Search

Black men have the highest rate of prostate cancer (PCa) morbidity and mortality in the US, and often receive delayed and/or poorer-quality treatment. This inequity has led many to turn to complementary and alternative medicine/therapies (CAM). However, little is known about the use of these therapies within the Black community. The purpose of this study was to describe types of CAM therapies used, and the reasons behind their use for overall health and PCa treatment and prevention among three groups of Black males, namely African Americans, Caribbean Immigrants and African Immigrants. This study used a mixed-methods design with a quantitative phase (n = 575) followed by a qualitative phase (n = 61) with participants recruited from various parts of the country. Results revealed differences among subgroups in CAM use for overall health and PCa, as well as differences in the types of CAM therapies used and differences in the reasons behind their use. The findings of this study reveal a prevalence of CAM use for overall health and PCa within three different groups of Black men and identifies the specific CAM used. There were significant differences in the types of CAM used by each subgroup for both overall health and PCa. This study also shows that there is value in looking at Black subgroups distinctively, for their rates of CAM use and reasons for use, are distinctly different.

Cytokine receptor-like factor 2 B-cell acute lymphoblastic leukemia (CRLF2 B-ALL) is a high-risk subtype characterized by CRLF2 overexpression with poor survival rates in children and adults. CRLF2 and interleukin-7 receptor alpha (IL-7Rα) form a receptor for the cytokine thymic stromal lymphopoietin (TSLP), which induces JAK/STAT and PI3K/AKT/mTOR pathway signals. Previous studies from our group showed that low TSLP doses increased STAT5, AKT, and S6 phosphorylation and contributed to CRLF2 B-ALL cell survival. Here we investigated the role of TSLP in the survival and proliferation of CRLF2 B-ALL cells in vitro and in vivo. We hypothesized that high doses of TSLP increase CRLF2 signals and contribute to increased proliferation of CRLF2 B-ALL cells in vitro and in vivo. Interestingly, we observed the opposite effect. Specifically, high doses of TSLP induced apoptosis in human CRLF2 B-ALL cell lines in vitro, prevented engraftment of CRLF2 B-ALL cells, and prolonged the survival of +TSLP patient-derived-xenograft mice. Mechanistically, we showed that high doses of TSLP induced loss of its receptor and loss of CRLF2 signals in vitro. These results suggest that high doses of TSLP could be further investigated as a potential therapy for the treatment of CRLF2 B-ALL.

Black men are disproportionately affected by prostate cancer (PCa) incidence and mortality. Limited research has been reported on the ethnic differences among Black men in regard to family history, knowledge, and screening habits. Thus, this study was conducted to understand and compare knowledge levels and family history of the three main Black subgroups (African Americans, Caribbean immigrants, and African immigrants) in the USA and to assess the influence of knowledge on past screening behavior and intentionality for screening in the future for PCa. A concurrent mixed-methods design was used with participants (N = 396) recruited from different parts of the country. The grounded theory method of analysis was used for qualitative data and a logistic regression was used to explain the relationship between screening intentionality and PCa knowledge and family history. Qualitative results indicated that subjective PCa knowledge between the three subgroups was relatively similar but differed based on whether a person knew a family member or friend who had been affected by the disease. Themes focused on risk, PCa education, screening, and impact on sexuality. Quantitatively, result revealed that there are ethnic differences in knowledge across the three subgroups. Additionally, regression results revealed that family history is a stronger predictor of screening behavior and intentionality than knowledge. This study was able to unveil a deeper understanding on the role of family history and knowledge on PCa among Black subgroups.

Recent advances in our understanding of racial disparities in prostate cancer (PCa) incidence and mortality that disproportionately affect African American (AA) men have provided important insights into the psychosocial, socioeconomic, environmental, and molecular contributors. There is, however, limited mechanistic knowledge of how the interplay between these determinants influences prostate tumor aggressiveness in AA men and other men of African ancestry. Growing evidence indicates that chronic psychosocial stress in AA populations leads to sustained glucocorticoid signaling through the glucocorticoid receptor (GR), with negative physiological and pathological consequences. Compelling evidence indicates that treatment of castration-resistant prostate cancer (CRPC) with anti-androgen therapy activates GR signaling. This enhanced GR signaling bypasses androgen receptor (AR) signaling and transcriptionally activates both AR-target genes and GR-target genes, resulting in increased prostate tumor resistance to anti-androgen therapy, chemotherapy, and radiotherapy. Given its enhanced signaling in AA men, GR—together with specific genetic drivers—may promote CRPC progression and exacerbate tumor aggressiveness in this population, potentially contributing to PCa mortality disparities. Ongoing and future CRPC clinical trials that combine standard of care therapies with GR modulators should assess racial differences in therapy response and clinical outcomes in order to improve PCa health disparities that continue to exist for AA men.

Therapy resistance hinders the efficacy of anti-androgen therapies and taxane-based chemotherapy for advanced prostate cancer (PCa). Glucocorticoid receptor (GR) signaling mediates resistance to androgen receptor signaling inhibitors (ARSI) and has also been recently implicated in PCa resistance to docetaxel (DTX), suggesting a role in therapy cross-resistance. Like GR, β-catenin is upregulated in metastatic and therapy-resistant tumors and is a crucial regulator of cancer stemness and ARSI resistance. β-catenin interacts with AR to promote PCa progression. Given the structural and functional similarities between AR and GR, we hypothesized that β-catenin also interacts with GR to influence PCa stemness and chemoresistance. As expected, we observed that treatment with the glucocorticoid dexamethasone promotednuclear accumulation of GR and active β-catenin in PCa cells. Co-immunoprecipitation studies showed that GR and β-catenin interact in DTX-resistant and DTX-sensitive PCa cells. Pharmacological co-inhibition of GR and β-catenin, using the GR modulator CORT-108297 and the selective β-catenin inhibitor MSAB, enhanced cytotoxicity in DTX-resistant PCa cells grown in adherent and spheroid cultures and decreased CD44+/CD24– cell populations in tumorspheres. These results indicate that GR and β-catenin influence cell survival, stemness, and tumorsphere formation in DTX-resistant cells. Their co-inhibition could be a promising therapeutic strategy to overcome PCa therapy cross-resistance.

Metastatic prostate cancer (PCa) is the leading cause of PCa-associated deaths and one of the leading causes of cancer mortality in men. Novel therapeutics, such as Prostate Specific Membrane Antigen (PSMA) ligand therapy, are emerging as effective treatment strategies for metastatic prostate cancer. However, neuroendocrine differentiated (NED) metastatic PCa, which lacks the PSMA antigen, is deprived of effective biomarkers for disease treatment. Magmas, a 13.8 kDa mitochondrial protein, imports nuclear-encoded mitochondrial proteins into the mitochondrial matrix. Magmas is overexpressed in several aggressive tumors, such as breast cancer, glioblastoma, and prostate cancer. When overexpressed, Magmas plays a role as a cytoprotective protein by acting as a reactive oxygen species (ROS) scavenger that maintains sufficient ROS levels to promote cell proliferation, but below the threshold levels that could lead to apoptosis. This study was designed to investigate the pro-survival and therapy-resistance functions of Magmas in PCa cells expressing NED markers. Predictively, we observed that the docetaxel (DTX)-resistant PC3-DR and DU145-DR PCa cell lines expressed significantly higher levels of Magmas compared to their drug-sensitive parental cell lines. We hypothesized that inhibiting Magmas reduces the aggressive properties of highly proliferative DTX- resistant metastatic PCa cell lines and re-sensitize them to DTX. Magmas knockdown in DTX-sensitive and DTX-resistant PC3 and DU145 cells in the presence of increasing DTX treatments enhanced sensitivity to DTX. Consistent with these results, pharmacological inhibition of Magmas with the novel BT#9 inhibitor in combination with increasing DTX concentrations also enhanced sensitivity to DTX in these cell lines. Additional studies using clonogenic assays, cell migration/invasion assays, and tumorsphere formation assays are currently underway to further establish Magmas as a potential therapeutic target to attenuate the aggressive properties of chemoresistant PCa cells. Lastly, we will investigate the diagnostic potential of Magmas as a biomarker for NED and BT#9 as an imaging/therapeutic-specific agent for NED. Citation Format: Alfonso M. Durán, Christian H. Yoo, Jennifer D. Tran, Krystal Santiago, Adil S. Mohammed, Carlos A. Casiano, Frankis A. Almaguel. Targeting the mitochondrial protein MAGMAS increases sensitivity to docetaxel in neuroendocrine prostate cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1754.

The cysteine-rich angiogenic inducer 61 (CYR61) is a member of the cellular communication network (CCN) protein family that can be induced by growth factors. CYR61-specific functions are dependent on cellular context. In prostate cancer (PCa), CYR61 contributes to cell growth and survival through its interactions with extracellular ligands, such as integrins avb3 and a6b4, in the extracellular matrix space. Interestingly, CYR61 contains an insulin-like growth factor-binding protein domain suggesting that it may interact with insulin-like growth factor-I (IGF-1). High serum levels of IGF-1 are directly linked to PCa development and recently have been studied as a predictor of metastatic disease. Given the important roles that IGF-1 and CYR61 play in PCa and their potential interaction, it is critical to investigate their molecular interplay. This study is designated to specifically determine and characterize the molecular interaction between CYR61 and IGF-1 in metastatic PCa and to determine if this interaction contributes to aggressive tumor properties (e.g., proliferation, tumorsphere formation). Using immunoblotting, we demonstrated that CYR61 is upregulated in the metastatic cell line PC3 and downregulated in the docetaxel-resistant cell line PC3-DR. Furthermore, optimized knockdown of CYR61 using siRNA significantly reduced PC3 cell proliferation, viability, and prostasphere formation. To examine the underlying mechanisms associated with IGF-1 signaling, we assessed the activation of either the PI3/Akt and MAPK pathways in PC3 cells with CYR61 silencing. CYR61 siRNA-mediated knockdown decreased activation of the PI3/Akt pathway but did not affect the MAPK pathway. We also initiated studies to determine the co-localization of CYR61 and IGF-1 using immunofluorescence microscopy (IF). Based on the initial IF observations, we will proceed to examine if their interaction is primarily intra- or extra-cellular. For intracellular interactions, we will co-immunoprecipitate CYR61 with IGF-1 and for extracellular interactions, we will use the AVidity-based EXtracellular Interaction Screen (AVEXIS) system. Our goal is to establish the contribution of CYR61-IGF1 protein-protein interaction to PCa cell proliferation. Specifically, the correlation between PCa aggressiveness and circulating levels of CYR61 and IGF-1 is poorly studied. Their combined role may explain a proportion of aggressive PCa. Citation Format: Greisha L. Ortiz-Hernandez, Mya Walker, Leanne Woods-Burnham, Rick A. Kittles, Carlos A. Casiano, Susan L. Neuhausen. CYR61, a member of the CCN protein family, regulates IGF-1 in metastatic prostate cancer. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3949.

Prostate cancer (PCa) is the second most common cancer in American men, with men of African ancestry (AA) having twice the mortality of men of European ancestry (AA). Although taxane-based chemotherapy is the last line of defense in men with advanced PCa, it ultimately fails due to chemoresistance. The protein-specific membrane antigen (PSMA) has been an effective target for the imaging and therapy of advanced PCa. Specifically, PSMA radioligand therapy (PSMA-RLT) is a theranostics (therapy + diagnostics) option for men with advanced PCa. However, about 30% of men with advanced PCa have limited response to PSMA-RLT due to the presence of neuroendocrine-like PCa (NEPC), which lacks PSMA expression. A promising alternative to PSMA targeting is the glycolytic enzyme enolase (ENO), which localizes to the cell surface in advanced tumors. There are three enolases with similar functions, with ENO-1 and ENO-2 implicated in PCa. Previously, we showed that AA and EA men with PCa show differential serum antibody reactivity to ENO. While circulating serum antibodies from EA-PCa patients recognized ENO in both docetaxel (DTX)-sensitive and -resistant PCa cell lines, sera from AA-PCa men only recognized ENO in DTX-sensitive cells, with loss of immunoreactivity in the resistant cells. Here, we demonstrate, using immunoblotting and specific monoclonal antibodies, that chemosensitive NEPC cells express both ENO-1 and ENO-2; however, DTX-resistant cells only express ENO-1 with a clear loss of ENO-2. This pattern is identical to that produced by the AA-PCa serum antibodies, suggesting the possibility that AA-PCa patients may generate a preferential antibody response to ENO-2, with EA-PCa patients preferentially targeting ENO-1. This differential immunoreactivity may reflect differences between AA and EA PCa patients in tumor immunobiology, consistent with emerging literature. The loss of ENO-2 in chemoresistant PCa cells also generates a metabolic vulnerability due to the loss of ENO redundancy. We hypothesize that ENO-1 is expressed on the surface of NEPC cell lines and can be targeted with small molecule inhibitors (SMIs) that could be used as potential theranostics agents. Current studies are identifying ENO-1 surface expression on NEPC cell lines using monoclonal antibodies as well as AA and EA patient antibodies, via immunofluorescence microscopy, membrane fractionation analysis, and flow cytometry. We also initiated the testing of small molecule inhibitors (SMIs) targeting ENO-1 in chemoresistant NEPC cells. Our long-term goal is to identify an alternative treatment for patients with NEPC by establishing ENO-1 as a novel theranostics target. This could benefit AA-PCa patients, which may not mount a strong antitumor ENO-1 immune response. Citation Format: Krystal R. Santiago, Alfonso M. Duran, Carlos A. Casiano, Frankis G. Almaguel, Bhaskar Das. Enolase-1 as a candidate theranostics target for neuroendocrine prostate cancer [abstract]. In: Proceedings of the 15th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2022 Sep 16-19; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2022;31(1 Suppl):Abstract nr C063.

Se realizó un análisis cognitivo de tareas de los dominios de lectura, escritura y matemáticas, enviadas a niños de transición durante la cuarentena por covid-19. La muestra estuvo compuesta por 56 tareas. Fueron creados criterios para identificar las demandas cognitivas en cada dominio. Los resultados evidencian que en las tareas generalmente hicieron demandas cognitivas básicas, como recordar y memorizar. Se discute alrededor de la brecha que existe entre los planteamientos realizados por la literatura alrededor del aprendizaje y habilidades cognitivas de los niños, que los ubican como sujetos activos e investigadores, y la manera como las tareas enviadas los posicionan como reproductores/copiadores de información. Se propone que los psicólogos educativos trabajen junto con los docentes para diseñar tareas que aprovechen las habilidades cognitivas de los preescolares.

El presente artículo tiene por objetivo determinar el impacto provocado por la actual crisis sanitaria de la covid-19 sobre el desempeño académico de los estudiantes de la UNTRM-A. La metodología utilizada fue de índole cuantitativo, y fue ejecutada a través de un análisis comparativo del rendimiento académico y los factores asociados al nivel familiar, de activos y personal del estudiante. Se utilizaron dos escenarios: precovid-19 (ciclo 2019-II) y poscovid-19 (ciclo 2020-I), en los cuales se aplicaron pruebas estadísticas (paramétricas y no paramétricas) para evaluar las diferencias en muestras pareadas. Los resultados permitieron concluir que existió un incremento significativo en el desempeño académico pospandemia, a pesar de que el impacto de la covid-19 fue negativo sobre los factores asociados a la variable de estudio.

Introduction: Anti-DFS70 antibodies and their clinical associations remain an immunological paradox. Unlike other antinuclear antibodies (ANA), there is a growing body of evidence that anti-DFS70 a...

B-cell acute lymphoblastic leukemia (B-ALL) is the most common type of leukemia in children. B-ALL characterized by cytokine receptor-like factor 2 (CRLF2) overexpression (CRLF2 B-ALL) has a survival rate of Citation Format: Hossam Alkashgari, Cornelia Stoian, Caleb Ruiz-Jimenez, Jacqueline Coats, Carlos A. Casiano, Sinisa Dovat, Kimberly J. Payne. Molecular mechanisms of TSLP as a therapy for CRLF2 B-Cell acute lymphoblastic leukemia [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1528.

Prostate cancer (PCa) is the second leading cause of cancer deaths in the U.S., disproportionally affecting African American (AA) men. Glucocorticoids (GCs) are administered to PCa patients and have been implicated in therapy resistance. This may be critical to AA men with PCa since they have elevated endogenous GCs levels compared to Caucasian American (CA) men. GCs bind to the glucocorticoid receptor (GR) to exert their actions. The mechanisms of GR-mediated chemoresistance, and its possible contribution to PCa mortality disparities are unknown. We demonstrated that GCs upregulate the chemoresistance-associated protein and transcription co-activator LEDGF/p75 in PCa cells and identified consensus GR binding sites in the promoter region of this protein. Given that both GR and LEDGF/p75 are components of the RNA polymerase II transcription complex, we hypothesized that GR transcriptionally upregulates LEDGF/p75 and then interacts with it to enhance taxane resistance in PCa cells. Pharmacological and genetic inhibition of GR in a panel of docetaxel (DTX)-sensitive and -resistant PCa cells decreased the expression of LEDGF/p75, confirming its status as a candidate GR target gene. However, silencing of LEDGF/p75 had no effects on GR expression. Immunoprecipitation studies revealed that GR and LEDGF/p75 interact in DTX-resistant PCa cells. This interaction was confirmed by confocal microscopy. Immunohistochemical analysis of GR and LEDGF/p75 expression in normal and tumor prostate tissues was performed, and the results are currently being analyzed. Our studies use a mechanistic approach to evaluate the potential contribution of the GR-LEDGF/p75 axis to PCa chemoresistance. Evaluating the co-expression of these proteins in racially diverse PCa tissues may also reveal race-related differential expression, providing insights into the potential contribution of this axis to PCa chemoresistance and mortality disparities. Citation Format: Evelyn S. Sanchez Hernandez, Greisha L. Ortiz Hernandez, Pedro T. Ochoa, Christian R. Gomez, Carlos A. Casiano. Contribution of the GR/LEDGFp75 axis to prostate cancer chemoresistance [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2348.

Aberrant lipid metabolism in prostate tumors is linked to aggressive disease and poor outcomes. The purpose of this study was to identify mechanisms by which lipid metabolism in prostate cancer cells influences the tumor immune microenvironment, with emphasis on the activation of macrophages. Our hypothesis that fatty acid synthase-driven de novo lipogenesis promotes immune evasion via alternative M2-like macrophage activation was tested using human monocyte (U937)-derived macrophages co-cultured with prostate cancer cells in the presence of fatty acid synthase inhibitors. Monocytes were differentiated to macrophages in vitro using phorbol-12-myristate-13-acetate for 48 hours prior to co-culture with prostate cancer cells. Macrophage polarization following co-culture with prostate cancer cells was evaluated using multi-parameter flow cytometry to detect established M1 (CD80, CD86) and M2 (CD163, CD206) markers. Furthermore, the expression of fatty acid synthase and pan-macrophage marker CD68 in human prostate tumor tissue microarrays was evaluated using multiplex immunohistochemistry. The lipogenic enzyme and macrophage staining correlated with disease progression, reaching peak levels in metastatic tissues. These findings indicate that tumoral fatty acid synthase is an important mediator of tumor-immune crosstalk, particularly in the context of aggressive and metastatic prostate cancer. These data further suggest that fatty acid synthesis represents a targetable complement to immune-enhancing therapies by modulating tumor cell metabolism, underscoring the need for further evaluation of agents targeting lipid metabolism in prostate cancer. Citation Format: Shannalee R. Martinez, Carla Barrientos Risso, Ralphdy Vergne, Nathan R. Wall, Julie Dutil, Carlos A. Casiano, Gilberto Ruiz-Deya, Carlos Joel Diaz Osterman. Tumor lipogenesis influences macrophage polarization in advanced prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2559.

The efficacy of anti-androgen receptor (AR) therapies and taxane-based chemotherapy for the treatment of advanced prostate cancer (PCa) is hindered by the development of therapy resistance. Our previous studies demonstrated that docetaxel (DTX)-resistant PCa cells activates a transcriptomic program associated with stemness and display cancer stem cell (CSC) properties, consistent with the notion that CSCs within prostate tumors contribute to chemoresistance. Glucocorticoid receptor (GR) signaling is a critical mediator of resistance to AR-targeted therapy, and has been recently implicated in the development of PCa cell tumorsphere formation and chemoresistance. Like GR, β-catenin is overexpressed in metastatic and therapy-resistant tumors, and is considered a key regulator of cancer stemness and androgen-targeted therapy resistance. Given the structural and functional overlap between GR and AR, a known interacting partner of β-catenin, we hypothesized that GR also interacts with β-catenin to support stemness and chemoresistance in PCa cells. We observed that treatment with the glucocorticoid dexamethasone induces enhanced nuclear accumulation of both GR and β-catenin in DTX-resistant PCa cells compared to their DTX-sensitive counterparts. Knockdown studies revealed that GR and β-catenin do no regulate each other at the protein level. However, using whole cell and nuclear co-immunoprecipitation, we demonstrated the interaction between GR and β-catenin in both DTX-resistant and DTX-sensitive PC3, DU145, and 22RV1 cells. Pharmacological inhibition and RNA interference-mediated silencing of GR with concomitant inhibition of β-catenin enhanced DTX cytotoxicity in resistant PCa cells grown in both adherent and spheroid cultures, and decreased CD44+/CD24- cell populations in tumorspheres. These results indicate that both GR and β-catenin interact and influence stemness, and may be promising therapeutic targets to overcome PCa chemoresistance. Citation Format: Shannalee R. Martinez, Catherine C. Elix, Pedro T. Ochoa, Evelyn S. Sanchez-Hernandez, Hossam R. Alkashgari, Greisha L. Ortiz-Hernandez, Lubo Zhang, Carlos A. Casiano. The glucocorticoid receptor and β-catenin interact in prostate cancer cells and their co-inhibition attenuates stemness and docetaxel resistance [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 399.

Black men are disproportionately affected by prostate cancer (PCa) incidence and mortality. Limited research has been reported on the ethnic differences among Black men in regard to family history, knowledge, and screening habits. Thus, this study was conducted to understand and compare knowledge levels and family history of the three main Black subgroups (African Americans, Caribbean immigrants, and African immigrants) in the USA and to assess the influence of knowledge on past screening behavior and intentionality for screening in the future for PCa. A concurrent mixed-methods design was used with participants (N = 396) recruited from different parts of the country. The grounded theory method of analysis was used for qualitative data and a logistic regression was used to explain the relationship between screening intentionality and PCa knowledge and family history. Qualitative results indicated that subjective PCa knowledge between the three subgroups was relatively similar but differed based on whether a person knew a family member or friend who had been affected by the disease. Themes focused on risk, PCa education, screening, and impact on sexuality. Quantitatively, result revealed that there are ethnic differences in knowledge across the three subgroups. Additionally, regression results revealed that family history is a stronger predictor of screening behavior and intentionality than knowledge. This study was able to unveil a deeper understanding on the role of family history and knowledge on PCa among Black subgroups.

Prostate cancer (PCa) is the second leading cause of cancer-related death among Black men who present with higher incidence, mortality, and survival compared to other racial groups. African immigrant men, however, are underrepresented in PCa research and thus this research sought to address that gap. This study applied a social determinants of health framework to understand the knowledge, perceptions, and behavioral tendencies regarding PCa in African immigrants. African immigrant men and women residing in different parts of the country (California, Texas, Colorado, Oklahoma, and Florida) from various faith-based organizations, African community groups, and social groups were recruited to participate in key informant interviews ( n = 10) and two focus groups ( n = 23). Four themes were identified in this study: (a) PCa knowledge and attitudes—while knowledge is very limited, perceptions about prostate health are very strong; (b) culture and gender identity strongly influence African health beliefs; (c) preservation of manhood; and (d) psychosocial stressors (e.g., financial, racial, immigration, lack of community, and negative perceptions of invasiveness of screening) are factors that play a major role in the overall health of African immigrant men. The results of this qualitative study unveiled perceptions, attitudes, beliefs, and knowledge of PCa among African immigrants that should inform the planning, development, and implementation of preventive programs to promote men’s health and PCa awareness.

Glucocorticoid receptor (GR) is emerging as a key driver of prostate cancer (PCa) progression and therapy resistance in the absence of androgen receptor (AR) signaling. Acting as a bypass mechanism, GR activates AR-regulated genes, although GR-target genes contributing to PCa therapy resistance remain to be identified. Emerging evidence also shows that African American (AA) men, who disproportionately develop aggressive PCa, have hypersensitive GR signaling linked to cumulative stressful life events. Using racially diverse PCa cell lines (MDA-PCa-2b, 22Rv1, PC3, and DU145) we examined the effects of glucocorticoids on the expression of two stress oncoproteins associated with PCa therapy resistance, Clusterin (CLU) and Lens Epithelium-Derived Growth Factor p75 (LEDGF/p75). We observed that glucocorticoids upregulated LEDGF/p75 and CLU in PCa cells. Blockade of GR activation abolished this upregulation. We also detected increased GR transcript expression in AA PCa tissues, compared to European American (EA) tissues, using Oncomine microarray datasets. These results demonstrate that glucocorticoids upregulate the therapy resistance-associated oncoproteins LEDGF/p75 and CLU, and suggest that this effect may be enhanced in AA PCa. This study provides an initial framework for understanding the contribution of glucocorticoid signaling to PCa health disparities.

Prostate cancer (PCa) is the second leading cause of cancer deaths in the U.S., disproportionally affecting African American (AA) men. Glucocorticoids (GCs) are administered to PCa patients and have been implicated in therapy resistance. This may be critical to AA men with PCa since they have elevated endogenous GCs levels compared to Caucasian American (CA) men. GCs bind to the glucocorticoid receptor (GR) to exert their actions. The mechanisms of GR-mediated chemoresistance, and its possible contribution to PCa mortality disparities are unknown. We demonstrated that GCs upregulate the chemoresistance-associated protein and transcription co-activator LEDGF/p75 in PCa cells and identified consensus GR binding sites in the promoter region of this protein. Given that both GR and LEDGF/p75 are components of the RNA polymerase II transcription complex, we hypothesized that GR transcriptionally upregulates LEDGF/p75 and then interacts with it to enhance taxane resistance in PCa cells. Pharmacological and genetic inhibition of GR in a panel of docetaxel (DTX)-sensitive and -resistant PCa cells decreased the expression of LEDGF/p75, confirming its status as a candidate GR target gene. However, silencing of LEDGF/p75 had no effects on GR expression. Immunoprecipitation studies revealed that GR and LEDGF/p75 interact in DTX-sensitive and -resistant PCa cells. This interaction was confirmed by confocal microscopy. Immunohistochemical analysis of GR and LEDGF/p75 expression in normal and tumor prostate tissues was performed and the results are currently being analyzed. Our studies use a mechanistic approach to evaluate the potential contribution of the GR-LEDGF/p75 axis to PCa chemoresistance. Evaluating the co-expression of these proteins in racially diverse PCa tissues may also reveal race-related differential expression, providing insights into the potential contribution of this axis to PCa chemoresistance and mortality disparities. Citation Format: Evelyn S Sanchez-Hernandez, Greisha L. Ortiz-Hernandez, Pedro T. Ochoa, Christian R Gomez, Carlos A Casiano. Contribution of the GR-LEDGF/p75 axis to prostate cancer chemoresistance [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-145.

Patients with prostate cancer (PCa) receiving docetaxel chemotherapy invariably develop chemoresistance. The transcription co-activator lens epithelium-derived growth factor p75 (LEDGF/p75), also known as DFS70 and PSIP1, is upregulated in several human cancers, including PCa and promotes resistance to docetaxel and other drugs. The C-terminal region of LEDGF/p75 contains an integrase binding domain (IBD) that tethers nuclear proteins, including the HIV-1 integrase and transcription factors, to active chromatin to promote viral integration and transcription of cellular survival genes. Here, we investigated the contribution of the LEDGF/p75 IBD interactome to PCa chemoresistance. Quantitative immunoblotting revealed that LEDGF/p75 and its IBD-interacting partners are endogenously upregulated in docetaxel-resistant PCa cell lines compared to docetaxel-sensitive parental cells. Using specific human autoantibodies, we co-immunoprecipitated LEDGF/p75 with its endogenous IBD-interacting partners JPO2, menin, MLL, IWS1, ASK1, and PogZ, as well as transcription factors c-MYC and HRP2, in docetaxel-resistant cells, and confirmed their nuclear co-localization by confocal microscopy. Depletion of LEDGF/p75 and selected interacting partners robustly decreased the survival, clonogenicity, and tumorsphere formation capacity of docetaxel-resistant cells. These results implicate the LEDGF/p75 IBD interactome in PCa chemoresistance and could lead to novel therapeutic strategies targeting this protein complex for the treatment of docetaxel-resistant tumors.

// Leslimar Rios-Colon 1 , Christina K. Cajigas-Du Ross 1 , Anamika Basu 1 , Catherine Elix 1 , Ivana Alicea-Polanco 1 , Tino W. Sanchez 1 , Vinodh Radhakrishnan 1 , Chien-Shing Chen 2 , Carlos A. Casiano 1, 3 1 Center for Health Disparities and Molecular Medicine, Department of Basic Sciences, Loma Linda University School of Medicine, Loma Linda, CA 92354, USA 2 Department of Medicine, Division of Hematology/Medical Oncology, Loma Linda University School of Medicine, Loma Linda, CA 92354, USA 3 Department of Medicine, Division of Rheumatology, Loma Linda University School of Medicine, Loma Linda, CA 92354, USA Correspondence to: Carlos A. Casiano, email: ccasiano@llu.edu Keywords: chemoresistance, LEDGF/p75, prostate cancer, cell death, taxanes Abbreviations: prostate cancer (PCa), docetaxel (DTX), paclitaxel (PTX), cabazitaxel (CBZ), TNF related apoptosis inducing ligand (TRAIL). Received: June 14, 2016 Accepted: October 13, 2016 Published: February 14, 2017 ABSTRACT Prostate cancer (PCa) is associated with chronic prostate inflammation resulting in activation of stress and pro-survival pathways that contribute to disease progression and chemoresistance. The stress oncoprotein lens epithelium-derived growth factor p75 (LEDGF/p75), also known as DFS70 autoantigen, promotes cellular survival against environmental stressors, including oxidative stress, radiation, and cytotoxic drugs. Furthermore, LEDGF/p75 overexpression in PCa and other cancers has been associated with features of tumor aggressiveness, including resistance to cell death and chemotherapy. We report here that the endogenous levels of LEDGF/p75 are upregulated in metastatic castration resistant prostate cancer (mCRPC) cells selected for resistance to the taxane drug docetaxel (DTX). These cells also showed resistance to the taxanes cabazitaxel (CBZ) and paclitaxel (PTX), but not to the classical inducer of apoptosis TRAIL. Silencing LEDGF/p75 effectively sensitized taxane-resistant PC3 and DU145 cells to DTX and CBZ, as evidenced by a significant decrease in their clonogenic potential. While TRAIL induced apoptotic blebbing, caspase-3 processing, and apoptotic LEDGF/p75 cleavage, which leads to its inactivation, in both taxane-resistant and -sensitive PC3 and DU145 cells, treatment with DTX and CBZ failed to robustly induce these signature apoptotic events. These observations suggested that taxanes induce both caspase-dependent and -independent cell death in mCRPC cells, and that maintaining the structural integrity of LEDGF/p75 is critical for its role in promoting taxane-resistance. Our results further establish LEDGF/p75 as a stress oncoprotein that plays an important role in taxane-resistance in mCRPC cells, possibly by antagonizing drug-induced caspase-independent cell death.

PROBLEM The Brown Norway (BN) rat is a model of T-helper 2 immune diseases, and also a model of pregnancy disorders that include placental insufficiency, fetal loss, and pre-eclampsia-like symptoms. The aim of this study was to investigate the plasma proteomic/cytokine profile of pregnant BN rats in comparison to that of the Lewis (LEW) rat strain. METHOD OF STUDY Plasma proteomics differences were studied at day 13 of pregnancy in pooled plasma samples by differential in-gel electrophoresis, and protein identification was performed by mass spectrometry. Key protein findings and predicted cytokine differences were validated by ELISA using plasma from rats at various pregnancy stages. Proteomics data were used for ingenuity pathway analysis (IPA). RESULTS In-gel analysis revealed 74 proteins with differential expression between BN and LEW pregnant dams. ELISA studies confirmed increased maternal plasma levels of complement 4, prothrombin, and C-reactive protein in BN compared to LEW pregnancies. LEW pregnancies showed higher maternal plasma levels of transthyretin and haptoglobin than BN pregnancies. Ingenuity pathway analysis revealed that BN pregnancies are characterized by activation of pro-coagulant, reactive oxygen species, and immune-mediated chronic inflammation pathways, and suggested increased interleukin 6 and decreased transforming growth factor-β1 as potential upstream events. Plasma cytokine analysis revealed that pregnant BN dams have a switch from anti- to pro-inflammatory cytokines with the opposite switch observed in pregnant LEW dams. CONCLUSION Brown Norway rats show a maternal pro-inflammatory response to pregnancy that likely contributes to the reproductive outcomes observed in this rat strain.

Los ecosistemas de bosque seco forman parte de los valles interandinos del noreste de Perú, y son considerados como una de las fronteras biogeográficas más importante de los Andes, que alberga especies endémicas de flora y fauna. Sin embargo, debido a la presión antrópica, como la quema para ampliar la frontera agrícola y ganadera, tala, cacería, invasiones, etc.; estos ecosistemas están siendo reducidos y amenazados, y por ende, los servicios ecosistémicos que brindan. Por lo cual, a pesar de los esfuerzos de titulares privados por invertir en la conservación de la diversidad biológica a través de modelos de aprovechamiento sostenible y la restauración de los mismos, aún se evidencia la desvinculación del cuidado de la biodiversidad de terceras personas, que constantemente atentan contra estos espacios. En consecuencia, se propone la valoración económica de los daños a los recursos naturales para cuantificar los daños y perjuicios causados sobre los valores de uso y no uso, en términos monetarios, para la compensación adecuada, por las pérdidas en recursos productivos y/o por gastos de limpieza y restauración del área, debido al incendio ocasionado en el ACP Milpuj – La Heredad. El análisis del valor económico del daño se hizo a través de la suma de los costos del daño, costos de las medidas de restauración y del valor económico de los servicios ecosistémicos del bosque seco; obteniendo la cantidad total de S/. 210, 279. 67, y S/. 8,963.33/ha.

La presente investigación tuvo por objetivo realizar un análisis de la evolución de la oferta laboral del departamento Amazonas entre 2004 y 2019. El diseño de la investigación fue no experimental del tipo longitudinal de tendencia y con enfoque cuantitativo. Para esto se analizó el conjunto de series temporales referidos a la oferta laboral (Población en Edad de Trabajar (PET) y Población Económicamente Activa (PEA)) dividas por niveles de empleo, estructuras de mercado, ramas de actividad económica, nivel educativo e ingreso laboral. Los resultados mostraron una tasa de desempleo promedio de 1.42%, reducción del subempleo de 20.34 puntos porcentuales y una tasa de actividad promedio de 78%. Así también, la existencia de oferta laboral con bajos niveles de capital humano (46.34% de la PEA sólo tuvo nivel primario) y bajos niveles de ingreso (22.28% en promedio de la PEA no tuvo ingresos). Estos resultados permiten concluir que la oferta laboral para el departamento Amazonas entre 2004 y 2019 tuvo una evolución positiva, explicada por la caída del subempleo y el aumento de la tasa de actividad. Sin embargo, los altos niveles de subempleo y bajos niveles de capital humano e ingresos podrían ser causantes de deterioros en el mercado laboral.

BACKGROUND The prostate-specific antigen (PSA) testing has been widely implemented for the early detection and management of prostate cancer (PCa). However, the lack of specificity has led to overdiagnosis, resulting in many possibly unnecessary biopsies and overtreatment. Therefore, novel serological biomarkers with high sensitivity and specificity are of vital importance needed to complement PSA testing in the early diagnosis and effective management of PCa. This is particularly critical in the context of PCa health disparities, where early detection and management could help reduce the disproportionately high PCa mortality observed in African-American men. Previous studies have demonstrated that sera from patients with PCa contain autoantibodies that react with tumor-associated antigens (TAAs). METHODS The serological proteome analysis (SERPA) approach was used to identify tumor-associated antigens (TAAs) of PCa. In evaluation study, the level of anti-NPM1 antibody was examined in sera from test cohort, validation cohort, as well as European-American (EA) and African-American (AA) men with PCa by using immunoassay. RESULTS Nucleophosmin 1 (NPM1) as a 33 kDa TAA in PCa was identified and characterized by SERPA approach. Anti-NPM1 antibody level in PCa was higher than in benign prostatic hyperplasia (BPH) patients and healthy individuals. Receiver operating characteristic (ROC) curve analysis showed similar high diagnostic value for PCa in the test cohort (area under the curve (AUC):0.860) and validation cohort (AUC: 0.822) to differentiate from normal individuals and BPH. Interestingly, AUC values were significantly higher for AA PCa patients. When considering concurrent serum measurements of anti-NPM1 antibody and PSA, 97.1% PCa patients at early stage were identified correctly, while 69.2% BPH patients who had elevated PSA levels were found to be anti-NPM1 negative. Additionally, anti-NPM1 antibody levels in PCa patients at early stage significantly increased after surgery treatment. CONCLUSION This intriguing data suggested that NPM1 can elicit autoantibody response in PCa and might be a potential biomarker for the immunodiagnosis and prognosis of PCa, and for supplementing PSA testing in distinguishing PCa from BPH. Prostate 76:1375–1386, 2016. © 2016 Wiley Periodicals, Inc.

Autoantibodies against intracellular tumor-associated antigens (TAAs) are commonly found in human cancers. In this study, we characterized the serum autoantibody response to the RalA, Ras-like GTPase, in patients with prostate cancer (PCa). The autoantibodies were detected by immunofluorescence assay in PCa cell lines, ELISA, and immunoblotting in 339 serum samples from patients with PCa and benign prostatic hyperplasia (BPH), and in normal human sera (NHS). The expression of RalA in prostate tumor tissues was evaluated by immunohistochemistry (IHC) in tumor microarrays. The autoantibody level to RalA (median) in NHS was significantly lower than in PCa (0.053 vs 0.138; P < 0.001) and BPH (0.053 vs 0.132; P < 0.005) groups. The circulating anti-RalA autoantibody could distinguish PCa patients from normal individuals with the area under the receiver operating characteristic (ROC) curve (AUC) performing at 0.861, with sensitivity of 52.9% and specificity of 91.0%. Elevation in serum immunoreactivity was observed in PCa patients after radical prostatectomy. The combined use of both anti-RalA autoantibody and PSA showed a significantly higher discriminatory ability compared with either of those markers alone. RalA protein expression was detected by IHC in 85.3% of tumor tissues from PCa patients, but without significant difference compared to BPH or normal control tissues. Together, our study shows the additional benefits of anti-RalA autoantibody as a potential serological biomarker for PCa, particularly in patients with normal PSA, and further demonstrate the utility of biomarker combinations in the immunodiagnosis of PCa.

Anti-DFS70 antibodies and their clinical associations remain an immunological paradox. Unlike other antinuclear antibodies (ANA), especially when present at high titres, anti-DFS70 antibodies are not prevalent in ANA associated rheumatic diseases. Despite significant interest and progress in understanding the clinical association of anti-DFS70 antibodies, no specific clinical associations have been confirmed. In reality, several studies reporting clinical association of these antibodies (i.e. atopic dermatitis, thrombosis, autoimmune thyroiditis) have added confusion instead of bringing significant insight. In addition, several groups have consistently reported on the occurrence of anti-DFS70 antibodies in a relevant fraction of apparently healthy individuals. This review aims to analyse the current knowledge and to provide future guidance to analyse potential clinical associations of anti-DFS70 antibodies by summarizing and interpreting recent findings.

Prostate Cancer (PCa) progression leads to an advanced stage called metastatic castration PCa (mCRPC), for which currently there is no cure in spite of advances in treatment with new generation anti-androgen drugs and chemotherapy with taxanes such as docetaxel (DTX). Our group demonstrated previously that the stress oncoprotein Lens Epithelium Derived Growth Factor of 75 kD (LEDGF/p75) is upregulated in clinical prostate tumors and contributes to DTX-resistance in mCRPC cells. However, little is known about the molecular mechanisms by which LEDGF/p75 promotes taxane resistance. The C-terminus of LEDGF/p75 contains a domain called the Integrase Binding Domain (IBD), which in T cells is responsible for tethering the HIV-integrase complex to transcriptionally active chromatin. In non-PCa cells, the LEDGF/p75 IBD interacts with transcription complexes, such as Menin-MLL and the c-MYC binding protein JPO2, to promote cell survival. However, the relevance of these and others protein-protein interactions (PPIs) in the context of PCa chemoresistance has never been explored. This study was designed to test the hypothesis that interactions between LEDGF/p75, the c-MYC binding protein JPO2, Menin and MLL in DTX-resistant mCRPC cells contribute to chemoresistance. We demonstrated by immunoblotting a significant co-upregulation of JPO2, c-MYC, Menin, MLL, and LEDGF/p75 in the DTX-resistant PC3-DR and DU145-DR cell lines, compared to the parental, drug sensitive cells. We also observed nuclear co-localization of these proteins by immunofluorescence microscopy and confocal microscopy. Using an immunoprecipitation approach, we confirmed that endogenous JPO2, c-MYC, Menin, and MLL co-immunoprecipitate with LEDGF/p75 in the DTX-resistant PCa cell lines. We are extending these studies to other known interacting partners of LEDGF/p75 to determine if they are also upregulated in DTX-resistant PCa cells and interact with this protein in the chemoresistance context. In addition, we have initiated studies to evaluate the effects of pharmacologic and genetic inhibition of LEDGF/p75 and its interacting partners on sensitization of DR cells to DTX. We predict that targeting LEDGF/p75 PPIs will disrupt transcriptional activity contributing to DTX resistance. Our goals are to establish the contribution of these PPIs to LEDGF/p75-mediated transactivation of DTX resistance-associated genes, and target these interactions to overcome PCa chemoresistance. Citation Format: Greisha L. Ortiz Hernandez, Evelyn S. Sanchez-Hernández, Carlos A. Casiano. Interaction of LEDGF/p75 with oncogenic transcription factors in docetaxel resistant prostate cancer cells [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 4688.

Prostate cancer (PCa) is the most commonly diagnosed male cancer, with men of African ancestry showing a disproportionately high incidence and mortality. There is increasing evidence that glucocorticoid signaling through glucocorticoid receptor (GR) is amplified in African American men due to cumulative life stress, and that GR signaling is a key driver of resistance to androgen-targeted therapy, radiotherapy, and taxane chemotherapy in advanced PCa. Recent studies indicate that GR also promotes in PCa cells the formation of tumorspheres, a property of cancer stem cells (CSC); however, the mechanisms remain unclear. CSCs are intrinsically resistant to therapies due to their low-frequency, expression of transporters and efflux pumps, quiescent cell cycle and metabolic profile. Our previous studies demonstrated that docetaxel (DTX)-resistant PCa cells exhibit increased capacity for CSC-like properties, suggesting that these properties contribute to chemoresistance. Like GR, beta-catenin is overexpressed in metastatic and therapy-resistant tumors, and is considered a key regulator of cancer stemness and androgen-targeted therapy resistance. Thus, we hypothesized that GR may interact with beta-catenin in PCa cells to support stemness and chemoresistance. Using whole-cell and nuclear co-immunoprecipitation, we demonstrated the interaction between GR and beta-catenin in several DTX-sensitive and -resistant PCa cell line pairs. Pharmacological inhibition of GR using the selective inhibitor CORT-108297 with concomitant inhibition of beta-catenin using the small molecule inhibitor MSAB significantly enhanced DTX cytotoxicity in resistant PCa cells grown in both adherent and spheroid cultures. The BET bromodomain inhibitor JQ1, an antagonist of enhancer-mediated GR upregulation, also significantly reduced tumorsphere formation and stemness in DTX-resistant PCa cells. In order to gain insights into transcriptomic profiles activated by GR signaling that may contribute to stemness and therapy resistance, we performed RNA sequencing in a racially diverse panel of PCa cell lines (MDA-PCa-2b, VCaP, 22RV1, and PC3) treated with and without dexamethasone, a potent glucocorticoid. We observed that the African American cell line MDA-PCa-2b yielded the largest number of differentially regulated genes, perhaps due to the ability of dexamethasone to signal through both AR and GR in this particular cell line. RNAseq data is currently being mined and validated in cellular models treated with glucocorticoids or androgens, in the presence or absence of anti-GR or anti-androgen inhibitors, in order to identify GR-regulated genes. Our results offer novel insights into mechanisms by which GR signaling may influence tumorsphere formation and stemness, and suggest that combinatorial targeting of GR and beta-catenin could be a promising therapeutic strategy to overcome PCa therapy resistance and consequently reduce PCa mortality and its racial disparities. Citation Format: Shannalee R Martinez, Evelyn S Sanchez-Hernandez, Xin Chen, Alfonso M Duran, Charles H Wang, Carlos A Casiano. Glucocorticoid receptor interacts with beta-catenin to promote stemness and therapy resistance in prostate cancer cells [abstract]. In: Proceedings of the Twelfth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2019 Sep 20-23; San Francisco, CA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2020;29(6 Suppl_2):Abstract nr D116.

Prostate cancer (PCa) is the second leading cause of cancer-related deaths in the U.S., with African American (AA) men showing a higher mortality than European American (EA) men. While biological determinants contributing to PCa health disparities remain to be clearly established, there is growing evidence of differences in immunobiology between AA and EA patients with PCa. We demonstrated previously, using immunoproteomic profiling of anti-tumor autoantibody responses in AA and EA patients with PCa, that the glycolytic enzyme enolase 1 (ENO1) is the target of an autoantibody response in subsets of these patients. AA patient sera showed immunoreactivity to ENO1 in a panel of PCa cell lines, as detected by immunoblotting, with lack of reactivity in docetaxel (DTX)-resistant PC3 and DU145 cells. By contrast, anti-ENO1 sera from EA patients and a monoclonal anti-ENO1 antibody (MoAB-ENO1) showed immunoreactivity across the same cell line panel, including DTX-resistant cells. We also noted differences in anti-ENO1 reactivity in ELISA and immunoblots of PCa cell lysates between AA-PCa and EA-PCa patients, suggesting a race-related generation of autoantibodies to different ENO1 variants. ENO1 is a surface protein in cancer cells with roles in plasminogen activation, cell migration, and metastasis. Thus, we explored if anti-ENO1 autoantibodies from AA and EA PCa patients exerted different anti-cancer effects against DTX-sensitive and DTX-resistant PCa cells. Using cell migration assays, we observed that anti-ENO1 sera from EA patients and MoAB-ENO1 reduced the migration of DTX-resistant PC3 and DU145 cells but not that of DTX-sensitive cells. This inhibitory effect was intrinsic to the autoantibodies since purified IgG fraction produced similar results. Further, these inhibitory effects were reversed by pre-absorption of anti-ENO1 sera and purified IgG with recombinant human ENO1. Intriguingly, anti-ENO1 sera from AA patients lacked the same inhibitory effects on the migration of DTX-resistant cells, consistent with their lack of immunoreactivity to ENO1 in these cells. In addition, we observed that MoAB-ENO1, which behaves similar to the anti-ENO1 EA sera, decreased viability without evident cell death, measured by MTT assays and imaging analysis, in both DTX-sensitive and DTX-resistant cells, with a more robust effect on the latter. Together, these results suggest that anti-ENO1 autoantibodies from EA-PCa patients may exert a protective effect by decreasing the migration and proliferation of chemoresistant PCa cells. By contrast, anti-ENO1 autoantibodies from AA PCa patients may lack these protective effects, which could contribute to increased cancer cell migration and metastasis. Further studies are needed to dissect the molecular basis for this race-related differential anti-ENO1 immunoreactivity in PCa patients, and exploit the immunotherapeutic potential of anti-ENO1 antibodies for the treatment of chemoresistant PCa. Citation Format: Carlos Diaz-Osterman, Tino Sanchez, Carlos A Casiano. Differential reactivity and cell migration inhibitory functions of autoantibodies to Enolase 1 from African American and European American men with prostate cancer [abstract]. In: Proceedings of the Twelfth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2019 Sep 20-23; San Francisco, CA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2020;29(6 Suppl_2):Abstract nr D117.

Our group and others established that the stress oncoprotein LEDGF/p75 is a tumor-associated antigen (TAA) targeted by serum autoantibodies in certain patients with prostate cancer (PCa). LEDGF/p75 is also upregulated in clinical prostate tumors and contributes to docetaxel (DTX)-resistance in advanced PCa cells. The C-terminus of LEDGF/p75 contains a domain called the Integrase Binding Domain (IBD), which in T cells is responsible for tethering the HIV-integrase complex to transcriptionally active chromatin. In cancer cells, the IBD interacts with oncogenic transcription complexes to promote cell survival. However, the relevance of these LEDGF/p75 protein-protein interactions (PPIs) in PCa and chemoresistance has never been explored. This study aims to test if the interactions between LEDGF/p75, JPO2, Menin, and MLL in DTX-resistant PCa cells contribute to chemoresistance. Also, we want to target these interactions with repurposed HIV-based small molecule inhibitors (SMIs) of LEDGF/p75, which target the IBD, to abrogate this resistance. We demonstrated a significant co-upregulation of these proteins in DTX-resistant PC3-DR and DU145-DR cell lines, compared to the parental cells. Also, we observed nuclear co-localization by immunofluorescence microscopy. Using human anti-LEDGFp75 autoantibodies, we confirmed that endogenous proteins co-immunoprecipitate in the DTX-resistant PCa cell lines. Besides, we are evaluating repurposed HIV-based SMIs for their efficacy in sensitizing resistant cells to DTX. Our goals are to use anti-LEDGFp75 autoantibodies to establish its endogenous-interactome, contribution to transactivation of DTX-resistant genes, and target this interactome to overcome PCa chemoresistance.

We explored potential barriers and facilitators for prostate cancer screening choices among high-risk Black men. In our sample of 264 Black men over 45 years of age living in the U.S. who met the American Cancer Society criteria for screening, we found that only 49.6% had ever been screened. We investigated potential barriers including screening intention, access to care, medical mistrust, and fatalism. Potential facilitating factors investigated were provider-patient conversations encompassing the pros and cons of screening, ethnicity taken into account, insurance, and previous prostate cancer screening. Recommendations and resources are suggested to increase screening of high-risk Black men.

Writing is a critical skill for graduate students, but few studies in the literature describe how it is supported in the training of biomedical graduate students. The Initiative for Maximizing Student Development program at Loma Linda University aims to develop this important skill in its students through an integrated, structured writing intervention. Specifically, the program hired a writing specialist who taught writing seminars, facilitated writing and publishing workshops, and mentored students in one-on-one writing conferences. Doctoral students in the program, primarily underrepresented minority students with some not having English as a first language, all exhibited writing apprehension and blocking behaviors. The percentage of students graduating, publishing, and entering science careers, all of which require writing, is high. To yield insight into how this intervention worked, we conducted in-depth interviews of six of the earliest graduates, derived themes, analyzed data from pre- and post-assessments, and described their publication records. Participating students increased their writing confidence, adopted productive writing strategies, decreased writing anxiety and blocking behaviors, and published successfully.

African American (AA)/Black men are more likely to develop aggressive prostate cancer (PCa), yet less likely to be screened despite guidelines espousing shared decision-making regarding PCa screening and prostate-specific antigen (PSA) testing. Given the documented racial disparities in PCa incidence and mortality, engaging interactions with physicians are especially important for AA/Black men. Thus, this study evaluated occurrence of physician–patient conversations among AA/Black men, and whether such conversations were associated with PCa knowledge. We also quantified the serum PSA values of participants who had, and had not, discussed testing with their physicians. Self-identified AA/Black men living in California and New York, ages 21–85, donated blood and completed a comprehensive sociodemographic and health survey ( n = 414). Less than half (45.2%) of participants had discussed PCa screening with their physicians. Multivariate analyses were used to assess whether physician–patient conversations predicted PCa knowledge after adjusting for key sociodemographic/economic and health-care variables. Increased PCa knowledge was correlated with younger age, higher income and education, and having discussed the pros and cons of PCa testing with a physician. Serum PSA values were measured by ELISA. Higher-than-normal PSA values were found in 38.5% of men who had discussed PCa screening with a physician and 29.1% who had not discussed PCa screening. Our results suggest that physician–AA/Black patient conversations regarding PCa risk need improvement. Encouraging more effective communication between physicians and AA/Black men concerning PCa screening and PSA testing has the potential to reduce PCa health disparities.

Patients with metastatic castration-resistant prostate cancer (mCRPC) develop resistance to conventional therapies including docetaxel (DTX). Identifying molecular pathways underlying DTX resistance is critical for developing novel combinatorial therapies to prevent or reverse this resistance. To identify transcriptomic signatures associated with acquisition of chemoresistance we profiled gene expression in DTX-sensitive and -resistant mCRPC cells using RNA sequencing (RNA-seq). PC3 and DU145 cells were selected for DTX resistance and this phenotype was validated by immunoblotting using DTX resistance markers (e.g. clusterin, ABCB1/P-gp, and LEDGF/p75). Overlapping genes differentially regulated in the DTX-sensitive and -resistant cells were ranked by Gene Set Enrichment Analysis (GSEA) and validated to correlate transcript with protein expression. GSEA revealed that genes associated with cancer stem cells (CSC) (e.g., NES, TSPAN8, DPPP, DNAJC12, and MYC) were highly ranked and comprised 70% of the top 25 genes differentially upregulated in the DTX-resistant cells. Established markers of epithelial-to-mesenchymal transition (EMT) and CSCs were used to evaluate the stemness of adherent DTX-resistant cells (2D cultures) and tumorspheres (3D cultures). Increased formation and frequency of cells expressing CSC markers were detected in DTX-resistant cells. DU145-DR cells showed a 2-fold increase in tumorsphere formation and increased DTX resistance compared to DU145-DR 2D cultures. These results demonstrate the induction of a transcriptomic program associated with stemness in mCRPC cells selected for DTX resistance, and strengthen the emerging body of evidence implicating CSCs in this process. In addition, they provide additional candidate genes and molecular pathways for potential therapeutic targeting to overcome DTX resistance.

Objetivos: Determinar los resultados maternos y perinatales de la analgesia de parto. Diseño: Estudio observacional, descriptivo, de casos y controles. Institución: Servicio de Ginecología y Obstetricia, Hospital Docente Madre Niño San Bartolomé, Lima, Perú. Participantes: Gestantes en trabajo de parto. Métodos: Se revisó los datos de 400 gestantes (grupo I=controles; grupo II=casos), atendidas en el periodo septiembre a diciembre de 2013. Principales medidas de resultados: Resultados maternos y perinatales. Resultados: La media de edad en el grupo de casos fue 24,2+/-3,5 años, el peso fue 72,3+/-3,7 kg y la edad gestacional 38,6+/-1,2 semanas. A los 30 minutos, el nivel de dolor descendió significativamente (p < 0,01) en el grupo de los casos, manteniéndose este descenso hasta el final de la dilatación. La dilatación completa para el grupo control se alcanzó a los 233 ± 28,7 minutos y a los 200,9 ± 29,5 minutos para el grupo de los casos, con una diferencia menor estadísticamente significativa. La duración del expulsivo para el grupo control fue 23,3 ± 5,3 minutos comparado con los casos de 27,5 ± 3,7, con una diferencia mayor estadísticamente significativa para el último grupo. Conclusiones: La analgesia de parto con bupivacaína-fentanil resultó un método eficaz para el alivio del dolor del parto cuando fue administrada en trabajo de parto bien establecido (dilatación 4 cm), acortando la duración de manera significativa y no interfiriendo con el reflejo de pujar. Aunque la duración del expulsivo fue significativamente mayor, no tuvo implicancia con la obtención de recién nacidos en buenas condiciones ni aumentó de manera significativa los partos instrumentados y las cesáreas. Objectives: To determine maternal and perinatal outcomes of intrapartum analgesia. Design: Observational, descriptive, case-control study. Setting: Obstetrics and Gynecology Department, Hospital Docente Madre Niño San Bartolomé, Lima, Peru. Participants: Women in labor. Methods: Four hundred medical charts from pregnant women in labor (Group 1= controls; Group 11= cases) attended between September and December 2013 were reviewed. Main outcome measures: Maternal and perinatal outcomes. Results: Mean age of control group was 24.2 +/-3.5 years. Mean weight was 72.3 +/- 3.7 kg, and mean gestational age 38.6 +/- 1.2 weeks. Pain decreased with significance 30 minutes following analgesia (p < 0.01) in the cases group and lasted until the end of dilatation. Mean complete dilatation time for the control group was 233 +/- 28.7 minutes and 200.9 +/- 29.5 for the cases group with statistical significant minar difference. Length of the expulsive period for the control group was 23.3 +/- 5.3 compared to the cases group time of 27.5 +/- 3.6, with statistical significant majar dif ference for the last group. Conclusions: Bupivacaine-Fentanil intrapartum analgesia was an effective method for pain relief during delivery when appropriately administered (dilatation 4 cm or over), shortening duration significantly and not interfering with the pushing reflex. The second stage was longer but did not have implications on neonates or increased operative vaginal delivery or cesarean section rateo

Human antinuclear autoantibodies (ANAs) targeting the dense fine speckled (DFS) nuclear protein DFS70, commonly known as lens epithelium derived growth factor p75 (LEDGFp75), present a clinical puzzle since their significance remains elusive. While their frequencies are low in ANA-positive autoimmune rheumatic diseases, they are relatively elevated in clinical laboratory referrals, diverse inflammatory conditions, and ‘apparently’ healthy individuals. We reported previously that DFS70/LEDGFp75 is an autoantigen in prostate cancer that closely interacts with another 70 kD DFS nuclear protein, methyl CpG binding protein 2 (MeCP2). This led us to investigate if anti-DFS sera exclusively target DFS70/LEDGFp75 or also recognize MeCP2. Using several complementary autoantibody detection platforms and cellular/molecular approaches we evaluated 65 human sera producing anti-DFS autoantibodies. Our results show that these antibodies are highly specific for DFS70/LEDGFp75 and do not target MeCP2. Establishing the specificity of anti-DFS autoantibodies has implications for increasing our understanding of their biological significance and clinical utility.

Prostate cancer (PCa) remains the most frequently diagnosed male malignancy in Western countries and the second most common cause of male cancer death in the United States. The relatively elevated PCa incidence and mortality among African American men makes this cancer type a challenging health disparity disease. To increase the chance for successful trea tment, earlier detection and prediction of tumor aggress iveness will be important and need to be resolved. This study demonstrates that small membrane-bound vesicles shed from the tumor called exosomes contain ethnically and tumor-specific biomarkers, and could be exploited for their diagnostic and therapeutic potential.

Antinuclear autoantibodies (ANAs) displaying the nuclear dense fine speckled immunofluorescence (DFS-IIF) pattern in HEp-2 substrates are commonly observed in clinical laboratory referrals. They target the dense fine speckled autoantigen of 70 kD (DFS70), most commonly known as lens epithelium-derived growth factor p75 (LEDGFp75). Interesting features of these ANAs include their low frequency in patients with systemic autoimmune rheumatic diseases (SARD), elevated prevalence in apparently healthy individuals, IgG isotype, strong trend to occur as the only ANA specificity in serum, and occurrence in moderate to high titers. These autoantibodies have also been detected at varied frequencies in patients with diverse non-SARD inflammatory and malignant conditions such as atopic diseases, asthma, eye diseases, and prostate cancer. These observations have recently stimulated vigorous research on their clinical and biological significance. Some studies have suggested that they are natural, protective antibodies that could serve as biomarkers to exclude a SARD diagnosis. Other studies suggest that they might be pathogenic in certain contexts. The emerging role of DFS70/LEDGFp75 as a stress protein relevant to human acquired immunodeficiency syndrome, cancer, and inflammation also points to the possibility that these autoantibodies could be sensors of cellular stress and inflammation associated with environmental factors. In this comprehensive review, we integrate our current knowledge of the biology of DFS70/LEDGFp75 with the clinical understanding of its autoantibodies in the contexts of health and disease.