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1.  Deciphering the anti-angiogenic effect of endostatin/cyclophosphamide to normalize tumor micrangium through notch signaling pathway in colon cancer 
Background
The invasion of colon cancer is associated with the tumor angiogenesis. Endostatin is an important anti-angiogenic agent, and the additive effect of endostatin with a chemotherapeutic agent, cyclophosphamide, on micrangium has not been established.
Methods
Male BALB/c strain nude mice were injected with human colorectal carcinoma cells (HCT-116). The mice were divided into four groups (n = 15, each group) and were treated with different concentrations of endostatin (15, 10, and 5 mg/kg/day), cyclophosphamide (20, 10, and 5 mg/kg/day), and combination of endostatin/cyclophosphamide (15 + 20, 15 + 10, and 15 + 5 mg/kg/day). The tumor inhibition rate was evaluated, followed by the quantification of messenger ribonucleic acid (mRNA) and protein expression of notch signaling components NOTCH-1, NOTCH-3, NOTCH-4, JAG-1, DLL-4, Hes-1, and Hey-1 using quantitative polymerase chain reaction (qPCR). The protein expression of NOTCH-3, JAG-1, and DLL-4 was confirmed using western blotting. Microvessel density (MVD) was evaluated to detect micrangium following the treatment.
Results
The endostatin/cyclophosphamide-treated samples exhibited an additive effect on the tumor inhibition rate and the microvessel count. NOTCH-1, NOTCH-3, NOTCH-4, JAG-1, Hes-1, and Hey-1 expression levels were highly correlated and downregulated in the treated samples, whereas DLL-4 expression was upregulated that accounted for its anti-angiogenic property.
Conclusions
The combination treatment of colon cancer with endostatin and a chemotherapeutic agent, cyclophosphamide proves to be an efficient therapeutic strategy to inhibit the rapid vasculature formation confirmed by the differential expression of notch signaling components.
doi:10.1186/s12957-015-0761-9
PMCID: PMC4712526  PMID: 26762567
Colon cancer; Angiogenesis; Micrangium; Endostatin; Cyclophosphamide
2.  The Impact of Tumor Deposits on Colonic Adenocarcinoma AJCC TNM Staging and Outcome 
The definition of tumor deposits (TD) in colonic adenocarcinoma has been modified in different editions of AJCC/TNM staging system. Studies have shown that the presence of TD is associated with advanced tumor growth and poor prognosis. Most of these data were obtained in patients with simultaneous lymph node (LN) metastases. Reports focusing on the impact of TD in patients without LN metastasis are limited. We retrospectively restaged all right-sided colonic adenocarcinoma over a 10-year period using criteria from the 5th, 6th, and 7th AJCC edition. We compared the number of tumor nodule interpreted as LN and TD in each edition, and evaluated the stage migration caused by TD definition change. We then assessed clinical significance of TD in AJCC 7th edition by comparing 5-year overall survival of N1c patients vs. other N category (N0, N1, N2) patients with similar T and M status. We showed that average number of tumor nodule interpreted as LN per case and number of cases with positive LN were significantly decreased with 7th edition compared to 5th/6th; however, numbers of cases with TD and <12 LN were significantly increased with 7th edition compared to 5th/6th. These changes, however, resulted in minimal effects on the final stage grouping. Our survival analysis showed that N1c patients had significantly worse survival compared to N0 patients. Although not statistically significant, the hazard ratios indicated that N1c group might have worse survival than N1 group and better survival than N2 group. Therefore, we conclude that TD predict patient outcome at least similarly to positive LN.
doi:10.1097/PAS.0000000000000320
PMCID: PMC4267920  PMID: 25229767
tumor deposits; lymph node; colonic adenocarcinoma; staging; survival
3.  Modulatory Effects of Astragalus Polysaccharides on T-Cell Polarization in Mice with Polymicrobial Sepsis 
Mediators of Inflammation  2015;2015:826319.
Background. This study evaluated the impact of different doses of Astragalus polysaccharides (APS) on the functional status and phenotype of T cells during polymicrobial sepsis. Methods. On day 1 after cecal ligation and puncture, mice were treated with either saline, 100 (A100), 200 (A200), or 400 mg APS/kg body weight (BW) (A400) by an intraperitoneal injection daily for 4 days. All mice were sacrificed 5 days after the operation. Results. APS treatment reversed the sepsis-induced decrement in the T helper (Th) cell population, and the percentage of activated Th cells also increased in the spleen and Peyer's patches. APS administration downregulated the percentages of circulating Th2 cells and regulatory T cells (Treg), and the percentage of Th17 cells in blood was upregulated in the A400 group. Weight loss and kidney injury were attenuated in the A100 and A200 groups but not in the A400 group at the end of the study. Conclusions. Treatments with 100 and 200 mg APS/kg BW reduced Treg populations and elicited a more-balanced Th1/Th2 response that consequently attenuated immunosuppression in polymicrobial sepsis. High-dose APS administration led to excessive responses of Th17 cells which may have adverse effects in sepsis-induced organ injury.
doi:10.1155/2015/826319
PMCID: PMC4674621  PMID: 26693207
4.  Expression of Toll-Like Receptors 2 and 4 and Related Cytokines in Patients with Hepatic Cystic and Alveolar Echinococcosis 
Mediators of Inflammation  2015;2015:632760.
Several studies have demonstrated the important role of Toll-like receptors in various parasitic infections. This study aims to explore expression of Toll-like receptors (TLRs) and related cytokines in patients with human cystic echinococcosis (CE) and alveolar echinococcosis (AE). 78 subjects including AE group (N = 28), CE group (N = 22), and healthy controls (HC, N = 28) were enrolled in this study. The mRNA expression levels of TLR2 and TLR4 in blood and hepatic tissue and plasma levels related cytokines were detected by using ELISA. Median levels of TLR2 mRNA in AE and CE groups were significantly elevated as compared with that in healthy control group. Median levels of TLR4 expression were increased in AE and CE. Plasma concentration levels of IL-5, IL-6, and IL-10 were slightly increased in AE and CE groups compared with those in HC group with no statistical differences (p > 0.05). The IL-23 concentration levels were significantly higher in AE and CE groups than that in HC subjects with statistical significance. The increased expression of TLR2 and IL-23 might play a potential role in modulating tissue infiltrative growth of the parasite and its persistence in the human host.
doi:10.1155/2015/632760
PMCID: PMC4655286  PMID: 26635448
5.  Expression of Pax8 is decreased and bortezomib does not increase the iodine uptake in thyroid carcinoma cells 
Thoracic Cancer  2015;6(6):792-796.
Fundamental treatment for papillary thyroid carcinoma (PTC) involves total or subtotal thyroidectomy. Iodine-131 (131I) is routinely utilized to target remnant thyroid cancer and metastasis after thyroidectomy. The effectiveness of other therapeutic modalities remains unsatisfactory; thus, these patients have a poor prognosis. The manner in which the ability of 131I uptake can be improved is vital for their prognosis. Bortezomib has been used as a re-differentiation agent for the treatment of patients with multiple myeloma; however, little is reported about the role of bortezomib in thyroid cancer. To evaluate the therapeutic potential of bortezomib in a human PTC cell line, expression of paired-box 8 (Pax8) protein was determined using Western blot in PTC, normal thyroid, and anaplastic/undifferentiated thyroid carcinoma (ATC) cells. The expression of Pax8 protein in PTC cells pretreated with bortezomib was determined using the same method. Iodine uptake was determined using 131I radioactivity assay. The level of Pax8 protein in normal thyroid cells was significantly higher than in PTC (P < 0.05) and ATC cells (P < 0.05); its expression in PTC cells was also significantly higher than in ATC cells (P < 0.05). The PTC cells in the bortezomib-treated group showed a higher expression of Pax8 protein than the control group (P < 0.05). These findings indicate that bortezomib can increase the expression of Pax8, but does not significantly increase the iodine uptake of PTC cells.
doi:10.1111/1759-7714.12277
PMCID: PMC4632934  PMID: 26557920
Bortezomib; iodine uptake; papillary thyroid carcinoma; thyrotropin
6.  False-positive diagnosis of disease progression by magnetic resonance imaging for response assessment in prostate cancer with bone metastases: A case report and review of the pitfalls of images in the literature 
Oncology Letters  2015;10(6):3585-3590.
Bone metastases are common in prostate cancer. However, differentiating neoplastic from non-neoplastic alterations of bone on images is challenging. In the present report, a rare case of bone marrow reconversion on magnetic resonance imaging (MRI) assessment, which may lead to a false-positive diagnosis of disease progression of bone metastases in hormone-resistant prostate cancer, is presented. Furthermore, a review of the literature regarding the pitfalls of images for response assessment, including the ‘flare’ phenomenon on bone scintigraphy, computed tomography (CT), positron emission tomography/CT and marrow reconversion on MRI is also provided. These inaccuracies, which may lead to a premature termination of an efficacious treatment, should be carefully considered by the radiologists and oncologists involved in clinical trials. The case reported in the present study showed how to assess the early therapeutic response and select the appropriate treatment for the patient when these pitfalls are encountered on clinical images.
doi:10.3892/ol.2015.3753
PMCID: PMC4665215  PMID: 26788174
pitfalls of images; prostate cancer; ‘flare’ phenomenon; marrow reconversion on magnetic resonance imaging
7.  Comorbid chronic diseases and their associations with quality of life among gynecological cancer survivors 
BMC Public Health  2015;15:965.
Background
Many gynecological cancer survivors (GCS) have comorbid chronic diseases (CCD). This study was to estimate the impacts of CCD on quality of life (QOL) in GCS.
Methods
We collected cross-sectional self-reported survey data from 598 GCS between April and July 2013, in Shanghai, China. All the subjects were asked to complete a questionnaire containing the European Organization for Research and Treatment quality of life version 3 questionnaire (EORTC QLQ-C30) and questions on socio-demographic characteristics and CCD. In order to mitigate the bias caused by confounding factors, multiple linear models were employed to calculate adjusted means of QOL scores.
Results
Approximately three-quarters of subjects reported at least one CCD. The highest overall prevalence of all CCD was found in endometrial cancer survivors. Subjects with CCD generally reported lower scores for most EORTC QLQ-C30 scales when compared to subjects without CCD, indicating poorer QOL, particularly for cardiovascular diseases, respiratory diseases, digestive diseases, and musculoskeletal disease.
Conclusions
The CCD are common health problems among GCS. CCD have significantly negative influence on QOL, and GCS with CCD generally reported lower QOL scores. These findings suggested comprehensive cares for GCS.
doi:10.1186/s12889-015-2240-1
PMCID: PMC4582736  PMID: 26408314
Gynecological cancer survivors; Quality of life; Comorbid chronic diseases; Cancer care
8.  Application of 3D reconstruction for surgical treatment of hepatic alveolar echinococcosis 
World Journal of Gastroenterology : WJG  2015;21(35):10200-10207.
AIM: To evaluate the reliability and accuracy of three-dimensional (3D) reconstruction for liver resection in patients with hepatic alveolar echinococcosis (HAE).
METHODS: One-hundred and six consecutive patients with HAE underwent hepatectomy at our hospital between May 2011 and January 2015. Fifty-nine patients underwent preoperative 3D reconstruction and “virtual” 3D liver resection before surgery (Group A). Another 47 patients used conventional imaging methods for preoperative assessment (Group B). Outcomes of hepatectomy were compared between the two groups.
RESULTS: There was no significant difference in preoperative data between the two groups. Compared with patients in Group B, those in Group A had a significantly shorter operation time (227.1 ± 51.4 vs 304.6 ± 88.1 min; P < 0.05), less intraoperative blood loss (308.1 ± 135.4 vs 458.1 ± 175.4 mL; P < 0.05), and lower requirement for intraoperative blood transfusion (186.4 ± 169.6 vs 289.4 ± 199.2 mL; P < 0.05). Estimated resection liver volumes in both groups had good correlation with actual graft weight (Group A: r = 0.978; Group B: r = 0.960). There was a significant higher serum level of albumin in Group A (26.3 ± 5.9 vs 22.6 ± 4.3 g/L, P < 0.05). Other postoperative laboratory parameters (serum levels of aminotransferase and bilirubin; prothrombin time) and duration of postoperative hospital stay were similar. Sixteen complications occurred in Group A and 19 in Group B. All patients were followed for 3-46 (mean, 17.3) mo. There was no recurrence of lesions in Group A, but two recurrences in Group B. There were three deaths: two from cerebrovascular accident, and one from car accident.
CONCLUSION: 3D reconstruction provides comprehensive and precise anatomical information for the liver. It also improves the chance of success and reduces the risk of hepatectomy in HAE.
doi:10.3748/wjg.v21.i35.10200
PMCID: PMC4572801  PMID: 26401085
Liver resection; Hepatic alveolar echinococcosis; Computed tomography; Three-dimensional reconstruction; Surgical planning
9.  Compound Danshen Dripping Pill for Treating Early Diabetic Retinopathy: A Randomized, Double-Dummy, Double-Blind Study 
This randomized, double-dummy, double-blind study was to observe the therapeutic effects of compound Danshen dripping pill (CDDP) in treating early diabetic retinopathy (DR). All the 57 type 2 diabetes cases in nonproliferative diabetic retinopathy (NPDR) stage were divided into two groups randomly: 28 cases treated with CDDP as the treated group and 29 cases treated with calcium dobesilate as the control group. The best corrected visual acuity (BCVA) in the treated group was significantly improved after treatment when compared to that before treatment (P < 0.05). Mean defect (MD) of visual field, hemorrhage area of the fundus, microaneurysm number, fluorescent leakage area, and capillary nonperfusion area evaluated by visual field, fundus photography, and fundus fluorescein angiography in the treated group had the same results as BCVA. However, there was no statistical difference in each index between the two groups. No obvious adverse events with clinical significance occurred. Our present study showed that CDDP has a similar improvement and safety to calcium dobesilate for NPDR. In future DR treatments, CDDP may function as the auxiliary drug.
doi:10.1155/2015/539185
PMCID: PMC4592726  PMID: 26457110
10.  Regulation of migration and invasion by Toll-like receptor-9 signaling network in prostate cancer 
Oncotarget  2015;6(26):22564-22574.
Toll-like receptors (TLRs) play an important role in tumorigenesis and progress of prostate cancer. However, the function and mechanism of Toll-like receptor-9 (TLR9) in prostate cancer is not totally understood. Here, we found that high expression of TLR9 was associated with a higher probability of lymph node metastasis and poor prognosis. Further in vitro functional study verified that silence of TLR9 inhibited migration and invasion of PC-3 cells, indicating expression of TLR9 involving in the migration and invasion of cancer cells. The data of microarray exhibited silence of TLR9 induced 205 genes with larger than 2-fold changes in expression levels, including 164 genes down-regulated and 41 genes up-regulated. Functional Gene Ontology (GO) processes annotation demonstrated that the top three scores of molecular and cellular functions were regulation of programmed cell death, regulation of locomotion and response to calcium ion. TLR9 signaling network analysis of the migration and invasion related genes identified several genes, like matrix metallopeptidase 2 (MMP2), matrix metallopeptidase 9 (MMP9), chemokine receptor 4 (CXCR4) and interleukin 8 (IL8), formed the core interaction network based on their known biological relationships. A few genes, such as odontogenic ameloblast-associated protein (ODAM), claudin 2 (CLDN2), gap junction protein beta 1 (GJB1) and Rho-associated coiled-coil containing protein kinase 1 pseudogene 1 (ROCK1P1), so far have not been found to interact with the other genes. This study provided the foundation to discover the new molecular mechanism in signaling networks of invasion and metastasis in prostate cancer.
PMCID: PMC4673182  PMID: 26087186
TLR9; migration; invasion; prostate cancer
11.  Glycemic Change After Pancreaticoduodenectomy 
Medicine  2015;94(27):e1109.
Abstract
The purpose of this population-based study was to determine the change of glucose metabolism in patients undergoing pancreaticoduodenectomy (PD).
We conducted a nationwide cohort study using data from Taiwan's National Health Insurance Research Database collected between 2000 and 2010. Our sample included 861 subjects with type 2 diabetes mellitus (DM) and 3914 subjects without DM.
Of 861 subjects with type 2 diabetes, 174 patients (20.2%) experienced resolution of their diabetes after PD, including patients with pancreatic ductal adenocarcinoma (PDAC) (20.5%), and non-PDAC (20.1%). Using a multiple logistic regression model, we found that subjects with comorbid chronic pancreatitis (odds ratio, 0.356; 95% CI, 0.167–0.759; P = 0.007) and use of insulin (odds ratio, 0.265; 95% CI, 0.171–0.412; P < 0.001) had significantly lower rates of resolution of diabetes. In the 3914 subjects without diabetes, the only statistically significant comorbidity contributing to pancreatogenic diabetes was chronic pancreatitis (odds ratio, 1.446; 95% CI, 1.146–1.823; P = 0.002).
Subjects with comorbid chronic pancreatitis and use of insulin had lower rates of resolution of DM after PD. In subjects without diabetes, chronic pancreatitis contributed significantly to the development of pancreatogenic DM.
doi:10.1097/MD.0000000000001109
PMCID: PMC4504605  PMID: 26166104
12.  Change of Both Endocrine and Exocrine Insufficiencies After Acute Pancreatitis in Non-Diabetic Patients 
Medicine  2015;94(27):e1123.
Abstract
Acute pancreatitis (AP) is the most common pancreatic disease and consists of an acute inflammation of the pancreas. AP can contribute to endocrine and exocrine insufficiencies in survivors as a result of the key role of the pancreas in both glucose metabolism and nutritional digestion. The aim of this population-based study was to determine the endocrine or exocrine insufficiencies in patients after initial AP with biliary or alcohol-associated causes.
We conducted a nationwide cohort study using data from Taiwan's National Health Insurance Research Database collected between 2001 and 2010. A total of 12,284 patients with AP were identified.
Alcohol-associated AP (odds ratio, 1.894; 95% CI, 1.520–2.268; P < 0.001) and ≥2 admissions for AP (odds ratio, 1.937; 95% CI, 1.483–2.391; P < 0.001) were significantly associated with newly diagnosed diabetes mellitus after AP. Further, only alcohol-associated AP (odds ratio, 1.215; 95% CI, 1.133–1.297; P < 0.001) was significantly associated with pancreatic exocrine insufficiency after AP. Additionally, alcohol-associated AP (odds ratio, 1.804; 95% CI, 1.345–2.263; P < 0.001) and ≥2 readmissions for AP (odds ratio, 3.190; 95% CI, 2.317–4.063; P < 0.001) were significantly associated with both exocrine and endocrine insufficiencies after AP.
Our data showed that alcohol-associated AP, rather than a biliary cause, contributed to a higher extent to exocrine or endocrine insufficiencies. Furthermore, recurrent AP also led to endocrine insufficiency.
doi:10.1097/MD.0000000000001123
PMCID: PMC4504627  PMID: 26166112
13.  Bacterial Flora Changes in Conjunctiva of Rats with Streptozotocin-Induced Type I Diabetes 
PLoS ONE  2015;10(7):e0133021.
Background
The microbiota of both humans and animals plays an important role in their health and the development of disease. Therefore, the bacterial flora of the conjunctiva may also be associated with some diseases. However, there are no reports on the alteration of bacterial flora in conjunctiva of diabetic rats in the literature. Therefore, we investigated the changes in bacterial flora in bulbar conjunctiva of rats with streptozotocin (STZ)-induced type I diabetes.
Methods
A high dose of STZ (60 mg/kg, i.p.) was injected into Sprague-Dawley (SD) rats to induce type I diabetes mellitus (T1DM). The diabetic rats were raised in the animal laboratory and at 8 months post-injection of STZ swab samples were taken from the bulbar conjunctiva for cultivation of aerobic bacteria. The bacterial isolates were identified by Gram staining and biochemical features. The identified bacteria from both diabetic and healthy rats were then compared.
Results
The diabetic and healthy rats had different bacterial flora present in their bulbar conjunctiva. In total, 10 and 8 bacterial species were found in the STZ and control groups, respectively, with only three species (Enterococcus faecium, Enterococcus gallinarum and Escherichia coli) shared between the two groups. Gram-positive bacteria were common in both groups and the most abundant was Enterococcus faecium. However, after the development of T1DM, the bacterial flora in the rat bulbar conjunctiva changed considerably, with a reduced complexity evident.
Conclusions
STZ-induced diabetes caused alterations of bacterial flora in the bulbar conjunctiva in rats, with some bacterial species disappearing and others emerging. Our results indicate that the conjunctival bacterial flora in diabetic humans should be surveyed for potential diagnostic markers or countermeasures to prevent eye infections in T1DM patients.
doi:10.1371/journal.pone.0133021
PMCID: PMC4503457  PMID: 26176548
14.  Methylation of sodium iodide symporter promoter correlated with aggressiveness and metastasis in papillary thyroid carcinoma: a meta-analysis 
Background: Methylation of sodium iodide symporter promoter has been reported to increase the incidence of papillary thyroid carcinoma (PTC). In this meta-analysis stratified via methylation of sodium iodide symporter promoter, we evaluate the relationship between methylation of sodium iodide symporter promoter and PTC. The association between methylation with aggressiveness and metastasis potential of PTC is also discussed. Methods: We searched electronic databases for original articles and references of included studies both in English and Chinese from 1966 to 2014. Two reviewers selected the case-control study and extracted data from relevant literature independently. Results: Seven articles, including 360 cases and 268 controls, were involved in this meta-analysis. The prevalence of PTC in patients with methylated sodium iodide symporter promoter was significantly higher than those with non-methylated promoter (OR=7.36, 95% CI: 4.25-12.74, P<0.001). Stratified analysis showed that PTC patients with multiple lesions, capsule invasion and lymphatic metastasis had significantly higher rates of methylation (OR=2.22, 95% CI: 1.12-4.41, P=0.02; OR=2.14, 95% CI: 1.12-4.08, P=0.02; OR=3.56, 95% CI: 1.97-6.46, P<0.0001). But no relationship was found among the methylation of sodium iodide symporter and age, gender and size of tumor. Conclusions: The methylation of sodium iodide symporter promoter is related with PTC and its aggressive and metastatic potential. Due to the limited sample size, more clinical researches should be taken in the future.
PMCID: PMC4565248  PMID: 26379865
Sodium iodide symporter; methylation; papillary thyroid carcinoma; aggressiveness; metastasis
15.  Change of Both Endocrine and Exocrine Insufficiencies After Acute Pancreatitis in Non-Diabetic Patients 
Medicine  2015;94(27):e1123.
Abstract
Acute pancreatitis (AP) is the most common pancreatic disease and consists of an acute inflammation of the pancreas. AP can contribute to endocrine and exocrine insufficiencies in survivors as a result of the key role of the pancreas in both glucose metabolism and nutritional digestion. The aim of this population-based study was to determine the endocrine or exocrine insufficiencies in patients after initial AP with biliary or alcohol-associated causes.
We conducted a nationwide cohort study using data from Taiwan's National Health Insurance Research Database collected between 2001 and 2010. A total of 12,284 patients with AP were identified.
Alcohol-associated AP (odds ratio, 1.894; 95% CI, 1.520–2.268; P < 0.001) and ≥2 admissions for AP (odds ratio, 1.937; 95% CI, 1.483–2.391; P < 0.001) were significantly associated with newly diagnosed diabetes mellitus after AP. Further, only alcohol-associated AP (odds ratio, 1.215; 95% CI, 1.133–1.297; P < 0.001) was significantly associated with pancreatic exocrine insufficiency after AP. Additionally, alcohol-associated AP (odds ratio, 1.804; 95% CI, 1.345–2.263; P < 0.001) and ≥2 readmissions for AP (odds ratio, 3.190; 95% CI, 2.317–4.063; P < 0.001) were significantly associated with both exocrine and endocrine insufficiencies after AP.
Our data showed that alcohol-associated AP, rather than a biliary cause, contributed to a higher extent to exocrine or endocrine insufficiencies. Furthermore, recurrent AP also led to endocrine insufficiency.
doi:10.1097/MD.0000000000001123
PMCID: PMC4504627  PMID: 26166112
16.  Glycemic Change After Pancreaticoduodenectomy 
Medicine  2015;94(27):e1109.
Abstract
The purpose of this population-based study was to determine the change of glucose metabolism in patients undergoing pancreaticoduodenectomy (PD).
We conducted a nationwide cohort study using data from Taiwan's National Health Insurance Research Database collected between 2000 and 2010. Our sample included 861 subjects with type 2 diabetes mellitus (DM) and 3914 subjects without DM.
Of 861 subjects with type 2 diabetes, 174 patients (20.2%) experienced resolution of their diabetes after PD, including patients with pancreatic ductal adenocarcinoma (PDAC) (20.5%), and non-PDAC (20.1%). Using a multiple logistic regression model, we found that subjects with comorbid chronic pancreatitis (odds ratio, 0.356; 95% CI, 0.167–0.759; P = 0.007) and use of insulin (odds ratio, 0.265; 95% CI, 0.171–0.412; P < 0.001) had significantly lower rates of resolution of diabetes. In the 3914 subjects without diabetes, the only statistically significant comorbidity contributing to pancreatogenic diabetes was chronic pancreatitis (odds ratio, 1.446; 95% CI, 1.146–1.823; P = 0.002).
Subjects with comorbid chronic pancreatitis and use of insulin had lower rates of resolution of DM after PD. In subjects without diabetes, chronic pancreatitis contributed significantly to the development of pancreatogenic DM.
doi:10.1097/MD.0000000000001109
PMCID: PMC4504605  PMID: 26166104
17.  Anatase TiO2 ultrathin nanobelts derived from room-temperature-synthesized titanates for fast and safe lithium storage 
Scientific Reports  2015;5:11804.
Lithium-ion batteries (LIBs) are promising energy storage devices for portable electronics, electric vehicles, and power-grid applications. It is highly desirable yet challenging to develop a simple and scalable method for constructions of sustainable materials for fast and safe LIBs. Herein, we exploit a novel and scalable route to synthesize ultrathin nanobelts of anatase TiO2, which is resource abundant and is eligible for safe anodes in LIBs. The achieved ultrathin nanobelts demonstrate outstanding performances for lithium storage because of the unique nanoarchitecture and appropriate composition. Unlike conventional alkali-hydrothermal approaches to hydrogen titanates, the present room temperature alkaline-free wet chemistry strategy guarantees the ultrathin thickness for the resultant titanate nanobelts. The anatase TiO2 ultrathin nanobelts were achieved simply by a subsequent calcination in air. The synthesis route is convenient for metal decoration and also for fabricating thin films of one/three dimensional arrays on various substrates at low temperatures, in absence of any seed layers.
doi:10.1038/srep11804
PMCID: PMC4488874  PMID: 26133276
18.  The association of APOC4 polymorphisms with premature coronary artery disease in a Chinese Han population 
Background
Hypercholesterolemia arising from abnormal lipid metabolism is one of the critical risk factors for coronary artery disease (CAD), however the roles of genetic variants in lipid metabolism-related genes on premature CAD (≤60 years old) development still require further investigation. We herein genotyped four single nucleotide polymorphisms (SNPs) in lipid metabolism-related genes (rs1132899 and rs5167 in APOC4, rs1801693 and rs7765781 in LPA), aimed to shed light on the influence of these SNPs on individual susceptibility to early-onset CAD.
Methods
Genotyping of the four SNPs (rs1132899, rs5167, rs1801693 and rs7765781) was performed in 224 premature CAD cases and 297 control subjects (≤60 years old) using polymerase chain reaction-ligation detection reaction (PCR–LDR) method. The association of these SNPs with premature CAD was performed with SPSS software.
Results
Multivariate logistic regression analysis showed that C allele (OR = 1.50, P = 0.027) and CC genotype (OR = 2.84, P = 0.022) of APOC4 rs1132899 were associated with increased premature CAD risk, while the other three SNPs had no significant effect. Further stratified analysis uncovered a more evident association with the risk of premature CAD among male subjects (C allele, OR = 1.65, and CC genotype, OR = 3.33).
Conclusions
Our data provides the first evidence that APOC4 rs1132899 polymorphism was associated with an increased risk of premature CAD in Chinese subjects, and the association was more significant among male subjects.
Electronic supplementary material
The online version of this article (doi:10.1186/s12944-015-0065-7) contains supplementary material, which is available to authorized users.
doi:10.1186/s12944-015-0065-7
PMCID: PMC4511022  PMID: 26129832
APOC4; Single nucleotide polymorphism; Premature coronary artery disease; Risk
19.  Trametinib modulates cancer multidrug resistance by targeting ABCB1 transporter 
Oncotarget  2015;6(17):15494-15509.
Overexpression of adenine triphosphate (ATP)-binding cassette (ABC) transporters is one of the main reasons of multidrug resistance (MDR) in cancer cells. Trametinib, a novel specific small-molecule mitogen-activated extracellular signal-regulated kinase (MEK) inhibitor, is currently used for the treatment of melanoma in clinic. In this study, we investigated the effect of trametinib on MDR mediated by ABC transporters. Trametinib significantly potentiated the effects of two ABCB1 substrates vincristine and doxorubicin on inhibition of growth, arrest of cell cycle and induction of apoptosis in cancer cells overexpressed ABCB1, but not ABCC1 and ABCG2. Furthermore, trametinib did not alter the sensitivity of non-ABCB1 substrate cisplatin. Mechanistically, trametinib potently blocked the drug-efflux activity of ABCB1 to increase the intracellular accumulation of rhodamine 123 and doxorubicin and stimulates the ATPase of ABCB1 without alteration of the expression of ABCB1. Importantly, trametinib remarkably enhanced the effect of vincristine against the xenografts of ABCB1-overexpressing cancer cells in nude mice. The predicted binding mode showed the hydrophobic interactions of trametinib within the large drug binding cavity of ABCB1. Consequently, our findings may have important implications for use of trametinib in combination therapy for cancer treatment.
PMCID: PMC4558166  PMID: 25915534
trametinib; multidrug resistance; ABCB1; chemotherapy
20.  Proliferation PET image to characterize pathological spatial features in patients with non-small cell lung cancer: a pilot study 
Purpose: 18F-FLT-PET imaging was proposed as a tool for measuring in vivo tumor cell proliferation and detecting sub-volumes to propose escalation in radiotherapy. The aim of this study was to validate whether high FLT uptake areas in 18F-FLT PET/CT are coincident with tumor cell proliferation distribution indicated by Ki-67 staining in non-small cell lung cancer, thus provide theoretical support for the application of dose painting guided by 18F-FLT PET/CT. Materials and methods: Twelve treatment naive patients with biopsy proven NSCLC underwent 18F-FLT PET/CT scans followed by lobectomy were enrolled. The surgical specimen was dissected into 4-7 μm sections at approximately 4-mm intervals. The best slice was sort out to complete Ki-67 staining. Maximum Ki-67 labelling Index and SUVmax of the corresponding PET image was calculated. The correlation between Ki-67 Labelling Index and SUVmax of FLT was determined using Spearman Correlation analysis. High uptake areas and high proliferating areas were delineated on the two images, respectively, and their location was compared. Results: The maximal SUV was 3.26 ± 0.97 (1.96-5.05), maximal Ki-67 labeling index was 49% ± 27.56% (5%-90%). Statistical analysis didn’t reveal a significant correlation between them (r = -0.157, P = 0.627, > 0.05). 9 patients can contour high proliferating area on Ki-67 staining slice, and eight can contour the high uptake areas. In 4 patients, we can observe a generally close distribution of high uptake areas and high proliferating areas, in one patient, both the uptake level and proliferation status was low, while the others didn’t not find a significant co-localization. Conclusion: Noninvasive 18F-FLT PET assessing the proliferative status may be a valuable aid to guide dose painting in NSCLC, but it needs to be confirmed further.
PMCID: PMC4538123  PMID: 26309653
18F-FLT PET; pathological spatial validation; non-small-cell lung cancer
21.  Inhibition of janus kinase 2 by compound AG490 suppresses the proliferation of MDA-MB-231 cells via up-regulating SARI (suppressor of AP-1, regulated by IFN) 
Objective(s):
The Janus kinase-signal transducers and activators of transcription signaling pathway (JAK/STAT pathway) play an important role in proliferation of breast cancer cells. Previous data showed that inhibition of STAT3 suppresses the growth of breast cancer cells, but the associated mechanisms are not well understood. This study aims to investigate the effect and associated mechanisms of JAK/STAT pathway inhibitor AG490 on proliferation and suppression of breast cancer cells.
Materials and Methods:
CCK-8 assay and trypan blue exclusion assay were used to investigate the cytotoxicity of AG490 to MDA-MB-231 cells. Real-time PCR was used to detect the mRNA level of SARI (suppressor of AP-1, regulated by IFN). Western blot was used to analyze the protein levels of SARI, phospho-STAT3 and total STAT3. Luciferase reporter assay was adopted to explore the mechanism of SARI mRNA upregulation.
Results:
AG490 suppressed the proliferation of MDA-MB-231 cells in a dose-dependent manner. AG490 significantly up-regulated the mRNA and protein levels of SARI in MDA-MB-231 cells. Knockdown of SARI obviously attenuated AG490-induced growth suppression effect in MDA-MB-231 cells. Furthermore, AG490 dramatically enhanced the transcription activity of SARI promoter. But the transcription activity of truncated SARI promoter, which does not contain STAT3 binding site, cannot be activated by AG490 treatment.
Conclusion:
We demonstrate in this study that AG490 suppresses the proliferation of MDA-MB-231 cells through transcriptional activation of SARI.
PMCID: PMC4509956  PMID: 26221484
AG490; MDA-MB-231; Proliferation; SARI; STAT3
22.  Clinical Efficacy Observation of Acupuncture Treatment for Nonarteritic Anterior Ischemic Optic Neuropathy 
Objective. To determine whether acupuncture treatment impacts the clinical efficacy of degenerative damage of the optic nerve caused by nonarteritic anterior ischemic optic neuropathy (NAION). Methods. 69 patients (93 eyes) with NAION who had been treated by acupuncture which is performed on different acupoints related to eyes by vertical insertion or Fingernail-pressure needle insertion. The best corrected visual acuity, mean defect (MD) and mean light sensitivity (MS) of the visual field, and latency and amplitude of pattern visual evoked potential (P-VEP) were compared before and after treatment. Results. After 2, 4, and 8 weeks of treatment, the total effective rates of visual acuity improvement were 74.19%, 78.89%, and 81.71%, respectively, and the decreased MD and increased MS were both statistically significant (P < 0.01). When compared with the situation before treatment, the average latency of the P100 wave was significantly reduced (P < 0.05), and the average amplitude was improved with no statistically significant difference (P > 0.05). Conclusions. Acupuncture treatment could obviously improve the visual function of patients with NAION and be used as complementary and alternative therapy in clinic.
doi:10.1155/2015/713218
PMCID: PMC4458289  PMID: 26089945
23.  Efficacy of radical and conservative surgery for hepatic cystic echinococcosis: a meta-analysis 
Objective: To systematically evaluate the efficacy and safety of radical surgery (RS) and conservative surgery (CS) in the treatment of hepatic cystic echinococcosis (HCE). Methods: We searched PubMed, Embase, MEDLINE, SCI, CNKI, CBM, and WanFang databases, and the Cochrane Library (2013, Issue 3) for references published before December 2013. Both randomized and non-randomized controlled trials of radical and conservative surgery for HCE were collected. After the literature was screened in accordance with inclusion and exclusion criteria, data were extracted and the quality of methodologies of selected references was determined independently by two evaluators. A meta-analysis was performed on eligible studies with RevMan 5.1 statistical software. Results: Five non-randomized controlled trials (1267 patients) were included in this study. Patients in the RS group had fewer postoperative complications compared with the CS group [OR = 0.42, 95% CI (0.32, 0.56), P < 0.00001], whereas there was no significant difference in rates of postoperative bile leakage between the two groups [OR = 0.22, 95% CI (0.05, 1.12), P = 0.07]. Postoperative follow-up of patients revealed a significantly lower HCE recurrence rate in the RS versus CS group [OR = 0.17, 95% CI (0.08, 0.38), P < 0.0001]. Additionally, no statistical differences in the number of days of hospitalization [MD = -2.47, 95% CI (-6.42, 1.49), P = 0.22] and perioperative mortality [OR = 0.87, 95% CI (0.27, 2.79), P = 0.82] were identified between groups. Conclusion: RS, especially total pericystectomy, has obvious advantages over CS: fewer complications, lower postoperative recurrence, and a lower incidence of biliary fistula and infection, making RS the preferred surgical method. This conclusion requires further validation with high-quality RCTs with large sample sizes. Surgical approach should be based upon comprehensive assessment of individual circumstances in HCE patients.
PMCID: PMC4509186  PMID: 26221241
Hepatic cystic echinococcosis; radical surgery; conservative surgery; total pericystectomy; endocystectomy
24.  Induction of autophagy contributes to crizotinib resistance in ALK-positive lung cancer 
Cancer Biology & Therapy  2014;15(5):570-577.
Use of the inhibitor of ALK fusion onco-protein, crizotinib (PF02341066), has achieved impressive clinical efficacy in patients with ALK-positive non-small cell lung cancer. Nevertheless, acquired resistance to this drug occurs inevitably in approximately a year, limiting the therapeutic benefits of this novel targeted therapy. In this study, we found that autophagy was induced in crizonitib-resistant lung cancer cells and contributed to drug resistance. We observed that ALK was downregulated in the crizotinib-resistant lung cancer cell line, H3122CR-1, and this was causally associated with autophagy induction. The degree of crizotinib resistance correlated with autophagic activity. Activation of autophagy in crizotinib-resistant H3122CR-1 cells involved alteration of the Akt/mTOR signaling pathway. Furthermore, we demonstrated that chloroquine, an inhibitor of autophagy, could restore sensitivity of H3122CR-1 to crizotinib and enhance its efficacy against drug-resistant lung cancer. Thus, modulating autophagy may be worth exploring as a new strategy to overcome acquired crizonitib resistance in ALK-positive lung cancer.
doi:10.4161/cbt.28162
PMCID: PMC4026079  PMID: 24556908
crizotinib; ALK; autophagy; drug resistance; lung cancer
25.  The NFκB inhibitor, SN50, induces differentiation of glioma stem cells and suppresses their oncogenic phenotype 
Cancer Biology & Therapy  2014;15(5):602-611.
The malignant phenotype of glioblastoma multiforme (GBM) is believed to be largely driven by glioma stem-like cells (GSCs), and targeting GSCs is now considered a promising new approach to treatment of this devastating disease. Here, we show that SN50, a cell-permeable peptide inhibitor of NFκB, induced robust differentiation of human GSCs, causing loss of their oncogenic potential. We observed that following treatment of GSCs with SN50, their differentiated progeny cells showed significant decreases in their capability to form neuro-spheres and to invade in vitro and a reduction in their tumorigenicity in mouse xenograft models, but had increased sensitivity to the chemotherapeutic drug temozolomide and to radiation treatment. These results suggest that blocking the NFκB pathway may be explored as a useful mean to induce differentiation of GSCs, and provide another supportive evidence for the promise of differentiation therapy in treatment of malignant brain tumors.
doi:10.4161/cbt.28158
PMCID: PMC4026083  PMID: 24557012
NFκB inhibitor; SN50; brain tumor; differentiation; glioma stem cells

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