In vitro conversion of ellagic acid to urolithin A by different gut microbiota of urolithin metabotype A.

The metabolite urolithin A, a metabolite of the dietary polyphenol ellagic acid (EA), has significant health benefits for humans. However, studies on the gut microbiota involved in ellagic acid metabolism are limited. In this study, we conducted in vitro fermentation of EA using human intestinal microbiome combined with antibiotics (vancomycin, polymyxin B sulfate, and amphotericin B). Liquid chromatography-mass spectrometry (LC-MS/MS) analysis demonstrated that the production capacity of urolithin A by gut microbiota co-treated with polymyxin B sulfate and amphotericin B (22.39 µM) was similar to that of untreated gut microbiota (24.26 µM). Macrogenomics (high-throughput sequencing) was used to analyze the composition and structure of the gut microbiota. The results showed that the abundance of Bifidobacterium longum, Bifidobacterium adolescentis, and Bifidobacterium bifidum in the gut microbiota without antibiotic treatment or co-treated with polymyxin B sulfate and amphotericin B during EA fermentation was higher than that in other antibiotic treatment gut microbiota. Therefore, B. longum, B. adolescentis, and B. bifidum may be new genera involved in the conversion of EA to urolithin A. In conclusion, the study revealed unique interactions between polyphenols and gut microbiota, deepening our understanding of the relationship between phenolic compounds like EA and the gut microbiota. These findings may contribute to the development of gut bacteria as potential probiotics for further development. KEY POINTS: • Intestinal microbiome involved in ellagic acid metabolism. • Gram-positive bacteria in the intestinal microbiome are crucial for ellagic acid metabolism. • Bifidobacterium longum, Bifidobacterium adolescentis, and Bifidobacterium bifidum participate in ellagic acid metabolism.

Characterization of a Novel Myrosinase with High Activity from Marine Bacterium Shewanella baltica Myr-37.

Myrosinase can hydrolyze glucosinolates to generate isothiocyanates, which have cancer prevention and anti-cancer properties. The main sources of myrosinase are cruciferous plants. To further improve the efficiency of isothiocyanates preparation, it is necessary to explore novel sources of myrosinases. In this study, we described a bacterium, Shewanella baltica Myr-37, isolated from marine mud, capable of producing a novel myrosinase (Smyr37) with a molecular weight of 100 kDa. The crude enzyme of Smyr37 showed the highest activity at 50 °C and pH 8.0. The sinigrin- and glucoraphanin-hydrolyzing activities of Smyr37 were 6.95 and 5.87 U/mg, respectively. Moreover, when the reaction temperature was 40 °C and pH was 7.0, the crude enzyme of Smyr37 could efficiently degrade glucoraphanin into sulforaphane within 25 min with a yield of 0.57 mg/mL. The corresponding conversion efficiency of sulforaphane from glucoraphanin was 89%. In summary, S. baltica Myr-37 myrosinase Smyr37, a novel myrosinase, can be used in the preparation of isothiocyanates.

Effects of potential risk factors on the development of cardiometabolic multimorbidity and mortality among the elders in China.

Objectives: To examine the impact of demographic, socioeconomic, and behavioral factors on the development of cardiometabolic multimorbidity and mortality in Chinese elders. Methods: Data from the Chinese Longitudinal Healthy Longevity Survey (CLHLS) 2002-2018 was used in the study. Cardiometabolic multimorbidity was defined as the presence of two or more cardiometabolic disorders, such as hypertension, diabetes, cardiovascular disease (CVD), heart disease, or stroke. Cox regression model and multi-state Markov model were developed to evaluate the association of the study factors with the progression of cardiometabolic conditions and mortality. The outcomes included three states (first cardiometabolic disease, cardiometabolic multimorbidity, and all-cause mortality) and five possible transitions among the three states. Results: Of the 13,933 eligible individuals, 7,917 (56.8%) were female, and 9,540 (68.50%) were over 80 years old. 2,766 (19.9%) participants had their first cardiometabolic disease, 975 (7.0%) participants suffered from cardiometabolic multimorbidity, and 9,365 (67.2%) participants died. The progression to cardiometabolic multimorbidity was positively associated with being female (HR = 1.42; 95%CI, 1.10 - 1.85), living in the city (HR = 1.41; 95%CI, 1.04 - 1.93), overweight (HR = 1.43; 95%CI, 1.08 - 1.90), and obesity (HR = 1.75; 95% CI, 1.03 - 2.98). A higher risk for the first cardiometabolic disease was associated with being female (HR = 1.26; 95% CI, 1.15 - 1.39), higher socioeconomic status (SES, HR = 1.17; 95%CI, 1.07 - 1.28), lack of regular physical activity (HR = 1.13; 95%CI, 1.04 - 1.23), smoking (HR = 1.20; 95%CI, 1.08 - 1.33), ≤ 5 h sleep time (HR = 1.15; 95%CI, 1.02 - 1.30), overweight (HR = 1.48; 95% CI, 1.32 - 1.66), and obesity (HR = 1.34; 95%CI, 1.06 - 1.69). It also should be noted that not in marriage, lower SES and unhealthy behavioral patterns were risk factors for mortality. Conclusion: This study emphasized the importance of lifestyle and SES in tackling the development of cardiometabolic conditions among Chinese elders and provided a reference for policy-makers to develop a tailored stage-specific intervention strategy.

Lactococcus garvieae FUA009, a Novel Intestinal Bacterium Capable of Producing the Bioactive Metabolite Urolithin A from Ellagic Acid.

Dietary polyphenol ellagic acid has anti-cancer and anti-inflammatory activities, and these biological activities require the conversion of ellagic acid to urolithins by intestinal microbes. However, few gut microbes are capable of metabolizing ellagic acid to produce urolithins, limiting the beneficial effects of ellagic acid on health. Here, we describe an intestinal bacterium Lactococcus garvieae FUA009 isolated from the feces of a healthy volunteer. It was demonstrated via HPLC and UPLC-MS analysis that the end product of ellagic acid metabolism of FUA009 was urolithin A. In addition, we also examined the whole genome sequence of FUA009 and then assessed the safety and probiotic properties of FUA009 based on a complete genome and phenotype analysis. We indicated that FUA009 was safe, which was confirmed by FUA009 being sensitive to multiple antibiotics, having no hemolytic activity, and being free of aggressive putative virulence factors. Moreover, 19 stress-responsive protein genes and 8 adhesion-related genes were predicted in the FUA009 genome. Furthermore, we demonstrated that FUA009 was tolerant to acid and bile salt by determining the cell viability in a stress environment. In summary, Lactococcus garvieae FUA009, as a novel UA-producing bacterium, not only contributes to the study of the metabolic pathway of ellagic acid but is also expected to be a novel probiotic candidate.

Metabolic Effects of Recombinant Human Growth Hormone Replacement Therapy on Juvenile Patients after Craniopharyngioma Resection.

Objective: To investigate the effect of short-term recombinant human growth hormone (rhGH) replacement therapy on metabolic parameters in juvenile patients following craniopharyngioma (CP) resection. Methods. This retrospective study included 42 cases of juvenile patients that had undergone CP resection in the Department of Endocrinology at the Peking Union Medical College Hospital, from April 2013 to August 2020. According to whether they received growth hormone replacement therapy, the patients were divided into either the growth hormone replacement therapy (GHRT) group (30 cases) or the control group (12 cases). Changes in body mass index (BMI), BMI z-score, transaminase activity, fasting blood glucose (FBG) levels, blood lipid profile, and high-sensitivity C-reactive protein (hsCRP) levels were evaluated after one year of GHRT treatment. Results. The average age of the GHRT group was 13.00 (8.00-14.00) years old and these patients had undergone a CP operation an average of 2.00 (1.62-3.15) years earlier. Prior to receiving GHRT treatment, they received appropriate doses of adrenocortical hormone and thyroid hormone replacement therapy. After one year of GHRT treatment, the average BMI z-score decreased from 1.60 ± 1.76 to 1.13 ± 1.73 (P=0.005). Alanine aminotransferase (ALT) activity decreased from 26.50 (17.00∼98.00) U/L to 18.00 (13.00∼26.48) U/L (P ≤ 0.001), and similar changes were observed with regard to aspartate aminotransferase (AST) and glutamyl transferase (GGT) activity in the GHRT treatment group. The average total cholesterol (TC) decreased from 4.67 (4.10-6.14) mmol/L to 4.32 ± 0.85 mmol/L (P=0.002), and low-density lipoprotein (LDL) levels decreased from 3.05 ± 0.95 mmol/L to 2.56 ± 0.65 mmol/L (P=0.001) in the GHRT treatment group. The average blood urea nitrogen level decreased from 4.53 ± 1.09 mmol/L to 3.92 ± 0.82 mmol/L (P=0.016) and the average serum creatinine (SCr) level decreased from 55.59 ± 12.54 µmol/L to 51.15 ± 10.51 µmol/L (P=0.005) in the GHRT treatment group. The average hsCRP level decreased from 3.23 (1.79∼4.34) mg/L to 0.92 (0.42∼1.21) mg/L in the GHRT treatment group. In the control group, the average ALT activity increased from 26.58 ± 8.75 U/L to 42.58 ± 24.59 U/L (P=0.039), GGT activity increased from 19.0 (13.25-29.25) U/L to 25.00 (14.75-34.75) U/L (P=0.026), and LDL levels increased from 2.27 ± 0.76 mmol/L to 3.43 ± 1.28 mmol/L (P=0.04). Conclusion. GHRT treatment improves the metabolic parameters of juvenile patients that have undergone craniopharyngioma resection by reducing BMI z-scores, low-density lipoprotein, and hsCRP levels and improving liver function.

Risk Factors and Clinical Impacts of Post-Pancreatectomy Acute Pancreatitis After Pancreaticoduodenectomy: A Single-Center Retrospective Analysis of 298 Patients Based on the ISGPS Definition and Grading System.

Background: The definition and grading system of post-pancreatectomy acute pancreatitis (PPAP) has recently been proposed by ISGPS. This study aimed to put this definition and classification into practice and investigate the potential risk factors and clinical impacts of PPAP. Methods: Demographic and perioperative data of consecutive patients who underwent pancreaticoduodenectomy (PD) from January 2019 to July 2021 were collected and analyzed retrospectively. The diagnostic criteria of PPAP published by ISGPS, consisting of biochemical, radiologic, and clinical parameters, were adopted. The risk factors were analyzed by univariate and multivariate analyses. Results: A total of 298 patients were enrolled in this study, and the total incidence of PPAP was 52.4% (150 patients). Stratified by clinical impacts of PPAP, the incidences of grades B and C PPAP were 48.9% and 3.5%, respectively. PPAP after PD was significantly associated with pancreatic fistula and other unfavorable complications. Soft pancreatic texture (OR 3.0) and CRP ≥ 180 mg/L (OR 3.6) were the independent predictors of PPAP, AUC 0.613. Stratified by the grade of PPAP, soft pancreatic texture (OR 2.7) and CRP ≥ 180 mg/L (OR 3.4) were the independent predictors of grade B PPAP, and soft pancreatic texture (OR 19.3), operation duration >360 min (OR 13.8), and the pancreatic anastomosis by using conventional duct to mucosa methods (OR 10.4) were the independent predictors of grade C PPAP. PPAP complicated with pancreatic fistula significantly increased the severe complications and mortality compared to only PPAP occurrence. Conclusion: PPAP was not an uncommon complication after PD and was associated with unfavorable clinical outcomes, especially since it was complicated with pancreatic fistula. Soft pancreatic texture and CRP ≥ 180 mg/L were the independent predictors of PPAP. Higher-volume multicenter and prospective studies are strongly needed.

Effect Analysis of Positive Molecular Therapy in Surgical Nursing Based on Data Transformation Analysis.

This paper briefly introduces the concept, classification, and mechanism of action of positive thinking therapy; reviews the application and research progress of positive thinking therapy in perioperative care of surgical patients at home and abroad; presents the shortcomings and defects in the development; and aims to provide intervention, reference, and basis for the development of positive thinking therapy in perioperative care of surgical patients. One hundred and eight patients are undergoing PCI surgery in our cardiology department; 50 patients undergoing percutaneous coronary intervention were selected as the control group, and 58 patients undergoing percutaneous coronary intervention were selected as the observation group. Traditional health education was employed in the control group, while empowerment education based on timing theory was used in the observation group. The two groups were observed and compared in terms of self-care competence, anxiety and depression, medication adherence score, and exercise adherence. Conclusion. Empowerment education based on timing theory can improve self-care ability of PCI patients, reduce patients' anxiety and depression, and improve patients' medication and exercise compliance.

A viral protein orchestrates rice ethylene signaling to coordinate viral infection and insect vector-mediated transmission.

Arthropod-borne viruses cause serious threats to human health and global agriculture by rapidly spreading via insect vectors. Southern rice black-streaked dwarf virus (SRBSDV) is the most damaging rice-infecting virus that is frequently transmitted by planthoppers. However, the molecular mechanisms underlying its propagation in the host plants and epidemics in the field are largely unknown. Here, we showed that the SRBSDV-encoded P6 protein is a key effector that regulates rice ethylene signaling to coordinate viral infection and transmission. In early SRBSDV infection, P6 interacts with OsRTH2 in the cytoplasm to activate ethylene signaling and enhance SRBSDV proliferation; this also repels the insect vector to reduce infestation. In late infection, P6 enters the nucleus, where it interacts with OsEIL2, a key transcription factor of ethylene signaling. The P6-OsEIL2 interaction suppresses ethylene signaling by preventing the dimerization of OsEIL2, thereby facilitating viral transmission by attracting the insect vector. Collectively, these findings reveal a novel molecular mechanism by which an arbovirus modulates the host defense system to promote viral infection and transmission.

Applications of System Dynamics Models in Chronic Disease Prevention: A Systematic Review.

INTRODUCTION: Chronic disease is a serious health problem worldwide. Given that health care resources are limited, a comprehensive, effective, and affordable way is needed to provide insights to prevent chronic diseases. System dynamics models provide a comprehensive and systematic method that can predict results over time. These models can simulate and predict appropriate prevention measures for chronic diseases to determine the best practice. METHODS: Two researchers (Y.W., B.H.) independently searched databases (PubMed, Web of Science, Scopus, and Embase) for full-text articles published from January 2000 through February 2021. A PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analysis) 2020-compliant search was carried out to review system dynamics models of chronic disease prevention. A total of 34 articles were included in our study. RESULTS: We divided the prevention measures of system dynamics models into 2 main categories: upstream prevention and downstream prevention. Upstream prevention measures include lifestyle (eg, tobacco control, balanced diet, mental health, moderate exercise), obesity prevention, and social factors. Downstream prevention measures include clinical treatment of chronic diseases. Results showed that effective upstream prevention measures could reduce the prevalence of chronic diseases, and downstream prevention measures could reduce the incidence of complications, improve quality of life, prolong life, save medical costs, and reduce mortality. CONCLUSION: To our knowledge, our systematic review is the first to evaluate the application of system dynamics models in preventing chronic diseases. Such models can provide effective simulations. Hence, we can use system dynamics models to design and implement effective prevention measures for people with chronic diseases.

Neuropilin-1 is up-regulated by cancer-associated fibroblast-secreted IL-8 and associated with cell proliferation of gallbladder cancer.

We previously demonstrated that cancer-associated fibroblasts (CAFs) promoted the proliferation of gallbladder cancer (GBC) cells, but the mechanism is not clear. Neuropilin-1 (NRP-1) plays an important role in various malignancies as transmembrane glycoprotein. Our goal was to reveal the relationship between CAFs and NRP-1 and their potential functions in GBC. In this study, we found NRP-1 was overexpressed in GBC tissue, associated with poor survival and was up-regulated by CAFs. The cytokine array cluster analysis revealed IL-8 secreted by CAFs facilitated the up-regulation of NRP-1 in tumour cells. NRP-1 knockdown suppressed tumour growth in vivo. Gene expression microarray analysis showed 581 differentially regulated genes under NRP-1 knockdown conditions. Ingenuity pathway analysis demonstrated that NRP-1 knockdown may inhibit tumour progression by affecting cell proliferation. We then confirmed that NRP-1 knockdown in NOZ and GBC-SD cells significantly inhibited cell proliferation. Additionally, the IL-8 mediated MDM2 and CCNA2 expression were affected by NRP-1 knockdown. Our findings suggested that NRP-1 was up-regulated by CAF-secreted IL-8, which subsequently promoted GBC cell proliferation, and these molecules may serve as useful prognostic biomarkers and therapeutic targets for GBC.

Geographical variations in maternal lifestyles during pregnancy associated with congenital heart defects among live births in Shaanxi province, Northwestern China.

In this study, we aimed to explore regional differences in maternal lifestyle during pregnancy related to congenital heart defects (CHD) in Shaanxi province, Northwestern China. A large-scale epidemiologic survey of birth defects among infants born during 2010-2013, was conducted in Shaanxi province. Non-spatial and geographic weighted logistic regression models were used for analysis. The spatial model indicated that passive smoking frequency was positively associated with CHD for 43.3% of participants (P < 0.05), with the highest OR in North Shaanxi and the lowest in South Shaanxi. Approximately 49.2% of all mothers who ever drink tea were more likely to have an infant with CHD (P < 0.05), with the highest OR values observed in North and Central Shaanxi. Additionally, maternal alcohol intake frequency ≥ 1/week was significantly correlated with CHD among about 24.7% of participants (P < 0.05), with OR values ranging from 0.738 (Central Shaanxi) to 1.198 (North Shaanxi). The rates of unhealthy maternal lifestyles during pregnancy associated with CHD differed in various areas of the province. The role of geographical variations in these factors may provide some possible clues and basis for tailoring site-specific intervention strategies.

Combined therapy with GnRH analogue and growth hormone increases adult height in children with short stature and normal pubertal onset.

OBJECTIVE: To investigate whether gonadotropin releasing hormone analogue (GnRHa) combined with recombinant human growth hormone (rhGH) can improve the adult height (AHt) of children with short stature and normal pubertal onset. METHODS: In this retrospective study, GnRHa/rhGH treatment was given to children with normal pubertal onset and short stature. Patients were followed up to measure their AHt. The primary outcomes were the disparity between AHt standard deviation score (AHt SDS) and pre-treatment height standard deviation score (Ht SDS) and the disparity between AHt and target height (THt). RESULTS: A total of 94 patients were included. Forty-nine boys were treated with GnRHa/rhGH for 24.84 ± 13.01 months, and 45 girls were treated for 23.89 ± 10.43 months. (2) Before treatment, the Ht SDS of boys and girls was -1.82 ± 1.30 and -1.10 ± 1.61, respectively, and the target height was 168.98 ± 3.51 cm and 157.90 ± 3.25 cm, respectively. (3) After treatment, for boys, the AHt SDS increased by 1.37 ± 1.28 (p = 0.000) and the disparity between AHt and THt was 0.98 ± 6.18 cm (p = 0.273); for girls, the AHtSDS increased by 1.28 ± 1.48 (p = 0.000), and the disparity between AHt and THt was 3.64 ± 4.86 cm (n = 45, p = 0.000). (4) Subgroup analysis showed that, for boys with idiopathic short stature (ISS) and non-ISS, AHt SDS increased by 2.00 ± 1.16 (p = 0.000) and 0.71 ± 1.06 (p = 0.003) respectively, compared with the pre-treatment HtSDS; The disparities between AHt and THt were -0.70 ± 6.54 cm and 2.73 ± 5.37 cm respectively. For girls with ISS and non-ISS, AHtSDS increased by 2.73 ± 1.21 (p = 0.000) and 0.748 ± 1.19 (p = 0.001), respectively; AHt increased by 2.63 ± 6.12 cm (p = 0.165) and 4.02 ± 4.37 cm (p = 0.000) compared with THt, respectively. (5) Multiple linear regression analysis showed that the baseline bone age (BA) (ß = -0.200, p = 0.003), basal IGF-1(ß = -0.002, p = 0.008) and HtSDS (ß = -0.679, p = 0.000) had negative effects on increment of AHtSDS. CONCLUSION: For adolescents with normal pubertal onset and short stature, with or without ISS, GnRHa/rhGH therapy can effectively improve AHtSDS. After treatment, ISS adolescents can reach the THts, and Non-ISS adolescents can exceed their THts.

Aromatase Inhibitor Increases the Height of Patients with Congenital Adrenal Hyperplasia Due to 21-Hydroxylase Deficiency.

OBJECTIVE: Patients with 21-hydroxylase deficiency (21OHD) typically suffer from short stature due to early exposure to adrenal-derived androgen. The aim of this study was to investigate whether adding aromatase inhibitor (AI) to gonadotropin-releasing hormone (GnRH) analogue (GnRHa) and recombinant human growth hormone (rhGH) therapy would increase the height of patients with 21OHD. METHODS: This retrospective study included 15 patients with 21OHD. The AI/GnRHa/rhGH group consisted of 9 patients, who were treated with AI for at least 12 months in addition to GnRHa/rhGH therapy. The other 6 patients, who received GnRHa/rhGH therapy only, were defined as the GnRHa/rhGH group. RESULTS: Patients were 6.3±1.7 years old, and 7/15 of patients were male. Among them, 12 patients exhibited simple virilization type, and 3 patients were salt-wasting type. In the AI/GnRHa/rhGH group, patients were 6.6±2.0 years old when AI therapy was initiated. Their bone age was 5.9±2.2 years ahead of their chronological age. They received the AI letrizole for an average of 25.1 months (range, 12 to 37 months). In the GnRHa/rhGH group, the patients were 5.9±0.9 years old when they started GnRHa/rhGH therapy, and their bone age was 6.2±1.7 years ahead of their chronological age. Patients received GnRHa/rhGH therapy for an average of 24.5 months (range, 12 to 41 months). The predicted final height increased from 145.9±7.9 to 158.0±8.4 cm in the AI/GnRHa/rhGH group (P = .001, compared with the baseline) and from 141.7±2.7 to 150.7±4.7 cm in the GnRHa/rhGH group (P = .001, compared with the baseline). Bone age progression was 0.15±0.05 per year versus 0.44±0.13 per year in the two groups, respectively (P = .032). CONCLUSION: Addition of letrizole to GnRHa/rhGH therapy significantly delays bone maturation and may increase the final height.

Immune Infiltration Profiling in Nonsmall Cell Lung Cancer and Their Clinical Significance: Study Based on Gene Expression Measurements.

Immune cell infiltration is associated with the prognosis of cancer. This study focused on the immune infiltration profiling and their association with survival outcome in nonsmall cell lung cancer (NSCLC). Research data were obtained from the Gene Expression Omnibus and The Cancer Genome Atlas databases. CIBERSORT algorithm was applied to assess the relative proportions of 22 kinds of immune cells. Log-rank test was performed to compare the survival outcome of patients with different proportions of immune cells. The estimated hazard ratios were presented with forest plot. Multivariate Cox regression analysis was conducted to estimate the adjusted associations between different types of infiltrating immune cells and survival prognosis controlling for other clinical features and confounders. With the CIBERSORT approach, we assessed the proportions of 22 infiltrating immune cells of 2050 cases with NSCLC. By conducting survival analysis, we found different survival outcomes among cases with different proportions of certain types of infiltrating immune cells. Among the cell subsets investigated, plasma cells (hazard ratio [HR] = 0.775, 95% confidence interval [CI]: 0.669-0.898) and regulatory T cells (HR = 1.258, 95% CI: 1.091-1.451) were associated with survival outcome of NSCLC patients controlling for other covariates. Subgroup analysis suggested a good consistency and robustness of our results. Our findings might provide useful information for prognosis prediction and cellular study in NSCLC.

Who benefits from R0 resection? A single-center analysis of patients with stage â £ gallbladder cancer.

OBJECTIVES: Most patients with gallbladder cancer (GBC) present with advanced-stage disease and have a poor prognosis. Radical resection remains the only therapeutic option to improve survival in patients with GBC. This study aimed to analyze the prognostic factors in patients with stage Ⅳ GBC and to identify a subgroup of patients who might benefit from R0 resection. METHODS: A total of 285 patients with stage Ⅳ GBC were retrospectively analyzed at our institution from January 2008 to December 2012. Factors potentially influencing the prognosis of GBC after surgery were analyzed by univariate and multivariate analyses. RESULTS: The 1-, 3-, and 5-year overall survival rates were 6.6% (15/229), 0.9% (2/229), and 0 (0/229), respectively. Ascites (relative risk [RR] = 1.631, 95% confidence interval [CI]: 1.221-2.180, P = 0.001), pathological grade (RR = 1.337, 95% CI: 1.050-1.702, P = 0.018), T stage (RR = 1.421, 95% CI: 1.099-1.837, P = 0.000), M stage (RR = 1.896, 95% CI: 1.409-2.552, P = 0.000), and surgery (RR = 1.542, 95% CI: 1.022-2.327, P = 0.039) were identified as independent risk factors influencing prognosis. The median survival time (MST) was significantly higher in patients undergoing R0 resection than in those undergoing R1/R2 resection (6.0 vs. 2.7 months; P < 0.001). In subgroup analyses, stage ⅣA patients benefited from R0 resection (MST for R0 vs. R1/R2, 11.0 vs. 4.0 months; P = 0.003), while R0 resection had a significant survival benefit than R1/R2 resection in patient with stage ⅣB GBC without distant metastasis (MST for R0 vs. R1/R2, 6.0 vs. 3.0 months; P = 0.007). CONCLUSION: Ascites, pathological grade, T stage, M stage, and surgery were independent risk factors influencing prognosis in patients with stage IV GBC. N2 lymph node metastasis did not preclude curative resection, and radical resection should be considered in patients with stage Ⅳ GBC without distant metastasis once R0 margin was achieved.

Comparison of apatinib and capecitabine (Xeloda) with capecitabine (Xeloda) in advanced triple-negative breast cancer as third-line therapy: A retrospective study.

The treatment of advanced triple-negative breast cancer, which failed in first-line or second-line therapy, is a significant challenge. We conducted this retrospective study to explore the efficacy and safety of apatinib and capecitabine as the third-line treatment for advanced triple-negative breast cancer.This retrospective study involved 44 advanced triple-negative breast cancer patients who failed in first-line or second-line therapy in Tangshan People's Hospital from January 2016 to February 2017. Twenty-two patients received apatinib and capecitabine, while 22 patients were treated with capecitabine monotherapy as third-line therapy. The progression-free survival (PFS), objective response rate (ORR), disease control rate (DCR), and adverse events were compared between 2 groups.The apatinib and capecitabine group exhibited a higher PFS than capecitabine group (P = .001). Meanwhile, ORR and DCR in apatinib and capecitabine group were better than in capecitabine group (P = .042; .016). The 2 groups showed no significant difference in adverse events except degree I-II bleeding (P = .021). Both the apatinib and capecitabine and the capecitabine regimens revealed good tolerability.The apatinib and capecitabine regimen can achieve a better efficacy and similar serious adverse events compared with capecitabine regimen as the third-line treatment for advanced triple-negative breast cancer.

Establishing RNA virus resistance in plants by harnessing CRISPR immune system.

Recently, CRISPR-Cas (clustered, regularly interspaced short palindromic repeats-CRISPR-associated proteins) system has been used to produce plants resistant to DNA virus infections. However, there is no RNA virus control method in plants that uses CRISPR-Cas system to target the viral genome directly. Here, we reprogrammed the CRISPR-Cas9 system from Francisella novicida to confer molecular immunity against RNA viruses in Nicotiana benthamiana and Arabidopsis plants. Plants expressing FnCas9 and sgRNA specific for the cucumber mosaic virus (CMV) or tobacco mosaic virus (TMV) exhibited significantly attenuated virus infection symptoms and reduced viral RNA accumulation. Furthermore, in the transgenic virus-targeting plants, the resistance was inheritable and the progenies showed significantly less virus accumulation. These data reveal that the CRISPR/Cas9 system can be used to produce plant that stable resistant to RNA viruses, thereby broadening the use of such technology for virus control in agricultural field.

Clinical epidemiological survey of gallbladder carcinoma in northwestern China, 2009-2013: 2379 cases in 17 centers.

OBJECTIVE: To analyze the clinical epidemiological characteristics of patients with gallbladder carcinoma recruited from 17 hospitals in five northwestern provinces of China (Shaanxi Province, Gansu Province, Qinghai Province, Ningxia Hui Autonomous Region, and Xinjiang Uygur Autonomous Region) from 2009 to 2013, and to summarize the clinical diagnosis and treatment data of gallbladder carcinoma. METHODS: Clinical information of 2379 patients with gallbladder carcinoma from 17 hospitals in five northwestern provinces of China was retrospectively collected and analyzed using the "Questionnaire for Gallbladder Carcinoma Patients in Northwestern Area of China." All information was verified with EpiData software and analyzed with SPSS 13.0 software. RESULTS: (1) Gallbladder carcinoma accounted for 2.7% (2379/86,609) of all biliary tract diseases during the study period, which was significantly higher than that from 1986 to 1998 (P < 0.001). (2) Gallbladder carcinoma was more prone to occur in elderly women. The male:female incidence ratio was 1.0:2.1, the average age of onset of disease was 63.7 ± 11.3 years, and the incidence was higher in farmers than in other occupational groups. (3) A total of 57.2% (1360/2379) of patients with gallbladder carcinoma also had gallstones. (4) Abdominal pain (1796/2379, 75.5%) and jaundice (727/2379, 30.6%) were the most common clinical manifestations, 81.2% (1527/1881) were positive in those receiving B ultrasound examinations and 90.7% (1567/1727) were positive in those undergoing computed tomography, and 64.5% (1124/1742) of patients with gallbladder carcinoma were positive for carbohydrate antigen (CA) 19-9. (5) The pathological type of gallbladder carcinoma was mainly moderately and poorly differentiated adenocarcinoma with a high degree of malignancy. At admission, 55.1% (1091/1981) of patients had stage IV cancer among patients with TNM staging information; 55.9% (1331/2379) had lymphatic metastasis, 29.7% (706/2379) had bile duct metastasis, and 53.1% (1263/2379) had liver metastasis. (6) A total of 283 patients (283/2379, 11.9%) had incidentally detected gallbladder carcinoma. (7) The rate of radical surgical resection was 30.4% (723/2379). CONCLUSION: The proportion of gallbladder carcinoma in biliary tract diseases in the northwestern area of China was significantly higher from 2009 to 2013 than from 1986 to 1998. Gallbladder carcinoma was common in older women and mainly diagnosed at an advanced stage. Compared with other surveys in different regions, the rate of metastasis in this survey was high, leading to a low resection rate. Populations at high risk should undergo B-ultrasound examinations at regular follow-up intervals to increase the rate of early diagnosis of gallbladder carcinoma.

Decision of surgical approach for advanced gallbladder adenocarcinoma based on a Bayesian network.

BACKGROUND AND OBJECTIVES: To determine whether radical resection can benefit patients with advanced gallbladder adenocarcinoma using a Bayesian network (BN) with clinical data. METHODS: In total, 362 patients who had undergone surgical treatment of gallbladder adenocarcinoma at a tertiary institute were evaluated to establish two BN models using a tree-augmented naïve Bayes algorithm. We then chose 250 patients with T3-4N0-2M0 stage gallbladder adenocarcinoma to test the posterior probability after the surgical type was taken into account. RESULTS: In total, 170 patients (≤7 months) and 137 patients (>7 months) were correctly classified in the median survival time model (accuracy, 84.81%), and 204 patients (≤12 months), 15 patients (12-36 months), 17 patients (36-60 months), and 34 patients (>60 months) were correctly classified in the 1-, 3-, and 5-year survival model (accuracy, 74.59%), respectively. Every posterior probability in the two models upregulated the ratio of the longer survival time and suggested a better prognosis for gallbladder adenocarcinoma that can be improved by R0 resection. CONCLUSIONS: These BN models indicate that stages T4 and N2 gallbladder adenocarcinoma are not contraindications for surgery and that R0 resection can improve survival in patients with advanced gallbladder adenocarcinoma.

Long-Term Outcomes and Prognostic Factors in Advanced Gallbladder Cancer: Focus on the Advanced T Stage.

BACKGROUND: Radical resection is an effective therapeutic method to increase the survival rate of patients with gallbladder cancer (GBC). In addition to the surgical approach, the relationships between various clinicopathologic factors and the outcome of patients with GBC remain controversial. METHODS: Clinical and laboratory examination characteristics, pathological and surgical data, and post-operative survival time of 338 patients with advanced GBC who received treatment at the First Affiliated Hospital of Xi'an Jiaotong University, China from January 2008 to December 2012 were analyzed retrospectively. Factors influencing the prognosis of GBC after surgery were analyzed by univariate and multivariate analysis. RESULTS: The overall survival rates for curative resection patients were significantly greater than those for non-curative resection patients (1-,3-,5-year survival rate and mean-survival time: 59.0%, 47.3%, 44.3% and 22.0 months vs. 12.7%, 8.3%, 7.7% and 3.0 months) (P < 0.001). For the curative resection patients, positive margin, lymph node metastasis, poorly pathological differentiation and the presence of ascites were all independent risk factors for poor prognosis. For patients with T3 stage, neither segmentectomy of IVb and V nor common bile duct resection improved the prognosis (P = 0.867 and P = 0.948). For patients with T4 stage, aggressive curative resection improved the prognosis (P = 0.007). CONCLUSIONS: An advanced T stage does not preclude curative resection. Positive margin, lymph node metastasis, poorly pathological differentiation and the presence of ascites are all independent risk factors for poor prognosis in the curative intent resection patients. The range of liver resection and whether common bile duct resection is performed do not influence the prognosis as long as R0 resection is achieved.