[Relationship between preoperative inflammatory indexes and prognosis of patients with rectal cancer and establishment of prognostic nomogram prediction model].

Objective: To compare the prognostic evaluation value of preoperative neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), lymphocyte-to-monocyte ratio (LMR), and systemic immune-inflammation index (SII) in rectal cancer patients. Nomogram survival prediction model based on inflammatory markers was constructed. Methods: The clinical and survival data of 585 patients with rectal cancer who underwent radical resection in the First Affiliated Hospital of Xi'an Jiao tong University from January 2013 to December 2016 were retrospectively analyzed. The optimal cut-off values of NLR, PLR, LMR, and SII were determined by the receiver operating characteristic (ROC) curve. The relationship between different NLR, PLR, LMR and SII levels and the clinic pathological characteristics of the rectal cancer patients were compared. Cox proportional risk model was used for univariate and multivariate regression analysis. Nomogram prediction models of overall survival (OS) and disease-free survival (DFS) of patients with rectal cancer were established by the R Language software. The internal validation and accuracy of the nomograms were determined by the calculation of concordance index (C-index). Calibration curve was used to evaluate nomograms' efficiency. Results: The optimal cut-off values of preoperative NLR, PLR, LMR and SII of OS for rectal cancer patients were 2.44, 134.88, 4.70 and 354.18, respectively. There was statistically significant difference in tumor differentiation degree between the low NLR group and the high NLR group (P<0.05), and there were statistically significant differences in T stage, N stage, TNM stage, tumor differentiation degree and preoperative carcinoembryonic antigen (CEA) level between the low PLR group and the high PLR group (P<0.05). There was statistically significant difference in tumor differentiation degree between the low LMR group and the high LMR group (P<0.05), and there were statistically significant differences in T stage, N stage, TNM stage, tumor differentiation degree and preoperative CEA level between the low SII group and the high SII group (P<0.05). The multivariate Cox regression analysis showed that the age (HR=2.221, 95%CI: 1.526-3.231), TNM stage (Ⅲ grade: HR=4.425, 95%CI: 1.848-10.596), grade of differentiation (HR=1.630, 95%CI: 1.074-2.474), SII level (HR=2.949, 95%CI: 1.799-4.835), and postoperative chemoradiotherapy (HR=2.123, 95%CI: 1.506-2.992) were independent risk factors for the OS of patients with rectal cancer. The age (HR=2.107, 95%CI: 1.535-2.893), TNM stage (Ⅲ grade, HR=2.850, 95%CI: 1.430-5.680), grade of differentiation (HR=1.681, 95%CI: 1.150-2.457), SII level (HR=2.309, 95%CI: 1.546-3.447), and postoperative chemoradiotherapy (HR=1.837, 95%CI: 1.369-2.464) were independent risk factors of the DFS of patients with rectal cancer. According to the OS and DFS nomograms predict models of rectal cancer patients established by multivariate COX regression analysis, the C-index were 0.786 and 0.746, respectively. The calibration curve of the nomograms showed high consistence of predict and actual curves. Conclusions: Preoperative NLR, PLR, LMR and SII levels are all correlated with the prognosis of rectal cancer patients, and the SII level is an independent prognostic risk factor for patients with rectal cancer. Preoperative SII level can complement with the age, TNM stage, differentiation degree and postoperative adjuvant chemoradiotherapy to accurately predict the prognosis of rectal cancer patients, which can provide reference and help for clinical decision.

Clinical calculator predictive of chemotherapy benefit in stage 1A uterine papillary serous cancers.

OBJECTIVE: Determine the utility of a clinical calculator to predict the benefit of chemotherapy in stage IA uterine papillary serous cancer (UPSC). PATIENTS AND METHODS: Data were collected from NCDB from years 2010-2014. Based on demographic and surgical characteristics, a clinical score was developed using the random survival forest machine learning algorithm. RESULTS: Of 1,751 patients with stage IA UPSC, 1,012 (58%) received chemotherapy and 739 (42%) did not. Older age (HR 1.06), comorbidities (HR 1.31), larger tumor size (HR 1.27), lymphovascular invasion (HR 1.86), positive peritoneal cytology (HR 2.62), no pelvic lymph node dissection (HR 1.51), and no chemotherapy (HR 2.16) were associated with poorer prognosis. Compared to no chemotherapy, patients who underwent chemotherapy had a 5-year overall survival of 80% vs. 67%. To better delineate those who may derive more benefit from chemotherapy, we designed a clinical calculator capable of dividing patients into low, moderate, and high-risk groups with associated 5-year OS of 86%, 73%, and 53%, respectively. Using the calculator to assess the relative benefit of chemotherapy in each risk group, chemotherapy improved the 5-year OS in the high (42% to 64%; p < 0.001) and moderate risk group (66% to 79%; p < 0.001) but did not benefit the low risk group (84% to 87%; p = 0.29). CONCLUSION: Our results suggest a clinical calculator is useful for counseling and personalizing chemotherapy for stage IA UPSC.

Prevalence of obesity was related to HLA-DQ in 2-4-year-old children at genetic risk for type 1 diabetes.

OBJECTIVES: Body size is postulated to modulate type 1 diabetes as either a trigger of islet autoimmunity or an accelerator to clinical onset after seroconversion. As overweight and obesity continue to rise among children, the aim of this study was to determine whether human leukocyte antigen DQ (HLA-DQ) genotypes may be related to body size among children genetically at risk for type 1 diabetes. METHODS: Repeated measures of weight and height were collected from 5969 children 2-4 years of age enrolled in The Environmental Determinants of Diabetes in the Young prospective study. Overweight and obesity was determined by the International Obesity Task Force cutoff values that correspond to body mass index (BMI) of 25 and 30 kg m(-)(2) at age 18. RESULTS: The average BMI was comparable across specific HLA genotypes at every age point. The proportion of overweight was not different by HL A, but percent obesity varied by age with a decreasing trend among DQ2/8 carriers (P for trend=0.0315). A multivariable regression model suggested DQ2/2 was associated with higher obesity risk at age 4 (odds ratio, 2.41; 95% confidence interval, 1.21-4.80) after adjusting for the development of islet autoantibody and/or type 1 diabetes. CONCLUSIONS: The HLA-DQ2/2 genotype may predispose to obesity among 2-4-year-old children with genetic risk for type 1 diabetes.

Next-generation sequencing for viruses in children with rapid-onset type 1 diabetes.

AIMS/HYPOTHESIS: Viruses are candidate causative agents in the pathogenesis of autoimmune (type 1) diabetes. We hypothesised that children with a rapid onset of type 1 diabetes may have been exposed to such agents shortly before the initiation of islet autoimmunity, possibly at high dose, and thus study of these children could help identify viruses involved in the development of autoimmune diabetes. METHODS: We used next-generation sequencing to search for viruses in plasma samples and examined the history of infection and fever in children enrolled in The Environmental Determinants of Diabetes in the Young (TEDDY) study who progressed to type 1 diabetes within 6 months from the appearance of islet autoimmunity, and in matched islet-autoantibody-negative controls. RESULTS: Viruses were not detected more frequently in plasma from rapid-onset patients than in controls during the period surrounding seroconversion. In addition, infection histories were found to be similar between children with rapid-onset diabetes and control children, although episodes of fever were reported less frequently in children with rapid-onset diabetes. CONCLUSIONS/INTERPRETATION: These findings do not support the presence of viraemia around the time of seroconversion in young children with rapid-onset type 1 diabetes.

Confirmation of novel type 1 diabetes risk loci in families.

AIMS/HYPOTHESIS: Over 50 regions of the genome have been associated with type 1 diabetes risk, mainly using large case/control collections. In a recent genome-wide association (GWA) study, 18 novel susceptibility loci were identified and replicated, including replication evidence from 2,319 families. Here, we, the Type 1 Diabetes Genetics Consortium (T1DGC), aimed to exclude the possibility that any of the 18 loci were false-positives due to population stratification by significantly increasing the statistical power of our family study. METHODS: We genotyped the most disease-predicting single-nucleotide polymorphisms at the 18 susceptibility loci in 3,108 families and used existing genotype data for 2,319 families from the original study, providing 7,013 parent-child trios for analysis. We tested for association using the transmission disequilibrium test. RESULTS: Seventeen of the 18 susceptibility loci reached nominal levels of significance (p < 0.05) in the expanded family collection, with 14q24.1 just falling short (p = 0.055). When we allowed for multiple testing, ten of the 17 nominally significant loci reached the required level of significance (p < 2.8 × 10(-3)). All susceptibility loci had consistent direction of effects with the original study. CONCLUSIONS/INTERPRETATION: The results for the novel GWA study-identified loci are genuine and not due to population stratification. The next step, namely correlation of the most disease-associated genotypes with phenotypes, such as RNA and protein expression analyses for the candidate genes within or near each of the susceptibility regions, can now proceed.

[Fkbp38 deletion induces premature ovarian insufficiency in mice by activating mTOR signaling and inducing granulosa cell apoptosis].

OBJECTIVE: To investigate the role of tacrolimus-binding protein 38 (FKBP38) in follicle development and the mechanism by which Fkbp38 gene deletion causes premature ovarian insufficiency (POI). METHODS: The Cre-loxp system was used to construct oocyte-specific Fkbp38 knockout transgenic mice. The genotype of the transgenic mice was identified using PCR, and the expression of FKBP38 in the oocytes was verified. The numbers of primordial follicles, primary follicles, secondary follicles and antral follicles in Fkbp38 knockout mice and non-transgenic littermate control mice were counted with HE staining under a microscope for analyzing the effect of Fkbp38 deletion on follicular development. The fertility and serum sex hormone levels of the mice were determined by reproduction experiments and ELISA to assess ovarian function. Ovarian granulosa cell apoptosis of the mice was assessed using TUNEL assay. The activity of the downstream target protein of phosphorylated ribosomal S6 (PS6) of mTOR signaling pathway was detected, and the expressions of BCL-2 and BAX proteins were determined using immunofluorescence assay for assessing oocyte development in the mice. RESULTS: The oocyte-specific Fkbp38 knockout transgenic mouse model was successfully constructed, which showed decreased fertility, disordered sex hormone levels, and significantly reduced primordial follicles, primary follicles and secondary follicles in the ovary (P < 0.05), demonstrating POI-like changes. Compared with the control mice, oocyte-specific Fkbp38 knockout caused activation of the mTOR signaling pathway, significantly increased apoptosis of the granulosa cells, and obviously increased the BAX/BCL- 2 ratio by increasing BAX expression and reducing BCL-2 expression in the oocytes (P < 0.05). CONCLUSION: FKBP38 plays an important role in follicle development, and Fkbp38 gene deletion in mice causes POI possibly by activating the mTOR signaling pathway and inducing granulosa cell apoptosis.

Association between type 1 diabetes and GWAS SNPs in the southeast US Caucasian population.

The present study was conducted to assess genetic associations for type 1 diabetes (T1D) reported in previous genome-wide association studies (GWAS). A total of 21 previously reported single-nucleotide polymorphisms (SNPs) were genotyped by TaqMan assays in 1434 Caucasian T1D patients and 1864 normal controls from Georgia. Analysis of the samples identified 18 SNPs (PTPN22, INS, IFIH1, SH2B3, ERBB3, CTLA4, C14orf181, CTSH, CLEC16A, CD69, ITPR3, C6orf173, SKAP2, PRKCQ, RNLS, IL27, SIRPG and CTRB2) with putative association.

Proximity of the superconducting dome and the quantum critical point in the two-dimensional Hubbard model.

We use the dynamical cluster approximation to understand the proximity of the superconducting dome to the quantum critical point in the two-dimensional Hubbard model. In a BCS formalism, T(c) may be enhanced through an increase in the d-wave pairing interaction (V(d)) or the bare pairing susceptibility (χ(0d)). At optimal doping, where V(d) is revealed to be featureless, we find a power-law behavior of χ(0d)(ω=0), replacing the BCS log, and strongly enhanced T(c). We suggest experiments to verify our predictions.

Essential and partially overlapping role of CD3gamma and CD3delta for development of alphabeta and gammadelta T lymphocytes.

CD3gamma and CD3delta are two highly related components of the T cell receptor (TCR)-CD3 complex which is essential for the assembly and signal transduction of the T cell receptor on mature T cells. In gene knockout mice deficient in either CD3delta or CD3gamma, early thymic development mediated by pre-TCR was either undisturbed or severely blocked, respectively, and small numbers of TCR-alphabeta+ T cells were detected in the periphery of both mice. gammadelta T cell development was either normal in CD3delta-/- mice or partially blocked in CD3gamma-/- mice. To examine the collective role of CD3gamma and CD3delta in the assembly and function of pre-TCR and in the development of gammadelta T cells, we generated a mouse strain with a disruption in both CD3gamma and CD3delta genes (CD3gammadelta-/-). In contrast to mice deficient in either CD3gamma or CD3delta chains, early thymic development mediated by pre-TCR is completely blocked, and TCR-alphabeta+ or TCR-gammadelta+ T cells were absent in the CD3gammadelta-/- mice. Taken together, these studies demonstrated that CD3gamma and CD3delta play an essential, yet partially overlapping, role in the development of both alphabeta and gammadelta T cell lineages.

Stress failure plays a major role in the development of high-altitude pulmonary oedema in rats.

Hypoxia and exertion are considered as the two main factors in the development of high-altitude pulmonary oedema (HAPE), however its pathophysiology remains unclear. Therefore, we established a model in which 32 Sprague-Dawley rats were randomly assigned to normoxic rest, hypoxic rest, normoxic exercise and hypoxic exercise. An altitude of 4,700 m was simulated using hypobaric hypoxia, while exercise consisted 48 h walk with 15-20 min breaks every 4 h. Arterial blood gas, bronchoalveolar lavage (BAL), lung wet-to-dry weight (W/D) ratio and histological measurements were conducted on each animal. In rats exercising in hypoxia, BAL protein and lung W/D ratio were significantly increased but no changes in BAL leukotriene B(4) and immunoglobulin M were observed. In the same group, lung histology showed typical haemorrhagic lung oedema and disruption of both alveolar epithelium and capillary endothelium while hypoxia or exertion alone only induced slight endothelium and epithelium swelling/disruption. Our study established a direct link between histological and physiological evidence of HAPE-like symptoms and we demonstrated that hypoxia and exertion can synergistically induce HAPE-like symptoms in Sprague-Dawley rats without inducing lung inflammation. We therefore propose that alveolar epithelium and capillary endothelium stress failure play a major role in the development of HAPE.

Piperine, a functional food alkaloid, exhibits inhibitory potential against TNBS-induced colitis via the inhibition of IκB-α/NF-κB and induces tight junction protein (claudin-1, occludin, and ZO-1) signaling pathway in experimental mice.

BACKGROUND: Inflammatory bowel disease is a chronic immunoinflammatory disease of the gastrointestinal tract. Piperine, an alkaloid, has been reported to possess antioxidant, anti-inflammatory, antiapoptotic, and antiulcer potential. AIM: To elucidate the plausible mechanisms of action of piperine on experimental trinitrobenzenesufonic acid (TNBS)-induced colitis by assessing various biochemical, molecular, histological, and ultrastructural modifications. METHODS: Colitis was induced in male Sprague-Dawley rats via intrarectal instillation of TNBS. Then, the rats were treated with piperine (10, 20, and 40 mg/kg, p.o.) for 14 days. RESULTS: TNBS induced significant (p < 0.05) colonic damage, which was assessed by disease activity index, macroscopic score, and stool consistency. The administration of piperine (20 and 40 mg/kg) significantly inhibited (p < 0.05) these damages. Treatments with piperine (20 and 40 mg/kg) notably inhibited (p < 0.05) the TNBS-induced elevation of oxido-nitrosative stress (superoxide dismutase, glutathione, malondialdehyde, and nitric oxide), 5-hydroxytryptamine, and hydroxyproline content in the colon. Furthermore, colonic inducible nitric oxide synthase (iNOs), tumor necrosis factor-alpha (TNF-α), interleukin (IL)-1ß, IL-6, interferon-gamma, and cyclooxygenase-2 (COX-2) messenger RNA (mRNA) expressions were upregulated after TNBS instillation and piperine (20 and 40 mg/kg) significantly attenuated (p < 0.05) these elevated mRNA expressions. TNBS decreased the expressions of tight junction (TJ) protein (claudin-1, occludin, and zonula occludens-1 (ZO-1)) and increased the expressions of proapoptotic (caspase-1) protein. These expressions were markedly inhibited (p < 0.05) by piperine treatment. Histological and ultrastructural studies of transmission electron microscopy suggested that piperine significantly ameliorated (p < 0.05) TNBS-induced colonic aberrations. CONCLUSION: Piperine ameliorated the progression of TNBS-induced colitis by modulating the nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor-alpha/nuclear factor-kappa B signaling pathway, thus inhibiting the overexpression of proinflammatory cytokines (TNF-α and IL's), COX-2, iNOs, oxido-nitrosative stress, and proapoptotic proteins (caspase-1) that may improve the expression of TJ protein (claudin-1, occludin, and ZO-1).

[Short-term efficacy of robotic-assisted total mesorectal excision with and without lateral lymph node dissection for mid-low advanced rectal cancer: a propensity score matching analysis].

Objective: To evaluate the feasibility, safety and efficacy of robotic-assisted lateral lymph node dissection for mid-low advanced rectal cancer. Methods: A retrospective cohort study was performed. Inclusion criteria: (1) age between 18 and 80 years old; (2) rectal adenocarcinoma diagnosed by pathology; (3) without distant metastasis by preoperative CT or MRI; (4) patients underwent robotic-assisted total mesorectal resection (TME). Exclusion criteria: (1) conversion to open surgery; (2) multiple primary tumors; (3) patients underwent combined multiple organ resection. According to the above criteria, 137 patients undergoing robotic-assisted mid-low rectal cancer resection in the First Affiliated Hospital of Xi'an Jiaotong University from December 2016 to April 2019 were enrolled. Ninety-seven cases underwent robotic-assisted total mesorectal excision (TME group) and 40 underwent robotic-assisted total mesorectal resection with lateral lymph node dissection (LLND) (TME+LLND group, pelvic LLND was performed with neurovascular guidance to retain pelvic autonomic nerves in the order of the left side the first and then the right side). The propensity score matching of 1:1 was performed with R software, based on age, sex, BMI, ASA classification, distance from tumor to the anal verge, preoperative chemoradiotherapy history, preoperative abdominal surgery history, the size of tumors and TNM stage. The operative indicators, postoperative recovery, pathology and postoperative complications within 30 days were compared between the two groups. Results: A total of 72 cases were successfully matched (36 in each group), and there were no statistically significant differences in baseline data between the two groups (all P>0.05). The operation time of TME+LLND group was significantly longer than that of TME group [275.0 (180-405) minutes vs. 220.0 (140-320) minutes, Z=-3.680, P<0.001], while there were no statistically significant differences in blood loss during operation, time to postoperative first flatus, postoperative hospital stay, total hospital cost, tumor differentiation, and distal resection length of margin (all P>0.05). Circumferential resection margin was all negative in both groups. The number of harvested lymph modes in the TME+LLND groups was higher than that in the TME group [26 (18-37) vs. 14 (9-36), Z=-6.407, P<0.001]. In addition, there were no statistically significant differences in postoperative morbidity and Clavien-Dindo classification of complication within 30 days between the two groups (both P>0.05). Conclusions: Although robotic lateral lymph node dissection requires longer operation time, it is a feasible, safe and effective procedure.

Analyses of multiple single-nucleotide polymorphisms in the SUMO4/IDDM5 region in affected sib-pair families with type I diabetes.

Previous studies suggested that the SUMO4 gene, located in the IDDM5 interval on chromosome 6q25, was associated with type I diabetes (T1D) and several other autoimmune diseases. Subsequent analyses of the SUMO4 variants with T1D suggested that the association was stronger and more consistent in the Asian populations. In addition, considerable heterogeneity has been observed in the Caucasian populations. In this report, a 40-kb genomic interval including the SUMO4 gene was tagged with 15 single-nucleotide polymorphisms. A total of 2317 affected sib-pair families from the Type I Diabetes Genetic Consortium were genotyped using both the Illumina and Sequenom genotyping platforms. In these Caucasian families, we found little evidence supporting an association between SUMO4 and T1D.

rs2476601 T allele (R620W) defines high-risk PTPN22 type I diabetes-associated haplotypes with preliminary evidence for an additional protective haplotype.

Protein tyrosine phosphatase non-receptor type 22 (PTPN22) is the third major locus affecting risk of type I diabetes (T1D), after HLA-DR/DQ and INS. The most associated single-nucleotide polymorphism (SNP), rs2476601, has a C->T variant and results in an arginine (R) to tryptophan (W) amino acid change at position 620. To assess whether this, or other specific variants, are responsible for T1D risk, the Type I Diabetes Genetics Consortium analyzed 28 PTPN22 SNPs in 2295 affected sib-pair (ASP) families. Transmission Disequilibrium Test analyses of haplotypes revealed that all three haplotypes with a T allele at rs2476601 were overtransmitted to affected children, and two of these three haplotypes showed statistically significant overtransmission (P=0.003 to P=5.9E-12). Another haplotype had decreased transmission to affected children (P=3.5E-05). All haplotypes containing the rs2476601 T allele were identical for all SNPs across PTPN22 and only varied at centromeric SNPs. When considering rs2476601 'C' founder chromosomes, a second haplotype (AGGGGC) centromeric of PTPN22 in the C1orf178 region was associated with protection from T1D (odds ratio=0.81, P=0.0005). This novel finding requires replication in independent populations. We conclude the major association of PTPN22 with T1D is likely due to the recognized non-synonymous SNP rs2476601 (R620W).

Damages of screen-printed carbon nanotube cold cathode during the field emission process.

The field emission properties of the screen-printed carbon nanotube (CNT) composite cathode have close relationship with its microstructure. In this study, carbon nanotube composite cold cathode with ZnO nano-particles as binding material was prepared using screen-printing method. Electric field cycles were used to post-treat the carbon nanotube composite cold cathode. During the process of electric field cycle treatment, obvious heat-induced damages were observed from the cathode. Scanning electron microscope and transmission electron microscope were employed to analyze the morphology and microstructure of the cathode. The possible mechanisms responsible for damages were discussed.

Achieving uniform field emission from carbon nanotube composite cold cathode with different carbon nanotube contents: effects of conductance and plasma treatment.

A carbon nanotube (CNT) composite cold cathode was studied for field emission display application. The CNT composite cold cathode was composed of CNTs and silicon dioxide binder. Field emission from CNT composite cold cathode with different CNT contents was studied. It was found that with increase in CNT contents, the threshold field decreased. The conductance of the composite cathode was measured and with increasing CNT content, there was a critical CNT content where the conductance increased several orders of magnitude. Plasma etching using SF(6) as the etchant was adopted to treat the cathode. Improvement in emission uniformity was achieved. It was also found that after post-treatment the threshold field of the cathode decreased. The morphology of the etched cathode was analyzed and the improvement of uniformity and lowering of the threshold field was attributed to the exposure of CNTs after etching.

Fabrication and field emission properties of boron nanowire bundles.

We have successfully synthesized large-scale crystalline boron nanowire bundles (BNBs) by chemical vapor deposition method. Fe(3)O(4) nanoparticles were used as catalysts spreading on ceramic substrate during the reaction process. The bundles consisted of many thin boron nanowires with a mean diameter of about 25nm and a length of several micrometers. In addition, boron nanowires are single crystals with an alpha-tetragonal structure and grow along [001] orientation. These nanowires have a surface electron affinity of 3.76eV and a work function of 4.54eV. A turn-on field of 5.1V/mum and a threshold field of 10.5V/mum were found in the nanowire bundles, and stable field emission was recorded at the same time.