Towards an integrated understanding of dietary phenotypes.

Diet and nutrition comprise a complex, multi-faceted interface between animal biology and food environments. With accumulating information on the many facets of this association arises a need for systems-based approaches that integrate dietary components and their links with ecology, feeding, post-ingestive processes and the functional and ecological consequences of these interactions. We briefly show how a modelling approach, nutritional geometry, has used the experimental control afforded in laboratory studies to begin to unravel these links. Laboratory studies, however, have limited ability to establish whether and how the feeding and physiological mechanisms interface with realistic ecological environments. We next provide an overview of observational field studies of free-ranging primates that have examined this, producing largely correlative data suggesting that similar feeding mechanisms operate in the wild as in the laboratory. Significant challenges remain, however, in establishing causal links between feeding, resource variation and physiological processes in the wild. We end with a more detailed account of two studies of temperate primates that have capitalized on the discrete variation provided by seasonal environments to strengthen causal inference in field studies and link patterns of intake to dynamics of nutrient processing. This article is part of the theme issue 'Food processing and nutritional assimilation in animals'.

Normal diet ameliorates obesity more safely and effectively than ketogenic diet does in high-fat diet-induced obesity mouse based on gut microbiota and lipid metabolism.

Growing evidence supports the efficacy of ketogenic diets for inducing weight loss, but there are also potential health risks due to their unbalanced nutrient composition. We aim at assessing relative effectiveness of a balanced diet and ketogenic diet for reversing metabolic syndrome in a diet-induced C57BL/6J mouse model. Mice were fed high-fat diet to induce obesity. Obese individuals were then fed either ketogenic or balanced diets as an obesity intervention. Serum, liver, fat and faecal samples were analysed. We observed that both diet interventions led to significant decrease in body weight. The ketogenic intervention was less effective in reducing adipocyte cell size and led to dyslipidaemia. The composition of the gut microbiome in the balanced diet intervention was more similar to the non-obese control group and had improved functional attributes. Our results indicate intervention with balanced diets ameliorates obesity more safely and effectively than ketogenic diets in diet-induced obesity mouse model.

FGFR inhibitors combined with nab-paclitaxel - A promising strategy to treat non-small cell lung cancer and overcome resistance.

Lung cancer has high morbidity and mortality rates worldwide, and NSCLC accounts for 85% of all lung cancer cases. Despite the development of targeted therapies and immunotherapy, many NSCLC patients do not effectively respond to treatment, and new treatment strategies are urgently needed. Aberrant activation of the FGFR signaling pathway is closely related to the initiation and progression of tumors. AZD4547, which is a selective inhibitor of FGFR 1-3, can suppress the growth of tumor cells with deregulated FGFR expression in vivo and in vitro. However, further exploration is needed to determine whether AZD4547 can play an antiproliferative role in tumor cells without deregulated FGFR expression. We investigated the antiproliferative effect of AZD4547 on NSCLC cells without deregulated FGFR expression. In vivo and in vitro experiments showed that AZD4547 exerted a weak antiproliferative effect on NSCLC cells without deregulated FGFR expression, but it significantly enhanced the sensitivity of NSCLC cells to nab-paclitaxel. We found that AZD4547 combined with nab-paclitaxel suppressed the phosphorylation of the MAPK signaling pathway, led to cell cycle arrest in the G2/M phase, promoted apoptosis, and inhibited cell proliferation more substantially than nab-paclitaxel alone. These findings provide insight into the rational use of FGFR inhibitors and personalized treatment of NSCLC patients.

Ketogenic Diet Combined with Moderate Aerobic Exercise Training Ameliorates White Adipose Tissue Mass, Serum Biomarkers, and Hepatic Lipid Metabolism in High-Fat Diet-Induced Obese Mice.

Obesity is a serious public health issue worldwide. Growing evidence demonstrates the efficacy of the ketogenic diet (KD) for weight loss, but there may be some adverse side effects such as dyslipidemia and hepatic steatosis. Aerobic exercise is a widely recognized approach for improving these metabolic markers. Here we explored the combined impacts of KD and moderate aerobic exercise for an 8-week intervention on body weight and fat loss, serum biomarkers, and hepatic lipid metabolism in a mouse model of high-fat diet-induced obesity. Both KD and KD combined with exercise significantly reduced body weight and fat mass. No significant adverse effects of KD were observed in serum biomarkers or hepatic lipid storage, except for an increase in circulating triglyceride level. However, aerobic exercise lowered serum triglyceride levels, and further ameliorated serum parameters, and hepatic steatosis in KD-fed mice. Moreover, gene and protein expression analysis indicated that KD combined with exercise was associated with increased expression of lipolysis-related genes and protein levels, and reduced expression of lipogenic genes relative to KD without exercise. Overall, our findings for mice indicate that further work on humans might reveal that KD combined with moderate aerobic exercise could be a promising therapeutic strategy for obesity.

An 8-week ketogenic diet improves exercise endurance and liver antioxidant capacity after weight loss in obese mice.

Evolving evidence supports the role of the ketogenic diet (KD) in weight loss. However, no coherent conclusions are drawn on its impact on the effect of KD on exercise and antioxidant capacity after weight loss in obese individuals. We evaluated the exercise performance, energy metabolism and antioxidant capacity of mice after weight loss using high-fat diet-induced obese mice, and used KD and normal diet (ND) intervention, respectively, to provide a theoretical basis for further study of the health effects of KD. Our results showed that the 8-week KD significantly reduced the body weight of obese mice and improved the performance of treadmill exercise, but had no significant effect on grip strength. Serum biochemical results suggest that KD has the risk of elevating blood lipid. In liver tissue, KD significantly reduced the level of oxidative stress and increased the antioxidant capacity of the liver. Our findings suggest that the intervention with KD led to weight loss, modulate energy metabolism and improve aerobic exercise endurance in obese mice. Despite its antioxidant potential in the liver, the utilization of KD still requires caution. This study underscores the need for further investigation into the health impacts of KD, especially in regard to its potential risks.

A simple arthroscopic technique for treatment of displaced "hinged" type of posterior cruciate ligament avulsion fractures.

BACKGROUND: The surgical technique for treatment of tibial avulsion fractures of the posterior cruciate ligament (PCL) remains challenging due to the deep-located lesion and the complexity of the anatomy. The purpose of this study was to report preliminary results of an arthroscopic technique in patients with the "hinged" type PCL tibial avulsion fractures. METHODS: Twenty-eight patients with the displaced "hinged" fractures with elevation of the posterior aspect of the bony fragment were arthroscopically treated. The bony fragment was reducted and fixed with the sutures passing through only one single tibial tunnel. The clinical outcomes were assessed by Lysholm score, Tegner activity score, and the side-to-side differences of KT-1000 measurement. The reduction and union of the fracture were assessed by radiography of the knee. RESULTS: Patients were followed up for a mean of 19 (12 to 24) months. There were no surgery-related complications, and all patients regained normal range of motion of the knees at the last follow-up. The Lysholm score significantly increased from preoperative 14.78 ± 8.23 to postoperative 96.96 ± 3.62 (P = 0.000). The Tegner score was 6.78 ± 1.35 pre-injury and 6.48 ± 1.20 at the last follow-up with no statistical difference (P = 0.688). The KT-1000 side-to-side differences significantly decreased from 8.26(SD 1.86; 6 to 12) pre-operatively to 0.91 (SD 0.85; 0 to 3) (P = 0.000). X-rays showed that satisfactory reduction and solid union was achieved in all patients. CONCLUSION: The arthroscopic suture fixation through single-tibial tunnel technique yielded good clinical and radiographic outcome for treatment of displaced "hinged" type of PCL avulsion fractures.

Identification and Validation of Autophagy-Related Genes as Potential Biomarkers and Therapeutic Targets in Atrial Fibrillation.

BACKGROUND: Autophagy is an evolutionary conserved important process for the turnover of intracellular substances in eukaryotes and is closely related to the development of atrial fibrillation (AF). The aim of this study is to identify and validate potential autophagy-related genes (ARGs) of AF through bioinformatics analysis and experimental validation. METHODS: We downloaded two data sets from the Gene Expression Omnibus (GEO) database, GSE14975 and GSE31821. After merging the data of the two microarrays, adjusting the batch effect, and integrating the differentially expressed genes (DEGs) with ARGs to obtain differentially expressed autophagy-related genes (DEARGs). Functional and pathway enrichment analyses were carried out based on Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG). Use the STRING database to construct a protein-protein interaction (PPI) network. Finally, mRNA expression levels of DEARGs were validated in right atrial tissue samples from AF patients and non-AF controls by qRT-PCR. RESULTS: Through bioinformatics analysis, we finally identified 11 DEARGs (CDKN1A, CXCR4, DIRAS3, HSP90AB1, ITGA3, PRKCD, TP53INP2, DAPK2, IFNG, PTK6, and TNFSF10) in AF using [log2 (fold change)] > 0.5 and P < 0.05. In the pathway enrichment analysis, the most significantly enriched pathway was the autophagy pathway. The results of validation showed that the expression levels of CXCR4, DAPK2, and TNFSF10 corroborating with our computational findings, and the results were statistically significant (P<0.05). CONCLUSION: Our study demonstrates that these 11 potential crucial ARGs, especially CXCR4, DAPK2, and TNFSF10, may be potential biomarkers and therapeutic targets in AF, which will help the personalized treatment of AF patients.

Secretagogin, a marker for neuroendocrine cells, is more sensitive and specific in large cell neuroendocrine carcinoma compared with the markers CD56, CgA, Syn and Napsin A.

A common method to distinguish large cell neuroendocrine carcinoma (LCNEC) from non-neuroendocrine large cell carcinoma (non-NE LCC) is from using specific immunohistochemistry markers, such as CgA, Syn, CD56 and Napsin A, however, the results remain controversial using these markers. Secretagogin (SCGN) is a newly discovered biomarker of neuroendocrine cells. In the present study, the expression of SCGN in 33 cases of human lung large cell carcinoma (LCC), including 17 cases of LCNEC and 16 cases of non-neuroendocrine (NE) LCC and lung cancer cell lines (A549, H1650, H358, H292 and H661). The association between SCGN expression and the clinicopathological characteristics of patients, including sex, age, clinical stage and metastasis, was analyzed. The results revealed that the different lung cancer cell lines had different expression levels of SCGN, and the SCGN protein was localized in the nucleus and cytoplasm of A549 cells detected using immunofluorescence. A total of 54.5% (18/33) of specimens positively expressed the SCGN protein. Of the 17 patients with LCNEC, only 23.5% (4/17) of cases were CgA positive, 35.29% (6/17) were Syn positive, 41.2% (7/17) were CD56 positive, and 41.2% (7/17) were Napsin A positive. However, SCGN was positively detected in 94.1% (16/17) of patients with LCNEC, which was more frequent compared with that in CgA, Syn, CD56 and Napsin A. Analysis of the clinical characteristics indicated that SCGN expression was only significantly associated with pathological type in patients with lung cancer (P<0.001). Furthermore, a positive correlation was observed between SCGN expression and CgA, Syn, and CD56 expression in patients with LCNEC. SCGN was co-localized with the NE markers (CgA, Syn, and CD56) in A549 lung cancer cells and in LCNEC tissues. Thus, SCGN displayed more sensitivity and specificity in lung cancer cells with NE differentiation. A combined analysis of SCGN and other common NE markers may be a potential tool for diagnosing these tumors.

Semi-Supervised Image Dehazing.

We present an effective semi-supervised learning algorithm for single image dehazing. The proposed algorithm applies a deep Convolutional Neural Network (CNN) containing a supervised learning branch and an unsupervised learning branch. In the supervised branch, the deep neural network is constrained by the supervised loss functions, which are mean squared, perceptual, and adversarial losses. In the unsupervised branch, we exploit the properties of clean images via sparsity of dark channel and gradient priors to constrain the network. We train the proposed network on both the synthetic data and real-world images in an end-to-end manner. Our analysis shows that the proposed semi-supervised learning algorithm is not limited to synthetic training datasets and can be generalized well to real-world images. Extensive experimental results demonstrate that the proposed algorithm performs favorably against the state-of-the-art single image dehazing algorithms on both benchmark datasets and real-world images.

Gastric carcinoma with a gastrointestinal stromal tumor - A case report and literature review.

Gastric carcinoma (GC) with gastrointestinal stromal tumor (GIST) is encountered very rarely in the clinic, and few cases have been reported in the literature. Here, we present a case involving a 72-year-old man who was diagnosed with gastric antrum adenocarcinoma accompanied by neuroendocrine differentiation and a GIST in the fundus, according to a preoperative examination and postoperative pathology. The patient then underwent a distal radical gastrectomy and GIST resection. After the operation, the patient was administered combined chemo-radiotherapy and subsequently underwent a 9-month follow-up examination. The gene mutations involved in this case were explored via high-throughput sequencing. The high-throughput gene mutation analysis indicated an exon5 mutation in the TP53 gene and copy number amplification of FGF19, CCND1, and FGFR2 in the gastric antrum adenocarcinoma. A gene sequencing analysis of the gastric fundus stromal tumor demonstrated an exon11 non-frame shift deletion mutation in the KIT gene. These findings suggested that this patient's cancer might be sensitive to AZD1775 (a TP53-targeted drug) or targeted drugs such as FGF19, CCND1 and FGFR2, and should be sensitive to imatinib.

Lymphatic vessel density as a prognostic indicator in Asian NSCLC patients: a meta-analysis.

BACKGROUND: To determine the association of lymphatic vessel density (LVD) with the prognosis of Asian non-small cell lung cancer (NSCLC) patients via a meta-analysis. METHODS: Eligible studies were selected by searching PubMed and EMBASE from inception to July 25, 2017. The reference lists of the retrieved articles were also consulted. The information was independently screened by two authors. When heterogeneity was significant, a random-effects model was used to determine overall pooled risk estimates. RESULTS: A total of 15 studies with 1075 patients were finally included in the meta-analysis. LVD was positively associated with the prognosis of NSCLC in the overall analysis (hazard ratio (HR) 1.14, 95% confidence interval (95% CI): 1.02-1.27, p = 0.000, I2 = 73.2%). Subgroup analyses were performed on 5 VEGFR-3 groups (p = 0.709, I2 = 0.0%), 3 LYVE-1 groups (p = 0.01, I2 = 86.4%), 5 D2-40 groups (p = 0.019, I2 = 66.2%), and 2 podoplanin groups (p = 0.094, I2 = 64.5%). Sensitivity analysis indicated robust results. There was no publication bias. CONCLUSIONS: LVD is an indicator of poor prognosis in Asian NSCLC patients.

Correction: Cholecystectomy can increase the risk of colorectal cancer: A meta-analysis of 10 cohort studies.

[This corrects the article DOI: 10.1371/journal.pone.0181852.].

Abdominal obesity and colorectal cancer risk: systematic review and meta-analysis of prospective studies.

The association between abdominal obesity (as measured by waist circumference (WC) and waist-to-hip ratio (WHR)) and colorectal cancer (CRC) has not been fully quantified, and the magnitude of CRC risk associated with abdominal obesity is still unclear. A meta-analysis of prospective studies was performed to elucidate the CRC risk associated with abdominal obesity. Pubmed and Embase were searched for studies assessing the association between abdominal obesity and CRC risk. Relative risks (RRs) with 95% confidence intervals (95% CIs) were pooled using random-effects model of meta-analysis. Nineteen prospective cohort studies from eighteen publications were included in this meta-analysis. A total of 12,837 CRC cases were identified among 1,343,560 participants. Greater WC and WHR were significantly associated with increased risk of total colorectal cancer (WC: RR 1.42, 95% CI 1.30, 1.55; WHR: RR 1.39, 95% CI 1.25, 1.53), colon cancer (WC: RR 1.53, 95% CI 1.36, 1.72; WHR: 1.39, 95% CI 1.18, 1.63), and rectal cancer (WC: RR 1.20, 95% CI 1.03, 1.39; WHR: RR 1.22, 95% CI 1.05, 1.42). Subgroup analyses further identified the robustness of the association above. No obvious risk of publication bias was observed. In summary, abdominal obesity may play an important role in the development of CRC.

MiR-146b-5p functions as a suppressor miRNA and prognosis predictor in non-small cell lung cancer.

Non-small cell lung cancer (NSCLC) is the leading cause of cancer-related death worldwide. However, science has not yet been able to substantially improve the prognosis of lung cancer patients. Accumulating evidence suggests that microRNAs (miRNAs) are key players in the regulation of tumor development and metastasis. Expression of six miRNAs previously shown to play roles in tumor development (miR-146b-5p, miR-128b, miR-21, miR-221, miR-34a, and Let-7a) in other tumor types was examined using real-time RT-PCR in 78 specimens of NSCLC. The results revealed that patients with low expression of miR-146b-5p had significant shorter median and mean survival time than those with high miR-146b-5p expression (33.00 and 30.44 months versus 42.0 and 36.90 months, respectively; log-rank test P=0.048), thus low miR-146b-5p expression level was associated with poor prognosis in NSCLC patients. Univariate Cox hazard regression analysis demonstrated that miR-146b-5p expression levels tended to be a significant prognostic indicator of NSCLC (adjusted hazard ratio=0.482, 95% CI: 1.409- 29.593, P=0.016). Multivariate Cox proportional hazard regression analysis showed that miR-146b-5p expression levels were an independent prognostic factor for NSCLC patients (hazard ratio=0.259, 95% CI: 0.083-0.809, P=0.020). Furthermore, the effects of miR-146b-5p and miR-146b-3p on NSCLC cell growth and invasion in vitro were investigated. Our findings demonstrate that ectopic expression of miR-146b-5p suppressed cell proliferation, clonogenicity, migration/ invasion and also induced G1 arrest in vitro, but did not induce cell apoptosis; whereas enforced expression of miR-146b-3p did not have a significant effect on cell growth and metastasis. Further experiments indicated that miR-146b-5p could reduce mRNA levels of MMP16 and TRAF6 in vitro and was negatively related to the expression of TRAF6 in human NSCLC tissues. In a mouse model, Ago-miR-146b-5p could significantly inhibit the growth of lung cancer xenografts in nude mice. In conclusion, our findings demonstrate that miR-146b-5p functions as a suppressor miRNA and prognosis predictor in NSCLC.

Cholecystectomy can increase the risk of colorectal cancer: A meta-analysis of 10 cohort studies.

OBJECTIVE: This study aimed to elucidate the effects of cholecystectomy on the risk of colorectal cancer (CRC) by conducting a meta-analysis of 10 cohort studies. METHODS: The eligible cohort studies were selected by searching the PubMed and EMBASE databases from their origination to June 30, 2016, as well as by consulting the reference lists of the selected articles. Two authors individually collected the data from the 10 papers. When the data showed marked heterogeneity, we used a random-effects model to estimate the overall pooled risk; otherwise, a fixed effects model was employed. RESULTS: The final analysis included ten cohort studies. According to the Newcastle-Ottawa Scale (NOS), nine papers were considered high quality. After the data of these 9 studies were combined, an increased risk of CRC was found among the individuals who had undergone cholecystectomy (risk ratio (RR) 1.22; 95% confidence interval (CI) 1.08-1.38). In addition, we also found a promising increased risk for colon cancer (CC) (RR 1.30, 95% CI 1.07-1.58), but no relationship between cholecystectomy and rectum cancer (RC) (RR 1.09; 95% CI 0.89-1.34) was observed. Additionally, in the sub-group analysis of the tumor location in the colon, a positive risk for ascending colon cancer (ACC) was found (RR 1.18, 95% CI 1.11-1.26). After combining the ACC, transverse colon cancer (TCC), sigmoid colon cancer (SCC) and descending colon cancer (DCC) patients, we found a positive relationship with cholecystectomy (RR 1.18, 95% CI 1.11-1.26). Furthermore, after combining the ACC and DCC patients, we also found a positive relationship with cholecystectomy (RR 1.28; 95% CI 1.11-1.26) in the sub-group analysis. In an additional sub-group analysis of patients from Western countries, there was a positive relationship between cholecystectomy and the risk of CRC (RR 1.20; 95% CI 1.05-1.36). Furthermore, a positive relationship between female gender and CRC was also found (RR 1.17; 95% CI 1.03-1.34). However, there was no relationship between gender and CC or RC. Furthermore, no publication bias was observed, and the sensitivity analysis indicated stable results. CONCLUSIONS: This meta-analysis of 10 cohort studies revealed that cholecystectomy is associated with an increased risk for CRC, CC and ACC, particularly in Western countries. No relationship between cholecystectomy and RC was observed. There was no relationship between gender and either CC or RC, but a positive relationship between female gender and CRC was observed.

[Aberrant Expression of Rb and pRb-780, pRb-795 in Lung Adenocarcinoma Patients with EGFR Mutations and Their Clinical Significance].

BACKGROUND: Rb is an important tumor suppressor gene that regulates cell cycle progression. Rb dysfunction can lead to over proliferation of cells and lead to the occurrence of tumor. Loss or reduced Rb expression as well as over phosphorylation of Rb are important mechanisms of Rb dysfunction. The mutated epidermal growth factor receptor (EGFR) gene is an important driver gene in lung adenocarcinoma, and plays an important role in the development of lung cancer. The purpose of this study was to investigate the status of Rb in lung adenocarcinoma patients with EGFR mutations and define the clinicopathologic features. METHODS: 23 cases pulmonary adenocarcinoma patients with EGFR mutations were collected. The status of Rb and pRb-780, pRb-795 were determined byimmunohistochemistry. RESULTS: Loss or reduced Rb expression were detected in 16 of 23 samples (69.6%). pRb-780 and pRb-795 over-expressed were identified in 17 (73.9%) and 16 (69.6%) of 23 samples respectively. All the 23 patients had showed loss/reduced Rb expression or over-expressed Rb phosphorylation. Further analysis showed that over expression of pRb-780 and pRb-795 occurred more frequently in advanced patients. CONCLUSIONS: Aberrant expressionof Rb is frequently occurred in lung adenocarcinoma patients with EGFR mutations and may be an important pathogenesis in patients with lung adenocarcinoma.
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[Methylation Status of the SOCS3 Gene Promoter in H2228 Cells and 
EML4-ALK-positive Lung Cancer Tissues].

BACKGROUND: The EML4-ALK fusion gene is a newly discovered driver gene of non-small cell lung cancer and exhibits special clinical and pathological features. The JAK-STAT signaling pathway, an important downstream signaling pathway of EML4-ALK, is aberrantly sustained and activated in EML4-ALK-positive lung cancer cells fusion gene, but the underlying reason remains unknown. The suppressor of cytokine signaling (SOCS) is a negative regulatory factor that mainly inhibits the proliferation, differentiation, and induction of apoptotic cells by inhibiting the JAK-STAT signaling pathway. The aberrant methylation of the SOCS gene leads to inactivation of tumors and abnormal activation of the JAK2-STAT signaling pathway. The aim of this study is to investigate the methylation status of the SOCS3 promoter in EML4-ALK-positive H2228 cells and lung cancer tissues. METHODS: The methylation status of the SOCS3 promoter in EML4-ALK-positive H2228 lung cancer cells and lung cancer tissues was detected by methylation-specific PCR (MSP) analysis and verified by DNA sequencing. The expression levels of SOCS3 in H2228 cells were detected by Western blot and Real-time PCR analyses after treatment with the DNA methyltransferase inhibitor 5'-Aza-dC. RESULTS: MSP and DNA sequencing assay results indicated the presence of SOCS3 promoter methylation in H2228 cells as well as in three cases of seven EML4-ALK-positive lung cancer tissues. The expression level of SOCS3 significantly increased in H2228 cells after 5'-Aza-dC treatment. CONCLUSIONS: The aerrant methylation of the SOCS3 promoter region in EML4-ALK (+) H2228 cells and lung cancer tissues may be significantly involved in the pathogenesis of EML4-ALK-positive lung cancer.