BAP1 dependent expression of long non-coding RNA NEAT-1 contributes to sensitivity to gemcitabine in cholangiocarcinoma

Expression of NEAT-1 in malignant cholangiocytes. (PDF 11 kb

Synergistic Effects Of Garcinol And Gemcitabine In Enhancing Therapeutic Efficacy In Pancreatic Adenocarcinoma Cells And Its Effect On Microrna Profile

SYNERGISTIC EFFECTS OF GARCINOL AND GEMCITABINE IN ENHANCING THERAPEUTIC EFFICACY IN PANCREATIC ADENOCARCINOMA CELLS AND ITS EFFECT ON MICRORNA PROFILE By MANSI PARASRAMKA ADVISOR: DR. SMITI V. GUPTA MAJOR: NUTRITION AND FOOD SCIENCE DEGREE: DOCTOR OF PHILOSPHY Human Pancreatic Cancer (PaCa) is one of the most hostile and fourth leading cause of cancer deaths in the United States. Current standard chemotherapeutic agent for advanced PaCa is gemcitabine, a cytotoxic nucleoside analogue which results in modest response due to high degree of inherent and acquired chemo resistance. Forthcoming evidence strongly supports that non-nutritive food components have therapeutic benefits attributable to pleiotropic effects including inactivation of survival signaling and simultaneously activating multiple death pathways in tumors. Garcinol from the plant Garcinia indica have exhibited anti-inflammatory, antioxidant, and anticarcinogenic activity in several cancer types including colon, tongue, breast, skin and liver. This study aims to test 1) therapeutic efficacy of garcinol against PaCa (BxPC-3 and Panc-1) cells 2A) its role in dietary interactions with curcumin and 2B) drug sensitization with gemcitabine and 3) identify microRNA targets in PaCa cells on treatment with garcinol and gemcitabine. The activity of transcription factor nuclear factor - ?;B (NF-?;B) has long been associated with pancreatic tumor growth and angiogenesis, playing an important role in cell survival, chemotaxis and inflammation. Angiogenesis, a very crucial process in tumorigenesis requires the interplay between NF-?;B with other proangiogenic and antiangiogenic factors such as vascular endothelial growth factor (VEGF), Interleukin-8 (IL-8) and matrix metalloproteinase (MMP-9). We hypothesize that molecular targeting of critical signaling pathways (NF- ?;B, VEGF, IL-8 and MMP-9) with gemcitabine in combination with garcinol may improve efficacy by enhancing the signaling response to treatment. Emerging evidence suggests that microRNAs regulate carcinogenesis by controlling gene expression either by their tumor suppressor or oncogenic abilities. We observed that garcinol individually or in combination with curcumin or gemcitabine exhibited potent anticancer abilities in PaCa cells by down-regulating cancer promoting pathways and up-regulating the tumor suppressor mechanisms. Decreased NF- ?;B activity was observed in both cell lines in combination treatment along with significantly reduced levels of angiogenic factors MMP-9, VEGF, IL-8 and PGE2. We also performed target analysis after treatment to identify those microRNAs that regulate several cancer signaling pathways. We observed a downregulation in expression of oncogenic miRNA - 21, - 196a and - 495 along with upregulation of tumor suppressor miRNA - 638 and - 453 on treatment with garcinol alone or in combination with gemcitabine. Overall, our results demonstrate that garcinol and gemcitabine in combination have higher efficacy in modulating levels of various factors involved in tumorigenesis and have potential in chemotherapy against PaCa

Synergistic Effect of Garcinol and Curcumin on Antiproliferative and Apoptotic Activity in Pancreatic Cancer Cells

Pancreatic cancer (PaCa) is a major health concern due to its aggressiveness and early metastasis. Current treatments for PaCa are limited by development of resistance against therapy. As an alternative strategy, we assessed the combinatorial effect of dietary compounds, garcinol and curcumin, on human PaCa cells (BxPC-3 and Panc-1). A significant (P < 0.05) dose-dependent reduction in cell viability and increase in apoptosis were observed in both cell lines as compared to untreated controls. A combination index (CI) value < 1, for a two-way comparison of curcumin and garcinol, suggests synergism. The potency (Dm) of the combination of garcinol and curcumin was 2 to 10 fold that of the individual agents. This indicates that curcumin and garcinol in combination exhibit a high level of synergism, with enhanced bioactivity, thereby reducing the required effective dose required for each individually. This combinatorial strategy may hold promise in future development of therapies against PaCa

Fast 3D Printing of Fine, Continuous, and Soft Fibers via Embedded Solvent Exchange

Nature uses fibrous structures for sensing and structural functions as observed in hairs, whiskers, stereocilia, spider silks, and hagfish slime thread skeins. Here, we demonstrate multi-nozzle printing of 3D hair arrays having freeform trajectories at a very high rate, with fiber diameters as fine as 1.5 µm, continuous lengths reaching tens of centimeters, and a wide range of materials with elastic moduli from 5 MPa to 3500 MPa. This is achieved via 3D printing by rapid solvent exchange in high yield stress micro granular gel, leading to radial solidification of the extruded polymer filament at a rate of 2.33 μm/s. This process extrudes filaments at 5 mm/s, which is 500,000 times faster than meniscus printing owing to the rapid solidification which prevents capillarity-induced fiber breakage. This study demonstrates the potential of 3D printing by rapid solvent exchange as a fast and scalable process for replicating natural fibrous structures for use in biomimetic functions

A role for low-abundance miRNAs in colon cancer: the miR-206/Krüppel-like factor 4 (KLF4) axis

Abstract Background MicroRNAs (miRNAs or miRs) are short non-coding RNAs that affect the expression of genes involved in normal physiology, but that also become dysregulated in cancer development. In the latter context, studies to date have focused on high-abundance miRNAs and their targets. We hypothesized that among the pool of low-abundance miRNAs are some with the potential to impact crucial oncogenic signaling networks in colon cancer. Results Unbiased screening of over 650 miRNAs identified miR-206, a low-abundance miRNA, as the most significantly altered miRNA in carcinogen-induced rat colon tumors. Computational modeling highlighted the stem-cell marker Krüppel-like factor 4 (KLF4) as a potential target of miR-206. In a panel of primary human colon cancers, target validation at the mRNA and protein level confirmed a significant inverse relationship between miR-206 and KLF4, which was further supported by miR-206 knockdown and ectopic upregulation in human colon cancer cells. Forced expression of miR-206 resulted in significantly increased cell proliferation kinetics, as revealed by real-time monitoring using HCT116 cells. Conclusions Evolutionarily conserved high-abundance miRNAs are becoming established as key players in the etiology of human cancers. However, low-abundance miRNAs, such as miR-206, are often among the most significantly upregulated miRNAs relative to their expression in normal non-transformed tissues. Low-abundance miRNAs are worthy of further investigation, because their targets include KLF4 and other pluripotency and cancer stem-cell factors. </jats:sec

Regulation of miR-200c and miR-141 by methylation in prostate cancer

BACKGROUND: In prostate cancer (PCa), abnormal expression of several microRNAs (miRNAs) has been previously reported. Increasing evidence shows that aberrant epigenetic regulation of miRNAs is a contributing factor to their altered expression in cancer. In this study, we investigate whether expression of miR‐200c and miR‐141 in PCa is related to the DNA methylation status of their promoter. METHODS: PCR analysis of miR‐200c and miR‐141, and CpG methylation analysis of their common promoter, was performed in PCa cell‐lines and in archived prostate biopsy specimens. The biological significance of miR‐200c and miR‐141 expression in prostate cancer cells was assessed by a series of in vitro bioassays and the effect on proposed targets DNMT3A and TET1/TET3 was investigated. The effect on promoter methylation status in cells treated with demethylating agents was also examined. RESULTS: miR‐200c and miR‐141 are both highly elevated in LNCaP, 22RV1, and DU145 cells, but significantly reduced in PC3 cells. This correlates inversely with the methylation status of the miR‐200c/miR‐141 promoter, which is unmethylated in LNCaP, 22RV1, and DU145 cells, but hypermethylated in PC3. In PC3 cells, miR‐200c and miR‐141 expression is subsequently elevated by treatment with the demethylating drug decitabine (5‐aza‐2′deoxycytidine) and by knockdown of DNA methyltransferase 1 (DNMT1), suggesting their expression is regulated by methylation. Expression of miR‐200c and miR‐141 in prostate biopsy tissue was inversely correlated with methylation in promoter CpG sites closest to the miR‐200c/miR‐141 loci. In vitro, over‐expression of miR‐200c in PC3 cells inhibited growth and clonogenic potential, as well as inducing apoptosis. Expression of the genes DNMT3A and TET1/TET3 were down‐regulated by miR‐200c and miR‐141 respectively. Finally, treatment with the soy isoflavone genistein caused demethylation of the promoter CpG sites closest to the miR‐200c/miR‐141 loci resulting in increased miR‐200c expression. CONCLUSIONS: Our findings provide evidence that miR‐200c and miR‐141 are under epigenetic regulation in PCa cells. We propose that profiling their expression and methylation status may have potential as a novel biomarker or focus of therapeutic intervention in the diagnosis and prognosis of PCa. Prostate 76:1146–1159, 2016. © 2016 The Authors. The Prostate published by Wiley Periodicals, Inc

Design of multijunction solar cells based on thin film silicon

Multijunction devices based on thin film silicon are useful for a range of applications due to their low costs, better performance at higher temperatures, potential for flexibility, and light weight. One particularly interesting application of such devices is in solar-to-fuel conversion. In light of this, the goal of this thesis was to suggest ways to better design multijunction devices based on thin film silicon. Three main research objectives were identified.The first objective was the development of a high VOC top junction. Cells based on a-Si and a-SiOX were optimized by varying gas flows during the deposition of the intrinsic absorber layer. A maximum VOC of around 890 mV was obtained from cells based on both absorbers. Based on these results, it was possible to identify unique advantages of using either a-Si or a-SiOX as the top junction. For the second research objective, solar cells based on a-SiGe were studied. The impact of varying the bandgap profile in a-SiGe absorbers on the device performance was investigated with a set of experiments. Subsequently, a set of semi-empirical equations were motivated and fitted to the experimental data. These relations could approximately show how bandgap profiling affects device performance in a more general way. The presented approach may be used to expedite the design of a-SiGe based cells for use in different types of multijunction devices. Finally, a systematic optimization of tunnel recombination junctions (TRJ) was conducted. Experiments were done to study the impact of using different TRJs in two types of tandem devices: a-Si/a-SiGe and a-SiGe/nc-Si. Different features of the TRJ were varied separately: p-doped layer(s) used, thicknesses of the p-doped layer(s), and the n-doped layer(s) used. The best performing p-doped layers was identified among the studied combinations. For the n-layer(s), the experimental data suggested the different roles played by n-a-Si, n-nc-SiOX, and n-nc-Si in the TRJ. This observation could be used to design an optimized combination of n-layers for the TRJ. Collectively, the work done as part of each research objective aims to contribute to the better design of multijunction devices based on thin film silicon alloys.DISCOElectrical Engineering | Sustainable Energy Technolog