Phosphatidylethanolamine (18:2e/18:2) may inhibit adipose tissue wasting in patients with cancer cachexia by increasing lysophosphatidic acid receptor 6.

BACKGROUND: Cancer associated cachexia is characterized by the significant loss of adipose tissue, leading to devastating weight loss and muscle wasting in the majority of cancer patients. The effects and underlying mechanisms of degradation metabolites on adipocytes in cachectic patients remain poorly understood. To address this knowledge gap, we conducted a comprehensive study combining lipidomic analysis of subcutaneous and visceral adipose tissue with transcriptomics data from the database to investigate the mechanisms of lipid regulation in adipocytes. METHODS: We collected subcutaneous and visceral adipose tissue samples from cachectic and noncachectic cancer patients. Lipidomic analysis was performed to identify differentially expressed lipids in both types of adipose tissue. Additionally, transcriptomics data from the GEO database were analyzed to explore gene expression patterns in adipocytes. Bioinformatics analysis was employed to determine the enrichment of differentially expressed genes in specific pathways. Furthermore, molecular docking studies were conducted to predict potential protein targets of specific lipids, with a focus on the PI3K-Akt signaling pathway. Western blot analysis was used to validate protein levels of the identified target gene, lysophosphatidic acid receptor 6 (LPAR6), in subcutaneous and visceral adipose tissue from cachectic and noncachectic patients. RESULTS: Significant lipid differences in subcutaneous and visceral adipose tissue between cachectic and noncachectic patients were identified by multivariate statistical analysis. Cachectic patients exhibited elevated Ceramides levels and reduced CerG2GNAc1 levels (P < 0.05). A total of 10 shared lipids correlated with weight loss and IL-6 levels, enriched in Sphingolipid metabolism, GPI-anchor biosynthesis, and Glyceropholipid metabolism pathways. LPAR6 expression was significantly elevated in both adipose tissues of cachectic patients (P < 0.05). Molecular docking analysis indicated strong binding of Phosphatidylethanolamine (PE) (18:2e/18:2) to LPAR6. CONCLUSIONS: Our findings suggest that specific lipids, including PE(18:2e/18:2), may mitigate adipose tissue wasting in cachexia by modulating the expression of LPAR6 through the PI3K-Akt signaling pathway. The identification of these potential targets and mechanisms provides a foundation for future investigations and therapeutic strategies to combat cachexia. By understanding the underlying lipid regulation in adipocytes, we aim to develop targeted interventions to ameliorate the devastating impact of cachexia on patient outcomes and quality of life. Nevertheless, further studies and validation are warranted to fully elucidate the intricate mechanisms involved and translate these findings into effective clinical interventions.

Development and application of the Cancer Cachexia Staging Index for the diagnosis and staging of cancer cachexia.

OBJECTIVE: The current tools for evaluating cancer cachexia are either too simple to reflect the far-reaching effects of cachexia or too complicated to be used in daily practice. This study aimed to develop a cancer cachexia staging index (CCSI) that is both practical and comprehensive. METHODS: Patients with gastrointestinal cancers were prospectively included in the study. Clinical data including weight change, body composition, systematic inflammation, nutrition, and function status were entered into regression models to determine the best variable combination as well as their respective cutoff values and score distribution in the CCSI. The CCSI's ability to predict outcomes and evaluate the consequences of cachexia for patients were then assessed. RESULTS: Clinical information and test results from 10 568 patients were used to develop a CCSI composed of subjective and objective measures. Subjective measures included body mass index-adjusted weight loss grade, rate of weight loss, inflammation (neutrophil-to-lymphocyte ratio and C-reactive protein level), and prealbumin level. Objective measures included appetite status and physical status. Patients were diagnosed and stratified by the total CCSI score into 3 subgroups: no cachexia, mild or moderate cachexia, and severe cachexia. The CCSI grades showed good survival discrimination and were independently predictive of survival in multivariate analysis. Compared with the traditional Fearon criteria for diagnosing cancer cachexia, the CCSI was more accurate in predicting postoperative complications (net reclassification index [NRI], 2.8%; 95% CI, 0.0104-0.0456%), death (NRI, 10.68%; 95% CI, 0.0429-0.1708%), recurrence (NRI, 3.71%; 95% CI, 0.0082-0.0685%), and overall survival (NRI, 8.5%; 95% CI, 0.0219-0.1533%). The CCSI also had better discriminative ability than Fearon criteria in discriminating nutritional status, body composition, and systematic inflammation in patients with or without cachexia. A more detailed evaluation of a randomly selected subgroup (n = 1566) showed that CCSI grades had good discrimination of appetite and food intake status, physical function and muscle strength, symptom burden, and quality of life. CONCLUSIONS: The CCSI is a comprehensive and practical evaluation tool for cancer cachexia. It can predict postoperative outcomes and survival. The CCSI stages showed good discrimination when evaluating patients with cancer in terms of nutritional status, physical function, systematic inflammation, body composition, symptom burden, and quality of life.

Tumor-derived semaphorin 3D promoting cancer cachexia via regulating hypothalamic pro-opiomelanocortin neurons.

Cachexia is very common in cancer patients and predicts a poor prognosis; however, the molecular basis for progress in these individuals remains unclear, especially the effect of tumors on the hypothalamus energy regulation center. To investigate the regulatory pathway of tumors associated with hypothalamic pro-opiomelanocortin (POMC) neurons known as appetite-inhibiting neurons, we conducted observations both on patients and mice models. Results showed that the highly expressed exocrine semaphorin 3D (SEMA3D) both in cachexia patients and mice was positively related to the expression of POMC and its proteolytic peptide. Compared with the control group, mice inoculated with the SEMA3D-knockout C26 cell line decreased the activity of POMC neurons resulting in a 1.3-fold increase in food intake, a 22.2% increase in body weight, and reduced skeletal muscle and fat catabolism. The effect of SEMA3D on cachexia progression can be partially alleviated by knocking-down POMC expression in the brain. In terms of mechanism, SEMA3D enhances the activity of POMC neurons by activating the expression of NRP2 (membrane receptor) and PlxnD1 (intracellular receptor). Our research revealed the overexpression of SEMA3D in tumors works as an activator of POMC neurons, which may play a vital role in suppressing appetite and promoting catabolic metabolism.

Development and validation of a cancer cachexia risk score for digestive tract cancer patients before abdominal surgery.

BACKGROUND: Cancer cachexia is prevalent in digestive tract cancer patients and has significant impacts on prognosis; it is vital to identify individuals who are at risk of cancer cachexia to allow for appropriate evaluation and treatment. This study evaluated whether digestive tract cancer patients with a risk of cancer cachexia and who had a risk of adverse survival could be identified before abdominal surgery. METHODS: This large-scale cohort study involved patients who underwent abdominal surgery between January 2015 and December 2020 to treat digestive tract cancer. Participants were allocated to the development cohort, the validation cohort, or the application cohort. Univariate and multivariate analyses of the development cohort were performed to detect distinct risk variables for cancer cachexia to create a cancer cachexia risk score. The performance of the risk score across all the three cohorts was assessed through calculating the area under the receiver operating characteristic curve (AUC), as well as calibration and decision curves. We tested how well the score predicted survival outcomes in the application cohort. RESULTS: A total of 16 264 patients (median 64 years of age; 65.9% male) were included, with 8743 in the development cohort, 5828 in the validation cohort, and 1693 in the application cohort. Seven variables were identified as independent predictive factors and were included in the cancer cachexia risk score: cancer site, cancer stage, time from symptom onset to hospitalization, appetite loss, body mass index, skeletal muscle index, and neutrophil-lymphocyte ratio. The risk score predicting cancer cachexia owns a good discrimination, with the mean AUC of 0.760 (P < 0.001) in the development cohort, 0.743 (P < 0.001) in the validation cohort, and 0.751 (P < 0.001) in the application cohort, respectively, and had an excellent calibration (all P > 0.05). The decision curve analysis revealed net benefits of the risk score across a range of risk thresholds in the three cohorts. In the application cohort, compared with the high-risk group, the low-risk group experienced significantly longer overall survival [hazard ratio (HR) 2.887, P < 0.001] as well as relapse-free survival (HR 1.482, P = 0.01). CONCLUSIONS: The cancer cachexia risk score constructed and validated demonstrated good performance in identifying those digestive tract cancer patients before abdominal surgery at a higher risk of cancer cachexia and unfavourable survival. This risk score can help clinicians to enhance their capabilities to screen for cancer cachexia, assess patient prognosis, and strengthen early decision-making on targeted approaches to attune cancer cachexia for digestive tract cancer patients before abdominal surgery.

Loss of body weight and skeletal muscle negatively affect postoperative outcomes after major abdominal surgery in geriatric patients with cancer.

OBJECTIVES: Malnutrition characterized by the involuntary loss of body weight and skeletal muscle can be the result of both aging and malignancy. As a result, geriatric patients could face an increased nutritional risk. This study aimed to investigate the nutritional and functional status of geriatric patients and their association with postoperative complications. METHODS: Patients who underwent abdominal surgery for digestive cancer in our center between January 2020 and August 2021 were included in the study. Computed tomography scans were collected to evaluate muscle mass and density. Changes in body weight, muscle strength, physical performances, nutritional risk, and status were evaluated upon admission. Postoperative outcomes collected included postoperative length of stay, complications, and 30-d readmission. RESULTS: A total of 1513 patients were included for the analysis. Of these, 72.8% were at risk for malnutrition (70.3% in the non-geriatric group and 75.4% in the geriatric group; P = 0.031), and 28.9% had malnutrition according to the Subjective Global Assessment (26.0% in the non-geriatric group and 31.8% in the geriatric group; P = 0.016). Compared with younger patients, geriatric patients have decreased muscle mass (skeletal muscle index, 44.8 versus 47.4; P < 0.001) and skeletal muscle density. Significant weight loss and loss of skeletal muscle occurred concurrently in 18.8% of the patients and were more frequent in the geriatric group (22.3% versus 14.7%; P < 0.001). In multivariate analysis, an age of 65 y or older (odds ratio [OR], 1.41; 95% confidence interval [CI], 1.07-1.86; P = 0.014), a serum albumin level ≤4.11 g/dL (OR, 1.35; 95% CI, 1.03-1.77; P = 0.03), skeletal muscle loss (OR, 1.69; 95% CI, 1.28-2.24; P < 0.001), declined functional status (OR, 1.5; 95% CI, 1.14-1.98; P = 0.004), systematic inflammation (OR, 1.71; 95% CI, 1.09-2.8; P = 0.026), and significant weight loss (OR, 1.4; 95% CI, 1.06-2.85; P = 0.017) were independent predictors of overall postoperative complications. Although there was a trend of interactions between advanced age, skeletal muscle loss, and significant weight loss, multivariate analysis showed none of the interactions were significantly predictive of overall postoperative complications. CONCLUSIONS: Geriatric patients are at greater risk for malnutrition. Their declined nutritional and functional status together with advanced age could increase the risk for postoperative complications. Nutrition evaluation should be part of the preoperative workup, and timely interventions should be initiated if needed, especially in geriatric patients.

Analysis of different adipose depot gene expression in cachectic patients with gastric cancer.

PURPOSE: This study aimed to identify the differentially expressed genes (DEGs) that contributed to the different amount of fat loss between subcutaneous adipose tissue (SAT) and visceral adipose tissue (VAT) among cachectic patients. METHODS: RNA sequencing was performed and bioinformatic tools were utilized to analyze the biological functions and construct regulation networks of DEGs. We presumed that iroquois homeobox 1 (IRX1) to be a hub gene and analyzed its clinical significance. Mouse model of cancer cachexia was established and differences between SAT and VAT were compared. The function of IRX1 on lipid metabolism was clarified by Oil Red O staining, qRT-PCR, and Western blotting in adipocytes. RESULTS: A total of 455 DEGs were screened between SAT and VAT in cachectic patients. Several hub genes were selected and IRX1 was presumed to contribute to the pathological difference between SAT and VAT in cancer cachexia. Patients with higher expression of IRX1 in SAT than VAT revealed significantly higher weight loss, IL-6 and TNF-α, as well as lower BMI, SAT, and VAT area. IRX1 expression in SAT was negatively correlated with SAT area. In cachectic mice, the expression of IRX1 in SAT was significantly higher than that in VAT. The inhibition effect on adipogenesis exerted by IRX1 was also proved in vitro. CONCLUSION: These data supported that DEGs contribute to the different degrees of fat loss among adipose depots in cachectic patients. IRX1 in SAT promoted fat loss by inhibiting adipocyte differentiation and adipogenesis.

Postoperative Loss of Skeletal Muscle Mass Predicts Poor Survival After Gastric Cancer Surgery.

BACKGROUND: Skeletal muscle mass deterioration is common in gastric cancer (GC) patients and is linked to poor prognosis. However, information regarding the effect of skeletal muscle mass changes in the postoperative period is scarce. This study was to investigate the link between postoperative loss of skeletal muscle mass and survival following GC surgery. METHODS: Patients who underwent GC surgery between January 2015 and December 2016 were recruited into the study. Computed tomography at L3 vertebral level was used to examine skeletal muscle index prior to surgery and about 6 months after surgery. Skeletal muscle index changes were categorized as presence or absence of ≥5% loss. Overall survival (OS) and disease-free survival (DFS) were analyzed, and Cox proportional hazard models used to identify their predictors. RESULTS: The study comprised of 318 gastric cancer patients of which 63.5% were male. The group's mean age was 58.14 ± 10.77 years. Sixty-five patients experienced postoperative skeletal muscle index loss ≥5% and had poorer OS (P = 0.004) and DFS (P = 0.020). We find that postoperative skeletal muscle index loss ≥ 5% predicts OS [hazard ratio (HR): 2.769, 95% confidence interval (CI): 1.865-4.111; P < 0.001] and DFS (HR: 2.533, 95% CI: 1.753-3.659; P < 0.001). CONCLUSIONS: Loss of skeletal muscle mass postoperatively is linked to poor survival following GC surgery. Further studies are needed to determine whether stabilizing or enhancing skeletal muscle mass after surgery improves survival.

Phosphorylation of Dynamin-Related Protein 1 (DRP1) Regulates Mitochondrial Dynamics and Skeletal Muscle Wasting in Cancer Cachexia.

BACKGROUND: Cancer-associated cachexia (CAC) is a syndrome characterized by skeletal muscle atrophy, and the underlying mechanisms are still unclear. Recent research studies have shed light on a noteworthy link between mitochondrial dynamics and muscle physiology. In the present study, we investigate the role of dynamin-related protein 1 (DRP1), a pivotal factor of mitochondrial dynamics, in myotube atrophy during cancer-associated cachexia. METHODS: Seventy-six surgical patients, including gastrointestinal tumor and benign disease, were enrolled in the study and divided to three groups: control, non-cachexia, and cancer-associated cachexia. Demographic data were collected. Their rectus abdominis samples were acquired intraoperatively. Muscle fiber size, markers of ubiquitin proteasome system (UPS), mitochondrial ultrastructure, and markers of mitochondrial function and dynamics were assayed. A cachexia model in vitro was established via coculturing a C2C12 myotube with media from C26 colon cancer cells. A specific DRP1 inhibitor, Mdivi-1, and a lentivirus of DRP1 knockdown/overexpression were used to regulate the expression of DRP1. Muscle diameter, mitochondrial morphology, mass, reactive oxygen species (ROS), membrane potential, and markers of UPS, mitochondrial function, and dynamics were determined. RESULTS: Patients of cachexia suffered from a conspicuous worsened nutrition status and muscle loss compared to patients of other groups. Severe mitochondrial swelling and enlarged area were observed, and partial alterations in mitochondrial function were found in muscle. Analysis of mitochondrial dynamics indicated an upregulation of phosphorylated DRP1 at the ser616 site. In vitro, cancer media resulted in the atrophy of myotube. This was accompanied with a prominent unbalance of mitochondrial dynamics, as well as enhanced mitochondrial ROS and decreased mitochondrial function and membrane potential. However, certain concentrations of Mdivi-1 and DRP1 knockdown rebalanced the mitochondrial dynamics, mitigating this negative phenotype caused by cachexia. Moreover, overexpression of DRP1 aggravated these phenomena. CONCLUSION: In clinical patients, cachexia induces abnormal mitochondrial changes and possible fission activation for the atrophied muscle. Our cachexia model in vitro further demonstrates that unbalanced mitochondrial dynamics contributes to this atrophy and mitochondrial impairment, and rebuilding the balance by regulating of DRP1 could ameliorate these alterations.

Post-discharge oral nutritional supplements with dietary advice in patients at nutritional risk after surgery for gastric cancer: A randomized clinical trial.

BACKGROUND & AIMS: Malnutrition frequently occurs and deteriorates in patients after surgery for gastric cancer, especially after hospital discharge, which has been consistently associated with negative outcomes. However, information regarding the impact of post-discharge nutritional interventions is poorly described. The aim of this study was thus to evaluate the impact of post-discharge oral nutritional supplements (ONS) with dietary advice compared with dietary advice alone on nutritional outcomes, including body mass index (BMI) and skeletal muscle index (SMI), sarcopenia prevalence, chemotherapy tolerance, the 90-day readmission rate, and quality of life in patients at nutritional risk after surgery for gastric cancer. METHODS: Three hundred and fifty-three patients who underwent surgery for gastric cancer and were at nutritional risk (Nutritional Risk Screening 2002 [NRS 2002] score ≥3 points) in our institution were randomly assigned to receive either ONS with dietary advice or dietary advice alone (control) for 3 months after discharge. The primary endpoints were nutritional outcomes and sarcopenia prevalence; the secondary endpoints included chemotherapy tolerance, the 90-day readmission rate, and quality of life. RESULTS: Three hundred and thirty-seven patients completed the study and were included in the analyses, consisting of 171 in the ONS group and 166 in the control group. The average daily intake of ONS in the intervention group was 370 mL. After 3 months of the intervention, the patients who received ONS and dietary advice had significantly less weight loss and higher BMI and SMI than those given dietary advice alone (P < 0.05). The incidence of sarcopenia was significantly lower in the ONS group than in the control group (P < 0.05). Similar number of patients in the two groups underwent postoperative chemotherapy, but the patients who received ONS and dietary advice had significantly less chemotherapy modifications, including delay, dose reduction, or termination (P < 0.05). The two groups had no significant differences in the 90-day readmission rate (P > 0.05). Regarding the quality of life, the patients who received ONS and dietary advice reported significantly less fatigue and appetite loss than those given dietary advice alone (P < 0.05), but the two groups showed no significant differences in the other outcomes (P > 0.05). CONCLUSIONS: Post-discharge ONS with dietary advice in patients at nutritional risk after surgery for gastric cancer improved nutritional outcomes, skeletal muscle maintenance, chemotherapy tolerance and some quality of life variables. These findings strongly support the concept of the introduction of post-discharge ONS with dietary advice to this patient cohort.

Impact of oral nutritional supplements in post-discharge patients at nutritional risk following colorectal cancer surgery: A randomised clinical trial.

BACKGROUND & AIMS: Guidelines on clinical nutrition recommend the use of appropriate nutritional support therapy for surgical cancer patients at risk of malnutrition both during hospital care and following discharge from the hospital. However, previous studies regarding nutritional interventions have mainly focused on patients during their hospital stay; there is limited evidence supporting the recommendation of nutritional interventions for post-discharge patients after cancer surgery, particularly those who underwent gastrointestinal cancer surgery and at high risk of malnutrition. To clearly address this issue, we designed and conducted two independent studies on two different groups of post-discharge patients at nutritional risk after gastrointestinal cancer surgery. The present study aimed to assess the impact of oral nutritional supplements (ONS) in post-discharge patients at nutritional risk following colorectal cancer surgery. Meanwhile, the sister study on the use of ONS in post-discharge patients following gastric cancer surgery will be reported separately. METHODS: Between January 2017 and June 2019, post-discharge patients following colorectal cancer surgery in our institution were randomised to receive either dietary advice alone (control group) or dietary advice in combination with ONS (ONS group) for three months if they were at nutritional risk based on the tool of Nutritional Risk Screening 2002. The primary endpoints were nutritional outcomes and sarcopenia prevalence. The secondary endpoints were 90-day readmission rate, chemotherapy tolerance, and quality of life (QoL). RESULTS: Of the 232 eligible patients, 212 (107 in the control group and 105 in the ONS group) completed the trial. Their data were then analyzed. The mean ONS intake was 410 mL every day. By the three-month intervention, the skeletal muscle index in the ONS group was significantly higher than that in the control group (39.75 ± 5.83 vs 38.01 ± 6.18 cm2/m2, P = 0.037), but no significant differences between the two groups were noted in weight, weight loss, body mass index, serum albumin and hemoglobin (P > 0.05). In addition, the ONS group had a significantly lower sarcopenia prevalence (28.6% vs 42.1%, P = 0.040). No significant difference between the two groups was found in the 90-day readmission rate (P > 0.05). The number of patients undergoing postoperative chemotherapy in the two groups was similar, but chemotherapy modifications, such as delay, dose reduction, or termination, were significantly reduced in the ONS group (21.2% vs 36.8%, P=0.024). However, ONS had no significant effect on QoL (P > 0.05). CONCLUSIONS: In post-discharge patients at nutritional risk following colorectal cancer surgery, the use of ONS may reduce skeletal muscle loss and sarcopenia prevalence, as well as improve chemotherapy tolerance, compared with dietary advice alone. These findings underline the importance of ONS treatment in post-discharge patients at nutritional risk following colorectal cancer surgery.

Beta-1 blocker reduces inflammation and preserves intestinal barrier function after open abdominal surgery.

BACKGROUND: Open abdominal surgery is frequently related to excessive inflammation and a compromised intestinal barrier, leading to poor clinical outcomes. The administration of beta-1 blocker has been shown to effectively reduce inflammation and preserve intestinal barrier function in patients with sepsis, shock, or other critical illnesses. The underlying mechanism of these effects may be associated with the autonomic nervous system's activation via cholecystokinin receptors. This study aimed to investigate the effect of beta-1 blocker on systemic and local inflammatory responses and the intestinal barrier function in the context of open abdominal surgery. METHODS: A rat model of open abdominal surgery was induced through peritoneal air exposure for 3 hours and treated via gavage with the beta-1 blocker, metoprolol, or saline. Cholecystokinin-receptor antagonists were administered before the metoprolol treatment. Peritoneal lavage fluid, serum, and tissues were collected 24 hours after surgery to determine systemic and local inflammation and intestinal integrity. RESULTS: The intervention with metoprolol significantly reduced serum tumor necrosis factor-alpha and interleukin-6 (P < .05) and peritoneal interleukin-6 (P < .01) compared with those of animals treated with saline. The intestinal myeloperoxidase indicating the influx of neutrophils was also significantly prevented by the administration of metoprolol (P < .05). Above all, this intervention resulted in a significant decrease in serum D-lactate and intestinal fatty acid-binding protein, intestinal permeability, bacterial translocation, and Chiu's score for intestinal mucosa injury (P < .05). However, the anti-inflammatory and intestinal integrity protective effects of metoprolol were prevented by the blockage of cholecystokinin receptors (P < .05). CONCLUSION: Our data indicate that beta-1 blocker reduces systemic and local inflammatory responses and preserves intestinal barrier function after open abdominal surgery through a mechanism that depends on cholecystokinin receptors. Clinically, these findings imply that perioperative intervention with a beta-1 blocker may be an effective new therapy to enhance recovery after open abdominal surgery.

Blood clearance kinetics and organ delivery of medium-chain triglyceride and fish oil-containing lipid emulsions: Comparing different animal species.

BACKGROUND & AIMS: Medium-chain triglycerides (TG) (MCT) and fish oil (FO) TG are incorporated as the core TG component into intravenous (IV) lipid emulsions for infusion in parenteral nutrition. Bolus injections of IV emulsions, on the other hand, have emerged as a novel therapeutic approach to treat various acute disorders. However, intravascular metabolism and organ delivery of acute IV injection of emulsions containing both MCT and FO are not fully defined, nor have they been characterized across common experimental animal models. We characterized and compared blood clearance kinetics and organ distribution of bolus injections of MCT/FO emulsions among different animal species. We also examined whether sex differences or feeding status can affect catabolic properties of MCT/FO lipid emulsions. DESIGN: Blood clearance rates of lipid emulsions with specific TG composition were compared in rats IV injected with [3H]cholesteryl hexadecyl ether labeled pure n-6 long-chain (LCT) and n-3 FO TG lipid emulsions, or emulsions containing MCT and FO at different ratios (wt/wt), which include 8:2 (80% MCT: 20% FO), 5:4:1 (50% MCT: 40% LCT: 10% FO) and SMOF (30% LCT: 30% MCT: 25% olive oil: 10% FO). Dose-response effects (0.016 mg-1.6 mg TG/g body weight) of the MCT/FO 8:2 emulsions on blood clearance properties and organ delivery were determined in both mice and rats. Blood clearance kinetics and organ uptake of MCT/FO 8:2 emulsions were compared between male and female rats and between fed and fasted rats. Changes in plasma lipid profiles after acute injections of MCT/FO 8:2 lipid emulsion at different doses (0.043, 0.133, and 0.4 mg TG/g body weight) were characterized in non-human primates (Cynomolgus monkeys). RESULTS: MCT/FO 8:2 emulsion was cleared faster in rats when compared with other emulsions with different TG contents. Mice had faster blood clearance and higher fractional catabolic rates (FCR) when compared with the rats injected with MCT/FO 8:2 emulsions regardless of the injected doses. Mice and rats had similar plasma TG and free fatty acid (FFA) levels after low- or high-dose injections of the MCT/FO emulsion. Tissue distribution of the MCT/FO 8:2 lipid emulsion are comparable between mice and rats, where liver had the highest uptake per recovered dose among all organs (>60%). Feeding status and sex differences did not alter the blood clearance rate of the MCT/FO 8:2 emulsion in rats. In a nonhuman primate model, dose-response increases in plasma TG and FFA were observed after IV injection of MCT/FO 8:2 emulsions within the 1st 10 min. CONCLUSION: A lipid emulsion containing both MCT and FO TG is cleared rapidly in blood and readily available for organ uptake in rodent and primate animal models. Characterization of the blood clearance properties of the MCT/FO 8:2 emulsion administered in various animal models may provide further insight into the safety and efficacy profiles for future therapeutic use of bolus injections of MCT/FO emulsions in humans.

Sarcopenia as a predictor of poor surgical and oncologic outcomes after abdominal surgery for digestive tract cancer: A prospective cohort study.

BACKGROUND & AIMS: Sarcopenia has been widely recognized as an important predictor of poor outcomes in patients with cancer after surgery, but the controversy remains, and its impact on surgical and oncologic outcomes in patients after abdominal surgery for digestive tract cancer is poorly described. The aim of this study was to evaluate the prognostic impact of sarcopenia on surgical and oncologic outcomes in patients after abdominal surgery for digestive tract cancer. METHODS: Six thousand four hundred and forty-seven consecutive patients who underwent abdominal surgery for digestive tract cancer in our institution were prospectively included. Sarcopenia was defined as skeletal muscle index below the lowest sex-specific quartile using computed tomography scan at L3 before surgery. The surgical and oncologic outcomes were recorded, and univariate and multivariate analyses were performed. RESULTS: Sarcopenia was present in 1638 of 6447 patients (25.4%) with digestive tract cancer before surgery based on the diagnostic cut-off values (43.13 cm2/m2 for men and 37.81 cm2/m2 for women). The incidence of postoperative total and pulmonary complications, and 30-day readmission were significantly higher in sarcopenic group than in nonsarcopenic group (37.4% vs 12.9%, P < 0.001; 3.1% vs 2.1%, P = 0.026; 1.1% vs 0.4%, P = 0.003, respectively). The postoperative hospital stay was significantly longer in sarcopenic patients (9.42 ± 3.40 vs 8.51 ± 3.17 days, P < 0.001). There were significantly more patients receiving postoperative chemotherapy or radiotherapy in sarcopenic group than in nonsarcopenic group (73.1% vs 69.2%, P = 0.003; 10.6% vs 8.8%, P = 0.038, respectively), and patients with sarcopenia had significantly more chemotherapy modifications including delay, dose reduction, or termination (48.5% vs 44.2%, P = 0.018). In addition, during the follow-up period, sarcopenic patients had significantly lower rate of overall survival and disease-free survival than nonsarcopenic patients (53.9% vs 69.3%, P = 0.002; 36.8% vs 59.7%, P = 0.000, respectively). In multivariate analysis, sarcopenia was found to be a risk factor for postoperative complications [odds ratio (OR) = 5.418, 95% confidence interval (CI) = 2.986-9.828, P < 0.001], and was an unfavorable prognostic factor for poor overall survival [hazard ratio (HR) = 0.649, 95% CI = 0.426-0.991, P = 0.045] and disease-free survival (HR = 0.514, 95% CI = 0.348-0.757, P = 0.001). CONCLUSIONS: Sarcopenia could be used as a strong and independent prognostic factor for poor surgical and oncologic outcomes in patients after abdominal surgery for digestive tract cancer. Identification of preoperative sarcopenia in digestive surgery for cancer and targeted approaches may improve its negative outcomes.

MORC4 is a novel breast cancer oncogene regulated by miR-193b-3p.

A better understanding of breast cancer pathogenesis would contribute to improved diagnosis and therapy and potentially decreased mortality rates. Here, we found that the MORC family CW-type zinc finger 4 (MORC4) overexpression in breast cancer tissues is associated with poor survival, and the short-interfering RNA knockdown of MORC4 suppresses the growth of breast cancer cells by promoting apoptosis. To investigate the mechanisms associated with MORC4 upregulation, microRNAs potentially targeting MORC4 were analyzed, with miR-193b-3p identified as the regulator and a negative correlation between miR-193b-3p and MORC4 expression determined in both breast cancer cell lines and tissues. Further analysis verified that MORC4 silencing did not affect miR-193b-3p expression, although altered miR-193b-3p expression attenuated MORC4 protein levels. Moreover, dual-luciferase reporter assays verified miR-193b-3p binding to the 3' untranslated region of MORC4. Furthermore, restoration of miR-193b-3p expression in breast cancer cells led to decreased growth and activation of apoptosis, which was consistent with results associated with MORC4 silencing in breast cancer cells. These results identified MORC4 as differentially expressed in breast cancer cells and tissues and its downregulation by miR-193b-3p, as well as its roles in regulating the growth of breast cancer cells via regulation of apoptosis. Our findings offer novel insights into potential mechanisms associated with breast cancer pathogenesis.

[Association of serum inflammatory cytokines and Resolvin D1 concentration with pathological stage of colon cancer].

OBJECTIVE: To investigate the levels of serum inflammatory cytokines and Resolvin D1 (RvD1) and their association with pathological staging of colon cancer. METHODS: Clinical data of 50 colon cancer patients (colon cancer group) admitted to the General Surgery Department of Zhongshan Hospital of Fudan University from January to December 2016 and 5 ml of whole blood specimen were collected at admission. During the same period, 50 healthy volunteers were enrolled (healthy volunteer group). Inclusion criteria for the colon cancer group: colon cancer diagnosed by preoperative colonoscopy and pathology; no recent enteral or parenteral nutrition support treatment or use of oral nutrition preparation; age ≤85 years; no surgical contraindications by preoperative evaluation; no history of taking fish oil-related preparations; no radiotherapy or chemotherapy before surgery. Healthy volunteer group enrollment criteria: no history of malignant tumors; no organ with organic lesions detected by the healthy examination center of our hospital; detection indicators in normal reference range; no administration of fish oil-related preparations; age ≤ 85 years. Serum inflammatory factors(IL-1ß, IL-6, IL-10 and TNF-α) concentrations were detected by chemiluminescence immunoassay; serum RvD1 concentration was measured by enzyme-linked immunosorbent assay. The levels of inflammatory factors and RvD1 were compared between the two groups, and their associations with TNM staging of colon cancer patients were analyzed. RESULTS: There were no significant differences in age, gender and nutrition-related indicators between the two groups (all P>0.05). There were 31 males and 19 females in the healthy volunteer group with age of (61.8±11.6) years. There were 23 males and 27 females in the colon cancer group with age of (65.4±12.4) years. According to the 7th edition of the American Cancer Society TNM staging criteria, 10 cases were stage I, 13 cases stage II, 17 cases stage III, and 10 cases stage IV. Compared with healthy volunteer group, colon cancer group had higher serum IL-1ß [(3.89±0.24)×10 3 µg/L vs.(1.55±0.37)×10 3 µg/L, t=37.52, P<0.01], higher IL-6 [(129.14±3.07)×10 3 µg/L vs.(51.46±3.14)×10 3 µg/L, t=125.08, P<0.01], higher IL-10 [(100.59±8.69)×103 µg/L vs.(27.57±4.77)×10 3 µg/L, t=52.09, P<0.01] and higher TNF-α [(114.31±4.43)×10 3 µg/L vs.(41.04±5.27)×10 3 µg/L, t=75.25, P<0.01], while lower RvD1 [(34.19±1.93)×10 3 µg/L vs.(77.76±1.02)×10 3 µg/L, t=140.56, P<0.01], all the differences were statistically significant. Subgroup analysis revealed that concentrations of IL-6, IL-1ß, IL-10 and TNF-α gradually increased with the advancement of TNM staging (P<0.01). In stage III, concentrations of IL-6, IL-1ß, and IL-10 were the highest, TNF-α concentration was the highest in stage IV. RvD1 concentration gradually decreased with the advancement of TNM staging(P<0.01). CONCLUSIONS: Compared with healthy volunteers, the levels of serum inflammatory cytokines in colon cancer patients increase significantly while the level of RvD1 decreases significantly. Both are associated with higher TNM stage of colon cancer.

Mitofusin-2 prevents skeletal muscle wasting in cancer cachexia.

Cancer cachexia remains a leading cause of morbidity and mortality worldwide, despite extensive research and clinical trials. The prominent clinical feature of cancer cachexia is the continuous loss of skeletal muscle that cannot be fully reversed by conventional nutritional support, and that leads to progressive functional impairment. The mechanism underlying muscle loss in patients with cachexia is poorly understood. The present study analyzed 21 cancer patients with or without cachexia, and demonstrated that mitofusin-2 (Mfn2) was downregulated in the rectus abdominis of patients with cachexia, which was associated with body weight loss. In vitro cell experiments indicated that loss of Mfn2 was associated with atrophy of the C2C12 mouse myoblast cell line. Furthermore, in vivo animal experiments demonstrated that cachexia decreased gastrocnemius muscle mass and Mfn2 expression, and overexpression of Mfn2 in gastrocnemius muscle was able to partially attenuate cachexia-induced gastrocnemius muscle loss. The results of the present study suggested that Mfn2 is involved in cachexia-induced muscle loss and may serve as a potential target for therapy of cachexia.

Laparoscopic versus open repair for perforated peptic ulcer: A meta analysis of randomized controlled trials.

INTRODUCTION: The role of laparoscopic surgery in the repair for peptic ulcer disease is unclear. The present study aimed to compare the safety and efficacy of laparoscopic versus open repair for peptic ulcer disease. METHODS: Randomized controlled trials (RCTs) comparing laparoscopic versus open repair for peptic ulcer disease were identified from MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials, and references of identified articles and relevant reviews. Primary outcomes were postoperative complications, mortality, and reoperation. Secondary outcomes were operative time, postoperative pain, postoperative hospital stay, nasogastric tube duration, and time to resume diet. Statistical analysis was carried out by Review Manage software. RESULTS: Five RCTs investigating a total of 549 patients, of whom, 279 received laparoscopic repair and 270 received open repair, were included in the final analysis. There were no significant differences between these two procedures in some primary outcomes including overal postoperative complication rate, mortality, and reoperation rate. Subcategory analysis of postoperative complications showed that laparoscopic repair had also similar rates of repair site leakage, intra-abdominal abscess, postoperative ileus, pneumonia, and urinary tract infection as open surgery, except of the lower surgical site infection rate (P < 0.05). In addition, there were also no significant differences between these two procedures in some second outcomes including operative time, postoperative hospital stay, and time to resume diet, but laparoscopic repair had shorter nasogastric tube duration (P < 0.05) and less postoperative pain (P < 0.05) than open surgery. CONCLUSIONS: Laparoscopic surgery is comparable with open surgery in the setting of repair for perforated peptic ulcer. The obvious advantages of laparoscopic surgery are the lower surgical site infection rate, shorter nasogastric tube duration and less postoperative pain. However, more higher quality studies should be undertaken to further assess the safety and efficacy of laparoscopic repair for peptic ulcer disease.

Interleukin-6 promotes tumor progression in colitis-associated colorectal cancer through HIF-1α regulation.

Interleukin-6 (IL-6) is a well-known etiological factor of colitis-associated colorectal cancer (CAC) and has a significant role in CAC progression. In addition, hypoxia-inducible factor 1α (HIF-1α) serves a primary role in the progression of CAC. However, the association between IL-6 and HIF-1α during the progression of CAC remains unclear. To investigate this association, the present study induced CAC in a mouse model using azoxymethane and dextran sulfate sodium. In addition, an anti-IL-6 receptor antibody was used to inhibit IL-6. In this model, anti-IL-6 receptor antibody treatment significantly inhibited the development of CAC and the expression of HIF-1α, in colorectal adenomas and adenocarcinomas. In patients with CAC, the HIF-1α gene was demonstrated to be overexpressed in tumor tissue compared with adjacent non-malignant tissue. Furthermore, HIF-1α mRNA expression was positively correlated with serum IL-6 concentration. The results of the present study suggest that IL-6 promotes CAC progression, in the early stage of the disease, through HIF-1α regulation.

Interleukin-6 stimulates aerobic glycolysis by regulating PFKFB3 at early stage of colorectal cancer.

Chronic inflammation is a well-known etiological factor for colorectal cancer (CRC) and cancer cells are known to preferentially metabolize glucose through aerobic glycolysis. However, the connection between chronic inflammation and aerobic glycolysis in the development of CRC is largely unexplored. The present study investigated whether interleukin-6 (IL-6), a pro-inflammatory cytokine, promotes the development of CRC by regulating the aerobic glycolysis and the underlying molecular mechanisms. In colitis-associated CRC mouse, anti-IL-6 receptor antibody treatment reduced the incidence of CRC and decreased the expression of key genes in aerobic glycolysis, whereas the plasma concentrations of glucose and lactate were not affected. Consistently, IL-6 treatment stimulated aerobic glycolysis, upregulated key genes in aerobic glycolysis and promoted cell proliferation and migration in SW480 and SW1116 CRC cells. 6-phoshofructo-2-kinase/fructose-2,6-bisphosphatase-3 (PFKFB3) was the most downregulated gene by anti-IL-6 receptor antibody in colorectal adenoma tissues. Further analysis in human samples revealed overexpression of PFKFB3 in colorectal adenoma and adenocarcinoma tissues, which was also associated with lymph node metastasis, intravascular cancer embolus and TNM stage. In addition, the effect of IL-6 on CRC cells can be abolished by knocking down PRKFB3 through siRNA transfection. Our data suggest that chronic inflammation promotes the development of CRC by stimulating aerobic glycolysis and IL-6 is functioning, at least partly, through regulating PFKFB3 at early stage of CRC.

The Effect of Silencing HIF-1α Gene in BxPC-3 Cell Line on Glycolysis-Related Gene Expression, Cell Growth, Invasion, and Apoptosis.

Hypoxia has been proved to be a typical character of solid tumors. Tumor cells prefer to use glucose through the glycolysis pathway instead of aerobic respiration. However, the precise molecular mechanism underlying this so-called Warburg effect remains elusive. In the current study, siRNA was synthesized and transfected into BxPC-3 cell line to silence the expression of HIF-1α gene. It was found that hypoxia induced hypoxia-inducible factor 1α (HIF-1α) overexpression in BxPC-3 cells, enhanced the expression of pyruvate dehydrogenase kinase 1 and lactate dehydrogenase A, thus facilitating glycolysis and making tumor cells more tolerant to hypoxic stress. The silencing of HIF-1α gene significantly attenuated glycolysis under hypoxic conditions, inhibited the growth and invasion ability of BxPC-3 cells, and enhanced hypoxia-induced cell apoptosis.