An 8-Year-Old Boy With a Giant Left Atrium.

CASE PRESENTATION: An 8-year-old boy was referred to our institution because of nausea and vomiting for 1 day. He had also been experiencing shortness of breath for more than 1 year. This symptom had progressed so that he could no longer run or walk upstairs without chest discomfort. There was no associated fever, diarrhea, or coughing. He had a history of heart murmur that was diagnosed in another clinic 4 years ago. Echocardiogram 4 years prior suggested mild to moderate biatrial enlargement with trivial mitral valve regurgitation. He did not go in for any follow-up until this admission. He had no other associated diseases, nor use of medicine.

Do underlying cardiovascular diseases have any impact on hospitalised patients with COVID-19?

OBJECTIVES: An outbreak of the highly contagious severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has sickened thousands of people in China. The purpose of this study was to explore the early clinical characteristics of COVID-19 patients with cardiovascular disease (CVD). METHODS: This is a retrospective analysis of patients with COVID-19 from a single centre. All patients underwent real-time reverse transcription PCR for SARS-CoV-2 on admission. Demographic and clinical factors and laboratory data were reviewed and collected to evaluate for significant associations. RESULTS: The study included 541 patients with COVID-19. A total of 144 (26.6%) patients had a history of CVD. The mortality of patients with CVD reached 22.2%, which was higher than that of the overall population of this study (9.8%). Patients with CVD were also more likely to develop liver function abnormality, elevated blood creatinine and lactic dehydrogenase (p<0.05). Symptoms of sputum production were more common in patients with CVD (p=0.026). Lymphocytes, haemoglobin and albumin below the normal range were pervasive in the CVD group (p<0.05). The proportion of critically ill patients in the CVD group (27.8%) was significantly higher than that in the non-CVD group (8.8%). Multivariable logistic regression analysis revealed that CVD (OR: 2.735 (95% CI 1.495 to 5.003), p=0.001) was associated with critical COVID-19 condition, while patients with coronary heart disease were less likely to reach recovery standards (OR: 0.331 (95% CI 0.125 to 0.880), p=0.027). CONCLUSIONS: Considering the high prevalence of CVD, a thorough CVD assessment at diagnosis and early intervention are recommended in COVID-19 patients with CVD. Patients with CVD are more vulnerable to deterioration.

Hesperetin ameliorates DSS-induced colitis by maintaining the epithelial barrier via blocking RIPK3/MLKL necroptosis signaling.

Hesperetin, a flavonoid from citrus fruits, possess various pharmacological properties, including anti-inflammatory, anti-oxidative, anti-tumor potentials. However, the role and its mechanism in ulcerative colitis (UC) remains unclear. This study aimed to investigate the protective effects and mechanisms of hesperetin on dextran sodium sulfate (DSS) -induced colitis. Our results showed that hesperetin significantly relieved the symptoms of DSS -induced colitis and increased the expressions of zonula occludens-1 (ZO-1), occludin and mucin2 (MUC-2) as well as the decrease of tumor necrosis factor-α (TNF-α), interleukin (IL)-1ß, IL-18, HMGB1 and IL-6. Of note, results from immunohistochemistry (IHC) and western blotting indicated that hesperetin inhibited the expressions of receptor-interacting protein kinase 3 (RIPK3) and mixed lineage kinase domain-like (MLKL), the two key proteins of necroptosis pathway, and inactivated RIPK3/MLKL necroptosis signalling. Meanwhile, in the cell-coculture system between Caco-2 and RAW264.7 cells, hesperetin treatment significantly ameliorated the decrease of trans epithelial electric resistance (TEER) value while HS-173 (necroptosis inducer) could obviously influence the effect of hesperetin. In addition, hesperetin attenuated the LPS-induced increasing in 4-kDa fluorescein isothiocyanate-dextran (FD4) permeability while HS-173 could weaken the protective effect of hesperetin. Meanwhile, HS-173 reduced the changes in the expressions of phosphorylated RIPK3, phosphorylated MLKL, ZO-1, occludin and MUC-2 as well as TNF-α, IL-1ß. These findings demonstrated hesperetin ameliorated DSS-induced colitis by maintaining the epithelial barrier via blocking the intestinal epithelial necroptosis.

α-Hederin Increases The Apoptosis Of Cisplatin-Resistant Gastric Cancer Cells By Activating Mitochondrial Pathway In Vivo And Vitro.

INTRODUCTION: Gastric cancer remains an important cancer worldwide, and conventional chemotherapeutic drugs have the defects of drug resistance and cell toxicity. α-Hederin has been found to have certain therapeutic effects on various types of human cancers. However, studies on the α-hederin that exert biological activities on the cisplatin-resistant gastric cancer cells are limited. In this study, we evaluated the effects of α-hederin in HGC27/DDP and the potential mechanisms both in vivo and in vitro. METHODS: HGC27/DDP cells were cultured in DMEM/F12 medium. Cell proliferation and viability were assessed quantitatively using Cell Counting Kit-8. Cell invasion and migration were detected by Transwell invasion assay and wound healing assay. Cell apoptosis was examined by employing Hoechst 33258 Staining Kit and an Annexin V-PE apoptosis kit. Intracellular GSH levels were examined by using a GSH Assay Kit. DCFH-DA and JC-1 Kit were used to detect levels of intracellular reactive oxygen species (ROS) and changes in mitochondrial membrane potential (∆Ψm). The protein levels of Apaf-1, AIF, Bax, Bcl-2, Cyt C, Survivin, cleaved caspase-3, cleaved caspase-9, MMP-9 and MMP-2 were detected by Western blot analysis. The effect of α-hederin in vivo was observed by xenograft tumor models in nude mice. RESULTS: The α-hederin treatment significantly inhibited the proliferation in a dose- and time-dependent manner of HGC27/DDP and induced obvious apoptosis compared with the control group (P<0.05). Meanwhile, the ability of cells to invade and migrate was suppressed (P<0.05). The α-hederin induced the depletion of GSH (P<0.05) and the accumulation of intracellular ROS (P<0.05), changed the mitochondrial membrane potential (P<0.05), increased the Bax, Apaf-1, AIF, Cyt C, cleaved caspase-3 and cleaved caspase-9 expression and decreased the protein level of Bcl-2, survivin, MMP-9 and MMP-2 (P<0.05). Pretreatment with NAC (12 mM) enhanced the tendency and pretreatment with BSO (8 mM) attenuated the tendency above (P<0.05). Meanwhile, α-hederin inhibited xenograft tumor growth in vivo (P<0.05). CONCLUSION: Our study provides strong molecular evidence to support our hypothesis that α-hederin inhibits the proliferation and induces the apoptosis of HGC27/DDP cells by increasing the levels of intracellular ROS and triggering mitochondrial pathway activation.

Descending-SHIP2-mediated radiosensitivity enhancement through PI3K/Akt signaling pathway in laryngeal squamous cell carcinoma.

Laryngeal squamous cell carcinoma (LSCC) is the major type of laryngeal carcinoma. SHIP2 plays a critical role in malignant tumors and is associated with activation of PI3K/Akt signaling pathway. Here, we aimed to explore the impacts of SHIP2 on LSCC Hep-2 cells and the relationship between SHIP2 and radiotherapy. SHIP2 knockdown impairs cell proliferation, invasion, migration and promotes cell apoptosis in this study, suggesting the oncogenic role of SHIP2 in laryngeal cancer. Radiation not only has the similar effect on laryngeal cancer as SHIP2 knockdown, but also causes significant cell cycle G2 arrest, all of which can be significantly enhanced by SHIP2 knockdown. This enhancement effect cause by SHIP2 knockdown derive from the inactivation of PI3K/Akt signaling pathway along with its downstream proteins. Our finding revealed a novel mechanism for sensitivity to radiotherapy caused by SHIP2 knockdown that called descending-SHIP2-mediated radiosensitivity enhancement (DSMRSE).

Effect of lenalidomide on the human gastric cancer cell line SGC7901/vincristine Notch signaling.

AIM OF STUDY: To examine the function of lenalidomide (LEN) on the human multidrug resistance (MDR)-type gastric cancer line SGC7901/vincristine (VCR) via regulating Notch signaling. MATERIALS AND METHODS: Quantitative polymerase chain reaction was used for checking the genes of Notch, DNA methyltransferase (DNMT), RBP-J, Hes1/5, Deltex1, MDR/multidrug resistant protein (MRP); the cell proliferation and cell death were detected by cell counting kit-8 (CCK8) staining, Ki-67 expression, and propidium-iodide staining, and methylated DNA immunoprecipitation assay (MeDIP) was used for checking the 5 mC enrichment, indicating the DNA methylation of the Notch2 gene loci. RESULTS: LEN reduced the mRNA expression of Notch2 (P < 0.01) and increased the expression of the DNMT3A (P < 0.001) in SGC7901/VCR cell, suggesting the involvement of epigenetic regulation by DNMT3A on Notch2 gene expression. Consistently, Notch2 gene expression showed no obvious change between the LEN treatment and the control when the DNMT3A was knockdown using the interference of shRNA. The modulation of DNA methylation process on gene expression was then confirmed by 5 mC enrichment on Notch2 gene loci after LEN treatment. Furthermore, LEN could suppress the downstream genes in Notch2 signaling including RBP-J (P < 0.05), Hes1 (P < 0.001), and Deltex1 (P < 0.01). Due to the changes of gene expression pattern in Notch pathway, LEN showed a phenotype of cell proliferation suppression using CCK8 staining. Meanwhile, the expression of the genes associated with MDR and MRP was also significantly decreased (MDR, P < 0.01; MRP, P < 0.001) after LEN treatment. Therefore, inhibition of cell proliferation by LEN via Notch2 signaling combined with the MDR/MRP expression modulation contributes to the efficacy of LEN on the gastric cancer cell line SGC7901/VCR. CONCLUSION: The data implicate that LEN would be an effective chemical for the therapy of drug-resistant human gastric cancer cell and the gastric cancer patients.

Genes with mutation significance were highly associated with the clinical pattern of patients with breast cancer.

In the United States, breast cancer is the second leading cause of cancer death in women. Over the past 20 years, breast cancer incidence and mortality rates increased rapidly in developing regions. We aimed to identify the gene mutation patterns that associated with the clinical patterns, including survival status, histo-pathological classes and so forth, of breast cancer. We retrieved 1098 cases of the clinical information, and level-3 legacy data of mRNA expression level, protein expression data and mutation files from GDC data portal. The genes with mutation significance were obtained. We studied the impacts of mutation types on the expression levels of mRNA and protein. Different statistics methods were used to calculate the correlation between the mutation types and the expression data or histo-clinical measures. There were 24 genes with mutation significance identified. The most mutated genes were selected to study the role of specific mutations played on the patients with breast cancer. One interesting finding was the missense mutations on TP53 were related with high expression levels of mRNA and protein. The missense mutations on TP53 were highly related with the morphology, race, ER status, PR status and HER2 Status, while the truncated mutations were only related with the morphology, ER status and PR status. The missense mutation on PIK3CA was highly associated with the morphology, race, ER status and PR status. The mutants with different mutants and the wild type of the most mutated genes had different impacts on the histo-clinical measures that might help personalized therapy.

The association between metformin use and colorectal cancer survival among patients with diabetes mellitus: An updated meta-analysis.

OBJECTIVE: Recent studies have reported conflicting results on the correlation between metformin use and outcomes in patients with colorectal cancer (CRC). A meta-analysis was performed to evaluate the efficacy of metformin therapy on the prognosis of CRC patients with type 2 diabetes mellitus (T2DM). METHODS: We conducted a systematic search of PubMed, EMBASE, the Cochrane Library, and the Web of Science for related articles up to August 2016. Two investigators independently identified and extracted information. Pooled risk estimates [hazard ratios (HRs)] and 95% confidence intervals (CIs) were calculated using fixed-effects models. The risk of publication bias was assessed by examining funnel plot asymmetry as well as Egger's test and Begg's test. RESULTS: Of 81 articles identified, 8 retrospective cohort studies, representing 6098 cases of CRC patients with T2DM who used metformin and 4954 cases of CRC patients with T2DM who did not use metformin, were included in this meta-analysis. There was no significant heterogeneity and quality difference between studies. Metformin users had significantly improved overall survival (OS) (HR = 0.82, 95% CI: 0.77-0.87, P = 0.000). However, Metformin use cannot affect CRC-specific survival (HR = 0.84, 95% CI: 0.69-1.02, P = 0.079) compared to non-users. CONCLUSION: This meta-analysis suggests that metformin use may improve survival among CRC patients with T2DM. However, prospective controlled studies are still needed to rigorously evaluate the efficacy of metformin as an anti-tumor agent.

Associations between the Genetic Polymorphisms of Osteopontin Promoter and Susceptibility to Cancer in Chinese Population: A Meta-Analysis.

BACKGROUND AND AIM: Several studies have been conducted to examine the associations between osteopontin (OPN) promoter gene SPP1 polymorphisms with human cancers in Chinese population, but the results remain inconsistent. The aim of this meta-analysis is to clarify the associations between SPP1 polymorphisms and cancer susceptibility. METHODS: All eligible case-control studies published up to March 2015 were identified by searching PubMed, Web of Science, Embase, and Cochrane Library without language restrictions. Pooled odds ratio (OR) and 95% confidence interval (95% CI) were calculated using fixed- or random-effect model. RESULTS: A total of 11 case-control studies were included; of those, there were eleven studies (3130 cases and 3828 controls) for -443T>C polymorphism, ten studies (3019 cases and 3615 controls) for -156G>GG polymorphism, eight studies (2258 cases and 2846 controls) for -66T>G polymorphism. Overall, no evidence indicated that the -443 T>C polymorphism was associated with cancer risk (OR = 0.93, 95%CI 0.62-1.38 for dominant model, OR = 1.06, 95%CI 0.73-1.55 for recessive model, OR = 0.88, 95%CI 0.62-1.26 for CT vs TT model, OR = 1.03, 95%CI 0.61-1.73 for CC vs TT model). While, a significantly increase risk was found for -156 G>GG polymorphism (OR = 1.22, 95%CI 1.10-1.35 for dominant model, OR = 1.25, 95%CI 1.10-1.41 for recessive model, OR = 1.18, 95%CI 1.06-1.32 for GGG vs GG model, OR = 1.35, 95%CI 1.09-1.68 for GGGG vs GG model). For -66T>G polymorphism, we found a decrease risk of cancer (OR = 0.84, 95% CI 0.71-0.98 for dominant model), but this result changed (OR = 0.93, 95% CI 0.77-1.12 for dominant model) when we excluded a study. CONCLUSION: This meta-analysis suggests that in Chinese population the -156G>GG polymorphism of SPP1 might be a risk factor for human cancers, while -443T>C mutation is not associated with cancer risk. For -66T>G polymorphism, it may be a protective factor for human cancers.

[Cyclooxygenase-2 -765G>C polymorphism and susceptibility to colorectal cancer: a meta-analysis].

OBJECTIVE: To explore the correlation between polymorphism of cyclooxygenase-2 (COX-2) -765G>C and susceptibility to colorectal cancer. METHODS: All eligible case-control studies published up to March 2013 were searched out from PubMed, EMABSE, CJFD, CBM, CNKI, VIP and WanFang databases, while 99 articles were concluded. Two reviewers independently identified the literature according to inclusion and exclusion criteria. Meta-analysis was performed using RevMan 5.1 and Stata 12.0 software. RESULTS: A total of eleven studies comprising 3432 cases and 5286 controls were finally included. The included studies showed good homogeneity in the three genetic models, except the model of GC/GG genotype (I(2) = 52%, P = 0.03). Overall, there were no significant association between polymorphism of COX-2-765G>C and the susceptibility to colorectal cancer (dominant model: (GC+CC)/GG: OR = 1.08, 95%CI:0.96-1.21; recessive model:CC/(GC+GG): OR = 1.09, 95%CI:0.76-1.56; GC/GG: OR = 1.05, 95%CI:0.87-1.28; CC/GG: OR = 1.11, 95%CI:0.77-1.60). In stratification analysis by ethnicity, we observed that the polymorphism of COX-2 -765G>C could increase the susceptibility to colorectal cancer among yellow populations ((GC+CC)/GG: OR = 1.41, 95%CI:1.15-1.75; GC/ GG: OR = 1.48, 95%CI:1.15-1.90), but there was no significant association found among Caucasian populations. CONCLUSION: This meta-analysis suggested that the polymorphism of COX-2 -765G>C may increase the susceptibility to colorectal cancer in the yellow population.

Associations between PTPN2 polymorphisms and susceptibility to ulcerative colitis and Crohn's disease: a meta-analysis.

OBJECTIVE: Ulcerative colitis (UC) and Crohn's disease (CD) result from an interaction between genetic and environmental factors. Though several polymorphisms have been identified in PTPN2, their roles in the incidence of UC and CD are conflicting. This meta-analysis was aimed to clarify the impact of these polymorphisms on UC and CD risk. METHOD: PubMed, EMBASE, Cochrane Library and CBM were searched until 23 July 2013 for eligible studies on three PTPN2 polymorphisms: rs2542151, rs1893217 and rs7234029. Data were extracted, and pooled odd ratios (ORs) as well as 95 % confidence intervals (95 % CIs) were calculated. CONCLUSION: The meta-analysis indicated that rs2542151, rs1893217 and rs1893217 were associated with increased CD risk, while the former was associated with increased UC risk. The differences in age of onset and ethnic groups may influence the associations. Gene-gene and gene-environment interactions should be investigated in the future. RESULTS: Seventeen studies with 18,308 cases and 20,406 controls were included. Significant associations were found between rs2542151 polymorphism and CD susceptibility (OR = 1.22, 95 % CI, 1.15-1.30, I (2) = 32 %), as well as between rs2542151 and UC susceptibility (OR = 1.16, 95 % CI, 1.07-1.25, I (2) = 39 %). A similar result was found in Caucasians, but not in Asians. Moreover, a significant increase in CD risk for all carriers of the minor allele of rs1893217 (OR = 1.45, 95 % CI, 1.23-1.70, I (2) = 0 %) and rs7234029 (OR = 1.36, 95 % CI, 1.16-1.59, I (2) = 0 %) were found. For children, the rs1893217 polymorphism appeared to confer susceptibility to CD (OR = 1.56, 95 % CI, 1.28-1.89, I (2) = 0 %).

Proton pump inhibitor for non-erosive reflux disease: a meta-analysis.

AIM: To evaluate the efficacy, safety and influential factors of proton pump inhibitor (PPI) treatment for non-erosive reflux disease (NERD). METHODS: PubMed, MEDLINE, EMBASE and the Cochrane Library were searched up to April 2013 to identify eligible randomized controlled trials (RCTs) that probed into the efficacy, safety and influential factors of PPI treatment for NERD. The rates of symptomatic relief and adverse events were measured as the outcomes. After RCT selection, assessment and data collection, the pooled RRs and 95%CI were calculated. This meta-analysis was performed using the Stata 12.0 software (Stata Corporation, College Station, Texas, United States). The level of evidence was estimated by the Grading of Recommendations Assessment, Development and Evaluation system. RESULTS: Seventeen RCTs including 6072 patients met the inclusion criteria. The results of the meta-analysis showed that PPI treatment was significantly superior to H2 receptor antagonists (H2RA) treatment (RR = 1.629, 95%CI: 1.422-1.867, P = 0.000) and placebo (RR = 1.903, 95%CI: 1.573-2.302, P = 0.000) for the symptomatic relief of NERD. However, there were no obvious differences between PPI and H2RA (RR = 0.928, 95%CI: 0.776-1.110, P = 0.414) or PPI and the placebo (RR = 1.000, 95%CI: 0.896-1.116, P = 0.997) regarding the rate of adverse events. The overall rate of symptomatic relief of PPI against NERD was 51.4% (95%CI: 0.433-0.595, P = 0.000), and relief was influenced by hiatal hernia (P = 0.030). The adverse rate of PPI against NERD was 21.0% (95%CI: 0.152-0.208, P = 0.000), and was affected by hiatal hernia (P = 0.081) and drinking (P = 0.053). CONCLUSION: PPI overmatched H2RA on symptomatic relief rate but not on adverse rate for NERD. Its relief rate and adverse rate were influenced by hiatal hernia and drinking.

Multi-equilibrium property of metabolic networks: SSI module.

BACKGROUND: Revealing the multi-equilibrium property of a metabolic network is a fundamental and important topic in systems biology. Due to the complexity of the metabolic network, it is generally a difficult task to study the problem as a whole from both analytical and numerical viewpoint. On the other hand, the structure-oriented modularization idea is a good choice to overcome such a difficulty, i.e. decomposing the network into several basic building blocks and then studying the whole network through investigating the dynamical characteristics of the basic building blocks and their interactions. Single substrate and single product with inhibition (SSI) metabolic module is one type of the basic building blocks of metabolic networks, and its multi-equilibrium property has important influence on that of the whole metabolic networks. RESULTS: In this paper, we describe what the SSI metabolic module is, characterize the rates of the metabolic reactions by Hill kinetics and give a unified model for SSI modules by using a set of nonlinear ordinary differential equations with multi-variables. Specifically, a sufficient and necessary condition is first given to describe the injectivity of a class of nonlinear systems, and then, the sufficient condition is used to study the multi-equilibrium property of SSI modules. As a main theoretical result, for the SSI modules in which each reaction has no more than one inhibitor, a sufficient condition is derived to rule out multiple equilibria, i.e. the Jacobian matrix of its rate function is nonsingular everywhere. CONCLUSIONS: In summary, we describe SSI modules and give a general modeling framework based on Hill kinetics, and provide a sufficient condition for ruling out multiple equilibria of a key type of SSI module.