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Volume 13 - 2009

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New trends in aptamer-based electrochemical biosensors

Author(s): Dr. Sotiris, Missailidis,

Abstract: The analytical characteristics of aptamers are comparable with those of antibodies for the development of biosensor technology. However, aptamers offer some crucial advantages over antibodies such as selection capability for a variety of targets, easy synthesis, improved reproducibility and stability, simple modification for immobilization to solid supports and enhanced selectivity. This article reviews aptamer technology as well as aptamer-based assay configurations and goes on to explore reported applications in electrochemical aptasensors.

Keywords: Aptamer, Biosensor, Aptasensor, Electrochemical detection, SELEX


Mapping of MHC class binding nonamers from lipid binding protein of Ascaridia galli

Author(s): Dr. Virendra S, Gomase,

Abstract: Mapping of MHC class binding nonamers from lipid binding protein of Ascaridia galli

Keywords: lipid binding protein, MHC, epitope, solvent accessibility, peptide vaccine


Curcumin is not a ligand for peroxisome proliferator-activated receptor-γ Research Article

Author(s): Dr. Venkata R., Narala,

Abstract: Curcumin, a compound found in the spice turmeric, has been shown to possess a number of beneficial biological activities exerted through a variety of different mechanisms. Some curcumin effects have been reported to involve activation of the nuclear transcription factor peroxisome proliferator-activated receptor-γ (PPAR-γ), but the concept that curcumin might be a PPAR-γ ligand remains controversial. Results reported here demonstrate that, in contrast to the PPAR-γ ligands ciglitazone and rosiglitazone, curcumin is inactive in five different reporter or DNA- binding assays, does not displace [3H]rosiglitazone from the PPAR-γ ligand-binding site, and does not induce PPAR-γ-dependent differentiation of preadipocytes, while its ability to inhibit fibroblast-to-myofibroblast differentiation is not affected by any of four PPAR-γ antagonists. These multiple lines of evidence conclusively demonstrate that curcumin is not a PPAR-γ ligand and indicate the need for further investigation of the mechanisms through which the compound acts.

Keywords: PPAR-γ, TGF-β, rosiglitazone, ciglitazone, PPRE, preadipocyte, fibroblast, turmeric, peroxisome, curcumin


FAK as a target for cancer therapy

Author(s): Dr. Steven N., N. Hochwald,

Abstract: We have learned that malignant cells are similar to normal cells in the signaling pathways that they use. However, cancer cells acquire aberrations that favor their growth in the complex environments of living tissues. This includes their ability to invade and metastasize and their ability to grow and divide indefinitely. The progression of human cancer is characterized by a process of tumor cell motility, invasion, and metastasis to distant sites, requiring the cancer cells to be able to survive the apoptotic pressures of anchorage-independent conditions. One of the main tyrosine kinases that are linked to this malignant phenotype is the Focal Adhesion Kinase (FAK). FAK is overexpressed in many types of tumors and recently has been proposed to be a target for anti-cancer therapy. In this review, we will review the FAK structure, its role in signaling, and FAK targeted therapy approaches in malignancy.

Keywords: ocal Adhesion Kinase; malignancy; cancer; Y15


Combination of immunotherapy with anaerobic bacteria for immunogene therapy of solid tumours

Author(s): Dr. Ming, Q Wei,

Abstract: Solid tumours possess unique microenvironment characterised by defective vessels, heterogeneous tumour cell, hypoxic regions, and anaerobic metabolisms. These often become intrinsic and acquired barriers to current therapeutical approaches, but they also create an ideal condition for the growth of anaerobic bacteria, which have shown specificity in their germination and multiplication. Spores from the strictly anaerobic clostridial had demonstrated ability in tumour specific colonisation and induction of tumour lysis following intravenous delivery. Clostridial strains genetically modified to act as “Trojan horse” gene therapy vectors have been developed. Similarly, recent development in immunotherapy strategies for cancer also utilizes gene transfer to facilitate a dormant host immune response directed against the tumour. Combination of anaerobic bacteria for cancer gene therapies with immunotherapy will probably be the most promising approach that can potentially generate a prolonged anti-tumour effect beyond the immediate treatment period of gene therapy, allowing for treatment of advanced primary tumours and disseminated disease. In this review, we introduce the recent understanding of tumour microenvironment and detail the advances in the use of anaerobic bacteria for cancer gene therapies and recent studies in immuno therapy for cancers. We believe that the use of combined treatment modalities of such will provide a rational paradigm to improve upon the clinical efficacy of cancer therapy.

Keywords: Tumour microenvironment, Immunotherapy, Anaerobic bacteria, Hypoxia, Clostridial spores


Differential expression of 14-3-3ε during physiological, pathological cardiac hypertrophy and chronic heart failure in mice

Author(s): Dr. Youyi , Zhang,

Abstract: Physiological cardiac hypertrophy associated with regular exercise is usually beneficial, in marked contrast to pathological hypertrophy associated with disease. 14-3-3 proteins play a critical antiapoptotic function in cardiomyocytes. Whether it or other genes activated in the athlete’s heart might have an impact on cardiac function and survival in a setting of heart failure is unknown. To examine whether different changes of 14-3-3 proteins expression in physiological cardiac hypertrophy, pathological cardiac hypertrophy and chronic heart failure (CHF), we constructed mouse models of physiological cardiac hypertrophy to swim training, pathological cardiac hypertrophy to transverse aortic constriction (TAC) for 4 weeks and chronic heart failure to TAC for 16 weeks. In response to swimming training and TAC, mice showed significant increases in left ventricular diastolic posterior wall thickness (LVPWd), heart weight and normalized heart weight to body weight ratio. However, in CHF mice, LVPWd decreased, end-diastolic volume (EDV) increased and marked cardiac fibrosis was formed. Thus, pressure overload induced decompensate heart failure and eccentric hypertrophy. Moreover, 14-3-3ε protein expression of hearts was increased in response to swimming training but decreased in CHF mice. However, other isoforms (β, ζ) of 14-3-3 proteins were no obvious changes in these three models. Therefore, our results suggest that the expressions of 14-3-3ε are different in physiological and pathological hypertrophy, which may provide a potential gene strategy for the treatment of heart failure.

Keywords: 14-3-3ε protein, Cardiac hypertrophy, Swimming training, Transverse aortic constriction


Genes and Happiness

Author(s): Dr. Kenneth, Blum,

Abstract: Since the discovery of the double helix, the study of brain function, in terms of both physiology and behavioral traits, has resulted in a plethora of research linking these activities to the genetic basis of neurotransmitter function. Knowledge about how genes are expressed, as well as their potential impairment due to polygenic inheritance, can shed light on predispositions to addiction and self-destructive behaviors. Genetic information derived from scientific explorations of genetic traits may have important links to understanding the basis for feelings of well-being and potentially the phenomena associated with human happiness. While non-genetic oriented research of social, political, and biological studies have addressed the impact of social and institutional environments on mass political attitudes and behaviors, there is a paucity of solid research on the interrelation and influence of genetic and environmental factors on these parameters. The separate fields of psychology and molecular biology are subject to inherent limitations that may only be resolved through collaboration across disciplines. Certainly areas relating to spirituality (“Genospirituality”) and political science are just two that are beginning to emerge as fruitful grounds for identification of specific polymorphic gene associations and may pave the way to advance a new science of human nature. We address the issue of “Nature vs. Nurture” as it relates to questions regarding the definition of happiness, its causes, and its promotion. These questions are central to understanding human nature and are emerging as an important target of research, especially in the area of nutrigenomics. The present commentary attempts to identify key “vector influences” that link genes, the brain, nutrition, and social behavior to a most desired, but misunderstood, and potentially fragile experience known as “happiness.” Specifically, we propose that successful changes in body composition/body mass index (BMI)/ percentage of body fat will increase not only positive self-image, but overall wellness that produces a state of happiness. We provide preliminary evidence that utilization of a customized dopaminergic agonist LG839 DNA directed 91 Blum et al: Genes and Happiness nutraceutical, significantly increased happiness in obese subjects. We detail genotypes that may play a role in determining happiness, based on current knowledge.

Keywords: Happiness, Genospirituality, Reward Deficiency Syndrome (RDS), Gene Map, Dopamine


Signaling and epigenetic mechanisms regulating stem cells

Author(s): Dr. Prithi , Rajan,

Abstract: The enormous potential of stem cells in human therapeutics heightens the relevance of studies addressing the cellular mechanisms, which control their proliferation and fate choice decisions. While embryonic stem cells retain the ability to differentiate into most if not all the cell types of the adult, somatic stem cells retain a restricted potential to differentiate into most or all the mature cell types of the tissue that they are derived from. In this report we review the literature and concepts related to cytoplasmic and nuclear regulatory mechanisms, which confer the properties of pluripotency or multipotency on stem cells. The recent flurry of activity related to the induction of pluripotency in fibroblasts and other relatively mature cells has given us pause in considering the actual nature of the two extremes of terminal differentiation and 'stemness', and the apparent reversibility of both phenomena. An analysis of the current literature on mechanisms of pluripotency and multipotency could lead to a better understanding of the possibilities by which a cell may be maintained in a preferred state of differentiation or de- differentiation at will.

Keywords: stem cells, embryonic, somatic, pluripotency, multipotency, and mechanisms


Human primary chondrocytes exhibit an anti- angiogenic effect despite of high secretion of VEGF

Author(s): Dr. Peter, Camaj,

Abstract: Cartilage tissue is one of the few avascular tissues in humans. This fact suggests that healthy cartilage is capable to prevent the influence of angiogenesis driven by environmental stimuli such as low oxygen partial pressure and changes in pH. The aim of this work was to demonstrate and to quantify the anti-angiogenic potential of normal human chondrocytes in comparison to de-differentiated human chondrocytes and chondrosarcoma cells. We found that conditioned medium of primary human chondrocytes exhibits strong anti-angiogenic properties (inhibition of human umbilical vein endothelial cell proliferation and sprouting). The effect was specific to differentiated chondrocytes, whereas it was absent in conditioned medium from de-differentiated chondrocytes. Furthermore, we revealed that the effect was specifically anti-angiogenic but not generally anti-proliferative, when we compared the effect of the above mentioned conditioned media on proliferation of human umbilical vein endothelial cell versus smooth muscle cell. In addition, we found that the inhibition of HUVEC proliferation caused by conditioned medium of differentiated chondrocyte was even stronger than the anti-proliferative effect of Rapamycin treatment. In contrast, we could demonstrate that conditioned medium of chondrosarcoma cells SW1353 exhibits pro- angiogenic effects. The results from vascular endothelial growth factor ELISA revealed that the inhibition of HUVEC proliferation and sprouting caused by conditioned medium of chondrocytes was not a result of a decreased amount of secreted VEGF. In contrast to our expectations, the results demonstrated that these anti-proliferative effects of conditioned medium of differentiated chondrocytes were present despite of a very high content of VEGF together with other bioactive substances secreted by differentiated chondrocytes. This fact indicates that there might exist potential anti-angiogenic substances secreted by differentiated chondrocytes that are able to overcome the pro-angiogenic effect of VEGF. Such factors might be a very beneficial source as natural anti-angiogenic compounds bearing minimal side effects.

Keywords: anti-angiogenic effect, chondrocytes, chondrosarcoma, VEGF


Association analysis of the Tumor necrosis factor gene polymorphisms (TNFA 238 and 302) in the development of schizophrenia: Impact on the antipsychotic treatment response

Author(s): Dr. Chi-Un, Pae,

Abstract: Chi-Un Pae, Antonio Drago, Alberto Chiesa, Laura Mandelli, Alessandro Serretti, Tae-Youn Jun

Keywords: schizophrenia, tumor necrosis factor-α gene, and clinical variables.


Kruppel like factor 4 (KLF4): a transcription factor with diverse context-dependent functions

Author(s): Dr. Walden, Ai,

Abstract: Kruppel like factor 4 (KLF4) is a zinc finger containing transcription factor, which is expressed in a variety of tissues and regulates numerous biological processes including proliferation, differentiation, development, inflammation, and apoptosis. Thereby, it helps in maintaining homeostasis. As a transcription factor KLF4 both activates and represses the transcription of different genes depending on the cellular context. Physiologically, KLF4 can function both as a tumor suppressor and an oncogene. A recent study reported that p21 status may be a switch that determines the tumor suppressive or oncogenic function of KLF4. Over expression of KLF4 has been found to promote embryonic stem cell renewal. In addition, KLF4 plays an important role in reprogramming both mouse and human differentiated fibroblasts into induced pluripotent stem cells (iPS cells), which highly resemble embryonic stem cells, along with other three transcription factors including Oct4, Sox2, and c-Myc. This review discusses the function of KLF4 in cancer development and the underlying mechanisms. The role of KLF4 in stem cell biology and the future directions of KLF4 studies in this area have also been speculated.

Keywords: KLF4, tumor suppressor, oncogene, Notch signaling, induced pluripotent stem cells (iPS cells)


Maintenance of a functional higher order chromatin structure: The role of the nuclear matrix in normal and disease states

Author(s): Dr. Stephen A., Krawetz,

Abstract: The ordered packaging of DNA within the nucleus of somatic cells reflects a dynamic supportive structure that facilitates stable transcription interrupted by intermittent cycles of extreme condensation. This dynamic mode of packing and unpacking chromatin is intimately linked to the ability of the genome to specifically complex with both histones and non-histone proteins. Understanding the underlying mechanism that governs the formation of higher order chromatin structures is a key to understanding how local architecture modulates transcription. In part, the formation of these structures appears to be regulated through genomic looping that is dynamically mediated by attachment to the nuclear scaffold/matrix at S/MARs, i.e., Scaffold/Matrix Attachment Regions. Although the mechanism guiding the formation and use of these higher-ordered structures remains unknown, S/MARs continue to reveal a multitude of roles in development and the pathogenesis of disease.

Keywords: S/MAR attachment, Nuclear Matrix, disease, scaffold, model, gene regulation, LIS, NaCl


Suppression of adenoviral-induced host immune response by TGFß1 expression

Author(s): Dr. Yi, Lu,

Abstract: Adenoviral vector (Ad) is the most commonly used viral vector in gene therapy because of its high transduction efficiency. However, Ad has its limitation due to its transient gene expression and reduced efficacy of repeated vector administration, thanks to host cellular and humoral immune responses. Although it is well known that Ad causes immune response to secondary Ad administration and thus hampers the repeated Ad-mediated gene transfer, the systemic comparison between different viral delivery routes and the optimal elapsed time between repetitive viral deliveries has yet to be extensively studied. In this study, in order to determine (i) to what extent the host immune system attenuates the function of the secondary-administrated Ad; and (ii) whether transforming growth factor-! 1 (TGFß1), an immune suppressor, would reduce this immune response, immune-competent C57BL/6 mice carrying subcutaneous prostate tumors were administrated by either intratumoral (i.t.) or intravenous (i.v.) injection of primary Ad (namely, the 1st viral administration: with either Ad expressing tumor suppressor gene p16, AdRSVp16, or Ad expressing reporter gene ß-galactosidase, AdRSVlacZ), then followed by i.t. injection of secondary Ad (AdRSVlacZ) in the presence or absence of co-delivery of Ad expressing TGFß1 (AdRSVTGFß1). Sera were purified from blood samples collected at various time points. Anti-adenoviral (anti-Ad) antibody in serum and its neutralizing ability to secondary Ad infection were evaluated. No immune response was observed in mice within 3 days after fisrt viral injection regardless of i.t. or i.v. injection. After 7 days, mice by i.v. viral injection developed a strong immune response and this immune potency was increased over the time up to 8 weeks. In contrast, mice by i.t. viral injection had only a minor immune response at day 7, and this response waned in 14 days after viral injection. The immune response was mainly caused by native Ad proteins rather than by transgenes. Moreover, expression of TGFß1 by co-delivery of AdRSVTGFß1 with secondary AdRSVlacZ reduced anti-Ad antibody in sera and prolonged transgene lacZ expression. These results suggest that repeated administration of therapeutic Ad for solid-tumor (such as gene therapy for prostate cancer) by directly i.t. injection with reasonable intervals may provide a rational approach in a clinical setting. The addition of immune suppressor like TGFß1 may be useful to minimize the immune response to the secondary Ad challenge. These results suggest that with reasonable and justified intervals between repeated viral administration, plus the aid of immune response suppressor, local delivery of Ad vector for solid tumor gene therapy should be efficacious with no or minimal immune response.

Keywords: TGFß1, immune response, adenovirus, intratumoral injection, intravenous injection, neutralizing anti-Ad antibody

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