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Purpose. A high number of diagnosed prostate cancer (PCa) tumors are indolent and will never become aggressive during a patient's lifetime, however, about 20%-40% will experience post-operative disease relapse with biochemical recurrence (BCR), and a fraction of these will progress towards metastatic disease, which is the leading cause of PCa death. Reliable biomarkers helping in management decision-making and avoiding resistant PCa are still needed. We aimed to identify differentially expressed genes (DEGs) associated with BCR in localized PCa and to explore their involvement in signaling pathways contributing to the progression of PCa in Hispanic/Latino patients. Methods. A total of 117 Hispanic/Latino cases with localized PCa were included. RNA was extracted from FFPE tissues of radical prostatectomy (RP), RNA-seq was performed in 75 cases and used to identify DEGs between BCR positive (BCR) and BCR negative (non-BCR) cases. Signaling pathway analysis was done in MetaCore and DAVID database. DEGs with a p-value < 0.1 were used for enrichment analysis. Results. We identified 21 DEGs between BCR and non-BCR cases, three upregulated and 19 downregulated. From the enriched pathway maps found through MetaCore, the most remarkable pathways related with BCR included metabolism of androgen hormones; differentiation, self-renewal and maintenance of stem cells; mechanisms operating in type 2 diabetes (T2DM) and the cooperative action by pioglitazone and rosiglitazone with metformin; and metabolism of triacylglycerol. In line with these findings, results from DAVID also found Diabetes mellitus as one of the keywords, with downregulation of adiponectin (ADIPOQ) and MCF2L2 as the main genes related to this pathway. Other studies have shown that, regardless of BMI, individuals with T2DM have lower plasma adiponectin levels, which, in turn, are associated with pathophysiological conditions such as obesity, metabolic syndrome and insulin resistance. In our study, BMI was not associated with BCR, however, other complementary measurements related to increased abdominal fat (e.g., waist circumference or waist-to-hip ratio), and with recent evidence of strong association with aggressive PCa, were not assessed by us. Additional pathways associated with BCR progression were those related to biosynthesis and metabolism of androgens, being AKR1C the main gene involved. This gene participates in alternative pathways of the biosynthesis of androgens; for example, downregulated AKR1C leads to the synthesis of dihydrotestosterone and circumvents testosterone as a precursor. Conclusions. Enrichment analyses suggest that pathways related to T2DM and metabolism of androgens are main drivers of BCR in Hispanic/Latino PCa patients, mainly through the downregulation of ADIPOQ and AKR1C. Our findings confirm recent discoveries in the molecular understanding of PCa progression, but more studies analyzing abdominal fat measures in independent and larger cohorts could lead as to more precise conclusions, as well as to identify potential biomarkers and therapeutic targets. Citation Format: Natalia L. Acosta-Vega, Rodolfo Varela, Jorge Andrés Mesa, Jone Garay, Melody C. Baddoo, Alberto Gómez-Gutiérrez, Silvia J. Serrano-Gómez, Martha Lucía Serrano, Jovanny Zabaleta, Alba L. Combita, María Carolina Sanabria-Salas. Major signaling pathways associated with biochemical recurrence in Hispanic/Latino patients with prostate cancer [abstract]. In: Proceedings of the AACR Virtual Conference: 14th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2021 Oct 6-8. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2022;31(1 Suppl):Abstract nr PO-136.

Purpose: Clinical progression of localized prostate cancer (PCa) is highly variable mainly because of its multifocality and heterogeneity nature. Recent advances in emerging techniques have allowed to explore the molecular basis of PCa allowing the identification of molecular subtypes for primary PCa based on genetic alterations. The most prevalent subtype harbors rearrangements between the androgen-regulated promoter of TMPRSS2 with a member of the ETS family of transcription factors, the oncogene ERG, present in about 40%-50% of cases, and leading to increased expression of ERG. Here, we characterized the two main molecular subtypes, tumors overexpressing ERG and tumors with downregulated ERG, in localized PCa from Hispanic patients and determined the association of these subtypes with the prognosis of biochemical recurrence (BCR). Methods: A total of 89 Hispanic cases with localized PCa were included. RNA from formalin-fixed paraffin-embedded tissues of radical prostatectomy (RP) was extracted and sequenced. We made differential expression analysis between ERGhigh and ERGlow cases and significant genes were submitted to MetaCore for enrichment analysis. Association with clinical and pathological variables was done and the impact of ERG subtypes on prognosis was determined by Kaplan-Meir analysis, Log-rank test and Cox proportional hazard regression, taking 5-year BCR-free survival as the event. Results: Comparison between ERGhigh and ERGlow tumors showed 150 differentially expressed genes (DEGs) that revealed enriched pathways related with the angiotensin system and its signal transduction, Notch and NF-κB pathways, Beta-catenin-dependent transcription regulation in colorectal cancer, mTORC1 upstream signaling, linoleic acid metabolism, and polyamine metabolism. The renin-angiotensin system is implicated in PCa development since it activates MAPK, STAT3 and VEGF, ultimately stimulating proliferation and formation of blood vessels. ERGlow demonstrated to be associated with higher Gleason Grade Groups at RP and with BCR, and log-rank test showed correlation with worse BCR-free survival within 5-years after RP, while ERGhigh subtype presented a better BCR-free survival. Conclusions: Our analysis illustrates different signaling pathways between the two main molecular subtypes in PCa, ERGhigh and ERGlow, which associates with different prognosis in Hispanic patients with localized PCa. Citation Format: Natalia Lizeth Acosta Vega, Rodolfo Varela, Jorge A. Mesa, Jone Garay, Melody Baddoo, Jovanny Zabaleta, Alba L. Combita-Rojas, María C. Sanabria-Salas. Molecular subtypes in prostate cancer with differential prognosis and tumor biology in Hispanic patients [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1503.

Infection with Helicobacter pylori (H. pylori) leads to inflammatory events that can promote gastric cancer development. Immune cells transition from the circulation into the infected mucosa through the interaction of their receptors and ligands in the endothelial compartment. CD44 expression is increased in advanced gastric lesions. However, the association of this molecule with the progression of these lesions over time has not been investigated. In addition, there is a lack of understanding of the CD44-dependent cellular processes that lead to gastritis, and possibly to gastric cancer. Here we studied H. pylori-positive subjects with gastric lesions that ranged from multifocal atrophic gastritis to dysplasia to determine gene expression changes associated with disease progression over a period of six years. We report that CD44 expression is significantly increased in individuals whose gastric lesions progressed along the gastric precancerous cascade. We also show that CD44−/− mice develop less severe and less extensive H. pylori-induced metaplasia, and show fewer infiltrating Gr1+ cells compared to wild type mice. We present data suggesting that CD44 is associated with disease progression. Mechanisms associated with these effects include induction of interferon gamma responses.

Background Increasing evidence has shown the close link between energy metabolism and the differentiation, function, and longevity of immune cells. Chronic inflammatory conditions such as parasitic infections and cancer trigger a metabolic reprogramming from the preferential use of glucose to the up-regulation of fatty acid oxidation (FAO) in myeloid cells, including macrophages and granulocytic and monocytic myeloid-derived suppressor cells. Asthma is another chronic inflammatory condition where macrophages, eosinophils, and polymorphonuclear cells play an important role in its pathophysiology. Objective We tested whether FAO might play a role in the development of asthma-like traits and whether the inhibition of this metabolic pathway could represent a novel therapeutic approach. Methods OVA and house dust mite (HDM)-induced murine asthma models were used in this study. Results Key FAO enzymes were significantly increased in the bronchial epithelium and inflammatory immune cells infiltrating the respiratory epithelium of mice exposed to OVA or HDM. Pharmacologic inhibition of FAO significantly decreased allergen-induced airway hyperresponsiveness, decreased the number of inflammatory cells, and reduced the production of cytokines and chemokines associated with asthma. Conclusions and clinical relevance These novel observations suggest that allergic airway inflammation increases FAO in inflammatory cells to support the production of cytokines, chemokines, and other factors important in the development of asthma. Inhibition of FAO may therefore provide a novel therapeutic approach for the treatment of asthma by re-purposing existing drugs that block FAO and are approved for the treatment of heart disease. This article is protected by copyright. All rights reserved.

Background: Breast cancer is the most common cancer in Colombian women. Five intrinsic subtypes have been described based on gene expression profiles and genetic signatures, such as PAM50, have been developed to classified tumors with different prognosis. In Colombia, we have previously reported that the most prevalent breast cancer subtype was luminal B based on immunohistochemistry (IHC) surrogates, which are routinely used in the clinical practice. We analyzed the concordance between IHC surrogates and PAM50 classification in luminal tumors from Colombian women and explored gene expression differences that may account for the observed differences. Methods: We performed whole-transcriptome RNA-seq analysis in 46 breast cancer samples from Colombian women diagnosed with estrogen receptor positive tumors (27 luminal A and 21 luminal B) at the Colombian National Cancer Institute. Genefu package from R was used to perform PAM50 classification, and the DESeq2package was used to test differential gene expression between discordant cases between PAM50 and IHC. Genes with adjusted p value less than 0.05 were considered statistical significant. Results: We found that 23 patients (50%) were discordant between both methodologies (IHC and PAM50). For the 27 luminal A tumors assessed by IHC, 10 (37%) were re-classified as luminal B by PAM50 and 3 (11.11%) as normal-like. On the other hand, for the 21 tumors classified as luminal B by IHC, 4 (19.04%) were re-assigned as HER2-enriched, 4 (19.04%) as luminal A and 2 (9.5%) as normal-like. Next, we tested differential expression in discordant vs. concordant cases with PAM50 within each luminal subtype assessed by IHC. For luminal B IHC-tumors, we found 67 differentially expressed genes. Some of the top differentially expressed genes are part of the ERBB2 signaling pathway (ERBB2, padj < 0.01, log2FC = 2.5; GRB7, padj < 0.01, log2FC = 2.95), which is consistent with the re-assignment of luminal A tumors to luminal B. Moreover, we found overexpression of ARID5B (padj< 0.01, log2FC=1.72) a histone modifier gene that has been described mutated in breast cancer. This result might suggest that an epigenetic mechanism may be involved in defining the luminal profile of these tumors. On the other hand, for luminal A IHC-tumors, we found 12 differentially expressed genes. The gene with the highest fold-change was DSCAM-AS1 (padj = 0.030, log2FC=3.43) which is very interesting as it is a estrogen-regulated long noncoding RNA (lncRNA) that has been recently associated with tumor progression and tamoxifen resistance. Conclusions: Our results suggest that epigenetic mechanisms such as histone modifications and the lncRNAs might be associated with luminal tumors in Colombian women and might also define the fate of the luminal profile of these tumors. Citation Format: Silvia J. Serrano-Gomez, Maria Carolina Sanabria-Salas, Jone Garay, Juan C. Mejia, Oscar Garcia, Jovanny Zabaleta, Laura Fejerman. Understanding transcriptomic profiles that might explain discordance of the PAM50 and immunohistochemistry classification methods in luminal tumors from Colombian women [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 460.

// Jone Garay 1 , M. Blanca Piazuelo 2 , Lizbeth Lopez-Carrillo 3 , Yelda A. Leal 4 , Sumana Majumdar 1 , Li Li 1 , Nataly Cruz-Rodriguez 1, 5, 6 , Silvia J. Serrano-Gomez 1, 5, 6 , Carlos S. Busso 7 , Barbara G. Schneider 2 , Alberto G. Delgado 2 , Luis E. Bravo 8 , Angela M. Crist 9 , Stryder M. Meadows 9 , M. Constanza Camargo 10 , Keith T. Wilson 2, 11 , Pelayo Correa 2 and Jovanny Zabaleta 1, 12 1 Stanley S. Scott Cancer Center, LSUHSC, New Orleans, LA, USA 2 Division of Gastroenterology, Hepatology, and Nutrition, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA 3 Instituto Nacional de Salud Publica, Cuernavaca, Morelos, Mexico 4 Unidad de Investigacion Medica Yucatan de la Unidad Medica de Alta Especialidad (UMAE) del Instituto Mexicano del Seguro Social (IMSS), Yucatan, Mexico 5 Pontificia Universidad Javeriana, Bogota, Colombia 6 Grupo de Investigacion en Biologia del Cancer, Instituto Nacional de Cancerologia, Bogota, Colombia 7 Department of Otorhinolaryngology, LSUHSC, New Orleans, LA, USA 8 Department of Pathology, Universidad del Valle, Cali, Colombia 9 Department of Cell and Molecular Biology Tulane University, New Orleans LA, USA 10 Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD, USA 11 Veterans Affairs Tennessee Valley Healthcare System, Nashville, TN, USA 12 Department of Pediatrics, LSUHSC, New Orleans, LA, USA Correspondence to: Jovanny Zabaleta, email: jzabal@lsuhsc.edu Keywords: precancerous gastric lesions, DMBT1 , H. pylori , inflammation, gastric cancer Received: October 25, 2016 Accepted: March 16, 2017 Published: April 03, 2017 ABSTRACT Helicobacter pylori infection triggers a cascade of inflammatory stages that may lead to the appearance of non-atrophic gastritis, multifocal atrophic, intestinal metaplasia, dysplasia, and cancer. Deleted in malignant brain tumors 1 (DMBT1) belongs to the group of secreted scavenger receptor cysteine-rich proteins and is considered to be involved in host defense by binding to pathogens. Initial studies showed its deletion and loss of expression in a variety of tumors but the role of this gene in tumor development is not completely understood. Here, we examined the role of DMBT1 in gastric precancerous lesions in Caucasian, African American and Hispanic individuals as well as in the development of gastric pathology in a mouse model of H. pylori infection. We found that in 3 different populations, mucosal DMBT1 expression was significantly increased (2.5 fold) in individuals with dysplasia compared to multifocal atrophic gastritis without intestinal metaplasia; the increase was also observed in individuals with advanced gastritis and positive H. pylori infection. In our animal model, H. pylori infection of Dmbt1-/- mice resulted in significantly higher levels of gastritis, more extensive mucous metaplasia and reduced Il33 expression levels in the gastric mucosa compared to H. pylori -infected wild type mice. Our data in the animal model suggest that in response to H. pylori infection DMBT1 may mediate mucosal protection reducing the risk of developing gastric precancerous lesions. However, the increased expression in human gastric precancerous lesions points to a more complex role of DMBT1 in gastric carcinogenesis.

The cAMP-dependent signaling pathways that orchestrate dendritic cell (DC) maturation remain to be defined in detail. Although cAMP was previously thought to signal exclusively through protein kinase A (PKA), it is now clear that cAMP also activates exchange protein activated by cAMP (Epac), a second major cAMP effector. Whether cAMP signaling via PKA is sufficient to drive DC maturation or whether Epac plays a role has not been examined. In this study, we used cAMP analogs to selectively activate PKA or Epac in human monocyte-derived DCs and examined the effect of these signaling pathways on several hallmarks of DC maturation. We show that PKA activation induces DC maturation as evidenced by the increased cell-surface expression of MHC class II, costimulatory molecules, and the maturation marker CD83. PKA activation also reduces DC endocytosis and stimulates chemotaxis to the lymph node-associated chemokines CXCL12 and CCL21. Although PKA signaling largely suppresses cytokine production, the net effect of PKA activation translates to enhanced DC activation of allogeneic T cells. In contrast to the stimulatory effects of PKA, Epac signaling has no effect on DC maturation or function. Rather, Epac suppresses the effects of PKA when both pathways are activated simultaneously. These data reveal a previously unrecognized crosstalk between the PKA and Epac signaling pathways in DCs and raise the possibility that therapeutics targeting PKA may generate immunogenic DCs, whereas those that activate Epac may produce tolerogenic DCs capable of attenuating allergic or autoimmune disease.

Background: Prediction of biochemical recurrence (BCR) using standard measures to assign risk classification in prostate cancer (PCa) patients at diagnosis is not precise. While in some patients BCR may happen sooner than expected in others, it may take several years before it appears. It is then necessary to devise better tools to predict accurately BCR. Our goal was to identify differentially expressed genes (DEGs) in cases with and without BCR within the risk groups determined by D'Amico (defined by the clinical stage, initial PSA, and Gleason stage in biopsy). Methods: We ran RNA-seq analysis in 52 Hispanic PCa patients with early BCR (within 5 years after the surgery) and 57 with no BCR in the same period of time. The cases were classified as high, intermediate, or low according to the D'Amico classification. Analyses were done using the DESeq2 package. Genes with p value adjusted by False Discovery Rate (padj) less than 0.05 and fold change (FC) > 2 were considered statistically significant. Pathway analysis was performed in MetaCore. Results: We found 4,281 DEGs (padj < 0.05) associated with tumor tissues in the BCR cases (7 of those with a FC > 2). In contrast, 4,647 DEGs were associated with tumor tissues in cases without BCR (16 with FC > 2). Of these genes, nine (CHRM3, CLDN8, ERG, GDF15, LUZP2, OR51E1, PTPRT, TRGC1, TPO) were exclusively found in cases without BCR, and one, ONECUT2, was exclusive for tissues with BCR. All these genes, except TRGC1, have been associated before with PCa: the Cholinergic Receptor Muscarinic 3 (CHRM3) and the Olfactory Receptor Family 51 Subfamily E Member 1 (OR51E1) have a growth-promoting role; Claudin 8 (CLDN8) is transcriptionally activated by the androgen receptor to promote progression of PCa; ETS Trancription Factor (ERG) participates in chromosomal translocation in PCa and is involved in cell proliferation, differentiation, angiogenesis, inflammation, and apoptosis; Growth Differentiation Factor 15 (GDF15) was reported to be part of a circulating tumor cell profile in castration-resistant PCa with high levels associated with poor survival; Leucine Zipper Protein 2 (LUZP2) seems to contribute to enzalutamide resistance in castration-resistant PCa; Protein Tyrosine Phosphatase Receptor Type T (PTPRT) was recently found overexpressed in localized PCa; Thyroid Peroxidase (TPO) promotes resistance to cell death and to chemotherapy in PCa; and ONECUT2 has been associated with different types of cancer and recently with prostate cancer. Pathway analysis of DEGs identified IL-6 signaling pathway via MEK/ERK and PI3K/AKT cascades; PPAR pathway activation (which involves transcription factors belonging to the nuclear hormone receptor superfamily and activated by fatty acids); and Adenosine A2B receptor signaling, which indirectly activates c-Myc, Cyclin D1, PI3K/AKT, and IL-6 in patients with BCR. On the other hand, IL-15 signaling via JAK-STAT cascade, WNT signaling pathway, G-protein signaling, apoptosis, and survival through NGF/TrkA PI3K-mediating signaling and mTORC2 downstream signaling pathways were identified in the group without BCR. These differences show that DEGs in both groups, even though implicated in processes related with tumor development, are involved in specific pathways that can be associated with the grade of aggressiveness of the tumors, and also, under specific circumstances, lead to BCR. In addition, we found that DEGs can separate BCR from no BCR cases within each risk group, suggesting that a genomic signature with DEGs is a better predictor of BCR than the clinically assigned risk groups. Conclusions: Tumor biology and signaling pathways activated in cases with BCR are different from those in cases without BCR, showing that aggressiveness of tumors can be found at the moment of surgery and that biomarkers of prognosis can be identified at this point. Citation Format: Natalia Acosta, Jovanny Zabaleta, Rodolfo Varela, Jorge Mesa, Silvia Serrano, Jone Garay, Melody Baddoo, Cruz Nataly, Alba Lucía Combita, María Carolina Sanabria-Salas. Aggressiveness and tumor biology in prostate cancer patients with and without biochemical recurrence [abstract]. In: Proceedings of the Tenth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2017 Sep 25-28; Atlanta, GA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2018;27(7 Suppl):Abstract nr B69.

The major cellular antioxidant glutathione is depleted during HIV infection and in obesity. Although the consequence of glutathione depletion on immune function is starting to emerge, it is currently not known whether glutathione dysregulation influences the differentiation and maturation of dendritic cells (DCs). Moreover, the effect of glutathione depletion on DC effector functions, such as Ag presentation, is poorly understood. Glutathione synthesis depends on the cystine/glutamate antiporter, which transports the rate-limiting precursor cystine into the cell in exchange for glutamate. In this paper, we present a detailed study of antiporter function in DCs and demonstrate a role for the antiporter in DC differentiation and cross-presentation. We show that the antiporter is the major mechanism for transport of cystine and glutamate and modulates the intracellular glutathione content and glutathione efflux from DCs. Blocking antiporter-dependent cystine transport decreases intracellular glutathione levels, and these effects correlate with reduced transcription of the functional subunit of the antiporter. We further demonstrate that blocking antiporter activity interferes with DC differentiation from monocyte precursors, but antiporter activity is not required for LPS-induced phenotypic maturation. Finally, we show that inhibiting antiporter uptake of cystine interferes with presentation of exogenous Ag to class II MHC-restricted T cells and blocks cross-presentation on MHC class I. We conclude that aberrant antiporter function disrupts glutathione homeostasis in DCs and may contribute to impaired immunity in the diseased host.