Publications by authors named "Victor Andrade"

68 Publications

Common variants in Alzheimer's disease and risk stratification by polygenic risk scores.

Nat Commun 2021 06 7;12(1):3417. Epub 2021 Jun 7.

Servei de Neurologia, Hospital Universitari i Politècnic La Fe, Valencia, Spain.

Genetic discoveries of Alzheimer's disease are the drivers of our understanding, and together with polygenetic risk stratification can contribute towards planning of feasible and efficient preventive and curative clinical trials. We first perform a large genetic association study by merging all available case-control datasets and by-proxy study results (discovery n = 409,435 and validation size n = 58,190). Here, we add six variants associated with Alzheimer's disease risk (near APP, CHRNE, PRKD3/NDUFAF7, PLCG2 and two exonic variants in the SHARPIN gene). Assessment of the polygenic risk score and stratifying by APOE reveal a 4 to 5.5 years difference in median age at onset of Alzheimer's disease patients in APOE ɛ4 carriers. Because of this study, the underlying mechanisms of APP can be studied to refine the amyloid cascade and the polygenic risk score provides a tool to select individuals at high risk of Alzheimer's disease.
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http://dx.doi.org/10.1038/s41467-021-22491-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8184987PMC
June 2021

NLRP3 inflammasome-mediated cytokine production and pyroptosis cell death in breast cancer.

J Biomed Sci 2021 Apr 12;28(1):26. Epub 2021 Apr 12.

Laboratory of Immunology and Inflammation, Department of Cell Biology, University of Brasilia, Brasilia, DF, Brazil.

Breast cancer is the most diagnosed malignancy in women. Increasing evidence has highlighted the importance of chronic inflammation at the local and/or systemic level in breast cancer pathobiology, influencing its progression, metastatic potential and therapeutic outcome by altering the tumor immune microenvironment. These processes are mediated by a variety of cytokines, chemokines and growth factors that exert their biological functions either locally or distantly. Inflammasomes are protein signaling complexes that form in response to damage- and pathogen-associated molecular patterns (DAMPS and PAMPS), triggering the release of pro-inflammatory cytokines. The dysregulation of inflammasome activation can lead to the development of inflammatory diseases, neurodegeneration, and cancer. A crucial signaling pathway leading to acute and chronic inflammation occurs through the activation of NLRP3 inflammasome followed by caspase 1-dependent release of IL-1β and IL-18 pro-inflammatory cytokines, as well as, by gasdermin D-mediated pyroptotic cell death. In this review we focus on the role of NLRP3 inflammasome and its components in breast cancer signaling, highlighting that a more detailed understanding of the clinical relevance of these pathways could significantly contribute to the development of novel therapeutic strategies for breast cancer.
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http://dx.doi.org/10.1186/s12929-021-00724-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8040227PMC
April 2021

Gas chromatography-mass spectrometry untargeted profiling of non-Hodgkin's lymphoma urinary metabolite markers.

Anal Bioanal Chem 2020 Nov 8;412(27):7469-7480. Epub 2020 Sep 8.

Laboratory of Analysis of Biomolecules Tiselius, University of Campinas-UNICAMP, Campinas, SP, 13083-970, Brazil.

Non-Hodgkin's lymphoma (NHL) is a cancer of the lymphatic system where the lymphoid and hematopoietic tissues are infiltrated by malignant neoplasms of B, T, and natural killer lymphocytes. Effective and less invasive methods for NHL screening are urgently needed. Herein, we report an untargeted gas chromatography-mass spectrometry (GC-MS) method to investigate metabolic changes in non-volatile derivatized compounds from urine samples of NHL patients (N = 15) and compare them to healthy controls (N = 34). Uni- and multivariate data analysis showed 18 endogenous metabolites, including amino acids and their metabolites, sugars, small organic acids, and vitamins, as statistically significant for group differentiation. A receiver operating characteristic curve (ROC) generated from a support vector machine (SVM) algorithm-based model achieved 0.998 of predictive accuracy, displaying the potential and relevance of GC-MS-detected urinary non-volatile compounds for predictive purposes. Furthermore, a specific panel of key metabolites was also evaluated, showing similar results. All in all, our results indicate that this robust GC-MS method is an effective screening tool for NHL diagnosis and it is able to highlight different pathways of the disease. Graphical Abstract.
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http://dx.doi.org/10.1007/s00216-020-02881-5DOI Listing
November 2020

Annexin A1 promotes the nuclear localization of the epidermal growth factor receptor in castration-resistant prostate cancer.

Int J Biochem Cell Biol 2020 10 25;127:105838. Epub 2020 Aug 25.

Laboratory of Genetics and Biotechnology, Institute of Biotechnology, Federal University of Uberlandia, Patos de Minas, MG, 387400-128, Brazil; Laboratory of Nanobiotechnology, Institute of Biotechnology, Federal University of Uberlandia, Uberlandia, MG, 38400-902, Brazil. Electronic address:

Epidermal growth factor receptor is a cancer driver whose nuclear localization has been associated with the progression of prostate cancer to the castration-resistant phenotype. Previous reports indicated a functional interaction between this receptor and the protein Annexin A1, which has also been associated with aggressive tumors. The molecular pathogenesis of castration-resistant prostate cancer remains largely unresolved, and herein we have demonstrated the correlation between the expression levels and localization of the epidermal growth factor receptor and Annexin A1 in prostate cancer samples and cell lines. Interestingly, a higher expression of both proteins was detected in castration-resistant prostate cancer cell lines and the strongest correlation was seen at the nuclear level. We verified that Annexin A1 interacts with the epidermal growth factor receptor, and by using prostate cancer cell lines knocked down for Annexin A1, we succeeded in demonstrating that Annexin A1 promotes the nuclear localization of epidermal growth factor receptor. Finally, we showed that Annexin A1 activates an autocrine signaling in castration-resistant prostate cells through the formyl peptide receptor 1. The inhibition of such signaling by Cyclosporin H inhibits the nuclear localization of epidermal growth factor receptor and its downstream signaling. The present work sheds light on the functional interaction between nuclear epidermal growth factor receptor and nuclear Annexin A1 in castration-resistant prostate cancer. Therefore, strategies to inhibit the nuclear localization of epidermal growth factor receptor through the suppression of the Annexin A1 autocrine loop could represent an important intervention strategy for castration-resistant prostate cancer.
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http://dx.doi.org/10.1016/j.biocel.2020.105838DOI Listing
October 2020

Flood-pulse disturbances as a threat for long-living Amazonian trees.

New Phytol 2020 09 19;227(6):1790-1803. Epub 2020 Jun 19.

Coordination of Environmental Dynamics (CODAM) & Botany Graduate Program, National Institute of Amazonian Research (INPA), Av. André Araújo 2936, Petropolis, Manaus, 69067-375, Brazil.

The long-lived tree species Eschweilera tenuifolia (O. Berg) Miers is characteristic of oligotrophic Amazonian black-water floodplain forests (igapó), seasonally inundated up to 10 months per year, often forming monodominant stands. We investigated E. tenuifolia' growth and mortality patterns in undisturbed (Jaú National Park - JNP) and disturbed igapós (Uatumã Sustainable Development Reserve - USDR, downstream of the Balbina hydroelectric dam). We analysed age-diameter relationships, basal area increment (BAI) through 5-cm diameter classes, growth changes and growth ratios preceding death, BAI clustering, BAI ratio, and dated the individual year of death ( C). Growth and mortality patterns were then related to climatic or anthropogenic disturbances. Results were similar for both populations for estimated maximum ages (JNP, 466 yr; USDR, 498 yr, except for one USDR tree with an estimated age of 820 yr) and slightly different for mean diameter increment (JNP: 2.04 mm; USDR: 2.28 mm). Living trees from JNP showed altered growth post-1975 and sparse tree mortality occurred at various times, possibly induced by extreme hydroclimatic events. In contrast with the JNP, abrupt growth changes and massive mortality occurred in the USDR after the dam construction began (1983). Even more than 30 yr after dam construction, flood-pulse alteration continues to affect both growth and mortality of E. tenuifolia. Besides its vulnerability to anthropogenic disturbances, this species is also susceptible to long-lasting dry and wet periods induced by climatic events, the combination of both processes may cause its local and regional extinction.
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http://dx.doi.org/10.1111/nph.16665DOI Listing
September 2020

N-Acetyl Cysteine and Catechin-Derived Polyphenols: A Path Toward Multi-Target Compounds Against Alzheimer's Disease.

J Alzheimers Dis 2020 ;75(4):1219-1227

International Center for Biomedicine (ICC), Santiago, Chile.

Background: Alzheimer's disease (AD) is a multifactorial disease, that involves neuroinflammatory processes in which microglial cells respond to "damage signals". The latter includes oligomeric tau, iron, oxidative free radicals, and other molecules that promotes neuroinflammation in the brain, promoting neuronal death and cognitive impairment. Since AD is the first cause of dementia in the elderly, and its pharmacotherapy has limited efficacy, novel treatments are critical to improve the quality of life of AD patients. Multitarget therapy based on nutraceuticals has been proposed as a promising intervention based on evidence from clinical trials. Several studies have shown that epicatechin-derived polyphenols from tea improve cognitive performance; also, the polyphenol molecule N-acetylcysteine (NAC) promotes neuroprotection.

Objective: To develop an approach for a rational design of leading compounds against AD, based on specific semisynthetic epicatechin and catechin derivatives.

Methods: We evaluated tau aggregation in vitro and neuritogenesis by confocal microscopy in mouse neuroblastoma cells (N2a), after exposing cells to either epicatechin-pyrogallol (EPIC-PYR), catechin-pyrogallol (CAT-PYR), catechin-phloroglucinol (CAT-PhG), and NAC.

Results: We found that EPIC-PYR, CAT-PYR, and CAT-PhG inhibit human tau aggregation and significantly increase neuritogenesis in a dose-dependent manner. Interestingly, modification with a phloroglucinol group yielded the most potent molecule of those evaluated, suggesting that the phloroglucinol group may enhance neuroprotective activity of the catechin-derived compounds. Also, as observed with cathechins, NAC promotes neuritogenesis and inhibits tau self-aggregation, possibly through a different pathway.

Conclusion: EPIC-PYR, CAT-PYR, CAT-PhG, and NAC increased the number of neurites in Na2 cell line and inhibits tau-self aggregation in vitro.
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http://dx.doi.org/10.3233/JAD-200067DOI Listing
May 2021

The Association of Modifiable Breast Cancer Risk Factors and Somatic Genomic Alterations in Breast Tumors: The Cancer Genome Atlas Network.

Cancer Epidemiol Biomarkers Prev 2020 03 13;29(3):599-605. Epub 2020 Jan 13.

Channing Division of Network Medicine, Department of Medicine, Harvard Medical School, Brigham and Women's Hospital, Boston, Massachusetts.

Background: The link between modifiable breast cancer risk factors and tumor genomic alterations remains largely unexplored. We evaluated the association of prediagnostic body mass index (BMI), cigarette smoking, and alcohol consumption with somatic copy number variation (SCNV), total somatic mutation burden (TSMB), seven single base substitution (SBS) signatures (SBS1, SBS2, SBS3, SBS5, SBS13, SBS29, and SBS30), and nine driver mutations (, and ) in a subset of The Cancer Genome Atlas (TCGA).

Methods: Clinical and genomic data were retrieved from the TCGA database. Risk factor information was collected from four TCGA sites ( = 219 women), including BMI (1 year before diagnosis), cigarette smoking (smokers/nonsmokers), and alcohol consumption (current drinkers/nondrinkers). Multivariable regression analyses were conducted in all tumors and stratified according to estrogen receptor (ER) status.

Results: Increasing BMI was associated with increasing SCNV in all women ( = 0.039) and among women with ER tumors ( = 0.031). Smokers had higher SCNV and TSMB versus nonsmokers ( < 0.05 all women). Alcohol drinkers had higher SCNV versus nondrinkers ( < 0.05 all women and among women with ER tumors). SBS3 (defective homologous recombination-based repair) was exclusively found in alcohol drinkers with ER disease. mutation was more likely to occur in women with higher BMI. No association was significant after multiple testing correction.

Conclusions: This study provides preliminary evidence that BMI, cigarette smoking, and alcohol consumption can influence breast tumor biology, in particular, DNA alterations.

Impact: This study demonstrates a link between modifiable breast cancer risk factors and tumor genomic alterations.
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http://dx.doi.org/10.1158/1055-9965.EPI-19-1087DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7060119PMC
March 2020

DESI-MSI Lipidomic Profiles of Breast Cancer Molecular Subtypes and Precursor Lesions.

Cancer Res 2020 03 7;80(6):1246-1257. Epub 2020 Jan 7.

Department of Surgical Pathology, A.C. Camargo Cancer Center, São Paulo, Brazil.

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 (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 metabolomic findings of the four molecular subtypes of breast cancer, DCIS, and normal tissue, and add to the understanding of their pathogenesis.
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http://dx.doi.org/10.1158/0008-5472.CAN-18-3574DOI Listing
March 2020

Stromal Cell Signature Associated with Response to Neoadjuvant Chemotherapy in Locally Advanced Breast Cancer.

Cells 2019 12 4;8(12). Epub 2019 Dec 4.

Departamento de Radiologia e Oncologia, Centro de Investigação Translacional em Oncologia, Instituto do Cancer do Estado de Sao Paulo, Hospital das Clinicas HCFMUSP, Faculdade de Medicina, Universidade de Sao Paulo, Sao Paulo 01246-000, SP, Brazil.

Breast cancer stromal compartment, may influence responsiveness to chemotherapy. Our aim was to detect a stromal cell signature (using a direct approach of microdissected stromal cells) associated with response to neoadjuvant chemotherapy (neoCT) in locally advanced breast cancer (LABC). The tumor samples were collected from 44 patients with LABC (29 estrogen receptor (ER) positive and 15 ER negative) before the start of any treatment. Neoadjuvant chemotherapy consisted of doxorubicin and cyclophosphamide, followed by paclitaxel. Response was defined as downstaging to maximum ypT1a-b/ypN0. The stromal cells, mainly composed of fibroblast and immune cells, were microdissected from fresh frozen tumor samples and gene expression profile was determined using Agilent SurePrint G3 Human Gene Expression microarrays. Expression levels were compared using MeV (MultiExperiment Viewer) software, applying SAM (significance analysis of microarrays). To classify samples according to tumor response, the order of median based on confidence statements (MedOr) was used, and to identify gene sets correlated with the phenotype downstaging, gene set enrichment analysis (GSEA). Nine patients presented disease downstaging. Eleven sequences (FDR 17) were differentially expressed, all of which (except ) more expressed in responsive tumors, including and genes involved in abnormal cytotoxic T cell physiology, , , and . The following four pairs of markers could correctly classify all tumor samples according to response: , , , and . Gene sets correlated with tumor downstaging (FDR < 0.01) were mainly involved in immune response or lymphocyte activation, including CD47, LCK, NCK1, CD24, CD3E, ZAP70, FOXP3, and CD74, among others. In locally advanced breast cancer, stromal cells may present specific features of immune response that may be associated with chemotherapy response.
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http://dx.doi.org/10.3390/cells8121566DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6953077PMC
December 2019

Neuroinflammation as a Common Feature of Neurodegenerative Disorders.

Front Pharmacol 2019 12;10:1008. Epub 2019 Sep 12.

Laboratory of Neuroscience, Faculty of Sciences, University of Chile & International Center for Biomedicine (ICC), Santiago, Chile.

Neurodegenerative diseases share the fact that they derive from altered proteins that undergo an unfolding process followed by formation of β-structures and a pathological tendency to self-aggregate in neuronal cells. This is a characteristic of tau protein in Alzheimer's disease and several tauopathies associated with tau unfolding, α-synuclein in Parkinson's disease, and huntingtin in Huntington disease. Usually, the self-aggregation products are toxic to these cells, and toxicity spreads all over different brain areas. We have postulated that these protein unfolding events are the molecular alterations that trigger several neurodegenerative disorders. Most interestingly, these events occur as a result of neuroinflammatory cascades involving alterations in the cross-talks between glial cells and neurons as a consequence of the activation of microglia and astrocytes. The model we have hypothesized for Alzheimer's disease involves damage signals that promote glial activation, followed by nuclear factor NF-kβ activation, synthesis, and release of proinflammatory cytokines such as tumor necrosis factor (TNF)-α, interleukin (IL)-1, IL-6, and IL-12 that affect neuronal receptors with an overactivation of protein kinases. These patterns of pathological events can be applied to several neurodegenerative disorders. In this context, the involvement of innate immunity seems to be a major paradigm in the pathogenesis of these diseases. This is an important element for the search for potential therapeutic approaches for all these brain disorders.
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http://dx.doi.org/10.3389/fphar.2019.01008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6751310PMC
September 2019

DNA Methylation-Based Method to Differentiate Malignant from Benign Thyroid Lesions.

Thyroid 2019 09 16;29(9):1244-1254. Epub 2019 Aug 16.

Department of Clinical Genetics, Vejle Hospital, Institute of Regional Health Research, University of Southern Denmark, Vejle, Denmark.

The differential diagnosis of thyroid nodules using fine-needle aspiration biopsy (FNAB) is challenging due to the inherent limitation of the cytology tests. The use of molecular markers has potential to complement the FNAB-based diagnosis and avoid unnecessary surgeries. In this study, we aimed to identify DNA methylation biomarkers and to develop a diagnostic tool useful for thyroid lesions. Genome-wide DNA methylation profiles (Illumina 450K) of papillary thyroid carcinoma (PTC = 60) and follicular thyroid carcinoma (FTC = 10) were compared with non-neoplastic thyroid tissue samples (NT = 50) and benign thyroid lesions (BTL = 17). The results were confirmed in publicly available databases from the Gene Expression Omnibus (GEO) and The Cancer Genome Atlas (TCGA) using the same DNA methylation platform. Two classifiers were trained to discriminate FTC and PTC from BTL. To increase the applicability of the method, six differentially methylated CpGs were selected and evaluated in 161 thyroid tumors and 69 BTL postsurgical specimens and 55 prospectively collected FNAB using bisulfite-pyrosequencing. DNA methylation analysis revealed 2130 and 19 differentially methylated CpGs in PTC and FTC, respectively. The CpGs confirmed by GEO and TCGA databases showing high areas under the receiver operating characteristic curve in all sample sets were used to train our diagnostic classifier. The model based on six CpGs was able to differentiate benign from malignant thyroid lesions with 94.3% sensitivity and 82.4% specificity. A similar performance was found applying the algorithm to TCGA and GEO external data sets (91.3-97.4% sensitivity and 87.5% specificity). We successfully evaluated the classifiers using a bisulfite-pyrosequencing technique, achieving 90.7% sensitivity and 75.4% specificity in surgical specimens (five of six CpGs). The study comprising FNAB cytology materials corroborated the applicability and performance of the methodology, demonstrating 86.7% sensitivity and 89.5% specificity in confirmed malignant tumors, and 100% sensitivity and 89% specificity in cases with indeterminate cytology. A novel diagnostic tool with potential application in preoperative screening of thyroid nodules is reported here. The proposed protocol has the potential to avoid unnecessary thyroidectomies.
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http://dx.doi.org/10.1089/thy.2018.0458DOI Listing
September 2019

SET: a robust 18-gene predictor for sensitivity to endocrine therapy for metastatic breast cancer.

NPJ Breast Cancer 2019 30;5:16. Epub 2019 May 30.

1Department of Pathology and Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX USA.

There is a clinical need to predict sensitivity of metastatic hormone receptor-positive and HER2-negative (HR+/HER2-) breast cancer to endocrine therapy, and targeted RNA sequencing (RNAseq) offers diagnostic potential to measure both transcriptional activity and functional mutation. We developed the SET index to measure gene expression microarray probe sets that were correlated with hormone receptors ( and ) and robust to preanalytical and analytical influences. We tested SET index in biopsies of metastastic HR+/HER2- breast cancer against the treatment outcomes in 140 patients. Then we customized the SET assay to measure 18 informative, 10 reference transcripts, and sequence the ligand-binding domain (LBD) of using droplet-based targeted RNAseq, and tested that in residual RNA from 53 patients. Higher SET index in metastatic samples predicted longer PFS and OS when patients received endocrine therapy as next treatment, even after adjustment for clinical-pathologic risk factors (PFS: HR 0.534, 95% CI 0.299 to 0.955,  = 0.035; OS: HR 0.315, 95% CI 0.157 to 0.631,  = 0.001). Mutated LBD was detected in 8/53 (15%) of metastases, involving 1-98% of transcripts (all had high SET index). A signature based on probe sets with good preanalytical and analytical performance facilitated our customization of an accurate targeted RNAseq assay to measure both phenotype and genotype of ER-related transcription. Elevated SET was associated with prolonged sensitivity to endocrine therapy in patients with metastatic HR+/HER2- breast cancer, especially in the absence of mutated transcript.
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http://dx.doi.org/10.1038/s41523-019-0111-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6542807PMC
May 2019

New Insights into the Role of Polybromo-1 in Prostate Cancer.

Int J Mol Sci 2019 Jun 12;20(12). Epub 2019 Jun 12.

Laboratory of Genetics and Biotechnology, Institute of Biotechnology, Federal University of Uberlandia, Patos de Minas-MG 387400-128, Brazil.

The human protein Polybromo-1 (PBMR1/BAF180) is a component of the SWI/SNF chromatin-remodeling complex that has been reported to be deregulated in tumors. However, its role in prostate cancer (PCa) is largely unknown. In this study, we described the PBRM1 transcriptional levels and the protein expression/localization in tissues of PCa patients and in prostatic cell lines. Increased mRNA levels were found in PCa samples, when compared to benign disease, and were correlated with higher Gleason score. We also verified that only the nuclear localization of PBRM1 protein is correlated with a more aggressive disease and high Prostate-Specific Antigen (PSA) levels in tissue microarrays. Intriguing expression patterns of mRNA and protein were identified in the cell lines. Although PBRM1 protein was restricted to the nuclei, in tumor cell lines in non-neoplastic cells, it was also present in vesicular-like structures that were dispersed within the cytoplasm. We knocked-down PBRM1 in the castration-resistant PCa (CRPC) cell line PC-3 and we verified that PBRM1 promotes the expression of several markers of aggressiveness, including EpCAM, TGF-β, and N-Cadherin. Therefore, our data supported the hypothesis that PBRM1 displays a pivotal role in the promotion and maintenance of the malignant behavior of PCa, especially in CRPC.
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http://dx.doi.org/10.3390/ijms20122852DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6627401PMC
June 2019

Polysome Profiling of a Human Glioblastoma Reveals Intratumoral Heterogeneity.

Int J Mol Sci 2019 May 2;20(9). Epub 2019 May 2.

International Research Center, A.C.Camargo Cancer Center, National Institute of Science and Technology in Oncogenomics, São Paulo 01509-010, Brazil.

Glioblastoma (GBM) is one of the most aggressive cancers, with median survival of less than 2 years. Despite of considerable advance in molecular classification of GBMs, no improvements in therapy have been described. The scenario is further complicated by tumor heterogeneity and the relationship among genetic, transcriptional and functional findings. Classically, gene expression has been evaluated by steady-state mRNA, however, this does not take translational control into consideration, which contributes considerably to the composition of the proteome. In this study, we evaluated the transcriptomic and translatomic signature of a GBM obtained from a single patient focusing in tumor heterogeneity. In a sampling of eight fragments, we investigated the translation rates, mTORC1 and ERK1/2 pathways and identified both total and polysome associated mRNAs. An increased translation rate was observed in fragments with high-grade histological features. High-grade histology was also associated with the expression of genes related to extracellular matrix (ECM) and angiogenesis, in both transcriptomes and translatomes. However, genes associated with epithelial to mesenchymal transition and stress response, were observed only in translatomes from high-grade fragments. Overall, our results demonstrate that isolation of translated mRNA can be used to identify biomarkers and reveal previously unrecognized determinants of heterogeneity in GBMs.
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http://dx.doi.org/10.3390/ijms20092177DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6539516PMC
May 2019

CDK5: A Unique CDK and Its Multiple Roles in the Nervous System.

J Alzheimers Dis 2019 ;68(3):843-855

Laboratory of Neurosciences, Faculty of Sciences, University of Chile, Santiago, Chile.

The cyclin-dependent kinase 5 (CDK5) is known as an exceptional component of the CDK family, due to its characteristic regulatory pathways and its atypical roles in comparison to the classical cyclins. Despite its functional uniqueness, CDK5 shares a great part of its structural similarity with other members of the cyclin-dependent kinase family. After its discovery 26 years ago, a progressive set of cellular functions has been associated with this protein kinase, ranging from neuronal migration, axonal guidance, and synaptic plasticity in diverse stages of brain development, including specific and complex cognitive functions. More than 30 substrates for CDK5 have been found in different cellular pathways. Together with its essential physiological roles, a major discovery was the finding twenty years ago that CDK5 participates in neurodegenerative diseases responsible for tau hyperphosphorylations, and, as a consequence, it becomes a neurotoxic factor. This review focuses on the wide roles of CDK5 in the central nervous system, its implications in neurodegeneration, and provides an integrative insight of its involvement in pain modulation, Alzheimer's disease, and other contexts.
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http://dx.doi.org/10.3233/JAD-180792DOI Listing
August 2020

Molecular mechanisms linking high body mass index to breast cancer etiology in post-menopausal breast tumor and tumor-adjacent tissues.

Breast Cancer Res Treat 2019 Feb 1;173(3):667-677. Epub 2018 Nov 1.

Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, 330 Brookline Ave, Dana 517B, Boston, MA, 02215, USA.

Purpose: In post-menopausal women, high body mass index (BMI) is an established breast cancer risk factor and is associated with worse breast cancer prognosis. We assessed the associations between BMI and gene expression of both breast tumor and adjacent tissue in estrogen receptor-positive (ER+) and estrogen receptor-negative (ER-) diseases to help elucidate the mechanisms linking obesity with breast cancer biology in 519 post-menopausal women from the Nurses' Health Study (NHS) and NHSII.

Methods: Differential gene expression was analyzed separately in ER+ and ER- disease both comparing overweight (BMI ≥ 25 to < 30) or obese (BMI ≥ 30) women to women with normal BMI (BMI < 25), and per 5 kg/m increase in BMI. Analyses controlled for age and year of diagnosis, physical activity, alcohol consumption, and hormone therapy use. Gene set enrichment analyses were performed and validated among a subset of post-menopausal cases in The Cancer Genome Atlas (for tumor) and Polish Breast Cancer Study (for tumor-adjacent).

Results: No gene was differentially expressed by BMI (FDR < 0.05). BMI was significantly associated with increased cellular proliferation pathways, particularly in ER+ tumors, and increased inflammation pathways in ER- tumor and ER- tumor-adjacent tissues (FDR < 0.05). High BMI was associated with upregulation of genes involved in epithelial-mesenchymal transition in ER+ tumor-adjacent tissues.

Conclusions: This study provides insights into molecular mechanisms of BMI influencing post-menopausal breast cancer biology. Tumor and tumor-adjacent tissues provide independent information about potential mechanisms.
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http://dx.doi.org/10.1007/s10549-018-5034-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6391202PMC
February 2019

Lobular Carcinomas Display Intralesion Genetic Heterogeneity and Clonal Evolution in the Progression to Invasive Lobular Carcinoma.

Clin Cancer Res 2019 01 5;25(2):674-686. Epub 2018 Sep 5.

Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York.

Purpose: Lobular carcinoma (LCIS) is a preinvasive lesion of the breast. We sought to define its genomic landscape, whether intralesion genetic heterogeneity is present in LCIS, and the clonal relatedness between LCIS and invasive breast cancers. We reanalyzed whole-exome sequencing (WES) data and performed a targeted amplicon sequencing validation of mutations identified in 43 LCIS and 27 synchronous more clinically advanced lesions from 24 patients [9 ductal carcinomas (DCIS), 13 invasive lobular carcinomas (ILC), and 5 invasive ductal carcinomas (IDC)]. Somatic genetic alterations, mutational signatures, clonal composition, and phylogenetic trees were defined using validated computational methods.

Results: WES of 43 LCIS lesions revealed a genomic profile similar to that previously reported for ILCs, with mutations present in 81% of the lesions. Forty-two percent (18/43) of LCIS were found to be clonally related to synchronous DCIS and/or ILCs, with clonal evolutionary patterns indicative of clonal selection and/or parallel/branched progression. Intralesion genetic heterogeneity was higher among LCIS clonally related to DCIS/ILC than in those nonclonally related to DCIS/ILC. A shift from aging to APOBEC-related mutational processes was observed in the progression from LCIS to DCIS and/or ILC in a subset of cases.

Conclusions: Our findings support the contention that LCIS has a repertoire of somatic genetic alterations similar to that of ILCs, and likely constitutes a nonobligate precursor of breast cancer. Intralesion genetic heterogeneity is observed in LCIS and should be considered in studies aiming to develop biomarkers of progression from LCIS to more advanced lesions.
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http://dx.doi.org/10.1158/1078-0432.CCR-18-1103DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6726436PMC
January 2019

Alzheimer´s Disease in the Perspective of Neuroimmunology.

Open Neurol J 2018 29;12:50-56. Epub 2018 Jun 29.

Laboratory of Neuroscience, Faculty of Science, University of Chile & International Center for Biomedicine (ICC), Santiago, Chile.

Background: Alzheimer's Disease (AD) is a severe neurodegenerative disorder that includes the occurrence of behavioral disorders as well as memory and cognitive impairment as major symptoms. AD affects around 12% of the aged population in the world. Considerable research efforts have pointed to the role of innate immunity as the main culprit in the pathogenesis of AD. In this context, and according to with our neuroimmunomodulation theory, microglial activation modifies the cross-talks between microglia and neurons. We postulated that glial activation triggered by "damage signals" activates a pathological molecular cascade that finally leads to hyperphosphorylation and oligomerization of the tau protein. Interestingly, these modifications correlate with the gradual cognitive impairment of patients with the AD. Microglial activation is determined by the nature and strength of the stimulus. In the AD, a continuous activation state of microglia appears to generate neuronal injury and neurodegeneration, producing the outflow of pathological tau from the inner of neurons to the extraneuronal space. Released tau, together with the contribution of ApoE4 protein, would then produce reactivation of microglia, thus inducing a positive feedback that stimulates the vicious cycle in neurodegeneration.

Conclusion: Nevertheless, from the pathophysiological perspective AD is significantly more than a loss of memory. In the initial stages of AD pathogenesis, variations in the dopaminergic pathway along with serotonin diminution play an important role. This may explain why depression is associated with the onset of AD. All these pathophysiological events take place together with immunomodulatory changes that trigger tau oligomerization in the course of neurofibrillary tangles formation. Interestingly, mood disorders appear to be followed by neuroinflammatory processes and structural/functional alterations that lead to cognitive impairment in the context of AD.
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http://dx.doi.org/10.2174/1874205X01812010050DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6040210PMC
June 2018

Hearing children of Deaf parents: Gender and birth order in the delegation of the interpreter role in culturally Deaf families.

Afr J Disabil 2018 30;7:365. Epub 2018 Apr 30.

Department of Speech Pathology and Audiology, School of Human and Community Development, University of the Witwatersrand, South Africa.

Background: Culturally, hearing children born to Deaf parents may have to mediate two different positions within the hearing and Deaf cultures. However, there appears to be little written about the experiences of hearing children born to Deaf parents in the South African context.

Objective: This study sought to investigate the roles of children of Deaf adults (CODAs) as interpreters in Deaf-parented families, more specifically, the influence of gender and birth order in language brokering.

Method: Two male and eight female participants between the ages of 21 and 40 years were recruited through purposive and snowball sampling strategies. A qualitative design was employed and data were collected using a semi-structured, open-ended interview format. Themes which emerged were analysed using thematic analysis.

Results: The findings indicated that there was no formal assignment of the interpreter role; however, female children tended to assume the role of interpreter more often than the male children. Also, it appeared as though the older children shifted the responsibility for interpreting to younger siblings. The participants in this study indicated that they interpreted in situations where they felt they were not developmentally or emotionally ready, or in situations which they felt were better suited for older siblings or for siblings of another gender.

Conclusion: This study highlights a need for the formalisation of interpreting services for Deaf people in South Africa in the form of professional interpreters rather than the reliance on hearing children as interpreters in order to mediate between Deaf and hearing cultures.
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http://dx.doi.org/10.4102/ajod.v7i0.365DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5968869PMC
April 2018

Behavioral and Neuropsychiatric Disorders in Alzheimer's Disease.

J Alzheimers Dis 2018 ;63(3):899-910

International Center for Biomedicine (ICC), Santiago, Chile.

Alzheimer's disease (AD) is the most frequent type of dementia in the elderly, severely affecting functional and executive skills of subjects suffering from this disease. Moreover, the distress of caregivers as well as the social implications constitute a critical issue for families. Furthermore, cognitive impairment, along with behavioral disorders and neuropsychiatric symptoms are characteristics of AD. Although these are present with variations in prevalence, intensity, and progression, an important core of them is visible before cognitive impairment, especially depression and apathy, which affect at least 50% of patients. The most updated literature shows that depression and/or behavioral and neuropsychiatric symptoms (BNS) are part of the initial phase of the disease rather than just a risk factor. Thus, mood disorders are associated with anomalies in specific brain regions that disturb the normal balance of neurotransmission. This in turn is linked with an inflammatory pathway that leads to microglial activation and aggregated neurofibrillary tangle formation, finally triggering neuronal loss, according to our neuroimmunomodulation theory. Altogether, inflammation and tau aggregation are observed in preclinical stages, preceding the BNS of patients, which in turn are exhibited earlier than cognitive and functional impairment detected in AD. This review is focused on the latest insights of cellular and molecular processes associated with BNS in asymptomatic early-onset stages of AD. An important medical research focus is to improve quality of life of patients, through prevention and treatments of AD, and the study of behavioral disorders and early event in AD pathogenesis has a major impact.
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http://dx.doi.org/10.3233/JAD-180005DOI Listing
June 2019

Neuroimmune Tau Mechanisms: Their Role in the Progression of Neuronal Degeneration.

Int J Mol Sci 2018 Mar 23;19(4). Epub 2018 Mar 23.

Laboratory of Neurosciences, International Center for Biomedicine (ICC), Santiago 7630457, Chile.

Progressive neurodegenerative pathologies in aged populations are an issue of major concern worldwide. The microtubule-associated protein tau is able to self-aggregate to form abnormal supramolecular structures that include small oligomers up to complex polymers. Tauopathies correspond to a group of diseases that share tau pathology as a common etiological agent. Since microglial cells play a preponderant role in innate immunity and are the main source of proinflammatory factors in the central nervous system (CNS), the alterations in the cross-talks between microglia and neuronal cells are the main focus of studies concerning the origins of tauopathies. According to evidence from a series of studies, these changes generate a feedback mechanism reactivating microglia and provoking constant cellular damage. Thus, the previously summarized mechanisms could explain the onset and progression of different tauopathies and their functional/behavioral effects, opening the window towards an understanding of the molecular basis of anomalous tau interactions. Despite clinical and pathological differences, increasing experimental evidence indicates an overlap between tauopathies and synucleinopathies, considering that neuroinflammatory events are involved and the existence of protein misfolding. Neurofibrillary tangles of pathological tau (NFT) and Lewy bodies appear to coexist in certain brain areas. Thus, the co-occurrence of synucleinopathies with tauopathies is evidenced by several investigations, in which NFT were found in the substantia nigra of patients with Parkinson's disease, suggesting that the pathologies share some common features at the level of neuroinflammatory events.
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http://dx.doi.org/10.3390/ijms19040956DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5979395PMC
March 2018

Wnt/β-catenin signaling stimulates the expression and synaptic clustering of the autism-associated Neuroligin 3 gene.

Transl Psychiatry 2018 03 5;8(1):45. Epub 2018 Mar 5.

Center for Biomedical Research, Faculty of Biological Sciences and Faculty of Medicine, Universidad Andres Bello, Santiago, Chile.

Synaptic abnormalities have been described in individuals with autism spectrum disorders (ASD). The cell-adhesion molecule Neuroligin-3 (Nlgn3) has an essential role in the function and maturation of synapses and NLGN3 ASD-associated mutations disrupt hippocampal and cortical function. Here we show that Wnt/β-catenin signaling increases Nlgn3 mRNA and protein levels in HT22 mouse hippocampal cells and primary cultures of rat hippocampal neurons. We characterized the activity of mouse and rat Nlgn3 promoter constructs containing conserved putative T-cell factor/lymphoid enhancing factor (TCF/LEF)-binding elements (TBE) and found that their activity is significantly augmented in Wnt/β-catenin cell reporter assays. Chromatin immunoprecipitation (ChIP) assays and site-directed mutagenesis experiments revealed that endogenous β-catenin binds to novel TBE consensus sequences in the Nlgn3 promoter. Moreover, activation of the signaling cascade increased Nlgn3 clustering and co- localization with the scaffold PSD-95 protein in dendritic processes of primary neurons. Our results directly link Wnt/β-catenin signaling to the transcription of the Nlgn3 gene and support a functional role for the signaling pathway in the dysregulation of excitatory/inhibitory neuronal activity, as is observed in animal models of ASD.
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http://dx.doi.org/10.1038/s41398-018-0093-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5835496PMC
March 2018

BRCA1 deficiency is a recurrent event in early-onset triple-negative breast cancer: a comprehensive analysis of germline mutations and somatic promoter methylation.

Breast Cancer Res Treat 2018 02 7;167(3):803-814. Epub 2017 Nov 7.

Laboratory of Genomics and Molecular Biology, CIPE - A. C. Camargo Cancer Center, São Paulo, Brazil.

Purpose: BRCA1 germline mutation is closely associated with triple-negative breast cancer. BRCA deficiency leads to impaired DNA repair and tumor development, and understanding this deficiency, in both hereditary and sporadic scenarios, is of great clinical and biological interest. Here, we investigated germline or somatic events that might lead to BRCA1 impairment in triple-negative breast cancer. We also analyzed the clinical implications associated with BRCA deficiency.

Methods: Next-generation sequencing for the BRCA1/2 genes and multiplex ligation-dependent probe amplification (MLPA) for the BRCA1 gene were performed for mutation screening. A customized bisulfite next-generation sequencing approach was used for assessing BRCA1 promoter methylation status in tumor tissue.

Results: A total of 131 triple-negative cases were assessed, and germline pathogenic variants were detected in 13.0% of all cases and in 26% of cases diagnosed in young women. Most germline pathogenic variants (88.2%) occurred in the BRCA1 gene. BRCA1 promoter hypermethylation was detected in 20.6% of tumors; none of these tumors were in BRCA1/2 pathogenic variant carriers. BRCA1 impairment by either germline or somatic events was significantly more frequent in young women (55% in those ≤ 40 years; 33% in those 41-50 years; 22% in those > 50 years of age) and associated with better overall and disease-free survival rates in this group of patients.

Conclusions: BRCA1 deficiency was recurrent in early-onset triple-negative breast cancer in Brazilian patients and associated with improved survival. With the new treatment modalities being investigated, including poly (ADP-ribose)-polymerase (PARP) inhibitor therapy, our results suggest that a significant proportion of young women with this subtype of tumor might benefit from PARP inhibitor treatment, which warrants further investigation.
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http://dx.doi.org/10.1007/s10549-017-4552-6DOI Listing
February 2018

Polysome-profiling in small tissue samples.

Nucleic Acids Res 2018 01;46(1):e3

Department of Oncology-Pathology, Science for Life Laboratory, Karolinska Institutet, Stockholm, Sweden.

Polysome-profiling is commonly used to study translatomes and applies laborious extraction of efficiently translated mRNA (associated with >3 ribosomes) from a large volume across many fractions. This property makes polysome-profiling inconvenient for larger experimental designs or samples with low RNA amounts. To address this, we optimized a non-linear sucrose gradient which reproducibly enriches for efficiently translated mRNA in only one or two fractions, thereby reducing sample handling 5-10-fold. The technique generates polysome-associated RNA with a quality reflecting the starting material and, when coupled with smart-seq2 single-cell RNA sequencing, translatomes in small tissues from biobanks can be obtained. Translatomes acquired using optimized non-linear gradients resemble those obtained with the standard approach employing linear gradients. Polysome-profiling using optimized non-linear gradients in serum starved HCT-116 cells with or without p53 showed that p53 status associates with changes in mRNA abundance and translational efficiency leading to changes in protein levels. Moreover, p53 status also induced translational buffering whereby changes in mRNA levels are buffered at the level of mRNA translation. Thus, here we present a polysome-profiling technique applicable to large study designs, primary cells and frozen tissue samples such as those collected in biobanks.
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http://dx.doi.org/10.1093/nar/gkx940DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5758873PMC
January 2018

Alcohol consumption and breast tumor gene expression.

Breast Cancer Res 2017 Sep 12;19(1):108. Epub 2017 Sep 12.

Department of Biostatistics and Epidemiology, School of Public Health and Health Sciences, University of Massachusetts Amherst, 715 N Pleasant Street, Amherst, MA, 01003, USA.

Background: Alcohol consumption is an established risk factor for breast cancer and the association generally appears stronger among estrogen receptor (ER)-positive tumors. However, the biological mechanisms underlying this association are not completely understood.

Methods: We analyzed messenger RNA (mRNA) microarray data from both invasive breast tumors (N = 602) and tumor-adjacent normal tissues (N = 508) from participants diagnosed with breast cancer in the Nurses' Health Study (NHS) and NHSII. Multivariable linear regression, controlling for other known breast cancer risk factors, was used to identify differentially expressed genes by pre-diagnostic alcohol intake. For pathway analysis, we performed gene set enrichment analysis (GSEA). Differentially expressed genes or enriched pathway-defined gene sets with false discovery rate (FDR) <0.1 identified in tumors were validated in RNA sequencing data of invasive breast tumors (N = 166) from The Cancer Genome Atlas.

Results: No individual genes were significantly differentially expressed by alcohol consumption in the NHS/NHSII. However, GSEA identified 33 and 68 pathway-defined gene sets at FDR <0.1 among 471 ER+ and 127 ER- tumors, respectively, all of which were validated. Among ER+ tumors, consuming 10+ grams of alcohol per day (vs. 0) was associated with upregulation in RNA metabolism and transport, cell cycle regulation, and DNA repair, and downregulation in lipid metabolism. Among ER- tumors, in addition to upregulation in RNA processing and cell cycle, alcohol intake was linked to overexpression of genes involved in cytokine signaling, including interferon and transforming growth factor (TGF)-β signaling pathways, and translation and post-translational modifications. Lower lipid metabolism was observed in both ER+ tumors and ER+ tumor-adjacent normal samples. Most of the significantly enriched gene sets identified in ER- tumors showed a similar enrichment pattern among ER- tumor-adjacent normal tissues.

Conclusions: Our data suggest that moderate alcohol consumption (i.e. 10+ grams/day, equivalent to one or more drinks/day) is associated with several specific and reproducible biological processes and pathways, which adds potential new insight into alcohol-related breast carcinogenesis.
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http://dx.doi.org/10.1186/s13058-017-0901-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5596493PMC
September 2017

The Natural Product Curcumin as a Potential Coadjuvant in Alzheimer's Treatment.

J Alzheimers Dis 2017 ;60(2):451-460

Laboratory of Cellular and Molecular Neurosciences, Faculty of Sciences, University of Chile, Santiago, Chile.

Alzheimer's disease (AD) is a neurodegenerative disease characterized by a progressive cognitive impairment of patients, affecting around 12% of people older than 65 years old. WHO estimated that over 48.6 million all over the world suffer this disease. On the basis of cumulative results on our research, we have postulated the neuroimmunomodulation hypothesis that appears to provide a reasonable explanation of both the preclinical and clinical observations. In this context, the long-term activation of the innate immune system triggers an anomalous cascade of molecular signals, finally leading to tau oligomerization in the pathway to neuronal degeneration. In the present scenario of the failure of many anti-AD drugs, nutraceutical compounds provide an avenue for AD prevention and possibly as coadjuvants in the treatment of this disease. Recent discoveries point to the relevance of curcumin, a natural anti-inflammatory agent, in controlling oxidative stress and improving cholinergic function in the brain, even though the mechanisms underlying these actions are unknown. We investigated the effects of curcumin in cultures of neuronal cells. For this study, we exposed cells to prooxidant conditions, both in the presence and absence of curcumin. Our data reveal that curcumin exert a strong neuroprotective effect in N2a cells, thus preventing toxicity by oxidative agents H2O2 and Fe+3. This is supported by results that indicate that curcumin control the neurodegenerative effects of both oxidative agents, relieving cells from the loss of neuritogenic processes induced by prooxidants. In addition, curcumin was able to slow down the tau aggregation curve and disassemble tau pathological oligomeric structures. Data suggest that curcumin could be a potential compound for prevention of cognitive disorders associated with AD.
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http://dx.doi.org/10.3233/JAD-170354DOI Listing
April 2018

Pleomorphic lobular carcinoma in situ of the breast: a single institution experience with clinical follow-up and centralized pathology review.

Breast Cancer Res Treat 2017 Sep 13;165(2):411-420. Epub 2017 Jun 13.

Department of Surgery, Brigham and Women's Hospital, Boston, MA, 02115, USA.

Purpose: The natural history of pleomorphic lobular carcinoma in situ (PLCIS) remains largely unknown.

Methods: A pathology database search (1995-2012) was performed to identify patients diagnosed with an LCIS variant. Patients with synchronous breast cancer and/or no evidence of pleomorphism were excluded. Original slides were re-evaluated by three pathologists to identify a consensus cohort of PLCIS. Borderline lesions with focal atypia were classified as LCIS with pleomorphic features (LCIS-PF). Clinical data were obtained from medical records.

Results: From 233 patients, we identified 32 with an LCIS variant diagnosis and no concurrent breast cancer. Following review, 16 cases were excluded due to lack of pleomorphism. The remaining 16 were classified as PLCIS (n = 11) and LCIS-PF (n = 5). 12/16 patients were treated with surgical excision ± chemoprevention. Patients with a prior breast cancer history and those having mastectomy were excluded from outcome analysis. Among the remaining 7 patients with PLCIS/LCIS-PF, 4/7 (57%) developed ipsilateral breast cancer at a median follow-up of 67 months. Median age at the time of breast cancer diagnosis was 56 years old and median time from PLCIS/LCIS-PF to cancer diagnosis was 59 months (range 45-66 months). The four cancers included 1 invasive lobular carcinoma (ILC), 1 microinvasive ILC, 1 invasive ductal carcinoma, and 1 ductal carcinoma in situ.

Conclusions: We confirm that PLCIS in isolation is indeed a rare entity, further contributing to the difficulty in determining the actual risk conferred by this lesion. Long-term follow-up data on larger cohorts are needed to define standardized management and outcomes for patients with PLCIS.
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http://dx.doi.org/10.1007/s10549-017-4334-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5634524PMC
September 2017

Invasive micropapillary carcinoma of the mammary gland in humans and canines: Clinicopathological, immunophenotypical and survival approaches.

Res Vet Sci 2017 Dec 20;115:189-194. Epub 2017 Apr 20.

Departamento de Patologia Geral, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Av. Antônio Carlos 6627, Belo Horizonte, Minas Gerais 31270-901, Brazil. Electronic address:

Invasive micropapillary carcinoma (IMPC) is a breast cancer with a proclivity for lymph node metastasis that affects women. In canines, this carcinoma has only recently been reported and appears to have similar histological aspects as its human counterpart. Thus, the aim of the present study was to compare clinicopathological, immunohistochemical and prognostic characteristics of mammary IMPC between humans and canines. In canines, regional metastasis was more frequently observed. Histopathologically, humans and canines predominantly showed a moderate histological grade. The pure subtype and neoplastic emboli were more frequently observed in canines. Regarding immunohistochemical evaluation, most canine and human IMPCs were positive for the estrogen and progesterone receptors. A reversed pattern of epithelial membrane antigen expression and a high proliferation index predominated in both species. The mortality due to the neoplastic disease was more frequently observed in canines (94%) than in humans (4%). Thus, canine IMPCs show a larger tumor size and higher rates of the pure subtype, regional metastasis and mortality than their human counterparts and appear to provide a good spontaneous model for achieving a better understanding of the biological behavior of human IMPCs.
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http://dx.doi.org/10.1016/j.rvsc.2017.04.012DOI Listing
December 2017

Early Transcriptional Changes Induced by Wnt/-Catenin Signaling in Hippocampal Neurons.

Neural Plast 2016 27;2016:4672841. Epub 2016 Dec 27.

Centro de Investigaciones Biomédicas (CIB), Facultad de Ciencias Biológicas y Facultad de Medicina, Universidad Andres Bello, Santiago, Chile.

Wnt/-catenin signaling modulates brain development and function and its deregulation underlies pathological changes occurring in neurodegenerative and neurodevelopmental disorders. Since one of the main effects of Wnt/-catenin signaling is the modulation of target genes, in the present work we examined global transcriptional changes induced by short-term Wnt3a treatment (4 h) in primary cultures of rat hippocampal neurons. RNAseq experiments allowed the identification of 170 differentially expressed genes, including known Wnt/-catenin target genes such as Notum, Axin2, and Lef1, as well as novel potential candidates Fam84a, Stk32a, and Itga9. Main biological processes enriched with differentially expressed genes included neural precursor (GO:0061364, -adjusted = 2.5 × 10), forebrain development (GO:0030900, -adjusted = 7.3 × 10), and stem cell differentiation (GO:0048863 -adjusted = 7.3 × 10). Likewise, following activation of the signaling cascade, the expression of a significant number of genes with transcription factor activity (GO:0043565, -adjusted = 4.1 × 10) was induced. We also studied molecular networks enriched upon Wnt3a activation and detected three highly significant expression modules involved in glycerolipid metabolic process (GO:0046486, -adjusted = 4.5 × 10), learning or memory (GO:0007611, -adjusted = 4.0 × 10), and neurotransmitter secretion (GO:0007269, -adjusted = 5.3 × 10). Our results indicate that Wnt/-catenin mediated transcription controls multiple biological processes related to neuronal structure and activity that are affected in synaptic dysfunction disorders.
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http://dx.doi.org/10.1155/2016/4672841DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5223035PMC
August 2017
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