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Aspirin is a cornerstone of therapy in the treatment of patients with acute coronary syndromes (ACS). However, dual antiplatelet therapy reduces the risk of stent thrombosis and cardiovascular events compared with aspirin alone in the treatment of patients with ACS. Recently, there has been debate as to which antiplatelet agent should be added to aspirin in the ACS treatment regimen. This review summarizes the pharmacologic and clinical data comparing clopidogrel, prasugrel, and ticagrelor, and provides a practical guide to clinicians for determining which antiplatelet to use for patients with ACS.

Brossard K.A.,State University of New York at Buffalo | Campagnari A.A.,State University of New York at Buffalo | Campagnari A.A.,Buffalo Center of Excellence
Infection and Immunity | Year: 2012

Acinetobacter baumannii is a significant source of nosocomial infections worldwide. This bacterium has the ability to survive and persist on multiple abiotic surfaces in health care facilities, and once a focus has been established, this opportunistic pathogen is difficult to eradicate. This paper demonstrates that the A. baumannii biofilm-associated protein (Bap) is necessary for mature biofilm formation on medically relevant surfaces, including polypropylene, polystyrene, and titanium. Scanning electron microscopy analyses of biofilms show that Bap is required for three-dimensional tower structure and water channel formation. In conjunction with persistence on abiotic surfaces, adherence to eukaryotic cells is an important step in bacterial colonization resulting in infection of the host. We have described Bap as the surface structure involved in adherence of A. baumannii to both normal human bronchial epithelial cells and normal human neonatal keratinocytes. However, Bap is not involved in internalization of the bacterium in these two cell lines. Furthermore, this study shows that the presence of Bap increases the bacterial cell surface hydrophobicity. The results of this study are pertinent, as the data lead to a better understanding of the role of Bap in biofilm formation on medical surfaces and in colonization of the host. © 2012, American Society for Microbiology.

Velagapudi S.P.,Buffalo Center of Excellence | Seedhouse S.J.,Buffalo Center of Excellence | Disney M.D.,Buffalo Center of Excellence
Angewandte Chemie - International Edition | Year: 2010

Hitting the target: A combined computational and experimental approach defines optimal and suboptimal RNA motifs as targets for small molecules through two dimensional combinatorial screening. The method, termed structure-activity relationships through sequencing (StARTS), uses information from the sequences of the RNA motifs selected to bind a ligand. © 2010 Wiley-VCH Verlag GmbH & Co. KGaA.

Velagapudi S.P.,Scripps Research Institute | Velagapudi S.P.,State University of New York at Buffalo | Gallo S.M.,Buffalo Center of Excellence | Disney M.D.,Scripps Research Institute
Nature Chemical Biology | Year: 2014

Oligonucleotides are designed to target RNA using base pairing rules, but they can be hampered by poor cellular delivery and nonspecific stimulation of the immune system. Small molecules are preferred as lead drugs or probes but cannot be designed from sequence. Herein, we describe an approach termed Inforna that designs lead small molecules for RNA from solely sequence. Inforna was applied to all human microRNA hairpin precursors, and it identified bioactive small molecules that inhibit biogenesis by binding nuclease-processing sites (44% hit rate). Among 27 lead interactions, the most avid interaction is between a benzimidazole (1) and precursor microRNA-96. Compound 1 selectively inhibits biogenesis of microRNA-96, upregulating a protein target (FOXO1) and inducing apoptosis in cancer cells. Apoptosis is ablated when FOXO1 mRNA expression is knocked down by an siRNA, validating compound selectivity. Markedly, microRNA profiling shows that 1 only affects microRNA-96 biogenesis and is at least as selective as an oligonucleotide. © 2014 Nature America, Inc. All rights reserved.

Wu J.,State University of New York at Buffalo | Tzanakakis E.S.,State University of New York at Buffalo | Tzanakakis E.S.,Buffalo Center of Excellence
PLoS Computational Biology | Year: 2013

Nanog is a principal pluripotency regulator exhibiting a disperse distribution within stem cell populations in vivo and in vitro. Increasing evidence points to a functional role of Nanog heterogeneity on stem cell fate decisions. Allelic control of Nanog gene expression was reported recently in mouse embryonic stem cells. To better understand how this mode of regulation influences the observed heterogeneity of NANOG in stem cell populations, we assembled a multiscale stochastic population balance equation framework. In addition to allelic control, gene expression noise and random partitioning at cell division were considered. As a result of allelic Nanog expression, the distribution of Nanog exhibited three distinct states but when combined with transcriptional noise the profile became bimodal. Regardless of their allelic expression pattern, initially uniform populations of stem cells gave rise to the same Nanog heterogeneity within ten cell cycles. Depletion of NANOG content in cells switching off both gene alleles was slower than the accumulation of intracellular NANOG after cells turned on at least one of their Nanog gene copies pointing to Nanog state-dependent dynamics. Allelic transcription of Nanog also raises issues regarding the use of stem cell lines with reporter genes knocked in a single allelic locus. Indeed, significant divergence was observed in the reporter and native protein profiles depending on the difference in their half-lives and insertion of the reporter gene in one or both alleles. In stem cell populations with restricted Nanog expression, allelic regulation facilitates the maintenance of fractions of self-renewing cells with sufficient Nanog content to prevent aberrant loss of pluripotency. Our findings underline the role of allelic control of Nanog expression as a prime determinant of stem cell population heterogeneity and warrant further investigation in the contexts of stem cell specification and cell reprogramming. © 2013 Wu, Tzanakakis.

Liang M.-S.,State University of New York at Buffalo | Andreadis S.T.,State University of New York at Buffalo | Andreadis S.T.,Buffalo Center of Excellence
Biomaterials | Year: 2011

We present a strategy to conjugate TGF-β1 into fibrin hydrogels to mimic the in vivo presentation of the growth factor in a 3D context. To this end, we engineered fusion proteins between TGF-β1 and a bi-functional peptide composed of a Factor XIII domain and a plasmin cleavage site. In another version the protease cleavage site was omitted to examine whether the growth factor that could not be released from the scaffold by cells had different effects on tissue constructs. The optimal insertion site which yielded correctly processed, functional protein was found between the latency associated peptide and mature TGF-β1 domains. In solution the fusion proteins exhibited similar biological activity as native TGF-β1 as evidenced by inhibition of cell proliferation and promoter activity assays. Immunoprecipitation experiments demonstrated that the fusion TGF-β1 protein bound to fibrinogen in a Factor XIII dependent manner and could be released from the peptide by the action of plasmin. In contrast to bolus delivery, immobilized TGF-β1 induced sustained signaling in fibrin-embedded cells for several days as evidenced by Smad2 phosphorylation. Prolonged pathway activation correlated with enhanced contractile function of vascular constructs prepared from hair follicle mesenchymal stem cells or bone marrow derived smooth muscle cells. Our results suggest that fibrin-immobilized TGF-β1 may be used to enhance the local microenvironment and improve the function of engineered tissues in vitro and potentially also after implantation in vivo where growth factor delivery faces overwhelming challenges. © 2011 Elsevier Ltd.

Duffner P.K.,Buffalo Center of Excellence
European Journal of Paediatric Neurology | Year: 2010

The long term effects of central nervous system therapy for children with brain tumors have been the subject of research since the 1970s. Many studies have demonstrated that children treated for brain tumors with surgery and standard radiation therapy have developed intellectual decline which is progressive over at least a decade. Risk factors for this cognitive deterioration have been identified and include perioperative complications, possibly hydrocephalus, high radiation dose, large volume radiation, chemotherapy (especially methotrexate), radiation vasculopathy and young age at the time of treatment. In an effort to reduce long-term neurotoxicity, efforts have been made to develop treatment regimens that reduce the impact of these risk factors. Some of these include reduced neuraxis radiation with and without adjuvant chemotherapy, conformal radiation, chemotherapy only protocols for children with optic pathway-hypothalamic tumors and a series of baby brain tumor studies in which chemotherapy (standard and high dose) has allowed radiation to be delayed, reduced or omitted. Whether these changes in therapy will ultimately improve the quality of life of the long-term survivors is uncertain. Close follow-up of these children will be required throughout their lives. © 2009 European Paediatric Neurology Society.

Wu J.,State University of New York at Buffalo | Tzanakakis E.S.,State University of New York at Buffalo | Tzanakakis E.S.,Buffalo Center of Excellence
Biotechnology Advances | Year: 2013

Isogenic stem cell populations display cell-to-cell variations in a multitude of attributes including gene or protein expression, epigenetic state, morphology, proliferation and proclivity for differentiation. The origins of the observed heterogeneity and its roles in the maintenance of pluripotency and the lineage specification of stem cells remain unclear. Addressing pertinent questions will require the employment of single-cell analysis methods as traditional cell biochemical and biomolecular assays yield mostly population-average data. In addition to time-lapse microscopy and flow cytometry, recent advances in single-cell genomic, transcriptomic and proteomic profiling are reviewed. The application of multiple displacement amplification, next generation sequencing, mass cytometry and spectrometry to stem cell systems is expected to provide a wealth of information affording unprecedented levels of multiparametric characterization of cell ensembles under defined conditions promoting pluripotency or commitment. Establishing connections between single-cell analysis information and the observed phenotypes will also require suitable mathematical models. Stem cell self-renewal and differentiation are orchestrated by the coordinated regulation of subcellular, intercellular and niche-wide processes spanning multiple time scales. Here, we discuss different modeling approaches and challenges arising from their application to stem cell populations. Integrating single-cell analysis with computational methods will fill gaps in our knowledge about the functions of heterogeneity in stem cell physiology. This combination will also aid the rational design of efficient differentiation and reprogramming strategies as well as bioprocesses for the production of clinically valuable stem cell derivatives. © 2013 Elsevier Inc.

Harrold J.M.,State University of New York at Buffalo | Straubinger R.M.,State University of New York at Buffalo | Straubinger R.M.,Buffalo Center of Excellence | Mager D.E.,State University of New York at Buffalo
Cancer Research | Year: 2012

Combination chemotherapy represents the standard-of-care for non-Hodgkin lymphoma. However, the development of new therapeutic regimens is empirical and this approach cannot be used prospectively to identify novel or optimal drug combinations. Quantitative system pharmacodynamic models could promote the discovery and development of combination regimens based upon first principles. In this study, we developed a mathematical model that integrates temporal patterns of drug exposure, receptor occupancy, and signal transduction to predict the effects of the CD20 agonist rituximab in combination with rhApo2L/TNF-related apoptosis inducing ligand or fenretinide, a cytotoxic retinoid, upon growth kinetics in non-Hodgkin lymphoma xenografts. The model recapitulated major regulatory mechanisms, including target-mediated disposition of rituximab, modulation of proapoptotic intracellular signaling induced by CD20 occupancy, and the relative efficacy of death receptor isoforms. The multiscale model coupled tumor responses to individual anticancer agents with their mechanisms of action in vivo, and the changes in Bcl-xL and Fas induced by CD20 occupancy were linked to explain the synergy of these drugs. Tumor growth profiles predicted by the model agreed with cell and xenograft data, capturing the apparent pharmacologic synergy of these agents with fidelity. Together, our findings provide a mechanism-based platform for exploring new regimens with CD20 agonists. ©2012 AACR.

Marks L.R.,State University of New York at Buffalo | Iyer Parameswaran G.,State University of New York at Buffalo | Hakansson A.P.,State University of New York at Buffalo | Hakansson A.P.,Buffalo Center of Excellence
Infection and Immunity | Year: 2012

The human nasopharynx is the main reservoir for Streptococcus pneumoniae (the pneumococcus) and the source for both horizontal spread and transition to infection. Some clinical evidence indicates that nasopharyngeal carriage is harder to eradicate with antibiotics than is pneumococcal invasive disease, which may suggest that colonizing pneumococci exist in biofilm communities that are more resistant to antibiotics. While pneumococcal biofilms have been observed during symptomatic infection, their role in colonization and the role of host factors in this process have been less studied. Here, we show for the first time that pneumococci form highly structured biofilm communities during colonization of the murine nasopharynx that display increased antibiotic resistance. Furthermore, pneumococcal biofilms grown on respiratory epithelial cells exhibited phenotypes similar to those observed during colonization in vivo, whereas abiotic surfaces produced less ordered and more antibiotic-sensitive biofilms. The importance of bacterial-epithelial cell interactions during biofilm formation was shown using both clinical strains with variable colonization efficacies and pneumococcal mutants with impaired colonization characteristics in vivo. In both cases, the ability of strains to form biofilms on epithelial cells directly correlated with their ability to colonize the nasopharynx in vivo, with colonization-deficient strains forming less structured and more antibiotic-sensitive biofilms on epithelial cells, an association that was lost when grown on abiotic surfaces. Thus, these studies emphasize the importance of host-bacterial interactions in pneumococcal biofilm formation and provide the first experimental data to explain the high resistance of pneumococcal colonization to eradication by antibiotics. © 2012, American Society for Microbiology.

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