Multi Drug Resistance on Cancer Cell Lines

This document can be treated as Final Thesis Report for the project titled "Multi-Drug Resistance on Cancer Cell Lines". Drug is said to be resistant on cancer site if it doesn't bind the specified cancer tumor target or site. Drug Resistant mutant is a major obstacle in cancer treatment and a lot of research have been done to overcome this phenomenon with the present technology and also with limited success. My interests lies in understanding drug resistance or more specifically multi-drug resistance with the help of mathematical modeling through the lens of system biology. The processes and underlying experimental research is much applied than the simple mathematics which explains it here. You may find some experimental quotations and results which I have to believe to be true in order to address the problem. The central theme of this project is two-fold. First, we look at a stochastic processes describing cancer growth, mutant formation and treatment success or failure based on whether resistant mutants are created prior-to/after treatment or based on the rate of growth of cancer cells under simultaneous treatment with single/multiple drugs. Further refinement in the existing model is necessary to include biological complexity and realism. So, we incorporate cross-resistance effects of drugs which happens when multiple drugs are used for treatment. Result shows that cross-resistant two drugs are superior than single drug in use as most of the mutation confers resistant to that single drug in first line therapy. Adding second drug in combination with the first drug, despite of cross-resistance effect, improves the treatment success. We will also look into the aspects of quiescence effects and its relation to drug resistance. Finally, at the end we will review an optimal drug dozing regimen based on continuous and pulsed dosing scheme to delay the resistance formation to a maximum extent that arises due to single (epi) genetic alteration only. The stochastic process described here is multi-type branching process. We will calculate the resistance generation probability based on initial cancer tumor load and growth or death rate of cell colony. We will also find an average population size of resistant cells over time scale and other useful parameters defining the multi-type branching process

Antibacterial activity of leaf extracts of some selected traditional medicinal plants of Uttarakhand, North East India

Screenings of methanolic leaf extracts of nine medicinal plants (Cotinus coggygria, Adhatoda vesica, Argemone mexicana, Zanthoxylum armatum, Berberis asiatica, Corissa opaca, Euphorbia hirta, Cassio fistula and Ricinus communis), belonging to selected areas of Uttarakhand, were tested against seven bacterial strains (Bacillus subtilis, Staphylococcus aureus, Escherichia coli, Enterobactor aerogenes, Klebsiella pneumoniae, Proteus vulgaris and Pseudomonas aeruginosa) by disc diffusion method. Leaf extracts of R. communis, B. asiatica and C. opaca showed high (13 – 23) effect on all the bacterial strains while E. hirta, Z. armatum and A. vesica exhibits minimum (6 – 15) effects. Remaining leaf extracts of plants were found moderately (10 - 19) effective

A COMPARATIVE STUDY OF MULTIDIMENSIONAL TRAIT ANXIETY BETWEEN INTERVARSITY AND NATIONAL LEVEL HANDBALL PLAYERS OF MADHYA PRADESH

ABSTRACT An investigation was conducted with a purpose of compare the level of multidimensional trait anxiety between university and national level handball players of Madhya Pradesh. For the purpose of this investigation 40 male subjects (20 university and 20 national level players) were recruited as subjects of the study

Antibacterial and antifungal evaluation of some chalcogen bearing ligands, their transition and nontransition metal complexes

Eight chalcogen bearing compounds, 3-(4-fluorophenyl telluro) propylamine (1), 3-(phenyl telluro)propylammonium acetate salt (2), 3-(phenyl telluro)propylacetamide (3) and α-(phenylseleno) acetic acid (4) (1-4 are ligands), [Ph2Sn(Cl).1](NO3 ) (5), [Ph3Sn.1](BPh4 ) (6), [ZnCl2 .2] (7) and [CdCl2.2] (8) (5-8 are complexes of 1 and 2) were synthesised and screened for antibacterial activity against Gram-positive bacterial strains of Staphylococcus aureus, Bacillus anthracis and the Gramnegative bacteria Escherchia coli. They were also tested for their antifungal activity against Candida tropicalis, Trichophyton rubrum and Asperegillus niger, by using the disk diffusion technique. Inhibition zones demonstrated that compounds 1–3 showed significant activity, due to the presence of N in the form of amine group however Compound 4 bearing an acidic group, shows higher activity against bacterial strains. Compounds 5–8 (having Sn, Zn and Cd in their framework) showed still higher activities, due to increase in the lipophilicity and easier penetration of the compounds into the outer cell wall of the microorganisms, which causes death due to cell membrane rupturing. Compounds 1–8 were most effective against E. coli (bacterial strains), as the cell wall of Gram-negative strains have thin outer lipid membrane, which is made up of lipopolysaccharides. These compounds showed slightly reduced antifungal activity, because the cell wall of fungi is made up of chitin, which is difficult to cross. It could be concluded, from the obtained results that the biological activity of compounds is essentially determined by the number and nature of the organic groups and central metal ion. The presence of NH2, COOH group as well as metal ion like Sn, Zn, Cd in the compounds leads to higher activity

High Fat Diet Upregulates Fatty Acid Oxidation and Ketogenesis via Intervention of PPAR-γ

Background/Aims: Systemic hyperlipidemia and intracellular lipid accumulation induced by chronic high fat diet (HFD) leads to enhanced fatty acid oxidation (FAO) and ketogenesis. The present study was aimed to determine whether activation of peroxisome proliferator-activated receptor-γ (PPAR-γ) by surplus free fatty acids (FA) in hyperlipidemic condition, has a positive feedback regulation over FAO and ketogenic enzymes controlling lipotoxicity and cardiac apoptosis. Methods: 8 weeks old C57BL/6 wild type (WT) or PPAR-γ-/- mice were challenged with 16 weeks 60% HFD to induce obesity mediated type 2 diabetes mellitus (T2DM) and diabetic cardiomyopathy. Treatment course was followed by echocardiographic measurements, glycemic and lipid profiling, immunoblot, qPCR and immunohistochemistry (IHC) analysis of PPAR-γ and following mitochondrial metabolic enzymes 3-hydroxy-3-methylglutaryl-CoA synthase (HMGCS2), mitochondrial β- hydroxy butyrate dehydrogenase (BDH1) and pyruvate dehydrogenase kinase isoform 4 (PDK4). In vivo model was translated in vitro, with neonatal rat cardiomyocytes (NRCM) treated with PPAR-γ agonist/antagonist and PPAR-γ overexpression adenovirus in presence of palmitic acid (PA). Apoptosis was determined in vivo from left ventricular heart by TUNEL assay and immunoblot analysis. Results: We found exaggerated circulating ketone bodies production and expressions of the related mitochondrial enzymes HMGCS2, BDH1 and PDK4 in HFD-induced diabetic hearts and in PA-treated NRCM. As a mechanistic approach we found HFD mediated activation of PPAR-γ is associated with the above-mentioned mitochondrial enzymes. HFD-fed PPAR-γ-/-mice display decreased hyperglycemia, hyperlipidemia associated with increased insulin responsiveness as compared to HFD-fed WT mice PPAR-γ-/–HFD mice demonstrated a more robust functional recovery after diabetes induction, as well as significantly reduced myocyte apoptosis and improved cardiac function. Conclusions: PPAR-γ has been described previously to regulate lipid metabolism and adipogenesis. The present study suggests for the first time that increased PPAR-γ expression by HFD is responsible for cardiac dysfunction via upregulation of mitochondrial enzymes HMGCS2, BDH1 and PDK4. Targeting PPAR-γ and its downstream mitochondrial enzymes will provide novel strategies in preventing metabolic and myocardial dysfunction in diabetes mellitus

A Doctor’s Training in COVID Era

Doctors have severely been impacted by COVID19 not only by overburden but also by a shift in training programmes. With objective to identify the impact of COVID19 on the present training programme of doctors and delineate the possible future impact and find ways to reduce it, a literature review was carried on. Various impacts and adaptations were found. These could be different for different individuals, specialities, and regions based on available resources and the direct impact of COVID19. Although long-term effects are yet to be seen, it has raised several brows, especially questioning the traditional way of training and competency of individuals trained in specialities. We recommend a hybrid model—a mixture of virtual and real training and assessment—for medical education even in the post-COVID era to reap the benefits of both

Mycobacterium indicus pranii Supernatant Induces Apoptotic Cell Death in Mouse Peritoneal Macrophages In Vitro

Mycobacterium indicus pranii (MIP), also known as Mw, is a saprophytic, non-pathogenic strain of Mycobacterium and is commercially available as a heat-killed vaccine for leprosy and recently tuberculosis (TB) as part of MDT. In this study we provide evidence that cell-free supernatant collected from original MIP suspension induces rapid and enhanced apoptosis in mouse peritoneal macrophages in vitro. It is demonstrated that the MIP cell-free supernatant induced apoptosis is mitochondria-mediated and caspase independent and involves mitochondrial translocation of Bax and subsequent release of AIF and cytochrome c from the mitochondria. Experiments with pharmacological inhibitors suggest a possible role of PKC in mitochondria-mediated apoptosis of macrophages

Kilonova Luminosity Function Constraints Based on Zwicky Transient Facility Searches for 13 Neutron Star Merger Triggers during O3

We present a systematic search for optical counterparts to 13 gravitational wave (GW) triggers involving at least one neutron star during LIGO/Virgo's third observing run (O3). We searched binary neutron star (BNS) and neutron star black hole (NSBH) merger localizations with the Zwicky Transient Facility (ZTF) and undertook follow-up with the Global Relay of Observatories Watching Transients Happen (GROWTH) collaboration. The GW triggers had a median localization area of 4480 deg², a median distance of 267 Mpc, and false-alarm rates ranging from 1.5 to 10⁻²⁵ yr⁻¹. The ZTF coverage in the g and r bands had a median enclosed probability of 39%, median depth of 20.8 mag, and median time lag between merger and the start of observations of 1.5 hr. The O3 follow-up by the GROWTH team comprised 340 UltraViolet/Optical/InfraRed (UVOIR) photometric points, 64 OIR spectra, and three radio images using 17 different telescopes. We find no promising kilonovae (radioactivity-powered counterparts), and we show how to convert the upper limits to constrain the underlying kilonova luminosity function. Initially, we assume that all GW triggers are bona fide astrophysical events regardless of false-alarm rate and that kilonovae accompanying BNS and NSBH mergers are drawn from a common population; later, we relax these assumptions. Assuming that all kilonovae are at least as luminous as the discovery magnitude of GW170817 (−16.1 mag), we calculate that our joint probability of detecting zero kilonovae is only 4.2%. If we assume that all kilonovae are brighter than −16.6 mag (the extrapolated peak magnitude of GW170817) and fade at a rate of 1 mag day⁻¹ (similar to GW170817), the joint probability of zero detections is 7%. If we separate the NSBH and BNS populations based on the online classifications, the joint probability of zero detections, assuming all kilonovae are brighter than −16.6 mag, is 9.7% for NSBH and 7.9% for BNS mergers. Moreover, no more than 10⁻⁴, or φ > 30° to be consistent with our limits. We look forward to searches in the fourth GW observing run; even 17 neutron star mergers with only 50% coverage to a depth of −16 mag would constrain the maximum fraction of bright kilonovae to <25%

Production of He-4 and (4) in Pb-Pb collisions at root(NN)-N-S=2.76 TeV at the LHC

Results on the production of He-4 and (4) nuclei in Pb-Pb collisions at root(NN)-N-S = 2.76 TeV in the rapidity range vertical bar y vertical bar <1, using the ALICE detector, are presented in this paper. The rapidity densities corresponding to 0-10% central events are found to be dN/dy4(He) = (0.8 +/- 0.4 (stat) +/- 0.3 (syst)) x 10(-6) and dN/dy4 = (1.1 +/- 0.4 (stat) +/- 0.2 (syst)) x 10(-6), respectively. This is in agreement with the statistical thermal model expectation assuming the same chemical freeze-out temperature (T-chem = 156 MeV) as for light hadrons. The measured ratio of (4)/He-4 is 1.4 +/- 0.8 (stat) +/- 0.5 (syst). (C) 2018 Published by Elsevier B.V.Peer reviewe