Prediction of Incontinence after Robot-Assisted Radical Prostatectomy: Development and Validation of a 24-Month Incontinence Nomogram.

Incontinence after robot-assisted radical prostatectomy (RARP) is feared by most patients with prostate cancer. Many risk factors for incontinence after RARP are known, but a paucity of data integrates them. Prospectively acquired data from 680 men who underwent RARP January 2008-December 2015 and met inclusion/exclusion criteria were queried retrospectively and then divided into model development (80%) and validation (20%) cohorts. The UCLA-PCI-Short Form-v2 Urinary Function questionnaire was used to categorize perfect continence (0 pads), social continence (1-2 pads), or incontinence (≥3 pads). The observed incontinence rates were 26% at 6 months, 7% at 12 months, and 3% at 24 months. Logistic regression was used for model development, with variables identified using a backward selection process. Variables found predictive included age, race, body mass index, and preoperative erectile function. Internal validation and calibration were performed using standard bootstrap methodology. Calibration plots and receiver operating curves were used to evaluate model performance. The initial model had 6-, 12-, and 24-month areas under the curves (AUCs) of 0.64, 0.66, and 0.80, respectively. The recalibrated model had 6-, 12-, and 24-month AUCs of 0.52, 0.52, and 0.76, respectively. The final model was superior to any single clinical variable for predicting the risk of incontinence after RARP.

Differential Associations of SLCO Transporters with Prostate Cancer Aggressiveness between African Americans and European Americans.

BACKGROUND: Androgen receptor signaling is crucial to prostate cancer aggressiveness. Members of the solute carrier family of the organic anion transporting peptides (SLCO) are potential regulators of androgen availability in prostate tissue. It remains unknown whether genetic variations in SLCOs contribute to the differences in prostate cancer aggressiveness in African Americans (AA) and European Americans (EA). METHODS: SNPs in 11 SLCO members were selected, with addition of 139 potentially functional SNPs and 128 ancestry informative markers. A total of 1,045 SNPs were genotyped and analyzed in 993 AAs and 1,057 EAs from the North Carolina-Louisiana Prostate Cancer Project. Expression and cellular localization of SLCOs were examined using qRT-PCR, IHC, and in situ RNA hybridization in independent sets of prostate cancer cases. RESULTS: Significant associations with prostate cancer characteristics were found for SNPs in SLCO2A1 and SLCO5A1. The associations differed by race (P interaction < 0.05). SNPs in SLCO2A1 were associated with reduced tumor aggressiveness and low Gleason score in AAs; whereas, SNPs in SLCO5A1 were associated with high clinical stage in EAs. In prostate tissue, SLCO2A1 and SLCO5A1 were the most expressed SLCOs at the mRNA level and were expressed predominantly in prostate endothelial and epithelial cells at the protein level, respectively. CONCLUSIONS: SLCO2A1 and SLCO5A1 play important but different roles in prostate cancer aggressiveness in AAs versus EAs. IMPACT: The finding calls for consideration of racial differences in biomarker studies of prostate cancer and for investigations on functions of SLCO2A1 and SLCO5A1 in prostate cancer.

Carotenoids, Fatty Acids, and Volatile Compounds in Apricot Cultivars from Romania-A Chemometric Approach.

Lipophilic constituents are important for the color and aroma of apricots, but also for their health benefits. In the present study, carotenoids, fatty acids, and volatiles were analyzed in 11 apricot cultivars, from which nine were obtained in Romania. High performance liquid chromatography coupled to a diode array detector with atmospheric pressure chemical ionization and mass spectrometry (HPLC-DAD-APCI-MS methodology applied on unsaponified carotenoid extracts allowed the identification and quantification of 19 compounds. The predominant carotenoids in all cultivars were all-trans-ß-carotene and its cis isomers. Lutein was present exclusively in non-esterified form, while ß-cryptoxanthin was predominantly esterified, mainly with oleic, palmitic, lauric, and stearic acid. Moreover, ß-cryptoxanthin linoleate, linolenate, and stearate were detected for the first time in Harogem cultivar. Variation in carotenoid content and composition was observed, with the highest carotenoid content being recorded in Tudor, Harogem, and Mamaia cultivars. The predominant fatty acids determined by gas chromatography-mass spectrometry (GC-MS) were linoleic (up to 47%), palmitic (up to 32.7%), and linolenic (up to 17.16%), with small variations among cultivars. In-tube extraction technique (ITEX)/GC-MS was applied for profiling the volatiles in apricot fruits and 120 compounds were identified, with terpenoids and esters as the most abundant classes. Principal component analysis (PCA) revealed that the carotenoids and the fatty acids profile can be used for variety authentication and discrimination in apricots.

Feasibility and continence outcomes of extended prostatic urethral preservation during robot-assisted radical prostatectomy.

BACKGROUND: The prostatic urethra is conventionally resected during robot-assisted radical prostatectomy (RARP). We describe the technical feasibility and urinary continence outcomes of extended prostatic urethral preservation (EPUP) during RARP. METHODS: A single surgeon at a National Comprehensive Cancer Network institute performed 48 consecutive RARP operations using EPUP from March 2014 to March 2016, during which time 177 conventional non-EPUP RARP operations were performed by other surgeons. Prior to this period, the EPUP surgeon had performed 17 non-EPUP RARP operations over 15 months. Total intracorporeal urethral length (IUL) preserved during EPUP was measured intraoperatively. Associations of EPUP and IUL with continence recovery rates and/or times were tested in Fisher's exact and log rank univariate analyses and Cox logistic regression multivariable analyses. RESULTS: Median IUL preserved during EPUP was 4.0 cm (range 2.5-6.0 cm), and urethral dissections typically spanned the prostatic apex to mid-gland or base. Seven-week continence rates were significantly higher with versus without EPUP. EPUP patient rates of using 0 or 0-1 pads per day immediately after catheter removal were 19% and 35%, respectively. These rates increased significantly (53% and 76%, respectively), as did the IUL preserved (median 5.0 cm), among more recent EPUP patients (n = 17), which suggested a learning curve. In multivariable analyses including all patients, an EPUP approach was an independent predictor of faster continence recovery. In multivariable analyses of the EPUP subset, a longer IUL preserved was independently associated with faster continence recovery. No EPUP patient had a urethral fossa positive margin, and apical positive margins were similarly infrequent among EPUP and non-EPUP patients. CONCLUSIONS: EPUP is technically feasible during RARP and associated with faster continence recovery. Future investigation into the generalizability of these findings and the oncologic safety of EPUP is warranted.

Adrenal androgens rescue prostatic dihydrotestosterone production and growth of prostate cancer cells after castration.

Adrenal androgens dehydroepiandrosterone (DHEA) and DHEA-sulfate (DHEAS) are potential substrates for intracrine production of testosterone (T) and dihydrotestosterone (DHT), or directly to DHT, by prostate cancer (PCa) cells. Production of DHT from DHEAS and DHEA, and the role of steroid sulfatase (STS), were evaluated ex vivo using fresh human prostate tissue and in vitro using human PCa cell lines. STS was expressed in benign prostate tissue and PCa tissue. DHEAS at a physiological concentration was converted to DHT in prostate tissue and PCa cell lines, which was STS-dependent. DHEAS activation of androgen receptor (AR) and stimulation of PCa cell growth were STS-dependent. DHEA at a physiological concentration was not converted to DHT ex vivo and in vitro, but stimulated in vivo tumor growth of the human PCa cell line, VCaP, in castrated mice. The findings suggest that targeting metabolism of DHEAS and DHEA may enhance androgen deprivation therapy.

Protein Kinase N1 control of androgen-responsive serum response factor action provides rationale for novel prostate cancer treatment strategy.

Sustained reliance on androgen receptor (AR) after failure of AR-targeting androgen deprivation therapy (ADT) prevents effective treatment of castration-recurrent (CR) prostate cancer (CaP). Interfering with the molecular machinery by which AR drives CaP progression may be an alternative therapeutic strategy but its feasibility remains to be tested. Here, we explore targeting the mechanism by which AR, via RhoA, conveys androgen-responsiveness to serum response factor (SRF), which controls aggressive CaP behavior and is maintained in CR-CaP. Following a siRNA screen and candidate gene approach, RNA-Seq studies confirmed that the RhoA effector Protein Kinase N1 (PKN1) transduces androgen-responsiveness to SRF. Androgen treatment induced SRF-PKN1 interaction, and PKN1 knockdown or overexpression severely impaired or stimulated, respectively, androgen regulation of SRF target genes. PKN1 overexpression occurred during clinical CR-CaP progression, and hastened CaP growth and shortened CR-CaP survival in orthotopic CaP xenografts. PKN1's effects on SRF relied on its kinase domain. The multikinase inhibitor lestaurtinib inhibited PKN1 action and preferentially affected androgen regulation of SRF over direct AR target genes. In a CR-CaP patient-derived xenograft, expression of SRF target genes was maintained while AR target gene expression declined and proliferative gene expression increased. PKN1 inhibition decreased viability of CaP cells before and after ADT. In patient-derived CaP explants, lestaurtinib increased AR target gene expression but did not significantly alter SRF target gene or proliferative gene expression. These results provide proof-of-principle for selective forms of ADT that preferentially target different fractions of AR's transcriptional output to inhibit CaP growth.

Proteomic Analysis of Charcoal-Stripped Fetal Bovine Serum Reveals Changes in the Insulin-like Growth Factor Signaling Pathway.

Charcoal-stripped fetal bovine serum (CS-FBS) is commonly used to study androgen responsiveness and androgen metabolism in cultured prostate cancer (CaP) cells. Switching CaP cells from FBS to CS-FBS may reduce the activity of androgen receptor (AR), inhibit cell proliferation, or modulate intracellular androgen metabolism. The removal of proteins by charcoal stripping may cause changes in biological functions and has not yet been investigated. Here we profiled proteins in FBS and CS-FBS using an ion-current-based quantitative platform consisting of reproducible surfactant-aided precipitation/on-pellet digestion, long-column nanoliquid chromatography separation, and ion-current-based analysis. A total of 143 proteins were identified in FBS, among which 14 proteins including insulin-like growth factor 2 (IGF-2) and IGF binding protein (IGFBP)-2 and -6 were reduced in CS-FBS. IGF-1 receptor (IGF1R) and insulin receptor were sensitized to IGFs in CS-FBS. IGF-1 and IGF-2 stimulation fully compensated for the loss of AR activity to maintain cell growth in CS-FBS. Endogenous production of IGF and IGFBPs was verified in CaP cells and clinical CaP specimens. This study provided the most comprehensive protein profiles of FBS and CS-FBS and offered an opportunity to identify new protein regulators and signaling pathways that regulate AR activity, androgen metabolism, and proliferation of CaP cells.

An anomalous origin of the gastrosplenic trunk and common hepatic artery arising independently from the abdominal aorta: a case report using MDCT angiography.

The authors describe a case of a 61-year-old female patient, which presented on multidetector computed tomographic (MDCT) angiography a gastrosplenic trunk (GST) and common hepatic artery (CHA) arose independently from abdominal aorta (AA). The GST arose from the anterior wall of the AA, at the level of upper edge of the L1 vertebral body. The left gastric artery (LGA) arose from the superior wall of the GST. The splenic artery (SA) continuous the path of GST. The CHA arose from the anterior wall of the AA, at the level of upper one third of the L1 vertebral body, at 15.3 mm above the origin of superior mesenteric artery (SMA). The incidence and developmental and clinical significance of this vascular variation is discussed with a detailed review of the literature.

Inhibition of dihydrotestosterone synthesis in prostate cancer by combined frontdoor and backdoor pathway blockade.

Androgen deprivation therapy (ADT) is palliative and prostate cancer (CaP) recurs as lethal castration-recurrent/resistant CaP (CRPC). One mechanism that provides CaP resistance to ADT is primary backdoor androgen metabolism, which uses up to four 3α-oxidoreductases to convert 5α-androstane-3α,17ß-diol (DIOL) to dihydrotestosterone (DHT). The goal was to determine whether inhibition of 3α-oxidoreductase activity decreased conversion of DIOL to DHT. Protein sequence analysis showed that the four 3α-oxidoreductases have identical catalytic amino acid residues. Mass spectrometry data showed combined treatment using catalytically inactive 3α-oxidoreductase mutants and the 5α-reductase inhibitor, dutasteride, decreased DHT levels in CaP cells better than dutasteride alone. Combined blockade of frontdoor and backdoor pathways of DHT synthesis provides a therapeutic strategy to inhibit CRPC development and growth.

Characterization of Prostate Cancer in a Functional Eunuch.

BACKGROUND: Eunuchs rarely, if ever, develop prostate cancer (CaP). This article reports on a 62-year-old functional eunuch from prepubertal mumps orchitis who developed clinically localized CaP. METHODS: Serum and CaP and benign prostate tissue androgen levels were measured using a validated liquid chromatography-tandem mass spectrometry assay. The assay measures testosterone; dihydrotestosterone (DHT); the adrenal androgens, androstenedione and dehydroepiandrosterone; and the androgen metabolites, androsterone and androstanedione. Gene and protein expression levels of androgen metabolism enzymes, and androgen receptor and androgen-regulated genes were measured using quantitative reverse-transcription polymerase chain reaction and immunohistochemistry, respectively. RESULTS: Intracrine androgen metabolism produced tissue DHT when serum and tissue testosterone levels were castrate and undetectable, respectively. Androgen receptor, androgen-regulated, and androgen metabolism enzyme genes were expressed but at lower levels in CaP than benign tissues. CONCLUSIONS: DHT was synthesized using the primary backdoor androgen metabolism pathway and not using androstenedione or dehydroepiandrosterone via the frontdoor or secondary backdoor pathways.

Intake of dietary antioxidants is inversely associated with biomarkers of oxidative stress among men with prostate cancer.

Prostate cancer is the most common non-cutaneous cancer and the second leading cause of cancer-related mortality among men in the USA. Growing evidence suggests that oxidative stress is involved in the development and progression of prostate cancer. In this study, the association between antioxidants from diet and supplements and biomarkers of oxidative stress in blood (n 278), urine (n 298) and prostate tissue (n 55) were determined among men from the North Carolina-Louisiana Prostate Cancer Project. The association between antioxidant intake and oxidative stress biomarkers in blood and urine was determined using linear regression, adjusting for age, race, prostate cancer aggressiveness and smoking status. Greater antioxidant intake was found to be associated with lower urinary 8-isoprostane concentrations, with a 10% increase in antioxidant intake corresponding to an unadjusted 1·1% decrease in urinary 8-isoprostane levels (95% CI -1·7, -0·3%; P value<0·01) and an adjusted 0·6% decrease (95% CI -1·4, 0·2%; P value=0·16). In benign prostate tissue, thioredoxin 1 was inversely associated with antioxidant intake (P=0·02). No significant associations were found for other blood or urinary biomarkers or for malignant prostate tissue. These results indicate that antioxidant intake may be associated with less oxidative stress among men diagnosed with prostate cancer.

Thioredoxin 1 in Prostate Tissue Is Associated with Gleason Score, Erythrocyte Antioxidant Enzyme Activity, and Dietary Antioxidants.

Background. Prostate cancer is the most common noncutaneous cancer and second leading cause of cancer-related mortality in men in the US. Growing evidence suggests that oxidative stress is involved in prostate cancer. Methods. In this study, thioredoxin 1 (Trx 1), an enzyme and subcellular indicator of redox status, was measured in prostate biopsy tissue from 55 men from the North Carolina-Louisiana Prostate Cancer Project. A pathologist blindly scored levels of Trx 1. The association between Trx 1 and the Gleason score, erythrocyte antioxidant enzyme activity, and dietary antioxidant intake was determined using Fisher's exact test. Results. Trx 1 levels in benign prostate tissue in men with incident prostate cancer were positively associated with the Gleason score (P = 0.01) and inversely associated with dietary antioxidant intake (P = 0.03). In prostate cancer tissue, Trx 1 levels were associated with erythrocyte glutathione peroxidase activity (P = 0.01). No association was found for other erythrocyte enzymes. Greater Gleason score of malignant tissue corresponds to a greater difference in Trx 1 levels between malignant and benign tissue (P = 0.04). Conclusion. These results suggest that the redox status of prostate tissue is associated with prostate cancer grade and both endogenous and exogenous antioxidants.

Mechanism of androgen receptor corepression by CKßBP2/CRIF1, a multifunctional transcription factor coregulator expressed in prostate cancer.

The transcription factor coregulator Casein kinase IIß-binding protein 2 or CR6-interacting factor 1 (CKßBP2/CRIF1) binds the androgen receptor (AR) in prostate cancer cells and in response to dihydrotestosterone localizes with AR on the prostate-specific antigen gene enhancer, but does not bind DNA suggesting CKßBP2/CRIF1 localization in chromatin is determined by AR. In this study we show also that CKßBP2/CRIF1 inhibits wild-type AR and AR N-terminal transcriptional activity, binds to the AR C-terminal region, inhibits interaction of the AR N- and C-terminal domains (N/C interaction) and competes with p160 coactivator binding to the AR C-terminal domain, suggesting CKßBP2/CRIF1 interferes with AR activation functions 1 and 2. CKßBP2/CRIF1 is expressed mainly in stromal cells of benign prostatic hyperplasia and in stroma and epithelium of prostate cancer. CKßBP2/CRIF1 protein is increased in epithelium of androgen-dependent prostate cancer compared to benign prostatic hyperplasia and decreased slightly in castration recurrent epithelium compared to androgen-dependent prostate cancer. The multifunctional CKßBP2/CRIF1 is a STAT3 interacting protein and reported to be a coactivator of STAT3. CKßBP2/CRIF1 is expressed with STAT3 in prostate cancer where STAT3 may help to offset the AR repressor effect of CKßBP2/CRIF1 and allow AR regulation of prostate cancer growth.

c-Kit expression in somatosensory nuclei of lower medulla oblongata.

Protein kinase signal-transduction pathways play critical roles in regulating nociception. The c-kit receptor contributes to pain regulation in the spinal cord and is present on both peripheral and central terminals. Expression of c-kit was demonstrated in human trigeminal and spinal ganglia. However, the brainstem expression of c-kit was overlooked. We aimed to evaluate it by immunohistochemistry, on eight samples of human lower medulla oblongata. We used two clones of CD117/c-kit antibodies, from different manufacturers, and neurofilament antibodies. Positive expression of CD117/c-kit was found within the spinal trigeminal nucleus, the gracilis, cuneate, and lateral cuneate nuclei, and within the olivary complex. CD117/c-kit positive interstitial networks of these nuclei were positively labeled with neurofilaments. CD117/c-kit labeled the olivary neurons, but not the magnocellular neurons of the trigeminal, gracilis and cuneate nuclei. c-kit interstitial systems of brainstem could play so an important role for the functional status along the somatosensory neural circuits.

Fenestrated vertebral artery.

Fenestrations of the vertebral arteries (VAs) are usually identified angiographically. A left fenestrated vertebral artery (fVA) is reported here, identified in an adult specimen by microdissection. The distal segment of this VA was fenestrated and it consisted of two arms, the caudal one being larger than the cranial one. The caudal end of the rostral arm and the left posterior inferior cerebellar artery (PICA) were inserted at the same point. The anterior spinal artery was leaving the caudal arm of the fVA. On that side the anterior inferior cerebellar artery (AICA) was rudimentary, its cerebellar hemispheric territory being supplied by the PICA. The rostral arm of the fVA and the AICA were united by an anastomosis coursing on the ventral side of the olive. The AICA-to-fVA anastomosis, as well as the PICA, were supplying perforator arteries of the retro-olivary sulcus. Anatomical details of various arterial morphologies are important during specific surgical and interventional procedures.

Hematogenous placental infection in acute respiratory infections.

The study focuses on the macroscopic and microscopic aspects of the placentae resulting from abortions or febrile births and their correlation with acute disorders of the upper or lower respiratory apparatus in pregnant women in various stages of pregnancy. The viral, bacterial or mycotic disorders were considered responsible for triggering septic abortion, premature or full-term deliveries, followed by septic complications of the child/fetus or of the mother. When the mother's acute respiratory infection is induced by highly virulent pathogens, in patients with low immunity or lacking adequate medical treatment, the infection may spread through the mother's bloodstream to the placenta. The study was conducted on 90 placentae. Microscopic analysis of the tissue samples revealed acute inflammatory infiltration. Two of the study cases should be mentioned here: a four-month pregnant woman suffering from septic abortion and a nine-month pregnant woman whose fetus died in the womb because of acute pneumopathy on a non-breathing lung. Both pregnant women had the same type of disorder and neither followed any medical treatment prescribed by a physician. The prevention of placental infection is closely connected to the prevention of acute respiratory diseases or their proper treatment after their onset.

Astrocitary niches in human adult medulla oblongata.

Astrocytes are considered as neuromodulators of the CNS. Whereas experimental studies on astrocitary functions are gaining importance, the anatomy of the astrocitary niches in the human CNS has been overlooked. The study was performed on the brainstem of 10 adult cadavers. We aimed to determine astrocitary niches in the human medulla oblongata using immunohistochemical labeling with vimentin and also CD34 immunostaining to accurately diagnose associated microvessels. Niches rich in astrocytes were identified as follows: (a) the superficial layer of astrocytes, ventral and ventrolateral, in the rostral medulla oblongata; (b) the median raphe; (c) medullary nuclei: arcuate nucleus, area postrema, nucleus of the solitary tract; (d) the subependymal zone (SEZ, caudal medulla) and subventricular zone (SVZ, rostral medulla). Astrocytes were scarce in the ventrolateral medulla, and mostly present within the pyramidal tract and the olivary nucleus. Apart from the SEZ and SVZ, the brainstem niches of astrocytes mostly overlap those regions known to perform roles as central respiratory chemoreceptors. The astrocytes of the SEZ and SVZ, which are known as stem cell niches, are related to an increased microvascular density.

Melanoma antigen-A11 (MAGE-A11) enhances transcriptional activity by linking androgen receptor dimers.

Prostate cancer growth and progression depend on androgen receptor (AR) signaling through transcriptional mechanisms that require interactions with coregulatory proteins, one of which is the primate-specific steroid receptor coregulator melanoma antigen-A11 (MAGE-A11). In this report, we provide evidence how increased expression of MAGE-A11 during prostate cancer progression enhances AR signaling and prostate cancer growth. MAGE-A11 protein levels were highest in castration-recurrent prostate cancer. The cyclic AMP-induced increase in androgen-dependent and androgen-independent AR transcriptional activity correlated with an increase in MAGE-A11 and was inhibited by silencing MAGE-A11 expression. MAGE-A11 mediated synergistic AR transcriptional activity in LAPC-4 prostate cancer cells. The ability of MAGE-A11 to rescue transcriptional activity of complementary inactive AR mutants and promote coimmunoprecipitation between unlike forms of AR suggests that MAGE-A11 links transcriptionally active AR dimers. A model for the AR·MAGE-A11 multidimeric complex is proposed in which one AR FXXLF motif of the AR dimer engages in the androgen-dependent AR NH(2)- and carboxyl-terminal interaction, whereas the second FXXLF motif region of the AR dimer interacts with dimeric MAGE-A11. The AR·MAGE-A11 multidimeric complex accounts for the dual functions of the AR FXXLF motif in the androgen-dependent AR NH(2)- and carboxyl-terminal interaction and binding MAGE-A11 and for synergy between reported AR splice variants and full-length AR. We conclude that the increased expression of MAGE-A11 in castration-recurrent prostate cancer, which is enhanced by cyclic AMP signaling, increases AR-dependent growth of prostate cancer by MAGE-A11 forming a molecular bridge between transcriptionally active AR dimers.

RhoA as a mediator of clinically relevant androgen action in prostate cancer cells.

Recently, we have identified serum response factor (SRF) as a mediator of clinically relevant androgen receptor (AR) action in prostate cancer (PCa). Genes that rely on SRF for androgen responsiveness represent a small fraction of androgen-regulated genes, but distinguish benign from malignant prostate, correlate with aggressive disease, and are associated with biochemical recurrence. Thus, understanding the mechanism(s) by which SRF conveys androgen regulation to its target genes may provide novel opportunities to target clinically relevant androgen signaling. Here, we show that the small GTPase ras homolog family member A (RhoA) mediates androgen-responsiveness of more than half of SRF target genes. Interference with expression of RhoA, activity of the RhoA effector Rho-associated coiled-coil containing protein kinase 1 (ROCK), and actin polymerization necessary for nuclear translocation of the SRF cofactor megakaryocytic acute leukemia (MAL) prevented full androgen regulation of SRF target genes. Androgen treatment induced RhoA activation, increased the nuclear content of MAL, and led to MAL recruitment to the promoter of the SRF target gene FHL2. In clinical specimens RhoA expression was higher in PCa cells than benign prostate cells, and elevated RhoA expression levels were associated with aggressive disease features and decreased disease-free survival after radical prostatectomy. Overexpression of RhoA markedly increased the androgen-responsiveness of select SRF target genes, in a manner that depends on its GTPase activity. The use of isogenic cell lines and a xenograft model that mimics the transition from androgen-stimulated to castration-recurrent PCa indicated that RhoA levels are not altered during disease progression, suggesting that RhoA expression levels in the primary tumor determine disease aggressiveness. Androgen-responsiveness of SRF target genes in castration-recurrent PCa cells continued to rely on AR, RhoA, SRF, and MAL and the presence of intact SRF binding sites. Silencing of RhoA, use of Rho-associated coiled-coil containing protein kinase 1 inhibitors, or an inhibitor of SRF-MAL interaction attenuated (androgen-regulated) cell viability and blunted PCa cell migration. Taken together, these studies demonstrate that the RhoA signaling axis mediates clinically relevant AR action in PCa.

Anatomical considerations on the corona mortis.

The corona mortis (CMOR) represents the vascular connection of the obturator and external iliac systems. We aimed to evaluate by dissections the morphological possibilities of the CMOR and their individual combinations. For the study we used 20 human adult cadavers that were bilaterally dissected (40 hemipelvises), with evidences of the vascular elements at the level of the superior pubic branch in 32 (80%) of hemipelvises. The morphological patterns we identified were classified in three types (I-III): I. arterial CMOR (10 hemipelvises): I.1. obturator artery (OA) from the external iliac artery (EIA); I.2. OA from the inferior epigastric artery (IEA); I.3. anastomosis of the OA and IEA; I.4. pubic branches of the OA, in the absence of any anastomosis with the EIA system; II. venous CMOR (6 hemipelvises): II.1. obturator vein (OV) draining into the external iliac vein (EIV); II.2. OV draining into the inferior epigastric vein (IEV); II.3. venous anastomosis of the OV and IEV and III combined, arterial and venous CMOR (16 hemipelvises). We classified the combined coronae mortis in nine different subtypes that mainly (but not exclusively) correspond to various combinations of types I and II. The surgical relevance of the vascular relations of the superior branch of pubis (in trauma, orthopedic approaches, hernia repair, embolizations and intra-arterial infusions) recommends a detailed knowledge of the morphological and topographical possibilities of the crown of death and the individual evaluation of this risky anatomical structure.