OncoOmics approaches to reveal essential genes in breast cancer: a panoramic view from pathogenesis to precision medicine

[Abstract] 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. RAC1, AKT1, CCND1, PIK3CA, ERBB2, CDH1, MAPK14, TP53, MAPK1, SRC, RAC3, BCL2, CTNNB1, EGFR, CDK2, GRB2, MED1 and GATA3 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.Instituto de Salud Carlos III; PI17/0182

Perspectives on the use and risk of adverse events associated with cytokine-storm targeting antibodies and challenges associated with development of novel monoclonal antibodies for the treatment of COVID-19 clinical cases

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the causative agent of the novel coronavirus disease 2019 (COVID-19) pandemic that lacks globally accessible effective antivirals or extensively available vaccines. Numerous clinical trials are exploring the applicability of repurposed monoclonal antibodies (mAbs) targeting cytokines that cause adverse COVID-19-related pathologies, and novel mAbs directly targeting SARS-CoV-2. However, comorbidities and the incidence of cytokine storm (CS)-associated pathological complexities in some COVID-19 patients may limit the clinical use of these drugs. Additionally, CS-targeting mAbs have the potential to cause adverse events that restrict their applicability in patients with comorbidities. Novel mAbs targeting SARS-CoV-2 require pharmacological and toxicological characterization before a marketable product becomes available. The affordability of novel mAbs across the global economic spectrum may seriously limit their accessibility. This review presents a perspective on antibody-based research efforts and their limitations for COVID-19

Identificación de antígenos IgG2 específicos en tres cepas mexicanas de Anaplasma marginale

In order to identify Anaplasma marginale antigens associated with protection, susceptible animals were inoculated on three occasions with inactivated Mex-17 A. marginale initial bodies mixed with saponin or an oil-based adjuvant. Animals were challenge inoculated with strain Mex-30 on d 164. With the exception of two animals which died at challenge, all other immunized animals showed minimum clinical signs compared with control animals. At ELISA, positive antibody titers were observed in immunized whereas no titers were detected in controls. In vitro proliferation indexes (PI) for mononuclear cells cultured in the presence of extracts of the three strains were positive (³2.0) for all immunized bovines, whereas all both vaccinated an control animals developed PI after challenge inoculation. Western blot (WB) analysis of vaccinates sera showed recognition of antigens in a range between 15 to 209 kDa, of which eleven were specifically recognized by IgG2 in Mex-17 and Mex-30 strains. Additionally, a 52 kDa protein was observed in the Mex-15 extract by the sera of immunized and protected bovines. Two- dimension WB analysis of Mex-17 showed an additional 37 kDa protein that co-migrated with a band of similar molecular weight of MSP-2. Our results indicate that these eleven IgG2 specific proteins are associated with an immunoprotective response induced by vaccination. Four of these proteins correspond to previously characterized major-surface proteins and seven are novel antigens previously unreported for their immunoprotective properties.Con objeto de identificar antígenos de Anaplasma marginale asociados a la protección, animales susceptibles se vacunaron tres veces con cuerpos iniciales de la cepa Méx-17, mezclados con saponina o un adyuvante oleoso, y desafiados 164 días después de la primera inmunización con la cepa Méx-30. Los bovinos inmunizados mostraron cambios mínimos de los parámetros clínicos en comparación con los testigos. Al Elisa, los sueros de los bovinos inmunizados mostraron valores positivos y ninguna respuesta para los testigos. Los índices de estimulación (IE) (= == ==2.0) para células mononucleares de sangre periférica cultivadas en presencia de extractos de cada una de las tres cepas de A. marginale fueron positivos sólo en los bovinos inmunizados, al desafío, los IE para los bovinos inmunizados y testigos también fueron positivos. Al inmunoblot, se reconocieron proteínas de entre 15 a 209 kDa de las cuales, 11 fueron específicamente reconocidas por IgG2 en la cepas Méx-17 y Méx-30 y adicionalmente una proteína de 52 kDa en Méx-15 sólo por los sueros de los bovinos inmunizados y protegidos. El inmunoblot de dos dimensiones de la cepa Méx-17 mostró una proteína adicional de 37 kDa que co-migraba con una proteína que corresponde a MSP-2. Los resultados indican que estas 11 proteínas específicamente reconocidas por IgG2 de animales protegidos, participaron en la respuesta protectora, cuatro de éstas corresponden a las MSPs ya caracterizadas, y siete son nuevos antígenos nunca antes publicados por sus propiedades inmunoprotectoras