Thursday, December 22, 2016

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Thursday, December 8, 2016

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Wednesday, December 7, 2016

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Monday, November 21, 2016

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Wednesday, November 9, 2016

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Wednesday, November 2, 2016

Highlighted Article: The Challenges of Modeling Drug Resistance to Antiangiogenic Therapy



The Challenges of Modeling Drug Resistance to Antiangiogenic Therapy


Author(s):

Michalis Mastri, Spencer Rosario, Amanda Tracz, Robin E. Frink, Rolf A. Brekken and John M. L. Ebos   Pages 1747 - 1754 ( 8 )

Abstract:


Drug resistance remains an ongoing challenge for the majority of patients treated with inhibitors of the vascular endothelial growth factor (VEGF) pathway, a key regulator of tumor angiogenesis. Preclinical models have played a significant role in identifying multiple complex mechanisms of antiangiogenic treatment failure. Yet questions remain about the optimal methodology to study resistance that may assist in making clinically relevant choices about alternative or combination treatment strategies. The origins of antiangiogenic treatment failure may stem from the tumor vasculature, the tumor itself, or both together, and preclinical methods that define resistance are diverse and rarely compared. We performed a literature search of the preclinical methodologies used to examine resistance to VEGF pathway inhibitors and identified 109 papers from more than 400 that use treatment failure as the starting point for mechanistic study. We found that definitions of resistance are broad and inconsistent, involve only a small number of reagents, and derive mostly from in vitro and in vivo methodologies that often do not represent clinically relevant disease stages or progression. Together, this literature analysis highlights the challenges of studying inhibitors of the tumor microenvironment in the preclinical setting and the need for improved methodology to assist in qualifying (and quantifying) treatment failure to identify mechanisms that will help predict alternative strategies in patients.

Keywords:

VEGF, drug resistance, metastasis, mouse models, GEMMs, syngeneic, orthotopic.

Affiliation:

Department of Cancer Genetics and Medicine, Roswell Park Cancer Institute, Elm & Carlton Streets, Buffalo, NY 142631, USA.

Graphical Abstract:



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Wednesday, October 26, 2016

Most Cited Article: Targeting the BRCA1/2 Tumor Suppressors



Targeting the BRCA1/2 Tumor Suppressors

Author(s):
Eliot M. Rosen and Michael J. PishvaianPages 17-31 (15)
Abstract:

The breast cancer susceptibility genes BRCA1 and BRCA2 are classic tumor suppressor genes that exhibit an autosomal dominant pattern of inheritance with high penetrance. BRCA carriers inherit one mutant BRCA allele and one wild-type allele; and the wild-type allele is invariably deleted or mutated within the tumor. These genes function as caretakers in the maintenance of genomic stability, in part, by participating in homology-directed DNA repair (HDR), an error- free mechanism for the repair of double-strand breaks (DSBs). PARP1 (poly (ADP-ribose) polymerase 1) is an enzyme that functions in the base excision repair (BER) pathway, where its ability to post-translationally modify histones and DNA damage response proteins is required for repair of single-strand breaks (SSBs). In 2005, it was observed that knockdown of PARP1 or treatment with a small molecule PARP inhibitor was far more toxic to cells with BRCA1 or BRCA2 mutations than BRCA1/2-competent cells. This observation is an example of “synthetic lethality”, a concept whereby two gene mutations combine to cause cell death, when neither mutation alone is lethal. These results spawned the idea to use PARP inhibitors to treat BRCA1/2 mutant cancers. Here, we will review the basic science underlying the discoveries described above, the preclinical research, and the clinical trials designed to exploit the sensitivity of BRCA1/2 mutant tumor cells to PARP inhibitors. We will also describe problems associated with the use of these agents, including development and mechanisms of drug resistance; and we will provide a forward look at new agents and strategies currently under development.
Keywords:
BRCA1, BRCA2, DNA repair, homology-directed repair (HDR), mutation, olaparib, PARP1, synthetic lethality.
Affiliation:
Department of Oncology, Lombardi Comprehensive Cancer Center/Georgetown University School of Medicine, Preclinical Sciences Building, Room GM12B, 3970 Reservoir Road, NW, Washington, DC 20057, USA.




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Thursday, October 20, 2016

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Thursday, October 6, 2016

Highlighted Article Flyer for the journal “Current Drug Targets” Volume 17, Number 11



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Wednesday, October 5, 2016

Highlighted Article Flyer for the journal “Current Drug Targets”



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Current Drug Targets



Current Drug Targets aims to cover the latest and most outstanding developments on the medicinal chemistry and pharmacology of molecular drug targets e.g. disease specific proteins, receptors, enzymes, genes.
Current Drug Targets publishes guest edited thematic issues written by leaders in the field covering a range of current topics of drug targets. The journal also accepts for publication mini- & full-length review articles and drug clinical trial studies.
As the discovery, identification, characterization and validation of novel human drug targets for drug discovery continues to grow; this journal is essential reading for all pharmaceutical scientists involved in drug discovery and development.
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Articles from the journal in Current Drug Targets, Volume 17, Issue 2:


  • Editorial (Thematic Issue: Targeting Defective DNA Damage Response Signaling)
  • Targeting the Ataxia Telangiectasia Mutated Protein in Cancer Therapy
  • The Role of JNK Signalling in Responses to Oxidative DNA Damage
  • Insights into a Critical Role of the FOXO3a-FOXM1 Axis in DNA Damage Response and Genotoxic Drug Resistance
  • Renin-Angiotensin-Aldosterone System: A Current Drug Target for the Management of Neuropathic Pain
  • The Epidemiological, Mechanistic and Potential Clinical Role of Androgen Receptor (AR) in Urothelial Carcinoma
  • Nanocarriers Based Anticancer Drugs: Current Scenario and Future Perceptions
  • The Use of Mesenchymal Stem Cells for the Treatment of Autoimmunity: From Animals Models to Human Disease
  • Liver Disease and Hepatocellular Carcinoma in Alcoholics: The Role of Anticraving Therapy
  • Practical Considerations for Omics Experiments in Biomedical Sciences

For details on the articles, please visit this link :: http://bit.ly/1WIpWvy

courtesy by: https://benthamsciencepublishers.wordpress.com/2016/02/25/new-issue-current-drug-targets-2/

New Issue :::Current Drug Targets , 17 Issue 11



Current Drug Targets aims to cover the latest and most outstanding developments on the medicinal chemistry and pharmacology of molecular drug targets e.g. disease specific proteins, receptors, enzymes, genes.
Current Drug Targets publishes guest edited thematic issues written by leaders in the field covering a range of current topics of drug targets. The journal also accepts for publication mini- & full-length review articles and drug clinical trial studies.
As the discovery, identification, characterization and validation of novel human drug targets for drug discovery continues to grow; this journal is essential reading for all pharmaceutical scientists involved in drug discovery and development.

Articles from the journal Current Drug Targets , 17 Issue 11

For details on the articles, please visit this link :: http://bit.ly/2bBUEph
courtesy by : https://benthamsciencepublishers.wordpress.com/2016/09/06/new-issue-current-drug-targets-17-issue-11/

Thursday, July 28, 2016

Pharmacological Chaperones that Protect Tetrahydrobiopterin Dependent Aromatic Amino Acid Hydroxylases Through Different Mechanisms

Author(s):

Magnus Hole, Ana Jorge-Finnigan, Jarl Underhaug, Knut Teigen and Aurora MartinezPages 1-12 (12)

Abstract:


The aromatic amino acid hydroxylase (AAAH) enzyme family includes phenylalanine hydroxylase (PAH), tyrosine hydroxylase (TH) and the tryptophan hydroxylases (TPH1 and TPH2). All four members of the AAAH family require iron, dioxygen and the cofactor (6R)-L-erythro-5,6,7,8-tetrahydrobiopterin (BH4) to hydroxylate their respective substrates. The AAAHs are involved in severe diseases; whereas polymorphisms and variants in the TPH genes are associated to neuropsychiatric disorders, mutations in PAH and TH are responsible for the autosomal recessive disorders phenylketonuria (PKU) and TH deficiency (THD), respectively. A large number of PKU and THD-causing mutations give rise to unstable, misfolded proteins. The degree of conformational instability correlates well with the severity of the patient phenotypes, underlying the relevance of searching for stabilizing compounds that may protect from loss of protein and activity in vivo. Supplementation with the cofactor BH4 exerts a multifactorial response in PAH, where one of the main mechanisms for the induced increase in PAH activity in BH4-responsive PKU patients appears to be a pharmacological chaperone effect. For TH the stabilizing effect of BH4 is less established. On the other hand, a number of compounds with pharmacological chaperone potential for PKU and THD mutants have been discovered. The stabilizing effect of these compounds has been established in vitro, in cells and in animal models. A recent study with TH has revealed different mechanisms for the action of pharmacological chaperones and identifies a subtype of compounds that preserve TH activity by weak binding to the catalytic iron. It is expected that synergistic combinations of different pharmacological chaperones could provide patient-tailored therapeutic options.

Keywords:

Mutation, protein stability, misfolding correction, pharmacological chaperones, phenylketonuria, tyrosine hydroxylase deficiency

Affiliation:

Department of Biomedicine and K.G. Jebsen Center for Research on Neuropsychiatric Disorders, University of Bergen, Bergen Norway


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Insights into a Critical Role of the FOXO3a-FOXM1 Axis in DNA Damage Response and Genotoxic Drug Resistance

Author(s):

Gabriela Nestal de Moraes, Laura Bella, Stefania Zona, Matthew J. Burton and Eric W.-F. LamPages 164-177 (14)

Abstract:


FOXO3a and FOXM1 are two forkhead transcription factors with antagonistic roles in cancer and DNA damage response. FOXO3a functions like a typical tumour suppressor, whereas FOXM1 is a potent oncogene aberrantly overexpressed in genotoxic resistant cancers. FOXO3a not only represses FOXM1 expression but also its transcriptional output. Recent research has provided novel insights into a central role for FOXO3a and FOXM1 in DNA damage response. The FOXO3a-FOXM1 axis plays a pivotal role in DNA damage repair and the accompanied cellular response through regulating the expression of genes essential for DNA damage sensing, mediating, signalling and repair as well as for senescence, cell cycle and cell death control. In this manner, the FOXO3a-FOXM1 axis also holds the key to cell fate decision in response to genotoxic therapeutic agents and controls the equilibrium between DNA repair and cell termination by cell death or senescence. As a consequence, inhibition of FOXM1 or reactivation of FOXO3a in cancer cells could enhance the efficacy of DNA damaging cancer therapies by decreasing the rate of DNA repair and cell survival while increasing senescence and cell death. Conceptually, targeting FOXO3a and FOXM1 may represent a promising molecular therapeutic option for improving the efficacy and selectivity of DNA damage agents, particularly in genotoxic agent resistant cancer. In addition, FOXO3a, FOXM1 and their downstream transcriptional targets may also be reliable diagnostic biomarkers for predicting outcome, for selecting therapeutic options, and for monitoring treatments in DNA-damaging agent therapy.

Keywords:

Cancer, DNA damage, drug resistance, FOXM1, FOXO3a, genotoxic agents, transcriptional targets.

Affiliation:

Department of Surgery and Cancer, Imperial College London, Hammersmith Hospital Campus, Du Cane Road, London, W12 0NN, UK.

Graphical Abstract:



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Targeted Thromboelastographic (TEG) Blood Component and Pharmacologic Hemostatic Therapy in Traumatic and Acquired Coagulopathy

Author(s):

Mark Walsh, Stephanie Fritz, Daniel Hake, Michael Son, Sarah Greve, Manar Jbara, Swetha Chitta, Braxton Fritz, Adam Miller, Mary K Bader, Jonathon McCollester, Sophia Binz, Alyson Liew-Spilger, Scott Thomas, Anton Crepinsek, Faisal Shariff, Victoria Ploplis and Francis J. CastellinoPages 954-970 (17)

Abstract:


Trauma-induced coagulopathy (TIC) is a recently described condition which traditionally has been diagnosed by the common coagulation tests (CCTs) such as prothrombin time/international normalized ratio (PT/INR), activated partial thromboplastin time (aPTT), platelet count, and fibrinogen levels. The varying sensitivity and specificity of these CCTs have led trauma coagulation researchers and clinicians to use Viscoelastic Tests (VET) such as Thromboelastography (TEG) to provide Targeted Thromboelastographic Hemostatic and Adjunctive Therapy (TTHAT) in a goal directed fashion to those trauma patients in need of hemostatic resuscitation. This review describes the utility of VETs, in particular, TEG, to provide TTHAT in trauma and acquired non-trauma-induced coagulopathy.

Keywords:

Thromboelastography, point-of-care, acquired coagulopathy, blood component therapy, systemic hemostatic agents, trauma-induced coagulopathy, hemostatic resuscitation, tranexamic acid, targeted pharmacologic therapy.

Affiliation:

Memorial Hospital of South Bend, South Bend, Indiana 46601, USA.

Graphical Abstract:



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Structural and Functional Aspects of Class A Carbapenemases

Author(s):

Thierry Naas, Laurent Dortet and Bogdan I. IorgaPages 1006-1028 (23)

Abstract:


The fight against infectious diseases is probably one of the greatest public health challenges faced by our society, especially with the emergence of carbapenem-resistant gram-negatives that are in some cases pan-drug resistant. Currently, β-lactamase-mediated resistance does not spare even the newest and most powerful β-lactams (carbapenems), whose activity is challenged by carbapenemases. The worldwide dissemination of carbapenemases in gram-negative organisms threatens to take medicine back into the pre-antibiotic era since the mortality associated with infections caused by these “superbugs” is very high, due to limited treatment options. Clinically-relevant carbapenemases belong either to metallo- β- lactamases (MBLs) of Ambler class B or to serine-β -lactamases (SBLs) of Ambler class A and D enzymes. Class A carbapenemases may be chromosomally-encoded (SME, NmcA, SFC-1, BIC-1, PenA, FPH-1, SHV-38), plasmid-encoded (KPC, GES, FRI-1) or both (IMI). The plasmid-encoded enzymes are often associated with mobile elements responsible for their mobilization. These enzymes, even though weakly related in terms of sequence identities, share structural features and a common mechanism of action. They variably hydrolyse penicillins, cephalosporins, monobactams, carbapenems, and are inhibited by clavulanate and tazobactam. Three-dimensional structures of class A carbapenemases, in the apo form or in complex with substrates/inhibitors, together with site-directed mutagenesis studies, provide essential input for identifying the structural factors and subtle conformational changes that influence the hydrolytic profile and inhibition of these enzymes. Overall, these data represent the building blocks for understanding the structure-function relationships that define the phenotypes of class A carbapenemases and can guide the design of new molecules of therapeutic interest.

Keywords:

Biochemical properties, carbapenemase, class A, crystallography, molecular modeling, mutagenesis.

Affiliation:

Service de Bactériologie- Hygiène, Hôpital de Bicêtre, APHP, EA7361, Faculté de Médecine Paris- Sud, LabEx LERMIT, Le Kremlin-Bicêtre, France.

Graphical Abstract:



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