Genome-wide association studies and Mendelian randomization analyses provide insights into the causes of early-onset colorectal cancer.

BACKGROUND: The incidence of early-onset colorectal cancer (EOCRC; diagnosed <50 years of age) is rising globally; however, the causes underlying this trend are largely unknown. CRC has strong genetic and environmental determinants, yet common genetic variants and causal modifiable risk factors underlying EOCRC are unknown. We conducted the first EOCRC-specific genome-wide association study (GWAS) and Mendelian randomization (MR) analyses to explore germline genetic and causal modifiable risk factors associated with EOCRC. PATIENTS AND METHODS: We conducted a GWAS meta-analysis of 6176 EOCRC cases and 65 829 controls from the Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO), the Colorectal Transdisciplinary Study (CORECT), the Colon Cancer Family Registry (CCFR), and the UK Biobank. We then used the EOCRC GWAS to investigate 28 modifiable risk factors using two-sample MR. RESULTS: We found two novel risk loci for EOCRC at 1p34.1 and 4p15.33, which were not previously associated with CRC risk. We identified a deleterious coding variant (rs36053993, G396D) at polyposis-associated DNA repair gene MUTYH (odds ratio 1.80, 95% confidence interval 1.47-2.22) but show that most of the common genetic susceptibility was from noncoding signals enriched in epigenetic markers present in gastrointestinal tract cells. We identified new EOCRC-susceptibility genes, and in addition to pathways such as transforming growth factor (TGF) ß, suppressor of Mothers Against Decapentaplegic (SMAD), bone morphogenetic protein (BMP) and phosphatidylinositol kinase (PI3K) signaling, our study highlights a role for insulin signaling and immune/infection-related pathways in EOCRC. In our MR analyses, we found novel evidence of probable causal associations for higher levels of body size and metabolic factors-such as body fat percentage, waist circumference, waist-to-hip ratio, basal metabolic rate, and fasting insulin-higher alcohol drinking, and lower education attainment with increased EOCRC risk. CONCLUSIONS: Our novel findings indicate inherited susceptibility to EOCRC and suggest modifiable lifestyle and metabolic targets that could also be used to risk-stratify individuals for personalized screening strategies or other interventions.

Effectiveness and safety of a ventricular septal occluder device for the treatment of Gastro-tracheal fistula.

BACKGROUND: Gastro-tracheal fistula (GTF) is one of the most serious complications after esophagogastrostomy and radiotherapy, with very high disability and mortality rates. To evaluate the effectiveness and safety of ventricular septal occluder devices (VSOD) for the treatment of Gastro-tracheal fistula (GTF). METHODS: From January 2020 to May 2022, 14 patients with GTF underwent VSOD under real-time fluoroscopy. The technical success, complications, quality of life (QoL), Eastern Cooperative Oncology Group (ECOG) score, Karnofsky score, and median overall survival (mOS) were recorded and analyzed. RESULTS: Technical success, and major complication rates were 71.4%, and 14.3%, respectively. Both the ECOG and the Karnofsky score showed significant improvement at the 2-month evaluation compared with the pretreatment value (p<0.05). For QoL, general health, physical function, vitality, role physical, and social function all improved at the 2-month evaluation (p<0.05), but bodily pain, role emotion, and mental health showed no significant difference (P>0.05). During the mean follow-up of 9.6 months, eight patients were alive, and the mOS was 11.4 months (95% CI, 8.5-14.3). CONCLUSIONS: VSOD is a simple and safe technique for GTF treatment, but long-term observation is needed at multiple centers to confirm our findings.

[Liver cancer treatment with mitochondrial homeostasis].

Systemic treatment, including molecular targeted therapy, immunotherapy, and chemotherapy, is an important means of achieving long-term survival in patients with intermediate-and advanced-stage liver cancer. However, some patients are insensitive to treatment and even develop drug resistance. Mitochondria are the center of cellular energy metabolism and, at the same time, are the priority targets for systemic therapy. Mitochondrial homeostasis plays an important role in the treatment of liver cancer. The relationship between the two advances is elucidated so as to provide better ideas for the clinical treatment of liver cancer.

Scanning near-field optical microscopy measurements and simulations of regularly arranged silver nanoparticles.

Silver nanoparticles on a glass substrate are experimentally investigated by aperture scanning near-field optical microscopy (a-SNOM). To understand the experimental results, finite-element-method simulations are performed building a theoretical model of the a-SNOM geometry. We systematically vary parameters like aperture size, aluminum-coating thickness, tip cone angle, and tip-surface distance and discuss their influence on the near-field enhancement. All these investigations are performed comparatively for constant-height and constant-gap scanning modes. In the end, we establish a reliable and stable optical model for simulating a-SNOM measurements, which is capable of reproducing trends observed in experimental data.

Breast cancer diagnosis and prognosis using a high b-value non-Gaussian continuous-time random-walk model.

AIM: To compare the diagnostic performance of mono-exponential model-derived apparent diffusion coefficient (ADC), continuous-time random-walk (CTRW) model-derived Dm, α, ß and their combinations in discriminating malignancy of breast lesions, and investigate the association between model-derived parameters and prognosis-related immunohistochemical indices. MATERIALS AND METHODS: A total of 85 patients with breast lesions (51 malignant, 34 benign) were analysed in this retrospective study. Clinical characteristics include oestrogen receptor (ER), progesterone receptor (PR), human epidermal receptor 2 (HER2), and Ki-67. The ADC was fitted using a mono-exponential model (b-values = 0, 800 s/mm2), while Dm, α, and ß were fitted using a CTRW model. Independent Student's t-test and the Mann-Whitney U-test were used for the comparison of parameters. Discrimination performance was accomplished by receiver operating characteristic (ROC) analysis, and Spearman's correlation analysis was used to explore the association between immunohistochemical indices and diffusion parameters, the statistical significance level was p<0.05. RESULTS: Dm and ADC demonstrated similar performance in differentiating malignant and benign lesions (AUC = 0.928 versus 0.930), while the combination of Dm, α, and ß could improve the AUC to 0.969. The combined parameter generated by ADC, Dm, α, and ß was effective in identifying the ER+/ER- and PR+/PR- patients. Temporal heterogeneity parameter α correlated significantly with the expression of PR. CONCLUSION: Diffusion parameters derived from the CTRW model could effectively discriminate the malignancy of breast lesions. Meanwhile, the hormone receptor expression could be distinguished by combined diffusion parameters, and have the potential to reflect the prognosis.

[Clinical efficacy of single/double 125I-seed strands combined with biliary stents in the treatment of malignant obstructive jaundice].

Objective: To compare the clinical efficacy of single/double 125I-seed strands combined with biliary stents in the treatment of malignant obstructive jaundice. Methods: Totally 67 cases of patients with malignant obstructive jaundice who received single/double125I-seed strands combined with biliary stents implantation from September 2018 to December 2021 were analyzed retrospectively. Among them, 36 patients received single 125I-seed strands combined with biliary stents (single strand group) and 31 patients received double 125I-seed strands combined with biliary stents(double strands group). The technical success rate, clinical success rate, complications, biochemical and tumor indexes at 8 weeks after operation [total bilirubin (TB), direct bilirubin (DB), alanine transaminase (ALT), aspartate transaminase (AST), carbohydrate antigen 19-9 (CA19-9)], stent patency time (SP), median progression-free survival time (mPFS) and median survival time (mOS) were analyzed. Results: There was no significant difference (P>0.05) in technical success rate (100% vs 100%), clinical success rate (97.2% vs 96.8%) and major complications (5.6% vs 6.5%) between single strand group and double strands group. There were significant differences in TB, DB, ALT, AST and CA19-9 indicators between the two groups before and 8 weeks after operation (all P<0.05), but there was no significant difference in the difference value of preoperative and postoperative 8-week indicators between the two groups (all P>0.05).The SP and mPFS of double-stranded stents were longer than those of single-stranded stents.[8.6 months (95%CI:6.9-10.4) vs 6.2 months (95%CI:5.8-6.6), 3.2 months (95%CI:3.0-3.4) vs 3.0 months (95%CI:2.9-3.1), all P<0.05]. The mOS of single and double strands groups was 11.2 months (95%CI:8.3-14.1) and 13.4 months (95%CI:9.9-16.9) respectively, with no statistical difference (P=0.137). Conclusion: Compared with single 125I-seed strands, double 125I-seed strands can prolong biliary SP and mPFS, but the long-term survival index still needs further observation.

[Clinical study of modified Shirodkar transvaginal cervical cerclage during pregnancy in the treatment of cervical insufficiency].

Objective: To investigate the clinical efficacy of modified Shirodkar transvaginal cervical cerclage (TVCC) in the treatment of cervical insufficiency (CI) and its impact on maternal and fetal outcomes. Methods: The clinical data of 218 pregnant women with CI admitted to Fu Xing Hospital, Capital Medical University from January 1, 2015 to August 31, 2021 was retrospectively analyzed. According to different surgical approaches, they were divided into modified Shirodkar TVCC treatment during pregnancy (TVCC group, 108 cases) and non-pregnant women underwent laparoscopic cervical cerclage (LACC) treatment (LACC group, 110 cases). The clinical data and pregnancy outcomes of the two groups were compared. Furthermore, the two groups of pregnant women were stratified according to cervical length (CL) to explore the effects of the two surgical methods on the pregnancy outcomes of CI women with different CL. Results: (1) Related indicators before and during cerclage: there were no complications such as massive hemorrhage, bladder injury and anesthesia accident in the two groups of pregnant women during cerclage. Compared with the LACC group, TVCC group had longer preoperative CL [(2.3±0.6) vs (2.7±0.6) cm], more intraoperative blood loss [(7.5±0.5) vs (14.4±1.4) ml] and longer hospital stay [(6.0±0.1) vs (7.3±0.4) day]. However, the operation time was shorter [(42.9±1.6) vs (25.9±1.4) minute] and the hospitalization cost was less [(9 912±120) vs (5 598±140) yuan], and the differences were statistically significant (all P<0.05). (2) Pregnancy outcomes: live birth rates were 95.4% (103/108) in the TVCC group and 96.4% (106/110) in the LACC group, showing no significant difference between the two groups (χ2=2.211, P=0.232). The preterm birth rate (12.0%, 13/108) in the TVCC group was higher than that in the LACC group (7.3%, 8/110), the neonatal birth weight was lower than that in the LACC group [(3 006±96) vs (3 225±42) g], and the proportion of low birth weight infants was higher than that in the LACC group [15.5% (16/103) vs 1.9% (2/106)], and the differences were statistically significant (all P<0.05). (3) Stratified analysis of CL: for pregnant women with CL<2.0 cm, the miscarriage rate of the TVCC group was higher than that of the LACC group (2/9 vs 3.0%), and the live birth rate was lower than that of the LACC group (7/9 vs 97.0%), and the differences were statistically significant (all P<0.05). For CL 2.0-<2.5 cm, 2.5-<3.0 cm, CL≥3.0 cm, there were no statistically significant differences in preterm birth rate and live birth rate between the two groups (all P>0.05). Conclusions: Modified Shirodkar TVCC is simple and easy to operate, which significantly reduces the cesarean section rate and medical cost compared with LACC, and there is no significant difference in the live birth rate. When there is inevitable late abortion, laparoscopic cerclage removal does not need to be performed again, which could reduce the second operation and is worthy of clinical application.

[Research progress on the mechanism and response strategies of molecular targeted drug resistance in liver cancer].

Molecular targeted drugs are one of the treatments for hepatocellular carcinoma (HCC), the primary factor influencing their therapeutic efficacy is drug resistance. Diminished drug intake, greater efflux, improved DNA damage repair capacity, aberrant signal pathways, hypoxia, epithelial-mesenchymal cell transition, and the cellular autophagy system are summarized herein as aspects of the drug resistance mechanism. Simultaneously, effective strategies for addressing drug resistance are elaborated, providing ideas for better clinical treatment of HCC.

[Immune function and research progress of pentraxin 3 in pulmonary infectious diseases].

Pentraxins3 (PTX3) is an acute-phase protein of the pentraxin family that is synthetized and stored in a variety of cells. As an important mediator of innate immunity, PTX3 is rapidly released during microbial invasion and inflammatory response. It promotes the recognition of pathogens by myeloid cells through regulating complement activation. Recent studies have indicated that PTX3 concentrations in peripheral blood or tissues increase rapidly after infection, and the increased level is associated with the severity of the disease. Thus, PTX3 appears to be a vital clinical biomarker in the diagnosis and prognosis of pulmonary infectious diseases.

[The mediating role of resilience between social capital at work and anxiety of medical staff].

Objective: To explore the influence of social capital at work on anxiety of medical staff, and the mediating role of resilience. Methods: From March to May 2022, a total of 201 medical staff in the Affiliated Hospital of Jining Medical University were investigated with the General Information Questionnaire, Workplace Social Capital Scale, Connor-Davidson Resilience Scale (CD-RISC-10) and Generalized Anxiety Disorder-7 (GAD-7) . K-S method was used for normdity test of econometic voriobles, and normal distribution data were represented by Mean±SD, Pearson correlation analysis and linear regression analysis were used to test correlation between variables and mediating effect, and Bootstrap method was carried out by SPSS macro program PROCESS v3.5 to verify the mediating effect. Results: The detection rate of anxiety was 59.20% (119/201) in medical staff. The scores of social capital at work (28.90±5.83) and resilience (31.55±4.98) were negatively correlated with the score of anxiety (7.20±2.06) (r=-0.338, -0.510, P<0.001) , while the score of social capital at work was positively correlated with resilience (r=0.392, P<0.001) . Workplace social capital positively predicted resilience (ß=0.392, P<0.001) , and both workplace social capital (ß=-0.222, P=0.001) and resilience at work (ß=-0.423, P<0.001) negatively predicted anxiety score. The direct effect of social capital in the workplace of medical staff on anxiety was -0.222 (95%CI: -0.349~-0.095, P=0.001) , and the indirect effect of resilience on anxiety was -0.166 (95%CI: -0.265~-0.080) . The resilience of medical staff had a partial mediating effect between workplace social capital and anxiety, which accounted for 42.78% of the total effect. Conclusion: The resilience of medical staff has a partial mediating effect between workplace social capital and anxiety. Workplace social capital can not only directly affect the anxiety of medical staff, but also indirectly affect it through resilience.

Integrin ß3 in forebrain Emx1-expressing cells regulates repetitive self-grooming and sociability in mice.

BACKGROUND: Autism spectrum disorder (ASD) is characterized by repetitive behaviors, deficits in communication, and overall impaired social interaction. Of all the integrin subunit mutations, mutations in integrin ß3 (Itgb3) may be the most closely associated with ASD. Integrin ß3 is required for normal structural plasticity of dendrites and synapses specifically in excitatory cortical and hippocampal circuitry. However, the behavioral consequences of Itgb3 function in the forebrain have not been assessed. We tested the hypothesis that behaviors that are typically abnormal in ASD-such as self-grooming and sociability behaviors-are disrupted with conditional Itgb3 loss of function in forebrain circuitry in male and female mice. METHODS: We generated male and female conditional knockouts (cKO) and conditional heterozygotes (cHET) of Itgb3 in excitatory neurons and glia that were derived from Emx1-expressing forebrain cells during development. We used several different assays to determine whether male and female cKO and cHET mice have repetitive self-grooming behaviors, anxiety-like behaviors, abnormal locomotion, compulsive-like behaviors, or abnormal social behaviors, when compared to male and female wildtype (WT) mice. RESULTS: Our findings indicate that only self-grooming and sociability are altered in cKO, but not cHET or WT mice, suggesting that Itgb3 is specifically required in forebrain Emx1-expressing cells for normal repetitive self-grooming and social behaviors. Furthermore, in cKO (but not cHET or WT), we observed an interaction effect for sex and self-grooming environment and an interaction effect for sex and sociability test chamber. LIMITATIONS: While this study demonstrated a role for forebrain Itgb3 in specific repetitive and social behaviors, it was unable to determine whether forebrain Itgb3 is required for a preference for social novelty, whether cHET are haploinsufficient with respect to repetitive self-grooming and social behaviors, or the nature of the interaction effect for sex and environment/chamber in affected behaviors of cKO. CONCLUSIONS: Together, these findings strengthen the idea that Itgb3 has a specific role in shaping forebrain circuitry that is relevant to endophenotypes of autism spectrum disorder.

Attenuation of intrinsic ageing of the skin via elimination of senescent dermal fibroblasts with senolytic drugs.

BACKGROUND: Skin ageing is caused by numerous factors that result in structural and functional changes in cutaneous components. Research has shown that senescent cells are known to accumulate in skin ageing, however, the role of senescent cells in skin ageing has not been defined. OBJECTIVES: To elucidate the role of the senescent cell in skin ageing, we evaluated the effect of known senolytic drugs on senescent dermal fibroblasts. METHODS: Primary human dermal fibroblasts (HDFs) were induced to senescence by long-term passaging, UV irradiation, and H2 O2 treatment. Cell viability was measured after treatment of ABT-263 and ABT-737 on HDFs. Young and aged hairless mice were intradermally injected with drugs or vehicle on the dorsal skin for 10 days. Skin specimens were obtained and reverse-transcription quantitative PCR, western blotting, and histological analysis were performed. RESULTS: We found that ABT-263 and ABT-737 induced selective clearance of senescent dermal fibroblasts, regardless of the method of senescence induction. Aged mouse skin treated with ABT-263 or ABT-737 showed increased collagen density, epidermal thickness, and proliferation of keratinocytes, as well as decreased senescence-associated secretory phenotypes, such as MMP-1 and IL-6. CONCLUSIONS: Taken together, our results indicate that selective clearance of senescent skin cells can attenuate and improve skin ageing phenotypes and that senolytic drugs may be of potential use as new therapeutic agents for treating ageing of the skin.

[The clinical value of oral robotic surgery in the treatment of oropharyngeal squamous cell carcinoma].

Objective: To explore the therapeutic effects of transoral robotic surgery (TORS) and traditional surgical modes in oropharyngeal squamous cell carcinoma (OPSCC). Methods: The clinicopathological data of patients with oropharyngeal squamous cell carcinoma treated at Sun Yat-sen University Cancer Center from 2010 to 2018 were retrospectively analyzed. 135 cases were treated with traditional surgery (non-TORS group), while 52 cases were treated with TORS (TORS group). The prognosis of the two groups of patients were analyzed by Kaplan-Meier method and Log rank test, the influencing factors were analyzed by Cox regression model. Results: The 2-year overall survival (OS, 94.2%) and 2-year progression-free survival (PFS, 93.8%) of patients in the TORS group were better than those in the non-TORS group (71.4% and 71.4%, respectively, P<0.05). The 2-year OS (93.3%) and 2-year PFS (92.8%) of TORS group patients in T1-2 stage were better than those of non-TORS group (73.1% and 72.8%, respectively, P<0.05). The 2-year OS (95.8%) and 2-year PFS (95.2%) of patients with stage Ⅰ to Ⅱ in the TORS group were not significantly different from those in the non-TORS group (84.1% and 83.9%, respectively, P>0.05). The 2-year OS (92.9%) and 2-year PFS rate (92.7%) of patients with stage Ⅲ to Ⅳ in the TORS group were better than those in the non-TORS group (64.7% and 63.9%, respectively, P<0.05). The 2-year OS (94.4%) of HPV-positive patients in the TORS group was not significantly different from that in the non-TORS group (83.3%, P=0.222). The 2-year OS of HPV-negative patients in the TORS group (94.1%) was significantly different from that in the non-TORS group (43.7%, P<0.001). HPV status was an independent prognostic factor (P=0.008). Conclusions: TORS has a better prognosis in the treatment of oropharyngeal squamous cell carcinoma compared with the traditional treatment methods. The patients with T1-T2 can achieve better survival benefits after TORS treatment. The HPV-positive OPSCC patients has a better prognosis than that of HPV-negative OPSCC patients, and regardless of HPV status, OPSCC patients in the TORS group could obtain a better survival prognosis.

[Retropharyngeal lymph node dissection in head and neck cancers treated with transoral robotic surgery].

Objective: To evaluate the indications, safety, feasibility, and surgical technique for patients with head and neck cancers undergoing transoral robotic retropharyngeal lymph node (RPLN) dissection. Methods: The current study enrolled 12 consecutive head and neck cancer patients (seven males and four females) who underwent transoral robotic RPLN dissection with the da Vinci surgical robotic system at the Sun Yat-sen University Cancer Center from May 2019 to July 2020. Seven patients were diagnosed as nasopharyngeal carcinoma with RPLN metastasis after initial treatments, 4 patients were diagnosed as thyroid carcinoma with RPLN metastasis after initial treatments, and one patient was diagnosed as oropharyngeal carcinoma with RPLN metastasis before initial treatments. The operation procedure and duration time, intraoperative blood loss volume and complications, nasogastric feeding tube dependence, tracheostomy dependence, postoperative complications, and hospitalization time were recorded and analyzed. Results: All patients were successfully treated by transoral robotic dissection of the metastatic RPLNs, none of which was converted to open surgery. RPLNs were completely resected in 10 patients, and partly resected in 2 patients (both were nasopharyngeal carcinoma patients). The mean number of RPLN dissected was 1.7. The operation duration time and intraoperative blood loss volume were (191.3±101.1) min and (150.0±86.6) ml, respectively. There was no severe intraoperative complication such as massive haemorrhage or adjacent organ injury during surgery. Nasogastric tube use was required in all patients with (17.1±10.6) days of dependence, while tracheotomy was performed in 8 patients with (11.6±10.7) days of dependence. The postoperative hospitalization stay was (8.5±5.7) days. Postoperative complications occurred in 4 patients, including 2 of retropharyngeal incision and 2 of dysphagia. During a follow-up of (6.5±5.1) months, disease-free progression was observed in all patients, 10 patients were disease-free survival and other 2 patients were survival with tumor burden. Conclusions: The transoral robotic RPLN dissection is safety and feasible. Compared with the traditional open surgical approach, it is less traumatic and safer, has fewer complications and good clinical application potentiality. The indications for transoral robotic RPLN dissection include thyroid carcinoma, oropharyngeal carcinoma, and some selected nasopharyngeal carcinoma and other head and neck cancers. Metastatic RPLNs from some nasopharyngeal carcinoma with incomplete capsule, unclear border and adhesion to the surrounding vessels are not suitable for transoral robotic RPLN dissection.

[Clinical and molecular pathological features of bronchopulmonary large cell neuroendocrine carcinoma].

Objective: To investigate the clinical manifestations, imaging, pathological and molecular features of bronchopulmonary large-cell neuroendocrine carcinoma (LCNEC). Methods: The clinical data of 216 LCNEC patients in the First Affiliated Hospital of Zhengzhou University from 2011 to 2021 were analyzed retrospectively. The clinical manifestations, tumor location and size, characteristics of CT images, immunohistochemical and molecular pathological features were analyzed and compared with 115 cases of mixed small cell carcinoma (M-SCLC) diagnosed in the same period. Results: Among the 216 LCNEC patients, there were 190 males and 26 females, with a median age of 65 years. The first symptoms of the patients were mainly cough (106 cases, 49.1%) and bloody sputum (48 cases, 22.2%). The median tumor length were 4.7cm, including 55 cases of nodular type (25.5%) and 161 cases of mass-forming type (74.5%). CT imaging results showed that LCNEC lesions had soft tissue density, and the proportion of slight enhancement lesions was significantly lower than that in M-SCLC group (52.3% vs 74.8%, P<0.001). In contrast, the proportion of necrosis (87.0% vs 58.3%, P<0.001) and calcification (26.9% vs 2.6%, P<0.001) in LCNEC patients was significantly higher than that in M-SCLC group. Immunohistochemical results showed that the positive rate of CK in LCNEC was significantly higher than that in M-SCLC (99.0 % vs 90.5%, P<0.05), while the positive rate of TTF-1 was significantly lower than that in M-SCLC (51.6% vs 67.0%, P<0.05). In LCNEC group, the proportion of patients with Ki-67 positive index between 50% and 80% was significantly higher than that of M-SCLC (41.2% vs 25.2%), while the proportion between 80% and 100% was lower than that of M-SCLC (51.9% vs 72.2%). There was no significant difference in the positive rates of CD56 (91.7% vs 94.6%, P=0.336), Syn (83.8% vs 84.7%, P=0.838) and CgA (54.8% vs 50.0%, P=0.632) in both tumor types. Molecular pathology results showed that frequent mutatios were TP53 (54.5%), RB1 (36.4%), KEAP1 (18.2%), MYC(18.2%), and PTEN (14.3%), and the rate of tumor mutation burden which is more than 25 mutation/Mb was 27.3%. Conclusions: LCNEC lacks specific clinical manifestations. CT imaging is powerful in distinguishing LCNEC from M-SCLC. LCNEC contains a specific mutation spectrum. Pathology combined with immunohistochemical staining is still the gold standard for LCNEC diagnosis, and the differentiation from M-SCLC mainly depends on cell size and nuclear chromatin pattern with light microscopy.

[Association of glutamate receptor metabotropic 5 polymorphisms with schizophrenia susceptibility in a Chinese Han population].

Objectives: To investigate the association of single nucleotide polymorphisms (SNP) of glutamate receptor metabotropic 5 (GRM5) gene with schizophrenia susceptibility(SZ) in a Chinese Han population. Methods: Twenty-two SNPs located in GRM5 gene in 528 paranoid SZ patients and 528 control subjects recruited from northern Henanwere analyzed. The clinical features of 267 first-episode SZ patients were assessed with the Positive and Negative Syndrome Scale (PANSS). Results: The SZ group included 264 males and 264 females, aged (27±8) years; the healthy control group had 264 males and 264 females, aged (28±8) years.The differences in the genotypic and allelic frequencies of two SNPs (rs567990 and rs12421343) were statistically significant between the SZ patients and control groups (all P<0.05). The allele frequency of rs504183 was also statistically different between the two groups (P=0.030). When the subjects were stratified by sex, the genotypic and allelic frequencies of rs12421343 in female subjects were statistically different between the SZ patients and control groups. The allele frequencies of SNPs (rs12422021, rs567990, and rs7101540) were also statisticallydifferent between the two groups (all P<0.05). Meanwhile, rs567990 AG+GG carriers had a higher risk for SZ than AA carriers in female subjects(OR=1.946, 95%CI: 1.264-2.995). In addition, the patients with different genotypes (GG, AA+AG) of rs12422021 showed statistically significant differences in PANSS total score(84.8±24.4 vs 75.3±18.6), positive (16.2±4.3 vs 14.4±4.2), excitement (12.4±5.1 vs 10.2±4.1) and cognitive impairment factor scores (15.2±6.8 vs 13.3±3.9) (all P<0.05). The patients with AC and the other two genotypes (AA and CC) of rs504183 showed statistically significant differences in PANSS negative factor score(27.4±9.9 vs 24.7±8.4 and 23.4±8.1, both P<0.05). Conclusion: The current study provides further evidence that GRM5 is associated with SZ, and suggests a putative sex difference.

[Predictive value of SYNTAX-â ¡ score on prognosis of patients with chronic total occlusion undergoing percutaneous coronary intervention].

Objective: To investigate the predictive value of SYNTAX-Ⅱ score on long term prognosis of patients diagnosed with chronic total occlusion (CTO) and received percutaneous coronary intervention (PCI). Methods: Patients undergoing CTO-PCI in Fuwai hospital from January 2010 to December 2013 were enrolled in this retrospective analysis. The SYNTAX-Ⅱ score of the patients was calculated. According to SYNTAX-Ⅱ score tertiles, patients were stratified as follows: SYNTAX-Ⅱ≤20, 2027. Primary endpoint was major adverse cardiac events (MACCE), including all-cause death, myocardial infarction, stroke and any revascularization. Secondary endpoints included stent thrombosis, heart failure and target lesion failure (TLF). Patients were followed up by outpatient visit or telephone call at 1 month, 6 months and 1 year after PCI, and annually up to 5 years. Multivariate Cox regression model was used to analyze the independent risk factors of all-cause death in patients undergoing CTO-PCI. The predictive value of SYNTAX score with SYNTAX-Ⅱ score for all-cause death was evaluated by the receiver operating characteristic (ROC) curve and the area under the curve (AUC). Results: A total of 2 391 patients with CTO and received PCI were enrolled in this study. The mean age was (57.0±10.5) years, 1 994 (83.40%) patients were male. There were 802 patients in lower tertile group (SYNTAX-Ⅱ≤20), 798 patients in intermediate group (2027). At the end of 5-year follow-up, the loss to follow-up rate of the three groups was 9.10%(73/802), 10.78%(86/798)and 8.85%(70/791), respectively. The rate of all-cause mortality (1.78% (13/729) vs. 3.65% (26/712) vs. 9.02% (65/721), P<0.001), cardiac death (1.37% (10/729) vs. 2.11% (15/712) vs. 4.85% (35/721), P<0.001), target vessel myocardial infarctions (4.25% (31/729) vs. 4.49% (32/712) vs. 7.07% (51/721), P=0.03), probable stent thrombosis (1.51% (11/729) vs. 2.81% (20/712) vs. 3.61% (26/721), P=0.04) and heart failure (1.78% (13/729) vs. 1.97% (14/712) vs. 5.41% (39/721), P<0.001) increased in proportion to increasing SYNTAX-Ⅱ score (all P<0.05). Multivariable Cox regression analysis indicated that female (HR=2.05, 95%CI 1.12-3.73, P=0.01), left ventricular ejection fraction (HR=0.97, 95%CI 0.95-1.00, P=0.05) and SYNTAX-Ⅱ score (HR=1.07, 95%CI 1.02-1.11,P=0.01) were independent predictors for all-cause mortality in patients undergoing CTO-PCI. The predicted value of the SYNTAX-Ⅱ score for all-cause death was significantly higher than the SYNTAX score (AUC 0.71 vs. 0.60, P=0.003). Conclusion: For CTO patients who underwent percutaneous coronary intervention, SYNTAX-Ⅱ score is an independent predictor for 5-year all-cause death, and SYNTAX-Ⅱ serves as an important predictor for all-cause death in these patients.

FMRP regulates the subcellular distribution of cortical dendritic spine density in a non-cell-autonomous manner.

Fragile X syndrome (FXS) is the most common form of intellectual disability that arises from the dysfunction of a single gene-Fmr1. The main neuroanatomical correlate of FXS is elevated dendritic spine density on cortical pyramidal neurons, which has been modeled in Fmr1-/Y mice. However, the cell-autonomous contribution of Fmr1 on cortical dendritic spine density has not been assessed. Even less is known about the role of Fmr1 in heterozygous female mosaic mice, which are a putative model for human Fmr1 full mutation carriers (i.e., are heterozygous for the full Fmr1-silencing mutation). In this neuroanatomical study, spine density in cortical pyramidal neurons of Fmr1+/- and Fmr1-/Y mice was studied at multiple subcellular compartments, layers, and brain regions. Spine density in Fmr1+/- mice is higher than WT but lower than Fmr1-/Y. Not all subcellular compartments in layer V Fmr1+/- and Fmr1-/Y cortical pyramidal neurons are equally affected: the apical dendrite, a key subcellular compartment, is principally affected over basal dendrites. Within apical dendrites, spine density is differentially affected across branch orders. Finally, identification of FMRP-positive and FMRP-negative neurons within Fmr1+/- permitted the study of the cell-autonomous effect of Fmr1 on spine density. Surprisingly, layer V cortical pyramidal spine density between FMRP-positive and FMRP-negative neurons does not differ, suggesting that the regulation of the primary neuroanatomical defect of FXS-elevated spine density-is non-cell-autonomous.

Prospective evaluation of dietary and lifestyle pattern indices with risk of colorectal cancer in a cohort of younger women.

BACKGROUND: Although colorectal cancer (CRC) incidence in the USA is declining overall, its incidence is increasing among those younger than 50 years of age. The reasons underlying the increasing trend are largely unknown, although behavioral changes, such as unhealthy diet and lifestyle factors, may be partially responsible. DESIGN: A prospective cohort study included 94 217 women aged 26-45 years at baseline. Validated anthropometric measures and lifestyle information were self-reported biennially. Exposures were four recommendation-based dietary indices-the prime diet quality score and three plant-based dietary indices; and two mechanism-based indices-the empirical dietary and lifestyle index for hyperinsulinemia (EDIH and ELIH). We calculated hazard ratios (HRs) and 95% confidence intervals (CIs) for overall CRC and for early-onset (before age 50) and after age 50 CRC separately. RESULTS: We documented 332 cases of CRC during 24 years of follow-up (2 113 655 person-years), with an average age of 52 ± 7 years at diagnosis. Hyperinsulinemic dietary and lifestyle patterns were associated with a higher risk of CRC. Multivariable-adjusted HRs (95% CIs) comparing participants in the highest versus lowest quartile were: 1.67 for EDIH (95% CI: 1.15-2.44, P-trend = 0.01) and 1.51 for ELIH (95% CI: 1.10-2.08, P-trend = 0.01). Moreover, per 75% increment in rank, ELIH appeared to be a stronger risk factor for early-onset CRC (HR = 1.86, 95% CI: 1.12-3.07) than after age 50 CRC (HR = 1.20, 95% CI: 0.83-1.73, P-heterogeneity = 0.16). The four recommendation-based indices were not significantly associated with overall, early-onset, or after age 50 CRC risk (per 75% increment in rank, HRs ranged from 0.75 to 1.28). CONCLUSION: Dietary and lifestyle patterns contributing to hyperinsulinemia were associated with greater CRC risk in younger women. Moreover, the hyperinsulinemic lifestyle showed a suggestively stronger positive association with early-onset CRC risk, compared with after age 50 CRC. Our findings suggest that dietary and lifestyle interventions to reduce insulinemic potential may be effective for CRC prevention among younger women.

Robust Surface States and Coherence Phenomena in Magnetically Alloyed SmB_{6}.

Samarium hexaboride is a candidate for the topological Kondo insulator state, in which Kondo coherence is predicted to give rise to an insulating gap spanned by topological surface states. Here we investigate the surface and bulk electronic properties of magnetically alloyed Sm_{1-x}M_{x}B_{6} (M=Ce, Eu), using angle-resolved photoemission spectroscopy and complementary characterization techniques. Remarkably, topologically nontrivial bulk and surface band structures are found to persist in highly modified samples with up to 30% Sm substitution and with an antiferromagnetic ground state in the case of Eu doping. The results are interpreted in terms of a hierarchy of energy scales, in which surface state emergence is linked to the formation of a direct Kondo gap, while low-temperature transport trends depend on the indirect gap.