis of NSCs in MCAO.

A Privacy-Preserving, Two-Party, Secure Computation Mechanism for Consensus-Based Peer-to-Peer Energy Trading in the Smart Grid.

Consumers in electricity markets are becoming more proactive because of the rapid development of demand-response management and distributed energy resources, which boost the transformation of peer-to-peer (P2P) energy-trading mechanisms. However, in the P2P negotiation process, it is a challenging task to prevent private information from being attacked by malicious agents. In this paper, we propose a privacy-preserving, two-party, secure computation mechanism for consensus-based P2P energy trading. First, a novel P2P negotiation mechanism for energy trading is proposed based on the consensus + innovation (C + I) method and the power transfer distribution factor (PTDF), and this mechanism can simultaneously maximize social welfare and maintain physical network constraints. In addition, the C + I method only requires a minimum set of information to be exchanged. Then, we analyze the strategy of malicious neighboring agents colluding to attack in order to steal private information. To defend against this attack, we propose a two-party, secure computation mechanism in order to realize safe negotiation between each pair of prosumers based on Paillier homomorphic encryption (HE), a smart contract (SC), and zero-knowledge proof (ZKP). The energy price is updated in a safe way without leaking any private information. Finally, we simulate the functionality of the privacy-preserving mechanism in terms of convergence performance, computational efficiency, scalability, and SC operations.

Circ_0062166 aggravates cerebral ischemia-reperfusion injury through targeting miR-526b-5p/BCL2L13 axis.

BACKGROUND: Cerebral ischemia-reperfusion (CIR) injury is a severe disease, which may cause serious dysfunction of the brain. Most circular RNAs (circRNAs) have been demonstrated to play a significant role in CIR injury. However, a novel circRNA, circ_0062166 (circ_BCL2L13) has not been investigated for CIR injury. Hence, we aim to disclose the role of circ_0062166 in CIR injury in this study. METHODS: Firstly, RT-qPCR was applied to examine the expression of circ_0062166 in oxygen-glucose deprivation and reoxygenation (OGD/R) cell model. Functional assays were conducted to detect the role of circ_0062166 in CIR injury. RNA pull down, RIP and luciferase reporter assays were implemented to probe into the regulatory mechanism of circ_0062166. RESULTS: Circ_0062166 was significantly up-regulated in neuro-2A (N2A) neuroblastoma cells following OGD/R. Functionally, the silencing of circ_0062166 inhibited cell proliferation and promoted cell apoptosis under OGD/R condition. From the perspective of mechanism, circ_0062166 functioned as a competing endogenous RNA (ceRNA) for microRNA-526b-5p (miR-526b-5p) and regulated BCL2 like 13 (BCL2L13). Eventually, the promoting role of the circ_0062166/miR-526b-5p/BCL2L13 axis in the CIR injury was verified. CONCLUSION: To sum up, the present study has demonstrated that circ_0062166/miR-526b-5p/BCL2L13 axis accelerated the progression of CIR injury, which might provide effective strategies for CIR injury therapy.

Value of echocardiography for mini-invasive per-atrial closure of perimembranous ventricular septal defect.

The purpose of this study was to assess the value of echocardiography for intraoperative guidance during closure of perimembranous ventricular septal defects (pmVSD) and to assess outcomes of these patients. We identified and assessed 78 patients who underwent 2- and 3-dimensional echocardiography-guided mini-invasive per-atrial closure of pmVSD in the cardiac surgery department of our institution, from February 2016 to August 2018, and 76 patients who underwent transcatheter closure of VSD guided by fluoroscopy at the pediatric department (percutaneous control group). All the patients underwent echocardiography. Their clinical data were retrospectively reviewed and analyzed. All patients were followed up using transthoracic echocardiography (TTE) for a maximum of 24 months after the closure. All patients underwent successful device implantation. Echocardiography showed that the major immediate complications included residual shunt, pericardial effusion, and tricuspid regurgitation in the per-atrial group. During the mid-term follow-up period, TTE revealed that the most common complication was tricuspid regurgitation (non-preexisting). There were no cases of VSD recurrence, device displacement, valvular injury, malignant arrhythmias, hemolysis, or death. Moreover, according to the TTE data, the intracardiac structure of the patients were improved. Compared to the control group, the intracardiac manipulation time was shorter and the number of patients with residual shunts, redeployment of devices, or immediate new tricuspid regurgitations was fewer when using 2- and 3-dimensional echocardiography. However, the procedure time in the per-atrial group was slightly longer than that in the control group. Two- and 3-dimensional echocardiography are feasible monitoring tools during mini-invasive per-atrial VSD closure. The short- and mid-term follow-up showed satisfactory results compared to fluoroscopy.

A new three-dimensional glass scaffold increases the in vitro maturation efficiency of buffalo (Bubalus bubalis) oocyte via remodelling the extracellular matrix and cell connection of cumulus cells.

At present, many three-dimensional (3D) culture systems have been reported, improving the oocyte quality of in vitro maturation (IVM), yet the mechanism still needs to be further explored. Here we examined the effects of a new self-made 3D glass scaffold on buffalo oocyte maturation; meanwhile, the underlying mechanism on buffalo oocyte maturation was also detected. Compared to the two-dimensional (2D) glass dish culture, results revealed that the 3D culture can improve the first polar body rate of oocytes, subsequent cleavage and blastocysts rate of parthenogenetic activation embryos (p < .05). The extracellular matrix-related proteins COL1A1, COL2A1, COL3A1, FN and cell connection-related proteins N-cadherin, E-cadherin, GJA1 were found higher in cumulus cells of 3D culture. Moreover, in cumulus cells, proteins of the PI3K/AKT pathway reported being regulated by FN and E-cadherin including PI3K P85 and p-AKT were also higher in 3D culture. Furthermore, proapoptosis proteins P53, BAX, caspase-3 were lower in both cumulus cells and oocytes in 3D culture, while proteins PCNA and BCL2 showed the opposite result. Results also showed that the apoptosis was inhibited, and the proliferation was enhanced in cumulus cells of 3D culture. Finally, the cumulus expansion-related genes HAS2, CD44, HMMR, PTX3, PTGS2 were found higher in cumulus cells of 3D culture. Taken together, the 3D culture could promote oocyte maturation by regulating proteins correlated with the ECM, cell connection and PI3K/AKT pathway, inhibiting the apoptosis of cumulus cells and oocytes, enhancing the proliferation of cumulus cells and the cumulus expansion.

Antihypertensive Therapy in the Acute Phase of Lacunar Infarcts.

BACKGROUND The optimal medical regimen for managing hypertension during acute phase of lacunar infarcts has not yet been clarified in real world setting. The aim of this study was to evaluate blood pressure lowering regimens on neurological progression and clinical outcomes during the acute phase of lacunar infarcts. MATERIAL AND METHODS For this study, 411 patients with first-episode lacunar infarcts and hypertension within 24 hours of symptom onset were included. All patients received antihypertension therapies, with different regimens, as well as routine medication during first 7 days after onset. There were 6 proposed antihypertensive treatments: calcium channel blockers (CCB), angiotensin-converting enzyme inhibitors (ACEI), angiotensin receptor blockers (ARB), ß-blocker (ß-B), and diuretic drug (DD) alone or in combination. Neurological progression was defined as worsening by ≥1 point in the National Institute of Health Stroke Scale (NIHSS) for motor function. The outcome was assessed using the modified Rankin Scale (mRS): favorable outcome (mRS of 0-1) or unfavorable outcome (mRS 2-5). RESULTS Logistic regression analysis showed that combination therapy with CCB, ACEI/ARB, and ß-B exhibited the lowest risk of deterioration (OR=0.48, P=0.019) and unfavorable outcomes (OR=0.50, P=0.022). Similarly, combination therapy with CCB, ACEI/ARB, and DD exhibited lower risk of deterioration (OR=0.63, P=0.033) and unfavorable outcome (OR=0.77, P=0.042) at 3 months. CONCLUSIONS Rational blood pressure lowering was beneficial to the functional outcomes of patients during acute phase of lacunar infarcts, and combination therapy was better than mono-drug therapy.

Clinical analysis of electrolyte imbalance in thalamic hemorrhage patients within 24 h after admission.

We have observed that patients with thalamic hemorrhage are more likely to have electrolyte disturbances than those with non-thalamic hemorrhage. Here, we are attempting to provide some comprehensive information on electrolyte disturbances in patients with thalamic hemorrhage. Retrospectively, 67 patients with thalamic hemorrhage (TH group) and 256 with non-thalamic hemorrhage (N-TH group) were found from computer tomography images. Electrolytes of these patients were tested within 24 h after hospitalization. Chi-square test was used to compare the incidence of electrolyte imbalance. Serum K+ levels were found to be abnormal in 37.31% of the patients in the TH group and 24.21% in the N-TH group, and the difference was significant (p<0.05). Such a difference was also observed for the levels of serum Na+ and Cl+. Incidences of abnormal serum K+ (p<0.05), Na+ (p<0.01) and Cl(-) (p<0.01) levels were different among thalamic hemorrhage, basal ganglia area hemorrhage and lobar hemorrhage patients. In the TH group, the mortality of patients with electrolyte disturbances (42.50%) was higher than that of patients with normal electrolyte levels (14.81%, p<0.05). The incidence of electrolyte imbalance is higher in patients with thalamic hemorrhage than in those with non-thalamic hemorrhage. The reason may be partly related to the location of the hemorrhage. Electrolyte disturbance may contribute to the higher mortality of patients with thalamic hemorrhage.