Search

Androgen receptor (AR) is closely associated with a group of hormone‐related diseases including the cancers of prostate, breast, ovary, pancreas, etc and anabolic deficiencies such as muscle atrophy and osteoporosis. Depending on the specific type and stage of the diseases, AR ligands including not only antagonists but also agonists and modulators are considered as potential therapeutics, which makes AR an extremely interesting drug target. Here, we at first review the current understandings on the structural characteristics of AR, and then address why and how AR is investigated as a drug target for the relevant diseases and summarize the representative antagonists and agonists targeting five prospective small molecule binding sites at AR, including ligand‐binding pocket, activation function‐2 site, binding function‐3 site, DNA‐binding domain, and N‐terminal domain, providing recent insights from a target and drug development view. Further comprehensive studies on AR and AR ligands would bring fruitful information and push the therapy of AR relevant diseases forward. [ABSTRACT FROM AUTHOR]

Aims: This investigation aimed to quantitatively characterize the relationship between the gonadotropin‐releasing hormone agonist leuprorelin, testosterone (T) and prostate specific antigen (PSA) concentrations over time, to aid identification of a target T concentration that optimises the balance of the benefits of T suppression whilst reducing the risk of side effects related to futile over‐suppression. Methods: Data from a single dose study to investigate the effect of leuprorelin in a 6‐month depot formulation on T and PSA in prostate cancer patients were analysed using a population pharmacokinetic–pharmacodynamic modelling approach. The developed model was qualified using external data from 3 studies, in which the effect of different formulations of leuprorelin on T and PSA was evaluated in prostate cancer patients. Results: The effect of leuprorelin on the relationship between T and PSA was adequately characterized by the Romero model with minor modifications, combined with a turnover model to describe the delay in response between T and PSA. The data were significantly better described when assuming a minimum PSA level that is independent on the treatment‐related reduction in T, as compared to a model with a proportional reduction in PSA and T. Conclusions: The model‐based analysis suggests that on a population level, reducing T concentrations below 35 ng/dL does not result in a further decrease in PSA levels (>95% of the minimal PSA level is reached). More data are required to support this relationship in the lower T and PSA range. [ABSTRACT FROM AUTHOR]

Prostate cancer (PCa) is the second most common cause of cancer‐related mortality in men in the United States. The androgen receptor (AR) and the physiological pathways it regulates are central to the initiation and progression of PCa. As a member of the nuclear steroid receptor family, it is a transcription factor with three distinct functional domains (ligand‐binding domain [LBD], DNA‐binding domain [DBD], and transactivation domain [TAD]) in its structure. All clinically approved drugs for PCa ultimately target the AR‐LBD. Clinically active drugs that target the DBD and TAD have not yet been developed due to multiple factors. Despite these limitations, the last several years have seen a rise in the discovery of molecules that could successfully target these domains. This review aims to present and comprehensively discuss such molecules that affect AR signaling through direct or indirect interactions with the AR‐TAD or the DBD. The compounds discussed here include hairpin polyamides, niclosamide, marine sponge–derived small molecules (eg, EPI compounds), mahanine, VPC compounds, JN compounds, and bromodomain and extraterminal domain inhibitors. We highlight the significant in vitro and in vivo data found for each compound and the apparent limitations and/or potential for further development of these agents as PCa therapies. [ABSTRACT FROM AUTHOR]

Prostate cancer is a major cause of cancer‐related death in males. Wnt/β‐catenin signaling plays a critical role in the pathogenesis of this disease by regulating angiogenesis, drug resistance, cell proliferation, and apoptosis. Suppression of Wnt canonical or noncanonical signaling pathways via Wnt biological or pharmacological antagonists is a potentially novel therapeutic approach for patients with prostate cancer. This review summarizes the role of Wnt signaling inhibitors in the pathogenesis of prostate cancer for a better understanding and hence a better management of this disease. Suppression of Wnt canonical or noncanonical signaling pathways via Wnt biological or pharmacological antagonists is a potentially novel therapeutic approach for patients with prostate cancer. This review summarizes the role of Wnt signaling inhibitors in the pathogenesis of prostate cancer for a better understanding and hence a better management of this disease. [ABSTRACT FROM AUTHOR]

Though Androgen deprivation therapy (ADT) is effective initially, numerous patients become resistant to it and develop castration resistant PCa (CRPC). Cytokines promotes ligand independent activation of AR. Interleukin‐6 (IL‐6) levels are elevated in CRPC patients and regulate AR activity. However, progression to CRPC is not fully understood. In this study, we analyzed differential protein expression in LNCaP cells treated with IL‐6 using proteomics. Results revealed altered expression of 27 proteins and Valosin‐containing protein (VCP)/p97 plays a predominant role in co‐regulation of altered proteins. Interestingly, IL‐6 induced VCP expression through Pim‐1 via STAT3 is AR independent there by suggesting a role for VCP in CRPC. Transfection of LNCaP cells for VCP overexpression showed an increased cell proliferation, migration, and invasion where as its inhibition by NMS‐873 showed the reverse effect causing cell death. Mechanistic studies demonstrate that cell death occurs due to apoptosis by endoplasmic reticulum (ER) stress, elevated cell cycle inhibitors p21, p27kip1, and active PARP and reduced Bcl‐2. VCP promotes cell invasion and migration by altering E‐cadherin and Vimentin levels inversely triggering EMT of PCa cells. VCP immunostaining revealed no staining in BPH but strong staining in PCa. This study determines VCP may play an important role in progression to CRPC and it can be a favorable target with to develop new therapies to treat ADT resistant prostate cancer. [ABSTRACT FROM AUTHOR]

Although androgen deprivation therapy (ADT) is a standard treatment for metastatic prostate cancer, this disease inevitably recurs and progresses to ADT‐resistant stage after this therapy. Accordingly, understanding the mechanism of resistance to ADT and finding new approach to enhance the efficacy of ADT may provide a major benefit to PCa patients. In our study, we found upregulated expression of Notch receptors is positive associated with ADT‐resistance progression. Using fluorescent Notch signaling reporter system, we observed that endogenous Notch signaling could be activated after treatment of androgen deprivation in LNCaP cells via activation of Notch3. In addition, exogenous activation of the Notch signaling though Dox‐induced overexpression of any Notch intracellular domains (NICD1‐4) could enhance the resistance of PCa cells to ADT under ex vivo 3D culture conditions and upregulate expression of ADT resistance‐associated phospho‐p38 and Bcl‐2 in LNCaP cells. As a result, pharmacological inhibition of the Notch pathway using γ‐secretase inhibitor (GSI), DAPT, downregulated both phospho‐p38 and Bcl‐2 expression and significantly enhanced the efficacy of ADT in androgen sensitive PCa cells with impaired proliferation and 3D colony formation, increased apoptosis and remarkable inhibition of tumor growth in murine subcutaneous xenograft model. These results indicate that activated Notch signaling contributes to ADT resistance, and suggest that inhibition of the Notch pathway may be a promising adjuvant therapy of ADT for PCa. [ABSTRACT FROM AUTHOR]

The testis‐specific Y‐encoded‐like protein (TSPYL) gene family includes TSPYL1 to TSPYL6. We previously reported that TSPYL5 regulates cytochrome P450 (CYP) 19A1 expression. Here we show that TSPYLs, especially TSPYL 1, 2, and 4, can regulate the expression of many CYP genes, including CYP17A1, a key enzyme in androgen biosynthesis, and CYP3A4, an enzyme that catalyzes the metabolism of abiraterone, a CYP17 inhibitor. Furthermore, a common TSPYL1 single nucleotide polymorphism (SNP), rs3828743 (G/A) (Pro62Ser), abolishes TSPYL1's ability to suppress CYP3A4 expression, resulting in reduced abiraterone concentrations and increased cell proliferation. Data from a prospective clinical trial of 87 metastatic castration‐resistant prostate cancer patients treated with abiraterone acetate/prednisone showed that the variant SNP genotype (A) was significantly associated with worse response and progression‐free survival. In summary, TSPYL genes are novel CYP gene transcription regulators, and genetic alteration within these genes significantly influences response to drug therapy through transcriptional regulation of CYP450 genes. [ABSTRACT FROM AUTHOR]

Vasculogenic mimicry ( VM)-positive melanomas are usually associated with poor prognosis. Rictor, the key component of the rapamycin-insensitive complex of mTOR ( mTORC2), is up-regulated in several cancers, especially in melanomas with poor prognosis. The aim of this study was to investigate the role of Rictor in the regulation of VM and the mechanism underlying this possible regulation. VM channels were found in 35 of 81 tested melanoma samples and high Rictor expression correlated with VM structures. Moreover, Kaplan-Meier survival curves indicated that VM structures and high Rictor expression correlated with shorter survival in patients with melanoma. In vitro, Rictor knockdown by short hairpin RNA (sh RNA) significantly inhibited the ability of A375 and MUM-2B melanoma cells to form VM structures, as evidenced by most tubes remaining open. Cell cycle analysis revealed that Rictor knockdown blocked cell growth and resulted in the accumulation of cells in G2/M phase, and cell migration and invasion were greatly affected after Rictor down-regulation. Western blotting assays indicated that down-regulating Rictor significantly inhibited the phosphorylation of AKT at Ser473 and Thr308, which subsequently inhibited the expression and activity of downstream MMP-2/9, as confirmed by real-time PCR and gelatin Zymography. MK-2206, a small-molecule inhibitor of AKT, similarly inhibited the activity of AKT and secretion of MMP-2/9, further supporting that Rictor down-regulation inhibits the phosphorylation of AKT and activity of downstream MMP-2/9 to affect VM formation. In conclusion, Rictor plays an important role in melanoma VM via the Rictor- AKT- MMP-2/9 signalling pathway. [ABSTRACT FROM AUTHOR]

Increasing attention has been focused on the use and validation of surrogate endpoints in cancer clinical trials. Previous literature on validation of surrogate endpoints are classified into four approaches: the proportion explained approach; the indirect effects approach; the meta-analytic approach; and the principal stratification approach. The mainstream in cancer research has seen the application of a meta-analytic approach. However, VanderWeele (2013) showed that all four of these approaches potentially suffer from the surrogate paradox. It was also shown that, if a principal surrogate satisfies additional criteria called one-sided average causal sufficiency, the surrogate cannot exhibit a surrogate paradox. Here, we propose a method for estimating principal effects under a monotonicity assumption. Specifically, we consider cancer clinical trials which compare a binary surrogate endpoint and a time-to-event clinical endpoint under two naturally ordered treatments (e.g. combined therapy vs. monotherapy). Estimation based on a mean score estimating equation will be implemented by the expectation-maximization algorithm. We will also apply the proposed method as well as other surrogacy criteria to evaluate the surrogacy of prostate-specific antigen using data from a phase III advanced prostate cancer trial, clarifying the complementary roles of both the principal stratification and meta-analytic approaches in the evaluation of surrogate endpoints in cancer. Copyright © 2017 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

ABSTRACT Background Body mass index (BMI) has been associated variably with head and neck cancer outcomes. We evaluated the association between BMI at either diagnosis or at early adulthood head and neck cancer outcomes. Methods Patients with invasive head and neck squamous cell cancer at Princess Margaret Cancer Centre in Toronto, Canada, were surveyed on tobacco and alcohol exposure, performance status, comorbidities, and BMI at diagnosis. A subset also had data collected for BMI at early adulthood. Results With a median follow-up of 2.5 years, in 1279 analyzed patients, being overweight (hazard ratio [HR], 0.55; 95% confidence interval [CI], 0.4-0.8; p = .001) at diagnosis was associated with improved survival when compared with individuals with normal weight. In contrast, underweight patients at diagnosis were associated with a worse outcome (HR, 1.89; 95% CI, 1.2-3.1; p < .01). Conclusion Being underweight at diagnosis was an independent, adverse prognostic factor, whereas being overweight conferred better prognosis. BMI in early adulthood was not associated strongly with head and neck cancer outcomes. © 2017 Wiley Periodicals, Inc. Head Neck 39: 1226-1233, 2017 [ABSTRACT FROM AUTHOR]

Purpose Sagittally reconstructed 3D ( SR3D) ultrasound imaging shows promise for improved needle localization for high-dose-rate prostate brachytherapy ( HDR- BT); however, needles must be manually segmented intraoperatively while the patient is anesthetized to create a treatment plan. The purpose of this article was to describe and validate an automatic needle segmentation algorithm designed for HDR- BT, specifically capable of simultaneously segmenting all needles in an HDR- BT implant using a single SR3D image with ~5 mm interneedle spacing. Materials and Methods The segmentation algorithm involves regularized feature point classification and line trajectory identification based on the randomized 3D Hough transform modified to handle multiple straight needles in a single image simultaneously. Needle tips are identified based on peaks in the derivative of the signal intensity profile along the needle trajectory. For algorithm validation, 12 prostate cancer patients underwent HDR- BT during which SR3D images were acquired with all needles in place. Needles present in each of the 12 images were segmented manually, providing a gold standard for comparison, and using the algorithm. Tip errors were assessed in terms of the 3D Euclidean distance between needle tips, and trajectory error was assessed in terms of 2D distance in the axial plane and angular deviation between trajectories. Results In total, 190 needles were investigated. Mean execution time of the algorithm was 11.0 s per patient, or 0.7 s per needle. The algorithm identified 82% and 85% of needle tips with 3D errors ≤3 mm and ≤5 mm, respectively, 91% of needle trajectories with 2D errors in the axial plane ≤3 mm, and 83% of needle trajectories with angular errors ≤3°. The largest tip error component was in the needle insertion direction. Conclusions Previous work has indicated HDR- BT needles may be manually segmented using SR3D images with insertion depth errors ≤3 mm and ≤5 mm for 83% and 92% of needles, respectively. The algorithm shows promise for reducing the time required for the segmentation of straight HDR- BT needles, and future work involves improving needle tip localization performance through improved image quality and modeling curvilinear trajectories. [ABSTRACT FROM AUTHOR]

ABSTRACT In the present study, it was evaluated the susceptibility of prostatic lesions in male adult rats exposed to Di- N-butyl-phthalate during fetal and lactational periods and submitted to MNU plus testosterone carcinogenesis protocol. Pregnant females were distributed into four experimental groups: CN (negative control); CMNU (MNU control); TDBP100 (100 mg/kg of DBP); TDBP500 (500 mg/kg of DBP). Females from the TDBP groups received DBP, by gavage, from gestation day 15 (GD15) to postnatal day 21 (DPN21), while C animals received the vehicle (corn oil). CMNU, TDBP100, and TDBP500 groups received a single intraperitoneal injection of MNU (50 mg/kg) on the sixth postnatal week. After that, testosterone cypionate was administered subcutaneously two times a week (2 mg/kg) for 24 weeks. The animals were euthanized on PND220. Distal segment fragments of the ventral (VP) and dorsolateral prostate (DLP) were fixed and processed for histopathological analysis. Protein extracts from ventral prostate were obtained, and western blotting was performed to AR, ERα, MAPK (ERK1/2), and pan-AKT. Stereological analysis showed an increase in the epithelial compartment in TDBP100 and TDBP500 compared to CN. In general, there was increase in the incidence of inflammation and metaplasia/dysplasia in the DBP-treated groups, mainly in DLP, compared to CN and CMNU. Proliferation index was significant higher in TDBP500 and PIN (prostatic intraepithelial neoplasia) was more frequent in this group compared to CMNU. Western blot assays showed an increase in the expressions of AR and MAPK (ERK1/2) in the TDBP100 compared to CN, and ERα and AKT expressions were higher in the TDBP500 group compared do CN. These results showed that different doses of DBP during prostate organogenesis in Wistar rats could increase the incidence of premalignant lesions in initiated rats inducing distinct biological responses in the adulthood. © 2015 Wiley Periodicals, Inc. Environ Toxicol 31: 1185-1195, 2016. [ABSTRACT FROM AUTHOR]

Key Clinical Message This manuscript describes a previously unreported clinical case of canine uveal melanoma in a miniature Schnauzer dog with an unusual location of metastasis (prostate) and delayed occurrence (3 years after primary tumor diagnosis and enucleation). Immunohistochemical labeling of both tumors with Melan A, Ki-67, and c-kit added some valuable information. [ABSTRACT FROM AUTHOR]

Abstracts of articles related to urology are presented including "Low Intensity Extracorporeal Shockwave Therapy in the Treatment of Erectile Dysfunction: Early Experience at Tan Tock Seng Hospital, "ED Treatment by Low Intensity Focused Shock Waves--A Comparison AF Available Devices and Therapeutic Techniques," and "Emphysematous Cystitis with Metastatic Infectious Foci."

Digital rectal examination, serum prostate-specific antigen screening and transrectal ultrasound-guided biopsy are conventionally used as screening, diagnostic and surveillance tools for prostate cancer. However, they have limited sensitivity and specificity. In recent years, the role of multiparametric magnetic resonance imaging has steadily grown, and is now part of the standard clinical management in many institutions. In multiparametric magnetic resonance imaging, the morphological assessment of T2-weighted imaging is correlated with diffusion-weighted imaging, dynamic contrast-enhanced imaging perfusion and/or magnetic resonance spectroscopic imaging. Multiparametric magnetic resonance imaging is currently regarded as the most sensitive and specific imaging technique for the evaluation of prostate cancer, including detection, staging, localization and aggressiveness evaluation. This article presents an overview of multiparametric magnetic resonance imaging, and discusses the current role of multiparametric magnetic resonance imaging in the different fields of prostate cancer management. [ABSTRACT FROM AUTHOR]

Background: To evaluate the regulation of blood supply in primary uveal melanomas through caveolin-1 (Cav-1)/phosphoinositol-3 kinase (PI3K). Methods: The expression of Cav-1 and PI3K was analysed in 51 paraffin sections of metastatic (n = 30) and non-metastastic uveal melanomas (n = 21). Two trained observers quantified Cav-1 and PI3K immunofluorescensce expression by determining intensity of staining and percentage of positive cells. The expression was correlated with known prognostic factors. Besides angiogenesis by means of endoglin expression, the normal vasculature (von Willebrand Factor expression) was evaluated semi-quantitatively. Vasculogenic mimicry (VM) was analysed by CD31/PAS staining. Results: All examined specimens expressed Cav-1 with a mean of 90.34% Cav-1 positive cells (range, 3.23-100%). Metastatic disease was associated with a higher Cav-1 expression. The correlation of Cav-1 with well-established prognostic factors showed a significant association between Cav-1 expression and largest tumour diameter (P = 0.022), tumour node metastasis classification (P = 0.008) and invasion of optic nerve head (P = 0.048). PI3K was expressed by all uveal melanomas with a mean of 87.28% cells showing PI3K expression. A higher level of PI3K was significantly associated with larger height (P = 0.042) and progressed tumour node metastasis stage (P = 0.016). The percentage of PI3K and Cav-1 positive cells were significantly associated (P = 0.034). For PI3K and Cav-1 expression a nonsignificant association with VM was shown (P = 0.064 and P=0.072, respectively). No correlation of PI3K or Cav-1 with angiogenesis or mature vasculature was seen (P>0.05). Conclusions: Cav-1 expression may be especially upregulated in larger uveal melanomas. As it was correlated with PI3K expression and VM in this series of uveal melanoma, Cav-1 might induce the formation of VM via the PI3K-signalling cascade. [ABSTRACT FROM AUTHOR]

It is estimated that approximately 90% of patients with advanced prostate cancer develop bone metastases; an occurrence that results in a substantial reduction in the quality of life and a drastic worsening of prognosis. The development of novel therapeutic strategies that impair the metastatic process and associated skeletal adversities is therefore critical to improving prostate cancer patient survival. Recognition of the importance of Cathepsin L (CTSL) to metastatic dissemination of cancer cells has led to the development of several CTSL inhibition strategies. The present investigation employed intra-cardiac injection of human PC-3ML prostate cancer cells into nude mice to examine tumor cell dissemination in a preclinical bone metastasis model. CTSL knockdown confirmed the validity of targeting this protease and subsequent intervention studies with the small molecule CTSL inhibitor KGP94 resulted in a significant reduction in metastatic tumor burden in the bone and an improvement in overall survival. CTSL inhibition by KGP94 also led to a significant impairment of tumor initiated angiogenesis. Furthermore, KGP94 treatment decreased osteoclast formation and bone resorptive function, thus, perturbing the reciprocal interactions between tumor cells and osteoclasts within the bone microenvironment which typically result in bone loss and aggressive growth of metastases. These functional effects were accompanied by a significant downregulation of NFjB signaling activity and expression of osteoclastogenesis related NFjB target genes. Collectively, these data indicate that the CTSL inhibitor KGP94 has the potential to alleviate metastatic disease progression and associated skeletal morbidities and hence may have utility in the treatment of advanced prostate cancer patients. [ABSTRACT FROM AUTHOR]

ABSTRACT The effects of six organophosphate flame retardants (OPFRs) tris(2-butoxyethyl) phosphate, tris(2-chloroethyl) phosphate, tris(1-chloro-2-propyl) phosphate, tris(methylphenyl) phosphate, tris(1,3-dichloro-2-propyl) phosphate (TDCIPP), and triethyl phosphate on the activities of androgen receptor (AR), estrogen receptor (ER), and aryl hydrocarbon receptor (AhR) were assessed in human prostate and endometrial cancer cells. OPFRs had no effect on ER or AhR target gene activation in ECC-1 cells. The effect of TDCIPP on mRNA and protein accumulation of AR target genes was examined further. AR-inducible gene and protein expression were significantly altered by TDCIPP exposure and repressed PSA levels in conditioned media of prostate cancer cells. We demonstrated that TDCIPP has no affinity for the AR ligand binding domain (AR-LBD) and exerts its antiandrogenic effects in a noncompetitive fashion. Thus, the clinical relevance of TDCIPP exposure on prostate cancer detection and progression to a therapeutically refractile state ought to be investigated further. [ABSTRACT FROM AUTHOR]

The Polycomb group of proteins (PcGs) are transcriptional repressor complexes that regulate important biological processes and play critical roles in cancer. Mutating or deleting EZH2 can have both oncogenic and tumor suppressive functions by increasing or decreasing H3K27me3. In contrast, mutations of SUZ12 and EED are reported to have tumor suppressive functions. EZH2 is overexpressed in many cancers, including prostate cancer, which can lead to silencing of tumor suppressors, genes regulating epithelial to mesenchymal transition (EMT), and interferon signaling. In some cases, EZH2 overexpression also leads to its use of non-histone substrates. Lastly, PRC2 associated factors can influence the progression of cancer through progressive mutations or by specific binding to certain target genes. Here, we discuss which mutations and deletions of the PRC2 complex have been detected in different cancers, with a specific focus on the overexpression of EZH2 in prostate cancer. [ABSTRACT FROM AUTHOR]

First-in-human (FIH) studies with AZD3514, a selective androgen receptor (AR) down-regulator, showed decreases of >30% in the prostate-specific antigen (PSA) in some patients. A modeling approach was adopted to understand these observations and define the optimum clinical use hypothesis for AZD3514 for clinical testing. Initial empirical modeling showed that only baseline PSA correlated significantly with this biological response, whereas drug concentration did not. To identify the mechanistic cause of this observation, a mechanism-based model was first developed, which described the effects of AZD3514 on AR protein and PSA mRNA levels in LNCaP cells with and without dihydrotestosterone (DHT). Second, the mechanism-based model was linked to a population pharmacokinetic (PK) model; PSA effects of clinical doses were subsequently simulated under different clinical conditions. This model was used to adjust the design of the ongoing clinical FIH study and direct the backup program. [ABSTRACT FROM AUTHOR]

Ductal adenocarcinoma of the prostate ( DAC) has morphological similarities to adenocarcinomas of other organs. DAC behaves in an aggressive manner and may present with metastases. These metastases may occur at unusual sites, which itself may cause diagnostic difficulties. It is important for therapeutic decisions that a prostatic origin of these metastases be established. Our aim was to compare the protein expression of DAC and adenocarcinomas of colon, endometrium, lung, pancreas, stomach and urinary bladder. A tissue microarray was constructed using 60 DAC, 6 colonic, 7 endometrial, 7 lung, 5 pancreatic, 5 gastric, and 9 urinary bladder adenocarcinomas. Slides were stained for estrogen, progesterone and androgen receptor, prolactin, PSA, prostein, PSMA, PSAP, CDX2, lysozyme, villin, monoclonal CEA, CK7, CK20, HMWCK, p63, p504s, c-Myc, EGFR, Ki-67, p16, p21, p27, p53, PTEN, ERG, and PAX-8. Androgen receptor, prostein, PSA, and PSAP were almost invariably expressed in DAC. Ki-67-labeling index was lower in DAC than in other adenocarcinomas. The expression patterns of intestinal markers and cytokeratins in DAC were less specific and may lead to diagnostic errors if not combined with prostate-specific markers. [ABSTRACT FROM AUTHOR]

Background: To assess mean apparent diffusion coefficient (ADC) and MR-derived tumor volume (Vt) as associative factors for extra-prostatic extension (EPE) in prostate cancer (PCa). Methods: With institutional review board approval, 73 consecutive patients diagnosed with PCa at trans-rectal ultrasound biopsy underwent preoperative multi-parametric (T2W+DWI+DCE) 3 Tesla MRI before radical prostatectomy between 2012 and 2014; 52% (38/73) patients had EPE. Clinical parameters including: age, prostate serum antigen (PSA), digital rectal examination (DRE) and percentage positive cores (PPC) were recorded. Two blinded radiologists subjectively evaluated for EPE using PI-RADS with T2W-MRI. A third blinded radiologist recorded: mean ADC (mm(2) /s) of tumor and tumor volume on ADC and T2W (derived from planar volumetry). VtMAX (the largest volume on ADC or T2W) was documented. Multivariate and receiver operator characteristic analyses were performed. Results: There were no significant differences in age, DRE, or Gleason score between groups (P = 0.52, 0.06, 0.61, 0.36). PSA approached significance being higher with EPE (12.9 ± 12.6 versus 8.2 ± 7.4; P = 0.06). PPC was higher with EPE (60.9 ± 21.9% versus 38.3 ± 21.6%; P < 0.01) with an area under the curve (AUC) of 0.78 and sensitivity/specificity = 75.7/75% when PPC ≥ 45%. AUC for T2W-MRI was 0.46-0.51 with sensitivity/specificity = 40.0-42.9/48.6-57.1% (R1, R2). Inter-observer agreement was fair, k = 0.39. There was no difference in mean ADC between groups (0.89 ± 0.25 versus 0.88 ± 0.19 [EPE] mm(2) /s), P = 0.70. T2W-Vt, ADC-Vt, and VtMAX were larger with EPE (5.1 ± 7.4, 5.8 ± 6.5, 6.3 ± 7.4 cm(3) versus 1.6 ± 1.8, 1.8 ± 1.3, 2.1 ± 1.8), P < 0.01. VtMAX AUC was 0.77 with sensitivity/specificity = 78.4/73.5% when VtMAX  ≥ 2.1 cm(3) which outperformed all other parameters (P > 0.05) except PPC (P = 0.6) for the diagnosis EPE. Conclusion: MR volumetry and percentage of positive core biopsies are associated with EPE; whereas, in this study, other clinical and MR parameters including mean ADC and subjective T2W-MR analysis were not useful for assessment of EPE. [ABSTRACT FROM AUTHOR]

Cancer drugs are broadly classified into two categories: cytotoxic chemotherapies and targeted therapies that specifically modulate the activity of one or more proteins involved in cancer. Major advances have been achieved in targeted cancer therapies in the past few decades, which is ascribed to the increasing understanding of molecular mechanisms for cancer initiation and progression. Consequently, monoclonal antibodies and small molecules have been developed to interfere with a specific molecular oncogenic target. Targeting gain-of-function mutations, in general, has been productive. However, it has been a major challenge to use standard pharmacologic approaches to target loss-of-function mutations of tumor suppressor genes. Novel approaches, including synthetic lethality and collateral vulnerability screens, are now being developed to target gene defects in p53, PTEN, and BRCA1/2. Here, we review and summarize the recent findings in cancer genomics, drug development, and molecular cancer biology, which show promise in targeting tumor suppressors in cancer therapeutics. [ABSTRACT FROM AUTHOR]

Targeting the androgen signalling pathway has long been the hallmark of anti-hormonal therapy for prostate cancer. However, development of androgen-independent prostate cancer is an inevitable outcome to therapies targeting this pathway, in part, owing to the shift from cancer dependence on androgen signalling for growth in favor of augmentation of other cellular pathways that provide proliferation-, survival- and angiogenesis-promoting signals. This review focuses on the role of the hormone relaxin in the development and progression of prostate cancer, prior to and after the onset of androgen independence, as well as its role in cancers of other reproductive tissues. As the body of literature expands, examining relaxin expression in cancerous tissues and its role in a growing number of in vitro and in vivo cancer models, our understanding of the important involvement of this hormone in cancer biology is becoming clearer. Specifically, the pleiotropic functions of relaxin affecting cell growth, angiogenesis, blood flow, cell migration and extracellular matrix remodeling are examined in the context of cancer progression. The interactions and intercepts of the intracellular signalling pathways of relaxin with the androgen pathway are explored in the context of progression of castration-resistant and androgen-independent prostate cancers. We provide an overview of current anti-hormonal therapeutic treatment options for prostate cancer and delve into therapeutic approaches and development of agents aimed at specifically antagonizing relaxin signalling to curb tumor growth. We also discuss the rationale and challenges utilizing such agents as novel anti-hormonals in the clinic, and their potential to supplement current therapeutic modalities. [ABSTRACT FROM AUTHOR]

Polycomb group (PcG) proteins are transcriptional repressors that regulate several crucial developmental and physiological processes in the cell. More recently, they have been found to play important roles in human carcinogenesis and cancer development and progression. The deregulation and dysfunction of PcG proteins often lead to blocking or inappropriate activation of developmental pathways, enhancing cellular proliferation, inhibiting apoptosis, and increasing the cancer stem cell population. Genetic and molecular investigations of PcG proteins have long been focused on their PcG functions. However, PcG proteins have recently been shown to exert non-classical-Pc-functions, contributing to the regulation of diverse cellular functions. We and others have demonstrated that PcG proteins regulate the expression and function of several oncogenes and tumor suppressor genes in a PcG-independent manner, and PcG proteins are associated with the survival of patients with cancer. In this review, we summarize the recent advances in the research on PcG proteins, including both the Pc-repressive and non-classical-Pc-functions. We specifically focus on the mechanisms by which PcG proteins play roles in cancer initiation, development, and progression. Finally, we discuss the potential value of PcG proteins as molecular biomarkers for the diagnosis and prognosis of cancer, and as molecular targets for cancer therapy. [ABSTRACT FROM AUTHOR]

Purpose: To evaluate the correlation between apparent diffusion coefficient measurements (ADCtumor and ADCratio ) and the Gleason score from radical prostatectomy specimens. Materials and Methods: Seventy-one patients with clinically localized prostate cancer scheduled for radical prostatectomy were prospectively enrolled. Multiparametric magnetic resonance imaging (MRI) was performed prior to prostatectomy and mean ADC values from both cancerous (ADCtumor ) and benign (ADCbenign ) tissue were measured to calculate the ADCratio (ADCtumor divided by ADCbenign ). The ADC measurements were correlated with the Gleason score from the prostatectomy specimens. Results: The association between ADC measurements and Gleason score showed a significant negative correlation (P < 0.001) with Spearman's rho for ADCtumor (-0.421) and ADCratio (-0.649). There was a statistically significant difference between ADC measurements and the Gleason score for all tumors (P = 0.001). Receiver operating characteristic curve analysis showed an overall area under the curve (AUC) of 0.73 (ADCtumor ) to 0.80 (ADCratio ) in discriminating Gleason score 6 from Gleason score ≥7 tumors. The AUC changed to 0.72 (ADCtumor ) and 0.90 (ADCratio ) when discriminating Gleason score ≤7(3+4) from Gleason score ≥7(4+3). Conclusion: ADC measurements showed a significant correlation with tumor Gleason score at final pathology. The ADCratio demonstrated the best correlation compared to the ADCtumor value and radically improved accuracy in discriminating Gleason score ≤7(3+4) from Gleason score ≥7(4+3) tumors. [ABSTRACT FROM AUTHOR]

The significance of marine creatures as a source of unique bioactive compounds is expanding. Marine organisms constitue nearly half of the wordwide biodiversity; thus, oceans and sea present a vast resource for new substances and it is considered the largest remaining reservoir of beneficial natural molecules that maight be used as functional constituents in the food sector. This review is an update to the information about recent functional seafood compounds (proteins, peptides, amino acids, fatty acids, sterols, polysaccharides, oligosaccharides, phenolic compounds, photosynthetic pigments, vitamins, and minerals) focusing on their potential use and health benefits. [ABSTRACT FROM AUTHOR]