19 results on '"Kelly S. Levano"'
Search Results
2. Comparative genomic analysis of Peruvian strains of Mycobacterium tuberculosis
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David Tarazona, Marco Galarza, Kelly S. Levano, and Heinner Guio
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tuberculosis ,genómica ,farmacorresistencia bacteriana ,Medicine ,Medicine (General) ,R5-920 - Abstract
Objectives. To comparatively analyze three genomic sequences of Mycobacterium tuberculosis (MTB), including sensitive (INS-SEN), multi-drug-resistant (INS-MDR), and extremely drug-resistant (INS-XDR) strains, collected in Lima, Peru. Materials and Methods. Specific single nucleotide polymorphisms (SNPs) were identified in the INS SEN, INSMDR, and INS-XDR strains according to the inclusion/exclusion criteria. The three MTB genomes were compared and a molecular phylogeny was constructed with 27 MTB strains from other studies available from the Genbank database. Results. The specific SNPs in each genome were organized in clusters of orthologous groups (COGs). The genomic analysis allowed for the identification of a set of SNPs associated mainly with virulence determinants (family of mce proteins, polyketides, phiRv1, transposase, and methyltransferases, and other related to vitamin synthesis). A close correlation between the INS-MDR and INS-XDR strains was observed, with only a 6.1% difference in SNPs; however, the INS-SEN strain had 50.2% and 50.3% different SNPs from the MDR and XDR strains, respectively. The molecular phylogeny grouped the Peruvian strains within the LAM lineage and closely to the F11 and KZN strains from South Africa. Conclusions. High similarity (99.9%) was noted between the INS-SEN strain and the F11 South African strain with broad global scope, while the analysis of the INS-MDR and INS-XDR strains showed a likely expansion of the KZN family, a South African strain with high virulence and pathogenicity.
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- 2016
- Full Text
- View/download PDF
3. The role of pharmacogenomics in the tuberculosis treatment regime
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Heinner Guio, Kelly S. Levano, Cesar Sánchez, and David Tarazona
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farmacogenética ,mycobacterium tuberculosis ,variación genética ,Medicine ,Medicine (General) ,R5-920 - Abstract
Tuberculosis is a health problem worldwide with one-third of the population infected with the Mycobacterium tuberculosis bacilli. The first-line of treatment for tuberculosis includes the drugs Isoniazid (INH) and Rifampicin (RIF) metabolized in the liver. Drug metabolism is directly related to the genetic variation of NAT2 and CYP2E1 (associated with INH metabolism) and AADAC (associated with RIF metabolism), and the effects produced in an individual may be a fast, intermediate or slow metobolizer. Polymorphisms in genes of people in standard tuberculosis treatment can cause effects on drug metabolism with consequences of hepatotoxicity and even drug resistance. Countries have began clinical trials focusedon personalization of tuberculosis treatment to reduce the consequences for patients in treatment. In countries like Peru, where high rates of tuberculosis are recorded and therefore more people in treatment, the pharmacogenomic of individuals becomes a crucial tool for an optimum tuberculosis treatment. This review highlights the importance of having pharmacogenomic studies and having the identification of polymorphisms associated to the metabolism of the anti-tuberculosis drugs in our Peruvian population.
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- 2015
- Full Text
- View/download PDF
4. Response to a comment on: comparative genomic analysis of Peruvian strains of Mycobacterium tuberculosis
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David Tarazona, Marco Galarza, Kelly S. Levano, and Heinner Guio
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Medicine ,Medicine (General) ,R5-920 - Published
- 2016
- Full Text
- View/download PDF
5. Allelic and genotypic frequencies of NAT2, CYP2E1, and AADAC genes in a cohort of Peruvian tuberculosis patients
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Christian Rojas, Luis Jaramillo-Valverde, Alonso Soto, Kelly S. Levano, Roberto Zegarra-Chapoñan, David Tarazona, Silvia Capristano, Lely Solari, Tania Vásquez-Loarte, Alberto Mendoza-Ticona, Heinner Guio, and César Cabezas Sánchez
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medicine.medical_specialty ,Tuberculosis ,Genotype ,Arylamine N-Acetyltransferase ,Population ,Single-nucleotide polymorphism ,QH426-470 ,Polymorphism, Single Nucleotide ,Linkage Disequilibrium ,Gene Frequency ,Internal medicine ,Peru ,Genetics ,medicine ,Humans ,Genetic Predisposition to Disease ,CYP2E1 ,Allele ,education ,Molecular Biology ,Genetics (clinical) ,Alleles ,Genetic Association Studies ,education.field_of_study ,biology ,business.industry ,Isoniazid ,Cytochrome P-450 CYP2E1 ,Original Articles ,medicine.disease ,NAT2 ,Phenotype ,tuberculosis ,Cohort ,Original Article ,Arylacetamide deacetylase ,biology.gene ,business ,AADAC ,Carboxylic Ester Hydrolases ,medicine.drug - Abstract
Background We determined the frequency of genetic polymorphisms in three anti‐TB drug metabolic proteins previously reported: N‐acetyltransferase 2 (NAT2), cytochrome P450 2E1 (CYP2E1), and arylacetamide deacetylase (AADAC) within a Peruvian population in a cohort of TB patients. Methods We genotyped SNPs rs1041983, rs1801280, rs1799929, rs1799930, rs1208, and rs1799931 for NAT2; rs3813867 and rs2031920 for CYP2E1; and rs1803155 for AADAC in 395 participants completed their antituberculosis treatment. Results Seventy‐four percent of the participants are carriers of slow metabolizer genotypes: NAT2*5, NAT2*6, and NAT2*7, which increase the sensitivity of INH at low doses and increase the risk of drug‐induced liver injuries. Sixty‐four percent are homozygous for the wild‐type CYP2E1*1A allele, which could increase the risk of hepatotoxicity. However, 16% had a NAT2 fast metabolizer phenotype which could increase the risk of acquiring resistance to INH, thereby increasing the risk of multidrug‐resistant (MDR) or treatment failure. The frequency of rs1803155 (AADAC*2 allele) was higher (99.9%) in Peruvians than in European American, African American, Japanese, and Korean populations. Conclusions This high prevalence of slow metabolizers for isoniazid in the Peruvian population should be further studied and considered to help individualize drug regimens, especially in countries with a great genetic diversity like Peru. These data will help the Peruvian National Tuberculosis Control Program develop new strategies for therapies., High prevalence of slow metabolizers for isoniazid in the Peruvian population should be further studied and considered to help individualize drug regimens, especially in countries with a great genetic diversity like Peru.
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- 2021
6. Effect of guinea pig blood and Physalis peruviana gummies in the reduction of anemia in children of Huanuco Peru
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Kelly S. Levano, Diana Palma, Gabriela Solano, David Tarazona, Juan Morales, and Lissette Yllanes
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0301 basic medicine ,Pediatrics ,medicine.medical_specialty ,High prevalence ,biology ,Anemia ,business.industry ,medicine.disease ,biology.organism_classification ,Guinea pig ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,medicine ,Physalis ,Hemoglobin ,business ,030217 neurology & neurosurgery - Abstract
Objective: To check the effectiveness of guinea pig blood and aguaymanto Gummies as a nutritional supplement in the reduction of anemia in children aged 2 to 5 years in an area of high prevalence of Huanuco, Peru in 2018. Methods: The study was longitudinal, analytical, prospective and experimental with only one group. The sample was probabilistic with 33 children from 2 to 5 years of age, who, with a signed informed consent from their parents, were given the gummies of guinea pig blood and Aguaymanto for 21 consecutive days. Results: Children before the consumption of gummies had a level of mild [39.4]% (14)] and moderate [60.6% (20)] anemia. After the consumption of the guinea pig blood and aguaymanto gummies, the 31 out of 33 children no longer had anemia (93.9%; Z = -5,014; p = 0.000) significantly demonstrating the increase in hemoglobin level after the consumption of the gummies. Conclusions: The guinea pig blood and aguaymanto gummies were effective as a nutritional supplement in the reduction of anemia in young children providing an innovative strategy to combat anemia in young children.
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- 2019
7. Guillain–Barre syndrome outbreak in Peru: Association with polymorphisms in IL‐17, ICAM1, and CD1
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Luis Jaramillo-Valverde, Pilar Mazzetti, Kelly S. Levano, Cesar Sanchez, Julio Valdivia-Silva, Isolina Villanueva, Meylin Hidalgo, Julio A. Poterico, Mario Cornejo-Olivas, Marco Cornejo, and Heinner Guio
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0301 basic medicine ,Male ,IL‐17 ,Guillain-Barre syndrome ,030105 genetics & heredity ,Body Mass Index ,Antigens, CD1 ,ICAM1 ,Risk Factors ,Genotype ,Peru ,genetic polymorphism ,Genetics (clinical) ,reproductive and urinary physiology ,education.field_of_study ,Interleukin-17 ,Middle Aged ,Intercellular Adhesion Molecule-1 ,IL-17 ,Regression Analysis ,Original Article ,Female ,Interleukin 17 ,lcsh:QH426-470 ,Population ,Single-nucleotide polymorphism ,Biology ,Polymorphism, Single Nucleotide ,03 medical and health sciences ,Genetics ,Genetic predisposition ,medicine ,Humans ,Genetic Predisposition to Disease ,education ,Gene ,Molecular Biology ,Aged ,Genetic polymorphism ,CD1 ,Outbreak ,Original Articles ,medicine.disease ,bacterial infections and mycoses ,lcsh:Genetics ,030104 developmental biology ,Genetic marker ,Case-Control Studies ,Immunology ,purl.org/pe-repo/ocde/ford#1.06.07 [https] - Abstract
SUMMARYGuillain-Barre Syndrome (GBS) is considered a complex disorder with significant environmental effect and genetic susceptibility. Genetic polymorphisms in CD1E, CD1A, IL-17 and/or ICAM-1 genes had been proposed as susceptibility genetic variants for GBS mainly in Caucasian population. This study explores the association between selected polymorphisms in these genes and GBS susceptibility in confirmed GBS cases reported in mestizo population from northern Peru during the most recent GBS outbreak of May 2018. A total of 9 non-related cases and 11 controls were sequenced for the polymorphic regions of CD1A, CD1E, IL-17 and ICAM-1 genes. We found a significant protective association between heterozygous GA genotype in ICAM-1 gene (241Gly / Arg) and GBS (p IL-17 was monomorphic in both controls and patients. No significant differences were found in the frequency of SNPs in CD1A and CD1E between the group with GBS patients and healthy controls. Further studies with larger sample size will be required to validate these findings.
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- 2019
8. A Genomic Signature for Genotyping Mycobacterium tuberculosis
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Kelly S. Levano, David Tarazona, Heinner Guio, Marco Galarza, Luis Jaramillo, and Victor Borda
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0301 basic medicine ,Genetics ,Genotyping ,Tuberculosis ,Molecular epidemiology ,Single-nucleotide polymorphism ,Genomic signature ,Mycobacterium tuberculosis ,General Medicine ,Hypothesis ,Biology ,medicine.disease ,biology.organism_classification ,Genome ,03 medical and health sciences ,030104 developmental biology ,Genotype ,medicine - Abstract
Mycobacterium tuberculosis (MTB), the causative agent of tuberculosis (TB), has a vast diversity of genotypes including Beijing, CAS, EAI, Haarlem, LAM, X, Ural, T, AFRI1 and AFRI2. However, genotyping can be expensive, time consuming and in some cases, results may vary depending on methodology used. Here, we proposed a new set of 10 SNPs using a total of 249 MTB genomes, and selected by first the inclusion/ exclusion (IE) criteria using spoligotyping and phylogenies, followed by the selection of the nonsynonymous SNPs present in the most conserved cluster of orthologous groups (COG) of each genotype of MTB. Genotype assignment of the new set of 10 SNPs was validated using an additional of 34 MTB genomes and results showed 100% correlation with their known genotypes. Our set of 10 SNPs have not been previously reported and cover the MTB genotypes that are prevalent worldwide. This set of SNPs could be used for molecular epidemiology with drug resistant markers.
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- 2017
9. High-resolution melting analysis for molecular detection of multidrug resistance tuberculosis in Peruvian isolates
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Mitzi Rodriguez, Heinner Guio, Edith Castillo, Nadia N. Barreda, Manuel Fasabi, Kelly S. Levano, and M. Galarza
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0301 basic medicine ,Tuberculosis ,030106 microbiology ,Antitubercular Agents ,Microbial Sensitivity Tests ,Sensitivity and Specificity ,High Resolution Melt ,Microbiology ,Mycobacterium tuberculosis ,03 medical and health sciences ,parasitic diseases ,Peru ,Tuberculosis, Multidrug-Resistant ,medicine ,Isoniazid ,Humans ,High Resolution Melting Analysis ,biology ,INHA ,Multi-drug resistance tuberculosis ,biology.organism_classification ,rpoB ,medicine.disease ,bacterial infections and mycoses ,Virology ,Multiple drug resistance ,Infectious Diseases ,Parasitology ,Rifampin ,medicine.drug ,Research Article - Abstract
Background The emergence of multidrug-resistant strains is a major health problem especially for countries with high TB incidence such as Peru. In this study, we evaluated High Resolution Melting (HRM) assay in Peruvian isolates for the detection of mutations within rpoB, katG genes and promoter region inhA to determine isoniazid and rifampicin resistance in Mycobacterium tuberculosis (Mtb). Methods DNA samples extracted from a total of 167 clinical isolates of Mtb, 89 drug-sensitive and 78 multidrug-resistant, were blindly analyzed by HRM analysis and verified by DNA sequencing. Results The HRM analysis generated patterns that were specific to distinguish between sensitive and resistance isolates. The sensitivity and specificity of the HRM assays in comparison with drug susceptibility testing (DST) for detection of rifampicin resistance were 98.7 % and 97.5 %, and for isoniazid resistance were 98.7 % and 100 %. Conclusion This study suggests that HRM Analysis could help with rapid diagnosis of MDR-TB cases in Peru.
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- 2016
10. Germline mutations of the DNA repair pathways in uterine serous carcinoma
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Marina Frimer, Gary L. Goldberg, June Y. Hou, Alicia Rodriguez-Gabin, Yanhua Wang, Kelly S. Levano, and Susan Band Horwitz
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0301 basic medicine ,DNA Repair ,DNA repair ,Genes, BRCA2 ,Genes, BRCA1 ,medicine.disease_cause ,Bioinformatics ,Germline ,Uterine serous carcinoma ,03 medical and health sciences ,0302 clinical medicine ,Germline mutation ,medicine ,Humans ,Homologous Recombination ,Exome sequencing ,Germ-Line Mutation ,Aged ,Mutation ,business.industry ,Obstetrics and Gynecology ,medicine.disease ,Cystadenocarcinoma, Serous ,030104 developmental biology ,Oncology ,030220 oncology & carcinogenesis ,Uterine Neoplasms ,Cancer research ,DNA mismatch repair ,Female ,Carcinogenesis ,business - Abstract
Objective Treatment options are limited for patients with uterine serous carcinoma (USC). Knowledge of USC's somatic mutation landscape is rapidly increasing, but its role in hereditary cancers remains unclear. We aim to evaluate the frequency and characteristics of germline mutations in genes commonly implicated in carcinogenesis, including those within homologous recombination (HR) and mismatch repair (MMR) pathways in patients with pure USC. Methods By using targeted capture exome sequencing, 43 genes were analyzed in a cohort of 7 consecutive patients with paired tumor and non-tumor USC samples in our institutional tumor repository. Mutations predicted to have damaging effects on protein function are validated by Sanger Sequencing. Results We found 21 germline mutations in 11 genes in our USC cohort. Five patients harbored 7 germline mutations (33.3%) within genes involved in the HR pathway, RAD51D being the most common. Four patients had 9 (42.8%) germline mutations in hereditary colon cancer genes, most commonly MLH. All patients (42.7%) who are platinum-sensitive had HR germline mutations (RAD50, NBN, ATM). Patients with HER2 overexpression (2/7, 28.6%) had germline HR mutations and were platinum-sensitive. Three patients in our cohort reported a personal history of breast cancer, one with HR germline mutation, and 2 in patients with germline mutations in HCC genes. In addition, 5 out of 7 patients had germline mutations in genes associated with growth factor signaling pathway. Conclusions A significant proportion of our cohort harbor germline mutations in DNA repair genes. This may be associated with the high rate of breast cancer in our patients and their family, and suggests a targeted cohort for genetic counseling. If validated in a larger cohort, our findings may allow clinicians to expand therapeutic options to include targeted therapies and inclusion of USC patient in preventative and genetic counseling.
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- 2015
11. Rol de la farmacogenómica en el régimen de tratamiento de tuberculosis
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David Tarazona, Kelly S. Levano, Heinner Guio, and César Cabezas Sánchez
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Tuberculosis ,Population ,lcsh:Medicine ,Drug resistance ,Variación genética ,Pharmacology ,farmacogenética ,Mycobacterium tuberculosis ,Medicine ,Genetic variation ,education ,pharmacogenetics ,mycobacterium tuberculosis ,lcsh:R5-920 ,education.field_of_study ,biology ,business.industry ,lcsh:R ,Farmacogenética ,Isoniazid ,Public Health, Environmental and Occupational Health ,General Medicine ,bacterial infections and mycoses ,medicine.disease ,biology.organism_classification ,variación genética ,Pharmacogenetics ,Pharmacogenomics ,genetic variation ,Immunology ,lcsh:Medicine (General) ,business ,Rifampicin ,medicine.drug - Abstract
La tuberculosis es un problema de salud Pública a nivel mundial con un tercio de la población infectada por el bacilo Mycobacterium tuberculosis. El tratamiento de primera línea incluye a las drogas isoniazida (INH) y rifampicina (RIF) metabolizadas en el hígado. La metabolización de drogas está directamente relacionada con la variación genética de NAT2 y CYP2E1 (asociados a metabolismo de INH) y AADAC (asociados a metabolismo de RIF), y los efectos pueden producir que un individuo sea metabolizador rápido, intermedio o lento. Los polimorfismos en genes de personas con tratamiento estándar de tuberculosis pueden ocasionar efectos en el metabolismo de drogas con consecuencias de hepatoxicidad e, incluso, posible drogorresistencia. Algunos países han empezado ensayos clínicos enfocados en la personalización del tratamiento a tuberculosis para reducir las consecuencias en pacientes en tratamiento. En países como el Perú, donde se registran altos índices de tuberculosis y, por consiguiente, más población en tratamiento, la farmacogenómica de individuos se convierte en una herramienta crucial para un óptimo tratamiento. La presente revisión destaca la importancia de tener estudios en farmacogenómica e identificar los polimorfismos asociados al metabolismo de las drogas antituberculosas en nuestra población peruana Tuberculosis is a health problem worldwide with one-third of the population infected with the Mycobacterium tuberculosis bacilli. The first-line of treatment for tuberculosis includes the drugs Isoniazid (INH) and Rifampicin (RIF) metabolized in the liver. Drug metabolism is directly related to the genetic variation of NAT2 and CYP2E1 (associated with INH metabolism) and AADAC (associated with RIF metabolism), and the effects produced in an individual may be a fast, intermediate or slow metobolizer. Polymorphisms in genes of people in standard tuberculosis treatment can cause effects on drug metabolism with consequences of hepatotoxicity and even drug resistance. Countries have began clinical trials focusedon personalization of tuberculosis treatment to reduce the consequences for patients in treatment. In countries like Peru, where high rates of tuberculosis are recorded and therefore more people in treatment, the pharmacogenomic of individuals becomes a crucial tool for an optimum tuberculosis treatment. This review highlights the importance of having pharmacogenomic studies and having the identification of polymorphisms associated to the metabolism of the anti-tuberculosis drugs in our Peruvian population
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- 2015
12. Breast cancer subtypes express distinct receptor repertoires for tumor-associated macrophage derived cytokines
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Paraic A. Kenny, Eric H. Jung, and Kelly S. Levano
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Proteases ,Tumor microenvironment ,medicine.medical_treatment ,Macrophages ,Biophysics ,Gene Expression ,Breast Neoplasms ,Cell Biology ,Tumor-associated macrophage ,MMP9 ,Biology ,medicine.disease ,Biochemistry ,Interleukin 10 ,Cytokine ,Breast cancer ,Immunology ,medicine ,Tumor Microenvironment ,Cytokines ,Humans ,Female ,Receptors, Cytokine ,Receptor ,Molecular Biology - Abstract
Infiltration of the tumor microenvironment by macrophages is associated with poor outcomes in breast cancer and other solid tumors, however the identity and roles of many of the soluble factors these macrophages produce remains to be elucidated in detail. In addition to producing angiogenic factors (e.g. VEGF), proteases (e.g. MMP9) and immunomodulatory factors (e.g. IL10) which, by modifying the local microenvironment, likely contribute to progression in the majority of solid tumors, we have evaluated the extent to which macrophage cytokines may differentially affect distinct breast cancer subtypes. We identified 23 cytokines produced in a culture model of human tumor-associated macrophages and report that basal and luminal breast cancer cell lines express different repertoires of receptors for these cytokines. These data suggest that tumor-associated macrophages make specific contributions to different breast cancer subtypes and that understanding the importance of these interactions will be crucial to developing subtype-specific therapies targeting the macrophage component of the breast tumor microenvironment.
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- 2011
13. The PI3K inhibitor GDC-0941 is synergistic with lapatinib and mediates endocrine sensitivity in uterine papillary serous carcinoma via AKT
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Gary L. Goldberg, June YiJuan Hou, Yihong Wang, Alicia Rodriguez-Gabin, Kelly S. Levano, Mark H. Einstein, and Susan Band Horwitz
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Oncology ,business.industry ,Cancer research ,Obstetrics and Gynecology ,Endocrine system ,Medicine ,business ,Lapatinib ,Protein kinase B ,PI3K/AKT/mTOR pathway ,medicine.drug ,Papillary Serous Carcinoma - Published
- 2014
14. Exome sequencing identifies germline mutations involving novel single nucleotide polymorphisms within DNA repair pathway genes in uterine serous carcinoma
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Mark H. Einstein, Susan Band Horwitz, Marina Frimer, June YiJuan Hou, C. Ouyang, Gary L. Goldberg, J. Cai, Alicia Rodriguez-Gabin, Yihong Wang, and Kelly S. Levano
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Genetics ,business.industry ,Obstetrics and Gynecology ,Single-nucleotide polymorphism ,DNA Repair Pathway ,medicine.disease ,Uterine serous carcinoma ,Germline mutation ,Oncology ,medicine ,business ,Exome ,Gene ,Exome sequencing - Published
- 2014
15. Abstract 1692: Antibody-drug conjugates to target cell surface TACE-cleaved amphiregulin in breast cancer
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Paraic A. Kenny, Kelly S. Levano, Edmund C. Jenkins, Eric H. Jung, and Matthew Levy
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Cancer Research ,biology ,business.industry ,Cancer ,Estrogen receptor ,medicine.disease ,chemistry.chemical_compound ,Breast cancer ,Oncology ,Monomethyl auristatin E ,chemistry ,Amphiregulin ,Tumor progression ,Immunology ,medicine ,Cancer research ,biology.protein ,Epidermal growth factor receptor ,skin and connective tissue diseases ,business ,Tamoxifen ,medicine.drug - Abstract
Approximately 70% of breast cancer cases are Estrogen Receptor (ER) positive. In many cases, these patients are well-served by endocrine therapies such as tamoxifen and aromatase inhibitors, however the emergence of endocrine-resistant disease in up to 40% of these patients is a major clinical concern. This necessitates treatment with more toxic chemotherapies which are often successful at delaying tumor progression, but are not curative. Recent work from our group and others has demonstrated that Amphiregulin, an Epidermal Growth Factor Receptor (EGFR) ligand, is a critical effector of ER signaling in both normal development and breast cancer pathogenesis, and is expressed in both endocrine-sensitive and endocrine-resistant breast cancer. Like other EGFR ligands, Amphiregulin is proteolytically processed at the cell surface to release a soluble EGFR-binding signaling domain and a residual cell-associated stalk. In this project, we are developing antibodies that selectively recognize the residual transmembrane Amphiregulin cleavage product with the goal of developing antibody-drug conjugates with which to selectively target tumor cells with high levels of Amphiregulin shedding. We have generated six humanized antibodies that recognize the cell-associated neo-epitope revealed following the TACE-mediated proteolytic release of Amphiregulin. Using both flow Cytometry and immunofluorescence, we demonstrate that these antibodies selectively recognize cleaved over full-length Amphiregulin in estrogen receptor positive breast cancer cells. Conjugation of these antibodies with a pH-sensitive dye, pHrodo, demonstrates robust and rapid antibody internalization in live cells. Conjugation of these antibodies with monomethyl auristatin E results in the disruption of the microtubule network of breast cancer cells followed by cell death. We propose that these agents may have utility in the treatment of breast and other cancers in which Amphiregulin expression and processing play a prominent role. This study is supported by the Department of Defense Breast Cancer Research Program (W81XWH-14-1-0294). Citation Format: Edmund C. Jenkins, Kelly S. Levano, Eric H. Jung, Matthew Levy, Paraic A. Kenny. Antibody-drug conjugates to target cell surface TACE-cleaved amphiregulin in breast cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1692. doi:10.1158/1538-7445.AM2015-1692
- Published
- 2015
16. Abstract 4687: The PI3K inhibitor GDC-0941 is synergistic with lapatinib, and mediates endocrine sensitivity in uterine papillary serous carcinoma
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June Y. Hou, Gary L. Goldberg, Alicia Rodriguez-Gabin, Kelly S. Levano, and Susan Band Horwitz
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Cancer Research ,medicine.medical_specialty ,Fulvestrant ,Cell growth ,business.industry ,Cancer ,Lapatinib ,medicine.disease ,Endocrinology ,Oncology ,ErbB ,Internal medicine ,medicine ,Cancer research ,business ,Protein kinase B ,PI3K/AKT/mTOR pathway ,Laser capture microdissection ,medicine.drug - Abstract
Objectives: Our objective is to determine the effect of PI3K activity in mediating ligand-independent estrogen signaling and endocrine sensitivity in Uterine Papillary Serous Carcinoma (UPSC). Methods: Drug effect on cell proliferation was calculated via Calcusyn in patient-derived UPSC cell lines ARK 1 and 2. PI3K mutation was analyzed after laser capture microdissection of tumor DNA in 7 consecutive patients with UPSC. Protein expression, via Western Blot, was correlated prospectively with clinical parameters. Results: Table 1 shows cells line baseline characteristics and IC50 to drugs. Fulvestrant, an ER antagonist, rendered the cells significantly more resistant to taxol in ARK1 and 2(p=0.035, 0.021 respectively). The concomitant decrease in pERS167 and pAKTS473 with Fulvestrant treatment is independent of baseline ER expression and PI3K mutation. In ARK2, a cell line that is ER-, disrupting AKT signaling via the PI3K inhibitor GDC-0941, or with the lapatinib is synergistic with Fulvestrant with Combination Index (CI)50 of 0.441 and 0.229, respectively. Independent of HER2 amplification or PI3K mutation, lapatinib and GDC-0941 exhibited synergistic cytotoxicity in both UPSC cell lines (CI50 of 0.577, ARK 1 and 0.233, ARK2). Finally, PI3K mutation and pAKTS473 expression was analyzed in 7 tumor samples. While none harbored PI3K mutation, patients who are chemotherapy resistant had significantly lower expression of baseline pAKTS473 in their tumor samples than those who are chemosensitive, similar to our cell line data. Conclusions: PI3K pathway dysregulation, either via upstream erbB amplification, or downstream constitutive activation of AKT, may be important in mediating endocrine and taxol sensitivity in UPSC. pAKTS473 may be an important biomarker of drug sensitivity. The combination of PI3K inhibitor and lapatinib is synergistic and warrant further therapeutic investigation. Baseline characteristics and drug sensitivities in UPSC cell linesARK1ARK2PI3KCA mutationfExon 9NoERα (WB)YesNopERα167 (WB)YesNopHER (WB)NoYesIC50 nM (mean ± STD)GDC-094193.1±5.9271±116.5LapatinibNo effect135.6±29.2FulvestrantNo effectNo effectTaxol4.6±1.97.8±5.6Cisplatin1103±65.72632.6±1797.9 Citation Format: Kelly S. Levano, Alicia Rodriguez-Gabin, Gary L. Goldberg, Susan B. Horwitz, June Y. Hou. The PI3K inhibitor GDC-0941 is synergistic with lapatinib, and mediates endocrine sensitivity in uterine papillary serous carcinoma. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4687. doi:10.1158/1538-7445.AM2014-4687
- Published
- 2014
17. Abstract LB-343: Defining mechanisms of endocrine resistance in breast cancer using whole exome sequencing
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Paraic A. Kenny, Esther A. Peterson, Natasha Chandiramani, and Kelly S. Levano
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Cancer Research ,biology ,Fulvestrant ,Estrogen receptor ,Cancer ,medicine.disease ,Bioinformatics ,chemistry.chemical_compound ,Breast cancer ,Oncology ,Exemestane ,chemistry ,biology.protein ,medicine ,Cancer research ,Aromatase ,Exome sequencing ,Tamoxifen ,medicine.drug - Abstract
About 70% of breast cancers are estrogen receptor positive (ER+) and current treatments target either ER activity (Tamoxifen and Fulvestrant) or the production of estrogen (aromatase inhibitors). These treatments have led to significant increases in disease-free and overall survival, but after initial response to these agents, many ER+ cancers progress to endocrine resistance. There have been several attempts to understand the molecular mechanisms that lead to acquired resistance, but a clear understanding is still lacking. We hypothesize that endocrine resistant cells in the tumor arise by acquiring compensatory somatic mutations, and that some of these driver mutations responsible for resistance are in oncogenes or tumor suppressor genes. To test this we performed whole exome sequencing on three of MCF7 breast cancer cell sublines that are resistant to either tamoxifen, fulvestrant or exemestane - drugs commonly used in the clinic to treat ER+ breast cancers. An Illumina TruSEQ adaptor-based exonic library was prepared using genomic DNA from the resistant and control cell lines, and multiplexed on an Illumina HiSeq 2000 sequencer (100bp paired-end reads). Reads were aligned to human genome build 19 using BWA, variants were called using SAMTools, somatic mutations in endocrine cell lines were determined with VarScan, and amino acid changes were annotated using ANNOVAR. We have identified several non-synonymous mutations in cancer-relevant genes and are currently working to validate these targets. Studying these genes will increase our understanding of how tumors overcome the requirement for estrogen signaling and ultimately, we hope that comparing tumor profiles of patients with endocrine resistance disease will lead to therapeutics targeted to these secondary mutational lesions. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr LB-343. doi:1538-7445.AM2012-LB-343
- Published
- 2012
18. Rol de la farmacogenómica en el régimen de tratamiento de tuberculosis
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Heinner Guio, Kelly S Levano, Cesar Sánchez, and David Tarazona
- Subjects
farmacogenética ,mycobacterium tuberculosis ,variación genética ,Medicine ,Medicine (General) ,R5-920 - Abstract
La tuberculosis es un problema de salud Pública a nivel mundial con un tercio de la población infectada por el bacilo Mycobacterium tuberculosis. El tratamiento de primera línea incluye a las drogas isoniazida (INH) y rifampicina (RIF) metabolizadas en el hígado. La metabolización de drogas está directamente relacionada con la variación genética de NAT2 y CYP2E1 (asociados a metabolismo de INH) y AADAC (asociados a metabolismo de RIF), y los efectos pueden producir que un individuo sea metabolizador rápido, intermedio o lento. Los polimorfismos en genes de personas con tratamiento estándar de tuberculosis pueden ocasionar efectos en el metabolismo de drogas con consecuencias de hepatoxicidad e, incluso, posible drogorresistencia. Algunos países han empezado ensayos clínicos enfocados en la personalización del tratamiento a tuberculosis para reducir las consecuencias en pacientes en tratamiento. En países como el Perú, donde se registran altos índices de tuberculosis y, por consiguiente, más población en tratamiento, la farmacogenómica de individuos se convierte en una herramienta crucial para un óptimo tratamiento. La presente revisión destaca la importancia de tener estudios en farmacogenómica e identificar los polimorfismos asociados al metabolismo de las drogas antituberculosas en nuestra población peruana
19. Rol de la farmacogenómica en el régimen de tratamiento de tuberculosis
- Author
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Heinner Guio, Kelly S Levano, Cesar Sánchez, and David Tarazona
- Subjects
pharmacogenetics ,mycobacterium tuberculosis ,genetic variation ,Medicine ,Medicine (General) ,R5-920 - Abstract
La tuberculosis es un problema de salud Pública a nivel mundial con un tercio de la población infectada por el bacilo Mycobacterium tuberculosis. El tratamiento de primera línea incluye a las drogas isoniazida (INH) y rifampicina (RIF) metabolizadas en el hígado. La metabolización de drogas está directamente relacionada con la variación genética de NAT2 y CYP2E1 (asociados a metabolismo de INH) y AADAC (asociados a metabolismo de RIF), y los efectos pueden producir que un individuo sea metabolizador rápido, intermedio o lento. Los polimorfismos en genes de personas con tratamiento estándar de tuberculosis pueden ocasionar efectos en el metabolismo de drogas con consecuencias de hepatoxicidad e, incluso, posible drogorresistencia. Algunos países han empezado ensayos clínicos enfocados en la personalización del tratamiento a tuberculosis para reducir las consecuencias en pacientes en tratamiento. En países como el Perú, donde se registran altos índices de tuberculosis y, por consiguiente, más población en tratamiento, la farmacogenómica de individuos se convierte en una herramienta crucial para un óptimo tratamiento. La presente revisión destaca la importancia de tener estudios en farmacogenómica e identificar los polimorfismos asociados al metabolismo de las drogas antituberculosas en nuestra población peruana
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