Single-cell RNA sequencing of human prostate basal epithelial cells reveals zone-specific cellular populations and gene expression signatures.

Despite evidence of genetic signatures in normal tissue correlating with disease risk, prospectively identifying genetic drivers and cell types that underlie subsequent pathologies has historically been challenging. The human prostate is an ideal model to investigate this phenomenon because it is anatomically segregated into three glandular zones (central, peripheral, and transition) that develop differential pathologies: prostate cancer in the peripheral zone (PZ) and benign prostatic hyperplasia (BPH) in the transition zone (TZ), with the central zone (CZ) rarely developing disease. More specifically, prostatic basal cells have been implicated in differentiation and proliferation during prostate development and regeneration; however, the contribution of zonal variation and the critical role of basal cells in prostatic disease etiology are not well understood. Using single-cell RNA sequencing of primary prostate epithelial cultures, we elucidated organ-specific, zone-specific, and cluster-specific gene expression differences in basal cells isolated from human prostate and seminal vesicle (SV). Aggregated analysis identified ten distinct basal clusters by Uniform Manifold Approximation and Projection. Organ specificity compared gene expression in SV with the prostate. As expected, SV cells were distinct from prostate cells by clustering, gene expression, and pathway analysis. For prostate zone specificity, we identified two CZ-specific clusters, while the TZ and PZ populations clustered together. Despite these similarities, differential gene expression was identified between PZ and TZ samples that correlated with gene expression profiles in prostate cancer and BPH, respectively. Zone-specific profiles and cell type-specific markers were validated using immunostaining and bioinformatic analyses of publicly available RNA-seq datasets. Understanding the baseline differences at the organ, zonal, and cellular level provides important insight into the potential drivers of prostatic disease and guides the investigation of novel preventive or curative treatments. Importantly, this study identifies multiple prostate basal cell populations and cell type-specific gene signatures within prostate basal epithelial cells that have potential critical roles in driving prostatic diseases. © 2023 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

Fusion-driven cutaneous and superficial mesenchymal and adnexal tumors-A clinicopathologic and molecular study of 15 cases, including a novel case of ACTB::ZMIZ2-rearranged adnexal carcinoma.

BACKGROUND: While the list of fusion-driven soft tissue neoplasms is expanding rapidly, their importance among cutaneous and superficial mesenchymal and adnexal neoplasms remains poorly understood. This challenge is especially evident in cases with ambiguous histopathology that are difficult to classify based on morphology. AIMS: Our goal was to investigate the benefits of next-generation sequencing in diagnosing complex cutaneous neoplasms. MATERIALS & METHODS: Departmental archives were searched for fusion-driven cutaneous neoplasms. Slides were retrieved and clinical information including follow-up was obtained. RESULTS: Fifteen cases occurred in eight female and seven male patients, with a median age of 26 years (range: 1-83) at diagnosis. Tumors involved the extremities (9), scalp (5), and head and neck (1). Predominant features included myoepithelial (5), nested spindled with clear cytoplasm (2), atypical adnexal/squamoid (2), small round blue cell (2), cellular spindled (3), and fibrohistiocytic morphology (1). Most frequently encountered fusions involved EWSR1 (6) fused to ERG (1), FLI1 (1), CREB1 (2), CREM (1), PBX3 (1), followed by PLAG1 (4) with LIFR (2), TRPS1 (1) and CHCHD7. Additional fusions encountered were YAP1::NUTM1, EML4::ALK, SS18::SSX1 (2), and a novel fusion: ACTB::ZMIZ2. Integration of histologic features and molecular findings led to final diagnoses of primary cutaneous Ewing sarcoma (2), soft tissue myoepithelioma (4), cutaneous syncytial myoepithelioma (1), cutaneous adnexal carcinoma (1), porocarcinoma (1), inflammatory myofibroblastic tumor (1), synovial sarcoma (2), clear cell sarcoma (2), and angiomatoid fibrous histiocytoma (1). DISCUSSION AND CONCLUSION: Our results show that fusion testing can be a helpful diagnostic tool, especially in cases with unusual or uncommon morphology in superficial sites. Furthermore, it can allow for the identification of potential therapeutic targets in some instances.

Protein tyrosine kinase 6 regulates activation of SRC kinase.

Expression of Protein tyrosine kinase 6 (PTK6) is upregulated in several human solid tumors, and it has oncogenic roles in prostate and breast cancer. PTK6 and SRC kinase are distantly related, share many substrates, and often regulate the same signaling pathways, but whether they interact to regulate signaling is not well understood. We characterized crosstalk between PTK6 and SRC and show that PTK6 can directly phosphorylate SRC to promote its activation. Stable knockdown of PTK6 in multiple cancer cell lines leads to decreased activating phosphorylation of SRC. We show that coexpression of kinase-dead SRC and active PTK6 in mouse embryonic fibroblasts lacking Src, Yes, and Fyn results in activating phosphorylation of SRC. However, there is no reciprocal effect, because active SRC does not promote activating phosphorylation of PTK6. Overexpression of active PTK6 maintained activation of epidermal growth factor receptor (EGFR), AKT, and FAK, but not SHP2 and ERK1/2 in cells with knockdown of SRC. Both PTK6 and SRC are regulated by EGFR, and its inhibition with erlotinib downregulated PTK6 and to a lesser degree SRC activation in LNCaP cells that overexpress active PTK6. Erlotinib treatment also led to AKT inhibition, but overexpression of active PTK6 prevented this. Our data demonstrate overlapping and unique functions for PTK6 and SRC. Finally, we show that PTK6 and SRC are coexpressed in subsets of human prostate and breast cancer cells, and active PTK6 and active SRC colocalize in prostate cancer, supporting a role for PTK6 in promoting SRC activity in cancer.

Carcinogenesis and Prognostic Utility of Arginine Methylation-Related Genes in Hepatocellular Cancer.

Protein arginine methylation is among the most important post-translational modifications and has been studied in cancers such as those of the lung and breast. However, comparatively less has been investigated regarding hepatocellular carcinoma, with an annual incidence of almost one million cases. Through using in silico methods, this study examined arginine methylation-related gene expression and methylation levels, and alongside network and enrichment analysis attempted to find how said genes can drive tumorigenesis and offer possible therapeutic targets. We found a robust relationship among the selected methylation genes, with ⅞ showing prognostic value regarding overall survival, and a medley of non-arginine methylation pathways also being highlighted through the aforementioned analysis. This study furthers our knowledge of the methylation and expression patterns of arginine histone methylation-related genes, offering jumping points for further wet-lab studies.

Vitamin D and genetic ancestry are associated with apoptosis rates in benign and malignant prostatic epithelium.

PURPOSE: Vitamin D metabolites may be protective against prostate cancer (PCa). We conducted a cross-sectional analysis to evaluate associations between in vivo vitamin D status, genetic ancestry, and degree of apoptosis using prostatic epithelial terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining. EXPERIMENTAL DESIGN: Benign and tumor epithelial punch biopsies of participants with clinically localized PCa underwent indirect TUNEL staining. Serum levels of 25 hydroxyvitamin D [25(OH)D] and 1,25 dihydroxyvitamin D were assessed immediately before radical prostatectomy; levels of prostatic 25(OH)D were obtained from the specimen once the prostate was extracted. Ancestry informative markers were used to estimate the percentage of genetic West African, Native American, and European ancestry. RESULTS: One hundred twenty-one newly diagnosed men, age 40-79, were enrolled between 2013 and 2018. Serum 25(OH)D correlated positively with both tumor (ρ = 0.17, p = 0.03), and benign (ρ = 0.16, p = 0.04) prostatic epithelial TUNEL staining. Similarly, prostatic 25(OH)D correlated positively with both tumor (ρ = 0.31, p < 0.001) and benign (ρ = 0.20, p = 0.03) epithelial TUNEL staining. Only Native American ancestry was positively correlated with tumor (ρ = 0.22, p = 0.05) and benign (ρ = 0.27, p = 0.02) TUNEL staining. In multivariate regression models, increasing quartiles of prostatic 25(OH)D (ß = 0.25, p = 0.04) and Native American ancestry (ß = 0.327, p = 0.004) were independently associated with tumor TUNEL staining. CONCLUSIONS: Physiologic serum and prostatic 25(OH)D levels and Native American ancestry are positively associated with the degree of apoptosis in tumor and benign prostatic epithelium in clinically localized PCa. Vitamin D may have secondary chemoprevention benefits in preventing PCa progression in localized disease.

Regulation of SELENOF translation by eIF4a3: Possible role in prostate cancer progression.

The levels of the SELENOF selenoprotein are dramatically reduced in prostate cancer compared to adjacent benign tissue and reducing SELENOF in prostate epithelial cells results in the acquisition of features of the transformed phenotype. It was hypothesized that the aberrant increase in the eiF4a3 translation factor, which has an established role in RNA splicing and the regulation of selenoprotein translation, contributes to the lower levels of SELENOF. Using the available databases, eIF4a3 messenger RNA (mRNA) levels are elevated in prostate cancer compared to normal tissue as is the hypomethylation of the corresponding gene. Using a prostate cancer tissue microarray, we established that eiF4a3 levels are higher in prostate cancer tissue. Ectopic expression of eIF4a3 in prostate cancer cells reduced SELENOF levels and attenuated the readthrough of the UGA codon using a specialized reporter construct designed to examine UGA decoding, with the opposite effects observed using eIF4a3 knock-down constructs. Direct binding of eIF4a3 to the regulatory regions of SELENOF mRNA was established with pull-down experiments. Lastly, we show that an eIF4a3 inhibitor, eIF4a3-IN-2, increases SELENOF levels, UGA readthrough, and reduces binding of eIF4a3 to the SELENOF mRNA 3'-UTR in exposed cells. These data establish eIF4a3 as a likely prostate cancer oncogene and a regulator of SELENOF translation.

In-Depth Comparison of Genetic Variants Demonstrates a Close Relationship Between Invasive and Intraductal Components of Prostate Cancer.

Intraductal carcinoma (IDC) of the prostate is often associated with concurrent high-grade invasive prostate cancer (PCa) and poor clinical outcomes. In this context, IDC is thought to represent the retrograde spread of invasive prostatic adenocarcinoma into the acini and ducts. Prior studies have demonstrated a concordance of PTEN loss and genomic instability between the IDC and high-grade invasive components of PCa, but larger genomic association studies to solidify our understanding of the relationship between these 2 lesions are lacking. Here, we evaluate the genomic relationship between duct-confined (high-grade prostatic intraepithelial neoplasia and IDC) and invasive components of high-grade PCa using genetic variants generated by whole exome sequencing. High-grade prostatic intraepithelial neoplasia and IDC were laser-microdissected, and PCa and nonneoplastic tissue was manually dissected from 12 radical prostatectomies. A targeted next-generation sequencing panel was used to identify disease-relevant variants. Additionally, the degree of overlap between adjacent lesions was determined by comparing exome-wide variants detected using whole exome sequencing data. Our results demonstrate that IDC and invasive high-grade PCa components show common genetic variants and copy number alterations. Hierarchical clustering of genome-wide variants suggests that in these tumors, IDC is more closely related to the high-grade invasive components of the tumor compared with high-grade prostatic intraepithelial neoplasia. In conclusion, this study reinforces the concept that, in the context of high-grade PCa, IDC likely represents a late event associated with tumor progression.

Associations of selenoprotein expression and gene methylation with the outcome of clear cell renal carcinoma.

Selenoproteins are a ubiquitous class of proteins defined by having a selenocysteine amino acid residue. While many of the selenoproteins have been well characterized with important roles in oxidation-reduction reactions and hormone synthesis among others, there exist some whose biological roles are not as well understood as denoted by the "SELENO" root. In this study, we explored associations between the reported RNA levels of "SELENO" proteins and clear cell renal cell carcinoma (ccRCC), the most common subtype of renal carcinoma in the US. Utilizing The Cancer Genome Atlas (TCGA) alongside other in silico tools, we discovered higher mRNA expression of Selenoprotein I, T, and P was associated with better overall survival outcomes and differential expression of other selenoproteins based on tumor stage. Additionally, we uncovered relative hypomethylation among selenoproteins in primary ccRCC tumor samples compared to normal tissue. Network and enrichment analysis showed numerous genes through which selenoproteins may modulate cancer progression and outcomes such as DERL1, PNPLA2/3, MIEN1, and FOXO1 which have been well-described in other cancers. In light of our findings highlighting an association of selenoprotein methylation and expression patterns with ccRCC outcome, further wet lab research is warranted.

All-digital histopathology by infrared-optical hybrid microscopy.

Optical microscopy for biomedical samples requires expertise in staining to visualize structure and composition. Midinfrared (mid-IR) spectroscopic imaging offers label-free molecular recording and virtual staining by probing fundamental vibrational modes of molecular components. This quantitative signal can be combined with machine learning to enable microscopy in diverse fields from cancer diagnoses to forensics. However, absorption of IR light by common optical imaging components makes mid-IR light incompatible with modern optical microscopy and almost all biomedical research and clinical workflows. Here we conceptualize an IR-optical hybrid (IR-OH) approach that sensitively measures molecular composition based on an optical microscope with wide-field interferometric detection of absorption-induced sample expansion. We demonstrate that IR-OH exceeds state-of-the-art IR microscopy in coverage (10-fold), spatial resolution (fourfold), and spectral consistency (by mitigating the effects of scattering). The combined impact of these advances allows full slide infrared absorption images of unstained breast tissue sections on a visible microscope platform. We further show that automated histopathologic segmentation and generation of computationally stained (stainless) images is possible, resolving morphological features in both color and spatial detail comparable to current pathology protocols but without stains or human interpretation. IR-OH is compatible with clinical and research pathology practice and could make for a cost-effective alternative to conventional stain-based protocols for stainless, all-digital pathology.

Advanced glycation end-products (AGEs) are lower in prostate tumor tissue and inversely related to proportion of West African ancestry.

BACKGROUND: The metabolism of normal prostate relies on glycolysis, with prostate cancer having reduced glycolysis and increased aerobic metabolism. Advanced glycation end products (AGEs) accumulate in tissues as a result of age and glycolytic rate. Differential AGE levels were recently observed in prostate cancer tissues. Herein we sought to quantify AGEs in benign and cancer prostate tissue in a diverse cohort of patients. METHODS: Levels of the AGE Nε-(carboxylethyl)lysine (CML) were quantified by immunohistochemistry (IHC) in a tissue microarray which consisted of 3 cores from tumor and 2 cores from benign areas from 118 patients (87 African American and 31 European American). Ancestry informative markers for African Ancestry were available for 79 patients. Epithelial and stromal areas were quantified separately using an E-cadherin mask. CML levels were compared with clinical grade group and ancestry by mixed linear effect models. Age, prostate-specific antigen (PSA) levels, body mass index (BMI), and hemoglobin A1C were included as covariates. RESULTS: CML levels were lower in areas of the tumor, for both epithelium and surrounding stroma, compared with benign, but did not significantly change with tumor grade group. Age, PSA levels, BMI, and hemoglobin A1C did not associate with CML levels. CML levels were inversely associated with the percentage of African Ancestry in all tissues. CONCLUSIONS: The low CML levels in cancer may reflect the reduced glycolytic state of the tissue. The inverse relationship between African Ancestry and CML levels in both benign and cancer areas suggests a state of reduced glycolysis. It is yet to be determined whether altered glycolysis and CML levels are bystanders or drivers of carcinogenesis.

Simultaneous cancer and tumor microenvironment subtyping using confocal infrared microscopy for all-digital molecular histopathology.

Histopathology based on spatial patterns of epithelial cells is the gold standard for clinical diagnoses and research in carcinomas; although known to be important, the tissue microenvironment is not readily used due to complex and subjective interpretation with existing tools. Here, we demonstrate accurate subtyping from molecular properties of epithelial cells using emerging high-definition Fourier transform infrared (HD FT-IR) spectroscopic imaging combined with machine learning algorithms. In addition to detecting four epithelial subtypes, we simultaneously delineate three stromal subtypes that characterize breast tumors. While FT-IR imaging data enable fully digital pathology with rich information content, the long spectral scanning times required for signal averaging and processing make the technology impractical for routine research or clinical use. Hence, we developed a confocal design in which refractive IR optics are designed to provide high-definition, rapid spatial scanning and discrete spectral tuning using a quantum cascade laser (QCL) source. This instrument provides simultaneously high resolving power (2-µm pixel size) and high signal-to-noise ratio (SNR) (>1,300), providing a speed increase of ∼50-fold for obtaining classified results compared with present imaging spectrometers. We demonstrate spectral fidelity and interinstrument operability of our developed instrument by accurate analysis of a 100-case breast tissue set that was analyzed in a day, considerably speeding research. Clinical breast biopsies typical of a patients' caseload are analyzed in ∼1 hour. This study paves the way for comprehensive tumor-microenvironment analyses in feasible time periods, presenting a critical step in practical label-free molecular histopathology.

Prostate cancer assessment using MR elastography of fresh prostatectomy specimens at 9.4 T.

PURPOSE: Despite its success in the assessment of prostate cancer (PCa), in vivo multiparametric MRI has limitations such as interobserver variability and low specificity. Several MRI methods, among them MR elastography, are currently being discussed as candidates for supplementing conventional multiparametric MRI. This study aims to investigate the detection of PCa in fresh ex vivo human prostatectomy specimens using MR elastography. METHODS: Fourteen fresh prostate specimens from men with clinically significant PCa without formalin fixation or prior radiation therapy were examined by MR elastography at 500 Hz immediately after radical prostatectomy in a 9.4T preclinical scanner. Specimens were divided into 12 segments for both calculation of storage modulus (G' in kilopascals) and pathology (Gleason score) as reference standard. Sensitivity, specificity, and area under the receiver operating characteristic curve were calculated to assess PCa detection. RESULTS: The mean G' and SD were as follows: all segments, 8.74 ± 5.26 kPa; healthy segments, 5.44 ± 4.40 kPa; and cancerous segments, 10.84 ± 4.65 kPa. The difference between healthy and cancerous segments was significant with P ≤ .001. Diagnostic performance assessed with the Youden index was as follows: sensitivity, 69%; specificity, 79%; area under the curve, 0.81; and cutoff, 10.67 kPa. CONCLUSION: Our results suggest that prostate MR elastography has the potential to improve diagnostic performance of multiparametric MRI, especially regarding its 2 major limitations: interobserver variability and low specificity. Particularly the high value for specificity in PCa detection is a stimulating result and encourages further investigation of this method.

Association of High miR-182 Levels with Low-Risk Prostate Cancer.

A subset of men with prostate cancer develops aggressive disease. We sought to determine whether miR-182, an miRNA with reported oncogenic functions in the prostate, is associated with biochemical recurrence and aggressive disease. Prostate epithelial miR-182 expression was quantified via in situ hybridization of two prostate tissue microarrays and by laser-capture microdissection of prostate epithelium. miR-182 was significantly higher in cancer epithelium than adjacent benign epithelium (P < 0.0001). The ratio of cancer to benign miR-182 expression per patient was inversely associated with recurrence in a multivariate logistic regression model (odds ratio = 0.18; 95% CI, 0.03-0.89; P = 0.044). Correlation of miR-182 with mRNA expression in laser-capture microdissected benign prostate epithelium was used to predict prostatic miR-182 targets. Genes that were negatively correlated with miR-182 were enriched for its predicted targets and for genes previously identified as up-regulated in prostate cancer metastases. miR-182 expression was also negatively correlated with genes previously identified as up-regulated in primary prostate tumors from African American patients, who are at an increased risk of developing aggressive prostate cancer. Taken together, these results suggest that although miR-182 is expressed at higher levels in localized prostate cancer, its levels are lower in aggressive cancers, suggesting a biphasic role for this miRNA that may be exploited for prognostic and/or therapeutic purposes to reduce prostate cancer progression.

Quantitative imaging of the receptor for advanced glycation end-products in prostate cancer.

PURPOSE: Current screening and monitoring of prostate cancer (PCa) is insufficient, producing inaccurate diagnoses. Presence of the receptor for advanced glycation end-products (RAGE) is associated with signature characteristics of PCa development such as cell proliferation, anchorage-independent growth, angiogenesis, migration, invasion, and poor patient survival. Therefore, we developed a preclinical multimodal imaging strategy targeted at RAGE to diagnose and monitor PCa. METHODS: In this work, RAGE-targeted multimodal nanoparticles (64Cu-Cy5-G4-CML) were synthesized and rendered functional for nuclear and optical imaging using previously established methods. The probe's binding affinity and targeting specificity was assessed in androgen-dependent (LNCaP) and androgen-independent (DU145) prostate cancer cells using flow cytometry and confocal microscopy. In vivo PET-CT imaging was used to evaluate RAGE levels in DU145 and LNCaP xenograft models in mice. Then, tumors were excised post-imaging for histological staining and autoradiography to further assess RAGE levels and targeting efficiency of the tracer. Finally, RAGE levels from human PCa samples of varying Gleason Scores were evaluated using Western blot and immunohistochemical staining. RESULTS: PCa cell culture studies confirmed adequate RAGE-targeting with 64Cu-Cy5-G4-CML with KD between 360 and 540 nM as measured by flow cytometry. In vivo PET-CT images of PCa xenografts revealed favorable kinetics, rapid blood clearance, and a non-homogenous, enhanced uptake in tumors, which varied based on cell type and tumor size with mean uptake between 0.5 and 1.4%ID/g. RAGE quantification of human samples confirmed increased RAGE uptake corresponding to increased Gleason scoring. CONCLUSIONS: Our study has shown that RAGE-targeted cancer imaging is feasible and could significantly impact PCa management.

Specific deletion of LKB1/Stk11 in the Müllerian duct mesenchyme drives hyperplasia of the periurethral stroma and tumorigenesis in male mice.

Nearly all older men will experience lower urinary tract symptoms associated with benign prostatic hyperplasia (BPH), the etiology of which is not well understood. We have generated Stk11CKO mice by conditional deletion of the liver kinase B1 (LKB1) tumor suppressor gene, Stk11 (serine threonine kinase 11), in the fetal Müllerian duct mesenchyme (MDM), the caudal remnant of which is thought to be assimilated by the urogenital sinus primordial mesenchyme in males during fetal development. We show that MDM cells contribute to the postnatal stromal cells at the dorsal aspect of the prostatic urethra by lineage tracing. The Stk11CKO mice develop prostatic hyperplasia with bladder outlet obstruction, most likely because of stromal expansion. The stromal areas from prostates of Stk11CKO mice, with or without significant expansion, were estrogen receptor positive, which is consistent with both MD mesenchyme-derived cells and the purported importance of estrogen receptors in BPH development and/or progression. In some cases, stromal hyperplasia was admixed with epithelial metaplasia, sometimes with keratin pearls, consistent with squamous cell carcinomas. Mice with conditional deletion of both Stk11 and Pten developed similar features as the Stk11CKO mice, but at a highly accelerated rate, often within the first few months after birth. Western blot analyses showed that the loss of LKB1 and phosphatase and tensin homolog deleted on chromosome 10 (PTEN) induces activation of the phospho-5' adenosine monophosphate-activated protein kinase and phospho-AKT serine/threonine kinase 1 signaling pathways, as well as increased total and active ß-catenin. These results suggest that activation of these signaling pathways can induce hyperplasia of the MD stroma, which could play a significant role in the etiology of human BPH.

Physiologic serum 1,25 dihydroxyvitamin D is inversely associated with prostatic Ki67 staining in a diverse sample of radical prostatectomy patients.

PURPOSE: To investigate the correlation between serum 25 hydroxyvitamin D, prostatic 25 hydroxyvitamin D, and serum 1,25 dihydroxyvitamin D, and their respective associations with prostatic tumor proliferation at the time of radical prostatectomy. METHODS: In this cross-sectional analysis of 119 men undergoing radical prostatectomy, serum from whole blood and expressed prostatic fluid was collected on the day of surgery. Tumor proliferation was measured in the dominant tumor on formalin-fixed prostatectomy tissues by immunohistochemical staining for Ki67 and quantified by Aperio imaging analysis. RESULTS: The sample included 88 African Americans (74%) and 31 (26%) European Americans. Serum and prostatic levels of 25 hydroxyvitamin D were correlated with each other (Spearman's rho (ρ) = 0.27, p = 0.004), and there was also a correlation between serum 25 hydroxyvitamin D and 1,25 dihydroxyvitamin D (ρ = 0.34, p < 0.001). Serum and prostatic 25 hydroxyvitamin D levels were not correlated with Ki67 staining in tumor cells. Serum 1,25 dihydroxyvitamin D was inversely correlated with Ki67 staining in tumor cells (ρ = - 0.30, p = 0.002). On linear regression, serum 1,25 dihydroxyvitamin D was negatively associated with Ki67 staining in tumor cells (ß - 0.46, 95% CI - 0.75, - 0.04, p = 0.04). CONCLUSION: The correlation between physiologic serum levels of 25 hydroxyvitamin D with both prostatic 25 hydroxyvitamin D and serum 1,25 dihydroxyvitamin D suggests that serum levels are reasonable biomarkers of vitamin D status. Furthermore, serum 1,25 dihydroxyvitamin D has an inverse association with Ki67 staining in tumor cells at physiologic levels and may protect against tumor progression.

Correlations of SELENOF and SELENOP genotypes with serum selenium levels and prostate cancer.

BACKGROUND: Selenium status is inversely associated with the incidence of prostate cancer. However, supplementation trials have not indicated a benefit of selenium supplementation in reducing cancer risk. Polymorphisms in the gene encoding selenoprotein 15 (SELENOF) are associated with cancer incidence/mortality and present disproportionately in African Americans. Relationships among the genotype of selenoproteins implicated in increased cancer risk, selenium status, and race with prostate cancer were investigated. METHODS: Tissue microarrays were used to assess SELENOF levels and cellular location in prostatic tissue. Sera and DNA from participants of the Chicago-based Adiposity Study Cohort were used to quantify selenium levels and genotype frequencies of the genes for SELENOF and the selenium-carrier protein selenoprotein P (SELENOP). Logistic regression models for dichotomous patient outcomes and regression models for continuous outcome were employed to identify both clinical, genetic, and biochemical characteristics that are associated with these outcomes. RESULTS: SELENOF is dramatically reduced in prostate cancer and lower in tumors derived from African American men as compared to tumors obtained from Caucasians. Differing frequency of SELENOF polymorphisms and lower selenium levels were observed in African Americans as compared to Caucasians. SELENOF genotypes were associated with higher histological tumor grade. A polymorphism in SELENOP was associated with recurrence and higher serum PSA. CONCLUSIONS: These results indicate an interaction between selenium status and selenoprotein genotypes that may contribute to the disparity in prostate cancer incidence and outcome experienced by African Americans.

Inflammation on Prostate Needle Biopsy is Associated with Lower Prostate Cancer Risk: A Meta-Analysis.

PURPOSE: We performed a comprehensive literature review and meta-analysis to evaluate the association of inflammation on prostate needle biopsies and prostate cancer risk. MATERIALS AND METHODS: We searched Embase®, PubMed® and Web of Science™ from January 1, 1990 to October 1, 2016 for abstracts containing the key words prostate cancer, inflammation and biopsy. Study inclusion criteria were original research, adult human subjects, cohort or case-control study design, histological inflammation on prostate needle biopsy and prostate cancer on histology. Two independent teams reviewed abstracts and extracted data from the selected manuscripts. Combined ORs and 95% CIs of any, acute and chronic inflammation were calculated using the random effects method. RESULTS: Of the 1,030 retrieved abstracts 46 underwent full text review and 25 were included in the final analysis, comprising a total of 20,585 subjects and 6,641 patients with prostate cancer. There was significant heterogeneity among studies (I2 = 84.4%, p <0.001). The presence of any inflammation was significantly associated with a lower prostate cancer risk in 25 studies (OR 0.455, 95% CI 0.337-0.573). There was no evidence of publication bias (p >0.05). When subanalyzed by inflammation type, acute inflammation in 4 studies and chronic inflammation in 15 were each associated with a lower prostate cancer risk (OR 0.681, 95% CI 0.450-0.913 and OR 0.499, 95% CI 0.334-0.665, respectively). CONCLUSIONS: In a meta-analysis of 25 studies inflammation on prostate needle biopsy was associated with a lower prostate cancer risk. Clinically the presence of inflammation on prostate needle biopsy may lower the risk of a subsequent prostate cancer diagnosis.

Implantable chemotherapy-loaded silk protein materials for neuroblastoma treatment.

Neuroblastoma is the most common extracranial childhood solid tumor. Treatment of high risk tumors require intense multicycle chemotherapies, resulting in short- and long-term toxicities. Here, we present treatment of an orthotopic neuroblastoma mouse model, with silk fibroin materials loaded with vincristine, doxorubicin or the combination as a intratumoral, sustained release system. The materials, loaded with vincristine with or without doxorubicin, significantly decreased neuroblastoma tumor growth compared to materials loaded without drug or doxorubicin only as well as intravenous (IV) drug treatment. The intratumoral drug concentration was significantly higher with intratumoral delivery versus IV. Furthermore, intratumor delivery decreased the maximum plasma concentration compared to IV delivery, reducing systemic exposure and possibly reduing long-term side effects of chemotherapy exposure. Histopathologically, tumors with remission periods >25 days before recurrence transformed from a "small-round-blue cell" (SBRC) to predominantly "large cell" neuroblastoma (LCN) histopathology, a more aggressive tumor subtype with unfavorable clinical outcomes. These results show that intratumoral chemotherapy delivery may be a treatment strategy for pediatric neuroblastoma, potentially translatable to other focal tumors types. Furthermore, this treatment modality allows for a clinically relevant mouse model of tumor transformation that may be used for studying the phenotypical tumor recurrence and developing more effective treatment strategies for recurrent tumors.

The Development of Prostate Adenocarcinoma in a Transgender Male to Female Patient: Could Estrogen Therapy Have Played a Role?

BACKGROUND: Prostate adenocarcinoma (PCa) is a rare diagnosis in the male to female transgender (MtFT) population with only a few case reports published in the current medical literature. Long standing beliefs of androgen suppression conferring a protective effect against prostate cancer development have been challenged by the literature citing adenocarcinoma development in the prostate of rodent models following combined estrogen and testosterone treatment. MATERIALS AND METHODS: We herein present a MtFT patient who presented with high grade PCa following 20 years of exogenous estrogen therapy. RESULTS: Immunohistochemical (IHC) localization of estrogen receptor alpha (ER-α) and progesterone receptor (PR) demonstrated positive staining in stromal cells; while, androgen receptor (AR) demonstrated positive staining in malignant glands and weak scattered staining in adjacent stroma. CONCLUSION: This pattern of staining raises concern for a possible contributing role of exogenous estrogen therapy in tumorigenesis. As awareness of gender dysphoria and acceptance of gender reassignment surgery has seen a recent increase, the unique needs of this population must be recognized. Prostate 77:824-828, 2017. © 2017 Wiley Periodicals, Inc.