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Cellular irinotecan resistance in colorectal cancer and overcoming irinotecan refractoriness through various combination trials including DNA methyltransferase inhibitors: a review

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Cancer Drug Resistance 2021年第4期4卷 946-964页

作者： Shogo Ozawa Toshitaka Miura Jun Terashima Wataru Habano division of pharmacodynamics and molecular genetics School of PharmacyIwate Medical UniversityYahabaIwate 0283694Japan

Treatment with pharmacological drugs for colorectal cancer(CRC)remains unsatisfactory.A major cause of failure in pharmacotherapy is the resistance of colon cancer cells to the drugs,creating an urgent *** this review,we summarize previous studies on the resistance of CRC cells to irinotecan and discuss possible reasons for *** review presents the following five major causes of irinotecan resistance in human CRC:(1)cellular irinotecan resistance is induced mainly through the increased expression of the drug efflux transporter,ABCG2;(2)cellular irinotecan resistance is also induced in association with a nuclear receptor,pregnane/steroid X receptor(PXR/SXR),which is enriched in the CYP3A4 gene enhancer region in CRC cells by exposing the cells to SN-38;(3)irinotecan-resistant cells possess either reduced DNA topoisomerase I(Top1)expression at both the mRNA and protein levels or Top1 missense mutations;(4)alterations in the tumor microenvironment lead to drug resistance through intercellular vesicle-mediated transmission of miRNAs;and(5)CRC stem cells are the most difficult targets to successfully treat *** the clinical setting,CRC gradually develops resistance to initially effective irinotecan-based *** solve this problem,several clinical trials,such as irinotecan plus cetuximab *** monotherapy,have been *** clinical trial on irinotecan plus guadecitabine,a DNA-methyltransferase inhibitor,has also been conducted.

关键词： Drug resistance colorectal cancer anti-cancer drugs irinotecan ABCG2 DNA topoisomerase I cancer stem cells epigenetics

Therapeutic targeting of cellular prion protein: toward the development of dual mechanism anti-prion compounds

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Neural Regeneration Research 2025年第4期20卷 1009-1014页

作者： Antonio Masone Chiara Zucchelli Enrico Caruso Giovanna Musco Roberto Chiesa Laboratory of Prion Neurobiology Department of NeuroscienceIstituto di Ricerche Farmacologiche Mario Negri IRCCSMilanItaly Biomolecular NMR Unit Division of Genetics and Cell BiologyIRCCS Ospedale San RaffaeleMilanItaly Department of Biotechnology and Life Sciences University of InsubriaVareseItaly

PrPSc,a misfolded,aggregation-prone isoform of the cellular prion protein(PrPC),is the infectious prion agent responsible for fatal neurodegenerative diseases of humans and other *** adopt different pathogenic conformations(prion strains),which can be resistant to potential drugs,or acquire drug resistance,posing challenges for the development of effective *** PrPCis the obligate precursor of any prion strain and serves as the mediator of prion neurotoxicity,it represents an attractive therapeutic target fo r prion *** this minireview,we briefly outline the approaches to target PrPCand discuss our recent identification of Zn(Ⅱ)-Bn PyP,a PrPC-targeting porphyrin with an unprecedented bimodal mechanism of *** argue that in-depth understanding of the molecular mechanism by which Zn(Ⅱ)-Bn PyP targets PrPCmay lead toward the development of a new class of dual mechanism anti-prion compounds.

关键词： anti-prion drug anti-PrPC antibody antisense oligonucleotide neurodegeneration pharmacological chaperone porphyrin prion disease PrPC degrader PrPC shedding zinc finger repressor

CHEMICAL SYNTHESIS AND CLONING OF SECRETIN GENE

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Science China Chemistry 1988年第6期31卷 687-694页

作者：钱苏雯陈常庆李载平 Academia Sinica division of molecular genetics Shanghai Institute of Biochemistry

A DNA duplex coding for the 27 amino acids of secretin has been synthesized and cloned. Indesigning the sequence of the gene, computer analysis has been applied. The following factors have beenconsidered: selection of codon usage in favour of expression in yeast; design of various sites useful ingene cloning, gene modification and expressed product purification; avoiding the repeat sequences whichmay interfere in the ligation of the synthetic fragments. The synthesis involved preparation of 12 oligo-deoxyribonucleotides (12-mer to 24-mer in length) by phosphate triester and phosphite triester method,purification by polyacrylamide gel electrophoresis (PAGE). A new plasmid pWS1 was constructed by inser-tion of the enzymatic ligated gene fragment into plasmid pWR13.

关键词： gene CHEMICAL SYNTHESIS AND CLONING OF SECRETIN GENE OC

Human epidermal growth factor receptor targeted inhibitors for the treatment of ovarian cancer

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Cancer Biology & Medicine 2018年第4期15卷 375-388页

作者： Maria Bonello ANDrew Harvey Sims Simon Peter Langdon Cancer Research UK Edinburgh Center and division of Pathology Laboratory MRC Institute of Genetics and Molecular Medicine University of Edinburgh

Ovarian cancer is the second most lethal gynecological cancer worldwide and while most patients respond to initial therapy, they often relapse with resistant disease. Human epidermal growth factor receptors(especially HER1/EGFR and HER2/ERBB2) are involved in disease progression; hence, strategies to inhibit their action could prove advantageous in ovarian cancer patients,especially in patients resistant to first line therapy. Monoclonal antibodies and tyrosine kinase inhibitors are two classes of drugs that act on these receptors. They have demonstrated valuable antitumor activity in multiple cancers and their possible use in ovarian cancer continues to be studied. In this review, we discuss the human epidermal growth factor receptor family; review emerging clinical studies on monoclonal antibodies and tyrosine kinase inhibitors targeting these receptors in ovarian cancer patients; and propose future research possibilities in this area.

关键词： Tyrosine kinase monoclonal antibodies ovarian cancer inhibitors HER receptors

The role of BRCA1 in DNA damage response

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Protein & Cell 2010年第2期1卷 117-123页

作者： Jiaxue Wu Lin-Yu Lu Xiaochun Yu division of molecular Medicine and genetics Department of Internal MedicineUniversity of Michigan Medical SchoolAnn ArborMI 48109USA

BRCA1 is a well-established tumor suppressor gene,which is frequently mutated in familial breast and ovarian *** gene product of BRCA1 functions in a number of cellular pathways that maintain genomic stability,including DNA damage-induced cell cycle checkpoint activation,DNA damage repair,protein ubiquitination,chromatin remodeling,as well as transcriptional regulation and *** this review,we discuss recent advances regarding our understanding of the role of BRCA1 in tumor suppression and DNA damage response,including DNA damage-induced cell cycle checkpoint activation and DNA damage repair.

关键词： BRCA1 DNA damage response tumorigenesis

Cholangiocyte anion exchange and biliary bicarbonate excretion

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World Journal of Gastroenterology 2006年第22期12卷 3496-3511页

作者： Jesús M Banales Jesús Prieto Juan F Medina Laboratory of molecular genetics division of Gene Therapy and Hepatology University of Navarra School of MedicineClinica Universitaria and CIMAPamplonaSpain

Primary canalicular bile undergoes a process of fluidization and alkalinization along the biliary tract that is influenced by several factors including hormones, innervation/neuropeptides, and biliary constituents. The excretion of bicarbonate at both the canaliculi and the bile ducts is an important contributor to the generation of the so-called bile-salt independent flow. Bicarbonate is secreted from hepatocytes and cholangiocytes through parallel mechanisms which involve chloride efflux through activation of Cl- channels, and further bicarbonate secretion via AE2/SLC4A2-mediated Cl-/HCO3- exchange. Glucagon and secretin are two relevant hormones which seem to act very similarly in their target cells （hepatocytes for the former and cholangiocytes for the latter）. These hormones interact with their specific G protein-coupled receptors, causing increases in intracellular levels of cAMP and activation of cAMP-dependent Cl- and HCO3- secretory mechanisms. Both hepatocytes and cholangiocytes appear to have cAMP-responsive intracellular vesicles in which AE2/SLC4A2 colocalizes with cell specific Cl- channels （CFTR in cholangiocytes and not yet determined in hepatocytes） and aquaporins （AQP8 in hepatocytes and AQP1 in cholangiocytes）, cAMP-induced coordinated trafficking of these vesicles to either canalicular or cholangiocyte lumenal membranes and further exocytosis results in increased osmotic forces and passive movement of water with net bicarbonate-rich hydrocholeresis.

关键词： AE2 anion exchanger Bile salt-independent flow Biliary bicarbonate excretion Regulation of intracellular pH Hydroionic fluxes in cholangiocytes

Obesity phenotype in relation to gene polymorphism among samples of Egyptian children and their mothers

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Genes & Diseases 2018年第2期5卷 150-157页

作者： Nayera E.Hassan Sahar A.El-Masry Waheba Zarouk Rokia A.El Banna Rehab M.Mosaad Muhammad Al-Tohamy Abeer Ramadan Salamah Biological Anthropology Department Medical Research DivisionNational Research CentreGizaEgypt molecular genetics and Enzymology Department Human Genetics and Genomic Research DivisionNational Research CentreGizaEgypt

Obesity is complex heterogeneous disease controlled by genes,environmental factors,and their *** factors account for 40e90%of the body mass index *** mass index(BMI)of children correlates more closely with maternal than paternal ***,this studu was aimed to investigate the role of leptin receptor LEPR Gln223Arg,the uncoupling protein 2(UCP2 G 866 A)and insulin receptor gene(INSR exon 17)polymorphisms in the pathogenesis of obesity.A cross-sectional study executed on 130 children and their obese mothers;classified into 2 groups according to their *** 2 groups were evaluated regarding the *** fragment length analysis for LEPR Gln223Arg,UCP2-866 G/A and INSR exon 17 polymorphisms were *** was reported that increased risk of obesity was found in LEPR AG t AA genotype and the A *** statistical difference was detected only in female *** UCP2,the AG followed by the GG genotype was the most frequent in all groups and the G allele was the mostly present in obese mothers and obese male children but with no statistical *** was difference in the INSR genotype and alleles between groups,but this difference was not statistically *** study concluded that the LEPR Gln223Arg,UCP2 G 866 A and INSR exon 17 polymorphisms are related to obesity in Egyptian *** researches on larger population are recommended to ascertain the implications of LEPR,UCP2 and INSR polymorphisms in obesity.

关键词： Egyptian Gene polymorphism Insulin receptor(INSR) Leptin receptor(LEPR) Obesity Uncoupling protein 2(UCP2) Phenotype

Do not curse the darkness of the spinal cord,light TDP-43

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Neural Regeneration Research 2021年第5期16卷 986-987页

作者： Kazuhide Asakawa Hiroshi Handa Koichi Kawakami Department of Chemical Biology Tokyo Medical UniversityTokyoJapan division of molecular and Developmental Biology National Institute of GeneticsDepartment of GeneticsGraduate University for Advanced Studies(SOKENDAI)ShizuokaJapan

Cytoplasmic inc lus ions containing the transactivation response element(TAR)DNAbinding protein-43(TDP-43)aggregates are hallmarks of neurodegenerative disorders,such as amyotrophic lateral sclerosis(ALS)and frontotemporal dementia(Arai et al.,2006;Neumann et al.,2006).Despite the well-recognized correlation between TDP-43 aggregation and neuronal degeneration,whether this relationship is causal has remained unclear.

关键词： al. degeneration TDP

Loss of Hox5 function results in myofibroblast mislocalization and distal lung matrix defects during postnatal development

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Science China(Life Sciences) 2018年第9期61卷 1030-1038页

作者： Steven M.Hrycaj Leilani Marty-Santos ANDrew J.Rasky Nicholas W.Lukacs Deneen M.Wellik Department of Internal Medicine Division of Molecular Medicine and Genetics University of Michigan Department of Pathology University of Michigan Department of Cell and Developmental Biology University of Michigan

Alveologenesis is the final stage of lung development and is responsible for the formation of the principle gas exchange units called alveoli. The lung mesenchyme, in particular the alveolar myofibroblasts, are drivers of alveolar development, however,few key regulators that govern the proper distribution and behavior of these cells in the distal lung during alveologenesis have been identified. While Hox5 triple mutants(Hox5 aabbcc) exhibit neonatal lethality, four-allele, compound mutant mice(Hox5 AabbCc) are born in Mendelian ratios and are phenotypically normal at birth. However, they exhibit defects in alveologenesis characterized by a BPD-like phenotype by early postnatal stages that becomes more pronounced at adult stages. Invasive pulmonary functional analyses demonstrate significant increases in total lung volume and compliance and a decrease in elastance in Hox5 compound mutants. SMA+ myofibroblasts in the distal lung are distributed abnormally during peak stages of alveologenesis and aggregate, resulting in the formation of a disrupted elastin network. Examination of other key components of the distal lung ECM, as well as other epithelial cells and lipofibroblasts reveal no differences in distribution. Collectively, these data indicate that Hox5 genes play a critical role in alveolar development by governing the proper cellular behavior of myofibroblasts during alveologenesis.

关键词： Hox5 alveologenesis alveolar myofibroblasts lung ECM postnatal lung development