SNS-023 sensitizes hepatocellular carcinoma to sorafenib by inducing degradation of cancer drivers SIX1 and RPS16.

Hepatocellular carcinoma (HCC) remains challenging due to the lack of efficient therapy. Promoting degradation of certain cancer drivers has become an innovative therapy. The nuclear transcription factor sine oculis homeobox 1 (SIX1) is a key driver for the progression of HCC. Here, we explored the molecular mechanisms of ubiquitination of SIX1 and whether targeting SIX1 degradation might represent a potential strategy for HCC therapy. Through detecting the ubiquitination level of SIX1 in clinical HCC tissues and analyzing TCGA and GEPIA databases, we found that ubiquitin specific peptidase 1 (USP1), a deubiquitinating enzyme, contributed to the lower ubiquitination and high protein level of SIX1 in HCC tissues. In HepG2 and Hep3B cells, activation of EGFR-AKT signaling pathway promoted the expression of USP1 and the stability of its substrates, including SIX1 and ribosomal protein S16 (RPS16). In contrast, suppression of EGFR with gefitinib or knockdown of USP1 restrained EGF-elevated levels of SIX1 and RPS16. We further revealed that SNS-023 (formerly known as BMS-387032) induced degradation of SIX1 and RPS16, whereas this process was reversed by reactivation of EGFR-AKT pathway or overexpression of USP1. Consequently, inactivation of the EGFR-AKT-USP1 axis with SNS-032 led to cell cycle arrest, apoptosis, and suppression of cell proliferation and migration in HCC. Moreover, we showed that sorafenib combined with SNS-032 or gefitinib synergistically inhibited the growth of Hep3B xenografts in vivo. Overall, we identify that both SIX1 and RPS16 are crucial substrates for the EGFR-AKT-USP1 axis-driven growth of HCC, suggesting a potential anti-HCC strategy from a novel perspective.

Total Laparoscopic Resection of an Extrahepatic Mucinous Biliary Cystadenoma with Liver Involvement (with Video).

BACKGROUND: Intrahepatic mucinous biliary cystadenoma is rare, and extrahepatic MBC is even rarer. To our knowledge, total laparoscopic resection of an extrahepatic MBC that had extended intrahepatically has never been reported. PATIENTS AND METHODS: A 28-year-old female presented to our hospital with upper abdomen pain. Radiological investigations demonstrated a 7-cm multiloculated cystic lesion arising from the left hepatic bile duct extending to involve the extrahepatic biliary system down to and posterior to the back of the head of pancreas. The entire extrahepatic bile duct was involved, except for the gallbladder. Laparoscopic surgery was carried out using a five-port approach. A gourd-shaped well-defined multiloculated cyst was found extending from the extrahepatic biliary system proximally to involve the left hepatic duct intrahepatically. After cholecystectomy, the gourd-shaped cyst was opened at its narrowest part at the hepatic hilus to facilitate subsequent resectional surgery. The distal sac was dissected to the distal bile duct end at the duodenal wall and transected. The proximal sac was dissected and resected en bloc with the bifurcation of the right/left hepatic ducts, combined with left hepatectomy plus caudate lobectomy. The reconstruction was done by anastomosing the right anterior and posterior sectional bile ducts to a Roux-en-Y jejunal loop. Multiple intraoperative frozen sections demonstrated the lesion to be a benign MBC. RESULTS: The patient was discharged home 12 days after surgery. She was well on follow-up 24 months after surgery. CONCLUSION: Total laparoscopic resection is technically feasible to treat an extrahepatic MBC with intrahepatic extension.

Fast-track programs versus traditional care in hepatectomy: a meta-analysis of randomized controlled trials.

BACKGROUND/AIMS: The role of fast-track programs in hepatectomy is unclear. This meta-analysis aimed to evaluate the efficacy and safety of fast-track programs versus traditional care. METHODS: We searched Pubmed, Embase, Cochrane Central Register of Controlled Trials, and Google Scholar for relevant randomized controlled trials (RCTs) comparing fast-track with traditional care in hepatectomy. Length of hospital stay, time to first flatus, postoperative complications, operating time, and intraoperative blood loss were assessed. Meta-analyses were performed using RevMan 5.2 software. RESULTS: Four original RCTs with 372 patients were included: 187 in the fast-track and 185 in the traditional care group. Fast-track patients had shorter hospital stay (WMD -2.32; 95% CI, -3.54 to -1.11; p < 0.001) and time to first flatus (WMD -0.99; 95% CI, -1.15 to -0.84; p < 0.001), and less postoperative complications (RR 0.66; 95% CI, 0.47 to 0.93; p < 0.05). However, there was significant heterogeneity between the studies regarding hospital stay (I(2) = 88%; p < 0.001). Operating time and intraoperative blood loss were not different. CONCLUSIONS: Patients in fast-track programs had less time to first flatus and postoperative complications compared to traditional care. Fast-track programs may reduce the length of hospital stay. Larger, higher quality prospective RCTs are necessary to draw more robust conclusions.

Development of a magnetic resonance imaging-derived radiomics model to predict microvascular invasion in patients with hepatocellular carcinoma.

Background: Hepatocellular carcinoma (HCC) with microvascular invasion (MVI) has a poor prognosis, is prone to recurrence and metastasis, and requires more complex surgical techniques. Radiomics is expected to enhance the discriminative performance for identifying HCC, but the current radiomics models are becoming increasingly complex, tedious, and difficult to integrate into clinical practice. The purpose of this study was to investigate whether a simple prediction model using noncontrast-enhanced T2-weighted magnetic resonance imaging (MRI) could preoperatively predict MVI in HCC. Methods: A total of 104 patients with pathologically confirmed HCC (training cohort, n=72; test cohort, n=32; ratio, about 7:3) who underwent liver MRI within 2 months prior to surgery were retrospectively included. A total of 851 tumor-specific radiomic features were extracted on T2-weighted imaging (T2WI) for each patient using AK software (Artificial Intelligence Kit Version; V. 3.2.0R, GE Healthcare). Univariate logistic regression and least absolute shrinkage and selection operator (LASSO) regression were used in the training cohort for feature selection. The selected features were incorporated into a multivariate logistic regression model to predict MVI, which was validated in the test cohort. The model's effectiveness was evaluated using the receiver operating characteristic and calibration curves in the test cohort. Results: Eight radiomic features were identified to establish a prediction model. In the training cohort, the area under the curve, accuracy, specificity, sensitivity, and positive and negative predictive values of the model for predicting MVI were 0.867, 72.7%, 84.2%, 64.7%, 72.7%, and 78.6%, respectively; while in the test cohort, they were 0.820, 75%, 70.6%, 73.3%, 75%, and 68.8%, respectively. The calibration curves displayed good consistency between the prediction of MVI by the model and actual pathological results in both the training and validation cohorts. Conclusions: A prediction model using radiomic features from single T2WI can predict MVI in HCC. This model has the potential to be a simple and fast method to provide objective information for decision-making during clinical treatment.

Nomograms for predicting the recurrence probability and recurrence-free survival in patients with hepatocellular carcinoma after conversion hepatectomy based on hepatic arterial infusion chemotherapy: a multicenter, retrospective study.

BACKGROUND: This study aimed to establish and validate nomograms to predict the probability of recurrence and recurrence-free survival (RFS) in patients with hepatocellular carcinoma (HCC) after conversion hepatectomy based on hepatic arterial infusion chemotherapy (HAIC). METHODS: Nomograms were constructed using data from a retrospective study of 214 consecutive patients treated with HAIC-based conversion liver resection between January 2016 and July 2020. Nomograms predicting the probability of tumor recurrence and RFS were established based on predictors selected by multivariate regression analysis. Predictive accuracy and discriminative ability of the nomogram were examined. Bootstrap method was used for internal validation. External validation was performed using cohorts ( n =128) from three other centers. RESULTS: Recurrence rates in the primary and external validation cohorts were 63.6 and 45.3%, respectively. Nomograms incorporating clinicopathological features of tumor recurrence and RFS were generated. Concordance index (C-index) scores of the nomograms for predicting recurrence probability and RFS were 0.822 (95% CI, 0.703-0.858) and 0.769 (95% CI, 0.731-0.814) in the primary cohort, and 0.802 (95% CI, 0.726-0.878) and 0.777 (95% CI, 0.719-0.835) in the external validation cohort, respectively. Calibration curves indicated good agreement between the nomograms and actual observations. Moreover, the nomograms outperformed the commonly used staging systems. Patients with low risk, stratified by the median nomogram scores had better RFS (low risk vs. high risk, 36.5 vs. 5.2 months, P <0.001). The external validation cohort supported these findings. CONCLUSIONS: The presented nomograms showed favorable accuracy for predicting recurrence probability and RFS in HCC patients treated with HAIC-based conversion hepatectomy. Identifying risk factors and estimating tumor recurrence may help clinicians in the decision-making process regarding adjuvant therapies for patients with HCC, which eventually achieves better oncological outcomes.

HSP90ß Impedes STUB1-Induced Ubiquitination of YTHDF2 to Drive Sorafenib Resistance in Hepatocellular Carcinoma.

YTH domain family 2 (YTHDF2) is the first identified N6-methyladenosine (m6 A) reader that regulates the status of mRNA. It has been reported that overexpressed YTHDF2 promotes carcinogenesis; yet, its role in hepatocellular carcinoma (HCC) is elusive. Herein, it is demonstrated that YTHDF2 is upregulated and can predict poor outcomes in HCC. Decreased ubiquitination levels of YTHDF2 contribute to the upregulation of YTHDF2. Furthermore, heat shock protein 90 beta (HSP90ß) and STIP1 homology and U-box-containing protein 1 (STUB1) physically interact with YTHDF2 in the cytoplasm. Mechanically, the large and small middle domain of HSP90ß is required for its interaction with STUB1 and YTHDF2. HSP90ß inhibits the STUB1-induced degradation of YTHDF2 to elevate the expression of YTHDF2 and to further boost the proliferation and sorafenib resistance of HCC. Moreover, HSP90ß and YTHDF2 are upregulated, while STUB1 is downregulated in HCC tissues. The expression of HSP90ß is positively correlated with the YTHDF2 protein level, whereas the expression of STUB1 is negatively correlated with the protein levels of YTHDF2 and HSP90ß. These findings deepen the understanding of how YTHDF2 is regulated to drive HCC progression and provide potential targets for treating HCC.

Postoperative Adjuvant Hepatic Arterial Infusion Chemotherapy With FOLFOX in Hepatocellular Carcinoma With Microvascular Invasion: A Multicenter, Phase III, Randomized Study.

PURPOSE: To report the efficacy and safety of postoperative adjuvant hepatic arterial infusion chemotherapy (HAIC) with 5-fluorouracil and oxaliplatin (FOLFOX) in hepatocellular carcinoma (HCC) patients with microvascular invasion (MVI). PATIENTS AND METHODS: In this randomized, open-label, multicenter trial, histologically confirmed HCC patients with MVI were randomly assigned (1:1) to receive adjuvant FOLFOX-HAIC (treatment group) or routine follow-up (control group). The primary end point was disease-free survival (DFS) by intention-to-treat (ITT) analysis while secondary end points were overall survival, recurrence rate, and safety. RESULTS: Between June 2016 and August 2021, a total of 315 patients (ITT population) at five centers were randomly assigned to the treatment group (n = 157) or the control group (n = 158). In the ITT population, the median DFS was 20.3 months (95% CI, 10.4 to 30.3) in the treatment group versus 10.0 months (95% CI, 6.8 to 13.2) in the control group (hazard ratio, 0.59; 95% CI, 0.43 to 0.81; P = .001). The overall survival rates at 1 year, 2 years, and 3 years were 93.8% (95% CI, 89.8 to 98.1), 86.4% (95% CI, 80.0 to 93.2), and 80.4% (95% CI, 71.9 to 89.9) for the treatment group and 92.0% (95% CI, 87.6 to 96.7), 86.0% (95% CI, 79.9 to 92.6), and 74.9% (95% CI, 65.5 to 85.7) for the control group (hazard ratio, 0.64; 95% CI, 0.36 to 1.14; P = .130), respectively. The recurrence rates were 40.1% (63/157) in the treatment group and 55.7% (88/158) in the control group. Majority of the adverse events were grade 0-1 (83.8%), with no treatment-related death in both groups. CONCLUSION: Postoperative adjuvant HAIC with FOLFOX significantly improved the DFS benefits with acceptable toxicities in HCC patients with MVI.

ARV-771 Acts as an Inducer of Cell Cycle Arrest and Apoptosis to Suppress Hepatocellular Carcinoma Progression.

Hepatocellular carcinoma (HCC) is the most commonly diagnosed liver cancer with limited treatment options and extremely poor prognosis worldwide. Recently, the proteolysis targeting chimeras (PROTACs), which aim to induce proteasome-mediated degradation of interesting proteins via recruiting E3 ligases, have become the advanced tools and attractive molecules for cancer treatment. However, the anticancer effects of PROTACs in HCC remain to be clarified. Here, we evaluate the anticancer activity of ARV-771, a previously reported PROTAC compound designed for bromodomain and extra-terminal domain (BET) proteins, in HCC. We show that ARV-771 suppresses the cell viability and colony formation of HCC cells via arresting cell cycle progression and triggering apoptosis. Further investigations reveal that ARV-771 notably downregulates multiple non-proteasomal deubiquitinases which are critical to the development of cancers. Additionally, HCC cells can decrease their sensitivity to ARV-771 via activating the MEK/ERK and p38 MAPKs. ARV-771 also inhibits HCC progression in vivo. Moreover, we show that ARV-771 and sorafenib, a Raf inhibitor that clinically used for targeted therapy of liver cancer, can synergistically inhibit the growth of HCC cells. Overall, this study not only explores the anticancer activity of ARV-771 and its underlying mechanisms in HCC, but also deepens our understanding of deubiquitinases, MAPKs, cell cycle, and apoptosis induction in cancer therapy.

Glucagon-Like Peptide-2 Modulates Enteric Paneth Cells Immune Response and Alleviates Gut Inflammation During Intravenous Fluid Infusion in Mice With a Central Catheter.

Background: Glucagon-like peptide-2 (GLP-2) has protective effects on gastrointestinal functions. Our previous study found that GLP-2 could significantly reduce intestinal permeability and bacterial translocation in total parenteral nutrition (TPN) animal model. However, the effects of GLP-2 on the impairment of the intestinal Paneth cells immune function and gut inflammation during intravenous fluid infusion mainly consisted of nutritional materials is currently scattered. Objective: The current study was aimed to investigate the efficacy of the GLP-2 in alleviating gut inflammation and modulating enteric Paneth cells immune response in parenterally fed mice and its underlying mechanisms. Methods: Thirty-six male ICR mice underwent venous catheterization were divided into 3 groups: Chow, TPN, and TPN+GLP-2 groups. GLP-2 was administered intravenously at 60 µg/day for 5 days. The small intestine tissue and serum samples were collected on the 7th day. Results: Compared with the TPN group, the expression of tight junction proteins occludin and claudin-1 were significantly increased in the TPN+GLP-2 group. In addition, the expression of lysozyme, sPLA2, insulin-like growth factor-1, and epithelial protection and repair genes were improved in the TPN+GLP-2 group. The levels of IL-6 and TNF-α proteins and mRNAs in the ileum tissues were remarkably reduced in the TPN+GLP-2 group, while IL-10 protein and mRNA level were elevated in the TPN+GLP-2 group (all p < 0.05). Moreover, the TPN+GLP-2 group has higher levels of serum endotoxin, D-lactic acid, and MPO than those of the TPN group. Conclusions: GLP-2 alleviated gut inflammation and improved enteric Paneth cells immune responses through intravenous fluid infusion, possibly by improving the functioning of epithelial protection and repair, and reducing mucosal inflammatory responses.

Zygomatic bone metastasis from hepatocellular carcinoma and the therapeutic efficacy of apatinib: A case report and literature review.

RATIONALE: Hepatocellular carcinoma (HCC) metastases to the zygomatic bone are extremely uncommon, and the treatment of target drugs against such case is unknown. PATIENT CONCERNS: A 48-year-old male patient was admitted to our hospital under suspicion of an advanced liver tumor due to an increase in levels of alpha-fetoprotein (AFP) after radiofrequency ablation for independent nodule in his liver 1 month before. He had a hepatitis B virus (HBV) history for 20 years without treatment. DIAGNOSIS AND INTERVENTIONS: A diagnosis of primary HCC was made based on pathological examination following right hepatectomy. Seven months after the surgery, a mass in S8 was identified and treated by ARF. Twenty days later, a right zygomatic mass was observed and the incisional biopsy revealed metastasis from HCC. Due to side effects of chemotherapy, the metastatic zygomatic mass was treated with radioactive seed implantation. Despite these interventions, there was steady increase in AFP values as well as increase in size of the zygomatic mass. Hence, the patient was started on apatinib with a dose of 500 mg/day from 1 to 28 days per cycle for a duration of 10 months. OUTCOMES: The AFP values were significantly decreased but the size of the zygomatic mass continued to increase indicating progression of disease. But the progression-free survival was more than 10 months. The patient exhibited adverse reactions which were controllable by symptomatic treatments. As of last follow-up, the patient is unwell with pain in the face, blurred vision in the right eye, dyscrasia, and exhibited difficulty in opening his mouth. LESSONS: HCC metastases to the zygomatic bone are very aggressive with a very low incidence and immunohistochemistry is useful diagnostic indicators. Still now, there is no optimal treatment strategy for these patients. Apatinib may be a promising drug in the treatment of HCC metastases to the zygomatic bone.

Glucagon-like peptide-2 improves intestinal immune function and diminishes bacterial translocation in a mouse model of parenteral nutrition.

Parenteral nutrition (PN) is associated with increased infectious risks due to impaired intestinal immunity. Although glucagon-like peptide-2 (GLP-2) enhances the gut barrier function, it is uncertain whether it improves mucosal immunologic barrier function. We hypothesized that injecting the PN mouse model with GLP-2 improved innate and acquired immunity, and prevented bacterial translocation. Forty-eight hours after venous cannulation, male Institute of Cancer Research mice were randomly divided into 3 groups based on their diet: chow with saline (n = 10), PN (n = 9), or PN + GLP-2 (30 µg bid per mouse, n = 10) provided for 5 days. Compared with chow, PN reduced interleukin (IL)-4 and IL-13 levels (P < .05, respectively), whereas, compared with PN alone, GLP-2 injection increased IL-4 and IL-13 levels (P < .05, respectively). Compared with chow, PN considerably suppressed, whereas GLP-2 improved, secretory phospholipase A2 and cryptdin-4 expression. PN, compared with chow, considerably decreased lysozyme and polymeric immunoglobulin receptor levels, whereas, compared with PN, GLP-2 significantly increased these protein levels (P < .01, respectively). In tissue and luminal samples, compared with chow, PN reduced secretory immunoglobulin A levels (P < .05), whereas, compared with PN alone, GLP-2 increased secretory immunoglobulin A levels (P < .05). Functionally, more bacterial translocation was observed in the PN group compared with the chow group (P < .001), and GLP-2 injection decreased bacterial translocation to chow levels (P < .05). In summary, GLP-2 treatment may improve intestinal innate and acquired immunity, and prevent bacterial translocation in mice on total parenteral nutrition.

Unusual bleeding from hepaticojejunostomy controlled by side-to-side splenorenal shunt: A case report.

RATIONALE: Ectopic variceal bleeding due to hepaticojejunostomy (HJ) is unusual and difficult to manage. Reports on the use of side-to-side splenorenal shunt for severe bleeding from varices at HJ anastomosis are lacking. PATIENT CONCERNS: A 43-year-old man was admitted to our hospital with repeated episodes of hematemesis. He has a history of right hemihepatectomy with HJ reconstruction to the left hepatic duct for hilar cholangiocarcinoma. Two years after surgery, he presented with repeated episodes of hematemesis and underwent blood transfusion. DIAGNOSES: Imaging tests and endoscopic investigation failed to identify the bleeding source. When conservative management failed to control his bleeding, he underwent emergency laparotomy, which revealed hemorrhage from ectopic varices at the HJ anastomosis. INTERVENTIONS: To arrest the bleeding, a side-to-side venovenal anastomosis was created between the splenic and left renal veins to form a shunt for decompression of the varices at the HJ anastomosis. OUTCOMES: After the surgery, the patient's symptoms ceased, and a no bleeding in the digestive tract was noted at 2-year follow-up. LESSONS: The present patient is the first reported case of unusual bleeding from HJ controlled by a side-to-side splenorenal shunt. We believe this approach is a useful and effective surgical treatment for severe bleeding from varices at the HJ anastomosis.

Partial enteral nutrition increases intestinal sIgA levels in mice undergoing parenteral nutrition in a dose-dependent manner.

BACKGROUND AND AIMS: Partial enteral nutrition (PEN) protects parenteral nutrition (PN) induced gut mucosal immunity impairment. However, the gastrointestinal function of most patients with PN is too poor to tolerate full dosage of PEN and no guidelines recommend PEN dose. We aimed to identify an optimal PEN dose and to understand the protective mechanism. METHODS: Mice were assigned to groups with total parenteral nutrition (TPN), total enteral nutrition (TEN), or various degrees of PEN with PN. Additionally, AS1517499 was used to inhibit STAT6. Five days after treatment, secretory immunoglobulin A (sIgA) levels of luminal washing fluid and JAK1-STAT6 signalling in ileum tissue of different groups were assessed. RESULTS: We found that TPN lowered luminal sIgA and down-regulated pIgR, phosphorylated JAK1 and STAT6, IL-4 and IL-13 as well relative to TEN. Moreover, 40% EN were lowest dose that reversed these detrimental consequences of PN to an equivalent level as TEN. The rescue of pIgR and luminal sIgA expression was decreased when the JAK1-STAT6 pathway was inhibited. CONCLUSION: We conclude that 40% EN is the optimal PEN dose that reverses PN-induced impairment of gut mucosal immunity. Additionally, we hypothesise that this benefit involves activation of the JAK1-STAT6 pathway.

Gut microbiota trajectory in patients with severe burn: A time series study.

PURPOSE: This time series experiments aimed to investigate the dynamic change of gut microbiomes after severe burn and its association with enteral nutrition (EN). MATERIALS AND METHODS: Seven severely burned patients who suffered from a severe metal dust explosion injury were recruited in this study. The dynamic changes of gut microbiome of fecal samples at six time points (1-3days, 2, 3, 4, 5 and 6weeks after severe burn) were detected using 16S ribosomal RNA pyrosequencing technology. RESULTS: Following the post-burn temporal order, gut microbiota dysbiosis was detected in the gut microbiome after severe burn, then it was gradually resolved. The bio-diversity of gut bacteria was initially decreased, and then returned to normal level. In addition, at the early stage (from 2 to 4weeks), the majority of those patients' gut microbiome were opportunistic pathogen genus, Enterococcus and Escherichia; while at the end of this study, the majority was a beneficial genus, Bacteroides. EN can promote the recovery of gut microbiota, especially in EN well-tolerated patients. CONCLUSIONS: Severe burn injury can cause a dramatic dysbiosis of gut microbiota. A trend of enriched beneficial bacteria and diminished opportunistic pathogen bacteria may serve as prognosis microbiome biomarkers of severe burn patients.

Effects of n-3 PUFAs on Intestinal Mucosa Innate Immunity and Intestinal Microbiota in Mice after Hemorrhagic Shock Resuscitation.

n-3 polyunsaturated fatty acids (PUFAs) can improve the function of the intestinal barrier after damage from ischemia-reperfusion or hemorrhagic shock resuscitation (HSR). However, the effects of n-3 PUFAs on intestinal microbiota and the innate immunity of the intestinal mucosa after HSR remain unclear. In the present study, 40 C57BL/6J mice were randomly assigned to five groups: control, sham, HSR, HSR + n-3 PUFAs and HSR + n-6 PUFAs. Mice were sacrificed 12 h after HSR. Liver, spleen, mesenteric lymph nodes and terminal ileal tissues were collected. Intestinal mucosae were scraped aseptically. Compared with the HSR group, the number of goblet cells increased, expression of mucin 2 was restored and disturbed intestinal microbiota were partly stabilized in the PUFA-administered groups, indicating that both n-3 and n-6 PUFAs reduced overproliferation of Gammaproteobacteria while promoting the growth of Bacteroidetes. Notably, n-3 PUFAs had an advantage over n-6 PUFAs in improving ileal tissue levels of lysozyme after HSR. Thus, PUFAs, especially n-3 PUFAs, partly improved the innate immunity of intestinal mucosa in mice after HSR. These findings suggest a clinical rationale for providing n-3 PUFAs to patients recovering from ischemia-reperfusion.

Whole Grain Intake Reduces Pancreatic Cancer Risk: A Meta-Analysis of Observational Studies.

Mounting evidence from epidemiology studies suggests that whole grain intake may reduce pancreatic cancer risk, but convincing evidence is scarce. We conducted a meta-analysis to assess the association between whole grain intake and pancreatic cancer risk. Relevant observational studies were identified by searching PubMed, Embase, Scopus, and Cochrane library databases for the period from January 1980 to July 2015, with no restrictions. We calculated the summary odds ratios (ORs) for pancreatic cancer using random-effects model meta-analysis. Between-study heterogeneity was analyzed using the I statistic. A total of 8 studies regarding whole grain intake were included in the meta-analysis. The pooled OR of pancreatic cancer for those with high versus low whole grain intake was 0.76 (95% confidence interval [CI], 0.64-0.91; P = 0.002). There was no significant heterogeneity across these studies (I²â€Š= 11.7%; Pheterogeneity = 0.339). In the subgroup analysis by geographic area, the summary ORs of developing pancreatic cancer were 0.64 (95% CI, 0.53-0.79; P < 0.001; I ²= 0%; Pheterogeneity = 0.482) in the United States (n = 4) and 0.95 (95% CI, 0.63-1.43; P = 0.803; I ²= 45.6%; Pheterogeneity = 0.175) in Europe (n = 2). In the subgroup analysis by type of whole grain, the summary ORs were 0.72 (95% CI, 0.60-0.87; P = .001; I²â€Š= 0; Pheterogeneity = 0.876) for grains (n = 4) and 0.74 (95% CI, 0.27-2.02; P = 0.554; I²â€Š= 86.3%; Pheterogeneity = 0.007) for wheat (n = 2). A high intake of whole grains was associated with a reduced risk of pancreatic cancer. Because of the absent of more cohort studies, further prospective studies need to be conducted to ensure conclusions that are more robust.

Apple-Derived Pectin Modulates Gut Microbiota, Improves Gut Barrier Function, and Attenuates Metabolic Endotoxemia in Rats with Diet-Induced Obesity.

This study was aimed at determining potential effects of apple-derived pectin on weight gain, gut microbiota, gut barrier and metabolic endotoxemia in rat models of diet-induced obesity. The rats received a standard diet (control; Chow group; n = 8) or a high-fat diet (HFD; n = 32) for eight weeks to induce obesity. The top 50th percentile of weight-gainers were selected as diet induced obese rats. Thereafter, the Chow group continued on chow, and the diet induced obese rats were randomly divided into two groups and received HFD (HF group; n = 8) or pectin-supplemented HFD (HF-P group; n = 8) for six weeks. Compared to the HF group, the HF-P group showed attenuated weight gain (207.38 ± 7.96 g vs. 283.63 ± 10.17 g, p < 0.01) and serum total cholesterol level (1.46 ± 0.13 mmol/L vs. 2.06 ± 0.26 mmol/L, p < 0.01). Compared to the Chow group, the HF group showed a decrease in Bacteroidetes phylum and an increase in Firmicutes phylum, as well as subordinate categories (p < 0.01). These changes were restored to the normal levels in the HF-P group. Furthermore, compared to the HF group, the HF-P group displayed improved intestinal alkaline phosphatase (0.57 ± 0.20 vs. 0.30 ± 0.19, p < 0.05) and claudin 1 (0.76 ± 0.14 vs. 0.55 ± 0.18, p < 0.05) expression, and decreased Toll-like receptor 4 expression in ileal tissue (0.76 ± 0.58 vs. 2.04 ± 0.89, p < 0.01). The HF-P group also showed decreased inflammation (TNFα: 316.13 ± 7.62 EU/mL vs. 355.59 ± 8.10 EU/mL, p < 0.01; IL-6: 51.78 ± 2.35 EU/mL vs. 58.98 ± 2.59 EU/mL, p < 0.01) and metabolic endotoxemia (2.83 ± 0.42 EU/mL vs. 0.68 ± 0.14 EU/mL, p < 0.01). These results suggest that apple-derived pectin could modulate gut microbiota, attenuate metabolic endotoxemia and inflammation, and consequently suppress weight gain and fat accumulation in diet induced obese rats.

GLP-2 Prevents Intestinal Mucosal Atrophy and Improves Tissue Antioxidant Capacity in a Mouse Model of Total Parenteral Nutrition.

We investigated the effects of exogenous glucagon-like peptide-2 (GLP-2) on mucosal atrophy and intestinal antioxidant capacity in a mouse model of total parenteral nutrition (TPN). Male mice (6-8 weeks old) were divided into three groups (n = 8 for each group): a control group fed a standard laboratory chow diet, and experimental TPN (received standard TPN solution) and TPN + GLP-2 groups (received TPN supplemented with 60 µg/day of GLP-2 for 5 days). Mice in the TPN group had lower body weight and reduced intestinal length, villus height, and crypt depth compared to the control group (all p < 0.05). GLP-2 supplementation increased all parameters compared to TPN only (all p < 0.05). Intestinal total superoxide dismutase activity and reduced-glutathione level in the TPN + GLP-2 group were also higher relative to the TPN group (all p < 0.05). GLP-2 administration significantly upregulated proliferating cell nuclear antigen expression and increased glucose-regulated protein (GRP78) abundance. Compared with the control and TPN + GLP-2 groups, intestinal cleaved caspase-3 was increased in the TPN group (all p < 0.05). This study shows GLP-2 reduces TPN-associated intestinal atrophy and improves tissue antioxidant capacity. This effect may be dependent on enhanced epithelial cell proliferation, reduced apoptosis, and upregulated GRP78 expression.

Superior mesenteric artery syndrome caused by surgery and radiation therapy for a brain tumor: A case report.

Superior mesenteric artery syndrome (SMAS) is defined as an obstruction of the third part of duodenum due to compression by the superior mesenteric artery. Although traumatic brain injury is a risk factor for SMAS, few cases of SMAS resulting from brain surgery have been reported. SMAS has been observed to occur following neurosurgical surgery in pediatric patients but, to the best of our knowledge, no such cases have been reported in adults. The present study reports the case of a 21-year-old female patient who developed SMAS after persistent vomiting and prolonged weight loss following cerebellar tumor resection and cranial irradiation. The SMAS was confirmed by computed tomography and resolved following successful nutritional management.

Peri-operative immunonutrition in patients undergoing liver transplantation: a meta-analysis of randomized controlled trials.

BACKGROUND AND OBJECTIVES: No consensus has been reached concerning the effects of peri-operative immunonutrition in patients undergoing liver transplantation. We conducted a meta-analysis to evaluate the effects of peri-operative immunonutrition on clinical outcomes and liver function in patients undergoing liver transplantation. METHODS AND STUDY DESIGN: The Pubmed, Embase, Cochrane Central Register of Controlled Trials, Web of Science, and google scholar were searched to identify all available randomized controlled studies which compared peri-operative immunonutrition support (glutamine, ω-3 polyunsaturated fatty acids, arginine and ribonucleic acids) with standard nutrition. The data analysis was performed using Revman 5.2 software. RESULTS: A total of 7 randomized controlled trials (RCTs) involving 501 patients were included. Peri-operative immunonutrition significantly reduced the risk of infectious complications (RR: 0.51; 95% CI: 0.27 to 0.98, p=0.04) and shortened the postoperative hospital stay [weighted mean difference (WMD): -3.89; 95% CI: -7.42 to -0.36; p=0.03]. Furthermore, perioperative immunonutrition improved liver function by decreasing the levels of aspartate aminotransferase (AST) in the blood (WMD: -25.4; 95% CI: -39.9 to -10.9, p=0.0006). However, we did not find statistically significant differences in serum alanine aminotransferase (ALT), total bilirubin (TB) and direct bilirubin (DB) levels. There were no statistically significant differences in mortality and rejection reaction. CONCLUSIONS: Peri-operative nutrition support adding immunonutrients like glutamine, ω-3 polyunsaturated fatty acids, arginine and ribonucleic acids may improve outcomes in patients undergoing liver transplantation. Due to the limited sample size of the included trials, further large-scale and rigorously designed RCTs are needed.