Survival outcomes of stage I colorectal cancer: development and validation of the ACEPLY model using two prospective cohorts.

BACKGROUND: Approximately 10% of stage I colorectal cancer (CRC) patients experience unfavorable clinical outcomes after surgery. However, little is known about the subset of stage I patients who are predisposed to high risk of recurrence or death. Previous evidence was limited by small sample sizes and lack of validation. METHODS: We aimed to identify early indicators and develop a risk stratification model to inform prognosis of stage I patients by employing two large prospective cohorts. Prognostic factors for stage II tumors, including T stage, number of nodes examined, preoperative carcinoma embryonic antigen (CEA), lymphovascular invasion, perineural invasion (PNI), and tumor grade were investigated in the discovery cohort, and significant findings were further validated in the other cohort. We adopted disease-free survival (DFS) as the primary outcome for maximum statistical power and recurrence rate and overall survival (OS) as secondary outcomes. Hazard ratios (HRs) were estimated from Cox proportional hazard models, which were subsequently utilized to develop a multivariable model to predict DFS. Predictive performance was assessed in relation to discrimination, calibration and net benefit. RESULTS: A total of 728 and 413 patients were included for discovery and validation. Overall, 6.7% and 4.1% of the patients developed recurrences during follow-up. We identified consistent significant effects of PNI and higher preoperative CEA on inferior DFS in both the discovery (PNI: HR = 4.26, 95% CI: 1.70-10.67, p = 0.002; CEA: HR = 1.46, 95% CI: 1.13-1.87, p = 0.003) and the validation analysis (PNI: HR = 3.31, 95% CI: 1.01-10.89, p = 0.049; CEA: HR = 1.58, 95% CI: 1.10-2.28, p = 0.014). They were also significantly associated with recurrence rate. Age at diagnosis was a prominent determinant of OS. A prediction model on DFS using Age at diagnosis, CEA, PNI, and number of LYmph nodes examined (ACEPLY) showed significant discriminative performance (C-index: 0.69, 95% CI:0.60-0.77) in the external validation cohort. Decision curve analysis demonstrated added clinical benefit of applying the model for risk stratification. CONCLUSIONS: PNI and preoperative CEA are useful indicators for inferior survival outcomes of stage I CRC. Identification of stage I patients at high risk of recurrence is feasible using the ACEPLY model, although the predictive performance is yet to be improved.

The effect of O-antigen length determinant wzz on the immunogenicity of Salmonella Typhimurium for Escherichia coli O2 O-polysaccharides delivery.

Attenuated Salmonella Typhimurium is a promising antigen delivery system for live vaccines such as polysaccharides. The length of polysaccharides is a well-known key factor in modulating the immune response induced by glycoconjugates. However, the relationship between the length of Lipopolysaccharide (LPS) O-antigen (OAg) and the immunogenicity of S. Typhimurium remains unclear. In this study, we assessed the effect of OAg length determined by wzzST on Salmonella colonization, cell membrane permeability, antimicrobial activity, and immunogenicity by comparing the S. Typhimurium wild-type ATCC14028 strain to those with various OAg lengths of the ΔwzzST mutant and ΔwzzST::wzzECO2. The analysis of the OAg length distribution revealed that, except for the very long OAg, the short OAg length of 2-7 repeat units (RUs) was obtained from the ΔwzzST mutant, the intermediate OAg length of 13-21 RUs was gained from ΔwzzST::wzzECO2, and the long OAg length of over 20 RUs was gained from the wild-type. In addition, we found that the OAg length affected Salmonella colonization, cell permeability, and antibiotic resistance. Immunization of mice revealed that shortening the OAg length by altering wzzST had an effect on serum bactericidal ability, complement deposition, and humoral immune response. S. Typhimurium mutant strain ΔwzzST::wzzECO2 possessed good immunogenicity and was the optimum option for delivering E. coli O2 O-polysaccharides. Furthermore, the attenuated strain ATCC14028 ΔasdΔcrpΔcyaΔrfbPΔwzzST::wzzECO2-delivered E. coli O2 OAg gene cluster outperforms the ATCC14028 ΔasdΔcrpΔcyaΔrfbP in terms of IgG eliciting, cytokine expression, and immune protection in chickens. This study sheds light on the role of OAg length in Salmonella characteristics, which may have a potential application in optimizing the efficacy of delivered polysaccharide vaccines.

Prognostic value of nucleotyping, DNA ploidy and stroma in high-risk stage II colon cancer.

BACKGROUND: Heterogeneity with respect to recurrence and survival in high-risk stage II colon cancer patients still exists, and further classification is urgently required. This study aimed to ascertain the prognostic value of DNA ploidy, stroma-tumour fraction and nucleotyping in the prognosis of high-risk stage II colon cancer. METHODS: A total of 188 high-risk stage II colon cancer patients received radical surgery in Peking University Cancer Hospital, from 2009 to 2015. Status of mismatch repair proteins in tumours was analysed using immunohistochemistry. DNA ploidy, stroma-tumour fraction and nucleotyping were estimated by automated digital imaging systems. RESULTS: Nucleotyping and DNA ploidy were significant prognostic factors, while stroma-tumour fraction were not significantly prognostic in the univariate analysis. In the multivariable model, the dominant contributory factor of disease-free survival was chromatin heterogeneous vs. chromatin homogeneous [HR 3.309 (95% CI: 1.668-6.564), P = 0.001]. CONCLUSIONS: Our study indicates that nucleotyping is an independent prognostic factor in high-risk stage II colon cancer. Therefore, it may help subdivide patients into different subgroups and give them different strategies for follow-up and treatment in the future.

Clinical Decision Support for High-Risk Stage II Colon Cancer: A Real-World Study of Treatment Concordance and Survival.

BACKGROUND: Prognostic and pathologic risk factors typically guide clinicians and patients in their choice of surveillance or adjuvant chemotherapy when managing high-risk stage II colon cancer. However, variations in treatment and outcomes in patients with stage II colon cancer remain. OBJECTIVE: This study aimed to assess the survival benefits of treatments concordant with suggested therapeutic options from Watson for Oncology, a clinical decision support system. DESIGN: This is a retrospective observational study of concordance between actual treatment and Watson for Oncology therapeutic options. SETTING: This study was conducted at a top-tier cancer center in China. PATIENTS: Postoperative treatment data were retrieved from the electronic health records of 306 patients with high-risk stage II colon adenocarcinoma. MAIN OUTCOME MEASURES: The primary outcomes measured were the treatment patterns plus 3- and 5-year overall and disease-free survival for concordant and nonconcordant cases. RESULTS: Overall concordance was 90%. Most nonconcordant care resulted from adjuvant chemotherapy use (rather than surveillance) in patients with high-level microsatellite instability and ≥70 years old. No difference in overall survival (p = 0.56) or disease-free survival (p = 0.19) was observed between concordance groups. Patients receiving adjuvant chemotherapy had significantly higher 5-year overall survival than those undergoing surveillance (94% vs 84%, p = 0.01). LIMITATIONS: This study was limited by the use of retrospective cases drawn from patients presenting for surgery, the lack of complete follow-up data for 58% of patients who could not be included in the analysis, and a survival analysis that assumes no unmeasured correlation between survival and censoring. CONCLUSIONS: Watson for Oncology produced therapeutic options highly concordant with human decisions at a top-tier cancer center in China. Treatment patterns suggest that Watson for Oncology may be able to guide clinicians to minimize overtreatment of patients with high-risk stage II colon cancer with chemotherapy. Survival analyses suggest the need for further investigation to specifically assess the association between surveillance, single-agent and multiagent chemotherapy, and survival outcomes in this population. See Video Abstract at http://links.lww.com/DCR/B291. APOYO A LA DECISIÓN CLÍNICA DEL CÁNCER DE COLON EN ESTADIO II DE ALTO RIESGO: UN ESTUDIO DEL MUNDO REAL SOBRE LA CONCORDANCIA DEL TRATAMIENTO Y LA SUPERVIVENCIA: Los factores de riesgo pronósticos y patológicos generalmente guían a los médicos y pacientes en su elección de vigilancia o quimioterapia adyuvante cuando se trata el cáncer de colon en estadio II de alto riesgo. Sin embargo, las variaciones en el tratamiento y los resultados en pacientes con cáncer de colon en estadio II permanecen.Evaluar los beneficios de supervivencia de los tratamientos concordantes con las opciones terapéuticas sugeridas por "Watson for Oncology" (Watson para la oncología), un sistema de apoyo a la decisión clínica.Estudio observacional retrospectivo de concordancia entre el tratamiento real y las opciones terapéuticas de Watson para oncología.Un centro oncológico de primer nivel en China.Datos de tratamiento postoperatorio de registros de salud electrónicos de 306 pacientes con adenocarcinoma de colon en estadio II de alto riesgo.Patrones de tratamiento más supervivencia global y libre de enfermedad a 3 y 5 años para casos concordantes y no concordantes.La concordancia general fue del 90%. La mayoría de la atención no concordante resultó del uso de quimioterapia adyuvante (en lugar de vigilancia) en pacientes de alto nivel con inestabilidad de microsatélites y pacientes ≥70 años. No se observaron diferencias en la supervivencia global (p = 0,56) o la supervivencia libre de enfermedad (p = 0,19) entre los grupos de concordancia. Los pacientes que recibieron quimioterapia adyuvante tuvieron una supervivencia global a los 5 años significativamente más alta que los que fueron sometidos a vigilancia (94% frente a 84%, p = 0,01).Uso de casos retrospectivos extraídos de pacientes que se presentan para cirugía, falta de datos de seguimiento completos para el 58% de los pacientes que no pudieron ser incluidos en el análisis, y análisis de supervivencia que asume que no exite una correlación no medida entre supervivencia y censura.Watson para Oncología produjo opciones terapéuticas altamente concordantes con las decisiones humanas en un centro oncológico de primer nivel en China. Los patrones de tratamiento sugieren que Watson para Oncología puede guiar a los médicos para minimizar el sobretratamiento de pacientes con cáncer de colon en estadio II de alto riesgo con quimioterapia. Los análisis de supervivencia sugieren la necesidad de realizar mas investigaciónes para evaluar específicamente la asociación entre la vigilancia, la quimioterapia con uno solo o múltiples agentes y los resultados de supervivencia en esta población. Consulte Video Resumen en http://links.lww.com/DCR/B291. (Traducción-Dr. Gonzalo Hagerman).

[Study on superposition law of drug bitterness based on tongue taste evaluation and electronic tongue evaluation].

Traditional Chinese medicine( TCM) decoction contains complex bitterness. In this paper,the simple mixing of TCM monomer bitter substances is used as the entry point to study the law of bitterness superposition. With berberine hydrochloride( alkaloids),geniposide( terpenoids),and arbutin( glycosides) as mother liquor,sophoridine( alkaloids),gentiopicroside( terpenoids),and puerarin( glycosides) as additive substances,these different additive substances were mixed with different mother liquor according to concentration gradients to form different liquid mixtures. The bitterness of the additive solution and the mixtures was evaluated by traditional human taste panel method( THTPM) and electronic tongue; the bitterness-concentration fitting model of the additive solution and the liquid mixtures was established by Weibull and logarithmic curves. By comparing and analyzing the bitterness-concentration model and the bitterness difference( ΔI_0/ΔI_e) of the additive solution and the mixture,the influence of mother liquor on the bitterness of the mixture was investigated. The results showed that both the additive solution bitterness model and the liquid mixture bitterness model were consistent with the Weibull model and the logarithmic model( THTPM: R~2≥0. 887 0,P<0. 01; electronic tongue test:R~2≥0. 753 2,P<0. 05). The fitting degree of the Weibull model was generally higher than that of the logarithmic model; the bitterness difference( ΔI_0) was monotonously decreasing; the fitting equation of tongue bitterness and electronic tongue bitterness: R~2≥0. 874 2,P<0. 01. In this article,through the superposition of different kinds of TCM bitter substances,THTPM and electronic tongue test was combined. It was found that the bitterness after superposition was still in Weibull or logarithmic relationship with the concentration of additive substances; THTPM showed that the effect of bitter mother liquor on the bitterness of the mixture decreased with the increase of the concentration of the additive; the bitterness of the electronic tongue was obviously related to the bitterness of THTPM. However,further verification is needed later by optimizing the concentration gradient and expanding the sample size.

Rectal cancer patients after neoadjuvant radiotherapy (30Gy/10f) with negative lymph node may not benefit from postoperative adjuvant chemotherapy: a retrospective study.

OBJECTIVE: The purpose of this study is to evaluate whether adjuvant chemotherapy could bring oncologic benefit to all patients who underwent neoadjuvant radiotherapy (30Gy/10f). METHODS: Rectal cancer patients receiving preoperative radiotherapy between July 2002 and April 2009 were retrospectively identified. RESULTS: A total of 225 patients were enrolled in this study. One hundred thirty-one patients received postoperative adjuvant chemotherapy, and 94 patients did not. The 120 ypN+ and 105 ypN- patients were divided into chemo and non-chemo groups. Two groups of patients did not show any significant difference in terms of gender, age, ypT stage, preoperative serum carcinoembryonic antigen (CEA) level, differentiation, circumferential margin (CRM), lymphovascular invasion (LVI), surgical approach, local recurrence, and distant metastasis (P > 0.05). Survival analysis showed that in ypN+ patients, the 5-year overall survival (OS) rate and 5-year disease-free survival (DFS) rate in chemo group were both significantly higher than non-chemo group (P < 0.05). In ypN- patients, the 5-year OS rate and 5-year DFS rate did not show any significant difference in the two groups (P > 0.05). Subgroup analysis showed that the 5-year OS rate and 5-year DFS rate in ypT0-2 N- patients (P > 0.05) and ypT3-4 N- patients (P > 0.05) did not show any significant difference, either. CONCLUSIONS: Based on a Chinese protocol, patients with ypN- stage may not benefit from adjuvant chemotherapy, regardless of the ypT stage, while the ypN+ patients may benefit from adjuvant chemotherapy. More randomized clinical trials are needed in the future.

[Retrospective analysis of 856 cases with stage 0 to III rectal cancer underwent curative surgery combined modality therapy].

OBJECTIVE: To investigate the survival and prognostic factors of stage 0 to III rectal cancer in 10 years. METHODS: Clinical data and follow-up of 856 rectal cancer patients with stage 0-III underwent curative surgery from January 2000 to December 2010 were retrospective analyzed. There were 470 male and 386 female patients, with a mean age of (58 ± 12) years. Kaplan-Meier method was used to analyze the overall survival and disease free survival. Log-rank test was used to compare the survival between groups. Cox regression was used to analyze the independent prognostic factors of rectal cancer. RESULTS: The patients in each stage were stage 0 with 18 cases, stage I with 209 cases, stage II with 235 cases, and stage III with 394 cases. All patients received curative surgery. There were 296 patients evaluated as cT3, cT4 and any T with N+ received preoperative radiotherapy. 5.4% patients got pathological complete response (16/296), and the recurrence rate was 4.7% (14/296). After a median time of 41.7 months (range 4.1 to 144.0 months) follow-up, the 5-year overall survival rate in stage 0 to I of was 91.0%, stage II 86.2%, and stage III 60.0%, with a significant difference (P=0.000). The cumulative local recurrence rate was 4.8% (41/856), of which 70.7% (29/41) occurred within 3 years postoperatively, 97.6% (40/41) in 5 years. The cumulative distant metastasis rate was 16.4% (140/856), of which 82.9% (129/140) occurred within 3 years postoperatively, 96.4% (135/140) in 5 years. The incidence of abnormal imaging findings was significantly higher in pulmonary than liver and other sites metastases (75.0% vs. 21.7%, χ² =25.691, P=0.000). The incidence of CEA elevation was significantly higher in liver than lung and other sites metastases (56.8% vs. 37.8%, χ² =25.691, P=0.000). Multivariable analysis showed that age (P=0.015, HR=1.385, 95% CI: 1.066 to 1.801), surgical approach (P=0.029, HR=1.337, 95% CI: 1.030 to 1.733), differentiation (P=0.000, HR=1.535, 95% CI: 1.222 to 1.928), TNM stage (P=0.000, HR=1.349, 95% CI: 1.260 to 1.444) and lymphovascular invasion (P=0.001, HR=1.715, 95% CI: 1.258 to 2.342) are the independent prognostic factors for rectal cancer. CONCLUSIONS: Age, surgical approach, differentiation, TNM stage and lymphovascular invasion are independent prognostic factors for rectal cancer. Preoperative evaluation and combined modality therapy can significant reduce the local recurrence and improve overall survival for rectal cancer patients.

Expression of HER-2 in rectal cancers treated with preoperative radiotherapy: a potential biomarker predictive of metastasis.

BACKGROUND: Evidence suggests HER-2 overexpression may be predictive of prognosis in colorectal cancer patients, though this remains controversial. OBJECTIVES: This study was performed to assess the prognostic value of HER-2 expression in locally advanced rectal cancer patients after preoperative radiotherapy. PATIENTS AND METHODS: HER-2 expression was evaluated based on immunohistochemical (IHC) staining of resected specimens from 142 mid-to-low rectal cancer patients. Fluorescence in situ hybridization (FISH) was performed to confirm HER-2 overexpression in samples with an IHC score of 2+. Tumor regression grading (TRG) of the primary tumors was determined semiquantitatively using a tumor regression grading scheme advocated in the AJCC Cancer Staging Manual 7 edition. RESULTS: When the total staining intensity was evaluated, 106 samples (74.6%) showed barely-perceptible positivity (0-1+; HER-2--negative), 15 samples (10.6%) showed moderate positivity (2+) and 21 samples (14.8%) showed strong positivity (3+, HER-2 positive). FISH confirmed that 2 cases showing moderate HER-2 positivity (2+) overexpressed HER2. There was no significant difference between the HER-2 positive and -negative groups with respect to age, gender, TRG, TNM stage, downstaging status, lymphovascular invasion or tumor differentiation. A significant correlation was found between HER-2 overexpression and the incidence of distant metastasis (p = 0.005). Subgroup analysis revealed this correlation was not significant (p = 0.247) in the radiation-insensitive (TRG0-2) subgroup, whereas a significant correlation (p = 0.026) between HER-2 overexpression and distant metastasis was found in the radiation-resistant (TRG3) subgroup. Multivariate analysis identified ypN stage (OR = 0.473, p = 0.002)and overexpression of HER-2 (OR = 3.704, p = 0.008) as independent risk factors for distant metastasis. There was no correlation between HER-2 overexpression and disease-free survival or overall survival among the study population. LIMITATIONS: We reported that HER-2 overexpression was correlated with distant metastasis in rectal cancer patients, especially in the radiation-insensitive group. However, there are certain limitations. First, this study was limited due to the fact that the number of rectal patients enrolled was only 142, which is relatively small. Second, HER-2 expression was measured by IHC with a positive ratio around 15%, which is fairly high according to the literature. Also, we collected the tissue samples preoperatively. It would be interesting to know the HER-2 expression levels pre- and postradiotherapy, as well as their correlation with local recurrence or distant metastasis. Finally, in rectal cancer patients, there is little information published on HER-2 and its role in tumor progression and metastasis. Therefore, we are pursuing the regulatory molecule underlined. CONCLUSIONS: HER-2 is overexpressed in around 15% of rectal cancer patients who receive neoadjuvant radiotherapy. Moreover, HER-2 overexpression could be a predictive biomarker of distant metastasis in rectal cancer patients after preoperative radiotherapy, especially patients showing a poor response to neoadjuvant radiotherapy.

Synthesis and biological evaluation of novel pyrimidine-benzimidazol hybrids as potential anticancer agents.

A series of pyrimidine-benzimidazol hybrids was synthesized and evaluated for anticancer activity on four human cancer cell lines including MCF-7, MGC-803, EC-9706 and SMMC-7721. Some of the synthesized compounds exhibited moderate to potent activity against MGC-803 and MCF-7. Among them, compounds 5a-b and 6a-b showed most effective activity. Compounds 5b and 6b were more cytotoxic than 5-fluorouracil against all tested four human cancer cell lines, with IC50 values ranging from 2.03 to 10.55 µM and 1.06 to 12.89 µM, respectively. Flow cytometry analysis demonstrated that treatment of MGC-803 with 6b led to cell cycle arrest at G2/M phase accompanied by an increase in apoptotic cell death.

Synthesis and antimicrobial activities of novel 1,2,4-triazolo [3,4-a] phthalazine derivatives.

A series of novel 1,2,4-triazolo [3,4-a] phthalazine derivatives were synthesized in five steps from a common precursor, phthalic anhydride. Most of synthesized phthalazine derivatives showed inhibitory activity against Staphylococcus aureus. One of phthalazine derivatives 5l showed inhibitory activity against all tested bacterial and fungal strains.

Synthesis, in vitro antimicrobial and cytotoxic activities of novel pyrimidine-benzimidazol combinations.

A series of novel 4-substituted-2-{[(1H-benzo[d]imidazol-2-yl)methyl] thio}-6-methylpyrimidine derivatives were designed, synthesized and evaluated for their cytotoxic activities against four human cancer cell lines and inhibitory activities against five type culture strains in vitro. Some of synthetic pyrimidine-benzimidazol combinations showed good inhibitory activities against Stenotrophomonas maltophilia, especially compounds 7b and 7c. Compounds 7a and 7d exhibited enhanced activities against MGC-803 in vitro, when compared to 5-Fu.

Genetic Characterization, Pathogenicity, and Epidemiology Analysis of Three Sub-Genotype Pigeon Newcastle Disease Virus Strains in China.

Pigeon Newcastle disease (ND) is a serious infectious illness caused by the pigeon Newcastle disease virus (NDV) or Paramyxovirus type 1 (PPMV-1). Genotype VI NDV is a primary factor in ND among Columbiformes (such as pigeons and doves). In a recent study, eight pigeon NDV strains were discovered in various provinces in China. These viruses exhibited mesogenic characteristics based on their MDT and ICPI values. The complete genome sequences of these eight strains showed a 90.40% to 99.19% identity match with reference strains of genotype VI, and a 77.86% to 80.45% identity match with the genotype II vaccine strain. Additionally, analysis of the F gene sequence revealed that these NDV strains were closely associated with sub-genotypes VI.2.2.2, VI.2.1.1.2.1, and VI.2.1.1.2.2. The amino acid sequence at the cleavage site of the F protein indicated virulent characteristics, with the sequences 112KRQKRF117 and 112RRQKRF117 observed. Pigeons infected with these sub-genotype strains had a low survival rate of only 20% to 30%, along with lesions in multiple tissues, highlighting the strong spread and high pathogenicity of these pigeon NDV strains. Molecular epidemiology data from the GenBank database revealed that sub-genotype VI.2.1.1.2.2 strains have been prevalent since 2011. In summary, the findings demonstrate that the prevalence of genotype VI NDV is due to strains from diverse sub-genotypes, with the sub-genotype VI.2.1.1.2.2 strain emerging as the current epidemic strain, highlighting the significance of monitoring pigeon NDV in China.

Bacteroides xylanisolvens possesses a potent anti-hyperuricemia effect in goslings fed on a high-protein diet.

Introduction: Hyperuricemia is widespread in humans and birds which is a necessary physiological factor leading to gout. Studies have shown an inextricable relationship between gut microbiota and hyperuricemia. This study explored the association between intestinal flora and hyperuricemia in Goslings. Methods and results: The hyperuricemia model was established in gosling by a high protein diet (HPD). 16S rDNA sequencing showed that the cecal microbiota differed significantly between the HPD and control groups (fed with the normal protein). The abundance of Firmicutes was higher in the HPD group, while the Bacteroidetes were lower than in controls. To investigate the role of intestinal flora in hyperuricemia, the cecum microbiotas from the HPD group and the control group were transplanted to the newly born goslings by gavage. The serum uric acid levels of the goslings that transplanted the cecal microbiota of the HPD group were significantly higher than the goslings that transplanted the cecal microbiota of the controls. Furthermore, the transplantation of cecal microbiota also affects the production and excretion of uric acid in goslings. Then we identify the gut bacterium Bacteroides xylanisolvens as an effective anti-hyperuricemia in the Goslings. B. xylanisolvens reduces serum uric acid concentrations in hyperuricemia in the Goslings' model, and it can up-regulation ABCG2 mRNA expression in the kidney and down-regulation XDH mRNA expression in the liver. Discussion: The intestinal flora acts as a novel target for the therapeutic approach to hyperuricemia and gout, suggest Bacteroides xylanisolvens is a possible route to therapy for hyperuricemia and gout in goslings.

BolA affects the biofilm formation ability, outer membrane permeability and virulence, thus is required for the adaptability of Salmonella enterica serotype Typhimurium to the harsh survival environment.

Salmonella enterica serotype Typhimurium, an important foodborne pathogen with high adaptability to the host's internal and external survival environment, seriously threatens public health. Therefore, to understand the mechanism underlying the high adaptability, this study investigated the transcription factor BolA by constructing BolA deletion strain 269△BolA, complemented strain 269BolAR and overexpression strain 269BolA+ based on WT269. BolA significantly inhibited motility; at 6 h, the BolA overexpression strain (269BolA+) showed 91.2% and 90.7% lower motility than the wild type (WT269) and BolA deletion strain (269△BolA), respectively, by downregulating motility-related flagellar genes. BolA promoted biofilm formation; 269BolA+ showed 3.6-fold and 5.2-fold higher biofilm formation ability than WT269 and 269ΔBolA, respectively, by upregulation biofilm formation-related genes. BolA overexpression downregulated the outer membrane gene OmpF and upregulated OmpC, thereby regulating cell permeability, and reducing the antibacterial effect of vancomycin, which can destruct the outer membrane. BolA improved adaptability; 269△BolA showed higher susceptibility to eight antibiotics and 2.5- and 4-fold lower acid and oxidative stress tolerance, respectively, than WT269. In Caco-2 and HeLa cells, 269△BolA showed 2.8- and 3-fold lower cell adhesion ability, respectively, and 4- and 2-fold lower cell invasion ability, respectively, than WT269, through downregulation of the virulence genes. Thus, BolA expression promotes biofilm formation and balances the membrane permeability, thereby improving the resistance of the strains, and enhances its host cell invasion ability by upregulating bacterial virulence factors. Results of this study suggest that the BolA gene may serve as a potential target of therapeutic or preventative strategies to control Salmonella Typhimurium infections.

Genetic characteristic of coexisting of mcr-1 and bla NDM-5 in Escherichia coli isolates from lesion-bearing animal organs.

The coexistence of mcr-1 and bla NDM-5 in the plasmid of Escherichia coli has been widely reported and such strains have been mainly isolated from animal and human feces. However, few reports have focused on the genetic diversity of mcr-1-carrying chromosomes and bla NDM-5-carrying plasmids in E. coli isolates from lesion-bearing animal organs. This study investigated the genetic characteristics of chromosome-mediated mcr-1 and plasmid-mediated bla NDM-5 in E. coli isolated from lesion-bearing animal organs. Nine mcr-1- and bla NDM-5-positive E. coli strains (MNPECs) showed extensive drug resistance (XDR). The predominant clonal complexes (CC) mainly belonged to CC156, CC10, and CC165 from the 56 MNEPCs (including nine strains in this study) retrieved from the literature. These strains were widely distributed in China, and originated from pig fecal samples, human stool/urine samples as well as intestinal contents of chicken. Two transconjugants harboring bla NDM-5 gene were also successfully obtained from two donors (J-8 and N-14) and this transfer increased the MIC for meropenem by 256 times. However, conjugative transfer of mcr-1 gene failed. Both J-8 and N-14 strains contained point mutations associated with quinolone resistance and more than three types of AMR genes, including the mcr-1 gene on the chromosome and the bla NDM-5 gene on the IncX3-type plasmid. The genetic structure of mcr-1 located on the chromosome was an intact Tn6330, and bla NDM-5-carrying IncX3-type plasmid was ISAb125-IS5-bla NDM-5-bleO-trpF-tat-cutA-IS26 gene cassette. Moreover, differences between chromosomes included additional partial sequence of phage integrated into host genome and the different genes associated with O-antigen synthesis.

Total neoadjuvant treatment for MRI-stratified high-risk rectal cancer: a single-center, single-arm, prospective Phase II trial (PKUCH-R02).

Background: Induction chemotherapy combined with neoadjuvant chemoradiotherapy has been recommended for patients with high-risk, locally advanced rectal cancer. However, the benefit of more intensive total neoadjuvant treatment (TNT) is unknown. This study aimed to assess the safety and efficacy of induction chemotherapy combined with chemoradiotherapy and consolidation chemotherapy for magnetic resonance imaging-stratified high-risk rectal cancer. Methods: This was a single-center, single-arm, prospective Phase II trial in Peking University Cancer Hospital (Beijing, China). Patients received three cycles of induction oxaliplatin and capecitabine (CapeOX) followed by chemoradiotherapy and two cycles of consolidation CapeOX. The primary end point was adverse event rate and the second primary end points were 3-year disease-free survival rate, completion of TNT, and pathological downstaging rate. Results: Between August 2017 and August 2018, 68 rectal cancer patients with at least one high risk factor (cT3c/3d/T4a/T4b, cN2, mesorectal fascia involvement, or extramural venous invasion involvement) were enrolled. The overall compliance of receiving the entire treatment was 88.2% (60/68). All 68 patients received induction chemotherapy, 65 received chemoradiotherapy, and 61 received consolidation chemotherapy. The Grade 3-4 adverse event rate was 30.8% (21/68). Nine patients achieved clinical complete response and then watch and wait. Five patients (7.4%) developed distant metastasis during TNT and received palliative chemotherapy. Fifty patients underwent surgical resection. The complete response rate was 27.9%. After a median follow-up of 49.2 months, the overall 3-year disease-free survival rate was 69.7%. Conclusions: For patients with high-risk rectal cancer, this TNT regimen can achieve favorable survival and complete response rates but with high toxicity. However, it is necessary to pay attention to the possibility of distant metastasis during the long treatment period.

MiR-143-3p targets ATG2B to inhibit autophagy and promote endothelial progenitor cells tube formation in deep vein thrombosis.

Deep vein thrombosis (DVT) is a common disease in vascular surgery. In recent study, microRNA (miRNA) plays a regulatory role in function of Endothelial progenitor cells (EPCs), which showed promising therapeutic choice for DVT. However, the function of miR-143-3p in EPCs remains incomplete. Flow cytometry was used to identify EPCs surface markers. Cell viability, migration, invasion and tube formation of EPCs were detected by 3-[4,5-dimethylthylthiazol-2-yl]-2,5 diphenyltetrazolium broide (MTT), wound healing, transwell and tube formation assay, respectively. TargetScan was used to predict miR-143-3p targeting genes. Dual-luciferase report assay was used to verify the interactions between miR-143-3p and autophagy-related 2B (ATG2B). Quantitative reverse transcription polymerase chain reaction (qRT-PCR) was used to examine the mRNA expression levels of ATG2B and miR-143-3p. Western blot was used to examine the protein expression levels of ATG2B, LC3 and p62. The cultured EPCs showed cobblestone morphology and were identified by cell surface markers. Overexpression of miR-143-3p enhanced the viability, migration, invasion and tube formation of EPCs, but low expression of miR-143-3p obtained the reverse results. ATG2B directly bound to miR-143-3p. Overexpression of miR-143-3p reduced the expression of ATG2B, but low expression of miR-143-3p increased. Overexpression of miR-143-3p decreased the expression of LC3I/II, but increased the expression of p62. Overexpression of ATG2B reversed the above-mentioned effects of EPCs which regulated by overexpression of miR-143-3p. MiR-143-3p targets ATG2B to modulate the function of EPCs and recanalization and resolution of DVT.

Surgical intervention for malignant bowel obstruction caused by gastrointestinal malignancies.

BACKGROUND: Malignant bowel obstruction (MBO) is a common event for end-stage gastrointestinal cancer patients. Previous studies had demonstrated manifestations and clinical management of MBO with mixed malignancies. There still lack reports of the surgical treatment of MBO. AIM: To analyze the short-term outcomes and prognosis of palliative surgery for MBO caused by gastrointestinal cancer. METHODS: A retrospective chart review of 61 patients received palliative surgery between January 2016 to October 2018 was performed, of which 31 patients underwent massive debulking surgery (MDS) and 30 underwent ostomy/by-pass surgery (OBS). The 60-d symptom palliation rate, 30-d morbidity and mortality, and overall survival rates were compared between the two groups. RESULTS: The overall symptom palliation rate was 75.4% (46/61); patients in the MDS group had significantly higher symptom palliation rate than OBS group (90% vs 61.2%, P = 0.016). Patients with colorectal cancer who were in the MDS group showed significantly higher symptom improvement rates compared to the OBS group (overall, 76.4%; MDS, 61.5%; OBS, 92%; P = 0.019). However, patients with gastric cancer did not show a significant difference in symptom palliation rate between the MDS and OBS groups (OBS, 60%; MDS, 80%; P = 1.0). The median survival time in the MDS group was significantly longer than in the OBS group (10.9 mo vs 5.3 mo, P = 0.05). CONCLUSION: For patients with MBO caused by peritoneal metastatic colorectal cancer, MDS can improve symptom palliation rates and prolong survival, without increasing mortality and morbidity rates.

Circular RNA circCTNNA1 promotes colorectal cancer progression by sponging miR-149-5p and regulating FOXM1 expression.

Circular RNAs (circRNAs) are an emerging class of non-coding RNAs, identified to participate in multiple malignancies. Nevertheless, the clinical significance, biological function, and regulatory mechanisms of circRNAs in colon cancer (CC) remain largely unclear. In this study, the circRNA expression profile in CC and matched normal tissues was analyzed using circRNA microarrays. A novel circRNA, circCTNNA1, was significantly upregulated in CC, and its level was associated with advanced tumor-node-metastasis stage and poor prognosis of patients with CC. Functional experiments, including Cell Counting Kit-8, colony formation, 5-ethynyl-2'-deoxyuridine, transwell, wound healing, flow cytometric analysis, and in vivo tumorigenesis assay were then performed to investigate the oncogenic role of circCTNNA1. The results revealed that circCTNNA1 promoted CC cell proliferation, migration, and invasion in vitro and in vivo. Mechanistically, RNA pull-down, RNA immunoprecipitation, dual-luciferase reporter assays, and fluorescent in situ hybridization were performed to unveil that circCTNNA1 can serve as a competing endogenous RNA of miR-149-5p to counteract the suppressive effect of miR-149-5p on downstream target Forkhead Box M1 (FOXM1). In summary, our study demonstrated that circCTNNA1 facilitated CC proliferation and invasion via the circCTNNA1/miR-149-5p/FOXM1 axis, and it might function as a novel diagnostic or therapeutic target for patients with CC.

Meta-replication, sampling bias, and multi-scale model selection: A case study on snow leopard (Panthera uncia) in western China.

Replicated multiple scale species distribution models (SDMs) have become increasingly important to identify the correct variables determining species distribution and their influences on ecological responses. This study explores multi-scale habitat relationships of the snow leopard (Panthera uncia) in two study areas on the Qinghai-Tibetan Plateau of western China. Our primary objectives were to evaluate the degree to which snow leopard habitat relationships, expressed by predictors, scales of response, and magnitude of effects, were consistent across study areas or locally landcape-specific. We coupled univariate scale optimization and the maximum entropy algorithm to produce multivariate SDMs, inferring the relative suitability for the species by ensembling top performing models. We optimized the SDMs based on average omission rate across the top models and ensembles' overlap with a simulated reference model. Comparison of SDMs in the two study areas highlighted landscape-specific responses to limiting factors. These were dependent on the effects of the hydrological network, anthropogenic features, topographic complexity, and the heterogeneity of the landcover patch mosaic. Overall, even accounting for specific local differences, we found general landscape attributes associated with snow leopard ecological requirements, consisting of a positive association with uplands and ridges, aggregated low-contrast landscapes, and large extents of grassy and herbaceous vegetation. As a means to evaluate the performance of two bias correction methods, we explored their effects on three datasets showing a range of bias intensities. The performance of corrections depends on the bias intensity; however, density kernels offered a reliable correction strategy under all circumstances. This study reveals the multi-scale response of snow leopards to environmental attributes and confirms the role of meta-replicated study designs for the identification of spatially varying limiting factors. Furthermore, this study makes important contributions to the ongoing discussion about the best approaches for sampling bias correction.