Abstract Association between alcohol intake and Coronavirus disease 2019 (COVID-19) risk has been explored in several observational studies, but the results are still controversial. These associations may be biased by reverse causation or confounded by other environmental exposures. To avoid potential biases, we used Mendelian randomization (MR) method to evaluate whether alcohol intake is the causal risk factor for COVID-19. Two-sample MR analyses were performed utilizing summary data from the UK Biobank with 38,984 COVID-19 patients and 1,644,784 control participants. Both inverse-variance weighted (IVW) and genetic risk score (GRS) methods were applied to estimate the relationship including COVID-19 vs. general population, hospitalized COVID-19 vs. not hospitalized COVID-19, hospitalized COVID-19 vs. general population, and severe COVID-19 vs. general population. Additionally, we conducted various sensitivity analyses to evaluate the impact of assumptions on the findings and ensure the robustness of the results. Using 80 single nucleotide polymorphisms as instrumental variables, we found that alcohol intake was not significantly associated with the occurrence of COVID-19 in both IVW and GRS methods (IVW: beta = 0.0372; 95% CI − 0.1817 to 0.2561; P = 0.74; GRS: beta = 0.0372, 95% CI − 0.1737 to 0.2481, P = 0.73). Furthermore, similar results were also observed in comparison hospitalized COVID-19 with not hospitalized COVID-19 (IVW: beta = − 0.3625; 95% CI − 1.4151 to 0.6900; P = 0.50; GRS: beta = − 0.3625, 95% CI − 1.3633 to 0.6383, P = 0.48), hospitalized COVID-19 with general population (IVW: beta = − 0.1203; 95% CI − 0.5997 to 0.3591; P = 0.62; GRS: beta = − 0.1203, 95% CI − 0.5352 to 0.2946, P = 0.57), and severe COVID-19 with general population (IVW: beta = 0.2963; 95% CI − 0.3682 to 0.9607; P = 0.38; GRS: beta = 0.2963, 95% CI − 0.3240 to 0.9166, P = 0.35). Besides, the heterogeneity and sensitivity tests suggested absence of bias due to pleiotropy. Our results highlight no evidence to support the causal role of alcohol consumption in COVID-19 risk. Further large-scale prospective studies are warranted to replicate our findings.
Abstract Background Recent data indicated that macrophages may mutually interact with cancer cells to promote tumor progression and chemoresistance, but the interaction in cholangiocarcinoma (CCA) is obscure. Methods 10x Genomics single-cell sequencing technology was used to identified the role of macrophages in CCA. Then, we measured the expression and prognostic role of macrophage markers and aPKC ɩ in 70 human CCA tissues. Moreover, we constructed monocyte-derived macrophages (MDMs) generated from peripheral blood monocytes (PBMCs) and polarized them into M1/M2 macrophages. A co-culture assay of the human CCA cell lines (TFK-1, EGI-1) and differentiated PBMCs-macrophages was established, and functional studies in vitro and in vivo was performed to explore the interaction between cancer cells and M2 macrophages. Furthermore, we established the cationic liposome-mediated co-delivery of gemcitabine and aPKC ɩ -siRNA and detect the antitumor effects in CCA. Results M2 macrophage showed tumor-promoting properties in CCA. High levels of aPKC ɩ expression and M2 macrophage infiltration were associated with metastasis and poor prognosis in CCA patients. Moreover, CCA patients with low M2 macrophages infiltration or low aPKC ɩ expression benefited from postoperative gemcitabine-based chemotherapy. Further studies showed that M2 macrophages-derived TGFβ1 induced epithelial-mesenchymal transition (EMT) and gemcitabine resistance in CCA cells through aPKC ɩ -mediated NF-κB signaling pathway. Reciprocally, CCL5 was secreted more by CCA cells undergoing aPKC ɩ -induced EMT and consequently modulated macrophage recruitment and polarization. Furthermore, the cationic liposome-mediated co-delivery of GEM and aPKC ɩ -siRNA significantly inhibited macrophages infiltration and CCA progression. Conclusion our study demonstrates the role of Macrophages-aPKC ɩ -CCL5 Feedback Loop in CCA, and proposes a novel therapeutic strategy of aPKC ɩ -siRNA and GEM co-delivered by liposomes for CCA.
Cholangiocarcinoma (CCA) invasion and metastasis are the primary causes of poor survival rates in patients. The epithelial-mesenchymal transition (EMT) is a crucial step in cancer invasion and metastasis. However, it is still unclear of the molecular mechanism. In this study, the expression of 14-3-3ζ and atypical protein kinase C-ι (aPKC-ι) was further detected in CCA tissues and cell lines. Meanwhile, we established the EMT model of CCA cells and investigated 14-3-3ζ and aPKC-ι co-regulatory effect on the EMT in vitro and in vivo. Further, we identified the downstream molecular glycogen synthase kinase 3 beta (GSK-3β)/Snail signalling pathway that contribute to regulating the EMT. Our data showed that the expression of 14-3-3ζ and aPKC-ι was synergistically increased in CCA tissues compared with adjacent noncancerous tissues and was intimately associated with differentiation and the tumour-node-metastasis (TNM) stage. Multivariate Cox regression analysis indicated that high 14-3-3ζ and aPKC-ι expression separately predicted a poor prognosis and were independent prognostic indicators in patients with CCA. The CO-IP experiment confirmed that the mutual binding relationship between 14-3-3ζ and aPKC-ι. Small interfering RNAs and siRNA rescue experiment demonstrated that 14-3-3ζ and aPKC-ι regulated each other. In addition, 14-3-3ζ and aPKC-ι pretreatment by si-RNA inhibit the phosphorylated GSK-3β and Snail expression during EMT. Meanwhile, silence of 14-3-3ζ or aPKC-ι suppressed CCA cells migration, metastasis and proliferation in vitro and in vivo. Our study demonstrates that 14-3-3ζ and aPKC-ι synergistically facilitate EMT of CCA via GSK-3β/Snail signalling pathway, and may be potential therapeutic target for CCA.
Objective To investigate the management of traumatic bile duct injury.Methods The clinical data of 26 patients with traumatic bile duct injury were retrospectively analyzed.All the patients were admitted to the Tongji Hospital of the Huazhong University of Science and Technology from July 2009 to May 2014.All the 26 patients had the history of trauma.The trauma of the patients were typed according to the Mattox injury typing system.Besides anti-shock treatment,cholecystectomy,bile duct repair,end-to-end anastomosis of bile duct,choledochojejunostomy and quadrate lobectomy + hilar bile duct reshaping + hepaticojejunostomy were selected according to the site and degree of the injury.Symptomatic treatment was applied to patients who were combined with other organs injury.Patients were followed up via out-patient examination and telephone interview till October 2014.Results Twenty-six patients received exploratory laparotomy,and gallbladder injury was detected in 15 patients,common bile duct injury in 5 patients,common hepatic duct injury in 3 patients,left hepatic duct injury in 2 patients,right hepatic duct in 1 patient.Eleven patients were combined with hepatic rupture,1 with splenic rupture,5 with renal rupture,4 with small intestinal rupture.Eleven patients were with type Ⅰ bile duct injury,4 with type Ⅱ bile duct injury,8 with type Ⅳ bile duct injury and 3 with type Ⅴ bile duct injury.Of the 15patients with gallbladder injury,5 patients with slight bruise of the gallbladder did not receive cholecystectomy.Six patients and 4 patients with type Ⅰ and Ⅱ bruise of the gallbladder received cholecystectomy.Of the 11 patients with hepatic and bile duct injury,5 patients with type Ⅳ received bile duct repair + T tube drainage,1 patient with type Ⅳ received end-to-end bile duct anastomosis + T tube drainage,1 patient with type Ⅳ received biliojejunostomy and 1 patient with type Ⅳ received quadrate lobectomy + hilar bile duct reshaping + hepatojejunostomy; 3 patients with type Ⅴ received biliojejunostomy.Eleven patients additionally received repair of the liver or hepatectomy,1 received splenectomy,5 received nephrectomy,4 received partial small bowel resection + endto-end anastomosis.One patient died of hemorrhagic shock perioperatively; 3 patients were complicated with bile leakage,1 with incisional infection,and they were cured by symptomatic treatment.Twenty-five patients were followed up at postoperative month 1,3,6,12,and no patient was complicated with delayed bile leakage and biliary stricture recurrence.Conclusions Traumatic bile duct injury is often diagnosed during the operation.Patients with traumatic bile duct are often combined with shock and other organs injury.As for the treatment,laparotomy should be applied as soon as possible on the base of anti-shock treatment,and the appropriate method for biliary reconstruction should be selected according to the site and degree of injury.
Key words:
Bile duct injury; Trauma; Management
Background Although there were a variety of strategies for the alimentary tract reconstruction of patients with gastric cancer who underwent laparoscopic radical distal gastrectomy, it remains controversial regarding which procedure is optimal. We developed a simple technique for Roux-en-Y reconstruction during laparoscopic surgery and evaluated its technical feasibility and safety. Methods Seventy-one cases of modified Roux-en-Y reconstructions after laparoscopic radical distal gastrectomy were consecutively performed in our hospital, from November 2020 to March 2022. A retrospective review of medical data was conducted. Intraoperative and postoperative outcomes, including operation time and incidence of postoperative complications, were collected and analyzed. Results All procedures of laparoscopic distal gastrectomy with D2 lymph node dissection were successfully completed without any intraoperative complication. The mean number of retrieved lymph node was 38.8 ± 10.6. Mean operative time was 223.5 ± 42.4 min, whereas intraoperative blood loss was 102.2 ± 96.3 ml. No postoperative mortality was recorded. Six patients (8.5%) experienced postoperative complications and were managed conservatively. In addition, only two patients (2.8%) required rehospitalization during a median short-term follow-up period of 6 months. Conclusions The modified method is a simple and safe approach for laparoscopic radical distal gastrectomy.
Several recent studies have reported that a few patients had positive SARS-CoV-2 RNA tests after hospital discharge. The high-risk factors associated with these patients remain to be identified. A total of 463 patients with COVID-19 discharged from Leishenshan Hospital in Wuhan, China, between February 8 and March 8, 2020 were initially enrolled, and 351 patients with at least two weeks of follow-up were finally included. Seventeen of the 351 discharged patients had positive tests for SARS-CoV-2 RNA. Based on clinical characteristics and mathematical modeling, patients with shorter hospital stays and less oxygen desaturation were at higher risk of SARS-CoV-2 RNA reoccurrence after discharge. Notably, traditional Chinese medicine treatment offered extensive benefits to reduce risk. Particular attention should be paid to those patients with high risk, and traditional Chinese medicine should be advocated.Funding Statement: The study was supported by National Key Research and Development Plan of China (2020YFC0845500).Declaration of Interests: All authors have no conflicts of interest or financial ties to disclose.Ethics Approval Statement: The study was approved by the ethics committee of Zhongnan Hospital of Wuhan University (No. 2020074). The informed consent of the patients was waived for this infectious disease by the ethics committee.
Objective
To illuminate the mechanism of 14-3-3ζ/atypical protein kinase C-iota (aPKC-ι) to promote the invasion and metastasis of cholangiocarcinoma (CCA).
Methods
The expression of 14-3-3ζ and aPKC-ιwereexamined in the samples of 64 CCA, peritumoural and normal tissues respectively by immunohistochemistry, Western blotting and quantitative real-time polymerase chain reaction. And the independent prognostic factors were analyzed by Kaplan-Meier survival analysis and Multivariate Cox regression analysis. Furthermore, theepithelial-mesenchymaltransition (EMT) model of CCA mediated by Transforming Growth Factor-β1 (TGF-β1) was established to analyze the regulation mechanism of 14-3-3ζand aPKC-ι. Finally, the capacity of invasion, migration, proliferation and metastasis of CCA cells with14-3-3ζdepleted were assessed by transwell cell invasion, wound healing, colony formation assays in vitro.
Results
Overexpression of 14-3-3ζ and aPKC-ιwas detected in CCA tissue (56.25%, 36/64, and 51.56%, 33/64), there was a significant positive correlation between 14-3-3ζ and aPKC-ι(r=0.406, P=0.001). Low expression of14-3-3ζ or aPKC-ιhad a better overall survival compared with those of overexpression (14-3-3ζ: χ2=10.140, P=0.001; aPKC-ι: χ2=12.575, P=0.000). Moreover, both 14-3-3ζ and aPKC-ιwere the independent prognostic factors of CCA. Interfering with 14-3-3ζ or aPKC-ιsignificantly suppressed the changes in EMT-related markers in CCA cells. In vitro, the inhibition of 14-3-3ζ impaired CCA cell invasion, metastasis and proliferation.
Conclusion
Our study demonstrated that 14-3-3ζ may combine with aPKC-ιandsynergistically facilitate EMT of CCA to promote CCA invasion and metastasis.
Key words:
14-3-3ζ; Atypical protein kinase C-iota; Cholangiocarcinoma; Epithelial-mesenchymal transition; Invasion and metastasis
Cholangiocarcinoma (CCA) is a highly malignant bile duct cancer that tends to invade and metastasize early. The epithelial–mesenchymal transition (EMT) has been implicated in cancer cell invasion and metastasis, as well as in cancer cell evasion of host immunity. In this study, we investigated the interaction between atypical protein kinase C‐iota (aPKC‐ι) and Snail in the regulation of EMT and its relationship to CCA immunosuppression. Our results demonstrated that aPKC‐ι, Snail, and infiltrated immunosuppressive cells were significantly up‐regulated in CCA tumor tissues and linked to poor prognosis. aPKC‐ι induced EMT and immunosuppression by regulating Snail in vitro and in vivo , although aPKC‐ι did not directly interact with Snail in coimmunoprecipitation experiments. To further clarify the molecular interaction between aPKC‐ι and Snail in relation to EMT, quantitative iTRAQ‐based phosphoproteomic analysis and liquid chromatography–tandem mass spectrometry were conducted to identify the substrates of aPKC‐ι‐dependent phosphorylation. Combined with coimmunoprecipitation, we showed that specificity protein 1 (Sp1) was directly phosphorylated by aPKC‐ι on Ser59 (P‐Sp1). Both Sp1 and P‐Sp1 were up‐regulated in CCA tumor tissues and associated with clinicopathological features and poor prognosis in CCA patients. Moreover, using chromatin immunoprecipitation assays, we found that P‐Sp1 regulated Snail expression by increasing Sp1 binding to the Snail promoter. P‐Sp1 also regulated aPKC‐ι/Snail‐induced EMT‐like changes and immunosuppression in CCA cells. Our findings further indicated that CCA cells with EMT‐like features appear to generate immunosuppressive natural T regulatory–like cluster of differentiation 4–positive (CD4 + )CD25 – cells rather than to increase CD4 + CD25 + natural T regulatory cells, in part by mediating T regulatory–inducible cytokines such as transforming growth factor β1 and interleukin 2. Conclusion: These results demonstrate that aPKC‐ι promotes EMT and induces immunosuppression through the aPKC‐ι/P‐Sp1/Snail signaling pathway and may be a potential therapeutic target for CCA. (H epatology 2017;66:1165‐1182).
With the advancement in early diagnosis and treatment, the prognosis for individuals diagnosed with breast cancer (BC) has improved significantly. The prognosis of primary breast cancer (PBC) survivors can be significantly influenced by the occurrence of colorectal cancer (CRC) as a secondary primary cancer (SPC). The objective of this study is to explore the possible genetic association between PBC and CRC, aiming to lay a groundwork for the development of preventive strategies against SPC-CRC following BC surgery.
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