Benzyl Isothiocyanate Suppresses Pancreatic Tumor Angiogenesis and Invasion by Inhibiting HIF-α/VEGF/Rho-GTPases: Pivotal Role of STAT-3

Our previous studies have shown that benzyl isothiocyanate (BITC) suppresses pancreatic tumor growth by inhibiting STAT-3; however, the exact mechanism of tumor growth suppression was not clear. Here we evaluated the effects and mechanism of BITC on pancreatic tumor angiogenesis. Our results reveal that BITC significantly inhibits neovasularization on rat aorta and Chicken-Chorioallantoic membrane. Furthermore, BITC blocks the migration and invasion of BxPC-3 and PanC-1 pancreatic cancer cells in a dose dependant manner. Moreover, secretion of VEGF and MMP-2 in normoxic and hypoxic BxPC-3 and PanC-1 cells was significantly suppressed by BITC. Both VEGF and MMP-2 play a critical role in angiogenesis and metastasis. Our results reveal that BITC significantly suppresses the phosphorylation of VEGFR-2 (Tyr-1175), and expression of HIF-α. Rho-GTPases, which are regulated by VEGF play a crucial role in pancreatic cancer progression. BITC treatment reduced the expression of RhoC whereas up-regulated the expression of tumor suppressor RhoB. STAT-3 over-expression or IL-6 treatment significantly induced HIF-1α and VEGF expression; however, BITC substantially suppressed STAT-3 as well as STAT-3-induced HIF-1α and VEGF expression. Finally, in vivo tumor growth and matrigel-plug assay show reduced tumor growth and substantial reduction of hemoglobin content in the matrigel plugs and tumors of mice treated orally with 12 µmol BITC, indicating reduced tumor angiogenesis. Immunoblotting of BITC treated tumors show reduced expression of STAT-3 phosphorylation (Tyr-705), HIF-α, VEGFR-2, VEGF, MMP-2, CD31 and RhoC. Taken together, our results suggest that BITC suppresses pancreatic tumor growth by inhibiting tumor angiogenesis through STAT-3-dependant pathway

Recasting the pedagogy of derivations as loading of reality into mathematics

Derivations constitute a major component of physics education, particularly in India. They are usually taught as a string of mathematical propositions and procedures with little to no connection to the physical world (Sirnoorkar et al., 2016). This results in the whole teaching/learning process getting restricted to symbolic manipulations and mathematical operations, with the aim of arriving at an equation (Tuminaro & Redish, 2007; Walsh et al., 2007). In an effort to improve the learning experience of derivations, specifically to present derivations as an instance of building a mathematical model, we designed and developed an interactive learning system and an associated teaching narrative. This combination presents derivations as a process of systematically loading reality into mathematical symbols, to develop an ‘enactive prediction machine’ (the equation; Redish & Kuo, 2015). Through this structure, we make explicit the key processes involved in mathematical modelling of a real-world process (Majumdar et al., 2014). Providing an appreciation of the thinking process underlying derivations was one of our primary design requirements. Some of the key design features of the system are: • Rootedness in familiar real-world contexts, with anchoring questions• Explicit rendition of the conceptual structure and key steps in the derivation process• Interactive visualization and manipulability • Enactive equations Our goal was to understand how participants’ nature of learning was influenced by this new learning system and narrative. We tested the system by inviting participants with a minimal background in physics to interact with it. Results suggest that the system and associated teaching narrative provided an improvement over prior learning experiences specific to derivations. We briefly discuss the inputs we received, plausible reasons, and implications of these results. REFERENCES Majumdar, R., Kothiyal, A., Pande, P., Ranka, A., Murthy, S., Agrawal, H., & Chandrasekharan, S. (2014, August). The Enactive equation: Exploring How Multiple External Representations are Integrated, Using a Fully Controllable Interface and Eye-Tracking. Proceedings - IEEE 6th International Conference on Technology for Education, T4E 2014. https://doi.org/10.1109/T4E.2014.31 Redish, E. F., & Kuo, E. (2015). Language of Physics, Language of Math: Disciplinary Culture and Dynamic Epistemology. Science & Education, 24(5), 561–590. https://doi.org/10.1007/s11191-015-9749-7 Sirnoorkar, A., Mazumdar, A., & Kumar, A. (2016). Students’ epistemic understanding of mathematical derivations in physics. European Journal of Physics, 38(1), 15703. https://doi.org/10.1088/0143-0807/38/1/015703 Tuminaro, J., & Redish, E. F. (2007). Elements of a cognitive model of physics problem solving: Epistemic games. Physical Review Special Topics – Physics Education Research, 3(2), 020101. https://doi.org/10.1103/PhysRevSTPER.3.020101 Walsh, L. N., Howard, R. G., & Bowe, B. (2007). Phenomenographic study of students’ problem-solving approaches in physics. Physical Review Special Topics – Physics Education Research, 3(2), 020108

Expression of 3-hydroxy-3-methylglutaryl-CoA reductase, p-hydroxybenzoate-m-geranyltransferase and genes of phenylpropanoid pathway exhibits positive correlation with shikonins content in arnebia [Arnebia euchroma (Royle) Johnston]

<p>Abstract</p> <p>Background</p> <p>Geranyl pyrophosphate (GPP) and <it>p</it>-hydroxybenzoate (PHB) are the basic precursors involved in shikonins biosynthesis. GPP is derived from mevalonate (MVA) and/or 2-<it>C</it>-methyl-D-erythritol 4-phosphate (MEP) pathway(s), depending upon the metabolite and the plant system under consideration. PHB, however, is synthesized by only phenylpropanoid (PP) pathway. GPP and PHB are central moieties to yield shikonins through the synthesis of <it>m</it>-geranyl-<it>p</it>-hydroxybenzoate (GHB). Enzyme <it>p</it>-hydroxybenzoate-<it>m</it>-geranyltransferase (PGT) catalyses the coupling of GPP and PHB to yield GHB.</p> <p>The present research was carried out in shikonins yielding plant arnebia [<it>Arnebia euchroma </it>(Royle) Johnston], wherein no molecular work has been reported so far. The objective of the work was to identify the preferred GPP synthesizing pathway for shikonins biosynthesis, and to determine the regulatory genes involved in the biosynthesis of GPP, PHB and GHB.</p> <p>Results</p> <p>A cell suspension culture-based, low and high shikonins production systems were developed to facilitate pathway identification and finding the regulatory gene. Studies with mevinolin and fosmidomycin, inhibitors of MVA and MEP pathway, respectively suggested MVA as a preferred route of GPP supply for shikonins biosynthesis in arnebia. Accordingly, genes of MVA pathway (eight genes), PP pathway (three genes), and GHB biosynthesis were cloned. Expression studies showed down-regulation of all the genes in response to mevinolin treatment, whereas gene expression was not influenced by fosmidomycin. Expression of all the twelve genes vis-à-vis shikonins content in low and high shikonins production system, over a period of twelve days at frequent intervals, identified critical genes of shikonins biosynthesis in arnebia.</p> <p>Conclusion</p> <p>A positive correlation between shikonins content and expression of <it>3-hydroxy-3-methylglutaryl-CoA reductase </it>(<it>AeHMGR</it>) and <it>AePGT </it>suggested critical role played by these genes in shikonins biosynthesis. Higher expression of genes of PP pathway was a general feature for higher shikonins biosynthesis.</p

Pore resistivity variation by Resistivity imaging technique in sedimentary part of main Gadilam river basin, Cuddalore District, Tamil Nadu, India

Electrical resistivity is the only property of physics which give information of subsurface moisture content in the formation, Hence geophysical electrical resistivity survey was carried out to investigate the nature of shallow subsurface formations and geological contact in the main Gadilam river basin of Cuddalore District in Tamil Nadu. Twenty-seven vertical electrical soundings (VES) were conducted by Schlumberger configuration in the basin. Data is interpreted by curve matching techniques using IPI2 WIN software, layer parameters like apparent resistivity (?a) and thickness (h) interpretation were exported to Geographic Information System (GIS). Interpretation distinguishes three major geoelectric layers like topsoil, sandy clay layer, clayey sand layer along the contact zone in the basin. Interpreted VES sounding curves are mostly four-layer cases of QH, H, HA and KH type. Investigation demarcates lithology of subsurface and hydrogeological set up by employing maximum possible electrode sounding to infer saline water and freshwater occurrence based on resistivity signals. Zone of groundwater potential map was prepared with the combination of resistivity (?= ?1+ ?2+ ?3+ ?4) and corresponding thickness (T= T1+T2+T3+T4). High resistivity value of &gt;200 ? m and low resistivity value of &lt;10 ? m show the occurrence of alkaline and saline water within the formation aquifers as a result of possible rock water interaction and saline water dissolution. Four-layer resistivity cases from the matched curve (namely KH, AH, QA, and KA type) show the resistivity distribution/variation. It separates the freshwater depth wish from 1 to 140 ? m in fluvial sediments. Flood basin, sandstone and clay layer with low resistivity value of 3.16 - 7.5 ? m indicates contact with saline and freshwater aquifer. The Iso – resistivity map delineates saline water and freshwater zones with in the fourth layer cases in the same locations to indicate the irrational way of abstracting groundwater, resulting in saltwater ingress

Is manipulation under anaesthesia still a better option than intra articular steroid injection in primary frozen shoulder?

Background: Frozen shoulder, also known as adhesive capsulitis, is a common cause of a painful shoulder with restricted motion. The best treatment of frozen shoulder is prevention (secondary frozen shoulder), but early intervention is paramount; a good understanding of the pathologic process by the patient and the physician also is important. The aim of study is comparison between closed manipulation under anaesthesia and intra articular steroid injection in primary periarthritis shoulder.Methods: 30 patients each with primary frozen shoulder who were treated either with closed manipulation under anaesthesia and intra articular steroid injection. The patient is reassessed after 2 weeks, 1 month, 3 month and 6 months using shoulder pain and disability index (SPADI) and visual analogue scales (VAS) to compare the groups.Results: The SPADI index found to be better with patients under went closed manipulation under anaesthesia than intra articular steroid injection in the first 2 weeks. Follow up shows 1st group shows better outcome than 2nd group at 1 month, but later on 3 months and 6 months shows comparable results. VAS score shows initial period of improvement in pain with steroid injection (2nd group). Final follow up shows better pain relief with manipulation under anaesthesia group.Conclusions: The immediate treatment outcome is better with patients with primary frozen shoulder underwent closed manipulation under anaesthesia although following months outcome shows almost equal effectiveness with steroid injection

BITC Sensitizes Pancreatic Adenocarcinomas to TRAIL-Induced Apoptosis

Pancreatic adenocarcinoma is an aggressive cancer with a greater than 95% mortality rate and short survival after diagnosis. Chemotherapeutic resistance hinders successful treatment. This resistance is often associated with mutations in codon 12 of the K-Ras gene (K-Ras 12), which is present in over 90% of all pancreatic adenocarcinomas. Codon 12 mutations maintain Ras in a constitutively active state leading to continuous cellular proliferation. Our study determined if TRAIL resistance in pancreatic adenocarcinomas with K-Ras 12 mutations could be overcome by first sensitizing the cells with Benzyl isothiocyanate (BITC). BITC is a component of cruciferous vegetables and a cell cycle inhibitor. BxPC3, MiaPaCa2 and Panc-1 human pancreatic adenocarcinoma cell lines were examined for TRAIL resistance. Our studies show BITC induced TRAIL sensitization by dual activation of both the extrinsic and intrinsic apoptotic pathways

Adjuvant drugs in management of osteoarthritis: spotlight on type II collagen

Osteoarthritis (OA) is a common musculoskeletal disorder that affects large and small joints and is seen in all ages due to diverse aetiologies. Pain, joint stiffness and limitation of daily activities affects the quality of life of individuals with OA. Conventional analgesics like non-steroidal anti-inflammatory drugs affect pain and inflammatory component but do not target the disease pathogenesis. Damage to the joint cartilage is central to the pathogenesis of OA. Better understanding of the pathogenesis has led to evolution of various adjuvant drugs in management of OA. Among them, undenatured type II collagen induces immune tolerance and thereby provide benefits by reducing the joint damage. Studies assessing efficacy and safety of undenatured type II collagen in OA have shown to reduce clinical symptoms like pain, joint stiffness and improvement in physical activities, and thus improving the quality of life. It is well tolerated and safe for use in OA. This article discusses the pathophysiology of OA with inflammation and beyond, and overviews the various drugs that are used as adjuvants in the management of OA with special focus on the use of type 2 collagen

A Neural Network Simulator for the Connnection Machine

In this paper we describe the design, development, and performance of a neural network simulator for the Connection Machine (CM)3. The design of the simulator is based on the Rochester Connectionist Simulator(RCS). RCS is a simulator for connectionist networks developed at the University of Rochester. The CM simulator can be used as a stand-alone system or as a high-performance parallel back-end to RCS. In the latter case, once the network has been built by RCS, the high-performance parallel back-end system constructs an equivalent network on the CM processor array and executes it. The CM simulator facilitates the exploitation of the massive parallelism inherent in connectionist networks. It can also enable substantial reduction in the training times of connectionist networks

Association of common genetic variants with lipid traits in the Indian population.

Genome-wide association studies (GWAS) have been instrumental in identifying novel genetic variants associated with altered plasma lipid levels. However, these quantitative trait loci have not been tested in the Indian population, where there is a poorly understood and growing burden of cardiometabolic disorders. We present the association of six single nucleotide polymorphisms in 1671 sib pairs (3342 subjects) with four lipid traits: total cholesterol, triglycerides, high density lipoprotein cholesterol (HDL-C) and low density lipoprotein cholesterol (LDL-C). We also investigated the interaction effects of gender, location, fat intake and physical activity. Each copy of the risk allele of rs964184 at APOA1 was associated with 1.06 mmol/l increase in triglycerides (SE = 0.049; p = 0.006), rs3764261 at CETP with 1.02 mmol/l increase in both total cholesterol (SE = 0.042; p = 0.017) and HDL-C (SE = 0.041; p = 0.008), rs646776 at CELSR2-PSRC1-SORT1 with 0.96 mmol/l decrease in cholesterol (SE = 0.043; p = 0.0003) and 0.15 mmol/l decrease in LDL-C levels (SE = 0.043; p = 0.0003) and rs2954029 at TRIB1 with 1.02 mmol/l increase in HDL-C (SE = 0.039; p = 0.047). A combined risk score of APOA1 and CETP loci predicted an increase of 1.25 mmol/l in HDL-C level (SE = 0.312; p = 0.0007). Urban location and sex had strong interaction effects on the genetic association of most of the studied loci with lipid traits. To conclude, we validated four genetic variants (identified by GWAS in western populations) associated with lipid traits in the Indian population. The interaction effects found here may explain the sex-specific differences in lipid levels and their heritability. Urbanization appears to influence the nature of the association with GWAS lipid loci in this population. However, these findings will require replication in other Indian populations