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Myc oncoproteins are commonly upregulated in human cancers of different organ origins, stabilized by Aurora A, degraded through ubiquitin–proteasome pathway-mediated proteolysis, and exert oncogenic effects by modulating gene and protein expression. Histone deacetylases are emerging as targets for cancer therapy. Here we demonstrated that the class III histone deacetylase SIRT2 was upregulated by N-Myc in neuroblastoma cells and by c-Myc in pancreatic cancer cells, and that SIRT2 enhanced N-Myc and c-Myc protein stability and promoted cancer cell proliferation. Affymetrix gene array studies revealed that the gene most significantly repressed by SIRT2 was the ubiquitin–protein ligase NEDD4. Consistent with this finding, SIRT2 repressed NEDD4 gene expression by directly binding to the NEDD4 gene core promoter and deacetylating histone H4 lysine 16. Importantly, NEDD4 directly bound to Myc oncoproteins and targeted Myc oncoproteins for ubiquitination and degradation, and small-molecule SIRT2 inhibitors reactivated NEDD4 gene expression, reduced N-Myc and c-Myc protein expression, and suppressed neuroblastoma and pancreatic cancer cell proliferation. Additionally, SIRT2 upregulated and small-molecule SIRT2 inhibitors decreased Aurora A expression. Our data reveal a novel pathway critical for Myc oncoprotein stability, and provide important evidences for potential application of SIRT2 inhibitors for the prevention and therapy of Myc-induced malignancies.

Background/Objectives: This study was aimed to assess the beneficial effects on metabolic syndrome of functional yogurt NY-YP901 (Namyang Dairy Product Co. Ltd and Nutra R&BT Inc., Seoul, Korea) supplemented with mixture of Streptococcus thermophilus , Lactobacillus acidophilus , Bifidobacterium infantis and extra-ingredients containing Bifidobacterium breve (CBG-C2), Enterococcus faecalis FK-23, fibersol-2 and so on. Subjects/Methods: This study was designed as an 8-week randomized, double-blind, placebo-controlled, parallel study. Treatment and control groups consumed a functional yogurt NY-YP901 (150 ml) and a placebo yogurt twice a day, respectively, for 8 weeks. Body weight and body mass index (BMI), blood pressure, lipid profiles, fasting glucose with HbA1C and waist circumference were measured before and after treatment. Inclusion criteria were healthy individuals between the ages 20–65 years old who submitted an informed consent. Results: During the period August 2009 to December 2009, 101 healthy participants (31 males and 70 females) finished the study. Treatment group were 53 individuals, and the control group were 48 individuals. In the treatment group consuming NY-YP901, statistically significant beneficial changes were observed in body weight (treatment group vs control group=−0.24±1.50 vs +0.64±1.39 kg, P <0.05), BMI (−0.10±0.58 vs +0.24±0.50 kg/m 2 , P <0.05 ) and low-density lipoprotein (LDL)-cholesterol (−7.71±14.14 vs −0.43±15.32 mg/dl, P <0.05) after 8 weeks. The change in other parameters was not different between the treatment and the control groups. Conclusions: The functional yogurt NY-YP901 reduced LDL-cholesterol, body weight and BMI in the subjects at a 300-ml consumption daily for 8 weeks. From these findings, regular intake of functional yogurt NY-YP901 may be consequently related to improve metabolic syndrome.

Background: Adjuvant chemotherapy improves survival for patients with resected pancreatic cancer. Elderly patients are under-represented in Phase III clinical trials, and as a consequence the efficacy of adjuvant therapy in older patients with pancreatic cancer is not clear. We aimed to assess the use and efficacy of adjuvant chemotherapy in older patients with pancreatic cancer. Methods: We assessed a community cohort of 439 patients with a diagnosis of pancreatic ductal adenocarcinoma who underwent operative resection in centres associated with the Australian Pancreatic Cancer Genome Initiative. Results: The median age of the cohort was 67 years. Overall only 47% of all patients received adjuvant therapy. Patients who received adjuvant chemotherapy were predominantly younger, had later stage disease, more lymph node involvement and more evidence of perineural invasion than the group that did not receive adjuvant treatment. Overall, adjuvant chemotherapy was associated with prolonged survival (median 22.1 vs 15.8 months; P <0.0001). Older patients (aged ⩾70) were less likely to receive adjuvant chemotherapy (51.5% vs 29.8%; P< 0.0001). Older patients had a particularly poor outcome when adjuvant therapy was not delivered (median survival=13.1 months; HR 1.89, 95% CI: 1.27–2.78, P= 0.002). Conclusion: Patients aged ⩾70 are less likely to receive adjuvant therapy although it is associated with improved outcome. Increased use of adjuvant therapy in older individuals is encouraged as they constitute a large proportion of patients with pancreatic cancer.

Myc oncoproteins and histone deacetylases (HDACs) modulate gene transcription and enhance cancer cell proliferation, and HDAC inhibitors are among the most promising new classes of anticancer drugs. Here, we show that N-Myc and c-Myc upregulated HDAC2 gene expression in neuroblastoma and pancreatic cancer cells, respectively, which contributed to N-Myc- and c-Myc-induced cell proliferation. Cyclin G2 (CCNG2) was commonly repressed by N-Myc and HDAC2 in neuroblastoma cells and by c-Myc and HDAC2 in pancreatic cancer cells, and could be reactivated by HDAC inhibitors. 5-bromo-2′-deoxyuridine incorporation assays showed that transcriptional repression of CCNG2 was, in part, responsible for N-Myc-, c-Myc- and HDAC2-induced cell proliferation. Dual crosslinking chromatin immunoprecipitation assay demonstrated that N-Myc acted as a transrepressor by recruiting the HDAC2 protein to Sp1-binding sites at the CCNG2 gene core promoter. Moreover, HDAC2 was upregulated, and CCNG2 downregulated, in pre-cancerous and neuroblastoma tissues from N-Myc transgenic mice, and c-Myc overexpression correlated with upregulation of HDAC2 and repression of CCNG2 in tumour tissues from pancreatic cancer patients. Taken together, our data indicate the critical roles of upregulation of HDAC2 and suppression of CCNG2 in Myc-induced oncogenesis, and have significant implications for the application of HDAC inhibitors in the prevention and treatment of Myc-driven cancers.

Pancreatic ductal adenocarcinoma (PDAC) is characterized by abundant stroma that harbors tumor-promoting properties. No good biomarkers exist to monitor the effect of stromal targeting therapies or to predict response. We set out to identify such non-invasive markers for PDAC stroma and predict response to therapy. Gene expression datasets, co-culture experiments, xenografts, and patient samples were analyzed. Serum samples were measured from a cohort of 58 resected patients, and 87 metastatic or locally advanced PDAC patients. Baseline and follow-up levels were assessed in 372 additional metastatic PDAC patients who received nab-paclitaxel with gemcitabine (n = 184) or gemcitabine monotherapy (n = 188) in the phase III MPACT trial. Increased levels of ADAM12 were found in PDAC patients compared to healthy controls (p < 0.0001, n = 157 and n = 38). High levels of ADAM12 significantly associated with poor outcome in resected PDAC (HR 2.07, p = 0.04). In the MPACT trial survival was significantly longer for patients who received nab-paclitaxel and had undetectable ADAM12 levels before treatment (OS 12.3 m vs 7.9 m p = 0.0046). Consistently undetectable or decreased ADAM12 levels during treatment significantly associated with longer survival as well (OS 14.4 m and 11.2 m, respectively vs 8.3, p = 0.0054). We conclude that ADAM12 is a blood-borne proxy for stromal activation, the levels of which have prognostic significance and correlate with treatment benefit.

New clinical scales for semiquantitating disease activity in systemic lupus erythematosus (SLE) are widely used in research. They are reliable and valid measures. One of the original scales, the Systemic Lupus Activity Measure (SLAM), has been modified based on experience with it in multiobserver studies and training of individuals in its use. We tested the psychometric properties of the revised SLAM (SLAM-R). SLAM-R was tested on 30 SLE patients, who fulfilled 1997 revised ACR criteria and were selected to represent a range of disease activity. The patients were evaluated independently by two physicians, who studied the instruction booklet and who had never used SLAM-R, on two occasions 2–4 weeks apart. At the first visit, the physician's global assessment of activity using visual analog scale, anti-dsDNA Ab, C3 and C4 were checked for construct validity. The psychometric properties were analyzed with nested analysis of variance and Pearson's correlation coefficient using SAS. All patients were female, the median age was 31 (15–52) y, and the mean score of SLAM-R was 10.5±5.3 (3–26). Estimates of reliability were 0.78 of inter-rater, 0.61 of inter-visit, 0.76 of physician 1 between visits, and 0.56 of physician 2 between visits. Among subcategories except ‘Eye,’ the ‘Gastrointestinal’ category had the highest (0.96) and the ‘Neuromotor’ category had the lowest inter-rater reliability (0.50). With respect to construct validity, the correlation of SLAM-R scores with the disease activity variables except C4 was high and statistically significant. In conclusion, the SLAM-R is reliable and valid for measuring clinical disease activity in SLE.

Background Postoperative inguinal hernia (IH) is a non-negligible sequelae with a wide array of rates after robot-assisted laparoscopic radical prostatectomy (RALP). Our aim was to evaluate the incidence and risk factors of postoperative IH development in men undergoing RALP. Methods A retrospective analysis of 839 patients “541 of conventional-RALP (C-RALP), and 298 of Retzius sparing-RALP (RS-RALP)” received treatment of prostate cancer between 2005 and 2016 and met with our inclusion criteria was performed. Primary endpoint was incidence of IH after RALP, while secondary endpoint was to assess risk factors of IH occurrence. Results Overall incidence of postoperative IH was 6.3% (53 out of 839). Mean follow-up period and median time of IH development were 24.1 and 14.0 months, respectively. Among patients who developed IH, there was a higher incidence in C-RALP compared to RS-RALP, (79.2 vs 20.8%, respectively, P  = 0.02). Multivariate analysis showed that BMI group (HR 0.471, P  = 0.023) and C-RALP (HR 2.834, P  = 0.002) were significant predictors of IH development. Kaplan–Meier curve showed that 3-year IH-disease progression free rate was significantly higher after RS-RALP compared to C-RALP (94.2 vs 71.6%, respectively, P  < 0.001), likewise in obese versus non-obese patients (87.7 vs 76.6%, respectively, P  < 0.003). Conclusion Our study showed that overall incidence of IH was 6.3% after RALP. Nevertheless, RS-RALP carries a lower incidence of IH after surgery, while C-RALP and low BMI are predictors of IH development.

Based on the three phases of remote sensing imageries in 2000, 2010 and 2020, taking Boao town as the study area, this paper analyzed the changes in the ecological environment and the driving forces of ecological environment. The results showed that: (1) The main land use type of Boao town was forest, followed by cultivated land. The main change of land use types in Boao town from 2000 to 2020 is from forest to other land types. (2) The average vegetation coverage of Boao town was 70.68% in 2000, 62.49% in 2010 and 71.65% in 2020, which indicated a trend of first decreasing and then increasing. (3) The changes of landscape pattern index of type level from 2000 to 2020 were as follows: the landscape shape index and landscape fragmentation of cultivated land decreased gradually, while the landscape shape index and landscape fragmentation of construction land and forest land increased. The trend of landscape pattern index of landscape level from 2000 to 2020 was as follows: landscape fragmentation continued to increase, landscape spread continued to decline, landscape separation continued to rise, and landscape diversity and evenness continued to increase. (4) In the driving force analysis of ecological environment changes in Boao Town, the results of principal component analysis showed that human factors were the leading factors of ecological environment changes in Boao Town, and economic factors such as GDP, output value of the third industry and per capita disposable income of farmers were the main driving forces of landscape pattern changes in Boao town.

Irritable bowel syndrome (IBS) is a common and chronic gastrointestinal disorder. Probiotics may have the potential to impact the management of IBS; however, the results of trials are conflicting. This study aimed to investigate whether a mixture of lactobacilli probiotics could improve abdominal symptoms in patients with unconstipated IBS. Fifty Vietnamese patients with unconstipated IBS were randomly assigned to either the probiotics or placebo groups. During the intervention, participants took the probiotic supplement, named Foodis Lactobacillus, or placebo capsule once a day. Patients recorded their subject global assessment (SGA) weekly and were assessed with the visual analogue scale (VAS) during the 4-week study period. Patients with SGA score of 2 points or more or a decrease of more than 30% in VAS score were considered responders. Patients who responded weekly for more than 2 of the 4 weeks were considered overall responders. There was no significant difference in demographic characteristics between the groups. Overall responder rates of improvement of global IBS symptoms assessed by SGA score were significantly higher in the probiotics group (80.8%) than in the placebo group (45.8%) (p = 0.009). The overall responder rates assessed by VAS score were also higher in the probiotics group (69.2%, 41.7%, p = 0.048). There were no adverse events in either group during the study period. Our findings suggest that the new combination of Lactobacilli appears to be promising in the relief of abdominal symptoms in Vietnamese patients with unconstipated IBS.

Objective: Depression and brief periods of manic symptoms are linked to a significant risk of progression to bipolar disorder (BD) in children who have a first-degree relative with BD I or II. However, little evidence exists to guide the pharmacologic management of children with these high-risk phenotypes. We propose a pharmacological treatment algorithm for high-risk youth and present results on its use in a study of children with a first-degree relative with BD. Methods: Subjects were 40 youth (mean 12.7 years, range 9–17 years) who had (1) a first-degree relative with lifetime history of BD I or II, (2) DSM-IV-TR diagnoses of BD not otherwise specified, major depressive disorder or cyclothymic disorder, and (3) active symptoms of depression, mania, or hypomania. Participants and their families were enrolled in a randomized trial examining the effects of two psychosocial interventions on the 1-year course of mood disorder. At study intake, participants received a psychiatric evaluation and were offered medications or had existing medications optimized to decrease symptom severity. During the 1-year study, psychiatrists treated participants using a medication algorithm to treat depressive or manic symptoms as well as comorbid anxiety and/or attention-deficit/hyperactivity disorder. Results: At study entry, 25 of 40 (62.5%) of the participants were taking at least one psychiatric medication. At 1 year, nearly an identical proportion were taking medications (22 of 35, 63%). Independent ratings indicated that in 84.7% of the study visits, physicians maintained adherence to the algorithm. No patients experienced antidepressant- or stimulant-induced mania during the study. Conclusions: An algorithmic approach to pharmacologic interventions may aid in the management of youth (i.e., age <18) at high risk for BD. Future studies should compare outcomes in high-risk patients receiving algorithm-prescribed treatment versus those receiving treatment as usual. Clinical Trial Registration Information: Early Family-Focused Treatment for Youth at Risk for Bipolar Disorder; www.clinicaltrials.gov/; NCT00943085.