Differences In Body Weight Loss Research Articles

PAS-004: A novel macrocyclic MEK inhibitor to inhibit cancer cell growth in vitro and tumor growth in mouse xenograft studies.

3126 Background: Three MEK inhibitors have been approved to date to treat melanomas driven by RAS pathway mutations and a 4th compound (selumetinib) is approved to treat Neurofibromatosis type 1 (NF1) in pediatric patients. PAS-004 is the first macrocyclic MEK inhibitor in development for solid tumors and NF1. Methods: Ten NRAS mutant cancer cell lines were cultured for 48 hrs in the presence of the MEK inhibitor PAS-004, trametinib, binimetinib (bini) and selumetinib (selu) and cell proliferation was assayed using a Cell Titer Glo luminescence assay. The anti-tumor activity of PAS-004 was compared with selu and bini in two mouse xenograft studies using NRAS mutant human hepatocellular carcinoma (HCC) and lung carcinoma cell lines. Dose response was assessed with treatment initiated when the tumor reached a volume of 150 mm3 and mice treated for 20 days. Body weights and tumor volumes were measured twice weekly. Tumors were excised at the end of the study and pERK inhibition was assessed by Western blot. Terminal plasma was collected for PK analysis. Results: PAS-004 strongly inhibited 5/10 NRAS mutant cancer lines with IC50 values ranging from 0.024 to 0.306 µM. Maximal growth inhibition of >50% was achieved by PAS-004 in 8 cell lines and PAS-004 achieved greater maximal inhibition in 7/10 lines vs selu and bini. PAS-004 inhibition was comparable to trametinib in 5/10 cell lines tested. However, in contrast to trametinib PAS-004 did not reach a plateau at the highest dose tested in three of these lines. In the HCC xenograft study the highest dose of PAS-004 completely prevented tumor growth and the same dose caused a 69% reduction in tumor volume in the lung carcinoma xenograft study. The anti-tumor efficacy of PAS-004, when taken at equivalent doses, was shown to be superior to that of bini and selu. Specifically, PAS-004 at dose levels of 10 mg/kg and 5 mg/kg, once daily, exhibited higher efficacy compared to bini and selu at dose levels of 5 mg/kg and 2.5 mg/kg, when administered twice daily, respectively. No significant differences in body weight loss were seen between the compounds. Conclusions: The novel macrocyclic MEK inhibitorPAS-004 inhibited NRAS mutant tumor growth in mouse xenograft studies with similar activity as the approved MEK inhibitors selu and bini. In vitro, PAS-004 provided greater maximal growth inhibition of NRAS lines than selu and bini. These results support investigating PAS-004 further and a clinical trial in patients with advanced solid tumors carrying RAS pathway mutations, including NRAS variants, is ongoing.

Areca nut extract increased stromal tumor-infiltrating lymphocytes in 4-nutriquinoline-1-oxide-tumor-induced Sprague-Dawley rats

Background Oral squamous cell carcinoma (OSCC) is one of the most common oral cancers with a high mortality rate. The biodiversity source in Indonesia makes areca nut a potential antioxidant in treating disease. Objective The study aimed to evaluate the effect of areca nut extract in 4-nutriquinoline-1-oxide (NQO)-tumor-induced rats. Methods Twenty-eight male Sprague-Dawley rats were divided into four groups. Group 1 served as the control group, group 2 was 4NQO-induced rats without treatment, and groups 3 and 4 were given 4NQO-tumor inducer with 500 and 1000 mg/kg BW of areca nut extract, respectively. The rats in groups 2,3, and 4 received 30 ppm of 4NQO tumor inducer in drinking water for 12 weeks. In the end, all rats were euthanized and the tongue was removed. The body, liver, kidney, heart, and lungs weights were measured. Tongue tumor volume and dysplasia lesions were analyzed. The tumor-infiltrating lymphocytes (TILs) in the tumor and stromal area were scored semi-quantitatively associating the infiltrate grade (0-3) and analyzed histologically. Results There were significant differences in body weight loss between the initial and final phases in groups 1 and 2 (p<0.05). The areca nut at doses of 500 and 1000 mg/kg BW significantly reduced the tumor size compared with groups 1 and 2 (p<0.05). The incidence of OSCC in rats with 500 and 1000 mg/kg BW of areca nut extract after 22 weeks was 0%, but the dysplasia lesions were observed at 28.57% and 85.71%, respectively. The highest mean of stromal TILs was in group 3 and there were significant differences in stromal TILs between groups 2 and 3 (p<0.05). Conclusion Areca nut extract in 4NQO-induced rats by inducing infiltrating lymphocytes in the stromal tumor area on the OSCC lesion of the tongue.

Oral Nutritional Supplements Reduce Body Weight Loss after Gastrectomy in Patients with Gastric Cancer: A Systematic Review and Meta-Analysis of Randomized Controlled Trials.

This systematic review and meta-analysis aimed to summarize the effects of oral nutritional supplements (ONSs) on body weight loss (BWL) after gastrectomy. A systematic search was conducted across the PubMed, Cochrane, and Embase databases through May 2023. The study inclusion criteria were as follows: (1) studies on interventions including ONSs after gastrectomy in patients with gastric cancer; (2) studies in which comparisons were specified according to standard, regular, or usual postoperative diets; and (3) randomized controlled trial studies including outcomes measured as mean differences in BWL. The data were pooled using the random-effects model and expressed as mean differences with 95% confidence intervals (CI). Based on data from seven studies including 1743 patients (891 for ONSs and 852 for the control), the overall pooled mean difference was 0.848 (95% CI: 0.466 to 1.230) and the Higgins I2 value was 86.0%. This systematic review and meta-analysis is the first study to show that ONSs are significantly associated with reducing BWL, compared with standard diets, after gastrectomy in patients with gastric cancer. Furthermore, we found that ONSs were more effective in patients with lower nutritional kilocalorie intake after gastrectomy.

The chemotherapeutic activity of areca nut extract increased stromal tumor-infiltrating lymphocytes in 4-nutriquinoline-1-oxide-tumor-induced Sprague-Dawley rats

Background: Oral squamous cell carcinoma (OSCC) is one of the most common oral cancers with a high mortality rate. The biodiversity source in Indonesia makes areca nut a potential antioxidant in treating disease. Objective: The study aimed to evaluate the chemotherapeutic effect of areca nut extract in 4-nutriquinoline-1-oxide (NQO)-tumor-induced rats. Methods: Twenty-eight male Sprague-Dawley rats were divided into four groups. Group 1 served as the control group, group 2 was 4NQO-induced rats without treatment, and groups 3 and 4 were given 4NQO-tumor inducer with 500 and 1000 mg/kg BW of areca nut extract, respectively. The rats in groups 2,3, and 4 received 30 ppm of 4NQO tumor inducer in drinking water for 12 weeks. In the end, all rats were euthanized and the tongue was removed. The body, liver, kidney, heart, and lungs weights were measured. Tongue tumor volume and dysplasia lesions were analyzed. The tumor-infiltrating lymphocytes (TILs) in the tumor and stromal area were scored semi-quantitatively associating the infiltrate grade (0-3) and analyzed histologically. Results: There were significant differences in body weight loss between the initial and final phases in groups 1 and 2 (p<0.05). The areca nut at doses of 500 and 1000 mg/kg BW significantly reduced the tumor size compared with groups 1 and 2 (p<0.05). The incidence of OSCC in rats with 500 and 1000 mg/kg BW of areca nut extract after 22 weeks was 0%, but the dysplasia lesions were observed at 28.57% and 85.71%, respectively. The highest mean of stromal TILs was in group 3 and there were significant differences in stromal TILs between groups 2 and 3 (p<0.05). Conclusion: Areca nut extract exerts a chemotherapeutic activity in 4NQO-induced rats by inducing infiltrating lymphocytes in the stromal tumor area on the OSCC lesion of the tongue.

The chemotherapeutic activity of areca nut extract increased stromal tumor-infiltrating lymphocytes in 4-nutriquinoline-1-oxide-tumor-induced Sprague-Dawley rats

Background: Oral squamous cell carcinoma (OSCC) is one of the most common oral cancers with a high mortality rate. The biodiversity source in Indonesia makes areca nut a potential antioxidant in treating disease. Objective: The study aimed to evaluate the chemotherapeutic effect of areca nut extract in 4-nutriquinoline-1-oxide (NQO)-tumor-induced rats. Methods: Twenty-eight male Sprague-Dawley rats were divided into four groups. Group 1 served as the control group, group 2 was 4NQO-induced rats without treatment, and groups 3 and 4 were given 4NQO-tumor inducer with 500 and 1000 mg/kg BW of areca nut extract, respectively. The rats in groups 2,3, and 4 received 30 ppm of 4NQO tumor inducer in drinking water for 12 weeks. In the end, all rats were euthanized and the tongue was removed. The body, liver, kidney, heart, and lungs weights were measured. Tongue tumor volume and dysplasia lesions were analyzed. The tumor-infiltrating lymphocytes (TILs) in the tumor and stromal area were scored semi-quantitatively associating the infiltrate grade (0-3) and analyzed histologically. Results: There were significant differences in body weight loss between the initial and final phases in groups 1 and 2 (p<0.05). The areca nut at doses of 500 and 1000 mg/kg BW significantly reduced the tumor size compared with groups 1 and 2 (p<0.05). The incidence of OSCC in rats with 500 and 1000 mg/kg BW of areca nut extract after 22 weeks was 0%, but the dysplasia lesions were observed at 28.57% and 85.71%, respectively. The highest mean of stromal TILs was in group 3 and there were significant differences in stromal TILs between groups 2 and 3 (p<0.05). Conclusion: Areca nut extract exerts a chemotherapeutic activity in 4NQO-induced rats by inducing infiltrating lymphocytes in the stromal tumor area on the OSCC lesion of the tongue.

Cross-neutralization and viral fitness of SARS-CoV-2 Omicron sublineages

ABSTRACT The rapid evolution of SARS-CoV-2 Omicron sublineages mandates a better understanding of viral replication and cross-neutralization among these sublineages. Here we used K18-hACE2 mice and primary human airway cultures to examine the viral fitness and antigenic relationship among Omicron sublineages. In both K18-hACE2 mice and human airway cultures, Omicron sublineages exhibited a replication order of BA.5 ≥ BA.2 ≥ BA.2.12.1 > BA.1; no difference in body weight loss was observed among different sublineage-infected mice. The BA.1-, BA.2-, BA.2.12.1-, and BA.5-infected mice developed distinguishable cross-neutralizations against Omicron sublineages, but exhibited little neutralization against the index virus (i.e. USA-WA1/2020) or the Delta variant. Surprisingly, the BA.5-infected mice developed higher neutralization activity against heterologous BA.2 and BA.2.12.1 than that against homologous BA.5; serum neutralizing titres did not always correlate with viral replication levels in infected animals. Our results revealed a distinct antigenic cartography of Omicron sublineages and support the bivalent vaccine approach.

A Systematic Review and Meta-Analysis on the Efficacy and Safety of Combination Therapy with Sodium-Glucose Cotransporter Type 2 Inhibitor (SGLT2i) and Dipeptidase-4 Inhibitor (DPP4i) in Treatment of Type 2 Diabetes

Background: The management and treatment of type 2 diabetes (T2D) remain difficult and complex, despite the wide range of pharmacotherapies available for glycemic control. As a result, researchers continue to look for new therapeutic molecules with modes of action that might fill in the gaps left by currently existing medications.The aim of this study was to assess the efficacy and safety of sodium-glucose cotransporter type2 inhibitor (SGLT2i) and dipeptidyl peptidase-4 inhibitor (DPP4i) in combination for treatment and management of type 2 diabetes (T2D). Methods: EMBASE, MEDLINE, PUBMED and Cochrane Central Register of Controlled Trials were subjected to literature search. RCTs comparing SGLT2i plus DPP4i (SGLT2i/DPP4i) to DPP4iplacebo or SGLT2iplacebo were eligible if they were published in English and compared SGLT2i plus DPP4i (SGLT2i/DPP4i) to DPP4iplacebo or SGLT2iplacebo. The change in HbA1c from baseline was the primary endpoint. Results: The study comprised of eight RCTs comparing SGLT2i/DPP4i and DPP4ionly, five RCTs comparing SGLT2i/DPP4i and SGLT2ionly, and three RCTs involving both comparisons. The combination of both inhibitors resulted in a greater average HbA1c reduction [WMD: 0.62 percent] than DPP4i alone, which resulted in a much lesser reduction (WMD: -0.35 percent) than SGLT2i alone. Furthermore, only SGLT2i/DPP4i vs. DPP4i revealed notable differences in body weight loss from baseline, but not SGLT2i.The risk of hypoglycemia was modest and consistent across treatment groups. Any reduction by SGLT2i/DPP4i in relation to DPP4i was proportionate to baseline HbA1c levels when patients were stratified based on baseline HbA1c levels. However, despite of baseline HbA1c, HbA1c reductions with combination were minor when compared to SGLT2i alone. Conclusion: Combination of these two inhibitors is found to be safe and effective. A significant extra glucose-lowering impact is observed when SGLT2i is used with or added to DPP4i, but not the other way around. The extra hypoglycemic effects of SGLT2i in combination with DPP4i were assessed by baseline HbA1c. Keywords: Efficacy, safety, DPP4i, SGLT2i, Treatment, Type 2 Diabetes

Allogeneic transplantation of epidermal cell sheets followed by endoscopic submucosal dissection to prevent severe esophageal stricture in a porcine model.

IntroductionEndoscopic submucosal dissection (ESD) is a minimally invasive treatment for early esophageal cancer. However, large mucosal defects after esophageal ESD result in refractory strictures. In the present study, we histologically evaluated the endoscopic transplantation of allogeneic epidermal cell sheets (ECSs) as a feasible therapy for preventing esophageal stricture after circumferential ESD in a porcine model.MethodsEpidermal cells were isolated from the skin tissue of allogeneic pigs and cultured on temperature-responsive cell culture inserts for 2 weeks. Transplantable ECSs were harvested by reducing the temperature and endoscopically transplanting the sheets to ulcer sites immediately after esophageal ESD. The engraftment of transplanted ECSs was then evaluated in two pigs at 7 days after transplantation. Next, ten pigs were divided into two groups to evaluate the endoscopic transplantation of allogeneic ECSs for the prevention of esophageal strictures after ESD. Allogeneic ECSs were transplanted immediately after esophageal ESD in the transplantation group (n = 5), whereas the control group (n = 5) did not undergo transplantation.ResultsMost of the transplanted allogeneic ECSs were successfully engrafted at the ulcer sites in the early phase. Fluorescence in situ hybridization analysis revealed that several allogeneic cells were present in the transplanted area at 7 days after ESD. At 14 days after ESD, significant differences in body weight loss, dysphagia scores, and mucosal strictures were observed between the control and transplantation groups. Transplanting allogeneic ECSs after esophageal ESD promotes mucosal healing and angiogenesis and prevents excessive inflammation and granulation tissue formation.ConclusionsEndoscopic and histological analyses revealed that allogeneic ECSs promoted artificial ulcer healing after ESD, preventing esophageal strictures after ESD.

Proximal incisal edge length and recent clinical observation of Siewert type Ⅱ advanced esophagogastric junction adenocarcinoma

Objective: To investigate the clinical effect of the radical resection with a proximal incisal edge length of 20-25 mm and 30-35 mm in Siewert type Ⅱ advanced esophagogastric junction adenocarcinoma, to shorten the minimum safe distance of the proximal incisal edge to 20-25 mm. Methods: A retrospective cohort study method was used. The clinical data of 166 patients with Siewert type Ⅱ advanced esophagogastric junction adenocarcinoma who underwent total gastrectomy from January 2017 to August 2020 in the Department of Gastrointestinal Surgery, Heji Hospital Affiliated to Changzhi Medical College were retrospectively collected. According to the proximal incisal edge length, the patients were divided into two groups: the proximal incisal edge length of 20-25 mm group (69 cases) and 30-35 mm group (97 cases). The perioperative conditions and the 6-month follow-up after the operation were compared between the two groups. Results: There was no statistically significant difference in baseline information between the patients in the two groups (P>0.05). The operations of both groups were completed. The intraoperative operation time of the proximal incisal edge length of 20-25 mm group was shorter than that in the proximal incisal edge length of 30-35 mm group ((172±24)and(206±27)min, P<0.001). There were no significant differences in the amount of intraoperative blood loss, the treatment of the diaphragm during the operation and the positive rate of intraoperative freezing of the upper incisal edge between the patients in the two groups (all P>0.05). And there was no significant differences in the first exhaust time, gastric tube removal time, first feeding time and hospital stay after the operation of the two groups (all P>0.05). There was no significant differences in the incidence of anastomotic leakage, anastomotic stenosis, reflux esophagitis and intestinal obstruction after the operation between the patients in the two groups (all P>0.05). And there was no anastomotic leakage case among the 69 cases in the proximal incisal edge length of 20-25 mm group. Postoperative pathological treatment showed no significant differences in the vascular tumor thrombus and nerve infiltration between the two groups (both P>0.05). During the 6-month follow-up, there was no death or tumor recurrence in the two groups, and there was no significant difference in body weight loss at 6 months after the operation between the two groups (P=0.178). Conclusion: When radical resection of Siewert type Ⅱ advanced esophagogastric junction adenocarcinoma is performed, it is feasible to shorten the minimum safe distance of the proximal incisal edge to 20-25 mm under the premise of ensuring R0 resection. The operation time is shortened. Due to the shortening the incisal edge distance, the anastomotic tension is decreased, and the incidence of postoperative anastomotic leakage is also reduced.

668-P: Body Weight Loss with Oral Semaglutide Is Predominantly Mediated by Effects Other than Gastrointestinal Adverse Events

Glucagon-like peptide-1 receptor agonists (GLP-1RAs) reduce body weight (BW). Evidence suggests that GLP-1RAs directly modulate appetite and reduce food intake through central mechanisms. However, GLP-1RAs are also associated with gastrointestinal (GI) adverse events (AEs), which may contribute to reduced appetite and food intake. We sought to assess whether the BW loss observed in phase 3 clinical trials with oral semaglutide was primarily due to indirect effects (defined as GI AEs, specifically nausea, vomiting, and diarrhea) or direct effects (not explained by GI AEs). Data from PIONEER 1-5, 7, and 8 were assessed and a mediation analysis (how a third variable [GI AEs] affects the relationship between two other variables [treatment and BW]) was performed to separate the overall contribution of direct and indirect effects to changes in BW. Significant total estimated treatment differences in BW loss were observed vs. all comparators with oral semaglutide 7 mg (1.0-3.7 kg vs. placebo, 1.7 kg vs. active comparator) and 14 mg (2.7-5.0 kg vs. placebo, 0.8-2.4 kg vs. active comparators). In the mediation analysis, GI AEs accounted for 0.0-0.3 kg of the BW loss across oral semaglutide doses vs. all comparators (Figure). In conclusion, GI AEs (indirect effects) appear to have no clinically relevant impact on total BW loss observed with oral semaglutide vs. placebo and most active comparators. Disclosure J. J. Meier: Advisory Panel; Self; AstraZeneca, MSD Corporation, Novo Nordisk, Speaker’s Bureau; Self; AstraZeneca, Boehringer Ingelheim International GmbH, Lilly Diabetes, MSD Corporation, Novo Nordisk, Sanofi. R. Agesen: Employee; Self; Novo Nordisk. L. Bardtrum: Employee; Self; Novo Nordisk A/S, Stock/Shareholder; Self; Novo Nordisk A/S. A. Y. Cheng: Advisory Panel; Self; Abbott, AstraZeneca, Bayer Inc., Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company, HLS Therapeutics Inc., Janssen Pharmaceuticals, Inc., Medtronic, Merck & Co., Inc., Merck Sharp & Dohme Corp., Novo Nordisk, Sanofi, Research Support; Self; Applied Therapeutics, The Medicine Company, Speaker’s Bureau; Self; Abbott, AstraZeneca, Bausch Health, Canada, Bayer Inc., Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company, HLS Therapeutics Inc., Janssen Pharmaceuticals, Inc., Medtronic, Merck & Co., Inc., Novartis Pharmaceuticals Corporation, Novo Nordisk, Sanofi. S. Deenadayalan: Employee; Self; Novo Nordisk A/S, Stock/Shareholder; Self; Novo Nordisk A/S. E. Montanya: Advisory Panel; Self; Sanofi, Consultant; Self; Merck Sharp & Dohme Corp., Employee; Spouse/Partner; Almirall, S. A., Research Support; Self; Menarini Group, Roche Diagnostics SL, Speaker’s Bureau; Self; Novo Nordisk A/S. R. E. Pratley: Other Relationship; Self; Hanmi Pharmaceutical, Merck Sharp & Dohme Corp., Metavention, Monster Energy Company, Inc., Novo Nordisk, Pfizer Inc., Poxel SA, Sanofi, Scohia Pharma Inc., Sun Pharmaceutical Industries Ltd. Funding Novo Nordisk A/S

Role of p40phox in host defense against Citrobacter rodentium infection.

NADPH oxidase (NOX) is a membrane‐bound enzyme complex that generates reactive oxygen species (ROS). Mutations in NOX subunit genes have been implicated in the pathogenesis of inflammatory bowel disease (IBD), indicating a crucial role for ROS in regulating host immune responses. In this study, we utilize genetically deficient mice to investigate whether defects in p40phox, one subunit of NOX, impair host immune response in the intestine and aggravate disease in an infection‐based (Citrobacter rodentium) model of colitis. We show that p40phox deficiency does not increase susceptibility of mice to C. rodentium infection, as no differences in body weight loss, bacterial clearance, colonic pathology, cytokine production, or immune cell recruitment were observed between p40phox −/− and wild‐type mice. Interestingly, higher IL‐10 levels were observed in the supernatants of MLN cells and splenocytes isolated from infected p40phox‐deficient mice. Further, a higher expression level of inducible nitric oxide synthase (iNOS) was also noted in mice lacking p40phox. In contrast to wild‐type mice, p40phox −/− mice exhibited greater NO production after LPS or bacterial antigen re‐stimulation. These results suggest that p40phox −/− mice do not develop worsened colitis. While the precise mechanisms are unclear, it may involve the observed alteration in cytokine responses and enhancement in levels of iNOS and NO.

A case study of liraglutide in an obese diabetic patient in a District General Hospital

A case study of liraglutide in an obese diabetic patient in a District General Hospital

1798-P: Chronic Administration of a Long-Acting Glucagon Analogue Results in Enhanced Insulin Secretory Activity in a Directly-Observed Murine Model

Aims: GLP-1 (GLP-1R) and glucagon (GCGR) receptor co-agonists are in development to treat type 2 diabetes. The effect of chronic GCGR agonism on weight loss is well-documented, but its direct influence on islet function remains poorly understood. We investigated the effects of a long-acting glucagon analogue G778 on pancreatic islet calcium dynamics. Methods: C57Bl/6 (n=9 per group) mice with diet-induced obesity (DIO) received daily subcutaneous injections of G778 100nmol/kg or saline (and calorie restricted to achieve weight matching) for 40 days. All mice had syngeneic islets with beta-cell specific expression of the calcium fluorophore GCaMP6f implanted in the anterior chamber of the eye, providing a direct, longitudinal readout of beta-cell function in vivo using confocal microscopy. Such islets were tested in vitro to measure the effects of G778 on whole islet calcium dynamics. Another experiment measured the effects of G778 administration on oxygen consumption in a CLAMS system. Results: G778 produced a small but significant rise in energy expenditure (EE) in mice. At 40 days, there was non-significant difference in body weight loss between the saline and G778-treated groups (0.9g ±1.1 vs. 3.4g ±0.7 p=0.07), but a marked improvement in glucose tolerance in mice treated long term with the glucagon analogue (15 min glucose on a 2mg/kg IPGTT 15.9 mmol/L vs. 9.2 mmol/L p&amp;lt;0.001). Islet readouts over the course of the experiment revealed that glucagon receptor agonism was able to restore calcium activity of islets in DIO mice in vivo. In vitro findings confirmed that G778 promoted calcium waves of longer duration and heightened connectivity above 7mM glucose (p=0.05). Summary: Our data suggest that the glucagon element of a glucagon/GLP-1 analogue contributes to weight-loss partly through an elevation in EE but also has independent effects on insulin secretory function, promoting more robust and sustained beta-cell calcium responses. Disclosure K. Suba: None. Y.S. Patel: None. A. Martin Alonso: None. R. Scott: None. J.S. Minnion: None. I. Leclerc: Consultant; Spouse/Partner; Sun Pharmaceutical Industries Ltd. Research Support; Spouse/Partner; Servier. B. Owen: None. W. Distaso: None. T.M. Tan: None. K. Murphy: None. S. Bloom: None. G.A. Rutter: Consultant; Self; Sun Pharmaceutical Industries Ltd. Research Support; Self; Servier, Sun Pharmaceutical Industries Ltd. V. Salem: None. Funding Diabetes UK (15/0005317)

Changes in Whole-Body Amino Acid Metabolism in Response to 2 Weeks of the Very-Low Calorie Diet Are Not Affected by Gender

Abstract Objectives Very Low-Calorie Diet (VLCD) is an approved method to safely achieve substantial short-term weight loss in obese patients. We previously reported that two weeks of the VLCD maintains whole-body protein and amino acid turnover despite a large reduction in lean body mass. Since the observed effects on body weight (BW) and composition differed between men and women, we hypothesized that the changes in amino acid metabolism in a response to the calorie-restricted diet is gender-specific. Methods 34 morbidly obese adults (BMI: 42 ± 0.9 kg/m2, 10 males and 24 females) underwent a VLCD for 2 weeks consisting of 820 kcal/day and 105-grams protein/day. Before the start of the VLCD (baseline), the whole-body production (WBP) rates of multiple amino acids involved in protein metabolism (e.g., glycine (GLY), glutamine (GLN), phenylalanine (PHE), tyrosine (TYR), and arginine (ARG)) were measured after IV pulse administration of their stable isotopes. Weight loss and body composition by dual-energy X-ray absorptiometry were assessed after 2 weeks of the VLCD. Baseline plasma enrichments were measured by LC-MS/MS. Data are presented as mean ± SE. Statistics are performed by Pearson correlation tests. Results The magnitude of the BW loss after 2 weeks of the VLCD differed between males and females (7.0 ± 0.7 kg vs. 4.1 ± 0.2 kg, P &amp;lt; 0.0001, respectively) with a higher reduction in lean body mass observed in men than women (4.3 ± 0.8 kg vs. 2.7 ± 0.4 kg, P &amp;lt; 0.05). Although, females had significantly reduced baseline WBP of ARG (7.3% vs. 2%, P = 0.0027), GLY (22.8% vs. 3.6%, P &amp;lt; 0.001), and PHE (4.8% vs. 3.1%, P = 0.018) in comparison to men, two weeks of the VLCD had a comparable effect on multiple amino acid WBP in both genders. Suppressed contractile myofibrillar protein breakdown rate was observed in both groups (13% vs. baseline, P = 0.02) with no gender difference in net protein breakdown (PHE to TYR conversion rate). Hence, increased catabolism in men cannot be explained by a different response to the 2 weeks of a calorie-restricted diet. Conclusions Despite gender differences in body weight loss and changes in composition in response to a Very Low-Calorie Diet, changes in whole-body amino acid kinetics are not differently affected in men and women. Funding Sources CTRAL Internal Funds.

Abstract 3228: Immune checkpoint blockade and autoimmune diseases: Development of a mouse model of colitis induced by anti-CTLA-4

Abstract Immunotherapies prime or activate patient’s immune system to fight disease and has recently been a source of registered and promising new cancer treatments with major beneficial clinical outcomes in several cancers. However, by increasing the activity of the immune system, therapies as such targeting the immune checkpoint blockade can have profound inflammatory side effects, termed immune-related adverse events, with particular organs affected such as gastrointestinal tract, endocrine glands, skin and liver. In patients treated with the anti-CTLA-4 antibody, Ipilimumab, the overall incidence of diarrhea and colitis has been reported as 32.8%. This side effect is also observed in patients treated with anti-PD-1 therapy. The reproduction of such aspects of immune checkpoint inhibitors side effects in preclinical animal models would serve to dig into deciphering mechanisms involved, but also to evaluate combination therapies and modalities to reduce and manage such incidence with potential beneficial translation in clinical practice. We thus first ought to establish a checkpoint blockade-related autoimmune mouse model of colitis, using female C57BL/6 mice which were tested to determine their response to orally administered dextran sulfate sodium (DSS) combined to multiple injections of anti-CTLA-4 antibody or an isotype control antibody. After administration of DSS in drinking water for 7 days, mice that received an anti-CTLA-4 antibody showed no difference in body weight loss and Disease Activity Index (composite of body weight loss, stool consistency and presence of blood in stools), when compared to mice that received DSS plus the isotype control antibody. Histological sections analysis from the colons of mice culled at Day 10 confirmed that the combined treatment did not change the colitis score.However, when looking at later time points corresponding to the usual recovery phase of colitis, the effect of anti-CTLA4 treatment was clearly revealed by a sustained body weight loss and the persistence of a high Disease Activity Index, while the isotype control-treated animals slowly returned to baseline values similar to untreated animals. At sacrifice on Day 19, these in life findings were confirmed by a decrease in colon length (- 0.94 cm), an increase in colon weight (+ 231 mg) and a high mucus colon production in the anti-CTLA4-treated group versus the isotype control-treated group. Histological analysis of colons, and a more in depth characterization of the immune infiltrates will be presented. Citation Format: Edwige Nicodeme, Florence Blandel, Valerie Boullay, Yannick Saintillan, Gael Krysa, Anne-Benedicte Boullay, Jean-Jacques Tousaint, Robin Artus, Laure Levenez, Jeremy Odillard, Ingrid Jacquet, Olivier Duchamp, Fabrice Viviani. Immune checkpoint blockade and autoimmune diseases: Development of a mouse model of colitis induced by anti-CTLA-4 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3228.

Long-term effects of regular exercise during pregnancy on overweight and obese gravidas: one-year follow-up of a previous randomized controlled trial

Objective To investigate the long-term effects of regular exercise during pregnancy on overweight and obese gravidas. Methods This study was based on a previous randomized controlled trial (RCT) regarding Effect of Regular Exercise Commenced in Early Pregnancy on the Incidence of Gestational Diabetes Mellitus in Overweight and Obese Pregnant Women conducted at Peking University First Hospital from December 2014 to July 2016. Totally 265 women whose prepregnant body mass index (BMI) ≥24.0 kg/m2 were enrolled in the RCT and were randomly assigned to exercise group (n=132) and control group (n=133). This study was a follow-up of all the participants at one year after delivery from March 2016 to August 2017. Body weight, body fat, fasting and 2 h glucose level in 75 g oral glucose tolerance test (OGTT), insulin resistance index and lipid profiles were compared. We also evaluated their physical activities with International Physical Activity Questionnaire (IPAQ), their dietary habits with modified Adult Dietary Behavior Assessment Scale and depression condition with Postpartum Depression Screen Scale (PDSS). Two independent samples t-test, Mann-Whitney U test and Chi-square test were used for statistical analysis. Results The overall follow-up rate was 51.7% (137/265), while 64.4% (85/132) in the exercise group and 39.1% (52/133) in the control group. No significant difference in body weight loss [2.3 (-6.0 to 5.0) vs 1.0 (-1.3 to 4.7) kg], body fat percentage [(38.04±4.54)% vs (37.51±4.90) %], 2 h glucose level in 75 g OGTT [(7.30±2.80) vs (7.32±1.61) mmol/L], abnormal glucose tolerance ratio [30.0% (9/30) vs 28.8% (17/59)] or insulin resistance index (2.92±1.77 vs 2.86±1.92) was found between the control and exercise group (t or Z=-0.940, 0.312, 3.415, 0.005, 1.743, all P>0.05). However, the fasting blood glucose in 75 g OGTT was higher in the control group [(5.53±0.92) vs (5.28±0.43) mmol/L, t=9.268, P=0.003]. The two groups showed no significant difference (exercise group vs control group) in physical activity level [219 (99-504) vs 195 (99-351)], total score of dietary habits [79.00 (72.50-87.50) vs 76.00 (70.00-82.00)] or PDSS score of depression [55.00 (41.00-77.00) vs 70.00 (46.25-84.75)] at follow-up (Z=-0.808, -1.822, -1.620, all P>0.05). Moreover, there was no significant difference in the level of serum triglyceride [(1.25±1.04) vs (1.42±0.85) mmol/L], total cholesterol [(4.56±0.71) vs (4.40±0.67) mmol/L], high density lipoprotein-cholesterol [(1.32±0.29) vs (1.22±0.21) mmol/L] or low density lipoprotein-cholesterol [(2.67±0.56) vs (2.55±0.52) mmol/L] between the exercise and control group (t=0.001, 0.020, 3.255, 0.303, all P>0.05). Conclusions Regular exercise during pregnancy has no long-term effect on maternal health in the absence of continuing lifestyle intervention after delivery. Therefore, postpartum follow-up and continued education on healthy lifestyle should be emphasized. Key words: High body mass index; Exercise intervention; Postpartum; Long-term outcomes of mothers and offspring

The impact of preoperative carbohydrate loading on intraoperative body temperature: a randomized controlled clinical trial.

Preoperative carbohydrate loading (CHO) is one element of the enhanced recovery after surgery protocol. No clinical trial has investigated the impact of preoperative CHO on intraoperative body temperature. This study was a single-center, prospective, randomized controlled clinical trial involving patients undergoing laparoscopic colon cancer surgery. The primary end point was the intraoperative core temperature during surgery, which was measured at 30-min intervals for 150min after starting surgery. The secondary end points were short-term outcomes and body composition changes. From July 2013 to May 2014, we randomized 70 patients into the control group (n = 33) or CHO group (n = 31); six patients were excluded. The core temperature of the CHO group 90, 120, and 150min after starting surgery was significantly lower than that of the control group (control vs. CHO, respectively: 90min; 36.26 ± 0.41 vs. 36.05 ± 0.43°C, p = 0.0233, 120min; 36.30 ± 0.44 vs. 36.06 ± 0.50°C, p = 0.0283, 150min; 36.33 ± 0.50 vs. 36.01 ± 0.56°C, p = 0.0186). We also found a significant difference in body weight loss (control vs. CHO, respectively: - 1.6 ± 0.8 vs. - 0.9 ± 1.4kg, p = 0.0304) and loss of lower limb muscle mass (- 0.7 ± 0.7 vs. - 0.3 ± 0.6kg, p = 0.0110) between the control and CHO groups, respectively. CHO had no effect on raising the intraoperative core temperature, and no negative impact on the perioperative outcome. CHO prevented the loss of lower limb muscle mass, which may lead to better postoperative recovery.

Efficacy and safety of combination therapy with SGLT2 and DPP4 inhibitors in the treatment of type 2 diabetes: A systematic review and meta-analysis

BackgroundThis review evaluated the efficacy and safety of a combination therapy comprising a sodium-glucose cotransporter type 2 inhibitor (SGLT2i) and dipeptidyl peptidase-4 inhibitor (DPP4i) in type 2 diabetes. MethodsA literature search through to May 2017 was carried out of PubMed, Embase and the Cochrane Central Register of Controlled Trials. Studies were eligible if they were randomized controlled trials (RCTs) comparing SGLT2i plus DPP4i (SGLT2i/DPP4i) against DPP4i±placebo or SGLT2i±placebo and published in English. The primary outcome was change in HbA1c from baseline. ResultsEight RCTs comparing SGLT2i/DPP4i and DPP4i, and five RCTs comparing SGLT2i/DPP4i and SGLT2i, with three RCTs involving both comparisons, were included in the present review. SGLT2i/DPP4i resulted in a greater mean HbA1c reduction [weighted mean difference (WMD]): −0.62%] than did DPP4i alone, which was a much less marked reduction (WMD: −0.35%) than with SGLT2i alone. Also, significant differences in body weight loss from baseline were observed only with SGLT2i/DPP4i vs. DPP4i, but not vs. SGLT2i. The risk of hypoglycaemic events was low and similar between treatment groups. When subjects were stratified based on baseline HbA1c, any reduction by SGLT2i/DPP4i in relation to DPP4i was proportional to baseline HbA1c levels. However, compared with SGLT2i, HbA1c reductions with SGLT2i/DPP4i were modest regardless of baseline HbA1c. ConclusionCombination therapy with SGLT2i and DPP4i is both efficacious and safe. In particular, a marked additional glucose-lowering effect is evident when SGLT2i is combined with or added to DPP4i, and not vice versa. However, baseline HbA1c determined the additional glucose-lowering effects of SGLT2i in combined treatment with DPP4i.

Scopolamine-induced convulsions in fasted animals after food intake: Sensitivity of C57BL/6J mice and Sprague-Dawley rats

Food intake triggers convulsions in fasted BALB/c mice and Wistar albino rats treated with antimuscarinic drugs, scopolamine or atropine. Inbred strain studies have yielded considerable information regarding genetic influences on seizure susceptibility and factors contribute to epileptogenesis in rodents. This study, therefore, investigated sensitivity to antimuscarinic-induced seizures in C57BL/6J mice and Sprague-Dawley rats. Food deprivation for 48h in mice and 52h in rats did not produce strain differences in body weight loss. Fasted animals treated i.p. with 3mg/kg scopolamine developed convulsions after food intake. The incidence of convulsions was indifferent in comparison to BALB/c mice and Wistar albino rats. Number of animals developing stage 5 was more and onset of convulsions was longer in C57BL/6J mice than in BALB/c mice. Strain-related differences in sensitivity to seizures in C57BL/6J mice may need further evaluation for investigating genetic influences on scopolamine-induced seizures.

Quality of Life After Bariatric Surgery.

Introduction and PurposeMorbid obesity together with obesity-related diseases has a negative impact on the quality of life. The aim of the study was to assess the quality of life amongst patients with morbid obesity as well as the impact of bariatric treatment on body weight and obesity-related diseases in addition to conducting an analysis of changes in the quality of life after surgical treatments, in the context of the surgical procedure type and degree of body weight loss.Material and MethodsSixty-five patients were treated for morbid obesity. The sample group consisted of 34 patients treated with laparoscopic sleeve gastrectomy (LSG) and 31 persons qualified for laparoscopic Roux-en-Y gastric bypass (LRYGB). The average body weight before the procedure was 146.2 kg. In the sample group, 89 % of persons qualified for the surgical treatments were diagnosed with hypertension and 52 % persons that were operated on were diagnosed with diabetes type 2 before the surgical procedure. Before commencement of the surgical treatment, the quality of life was assessed, which in both groups qualified for given types of bariatric procedures was considerably low.Results and ConclusionsPercentage excessive weight loss (%EWL) was 58.8 %. No significant differences in body weight loss were noted between the two types of procedures. Improvement was observed in the treatment of obesity-related diseases. Also, the quality of life was enhanced significantly. No differences were noted in terms of the quality of life improvement between particular types of surgical procedures. No significant differences were observed during the analysis of body weight loss impact on the quality of life improvement.