Duocarmycin SA Reduces Proliferation and Increases Apoptosis in Acute Myeloid Leukemia Cells In Vitro.

Acute myeloid leukemia (AML) is a hematological malignancy that is characterized by an expansion of immature myeloid precursors. Despite therapeutic advances, the prognosis of AML patients remains poor and there is a need for the evaluation of promising therapeutic candidates to treat the disease. The objective of this study was to evaluate the efficacy of duocarmycin Stable A (DSA) in AML cells in vitro. We hypothesized that DSA would induce DNA damage in the form of DNA double-strand breaks (DSBs) and exert cytotoxic effects on AML cells within the picomolar range. Human AML cell lines Molm-14 and HL-60 were used to perform 3-(4,5-dimethylthiazolyl-2)-2,5-diphenyltetrazolium bromide (MTT), DNA DSBs, cell cycle, 5-ethynyl-2-deoxyuridine (EdU), colony formation unit (CFU), Annexin V, RNA sequencing and other assays described in this study. Our results showed that DSA induced DNA DSBs, induced cell cycle arrest at the G2M phase, reduced proliferation and increased apoptosis in AML cells. Additionally, RNA sequencing results showed that DSA regulates genes that are associated with cellular processes such as DNA repair, G2M checkpoint and apoptosis. These results suggest that DSA is efficacious in AML cells and is therefore a promising potential therapeutic candidate that can be further evaluated for the treatment of AML.

Plasma metabolomics profiles in Black and White participants of the Adventist Health Study-2 cohort.

BACKGROUND: Black Americans suffer disparities in risk for cardiometabolic and other chronic diseases. Findings from the Adventist Health Study-2 (AHS-2) cohort have shown associations of plant-based dietary patterns and healthy lifestyle factors with prevention of such diseases. Hence, it is likely that racial differences in metabolic profiles correlating with disparities in chronic diseases are explained largely by diet and lifestyle, besides social determinants of health. METHODS: Untargeted plasma metabolomics screening was performed on plasma samples from 350 participants of the AHS-2, including 171 Black and 179 White participants, using ultrahigh-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) and a global platform of 892 metabolites. Differences in metabolites or biochemical subclasses by race were analyzed using linear regression, considering various models adjusted for known confounders, dietary and/or other lifestyle behaviors, social vulnerability, and psychosocial stress. The Storey permutation approach was used to adjust for false discovery at FDR < 0.05. RESULTS: Linear regression revealed differential abundance of over 40% of individual metabolites or biochemical subclasses when comparing Black with White participants after adjustment for false discovery (FDR < 0.05), with the vast majority showing lower abundance in Blacks. Associations were not appreciably altered with adjustment for dietary patterns and socioeconomic or psychosocial stress. Metabolite subclasses showing consistently lower abundance in Black participants included various lipids, such as lysophospholipids, phosphatidylethanolamines, monoacylglycerols, diacylglycerols, and long-chain monounsaturated fatty acids, among other subclasses or lipid categories. Among all biochemical subclasses, creatine metabolism exclusively showed higher abundance in Black participants, although among metabolites within this subclass, only creatine showed differential abundance after adjustment for glomerular filtration rate. Notable metabolites in higher abundance in Black participants included methyl and propyl paraben sulfates, piperine metabolites, and a considerable proportion of acetylated amino acids, including many previously found associated with glomerular filtration rate. CONCLUSIONS: Differences in metabolic profiles were evident when comparing Black and White participants of the AHS-2 cohort. These differences are likely attributed in part to dietary behaviors not adequately explained by dietary pattern covariates, besides other environmental or genetic factors. Alterations in these metabolites and associated subclasses may have implications for the prevention of chronic diseases in Black Americans.

A Health Profile of African Immigrant Men in the United States.

African immigrants (AI) are the fastest growing group of immigrants to the U.S. however, their health and health practices remains poorly characterized. Thus, this study aimed to describe the health profile of this under-described U.S. population. In order to contextualize their health profiles, we compared AI (n=95) to other U.S. Black populations, namely African Americans (AA, n=271) and Caribbean American (CA, n=203) immigrants. We used cross-sectional survey data from a prostate cancer health study with 569 Black adult male participants, ages 21 years or older. Demographic characteristics were compared using Chi-square tests and prevalence ratios, and prevalence odds ratios (POR) were estimated for AIs compared to AA and CA immigrants using a log-binomial regression model. Results revealed that AI exhibited significantly lower prevalence of asthma and diabetes, when compared to AA and CA immigrants. Furthermore, AI reported lower consumption of alcohol than AA (POR, 0.43, 95%CI 0.24, 0.75) and lower smoking prevalence than AA (POR, 0.19, 95%CI 0.05, 0.70) and CA immigrants (POR, 0.21, 95%CI 0.05, 0.76). Additionally, AI reported significantly lower medical mistrust than CA (POR, 0.51, 95%CI 0.26, 0.95), significantly low financial strain than CAs immigrants (POR, 1.66, 95%CI 1.00, 2.75) and significantly higher levels of religious coping than both AA (POR, 2.43, 95%CI 1.43, 4.12) and CA immigrant men (POR, 1.78, 95%CI 1.03, 3.08). This study further supports emerging evidence that Blacks in the U.S. are not a monolithic group and that it is necessary to assess the Black subgroups separately. In addition, as one of the fastest growing immigrant populations, it is critical for future research to understand African immigrant's health needs and its correlates.

Glucocorticoid Receptor Regulates and Interacts with LEDGF/p75 to Promote Docetaxel Resistance in Prostate Cancer Cells.

Patients with advanced prostate cancer (PCa) invariably develop resistance to anti-androgen therapy and taxane-based chemotherapy. Glucocorticoid receptor (GR) has been implicated in PCa therapy resistance; however, the mechanisms underlying GR-mediated chemoresistance remain unclear. Lens epithelium-derived growth factor p75 (LEDGF/p75, also known as PSIP1 and DFS70) is a glucocorticoid-induced transcription co-activator implicated in cancer chemoresistance. We investigated the contribution of the GR-LEDGF/p75 axis to docetaxel (DTX)-resistance in PCa cells. GR silencing in DTX-sensitive and -resistant PCa cells decreased LEDGF/p75 expression, and GR upregulation in enzalutamide-resistant cells correlated with increased LEDGF/p75 expression. ChIP-sequencing revealed GR binding sites in the LEDGF/p75 promoter. STRING protein-protein interaction analysis indicated that GR and LEDGF/p75 belong to the same transcriptional network, and immunochemical studies demonstrated their co-immunoprecipitation and co-localization in DTX-resistant cells. The GR modulators exicorilant and relacorilant increased the sensitivity of chemoresistant PCa cells to DTX-induced cell death, and this effect was more pronounced upon LEDGF/p75 silencing. RNA-sequencing of DTX-resistant cells with GR or LEDGF/p75 knockdown revealed a transcriptomic overlap targeting signaling pathways associated with cell survival and proliferation, cancer, and therapy resistance. These studies implicate the GR-LEDGF/p75 axis in PCa therapy resistance and provide a pre-clinical rationale for developing novel therapeutic strategies for advanced PCa.

A Luminex Approach to Develop an Anti-Tumor-Associated Antigen Autoantibody Panel for the Detection of Prostate Cancer in Racially/Ethnically Diverse Populations.

(1) Background: Autoantibodies to tumor-associated antigens (TAAs) have emerged as promising cancer biomarkers. Luminex technology offers a powerful approach for the simultaneous detection of multiple anti-TAA autoantibodies. (2) Methods: We aimed to utilize Luminex technology to evaluate and optimize a panel of anti-TAAs autoantibodies for detecting prostate cancer (PCa), which included autoantibodies to fourteen TAAs. A total of 163 serum samples (91 PCa, 72 normal controls) were screened to determine the levels of the autoantibodies using the Luminex assay. (3) Results: Twelve autoantibodies exhibited significantly high frequencies ranging from 19.8% to 51.6% in the PCa group. Receiver operating characteristic (ROC) curve analysis revealed area under the curve (AUC) values ranging from 0.609 to 0.868 for the twelve autoantibodies individually. We further confirmed the performance of the HSP60 autoantibody by using an enzyme-linked immunosorbent assay (ELISA) in a larger sample comprising 200 PCa sera, 20 benign prostatic hyperplasia (BPH) sera, and 137 normal control sera. The results obtained from the Luminex assay were consistent with the ELISA findings. We developed a panel consisting of three autoantibodies (p16, IMP2, and HSP60) which achieved an impressive AUC of 0.910 with a sensitivity of 71.4% and a specificity of 95.8%. The panel was also evaluated in PCa patients from different races/ethnicities with the best performance observed in distinguishing the Hispanic American patients with PCa from normal controls. (4) Conclusions: We developed an anti-TAA autoantibody panel for the detection of PCa that exhibits promising performance. This panel holds significant potential as a high-throughput tool to facilitate PCa detection.

Glucocorticoid Receptor and ß-Catenin Interact in Prostate Cancer Cells and Their Co-Inhibition Attenuates Tumorsphere Formation, Stemness, and Docetaxel Resistance.

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, ß-catenin is upregulated in metastatic and therapy-resistant tumors and is a crucial regulator of cancer stemness and ARSI resistance. ß-catenin interacts with AR to promote PCa progression. Given the structural and functional similarities between AR and GR, we hypothesized that ß-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 ß-catenin in PCa cells. Co-immunoprecipitation studies showed that GR and ß-catenin interact in DTX-resistant and DTX-sensitive PCa cells. Pharmacological co-inhibition of GR and ß-catenin, using the GR modulator CORT-108297 and the selective ß-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 ß-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.

The Nuclear Dense Fine Speckled (DFS) Immunofluorescence Pattern: Not All Roads Lead to DFS70/LEDGFp75.

The monospecific dense fine speckled (DFS) immunofluorescence assay (IFA) pattern is considered a potential marker to aid in exclusion of antinuclear antibody (ANA)-associated rheumatic diseases (AARD). This pattern is typically produced by autoantibodies against transcription co-activator DFS70/LEDGFp75, which are frequently found in healthy individuals and patients with miscellaneous inflammatory conditions. In AARD patients, these antibodies usually co-exist with disease-associated ANAs. Previous studies reported the occurrence of monospecific autoantibodies that generate a DFS-like or pseudo-DFS IFA pattern but do not react with DFS70/LEDGFp75. We characterized this pattern using confocal microscopy and immunoblotting. The target antigen associated with this pattern partially co-localized with DFS70/LEDGFp75 and its interacting partners H3K36me2, an active chromatin marker, and MLL, a transcription factor, in HEp-2 cells, suggesting a role in transcription. Immunoblotting did not reveal a common protein band immunoreactive with antibodies producing the pseudo-DFS pattern, suggesting they may recognize diverse proteins or conformational epitopes. Given the subjectivity of the HEp-2 IFA test, the awareness of pseudo-DFS autoantibodies reinforces recommendations for confirmatory testing when reporting patient antibodies producing a putative DFS pattern in a clinical setting. Future studies should focus on defining the potential diagnostic utility of the pseudo-DFS pattern and its associated antigen(s).

TSLP as a Potential Therapy in the Treatment of CRLF2 B Cell Acute Lymphoblastic Leukemia.

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.

Ethnic Differences Among Black Men in Prostate Cancer Knowledge and Screening: a Mixed-Methods Study.

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.

The LEDGF/p75 Integrase Binding Domain Interactome Contributes to the Survival, Clonogenicity, and Tumorsphere Formation of Docetaxel-Resistant Prostate Cancer Cells.

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.

Docosahexaenoic acid protection against palmitic acid-induced lipotoxicity in NGF-differentiated PC12 cells involves enhancement of autophagy and inhibition of apoptosis and necroptosis.

Lipotoxicity (LTx) leads to cellular dysfunction and cell death and has been proposed to be an underlying process during traumatic and hypoxic injuries and neurodegenerative conditions in the nervous system. This study examines cellular mechanisms responsible for docosahexaenoic acid (DHA 22:6 n-3) protection in nerve growth factor-differentiated pheochromocytoma (NGFDPC12) cells from palmitic acid (PAM)-mediated lipotoxicity (PAM-LTx). NGFDPC12 cells exposed to PAM show a significant lipotoxicity demonstrated by a robust loss of cell viability, apoptosis, and increased HIF-1α and BCL2/adenovirus E1B 19 kDa protein-interacting protein 3 gene expression. Treatment of NGFDPC12 cells undergoing PAM-LTx with the pan-caspase inhibitor ZVAD did not protect, but shifted the process from apoptosis to necroptosis. This shift in cell death mechanism was evident by the appearance of the signature necroptotic Topo I protein cleavage fragments, phosphorylation of mixed lineage kinase domain-like, and inhibition with necrostatin-1. Cultures exposed to PAM and co-treated with necrostatin-1 (necroptosis inhibitor) and rapamycin (autophagy promoter), showed a significant protection against PAM-LTx compared to necrostatin-1 alone. In addition, co-treatment with DHA, as well as 20:5 n-3, 20:4 n-6, and 22:5 n-3, in the presence of PAM protected NGFDPC12 cells against LTx. DHA-induced neuroprotection includes restoring normal levels of HIF-1α and BCL2/adenovirus E1B 19 kDa protein-interacting protein 3 transcripts and caspase 8 and caspase 3 activity, phosphorylation of beclin-1, de-phosphorylation of mixed lineage kinase domain-like, increase in LC3-II, and up-regulation of Atg7 and Atg12 genes, suggesting activation of autophagy and inhibition of necroptosis. Furthermore, DHA-induced protection was suppressed by the lysosomotropic agent chloroquine, an inhibitor of autophagy. We conclude that DHA elicits neuroprotection by regulating multiple cell death pathways including enhancement of autophagy and inhibiting apoptosis and necroptosis.

Twenty years of research on the DFS70/LEDGF autoantibody-autoantigen system: many lessons learned but still many questions.

The discovery and initial characterization 20 years ago of antinuclear autoantibodies (ANAs) presenting a dense fine speckled (DFS) nuclear pattern with strong staining of mitotic chromosomes, detected by indirect immunofluorescence assay in HEp-2 cells (HEp-2 IIFA test), has transformed our view on ANAs. Traditionally, ANAs have been considered as reporters of abnormal immunological events associated with the onset and progression of systemic autoimmune rheumatic diseases (SARD), also called ANA-associated rheumatic diseases (AARD), as well as clinical biomarkers for the differential diagnosis of these diseases. However, based on our current knowledge, it is not apparent that autoantibodies presenting the DFS IIF pattern fall into these categories. These antibodies invariably target a chromatin-associated protein designated as dense fine speckled protein of 70 kD (DFS70), also known as lens epithelium-derived growth factor protein of 75 kD (LEDGF/p75) and PC4 and SFRS1 Interacting protein 1 (PSIP1). This multi-functional protein, hereafter referred to as DFS70/LEDGF, plays important roles in the formation of transcription complexes in active chromatin, transcriptional activation of specific genes, regulation of mRNA splicing, DNA repair, and cellular survival against stress. Due to its multiple functions, it has emerged as a key protein contributing to several human pathologies, including acquired immunodeficiency syndrome (AIDS), leukemia, cancer, ocular diseases, and Rett syndrome. Unlike other ANAs, "monospecific" anti-DFS70/LEDGF autoantibodies (only detectable ANA in serum) are not associated with SARD and have been detected in healthy individuals and some patients with non-SARD inflammatory conditions. These observations have led to the hypotheses that these antibodies could be considered as negative biomarkers of SARD and might even play a protective or beneficial role. In spite of 20 years of research on this autoantibody-autoantigen system, its biological and clinical significance still remains enigmatic. Here we review the current state of knowledge of this system, focusing on the lessons learned and posing emerging questions that await further scrutiny as we continue our quest to unravel its significance and potential clinical and therapeutic utility.

Psychosocial Stress, Glucocorticoid Signaling, and Prostate Cancer Health Disparities in African American Men.

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.

Alpha-Enolase: Emerging Tumor-Associated Antigen, Cancer Biomarker, and Oncotherapeutic Target.

Alpha-enolase, also known as enolase-1 (ENO1), is a glycolytic enzyme that "moonlights" as a plasminogen receptor in the cell surface, particularly in tumors, contributing to cancer cell proliferation, migration, invasion, and metastasis. ENO1 also promotes other oncogenic events, including protein-protein interactions that regulate glycolysis, activation of signaling pathways, and resistance to chemotherapy. ENO1 overexpression has been established in a broad range of human cancers and is often associated with poor prognosis. This increased expression is usually accompanied by the generation of anti-ENO1 autoantibodies in some cancer patients, making this protein a tumor associated antigen. These autoantibodies are common in patients with cancer associated retinopathy, where they exert pathogenic effects, and may be triggered by immunodominant peptides within the ENO1 sequence or by posttranslational modifications. ENO1 overexpression in multiple cancer types, localization in the tumor cell surface, and demonstrated targetability make this protein a promising cancer biomarker and therapeutic target. This mini-review summarizes our current knowledge of ENO1 functions in cancer and its growing potential as a cancer biomarker and guide for the development of novel anti-tumor treatments.

Maternal plasma proteomics in a rat model of pregnancy complications reveals immune and pro-coagulant gene pathway activation.

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-ß1 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.

Anti-DFS70 antibodies: an update on our current understanding and their clinical usefulness.

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 antibodies, when present in high titers and in isolation (without accompanying other antibodies), are useful to aid in the exclusion of ANA associated rheumatic diseases. Areas covered: This review aims to analyze and interpret the current published knowledge and recent findings to provide guidance in the use of anti-DFS70 antibodies to analyze associations of this unique autoantibody. Expert commentary: Although the association of anti-DFS70 antibodies is still unknown, their use as a biomarker that can aid in the exclusion of ANA related diseases is well-established.

Glucocorticoids Induce Stress Oncoproteins Associated with Therapy-Resistance in African American and European American Prostate Cancer Cells.

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.

Supporting the Writing Productivity of Biomedical Graduate Students: An Integrated, Structured Writing Intervention.

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.