CYP1B1 Polymorphisms and K-ras Mutations in Patients with Pancreatic Ductal Adenocarcinoma

The frequency of CYP1B1 polymorphisms in pancreatic cancer has never been reported. There is also no evidence on the relationship between CYP1B1 variants and mutations in ras genes (K-, H- or N-ras) in any human neoplasm. We analyzed the following CYP1B1 polymorphisms in 129 incident cases of pancreatic ductal adenocarcinoma (PDA): the m1 allele (Val to Leu at codon 432) and the m2 allele (Asn to Ser at codon 453). The calculated frequencies for the m1 Val and m2 Asn alleles were 0.45 and 0.68, respectively. CYP1B1 genotypes were out of Hardy–Weinberg equilibrium; this was largely due to K-ras mutated PDA cases. The Val/Val genotype was over five times more frequent in PDA cases with a K-ras mutation than in wild-type cases (OR = 5.25; P = 0.121). In PDA, polymorphisms in CYP1B1 might be related with K-ras activation pathways. PANKRAS II study group—Members of the multicenter prospective study on the role of K-ras and other genetic alterations in the diagnosis, prognosis and etiology of pancreatic and biliary diseases (PANKRAS II) study group are mentioned in previous publications.     

Demystifying Excess Immune Response in COVID-19 to Reposition an Orphan Drug for Down-Regulation of NF-κB: A Systematic Review

The immunological findings from autopsies, biopsies, and various studies in COVID-19 patients show that the major cause of morbidity and mortality in COVID-19 is excess immune response resulting in hyper-inflammation. With the objective to review various mechanisms of excess immune response in adult COVID-19 patients, Pubmed was searched for free full articles not related to therapeutics or co-morbid sub-groups, published in English until 27 October 2020, irrespective of type of article, country, or region. Joanna Briggs Institute’s design-specific checklists were used to assess the risk of bias. Out of 122 records screened for eligibility, 42 articles were included in the final review. The review found that eventually, most mechanisms result in cytokine excess and up-regulation of Nuclear Factor-κB (NF-κB) signaling as a common pathway of excess immune response. Molecules blocking NF-κB or targeting downstream effectors like Tumour Necrosis Factor α (TNFα) are either undergoing clinical trials or lack specificity and cause unwanted side effects. Neutralization of upstream histamine by histamine-conjugated normal human immunoglobulin has been demonstrated to inhibit the nuclear translocation of NF-κB, thereby preventing the release of pro-inflammatory cytokines Interleukin (IL) 1β, TNF-α, and IL-6 and IL-10 in a safer manner. The authors recommend repositioning it in COVID-19.     

Clinicopathological and Prognostic Value of Programmed Cell Death 1 Expression in Hepatitis B Virus-related Hepatocellular Carcinoma: A Meta-analysis

Background and AimsThe efficacy of targeted programmed cell death 1/programmed death ligand 1 (PD-1/PD-L1) monoclonal antibodies (mAbs) has been confirmed in many solid malignant tumors. The overexpression of PD-1/PD-L1 serves as a biomarker to predict prognosis and clinical progression. However, the role of PD-1 in patients with hepatitis B virus-related hepatocellular carcinoma (HBV-HCC) remains indeterminate. Given that HBV is the most important cause for HCC, this study aimed to investigate the prognostic and clinicopathological value of PD-1 in HBV-HCC via a meta-analysis.MethodsWe searched PubMed, Embase, Scopus, the Cochrane Library, Web of Science and Google Scholar up to January 2021 for studies on the correlation between clinicopathology/prognosis and PD-1 in patients with HBV-HCC. The pooled hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated to investigate the prognostic significance of PD-1 expression. The odds ratios (ORs) and 95% CIs were determined to explore the association between PD-1 expression and clinicopathological features.ResultsOur analysis included seven studies with 658 patients, which showed that high PD-1 expression was statistically correlated with poorer overall survival (HR=2.188, 95% CI: [1.262–3.115], p<0.001) and disease-free survival (HR=2.743, 95% CI: [1.980–3.506], p<0.001). PD-1 overexpression was correlated with multiple tumors (OR=2.268, 95% CI: [1.209–4.257], p=0.011), high level of alpha fetoprotein (AFP; OR=1.495, 95% CI: [1.005–2.223], p=0.047) and advanced Barcelona Clinic Liver Cancer (BCLC) stage (OR=3.738, 95% CI: [2.101–6.651], p<0.001).ConclusionsOur meta-analysis revealed that the high level of PD-1 expression was associated with multiple tumors, high level of AFP and advanced BCLC stage. It significantly predicted a poor prognosis of HBV-HCC, which suggests that anti-PD-1 therapy for HBV-HCC patients is plausible.     

Immunoglobulin Response and Prognostic Factors in Repeated SARS-CoV-2 Positive Patients: A Systematic Review and Meta-Analysis

With repeated positivity being an undiscovered and major concern, we aimed to evaluate which prognostic factors may impact repeated SARS-CoV-2 positivity (RSP) and their association with immunoglobulin detectability among recovered patients. A systematic literature search was performed on 5 April 2021. Cohort studies with risk factors for repeated RSP or information about the immunoglobulin response (immunoglobulin M (IgM) and/or immunoglobulin G (IgG)) were included in this analysis. The main examined risk factors were severity of the initial infection, body mass index (BMI), length of hospitalization (LOH), age, and gender, for which we pooled mean differences and odds ratios (ORs). Thirty-four cohort studies (N = 9269) were included in our analysis. We found that increased RSP rate might be associated with IgG positivity; IgG presence was higher in RSP patients (OR: 1.72, CI: 0.87–3.41, p = 0.117). Among the examined risk factors, only mild initial disease course showed a significant association with RSP (OR: 0.3, CI: 0.14–0.67, p = 0.003). Age, male gender, BMI, LOH, and severity of the first episode do not seem to be linked with repeated positivity. However, further prospective follow-up studies focusing on this topic are required.     

Human Adenovirus Type 26 Induced IL-6 Gene Expression in an αvβ3 Integrin- and NF-κB-Dependent Manner

The low seroprevalent human adenovirus type 26 (HAdV26)-based vaccine vector was the first adenovirus-based vector to receive marketing authorization from European Commission. HAdV26-based vaccine vectors induce durable humoral and cellular immune responses and, as such, represent a highly valuable tool for fighting infectious diseases. Despite well-described immunogenicity in vivo, the basic biology of HAdV26 still needs some refinement. The aim of this study was to determine the pro-inflammatory cytokine profile of epithelial cells infected with HAdV26 and then investigate the underlying molecular mechanism. The expression of studied genes and proteins was assessed by quantitative polymerase chain reaction, western blot, and enzyme-linked immunosorbent assay. Confocal microscopy was used to visualize HAdV26 cell uptake. We found that HAdV26 infection in human epithelial cells triggers the expression of pro-inflammatory cytokines and chemokines, namely IL-6, IL-8, IL-1β, and TNF-α, with the most pronounced difference shown for IL-6. We investigated the underlying molecular mechanism and observed that HAdV26-induced IL-6 gene expression is αvβ3 integrin dependent and NF-κB mediated. Our findings provide new data regarding pro-inflammatory cytokine and chemokine expression in HAdV26-infected epithelial cells, as well as details concerning HAdV26-induced host signaling pathways. Information obtained within this research increases our current knowledge of HAdV26 basic biology and, as such, can contribute to further development of HAdV26-based vaccine vectors.     

TNF-Mediated Inhibition of Classical Swine Fever Virus Replication Is IRF1-, NF-κB- and JAK/STAT Signaling-Dependent

The sera from pigs infected with virulent classical swine fever virus (CSFV) contain substantial amounts of tumor necrosis factor (TNF), a prototype proinflammatory cytokine with pleiotropic activities. TNF limits the replication of CSFV in cell culture. In order to investigate the signaling involved in the antiviral activity of TNF, we employed small-molecule inhibitors to interfere specifically with JAK/STAT and NF-κB signaling pathways in near-to-primary endothelial PEDSV.15 cells. In addition, we knocked out selected factors of the interferon (IFN) induction and signaling pathways using CRISPR/Cas9. We found that the anti-CSFV effect of TNF was sensitive to JAK/STAT inhibitors, suggesting that TNF induces IFN signaling. Accordingly, we observed that the antiviral effect of TNF was dependent on intact type I IFN signaling as PEDSV.15 cells with the disrupted type I IFN receptor lost their capacity to limit the replication of CSFV after TNF treatment. Consequently, we examined whether TNF activates the type I IFN induction pathway. With genetically modified PEDSV.15 cells deficient in functional interferon regulatory factor 1 or 3 (IRF1 or IRF3), we observed that the anti-CSFV activity exhibited by TNF was dependent on IRF1, whereas IRF3 was dispensable. This was distinct from the lipopolysaccharide (LPS)-driven antiviral effect that relied on both IRF1 and IRF3. In agreement with the requirement of IRF1 to induce TNF- and LPS-mediated antiviral effects, intact IRF1 was also essential for TNF- and LPS-mediated induction of IFN-β mRNA, while the activation of NF-κB was not dependent on IRF1. Nevertheless, NF-κB activation was essential for the TNF-mediated antiviral effect. Finally, we observed that CSFV failed to counteract the TNF-mediated induction of the IFN-β mRNA in PEDSV.15 cells, suggesting that CSFV does not interfere with IRF1-dependent signaling. In summary, we report that the proinflammatory cytokine TNF limits the replication of CSFV in PEDSV.15 cells by specific induction of an IRF1-dependent antiviral type I IFN response.     

Differential Effects of ET-1, ET-2, and ET-3 on Pancreatic Microcirculation, Tissue Integrity, and Inflammation

The differential effects of endothelin-1, -2, and -3 (ET-1, ET-2, and ET-3) on pancreatic microcirculation, pancreatic tissue integrity, and an initial inflammatory response, which are three distinct characteristics of acute necrotizing pancreatitis, were investigated in a dose-dependent manner in rats using in vivo microscopy. Red blood cell (RBC) velocity and functional capillary density (FCD) were estimated after topical superfusion of the pancreas with ET-1, ET-2, and ET-3 (100, 10, 1 pmol), revealing that ET-1 (100, 10, 1 pmol) or high ET-2 (100 pmol) and ET-3 (100 pmol) cause a dose-related deterioration of exocrine nutritive pancreatic blood flow. Analysis of pancreatic exocrine tissue damage employing the Spormann score displayed that the ET-mediated microcirculatory impairment was paralleled by dose-dependent tissue damage, which was significant compared to the control group (topical superfusion with 1 ml, saline solution 0.9%). Estimation of pancreatic postcapillary leukocyte accumulation by histomorphologically counting choracetate esterase (CAE) stained leukocytes in 50 high-power fields per animal demonstrated a significant increase in postcapillary accumulation of white blood cells, after topical administration of ET-1, ET-2, and ET-3 compared to controls. In contrast to ET-caused effects on microcirculation and tissue impairment, quantitative analysis of postcapillary leukocyte accumulation revealed the most pronounced effect after ET-2 administration but not after ET-1 administration. This demonstrates that ET-1, ET-2, and ET-3 are all able to mediate microcirculatory impairment, tissue damage, and inflammation. However, ET-3-induced damaging effects are less pronounced, while ET-1 most severely alters microcirculation and ET-2 preferentially induces leukocyte-dependent inflammation.     

Clinicopathologic Significance and Prognostic Value of B7 Homolog 1 in Gastric Cancer: A Systematic Review and Meta-Analysis

Immunologic checkpoint marker B7 homolog 1 (B7-H1) plays a fundamental role in the initiation and progression of gastric cancer (GC); however, the clinicopathologic significance and prognostic value of B7-H1 in GC remains controversial. In this study, we aimed to assess their relationship through a meta-analysis.Medline/PubMed, EMBASE, the Cochrane Library databases, and Grey literature were searched up to August 10, 2015, for eligible studies of the association between B7-H1 expression and overall survival in GC. The hazard ratio and its 95% confidence interval (CI) were calculated from the included studies. Moreover, the odds ratio (OR) was also extracted to evaluate the association between the clinicopathologic parameters of participants and B7-H1 expression.Five studies involving 481 patients were included in the meta-analysis. The pooled results showed that positive B7-H1 expression was a negative predictor for overall survival with hazard ratio of 1.74 (95% CI: 1.40–2.17; P_{heterogeneity} = 0.146) in GC. Additionally, increased B7-H1 was found to be significantly associated with positive lymph node metastasis (OR = 2.61, 95% CI: 1.78–3.84; P_{heterogeneity} = 0.004) and poorer tumor stage (OR = 2.28, 95% CI: 1.39–3.74; P_{heterogeneity} = 0.006); however, higher B7-H1 expression was not significantly correlated with poorer tumor differentiation (OR = 1.29, 95% CI: 0.90–1.86; P_{heterogeneity} = 0.013) and bigger tumor size (OR = 1.18, 95% CI: 0.81–1.73; P_{heterogeneity} = 0.104).The meta-analysis suggested that B7-H1 could act as a significant biomarker in the poor prognosis of gastric carcinoma.     

Prognostic value of aldo-keto reductase family 1 member B10 (AKR1B10) in digestive system cancers: A meta-analysis

Background:Numbers of studies have reported that the expression of aldo-keto reductase family 1 member B10 (AKR1B10) is abnormal in digestive system cancers, and could be used as a prognostic biomarker. However, the results are argued. Therefore, we conduct a meta-analysis to comprehensively evaluate the prognostic value of high AKR1B10 expression for overall survival (OS), disease specific survival (DSS), and disease-free survival/recurrence-free survival (DFS/PFS) in digestive system cancers.Methods:Hazard ratios (HRs) with its 95% confidence intervals (CIs) were calculated to assess the prognostic value of AKR1B10 by using the random effects model. The STATA version 12.0 software were used to perform all the analyses.Results:Eleven articles including 1428 patients involved in this meta-analysis. The pooled analysis suggested that high AKR1B10 expression was not associated with OS (HR: 1.18; 95% CI: 0.69–2.00) and DFS/PFS (HR: 1.08, 95% CI: 0.67–1.76) in digestive system cancers. However, Further analysis revealed that high AKR1B10 expression indicated poor OS in oral squamous cell carcinomas (OSCC) (HR: 2.92, 95% CI: 1.86–4.58) and favorable DSS in hepatocellular carcinoma (HCC) (HR: 0.71, 95% CI: 0.52–0.97).Conclusions:The prognostic value of high AKR1B10 expression varied in different types of digestive system cancers. Further studies exploring the prognostic role of AKR1B10 in digestive system cancers are needed.     

CDX2与DNMT1 mRNA在胃癌组织中的表达及临床意义

目的:研究尾型同源盒转录因子2(CDX2)mRNA和DNA甲基化转移酶1(DNMT1)mRNA在胃癌组织中的表达,探讨其临床意义.方法:应用实时定量PCR(qRT-PCR)检测60例患者胃癌与相应远癌胃组织中CDX2与DNMT 1mRNA的表达,并分析其与胃癌临床病理特征的关系以及两者表达的相关性.结果:CDX2和DNMT1 mRNA在远癌胃组织中表达较低,在胃癌组织中表达显著升高;CDX2 mRNA的表达与胃癌的Lauren分型、临床TNM分期和淋巴结转移等因素有关(P<0.05),而DNMT1 mRNA的表达与分化程度、临床TNM分期和淋巴结转移等因素有关(P<0.05).两者在胃癌中的表达呈明显负相关(r=-0.385,P<0.05).结论:胃癌组织中CDX2表达下调与病情进展有关,DNMT1可能参与该过程的调控.     

干扰素α2b联合拉米夫定治疗慢性乙型肝炎患者血清HBeAg阴转和肝功能的变化*

目的分析抗病毒治疗对慢性乙型肝炎患者HBeAg阴转及肝功能的影响。方法选择2013年2月至2013年11月在本院进行治疗的慢性乙型肝炎患者130例,随机分为观察组和对照组各65例。给予对照组患者干扰素α2b治疗,观察组在此基础上联合拉米夫定治疗。采用ELISA法检测血清乙型肝炎病毒标记物;采用实时荧光定量PCR法检测HBV DNA,分别在治疗6个月和12个月观察患者肝功能、HBV DNA阴转率和HBeAg转阴率的变化。结果在治疗6个月时,观察组谷丙转氨酶和谷草转氨酶水平分别为（45.7±23.8） U/L和（62.3±23.7） U/L,显著低于对照组的[（55.8±25.3） U/L和（73.2±25.3） U/L,P<0.05];在治疗12个月时,观察组谷丙转氨酶和谷草转氨酶水平分别为（32.7±19.4） U/L和（46.4±6.3） U/L,显著低于对照组的[（44.6±17.3） U/L和（52.8±5.2） U/L,P<0.05];两组患者血清HBV DNA阴转率和HBeAg阴转率的差异无统计学差异（P>0.05）。结论抗病毒治疗能够有效地改善慢性乙型肝炎患者肝功能,促进HBeAg阴转,使用干扰素α2b联合拉米夫定治疗的效果更为显著,且安全性较高。     

恩替卡韦联合聚乙二醇干扰素或胸腺素治疗代偿期乙型肝炎肝硬化2年疗效随访*

目的 探讨应用恩替卡韦联合聚乙二醇干扰素α-2a（PEG-IFNα-2a）或胸腺素治疗代偿期乙型肝炎肝硬化患者的效果。方法 在88例代偿期乙型肝炎肝硬化患者中,接受恩替卡韦治疗者38例,接受恩替卡韦联合PEG-IFNα-2a治疗者17例,联合胸腺素治疗者33例,随访2年。结果 恩替卡韦治疗组治疗前和治疗104 w末血清HBV DNA水平分别为（5.6±1.7） IU/ml和（1.0±0.7） IU/ml（P<0.05）,联合PEG-IFNα-2a组分别为（5.8±1.3） IU/ml和（1.0±0.7） IU/ml（P<0.05）,联合胸腺素组分别为（6.1±2.0） IU/ml和（1.0±0.9） IU/ml（P<0.05）;恩替卡韦组治疗前和治疗104 w末血清ALB水平分别为（43.1±5.4） g/L和（46.9±4.9） g/L（P<0.05）,联合胸腺素组分别为（43.0±4.0） g/L和（46.8±5.4） g/L（P<0.05）;三组治疗前和治疗104 w末肝脏硬度值和INR无统计学差异（P>0.05）。结论 恩替卡韦能有效抑制HBV DNA复制,维持代偿期肝硬化患者的肝功能,本研究结果看不出联合用药有任何好处,需要进一步观察。