Israel Tojal da Silva

AC Camargo Hospital

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Emmanuel Dias‐Neto

AC Camargo Hospital

Renan Valieris

AC Camargo Hospital

Diana Noronha Nunes

AC Camargo Hospital

Rodrigo D. Drummond

AC Camargo Hospital

Alexandre Defelicibus

AC Camargo Hospital

Rafael Rosales

Universidade de São Paulo

Thais Fernanda Bartelli

AC Camargo Hospital

María Galli de Amorim

Universidade Federal do Maranhão

Wilson A. Silva

Universidade de São Paulo

Giuseppe Palmisano

Universidade de São Paulo

Cooperative Institutions

Universidade de São Paulo

174

AC Camargo Hospital

136

Universidade Federal de São Paulo

Hospital São Paulo

Universidade de Ribeirão Preto

Universidade Estadual Paulista (Unesp)

Rockefeller University

Universidade Federal de Minas Gerais

Fundação Oswaldo Cruz

Clinics Hospital of Ribeirão Preto

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Epigenetic targeting of activation-induced cytidine deaminase

Proceedings of the National Academy of Sciences (2014)

Qiao Wang Thiago Y. Oliveira Mila Janković Israel Tojal da Silva Ofir Hakim

Significance Activation-induced cytidine deaminase (AID) is a DNA modifying enzyme crucial for the generation of efficacious antibodies. AID also promiscuously introduces DNA lesions at cancer genes, leading to their chromosome translocation and lymphoma. However, how AID is recruited to these off targets is not well understood. Here, we compare AID-induced translocations in two different cell types, B cells and mouse embryonic fibroblasts. By analyzing the sites where AID is active in a cell type-specific manner, we find that, in addition to transcriptional activity, AID recruitment is mediated by specific epigenetic features associated with active enhancers and transcription elongation. Understanding AID’s targeting mechanism is a fundamental question of immunology with implications for the biology of cancer.

Activation-induced (cytidine) deaminase

Cytidine

10.1073/pnas.1420575111

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Citations (51)

Author response: A Plasmodium falciparum MORC protein complex modulates epigenetic control of gene expression through interaction with heterochromatin

Maneesh Kumar Singh Victoria A. Bonnell Israel Tojal da Silva Verônica Feijoli Santiago Miriam S. Moraes

Heterochromatin protein 1

10.7554/elife.92201.2.sa2

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Citations (0)

A Multi-Learning Training Approach for Distinguishing Low and High Risk Cancer Patients

IEEE Access (2021)

Lucas Venezian Povoa Uriel Caire Balan Calvi Ana Carolina Lorena Carlos H. C. Ribeiro Israel Tojal da Silva

All cancers are caused by changes in the DNA within cells that occur over the course of an individual's lifetime. These mutations confer extensive genetic and phenotype variations within individuals, making the identification of appropriate treatments hard and costly. Moreover, cancer datasets are usually highly sparse due to the presence of few samples and many input features, making it difficult to design accurate predictors to classify patients into risk groups. Here, we report on the Multi Learning Training (MuLT) algorithm, which employs supervised, unsupervised, and self-supervised learning methods in order to take advantage of the interplay of clinical and molecular features for distinguishing low and high risk cancer patients. Our solution is evaluated using three independent and public cancer data sets considering three different performance aspects, through 5-fold cross-validation experiments. MuLT outranks other methods achieving AUCs between 0.65 and 0.77 and mean squared errors smaller than 0.24, while reducing classification complexity. These findings confirm the benefits of combining different learning algorithms and of coupling molecular and clinical data for supporting clinical decision making in Oncology.

10.1109/access.2021.3104820

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Citations (4)

In SituDESI-MSI Lipidomic Profiles of Breast Cancer Molecular Subtypes and Precursor Lesions

Cancer Research (2020)

Adriana Leandra Santoro Rodrigo D. Drummond Israel Tojal da Silva Severino S. Ferreira Luiz Juliano

Clinically meaningful molecular subtypes for classification of breast cancers have been established, however, initiation and progression of these subtypes remain poorly understood. The recent development of desorption electrospray ionization-mass spectrometry imaging (DESI-MSI) facilitates the convergence of analytical chemistry and traditional pathology, allowing chemical profiling with minimal tissue pretreatment in frozen samples. Here, we characterized the chemical composition of molecular subtypes of breast cancer with DESI-MSI. Regions of interest were identified, including invasive breast cancer (IBC), ductal carcinoma in situ (DCIS), and adjacent benign tissue (ABT), and metabolomic profiles at 200 μm elaborated using Biomap software and the Lasso method. Top ions identified in IBC regions included polyunsaturated fatty acids, deprotonated glycerophospholipids, and sphingolipids. Highly saturated lipids, as well as antioxidant molecules [taurine (m/z 124.0068), uric acid (m/z 167.0210), ascorbic acid (m/z 175.0241), and glutathione (m/z 306.0765)], were able to distinguish IBC from ABT. Moreover, luminal B and triple-negative subtypes showed more complex lipid profiles compared with luminal A and HER2 subtypes. DCIS and IBC were distinguished on the basis of cell signaling and apoptosis-related ions [fatty acids (341.2100 and 382.3736 m/z) and glycerophospholipids (PE (P-16:0/22:6, m/z 746.5099, and PS (38:3), m/z 812.5440)]. In summary, DESI-MSI identified distinct lipid composition between DCIS and IBC and across molecular subtypes of breast cancer, with potential implications for breast cancer pathogenesis. SIGNIFICANCE: These findings present the first in situ metabolomic findings of the four molecular subtypes of breast cancer, DCIS, and normal tissue, and add to the understanding of their pathogenesis.

Sphingolipid

10.1158/0008-5472.can-18-3574

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Citations (77)

Human endogenous retrovirus and multiple sclerosis: A review and transcriptome findings

Multiple Sclerosis and Related Disorders (2021)

Luiz Henrique da Silva Nali Guilherme Sciascia do Olival Horácio Montenegro Israel Tojal da Silva Emmanuel Dias‐Neto

Endogenous retrovirus

Pathogenesis

10.1016/j.msard.2021.103383

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Citations (19)

Influence of BRCA1 Germline Mutations in the Somatic Mutational Burden of Triple-Negative Breast Cancer

Translational Oncology (2019)

Elisa Napolitano Ferreira Rafael Canfield Brianese Renan Almeida Rodrigo D. Drummond Jorge Estefano de Souza

The majority of the hereditary triple-negative breast cancers (TNBCs) are associated with BRCA1 germline mutations. Nevertheless, the understanding of the role of BRCA1 deficiency in the TNBC tumorigenesis is poor. In this sense, we performed whole-exome sequencing of triplet samples (leucocyte, tumor, and normal-adjacent breast tissue) for 10 cases of early-onset TNBC, including 5 hereditary (with BRCA1 germline pathogenic mutation) and 5 sporadic (with no BRCA1 or BRCA2 germline pathogenic mutations), for assessing the somatic mutation repertoire. Protein-affecting somatic mutations were identified for both mammary tissues, and Ingenuity Pathway Analysis was used to investigate gene interactions. BRCA1 and RAD51C somatic promoter methylation in tumor samples was also investigated by bisulfite sequencing. Sporadic tumors had higher proportion of driver mutations (≥25% allele frequency) than BRCA1 hereditary tumors, whereas no difference was detected in the normal breast samples. Distinct gene networks were obtained from the driver genes in each group. The Cancer Genome Atlas data analysis of TNBC classified as hereditary and sporadic reinforced our findings. The data presented here indicate that in the absence of BRCA1 germline mutations, a higher number of driver mutations are required for tumor development and that different defective processes are operating in the tumorigenesis of hereditary and sporadic TNBC in young women.

Triple-negative breast cancer

10.1016/j.tranon.2019.07.016

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Citations (10)

APOBEC‐mediated DNA alterations: A possible new mechanism of carcinogenesis in EBV‐positive gastric cancer

International Journal of Cancer (2019)

Irina G. Bobrovnitchaia Renan Valieris Rodrigo D. Drummond João Paulo da Silveira Nogueira Lima H. Freitas

Mechanisms of viral oncogenesis are diverse and include the off-target activity of enzymes expressed by the infected cells, which evolved to target viral genomes for controlling their infection. Among these enzymes, the single-strand DNA editing capability of APOBECs represent a well-conserved viral infection response that can also cause untoward mutations in the host DNA. Here we show, after evaluating somatic single-nucleotide variations and transcriptome data in 240 gastric cancer samples, a positive correlation between APOBEC3s mRNA-expression and the APOBEC-mutation signature, both increased in EBV+ tumors. The correlation was reinforced by the observation of APOBEC mutations preferentially occurring in the genomic loci of the most active transcripts. This EBV infection and APOBEC3 mutation-signature axis were confirmed in a validation cohort of 112 gastric cancer patients. Our findings suggest that APOBEC3 upregulation in EBV+ cancer may boost the mutation load, providing further clues to the mechanisms of EBV-induced gastric carcinogenesis. After further validation, this EBV-APOBEC axis may prove to be a secondary driving force in the mutational evolution of EBV+ gastric tumors, whose consequences in terms of prognosis and treatment implications should be vetted.

APOBEC

10.1002/ijc.32411

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Citations (25)

Relating mutational signature exposures to clinical data in cancers via signeR 2.0

BMC Bioinformatics (2023)

Rodrigo D. Drummond Alexandre Defelicibus Mathilde Meyenberg Renan Valieris Emmanuel Dias‐Neto

Abstract Background Cancer is a collection of diseases caused by the deregulation of cell processes, which is triggered by somatic mutations. The search for patterns in somatic mutations, known as mutational signatures, is a growing field of study that has already become a useful tool in oncology. Several algorithms have been proposed to perform one or both the following two tasks: (1) de novo estimation of signatures and their exposures, (2) estimation of the exposures of each one of a set of pre-defined signatures. Results Our group developed signeR, a Bayesian approach to both of these tasks. Here we present a new version of the software, signeR 2.0, which extends the possibilities of previous analyses to explore the relation of signature exposures to other data of clinical relevance. signeR 2.0 includes a user-friendly interface developed using the R-Shiny framework and improvements in performance. This version allows the analysis of submitted data or public TCGA data, which is embedded in the package for easy access. Conclusion signeR 2.0 is a valuable tool to generate and explore exposure data, both from de novo or fitting analyses and is an open-source R package available through the Bioconductor project at ( https://doi.org/10.18129/B9.bioc.signeR ).

Signature (topology)

10.1186/s12859-023-05550-3

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Citations (1)

Circulating Soluble Factors and T-Cell Subsets as Immunological Predictors of Therapy Response in Human Cutaneous Leishmaniasis

The Journal of Infectious Diseases (2025)

Amanda Braga Figueiredo Kátia L.P. Morais Israel Tojal da Silva Liliana Maia Jaqueline Ramalho Buttura

Abstract Background Human cutaneous leishmaniasis, a neglected tropical disease caused by Leishmania braziliensis, presents treatment challenges due to varying therapeutic responses. Current therapies often encounter limited efficacy and treatment failure, demanding a deeper understanding of immunopathogenesis and predictive markers. Methods We explored the immunological determinants influencing therapy response in human cutaneous leishmaniasis, focusing on the intricate host–parasite immune interactions. We evaluated blood and lesions from the same individuals before therapeutic intervention and followed the patients for 60 days to determine treatment efficacy. We employed multiparameter flow cytometry methods for peripheral blood analysis of soluble factors and T-cell subpopulations, and RNA sequencing for analysis of lesion biopsies. Results Our investigation identified a combined set of circulating soluble factors as promising noninvasive predictive markers for treatment outcomes. Additionally, we reveal an association between circulating CD8+ mucosal-associated invariant T (MAIT) cells with increased lesion pathology, and a gene signature in lesions associated with CD8+ MAIT cells in refractory patients. Conclusions These findings highlight the potential for tailored interventions and novel immunomodulatory strategies to enhance treatment efficacy and address challenges in unresponsive cases of this debilitating disease.

10.1093/infdis/jiaf042

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Two novel pathogenic variants in MED13L: one familial and one isolated case

Journal of Intellectual Disability Research (2021)

Laura Machado Lara Carvalho Silvia Souza da Costa Francine Campagnari Arthur Kaufman Débora Romeo Bertola

Abstract Background Genetic variants involving the MED13L gene can lead to an autosomal dominant syndrome characterised by intellectual disability/developmental delay and facial dysmorphism. Methods We investigated two cases (one familial and one isolated) of intellectual disability with speech delay and dysmorphic facial features by whole‐exome sequencing analyses. Further, we performed a literature review about clinical and molecular aspects of MED13L gene and syndrome. Results Two MED13L variants have been identified [ MED13L (NM_015335.5):c.4417C>T and MED13L (NM_015335.5):c.2318delC] and were classified as pathogenic according to the ACMG (American College of Medical Genetics and Genomics) guidelines. One of the variants was present in sibs. Conclusions The two pathogenic variants identified have not been previously reported. Importantly, this is the first report of a familial case of MED13L nonsense mutation. Although the parents of the affected children were no longer available for analysis, their apparently normal phenotypes were surmised from familial verbal descriptions corresponding to normal mental behaviour and phenotype. In this situation, the familial component of mutation transmission might be caused by gonadal mosaicism of a MED13L mutation in a gonad from either the father or the mother. The case reports and the literature review presented in this manuscript can be useful for genetic counselling.

Medical genetics

Nonsense

Exome

10.1111/jir.12891

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Citations (8)