Integrative proteomic characterization of adenocarcinoma of esophagogastric junction.

The incidence of adenocarcinoma of the esophagogastric junction (AEG) has been rapidly increasing in recent decades, but its molecular alterations and subtypes are still obscure. Here, we conduct proteomics and phosphoproteomics profiling of 103 AEG tumors with paired normal adjacent tissues (NATs), whole exome sequencing of 94 tumor-NAT pairs, and RNA sequencing in 83 tumor-NAT pairs. Our analysis reveals an extensively altered proteome and 252 potential druggable proteins in AEG tumors. We identify three proteomic subtypes with significant clinical and molecular differences. The S-II subtype signature protein, FBXO44, is demonstrated to promote tumor progression and metastasis in vitro and in vivo. Our comparative analyses reveal distinct genomic features in AEG subtypes. We find a specific decrease of fibroblasts in the S-III subtype. Further phosphoproteomic comparisons reveal different kinase-phosphosubstrate regulatory networks among AEG subtypes. Our proteogenomics dataset provides valuable resources for understanding molecular mechanisms and developing precision treatment strategies of AEG.

Endoscopic submucosal dissection for early signet ring cell gastric cancer: A systematic review and meta-analysis.

BACKGROUND: The use of endoscopic submucosal dissection (ESD) for treating early signet ring cell carcinoma (SRC) is controversial due to the risk of lymph node metastasis. AIM: To carry out a meta-analysis to evaluate ESD for therapeutic efficacy and safety in early signet ring cell gastric cancer. METHODS: The PubMed, Web of Science, Cochrane Library, and EMBASE databases were used to search for relevant studies evaluating the therapeutic efficacy and safety of ESD in SRC. The rates of recurrence, complete resection, incomplete resection, curative resection, en bloc resection, and adverse events were extracted and analyzed. The methodological quality of the enrolled studies was assessed using the Newcastle-Ottawa Scale. Publication bias was evaluated by the Egger's test. Institutional review board approval and written consent were not needed for this report. RESULTS: This meta-analysis enrolled seven studies with 653 participants undergoing ESD treatment for early SRC. The overall recurrence rate was 0.010 [95% confidence interval (CI): 0.000-0.040, Z = 1.422, P = 0.155]. The total lymphovascular invasion rate was 0.038 (95%CI: 0.007-0.088, Z = 3.026, P = 0.002). The total en bloc resection rate was estimated at 0.984 (95%CI: 0.925-1.000, Z = 19.463, P = 0.000). The total complete and incomplete resection rates were estimated at 0.785 (95%CI: 0.596-0.928, Z = 9.789, P = 0.000) and 0.188 (95%CI: 0.016-0.468, Z = 2.531, P = 0.011), respectively. The total procedure-associated gastric hemorrhage and perforation rates were estimated at 0.026 (95%CI: 0.005-0.061, Z = 3.006 P = 0.003) and 0.004 (95%CI: 0.000-0.028, Z = 0.938, P = 0.348), respectively. The curative resection, vertical margin invasion, and lateral margin invasion rates were 72.1% (145/341), 2.3% (8/348), and 34.45% (41/119), respectively. CONCLUSION: ESD constitutes a promising therapeutic approach for early undifferentiated SRC gastric cancer. However, further improvements are required for increasing its treatment efficacy and reducing adverse outcomes.

Discovery of benzochalcone derivative as a potential antigastric cancer agent targeting signal transducer and activator of transcription 3 (STAT3).

Gastric cancer remains a significant health burden worldwide. In continuation of our previous study and development of effective small molecules against gastric cancer, a series of benzochalcone analogues involving heterocyclic molecules were synthesised and biologically evaluated in vitro and in vivo. Among them, the quinolin-6-yl substituted derivative KL-6 inhibited the growth of gastric cancer cells (HGC27, MKN28, AZ521, AGS, and MKN1) with a submicromolar to micromolar range of IC50, being the most potent one in this series. Additionally, KL-6 significantly inhibited the colony formation, migration and invasion, and effectively induced apoptosis of MKN1 cells in a concentration-dependent manner. The mechanistic study revealed that KL-6 could concentration-dependently suppress STAT3 phosphorylation, which may partly contribute to its anticancer activity. Furthermore, in vivo antitumour study on the MKN1 orthotopic tumour model showed that KL-6 effectively inhibited tumour growth (TGI of 78%) and metastasis without obvious toxicity. Collectively, compound KL-6 may support the further development of candidates for gastric cancer treatment.

Trametes robiniophila Murr Sensitizes Gastric Cancer Cells to 5-Fluorouracil by Modulating Tumor Microenvironment.

Trametes robiniophila Murr (TRM) is a traditional Chinese medicine which has been used in clinics for enhancing immunity and improving the efficacy of chemotherapy. However, the mechanisms of action of TRM are unknown. In the previous study, we found that the Trametes robiniophila Murr n-butanol extract (TRMBE) comprises the major bioactive components of TRM. In the present study, we aimed to assess the combinational effects of TRMBE and 5-fluorouracil (5-FU) on the treatment of gastric cancer (GC) and explore its mechanism of action. It was found that TRMBE significantly potentiated the anticancer activity of 5-FU and prolonged the survival time of mice bearing Mouse Forestomach Carcinoma (MFC) xenograft tumors. We observed that the combination of TRMBE and 5-FU decreased the risk of liver metastasis in vivo. Furthermore, the combination of TRMBE and 5-FU reduced the levels of immune cytokines IL-6, IL-10, and TGF-ß and increased the level of IFN-γ in peripheral blood. This combination therapy also significantly decreased the levels of polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs) and PD-1-positive CD8+ T cells and increased the levels of NK cells in tumor microenvironment (TME). However, TRMBE treatment was unable to enhance the chemosensitivity of GC to 5-FU in vivo after the depletion of CD8+ T and NK cells. Taken together, our results demonstrate that TRMBE can reshape the TME of GC by regulating PMN-MDSCs, CD8+ T cells, and NK cells, therefore improving the therapeutic effects of 5-FU. This study suggests that the combination of TRMBE and 5-FU could enhance immunity and could be a promising approach for GC treatment.

Peroral endoscopic longer vs shorter esophageal myotomy for achalasia treatment: A systematic review and meta-analysis.

BACKGROUND: Peroral endoscopic myotomy (POEM) has been demonstrated to be safe and effective in the treatment of achalasia. Longer myotomy is the standard POEM procedure for achalasia but when compared with shorter myotomy, its effectiveness is not as well known. AIM: To compare the clinical effectiveness of longer and shorter myotomy. METHODS: PubMed, EmBase, Cochrane Library, web of science and clinicaltrials.gov were queried for studies comparing shorter and longer POEM for achalasia treatment. The primary outcome was clinical success rate. Secondary outcomes comprised of operative time, adverse events (AEs) rate, gastroesophageal reflux disease (GERD) and procedure-related parameters. The Mantel-Haenszel fixed-effects model was primarily used for the analysis. Publication bias was assessed. RESULTS: Six studies were included in this analysis with a total of 514 participants. During the follow-up period of 1-28.7 mo, longer and shorter myotomy in treating achalasia showed similar excellent effectiveness [overall clinical success (OR = 1, 95%CI: 0.46-2.17, P = 1, I2: 0%; subgroup of abstract (OR = 1.19, 95%CI: 0.38 to 3.73; P = 0.76; I2: 0%); subgroup of full text (OR = 0.86 95%CI: 0.30 to 2.49; P = 0.78; I2: 0%)]. Shorter myotomy had significantly reduced mean operative time compared with the longer procedure. There were no statistically significant differences in AEs rates, including GERD (overall OR = 1.21, 95%CI: 0.76-1.91; P = 0.42; I2: 9%; subgroup of abstract OR = 0.77, 95%CI: 0.40-1.47; P = 0.43; I2: 0%; subgroup of full text OR = 1.91, 95%CI: 0.98-3.75; P = 0.06; I2: 0%), hospital stay (overall MD = -0.07, 95%CI: -0.30 to 0.16; P = 0.55; I2: 24%; subgroup of abstract MD = 0.20, 95%CI: -0.25 to 0.65; P = 0.39; I2: 0; subgroup of full text MD = -0.16, 95%CI: -0.42 to 0.10; P = 0.23; I2: 42%), and major bleeding (overall OR = 1.25, 95%CI: 0.58-2.71; P = 0.56; I2: 0%) between the two procedures. These differences remained statistically non-significant in all sensitivity analyses. CONCLUSION: POEM was effective in treating achalasia. Shorter and longer myotomy procedures provided similar therapeutic effects in terms of long-term effectiveness. In addition, shorter myotomy reduced the operative time.

GPR30 Activation Promotes the Progression of Gastric Cancer and Plays a Significant Role in the Anti-GC Effect of Huaier.

Gastric cancer (GC) is one of the most common types of cancer. The n-butanol extract of Huaier (NEH) is the alcohol-soluble part extracted by the systematic solvent method, which is effective against gastric cancer (GC). However, the mechanism of action of NEH remains unclear. In this study, we aim to evaluate the clinical relevance of GPR30 expression in GC patients and the role of the GPR30/PI3K/AKT signalling pathway in the anti-GC effect of NEH. The expression of GPR30 was examined using immunohistochemistry. Cell counting kit 8 (CCK-8) assay, wound healing, and transwell experiments were used to investigate the viability, migration, and invasion of gastric cancer cells. Western blotting was used to detect the expression of GPR30 and its downstream signalling molecules of the PI3K/AKT signalling pathway. Gastric cancer patient-derived xenografts (PDX) mouse model was used to evaluate the antitumor effect of NEH in vivo. In addition, the graded doses and the maximum tolerated dose of NEH were administered intraperitoneally into the mice for acute toxicity test. We demonstrate that GPR30 expression in GC tissues was significantly higher than that in corresponding adjacent noncancerous tissues and the expression of GPR30 was correlated with a poor prognosis in GC patients. Moreover, GPR30 expression was involved in the migration and invasion of GC cells in vitro. Additionally, we found that NEH can suppress the growth of GC in patient-derived xenograft tumors in vivo. Furthermore, NEH inhibited the proliferation, migration, and invasion in GC cells in a concentration-dependent manner through inhibiting the GPR30-mediated PI3K/AKT signalling pathway in vitro. Acute toxicity test showed that NEH caused no toxic reaction or death and the maximum tolerated dose of NEH in mice was greater than 1600 mg/kg. Our results demonstrate that the high expression of GPR30 is an independent factor of poor prognosis in patients with GC and NEH could be a new agent for the treatment of gastric cancer.

Helicobacter pylori eradication: Exploring its impacts on the gastric mucosa.

Helicobacter pylori (H. pylori) infects approximately 50% of all humans globally. Persistent H. pylori infection causes multiple gastric and extragastric diseases, indicating the importance of early diagnosis and timely treatment. H. pylori eradication produces dramatic changes in the gastric mucosa, resulting in restored function. Consequently, to better understand the importance of H. pylori eradication and clarify the subsequent recovery of gastric mucosal functions after eradication, we summarize histological, endoscopic, and gastric microbiota changes to assess the therapeutic effects on the gastric mucosa.

p-MEK expression predicts prognosis of patients with adenocarcinoma of esophagogastric junction (AEG) and plays a role in anti-AEG efficacy of Huaier.

The incidence rate of adenocarcinoma of the esophagogastric junction (AEG) is increasing worldwide with poor prognosis and unclear pathogenesis. Trametes robiniophila Murr. (Huaier), a traditional Chinese medicine has been used in the clinical treatment of a variety of solid tumors, including AEG. However, its anticancer components and molecular mechanisms are still unclear. In our previous studies, we have found that Huaier n-butanol extract (HBE) shows the most potent anticancer activity among different extracts. In the present study, we aimed to investigate the clinical relevance of p-MEK expression in AEG patients and the role of the MEK/ERK signaling pathway in the anti-AEG efficacy of HBE in vitro and in vivo. We herein demonstrate that p-MEK expression in AEG tissues was significantly higher than that in paracancerous tissues and correlated with a poor prognosis in AEG patients. We further found that HBE inhibited the colony formation, migration, and invasion in AEG cell lines in a concentration-dependent manner in vitro. HBE also suppressed the growth of AEG xenograft tumors without causing any host toxicity in vivo. Mechanistically, HBE caused the inactivation of the MEK/ERK signaling pathway by dephosphorylating MEK1 at S298, ERK1 at T202, and ERK2 at T185 and modulating the expression of EMT-related proteins. In summary, our results demonstrate that the high expression of p-MEK may be an independent factor of poor prognosis in patients with AEG. The clinically used anticancer drug Huaier may exert its anti-AEG efficacy by inhibiting the MEK/ERK signaling pathway.

The Role of Autophagy in Gastric Cancer Chemoresistance: Friend or Foe?

Gastric cancer is the third most common cause of cancer-related death worldwide. Drug resistance is the main inevitable and vital factor leading to a low 5-year survival rate for patients with gastric cancer. Autophagy, as a highly conserved homeostatic pathway, is mainly regulated by different proteins and non-coding RNAs (ncRNAs) and plays dual roles in drug resistance of gastric cancer. Thus, targeting key regulatory nodes in the process of autophagy by small molecule inhibitors or activators has become one of the most promising strategies for the treatment of gastric cancer in recent years. In this review, we provide a systematic summary focusing on the relationship between autophagy and chemotherapy resistance in gastric cancer. We comprehensively discuss the roles and molecular mechanisms of multiple proteins and the emerging ncRNAs including miRNAs and lncRNAs in the regulation of autophagy pathways and gastric cancer chemoresistance. We also summarize the regulatory effects of autophagy inhibitor and activators on gastric cancer chemoresistance. Understanding the vital roles of autophagy in gastric cancer chemoresistance will provide novel opportunities to develop promising therapeutic strategies for gastric cancer.

Finite element modeling of proximal femur with quantifiable weight-bearing area in standing position.

BACKGROUND: The positional distribution and size of the weight-bearing area of the femoral head in the standing position as well as the direct active surface of joint force can directly affect the result of finite element (FE) stress analysis. However, the division of this area was vague, imprecise, and un-individualized in most studies related to separate FE models of the femur. The purpose of this study was to quantify the positional distribution and size of the weight-bearing area of the femoral head in standing position by a set of simple methods, to realize individualized reconstruction of the proximal femur FE model. METHODS: Five adult volunteers were recruited for an X-ray and CT examination in the same simulated bipedal standing position with a specialized patented device. We extracted these image data, calculated the 2D weight-bearing area on the X-ray image, reconstructed the 3D model of the proximal femur based on CT data, and registered them to realize the 2D weight-bearing area to 3D transformation as the quantified weight-bearing surface. One of the 3D models of the proximal femur was randomly selected for finite element analysis (FEA), and we defined three different loading surfaces and compared their FEA results. RESULTS: A total of 10 weight-bearing surfaces in 5 volunteers were constructed, and they were mainly distributed on the dome and anterolateral of the femoral head with a crescent shape, in the range of 1218.63-1,871.06 mm2. The results of FEA showed that stress magnitude and distribution in proximal femur FE models among three different loading conditions had significant differences, and the loading case with the quantized weight-bearing area was more in accordance with the physical phenomenon of the hip. CONCLUSION: This study confirmed an effective FE modeling method of the proximal femur, which can quantify the weight-bearing area to define a more reasonable load surface setting without increasing the actual modeling difficulty.

Correlation between Body Mass Index and Periprosthetic Joint Infection following Total Joint Arthroplasty: A protocol for systematic review and meta analysis.

BACKGROUND: Despite rapid reports on the correlation between body mass index (BMI) and periprosthetic joint infection (PJI) after total joint arthroplasty, some have conducted regression tests or meta-analyses with controversial results. In this study, we systematically meta-analyzed relevant trials and carefully evaluated the correlation for verification. METHODS: Literature on the correlation between BMI and PJI following total joint arthroplasty was retrieved in PubMed, Embase and Cochrane Library due September 2019. Stata 13.0 software was adopted for data synthesis and analyses of publication bias and sensitivity. Random-effect models were used to summary the overall estimate of the multivariate adjusted odds ratio (OR)/hazard ratio/rate ratio with 95% confidence intervals (CIs). RESULTS: A total of 29 observational studies representing 3,204,887 patients were included. The meta-analysis revealed that the risk of postoperative PJI significantly increased by 1.51 times in the obese group (OR = 1.51; 95% CI = 1.30-1.74 for the obese group vs. the non-obese group), and by 3.27 times in the morbid obese group (OR = 3.27; 95% CI = 2.46-4.34 for the morbid obese group vs the non-morbid obese group). A significant association remained consistent, as indicated by subgroup analyses and sensitivity analyses. CONCLUSION: Our findings demonstrate that postoperative PJI is positively correlated with BMI, with obese patients showing a greater risk of developing PJI than non-obese patients. Similarly, morbid obese patients present a higher risk of PJI than non-morbid obese patients. However, this conclusion needs to be corroborated by more prospective studies.

Risk factors associated with osteonecrosis of femoral head after internal fixation of femoral neck fracture:a systematic review and meta-analysis.

BACKGROUND: Although the risk factors associated with osteonecrosis of femoral head (ONFH) after internal fixation of femoral neck fracture (IFFNF) have been frequently reported, the results remain controversial. Therefore, its related risk factors were systematically evaluated and meta-classified in this study. METHODS: Literature on risk factors of ONFH caused by IFFNF was retrieved in PubMed, Embase and Cochrane Library due June 2019. Review Manager 5.3 software was applied to data synthesis, and Stata 13.0 software was adopted for analyses of publication bias and sensitivity. RESULTS: A total of 17 case-control studies with 2065 patients were included. The risk of ONFH after IF was 0.40-fold higher in patients with Garden III-IV FNF than that in patients with Garden I-II (OR: 0.40, 95%CI: 0.29-0.55). The risk of OFNH with retained IF was uplifted by 0.04 times (OR: 0.04, 95%CI: 0.02-0.07). There was nonsignificant relationship between gender and ONFH after IFFNF (OR: 1.27, 95%CI: 0.84-1.94). Moreover, ONFH after IFFNF presented no association with age (OR:1.66, 95%CI: 0.89-3.11), injury-operation interval (OR:1.29, 95%CI: 0.82-2.04), fracture reduction mode (OR:1.98, 95%CI: 0.92-4.26), preoperative traction (OR:1.69, 95%CI: 0.29-9.98) and mechanism of injury (OR:0.53, 95%CI: 0.06-4.83). Egger's and Begg's tests indicated a publication bias (P = 0.001). CONCLUSION: It was demonstrated that Garden classification and retained IF were important influencing factors of ONFH after IFFNF. Gender, age, injury-operation interval, fracture reduction mode, preoperative traction and the mechanism of ONFH were irrelevant to the complication.

[Effect of electroacupunture on supplementary analgesia and the levels of serum ß-endorphin and prostaglandin E2 in patients with total knee arthroplasty].

OBJECTIVE: To observe the effect on supplementary analgesia after total knee arthroplasty (TKA) treated with electroacupunture, and explore it's mechanism. METHODS: A total of 40 patients with severe knee osteoarthritis were randomized into an observation group and a control group, 20 cases in each one. During the operation, patients were given epidural anesthesia in the two groups, conventional patient controlled epidural analgesia and oral celecoxib were applied after the operation. In the observation group, electroacupunture was used at Liangqiu (ST 34), Xuehai (SP 10), Yinlingquan (SP 9), Zusanli (ST 36), Fenglong (ST 40) and Qiuxu (GB 40) on the operation side from the 1st to 7th day after the operation to support analgesia, 30 min for each time, once a day. The visual analogue scale (VAS) was used to record postoperative pain of resting state and active state. The levels of serum prostaglandin E2 and ß-endorphin were measured on the 1st and 7th day after surgery in the two groups. RESULTS: In the observation group, the VAS scores of resting state and active state were superior to the control group on the 3rd, 5th and 7th day after the operaton (all P<0.05); after the treatment, the level of serum ß-endorphin was increased and the level of serum prostaglandin E2 was reduced in the two groups (all P<0.05), and the change of the observation group was larger than that of the control group (both P<0.05). CONCLUSION: Electroacupunture has the effect of supplementary analgesia for patients after TKA, the mechanism may be related to promote the synthesis of ß-endorphin and inhibit the synthesis of prostaglandin E2.

[Electroacupuncture Intervention Reduces Post-surgical Pain of Patients Undergoing Total Knee Arthroplasty].

OBJECTIVE: To observe the analgesic effect and safety of electroacupuncture (EA) intervention for patients undergoing total knee arthroplasty (TKA). METHODS: A total of 40 patients undergoing TKA were randomly assigned to control group (simple multi-mode analgesia, n＝20) and EA group (EA combined with multi-mode analgesia, n＝20). Both groups were treated with epidural anesthesia during surgical operation, and conventional epidural automatic analgesia and oral Celecoxib after surgery. Following surgery, EA was applied to Liangqiu (ST 34)-Xuehai (SP 10), Yinlingquan (SP 9)-Zusanli (ST 36), Fenglong (ST 40)-Qiuxu(GB 40) on the operation side for 30 min, once daily for 7 consecutive days. The patients' pain state during rest and motion was assessed by using visual analogue scale (VAS). The active and passive knee flexion range of motion (ROM), use of painkillers including the number of patient's controlled epidural analgesia (PCEA) during 48 h after surgery, and other complications were recorded. RESULTS: After the treatment, the VAS scores under rest and motion state were both significantly lower in the EA group than in the control group on day 3, 5 and 7 after surgery (P<0.05). During 48 h after surgery, the number of PECA was significantly lower in the EA group than in the control group (P<0.05). Of the two 20 cases in the control and EA groups, 3 and 1 asked to receive muscular injection of Tramadol Hydrochloride for pain relief, 3 and 2 experienced nausea-vomiting, 2 and 1 had dizziness and headache, and 2 and 1 had a chest distress feeling, respectively, which had no significant differences between the two groups (P>0.05). The white blood cell (WBC) count in both groups were decreased gradually from day 1 to 7 after surgery, and plasma C-reactive protein content on day 5 and 7 were also lowered in both groups, without statistical differences between the two groups in the post-operative complications, dosages of additional postoperative analgesic drugs, and levels of plasma WBC and C-reactive protein (P>0.05). CONCLUSION: EA can effectively improve the early postoperative pain of TKA, reduce the incidence of postoperative complications and the use of analgesic drugs in TKA patients.

Vasectomy and cardiovascular disease risk: A systematic review and meta-analysis.

BACKGROUND: Even though several studies comparing vasectomy and cardiovascular disease (CVD) risk have been reported, most are small series with conflicting results. However, the extent of the risk is still uncertain. We therefore explored whether an association exists between vasectomy and CVD incidence and mortality. METHODS: We searched PubMed, Embase, Web of Science, and Cochrane Library databases for relevant studies published before January 2017. Multivariate adjusted odds ratio (OR) and associated 95% confidence intervals (CIs) and those by subgroups were extracted and pooled using random-effects models. RESULTS: Overall, 12 observational studies (2 cross-sectional studies, 4 case-control studies, and 6 retrospective cohort studies) comprising 299,436 participants were identified. There was no statistically significant relationship between vasectomy and CVD risk (OR: 0.90, 95% CI: 0.81-1.00). Moreover, vasectomy was not associated with CVD mortality (OR: 0.90, 95% CI: 0.81-1.00), coronary heart disease (CHD) incidence (OR: 0.94, 95% CI: 0.88-1.01), stroke incidence (OR: 0.90, 95% CI: 0.72-1.13), and myocardial infarction (MI) incidence (OR: 0.95, 95% CI: 0.88-1.02), with no significant publication bias. In subgroup analyses, the findings on the association between vasectomy and CVD risk were consistent. CONCLUSION: Our findings suggest that vasectomy is not associated with the excess risk of CVD incidence and mortality. Nevertheless, large-volume, well-designed observational studies, with different ethnic populations, low risk of bias, and adjusted confounding factors, are awaited to confirm and update the findings of this analysis.