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MEDICAL SCIENCES (2268 journals)            First | 1 2 3 4 5 6 7 8 | Last

Showing 201 - 400 of 3562 Journals sorted alphabetically
Audiology - Communication Research     Open Access   (Followers: 10)
Auris Nasus Larynx     Full-text available via subscription  
Australasian Journal of Ultrasound in Medicine (AJUM)     Hybrid Journal  
Australian Coeliac     Full-text available via subscription   (Followers: 1)
Australian Family Physician     Full-text available via subscription   (Followers: 3)
Australian Journal of Medical Science     Full-text available via subscription   (Followers: 2)
Autopsy and Case Reports     Open Access  
Avicenna     Open Access   (Followers: 3)
Avicenna Journal of Clinical Medicine     Open Access  
Avicenna Journal of Medicine     Open Access   (Followers: 1)
Bangabandhu Sheikh Mujib Medical University Journal     Open Access   (Followers: 1)
Bangladesh Journal of Anatomy     Open Access   (Followers: 2)
Bangladesh Journal of Bioethics     Open Access  
Bangladesh Journal of Medical Biochemistry     Open Access   (Followers: 4)
Bangladesh Journal of Medical Education     Open Access   (Followers: 2)
Bangladesh Journal of Medical Microbiology     Open Access   (Followers: 4)
Bangladesh Journal of Medical Physics     Open Access   (Followers: 1)
Bangladesh Journal of Medical Science     Open Access  
Bangladesh Journal of Medicine     Open Access   (Followers: 1)
Bangladesh Journal of Physiology and Pharmacology     Open Access  
Bangladesh Journal of Scientific Research     Open Access   (Followers: 1)
Bangladesh Medical Journal     Open Access  
Bangladesh Medical Journal Khulna     Open Access  
Basal Ganglia     Hybrid Journal  
Basic Sciences of Medicine     Open Access   (Followers: 2)
Batı Karadeniz Tıp Dergisi / Medical Journal of Western Black Sea     Open Access  
Baylor University Medical Center Proceedings     Hybrid Journal  
BBA Clinical     Open Access  
BC Medical Journal     Free  
Benha Medical Journal     Open Access  
Beni-Suef University Journal of Basic and Applied Sciences     Open Access   (Followers: 4)
Bijblijven     Hybrid Journal  
Bijzijn     Hybrid Journal   (Followers: 1)
Bijzijn XL     Hybrid Journal  
Bio-Algorithms and Med-Systems     Hybrid Journal   (Followers: 2)
BioDiscovery     Open Access   (Followers: 2)
Bioelectromagnetics     Hybrid Journal   (Followers: 2)
Bioelectronic Medicine     Open Access   (Followers: 1)
Bioengineering & Translational Medicine     Open Access  
Bioethics     Hybrid Journal   (Followers: 17)
Bioethics Research Notes     Full-text available via subscription   (Followers: 14)
Biologics in Therapy     Open Access  
Biology of Sex Differences     Open Access   (Followers: 2)
Biomarker Research     Open Access   (Followers: 3)
Biomarkers in Medicine     Hybrid Journal   (Followers: 2)
BioMed Research International     Open Access   (Followers: 4)
Biomédica     Open Access  
Biomedical & Life Sciences Collection     Full-text available via subscription   (Followers: 3)
Biomedical and Biotechnology Research Journal     Open Access   (Followers: 1)
Biomedical Engineering     Hybrid Journal   (Followers: 17)
Biomedical Engineering and Computational Biology     Open Access   (Followers: 13)
Biomedical Engineering Letters     Hybrid Journal   (Followers: 6)
Biomedical Engineering Research     Open Access   (Followers: 7)
Biomedical Informatics Insights     Open Access   (Followers: 8)
Biomedical Journal     Open Access   (Followers: 3)
Biomedical Materials     Hybrid Journal   (Followers: 7)
Biomedical Microdevices     Hybrid Journal   (Followers: 8)
Biomedical Optics Express     Open Access   (Followers: 6)
Biomedical Photonics     Open Access  
Biomedical Reports     Full-text available via subscription  
Biomedical Research Reports     Full-text available via subscription   (Followers: 2)
Biomedical Safety & Standards     Full-text available via subscription   (Followers: 8)
Biomedical Science and Engineering     Open Access   (Followers: 7)
BioMedicine     Open Access  
Biomedicine Hub     Open Access  
Biomedicines     Open Access   (Followers: 1)
Biomedika     Open Access  
Biomolecular and Health Science Journal     Open Access   (Followers: 1)
Biophysics Reports     Open Access  
BioPsychoSocial Medicine     Open Access   (Followers: 8)
Biosalud     Open Access   (Followers: 1)
Biostatistics & Epidemiology     Hybrid Journal   (Followers: 1)
Birat Journal of Health Sciences     Open Access  
BIRDEM Medical Journal     Open Access   (Followers: 1)
Birth Defects Research     Hybrid Journal  
Birth Defects Research Part A : Clinical and Molecular Teratology     Hybrid Journal   (Followers: 3)
Birth Defects Research Part C : Embryo Today : Reviews     Hybrid Journal  
BJR|Open     Open Access   (Followers: 1)
BJS Open     Open Access   (Followers: 1)
Black Sea Journal of Health Science     Open Access  
BLDE University Journal of Health Sciences     Open Access  
Blickpunkt Medizin     Hybrid Journal  
BMC Biomedical Engineering     Open Access  
BMC Medical Ethics     Open Access   (Followers: 21)
BMC Medical Research Methodology     Open Access   (Followers: 9)
BMC Medicine     Open Access   (Followers: 13)
BMC Obesity     Open Access   (Followers: 8)
BMC Proceedings     Full-text available via subscription   (Followers: 1)
BMC Research Notes     Open Access   (Followers: 4)
BMC Sports Science, Medicine and Rehabilitation     Open Access   (Followers: 34)
BMH Medical Journal     Open Access   (Followers: 2)
BMI Journal : Bariátrica & Metabólica Iberoamericana     Open Access  
BMJ     Hybrid Journal   (Followers: 1751)
BMJ Case Reports     Hybrid Journal   (Followers: 26)
BMJ Evidence-Based Medicine     Hybrid Journal   (Followers: 3)
BMJ Global Health     Open Access   (Followers: 3)
BMJ Innovations     Hybrid Journal   (Followers: 6)
BMJ Leader     Hybrid Journal  
BMJ Open     Open Access   (Followers: 42)
BMJ Open Quality     Open Access   (Followers: 19)
BMJ Open Science     Open Access   (Followers: 1)
BMJ Sexual & Reproductive Health     Hybrid Journal   (Followers: 2)
BMJ Surgery, Interventions, & Health Technologies     Open Access  
Bodine Journal     Open Access  
Boletín del Consejo Académico de Ética en Medicina     Open Access  
Boletín del ECEMC     Open Access  
Boletin Médico de Postgrado     Open Access  
Boletín Médico del Hospital Infantil de México     Open Access  
Bone     Hybrid Journal   (Followers: 18)
Bone and Tissue Regeneration Insights     Open Access   (Followers: 2)
Bone Marrow Research     Open Access   (Followers: 2)
Bone Reports     Open Access  
Bosnian Journal of Basic Medical Sciences     Open Access  
Bozok Tıp Dergisi / Bozok Medical Journal     Open Access  
Brachytherapy     Full-text available via subscription   (Followers: 6)
Brain and Development     Full-text available via subscription   (Followers: 5)
Brain Connectivity     Hybrid Journal   (Followers: 5)
Brain Impairment     Full-text available via subscription   (Followers: 2)
Brazilian Journal of Medical and Biological Research     Open Access  
Brazilian Journal of Medicine and Human Health     Open Access  
Brazilian Journal of Pain (BrJP)     Open Access  
Brazilian Journal of Physical Therapy     Open Access   (Followers: 1)
Breastfeeding Review     Full-text available via subscription   (Followers: 18)
British Journal of Biomedical Science     Full-text available via subscription   (Followers: 7)
British Journal of General Practice     Full-text available via subscription   (Followers: 38)
British Journal of Hospital Medicine     Full-text available via subscription   (Followers: 16)
British Medical Bulletin     Hybrid Journal   (Followers: 6)
Buddhachinaraj Medical Journal     Open Access  
Bulletin Amades     Open Access  
Bulletin de la Société de pathologie exotique     Hybrid Journal   (Followers: 1)
Bulletin of Legal Medicine     Open Access  
Bulletin of Medical Sciences     Open Access  
Bulletin of the History of Medicine     Full-text available via subscription   (Followers: 18)
Bulletin of the Menninger Clinic     Full-text available via subscription  
Bulletin of The Royal College of Surgeons of England     Free  
Bulletin of the Scientific Centre for Expert Evaluation of Medicinal Products     Open Access  
Bundesgesundheitsblatt - Gesundheitsforschung - Gesundheitsschutz     Hybrid Journal   (Followers: 6)
Burapha Journal of Medicine     Open Access  
Burns     Hybrid Journal   (Followers: 10)
Cadernos de Naturologia e Terapias Complementares     Open Access   (Followers: 1)
Calcified Tissue International     Hybrid Journal   (Followers: 2)
Canadian Bulletin of Medical History     Hybrid Journal  
Canadian Family Physician     Partially Free   (Followers: 13)
Canadian Journal of Pain     Open Access   (Followers: 2)
Canadian Journal of Rural Medicine     Full-text available via subscription   (Followers: 1)
Canadian Medical Association Journal     Open Access   (Followers: 17)
Canadian Medical Education Journal     Open Access   (Followers: 10)
Canadian Prosthetics & Orthotics Journal     Open Access  
Cannabis and Cannabinoid Research     Hybrid Journal   (Followers: 1)
Cardiac Electrophysiology Clinics     Full-text available via subscription   (Followers: 1)
Care Management Journals     Hybrid Journal   (Followers: 5)
Case Reports     Open Access  
Case Reports in Acute Medicine     Open Access  
Case Reports in Clinical Medicine     Open Access   (Followers: 1)
Case Reports in Clinical Nutrition     Open Access   (Followers: 1)
Case Reports in Medicine     Open Access   (Followers: 2)
Case Reports in Transplantation     Open Access  
Case Reports in Vascular Medicine     Open Access  
Case Reports in Women's Health     Open Access   (Followers: 4)
Case Study and Case Report     Open Access   (Followers: 5)
CBU International Conference Proceedings     Open Access   (Followers: 3)
Cell & Bioscience     Open Access   (Followers: 6)
Cell Adhesion & Migration     Open Access   (Followers: 9)
Cell and Molecular Response to Stress     Full-text available via subscription   (Followers: 2)
Cell and Tissue Transplantation and Therapy     Open Access   (Followers: 2)
Cell Cycle     Full-text available via subscription   (Followers: 6)
Cell Death and Differentiation     Hybrid Journal   (Followers: 7)
Cell Death Discovery     Open Access   (Followers: 1)
Cell Health and Cytoskeleton     Open Access   (Followers: 1)
Cell Medicine     Open Access   (Followers: 6)
Cell Research     Hybrid Journal   (Followers: 8)
Cell Transplantation     Open Access   (Followers: 4)
CEN Case Reports     Hybrid Journal  
Central African Journal of Medicine     Full-text available via subscription  
Ceylon Journal of Medical Science     Open Access  
Ceylon Medical Journal     Open Access  
Chattagram Maa-O-Shishu Hospital Medical College Journal     Open Access  
Chiang Mai Medical Journal     Open Access  
ChiangRai Medical Journal     Open Access  
Chimerism     Full-text available via subscription  
Chinese Journal of Integrative Medicine     Hybrid Journal   (Followers: 3)
Chinese Journal of Natural Medicines     Full-text available via subscription   (Followers: 1)
Chinese Medical Journal     Open Access   (Followers: 10)
Chinese Medical Record English Edition     Hybrid Journal  
Chinese Medical Sciences Journal     Full-text available via subscription   (Followers: 2)
Chinese Medicine     Open Access   (Followers: 2)
Chinese Medicine     Open Access   (Followers: 4)
Chisholm Health Ethics Bulletin     Full-text available via subscription   (Followers: 1)
CHRISMED Journal of Health and Research     Open Access   (Followers: 2)
Christian Journal for Global Health     Open Access  
Chronic Diseases and Translational Medicine     Open Access  
Chronic Illness     Hybrid Journal   (Followers: 6)
Chronic Wound Care Management and Research     Open Access   (Followers: 4)
Chronobiology International     Hybrid Journal   (Followers: 3)
ChronoPhysiology and Therapy     Open Access  
Chulalongkorn Medical Bulletin     Open Access  
Chulalongkorn Medical Journal     Open Access  
Ciencia e Innovación en Salud     Open Access  
Ciencia e Investigación Medico Estudiantil Latinoamericana     Open Access  
Ciencias Clínicas     Open Access  

  First | 1 2 3 4 5 6 7 8 | Last

Similar Journals
Journal Cover
BioDiscovery
Number of Followers: 2  

  This is an Open Access Journal Open Access journal
ISSN (Online) 2050-2966
Published by Pensoft Homepage  [27 journals]
  • An old wives' tale. Reproductive outcomes in pregnant women aged 35 or
           older: the role of individual repair capacity

    • Abstract: BioDiscovery 18: e8970
      DOI : 10.7750/BioDiscovery.2015.18.2
      Authors : Rumena Petkova, V Dimitrova, Nikolai Zhelev, Stoyan Chakarov : At present, childbirth is being progressively postponed until later age. Women aged 35 or older may have to wait longer to conceive than younger women and are more likely to be referred to fertility evaluations, but in a significant proportion a spontaneous conception would be achieved in the timeframe typical of younger women. Pregnancies where mothers are ≥ 35 are associated with more risks for pregnancy loss, chromosomal disease, pregnancy-associated complications, prematurity and low birthweight. These concerns, however, are not uncommon in younger women as well. This puts forward the question whether advanced age per se is the underlying cause for the increased risk for adverse outcomes in older pregnant women, or whether there might be other factors that account for it but do not radically worsen the prospects for favourable outcomes. The individual risks associated with childbirth late in life may stem from maternal genetic background rather than being a simple function of age. There is plenty of preliminary evidence that individual capacity for identification and repair of DNA damage may constitute a major factor in female fertility and fecundity. Subtle deficiencies in the repair capacity may have little to no importance in younger pregnant women but may make a significant difference in older women. The outcomes of pregnancies in women >35 are largely dependent on the pre-pregnancy health status and the quality of antenatal care, and may not be dramatically different from outcomes in younger women. HTML XML PDF
      PubDate: Wed, 23 Dec 2015 0:00:00 +0200
       
  • A de novo microdeletion 2p24.3-25.1 identified in a girl with global
           development delay

    • Abstract: BioDiscovery 18: e8967
      DOI : 10.7750/BioDiscovery.2015.18.1
      Authors : Hristo Y. Ivanov, Vili K. Stoyanova, Radoslava Vazharova, Aleksandar Linev, Ivan Ivanov, Samuil Ivanov, Lubomir Balabanski, Draga Toncheva : Interstitial microdeletions of the distal 2p are very rare. A small number of cases have been reported in the literature, involving regions 2p23-p25, 2p23-p24 and 2p24-p25. The most common symptoms involve: intrauterine growth retardation, developmental delay, mental retardation, microcephaly, craniofacial anomalies, musculoskeletal abnormalities, congenital heart defect and hearing impairment. Herein we report on a Caucasian girl, born after in vitro fertilization with discrete facial dysmorphism, growth failure, borderline neurodevelopment and congenital heart defect. A de novo pericentric inversion of chromosome 2 was identified by routine karyotyping. An interstitial microdeletion of 2p24.3p25.1 was found by array karyotyping and following FISH analysis revealed that the deletion affects the inverted chromosome 2. This case illustrates the utility of high resolution methods to identify submicroscopic quantitative changes in structurally rearranged chromosomes. The precise determination of the genetic content of small quantitative changes in the genome provides important information for genetic counseling, enabling to predict the course of disease and the planning of adequate therapy and prophylaxis in affected families. HTML XML PDF
      PubDate: Sat, 10 Oct 2015 0:00:00 +0300
       
  • Blood-Based Gene Expression in children with Autism spectrum disorder

    • Abstract: BioDiscovery 17: e8966
      DOI : 10.7750/BioDiscovery.2015.17.2
      Authors : Hristo Y. Ivanov, Vili K. Stoyanova, Nikolay T. Popov, M. Bosheva, Tihomir I. Vachev : Comparative gene expression profiling analysis is useful in discovering differentially expressed genes associated with various diseases, including mental disorders. Autism spectrum disorder (ASD) is a severe neuropsychiatric disorder which has complex pathobiology with profound influences of genetic factors in its development. Although numerous autism susceptible genes were identified, the etiology of autism is not fully explained. The study aimed to examine gene expression profiling in peripheral blood from 60 individuals divided into two groups: children with ASD and age- and gender-matched healthy subjects (ASD control). A genome-wide sequencing of copy DNA molecules was conducted to obtain information for quantitative expression of all genes subject to this study and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway-based analysis was used to further understand genes’ biological functions. Based on the conducted expression analysis 23 differentially expressed genes and 21 KEGG signaling pathways with statistical significant change were identified. Blood-based comparative gene expression profiling analysis is useful in discovering genetic markers associated with ASD. Our data will provide a valuable resource for discovery purposes and for comparison to other gene expression-based, genome-wide studies and other functional data. HTML XML PDF
      PubDate: Wed, 30 Sep 2015 0:00:00 +0300
       
  • APOE4, oxidative stress and decreased repair capacity - a no-brainer.
           Faulty lipid metabolism and increased levels of oxidative damage may be
           risk factors in the pathogenesis of late-onset dementia

    • Abstract: BioDiscovery 17: e8969
      DOI : 10.7750/BioDiscovery.2015.17.1
      Authors : Ashima Nayyar, Lubomira Chakalova : Dementia is very common in the elderly and its incidence increases in an age-dependent fashion. Alzheimer''s disease and vascular cognitive decline are the most common cases of dementia in the elderly. Amyloid burden and increased levels of oxidative damage have been implicated to play significant roles in the pathogenesis of late-onset dementia. In this paper we propose that there are three major genetic factors that may modulate the risk for dementia in later life: carriership of <em>APOE</em> variant alleles, carriership of mitochondrial DNA of haplogroups associated with ineffective oxygen utilisation (specifically, haplogroup H) and carriership of genetic polymorphisms conferring subtly deficient DNA repair. All three factors are quite common in the European populations. Each of these three factors may not have significant effect on the phenotype when taken separately, but when combined in the same genotype, the effects may be cumulative. Further studies are needed in order to elucidate the genotype-phenotype relationships and provide a reliable basis for assessment of the genetic risk for sporadic late-onset dementia. Lifestyle alterations and therapies targeted at decreasing the oxidative burden to aging cells and tissues may decrease the risk for neurological decline in later life. HTML XML PDF
      PubDate: Thu, 24 Sep 2015 0:00:00 +0300
       
  • Human pluripotent stem-cell-derived cardiomyocytes in cardiovascular drug
           discovery and development

    • Abstract: BioDiscovery 16: e8965
      DOI : 10.7750/BioDiscovery.2015.16.1
      Authors : Kirsty Lewis, Kerry Falconer : Cardiovascular disease (CVD) is an alarming health problem responsible for a large percentage of fatality worldwide. Current treatment is limited and research is ongoing to address this serious health problem. As mortality rates rise, the demand for novel therapeutics has pressed the pharmaceutical industry to explore alternative approaches for CVD drug development. Human pluripotent stem cells (hPSCs) hold great promise in bringing new effective cardiovascular treatments to the market through providing an improved testing platform for pre-clinical drug screening. Both stem cells derived from pre-implantation human embryos or somatic cells by reprogramming are under intense investigation for their potentially valuable attributes of cell renewal and pluripotency. This approach aims to overcome the lack of appropriate human cardiac disease models for toxicology testing by providing a novel system that is scalable, reproducible and from an inexhaustible source. Here we review the opportunities for cardiomyocytes derived from human stem cells in the field of cardiovascular drug development. HTML XML PDF
      PubDate: Sun, 28 Jun 2015 0:00:00 +0300
       
  • Small molecules and human cardiomyogenesis: Is there a bottleneck in
           current research'

    • Abstract: BioDiscovery 15: e8968
      DOI : 10.7750/BioDiscovery.2015.15.2
      Authors : Dimitar Trifonov : Human pluripotent stem cell derived cardiomyocytes (hPSC-derived CMs) have a vast potential in drug discovery, disease modeling and regenerative medicine. In recent years various differentiation protocols for hPSC-derived CMs have been developed. Most of them utilize the modulation of human cardiomyogenesis via small-molecule compounds. However, setbacks to the large-scale application of hPSC-derived CMs still abound: insufficient insight into important signaling pathways for cardiac lineage-specific differentiation and identification of suitable small-molecule modulators; inconsistent results due to unstandardised culturing techniques; lack of effective maturation of hPSC-derived CMs in vitro. So is there a bottleneck in current research' This paper attempts to answer this question. HTML XML PDF
      PubDate: Tue, 31 Mar 2015 0:00:00 +0300
       
  • NRF2 inhibition causes repression of ATM and ATR expression leading to
           aberrant DNA Damage Response

    • Abstract: BioDiscovery 15: e8964
      DOI : 10.7750/BioDiscovery.2015.15.1
      Authors : Hilal S Khalil, Yusuf Deeni : Nuclear factor (erythroid-derived 2)-like 2 (NRF2) is a master regulator of the antioxidant response (AR) pathway and functions as a transcription factor for basal and oxidative stress-induced expression of a battery of detoxification enzymes and cytoprotective genes. Recent evidence has also demonstrated a role of NRF2 in driving resistance of numerous cancers to chemotherapeutic agents. ATM and ATR are serine/threonine kinases that are activated following DNA damage and function as central components of DNA Damage Response (DDR) pathway. Activities of these kinases cause cell cycle arrest and activate DNA repair signals leading to cytoprotection against genotoxic agents. In this study, we elucidated the roles of ATM- and ATR- dependent DDR and NRF2- mediated AR pathways in promoting cytoprotection following cisplatin challenge in ovarian cancer cell line models. We also determined whether these pathways were inter-dependent for full activation following genotoxic insults and as such demonstrated crosstalk in their signaling mechanism to elicit cytoprotective pathways. Treatment with cisplatin caused NRF2 induction and generation of reactive oxygen species (ROS) that caused cytotoxicity in ovarian cancer cells. This was attenuated by the ROS scavenger N-Acetyl cysteine, implicating NRF2 function in cytoprotection against cisplatin. Treatment with retinoic acid (RA) caused down regulation of NRF2, disruption of AR pathway, significant accumulation of ROS and enhanced cisplatin cytotoxicity. Interestingly, RA treatment also led to repression of total ATM and ATR proteins and aberrant DDR activation following cisplatin challenge. In order to determine whether the RA induced ATM and ATR repression was dependent on NRF2 inhibition, we silenced NRF2 using SiRNA. This caused transcriptional repression of both <em>ATM</em> and <em>ATR</em> expression as determined by their promoter driven luciferase assays. Thus, NRF2 inhibition led to DDR suppression by down-regulating ATM and ATR that led to enhanced cytotoxicity. These findings demonstrate mechanism of crosstalk between the AR and the DDR pathways and extend the scope of NRF2 in promoting cancer therapeutic resistance. HTML XML PDF
      PubDate: Sat, 28 Mar 2015 0:00:00 +0200
       
  • We heart cultured hearts. A comparative review of methodologies for
           targeted differentiation and maintenance of cardiomyocytes derived from
           pluripotent and multipotent stem cells

    • Abstract: BioDiscovery 14: e8962
      DOI : 10.7750/BioDiscovery.2014.14.2
      Authors : A. Arabadjiev, Rumena Petkova, Stoyan Chakarov, Rumen Pankov, Nikolai Zhelev : Human cell lines, including disease cell lines are often superior to routine animal models for the purposes of rapid and safe assessment of the effects of different agents that may modulate myocardial functioning under physiological and pathological conditions. There are several currently existing methodologies for derivation of cardiomyocyte-like cells by targeted differentiation from pluripotent cells and by reprogramming/transdifferentiation from other types of cells (multipotent progenitors, somatic cells, etc). The present paper reviews the potential sources of cells capable of differentiation along the cardiomyocyte lineage; the existing methodologies for targeted differentiation, outlining the specificities of each method; and the markers for differentiation along the mesodermal and the cardiogenic lineage. The yield of robustly beating cells expressing cardio-specific proteins derived by any of the existing methods, however, still rarely exceeds 70-90 %, even with the newly developed approaches for increasing the differentiation capacity. There still is significant variance in the results obtained by different research groups and even between different experiments carried out in the same laboratory, with the same type of cells and same general type of protocol. Derivation of new lines of human pluripotent and multipotent stem cells according to standardised protocols and in completely defined; xeno-free conditions may increase the reliability and reproducibility of research and speed up the development of potential clinical applications. HTML XML PDF
      PubDate: Tue, 23 Dec 2014 0:00:00 +0200
       
  • Multiplexed heat shock protein microarray as a screening platform for the
           selection of novel drug compounds

    • Abstract: BioDiscovery 14: e8963
      DOI : 10.7750/BioDiscovery.2014.14.1
      Authors : Emilia Schax, Janek Neunaber, Frank Stahl, Johanna-Gabriela Walter, Thomas Scheper, Simone Eichner, Andreas Kirschning, Carsten Zeilinger : In diseases such as cancer, Alzheimer’s disease or malaria, disease-related proteins take advantage of the heat shock protein (HSP) control system for their own activation or maturation. There is a quest to find inhibitors that specifically bind to the HSPs. Here, we report on a novel multiplexed assay system for inhibitor screening based on a protein microarray (MA) technique that was developed for routine applications with storable MAs. Purified HSPs are printed as full-length proteins on microarrays and used as a drug target for the screening of new inhibitors. Derivatives obtained by a combination of biological and chemical synthesis were tested as competitors of ATP with a suggested affinity for several HSP proteins which are hHSP from human, AtHSP83 (<em>Arabidopsis thaliana</em>) and HtpG from <em>Helicobacter pylori</em>. Some of these new derivatives exerted selectivity between human and bacterial heat shock proteins. Printed human HSP90 was used to test the binding of denatured proteins on the client binding site of human HSP90, since the full-length HSP maintains the capability to bind putative clients or cochaperones. Initial data revealed that the microarray application can be used to identify directly elevated heat-shock protein levels in cancer cell lysates. We suggest that microarray-based assaying of HSP levels can be used as a marker for determining stress levels. HTML XML PDF
      PubDate: Mon, 22 Dec 2014 0:00:00 +0200
       
  • DNA repair systems

    • Abstract: BioDiscovery 13: e8961
      DOI : 10.7750/BioDiscovery.2014.13.2
      Authors : Stoyan Chakarov, Rumena Petkova, George Ch Russev : This paper provides detailed insight into the mechanisms of repair of different types of DNA damage and the direct molecular players (enzymes repairing the damage or tagging the damaged site for further processing; damage sensor molecules; other signalling and effector molecules). The genetic bases of diseases and conditions associated with defective DNA repair are comprehensively reviewed, from the ''classic'' severe diseases such as xeroderma pigmentosum and Cockayne syndrome to the much more subtle UV sensitivity syndromes. The review analyses the basic molecular mechanisms underlying the relatively rare monogenic diseases of DNA repair and management of genome integrity as well as the common multifactorial diseases and conditions with late onset that are associated with increased levels of oxidative stress (metabolic syndrome, diabetes type 2, cardiovascular disease) and with accumulation of ''errors'' in DNA (normal and pathological ageing phenotypes, various cancers). The role of cell cycle checkpoints in dividing cells and the mechanisms of decision-making for the fate of a damaged cell are discussed with regards to the cell homeostasis in normal and cancerous tissues. The role of major DNA damage-associated signalling and effector molecules (p53, ATM, poly-(ADP-ribose)-polymerase, DNA-dependent protein kinase, BRCA proteins, retinoblastoma protein, and others) is discussed and illustrated with examples in the context of health and disease. DNA repair and programmed cell death are viewed together as a unified mechanism for limiting the presence of damaged cells and cells with potentially oncogenic transformation in multicellular organisms. Special attention is paid to ageing as a natural phenomenon and an adaptive evolutionary mechanism, with a brief outline of ''successful ageing''. The differential rates of repair of DNA in transcribed and nontranscribed regions of the genome and the specificities of DNA repair profile in some types of cells (terminally differentiated cells, pluripotent stem cells, etc.) and in certain taxonomic groups (e.g. ''the rodent repairadox'') are discussed with regards to replicative ageing and the evolutionary processes on micro- and macroscale. The role of mutagenesis as a ''hit and miss'' mechanism and the ''leakiness'' of DNA repair for increasing genetic diversity in the course of individual life and on evolutionary scale and the phenomenology of ongoing molecular evolution are extensively reviewed. HTML XML PDF
      PubDate: Mon, 22 Sep 2014 0:00:00 +0300
       
  • DNA damage and the circadian clock

    • Abstract: BioDiscovery 13: e8960
      DOI : 10.7750/BioDiscovery.2014.13.1
      Authors : Stoyan Chakarov, Rumena Petkova, George Ch Russev, Nikolai Zhelev : The role of the circadian clock has already been demonstrated for virtually all physiological processes, but it was only recently shown that cells were more sensitive to DNA damage at specific times of the day; that the peak of synthesis of mRNA and proteins of genes coding for products involved directly or indirectly in DNA repair was differentially timed in different tissues; and that the growth of some types of cancer followed a circadian pattern. The paper reviews the specificities of the clockwork mechanism in living cells associated with repair of DNA damage with regards to its role in ageing and carcinogenesis. The role of heritable polymorhisms and somatic mutations in the risk for development of common diseases (cancer, but also other types of diseases and conditions, such as obesity and metabolic syndrome), their course and the possible outcomes is reviewed in animal models and in man. The circadian oscillations in the levels of major proteins of DNA-damage related signalling and DNA repair are discussed in relation to differential mechanisms of defence against genotoxic damage. The paper outlines the modern concept of ''chronotherapy'' - that is, anticancer therapy administered at specific times of the day/ night cycle that could be associated with better outcomes in some patients and analyses the individual variance in the tolerability of chronotherapy vs. maximum-dose anticancer therapy. HTML XML PDF
      PubDate: Sun, 14 Sep 2014 0:00:00 +0300
       
  • DNA repair and carcinogenesis

    • Abstract: BioDiscovery 12: e8959
      DOI : 10.7750/BioDiscovery.2014.12.1
      Authors : Stoyan Chakarov, Rumena Petkova, George Ch Russev, Nikolai Zhelev : The paper is dedicated to the natural phenomenon of cancer, with its possible causes, lifetime risks, mechanisms and possible outcomes discussed in fine detail. The molecular events resulting in uncontrolled cell growth and increased capacity to colonise distant topological sites are reviewed with regards to their impact as separate factors as well as their function as parts of a common mechanism. The basic classifications of cell genes coding for products involved directly or indirectly in carcinogenesis (proto-oncogenes, tumour-suppressor genes, mutator genes and gatekeeper/caretaker genes) are given in parallel in order to provide a better understanding of the functions of the encoded proteins. The mechanisms commonly used by cancer cells to evade the control of the DNA damage check/DNA repair/apoptosis system and for deactivation and/or elimination of anticancer drugs are reviewed. The current and future opportunities for establishing control over carcinogenesis (for common types of cancer as well as for ''cancer'' in general) are evaluated in the light of the theory that cancer is a physiological mechanism set in place by Nature so as to minimise the risk of evolutionary stagnation. HTML XML PDF
      PubDate: Sun, 8 Jun 2014 0:00:00 +0300
       
  • Individual capacity for detoxification of genotoxic compounds and repair
           of DNA damage. Commonly used methods for assessment of capacity for DNA
           repair

    • Abstract: BioDiscovery 11: e8958
      DOI : 10.7750/BioDiscovery.2014.11.2
      Authors : Stoyan Chakarov, Rumena Petkova, George Ch Russev : The first part of this paper reviews the major achievements in the rapidly expanding field of research of individual capacity for repair of genotoxic damage. The issues of individual repair capacity are addressed from multiple sides, analyzing the impact of the heritable components of the capacity for detoxification of genotoxic compounds, on the one hand (determining the risk for occurrence of DNA damage) and of the capacity for repair of DNA damage (when it has already occurred), on the other hand. The role of the capacity for repair of damage to DNA is discussed in the constitution of the risk for development of disease (mainly cancer, but also other common diseases and conditions, such as diabetes, atherosclerosis and cardiovascular disease) and as a major factor in the outcomes of genotoxic therapies (eligibility for therapy with specific agents, risk for severe adverse effects, post-therapeutic survival rates, etc.). The paper contains an extensive list of biomarkers (mainly DNA polymorphisms, but also enzymes and other phenotypic markers, such as markers of the capacity for self-renewal of cell populations) that may be potentially applicable in the assessment of the risk for carcinogenesis or for development other types of human disease.The second part of the paper provides a brief glimpse of the basic methodology used to obtain experimental results in assessment of the efficiency of DNA repair in living cells for research and diagnostic purposes. HTML XML PDF
      PubDate: Fri, 28 Mar 2014 0:00:00 +0200
       
  • DNA damage and mutation. Types of DNA damage

    • Abstract: BioDiscovery 11: e8957
      DOI : 10.7750/BioDiscovery.2014.11.1
      Authors : Stoyan Chakarov, Rumena Petkova, George Ch Russev, Nikolai Zhelev : This review outlines the basic types of DNA damage caused by exogenous and endogenous factors, analyses the possible consequences of each type of damage and discusses the need for different types of DNA repair. The mechanisms by which a minor damaging event to DNA may eventually result in the introduction of heritable mutation/s are reviewed. The major features of the role of DNA damage in ageing and carcinogenesis are outlined and the role of iatrogenic DNA damage in human health and disease (with curative intent as well as a long-term adverse effect of genotoxic therapies) are discussed in detail. HTML XML PDF
      PubDate: Sun, 23 Feb 2014 0:00:00 +0200
       
  • From Roscovitine to CYC202 to Seliciclib – from bench to bedside:
           discovery and development

    • Abstract: BioDiscovery 10: e8956
      DOI : 10.7750/BioDiscovery.2013.10.1
      Authors : Nikolai Zhelev, Dimitar Trifonov, Shudong Wang, Moustapha Hassan, Ibrahim El Serafi : This monograph reviews the discovery and development of the cyclin-dependent kinase inhibitor roscovitine (R-roscovitine, CYC202, Seliciclib). The authors summarise the in vitro and in vivo data that have formed the basis for clinical investigation of Seliciclib as an anti-cancer drug. Kinase selectivity, cellular effects and the pharmacological properties of the drug are discussed in addition to the clinical results of Seliciclib being reviewed. Novel results on the effect of the drug in cardiac hypertrophy are summarized and potential applications of Seliciclib in other therapeutic areas, including, inflammation, virology, glomerulonephritis and polycystic kidney disease, are discussed. Finally the authors argue that optimisation of the therapeutic effect of kinase inhibitors such as Seliciclib can be enhanced using a systems biology approach involving mathematical modelling of the molecular pathways regulating cell growth and division. HTML XML PDF
      PubDate: Mon, 30 Dec 2013 0:00:00 +0200
       
  • Reverse engineering of drug induced DNA damage response signalling pathway
           reveals dual outcomes of ATM kinase inhibition

    • Abstract: BioDiscovery 9: e8954
      DOI : 10.7750/BioDiscovery.2013.9.4
      Authors : Michael A. Idowu, Hilal S Khalil, James L. Bown, Nikolai Zhelev : The DNA Damage Response (DDR) pathway represents a signalling mechanism that is activated in eukaryotic cells following DNA damage and comprises of proteins involved in DNA damage detection, DNA repair, cell cycle arrest and apoptosis. This pathway consists of an intricate network of signalling interactions driving the cellular ability to recognise DNA damage and recruit specialised proteins to take decisions between DNA repair or apoptosis. ATM and ATR are central components of the DDR pathway. The activities of these kinases are vital in DNA damage induced phosphorylational induction of DDR substrates. Here, firstly we have experimentally determined DDR signalling network surrounding the ATM/ATR pathway induced following double stranded DNA damage by monitoring and quantifying time dependent inductions of their phosphorylated forms and their key substrates. We next involved an automated inference of unsupervised predictive models of time series data to generate <em>in silico</em> (molecular) interaction maps. We characterized the complex signalling network through system analysis and gradual utilisation of small time series measurements of key substrates through a novel network inference algorithm. Furthermore, we demonstrate an application of an assumption-free reverse engineering of the intricate signalling network of the activated ATM/ATR pathway. We next studied the consequences of such drug induced inductions as well as of time dependent ATM kinase inhibition on cell survival through further biological experiments. Intermediate and temporal modelling outcomes revealed the distinct signaling profile associated with ATM kinase activity and inhibition and explained the underlying signalling mechanism for dual ATM functionality in cytotoxic and cytoprotective pathways. HTML XML PDF
      PubDate: Wed, 11 Dec 2013 0:00:00 +0200
       
  • Progesterone significantly enhances the mobility of boar spermatozoa

    • Abstract: BioDiscovery 9: e8955
      DOI : 10.7750/BioDiscovery.2013.9.5
      Authors : Johan M. Campbell, Anne L. Savage, Oladipo Madamidola, Kshitij Tamhane, Renalyn Soriano, Ashok K. Adya, Sean G. Brown : Progesterone released from the cumulus cells of the oocyte causes a number of physiological responses in human sperm cells including hyperactivation, acrosome reaction and chemotaxis. We employed a validated sperm mobility assay, which involves measuring the ability of sperm to penetrate an inert cell separation solution over time, to assess the ability of progesterone to enhance the mobility of boar spermatozoa. Cells maximally penetrate the solution over 50 minutes. 100nM progesterone significantly (P = 0.01) increased the mobility of non-capacitated sperm cells causing a doubling in the rate at which the cells penetrated through the cell separation solution (control half maximal penetration rate [Km] = 18.0±2.2; +100nM progesterone Km = 8.8±0.8min). Similarly, capacitated cells penetrated at a rate (Km = 19.2±3.0 min) not significantly different from non-capacitated cells and 100nM progesterone also significantly increased the rate of penetration of capacitated cells (Km = 9.5±1.0 min, P&lt;0.05). The T-type voltage gated calcium channel blocker mibefradil (30mM) significantly inhibited both the control and progesterone enhanced mobility in non-capacitated and capacitated sperm. Only capacitated cells showed a significant increase in the acrosome reaction in response to 100nM progesterone (control non-reacted = 75±4%, +100nM progesterone non-reacted = 47±10%). Western blot analysis confirmed that there was an increase in the total protein tyrosine phosphorylation levels in capacitated cells. In conclusion, we have demonstrated that 100nM progesterone accelerates the mobility of boar sperm cells through an inert cell separation solution in an extracellular calcium dependent manner. HTML XML PDF
      PubDate: Wed, 11 Dec 2013 0:00:00 +0200
       
  • The alternate GNB3 splice variant, Gβ3s, exhibits an altered signalling
           response to EGF stimulation, which leads to enhanced cell migration

    • Abstract: BioDiscovery 9: e8953
      DOI : 10.7750/BioDiscovery.2013.9.3
      Authors : Hemanth Tummala, Hilal S Khalil, Mohammad R. Islam, Sarah J. Jones, Ian R. Ellis, Isabella D’Ascanio, Nikolai Zhelev, Douglas H. Lester : It has recently been reported that the duplication of the GNB3 gene has been shown to be directly linked to an obesity phenotype, both in humans and also in a humanised mouse model. Moreover, the common human GNB3 c.825C&gt;T polymorphism (rs5443) causes this ubiquitously expressed gene to be aberrantly spliced approximately 50% of the time leading to the production of both a normal Gβ3 protein and a truncated, possibly less stable subunit, known as Gβ3s. The presence of the GNB3 825T allele has previously been shown to be associated with predisposition to hypertension, obesity, various cancers, Alzheimers, age related cognitive function, erectile dysfunction as well as a marker for pharmacogenetic drug action. Great controversy, however, currently exists as to whether these phenotypes associated with the 825T allele are a) mainly due to the presence of the smaller, possibly more active, Gβ3s subunit or b) merely down to the haploinsufficiency of the normal GNB3 transcript, due to its frequent aberrant splicing. In order to try and address these two conflicting hypothesis, we report on the identification and characterisation of signalling alterations unique to the presence of Gβ3s protein subunit. Moreover we also show the physiological consequences associated with altered signalling, directly induced by the Gβ3s subunit. For this, we used both an EBV transformed lymphoblast cell line homozygote for GNB3 825T/825T (TT) and a stable Gβ3s expressing recombinant COS-7 clone. In both of these cell lines that express the Gβ3s subunit, we found enhanced cytosolic calcium influx upon stimulation with EGF, TGFα and VEGF ligands, as compared to "normal" GNB3 controls with the 825C/825C (CC) genotype. This aberrant calcium influx also led to an increase in ERK, but not AKT1, phosphorylation. Despite the lack of AKT1 activation, we paradoxically observed a significant increase in phosphorylation of its downstream substrates, namely mTOR and p70<sup>S6k</sup> (KS6B2). Moreover we observed a decrease in phospho FoxO3a only in Gβ3s expressing cells, but not in the "normal" GNB3 (CC) control cell line. The presence of the Gβ3s subunit also appeared to alter the distinct localisation patterns of both Foxo3a and AKT1, while also increasing the colocalisation of mTOR and p70<sup>S6K</sup>. Subsequent growth factor stimulation studies revealed that EGF treatment, of Gβ3s expressing cells, appeared to cause a significant decrease in cAMP levels, which, in turn resulted in both enhanced caveolin-1a phosphorylation, and an increase in actin stress fibre formation. The identification of these distinct Gβ3s specific signalling alterations were indicative of a more aggressive migratory phenotype. This led us to further investigate and confirm that the presence of the Gβ3s subunit also appears to cause significantly enhanced migration and robust scratch wound healing kinetics, as compared to cells harbouring only the normal copy of the gene. These data therefore present convincing evidence that the Gβ3s subunit is stable, functional and its presence can significantly alter signalling pathways, in different cell types. HTML XML PDF
      PubDate: Sat, 30 Nov 2013 0:00:00 +0200
       
  • Evolution of Conformational Disorder & Diversity of the P53
           Interactome

    • Abstract: BioDiscovery 8: e8952
      DOI : 10.7750/BioDiscovery.2013.8.5
      Authors : Anne-Sophie Huart, Ted R. Hupp : The tumour suppressor p53 is now known to be an ancient transcription factor that had already evolved interaction sites with its partner protein MDM2 at the dawn of multi-cellular eukaryotic animal life. The billion-year life history of the p53-MDM2 axis has permitted significant time for the proteins to integrate into a distinct range of cellular pathways including binding to hundreds of genomic promoters and regulatory protein-protein interactions with hundreds of distinct functions. This long age of p53 allows us to understand how the protein can regulate a range of functions such as energy generation of the cell, cell motility, genome integrity, virus infection, immune cell response, ageing, and oxidative stress. Due to this deep integration of p53 into the core of eukaryotic life, it is not surprising that the p53 pathway requires inactivation in order for human cancer cells to evade the normal growth controlling processes that have been shaped through evolution by natural selection. This review will focus on the emerging concepts in the protein science field that shed light on p53 protein evolution and function including the nature of thermodynamically unstable regulatory proteins and the growing realisation that the majority of protein-protein interactions in complex eukaryotic cells are driven by intrinsically unstructured and weakly interacting peptide motifs. These concepts help to explain how the vast number of dynamic and specific protein-protein interactions in the p53 pathway evolved, suggest how amino acid modifications like phosphorylation or acetylation in turn evolved to regulate dynamically the p53 interactome, and finally reveal therapeutic strategies for targeting the p53 interactome in human cancers. HTML XML PDF
      PubDate: Wed, 14 Aug 2013 0:00:00 +0300
       
  • Changes in the connective tissue element of the thyroid gland in normal
           and recurrent euthyroid goiter

    • Abstract: BioDiscovery 9: e8951
      DOI : 10.7750/BioDiscovery.2013.9.1
      Authors : Kalin Vidinov, Nikolay Vidinov, Manol Kalniev, Dimo Krastev : Goitre recurrence is a common problem following subtotal thyroid gland resection for multinodular goitre disease. The aim of our study was to trace out the ultrastructure of the thyroid gland of man after primary and redo operations for struma nodosa. We undertook the task to study the fine ultrastructural changes taking place in the stromal part of the gland. For ultrastructural examination we used routine transmission electron microscopy. The electron microscopy has been made on Hitachi H-500 microscope Our main goal was to compare the ultrastructural characteristics of the thyroid gland in two different groups - patients with primary disease and patients with recurrence.The results from our research showed that in the first group the stroma was presented by one or two rows of cells in the septum or in small groups in the interfolicular space. Studies by electron microscopically showed that the cells of the stroma had the ultrastructural characteristics of fibroblasts, but there was an increased number cisterne of Granular endoplasmic reticulum, well developed Goldgi complex, as well as relatively small amount of vesicles and vacuoles. The examination of the specimens from the second group showed a much thicker stroma between the follicles. There was an increased amount of stromal cells and collagen bundles in the interfolicular space. The proteoglycan complexes in the extracellular matrix were rarely situated.Our results suggest that the connective tissue of the thyroid gland reacts faster to the changes of the structure of the gland than the epithelial cells of the follicles. HTML XML PDF
      PubDate: Sat, 27 Jul 2013 0:00:00 +0300
       
  • Small Molecule Inhibitors of MDM2-p53 and MDMX-p53 Interactions as New
           Cancer Therapeutics

    • Abstract: BioDiscovery 8: e8950
      DOI : 10.7750/BioDiscovery.2013.8.4
      Authors : Yujun Zhao, Denzil Bernard, Shaomeng Wang : Inactivation of the function of tumor suppressor p53 is common in human cancers. In approximately half of human cancers, the tumor suppressor function of p53 is inactivated by deletion or mutation of TP53, the gene encoding p53 protein. In the remaining 50% of human cancers, p53 tumor suppressor function can be effectively inhibited by oncoprotein MDM2 or its homolog MDMX. Since inhibition of p53 by MDM2 or MDMX protein is mediated by their direct interaction with p53, small-molecule inhibitors designed to block the MDM2-p53 or MDMX-p53 protein-protein interaction (MDM2 or MDMX inhibitors) can activate p53 in tumor cells retaining wild-type p53. In the last few years, several classes of potent, selective, and efficacious small molecule MDM2 inhibitors have been designed and developed, and six such compounds are being evaluated in clinical trials as new anticancer drugs. Additionally, non-peptide, small-molecule MDMX inhibitors have been reported. We review herein the design and development of potent small-molecule MDM2 and MDMX inhibitors. HTML XML PDF
      PubDate: Mon, 8 Jul 2013 0:00:00 +0300
       
  • Distinct target genes and effector processes appear to be critical for
           p53-activated responses to acute DNA damage versus p53-mediated tumour
           suppression

    • Abstract: BioDiscovery 8: e8948
      DOI : 10.7750/BioDiscovery.2013.8.3
      Authors : Liz J Valente, Andreas Strasser : The p53 tumour suppressor is the most frequently mutated gene in human cancer. This transcription factor can be activated by diverse cellular stresses, including DNA damage and oncogene activation. Through transcriptional induction of appropriate target genes, p53 can stimulate activity in a broad range of effector pathways, most notably cell cycle arrest, cellular senescence and apoptotic cell death. Insensitivity to cell death-inducing signals and deregulated proliferation are two key hallmarks of cancer cells. Given that p53 inhibits proliferation and induces apoptosis, it was widely believed that these processes are the most critical ones for p53-mediated tumour suppression. However, this dogma has been challenged. In striking contrast to p53-deficient mice, which all develop tumours before 250 days of age, mutant mice in which expression of the p53 target genes that are critical for induction of cell cycle arrest and apoptosis is impaired or abrogated are not cancer-prone. This demonstrates that distinct effector processes are critical for the p53-mediated acute response to DNA damage versus p53-mediated tumour suppression. The discovery that cell cycle arrest, senescence and apoptosis are not essential for p53-mediated tumour suppression re-launches the search for the p53 target genes and effector processes that are critical to prevent tumour development, with coordination of DNA repair being a leading contender. HTML XML PDF
      PubDate: Sun, 30 Jun 2013 0:00:00 +0300
       
  • Modulation of immune responses by the tumor suppressor p53

    • Abstract: BioDiscovery 8: e8947
      DOI : 10.7750/BioDiscovery.2013.8.2
      Authors : Julie Lowe, Maria Shatz, Michael A. Resnick, Daniel Menendez : The commonly held view of the tumor suppressor p53 as a regulator of cell proliferation, apoptosis and senescence has expanded greatly in recent years to cover many biological processes as well as external and internal stress responses. Since the discovery over 30 years ago of p53 as a cellular protein that co-precipitates with the large T antigen of Simian Virus SV40, there has been an intertwining of p53 activities with immune-related processes, especially as relates to cancer. A variety of interactions between the p53 and the immune stress systems are currently being addressed that suggest opportunities to utilize p53 in modulating immunological activities. Here, we discuss those interactions along with implications for human disease. HTML XML PDF
      PubDate: Fri, 31 May 2013 0:00:00 +0300
       
  • Switching on p53: an essential role for protein phosphorylation'

    • Abstract: BioDiscovery 8: e8946
      DOI : 10.7750/BioDiscovery.2013.8.1
      Authors : Jayne Loughery, David Meek : The p53 tumour suppressor protein coordinates widespread changes in gene expression in response to a range of stress stimuli. p53 is regulated primarily through ubiquitylation and protein turnover mediated by its transcriptional target, MDM2. Induction and activation of p53 is achieved largely through uncoupling the p53/MDM2 interaction, with various stress stimuli employing different but overlapping mechanisms to achieve this. p53 undergoes a range of post-translational modifications including multi-site phosphorylation, acetylation, methylation and ubiquitylation. DNA damage pathways in particular engender a large number of phosphorylation events, both in p53 itself and in regulatory partners including MDM2 and MDM4; these modifications mediate both the induction of p53 and stimulation of its activity. Surprisingly, other p53-activating stimuli do not promote multi-site phosphorylation. Moreover, simply uncoupling p53 and MDM2 pharmacologically can induce a robust p53 response. Various lines of evidence propose that activation of p53 via the DNA damage pathways is dispensable for p53-mediated tumour suppression and, by implication, that phosphorylation is not required. In contrast to this view, however, emerging evidence from animal models indicates that phosphorylation may indeed impact on tumour suppression, albeit in a possibly selective manner. Here we review the role of phosphorylation in regulating the p53 response in comparison to mechanisms employed by other stress signalling pathways. We consider its effects on biological outcome and reflect on issues that have yet to be addressed. HTML XML PDF
      PubDate: Mon, 29 Apr 2013 0:00:00 +0300
       
  • Modelling c-Abl Signalling in Activated Neutrophils: The Anti-inflammatory
           Effect of Seliciclib

    • Abstract: BioDiscovery 7: e8945
      DOI : 10.7750/BioDiscovery.2013.7.4
      Authors : Robert C. Jackson, Tomas Radivoyevitch : When mammalian tissues are infected by bacteria or fungi, inflammatory cytokines are released that cause circulating neutrophils to invade the infected tissue. The cytosolic tyrosine kinase, c-Abl, in these tissue neutrophils is activated by TNFα. c-Abl then phosphorylates STAT transcription factors, which results in production of the antiapoptotic protein Mcl-1. The normally short-lived tissue neutrophils are then unable to enter apoptosis. c-Abl also causes release of reactive oxygen species (ROS) from the mitochondria of the activated neutrophils. These ROS, and ROS generated by NADPH oxidase, are bactericidal agents of the innate immune system. In some inflammatory diseases, such as chronic obstructive pulmonary disease (COPD), the invading neutrophils become permanently activated, and the resulting ROS overproduction causes severe tissue damage. The cyclin-dependent kinase inhibitor, seliciclib, blocks transcription through inhibition of cdk9. This results in a relatively rapid decline of antiapoptotic Mcl-1 transcripts in activated neutrophils, an increase in neutrophil apoptosis, and less ROS leakage and oxidative damage. We present here a model of neutrophil kinetics that simulates the principal pathways of c-Abl signalling and use it to explore possible treatment options for inflammatory lung disease. HTML XML PDF
      PubDate: Sun, 31 Mar 2013 0:00:00 +0200
       
  • Herpetofauna in the city of Blagoevgrad, south-western Bulgaria

    • Abstract: BioDiscovery 7: e8943
      DOI : 10.7750/BioDiscovery.2013.7.3
      Authors : Alexander Pulev, Lidia Sakelarieva : The city of Blagoevgrad and its surroundings (about 16.4 km<sup>2</sup>) were researched in order to establish the diversity, distribution and level of synanthropy of the amphibian and reptile species. Data about the herpetofauna were obtained in the period 1988–2012. Totally 25 species were registered – 10 amphibians and 15 reptiles. The number of species, discovered around the city, was 23, and 6 of them were not found within the administrative boundaries of the city. The different urban zones are inhabited by 19 species. They represent 37% of the amphibians and 31% of the reptiles, found in Bulgaria, and 64% of the amphibians and 60% of the reptiles, distributed in the Blagoevgrad municipality, which is very high species richness. The herpetofauna has found quite favourable conditions in the territory of the city as a whole, and especially in the sparsely populated and built up areas and city periphery. The presence of great variety of urban habitats and the pattern of situation of the city residential districts are very important for the successful adaptation of herpetofauna for inhabiting in urban environment. The high species richness could be explained also by the fact, that comparatively great number of amphibians and reptiles are hemerodiaphoric species, which easily exist in landscapes, transformed by man. The results from the case study of the herpetofauna in Blagoevgrad show that the urban areas could provide good conditions for the wild animals and could be places of substantial biological diversity. HTML XML PDF
      PubDate: Thu, 28 Mar 2013 0:00:00 +0200
       
  • Skeletal muscle: novel and intriguing characteristics as a secretory organ

    • Abstract: BioDiscovery 7: e8942
      DOI : 10.7750/BioDiscovery.2013.7.2
      Authors : Wataru Aoi, Kunihiro Sakuma : Growing evidence has shown that skeletal muscle secretes several bioactive proteins from within the cell into extracellular fluid. The secretion of several proteins, whose levels increase in response to exercise, can regulate the functions of several organs via autocrine and paracrine actions, and mediate exercise-induced benefits such as metabolic improvement, anti-inflammation, and muscle building; this is known as the myokine theory. In addition, we found a novel muscle-secreted protein, secreted protein acidic and rich in cysteine (SPARC), a secreted matricellular glycoprotein. The muscle-secreted protein SPARC can support underlying mechanisms of epidemiological studies that suggest that regular exercise can prevent the incidence of colon cancer. Many different types of studies have suggested that many other proteins secreted from muscle have yet to be identified. In addition to the proteins, non-coding small RNA in exosome and metabolites which generate in process of nutrients metabolism with muscle contraction are also suggested to be secretory bioactive factors. These secretory factors may be biomarkers that reflect muscular function and beneficial adaptation achieved by exercise training, and could estimate adequate condition of exercise to obtain its beneficial effects. HTML XML PDF
      PubDate: Sat, 2 Mar 2013 0:00:00 +0200
       
  • Chromosome rearrangements in sublines of human embryonic stem cell lines
           hESM01 and hESM03

    • Abstract: BioDiscovery 7: e8941
      DOI : 10.7750/BioDiscovery.2013.7.1
      Authors : T.V. Karamysheva, Мaria А. Prokhorovich, Maria A. Lagarkova, Sergey L. Kiselev, Thomas Liehr, Nicolay Rubtsov : Due to possible proliferative effects of karyotypic reorganization of human embryonic stem cell (hESC) lines detailed genetic analysis are indicated prior to any application of hESCs. Molecular cytogenetic analysis of two different hESC sublines was performed and revealed aberrant chromosomes in both of them, i.e. in hESM01r18 (46,ХХ,-18,+mar) and hESM0309 (46,ХХ,del(4),dup(9)). This study shows that microdissection and multicolor fluorescence <em>in situ</em> hybridization (mFISH) can be used to detect the chromosomal changes precisely of the derivative chromosomes that are difficult to identify by conventional G-banded chromosome analysis. In the present study chromosome microdissection and reverse FISH were applied using multicolor fluorescence <em>in situ</em> hybridization (mFISH) for detailed characterization of the derivative chromosomes. The karyotypes of hESC lines were described as: 46,ХХ,r(18)(::p11.31→q21.2::q21.2→p11.31::) and 46,XX,del(4)(q25q31.1),dup(9)(q12q33), respectively. The potential role of the chromosomal regions involved in rearrangements for cell proliferation is discussed. HTML XML PDF
      PubDate: Fri, 25 Jan 2013 0:00:00 +0200
       
  • Advocating the need of a systems biology approach for personalised
           prognosis and treatment of B-CLL patients

    • Abstract: BioDiscovery 6: e8939
      DOI : 10.7750/BioDiscovery.2012.6.4
      Authors : Hemanth Tummala, Alexey Goltsov, Hilal S Khalil, Anne Sproul, Fiona Scott, Vanio Mitev, Nikolai Zhelev : The clinical course of B-CLL is heterogeneous. This heterogeneity leads to a clinical dilemma: can we identify those patients who will benefit from early treatment and predict the survival' In recent years, mathematical modelling has contributed significantly in understanding the complexity of diseases. In order to build a mathematical model for determining prognosis of B-CLL one has to identify, characterise and quantify key molecules involved in the disease. Here we discuss the need and role of mathematical modelling in predicting B-CLL disease pathogenesis and suggest a new systems biology approach for a personalised therapy of B-CLL patients. HTML XML PDF
      PubDate: Sun, 30 Dec 2012 0:00:00 +0200
       
  • The aromatase inhibitor letrozole enhances the effect of doxorubicin and
           docetaxel in an MCF7 cell line model

    • Abstract: BioDiscovery 6: e8940
      DOI : 10.7750/BioDiscovery.2012.6.2
      Authors : Mary O’Neill, Fiona E.M. Paulin, Julie Vendrell, Clinton W. Ali, Alastair M. Thompson : <p>Introduction: Post-menopausal women with estrogen receptor (ER) positive breast cancer receive adjuvant chemotherapy and endocrine therapy sequentially since tamoxifen may antagonise the cytotoxicity of chemotherapy drugs. With increased use of aromatase inhibitors (AIs) in place of tamoxifen, the potential use of concomitant chemo-endocrine treatments with the AI letrozole, before clinical trials are undertaken, requires evaluation. </p><p>Methods: MCF7-aro cells expressing the aromatase gene were treated with letrozole, doxorubicin and docetaxel. The effects of different drug concentrations, drug combinations and scheduling on cytotoxicity and aromatase activity were investigated. Key receptor, cell cycle regulation and apoptosis proteins were examined by immunoblotting.</p><p>Results: Administration of letrozole with either doxorubicin or docetaxel resulted in increased levels of cytotoxicity under all treatment schedules (add in, sequential or simultaneous drug administration) with the greatest anti-proliferative effect observed using concomitant treatment (letrozole first with chemotherapy added in). The inhibitory effect of letrozole on aromatase activity was unchanged by the addition of doxorubicin or docetaxel. Letrozole treatment resulted in decreased HER2 expression and addition of doxorubicin and docetaxel to letrozole led to elevated ER-ß levels.</p><p>Conclusions: <em>In vitro</em>, letrozole, unlike tamoxifen, enhances the cytotoxicity of both doxorubicin and docetaxel. This supports the prospect of trials using letrozole with chemotherapy in postmenopausal women with ER positive breast cancer. </p> HTML XML PDF
      PubDate: Wed, 19 Dec 2012 0:00:00 +0200
       
  • Primed for the kill: occupying Bcl-2 to target death in acute myeloid
           leukaemia

    • Abstract: BioDiscovery 6: e8938
      DOI : 10.7750/BioDiscovery.2012.6.1
      Authors : Andrew Wei, Tse-Chieh Teh : ss="articleHead"> HTML XML PDF
      PubDate: Fri, 7 Dec 2012 0:00:00 +0200
       
  • Bringing together all aspects of cancer research, prevention and
           treatment. A report from the 8th NCRI Cancer Conference

    • Abstract: BioDiscovery 6: e8937
      DOI : 10.7750/BioDiscovery.2012.6.3
      Authors : Dimitar Trifonov : The 8<sup>th</sup> NCRI Cancer Conference took place from 4<sup>th</sup> until 7<sup>th</sup> of November 2012 in the BT Convention Centre, Liverpool, UK. This scientific event has established itself as the leading international oncology meeting in the UK and this year attracted more than 2,000 delegates: from researchers and data managers to clinicians, nurses and policy makers. The conference covered six main topics: 1) Diagnosis and therapy 2) Epidemiology and prevention 3) Information, patients and the public 4) Survivorship and end-of-life care 4) The cancer cell and model systems 6) Tumour specific research. This report presents the highlights of the conference. HTML XML PDF
      PubDate: Sat, 1 Dec 2012 0:00:00 +0200
       
  • ATM in focus: A damage sensor and cancer target

    • Abstract: BioDiscovery 5: e8936
      DOI : 10.7750/BioDiscovery.2012.5.1
      Authors : Hilal S Khalil, Hemanth Tummala, Nikolai Zhelev : The ability of a cell to conserve and maintain its native DNA sequence is fundamental for the survival and normal functioning of the whole organism and protection from cancer development. Here we review recently obtained results and current topics concerning the role of the ataxia-telangiectasia mutated (ATM) protein kinase as a damage sensor and its potential as therapeutic target for treating cancer. This monograph discusses DNA repair mechanisms activated after DNA double-strand breaks (DSBs), i.e. non-homologous end joining, homologous recombination and single strand annealing and the role of ATM in the above types of repair. In addition to DNA repair, ATM participates in a diverse set of physiological processes involving metabolic regulation, oxidative stress, transcriptional modulation, protein degradation and cell proliferation. Full understanding of the complexity of ATM functions and the design of therapeutics that modulate its activity to combat diseases such as cancer necessitates parallel theoretical and experimental efforts. This could be best addressed by employing a systems biology approach, involving mathematical modelling of cell signalling pathways. HTML XML PDF
      PubDate: Fri, 30 Nov 2012 0:00:00 +0200
       
  • To see an interphase chromosome or: How a disease can be associated with
           specific nuclear genome organization

    • Abstract: BioDiscovery 4: e8932
      DOI : 10.7750/BioDiscovery.2012.4.5
      Authors : Ivan Y. Iourov : The last hierarchical level of cellular genome organization is the spatial arrangement of chromosomes within the nuclear space. Despite of high regulatory potential and functional implications, issues concerning nuclear organization at chromosomal level are rarely addressed because of limitations in visualizing interphase chromosomes. The problem is especially seen when an attempt to associate specific patterns of nuclear genome organization with a pathological condition is made. Fortunately, advances in molecular cytogenetics have provided for a solution to visualize chromosomes in interphase nuclei at molecular resolution. A study in this issue of <em>BioDiscovery</em> shows the way of how to identify interphase chromosome architecture at molecular resolutions and demonstrates the involvement of specific nuclear genome organization in generating a cancer-causing chromosomal aberration (translocation between chromosomes 8 and 21 in acute myelogenous leukemia).
      Authors ’ findings suggest interphase molecular cytogenetic techniques (i.e. interphase chromosome-specific multicolor banding or ICS-MCB) to be required to perform studies regarding nuclear genome organization at chromosomal level and its role in disease pathogenesis. HTML XML PDF
      PubDate: Wed, 31 Oct 2012 0:00:00 +0200
       
  • What can systems pharmacology contribute to drug development' Disease
           modelling as a predictive tool

    • Abstract: BioDiscovery 4: e8933
      DOI : 10.7750/BioDiscovery.2012.4.4
      Authors : Robert C. Jackson : ss="articleHead"> HTML XML PDF
      PubDate: Wed, 31 Oct 2012 0:00:00 +0200
       
  • Prevalence of oral lesions in HIV infected adult population of Mangalore,
           Karnataka, India

    • Abstract: BioDiscovery 4: e8935
      DOI : 10.7750/BioDiscovery.2012.4.3
      Authors : Mithra N. Hegde, Nidarsh D. Hegde, Amit Malhotra : The aim of this study was to find the prevalence of oral lesions in human immunodeficiency virus (HIV) positive patients and investigate if there was a relationship between oral manifestations and the level of immunosuppression. 125 patients infected with HIV in the age group of 20-40 years were examined for the presence of different oral lesions according to the EEC criterion. The CD4 count, as well as any therapy being instituted was recorded and correlated with the oral manifestations seen. Comparison of common oral lesions present to absent was done by chi square test using linear by linear association. The prevalence of oral lesions among the investigated HIV patients was found to be 71%, with periodontitis – 52% and erythematous candidiasis – 48% being the most prevalent oral lesions; as well, periodontitis and oral hairy leukoplakia were found to be significantly associated with the immunosuppression in the disease. Thus, oral lesions have been found to be associated with the early manifestation of HIV and a measure of disease severity. HTML XML PDF
      PubDate: Tue, 23 Oct 2012 0:00:00 +0300
       
  • Does positioning of chromosomes 8 and 21 in interphase drive t(8;21) in
           acute myelogenous leukemia'

    • Abstract: BioDiscovery 4: e8934
      DOI : 10.7750/BioDiscovery.2012.4.2
      Authors : Moneeb A.K. Othman, Amelie Lier, Susann Junker, Philipp Kempf, Franziska Dorka, Erich Gebhart, Frenny J. Sheth, Beata Grygalewicz, Samarth Bhatt, Anja Weise, Kristin Mrasek, Thomas Liehr, Marina Manvelyan : The impact of chromosome architecture in the formation of chromosome aberrations is a recent finding of interphase directed molecular cytogenetic studies. There evidence was provided that disease specific chromosomal translocations could be due to tissue specific genomic organization. In a recent small pilot study using three-dimensional interphase fluorescence in situ hybridization, we showed that there might be a specific chromosome positioning in myeloid bone marrow cells, i.e. a co-localization of chromosomes 8 and 21. Here we could substantiate this finding in overall 21 studied cases with acute myeloid leukemia (AML) that there is even a co-localization of the genes AML1 and ETO. This finding led to the suggestion that a specific interphase architecture of myeloid bone marrow cells might promote the typical t(8;21)(q22;q22) leading to AML-M2. HTML XML PDF
      PubDate: Tue, 23 Oct 2012 0:00:00 +0300
       
  • In vitro assessment of the cytotoxic effects of novel RGD analogues

    • Abstract: BioDiscovery 4: e8931
      DOI : 10.7750/BioDiscovery.2012.4.1
      Authors : Anelia Balacheva, Ivan Iliev, Roumyana Detcheva, Tatyana Dzimbova, Tamara Pajpanova, Evgeny Golovinsky : The RGD sequence is present in many extracellular matrix proteins and intracellular proteins, including caspases. Synthetic RGD peptides may affect adhesion, migration and tumour metastasis, or directly induce apoptosis. Several RGD peptides were synthesized, and their anti-adhesive and cytotoxic properties were analyzed in vitro. Here we present the cytotoxic activities of RGD, R(NO2)GD, CavGD and RGD-OMe on non-tumour 3T3 cells and tumour cell lines HepG2 and MCF-7. The cell growth inhibitory effects of RGD-OMe are significantly higher than those of RGD on the cell lines used. Evidently the modification in the carboxylic group of RGD with simple esterification increases the cell growth inhibitory effects of the parent compound. HTML XML PDF
      PubDate: Tue, 16 Oct 2012 0:00:00 +0300
       
  • Lifestyle characteristics and dietary impact on plasma concentrations of
           beta-carotene and retinol

    • Abstract: BioDiscovery 3: e8928
      DOI : 10.7750/BioDiscovery.2012.3.3
      Authors : Rabindra Nath Das, Pradip K. Sarkar : Mechanisms of dietary micronutrients and personal characteristics of the human body are intricately complicated. These mechanisms, however, can be easily interpreted through appropriate mathematical relationships. The present study aims to detect the statistically significant impact of personal characteristics and diet on plasma concentrations of retinol and beta-carotene using statistical modeling. The present analyses indicate that age, sex, smoking habit, quetelet, vitamin use, consumed calories, fiber, and dietary beta-carotene are statistically significant factors on plasma beta-carotene levels. On the other hand age, sex, smoking status, consumed fat, and dietary beta-carotene are significant factors on plasma retinol. These analyses indicate that changes in the variances of plasma beta-carotene and retinol are non-constant. Impacts of personal characteristics and dietary factors on human plasma concentrations of retinol and beta-carotene are explained based on mathematical relationships. These analyses support many earlier researches findings. However, the analyses also identify many additional casual factors that explain the means and variances of plasma beta-carotene and retinol, which earlier researches have not reported. HTML XML PDF
      PubDate: Sun, 30 Sep 2012 0:00:00 +0300
       
  • The dark side of light. Light pollution kills leatherback turtle
           hatchlings

    • Abstract: BioDiscovery 3: e8930
      DOI : 10.7750/BioDiscovery.2012.3.4
      Authors : Marina Zheleva : The leatherback turtle is the largest and most migratory of all sea turtles and deepest diving air-breathing animal. It has unique physiology which allows it to adapt to various habitats ranging from sub-polar to equatorial during its migrations. The leatherback turtle is also the only sea turtle where no cases of tumours have been diagnosed. These unique features add to the arguments for preservation of this endangered species. Here we discuss the effect of light pollution on leatherback turtle hatchlings in Tobago and the measures for their protection. HTML XML PDF
      PubDate: Sun, 30 Sep 2012 0:00:00 +0300
       
  • The Apoe-/- Mouse PhysioLab® Platform: A Validated Physiologically-based
           Mathematical Model of Atherosclerotic Plaque Progression in the Apoe-/-
           Mouse

    • Abstract: BioDiscovery 3: e8929
      DOI : 10.7750/BioDiscovery.2012.3.2
      Authors : Jason R Chan, Gregory Vuillaume, Caitlin Bever, Stefan Lebrun, Michael Lietz, Yvonne Steffen, Katrin Stolle, Karim Wahba, Xiao Wang, Shonna Moodie, Julia Hoeng, Manuel C Peitsch, Lyn M Powell : <em>Motivation:</em>Atherosclerosis is a complex multi-pathway inflammatory disease where accumulation of oxidatively modified lipids and leukocytes in the arterial intima leads to plaque formation over time. Translating Apoe<sup>-/-</sup> mouse results to the clinical setting is complicated by uncertainty around (a) mechanisms underlying disease etiology, (b) relative importance of these mechanisms as drivers of progression, and (c) how these roles change in response to perturbation by therapeutic intervention or lifestyle changes. <br><em>Results: </em>We describe a large-scale mechanistic, mathematical model of atherosclerosis in the Apoe<sup>-/-</sup> mouse and its validation with <em>in vivo</em> Apoe <sup>-/-</sup> data. Major physiological components include cholesterol/macrophage trafficking, inflammation, endothelial function, oxidative stress, and thrombosis. Heterogeneity in disease progression, observed despite genetic uniformity and experimentally controlled conditions, was captured through “virtual mice”. This model may be used to optimize <em>in vivo</em> experiments and paves the way for a similar modeling approach for human disease.<br><em>Availability: </em>The model is available by remote desktop client at Apoe.entelos.com. HTML XML PDF
      PubDate: Sun, 30 Sep 2012 0:00:00 +0300
       
  • Of mice and men – differential mechanisms of maintaining the
           undifferentiated state in mESC and hESC

    • Abstract: BioDiscovery 3: e8927
      DOI : 10.7750/BioDiscovery.2012.3.1
      Authors : Borislav Arabadjiev, Rumena Petkova, Albena Momchilova, Stoyan Chakarov, Rumen Pankov : The persistence of the defining characteristics of undifferentiated cells in vivo and in vitro is maintained via a complex interplay of several mechanisms, employing molecular events internal to the cell as well as signals originating outside the cell. The exogenous and the endogenous mechanisms maintaining stemness qualities of the cell are intricately interwoven with one another and susceptible to cross-interference. Mice and rats as animal models are almost universally considered to be close enough to humans so as to be used in research and applications eventually intended for use in human biology and medicine, at the same time being related distantly enough from primates so as not to overstep ethical boundaries. Studying the specific molecular features of both species in the context of maintenance of the undifferentiated state of mESC and hESC can provide researchers with an unique opportunity to unravel the network of interactions which take part in the decision about cell fate under different conditions; to glean interesting insights into the parallel evolution of the two species and to observe how different variants of basic cellular processes have been tried and tested in the evolutionary process. The present paper reviews the basic signalling pathways responsible for the maintenance of the undifferentiated state in mESC and hESC and analyses some specific aspects of the molecular physiology that are unique to the particular species. HTML XML PDF
      PubDate: Thu, 20 Sep 2012 0:00:00 +0300
       
  • Parallel Researching with Online Collaboration (PROC), a new cost
           effective model for multicentre multinational research

    • Abstract: BioDiscovery 2: e8926
      DOI : 10.7750/BioDiscovery.2012.2.3
      Authors : Chaturaka Rodrigo, Senaka Rajapakse : The traditional model of multicentre multinational studies is a costly exercise that limits its feasibility for resource limited settings. We propose an alternate model for such studies named Parallel Researching with Online Collaboration (PROC). If implemented, this hypothetical model will make multicentre trials feasible in many resource limited settings. PROC can be summarized in five phases; phase I – academics using free access social networking sites to collaborate and develop research questions, phase II – further consolidation of an idea and expansion of it with online contributions from experts, identification of key persons to carry out the study in parallel at different centres, phase III – drawing up a common research protocol and study tools, phase IV – each satellite centre functioning independently to carry out the common protocol, Phase V – pooling of data in a common summarized format and writing up the findings. HTML XML PDF
      PubDate: Sun, 26 Aug 2012 0:00:00 +0300
       
  • Viability of unstimulated lymphocytes exposed to extremely low frequency
           electromagnetic fields is dependent on intensity

    • Abstract: BioDiscovery 2: e8925
      DOI : 10.7750/BioDiscovery.2012.2.2
      Authors : P Rajendra, HN Sujatha, RB Sashidhar, C Subramanyam, D Devendranath, RSS Aradhya : The cell viability and DNA damage in unstimulated sheep primary lymphocytes subjected to different extremely low electromagnetic field intensities (5, 50 and 100 µT; 50 Hz) were studied with special emphasis on apoptosis. Sheep primary lymphocytes cultured in RPMI, supplemented with 10% FBS in the absence of mitogens, were exposed till 16 h. The cell viability assessment by 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyl tetrazolium bromide (MTT) assay showed a dose dependent enhancement of viability at 16 h. Further, quantitative DNA laddering and flow cytometric analysis showed a significant decrease in apoptosis of the cells subjected to 100 (p HTML XML PDF
      PubDate: Wed, 22 Aug 2012 0:00:00 +0300
       
  • Up-regulation of Gr1 + CD11b + cell population in the spleen of
           NaClO-administered mice works to repair skin wounds

    • Abstract: BioDiscovery 2: e8924
      DOI : 10.7750/BioDiscovery.2012.2.1
      Authors : Mayu Hara, Naomi Nishio, Sachiko Ito, Masashi Akiyama : In wound healing, early infiltration of neutrophils followed by macrophage infiltration are important defense mechanisms for repair of tissue damage. Here we examined the effects of neutrophils on wound healing. Administration of sodium hypochlorite (NaClO) to mouse skin induces neutrophil recruitment to the wound site and repeated administration of NaClO was shown to prolong wound healing. Examination of the spleens of mice whose wounds were repeatedly treated with NaClO, showed that GR-1<sup>+</sup>CD11b<sup>+</sup> cells were up regulated in the recovery phase of wounding. Many of the GR-1<sup>+</sup>CD11b <sup>+</sup> cells in the mouse bone marrow were neutrophils, as indicated by a ring-shaped nucleus, and some of the cells were immature myeloid-lineage cells. GR-1<sup>+</sup>CD11b<sup>+</sup> cells from bone marrow were sorted and injected intravenously to syngeneic Imprinting Control Region (ICR) mice. The mice that received GR-1<sup>+</sup>CD11b<sup>+</sup> cells recovered faster than the mice injected with the control, phosphate buffer saline (PBS). HTML XML PDF
      PubDate: Mon, 6 Aug 2012 0:00:00 +0300
       
  • Targeting ATM pathway for therapeutic intervention in cancer

    • Abstract: BioDiscovery 1: e8920
      DOI : 10.7750/BioDiscovery.2012.1.3
      Authors : Hilal S Khalil, Hemanth Tummala, Stoyan Chakarov, Nikolai Zhelev, David P. Lane : The Ataxia Telangiectasia Mutated gene encodes the ATM protein, a key element in the DNA damage response (DDR) signalling pathway responsible for maintaining genomic integrity within the cell. The ATM protein belongs to a family of large protein kinases containing the phosphatidylinositol-3 catalytic domain, including ATM, ATR and PI3K. ATM provides the crucial link between DNA damage, cell cycle progression and cell death by first sensing double stranded DNA breaks and subsequently phosphorylating and activating other downstream proteins functioning in DNA damage repair, cell cycle arrest and apoptotic pathways,. Mammalian cells are constantly challenged by genotoxic agents from a variety of sources and therefore require a robust sensing and repair mechanism to maintain DNA integrity or activate alternative cell fate pathways. This review covers the role of ATM in DDR signalling and describes the interaction of the ATM kinase with other proteins in order to fulfil its various functions. Special emphasis is given to how the growing knowledge of the DDR can help identify drug targets for cancer therapy, thus providing a rationale for exploiting the ATM pathway in anticancer drug development. Moreover, we discuss how a network modelling approach can be used to identify and characterise ATM inhibitors and predict their therapeutic potential. HTML XML PDF
      PubDate: Sun, 29 Jul 2012 0:00:00 +0300
       
  • Identification of a novel deletion mutant strain in Saccharomyces
           cerevisiae that results in a microsatellite instability phenotype

    • Abstract: BioDiscovery 1: e8918
      DOI : 10.7750/BioDiscovery.2012.1.4
      Authors : Hanlee P. Ji, Shannon Morales, Katrina Welch, Cam Yuen, Kyle Farnam, James M Ford : The DNA mismatch repair (MMR) pathway corrects specific types of DNA replication errors that affect microsatellites and thus is critical for maintaining genomic integrity. The genes of the MMR pathway are highly conserved across different organisms. Likewise, defective MMR function universally results in microsatellite instability (MSI) which is a hallmark of certain types of cancer associated with the Mendelian disorder hereditary nonpolyposis colorectal cancer. (Lynch syndrome). To identify previously unrecognized deleted genes or loci that can lead to MSI, we developed a functional genomics screen utilizing a plasmid containing a microsatellite sequence that is a host spot for MSI mutations and the comprehensive homozygous diploid deletion mutant resource for Saccharomyces cerevisiae. This pool represents a collection of non-essential homozygous yeast diploid (2N) mutants in which there are deletions for over four thousand yeast open reading frames (ORFs). From this screen, we identified a deletion mutant strain of the <i>PAU24</i> gene that leads to MSI. In a series of validation experiments, we determined that this <i>PAU24</i> mutant strain had an increased MSI-specific mutation rate in comparison to the original background wildtype strain, other deletion mutants and comparable to a MMR mutant involving the MLH1 gene. Likewise, in yeast strains with a deletion of <i>PAU24</i>, we identified specific de novo indel mutations that occurred within the targeted microsatellite used for this screen. HTML XML PDF
      PubDate: Mon, 23 Jul 2012 0:00:00 +0300
       
  • Bisphosphonate-related osteonecrosis of the jaws: Report of two cases with
           breast cancer, a dental concern and review of the literature

    • Abstract: BioDiscovery 1: e8917
      DOI : 10.7750/BioDiscovery.2012.1.2
      Authors : Ahmet Ercan Şekerci, Halil Sahman, Murat Ulu, Osman A Etoz, Yıldıray Sisman : Bisphosphonates are becoming increasingly important in the treatment of metabolic and oncological diseases involving the skeleton. In recent years, several cases of necrosis of the jaws associated with long-term use of bisphoshponates have been reported. The management of bisphosphonate-related osteonecrosis of the jaws (BRONJ) is emerging as a significant problem in the field of dentistry. In this article, we report two new cases of patients with osteonecrosis induced by bisphosphonates. Two unrelated female patients undergoing treatment with bisphosphonates for metastatic breast cancer were referred to the department of oral surgery due to non-healing extraction sockets and intraoral exposed bone after dental extraction. The treatment modality of case 1 included antibiotic therapy, sequestrectomy, periodontal flap, and chlorhexidine mouthwashes. After an eleven-month follow-up period the affected area has healed totally. The other patient refused any surgical intervention. In addition, this article reviews the current literature describing the dental procedures for patients with BRONJ. HTML XML PDF
      PubDate: Sun, 15 Jul 2012 0:00:00 +0300
       
  • Modelling malignant progression with a finite state machine supports a two
           checkpoint theory of cancer

    • Abstract: BioDiscovery 1: e8916
      DOI : 10.7750/BioDiscovery.2012.1.1
      Authors : Robert C. Jackson : We postulate the two checkpoints theory of cancer, a model of cancer development suggesting that malignant transformation of cells requires loss of function of both the G1 checkpoint and the mitotic spindle checkpoint. Malignant progression can be described as a process analogous to a genetic algorithm, which we term the malignant progression algorithm. There are two prerequisites for this process: first, there must be competition for reproductive resources, and this is driven by loss of the G1 checkpoint; second, there must be a source of genetic variation, and this is provided by loss of the mitotic spindle checkpoint, resulting in aneuploidy. These two factors then trigger a process of Darwinian selection, driving the emergence of cells with the various abnormalities that have been termed the “hallmarks of cancer”. Malignant progression is iterative, autocatalytic, and irreversible. The process can be modelled mathematically by describing the system as a finite state machine. The model indicates that loss of the two checkpoints is necessary and sufficient for tumour progression. The order of loss of the two checkpoints appears to be important: loss of the G1 checkpoint results in premalignant cells that replicate independently of physiological growth signals, but which remain diploid. Loss of the mitotic spindle checkpoint then results in aneuploid, malignant cells with highly error-prone replication, which rapidly progress to invasive, metastatic, hypoxia-tolerant, immortalised cells. This model of malignant progression has implications for the selection of anticancer drug targets and for tumour prevention strategies. HTML XML PDF
      PubDate: Thu, 5 Jul 2012 0:00:00 +0300
       
  • Man of Science: Celebrating Professor Sir David Lane’s 60th
           anniversary

    • Abstract: BioDiscovery 1: e8921
      DOI : 10.7750/BioDiscovery.2012.1.5
      Authors : Nikolai Zhelev : This article is devoted to the 60th anniversary of Professor Sir David Lane and summarises his renowned research career and scientific and business achievements to date. Professor Lane is one of the world’s foremost cancer biologists with more than 350 publications in the world leading science journals and was the second most highly cited UK-based scientist in the 1990’s. Sir David is best known for the discovery of the p53 protein which he termed “the guardian of the genome” due to its vital role in the defence against cancer. A decade later p53 was named “molecule of the year” by the scientific journal Science. Professor Lane has won many international prizes and awards for his outstanding work in the field of cancer research and drug development. HTML XML PDF
      PubDate: Sun, 1 Jul 2012 0:00:00 +0300
       
 
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