421 results on '"Thomas M. Harris"'
Search Results
2. Supp Table S1, S3-8 from Integrated Genomic and Functional microRNA Analysis Identifies miR-30-5p as a Tumor Suppressor and Potential Therapeutic Nanomedicine in Head and Neck Cancer
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Carter Van Waes, Zhong Chen, Esther H. Chang, Kathleen F. Pirollo, Antonina Rait, Sang S. Kim, Andrew D. Cherniack, Steven J. M. Jones, A. Gordon Robertson, Richard V. Smith, Geoffrey J. Childs, Michael B. Prystowsky, Thomas M. Harris, Ludmila Danilova, Douglas Chepeha, Jamie Couper, Shaleeka Cornelius, Rita Das, Xinping Yang, Paul E. Clavijo, Sophie Carlson, Pinar Ormanoglu, Han Si, Scott E. Martin, Hui Cheng, and Anthony D. Saleh
- Abstract
Supplementary Table S1, S3-8
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- 2023
3. Supplementary Table 5 from Unique DNA Methylation Loci Distinguish Anatomic Site and HPV Status in Head and Neck Squamous Cell Carcinoma
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Thomas J. Belbin, Michael B. Prystowsky, Geoffrey Childs, Thomas M. Harris, Robert D. Burk, Nicolas F. Schlecht, Leslie R. Adrien, Richard V. Smith, and Roberto A. Lleras
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PDF file, 1045K, Validation of hypermethylated CpG loci identified in HNSCC using TCGA data.
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- 2023
4. Supplementary Table 6 and Figure from Unique DNA Methylation Loci Distinguish Anatomic Site and HPV Status in Head and Neck Squamous Cell Carcinoma
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Thomas J. Belbin, Michael B. Prystowsky, Geoffrey Childs, Thomas M. Harris, Robert D. Burk, Nicolas F. Schlecht, Leslie R. Adrien, Richard V. Smith, and Roberto A. Lleras
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PDF file, 231K, Sequenom validation of hypermethylation and hypomethylation.
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- 2023
5. Supplementary Table 3 from Unique DNA Methylation Loci Distinguish Anatomic Site and HPV Status in Head and Neck Squamous Cell Carcinoma
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Thomas J. Belbin, Michael B. Prystowsky, Geoffrey Childs, Thomas M. Harris, Robert D. Burk, Nicolas F. Schlecht, Leslie R. Adrien, Richard V. Smith, and Roberto A. Lleras
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PDF file, 982K, List of hypermethylated and hypomethylated CpG loci identified in LXSCC.
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- 2023
6. Supplementary Table 4 from Unique DNA Methylation Loci Distinguish Anatomic Site and HPV Status in Head and Neck Squamous Cell Carcinoma
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Thomas J. Belbin, Michael B. Prystowsky, Geoffrey Childs, Thomas M. Harris, Robert D. Burk, Nicolas F. Schlecht, Leslie R. Adrien, Richard V. Smith, and Roberto A. Lleras
- Abstract
PDF file, 1946K, Validation of hypermethylated CpG loci identified in HNSCC using TCGA data.
- Published
- 2023
7. Data from Integrated Genomic and Functional microRNA Analysis Identifies miR-30-5p as a Tumor Suppressor and Potential Therapeutic Nanomedicine in Head and Neck Cancer
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Carter Van Waes, Zhong Chen, Esther H. Chang, Kathleen F. Pirollo, Antonina Rait, Sang S. Kim, Andrew D. Cherniack, Steven J. M. Jones, A. Gordon Robertson, Richard V. Smith, Geoffrey J. Childs, Michael B. Prystowsky, Thomas M. Harris, Ludmila Danilova, Douglas Chepeha, Jamie Couper, Shaleeka Cornelius, Rita Das, Xinping Yang, Paul E. Clavijo, Sophie Carlson, Pinar Ormanoglu, Han Si, Scott E. Martin, Hui Cheng, and Anthony D. Saleh
- Abstract
Purpose:To identify deregulated and inhibitory miRNAs and generate novel mimics for replacement nanomedicine for head and neck squamous cell carcinomas (HNSCC).Experimental Design:We integrated miRNA and mRNA expression, copy number variation, and DNA methylation results from The Cancer Genome Atlas (TCGA), with a functional genome-wide screen.Results:We reveal that the miR-30 family is commonly repressed, and all 5 members sharing these seed sequence similarly inhibit HNSCC proliferation in vitro. We uncover a previously unrecognized inverse relationship with overexpression of a network of important predicted target mRNAs deregulated in HNSCC, that includes key molecules involved in proliferation (EGFR, MET, IGF1R, IRS1, E2F7), differentiation (WNT7B, FZD2), adhesion, and invasion (ITGA6, SERPINE1). Reexpression of the most differentially repressed family member, miR-30a-5p, suppressed this mRNA program, selected signaling proteins and pathways, and inhibited cell proliferation, migration, and invasion in vitro. Furthermore, a novel miR-30a-5p mimic formulated into a targeted nanomedicine significantly inhibited HNSCC xenograft tumor growth and target growth receptors EGFR and MET in vivo. Significantly decreased miR-30a/e family expression was related to DNA promoter hypermethylation and/or copy loss in TCGA data, and clinically with decreased disease-specific survival in a validation dataset. Strikingly, decreased miR-30e-5p distinguished oropharyngeal HNSCC with poor prognosis in TCGA (P = 0.002) and validation (P = 0.007) datasets, identifying a novel candidate biomarker and target for this HNSCC subset.Conclusions:We identify the miR-30 family as an important regulator of signal networks and tumor suppressor in a subset of HNSCC patients, which may benefit from miRNA replacement nanomedicine therapy.
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- 2023
8. Supplementary Table 1 from Unique DNA Methylation Loci Distinguish Anatomic Site and HPV Status in Head and Neck Squamous Cell Carcinoma
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Thomas J. Belbin, Michael B. Prystowsky, Geoffrey Childs, Thomas M. Harris, Robert D. Burk, Nicolas F. Schlecht, Leslie R. Adrien, Richard V. Smith, and Roberto A. Lleras
- Abstract
PDF file, 1284K, List of hypermethylated and hypomethylated CpG loci identified in OCSCC.
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- 2023
9. Supplementary Table 2 from Unique DNA Methylation Loci Distinguish Anatomic Site and HPV Status in Head and Neck Squamous Cell Carcinoma
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Thomas J. Belbin, Michael B. Prystowsky, Geoffrey Childs, Thomas M. Harris, Robert D. Burk, Nicolas F. Schlecht, Leslie R. Adrien, Richard V. Smith, and Roberto A. Lleras
- Abstract
PDF file, 2377K, List of hypermethylated and hypomethylated CpG loci identified in OPSCC.
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- 2023
10. Supplementary Data from Integrated Genomic and Functional microRNA Analysis Identifies miR-30-5p as a Tumor Suppressor and Potential Therapeutic Nanomedicine in Head and Neck Cancer
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Carter Van Waes, Zhong Chen, Esther H. Chang, Kathleen F. Pirollo, Antonina Rait, Sang S. Kim, Andrew D. Cherniack, Steven J. M. Jones, A. Gordon Robertson, Richard V. Smith, Geoffrey J. Childs, Michael B. Prystowsky, Thomas M. Harris, Ludmila Danilova, Douglas Chepeha, Jamie Couper, Shaleeka Cornelius, Rita Das, Xinping Yang, Paul E. Clavijo, Sophie Carlson, Pinar Ormanoglu, Han Si, Scott E. Martin, Hui Cheng, and Anthony D. Saleh
- Abstract
Supplementary Methods, References, Figure legends, Table S2
- Published
- 2023
11. Data from Unique DNA Methylation Loci Distinguish Anatomic Site and HPV Status in Head and Neck Squamous Cell Carcinoma
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Thomas J. Belbin, Michael B. Prystowsky, Geoffrey Childs, Thomas M. Harris, Robert D. Burk, Nicolas F. Schlecht, Leslie R. Adrien, Richard V. Smith, and Roberto A. Lleras
- Abstract
Purpose: We have used a genome-wide approach to identify novel differentially methylated CpG dinucleotides that are seen in different anatomic sites of head and neck squamous cell carcinoma (HNSCC), as well as those that might be related to HPV status in the oropharynx.Experimental Design: We conducted genome-wide DNA methylation profiling of primary tumor samples and corresponding adjacent mucosa from 118 HNSCC patients undergoing treatment at Montefiore Medical Center, Bronx, NY, using the Illumina HumanMethylation27 beadchip. For each matched tissue set, we measured differentially methylated CpG loci using a change in methylation level (M-value).Results: When datasets were individually analyzed by anatomic site of the primary tumor, we identified 293 differentially methylated CpG loci in oral cavity squamous cell carcinoma (SCC), 219 differentially methylated CpG loci in laryngeal SCC, and 460 differentially methylated in oropharyngeal SCC. A subset of these differentially methylated CpG loci was common across all anatomic sites of HNSCC. Stratification by HPV status revealed a significantly higher number of differentially methylated CpG loci in HPV+ patients.Conclusion: Novel epigenetic biomarkers derived from clinical HNSCC specimens can be used as molecular classifiers of this disease, revealing many new avenues of investigation for this disease. Clin Cancer Res; 19(19); 5444–55. ©2013 AACR.
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- 2023
12. Alkali Metal- and Acid-Catalyzed Interconversion of Goniodomin A with Congeners B and C
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Constance M. Harris, Kimberly S. Reece, Urban Tillmann, Bernd Krock, Thomas M. Harris, Craig J. Tainter, Donald F. Stec, Aaron John Christian Andersen, and Thomas Ostenfeld Larsen
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Ketone ,Stereochemistry ,Pharmaceutical Science ,chemistry.chemical_element ,Molecular Dynamics Simulation ,010402 general chemistry ,Ring (chemistry) ,Cleavage (embryo) ,01 natural sciences ,Oxygen ,Catalysis ,Analytical Chemistry ,Polyketide ,chemistry.chemical_compound ,Drug Discovery ,Pharmacology ,chemistry.chemical_classification ,Molecular Structure ,Metals, Alkali ,010405 organic chemistry ,Organic Chemistry ,Alkali metal ,0104 chemical sciences ,Complementary and alternative medicine ,chemistry ,Pyran ,Dinoflagellida ,Molecular Medicine ,Macrolides ,Nonane ,Acids ,Ethers - Abstract
Goniodomin A (GDA, 1) is a phycotoxin produced by at least four species of Alexandrium dinoflagellates that are found globally in brackish estuaries and lagoons. It is a linear polyketide with six oxygen heterocyclic rings that is cyclized into a macrocyclic structure via lactone formation. Two of the oxygen heterocycles in 1 comprise a spiro-bis-pyran, whereas goniodomin B (GDB) contains a 2,7-dioxabicyclo[3.3.1]nonane ring system fused to a pyran. When H2O is present, 1 undergoes facile conversion to isomer GDB and to an α,β-unsaturated ketone, goniodomin C (GDC, 7). GDB and GDC can be formed from GDA by cleavage of the spiro-bis-pyran ring system. GDA, but not GDB or GDC, forms a crown ether-type complex with K+. Equilibration of GDA with GDB and GDC is observed in the presence of H+ and of Na+, but the equilibrated mixtures revert to GDA upon addition of K+. Structural differences have been found between the K+ and Na+ complexes. The association of GDA with K+ is strong, while that with Na+ is weak. The K+ complex has a compact, well-defined structure, whereas Na+ complexes are an ill-defined mixture of species. Analyses of in vitro A. monilatum and A. hiranoi cultures indicate that only GDA is present in the cells; GDB and GDC appear to be postharvest transformation products.
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- 2021
13. Synthesis, characterization and absolute configurations of methyl ladderanoates
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Constance M. Harris, Thomas M. Harris, Donald F. Stec, Nathan D. Schley, Jordan L. Johnson, Cody L. Covington, and Prasad L. Polavarapu
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Pharmacology ,Optical Rotation ,Circular Dichroism ,Organic Chemistry ,Drug Discovery ,Solvents ,Stereoisomerism ,Esters ,Spectroscopy ,Catalysis ,Analytical Chemistry - Abstract
Methyl esters of [5]-ladderanoic acid and [3]-ladderanoic acid were prepared by esterification of the acids isolated from biomass at a wastewater treatment plant. Optical rotations at six different wavelengths (633, 589, 546, 436, 405 and 365 nm) and vibrational circular dichroism (VCD) spectra in the 1800-900 cm
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- 2022
14. Mass spectrometric characterization of the seco acid formed by cleavage of the macrolide ring of the algal metabolite goniodomin A
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Constance M. Harris, Luisa Hintze, Sylvain Gaillard, Simon Tanniou, Hamish Small, Kimberly S. Reece, Urban Tillmann, Bernd Krock, and Thomas M. Harris
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Toxicology - Published
- 2023
15. Thermal Management as Key to Euro VII Emissions Compliance
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Matthew Muhleck, Bernd-Peter Scherer, and Thomas M. Harris
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Risk analysis (engineering) ,Key (cryptography) ,General Medicine ,Business ,Thermal management of electronic devices and systems ,Compliance (psychology) - Published
- 2021
16. Thermomanagement als Schlüssel zur Einhaltung der Euro-VII-Emissionsvorschriften
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Bernd-Peter Scherer, Thomas M. Harris, and Matthew Muhleck
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Engineering ,business.industry ,Business administration ,General Medicine ,business - Published
- 2021
17. Timberland Investing and Private Property Rights in the United States of America
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Caroline Harris, Jacek P. Siry, and Thomas M. Harris
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Legal research ,Property rights ,Commercial law ,Property law ,Real estate ,General Medicine ,Legal history ,Business ,United States constitutional law ,Law and economics ,Rule of law - Abstract
Investments in rural land for agriculture, timber, and other natural resource purposes occur frequently and globally. Fundamental principles of liberty and property found in the United States of America’s (“US”) legal system, from its origins to recent US Supreme Court decisions, continue to positively benefit holders of real estate in the Southern US, through a deep-rooted public policy of supporting private property rights and rural economic development. This stable rule of law enhances the long-term adaptability and sustainability of timberland as an asset class. This article is a commentary. It combines legal research methodology with the observations and conclusions of the authors. Its purpose is to demonstrate that the existence of alienable, documentable ownership, and related property rights create inherent stability and security. These principles form the basis of a culture that is defined by the rule of law and is “open for business.” This business mindset is particularly prevalent in the Southern US.
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- 2020
18. Meeting Future NOx Emissions Limits with Improved Total Fuel Efficiency
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Thomas M. Harris, James McCharthy, Chris Sharp, Bryan Zavala, and Andrew Matheaus
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- 2022
19. Integrated Genomic and Functional microRNA Analysis Identifies miR-30-5p as a Tumor Suppressor and Potential Therapeutic Nanomedicine in Head and Neck Cancer
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Carter Van Waes, Scott E. Martin, Antonina Rait, Anthony Saleh, Geoffrey J. Childs, Thomas M. Harris, Pinar Ormanoglu, Rita Das, Andrew D. Cherniack, Jamie Couper, Michael B. Prystowsky, A. Gordon Robertson, Hui Cheng, Douglas B. Chepeha, Esther H. Chang, Shaleeka Cornelius, Zhong Chen, Sang S. Kim, Ludmila Danilova, Richard V. Smith, Han Si, Kathleen F. Pirollo, Sophie Carlson, Steven J.M. Jones, Paul E. Clavijo, and Xinping Yang
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0301 basic medicine ,Cancer Research ,DNA Copy Number Variations ,Cell ,Mice, Nude ,Apoptosis ,Biology ,Article ,Mice ,03 medical and health sciences ,0302 clinical medicine ,Cell Movement ,microRNA ,Biomarkers, Tumor ,Tumor Cells, Cultured ,medicine ,Animals ,Humans ,Genes, Tumor Suppressor ,Prospective Studies ,Cell Proliferation ,Insulin-like growth factor 1 receptor ,Regulation of gene expression ,Mice, Inbred BALB C ,Squamous Cell Carcinoma of Head and Neck ,Cell growth ,Gene Expression Profiling ,Genomics ,Prognosis ,Xenograft Model Antitumor Assays ,Gene Expression Regulation, Neoplastic ,Survival Rate ,Gene expression profiling ,MicroRNAs ,Nanomedicine ,030104 developmental biology ,medicine.anatomical_structure ,Oncology ,Head and Neck Neoplasms ,Case-Control Studies ,030220 oncology & carcinogenesis ,DNA methylation ,Cancer research ,Nanoparticles ,Female ,ITGA6 ,Follow-Up Studies - Abstract
Purpose: To identify deregulated and inhibitory miRNAs and generate novel mimics for replacement nanomedicine for head and neck squamous cell carcinomas (HNSCC). Experimental Design: We integrated miRNA and mRNA expression, copy number variation, and DNA methylation results from The Cancer Genome Atlas (TCGA), with a functional genome-wide screen. Results: We reveal that the miR-30 family is commonly repressed, and all 5 members sharing these seed sequence similarly inhibit HNSCC proliferation in vitro. We uncover a previously unrecognized inverse relationship with overexpression of a network of important predicted target mRNAs deregulated in HNSCC, that includes key molecules involved in proliferation (EGFR, MET, IGF1R, IRS1, E2F7), differentiation (WNT7B, FZD2), adhesion, and invasion (ITGA6, SERPINE1). Reexpression of the most differentially repressed family member, miR-30a-5p, suppressed this mRNA program, selected signaling proteins and pathways, and inhibited cell proliferation, migration, and invasion in vitro. Furthermore, a novel miR-30a-5p mimic formulated into a targeted nanomedicine significantly inhibited HNSCC xenograft tumor growth and target growth receptors EGFR and MET in vivo. Significantly decreased miR-30a/e family expression was related to DNA promoter hypermethylation and/or copy loss in TCGA data, and clinically with decreased disease-specific survival in a validation dataset. Strikingly, decreased miR-30e-5p distinguished oropharyngeal HNSCC with poor prognosis in TCGA (P = 0.002) and validation (P = 0.007) datasets, identifying a novel candidate biomarker and target for this HNSCC subset. Conclusions: We identify the miR-30 family as an important regulator of signal networks and tumor suppressor in a subset of HNSCC patients, which may benefit from miRNA replacement nanomedicine therapy.
- Published
- 2019
20. Optimal targeting of BCL-family proteins in head and neck squamous cell carcinoma requires inhibition of both BCL-xL and MCL-1
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Cory D. Fulcher, Carlos Thomas, Nicolas F. Schlecht, Michael B. Prystowsky, Bradley A. Schiff, Richard V. Smith, Andrea Lopez, Nicole Kawachi, Thomas J. Belbin, Gregory Rosenblatt, Evripidis Gavathiotis, Catherine Sarta, Geoffrey Childs, Chandan Guha, Thomas M. Harris, Denis E. Reyna, Thomas J. Ow, and Pilib Ó Broin
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0301 basic medicine ,Bcl-xL ,A-1210477 ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Gene expression ,Medicine ,head and neck squamous carcinoma ,IC50 ,Cisplatin ,Navitoclax ,biology ,navitoclax ,business.industry ,medicine.disease ,Head and neck squamous-cell carcinoma ,3. Good health ,030104 developmental biology ,Oncology ,chemistry ,Cell culture ,BCL-xL ,030220 oncology & carcinogenesis ,Cancer cell ,Cancer research ,biology.protein ,MCL-1 ,business ,Research Paper ,medicine.drug - Abstract
Mechanisms of treatment resistance in head and neck squamous cell carcinoma (HNSCC) are not well characterized. In this study, HNSCC tumors from a cohort of prospectively enrolled subjects on an ongoing tissue banking study were divided into those that persisted or recurred locoregionally (n=23) and those that responded without recurrence (n=35). Gene expression was evaluated using llumina HumanHT-12-v3 Expression BeadChip microarrays. Sparse Partial Least Squares – Discriminant Analysis (sPLS-DA) identified 135 genes discriminating treatment-resistant from treatment-sensitive tumors. BCL-xL was identified among 23% of canonical pathways derived from this set of genes using Ingenuity Pathway analysis. The BCL-xL protein was expressed in 8 HNSCC cell lines examined. Cells were treated with the BCL-xL inhibitor, ABT-263 (navitoclax): the average half maximal inhibitory concentration (IC50) was 8.9μM (range 6.6μM – 13.9μM). Combining ABT-263 did not significantly increase responses to 2 Gy radiation or cisplatin in the majority of cell lines. MCL-1, a potential mediator of resistance to ABT-263, was expressed in all cell lines and HNSCC patient tumors, in addition to BCL-xL. Treatment with the MCL-1 inhibitor, A-1210477, in HNSCC cell lines showed an average IC50 of 10.7μM (range, 8.8μM to 12.7μM). Adding A-1210477 to ABT-263 (navitoclax) treatment resulted in an average 7-fold reduction in the required lethal dose of ABT-263 (navitoclax) when measured across all 8 cell lines. Synergistic activity was confirmed in PCI15B, Detroit 562, MDA686LN, and HN30 based on Bliss Independence analysis. This study demonstrates that targeting both BCL-xL and MCL-1 is required to optimally inhibit BCL-family pro-survival molecules in HNSCC, and co-inhibition is synergistic in HNSCC cancer cells.
- Published
- 2019
21. FE vibration analyses of novel conforming meta-structures and standard lattices for simple bricks and a topology-optimized aerodynamic bracket
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William C. Nelson, Todd C. Doehring, Thomas M. Harris, and Alan D. Freed
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Materials science ,Mathematics and computing ,Science ,02 engineering and technology ,Topology ,01 natural sciences ,Article ,Stress (mechanics) ,Engineering ,0103 physical sciences ,Civil engineering ,Topology (chemistry) ,Parametric statistics ,010302 applied physics ,Multidisciplinary ,Series (mathematics) ,Basis (linear algebra) ,Aerodynamics ,021001 nanoscience & nanotechnology ,Mechanical engineering ,Vibration ,Aerospace engineering ,Bracket (mathematics) ,Medicine ,0210 nano-technology ,Biomedical engineering - Abstract
Additive manufacturing (AM) enables production of components that are not possible to make using traditional methods. In particular, lattice-type structures are of recent interest due to their potential for high strength-to-weight ratios and other desirable properties. However, standard periodic lattice structures have problems conforming to complex curved and multi-connected shapes (e.g. holes or sharp-to-smooth mating edges). In addition, standard lattices have well known shear and fatigue weaknesses due to their periodic basis/structure. To address these problems, we developed a new type of shape-conforming meta-structure (HGon) that extends lattices, enabling automated conforming to complex shapes and parametric meta-topology control. HGons also have unique vibration dampening and optimization capabilities. This study presents initial FE analyses of (Part 1) dynamic vibration responses of new HGon meta-structures compared with periodic lattices of equivalent density for a series of basic rectangular structures and (Part 2) a complex multi-connected aerodynamic bracket with field-based stress meta-topology optimization. Results show significantly enhanced vibration dampening behavior and superior strength-to-weight ratios for HGon meta-structures as compared to standard lattices.
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- 2020
22. Simulation of Aftertreatment Thermal Management Strategies for Low-Load Operation
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Thomas M. Harris
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Low load ,Environmental science ,Thermal management of electronic devices and systems ,Automotive engineering - Published
- 2020
23. In Response to Regarding: Apoptosis Signaling Molecules as Treatment Targets in Head and Neck Squamous Carcinoma
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Andrea Lopez, Michael B. Prystowsky, Bradley A. Schiff, Gregory Rosenblatt, Thomas M. Harris, Geoffrey Childs, Jianhong Chen, Denis E. Reyna, Richard V. Smith, Thomas J. Ow, Nicolas F. Schlecht, Thomas J. Belbin, Evripidis Gavathiotis, Carlos Thomas, Cory D. Fulcher, and Nicole Kawachi
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business.industry ,Squamous Cell Carcinoma of Head and Neck ,Apoptosis ,Apoptosis signaling ,Article ,Squamous carcinoma ,Treatment targets ,Text mining ,Otorhinolaryngology ,Head and Neck Neoplasms ,Cancer research ,Medicine ,Humans ,business ,Head and neck - Published
- 2020
24. Revisiting the toxin profile of Alexandrium pseudogonyaulax; Formation of a desmethyl congener of goniodomin A
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Thomas M. Harris, Kimberly S. Reece, and Constance M. Harris
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0106 biological sciences ,0303 health sciences ,Chemistry ,Stereochemistry ,Toxin ,010604 marine biology & hydrobiology ,030302 biochemistry & molecular biology ,Desmethyl ,Toxicology ,medicine.disease_cause ,01 natural sciences ,Goniodomin A ,03 medical and health sciences ,chemistry.chemical_compound ,Congener ,Alexandrium pseudogonyaulax ,medicine ,Dinoflagellida ,Experimental work ,Macrolides ,Methylene ,Ethers ,Toxins, Biological - Abstract
During a survey of the production of goniodomin A (GDA) by Alexandrium pseudogonyaulax in Danish coastal waters, Krock et al. (2018) obtained mass spectral evidence for the presence of a truncated congener, herein termed GD754, having a molecular weight 14 Da lower than GDA and assigned it as goniodomin B (GDB). An erroneous structure of GDB involving deletion of a methylene group between rings B and D had previously been reported by Espina et al. (2016) but without experimental details. HPLC properties reported by Krock for GD754 point to it being a homolog of GDA. Comparison of mass spectral fragmentation data reported for GD754 with fragmentation data for GDA, show it to be a truncated form of GDA with the deletion involving a CH2 group from ring F or one of the two methyl substituents on ring F, not elsewhere on the molecule. On biosynthetic grounds, the GD754 congener is proposed to be 34-desmethyl-GDA. Further experimental work will be required to confirm this hypothesis.
- Published
- 2020
25. Algal Toxin Goniodomin A Binds Potassium Selectively to Yield a Conformationally Altered Complex with Potential Biological Consequences
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Thomas M. Harris, Donald F. Stec, Jody C. May, Andrzej Balinski, John A. McLean, Anna K. Song, Kimberly S. Reece, Constance M. Harris, Craig J. Tainter, and Nathan D. Schley
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Magnetic Resonance Spectroscopy ,Stereochemistry ,Potassium ,Red tide ,Pharmaceutical Science ,chemistry.chemical_element ,Ring (chemistry) ,01 natural sciences ,Algal bloom ,Article ,Analytical Chemistry ,Ethers, Cyclic ,Drug Discovery ,Animals ,Humans ,Actin ,Pharmacology ,Ions ,Molecular Structure ,010405 organic chemistry ,Organic Chemistry ,Absolute configuration ,Actins ,0104 chemical sciences ,010404 medicinal & biomolecular chemistry ,Actin Cytoskeleton ,Complementary and alternative medicine ,chemistry ,Yield (chemistry) ,Dinoflagellida ,Molecular Medicine ,Macrolides ,Marine toxin ,Ethers - Abstract
The marine toxin goniodomin A (GDA) is a polycyclic macrolide containing a spiroacetal and three cyclic ethers as part of the macrocycle backbone. GDA is produced by three species of the Alexandrium genus of dinoflagellates, blooms of which are associated with “red tides”, which are widely dispersed and can cause significant harm to marine life. The toxicity of GDA has been attributed to stabilization of the filamentous form of the actin group of structural proteins, but the structural basis for its binding is not known. Japanese workers, capitalizing on the assumed rigidity of the heavily substituted macrolide ring, assigned the relative configuration and conformation by relying on NMR coupling constants and NOEs; the absolute configuration was assigned by degradation to a fragment that was compared with synthetic material. We have confirmed the absolute structure and broad features of the conformation by X-ray crystallography but have found GDA to complex with alkali metal ions in spite of two of the heterocyclic rings facing outward. Such an arrangement would have been expected to impair the ability of GDA to form a crown-ether-type multidentate complex. GDA shows preference for K+, Rb+, and Cs+ over Li+ and Na+ in determinations of relative affinities by TLC on metal-ion-impregnated silica gel plates and by electrospray mass spectrometry. NMR studies employing the K+ complex of GDA, formed from potassium tetrakis[pentafluorophenyl]borate (KBArF(20)), reveal a major alteration of the conformation of the macrolide ring. These observations argue against the prior assumption of rigidity of the ring. Alterations in chemical shifts, coupling constants, and NOEs indicate the involvement of most of the molecule other than ring F. Molecular mechanics simulations suggest K+ forms a heptacoordinate complex involving OA, OB, OC, OD, OE, and the C-26 and C-27 hydroxy groups. We speculate that complexation of K+ with GDA electrostatically stabilizes the complex of GDA with filamentous actin in marine animals due to the protein being negatively charged at physiological pH. GDA may also cause potassium leakage through cell membranes. This study provides insight into the structural features and chemistry of GDA that may be responsible for significant ecological damage associated with the GDA-producing algal blooms.
- Published
- 2020
26. Identification of N-{cis-3-[Methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]cyclobutyl}propane-1-sulfonamide (PF-04965842): A Selective JAK1 Clinical Candidate for the Treatment of Autoimmune Diseases
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Seungil Han, Martin E. Dowty, Ralph P. Robinson, Steven E. Heasley, Peter T. Symanowicz, Jason Jussif, Thomas M. Harris, Neelu Kaila, Lu Wang, Matthew Frank Brown, Jeffrey M. Casavant, Nicole Caspers, Sarah H. Griffin, Mark J. Mitton-Fry, Martin Hegen, Johnson Timothy Allan, Tenbrink Ruth E, Mary Ellen Banker, Jonathan Langille, Mihir D. Parikh, Tsung H. Lin, Arindrajit Basak, Jean-Baptiste Telliez, James D. Clark, Strohbach Joseph Walter, Eric P. Arnold, Ray Unwalla, Li Li, Brian A. Duclos, Xin Yang, Mark Edward Flanagan, John David Trzupek, Michael L. Vazquez, Soojin Kwon, and Ashley Edward Fenwick
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Models, Molecular ,0301 basic medicine ,Protein Conformation ,Drug Evaluation, Preclinical ,Arthritis ,Inflammation ,Pharmacology ,Autoimmune Diseases ,Substrate Specificity ,Inhibitory Concentration 50 ,03 medical and health sciences ,Dogs ,Immune system ,Drug Discovery ,medicine ,Animals ,Humans ,Pyrroles ,Tissue Distribution ,Protein Kinase Inhibitors ,Thrombopoietin ,Sulfonamides ,Tofacitinib ,Chemistry ,Janus Kinase 1 ,Janus Kinase 2 ,medicine.disease ,Arthritis, Experimental ,Rats ,Pyrimidines ,030104 developmental biology ,Tyrosine kinase 2 ,Molecular Medicine ,medicine.symptom ,Janus kinase ,Tyrosine kinase ,Cyclobutanes - Abstract
Janus kinases (JAKs) are intracellular tyrosine kinases that mediate the signaling of numerous cytokines and growth factors involved in the regulation of immunity, inflammation, and hematopoiesis. As JAK1 pairs with JAK2, JAK3, and TYK2, a JAK1-selective inhibitor would be expected to inhibit many cytokines involved in inflammation and immune function while avoiding inhibition of the JAK2 homodimer regulating erythropoietin and thrombopoietin signaling. Our efforts began with tofacitinib, an oral JAK inhibitor approved for the treatment of rheumatoid arthritis. Through modification of the 3-aminopiperidine linker in tofacitinib, we discovered highly selective JAK1 inhibitors with nanomolar potency in a human whole blood assay. Improvements in JAK1 potency and selectivity were achieved via structural modifications suggested by X-ray crystallographic analysis. After demonstrating efficacy in a rat adjuvant-induced arthritis (rAIA) model, PF-04965842 (25) was nominated as a clinical candidate for the treatment of JAK1-mediated autoimmune diseases.
- Published
- 2018
27. Erratum zu: Thermomanagement als Schlüssel zur Einhaltung der Euro-VII-Emissionsvorschriften
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Bernd-Peter Scherer, Matthew Muhleck, and Thomas M. Harris
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Philosophy ,General Medicine ,Humanities - Abstract
In: ATZheavyduty 14, Nr. 2, S. 42-45 (2021), DOI 10.1007/s35746-021-0418-2Autoren: Thomas M. Harris, Matthew Muhleck, Bernd-Peter SchererDieses Erratum wird veroffentlicht, um eine Korrektur in Bild 5 auf Seite 45 zu melden. Die Originalversion wurde geandert in:Vor SCR-Katalysator, BasisWir bitten um Beacht...
- Published
- 2021
28. Gene Expression Signature for Distant Metastasis in Loco-regionally Advanced Head and Neck Squamous Cell Carcinoma
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Richard V. Smith, Nicolas F. Schlecht, C. Hochfelder, Thomas M. Harris, Madhur Garg, Geoffrey J. Childs, Nicole Kawachi, A. Berlot, Thomas J. Ow, Vikas Mehta, Thomas J. Belbin, A. Mo, Michael B. Prystowsky, G. Rosenblatt, Bradley A. Schiff, Chandan Guha, and R. Kabarriti
- Subjects
Cancer Research ,Radiation ,Oncology ,business.industry ,Gene expression ,medicine ,Cancer research ,Distant metastasis ,Radiology, Nuclear Medicine and imaging ,medicine.disease ,business ,Head and neck squamous-cell carcinoma - Published
- 2020
29. Apolipoprotein E Promotes Invasion in Oral Squamous Cell Carcinoma
- Author
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Michael B. Prystowsky, Olivier Loudig, Berrin Ustun, Thomas J. Belbin, Jeffrey E. Segall, Ryung S. Kim, Thomas M. Harris, Thomas J. Ow, Sangeeta K. Jayakar, Margaret Brandwein-Gensler, and Geoffrey Childs
- Subjects
0301 basic medicine ,Apolipoprotein E ,Cell signaling ,Pathology ,medicine.medical_specialty ,Proto-Oncogene Proteins c-jun ,Biology ,Models, Biological ,MMP7 ,Article ,Pathology and Forensic Medicine ,03 medical and health sciences ,Apolipoproteins E ,Cell Line, Tumor ,Gene Knockdown Techniques ,medicine ,Humans ,Neoplasm Invasiveness ,RNA, Messenger ,Phosphorylation ,RNA, Small Interfering ,Extracellular Signal-Regulated MAP Kinases ,Gene knockdown ,Genome, Human ,Kinase ,JNK Mitogen-Activated Protein Kinases ,Extracellular Matrix ,Gene Expression Regulation, Neoplastic ,Transcription Factor AP-1 ,Cholesterol ,030104 developmental biology ,Cell culture ,Matrix Metalloproteinase 7 ,Podosomes ,Invadopodia ,Carcinoma, Squamous Cell ,Cancer research ,Mouth Neoplasms ,Transcriptome ,Signal Transduction - Abstract
Oral squamous cell carcinoma (OSCC) patients generally have a poor prognosis, because of the invasive nature of these tumors. In comparing transcription profiles between OSCC tumors with a more invasive (worst pattern of tumor invasion 5) versus a less invasive (worst pattern of tumor invasion 3) pattern of invasion, we identified a total of 97 genes that were overexpressed at least 1.5-fold in the more invasive tumor subtype. The most functionally relevant genes were assessed using in vitro invasion assays with an OSCC cell line (UM-SCC-1). Individual siRNA knockdown of 15 of these 45 genes resulted in significant reductions in tumor cell invasion compared to a nontargeting siRNA control. One gene whose knockdown had a strong effect on invasion corresponded to apolipoprotein E ( APOE ). Both matrix degradation and the number of mature invadopodia were significantly decreased with APOE knockdown. APOE knockdown also resulted in increased cellular cholesterol, consistent with APOE's role in regulating cholesterol efflux. APOE knockdown resulted in decreased levels of phospho–extracellular signal–regulated kinase 1/2, phospho–c-Jun N-terminal kinase, and phospho-cJun, as well as decreased activator protein 1 (AP-1) activity. Expression of matrix metalloproteinase 7 ( MMP7 ), an AP-1 target, was also significantly decreased. Our findings suggest that APOE protein plays a significant role in OSCC tumor invasion because of its effects on cellular cholesterol and subsequent effects on cell signaling and AP-1 activity, leading to changes in the expression of invasion-related proteins, including MMP7.
- Published
- 2017
30. The toxin goniodomin, produced by Alexandrium spp., is identical to goniodomin A
- Author
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Thomas M. Harris, Patrice L.M. Hobbs, Donald F. Stec, Kimberly S. Reece, William M. Jones, Constance M. Harris, and Gail P. Scott
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0106 biological sciences ,Antifungal ,Alexandrium hiranoi ,biology ,Toxin ,medicine.drug_class ,010604 marine biology & hydrobiology ,Red tide ,Dinoflagellate ,Puerto rican ,Zoology ,Plant Science ,010501 environmental sciences ,Aquatic Science ,medicine.disease_cause ,biology.organism_classification ,01 natural sciences ,Goniodomin A ,Caribbean Region ,Japan ,medicine ,Dinoflagellida ,Macrolides ,0105 earth and related environmental sciences ,Ethers - Abstract
In 1968 Burkholder and associates (J. Antibiot. (Tokyo) 1968, 21, 659–664) isolated the antifungal toxin goniodomin from an unidentified Puerto Rican dinoflagellate and partially characterized its structure. Subsequently, a metabolite of Alexandrium hiranoi was isolated by Murakami et al. from a bloom in Japan and its structure was established (Tetrahedron Lett. 1988, 29, 1149–1152). The Japanese substance had strong similarities to Burkholder's but due to uncertainty as to whether it was identical or only similar, Murakami named his toxin goniodomin A. A detailed study of this question now provides compelling evidence that Burkholder's goniodomin is identical to goniodomin A. Morphological characterization of the dinoflagellate suggests that it was the genus Alexandrium but insufficient evidence is available to make a definite identification of the species. This is the only report of goniodomin in the Caribbean region.
- Published
- 2019
31. Modeling Heavy-Duty Engine Thermal Management Technologies to Meet Future Cold Start Requirements
- Author
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Reza Rezaei, Thomas M. Harris, Yinyan Huang, David Kovacs, and Hendrik Rauch
- Subjects
Cold start (automotive) ,Heavy duty ,Environmental science ,Thermal management of electronic devices and systems ,Automotive engineering - Published
- 2019
32. Modeling of Close-Coupled SCR Concepts to Meet Future Cold Start Requirements for Heavy-Duty Engines
- Author
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David Kovacs, Kristoffer Mc Pherson, Yinyan Huang, Thomas M. Harris, Hendrik Rauch, and Reza Rezaei
- Subjects
Cold start (automotive) ,Heavy duty ,Environmental science ,Automotive engineering - Published
- 2019
33. Modeling of Aftertreatment Technologies to Meet a Future HD Low-NOx Standard
- Author
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Thomas M. Harris and Timothy Gardner
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business.industry ,Environmental science ,Process engineering ,business ,NOx - Published
- 2019
34. Developing Design Guidelines for an SCR Assembly Equipped for RF Sensing of NH3 Loading
- Author
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Paul Ragaller, Leslie Bromberg, Thomas M. Harris, Alexander Guarino, and Alexander Sappok
- Subjects
020303 mechanical engineering & transports ,Materials science ,0203 mechanical engineering ,business.industry ,020209 energy ,Transmitter ,0202 electrical engineering, electronic engineering, information engineering ,Optoelectronics ,Selective catalytic reduction ,02 engineering and technology ,business ,Nitrogen oxides ,Catalysis - Published
- 2018
35. Absolute configurations of naturally occurring [5]- and [3]-ladderanoic acids : isolation, chiroptical spectroscopy, and crystallography
- Author
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Donald F. Stec, Vijay V. Raghavan, Nathan D. Schley, Bongkeun Song, Thomas M. Harris, Malgorzata Baranska, Grzegorz Zajac, Jordan L. Johnson, Prasad L. Polavarapu, and Constance M. Harris
- Subjects
Molecular Conformation ,Pharmaceutical Science ,Crystallography, X-Ray ,Spectrum Analysis, Raman ,010402 general chemistry ,Phenacyl ,01 natural sciences ,High-performance liquid chromatography ,Spectral line ,Analytical Chemistry ,chemistry.chemical_compound ,Bioreactors ,Drug Discovery ,Biomass ,Spectroscopy ,Pharmacology ,Quantum chemical ,Molecular Structure ,010405 organic chemistry ,Circular Dichroism ,Organic Chemistry ,Esters ,Stereoisomerism ,Lipids ,0104 chemical sciences ,Crystallography ,Complementary and alternative medicine ,chemistry ,Molecular Medicine ,Raman optical activity - Abstract
We have isolated mixtures of [5]- and [3]-ladderanoic acids 1a and 2a from the biomass of an anammox bioreactor and have separated the acids and their phenacyl esters for the first time by HPLC. The absolute configurations of the naturally occurring acids and their phenacyl esters are assigned as R at the site of side-chain attachment by comparison of experimental specific rotations with corresponding values predicted using quantum chemical (QC) methods. The absolute configurations for 1a and 2a were independently verified by comparison of experimental Raman optical activity spectra with corresponding spectra predicted using QC methods. The configurational assignments of 1a and 2a and of the phenacyl ester of 1a were also confirmed by X-ray crystallography.
- Published
- 2018
36. MicroRNA-375 Suppresses Extracellular Matrix Degradation and Invadopodial Activity in Head and Neck Squamous Cell Carcinoma
- Author
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Thomas J. Ow, Jeffrey E. Segall, Michael B. Prystowsky, Ved P. Sharma, Thomas M. Harris, John S. Condeelis, Geoffrey Childs, and Lizandra Jimenez
- Subjects
Proteases ,Proteome ,Blotting, Western ,Protein Array Analysis ,Article ,Pathology and Forensic Medicine ,Extracellular matrix ,chemistry.chemical_compound ,Cell Line, Tumor ,Endopeptidases ,microRNA ,medicine ,Humans ,Protein Interaction Maps ,biology ,Reverse Transcriptase Polymerase Chain Reaction ,Serine Endopeptidases ,Tyrosine phosphorylation ,General Medicine ,medicine.disease ,Head and neck squamous-cell carcinoma ,Extracellular Matrix ,Gene Expression Regulation, Neoplastic ,MicroRNAs ,Medical Laboratory Technology ,Matrix Metalloproteinase 9 ,chemistry ,Head and Neck Neoplasms ,Invadopodia ,Carcinoma, Squamous Cell ,biology.protein ,Cancer research ,Kallikreins ,Cell Surface Extensions ,Cortactin ,Extracellular Matrix Degradation ,Protein Binding - Abstract
ContextHead and neck squamous cell carcinoma (HNSCC) is a highly invasive cancer with an association with locoregional recurrence and lymph node metastasis. We have previously reported that low microRNA-375 (miR-375) expression levels correlate with poor patient survival, increased locoregional recurrence, and distant metastasis. Increasing miR-375 expression in HNSCC cell lines to levels found in normal cells results in suppressed invasive properties. HNSCC invasion is mediated in part by invadopodia-associated degradation of the extracellular matrix.ObjectiveTo determine whether elevated miR-375 expression in HNSCC cell lines also affects invadopodia formation and activity.DesignFor evaluation of the matrix degradation properties of the HNSCC lines, an invadopodial matrix degradation assay was used. The total protein levels of invadopodia-associated proteins were measured by Western blot analyses. Immunoprecipitation experiments were conducted to evaluate the tyrosine phosphorylation state of cortactin. Human protease arrays were used for the detection of the secreted proteases. Quantitative real time–polymerase chain reaction measurements were used to evaluate the messenger RNA (mRNA) expression of the commonly regulated proteases.ResultsIncreased miR-375 expression in HNSCC cells suppresses extracellular matrix degradation and reduces the number of mature invadopodia. Higher miR-375 expression does not reduce cellular levels of selected invadopodia-associated proteins, nor is tyrosine phosphorylation of cortactin altered. However, HNSCC cells with higher miR-375 expression had significant reductions in the mRNA expression levels and secreted levels of specific proteases.ConclusionsMicroRNA-375 regulates invadopodia maturation and function potentially by suppressing the expression and secretion of proteases.
- Published
- 2015
37. Proteomic Analysis of Oral Cavity Squamous Cell Carcinoma Specimens Identifies Patient Outcome–Associated Proteins
- Author
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Richard V. Smith, Thomas J. Ow, Yanhua Wang, Michael B. Prystowsky, Ruth Hogue Angeletti, Thomas M. Harris, Nicolas F. Schlecht, Christian E. Keller, Geoffrey J. Childs, Peicheng Du, Thomas J. Belbin, Jihyeon Lim, and Nicole Kawachi
- Subjects
Male ,Proteomics ,Pathology ,medicine.medical_specialty ,Proteome ,Kaplan-Meier Estimate ,Biology ,Tandem mass spectrometry ,Disease-Free Survival ,Article ,Mass spectrometry imaging ,Pathology and Forensic Medicine ,Sequence Analysis, Protein ,Tandem Mass Spectrometry ,Carcinoma ,medicine ,Transcriptional regulation ,Humans ,Oral Cavity Squamous Cell Carcinoma ,Aged ,Mouth neoplasm ,General Medicine ,Middle Aged ,Prognosis ,medicine.disease ,Gene Expression Regulation, Neoplastic ,Medical Laboratory Technology ,Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization ,Carcinoma, Squamous Cell ,Female ,Mouth Neoplasms ,Peptides ,Chromatography, Liquid - Abstract
Global proteomic analysis of oral cavity squamous cell carcinoma was performed to identify changes that reflect patient outcomes.To identify differentially expressed proteins associated with patient outcomes and to explore the use of imaging mass spectrometry as a clinical tool to identify clinically relevant proteins.Two-dimensional separation of digested peptides generated from 43 specimens with high-resolution mass spectrometry identified proteins associated with disease-specific death, distant metastasis, and loco-regional recurrence. RNA expressions had been correlated to protein levels to test transcriptional regulation of clinically relevant proteins. Imaging mass spectrometry explored an alternative platform for assessing clinically relevant proteins that would complement surgical pathologic diagnosis.Seventy-two peptide features were found to be associated with 3 patient outcomes: disease-specific death (9), distant metastasis (16), and loco-regional recurrence (39); 8 of them were associated with multiple outcomes. Functional ontology revealed major changes in cell adhesion and calcium binding. Thirteen RNAs showed strong correlation with their encoded proteins, implying transcriptional control. Reduction of DSP, PKP1, and TRIM29 was associated with significantly shorter time to onset of distant metastasis. Reduction of PKP1 and TRIM29 correlated with poorer disease-specific survival. Additionally, S100A8 and S100A9 reductions were verified for their association with poor prognosis using imaging mass spectrometry, a platform more adaptable for use with surgical pathology.Using global proteomic analysis, we have identified proteins associated with clinical outcomes. The list of clinically relevant proteins observed will provide a means to develop clinical assays for prognosis and optimizing treatment selection.
- Published
- 2015
38. Epigenetic changes in the CDKN2A locus are associated with differential expression of P16INK4A and P14ARF in HPV‐positive oropharyngeal squamous cell carcinoma
- Author
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Robert D. Burk, Carlos Thomas, Roberto A. Lleras, Richard V. Smith, Nicolas F. Schlecht, Michael B. Prystowsky, Geoffrey Childs, Thomas J. Belbin, Yanhua Wang, Thomas M. Harris, Thomas J. Ow, Miriam M. Ben-Dayan, and Nicole Anayannis
- Subjects
Adult ,Male ,HPV ,Cancer Research ,Locus (genetics) ,Epigenesis, Genetic ,03 medical and health sciences ,0302 clinical medicine ,p14arf ,CDKN2A ,Tumor Suppressor Protein p14ARF ,Humans ,Radiology, Nuclear Medicine and imaging ,RNA, Messenger ,squamous ,Epigenetics ,Papillomaviridae ,Cyclin-Dependent Kinase Inhibitor p16 ,Aged ,030304 developmental biology ,Aged, 80 and over ,0303 health sciences ,biology ,Papillomavirus Infections ,Carcinoma ,Methylation ,DNA Methylation ,Middle Aged ,biology.organism_classification ,Molecular biology ,3. Good health ,Oropharyngeal Neoplasms ,Oncology ,CpG site ,030220 oncology & carcinogenesis ,DNA methylation ,Carcinoma, Squamous Cell ,Cancer research ,CpG Islands ,Female ,methylation ,oropharynx - Abstract
Human papillomavirus (HPV)-positive oropharyngeal squamous cell carcinoma (OPSCC) is recognized as a distinct disease entity associated with improved survival. DNA hypermethylation profiles differ significantly by HPV status suggesting that a specific subset of methylated CpG loci could give mechanistic insight into HPV-driven OPSCC. We analyzed genome-wide DNA methylation of primary tumor samples and adjacent normal mucosa from 46 OPSCC patients undergoing treatment at Montefiore Medical Center, Bronx, NY using the Illumina HumanMethylation27 beadchip. For each matched tissue set, we measured differentially methylated CpG loci using a change in methylation level (M value). From these analyses, we identified a 22 CpG loci panel for HPV+ OPSCC that included four CDKN2A loci downstream of the p16(INK4A) and p14(ARF) transcription start sites. This panel was significantly associated with overall HPV detection (P
- Published
- 2015
39. Comprehensive genomic characterization of head and neck squamous cell carcinomas
- Author
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Ni Zhao, Carter Van Waes, Lori Boice, Ashley H. Salazar, Petar Stojanov, Michael B. Prystowsky, Akinyemi I. Ojesina, Tara M. Lichtenberg, Nikolaus Schultz, Joshua M. Stuart, Mitchell J. Frederick, Julie M. Gastier-Foster, Jeffrey N. Myers, Bradley A. Ozenberger, Margaret L. Gulley, Jean C. Zenklusen, Inanc Birol, Christina Yau, Mark E. Sherman, Saianand Balu, Angela Hadjipanayis, Barry S. Taylor, Piotr A. Mieczkowski, Anthony Saleh, Carol G. Shores, Ezra E.W. Cohen, Joonil Jung, Ari B. Kahn, Lisa Wise, Peter S. Hammerman, Pei Lin, Marc Ladanyi, Mark C. Weissler, Scott L. Carter, Michele C. Hayward, Rehan Akbani, Todd Pihl, J. Jack Lee, Sophie C. Egea, Harshad S. Mahadeshwar, Leigh B. Thorne, Matthew G. Soloway, Troy Shelton, Andrea Haddad, William N. William, Wiktoria Maria Suchorska, Johanna Gardner, Marco A. Marra, Julie Ahn, Travis I. Zack, Lihua Zou, Bayardo Perez-Ordonez, David A. Wheeler, Daniel Crain, Adrian Ally, Deepak Srinivasan, Jay Bowen, Aaron D. Black, Jing Wang, Ludmila Danilova, Roy Tarnuzzer, Brenda Diergaarde, Tod D. Casasent, Dean Cheng, Giovanni Ciriello, Ken Burnett, Jeff Bruce, Wojciech Golusiński, Jonathan G. Seidman, Corbin D. Jones, Daniel J. Weisenberger, Lisa A. Peterson, Thomas M. Harris, Angeliki Pantazi, Nina Thiessen, Curtis R. Pickering, Chandra Sekhar Pedamallu, Yingchun Liu, William Lee, Andrzej Mackiewicz, Hailei Zhang, Ronglai Shen, B. Arman Aksoy, Lixing Yang, Jeffrey Roach, Simion I. Chiosea, John Waldron, David Van Den Berg, James Stephen Marron, Tanja Davidsen, Liming Yang, Maciej Wiznerowicz, Benjamin Gross, Paul M. Weinberger, Yufeng Liu, Reanne Bowlby, Zhixiang Zuo, Bartosz Szybiak, Roni J. Bollag, Samuel S. Freeman, Heather M. Walline, Gad Getz, Scott Morris, Michael S. Noble, Charles Saller, Sahil Seth, Richard A. Gibbs, Jonathan C. Irish, Hollie A. Harper, George E. Sandusky, S. Onur Sumer, Trevor Hackman, Gordon B. Mills, Carol R. Bradford, Payal Sipahimalani, Nipun Kakkar, Robert Penny, Jennifer Drummond, Adam M. Zanation, Rebecca Carlsen, Andrew J. Mungall, Harshavardhan Doddapaneni, James G. Herman, Sylvia Wrenn, Andy Chu, Nilsa C. Ramirez, Patrick Kwok Shing Ng, Patrick K. Kimes, Tina Wong, Mark E. Prince, Han Si, Kristian Cibulskis, Katherine Tarvin, Peter W. Laird, Jiabin Tang, Raja R. Seethala, Michael Parfenov, Jan F. Prins, Erin Curley, Hui Cheng, Donna M. Muzny, Lynda Chin, D. Neil Hayes, Margi Sheth, Carmen Gomez-Fernandez, Jessica Walton, Paul C. Boutros, Ariane Nguyen, Kristen M. Leraas, Robert L. Ferris, Greg Eley, Christopher C. Benz, Jaegil Kim, Thomas E. Carey, Douglas B. Chepeha, Janae V. Simons, Jiexin Zhang, Laura S. Rozek, Maureen A. Sartor, Christopher A. Bristow, Justin A. Bishop, Adel K. El-Naggar, Nishant Agrawal, Yiling Lu, Carrie Sougnez, Evan G. Taylor, Raju Kucherlapati, Scott M. Lippman, Colleen Mitchell, Wendell G. Yarbrough, Chu Chen, Donghui Tan, Bhishamjit S. Chera, Michael Mayo, Wenbin Liu, Ranabir Guin, W. Kimryn Rathmell, Mayya Malakh, Jessica Frick, John N. Weinstein, Kevin Lau, Michelle Q. Pham, Gideon Dresdner, Luc G. T. Morris, David Mallery, Zhining Wang, Yichao Sun, Lynn M. Herbert, Christine M. Komarck, Lauren Averett Byers, Angela Tam, Thomas Bodenheimer, Doug Voet, Christie Kovar, Junyuan Wu, Walker Hale, Charles M. Perou, Angela B.Y. Hui, Kenna R. Mills Shaw, Timothy J. Triche, Dong Zeng, Steven J.M. Jones, Matthew D. Wilkerson, Jinze Liu, Yan Guo, Hsu Chao, Tamara R. Jones, Katherine A. Hoadley, Stuart R. Jefferys, Thomas C. Motter, Matthew Meyerson, Konstanty Korski, Timothy A. Chan, Mark A. Jensen, Julien Baboud, Alexei Protopopov, David I. Heiman, Nils Gehlenborg, Heidi J. Sofia, Aaron D. Tward, Eric S. Lander, Yunhu Wan, Scot Waring, Peggy Yena, Robert I. Haddad, Daniel DiCara, Gordon Saksena, Juok Cho, Richard A. Moore, Darshan Singh, Peter J. Park, Matthew Ibbs, Robert A. Holt, Andrew D. Cherniack, Tanguy Y. Seiwert, Lee Lichtenstein, Anders Jacobsen, Rameen Beroukhim, Brandee T. Brown, Stephen C. Benz, Paweł Golusiński, Vonn Walter, Lixia Diao, Erik Zmuda, Scott Frazer, Michael S. Lawrence, Nils Weinhold, Jacqueline E. Schein, Xiaojia Ren, Denise Brooks, Elizabeth Buda, Jianjiong Gao, Jianhua Zhang, William W. Shockley, J. Todd Auman, Xingzhi Song, Jennifer R. Grandis, Jonathan B. McHugh, Stacey Gabriel, Martin L. Ferguson, Jeffrey S. Reid, Joseph Paulauskis, Umadevi Veluvolu, John A. Demchok, Moiz S. Bootwalla, Fei-Fei Liu, Alan P. Hoyle, Shaowu Meng, Mei Huang, Ann Marie Egloff, Christina Beard, Liu Xi, Ricardo Ramirez, Donna Morton, Lisle E. Mose, Leslie Cope, Marjorie Romkes, Zubair Khan, Noreen Dhalla, Candace Shelton, Boris Reva, Stephen B. Baylin, Miruna Balasundaram, Psalm Haseley, Andrew Wei Xu, Yan Shi, A. Gordon Robertson, Gregory T. Wolf, Darlene Lee, Steven E. Schumacher, Semin Lee, Rileen Sinha, Dennis T. Maglinte, Haiyan I. Li, William K. Funkhouser, Yi Han, Sam Ng, Joel S. Parker, Kai Wang, Zhong Chen, You Hong Fan, Yaron S.N. Butterfield, Jeffrey S. Moyer, Robert A. Burton, David Pot, Chris Sander, Daryl Waggott, Joseph A. Califano, Netty Santoso, and Kyle Chang
- Subjects
Male ,DNA Copy Number Variations ,Somatic cell ,Biology ,Article ,03 medical and health sciences ,0302 clinical medicine ,CDKN2A ,Humans ,HRAS ,Molecular Targeted Therapy ,RNA, Neoplasm ,Gene ,neoplasms ,030304 developmental biology ,Genetics ,0303 health sciences ,Multidisciplinary ,Oncogene ,Genome, Human ,Squamous Cell Carcinoma of Head and Neck ,Wnt signaling pathway ,DNA, Neoplasm ,Genomics ,Oncogenes ,Cell cycle ,3. Good health ,Gene Expression Regulation, Neoplastic ,Head and Neck Neoplasms ,030220 oncology & carcinogenesis ,Mutation ,Cancer research ,Carcinoma, Squamous Cell ,Female ,FAT1 ,Signal Transduction ,Transcription Factors - Abstract
The Cancer Genome Atlas profiled 279 head and neck squamous cell carcinomas (HNSCCs) to provide a comprehensive landscape of somatic genomic alterations. Here we show that human-papillomavirus-associated tumours are dominated by helical domain mutations of the oncogene PIK3CA, novel alterations involving loss of TRAF3, and amplification of the cell cycle gene E2F1. Smoking-related HNSCCs demonstrate near universal loss-of-function TP53 mutations and CDKN2A inactivation with frequent copy number alterations including amplification of 3q26/28 and 11q13/22. A subgroup of oral cavity tumours with favourable clinical outcomes displayed infrequent copy number alterations in conjunction with activating mutations of HRAS or PIK3CA, coupled with inactivating mutations of CASP8, NOTCH1 and TP53. Other distinct subgroups contained loss-of-function alterations of the chromatin modifier NSD1, WNT pathway genes AJUBA and FAT1, and activation of oxidative stress factor NFE2L2, mainly in laryngeal tumours. Therapeutic candidate alterations were identified in most HNSCCs.
- Published
- 2015
40. miR-375 Regulates Invasion-Related Proteins Vimentin and L-Plastin
- Author
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Jihyeon Lim, Ruth Hogue Angeletti, Thomas J. Belbin, Nicole Kawachi, Thomas J. Ow, Thomas M. Harris, Jeffrey E. Segall, Michael B. Prystowsky, Berta Burd, Geoffrey Childs, and Lizandra Jimenez
- Subjects
0301 basic medicine ,Proteomics ,Invadopodium ,Down-Regulation ,Vimentin ,Biology ,Models, Biological ,Pathology and Forensic Medicine ,03 medical and health sciences ,Downregulation and upregulation ,Mir-375 ,medicine ,Humans ,Neoplasm Invasiveness ,Transcription factor ,Regulation of gene expression ,Gene knockdown ,Squamous Cell Carcinoma of Head and Neck ,Microfilament Proteins ,Regular Article ,medicine.disease ,Molecular biology ,Head and neck squamous-cell carcinoma ,Neoplasm Proteins ,Gene Expression Regulation, Neoplastic ,MicroRNAs ,030104 developmental biology ,Head and Neck Neoplasms ,Gene Knockdown Techniques ,Core Binding Factor Alpha 2 Subunit ,biology.protein ,Carcinoma, Squamous Cell - Abstract
Invasion is a hallmark of advanced head and neck squamous cell carcinoma (HNSCC). We previously determined that low relative miR-375 expression was associated with poor patient prognosis. HNSCC cells with increased miR-375 expression have lower invasive properties and impaired invadopodium activity. Using stable isotope labeling with amino acids in cell culture and reverse-phase liquid chromatography mass spectrometry, we assessed the impact of miR-375 expression on protein levels in UM-SCC-1 cells. Increased miR-375 expression was associated with down-regulation of proteins involved in cellular assembly and organization, death and survival, and movement. Two invasion-associated proteins, vimentin and L-plastin, were strongly down-regulated by miR-375. Luciferase reporter assays demonstrated that high miR-375 expression reduced vimentin promoter activity, suggesting that vimentin is an indirect target of miR-375. Runt-related transcription factor 1 (RUNX1) is a potential miR-375 direct target, and its knockdown reduced vimentin and L-plastin expression. Data in The Cancer Genome Atlas HNSCC database showed a significant inverse correlation between miR-375 expression and RUNX1, vimentin, and L-plastin RNA expression. These clinical correlations validate our in vitro model findings and support a mechanism in which miR-375 suppresses RUNX1 levels, resulting in reduced vimentin and L-plastin expression. Furthermore, knockdown of RUNX1, L-plastin, and vimentin resulted in significant reductions in cell invasion in vitro , indicating the functional significance of miR-375 regulation of specific proteins involved in HNSCC invasion.
- Published
- 2017
41. Pyridone-Conjugated Monobactam Antibiotics with Gram-Negative Activity
- Author
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Rose Barham, Thuy Hoang, Jeremy T. Starr, Jennifer A. Young, M. Megan Lemmon, Joseph Penzien, Mark J. Mitton-Fry, Thomas M. Harris, Antonia A. Nikitenko, Brian S. Gerstenberger, Sandra P. McCurdy, Veerabahu Shanmugasundaram, Lisa Mullins, Joel R. Hardink, Jeffrey M. Casavant, Eric S. Marr, Jian Lin, Seungil Han, Joel T. Arcari, John P. Mueller, Brandon P. Schuff, Mark S. Plummer, Craig J. McPherson, Michael D. Huband, Mark C. Noe, Manjinder S. Lall, Richard P. Zaniewski, Chao Li, Matthew Frank Brown, Jianmin Sun, Eric B. McElroy, and Andrew P. Tomaras
- Subjects
Male ,Gram-negative bacteria ,Pyridones ,Klebsiella pneumoniae ,Microbial Sensitivity Tests ,Plasma protein binding ,medicine.disease_cause ,Microbiology ,Inhibitory Concentration 50 ,Gram-Negative Bacteria ,Drug Discovery ,Escherichia coli ,medicine ,Animals ,Monobactam ,Rats, Wistar ,Molecular Structure ,biology ,Pseudomonas aeruginosa ,Chemistry ,biology.organism_classification ,In vitro ,Anti-Bacterial Agents ,Rats ,Biochemistry ,Molecular Medicine ,Antibacterial activity ,Monobactams ,medicine.drug - Abstract
Herein we describe the structure-aided design and synthesis of a series of pyridone-conjugated monobactam analogues with in vitro antibacterial activity against clinically relevant Gram-negative species including Pseudomonas aeruginosa , Klebsiella pneumoniae , and Escherichia coli . Rat pharmacokinetic studies with compound 17 demonstrate low clearance and low plasma protein binding. In addition, evidence is provided for a number of analogues suggesting that the siderophore receptors PiuA and PirA play a role in drug uptake in P. aeruginosa strain PAO1.
- Published
- 2013
42. Catalysts of DNA Strand Cleavage at Apurinic/Apyrimidinic Sites
- Author
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Amanda K. McCullough, Carmelo J. Rizzo, Nathan Donley, R. Stephen Lloyd, Aaron C. Jacobs, Arnie R. de Leon, Irina G. Minko, Francesca Gruppi, and Thomas M. Harris
- Subjects
0301 basic medicine ,Apurinic Acid ,DNA Repair ,Article ,Nucleobase ,AP endonuclease ,03 medical and health sciences ,chemistry.chemical_compound ,DNA-(Apurinic or Apyrimidinic Site) Lyase ,AP site ,DNA Cleavage ,Binding Sites ,Multidisciplinary ,Base Sequence ,030102 biochemistry & molecular biology ,biology ,DNA replication ,DNA ,Base excision repair ,3. Good health ,030104 developmental biology ,Deoxyribose ,chemistry ,Biochemistry ,DNA glycosylase ,Biocatalysis ,biology.protein ,DNA Damage - Abstract
Apurinic/apyrimidinic (AP) sites are constantly formed in cellular DNA due to instability of the glycosidic bond, particularly at purines and various oxidized, alkylated, or otherwise damaged nucleobases. AP sites are also generated by DNA glycosylases that initiate DNA base excision repair. These lesions represent a significant block to DNA replication and are extremely mutagenic. Some DNA glycosylases possess AP lyase activities that nick the DNA strand at the deoxyribose moiety via a β- or β,δ-elimination reaction. Various amines can incise AP sites via a similar mechanism, but this non-enzymatic cleavage typically requires high reagent concentrations. Herein, we describe a new class of small molecules that function at low micromolar concentrations as both β- and β,δ-elimination catalysts at AP sites. Structure-activity relationships have established several characteristics that appear to be necessary for the formation of an iminium ion intermediate that self-catalyzes the elimination at the deoxyribose ring.
- Published
- 2016
43. Novel monobactams utilizing a siderophore uptake mechanism for the treatment of gram-negative infections
- Author
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Hongying Gao, Jennifer A. Young, Joel R. Hardink, Veerabahu Shanmugasundaram, Steven M. Finegan, David Pattavina, Joel T. Arcari, Jian Lin, Jianmin Sun, Mark J. Mitton-Fry, Thuy Hoang, Matthew Frank Brown, Hud Lawrence Risley, Rebecca Irvine, Mark Edward Flanagan, Brandon P. Schuff, Seungil Han, Manjinder S. Lall, Brian S. Gerstenberger, Mark Niosi, Thomas M. Harris, Michael D. Huband, Chao Li, Lisa Mullins, Sandra P. McCurdy, M. Megan Lemmon, John P. Mueller, Jennifer Winton, Jeffrey M. Casavant, Mark S. Plummer, Mark C. Noe, Joseph Penzien, Jeremy T. Starr, and David M. George
- Subjects
Models, Molecular ,Siderophore ,Klebsiella pneumoniae ,Clinical Biochemistry ,Pharmaceutical Science ,Microbial Sensitivity Tests ,Crystallography, X-Ray ,medicine.disease_cause ,Biochemistry ,Microbiology ,Mice ,Structure-Activity Relationship ,In vivo ,Drug Resistance, Multiple, Bacterial ,Gram-Negative Bacteria ,Drug Discovery ,medicine ,Animals ,Humans ,Monobactam ,Monobactams ,Molecular Biology ,Escherichia coli ,Binding Sites ,Dose-Response Relationship, Drug ,Molecular Structure ,biology ,Chemistry ,Pseudomonas aeruginosa ,Organic Chemistry ,Blood Proteins ,biology.organism_classification ,In vitro ,Rats ,Molecular Medicine ,Gram-Negative Bacterial Infections ,medicine.drug - Abstract
Novel siderophore-linked monobactams with in vitro and in vivo anti-microbial activity against MDR Gram-negative pathogens are described.
- Published
- 2012
44. Towards Active Citizen-Centric E-Government Systems for Developing Countries
- Author
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Nazim U. Ahmed, Catherine Chen, Thomas M. Harris, and Olusegun Folorunso
- Subjects
Government ,E-Government ,Computer Networks and Communications ,business.industry ,Developing country ,ComputingMilieux_LEGALASPECTSOFCOMPUTING ,Citizen journalism ,Public relations ,Architecture framework ,Work (electrical) ,ComputerSystemsOrganization_MISCELLANEOUS ,Spite ,business ,Information Systems - Abstract
The importance of citizen’s participation in government cannot be overemphasized. Governments in many developing countries have made efforts, in spite of their infrastructural and financial limitations, to uphold the virtues of participatory e-governance with limited success. A major cause of this elusive success is the design of e-government platforms, which doesn’t encourage usage by the stakeholders of e-government. Many governments in developing countries are settling for other means to communicate with citizens. In this work, a new architectural framework is proposed that uses knowledge management facilities to enhance web-based e-governance and encourage participation, thus allowing for the elicitation of knowledge from online discourse. The country examined in this article is Nigeria. However, it is likely that many other African and developing countries have similar experiences. This work will aid in the improvement of web-based e-government platforms for such countries.
- Published
- 2012
45. Cytoplasmic Ezrin and Moesin Correlate with Poor Survival in Head and Neck Squamous Cell Carcinoma
- Author
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Thomas M. Harris, Nicole Kawachi, Juan Lin, Darcy Broughel, Thomas J. Belbin, Paul A. Reynolds, Richard V. Smith, Michael B. Prystowsky, Nicolas F. Schlecht, Margaret Brandwein-Gensler, Frank J. Gunn-Moore, Geoffrey Childs, and Christian E. Keller
- Subjects
Adult ,Male ,Cytoplasm ,Pathology ,medicine.medical_specialty ,Moesin ,Kaplan-Meier Estimate ,macromolecular substances ,Biology ,environment and public health ,Pathology and Forensic Medicine ,Ezrin ,Biomarkers, Tumor ,medicine ,Carcinoma ,Humans ,Aged ,Neoplasm Staging ,Proportional Hazards Models ,Aged, 80 and over ,Original Paper ,Tissue microarray ,Microfilament Proteins ,Cancer ,Middle Aged ,Prognosis ,medicine.disease ,Immunohistochemistry ,Head and neck squamous-cell carcinoma ,Merlin (protein) ,Cytoskeletal Proteins ,Oncology ,Otorhinolaryngology ,Head and Neck Neoplasms ,Tissue Array Analysis ,Tumor progression ,Carcinoma, Squamous Cell ,Female - Abstract
Members of the 4.1 superfamily of proteins, including ezrin, moesin, merlin, and willin regulate many normal physiologic processes such as cellular shape, motility, and proliferation. In addition, they contribute both to tumor development and tumor progression. We reported previously that strong cytoplasmic ezrin expression was independently associated with poorer patient survival. One hundred and thirty-one histologically confirmed primary head and neck squamous cell carcinomas were examined prospectively for cancer progression and survival at a large health care center in the Bronx, NY, USA. Immunohistochemical analysis of ezrin, moesin, merlin, and willin expression in tissue microarray samples of primary head and neck squamous cell carcinoma revealed a significant association of increased cytoplasmic ezrin with poor cancer survival. Global RNA analyses suggest that cancers with high cytoplasmic ezrin have a more invasive phenotype. This study supports our previous findings associating cytoplasmic ezrin with more aggressive behavior and poorer outcome and indicates the need for a multi-institutional study to validate the use of cytoplasmic ezrin as a biomarker for treatment planning in head and neck squamous cell carcinoma.
- Published
- 2012
46. Deoxyguanosine Forms a Bis-Adduct with E,E-Muconaldehyde, an Oxidative Metabolite of Benzene: Implications for the Carcinogenicity of Benzene
- Author
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Plamen P. Christov, Donald F. Stec, Ivan D. Kozekov, Thomas M. Harris, Constance M. Harris, and Carmelo J. Rizzo
- Subjects
Magnetic Resonance Spectroscopy ,Stereochemistry ,Metabolite ,Environmental pollution ,Stereoisomerism ,Toxicology ,Article ,Adduct ,DNA Adducts ,chemistry.chemical_compound ,Biotransformation ,Humans ,Deoxyguanosine ,Spiro Compounds ,Amino Acids ,Benzene ,Carcinogen ,Aldehydes ,Chemistry ,Circular Dichroism ,DNA ,General Medicine ,Solutions ,Carcinogens ,Nucleic Acid Conformation ,Environmental Pollution ,Peptides ,Oxidation-Reduction - Abstract
Benzene is employed in large quantities in the chemical industry and is an ubiquitous contaminant in the environment. There is strong epidemiological evidence that benzene exposure induces hematopoietic malignancies, especially acute myeloid leukemia, in humans, but the chemical mechanisms remain obscure. E,E-Muconaldehyde is one of the products of metabolic oxidation of benzene. This paper explores the proposition that E,E-muconaldehyde is capable of forming Gua-Gua cross-links. If formed in DNA, the replication and repair of such cross-links might introduce structural defects that could be the origin of the carcinogenicity. We have investigated the reaction of E,E-muconaldehyde with dGuo and found that the reaction yields two pairs of interconverting diastereomers of a novel heptacyclic bis-adduct having a spiro ring system linking the two Gua residues. The structures of the four diastereomers have been established by NMR spectroscopy and their absolute configurations by comparison of CD spectra with those of model compounds having known configurations. The final two steps in the formation of the bis-nucleoside (5-ring → 6-ring → 7-ring) have significant reversibility, which is the basis for the observed epimerization. The 6-ring precursor was trapped from the equilibrating mixture by reduction with NaBH(4). The anti relationship of the two Gua residues in the heptacyclic bis-adduct precludes it from being formed in B DNA, but the 6-ring precursor could readily be accommodated as an interchain or intrachain cross-link. It should be possible to form similar cross-links of dCyt, dAdo, the ε-amino group of lysine, the imidazole NH of histidine, and N termini of peptides with the dGuo-muconaldehyde monoadduct.
- Published
- 2011
47. Hypermethylation of a Cluster of Krüppel-Type Zinc Finger Protein Genes on Chromosome 19q13 in Oropharyngeal Squamous Cell Carcinoma
- Author
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Benjamin Brown, Roberto A. Lleras, Michael B. Prystowsky, Richard V. Smith, Geoffrey Childs, L. Adrien, Thomas M. Harris, Thomas J. Belbin, Cathy Sarta, Naheed Jivraj, Nicolas F. Schlecht, and Christopher Keller
- Subjects
Adult ,Male ,Kruppel-Like Transcription Factors ,Biology ,Pathology and Forensic Medicine ,Chromosome 19 ,Humans ,Gene ,Aged ,Oligonucleotide Array Sequence Analysis ,Zinc finger ,Genetics ,Reverse Transcriptase Polymerase Chain Reaction ,Chromosome ,Regular Article ,Methylation ,DNA Methylation ,Middle Aged ,Oropharyngeal Neoplasms ,genomic DNA ,CpG site ,DNA methylation ,Carcinoma, Squamous Cell ,Cancer research ,CpG Islands ,Female ,Chromosomes, Human, Pair 19 - Abstract
Identification of epigenetically affected genes has become an important tool for understanding both normal and aberrant gene expression in cancer. Here we report a whole-genome analysis of DNA methylation profiles in fresh-frozen oropharyngeal squamous cell carcinoma (OPSCC) tissues and normal mucosa samples using microarray technology with patient genomic DNA. We initially compared whole-genome patterns of DNA methylation among 24 OPSCC primary tumors and 24 matched normal mucosal samples. From a survey of 27,578 CpG dinucleotide loci spanning more than 14,000 genes, we identified 958 CpG loci in which measurements of DNA methylation were altered in the primary tumors relative to the normal mucosal samples. These alterations were validated in an independent set of 21 OPSCC patients. A survey of these loci by chromosomal location revealed an abnormally high number of differentially methylated loci on chromosome 19. Many of the loci on chromosome 19 are associated with genes belonging to the Krüppel-type zinc finger protein genes. Hypermethylation was accompanied by a significant decrease in expression of these genes in OPSCC primary tumors relative to adjacent mucosa. This study reports the epigenetic silencing of Krüppel-type zinc finger protein genes on chromosome 19q13 in oropharyngeal cancer. The aberrant methylation of these genes represents a new avenue of exploration for pathways affected in this disease.
- Published
- 2011
48. Abstract 4401: Integrated genomic and functional microRNA analysis identifies miR-30-5p as a tumor suppressor and novel therapeutic nanomedicine in head and neck cancer
- Author
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Kathleen F. Pirollo, Rita Das, Gordon Robertson, Thomas M. Harris, Hui Cheng, Carter Van Waes, Geoffrey Childs, Robert F. Place, Anthony Saleh, Zhong Chen, and Esther H. Chang
- Subjects
Cancer Research ,Head and neck cancer ,Cell ,Cancer ,Biology ,medicine.disease ,law.invention ,medicine.anatomical_structure ,Oncology ,law ,DNA methylation ,microRNA ,Cancer research ,medicine ,Suppressor ,Copy-number variation ,Insulin-like growth factor 1 receptor - Abstract
We have developed an integrative approach to elucidate the functional role of deregulated microRNAs (miRs) and identify candidates for miR replacement therapy in cancer, applied here to head and neck squamous cell carcinomas (HNSCC). Our method involves integration of results from TCGA and other validation databases of genetic and expression data, including: miR expression, mRNA expression, copy number variation, DNA methylation. This data is then intersected with functional in vitro genome-wide miR screening for anti-proliferative miR mimics. We report that the miR-30-5p family is commonly repressed and correlates with overexpression of a broad network of proliferative and metastasis-related oncogenic mRNAs, including the growth receptors EGFR, MET and IGF1R. We show that re-expression of miR-30a-5p repressed this gene program, downstream signaling, proliferation, migration, and invasion in vitro. We have developed a chemically modified mimic of miR-30-5p with 50x improved stability in human serum, and 5X improvement in IC50 in vitro by XTT assay. We have formulated our novel miR-30a-5p mimic into Transferrin Receptor targeted nanoparticles which strongly inhibited HNSCC xenograft tumor growth, and regulated miR-30-5p family targets in vivo. Together with data linking decreased miR-30 family expression with DNA copy loss and promoter hypermethylation, and clinical disease-specific survival, for the first time, we have reported a more global picture of the function of this important tumor suppressor and identified a subset of patients that may benefit from miR replacement therapy with our novel miR-30-5p based nanomedicine. This research was supported by NIDCD intramural projects ZIA-DC-000073, 74, and NCI grant U43CA22156701. Citation Format: Anthony D. Saleh, Robert F. Place, Hui Cheng, Rita Das, Thomas M. Harris, Geoffrey Childs, Gordon A. Robertson, Kathleen F. Pirollo, Esther H. Chang, Zhong Chen, Carter Van Waes. Integrated genomic and functional microRNA analysis identifies miR-30-5p as a tumor suppressor and novel therapeutic nanomedicine in head and neck cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4401.
- Published
- 2018
49. Structure–activity relationships and hepatic safety risks of thiazole agonists of the thrombopoietin receptor
- Author
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James P. Driscoll, Eric B. McElroy, Christopher S. Jones, Matthew Frank Brown, Jonathan L. Doty, William H. Brissette, Sharon L. Ripp, Mark J. Mitton-Fry, Marc I. Smeets, Thomas M. Harris, Kristen A. Trevena, Amy S. Antipas, Jeffrey M. Casavant, Laura Cook Blumberg, David A. Reim, Lawrence A. Reiter, Michael John Munchhof, Sandra P. McCurdy, and Andrei Shavnya
- Subjects
Agonist ,medicine.drug_class ,Clinical Biochemistry ,Pharmaceutical Science ,Pharmacology ,Biochemistry ,Structure-Activity Relationship ,chemistry.chemical_compound ,Aminothiazole ,Drug Discovery ,medicine ,Animals ,Structure–activity relationship ,Receptor ,Thiazole ,Molecular Biology ,Thrombopoietin ,Thrombopoietin receptor ,Organic Chemistry ,In vitro ,Thiazoles ,Liver ,chemistry ,Molecular Medicine ,Receptors, Thrombopoietin - Abstract
5-F substitution of an aminothiazole moiety within a series of thrombopoietin receptor agonists leads to potent agents with an improved hepatic safety profile in rodent toxicology studies.
- Published
- 2010
50. Interstrand DNA Cross‐Linking 1, N 2‐Deoxyguanosine Adducts Derived from α,β‐Unsaturated Aldehydes: Structure–Function Relationships
- Author
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Ivan D. Kozekov, Thomas M. Harris, Carmelo J. Rizzo, Hao Wang, Irina G. Minko, Young Jin Cho, R. Stephen Lloyd, Albena Kozekova, Hai Huang, Hye-Young H. Kim, and Michael P. Stone
- Subjects
chemistry.chemical_compound ,chemistry ,Stereochemistry ,Crosslinking of DNA ,Acrolein ,Structure function ,DNA adduct ,Organic chemistry ,Deoxyguanosine ,Crotonaldehyde ,Adduct ,4-Hydroxynonenal - Published
- 2010
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