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Nuclear density analysis in microscopic images for the characterization of retinal geographic atrophy

2020 , Peralta Ildefonso, Martha Janneth , Moya-Albor, Ernesto , Brieva, Jorge , Lira, Esmeralda , Pérez Ortiz, Andric Christopher , Coral-Vázquez, Ramón , Estrada Mena, Francisco Javier

Age-related macular degeneration (AMD) is the leading cause of irreversible blindness in industrialized countries. It is estimated that AMD affects at least 1 in 10 Hispanics. Previous reports have shown that AMD has multiple risk factors. Recently, we demonstrated that some genetic variants in the SGCD gene are involved in AMD developments, especially in early-stage (geographic atrophy, GA). Therefore, to evaluate the relationship between SGCD's absence and the loss of photoreceptors in GA, we worked with a genetically modified mouse model, SGCD deficient (Sgcd-/-) and a control mouse C57BL/6J (Sgcd+/+). First, we obtained hematoxylin and eosin (H&E) retina staining microscopic images. Then, we coarsely selected the outer and inner nuclear retinal layer (ONL and INL respectively) and finally, we applied an automatic nuclei segmentation to calculate the nuclear density in each region. Our results showed that Sgcd absence does not result in photoreceptor loss, on the contrary, it promotes an increment in nuclear density by 8.7% in ONL and 20.1% in INL compared with control eyes (p = 0.0033 and p < 0.0001 respectively). This could be explained by the fact that SGCD codifies the delta-sarcoglycan protein and there is evidence that showed a relationship between the absence of this protein with the activation of a cell proliferation signaling pathway. Finally, our results show that the delta-sarcoglycan protein could play an important role in the pathogenesis of the geographic atrophy. Moreover, there are promising perspectives for the systematic approach applied for cell image analysis, as an important tool to determine the nuclear density for assessing the progression of AMD. ©COPYRIGHT SPIE. Downloading of the abstract is permitted for personal use only.

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Development of muscle atrophy and loss of function in a Gulf-War illness model: underlying mechanisms

2020 , Ramírez-Sánchez, Israel , Navarrete-Yañez, Viridiana , Garate-Carrillo, Alejandra , Loredo Mendoza, María Lilia , Lira, Esmeralda , Campeau, Anaamika , Estrada Mena, Francisco Javier , González, David , Carrillo-Terrazas, Marvic , Moreno-Ulloa, Aldo , Guillermo Ceballos , Villarreal, Francisco J.

Gulf War illness (GWI) afflicts military personnel who served during the Persian Gulf War and is notable for cognitive deficits, depression, muscle pain, weakness, intolerance to exercise, and fatigue. Suspect causal agents include the chemicals pyridostigmine (PB), permetrim (PM) and N,N-diethyl-m-toluamide (DEET) used as protectants against insects and nerve gases. No pre-clinical studies have explored the effects on skeletal muscle (SkM). Young male rats were provided PB, PM and DEET at equivalent human doses and physical restraint (to induce stress) for 3 weeks followed a 3-week recovery. GWI gastrocnemius weight was ~ 35% lower versus controls, which correlated with decreases in myofiber area, limb strength, and treadmill time/distance. In GWI rats, SkM fiber type relative abundance changed towards slow type I. Muscle wasting pathway proteins were upregulated while those that promote growth decreased as did mitochondrial endpoints and muscle ATP levels. Proteomic analysis of SkM also documented unique alterations in mitochondrial and metabolic pathways. Thus, exposure to GWI chemicals/stress adversely impacts key metabolic pathways leading to muscle atrophy and loss of function. These changes may account for GWI Veterans symptoms.

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A familial reciprocal translocation t(1;15) in three generations identified in a regular trisomy 21 patient

2010 , García-Delgado, C. , Bahena-Martínez, E. , Aparicio-Onofre, A. , Guevara-Yañez, R. , Cervantes-Peredo, A. , Azotla-Vilchis, O. C. , Estrada Mena, Francisco Javier , Luna-Angulo, Alexandra , Villa-Morales, J. , Morrán-Barroso, V. F.

The concurrence of a reciprocal translocation and an aneuploidy represent a rare coincidence and an interchromosome effect between these two events has been suggested. We report the case of a family with a t(1;15) in three generations which was identified through the evaluation ofa patient with classical trisomy 21 or Down syndrome. The cytogenetic analysis with GTG banding showed that the proband had a regular trisomy 21 and a balanced translocation t(1;15). FISH and microsatellite analysis were carried out in the family in order to discard an interchromosomal effect. The implications for genetic assessment are discussed. © Genetic Counseling

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Pharmacogenetics of taxane‐induced neurotoxicity in breast cancer: Systematic review and meta‐analysis

2022 , Guijosa, Alberto , Freyria, Ana , Espinosa‐Fernández, José Rodrigo , Estrada Mena, Francisco Javier , Antonio‐Aguirre, Bani , Armenta‐Quiroga, Ana Sofía , Ortega‐Treviño, María Fernanda , Catalán, Rodrigo , Villarreal-Garza, Cynthia , Pérez Ortiz, Andric Christopher

Taxane-based chemotherapy regimens are used as first-line treatment for breast cancer. Neurotoxicity, mainly taxane-induced peripheral neuropathy (TIPN), remains the most important dose-limiting adverse event. Multiple genes may be associated with TIPN; however, the strength and direction of the association remain unclear. For this reason, we systematically reviewed observational studies of TIPN pharmacogenetic markers in breast cancer treatment. We conducted a systematic search of terms alluding to breast cancer, genetic markers, taxanes, and neurotoxicity in Ovid, ProQuest, PubMed, Scopus, Virtual Health, and Web of Science. We assessed the quality of evidence and bias profile. We extracted relevant variables and effect measures. Whenever possible, we performed random-effects gene meta-analyses and examined interstudy heterogeneity with meta-regression models and subgroup analyses. This study follows the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) and STrengthening the REporting of Genetic Association Studies (STREGA) reporting guidance. A total of 42 studies with 19,431 participants were included. These evaluated 262 single-nucleotide polymorphisms (SNPs) across 121 genes. We conducted meta-analyses on 23 genes with 60 SNPs (19 studies and 6246 participants). Thirteen individual SNPs (ABCB1-rs2032582, ABCB1-rs3213619, BCL6/-rs1903216, /CAND1-rs17781082, CYP1B1-rs1056836, CYP2C8-rs10509681, CYP2C8-rs11572080, EPHA5-rs7349683, EPHA6-rs301927, FZD3-rs7001034, GSTP1-rs1138272, TUBB2A-rs9501929, and XKR4-rs4737264) and the overall SNPs' effect in four genes (CYP3A4, EphA5, GSTP1, and SLCO1B1) were statistically significantly associated with TIPN through meta-analysis. In conclusion, through systematic review and meta-analysis, we found that polymorphisms, and particularly 13 SNPs, are associated with TIPN, suggesting that genetics does play a role in interindividual predisposition. Further studies could potentially use these findings to develop individual risk profiles and guide decision making.

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Pharmacogenetics of response to neoadjuvant paclitaxel treatment for locally advanced breast cancer

2017 , Pérez Ortiz, Andric Christopher , Ramírez, Israel , Cruz-López, Juan C. , Villarreal-Garza, Cynthia , Luna-Angulo, Alexandra , Lira, Esmeralda , Díaz-Chávez, José , Jiménez-Chaidez, Salvador , Matus-Santos, Juan A. , Sánchez-Chapul, Laura , Mendoza-Lorenzo, Patricia , Estrada Mena, Francisco Javier

Locally advanced breast cancer (LABC) cases have a varying five-year survival rate, mainly influenced by the tumor response to chemotherapy. Paclitaxel activity (response rate) varies across populations from 21.5% to 84%. There are some reports on genetic traits and paclitaxel; however, there is still considerable residual unexplained variability. In this study, we aimed to test the association between eleven novel markers and tumor response to paclitaxel and to explore if any of them influenced tumor protein expression. We studied a cohort of 140 women with LABC. At baseline, we collected a blood sample (for genotyping), fine needle aspirates (for Western blot), and tumor measurements by imaging. After follow-up, we ascertained the response to paclitaxel monotherapy by comparing the percent change in the pre-, post- tumor measurements after treatment. To allocate exposure, we genotyped eleven SNPs with TaqMan probes on RT-PCR and regressed them to tumor response using linear modeling. In addition, we compared protein expression, between breast tumors and healthy controls, of those genes whose genetic markers were significantly associated with tumor response. After adjusting for multiple clinical covariates, SNPs on the LPHN2, ROBO1, SNTG1, and GRIK1 genes were significant independent predictors of poor tumor response (tumor growth) despite paclitaxel treatment. Moreover, proteins encoded by those genes are significantly downregulated in breast tumor samples.

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The Relevance of Cataract as a Risk Factor for Age-Related Macular Degeneration: A Machine Learning Approach

2019 , Martínez Velasco, Antonieta Teodora , Martinez-Villaseñor, Lourdes , Miralles-Pechuán, Luis , Pérez Ortiz, Andric Christopher , Zenteno, Juan Carlos , Estrada Mena, Francisco Javier

Age-related macular degeneration (AMD) is the leading cause of visual dysfunction and irreversible blindness in developed countries and a rising cause in underdeveloped countries. There is a current debate on whether or not cataracts are significant risk factors for AMD development. In particular, research regarding this association is so far inconclusive. For this reason, we aimed to employ here a machine-learning approach to analyze the relevance and importance of cataracts as a risk factor for AMD in a large cohort of Hispanics from Mexico. We conducted a nested case control study of 119 cataract cases and 137 healthy unmatched controls focusing on clinical data from electronic medical records. Additionally, we studied two single nucleotide polymorphisms in the CFH gene previously associated with the disease in various populations as positive control for our method. We next determined the most relevant variables and found the bivariate association between cataracts and AMD. Later, we used supervised machine-learning methods to replicate these findings without bias. To improve the interpretability, we detected the five most relevant features and displayed them using a bar graph and a rule-based tree. Our findings suggest that bilateral cataracts are not a significant risk factor for AMD development among Hispanics from Mexico. © 2019 by the authors.

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Novel genome-wide associations for age-related macular degeneration in the sarcoglycan-sarcospan protein complex

2020 , Asaf Calderon, Andrea Michelle , Dewan, Andrew , Ramírez, Israel , Zepeda-Palacio, Claudia , Palacio, Claudia , Antonio-Aguirre, Bani , Mendoza Velásquez, Cristina , Camacho-Ordóñez, Azyadeh , Estrada Mena, Francisco Javier , Pérez Ortiz, Andric Christopher

Purpose : Since the advent of genomic approaches, many chromosomal regions and polymorphisms have been associated with age-related macular degeneration (AMD). However, most of the disease variability might not be still captured by current researched genetic markers due to power issues. We have evidence that at least one component of the sarcoglycan-sarcospan protein complex (Sg-Sspn) gene is associated with increased odds of geographic atrophy (GA) AMD. Moreover, the retina of the knocked-out mouse model for the Sg-Sspn phenotypically resembles GA. Here, we aimed to explore the genome-wide association of the Sg-Sspn complex gene regions with AMD.

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Neurological Restorative Effects of (-)-Epicatechin in a Model of Gulf War Illness

2024 , Ramirez-Sanchez, Israel , Navarrete-Yañez, Viridiana , Espinosa-Raya, Judith , Rubio-Gayosso, Ivan , Palma-Flores, Carlos , Mendoza-Lorenzo, Patricia , Ordoñez-Razo, Rosa , Estrada Mena, Francisco Javier , Ceballos, Guillermo , Villarreal, Francisco

Gulf War Illness (GWI) afflicts US military personnel who served in the Persian Gulf War. Suspect causal agents include exposure to pyridostigmine (PB), permethrin (PM) and N,N-diethyl-m-toluamide (DEET). Prominent symptoms include cognitive deficits, such as memory impairment. In aging animal models, we have documented the beneficial effect of the flavanol (-)-epicatechin (Epi) on hippocampus structure and related function. Using a rat model of GWI, we examined the effects of Epi on hippocampus inflammation, oxidative stress, mitochondrial dysfunction, cell death/survival pathways, and memory endpoints. Male Wistar rats underwent 3 weeks of exposure to either vehicles or DEET, PM, PB, and stress. Subgroups of GWI rats were then allocated to receive orally 15 days of either water (vehicle) or 1 mg/kg/day of Epi treatment. Object recognition tasks were performed to assess memory. Hippocampus samples were analyzed. Epi treatment yields significant improvements in short- and long-term memory versus GWI rats. Hippocampus oxidative stress and pro-inflammatory cytokine levels showed significant increases with GWI that were largely normalized with Epi becoming comparable to controls. Significant increases in markers of hippocampus neuroinflammation and cell death were noted with GWI and were also largely reduced with Epi. Neuronal survival signaling pathways were adversely impacted by GWI and were partially or fully restored by Epi. Markers of mitochondrial function were adversely impacted by GWI and were fully restored by Epi. In conclusion, in an animal model of GWI, Epi beneficially impacts recognized markers of hippocampus neuroinflammation, oxidative stress, cell survival, neurotoxicity and mitochondrial function leading to improved memory. ©The authors ©Journal of Medicinal Food ©Mary Ann Liebert.

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The sarcoglycan–sarcospan complex localization in mouse retina is independent from dystrophins

2005 , Fort, Patrice , Estrada Mena, Francisco Javier , Bordais, Agnès , Mornet, Dominique , Sahel, Jose-Alain , Picaud, Serge , Rosas Vargas, Haydeé , Coral-Vázquez, Ramón , Rendon, Álvaro

The sarcoglycan–sarcospan (SG–SSPN) complex is part of the dystrophin–glycoprotein complex that has been extensively characterized in muscle. To establish the framework for functional studies of sarcoglycans in retina here, we quantified sarcoglycans mRNA levels with real-time reverse transcriptase-polymerase chain reaction (RT-PCR) and performed immunohistochemistry to determine their cellular and subcellular distribution. We showed that the β-, δ-, γ-, ɛ-sarcoglycans and sarcospan are expressed in mouse retina. They are localized predominantly in the outer and the inner limiting membranes, probably in the Müller cells and also in the ganglion cells axons where the expression of dystrophins have never been reported. We also investigated the status of the sarcoglycans in the retina of mdx3cv mutant mice for all Duchene Muscular Dystrophy (DMD) gene products. The absence of dystrophin did not produce any change in the sarcoglycan–sarcospan components expression and distribution.

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Genetic analysis of Mexican Criollo cattle populations

2008 , Ulloa-Arvizu, Raúl , Gayosso-Vázquez, A. , Ramos Kuri, Manuel , Montaño, M. , Estrada Mena, Francisco Javier , Alonso, R. A.

The objective of this study was to evaluate the genetic structure of Mexican Criollo cattle populations using microsatellite genetic markers. DNA samples were collected from 168 animals from four Mexican Criollo cattle populations, geographically isolated in remote areas of Sierra Madre Occidental (West Highlands). Also were included samples from two breeds with Iberian origin: the fighting bull (n = 24) and the milking central American Criollo (n = 24) and one Asiatic breed: Guzerat (n = 32). Genetic analysis consisted of the estimation of the genetic diversity in each population by the allele number and the average expected heterozygosity found in nine microsatellite loci. Furthermore, genetic relationships among the populations were defined by their genetic distances. Our data shows that Mexican cattle populations have a relatively high level of genetic diversity based either on the mean number of alleles (10.2–13.6) and on the expected heterozygosity (0.71–0.85). The degree of observed homozygosity within the Criollo populations was remarkable and probably caused by inbreeding (reduced effective population size) possibly due to reproductive structure within populations. Our data shows that considerable genetic differentiation has been occurred among the Criollo cattle populations in different regions of Mexico.