Discovery and SAR exploration of N-aryl-N-(3-aryl-1,2,4-oxadiazol-5-yl)amines as potential therapeutic agents for prostate cancer

A new chemical series of antiproliferative compounds was identified via high-throughput screening on DU-145 human prostate carcinoma cell line (hit compound potency - 5.7 μM). Exploration of the two peripheral diversity vectors of the hit molecule in a hit-targeted library and testing of the resulting compounds led to SAR generalizations and identification of the 'best' pharmacophoric moieties. The latter were merged in a single compound that exhibited a 200-fold better potency than the original hit compound. Specific cancer cell cytotoxicity was confirmed for the most potent compounds

Prognostic Significance of Vitamin D Receptor Polymorphisms in Head and Neck Squamous Cell Carcinoma

BACKGROUND:In patients with advanced non-small-cell lung cancer, vitamin D receptor (VDR) polymorphisms and haplotypes are reported to be associated with survival. We hypothesized that a similar association would be observed in patients with head and neck squamous-cell carcinoma (HNSCC). METHODS:In a post-hoc analysis of our previous prospective cohort study, VDR polymorphisms including Cdx2 G/A (rs11568820), FokI C/T (rs10735810), BsmI A/G (rs1544410), ApaI G/T (rs7976091), and TaqI T/C (rs731236) were genotyped by sequencing in 204 consecutive patients with HNSCC who underwent tumor resection. Progression-free survival was compared between VDR polymorphisms using Kaplan-Meier survival curves with log-rank tests and Cox proportional hazard models adjusting for age, gender, smoking status, primary tumor sites, postoperative stages, existence of residual tumor, and postoperative treatment with chemotherapy or radiotherapy. RESULTS:During a median follow-up of 1,047 days, tumor progression and death occurred in 76 (37.3%) and 27 (13.2%) patients, respectively. The FokI T/T genotype was associated with poor progression-free survival: median survival for T/T was 265 days compared with 1,127 days for C/C or C/T (log-rank test: P = 0.0004; adjusted hazard ratio, 3.03; 95% confidence interval, 1.62 to 5.67; P = 0.001). In contrast, the other polymorphisms (Cdx2, BsmI, ApaI, TaqI) showed no significant association with progression-free survival. The A-T-G (Cdx2-FokI-ApaI) haplotype demonstrated a significant association with a higher progression rate (P = 0.02). CONCLUSION:These results suggest that VDR polymorphisms and haplotypes may be associated with prognosis in patients with HNSCC, although the sample size is not large enough to draw definitive conclusions

Anticancer activity of a sub-fraction of dichloromethane extract of Strobilanthes crispus on human breast and prostate cancer cells in vitro

<p>Abstract</p> <p>Background</p> <p>The leaves of <it>Strobilanthes crispus </it>(<it>S. crispus</it>) which is native to the regions of Madagascar to the Malay Archipelago, are used in folk medicine for their antidiabetic, diuretic, anticancer and blood pressure lowering properties. Crude extracts of this plant have been found to be cytotoxic to human cancer cell lines and protective against chemically-induced hepatocarcinogenesis in rats. In this study, the cytotoxicity of various sub-fractions of dichloromethane extract isolated from the leaves of <it>S. crispus </it>was determined and the anticancer activity of one of the bioactive sub-fractions, SC/D-F9, was further analysed in breast and prostate cancer cell lines.</p> <p>Methods</p> <p>The dichloromethane extract of <it>S. crispus </it>was chromatographed on silica gel by flash column chromatography. The ability of the various sub-fractions obtained to induce cell death of MCF-7, MDA-MB-231, PC-3 and DU-145 cell lines was determined using the LDH assay. The dose-response effect and the EC₅₀values of the active sub-fraction, SC/D-F9, were determined. Apoptosis was detected using Annexin V antibody and propidium iodide staining and analysed by fluorescence microscopy and flow cytometry, while caspase 3/7 activity was detected using FLICA caspase inhibitor and analysed by fluorescence microscopy.</p> <p>Results</p> <p>Selected sub-fractions of the dichloromethane extract induced death of MCF-7, MDA-MB-231, PC-3 and DU-145 cells. The sub-fraction SC/D-F9, consistently killed breast and prostate cancer cell lines with low EC₅₀values but is non-cytotoxic to the normal breast epithelial cell line, MCF-10A. SC/D-F9 displayed relatively higher cytotoxicity compared to tamoxifen, paclitaxel, docetaxel and doxorubicin. Cell death induced by SC/D-F9 occurred via apoptosis with the involvement of caspase 3 and/or 7.</p> <p>Conclusions</p> <p>A dichloromethane sub-fraction of <it>S. crispus </it>displayed potent anticancer activities <it>in vitro </it>that can be further exploited for the development of a potential therapeutic anticancer agent.</p

MiR-34a Represses Numbl in Murine Neural Progenitor Cells and Antagonizes Neuronal Differentiation

MicroRNA (miRNA) function is required for normal animal development, in particular in differentiation pathways from stem cell and precursor populations. In neurogenesis, it is becoming increasingly appreciated that miRNAs act at many stages to ensure proper progression. In this study we examined the role of miR-34a in neural progenitor cells (NPC) derived from murine embryonic cortex. We found that over-expression of miR-34a in NPC significantly reduced the neuron yield upon in vitro induction of differentiation. MiR-34a has several predicted targets in the Notch pathway, which operates to balance progenitor self-renewal and differentiation during cortical neurogenesis. We tested several Notch pathway players for regulation by miR-34a in undifferentiated NPC, and found that mRNA and protein levels of Numbl, a negative regulator of Notch signaling, as well as two downstream pro-neural genes usually blocked by Notch signaling, NeuroD1 and Mash1, were diminished, while Notch1 and Cbf1 transcripts were enhanced by miR-34a over-expression. Using a luciferase reporter assay, we verified the Numbl 3′-UTR as a direct miR-34a target. Correspondingly, knock-down of endogenous miR-34a resulted in increased Numbl, NeuroD1 and Mash1, and reduced Notch1 transcript levels. Together these results implicate Numbl as a physiologically relevant target of miR-34a in NPC, allowing for enhanced Notch signaling and inhibition of neuronal differentiation. This work extends our understanding of miR-34a-mediated control of cell differentiation from cancer to mammalian nervous system development

Regular consumption of vitamin D-fortified yogurt drink (Doogh) improved endothelial biomarkers in subjects with type 2 diabetes: a randomized double-blind clinical trial

<p>Abstract</p> <p>Background</p> <p>Endothelial dysfunction has been proposed as the underlying cause of diabetic angiopathy that eventually leads to cardiovascular disease, the major cause of death in diabetes. We recently demonstrated the ameliorating effect of regular vitamin D intake on the glycemic status of patients with type 2 diabetes (T2D). In this study, the effects of improvement of vitamin D status on glycemic status, lipid profile and endothelial biomarkers in T2D subjects were investigated.</p> <p>Methods</p> <p>Subjects with T2D were randomly allocated to one of the two groups to receive either plain yogurt drink (PYD; containing 170 mg calcium and no vitamin D/250 mL, n₁= 50) or vitamin D3-fortified yogurt drink (FYD; containing 170 mg calcium and 500 IU/250 mL, n₂= 50) twice a day for 12 weeks. Anthropometric measures, glycemic status, lipid profile, body fat mass (FM) and endothelial biomarkers including serum endothelin-1, E-selectin and matrix metalloproteinase (MMP)-9 were evaluated at the beginning and after the 12-week intervention period.</p> <p>Results</p> <p>The intervention resulted in a significant improvement in fasting glucose, the Quantitative Insulin Check Index (QUICKI), glycated hemoglobin (HbA1c), triacylglycerols, high-density lipoprotein cholesterol (HDL-C), endothelin-1, E-selectin and MMP-9 in FYD compared to PYD (<it>P </it>< 0.05, for all). Interestingly, difference in changes of endothelin-1, E-selectin and MMP-9 concentrations in FYD compared to PYD (-0.35 ± 0.63 versus -0.03 ± 0.55, <it>P </it>= 0.028; -3.8 ± 7.3 versus 0.95 ± 8.3, <it>P </it>= 0.003 and -2.3 ± 3.7 versus 0.44 ± 7.1 ng/mL, respectively, <it>P </it>< 0.05 for all), even after controlling for changes of QUICKI, FM and waist circumference, remained significant for endothelin-1 and MMP-9 (<it>P </it>= 0.009 and <it>P </it>= 0.005, respectively) but disappeared for E-selectin (<it>P </it>= 0.092). On the contrary, after controlling for serum 25(OH)D, the differences disappeared for endothelin-1(<it>P </it>= 0.066) and MMP-9 (<it>P </it>= 0.277) but still remained significant for E-selectin (<it>P </it>= 0.011).</p> <p>Conclusions</p> <p>Ameliorated vitamin D status was accompanied by improved glycemic status, lipid profile and endothelial biomarkers in T2D subjects. Our findings suggest both direct and indirect ameliorating effects of vitamin D on the endothelial biomarkers.</p> <p>Trial registration</p> <p>ClinicalTrials.gov: <a href="http://www.clinicaltrials.gov/ct2/show/NCT01236846">NCT01236846</a></p

Oncogenic senescence: a multi-functional perspective

Contains fulltext : 174435.pdf (publisher's version ) (Open Access)Cellular senescence is defined as an irreversible growth arrest with the acquisition of a distinctive secretome. The growth arrest is a potent anticancer mechanism whereas the secretome facilitates wound healing, tissue repair, and development. The senescence response has also become increasingly recognized as an important contributor to aging and age-related diseases, including cancer. Although oncogenic mutations are capable of inducing a beneficial senescence response that prevents the growth of premalignant cells and promotes cancer immune-surveillance, the secretome of senescent cells also includes factors with pro-tumorigenic properties. On June 23rd and 24th, 2016, the Division of Cancer Biology of the National Cancer Institute sponsored a workshop to discuss the complex role of cellular senescence in tumorigenesis with the goal to define the major challenges and opportunities within this important field of cancer research. Additionally, it was noted how the development of novel tools and technologies are required to accelerate research into a mechanistic understanding of senescent cells in carcinogenesis in order to overcome the current limitations in this exciting, yet ill-defined area

Interferon-inducible IFI16, a negative regulator of cell growth, down-regulates expression of human telomerase reverse transcriptase (hTERT) gene

10.1371/journal.pone.0008569PLoS ONE51e856

Monitoring and Management of Proteinuria Is Often Ignored in Patients Receiving mTOR Therapy Following Orthotopic Liver Transplantation

Purpose: Use of mTOR inhibitors, such as Everolimus (EVL), in liver transplant (LT) patients continues to rise as the side effect profile becomes more evident. Calcineurin inhibitors, suchas Tacrolimus, have an increased incidence of nephrotoxicity whereas EVL remains a viable option to decrease the likelihood of renal dysfunction. In renal transplant patients, standard of care involves regular monitoring urine protein levels. however no such consensus exists amongst LT patients. We analyzed renal function by assessing proteinuria in LT patients started on EVL. Methods: All patients receiving a LT between 2011 and 2014 treated with EVL were evaluated. Background infonnation included age, gender and race. Assessment of urine protein to creatinine (UP/C) ratios was done prior to starting EVL. Follow up UP/C ratios were analyzed after starting EVL at 3 months and anytime past 6 months. Nephrotic range was defined as spot urine protein to creatinine ratio greater than 1 gram (g). Statistics were calculated using ANOVA, T-test and Chi-squared tests. Results: 75 LT patients composed primarily of males (76%) with an average age of 60.9 years were analyzed. There were 58 Caucasians (77%) and 11 African Americans (14.7%). Out of 75 total patients, 84% of patients had a UP/C ratio measured before starting EVL. After starting EVL, 30.7% had a follow up UP/C ratio measured at any given time. 11 patients had a UP/C ratio measured at 3 months and 17 patients at any time after 6 months. Before starting EVL the mean UP/C ratio was 0.17g. At the 3 month follow-up, mean UP/C ratio was 1.30g (p=0.112). At any point past 6 months from the time EVL therapy was started, mean UP/C ratio was 1.45g (p=0.504). 56.5% of patients that had their UP/C ratio checked, EVL was discontinued. The mean number of months was 17.2 at which EVL was stopped from time of initiation. Conclusions: EVL appears to lead to a significant increase in proteinuria in LT patients with the progression of time. There is a potential for worsening renal function, however regular follow up is lacking. It remains imperative that substantial proteinuria should lead to the discontinuation of EVL to prevent further renal toxicity

Monitoring and Management of Proteinuria Is Often Ignored in Patients Receiving mTOR Therapy Following Orthotopic Liver Transplantation

Purpose: Use ofmTOR inhibitors, such as Everolimus(EVL), in liver transplant (LT) patients continues to rise as the side effect profile becomes more evident. Calcineurin inhibitors, suchas Tacrolimus, have an increased incidence of nephrotoxicity whereas EVLremainsaviableoptiontodecreasethelikelihood of renal dysfunction. In renal transplant patients, standardof care involves regular monitoring urine protein levels. however no such consensus exists amongst LT patients. We analyzed renal function by assessing proteinuria in LT patients started on EVL. Methods: All patients receivingaLTbetween2011 and 2014 treated withEVLwere evaluated. Background infonnation included age, gender and race. Assessment of urine protein to creatinine (UP/C) ratios was done prior to starting EVL. Follow up UP/C ratios were analyzed after starting EVL at 3 months and anytime past 6 months. Nephrotic range was defined as spot urine protein to creatinine ratio greater than 1 gram (g). Statistics were calculated using ANOVA, T-test and Chi-squared tests. Results: 75 LT patients composed primarily of males (76%) with an average age of 60.9years were analyzed. There were 58 Caucasians (77%) and 11 African Americans (14.7%). Out of 75 total patients, 84% of patients had a UP/C ratio measured before starting EVL. After starting EVL, 30.7% had a follow up UP/C ratio measured at any given time. 11 patients had a UP/C ratio measured at 3 months and 17 patients at any time after 6 months. Before starting EVL the mean UP/C ratio was 0.17g. At the 3 monthfollow-up, mean UP/C ratio was 1.30g (p=0.112). At any point past 6 months from the time EVL therapy was started, mean UP/C ratio was 1.45g (p=0.504). 56.5% of patients that had their UP/C ratio checked, EVL was discontinued. The meannumber of months was 17.2 at which EVL was stopped from time ofinitiation. Conclusions: EVL appears to lead to a significant increase in proteinuria in LT patients with the progression of time. There is a potential for worsening renal func-tion, however regular follow up is lacking. It remains imperative that substantial proteinuria shouldlead to the discontinuation of EVL to prevent further renal toxicity

Inpatient Burden of Esophageal Varices in the United States: Analysis of Rrends in Demographics, Cost of Care, and Outcomes

Background: Esophageal variceal bleeding remains a common reason for hospitalization in the United States. The main objective of this study was to analyze demographic variations and outcomes in hospitalizations related to esophageal varices (EV) in the US. Methods: We performed a retrospective observational cohort study using National Inpatient Sample (NIS) database for all hospitalizations with discharge diagnoses of EV, with and without hemorrhage from 2001 to 2011. Results: In 2001, there were 19,167 hospitalizations with discharge diagnoses of EV with and without bleeding compared to 45,578 in 2011 (P\u3c0.001). There was a 138% increase in the number of total EV hospitalizations, a 221% increase in hospitalizations with EV without hemorrhage, and a 7% increase in hospitalizations for patients with EV and hemorrhage. Age group 50-64 was the most affected, accounting for 31.4% of EV hospitalizations in 2001 and 46.7% of EV hospitalizations in 2011 (P\u3c0.001). The overall in-hospital mortality rate was 3.4% for patients with EV without hemorrhage and 8.7% for patients with EV with hemorrhage (P=0.0003). Conclusions: The number of hospitalizations for patients with asymptomatic EV increased significantly between 2001 to 2011, with only a small concurrent increase in the number of hospitalizations for patients with esophageal variceal bleeding