The estrogen/miR-338-3p/ADAM17 axis enhances the viability of breast cancer cells via suppressing NK cell's function.

Natural killer (NK) cells are the critical elements of the innate immune response and implicated in rapidly recognizing and eliminating cancer cells. However, the tumor-suppressive ability of NK cells is often impaired in several cancer types. The critical roles of microRNAs have been elucidated by increasing evidences, while the regulation of miR-338-3p in anti-tumor activation of NK cells and its relationship with estrogen in breast cancer (BC) are still confusing. Here, miR-338-3p level was found to be significantly downregulated in BC tissues and estrogen receptor positive (ER+ ) cells, this difference was more obvious in ER+ patients or BC patients at advanced stage (TNM III and IV). MiR-338-3p level was shown to be downregulated by 17ß-estradiol in BC cells (MDA-MB-231 cells and MCF-7) in vitro. MiR-338-3p overexpression decreased disintegrin and metalloprotease-17 (ADAM17) secretion in MDA-MB-231 (ER- ) and MCF-7 (ER+ ) cells. In addition, miR-338-3p overexpression or treatment with anti-ADAM17 antibody could down-regulate granzyme B, CD16, and NKG2D in NK cells, which was reversed by human recombinant ADAM17. Furthermore, these educated NK cells could promote the viability of MDA-MB-231 or MCF-7 cells. Taken together, our results demonstrate that miR-338-3p was negatively regulated by estrogen in BC cells, impairing NK cell's activity by the up-regulation of ADAM17, and conversely promoted the viability of BC cells. Therefore, the estrogen/miR-338-3p/ADAM17 axis is critically implicated in BC pathogenesis and may provide potential targets for BC diagnosis and treatment.

Serum Fibrinogen-Like Protein 1 Levels in Obese Patients Before and After Laparoscopic Sleeve Gastrectomy: A Six-Month Longitudinal Study.

Purpose: Fibrinogen-like protein (FGL)-1 is an original hepatokine with a critical role in developing hepatic steatosis. This study intends to examine the pre- and postoperative serum FGL-1 levels in bariatric patients and identify its relationship with other clinical indicators. Patients and Methods: Ninety-two individuals (60 bariatric patients and 32 people with normal weight) were enrolled in this research between July 2018 and April 2021. All bariatric patients finished follow-up visits 6 months after laparoscopic sleeve gastrectomy (LSG). Clinical data, anthropometric parameters, biochemical variables, FibroScan, and serum FGL-1 levels were collected at baseline and 6 months after LSG. Results: FGL-1 levels in patients with obesity (44.66±20.03 ng/mL) were higher than in individuals with normal weight (20.73±9.73 ng/mL, p < 0.001). After LSG, FGL-1 levels were significantly decreased (27.53±11.45 ng/mL, p < 0.001). Besides, body mass index (BMI), liver enzyme levels, glucose metabolism, lipid metabolism, uric acid (UA), controlled attenuation parameter (CAP), and liver stiffness measurement (LSM) were significantly improved. After adjusting possible confounders, FGL-1 levels at baseline were negatively associated with changes in LSM levels; changes in FGL-1 levels showed positive correlations with changes in alanine aminotransferase (ALT), aspartate aminotransferase (AST) and UA levels at 6 months after surgery. Conclusion: Serum FGL-1 levels were significantly decreased following LSG in patients with obesity. The preoperative serum FGL-1 levels could be a predictor of postoperative liver fibrosis improvement. Furthermore, the decreased FGL-1 levels were associated with improved liver enzymes and UA but not with bodyweight or glucolipid metabolism.

Machine Learning to Identify Metabolic Subtypes of Obesity: A Multi-Center Study.

Background and objective: Clinical characteristics of obesity are heterogenous, but current classification for diagnosis is simply based on BMI or metabolic healthiness. The purpose of this study was to use machine learning to explore a more precise classification of obesity subgroups towards informing individualized therapy. Subjects and Methods: In a multi-center study (n=2495), we used unsupervised machine learning to cluster patients with obesity from Shanghai Tenth People's hospital (n=882, main cohort) based on three clinical variables (AUCs of glucose and of insulin during OGTT, and uric acid). Verification of the clustering was performed in three independent cohorts from external hospitals in China (n = 130, 137, and 289, respectively). Statistics of a healthy normal-weight cohort (n=1057) were measured as controls. Results: Machine learning revealed four stable metabolic different obese clusters on each cohort. Metabolic healthy obesity (MHO, 44% patients) was characterized by a relatively healthy-metabolic status with lowest incidents of comorbidities. Hypermetabolic obesity-hyperuricemia (HMO-U, 33% patients) was characterized by extremely high uric acid and a large increased incidence of hyperuricemia (adjusted odds ratio [AOR] 73.67 to MHO, 95%CI 35.46-153.06). Hypermetabolic obesity-hyperinsulinemia (HMO-I, 8% patients) was distinguished by overcompensated insulin secretion and a large increased incidence of polycystic ovary syndrome (AOR 14.44 to MHO, 95%CI 1.75-118.99). Hypometabolic obesity (LMO, 15% patients) was characterized by extremely high glucose, decompensated insulin secretion, and the worst glucolipid metabolism (diabetes: AOR 105.85 to MHO, 95%CI 42.00-266.74; metabolic syndrome: AOR 13.50 to MHO, 95%CI 7.34-24.83). The assignment of patients in the verification cohorts to the main model showed a mean accuracy of 0.941 in all clusters. Conclusion: Machine learning automatically identified four subtypes of obesity in terms of clinical characteristics on four independent patient cohorts. This proof-of-concept study provided evidence that precise diagnosis of obesity is feasible to potentially guide therapeutic planning and decisions for different subtypes of obesity. Clinical Trial Registration: www.ClinicalTrials.gov, NCT04282837.

Correlation Between Sex Hormones and Non-alcoholic Fatty Liver Disease Before and After Laparoscopic Sleeve Gastrectomy.

OBJECTIVES: To investigate the cross-sectional and longitudinal correlation between sex hormones and non-alcoholic fatty liver disease (NAFLD) in patients with obesity before and after laparoscopic sleeve gastrectomy (LSG). METHODS: A total of 360 patients with obesity aged 16-48 years (170 men and 190 women) were enrolled between May 2017 and March 2021. Among them, 132 patients (55 men and 77 women) who underwent LSG had follow-up data. Anthropometric parameters, metabolic variables, and sex hormones were measured. NAFLD was assessed by FibroScan with controlled attenuation parameter (CAP) and liver stiffness measurement (LSM). RESULTS: In the preoperative cohort, levels of CAP and LSM were significantly higher in men than women. Lower total testosterone (TT) was associated with higher CAP and LSM in men, whereas higher TT was associated with higher CAP in women. In the postoperative cohort, TT levels and NAFLD were significantly modified after LSG in both genders. Changes in TT levels at 3 months after surgery were negatively correlated with changes in CAP levels in men, and changes in TT levels at 6 months after surgery were positively correlated with changes in CAP levels in women. After adjusting possible confounders, the changes in TT levels were independently correlated with CAP variation in both genders. CONCLUSIONS: LSG significantly modified TT levels and NAFLD in both genders. The correlation between TT levels and NAFLD at baseline as well as the changes after surgery suggested TT levels play an important role in the development and regression of NAFLD in both genders.

The Changes in Body Composition in Obese Patients with Polycystic Ovary Syndrome after Laparoscopic Sleeve Gastrectomy:a 12-Month Follow-up.

OBJECTIVES: To investigate the changes in body fat distribution and predicting factors of these changes in polycystic ovary syndrome (PCOS) patients with obesity, after laparoscopic sleeve gastrectomy (LSG). METHODS: This study consecutively enrolled 153 patients with obesity aged 18-45 years (83 with PCOS and 70 control patients) who underwent LSG from May 2013 to September 2020 at the Department of Endocrinology, Shanghai Tenth People's Hospital, with a 12-month follow-up. Dual-energy X-ray absorptiometry (DEXA) was used to assess body fat distribution. RESULTS: The percentage of fat mass loss in the visceral adipose tissue (VAT) region (55.08%) was more than that in any other body regions at 12 months post-surgery in the PCOS group yet insignificant. Homeostatic model assessment of insulin resistance (HOMA-IR) at baseline and Δ HOMA-IR were only negatively correlated with the variations in VAT mass and volume at 3 months post-surgery in the PCOS group. Logistic regression analysis showed that HOMA-IR <6.65 was an independent predictive factor for the changes in VAT mass and volume at 3 months post-surgery in the PCOS group. CONCLUSIONS: In this study, the percentage loss of fat mass was greater in the VAT region than in any other body regions in all patients. The rate of VAT decrease in the PCOS group was higher than that in the control group yet insignificant. Compared with control patients, HOMA-IR at baseline was an independent risk factor for the changes in VAT mass and volume at 3 months post-surgery in patients with PCOS. KEY POINTS: • The percentage loss of fat mass was greater in the VAT region than in any other body regions in all patients. • The rate of VAT decrease in the PCOS group was higher than that in the control group yet insignificant. • HOMA-IR at baseline was an independent risk factor for the changes of VAT mass in patients with PCOS.

circUSP42 Is Downregulated in Triple-Negative Breast Cancer and Associated With Poor Prognosis.

We previously showed that microRNA-182 (miR-182) might promote cell proliferation and migration in triple-negative breast cancer (TNBC). This study aimed to investigate circular RNAs (circRNAs) that interact with miR-182 and play important roles in TNBC. Thirty patients with TNBC were enrolled. One pair of tumor and adjacent tissue samples (control) were submitted for circRNA sequencing to establish the expression profile of circRNAs. Concomitantly, circRNAs aberrantly expressed between TNBC and control groups were identified, and these differentially expressed circRNAs (DEcircRNAs) were subjected to Gene Ontology and KEGG pathway enrichment analyses, as well as prediction of interactions with miRNAs. The expression levels of 5 circRNAs interacting with miR-182 were validated using qRT-PCR. Associations between the expression of circUSP42 and clinicopathological features and prognosis were evaluated. A total of 825 upregulated and 1127 downregulated DEcircRNAs were identified between tumor and control groups. Upregulated DEcircRNAs were significantly involved in proteoglycans in cancer, and endocytosis. Downregulated DEcircRNAs were involved in the pathway of resistance to EGFR tyrosine kinase inhibitors. Prediction of circRNA-miRNA interactions showed that hsa_circ_0002032, chr6:131973682-132047340+, hsa_circ_0005982, hsa_circ_0007823 (circUSP42), and hsa_circ_0001777 might act as miRNA sponges for miR-182. qRT-PCR showed consistent results with circRNA sequencing data (P < 0.05). Downregulation of circUSP42 was significantly associated with lymph node metastasis (P = 0.005) and advanced clinical stage (P = 0.032). Furthermore, Kaplan-Meier plots showed that low expression of circUSP42 was closely associated with poor outcome (log-rank test, P < 0.001). Our data suggested that dysregulation of circUSP42 might contribute to the development and progression of TNBC.

The Mechanism of Metabolic Surgery: Gastric Center Hypothesis.

BACKGROUND: There is growing evidence that bariatric surgery can lead to remission of metabolic syndrome. But the mechanism by which bariatric surgery alleviates metabolic syndrome is unclear. MATERIALS AND METHODS: Several present hypotheses which include decreased caloric intake following the surgeries, foregut and hindgut hypothesis, bile acid and bacterial flora changes, and proposed gastric center hypothesis were discussed. RESULTS: None of the currently available hypotheses is solely capable to lead to a reasonable explanation regarding improvement of metabolic syndrome by various bariatric surgical procedures. Proposed gastric center hypothesis could give a better explanation of the mechanism. CONCLUSIONS: All the present bariatric surgeries are involved in changes of the stomach. There could be some particular cells on the stomach, which could secrete unknown special hormones, and then lead to control the metabolic process.

Effect of Sleeve Gastrectomy Plus Side-to-Side Jejunoileal Anastomosis for Type 2 Diabetes Control in an Obese Rat Model.

BACKGROUND: Sleeve gastrectomy plus side-to-side jejunoileal anastomosis (JI-SG), a relatively new approach to bariatric surgeries, has shown promising results for treating obesity and metabolic comorbidities. This study investigated the feasibility and safety of JI-SG in weight loss and diabetes remission compared with sleeve gastrectomy (SG) and Roux-en-Y gastric bypass (RYGB). METHODS: Forty 10-week-old male Zucker diabetic fatty rats were randomly assigned to four groups: control, SG, JI-SG, and RYGB. Their body weights, food intake, and levels of gut hormones (ghrelin, insulin, and glucagon-like peptide-1 (GLP-1)) and lipids were measured. RESULTS: Rats in the SG, JI-SG, and RYGB groups demonstrated lower food intake and more weight loss 2 weeks postoperatively compared with control rats. Furthermore, rats in the JI-SG group achieved more weight loss (mean 242.7 ± 11.2 g) compared with those in the SG and RYGB groups (SG, 401.4 ± 15.1 g and RYGB, 298 ± 12 g, both P < 0.01). All surgery groups demonstrated a decreased fasting insulin, serum glucose, lipid levels, and increased GLP-1 postoperatively. The JI-SG group had lower fasting ghrelin levels than the RYGB group (168 ± 19.8 ng/L vs. 182 ± 16.7 ng/L, P < 0.01) and higher fasting GLP-1 levels than the SG group (1.99 ± 0.11 pmol/L vs. 1.71 ± 0.12 pmol/L, P < 0.01) at 12 weeks postoperatively. Over the experimental period, the ghrelin levels slowly increased in all surgical groups but remained lower than the preoperative and control levels. CONCLUSIONS: JI-SG induced higher ghrelin and GLP-1 levels and improved glycemic control in Zucker diabetic fatty rats. Compared with SG and RYGB, JI-SG appeared to be a simple, relatively safe, and more effective procedure for treating type 2 diabetes and obesity in this animal model.

Impact of sleeve gastrectomy verses sleeve gastrectomy plus side-to-side jejunoileal anastomosis on weight loss and metabolic control in an obese rat model.

AIM: To study the impact of sleeve gastrectomy plus side-to-side jejunoileal anastomosis on weight loss and the remission of type 2 diabetes mellitus. METHODS: Thirty-three 7 weeks old male Zucker diabetic fatty rats were randomized into three groups: sleeve gastrectomy plus side-to-side jejunoileal anastomosis (JI-SG group), sleeve gastrectomy (SG group), sham surgery (Control group). RESULTS: The weight of rats in JI-SG group and SG group was significantly lower than control group at 2 weeks postoperatively, and body weight in JI-SG group was lower than SG group since 4 week postoperatively. The blood Glucose was significantly improved for both JI-SG group and SG group, and increased in Control group at 2 weeks after surgery. The serum ghrelin level of rats in JI-SG, SG group was significantly decreased, but without difference between two groups; compared with that preoperatively, the GLP-1 level of rats in JI-SG group was significantly higher at 12 weeks postoperatively; SG group and SO group had no difference in the GLP-1. The serum insulin level in rats was also decreased in JI-SG group and SG group at 6 weeks postoperatively, and plasma insulin level in JI-SG group was significantly lower than those in the SG group at 12 weeks postoperatively. CONCLUSIONS: JI-SG is superior to SG as the treatment of type 2 diabetes mellitus and weight control in obese diabetic rodents.

The effect of oxoguanine glycosylase 1 rs1052133 polymorphism on colorectal cancer risk in Caucasian population.

Human oxoguanine glycosylase 1 (OGG1) is an important part of the base excision repair pathway in the DNA repair. Numerous epidemiological studies have evaluated the association between OGG1 rs1052133 polymorphism and the risk of colorectal cancer, but the results of these studies from the Caucasian population were conflicting. To derive a more precise assessment on the association between OGG1 rs1052133 polymorphism and risk of colorectal cancer in Caucasian population, we performed a meta-analysis. The odds ratios (OR) with 95% confidence intervals (CI) were used to assess the strength of the association. Thirteen case-control studies with a total of 4,103 cases and 5,400 controls were finally included into the meta-analysis. Meta-analysis of all 13 studies showed that OGG1 rs1052133 polymorphism was significantly associated with the risk of colorectal cancer in Caucasian population (Cys versus Ser OR = 1.20, 95% CI = 1.03-1.39, P = 0.02; CysCys versus SerSer OR = 1.44, 95% CI = 1.04-2.00, P = 0.03; CysCys versus SerSer/SerCys OR = 1.39, 95% CI = 1.15-1.67, P = 0.0005). In the sensitivity analysis, omitting each study one at a time had no obvious influence on the pooled OR, which confirmed the stability of meta-analysis. The meta-analysis suggests that OGG1 rs1052133 polymorphism is significantly associated with the risk of colorectal cancer in Caucasian population.

Mechanical evaluation of three access devices for laparoendoscopic single-site surgery.

BACKGROUND: Many access devices have been developed for laparoendoscopic single-site surgery (LESS) during recent years. However, investigations are needed to determine which port is most suitable for this relatively new technique. The aim of this study was to evaluate commonly used ports using mechanical approaches in a training simulator. Any port that required less force and shorter surgery times had superior maneuverability. METHODS: The following three commercially available access devices were evaluated: Multi-ports, TriPort, and single-incision laparoscopic surgery (SILS) Port. A LESS mechanical evaluation platform was developed to investigate the forces that acted on the instruments in the ports while moving along horizontal and vertical axes. In addition, a strain-force measurement system was used to compare the average load on the ports when performing standard maneuvers. Additionally, the task completion time was recorded when the maneuvers in these ports were completed. RESULTS: During the horizontal displacement of the instrument, the traction forces of the Multi-ports were lower than those of the SILS Port, which were lower than those of the TriPort. The average traction forces were significantly different in pairwise multiple comparisons (P < 0.05). When the instrument was inserted into the ports, the vertical friction forces of the Multi-ports were the lowest and those of the TriPort were the highest. On extraction of the instrument, the friction forces of the Multi-ports remained the lowest, followed by those of the TriPort and SILS Port. There were statistically significant results among all the devices (P < 0.05). The average load required to perform the task was less for the SILS Port than that for the TriPort (P < 0.05). Similarly, the average load for the Multi-ports was significantly less than that for the TriPort (P < 0.001). The participants who used the Multi-ports had significantly faster task times than those who used the SILS Port or TriPort (P < 0.005). CONCLUSIONS: Compared with the TriPort and SILS Port, the Multi-ports was associated with the least average load and the shortest task performance times in a training simulator. This study demonstrates that the Multi-ports may offer superior maneuverability for LESS.

Transumbilical endoscopic surgery: History, present situation and perspectives.

Transumbilical endoscopic surgery or laparo-endoscopic single site (LESS) surgery has become an exciting area of surgical development as innovation continues to move in the 21(st) century to minimally invasive surgery. The history, present situation and perspectives are reviewed and the nomenclature of this technique is discussed in this article. The range of this technique has been applied in almost all abdominal diseases, surgeries for morbid obesity, hernia and so on, in recent years. It is estimated that 50%-80% of traditional laparoscopic surgery could be performed transumbilically in the next five years according to the LESSCAR consensus. Although the concept of transumbilical laparoscopic surgery is gaining traction rapidly and the instruments have been improved greatly, we should not advocate for slightly improved cosmetic value over safety. Multicenter, randomized and clinical trials are necessary to further elucidate the safety and efficiency of this new technique. Research that examines the efficacy of the new instruments on the market may be helpful to simplify the confusing landscape of new and novel products designed for this purpose.