Pharmacogenetics and Cancer Treatment: Progress and Prospects

The response of cancer patients to chemotherapy follows a very heterogeneous pattern. Pharmacogenetics is the study of inherited differences in interindividual drug disposition and effects, with the goal of selecting the optimal drug therapy and dosage for each patient. Pharmacogenetics for cancer treatment is very significant, as cancer therapies exhibit severe systemic toxicity and unpredictable efficacy. There is presence of genetic polymorphisms in the genes which code for the metabolic enzymes and cellular targets for the majority of chemotherapy agents, but to predict the outcome of chemotherapy in patients is not currently possible for most treatments. A greater understanding of the genetic determinants of drug response can revolutionize the use of many medications. By identifying the patients at risk for severe toxicity, or those likely to benefit from a particular treatment, individualized cancer therapy can be achieved for most cancer patients. The prediction of cancer treatment outcome based on gene polymorphisms is becoming possible for many classes of chemotherapy agents, and the most clinically significant examples of chemotherapy agents are discussed in the chapter. However, further studies are needed in well characterized and larger cancer populations with proper validation of pharmacogenetic markers in experimental settings before application in clinical routine diagnostics

Comparative genetic diversity analysis of oat (Avena sativa L.) by microsatellite markers and morphological rainfed expressions

Equivalence was appraised between phenotypic and molecular markers (ISSR) to analyze the genetic diversity of 20 high yielding genotypes representing different geographical zones of the world. A moderate range of genetic similarity (0.84 to 0.20) was observed on the basis of 20 inter-simple sequence repeats (ISSR) markers, where it was found high (0.995 – 0.204) on the basis of 7 primary morphological rainfed expression. Genotypes in morphological character based dendogram were clustered into their respective geographic groups, while a random grouping was observed in dendogram based on the ISSR markers. A negative correlation (r = -0.186) was found among morphological and molecular marker systems, but the latter was found effective in distinguishing the genotypes using specific band positions for them. The genotypic classification agreed closely with the grouping observed in ISSR based 3D analysis.Keywords: Avena sativa, diversity, inter-simple sequence repeats (ISSR), morphology, oat, relationshipAfrican Journal of Biotechnology Vol. 12(22), pp. 3414-342

PHYTOCHEMICAL AND ANTIOXIDANT PROPERTIES OF VARIOUS EXTRACTS OF MICHELIA CHAMPACA LEAVES

Objective: To investigate and compare the phytochemicals, antioxidant activities of various crude extracts from fresh leaves of locally available plant Michelia champaca belonging to family Magnoliaceae. Methods: The present study was designed to perform preliminary phytochemical (qualitative and quantitative) analysis of various extracts. The crude extracts from the leaves of M. champaca were prepared using various organic solvents viz. Methanol (MCMET), Ethanol (MCETH), Hexane (MCHEX), and Chloroform (MCCHLO). In addition, total phenolic (TPC) and total flavonoid (TFC) contents of various extracts were also measured along with the evaluation of the antioxidant capacities using most widely accepted in vitro chemical tests such as DPPH and ABTS radical scavenging assay. Results: The methanolic extract of M. champaca showed the presence of maximum phytochemicals (12) when compared to other solvent extracts viz. Hexane (10), Ethanol (8) and Chloroform(7). The amount of phenolic and flavonoids present in solvents were in the order of Methanol>Hexane>Ethanol>Chloroform. The best antioxidant potential was found in the Methanol extract. The Methanolic extract exhibited an IC50 value of 72.03µg/ml (DPPH) and of 185.21µg/ml (ABTS), respectively for the two radical scavenging assays. Conclusion: Phytochemical analysis of M. champaca (leaves) various extracts showed good amounts of phenolic and flavonoid contents and also exhibited significant antioxidant activity. A positive linear correlation between the antioxidant activities and the total phenolic and flavonoid contents of the plant extracts was observed. Study revealed variations in such reported activities due to different organic extraction solvents used. In overall conclusion, Michelia champaca has good potential as a source of natural antioxidant for animal health and food industry and further relevant studies on similar lines would be worthwhile

Molecular diversity analysis in selected fodder and dual purpose oat (Avena sativa L.) genotypes by using random amplified polymorphic DNA (RAPD)

Genetic variability among 15 oat genotypes comprising fodder and dual purpose oat varieties from different geographical regions was analyzed by random amplified polymorphic DNA (RAPD) marker method in Department of Genetics and Plant Breeding, College of Agriculture, Pant University of Agriculture and Technology (G.B.P.U.A. & T.), Pantnagar. The results show appreciably high genetic diversity among the oat genotypes studied. Fifteen (15) primers selected from 20 RAPD primers could amplify 259 clear and identifiable bands, of which 250 bands were polymorphic, accounting for 96.52% genetic polymorphism. All the oat genotypes studied could be distinctly divided into two major groups with the genetic distance level at 0.46 by cluster analysis based on the Jaccard’s coefficient of similarity. The cluster break indicated sufficient genetic variability among the genotypes. Clustering pattern of the varieties appeared such that it can be grouped in the genotypes suitable for the fodder purpose and the dual purpose varieties separately. Several polymorphic bands were also found in different genotypes which helped in molecular diversity analysis of these genotypes. The results found are encouraging and indicate that RAPD technique is an easy, quick and reliable technique used for molecular diversity analysis for preliminary selection.Keywords: Oats, RAPD, genetic diversity, polymorphism.African Journal of Biotechnology Vol. 12(22), pp. 3425-342

ECONOMIC IMPACTS ON THE ILLINOIS ECONOMY OF ALTERNATIVE DAIRY PRODUCTION SYSTEMS

Dairy in Illinois has declined in farm numbers, cows, and value of dairy product. Alternative dairy systems (intensive grazing, traditional, and a concentrated feeding system) were evaluated for their potential to sustain dairy in Illinois. The economic impact of each system on the Illinois economy was evaluated using IMPLAN.Livestock Production/Industries,

Further Development of the Sextupole and Decapole Spool Corrector Magnets for the LHC

In the Large Hadron Collider (LHC) the main dipoles will be equipped with sextupole (MCS) and decapole (MCD) spool correctors to meet the very high demands of field quality required for the satisfactory operation of the machine. Each decapole corrector will in addition have an octupole insert (MCO) and the assembly of the two is designated MCDO. These correctors are needed in relatively large quantities, i.e. 2464 MCS Sextupoles and 1232 MCDO Decapole-Octupole assemblies. Half the number of the required spool correctors will be made in India through a collaboration between CERN and CAT (Centre for Advanced Technology, Indore, India), the other half will be built by European industry. The paper describes final choices concerning design, materials, production techniques, and testing so as to assure economic magnet manufacture but while maintaining a homogenous magnetic quality that results in a robust product

Updates in Pharmacogenetics of Non-Small Cell Lung Cancer

Though significant clinical advances have been made, lung cancer remains the most lethal, with a low 5-year survival rate. The variability in patient response towards therapy is substantial and is associated with lung cancer’s genomic landscape. Pharmacogenetic studies have deciphered many clinically relevant associations between tumor genetic alterations and their influences on drug efficacy, toxicity sensitivity and overall outcomes of cancer treatment. Biomarkers are tools in the arsenal that can help in the prediction, prognosis, diagnosis and follow-up of cancer treatment. Bulk and single-cell next-generation sequencing of large patient cohorts have generated a better understanding of the genetic underpinnings of lung cancer, and opening up personalized therapeutic opportunities. Immunotherapy and personalized medicine are providing hope for lung cancer patients. This review highlights the genetic alterations and important lung cancer biomarkers. The pharmacogenetic associations, personalized immunotherapy and challenges associated with effective therapy are also discussed. Pharmacogenetics and pharmacogenomics can open up new vistas for optimized, personalized NSCLC treatment

Current trends in drug metabolism and pharmacokinetics.

Pharmacokinetics (PK) is the study of the absorption, distribution, metabolism, and excretion (ADME) processes of a drug. Understanding PK properties is essential for drug development and precision medication. In this review we provided an overview of recent research on PK with focus on the following aspects: (1) an update on drug-metabolizing enzymes and transporters in the determination of PK, as well as advances in xenobiotic receptors and noncoding RNAs (ncRNAs) in the modulation of PK, providing new understanding of the transcriptional and posttranscriptional regulatory mechanisms that result in inter-individual variations in pharmacotherapy; (2) current status and trends in assessing drug-drug interactions, especially interactions between drugs and herbs, between drugs and therapeutic biologics, and microbiota-mediated interactions; (3) advances in understanding the effects of diseases on PK, particularly changes in metabolizing enzymes and transporters with disease progression; (4) trends in mathematical modeling including physiologically-based PK modeling and novel animal models such as CRISPR/Cas9-based animal models for DMPK studies; (5) emerging non-classical xenobiotic metabolic pathways and the involvement of novel metabolic enzymes, especially non-P450s. Existing challenges and perspectives on future directions are discussed, and may stimulate the development of new research models, technologies, and strategies towards the development of better drugs and improved clinical practice

Experimental study of superconducting wire motion on the base insulating material in magnetic field

　　　One of the most prominent applications of superconductivity is high fieldmagnet. Mechanical disturbance such as abrupt conductor motion is one of the mainorigin of premature quench (transition from superconducting state to the normalresistive state) in high current density superconducting coils. The wire motion occurswhen electromagnetic force to conductor exceeds constrain force including frictionalforce on the surface of conductor. Behavior of superconducting wire motion dependson the electromagnetic force acting on it, frictional property of the insulating materialand thrust force applied to the superconducting wire.　　　The experiments for superconducting wire motion in magnetic field wascarried out using small coil wound on stainless steel (SUS) bobbin using Polyimidefilm as an insulating material and high strength polyethylene fiber (Dyneema: DF)reinforced plastic (DFRP) bobbin [1]. The Dyneema fiber has negative thermalexpansion [2] and low coefficient of friction [3]. It was found that voltage spikesgenerated due to sudden wire motion in case of DFRP bobbin are a few and small inamplitude. The speculations are; the negative thermal expansion of the DFRP bobbinrestrains the wire motion and low coefficient of friction between superconductingwire and DFRP bobbin reduces sudden motion.　　　In order to study the effect of frictional coefficient of insulating material onsuperconducting wire motion under the influence of electromagnetic force, a specialexperimental setup was designed and fabricated. The main distinctiveness of theexperimental setup is that the tension of the superconducting wire can be changedduring the experiments. The experimental set up consists of a cryostat,superconducting solenoid magnet, sample holder, tensional unit to apply tension tothe superconducting wire, power supplies and pen recorder or a 16-bit data recorderto measure the voltage tap signal. The sample holder consists of two parts, a semi-circular head and a body part. Experiments were conducted at 4.2 K by varying theexperimental conditions such as the tension to the superconducting wire,superconducting wire current ramp rate and different insulating materials at theinterface of the superconducting wire and semi-circular head. 　　　Voltage taps to measure the signal generated due to the superconducting wiremotion are connected at the end of the semi-circular head. To reduce the voltage taploop area, a groove was incorporated in the semi-circular head and the voltage tapwire was passed through it. The voltage tap signal is measured by a pen recorder or a16-bit data recorder with a sampling rate of 1 MS/s. Sudden wire motion wasindicated by observing the voltage spikes. 　　　In order to examine the effect of the current ramp rate on the superconductingwire motion, ramp rate was changed from 0.4 A/s to 1.69 A/s. The superconductingwire tension was varied from 7.1 N to 35.8 N to study the effect of tension on thesuperconducting wire motion. During all experiments, a constant magnetic field of 6T was applied by superconducting solenoid magnet. 　　　In the thesis work, different types of insulating material were used to studysuperconducting wire motion under electromagnetic force. They are Polyimide film,cloth / sheet material fabricated using Dyneema fiber, Zylon fiber and Teflon. TheDyneema / Zylon fiber has negative thermal expansion and a low coefficient offriction.　　　We have verified the effectiveness of this system. We could measure thepattern of voltage spikes. The time duration of voltage spikes are of the same orderfor all the samples. The peak voltage tap signal amplitude, velocity of wire motion,distance moved by wire and energy dissipated due to wire motion in case ofPolyimide film is more than 2 order of magnitude larger than Dyneema basedinsulating materials and Zylon cloth. Hence use of Dyneema / Zylon based materialsas an interface material between layers of superconducting wire may reduce thefrictional heat generated due to wire motion and could make superconducting magnetperformance more reliable

Association of functionally important polymorphisms in cytochrome P450s with squamous cell carcinoma of head and neck

651-665Head and neck squamous cell carcinoma (HNSCC), a common malignancy that possibly involves a combination of exposure to the carcinogens and inherited genetic differences in the enzymes catalyzing their metabolism. Alcohol and tobacco consumption are the primary environmental risk factors, while polymorphism in various biotransformation enzymes such as cytochrome P450s (CYPs) and glutathione S-transferases, (GSTs) has been implicated as the major genetic risk factors for the development of HNSCC. The functionally important polymorphisms in these CYPs (1A1*2A, 1A1*2C, 1B1*2, 2E1*5B, 2E1*6, 2C19*2, 2D6*4, 2D6*10) and GSTs (GSTM1-null or GSTT1-null) were found to be significantly associated with HNSCC risk. Significant differences in the distribution of certain haplotypes of CYPs have also been reported and prevalence of certain genotype combinations of CYPs and GSTS in cases has indicated the importance of gene-gene interactions in HNSCC risk. Alcohol or tobacco use (smoking and chewing) were also found to interact synergistically with variant genotypes of these CYPs and GSTS in significantly enhancing HNSCC risk. This increase in risk associated with the variant genotypes with tobacco or alcohol use have further demonstrated the importance of gene–environment interactions in determining the susceptibility to HNSCC.</b