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Case Report: CYLD cutaneous syndrome with malignant transformation to spiradenocarcinoma: cooperative effects of CYLD truncation and an MSH2 clamp-domain variant in an Ecuadorian patient
(Frontiers Media SA, 2026-02-18)
Carlos Reyes-Silva
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Gabriela Jaramillo-Koupermann
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Maritza Quishpe
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Rosa Pacheco
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Skehirly Burgos-Tapia
Background: CYLD cutaneous syndrome (CCS) is a rare autosomal dominant disorder caused by germline CYLD variants and characterized by multiple skin adnexal tumors. Malignant transformation is uncommon, and cooperative genetic events remain poorly defined, particularly in underrepresented populations. Case presentation: We report a 61-year-old Ecuadorian woman with multiple scalp cylindromas and spiradenomas, including one spiradenocarcinoma. Family history was notable for malignancies in first- and second-degree relatives. Whole-exome sequencing identified a heterozygous nonsense CYLD variant (c.1207C > T; p.Gln403Ter), classified as likely pathogenic, and a homozygous missense MSH2 variant (c.1609A > G; p.Lys537Glu) of uncertain significance. Histopathology confirmed malignant transformation, while immunohistochemistry showed preserved MSH2 expression with a microsatellite-stable phenotype. Nevertheless, a functional impact of the MSH2 variant cannot be excluded. Consistent with these observations, in silico modeling demonstrated that CYLD truncation eliminates the catalytic USP domain and regulatory motifs, abolishing deubiquitinase activity, whereas the MSH2 substitution affects a conserved residue in the clamp domain, likely destabilizing the MSH2–MSH6 complex despite intact nuclear localization. Conclusion: This is the first genetically confirmed case of CCS in Ecuador and among the few reported in South America. Beyond expanding the geographic spectrum, our findings highlight the value of integrating genomic and protein analyses to uncover cooperative mechanisms of malignant progression. Such integrative genomic approaches refine diagnosis, enhance genotype–phenotype interpretation, and deepen understanding of malignant transformation in CCS, particularly in underrepresented populations.
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Gut Microbiota Disruption in Hematologic Cancer Therapy: Molecular Insights and Implications for Treatment Efficacy
(MDPI AG, 2024-09-24)
GUEVARA RAMIREZ, ALEXANDRA PATRICIA
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CADENA ULLAURI, SANTIAGO ANDRE
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PAZ CRUZ, ELUIS ANDRES
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RUIZ POZO, VIVIANA ALEJANDRA
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TAMAYO TRUJILLO, VICTOR RAFAEL
Hematologic malignancies (HMs), including leukemia, lymphoma, and multiple myeloma, involve the uncontrolled proliferation of abnormal blood cells, posing significant clinical challenges due to their heterogeneity and varied treatment responses. Despite recent advancements in therapies that have improved survival rates, particularly in chronic lymphocytic leukemia and acute lymphoblastic leukemia, treatments like chemotherapy and stem cell transplantation often disrupt gut microbiota, which can negatively impact treatment outcomes and increase infection risks. This review explores the complex, bidirectional interactions between gut microbiota and cancer treatments in patients with HMs. Gut microbiota can influence drug metabolism through mechanisms such as the production of enzymes like bacterial β-glucuronidases, which can alter drug efficacy and toxicity. Moreover, microbial metabolites like short-chain fatty acids can modulate the host immune response, enhancing treatment effectiveness. However, therapy often reduces the diversity of beneficial bacteria, such as Bifidobacterium and Faecalibacterium, while increasing pathogenic bacteria like Enterococcus and Escherichia coli. These findings highlight the critical need to preserve microbiota diversity during treatment. Future research should focus on personalized microbiome-based therapies, including probiotics, prebiotics, and fecal microbiota transplantation, to improve outcomes and quality of life for patients with hematologic malignancies.
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Gene Prioritization through Consensus Strategy, Enrichment Methodologies Analysis, and Networking for Osteosarcoma Pathogenesis
(MDPI AG, 2020-02-05)
Alejandro Cabrera-Andrade
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Andrés López-Cortés
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Gabriela Jaramillo-Koupermann
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PAZ Y MIÑO CEPEDA, CESAR ANTONIO
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Yunierkis Pérez-Castillo
<jats:p>Osteosarcoma is the most common subtype of primary bone cancer, affecting mostly adolescents. In recent years, several studies have focused on elucidating the molecular mechanisms of this sarcoma; however, its molecular etiology has still not been determined with precision. Therefore, we applied a consensus strategy with the use of several bioinformatics tools to prioritize genes involved in its pathogenesis. Subsequently, we assessed the physical interactions of the previously selected genes and applied a communality analysis to this protein–protein interaction network. The consensus strategy prioritized a total list of 553 genes. Our enrichment analysis validates several studies that describe the signaling pathways PI3K/AKT and MAPK/ERK as pathogenic. The gene ontology described TP53 as a principal signal transducer that chiefly mediates processes associated with cell cycle and DNA damage response It is interesting to note that the communality analysis clusters several members involved in metastasis events, such as MMP2 and MMP9, and genes associated with DNA repair complexes, like ATM, ATR, CHEK1, and RAD51. In this study, we have identified well-known pathogenic genes for osteosarcoma and prioritized genes that need to be further explored.</jats:p>
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A Multi-Objective Approach for Anti-Osteosarcoma Cancer Agents Discovery through Drug Repurposing
(MDPI AG, 2020-11-22)
Alejandro Cabrera-Andrade
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Andrés López-Cortés
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Gabriela Jaramillo-Koupermann
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Humberto González-Díaz
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Alejandro Pazos
<jats:p>Osteosarcoma is the most common type of primary malignant bone tumor. Although nowadays 5-year survival rates can reach up to 60–70%, acute complications and late effects of osteosarcoma therapy are two of the limiting factors in treatments. We developed a multi-objective algorithm for the repurposing of new anti-osteosarcoma drugs, based on the modeling of molecules with described activity for HOS, MG63, SAOS2, and U2OS cell lines in the ChEMBL database. Several predictive models were obtained for each cell line and those with accuracy greater than 0.8 were integrated into a desirability function for the final multi-objective model. An exhaustive exploration of model combinations was carried out to obtain the best multi-objective model in virtual screening. For the top 1% of the screened list, the final model showed a BEDROC = 0.562, EF = 27.6, and AUC = 0.653. The repositioning was performed on 2218 molecules described in DrugBank. Within the top-ranked drugs, we found: temsirolimus, paclitaxel, sirolimus, everolimus, and cabazitaxel, which are antineoplastic drugs described in clinical trials for cancer in general. Interestingly, we found several broad-spectrum antibiotics and antiretroviral agents. This powerful model predicts several drugs that should be studied in depth to find new chemotherapy regimens and to propose new strategies for osteosarcoma treatment.</jats:p>
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Prediction of breast cancer proteins involved in immunotherapy, metastasis, and RNA-binding using molecular descriptors and artificial neural networks
(Springer Science and Business Media LLC, 2020-05-22)
Andrés López-Cortés
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Alejandro Cabrera-Andrade
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José M. Vázquez-Naya
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Alejandro Pazos
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Humberto González-Díaz
<jats:title>Abstract</jats:title><jats:p>Breast cancer (BC) is a heterogeneous disease where genomic alterations, protein expression deregulation, signaling pathway alterations, hormone disruption, ethnicity and environmental determinants are involved. Due to the complexity of BC, the prediction of proteins involved in this disease is a trending topic in drug design. This work is proposing accurate prediction classifier for BC proteins using six sets of protein sequence descriptors and 13 machine-learning methods. After using a univariate feature selection for the mix of five descriptor families, the best classifier was obtained using multilayer perceptron method (artificial neural network) and 300 features. The performance of the model is demonstrated by the area under the receiver operating characteristics (AUROC) of 0.980 ± 0.0037, and accuracy of 0.936 ± 0.0056 (3-fold cross-validation). Regarding the prediction of 4,504 cancer-associated proteins using this model, the best ranked cancer immunotherapy proteins related to BC were RPS27, SUPT4H1, CLPSL2, POLR2K, RPL38, AKT3, CDK3, RPS20, RASL11A and UBTD1; the best ranked metastasis driver proteins related to BC were S100A9, DDA1, TXN, PRNP, RPS27, S100A14, S100A7, MAPK1, AGR3 and NDUFA13; and the best ranked RNA-binding proteins related to BC were S100A9, TXN, RPS27L, RPS27, RPS27A, RPL38, MRPL54, PPAN, RPS20 and CSRP1. This powerful model predicts several BC-related proteins that should be deeply studied to find new biomarkers and better therapeutic targets. Scripts can be downloaded at<jats:ext-link xmlns:xlink="http://www.w3.org/1999/xlink" ext-link-type="uri" xlink:href="https://github.com/muntisa/neural-networks-for-breast-cancer-proteins">https://github.com/muntisa/neural-networks-for-breast-cancer-proteins</jats:ext-link>.</jats:p>
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Perturbation-Theory Machine Learning (PTML) Multilabel Model of the ChEMBL Dataset of Preclinical Assays for Antisarcoma Compounds
(American Chemical Society (ACS), 2020-10-15)
Alejandro Cabrera-Andrade
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Andrés López-Cortés
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Cristian R. Munteanu
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Alejandro Pazos
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Yunierkis Pérez-Castillo
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15q Duplication Syndrome: Report on the First Patient from Ecuador with an Unusual Clinical Presentation
(Hindawi Limited, 2021-05-03)
Esteban Ortiz Prado
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Ana Lucía Iturralde
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Katherine Simbaña-Rivera
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Lenin Gómez-Barreno
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Iván Hidalgo
<jats:p>Background. The 15q11.1-13.1 duplication, also known as Dup15q syndrome, is a rare congenital disease affecting 1 in 30,000 to 1 in 60,000 children worldwide. This condition is characterized by the presence of at least one extra copy of genetical material within the Prader-Willi/Angelman Critical Region (PWACR) of the referred 15q11.2-q13.1 chromosome. Case Report. Our study presents the clinical and genetical features of the first patient with a denovo 15q11.2 interstitial duplication on the maternal allele (inv Dup15q) that mimics a milder Prader-Willi syndrome probably due to an atypical disruption of the SNHG14 gene. Methylation-specific MLPA analysis has confirmed the presence of a very unlikely duplication that lies between breakpoint 1 (BP1) and the middle of BP2 and BP3 (BP3). This atypical alteration might be linked to the milder patient’s clinical phenotype. Conclusions. This is the first Dup15q patient reported in Ecuador and of the very few in South America. This aberration has never been described in a patient with Dup15q, and the unusual clinical presentation is probably due to the atypical distal breakpoint occurring within the gene SNHG14 which lies between BP2 and BP3 and does not therefore contain the whole PWACR. If the duplication disrupted the gene, then it is possible that it is the cause of, or contributing to, the patient’s clinical phenotype.</jats:p>
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Drugs Repurposing Using QSAR, Docking and Molecular Dynamics for Possible Inhibitors of the SARS-CoV-2 Mpro Protease
(MDPI AG, 2020-11-06)
Eduardo Tejera
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Cristian R. Munteanu
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Andrés López-Cortés
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Alejandro Cabrera-Andrade
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Yunierkis Pérez-Castillo
<jats:p>Wuhan, China was the epicenter of the first zoonotic transmission of the severe acute respiratory syndrome coronavirus clade 2 (SARS-CoV-2) in December 2019 and it is the causative agent of the novel human coronavirus disease 2019 (COVID-19). Almost from the beginning of the COVID-19 outbreak several attempts were made to predict possible drugs capable of inhibiting the virus replication. In the present work a drug repurposing study is performed to identify potential SARS-CoV-2 protease inhibitors. We created a Quantitative Structure–Activity Relationship (QSAR) model based on a machine learning strategy using hundreds of inhibitor molecules of the main protease (Mpro) of the SARS-CoV coronavirus. The QSAR model was used for virtual screening of a large list of drugs from the DrugBank database. The best 20 candidates were then evaluated in-silico against the Mpro of SARS-CoV-2 by using docking and molecular dynamics analyses. Docking was done by using the Gold software, and the free energies of binding were predicted with the MM-PBSA method as implemented in AMBER. Our results indicate that levothyroxine, amobarbital and ABP-700 are the best potential inhibitors of the SARS-CoV-2 virus through their binding to the Mpro enzyme. Five other compounds showed also a negative but small free energy of binding: nikethamide, nifurtimox, rebimastat, apomine and rebastinib.</jats:p>
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OncoOmics approaches to reveal essential genes in breast cancer: a panoramic view from pathogenesis to precision medicine
(Springer Science and Business Media LLC, 2020-03-24)
Andrés López-Cortés
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PAZ Y MIÑO CEPEDA, CESAR ANTONIO
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Santiago Guerrero
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Alejandro Cabrera-Andrade
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Stephen J. Barigye
<jats:title>Abstract</jats:title><jats:p>Breast cancer (BC) is the leading cause of cancer-related death among women and the most commonly diagnosed cancer worldwide. Although in recent years large-scale efforts have focused on identifying new therapeutic targets, a better understanding of BC molecular processes is required. Here we focused on elucidating the molecular hallmarks of BC heterogeneity and the oncogenic mutations involved in precision medicine that remains poorly defined. To fill this gap, we established an OncoOmics strategy that consists of analyzing genomic alterations, signaling pathways, protein-protein interactome network, protein expression, dependency maps in cell lines and patient-derived xenografts in 230 previously prioritized genes to reveal essential genes in breast cancer. As results, the OncoOmics BC essential genes were rationally filtered to 140. mRNA up-regulation was the most prevalent genomic alteration. The most altered signaling pathways were associated with basal-like and Her2-enriched molecular subtypes. <jats:italic>RAC1</jats:italic>, <jats:italic>AKT1</jats:italic>, <jats:italic>CCND1</jats:italic>, <jats:italic>PIK3CA</jats:italic>, <jats:italic>ERBB2</jats:italic>, <jats:italic>CDH1</jats:italic>, <jats:italic>MAPK14</jats:italic>, <jats:italic>TP53</jats:italic>, <jats:italic>MAPK1</jats:italic>, <jats:italic>SRC</jats:italic>, <jats:italic>RAC3</jats:italic>, <jats:italic>BCL2</jats:italic>, <jats:italic>CTNNB1</jats:italic>, <jats:italic>EGFR</jats:italic>, <jats:italic>CDK2</jats:italic>, <jats:italic>GRB2</jats:italic>, <jats:italic>MED1</jats:italic> and <jats:italic>GATA3</jats:italic> were essential genes in at least three OncoOmics approaches. Drugs with the highest amount of clinical trials in phases 3 and 4 were paclitaxel, docetaxel, trastuzumab, tamoxifen and doxorubicin. Lastly, we collected ~3,500 somatic and germline oncogenic variants associated with 50 essential genes, which in turn had therapeutic connectivity with 73 drugs. In conclusion, the OncoOmics strategy reveals essential genes capable of accelerating the development of targeted therapies for precision oncology.</jats:p>
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INFECTION DYNAMICS OF BATRACHOCHYTRIUM DENDROBATIDIS IN TWO FROG SPECIES INHABITING QUITO'S METROPOLITAN GUANGÜILTAGUA PARK, ECUADOR
(Wildlife Disease Association, 2021-10-11)
David A. Narváez-Narváez
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Alejandro Cabrera-Andrade
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Andrés Merino-Viteri
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PAZ Y MIÑO CEPEDA, CESAR ANTONIO
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Germán Burgos

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