miR-124 mediates the expression of ccBax to regulate Cyprinid herpesvirus 2 (CyHV-2)-induced apoptosis and viral replication.

Cyprinid herpesvirus 2 (CyHV-2), the etiological agent of herpesvirus haematopoietic necrosis (HVHN) in carp and goldfish, has caused significant economic losses in the aquaculture industry. During viral infection, the host initiates a series of active or passive defences to regulate the process of virus infection. Apoptosis is a key component of active cellular defence, and members of the Bcl-2 family have been shown to play a critical role in the apoptotic process. However, the mechanism of action of the Bcl-2 family in inducing apoptosis during CyHV-2 infection remains unclear. In this study, we revealed the molecular mechanism of miRNA-mediated silver crucian carp BAX (ccBax) in CyHV-2-induced apoptosis for the first time and demonstrated that the overexpression of miR-124 suppressed ccBax expression and significantly down-regulated apoptosis in caudal fin cells of Carassius auratus gibelio (GiCF), while miR-124 inhibitors were the opposite. These studies indicated that miR-124 inhibits CyHV-2-induced apoptosis by reducing the expression of ccBax. Furthermore, the fact that transfection of miR-124 mimics promoted CyHV-2 replication, whereas miR-124 inhibitors inhibited CyHV-2 replication, indicated that miR-124 inhibited CyHV-2-induced apoptosis and contributed to viral replication. All these results suggested that miR-124 suppresses virus-induced apoptosis and promotes viral replication by targeting and regulating ccBax expression.

Neoadjuvant versus adjuvant imatinib in primary localized gastrointestinal stromal tumor.

Background: The effect of neoadjuvant therapy (NAT) with imatinib versus upfront resection (UR) followed by adjuvant therapy (AT) with imatinib on the outcomes of gastrointestinal stromal tumors (GIST) is unknown. Methods: This is a retrospective study at a high-volume center. All the patients with primary localized GIST were identified in a hospital database from 2007 to 2021. The endpoints included local recurrence-free survival (LRFS), distance recurrence-free survival (DRFS), and overall survival (OS). Cox regression was used to perform multivariate survival analyses. The sensitivity analysis was conducted with the inverse probability of treatment weighting (IPTW) method. Results: A total of 211 patients were included (Group A: UR + AT, n=140; Group B: NAT + resection + AT, n=71). In the entire cohort, 5-year DRFS, LRFS, and OS were 85.6%, 90.7%, and 92.5%, respectively. In the multivariate analysis, better DRFS was linked to NAT, tumor size of 5 cm, and AT. Sixteen patients (11.4%) in Group A and 1 (1.4%) in Group B had distant recurrences after AT discontinuation. The sensitivity analysis by IPTW provided approximately similar results. An interaction effect was observed between NAT and tumor location on DRFS. In non-gastric GISTs, NAT was associated with better DRFS [hazard ratio =0.131, 95% confidence interval (CI): 0.017-0.989, P=0.049], which was not the case in gastric GIST (P=0.08). NAT was not independently associated with LRFS or OS. Conclusions: When compared to UR + AT, NAT + resection + AT may reduce the risk of distant recurrence in localized GIST and may be especially beneficial for patients with non-gastric GISTs.

Coordinated activity of a central pathway drives associative opioid analgesic tolerance.

Opioid analgesic tolerance, a root cause of opioid overdose and misuse, can develop through an associative learning. Despite intensive research, the locus and central pathway subserving the associative opioid analgesic tolerance (AOAT) remains unclear. Using a combination of chemo/optogenetic manipulation with calcium imaging and slice physiology, here we identify neuronal ensembles in a hierarchically organized pathway essential for AOAT. The association of morphine-induced analgesia with an environmental condition drives glutamatergic signaling from ventral hippocampus (vHPC) to dorsomedial prefrontal cortex (dmPFC) cholecystokininergic (CCKergic) neurons. Excitation of CCKergic neurons, which project and release CCK to basolateral amygdala (BLA) glutamatergic neurons, relays AOAT signal through inhibition of BLA µ-opioid receptor function, thereby leading to further loss of morphine analgesic efficacy. This work provides evidence for a circuit across different brain regions distinct for opioid analgesic tolerance. The components of this pathway are potential targets to treat opioid overdose and abuse.

Expression Analysis of Outer Membrane Protein HPS_06257 in Different Strains of Glaesserella parasuis and Its Potential Role in Protective Immune Response against HPS_06257-Expressing Strains via Antibody-Dependent Phagocytosis.

HPS_06257 has been identified as an important protective antigen against Glaesserella parasuis infection. However, little is known about the role of HPS_06257 in the protective immune response. A whole-genome data analysis showed that among 18 isolates of Glaesserella parasuis, 11 were positive for the HPS_06257 gene, suggesting that not every strain contains this gene. We used PCR to investigate the presence of the HPS_06257 gene among 13 reference strains and demonstrated that 5 strains contained the gene. A polyclonal antibody against HPS_06257 was generated with a recombinant protein to study the expression of HPS_06257 in those 13 strains. Consistent with the PCR data, five strains expressed HPS_06257, whereas eight strains were HPS_06257 null. We also compared the protective effects of HPS_06257 against an HPS_06257-expressing strain (HPS5) and an HPS_06257-null strain (HPS11). Immunization with HPS_06257 only protected against HPS5 and not HPS11. Moreover, phagocytosis of antibody-opsonized bacteria demonstrates that the antibody against HPS_06257 increased the phagocytosis of the HPS5 strain by macrophages but not the phagocytosis of the HPS11 strain, suggesting that antibody-dependent phagocytosis is responsible for the protective role exerted by HPS_06257 in the immune response to HPS5. Our data also show that the antibody against HPS_06257 increased the phagocytosis of the other HPS_06257-expressing strains by macrophages but not that of HPS_06257-null strains. In summary, our findings demonstrate that antibody-dependent phagocytosis contributes to the protective immune response induced by immunization with HPS_06257 against HPS_06257-expressing strains.

Will Proton Pump Inhibitors Increase the Risk of Diabetes Mellitus? A Systemic Review and Meta-Analysis.

BACKGROUND: Proton pump inhibitor use was reported to potentially provide benefits to prevent diabetes mellitus. This study aims to investigate the association between proton pump inhibitor use and the risk of developing diabetes mellitus. METHODS: This study was registered on the International Prospective Register of Systematic Reviews (PROSPERO) (ID: CRD42021238481). A systematic literature search was conducted to identify eligible studies up to February 2021. Quality assessment was conducted according to Jadad Scoring Scale and Newcastle-Ottawa Scale. The heterogeneity among studies was tested and estimated by Q test and I2. Pooled hazard ratio with 95% CI was calculated using the random-effects or fixed-effects model depending on the heterogeneity. Subgroup analyses, sensitivity analysis, and publication bias assessment were also performed. RESULTS: Eight studies including 850 019 participants were included. We found that proton pump inhibitor use was associated with a statistically non-significant increased risk of diabetes mellitus (pooled hazard ratio was 1.06, 95% CI = 0.89-1.28, P = .50). In subgroup analysis, 5 studies conducted in North America confirmed the overall result; however, one study conducted in Europe demonstrated a statistically significant increased risk, while one study in Asia revealed a statistically significant decreased risk. CONCLUSION: Proton pump inhibitor use is not associated with either increased or decreased risk of diabetes mellitus. However, more well- designed studies focusing on proton pump inhibitor use and the risk of diabetes mellitus, especially among populations with different backgrounds, are still needed.

Is metformin use associated with a reduced risk of oesophageal cancer? A systematic review and meta-analysis.

OBJECTIVES: Studies on the association between metformin use and the risk of oesophageal cancer (OC) have generated controversial findings. This updated meta-analysis was conducted to reassess the effects of metformin on OC. METHODS: A comprehensive search strategy was conducted to select relevant studies from origination to February 2021. Heterogeneity was evaluated through the Q test and I2 statistics. HRs and 95% CIs were pooled through either random-effect or fixed-effect models. Meta-regression, subgroup analyses, sensitivity analysis and publication bias diagnosis were also performed. RESULTS: Seven studies with 5 426 343 subjects were included. Metformin use was associated with reduced risk of OC (HR=0.69, 95% CI 0.54 to 0.87, p<0.001). Sensitivity analysis suggested that the results were relatively stable. CONCLUSION: Metformin is associated with a reduced risk of OC. More well-designed studies are still needed to further elaborate on these associations. PROSPERO REGISTRATION NUMBER: CRD42021237127.

Is endoscopic retrograde appendicitis therapy a better modality for acute uncomplicated appendicitis? A systematic review and meta-analysis.

BACKGROUND: Previous studies had shown endoscopic retrograde appendicitis therapy (ERAT) is an effective treatment for acute appendicitis. However, different studies reported conflicting outcomes regarding the effectiveness of ERAT in comparison with laparoscopic appendectomy (LA). AIM: To compare the effectiveness of ERAT with LA. METHODS: Randomized controlled trials (RCTs) and retrospective studies of ERAT for acute uncomplicated appendicitis were searched in PubMed, Cochrane Library, Web of Science, Embase database, China National Knowledge Infrastructure (CNKI), the WanFang Database, and Chinese Scientific Journals Database (VIP) from the establishment date to March 1 2021. Heterogeneity was assessed using the I-squared statistic. Pooled odds ratios (OR), weighted mean difference (WMD), and standard mean difference (SMD), with 95% confidence intervals (CI) were calculated through either fixed-effects or random-effects model. Sensitivity analysis was also performed. Publication bias was tested by Egger's test, and Begg's test. The quality of included RCT were evaluated by the Jadad scale, while Newcastle-Ottawa scale is adopted for assessing the methodological quality of case-control studies. All statistical analysis was performed using Stata 15.1 statistical software. All statistical analysis was performed using Stata 15.1 statistical software. This study is registered with PROSPERO, CRD42021243955. RESULTS: After screening, 10 RCTs and 2 case-control studies were included in the current systematic review. Firstly, the length of hospitalizations [WMD = -1.15, 95%CI: -1.99, -0.31; P = 0.007] was shorter than LA group. Secondly, the level of post-operative CRP [WMD = -10.06, 95%CI: (-17.39, -2.73); P = 0.007], TNF-α [WMD = -7.70, 95%CI: (-8.47, -6.93); P < 0.001], and IL-6 Levels [WMD = -9.78, 95%CI: (-10.69, -8.88); P < 0.001; P < 0.001] in ERAT group was significantly lower than LA group. Thirdly, ERAT group had a lower incidence of intestinal obstruction than LA group. [OR = 0.19, 95%CI: (0.05, 0.79); P = 0.020]. Moreover, the quality of 10 RCTs were low with 0-3 Jadad scores, while the methodological quality of two case-control studies were fair with a score of 2 (each). CONCLUSION: Compared with LA, ERAT reduces operation time, the level of postoperative inflammation, and results in fewer complications and shorter recovery time, with preserving the appendix and its immune and biological functions.

High Perceived Stress May Shorten Activated Partial Thromboplastin Time and Lead to Worse Clinical Outcomes in Patients With Coronary Heart Disease.

Objective: To determine the association of perceived stress with coagulation function and their predictive values for clinical outcomes. Methods: This prospective cohort study derived from a cross-sectional study for investigating the psychological status of inpatients with suspicious coronary heart disease (CHD). In this study, the 10-item Perceived Stress Scale (PSS-10) as an optional questionnaire was used to assess the severity of perceived stress. Coagulation function tests, such as activated partial thromboplastin time (APTT), prothrombin time (PT), and fibrinogen were measured within 1 h after admission. Furthermore, 241 patients with CHD out of 705 consecutive inpatients were included in the analyses and followed with a median of 26 months for the clinical outcomes. Results: The patients in high perceived stress status (PSS-10 score > 16) were with shorter APTT (36.71 vs. 38.45 s, p = 0.009). Shortened APTT ( ≤ 35.0 s) correlated with higher PSS-10 score (14.67 vs. 11.22, p = 0.003). The association of APTT with depression or anxiety was not found. Multiple linear models adjusting for PT estimated that every single point increase in PSS-10 was relevant to approximately 0.13 s decrease in APTT (p = 0.001) regardless of the type of CHD. APTT (every 5 s increase: hazard ratio (HR) 0.68 [0.47-0.99], p = 0.041) and perceived stress (every 5 points increase: HR 1.31 [1.09-1.58], p = 0.005) could predict the cardiovascular outcomes. However, both predictive values would decrease when they were simultaneously adjusted. After adjusting for the physical clinical features, the associated of perceived stress on cardiac (HR 1.25 [1.04-1.51], p = 0.020) and composite clinical outcomes (HR 1.24 [1.05-1.47], p = 0.011) persisted. Conclusions: For the patients with CHD, perceived stress strongly correlates with APTT. The activation of the intrinsic coagulation pathway is one of the mechanisms that high perceived stress causes cardiovascular events. This hints at an important role of the interaction of mental stress and coagulation function on cardiovascular prognosis. More attention needs to be paid to the patients with CHD with high perceived stress.

Exploring the Interdisciplinary Nature of Precision Medicine：Network Analysis and Visualization.

BACKGROUND: Interdisciplinary research is an important feature of precision medicine. However, the accurate cross-disciplinary status of precision medicine is still unclear. OBJECTIVE: The aim of this study is to present the nature of interdisciplinary collaboration in precision medicine based on co-occurrences and social network analysis. METHODS: A total of 7544 studies about precision medicine, published between 2010 and 2019, were collected from the Web of Science database. We analyzed interdisciplinarity with descriptive statistics, co-occurrence analysis, and social network analysis. An evolutionary graph and strategic diagram were created to clarify the development of streams and trends in disciplinary communities. RESULTS: The results indicate that 105 disciplines are involved in precision medicine research and cover a wide range. However, the disciplinary distribution is unbalanced. Current cross-disciplinary collaboration in precision medicine mainly focuses on clinical application and technology-associated disciplines. The characteristics of the disciplinary collaboration network are as follows: (1) disciplinary cooperation in precision medicine is not mature or centralized; (2) the leading disciplines are absent; (3) the pattern of disciplinary cooperation is mostly indirect rather than direct. There are 7 interdisciplinary communities in the precision medicine collaboration network; however, their positions in the network differ. Community 4, with disciplines such as genetics and heredity in the core position, is the most central and cooperative discipline in the interdisciplinary network. This indicates that Community 4 represents a relatively mature direction in interdisciplinary cooperation in precision medicine. Finally, according to the evolution graph, we clearly present the development streams of disciplinary collaborations in precision medicine. We describe the scale and the time frame for development trends and distributions in detail. Importantly, we use evolution graphs to accurately estimate the developmental trend of precision medicine, such as biological big data processing, molecular imaging, and widespread clinical applications. CONCLUSIONS: This study can help researchers, clinicians, and policymakers comprehensively understand the overall network of interdisciplinary cooperation in precision medicine. More importantly, we quantitatively and precisely present the history of interdisciplinary cooperation and accurately predict the developing trends of interdisciplinary cooperation in precision medicine.

Assessment of Coproduction of Ethanol and Methane from Pennisetum purpureum: Effects of Pretreatment, Process Performance, and Mass Balance.

To overcome the structural complexity and improve the bioconversion efficiency of Pennisetum purpureum into bioethanol or/and biomethane, the effects of ensiling pretreatment, NaOH pretreatment, and their combination on digestion performance and mass flow were comparatively investigated. The coproduction of bioethanol and biomethane showed that 65.2 g of ethanol and 102.6 g of methane could be obtained from 1 kg of untreated Pennisetum purpureum, and pretreatment had significant impacts on the production; however, there is no significant difference between the results of NaOH pretreatment and ensiling-NaOH pretreatment in terms of production improvement. Among them, 1 kg of ensiling-NaOH treated Pennisetum purpureum could yield 269.4 g of ethanol and 144.5 g of methane, with a respective increase of 313.2% and 40.8% compared to that from the untreated sample; this corresponded to the final energy production of 14.5 MJ, with the energy conversion efficiency of 46.8%. In addition, for the ensiling-NaOH treated Pennisetum purpureum, the energy recovery from coproduction (process III) was 98.9% higher than that from enzymatic hydrolysis and fermentation only (process I) and 53.6% higher than that from anaerobic digestion only (process II). This indicated that coproduction of bioethanol and biomethane from Pennisetum purpureum after ensiling and NaOH pretreatment is an effective method to improve its conversion efficiency and energy output.

Aggregate analysis based on TCGA: TTN missense mutation correlates with favorable prognosis in lung squamous cell carcinoma.

PURPOSE: Lung cancer prevalence with its high mortality rate is a trending topic globally. Non-small cell lung cancer (NSCLC) is the most common type of lung cancer. The human gene TTN encoding for TITIN protein is known as major mutation gene in many types of tumor including NSCLC. However, it is still controversial that TTN is a cancer-associated candidate considering tumor heterogeneity and complex genetic structure. In-depth researches on correlation between TTN mutation and NSCLC are still limited and discussable. METHODS: Related somatic mutation profiles and attached clinical data were from The Cancer Genome Atlas (TCGA) lung project. Clinical relevance analysis of TTN mutation was evaluated using univariate analysis and a binary logistic regressive model. Survival analysis and screening of independent prognostic factors in mutation types were conducted by Cox proportional hazards models and Kaplan-Meier methods. RESULTS: Available data covering lung adenocarcinoma (n = 517) and lung squamous cell carcinoma (n = 492) were analyzed. TTN genetic mutations exhibited significant association with lung squamous cell carcinoma. Patients with lung squamous cell carcinoma possessed favorable overall survival benefits from TTN mutant type and both favorable overall survival and disease-free survival benefits from TTN/TP53 double mutation. For patients with lung squamous cell carcinoma, about 85% of subjects with TTN mutation harbored missense variations, which was an independent indicator of good prognosis. CONCLUSIONS: Missense mutation of TTN may act as a beneficial role in lung squamous cell carcinoma, but not in lung adenocarcinoma.

[Circular RNA in Lung Cancer Research: Biogenesis, Functions and Roles].

Lung cancer is the most commonly diagnosed cancer and the leading cause of cancer death in China. In recent years, therapies for oncogenedrivers and immune checkpoints have proved inspiring. Circular RNA (circRNA), which is a kind of RNA with covalent ring structure relating to stages and metastasis of cancer, has many special biological functions in physiological processes, diseases and so on. Thus, circRNA is expected to be a potential biomarker for cancer prediction and treatment in view of its high conservation and tissue-specific. However, function analysis and regulatory mechanism of circRNA in lung cancer come so far remains unclear and limited literatures are available. In this review, we highlight the research history, formation mechanism, biological function of circRNA and research progress in cancer, especially in lung cancer. We mean to provide theoretical evidences and new ideas for researches on circRNAs in lung cancer.