The potassium channel protein KCNH2 is encoded by KCNH2 gene, and there are more than 300 mutations of KCNH2. Unfolded protein response (UPR) is typically initiated in response to an accumulation of unfolded and/or misfolded proteins in the endoplasmic reticulum (ER). The present study aimed to explore the UPR process and the role of activating transcription factor 6 (ATF6) in the abnormal expression of potassium voltage-gated channel subfamily H member 2 (KCNH2)A561V. The wild-type (wt) KCNH2 and A561V mutant KCNH2 was constructed with his-tag. The 293 cells were used and divided into KCNH2wt+KCNH2A561V, KCNH2wt and KCNH2A561V groups. The expression levels of ATF6 and KCNH2 in different groups were detected by Western blotting, reverse transcription-quantitative PCR, immunofluorescence and immuno-coprecipitation assays. The protein types and abundance of immuno-coprecipitation samples were analyzed by mass spectrometry. The proteomic analysis of the mass spectrometry results was carried out by using the reactome database and GO (Gene Ontology) tool. The mRNA expression levels of KCNH2 and ATF6 in the KCNH2wt+KCNH2A561V group were higher compared with the KCNH2A561V group. However, the full-length protein expression of ATF6 was inhibited, indicating that ATF6 was highly activated and a substantial number of ATF6 was sheared in KCNH2wt+KCNH2A561V group compared with control group. Furthermore, A561V-KCNH2 mutation leading to the accumulation of the immature form of KCNH2 (135 kDa bands) in ER, resulting in the reduction of the ratio of 155 kDa/135 kDa. In addition, the abundance of UPR-related proteins in the KCNH2A561V group was higher compared with the KCNH2wt+KCNH2A561V group. The 'cysteine biosynthetic activity' of GO:0019344 process and the 'positive regulation of cytoplasmic translation activity' of GO:2000767 process in the KCNH2A561V group were higher compared with the KCNH2wt+KCNH2A561V group. Hence, co-expression of wild-type and A561V mutant KCNH2 in 293 cells activated the UPR process, which led to the inhibition of protein translation and synthesis, in turn inhibiting the expression of KCNH2. These results provided a theoretical basis for clinical treatment of Long QT syndrome.

INTRODUCTION:The purpose of this meta-analysis is to evaluate the efficacy and safety of cyclin-dependent kinase4/6 inhibitors (CDK4/6i) combined with endocrine therapy (ET) on hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) breast cancer (BC).MATERIAL AND METHODS:A search was conducted in the PubMed, Embase, Web of Science, and Cochrane Library databases before July 2022.RESULTS:A total of 19 studies comprising 19,004 patients were eligible for this meta-analysis. This meta-analysis found that for unresectable locally advanced or metastatic HR+, HER2- BC, CDK4/6i combined with ET can significantly improve the progression-free survival (PFS) (hazard ratio = 0.59, p < 0.001), overall survival (OS) (hazard ratio = 0.77, p < 0.001), objective response rate (ORR) [risk ratio (RR) = 1.32, p = 0.001)], disease control rate (DCR) (RR = 1.10, p < 0.001), and clinical benefit response (CBR) (RR = 1.15, p = 0.001). For early HR+, HER2- BC, CDK4/6i combined with ET improved ORR (RR = 1.14, p = 0.05) and invasive disease free survival (iDFS) (hazard ratio = 0.87, p = 0.045) but had no effect on pathologic complete response (pCR) (RR = 1.75, p = 0.33), distant recurrence free survival (DRFS) (hazard ratio = 0.83, p = 0.311), and OS (hazard ratio = 1.08, p = 0.705).CONCLUSION:CDK4/6i combined with ET can improve the prognosis of patients with unresectable locally advanced or metastatic HR+, HER2- BC, but it has no obvious effect on patients with early HR+, HER2- BC. It is generally safe and manageable.

Pathological cardiac hypertrophy (CH) is featured by myocyte enlargement and cardiac malfunction. Multiple signaling pathways have been implicated in diverse pathological and physiological processes in CH. However, the function of LOC102549726/miR-760-3p network in CH remains unclear. Here, we characterize the functional role of LOC102549726/miR-760-3p network in CH and delineate the underlying mechanism. The expression of LncRNA LOC102549726 and hypertrophic markers was significantly increased compared to the control, while the level of miR-760-3p was decreased. Next, we examined ER stress response in a hypertrophic cardiomyocyte model. The expression of ER stress markers was greatly enhanced after incubation with ISO. The hypertrophic reaction, ER stress response, and increased potassium and calcium ion channels were alleviated by genetic downregulation of LOC102549726. It has been demonstrated that LOC102549726 functions as a competitive endogenous RNA (ceRNA) of miR-760-3p. Overexpression of miR-760-3p decreased cell surface area and substantially mitigated ER stress response; protein levels of potassium and calcium channels were also significantly up-regulated compared to the NC control. In contrast, miR-760-3p inhibition increased cell size, aggravated CH and ER stress responses, and reduced ion channels. Collectively, in this study we demonstrated that the LOC102549726/miR-760-3p network was a crucial regulator of CH development. Ion channels mediate the ER stress response and may be a downstream sensor of the LOC102549726/miR-760-3p network. Therefore, these findings advance our understanding of pathological CH and provide new insights into therapeutic targets for cardiac remodeling.

Aims: The purpose of this study was to explore the efficacy of immunotherapy for patients with triple-negative breast cancer (TNBC). Materials & methods: Randomized clinical trials comparing immunotherapy with chemotherapy for advanced TNBC patients were included. Results: A total of six articles (3183 patients) were eligible for this meta-analysis. PD-1/PD-L1 inhibitor-based immunotherapy combined with chemotherapy can significantly increase the progression-free survival (hazard ratio [HR] = 0.82; 95% CI = 0.76-1.14; p < 0.001) of unresectable locally advanced or metastatic TNBC patients without effect on overall survival, compared with chemotherapy. Conclusion: PD-1/PD-L1 inhibitors-based immunotherapy can safely improve progression-free survival in patients with unresectable locally advanced or metastatic TNBC, but has no effect on overall survival.

The purpose of this study was to investigate the relationship between night shift work and breast cancer (BC) incidence. A search was performed in PubMed, EBSCO, Web of Science, and Cochrane Library databases before June 2021. The exposure factor of this study is night shift work, the primary outcome is the risk of BC. A total of 33 observational studies composed of 4,331,782 participants were included. Night shift work increases the risk of BC in the female population (hazard ratio [HR] = 1.20, 95% confidence interval [Cl] = 1.10-1.31, p < 0.001), especially receptor-positive BC, including estrogen receptor (ER)+ BC (HR = 1.35, p < 0.001), progesterone receptor (PR)+ BC (HR = 1.30, p = 0.003), and human epidermal growth factor receptor 2 (HER2)+ BC (HR = 1.42, p < 0.001), but has no effect on HER2- BC (HR = 1.10, p = 0.515) and ER-/PR- BC (HR = 0.98, p = 0.827). The risk of BC was positively correlated with night shift working duration, frequency, and cumulative times. For women who start night work before menopause, night work will increase the incidence of BC (HR = 1.17, p = 0.020), but for women who start night work after menopause, night work does not affect BC (HR = 1.04, p = 0.293). Night work can increase the incidence of BC in the female population. The effect of long working hours, frequency, and the cumulative number of night shifts on BC is influenced by menopausal status.

Objective To investigate the role of Rer1 in hERG potassium channel protein transport,and to study the medicine Baf A1 that may restore abnormal hERG transport. Methods HEK293T cells were transiently transfected with constructed A561V mutant and WT plasmids, the wild-type,mutant and mixed transfection cell models were established.The expressions of hERG and Rer1 were detected by immunofluorescence and Western blot.siRNA was used to knockdown the expression of Rer1 and detect the expression of hERG;Bafilomycin A1,a V-ATPase inhibitor was incubated with 1 mmol/L for 6 hours.Western blot was used to detect the changes of hERG protein before and after the incubation.Patch clamp was used to measure the current of potential functional in mixed transfection cells. Results Compared with the WT group,A561V-mutation could cause trafficking deficient of hERG protein.The PM expression of hERG in mutant group was significantly reduced(P＜0.01).The expression of Rer1 in mutation and mixed transfection groups decreased significantly(P＜0.01).Knockdown of Rer1 promoted the forward transport of mature hERG.Besides,after incubation with Baf A1,the mature hERG protein in WT and mutant groups increased significantly(P＜0.05),while the immature hERG in the mixed transformation group was significantly increased(P＜0.05).Relative density of tail current was elevated following incubation with Baf A1 compared with control. Conclusions Rer1 is involved in the transport of hERG potassium channel and inhibits the forward transport of some abnormal hERG.Baf A1 significantly enhances the tail current density of mixed transfection cells.

Background: HER2-positive breast cancer patients account for one-fifth of the total breast cancer population. Besides, more anti-HER2-targeting drugs have appeared clinically. Objective: This study aimed to analyze the efficacy and safety of additional anti-HER2 (Human Epidermal growth Factor Receptor 2)-targeting drugs in the treatment of HER2-positive advanced breast cancers. Methods: The following databases were searched for published articles containing data on the efficacy and safety of additional anti-HER2-targeting drugs in HER2-positive advanced breast cancer from the time of their inception until December 2019: PubMed, Web of Science, EBSCO, and Cochrane library. The primary outcomes were Progression-Free Survival (PFS) and Overall Survival (OS). Results: The additional anti-HER2-targeting drugs significantly improved the PFS (HR: 0.66, p<0.001) and OS (HR: 0.77, p<0.001) of HER2-positive advanced breast cancer patients. Regarding drug types, lapatinib was the most effective (HR: 0.53, 95% Cl: 0.39-0.67, p<0.001), followed by pertuzumab (HR: 0.72, 95% Cl: 0.55-0.89, p=0.001). Trastuzumab was the least beneficial (HR: 0.87, 95% Cl: 0.31-1.44, p=0.594). Concerning treatment regimen, first-line treatment (HR: 0.67, 95% Cl: 0.52-0.82, p<0.001) was more effective than non-first-line treatment (HR: 0.82, 95% Cl: 0.71-0.94, p=0.004). The main Adverse Events (AEs) observed were diarrhea and decreased ejection fraction. Conclusion: Additional anti-HER2-targeting drugs can improve long-term prognosis in HER2-positive advanced breast cancers. Besides, they are associated with fewer AEs and are tolerable. Lapatinib is the most effective drug, followed by pertuzumab, whereas trastuzumab is the least effective. Concerning treatment, we recommend the use of anti-HER2-targeting drugs in first-line therapy of HER2-positive advanced breast cancers.

Abstract Purpose The purpose of this research is to investigate the prognostic factors of patients with stage I gastric cancer (GC) and to determine whether adjuvant chemotherapy improves the prognosis for high-risk patients. Methods We performed a retrospective analysis at Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, and HwaMei Hospital, University of Chinese Academy of Sciences from January 2001 to December 2015. Cox regression and Kaplan-Meier were used to evaluate the relationship between the patients’ clinicopathologic characteristics and prognosis. Results A total of 1,550 patients were eligible for the study. The 5-year disease-free survival (DFS) rate of all enrolled patients was 96.5%. The pT and pN stages were significantly associated with the prognosis. The 5-year DFS rates of the three subgroups (T1N0, T2N0, and T1N1) were 97.8%, 95.7%, and 90.5%, respectively (p < 0.001). In the T1N1 subgroup, patients not undergoing chemotherapy showed a lower 5-year DFS rate compared to those undergoing chemotherapy, although the difference was not statistically significant. Conclusions Both the pT and pN stages were closely associated with the prognosis of patients with stage I GC. We also found that the danger coefficient of the pN stage was higher than that of the pT stage, and that postoperative adjuvant chemotherapy might be a reasonable approach to improve outcomes of high-risk patients, particularly in the T1N1 group.

This study assesses the differences in postoperative nutritional status between laparoscopic sleeve gastrectomy (LSG) and laparoscopic Roux-en-Y gastric bypass (LRYGB). We searched the literature from PubMed, Web of Science, Embase, and the Cochrane Library database. Twenty-nine articles were included, with a total of 5437 obese patients. After bariatric surgery, the LSG group had less anemia and iron deficiency anemia than the LRYGB group. The serum iron, ferritin deficiency, and vitamin B12 rates after LSG were lower than patients receiving LRYGB. And PTH and serum phosphorus concentration of patients after LSG were both lower than those after LRYGB. The postoperative results of LSG were better than that of LRYGB. Therefore, we recommend LSG for a better postoperative nutrition, but only for reference.

Background The prognostic significance of peripheral blood-derived inflammation markers in patients with gastric cancer (GC) has not been elucidated. This study aimed to investigate the relationship between systemic inflammatory markers and GC prognosis. Methods A prospective observational cohort study involving 598 patients was conducted to analyze the prognosis of GC based on systemic inflammatory markers. The following peripheral blood-derived inflammation markers were evaluated: the neutrophil-lymphocyte ratio (NLR), platelet lymphocyte ratio (PLR), systemic immune-inflammation index (SII), C-reactive protein/albumin (CRP/Alb) ratio, Glasgow Prognostic Score (GPS), modified Glasgow Prognostic Score (mGPS), prognostic nutrition index (PNI), and prognostic index (PI). The receiver operating characteristics (ROC) curve and the Youden index were used to determine the optimal cutoff values. Univariate and multivariate analysis of prognostic factors was conducted accordingly. Results The optimal cutoff values of the PNI, fibrinogen, NLR, PLR, SII, and CRP/Alb were 49.5, 397 ng/dl, 2.5, 154, 556, and 0.05, respectively. Multivariate analysis showed that age, PLR, TNM stage, and chemotherapy were the independent prognostic factors for advanced gastric cancer (AGC). Adjuvant chemotherapy improved the long-term prognosis of patients with PLR ≥154, but chemotherapy had no significant effect on the survival of patients with PLR < 154. Conclusions Our findings show that higher PLR (≥154) is an independent risk factor for poor prognosis in GC patients. Besides, PLR can predict adjuvant chemotherapy (oxaliplatin/5-fluorouracil combination) response in patients with GC after surgery.

目的 探讨输尿管结石的不同嵌顿部位与患者临床特征的相关性.方法 收集289例输尿管结石患者的临床资料,根据CT扫描结果对患者进行分组,比较各组间一般资料的差异性及相关性,并对不同结石部位和各症状特征的相关性进行分析.结果 对289例患者进行分析,男性显著多于女性,按结石嵌顿部位分组后,发现腹段及盆段结石的表现以括约肌功能障碍为主,而壁内段则以尿路刺激症状为主,各组间差异有统计学意义(P<0.05),但不同嵌顿部位输尿管结石与各特征表现分别与年龄、性别进行多元无序lo-gistic回归分析,结果无统计学意义(P>0.05).结论 输尿管结石嵌顿部位不同与临床特征呈一定相关性,括约肌功能障碍在腹段及盆段结石患者中多见,而壁内段则多表现为尿路刺激征,考虑与输尿管平滑肌的神经体液调节机制相关,这对于理解及早期正确诊治输尿管结石及改善患者预后有一定临床价值.

Studies had shown that tenofovir (TDF) and entecavir (ETV) are widely used as the first‐line therapy to inhibit hepatitis B virus replication, which can reduce the risk of hepatocellular carcinoma (HCC) in chronic hepatitis B (CHB) patients, but it was unclear which nucleos(t)ide analogue was most effective. Therefore, we performed a meta‐analysis and a systematic review to compare the incidence of HCC in CHB patients who are either on TDF or ETV.

Background Currently, nivolumab and ipilimumab are the most widely used immune checkpoint inhibitors. We performed a meta-analysis to evaluate the efficacy and treatment-related adverse events (TRAEs) of nivolumab plus ipilimumab therapy in cancer treatment. Methods We examined data from PubMed, Web of Science, EBSCO, and Cochrane Library. Eleven articles fulfilled our criteria, which we divided into 3 groups: nivolumab plus ipilimumab versus nivolumab (the dose used for monotherapy is 3 mg/kg), nivolumab plus ipilimumab versus ipilimumab (the dose used for monotherapy is 3 mg/kg), and nivolumab 1 mg/kg plus ipilimumab 3 mg/kg (N1I3) versus nivolumab 3 mg/kg plus ipilimumab 1 mg/kg (N3I1). We measured the complete response (CR), partial response (PR), objective response rate (ORR), and TRAEs in any grade and grade 3 or higher. Results The overall effect estimate favored the combined immunotherapy group in terms of the ORR (RR: 1.40, p < 0.001) and PR (RR: 1.50, p < 0.001) than nivolumab alone. Compared with ipilimumab alone, the combined immunotherapy group had better CR (RR: 4.89, p < 0.001), PR (RR: 2.75, p < 0.001), and ORR (RR: 3.31, p < 0.001). Finally, N1I3 showed better PR (RR: 1.35, p = 0.006) and ORR (RR: 1.21, p = 0.03) than N3I1. The incidence of any TRAEs was similar between both groups (RR: 1.05, p = 0.06). However, the incidence of serious adverse events (grade 3 or higher) was lower in group N3I1 than group N1I3 (RR: 1.51, p < 0.001). Conclusion This meta-analysis showed that the curative effect of nivolumab plus ipilimumab was better than that of nivolumab or ipilimumab monotherapy. In the combined immunotherapy group, N1I3 was more effective than N3I1. Although the side effects were slightly increased in N1I3 group, overall safety was acceptable.

The purpose of this research was to investigate the relationship between the number of examined lymph nodes (eLNs) and the prognosis. A retrospective examination of reports and studies carried out at two institutions was conducted. According to TNM stages, the relationship between the number of eLNs and the prognosis was analyzed. The 5-year disease-specific survival (DSS) of all enrolled patients was 66.3%. A multivariate analysis showed the type of gastrectomy, histologic type, perineural invasion, pT stage, pN stage, chemotherapy and eLNs to be independent prognostic markers. Additionally, with the exception of patients with stage I disease, the 5-year DSS of patients who had < 25 eLNs removed had a higher risk of having a worst prognosis compared to patients who had ≥ 25 eLNs removed. Through this study, a hypothetical TNM staging system was obtained for predicting the prognosis according to the number of eLNs. Chemotherapy was able to improve the prognosis of patients with stage III and < 25 eLNs in stage II. Extended lymphadenectomy with a new goal of dissecting 25 LNs for the evaluation of stage II–III cancer cases is recommended. Our hypothetical TNM staging system may be able to stratify the risk more accurately compared to the current AJCC 8th system. Chemotherapy can improve the prognosis in advanced gastric cancer, but its benefit may be affected by the surgical quality.

The purpose of this study was to investigate the relationship between bariatric surgery (laparoscopic sleeve gastrectomy [LSG] and laparoscopic Roux-en-Y gastric bypass [LRYGB]) and gastroesophageal reflux disease (GERD). The number of obese patients with newly onset, worsened, or improved GERD after bariatric surgery in each article were extracted. In the pooled analysis, LSG was associated with a higher risk of GERD than LRYGB (odds ratio [OR] = 5.10, 95% confidence interval [CI] 3.60–7.23, p < 0.001). Compared with LSG, LRYGB had a better effect on GERD (OR = 0.19, 95% CI 0.12–0.30, p < 0.001). LRYGB was more effective for treating GERD in obese patients than LSG and the incidence of newly onset GERD after LRYGB was lower.