Novel Optical Methods for Identification, Imaging, and Preservation of the Cavernous Nerves Responsible for Penile Erections during Prostate Cancer Surgery

DTIC Science & Technology

2009-03-01

wavelength, pulse energy, and pulse rate) to produce strongest and most rapid erectile response as measured by intracavernosal pressure in the penis ...PC Fiber Rod Housing Optics 5-mm-ID Port Probe Handle Probe Stem Enlarged View of Probe Tip Oscilloscope FunctionGenerator Thulium Fiber Laser Shutter...rapid erectile response as measured by intracavernosal pressure (ICP) in the penis . ICP values were increased from an initial range of 30-40 mmHg

Preparation of 68Ga-PSMA-11 with a Synthesis Module for Micro PET-CT Imaging of PSMA Expression during Prostate Cancer Progression

PubMed Central

Shao, Guoqiang; Wu, Jianping; Cui, Can; Zang, Shimin; Qiu, Fan

2018-01-01

Objective To synthesize 68Ga-Glu-urea-Lys(Ahx)-HBED-CC (68Ga-PSMA-11) with a synthesis module and investigate PET-CT imaging to monitor PSMA expression during prostate cancer (PCa) progression and tumor growth in mice bearing subcutaneous PCa xenografts. Method The radiochemical purity and stability of  68Ga-PSMA-11 were determined via radio-HPLC. The PCa cell lines of different PSMA expression levels (PC3, VCAP±, CWR22RV1+, and LNCaP++) were selected to mimic the PCa progression. 68Ga-PSMA-11 biodistribution was studied by dissection method and in vivo imaging with micro PET-CT. The expression levels of PSMA in tumor cells and tissues were analyzed by immunofluorescence, flow cytometry, and western blot. The correlation between PSMA expression and radio-uptake was also evaluated. 2-PMPA preadministration served as a block group. Results The radiochemical purity of  68Ga-PSMA-11 was 99.6 ± 0.1% and stable in vitro for 2 h. The equilibrium binding constant (Kd) of  68Ga-PSMA-11 to LNCaP, CWR22Rv1, PC-3, and VCAP cells was 4.3 ± 0.8 nM, 16.4 ± 1.3 nM, 225.3 ± 20.8 nM, and 125.6 ± 13.1 nM, respectively. Results of tumor uptake (% ID and % ID/g or % ID/cm3) of  68Ga-PSMA-11 in biodistribution and micro PET imaging were LNCaP > CWR22RV1 > PC-3 and VCAP due to different PSMA expression levels. It was confirmed by flow cytometry, western blot, and immunofluorescence. Tumor uptake (% ID/cm3) of  68Ga-PSMA-11 increased with the tumor anatomical volume in quadratic polynomial fashion and reached the peak (when tumor volume was 0.5 cm3) earlier than tumor uptake (% ID). Tumor uptake (% ID/cm3) of  68Ga-PSMA-11 based on functional volume correlated well with the PSMA expression in a linear manner (y = 9.35x + 2.59, R2 = 0.8924, and p < 0.0001); however, low dose 2-PMPA causes rapid renal clearance of increased tumor/kidney uptake of  68Ga-PSMA-11. Conclusions The 68Ga-PSMA-11 PET-CT imaging could invasively evaluate PSMA expression during PCa progression and tumor growth with % ID/cm3 (based on functional volume) as an important index. Low dose 2-PMPA preadministration might be a choice to decrease kidney uptake of  68Ga-PSMA-11. PMID:29853810

Time to diagnosis and treatment for cancer patients in the Netherlands: Room for improvement?

PubMed

Helsper, Charles C W; van Erp, Nicole N F; Peeters, Petra P H M; de Wit, Niek N J

2017-12-01

Reducing the duration of the diagnostic cancer care pathway is intensively pursued. The aim of this study was to chart the diagnostic pathway for the five most common cancers in the Netherlands. A retrospective cohort study using cancer patients' anonymised primary care data (free text and coded) linked to the Netherlands Cancer Registry. We determined the median duration of the following: 1. Primary care intervals (IPCs): the first cancer-related general practitioner consultation to referral, 2. Referral intervals (IRs): referral to diagnosis, 3. Treatment intervals (ITs): diagnosis to treatment and the overarching intervals, 4. Diagnostic intervals (IDs): IPC and IR combined and 5. Health care intervals (IHCs): IPC, IR and IT combined. For 465, 309, 197, 237 and 149 patients diagnosed with breast-, colorectal-, lung-, prostate cancer and melanoma, respectively; median IPC, IR and ID durations were shortest for breast cancer and melanoma (ID duration 7 and 21 days, respectively), intermediate for lung- and colon cancer (ID duration 49 and 54 days) and the longest for prostate cancer (ID duration 137 days). For all cancers, the duration of intervals increased steeply for the 10-25% with longest durations. For colorectal cancer, increasing ID durations showed increasing proportions of time attributable to primary care (IPC). Approximately 10-25% of cancer patients show substantially long duration of diagnostic intervals. Reducing primary care delay seems particularly relevant for colorectal cancer. Copyright © 2017 Elsevier Ltd. All rights reserved.

Mangiferin functionalized radioactive gold nanoparticles (MGF-198AuNPs) in prostate tumor therapy: green nanotechnology for production, in vivo tumor retention and evaluation of therapeutic efficacy.

PubMed

Al-Yasiri, A Y; Khoobchandani, M; Cutler, C S; Watkinson, L; Carmack, T; Smith, C J; Kuchuk, M; Loyalka, S K; Lugão, A B; Katti, K V

2017-10-31

We report here an innovative feature of green nanotechnology-focused work showing that mangiferin-a glucose functionalized xanthonoid, found in abundance in mango peels-serves dual roles of chemical reduction and in situ encapsulation, to produce gold nanoparticles with optimum in vivo stability and tumor specific characteristics. The interaction of mangiferin with a Au-198 gold precursor affords MGF- 198 AuNPs as the beta emissions of Au-198 provide unique advantages for tumor therapy while gamma rays are used for the quantitative estimation of gold within the tumors and various organs. The laminin receptor specificity of mangiferin affords specific accumulation of therapeutic payloads of this new therapeutic agent within prostate tumors (PC-3) of human prostate tumor origin induced in mice which overexpress this receptor subtype. Detailed in vivo therapeutic efficacy studies, through the intratumoral delivery of MGF- 198 AuNPs, show the retention of over 80% of the injected dose (ID) in prostate tumors up to 24 h. By three weeks post treatment, tumor volumes of the treated group of animals showed an over 5 fold reduction as compared to the control saline group. New opportunities for green nanotechnology and a new paradigm of using mangiferin as a tumor targeting agent in oncology for the application of MGF- 198 AuNPs in the treatment of cancer are discussed.

The Role of the Sonic Hedgehog Pathway for Prostate Cancer Progression

DTIC Science & Technology

2008-02-01

lo ap m in e TS U -t om at id in e...TS U -c yc lo ap m in e D U 14 5- to m at id in e D u1 45 -c yc lo pa m in e Page 8 of 13 (page number not for citation purposes) Molecular Cancer...without matrigels) (B). 0 10 20 30 40 50 60 P C 3- to m at id in e P C 3- cy cl op am in e LN -C A P -t om at id in e LN -C A P -c yc lo ap m in e TS U

Inhibitory Effects of Megakaryocytes in Prostate Cancer Bone Metastasis

DTIC Science & Technology

2010-04-01

meeting, Feb. 2010, Seattle, WA) 3. Inhibitory effects of megakaryocytes in prostate cancer bone metastasis. (Oral presentation and Young ...cancer bone metastasis. (Oral presentation and ASBMR-Harold M. Frost Young Investigator Award, Aug. 2009, Sun Valley, ID) 5. Career development...valuable new scientific information and also provided critical career development support for an a spiring young scientist. References Please refer

The Impact of Prostate Cancer Treatment-Related Symptoms on Low-Income Latino Couples

DTIC Science & Technology

2011-03-01

decir la…la…palabra cáncer para usted? Patient ID#1866: Pues…casi es básicamente “aguas, que estás en peligro !” ¿Si? Interviewer AS: Uh huh...primero era acabar con el cáncer Interviewer AS: Si Principal Investigator: Maliski, SL 36 Patient ID#1866: Eso es el peligro de perder la vida

Radioligand Therapy of Prostate Cancer with a Long-Lasting Prostate-Specific Membrane Antigen Targeting Agent 90Y-DOTA-EB-MCG.

PubMed

Wang, Zhantong; Jacobson, Orit; Tian, Rui; Mease, Ronnie C; Kiesewetter, Dale O; Niu, Gang; Pomper, Martin G; Chen, Xiaoyuan

2018-06-15

Several radioligands targeting prostate-specific membrane antigen (PSMA) have been clinically introduced as a new class of radiotheranostics for the treatment of prostate cancer. Among them, ((( R)-1-carboxy-2-mcercaptoethyl)carbamoyl)-l-glutamic acid (MCG) has been successfully labeled with radioisotopes for prostate cancer imaging. The aim of this study is to conjugate MCG with an albumin binding moiety to further improve the in vivo pharmacokinetics. MCG was conjugated with an Evans blue (EB) derivative for albumin binding and a DOTA chelator. PSMA positive (PC3-PIP) and PSMA negative (PC3) cells were used for both in vitro and in vivo studies. Longitudinal PET imaging was performed at 1, 4, 24, and 48 h post-injection to evaluate the biodistribution and tumor uptake of 86 Y-DOTA-EB-MCG. DOTA-EB-MCG was also labeled with 90 Y for radionuclide therapy. Besides tumor growth measurement, tumor response to escalating therapeutic doses were also evaluated by immunohistochemistry and fluorescence microscopy. Based on quantification from 86 Y-DOTA-EB-MCG PET images, the tracer uptake in PC3-PIP tumors increased from 22.33 ± 2.39%ID/g at 1 h post-injection (p.i.), to the peak of 40.40 ± 4.79%ID/g at 24 h p.i. Administration of 7.4 MBq of 90 Y-DOTA-EB-MCG resulted in significant regression of tumor growth in PSMA positive xenografts. No apparent toxicity or body weight loss was observed in all treated mice. Modification of MCG with an Evans blue derivative resulted in a highly efficient prostate cancer targeting agent (EB-MCG), which showed great potential in prostate cancer treatment after being labeled with therapeutic radioisotopes.

Efficacy of a multi-component exercise programme and nutritional supplementation on musculoskeletal health in men treated with androgen deprivation therapy for prostate cancer (IMPACT): study protocol of a randomised controlled trial.

PubMed

Owen, Patrick J; Daly, Robin M; Livingston, Patricia M; Mundell, Niamh L; Dalla Via, Jack; Millar, Jeremy L; Fraser, Steve F

2017-10-03

Prostate cancer is the most commonly diagnosed cancer in men in developed countries. Androgen deprivation therapy (ADT) is a systemic treatment shown to increase survival in selected patients with prostate cancer. The use of ADT continues to increase for all stages and grades of prostate cancer despite known treatment-induced adverse effects. The primary aim of this study is to examine the efficacy of a targeted, multi-component resistance and impact-loading exercise programme together with a daily protein-, calcium- and vitamin D-enriched supplement on bone health in men treated with ADT for prostate cancer. Secondary aims are to determine the effects of this intervention on measures of total body and regional body composition, cardiometabolic risk, inflammatory markers, health-related quality of life and cognitive function. This study is a two-arm randomised controlled trial. Men currently treated with ADT for prostate cancer will be randomised to either a 52-week, community-based, exercise training and nutritional supplementation intervention (n = 51) or usual care control (n = 51). Participants will be assessed at baseline, 26 weeks and 52 weeks for all measures. The primary outcome measures are proximal femur and lumbar spine areal bone mineral density (BMD). Secondary outcomes comprise: changes in tibial and radial bone structure and strength, total body and regional body composition, muscle strength and function, as well as cardiometabolic health, catabolic/inflammatory and anabolic/anti-inflammatory cytokines, health-related quality of life and cognitive function. This study investigates whether a multi-component intervention incorporating a targeted bone and muscle-loading programme in combination with a protein-, calcium- and vitamin D-enriched supplement can ameliorate multiple adverse effects of ADT when compared to usual care. The results will contribute to the development of exercise training and nutrition guidelines for optimising overall health in men treated with ADT for prostate cancer. Australia New Zealand Clinical Trial Registry (ANZCTR), ID: ACTRN12614000317695 . Registered on 25 march 2014.

Evaluation of Multimodal Imaging Biomarkers of Prostate Cancer

DTIC Science & Technology

2015-09-01

and PET images. Figure 2 highlights the dynamic uptake of TSPO as compared to muscle. Across 60 minutes the %ID/cc continues to increase which is...p53 double null mutant mouse model. Towards that end, we have successfully acquired anatomic MRI and PET data in orthotopic tumors within the Pten...castration resistant prostate cancer, MRI, PET , FDHT, image optimization 16. SECURITY CLASSIFICATION OF: 17. LIMITATION OF ABSTRACT 18. NUMBER OF PAGES

Interactive Dose Shaping - efficient strategies for CPU-based real-time treatment planning

NASA Astrophysics Data System (ADS)

Ziegenhein, P.; Kamerling, C. P.; Oelfke, U.

2014-03-01

Conventional intensity modulated radiation therapy (IMRT) treatment planning is based on the traditional concept of iterative optimization using an objective function specified by dose volume histogram constraints for pre-segmented VOIs. This indirect approach suffers from unavoidable shortcomings: i) The control of local dose features is limited to segmented VOIs. ii) Any objective function is a mathematical measure of the plan quality, i.e., is not able to define the clinically optimal treatment plan. iii) Adapting an existing plan to changed patient anatomy as detected by IGRT procedures is difficult. To overcome these shortcomings, we introduce the method of Interactive Dose Shaping (IDS) as a new paradigm for IMRT treatment planning. IDS allows for a direct and interactive manipulation of local dose features in real-time. The key element driving the IDS process is a two-step Dose Modification and Recovery (DMR) strategy: A local dose modification is initiated by the user which translates into modified fluence patterns. This also affects existing desired dose features elsewhere which is compensated by a heuristic recovery process. The IDS paradigm was implemented together with a CPU-based ultra-fast dose calculation and a 3D GUI for dose manipulation and visualization. A local dose feature can be implemented via the DMR strategy within 1-2 seconds. By imposing a series of local dose features, equal plan qualities could be achieved compared to conventional planning for prostate and head and neck cases within 1-2 minutes. The idea of Interactive Dose Shaping for treatment planning has been introduced and first applications of this concept have been realized.

Preclinical evaluation of a bispecific low-molecular heterodimer targeting both PSMA and GRPR for improved PET imaging and therapy of prostate cancer.

PubMed

Eder, Matthias; Schäfer, Martin; Bauder-Wüst, Ulrike; Haberkorn, Uwe; Eisenhut, Michael; Kopka, Klaus

2014-05-01

It has recently been reported that metastases of prostate cancer usually show highly heterogeneous or partly lost prostate-specific membrane antigen (PSMA) expression. In order to image and treat both PSMA positive and negative tissues PSMA targeting probes need to be extended by a further specificity. Since prostate cancer cells usually express both PSMA and gastrin-releasing peptide receptor (GRPR) a bispecific low-molecular heterodimeric molecule, addressing both targets at the same time, may significantly improve prostate cancer imaging and therapy. The nonapeptide BZH3 representing the GRPR binding part was combined with the urea-based PSMA inhibitor Glu-urea-Lys(Ahx)-HBED-CC. The syntheses of the compounds were performed according to standard Fmoc-solid phase peptide synthesis. The binding properties were analyzed by competitive cell binding and internalization experiments. The in vivo targeting properties were investigated by means of biodistribution studies. Cell binding experiments revealed high binding affinities to both GRPR and PSMA expressing cell lines. The heterodimer bound with IC50 -values essentially matching the IC50 values of the respective monomers (25.0 ± 5.4 nM for PSMA and 9.0 ± 1.8 nM for GRPR, respectively). In vivo, the heterodimer showed dual targeting of PSMA (5.4%ID/g for PSMA-positive tumors) and GRPR receptors (3.3% ID/g for GRPR-positive tumors) while exhibiting fast pharmacokinetic properties. The clearance from background was comparable to the monomeric PSMA-targeting reference. The heterodimeric molecule is a promising agent for PET imaging of primary and recurrent prostate cancer covering two receptor entities which might lead to an improved diagnostic sensitivity and therapeutic efficiency. © 2014 Wiley Periodicals, Inc.

Enhanced Peptide of Prostate Cancer Using Targeted Adenoviral Vectors

DTIC Science & Technology

2005-06-01

receptor subtype 2 has been constructed and evaluated in-human prostate cancer cells with regard to binding: of 64Cu - octreotide. In vivo experiments...of 64CU -octreotide.. The mice wer.e. sacrificed 1. h after peptide injection for biodistribution analysis. In vivo biodistribution studies showed...similar uptake of 64Cu - octreotide in both DU-145 and PC-3 tumors after infection with-AdSSTR2. (2.5. and 2.7% ID/g, respectively). This uptake was

The biodistribution and pharmacokinetic evaluation of choline-bound gold nanoparticles in a human prostate tumor xenograft model.

PubMed

Razzak, Rene; Zhou, Joe; Yang, XiaoHong; Pervez, Nadim; Bédard, Eric Lr; Moore, Ronald B; Shaw, Andrew; Amanie, John; Roa, Wilson H

2013-06-01

Gold nanoparticles (GNPs) have attracted significant attention in the treatment of cancer due to their potential as novel radiation enhancers, particularly when functionalized with various targeting ligands. The aim of this study was to assess the biodistribution and pharmacokinetic characteristics of a novel choline-bound GNP (choline-GNP) stabilized with polyethelenimine (PEI). Choline bound to 27 nm diameter GNPs was characterized using transmission electron microscopy (TEM), X-ray photoelectron spectroscopy (XPS) and Fourier transform infrared spectroscopy (FTIR). Toxicity of choline-GNPs was examined on DU-145 prostate cancer cells using an MTT assay. Using balb/c mice bearing flank DU-145 prostate tumors, choline-GNPs bio-distribution was measured using inductively coupled mass spectroscopy (ICP-MS). Blood, heart, lung, liver, spleen, brain, kidney and tumor gold content were examined at multiple time points over a 24-hour period after tail vein injection. An MTT assay using DU-145 prostate cancer cells yielded a 95% cell viability 72 hours after choline-GNP administration. The tumor GNP area under the concentration-time curve during the first 4 hours (AUC0-4) was 2.2 µg/ml h, representing 13% of the circulating blood GNP concentration over the same time period. The maximum intra-tumor GNP concentration observed was 1.4% of the injected dose per gram of tumor tissue (%ID/g) one hour post injection. GNPs functionalized with choline demonstrates a viable future nanoparticle platform with increased intra-tumor uptake as compared to unconjugated GNPs. Decreased intra-hepatic accumulation appears to be the reason for the improved systemic bioavailability. The next logical translational investigation will incorporate external beam radiation with the observed maximum intra-tumor uptake.

Imaging Prostate Cancer with Positron Emission Tomography

DTIC Science & Technology

2016-07-01

pool. Radioactivity was retained in kidney tissue and suggests that this is the primary route of excretion. Tumor targeting was inefficient.    15...radioactivity in hepatic tissue. Elevated levels of radioactivity were observed in kidney tissue suggesting that these radiotracers are excreted...20, 21], and its Blood 0 10 20 30 0.00 0.05 0.10 0.15 0.20 Time (h) % ID /g Liver 0 10 20 30 0.0 0.5 1.0 1.5 2.0 Time (h) % ID /g Kidney 0 10 20 30

Sunitinib reduces tumor hypoxia and angiogenesis, and radiosensitizes prostate cancer stem-like cells.

PubMed

Diaz, Roque; Nguewa, Paul A; Redrado, Miriam; Manrique, Irene; Calvo, Alfonso

2015-08-01

The need for new treatments for advanced prostate cancer has fostered the experimental use of targeted therapies. Sunitinib is a multi-tyrosine kinase inhibitor that mainly targets membrane-bound receptors of cells within the tumor microenvironment, such as endothelial cells and pericytes. However, recent studies suggest a direct effect on tumor cells. In the present study, we have evaluated both direct and indirect effects of Sunitinib in prostate cancer and how this drug regulates hypoxia, using in vitro and in vivo models. We have used both in vitro (PC-3, DU145, and LNCaP cells) and in vivo (PC-3 xenografts) models to study the effect of Sunitinib in prostate cancer. Analysis of hypoxia based on HIF-1α expression and FMISO uptake was conducted. ALDH activity was used to analyze cancer stem cells (CSC). Sunitinib strongly reduced proliferation of PC-3 and DU-145 cells in a dose dependent manner, and decreased levels of p-Akt, p-Erk1/2, and Id-1, compared to untreated cells. A 3-fold reduction in tumor growth was also observed (P < 0.001 with respect to controls). Depletion of Hif-1α levels in vitro and a decrease in FMISO uptake in vivo showed that Sunitinib inhibits tumor hypoxia. When combined with radiotherapy, this drug enhanced cell death in vitro and in vivo, and significantly decreased CD-31, PDGFRβ, Hif-1α, Id1, and PCNA protein levels (whereas apoptosis was increased) in tumors as compared to controls or single-therapy treated mice. Moreover, Sunitinib reduced the number of ALDH + cancer stem-like cells and sensitized these cells to radiation-mediated loss of clonogenicity. Our results support the use of Sunitinib in prostate cancer and shows that both hypoxia and cancer stem cells are involved in the effect elicited by this drug. Combination of Sunitinib with radiotherapy warrants further consideration to reduce prostate cancer burden. © 2015 Wiley Periodicals, Inc.

Noninvasive Imaging of PSMA in prostate tumors with (89)Zr-Labeled huJ591 engineered antibody fragments: the faster alternatives.

PubMed

Viola-Villegas, Nerissa Therese; Sevak, Kuntal K; Carlin, Sean D; Doran, Michael G; Evans, Henry W; Bartlett, Derek W; Wu, Anna M; Lewis, Jason S

2014-11-03

Engineered antibody fragments offer faster delivery with retained tumor specificity and rapid clearance from nontumor tissues. Here, we demonstrate that positron emission tomography (PET) based detection of prostate specific membrane antigen (PSMA) in prostatic tumor models using engineered bivalent antibodies built on single chain fragments (scFv) derived from the intact antibody, huJ591, offers similar tumor delineating properties but with the advantage of rapid targeting and imaging. (89)Zr-radiolabeled huJ591 scFv (dimeric scFv-CH3; (89)Zr-Mb) and cysteine diabodies (dimeric scFv; (89)Zr-Cys-Db) demonstrated internalization and similar Kds (∼2 nM) compared to (89)Zr-huJ591 in PSMA(+) cells. Tissue distribution assays established the specificities of both (89)Zr-Mb and (89)Zr-Cys-Db for PSMA(+) xenografts (6.2 ± 2.5% ID/g and 10.2 ± 3.4% ID/g at 12 h p.i. respectively), while minimal accumulation in PSMA(-) tumors was observed. From the PET images, (89)Zr-Mb and (89)Zr-Cys-Db exhibited faster blood clearance than the parent huJ591 while tumor-to-muscle ratios for all probes show comparable values across all time points. Ex vivo autoradiography and histology assessed the distribution of the probes within the tumor. Imaging PSMA-expressing prostate tumors with smaller antibody fragments offers rapid tumor accumulation and accelerated clearance; hence, shortened wait periods between tracer administration and high-contrast tumor imaging and lower dose-related toxicity are potentially realized.

Cancer stem cell-related gene expression as a potential biomarker of response for first-in-class imipridone ONC201 in solid tumors.

PubMed

Prabhu, Varun V; Lulla, Amriti R; Madhukar, Neel S; Ralff, Marie D; Zhao, Dan; Kline, Christina Leah B; Van den Heuvel, A Pieter J; Lev, Avital; Garnett, Mathew J; McDermott, Ultan; Benes, Cyril H; Batchelor, Tracy T; Chi, Andrew S; Elemento, Olivier; Allen, Joshua E; El-Deiry, Wafik S

2017-01-01

Cancer stem cells (CSCs) correlate with recurrence, metastasis and poor survival in clinical studies. Encouraging results from clinical trials of CSC inhibitors have further validated CSCs as therapeutic targets. ONC201 is a first-in-class small molecule imipridone in Phase I/II clinical trials for advanced cancer. We have previously shown that ONC201 targets self-renewing, chemotherapy-resistant colorectal CSCs via Akt/ERK inhibition and DR5/TRAIL induction. In this study, we demonstrate that the anti-CSC effects of ONC201 involve early changes in stem cell-related gene expression prior to tumor cell death induction. A targeted network analysis of gene expression profiles in colorectal cancer cells revealed that ONC201 downregulates stem cell pathways such as Wnt signaling and modulates genes (ID1, ID2, ID3 and ALDH7A1) known to regulate self-renewal in colorectal, prostate cancer and glioblastoma. ONC201-mediated changes in CSC-related gene expression were validated at the RNA and protein level for each tumor type. Accordingly, we observed inhibition of self-renewal and CSC markers in prostate cancer cell lines and patient-derived glioblastoma cells upon ONC201 treatment. Interestingly, ONC201-mediated CSC depletion does not occur in colorectal cancer cells with acquired resistance to ONC201. Finally, we observed that basal expression of CSC-related genes (ID1, CD44, HES7 and TCF3) significantly correlate with ONC201 efficacy in >1000 cancer cell lines and combining the expression of multiple genes leads to a stronger overall prediction. These proof-of-concept studies provide a rationale for testing CSC expression at the RNA and protein level as a predictive and pharmacodynamic biomarker of ONC201 response in ongoing clinical studies.

Cancer stem cell-related gene expression as a potential biomarker of response for first-in-class imipridone ONC201 in solid tumors

PubMed Central

Zhao, Dan; Kline, Christina Leah B.; Van den Heuvel, A. Pieter J.; Lev, Avital; Garnett, Mathew J.; McDermott, Ultan; Benes, Cyril H.; Batchelor, Tracy T.; Chi, Andrew S.; Elemento, Olivier; Allen, Joshua E.

2017-01-01

Cancer stem cells (CSCs) correlate with recurrence, metastasis and poor survival in clinical studies. Encouraging results from clinical trials of CSC inhibitors have further validated CSCs as therapeutic targets. ONC201 is a first-in-class small molecule imipridone in Phase I/II clinical trials for advanced cancer. We have previously shown that ONC201 targets self-renewing, chemotherapy-resistant colorectal CSCs via Akt/ERK inhibition and DR5/TRAIL induction. In this study, we demonstrate that the anti-CSC effects of ONC201 involve early changes in stem cell-related gene expression prior to tumor cell death induction. A targeted network analysis of gene expression profiles in colorectal cancer cells revealed that ONC201 downregulates stem cell pathways such as Wnt signaling and modulates genes (ID1, ID2, ID3 and ALDH7A1) known to regulate self-renewal in colorectal, prostate cancer and glioblastoma. ONC201-mediated changes in CSC-related gene expression were validated at the RNA and protein level for each tumor type. Accordingly, we observed inhibition of self-renewal and CSC markers in prostate cancer cell lines and patient-derived glioblastoma cells upon ONC201 treatment. Interestingly, ONC201-mediated CSC depletion does not occur in colorectal cancer cells with acquired resistance to ONC201. Finally, we observed that basal expression of CSC-related genes (ID1, CD44, HES7 and TCF3) significantly correlate with ONC201 efficacy in >1000 cancer cell lines and combining the expression of multiple genes leads to a stronger overall prediction. These proof-of-concept studies provide a rationale for testing CSC expression at the RNA and protein level as a predictive and pharmacodynamic biomarker of ONC201 response in ongoing clinical studies. PMID:28767654

Synthesis and characterization of theranostic poly(HPMA)-c(RGDyK)-DOTA-64Cu copolymer targeting tumor angiogenesis: tumor localization visualized by positron emission tomography.

PubMed

Yuan, Jianchao; Zhang, Haiyuan; Kaur, Harpreet; Oupicky, David; Peng, Fangyu

2013-05-01

Poly(HPMA)-c(RGDyK)-DOTA-64Cu copolymers were synthesized and characterized for tumor localization in vivo as a theranostic scaffold for cancer imaging and anticancer drug delivery targeting tumor angiogenesis. Tumor localization of the poly(HPMA)-c(RGDyK)-DOTA-64Cu copolymers was visualized in mice bearing human prostate cancer xenografts by positron emission tomography (PET) using a microPET scanner. PET quantitative analysis demonstrated that tumor 64Cu radioactivity (2.75 ± 0.34 %ID/g) in tumor-bearing mice 3 hours following intravenous injection of the poly(HPMA)-c(RGDyK)-DOTA-64Cu copolymers was significantly higher than the tumor 64Cu radioactivity (1.29 ± 0.26 %ID/g) in tumor-bearing mice injected with the nontargeted poly(HPMA)-DOTA-64Cu copolymers (p = .004). The poly(HPMA)-c(RGDyK)-DOTA-64Cu copolymers hold potential as a theranostic scaffold for cancer imaging and radiochemotherapy of prostate cancer targeting tumor angiogenesis by noninvasive tracking with PET.

Circular RNA Myosin Light Chain Kinase (MYLK) Promotes Prostate Cancer Progression through Modulating Mir-29a Expression.

PubMed

Dai, Yuanqing; Li, Dongjie; Chen, Xiong; Tan, Xinji; Gu, Jie; Chen, Mingquan; Zhang, Xiaobo

2018-05-25

BACKGROUND In developed countries, prostate cancer (PCa) is a frequently diagnosed cancer with the second highest fatality rate. Circular RNAs (circRNAs) are a class of endogenous non-coding RNAs (ncRNAs) stably expressed in cells and involved in a series of carcinomas. However, few research studies have reported on the role of circRNAs in PCa. MATERIAL AND METHODS We used qRT-PCR to detect the expression of circMYLK (circRNA ID: hsa_circ_0141940) and miR-29a in PCa tissues and cell lines. MTT, colony formation, and TUNEL assays were performed to analysis the cell viability of PCa cells. Transwell and wound scratch assays were performed to investigate the cell invasion and migration of PCa cells. RESULTS In the present study, we confirmed that circMYLK expression level was significantly higher in PCa samples and PCa cells than in normal tissues and normal prostatic cells. The upregulated circRNA-MYLK promoted PCa cells proliferation, invasion, and migration; however, si-circRNA-MYLK significantly accelerated the PCa cell apoptosis. We also observed that the aforementioned function of circRNA-MYLK on PCa cells was affected through targeting miR-29a. CONCLUSIONS We confirmed circRNA-MYLK was an oncogene in PCa and revealed a novel mechanism underlying circRNA-MYLK in PC progression.

Overcoming Resistance of Prostate Cancer to TRAIL-Mediated Apoptosis

DTIC Science & Technology

2004-06-01

Box 347 , Boulder, CO, triggers for the apoptotic signal, whereas Bax and Bak act 80309-0347. T. Johnson is currently at the Department of Surgery...that some PI 3-id- 1w: nase activity can be restored by de nowo synthesis in the course of the experiment. LY-294002 does not bind the enzyme eo

Therapeutic Roles of Bmi-1 Inhibitors in Eliminating Prostate Tumor Stem Cells

DTIC Science & Technology

2013-10-01

KW, Suri P, Wicha MS. Hedgehog signaling and Bmi-1 regulate self- renewal of normal and malignant human mammary stem cells. Cancer Res 66:6063-71...ID, Patel S, Ahn NS, Jackson KW, Suri P, Wicha MS. Hedgehog signaling and bmi-1 regulate self-renewal of normal and malignant human mammary stem cells

Development of glycan specific lectin based immunoassay for detection of prostate specific antigen.

PubMed

Bhanushali, Paresh B; Badgujar, Shamkant B; Tripathi, Mukesh M; Gupta, Sanjeev; Murthy, Vedang; Krishnasastry, Musti V; Puri, Chander P

2016-05-01

We describe an analytical approach for the detection and verification of glycosylation patterns of prostate specific antigen (PSA), a key biomarker currently used for understanding the onset and prognosis of prostate cancer. PSA has been purified from the human seminal plasma and total PSA from prostate cancer sera. PSA is a monomeric glycoprotein with an apparent molecular mass 28040.467 Da, which exhibits a characteristic protease activity against casein and gelatin. Its optimal protease activity is centered on neutral pH. Peptide mass fingerprint analysis of the purified PSA has yielded peptides that partially match with known database sequences (Uniprot ID P07288). Tryptic digestion profile of isolated PSA, infer the exclusive nature of PSA and may be additive molecule in the dictionary of seminal proteins. Surface plasmon resonance and lectin immunoassay revealed direct interaction between a newly developed anti-PSA monoclonal antibody (C4E6) and PSA. A lectin based immunoassay is reported here which was achieved with the C4E6 anti-PSA antibody and biotinylated plant lectins. This investigation provides an alternative method to isolate and quantify PSA with altered glycosylation which might be seen in the prostate cancer and developing a lectin based immunoassay to detect PSA in serum of prostate cancer patients. Copyright © 2016 Elsevier B.V. All rights reserved.

Preclinical and first clinical experience with the gastrin-releasing peptide receptor-antagonist [⁶⁸Ga]SB3 and PET/CT.

PubMed

Maina, Theodosia; Bergsma, Hendrik; Kulkarni, Harshad R; Mueller, Dirk; Charalambidis, David; Krenning, Eric P; Nock, Berthold A; de Jong, Marion; Baum, Richard P

2016-05-01

Gastrin-releasing peptide receptors (GRPR) represent attractive targets for tumor diagnosis and therapy because of their overexpression in major human cancers. Internalizing GRPR agonists were initially proposed for prolonged lesion retention, but a shift of paradigm to GRPR antagonists has recently been made. Surprisingly, radioantagonists, such as [(99m)Tc]DB1 ((99m)Tc-N4'-DPhe(6),Leu-NHEt(13)]BBN(6-13)), displayed better pharmacokinetics than radioagonists, in addition to their higher inherent biosafety. We introduce here [(68)Ga]SB3, a [(99m)Tc]DB1 mimic-carrying, instead of the (99m)Tc-binding tetraamine, the chelator DOTA for labeling with the PET radiometal (68)Ga. Competition binding assays of SB3 and [(nat)Ga]SB3 were conducted against [(125)I-Tyr(4)]BBN in PC-3 cell membranes. Blood samples collected 5 min postinjection (pi) of the [(67)Ga]SB3 surrogate in mice were analyzed using high-performance liquid chromatography (HPLC) for degradation products. Likewise, biodistribution was performed after injection of [(67)Ga]SB3 (37 kBq, 100 μL, 10 pmol peptide) in severe combined immunodeficiency (SCID) mice bearing PC-3 xenografts. Eventually, [(68)Ga]SB3 (283 ± 91 MBq, 23 ± 7 nmol) was injected into 17 patients with breast (8) and prostate (9) cancer. All patients had disseminated disease and had received previous therapies. PET/CT fusion images were acquired 60-115 min pi. SB3 and [(nat)Ga]SB3 bound to the human GRPR with high affinity (IC50: 4.6 ± 0.5 nM and 1.5 ± 0.3 nM, respectively). [(67)Ga]SB3 displayed good in vivo stability (>85 % intact at 5 min pi). [(67)Ga]SB3 showed high, GRPR-specific and prolonged retention in PC-3 xenografts (33.1 ± 3.9%ID/g at 1 h pi - 27.0 ± 0.9%ID/g at 24 h pi), but much faster clearance from the GRPR-rich pancreas (≈160%ID/g at 1 h pi to <17%ID/g at 24 h pi) in mice. In patients, [(68)Ga]SB3 elicited no adverse effects and clearly visualized cancer lesions. Thus, 4 out of 8 (50 %) breast cancer and 5 out of 9 (55 %) prostate cancer patients showed pathological uptake on PET/CT with [(68)Ga]SB3. [(67)Ga]SB3 showed excellent pharmacokinetics in PC-3 tumor-bearing mice, while [(68)Ga]SB3 PET/CT visualized lesions in about 50 % of patients with advanced and metastasized prostate and breast cancer. We expect imaging with [(68)Ga]SB3 to be superior in patients with primary breast or prostate cancer.

Evaluation of a PSMA-targeted BNF nanoparticle construct

NASA Astrophysics Data System (ADS)

Behnam Azad, Babak; Banerjee, Sangeeta R.; Pullambhatla, Mrudula; Lacerda, Silvia; Foss, Catherine A.; Wang, Yuchuan; Ivkov, Robert; Pomper, Martin G.

2015-02-01

Early detection enables improved prognosis for prostate cancer (PCa). A promising target for imaging and therapy of PCa is the prostate-specific membrane antigen (PSMA), which exhibits both expression within the epithelium of PCa cells, and becomes internalized upon ligand binding. Here we report the synthesis of a PSMA-targeted bionized nanoferrite (BNF) nanoparticle and its biological evaluation in an experimental model of PCa. The BNF nanoparticle formulation exhibits properties conducive to targeted imaging such as stealth, prolonged circulation time and enhanced clearance from non-target sites. Optical imaging of the targeted BNF in vivo indicates preferential accumulation in PSMA+ tumors 4 h post-injection, suggesting target specificity. On the other hand, non-targeted nanoparticles exhibit lower uptake with similar accumulation in both PSMA+ and PSMA- tumors indicating tumor access without preferential accumulation. Imaging with single photon emission computed tomography (SPECT) and biodistribution studies of a modified construct indicate highest tumor accumulation at 48 h post-injection [4.3 +/- 0.4 percentage injected dose per gram of tissue (%ID g-1)], with tumor/blood and tumor/muscle ratios of 7.5 +/- 2.4 and 11.6 +/- 1.2 %ID g-1, respectively. Ex vivo fluorescence microscopy, Prussian blue staining, immunohistochemistry and biodistribution studies confirm enhanced nanoparticle uptake in PSMA+ tumors compared to those not expressing PSMA. The BNF nano-formulation described is promising for PSMA-targeted imaging applications in vivo.Early detection enables improved prognosis for prostate cancer (PCa). A promising target for imaging and therapy of PCa is the prostate-specific membrane antigen (PSMA), which exhibits both expression within the epithelium of PCa cells, and becomes internalized upon ligand binding. Here we report the synthesis of a PSMA-targeted bionized nanoferrite (BNF) nanoparticle and its biological evaluation in an experimental model of PCa. The BNF nanoparticle formulation exhibits properties conducive to targeted imaging such as stealth, prolonged circulation time and enhanced clearance from non-target sites. Optical imaging of the targeted BNF in vivo indicates preferential accumulation in PSMA+ tumors 4 h post-injection, suggesting target specificity. On the other hand, non-targeted nanoparticles exhibit lower uptake with similar accumulation in both PSMA+ and PSMA- tumors indicating tumor access without preferential accumulation. Imaging with single photon emission computed tomography (SPECT) and biodistribution studies of a modified construct indicate highest tumor accumulation at 48 h post-injection [4.3 +/- 0.4 percentage injected dose per gram of tissue (%ID g-1)], with tumor/blood and tumor/muscle ratios of 7.5 +/- 2.4 and 11.6 +/- 1.2 %ID g-1, respectively. Ex vivo fluorescence microscopy, Prussian blue staining, immunohistochemistry and biodistribution studies confirm enhanced nanoparticle uptake in PSMA+ tumors compared to those not expressing PSMA. The BNF nano-formulation described is promising for PSMA-targeted imaging applications in vivo. Electronic supplementary information (ESI) available. See DOI: 10.1039/c4nr06069e

The relationship between histological prostatitis and lower urinary tract symptoms and sexual function.

PubMed

Kumsar, Sukru; Kose, Osman; Aydemir, Huseyin; Halis, Fikret; Gokce, Ahmet; Adsan, Oztug; Akkaya, Zeynep Kahyaoglu

2016-01-01

This prospective analysis assessed the effect of histological prostatitis on lower urinary tract functions and sexual function. The patients were separated into two groups as histologically observed prostatitis (Group A) and no prostatitis (Group B) according to the biopsy outcomes. International prostate symptom score, international index of erectile function-5 scores, maximal and average flow rate, and residual urine volumes were compared statistically between groups. There was no significant difference (P>0.05) in baseline age (t=0.64), body mass index value (t=0.51), prostate volume (t=0.87), prostate-specific antigen levels (t=0.43), maximal (t=0.84) and average flow rate (t=0.59), and post-void residual urine volume (t=0.71). Mean international prostate symptom score in patients with prostatitis was numerically but not significantly higher than that in those without prostatitis (t=0.794, P=0.066). Mean international index of erectile function-5 score in the prostatitis group was significantly lower than that in those without prostatitis (t=1.854, P=0.013). Histological prostatitis notably affected sexual function of patients and may serve as a major risk factor for sexual dysfunction while having little effect on lower urinary tract symptoms.

The relationship between histological prostatitis and lower urinary tract symptoms and sexual function

PubMed Central

Kumsar, Sukru; Kose, Osman; Aydemir, Huseyin; Halis, Fikret; Gokce, Ahmet; Adsan, Oztug; Akkaya, Zeynep Kahyaoglu

2016-01-01

ABSTRACT This prospective analysis assessed the effect of histological prostatitis on lower urinary tract functions and sexual function. The patients were separated into two groups as histologically observed prostatitis (Group A) and no prostatitis (Group B) according to the biopsy outcomes. International prostate symptom score, international index of erectile function-5 scores, maximal and average flow rate, and residual urine volumes were compared statistically between groups. There was no significant difference (P>0.05) in baseline age (t=0.64), body mass index value (t=0.51), prostate volume (t=0.87), prostate-specific antigen levels (t=0.43), maximal (t=0.84) and average flow rate (t=0.59), and post-void residual urine volume (t=0.71). Mean international prostate symptom score in patients with prostatitis was numerically but not significantly higher than that in those without prostatitis (t=0.794, P=0.066). Mean international index of erectile function-5 score in the prostatitis group was significantly lower than that in those without prostatitis (t=1.854, P=0.013). Histological prostatitis notably affected sexual function of patients and may serve as a major risk factor for sexual dysfunction while having little effect on lower urinary tract symptoms. PMID:27286118

Targeting GPR30 in Abiraterone and MDV3100 Resistant Prostate Cancer

DTIC Science & Technology

2017-12-01

ID Labs, London, ON, Canada) following the manufacturer’s protocols. Quantitative real- time PCR Total RNA was treated with RNase-free DNase (Qiagen...99-gene panel for confirmation based on a literature search showing their relatedness to cell-mediated immune responses. Quantitative real- time PCR...mouse neutrophils (Geiser et al. 1993, Schaider et al. 2003), we analyzed murine neutrophil-related cytokine genes using quantitative real- time PCR

Executive function in children with intellectual disability--the effects of sex, level and aetiology of intellectual disability.

PubMed

Memisevic, H; Sinanovic, O

2014-09-01

Executive function is very important in the children's overall development. The goal of this study was to assess the executive function in children with intellectual disability (ID) through the use of the Behavior Rating Inventory of Executive Function (BRIEF) teacher version. An additional goal was to examine the differences in executive function in relation to child's sex, level and aetiology of ID. The sample consisted of 90 children with ID attending two special education schools in Sarajevo, Bosnia and Herzegovina. There were 42 children with mild ID and 48 children with moderate ID. Of those, 54 were boys and 36 were girls. Children were classified into three etiological categories: 30 children with Down syndrome, 30 children with other genetic cause or organic brain injury and 30 children with unknown aetiology of ID. Special education teachers, who knew the children for at least 6 months filled the BRIEF. Children with ID had a significant deficit in executive function as measured by the BRIEF. There were no statistically significant differences in executive function in relation to the child's sex. Level of ID had a significant effect on executive function. In relation to the aetiology of ID, the only significant difference was on the Shift scale of the BRIEF. Knowing what executive function is most impaired in children with ID will help professionals design better intervention strategies. More attention needs to be given to the assessment of executive function and its subsequent intervention in the school settings. © 2013 MENCAP and International Association of the Scientific Study of Intellectual and Developmental Disabilities and John Wiley & Sons Ltd.

Isothiocyanate-Functionalized Bifunctional Chelates and fac-[M(I)(CO)3](+) (M = Re, (99m)Tc) Complexes for Targeting uPAR in Prostate Cancer.

PubMed

Kasten, Benjamin B; Ma, Xiaowei; Cheng, Kai; Bu, Lihong; Slocumb, Winston S; Hayes, Thomas R; Trabue, Steven; Cheng, Zhen; Benny, Paul D

2016-01-20

Developing new strategies to rapidly incorporate the fac-[M(I)(CO)3](+) (M = Re, (99m)Tc) core into biological targeting vectors in radiopharmaceuticals continues to expand as molecules become more complex and as efforts to minimize nonspecific binding increase. This work examines a novel isothiocyanate-functionalized bifunctional chelate based on 2,2'-dipicolylamine (DPA) specifically designed for complexing the fac-[M(I)(CO)3](+) core. Two strategies (postlabeling and prelabeling) were explored using the isothiocyanate-functionalized DPA to determine the effectiveness of assembly on the overall yield and purity of the complex with amine containing biomolecules. A model amino acid (lysine) examined (1) amine conjugation of isothiocyanate-functionalized DPA followed by complexation with fac-[M(I)(CO)3](+) (postlabeling) and (2) complexation of fac-[M(I)(CO)3](+) with isothiocyanate-functionalized DPA followed by amine conjugation (prelabeling). Conducted with stable Re and radioactive (99m)Tc analogs, both strategies formed the product in good to excellent yields under macroscopic and radiotracer concentrations. A synthetic peptide (AE105) which targets an emerging biomarker in CaP prognosis, urokinase-type plasminogen activator receptor (uPAR), was also explored using the isothiocyanate-functionalized DPA strategy. In vitro PC-3 (uPAR+) cell uptake assays with the (99m)Tc-labeled peptide (8a) showed 4.2 ± 0.5% uptake at 4 h. In a murine model bearing PC-3 tumor xenografts, in vivo biodistribution of 8a led to favorable tumor uptake (3.7 ± 0.7% ID/g) at 4 h p.i. with relatively low accumulation (<2% ID/g) in normal organs not associated with normal peptide excretion. These results illustrate the promise of the isothiocyanate-functionalized approach for labeling amine containing biological targeting vectors with fac-[M(I)(CO)3](+).

Does visual impairment lead to additional disability in adults with intellectual disabilities?

PubMed

Evenhuis, H M; Sjoukes, L; Koot, H M; Kooijman, A C

2009-01-01

This study addresses the question to what extent visual impairment leads to additional disability in adults with intellectual disabilities (ID). In a multi-centre cross-sectional study of 269 adults with mild to profound ID, social and behavioural functioning was assessed with observant-based questionnaires, prior to expert assessment of visual function. With linear regression analysis the percentage of variance, explained by levels of visual function, was calculated for the total population and per ID level. A total of 107/269 participants were visually impaired or blind (WHO criteria). On top of the decrease by ID visual impairment significantly decreased daily living skills, communication & language, recognition/communication. Visual impairment did not cause more self-absorbed and withdrawn behaviour or anxiety. Peculiar looking habits correlated with visual impairment and not with ID. In the groups with moderate and severe ID this effect seems stronger than in the group with profound ID. Although ID alone impairs daily functioning, visual impairment diminishes the daily functioning even more. Timely detection and treatment or rehabilitation of visual impairment may positively influence daily functioning, language development, initiative and persistence, social skills, communication skills and insecure movement.

Automatic recognition of topic-classified relations between prostate cancer and genes using MEDLINE abstracts

PubMed Central

Chun, Hong-Woo; Tsuruoka, Yoshimasa; Kim, Jin-Dong; Shiba, Rie; Nagata, Naoki; Hishiki, Teruyoshi; Tsujii, Jun'ichi

2006-01-01

Background Automatic recognition of relations between a specific disease term and its relevant genes or protein terms is an important practice of bioinformatics. Considering the utility of the results of this approach, we identified prostate cancer and gene terms with the ID tags of public biomedical databases. Moreover, considering that genetics experts will use our results, we classified them based on six topics that can be used to analyze the type of prostate cancers, genes, and their relations. Methods We developed a maximum entropy-based named entity recognizer and a relation recognizer and applied them to a corpus-based approach. We collected prostate cancer-related abstracts from MEDLINE, and constructed an annotated corpus of gene and prostate cancer relations based on six topics by biologists. We used it to train the maximum entropy-based named entity recognizer and relation recognizer. Results Topic-classified relation recognition achieved 92.1% precision for the relation (an increase of 11.0% from that obtained in a baseline experiment). For all topics, the precision was between 67.6 and 88.1%. Conclusion A series of experimental results revealed two important findings: a carefully designed relation recognition system using named entity recognition can improve the performance of relation recognition, and topic-classified relation recognition can be effectively addressed through a corpus-based approach using manual annotation and machine learning techniques. PMID:17134477

Automatic recognition of topic-classified relations between prostate cancer and genes using MEDLINE abstracts.

PubMed

Chun, Hong-Woo; Tsuruoka, Yoshimasa; Kim, Jin-Dong; Shiba, Rie; Nagata, Naoki; Hishiki, Teruyoshi; Tsujii, Jun'ichi

2006-11-24

Automatic recognition of relations between a specific disease term and its relevant genes or protein terms is an important practice of bioinformatics. Considering the utility of the results of this approach, we identified prostate cancer and gene terms with the ID tags of public biomedical databases. Moreover, considering that genetics experts will use our results, we classified them based on six topics that can be used to analyze the type of prostate cancers, genes, and their relations. We developed a maximum entropy-based named entity recognizer and a relation recognizer and applied them to a corpus-based approach. We collected prostate cancer-related abstracts from MEDLINE, and constructed an annotated corpus of gene and prostate cancer relations based on six topics by biologists. We used it to train the maximum entropy-based named entity recognizer and relation recognizer. Topic-classified relation recognition achieved 92.1% precision for the relation (an increase of 11.0% from that obtained in a baseline experiment). For all topics, the precision was between 67.6 and 88.1%. A series of experimental results revealed two important findings: a carefully designed relation recognition system using named entity recognition can improve the performance of relation recognition, and topic-classified relation recognition can be effectively addressed through a corpus-based approach using manual annotation and machine learning techniques.

Human Intellectual Disability Genes Form Conserved Functional Modules in Drosophila

PubMed Central

Oortveld, Merel A. W.; Keerthikumar, Shivakumar; Oti, Martin; Nijhof, Bonnie; Fernandes, Ana Clara; Kochinke, Korinna; Castells-Nobau, Anna; van Engelen, Eva; Ellenkamp, Thijs; Eshuis, Lilian; Galy, Anne; van Bokhoven, Hans; Habermann, Bianca; Brunner, Han G.; Zweier, Christiane; Verstreken, Patrik; Huynen, Martijn A.; Schenck, Annette

2013-01-01

Intellectual Disability (ID) disorders, defined by an IQ below 70, are genetically and phenotypically highly heterogeneous. Identification of common molecular pathways underlying these disorders is crucial for understanding the molecular basis of cognition and for the development of therapeutic intervention strategies. To systematically establish their functional connectivity, we used transgenic RNAi to target 270 ID gene orthologs in the Drosophila eye. Assessment of neuronal function in behavioral and electrophysiological assays and multiparametric morphological analysis identified phenotypes associated with knockdown of 180 ID gene orthologs. Most of these genotype-phenotype associations were novel. For example, we uncovered 16 genes that are required for basal neurotransmission and have not previously been implicated in this process in any system or organism. ID gene orthologs with morphological eye phenotypes, in contrast to genes without phenotypes, are relatively highly expressed in the human nervous system and are enriched for neuronal functions, suggesting that eye phenotyping can distinguish different classes of ID genes. Indeed, grouping genes by Drosophila phenotype uncovered 26 connected functional modules. Novel links between ID genes successfully predicted that MYCN, PIGV and UPF3B regulate synapse development. Drosophila phenotype groups show, in addition to ID, significant phenotypic similarity also in humans, indicating that functional modules are conserved. The combined data indicate that ID disorders, despite their extreme genetic diversity, are caused by disruption of a limited number of highly connected functional modules. PMID:24204314

Human intellectual disability genes form conserved functional modules in Drosophila.

PubMed

Oortveld, Merel A W; Keerthikumar, Shivakumar; Oti, Martin; Nijhof, Bonnie; Fernandes, Ana Clara; Kochinke, Korinna; Castells-Nobau, Anna; van Engelen, Eva; Ellenkamp, Thijs; Eshuis, Lilian; Galy, Anne; van Bokhoven, Hans; Habermann, Bianca; Brunner, Han G; Zweier, Christiane; Verstreken, Patrik; Huynen, Martijn A; Schenck, Annette

2013-10-01

Intellectual Disability (ID) disorders, defined by an IQ below 70, are genetically and phenotypically highly heterogeneous. Identification of common molecular pathways underlying these disorders is crucial for understanding the molecular basis of cognition and for the development of therapeutic intervention strategies. To systematically establish their functional connectivity, we used transgenic RNAi to target 270 ID gene orthologs in the Drosophila eye. Assessment of neuronal function in behavioral and electrophysiological assays and multiparametric morphological analysis identified phenotypes associated with knockdown of 180 ID gene orthologs. Most of these genotype-phenotype associations were novel. For example, we uncovered 16 genes that are required for basal neurotransmission and have not previously been implicated in this process in any system or organism. ID gene orthologs with morphological eye phenotypes, in contrast to genes without phenotypes, are relatively highly expressed in the human nervous system and are enriched for neuronal functions, suggesting that eye phenotyping can distinguish different classes of ID genes. Indeed, grouping genes by Drosophila phenotype uncovered 26 connected functional modules. Novel links between ID genes successfully predicted that MYCN, PIGV and UPF3B regulate synapse development. Drosophila phenotype groups show, in addition to ID, significant phenotypic similarity also in humans, indicating that functional modules are conserved. The combined data indicate that ID disorders, despite their extreme genetic diversity, are caused by disruption of a limited number of highly connected functional modules.

Development of a Ga-68 labeled PET tracer with short linker for prostate-specific membrane antigen (PSMA) targeting.

PubMed

Moon, Sung-Hyun; Hong, Mee Kyung; Kim, Young Ju; Lee, Yun-Sang; Lee, Dong Soo; Chung, June-Key; Jeong, Jae Min

2018-05-15

Glu-Urea-Lys (GUL) derivatives have been reported as prostate-specific membrane antigen (PSMA) agent. We developed derivatives of GUL conjugated with NOTA or DOTA via a thiourea linker and tested their feasibility as PSMA imaging agents after labeling with 68 Ga. NOTA-GUL and DOTA-GUL were synthesized and labeled with 68 Ga using generator-eluted 68 GaCl 3 in 0.1 M HCl in the presence of 1 M NaOAc at pH 5.5. The stabilities of 68 Ga-labeled compounds in human serum were tested at 37.5 °C. A competitive binding assay was performed using the PSMA-positive prostate cancer cell line 22Rv1 and [ 125 I]MIP-1072 (PSMA-specific binding agent) as a tracer. Biodistribution and micro-PET studies were performed using 22Rv1-xenograft BALB/c nude mice. The radiolabeling efficiency of NOTA-GUL (>99%) was higher than that of DOTA-GUL (92%). The IC 50 of Ga-NOTA-GUL was 18.3 nM. In the biodistribution study, tumor uptake of 68 Ga-NOTA-GUL (5.40% ID/g) was higher than that of 68 Ga-DOTA-GUL (4.66% ID/g) at 1 h. Tumor/muscle and tumor/blood uptake ratios of 68 Ga-NOTA-GUL (31.8 and 135, respectively) were significantly higher than those of 68 Ga-DOTA-GUL (16.1 and 31.1, respectively). The tumor/kidney uptake ratio of 68 Ga-NOTA-GUL was 3.4-fold higher than that of 68 Ga-DOTA-GUL. 68 Ga-NOTA-GUL showed specific uptake to PSMA positive tumor xenograft and was blocked by co-injection of the cold ligand. In conclusion, we successfully synthesized 68 Ga-NOTA-GUL and 68 Ga-DOTA-GUL for prostate cancer imaging. 68 Ga-NOTA-GUL showed better radiochemical and biodistribution results. 68 Ga-NOTA-GUL may be a promising PSMA targeting radiopharmaceutical. Copyright © 2018 Elsevier Ltd. All rights reserved.

NFKB1 -94insertion/deletion ATTG polymorphism and cancer risk: Evidence from 50 case-control studies.

PubMed

Fu, Wen; Zhuo, Zhen-Jian; Chen, Yung-Chang; Zhu, Jinhong; Zhao, Zhang; Jia, Wei; Hu, Jin-Hua; Fu, Kai; Zhu, Shi-Bo; He, Jing; Liu, Guo-Chang

2017-02-07

Nuclear factor-kappa B1 (NF-κB1) is a pleiotropic transcription factor and key contributor to tumorigenesis in many types of cancer. Numerous studies have addressed the association of a functional insertion (I)/deletion (D) polymorphism (-94ins/delATTG, rs28362491) in the promoter region of NFKB1 gene with the risk of various types of cancer; however, their conclusions have been inconsistent. We therefore conducted a meta-analysis to reevaluate this association. PubMed, EMBASE, China National Knowledge infrastructure (CNKI), and WANFANG databases were searched through July 2016 to retrieve relevant studies. After careful assessment, 50 case-control studies, comprising 18,299 cases and 23,484 controls were selected. Crude odds ratios (ORs) and 95% confidence intervals (CIs) were used to determine the strength of the association. The NFKB1 -94ins/delATTG polymorphism was associated with a decreased risk of overall cancer in the homozygote model (DD vs. II): OR = 0.75, 95% CI = 0.64-0.87); heterozygote model (ID vs. II): OR = 0.91, 95% CI = 0.83-0.99; recessive model (DD vs. ID/II): OR = 0.81, 95% CI = 0.71-0.91; dominant model (ID/DD vs. II): OR = 0.86, 95% CI = 0.78-0.95; and allele contrast model (D vs. I): OR = 0.88, 95% CI = 0.81-0.95). Subgroup and stratified analyses revealed decreased risks for lung cancer, nasopharyngeal carcinoma, prostate cancer, ovarian cancer, and oral squamous cell carcinoma, and this association held true also for Asians (especially Chinese subjects) in hospital-based studies, and in studies with quality scores less than nine. Well-designed, large-scale case-control studies are needed to confirm these results.

In vivo evaluation and small-animal PET/CT of a prostate cancer mouse model using 64Cu bombesin analogs: side-by-side comparison of the CB-TE2A and DOTA chelation systems.

PubMed

Garrison, Jered C; Rold, Tammy L; Sieckman, Gary L; Figueroa, Said Daibes; Volkert, Wynn A; Jurisson, Silvia S; Hoffman, Timothy J

2007-08-01

The BB2 receptor subtype, of the bombesin family of receptors, has been shown to be highly overexpressed in a variety of human tumors, including prostate cancer. Bombesin (BBN), a 14-amino acid peptide, has been shown to target the BB2 receptor with high affinity. 64Cu (half-life = 12.7 h, beta+: 18%, E(beta+ max) = 653 keV; beta-: 37%, E(beta- max) = 578 keV) is a radioisotope that has clinical potential for application in both diagnostic imaging and radionuclide therapy. Recently, new chelation systems such as 1,4,8,11-tetraazabicyclo[6.6.2]hexadecane-4,11-diacetic acid (CB-TE2A) have been reported to significantly stabilize the 64Cu radiometal in vivo. The increased stability of the 64Cu-CB-TE2A chelate complex has been shown to significantly reduce nontarget retention compared with tetraazamacrocycles such as 1,4,7,10-tetraazacyclodoadecane-N,N',N'',N'''-tetraacetic acid (DOTA). The aim of this study was to determine whether the CB-TE2A chelation system could significantly improve the in vivo stability of 64Cu bombesin analogs. The study directly compares 64Cu bombesin analogs using the CB-TE2A and DOTA chelation systems in a prostate cancer xenograft SCID (severely compromised immunodeficient) mouse model. The CB-TE2A-8-AOC-BBN(7-14)NH2 and DOTA-8-AOC-BBN(7-14)NH2 conjugates were synthesized and radiolabeled with 64Cu. The receptor-binding affinity and internalization profile of each metallated conjugate was evaluated using PC-3 cells. Pharmacokinetic and small-animal PET/CT studies were performed using female SCID mice bearing PC-3 xenografts. In vivo BB2 receptor targeting was confirmed by tumor uptake values of 6.95 +/- 2.27 and 4.95 +/- 0.91 %ID/g (percentage injected dose per gram) at the 15-min time point for the 64Cu-CB-TE2A and 64Cu-DOTA radioconjugates, respectively. At the 24-h time point, liver uptake was substantially reduced for the 64Cu-CB-TE2A radioconjugate (0.21 +/- 0.06 %ID/g) compared with the 64Cu-DOTA radioconjugate (7.80 +/- 1.51 %ID/g). The 64Cu-CB-TE2A-8-AOC-BBN(7-14)NH2 radioconjugate demonstrated significant clearance, 98.60 +/- 0.28 %ID, from the mouse at 24 h after injection. In contrast, only 67.84 +/- 5.43 %ID of the 64Cu activity was excreted using the 64Cu-DOTA-8-AOC-BBN(7-14)NH2 radioconjugate because of nontarget retention. The pharmacokinetic and small-animal PET/CT studies demonstrate significantly improved nontarget tissue clearance for the 64Cu-CB-TE2A8-AOC-BBN(7-14)NH2. This is attributed to the improved in vivo stability of the 64Cu-CB-TE2A chelate complex as compared with the 64Cu-DOTA chelate complex.

Neuropsychological Predictors of Everyday Functioning in Adults with Intellectual Disabilities

ERIC Educational Resources Information Center

Su, C. Y.; Chen, C. C.; Wuang, Y. P.; Lin, Y. H.; Wu, Y. Y.

2008-01-01

Background: Very little is known about the neuropsychological correlates of adaptive functioning in people with intellectual disabilities (ID). This study examined whether specific cognitive deficits and demographic variables predicted everyday functioning in adults with ID. Method: People with ID (n = 101; ages 19-41 years; mean education = 11…

Inhibition of muscle-specific gene expression by Id3: requirement of the C-terminal region of the protein for stable expression and function.

PubMed

Chen, B; Han, B H; Sun, X H; Lim, R W

1997-01-15

We have examined the role of an Id-like protein, Id3 (also known as HLH462), in the regulation of muscle-specific gene expression. Id proteins are believed to block expression of muscle-specific genes by preventing the dimerization between ubiquitous bHLH proteins (E proteins) and myogenic bHLH proteins such as MyoD. Consistent with its putative role as an inhibitor of differentiation, Id3 mRNA was detected in proliferating skeletal muscle cells, was further induced by basic fibroblast growth factor (bFGF) and was down-regulated in differentiated muscle cultures. Overexpression of Id3 efficiently inhibited the MyoD-mediated activation of the muscle-specific creatine kinase (MCK) reporter gene. Deletion analysis indicated that the C-terminal 15 amino acids of Id3 are critical for the full inhibitory activity while deleting up to 42 residues from the C-terminus of the related protein, Id2, did not affect its ability to inhibit the MCK reporter gene. Chimeric protein containing the N-terminal region of Id3 and the C-terminus of Id2 was also non-functional in transfected cells. In contrast, wild-type Id3, the C-terminal mutants, and the Id3/Id2 chimera could all interact with the E-protein E47in vitro. Additional studies indicated that truncation of the Id3 C-terminus might have adversely affected the expression level of the mutant proteins but the Id3/Id2 chimera was stably expressed. Taken together, our results revealed a more complex requirement for the expression and proper function of the Id family proteins than was hitherto expected.

Inhibition of muscle-specific gene expression by Id3: requirement of the C-terminal region of the protein for stable expression and function.

PubMed Central

Chen, B; Han, B H; Sun, X H; Lim, R W

1997-01-01

We have examined the role of an Id-like protein, Id3 (also known as HLH462), in the regulation of muscle-specific gene expression. Id proteins are believed to block expression of muscle-specific genes by preventing the dimerization between ubiquitous bHLH proteins (E proteins) and myogenic bHLH proteins such as MyoD. Consistent with its putative role as an inhibitor of differentiation, Id3 mRNA was detected in proliferating skeletal muscle cells, was further induced by basic fibroblast growth factor (bFGF) and was down-regulated in differentiated muscle cultures. Overexpression of Id3 efficiently inhibited the MyoD-mediated activation of the muscle-specific creatine kinase (MCK) reporter gene. Deletion analysis indicated that the C-terminal 15 amino acids of Id3 are critical for the full inhibitory activity while deleting up to 42 residues from the C-terminus of the related protein, Id2, did not affect its ability to inhibit the MCK reporter gene. Chimeric protein containing the N-terminal region of Id3 and the C-terminus of Id2 was also non-functional in transfected cells. In contrast, wild-type Id3, the C-terminal mutants, and the Id3/Id2 chimera could all interact with the E-protein E47in vitro. Additional studies indicated that truncation of the Id3 C-terminus might have adversely affected the expression level of the mutant proteins but the Id3/Id2 chimera was stably expressed. Taken together, our results revealed a more complex requirement for the expression and proper function of the Id family proteins than was hitherto expected. PMID:9016574

Solution structure and function of the "tandem inactivation domain" of the neuronal A-type potassium channel Kv1.4.

PubMed

Wissmann, Ralph; Bildl, Wolfgang; Oliver, Dominik; Beyermann, Michael; Kalbitzer, Hans-Robert; Bentrop, Detlef; Fakler, Bernd

2003-05-02

Cumulative inactivation of voltage-gated (Kv) K(+) channels shapes the presynaptic action potential and determines timing and strength of synaptic transmission. Kv1.4 channels exhibit rapid "ball-and-chain"-type inactivation gating. Different from all other Kvalpha subunits, Kv1.4 harbors two inactivation domains at its N terminus. Here we report the solution structure and function of this "tandem inactivation domain" using NMR spectroscopy and patch clamp recordings. Inactivation domain 1 (ID1, residues 1-38) consists of a flexible N terminus anchored at a 5-turn helix, whereas ID2 (residues 40-50) is a 2.5-turn helix made up of small hydrophobic amino acids. Functional analysis suggests that only ID1 may work as a pore-occluding ball domain, whereas ID2 most likely acts as a "docking domain" that attaches ID1 to the cytoplasmic face of the channel. Deletion of ID2 slows inactivation considerably and largely impairs cumulative inactivation. Together, the concerted action of ID1 and ID2 may promote rapid inactivation of Kv1.4 that is crucial for the channel function in short term plasticity.

Targeting the Kinase-Independent Pro-survival Function of EGFR in Prostate Cancer

DTIC Science & Technology

2013-06-01

AD AWARD NUMBER: W81XWH-09-1-0343 TITLE: Targeting the Kinase-Independent Pro -survival Function of EGFR in Prostate Cancer...SUBTITLE Targeting the Kinase-Independent, Pro -survival Function of EGFR in Prostate Cancer 5a. CONTRACT NUMBER 5b. GRANT NUMBER W81XWH-09-1...Unlimited 13. SUPPLEMENTARY NOTES 14. ABSTRACT The proposed study, targeting the kinase independent pro -survival function of EGFR in prostate

Cellular prostatic acid phosphatase, a PTEN-functional homologue in prostate epithelia, functions as a prostate-specific tumor suppressor

PubMed Central

Muniyan, Sakthivel; Ingersoll, Matthew A.; Batra, Surinder K.; Lin, Ming-Fong

2014-01-01

The inactivation of tumor suppressor genes (TSGs) plays a vital role in the progression of human cancers. Nevertheless, those ubiquitous TSGs have been shown with limited roles in various stages of diverse carcinogenesis. Investigation on identifying unique TSG, especially for early stage of carcinogenesis, is imperative. As such, the search for organ-specific TSGs has emerged as a major strategy in cancer research. Prostate cancer (PCa) has the highest incidence in solid tumors in US males. Cellular prostatic acid phosphatase (cPAcP) is a prostate-specific differentiation antigen. Despite intensive studies over the past several decades on PAcP as a PCa biomarker, the role of cPAcP as a PCa-specific tumor suppressor has only recently been emerged and validated. The mechanism underlying the pivotal role of cPAcP as a prostate-specific TSG is, in part, due to its function as a protein tyrosine phosphatase (PTP) as well as a phosphoinositide phosphatase (PIP), an apparent functional homologue to Phosphatase and tensin homolog (PTEN) in PCa cells. This review is focused on discussing the function of this authentic prostate-specific tumor suppressor and the mechanism behind the loss of cPAcP expression leading to prostate carcinogenesis. We review other phosphatases’ roles as TSGs which regulate oncogenic PI3K signaling in PCa and discuss the functional similarity between cPAcP and PTEN in prostate carcinogenesis. PMID:24747769

Therapeutic Role of Bmi-1 Inhibitors in Eliminating Prostate Tumor Stem Cells

DTIC Science & Technology

2014-10-01

Res 62:4736-45, (2002). PMC: 12183433. 14. Liu S, Dontu G, Mantle ID, Patel S, Ahn NS, Jackson KW, Suri P, Wicha MS. Hedgehog signaling and Bmi-1...Among these interacting pathways are BMI-1, OCT3/4, Hedgehog (Hh), Wnt/β-catenin, Notch signaling, Hox gene family, PTEN/Akt pathway, efflux...cancer, and cancer stem cells. Nature 414, 105-111 (2001). 50. Liu, S., et al. Hedgehog signaling and Bmi-1 regulate self-renewal of normal and

Therapeutic Role of Bmi-1 Inhibitors in Eliminating Prostate Tumor Stem Cells

DTIC Science & Technology

2014-10-01

G, Mantle ID, Patel S, Ahn NS, Jackson KW, Suri P, Wicha MS. Hedgehog signaling and Bmi-1 regulate self-renewal of normal and malignant human...1, OCT3/4, Hedgehog (Hh), Wnt/β-catenin, Notch signaling, Hox gene family, PTEN/Akt pathway, efflux transporters such as ABCG markers of self...105-111 (2001). 50. Liu, S., et al. Hedgehog signaling and Bmi-1 regulate self-renewal of normal and malignant human mammary stem cells. Cancer

Ejaculatory Function After Permanent {sup 125}I Prostate Brachytherapy for Localized Prostate Cancer

DOE Office of Scientific and Technical Information (OSTI.GOV)

Huyghe, Eric; Department of Urology and Andrology, Paul Sabatier University, CHU Paule de Viguier, Toulouse; Delannes, Martine

Purpose: Ejaculatory function is an underreported aspect of male sexuality in men treated for prostate cancer. We conducted the first detailed analysis of ejaculatory function in patients treated with permanent {sup 125}I prostate brachytherapy for localized prostate cancer. Patients and Methods: Of 270 sexually active men with localized prostate cancer treated with permanent {sup 125}I prostate brachytherapy, 241 (89%), with a mean age of 65 years (range, 43-80), responded to a mailed questionnaire derived from the Male Sexual Health Questionnaire regarding ejaculatory function. Five aspects of ejaculatory function were examined: frequency, volume, dry ejaculation, pleasure, and pain. Results: Of themore » 241 sexually active men, 81.3% had conserved ejaculatory function after prostate brachytherapy; however, the number of patients with rare/absent ejaculatory function was double the pretreatment number (p < .0001). The latter finding was correlated with age (p < .001) and the preimplant International Index of Erectile Function score (p < .001). However, 84.9% of patients with maintained ejaculatory function after implantation reported a reduced volume of ejaculate compared with 26.9% before (p < .001), with dry ejaculation accounting for 18.7% of these cases. After treatment, 30.3% of the patients experienced painful ejaculation compared with 12.9% before (p = .0001), and this was associated with a greater number of implanted needles (p = .021) and the existence of painful ejaculation before implantation (p < .0001). After implantation, 10% of patients who continued to be sexually active experienced no orgasm compared with only 1% before treatment. in addition, more patients experienced late/difficult or weak orgasms (p = .001). Conclusion: Most men treated with brachytherapy have conserved ejaculatory function after prostate brachytherapy. However, most of these men experience a reduction in volume and a deterioration in orgasm.« less

Ejaculatory function after permanent 125I prostate brachytherapy for localized prostate cancer.

PubMed

Huyghe, Eric; Delannes, Martine; Wagner, Fabien; Delaunay, Boris; Nohra, Joe; Thoulouzan, Matthieu; Shut-Yee, J Yeung; Plante, Pierre; Soulie, Michel; Thonneau, Patrick; Bachaud, Jean Marc

2009-05-01

Ejaculatory function is an underreported aspect of male sexuality in men treated for prostate cancer. We conducted the first detailed analysis of ejaculatory function in patients treated with permanent (125)I prostate brachytherapy for localized prostate cancer. Of 270 sexually active men with localized prostate cancer treated with permanent (125)I prostate brachytherapy, 241 (89%), with a mean age of 65 years (range, 43-80), responded to a mailed questionnaire derived from the Male Sexual Health Questionnaire regarding ejaculatory function. Five aspects of ejaculatory function were examined: frequency, volume, dry ejaculation, pleasure, and pain. Of the 241 sexually active men, 81.3% had conserved ejaculatory function after prostate brachytherapy; however, the number of patients with rare/absent ejaculatory function was double the pretreatment number (p < .0001). The latter finding was correlated with age (p < .001) and the preimplant International Index of Erectile Function score (p < .001). However, 84.9% of patients with maintained ejaculatory function after implantation reported a reduced volume of ejaculate compared with 26.9% before (p < .001), with dry ejaculation accounting for 18.7% of these cases. After treatment, 30.3% of the patients experienced painful ejaculation compared with 12.9% before (p = .0001), and this was associated with a greater number of implanted needles (p = .021) and the existence of painful ejaculation before implantation (p < .0001). After implantation, 10% of patients who continued to be sexually active experienced no orgasm compared with only 1% before treatment. in addition, more patients experienced late/difficult or weak orgasms (p = .001). Most men treated with brachytherapy have conserved ejaculatory function after prostate brachytherapy. However, most of these men experience a reduction in volume and a deterioration in orgasm.

Apoptosis-Dependent and Apoptosis-Independent Functions Bim in Prostate Cancer Cells

DTIC Science & Technology

2004-03-01

AD_ Award Number: DAMD17-03-1-0146 TITLE: Apoptosis-Dependent and Apoptosis-Independent Functions of Bim in Prostate Cancer Cells PRINCIPAL...FUNDING NUMBERS Apoptosis-Dependent and Apoptosis-Independent Functions of DAMD17-03-1-0146 Bim in Prostate Cancer Cells 6. A UTHORs) Junwei Liu, M.D...extended cell survival have been implicated in prostate cancer (PCa) development and progression. We recently found that Bim , a BH3-only pro

Functional Imaging for Prostate Cancer: Therapeutic Implications

PubMed Central

Aparici, Carina Mari; Seo, Youngho

2012-01-01

Functional radionuclide imaging modalities, now commonly combined with anatomical imaging modalities CT or MRI (SPECT/CT, PET/CT, and PET/MRI) are promising tools for the management of prostate cancer particularly for therapeutic implications. Sensitive detection capability of prostate cancer using these imaging modalities is one issue; however, the treatment of prostate cancer using the information that can be obtained from functional radionuclide imaging techniques is another challenging area. There are not many SPECT or PET radiotracers that can cover the full spectrum of the management of prostate cancer from initial detection, to staging, prognosis predictor, and all the way to treatment response assessment. However, when used appropriately, the information from functional radionuclide imaging improves, and sometimes significantly changes, the whole course of the cancer management. The limitations of using SPECT and PET radiotracers with regards to therapeutic implications are not so much different from their limitations solely for the task of detecting prostate cancer; however, the specific imaging target and how this target is reliably imaged by SPECT and PET can potentially make significant impact in the treatment of prostate cancer. Finally, while the localized prostate cancer is considered manageable, there is still significant need for improvement in noninvasive imaging of metastatic prostate cancer, in treatment guidance, and in response assessment from functional imaging including radionuclide-based techniques. In this review article, we present the rationale of using functional radionuclide imaging and the therapeutic implications for each of radionuclide imaging agent that have been studied in human subjects. PMID:22840598

SNP ID-info: SNP ID searching and visualization platform.

PubMed

Yang, Cheng-Hong; Chuang, Li-Yeh; Cheng, Yu-Huei; Wen, Cheng-Hao; Chang, Phei-Lang; Chang, Hsueh-Wei

2008-09-01

Many association studies provide the relationship between single nucleotide polymorphisms (SNPs), diseases and cancers, without giving a SNP ID, however. Here, we developed the SNP ID-info freeware to provide the SNP IDs within inputting genetic and physical information of genomes. The program provides an "SNP-ePCR" function to generate the full-sequence using primers and template inputs. In "SNPosition," sequence from SNP-ePCR or direct input is fed to match the SNP IDs from SNP fasta-sequence. In "SNP search" and "SNP fasta" function, information of SNPs within the cytogenetic band, contig position, and keyword input are acceptable. Finally, the SNP ID neighboring environment for inputs is completely visualized in the order of contig position and marked with SNP and flanking hits. The SNP identification problems inherent in NCBI SNP BLAST are also avoided. In conclusion, the SNP ID-info provides a visualized SNP ID environment for multiple inputs and assists systematic SNP association studies. The server and user manual are available at http://bio.kuas.edu.tw/snpid-info.

The validity and reliability of the Functional Strength Measurement (FSM) in children with intellectual disabilities.

PubMed

Aertssen, W F M; Steenbergen, B; Smits-Engelsman, B C M

2018-06-07

There is lack of valid and reliable field-based tests for assessing functional strength in young children with mild intellectual disabilities (IDs). The aim of this study was to investigate the test-retest reliability and construct validity of the Functional Strength Measurement in children with ID (FSM-ID). Fifty-two children with mild ID (40 boys and 12 girls, mean age 8.48 years, SD = 1.48) were tested with the FSM. Test-retest reliability (n = 32) was examined by a two-way interclass correlation coefficient for agreement (ICC 2.1A). Standard error of measurement and smallest detectable change were calculated. Construct validity was determined by calculating correlations between the FSM-ID and handheld dynamometry (HHD) (convergent validity), FSM-ID, FSM-ID and subtest strength of the Bruininks-Oseretsky test of motor proficiency - second edition (BOT-2) (convergent validity) and the FSM-ID and balance subtest of the BOT-2 (discriminant validity). Test-retest reliability ICC ranged 0.89-0.98. Correlation between the items of the FSM-ID and HHD ranged 0.39-0.79 and between FSM-ID and BOT-2 (strength items) 0.41-0.80. Correlation between items of the FSM-ID and BOT-2 (balance items) ranged 0.41-0.70. The FSM-ID showed good test-retest reliability and good convergent validity with the HHD and BOT-2 subtest strength. The correlations assessing discriminant validity were higher than expected. Poor levels of postural control and core stability in children with mild IDs may be the underlying factor of those higher correlations. © 2018 MENCAP and International Association of the Scientific Study of Intellectual and Developmental Disabilities and John Wiley & Sons Ltd.

Smooth muscle cell-specific knockout of androgen receptor: a new model for prostatic disease.

PubMed

Welsh, Michelle; Moffat, Lindsey; McNeilly, Alan; Brownstein, David; Saunders, Philippa T K; Sharpe, Richard M; Smith, Lee B

2011-09-01

Androgen-driven stromal-epithelial interactions play a key role in normal prostate development and function as well as in the progression of common prostatic diseases such as benign prostatic hyperplasia and prostate cancer. However, exactly how, and via which cell type, androgens mediate their effects in the adult prostate remains unclear. This study investigated the role for smooth muscle (SM) androgen signaling in normal adult prostate homeostasis and function using mice in which androgen receptor was selectively ablated from prostatic SM cells. In adulthood the knockout (KO) mice displayed a 44% reduction in prostate weight and exhibited histological abnormalities such as hyperplasia, inflammation, fibrosis, and reduced expression of epithelial, SM, and stem cell identify markers (e.g. p63 reduced by 27% and Pten by 31%). These changes emerged beyond puberty and were not explained by changes in serum hormones. Furthermore, in response to exogenous estradiol, adult KO mice displayed an 8.5-fold greater increase in prostate weight than controls and developed urinary retention. KO mice also demonstrated a reduced response to castration compared with controls. Together these results demonstrate that prostate SM cells are vital in mediating androgen-driven stromal-epithelial interactions in adult mouse prostates, determining cell identity and function and limiting hormone-dependent epithelial cell proliferation. This novel mouse model provides new insight into the possible role for SM androgen action in prostate disease.

Changes in physical functioning and muscle strength in men receiving androgen deprivation therapy for prostate cancer: a controlled comparison.

PubMed

Gonzalez, Brian D; Jim, Heather S L; Small, Brent J; Sutton, Steven K; Fishman, Mayer N; Zachariah, Babu; Heysek, Randy V; Jacobsen, Paul B

2016-05-01

The purpose of the study is to examine changes in muscle strength and self-reported physical functioning in men receiving androgen deprivation therapy (ADT) for prostate cancer compared to matched controls. Prostate cancer patients scheduled to begin ADT (n = 62) were assessed within 20 days of starting ADT and 6 and 12 months later. Age and geographically matched prostate cancer controls treated with prostatectomy only (n = 86) were assessed at similar time intervals. Grip strength measured upper body strength, the Chair Rise Test measured lower body strength, and the SF-12 Physical Functioning scale measured self-reported physical functioning. As expected, self-reported physical functioning and upper body muscle strength declined in ADT recipients but remained stable in prostate cancer controls. Contrary to expectations, lower body muscle strength remained stable in ADT recipients but improved in prostate cancer controls. Higher Gleason scores, more medical comorbidities, and less exercise at baseline predicted greater declines in physical functioning in ADT recipients. ADT is associated with declines in self-reported physical functioning and upper body muscle strength as well as worse lower body muscle strength relative to prostate cancer controls. These findings should be included in patient education regarding the risks and benefits of ADT. Findings also underscore the importance of conducting research on ways to prevent or reverse declines in physical functioning in this patient population.

Intense Exercise for Survival among Men with Metastatic Castrate-Resistant Prostate Cancer (INTERVAL-GAP4): a multicentre, randomised, controlled phase III study protocol.

PubMed

Newton, Robert U; Kenfield, Stacey A; Hart, Nicolas H; Chan, June M; Courneya, Kerry S; Catto, James; Finn, Stephen P; Greenwood, Rosemary; Hughes, Daniel C; Mucci, Lorelei; Plymate, Stephen R; Praet, Stephan F E; Guinan, Emer M; Van Blarigan, Erin L; Casey, Orla; Buzza, Mark; Gledhill, Sam; Zhang, Li; Galvão, Daniel A; Ryan, Charles J; Saad, Fred

2018-05-14

Preliminary evidence supports the beneficial role of physical activity on prostate cancer outcomes. This phase III randomised controlled trial (RCT) is designed to determine if supervised high-intensity aerobic and resistance exercise increases overall survival (OS) in patients with metastatic castrate-resistant prostate cancer (mCRPC). Participants (n=866) must have histologically documented metastatic prostate cancer with evidence of progressive disease on androgen deprivation therapy (defined as mCRPC). Patients can be treatment-naïve for mCRPC or on first-line androgen receptor-targeted therapy for mCRPC (ie, abiraterone or enzalutamide) without evidence of progression at enrolment, and with no prior chemotherapy for mCRPC. Patients will receive psychosocial support and will be randomly assigned (1:1) to either supervised exercise (high-intensity aerobic and resistance training) or self-directed exercise (provision of guidelines), stratified by treatment status and site. Exercise prescriptions will be tailored to each participant's fitness and morbidities. The primary endpoint is OS. Secondary endpoints include time to disease progression, occurrence of a skeletal-related event or progression of pain, and degree of pain, opiate use, physical and emotional quality of life, and changes in metabolic biomarkers. An assessment of whether immune function, inflammation, dysregulation of insulin and energy metabolism, and androgen biomarkers are associated with OS will be performed, and whether they mediate the primary association between exercise and OS will also be investigated. This study will also establish a biobank for future biomarker discovery or validation. Validation of exercise as medicine and its mechanisms of action will create evidence to change clinical practice. Accordingly, outcomes of this RCT will be published in international, peer-reviewed journals, and presented at national and international conferences. Ethics approval was first obtained at Edith Cowan University (ID: 13236 NEWTON), with a further 10 investigator sites since receiving ethics approval, prior to activation. NCT02730338. © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

A polysaccharide from Dictyophora indusiata inhibits the immunosuppressive function of cancer-associated fibroblasts.

PubMed

Han, Shuyu; Ma, Chaoxiong; Hu, Minghua; Wang, Yuanyuan; Ma, Fangli; Tao, Ning; Qin, Zhihai

2017-10-01

Reversing the function of cancer-associated fibroblasts (CAFs) may improve the efficacy of cancer therapy. Here, we isolated a novel polysaccharide from Dictyophora indusiata (ZSP4) and examined its effects on the function of prostate CAFs. The supernatant of prostate CAFs can stimulate the proliferation of immune cells and inhibit the growth of CD4+/CD8+ T cells. However, after ZSP4 stimulation, the functions of prostate CAFs were inhibited. The mechanism experiment shows that ZSP4 can stimulate prostate CAFs by down-regulating the expression of α-smooth muscle actin. Polysaccharides extracted from Dictyophora indusiata stimulate the proliferation of immune cells and reverse the immune-suppressive functions of prostate CAFs, shedding new light on the development of novel anticancer strategies. The endocrine therapy used to treat prostate cancer aims to eliminate androgenic activity from prostatic tissue; these therapies are painful and of poor therapeutic effect. In this study, we found that polysaccharides extracted from Dictyophora indusiata may affect the micro-environment of tumours and inhibit the growth of the tumours. Our results suggest that polysaccharides may modulate negative immune regulation and enhance antitumour immunity, which is important for clinical therapy. Copyright © 2017 John Wiley & Sons, Ltd.

Prediction of Erectile Function Following Treatment for Prostate Cancer

PubMed Central

Alemozaffar, Mehrdad; Regan, Meredith M.; Cooperberg, Matthew R.; Wei, John T.; Michalski, Jeff M.; Sandler, Howard M.; Hembroff, Larry; Sadetsky, Natalia; Saigal, Christopher S.; Litwin, Mark S.; Klein, Eric; Kibel, Adam S.; Hamstra, Daniel A.; Pisters, Louis L.; Kuban, Deborah A.; Kaplan, Irving D.; Wood, David P.; Ciezki, Jay; Dunn, Rodney L.; Carroll, Peter R.; Sanda, Martin G.

2013-01-01

Context Sexual function is the health-related quality of life (HRQOL) domain most commonly impaired after prostate cancer treatment; however, validated tools to enable personalized prediction of erectile dysfunction after prostate cancer treatment are lacking. Objective To predict long-term erectile function following prostate cancer treatment based on individual patient and treatment characteristics. Design Pretreatment patient characteristics, sexual HRQOL, and treatment details measured in a longitudinal academic multicenter cohort (Prostate Cancer Outcomes and Satisfaction With Treatment Quality Assessment; enrolled from 2003 through 2006), were used to develop models predicting erectile function 2 years after treatment. A community-based cohort (community-based Cancer of the Prostate Strategic Urologic Research Endeavor [CaPSURE]; enrolled 1995 through 2007) externally validated model performance. Patients in US academic and community-based practices whose HRQOL was measured pretreatment (N = 1201) underwent follow-up after prostatectomy, external radiotherapy, or brachytherapy for prostate cancer. Sexual outcomes among men completing 2 years’ follow-up (n = 1027) were used to develop models predicting erectile function that were externally validated among 1913 patients in a community-based cohort. Main Outcome Measures Patient-reported functional erections suitable for intercourse 2 years following prostate cancer treatment. Results Two years after prostate cancer treatment, 368 (37% [95% CI, 34%–40%]) of all patients and 335 (48% [95% CI, 45%–52%]) of those with functional erections prior to treatment reported functional erections; 531 (53% [95% CI, 50%–56%]) of patients without penile prostheses reported use of medications or other devices for erectile dysfunction. Pretreatment sexual HRQOL score, age, serum prostate-specific antigen level, race/ethnicity, body mass index, and intended treatment details were associated with functional erections 2 years after treatment. Multivariable logistic regression models predicting erectile function estimated 2-year function probabilities from as low as 10% or less to as high as 70% or greater depending on the individual’s pretreatment patient characteristics and treatment details. The models performed well in predicting erections in external validation among CaPSURE cohort patients (areas under the receiver operating characteristic curve, 0.77 [95% CI, 0.74–0.80] for prostatectomy; 0.87 [95% CI, 0.80–0.94] for external radiotherapy; and 0.90 [95% CI, 0.85–0.95] for brachytherapy). Conclusion Stratification by pretreatment patient characteristics and treatment details enables prediction of erectile function 2 years after prostatectomy, external radiotherapy, or brachytherapy for prostate cancer. PMID:21934053

PROSTATE REGULATION: MODELING ENDOGENOUS ...

EPA Pesticide Factsheets

Prostate function is an important indicator of androgen status in toxicological studies making predictive modeling of the relevant pharmacokinetics and pharmacodynamics desirable. Prostate function is an important indicator of androgen status in toxicological studies making predictive modeling of the relevant pharmacokinetics and pharmacodynamics desirable.

The Utility of [18F]DASA-23 for Molecular Imaging of Prostate Cancer with Positron Emission Tomography.

PubMed

Beinat, Corinne; Haywood, Tom; Chen, Yun-Sheng; Patel, Chirag B; Alam, Israt S; Murty, Surya; Gambhir, Sanjiv Sam

2018-05-07

There is a strong, unmet need for superior positron emission tomography (PET) imaging agents that are able to measure biochemical processes specific to prostate cancer. Pyruvate kinase M2 (PKM2) catalyzes the concluding step in glycolysis and is a key regulator of tumor growth and metabolism. Elevation of PKM2 expression was detected in Gleason 8-10 tumors compared to Gleason 6-7 carcinomas, indicating that PKM2 may potentially be a marker of aggressive prostate cancer. We have recently reported the development of a PKM2-specific radiopharmaceutical [ 18 F]DASA-23 and herein describe its evaluation in cell culture and preclinical models of prostate cancer. The cellular uptake of [ 18 F]DASA-23 was evaluated in a panel of prostate cancer cell lines and compared to that of [ 18 F]FDG. The specificity of [ 18 F]DASA-23 to measure PKM2 levels in cell culture was additionally confirmed through the use of PKM2-specific siRNA. PET imaging studies were then completed utilizing subcutaneous prostate cancer xenografts using either PC3 or DU145 cells in mice. [ 18 F]DASA-23 uptake values over 60-min incubation period in PC3, LnCAP, and DU145 respectively were 23.4 ± 4.5, 18.0 ± 2.1, and 53.1 ± 4.6 % tracer/mg protein. Transient reduction in PKM2 protein expression with siRNA resulted in a 50.1 % reduction in radiotracer uptake in DU145 cells. Small animal PET imaging revealed 0.86 ± 0.13 and 1.6 ± 0.2 % ID/g at 30 min post injection of radioactivity in DU145 and PC3 subcutaneous tumor bearing mice respectively. Herein, we evaluated a F-18-labeled PKM2-specific radiotracer, [ 18 F]DASA-23, for the molecular imaging of prostate cancer with PET. [ 18 F]DASA-23 revealed rapid and extensive uptake levels in cellular uptake studies of prostate cancer cells; however, there was only modest tumor uptake when evaluated in mouse subcutaneous tumor models.

Cross-cultural adaptation, reliability, and validation of the Korean version of the identification functional ankle instability (IdFAI).

PubMed

Ko, Jupil; Rosen, Adam B; Brown, Cathleen N

2017-09-12

To cross-culturally adapt the Identification Functional Ankle Instability for use with Korean-speaking participants. The English version of the IdFAI was cross-culturally adapted into Korean based on the guidelines. The psychometric properties in the Korean version of the IdFAI were measured for test-retest reliability, internal consistency, criterion-related validity, discriminative validity, and measurement error 181 native Korean-speakers. Intra-class correlation coefficients (ICC 2,1 ) between the English and Korean versions of the IdFAI for test-retest reliability was 0.98 (standard error of measurement = 1.41). The Cronbach's alpha coefficient was 0.89 for the Korean versions of IdFAI. The Korean versions of the IdFAI had a strong correlation with the SF-36 (r s  = -0.69, p < .001) and the Korean version of the Cumberland Ankle Instability Tool (r s  = -0.65, p < .001). The cutoff score of >10 was the optimal cutoff score to distinguish between the group memberships. The minimally detectable change of the Korean versions of the IdFAI score was 3.91. The Korean versions of the IdFAI have shown to be an excellent, reliable, and valid instrument. The Korean versions of the IdFAI can be utilized to assess the presence of Chronic Ankle Instability by researchers and clinicians working among Korean-speaking populations. Implications for rehabilitation The high recurrence rate of sprains may result into Chronic Ankle Instability (CAI). The Identification of Functional Ankle Instability Tool (IdFAI) has been validated and recommended to identify patients with Chronic Ankle Instability (CAI). The Korean version of the Identification of Functional Ankle Instability Tool (IdFAI) may be also recommend to researchers and clinicians for assessing the presence of Chronic Ankle Instability (CAI) in Korean-speaking population.

Mitochondrial β-Carotene 9',10' Oxygenase Modulates Prostate Cancer Growth via NF-κB Inhibition: A Lycopene-Independent Function.

PubMed

Gong, Xiaoming; Marisiddaiah, Raju; Zaripheh, Susan; Wiener, Doris; Rubin, Lewis P

2016-10-01

Despite numerous inquiries into protective roles of lycopene in prostate cancer prevention or therapy, little is known about mechanisms by which lycopene or its metabolites inhibit prostate cancer. The enzyme β-carotene 9',10'-oxygenase (BCO2), which catalyzes asymmetric cleavage of several carotenoids, is the principal regulator of lycopene metabolism, but the range of BCO2 biological functions is incompletely understood. This study investigated expression and functional roles of BCO2 in human prostate cancer. Expression of the bco2 gene is dramatically decreased in prostate cancer tissue and in a range of prostate cancer cell lines as compared with nonneoplastic prostate tissue and normal prostatic epithelial cells, respectively. Inhibition of DNA methyltransferase activity restored bco2 expression in prostate cancer cell lines tested. Treatment with lycopene or its metabolite, apo-10-lycopenal, also increased bco2 expression and reduced cell proliferation in androgen-sensitive cell lines, but lycopene neither altered bco2 expression nor cell growth in androgen-resistant cells. Notably, restoring bco2 expression in prostate cancer cells inhibited cell proliferation and colony formation, irrespective of lycopene exposure. Exogenous expression of either wild-type BCO2 or a mutant (enzymatically inactive) BCO2 in prostate cancer cells reduced NF-κB activity and decreased NF-κB nuclear translocation and DNA binding. Together, these results indicate epigenetic loss of BCO2 expression is associated with prostate cancer progression. Moreover, these findings describe previously unanticipated functions of BCO2 that are independent of its enzymatic role in lycopene metabolism. This study identifies BCO2 as a tumor suppressor in prostate cancer. BCO2-mediated inhibition of NF-κB signaling implies BCO2 status is important in prostate cancer progression. Mol Cancer Res; 14(10); 966-75. ©2016 AACR. ©2016 American Association for Cancer Research.

Human Prostate Cancer Hallmarks Map

PubMed Central

Datta, Dipamoy; Aftabuddin, Md.; Gupta, Dinesh Kumar; Raha, Sanghamitra; Sen, Prosenjit

2016-01-01

Human prostate cancer is a complex heterogeneous disease that mainly affects elder male population of the western world with a high rate of mortality. Acquisitions of diverse sets of hallmark capabilities along with an aberrant functioning of androgen receptor signaling are the central driving forces behind prostatic tumorigenesis and its transition into metastatic castration resistant disease. These hallmark capabilities arise due to an intense orchestration of several crucial factors, including deregulation of vital cell physiological processes, inactivation of tumor suppressive activity and disruption of prostate gland specific cellular homeostasis. The molecular complexity and redundancy of oncoproteins signaling in prostate cancer demands for concurrent inhibition of multiple hallmark associated pathways. By an extensive manual curation of the published biomedical literature, we have developed Human Prostate Cancer Hallmarks Map (HPCHM), an onco-functional atlas of human prostate cancer associated signaling and events. It explores molecular architecture of prostate cancer signaling at various levels, namely key protein components, molecular connectivity map, oncogenic signaling pathway map, pathway based functional connectivity map etc. Here, we briefly represent the systems level understanding of the molecular mechanisms associated with prostate tumorigenesis by considering each and individual molecular and cell biological events of this disease process. PMID:27476486

LSD1 activates a lethal prostate cancer gene network independently of its demethylase function.

PubMed

Sehrawat, Archana; Gao, Lina; Wang, Yuliang; Bankhead, Armand; McWeeney, Shannon K; King, Carly J; Schwartzman, Jacob; Urrutia, Joshua; Bisson, William H; Coleman, Daniel J; Joshi, Sunil K; Kim, Dae-Hwan; Sampson, David A; Weinmann, Sheila; Kallakury, Bhaskar V S; Berry, Deborah L; Haque, Reina; Van Den Eeden, Stephen K; Sharma, Sunil; Bearss, Jared; Beer, Tomasz M; Thomas, George V; Heiser, Laura M; Alumkal, Joshi J

2018-05-01

Medical castration that interferes with androgen receptor (AR) function is the principal treatment for advanced prostate cancer. However, clinical progression is universal, and tumors with AR-independent resistance mechanisms appear to be increasing in frequency. Consequently, there is an urgent need to develop new treatments targeting molecular pathways enriched in lethal prostate cancer. Lysine-specific demethylase 1 (LSD1) is a histone demethylase and an important regulator of gene expression. Here, we show that LSD1 promotes the survival of prostate cancer cells, including those that are castration-resistant, independently of its demethylase function and of the AR. Importantly, this effect is explained in part by activation of a lethal prostate cancer gene network in collaboration with LSD1's binding protein, ZNF217. Finally, that a small-molecule LSD1 inhibitor-SP-2509-blocks important demethylase-independent functions and suppresses castration-resistant prostate cancer cell viability demonstrates the potential of LSD1 inhibition in this disease.

Visual local and global processing in low-functioning deaf individuals with and without autism spectrum disorder.

PubMed

Maljaars, J P W; Noens, I L J; Scholte, E M; Verpoorten, R A W; van Berckelaer-Onnes, I A

2011-01-01

The ComFor study has indicated that individuals with intellectual disability (ID) and autism spectrum disorder (ASD) show enhanced visual local processing compared with individuals with ID only. Items of the ComFor with meaningless materials provided the best discrimination between the two samples. These results can be explained by the weak central coherence account. The main focus of the present study is to examine whether enhanced visual perception is also present in low-functioning deaf individuals with and without ASD compared with individuals with ID, and to evaluate the underlying cognitive style in deaf and hearing individuals with ASD. Different sorting tasks (selected from the ComFor) were administered from four subsamples: (1) individuals with ID (n = 68); (2) individuals with ID and ASD (n = 72); (3) individuals with ID and deafness (n = 22); and (4) individuals with ID, ASD and deafness (n = 15). Differences in performance on sorting tasks with meaningful and meaningless materials between the four subgroups were analysed. Age and level of functioning were taken into account. Analyses of covariance revealed that results of deaf individuals with ID and ASD are in line with the results of hearing individuals with ID and ASD. Both groups showed enhanced visual perception, especially on meaningless sorting tasks, when compared with hearing individuals with ID, but not compared with deaf individuals with ID. In ASD either with or without deafness, enhanced visual perception for meaningless information can be understood within the framework of the central coherence theory, whereas in deafness, enhancement in visual perception might be due to a more generally enhanced visual perception as a result of auditory deprivation. © 2010 The Authors. Journal of Intellectual Disability Research © 2010 Blackwell Publishing Ltd.

Apoptosis-Dependent and Apoptosis-Independent Functions of Bim in Prostate Cancer Cells

DTIC Science & Technology

2005-03-01

Independent Functions of Bim in Prostate Cancer Cells PRINCIPAL INVESTIGATOR: Dr. Dean Tang...SUBTITLE 5a. CONTRACT NUMBER Apoptosis-Dependent and Apoptosis-Independent Functions of Bim in Prostate Cancer Cells 5b. GRANT NUMBER DAMD17-03-1...Unlimited 13. SUPPLEMENTARY NOTES Original contains colored plates: ALL DTIC reproductions will be in black and white. 14. ABSTRACT

Relation between histological prostatitis and lower urinary tract symptoms and erectile function.

PubMed

Mizuno, Taiki; Hiramatsu, Ippei; Aoki, Yusuke; Shimoyama, Hirofumi; Nozaki, Taiji; Shirai, Masato; Lu, Yan; Horie, Shigeo; Tsujimura, Akira

2017-09-01

Chronic prostatitis (CP) significantly worsens a patient's quality of life (QOL), but its etiology is heterogeneous. Although the inflammatory process must be associated with CP symptoms, not all patients with benign prostatic hyperplasia and histological prostatitis complain of CP symptoms. The relation between the severity of histological inflammation and lower urinary tract symptoms (LUTS) and erectile function is not fully understood. This study comprised 26 men with suspected prostate cancer but with no malignant lesion by pathological examination of prostate biopsy specimens. LUTS were assessed by several questionnaires including the International Prostate Symptom Score (IPSS), QOL index, Overactive Bladder Symptom Score (OABSS), and the National Institutes of Health-Chronic Prostatitis Symptom Index (NIH-CPSI), and erectile function was assessed by the Sexual Health Inventory for Men. Prostate volume (PV) measured by transabdominal ultrasound, maximum flow rate by uroflowmetry, and serum concentration of prostate-specific antigen were also evaluated. All data collections were performed before prostate biopsy. Histological prostatitis was assessed by immunohistochemical staining with anti-CD45 antibody as the Quick score. The relation between the Quick score and several factors was assessed by Pearson correlation coefficient and a multivariate linear regression model after adjustment for PV. The Pearson correlation coefficient showed a correlation between the Quick score and several factors including PV, IPSS, QOL index, OABSS, and NIH-CPSI. A multivariate linear regression model after adjustment for PV showed only the NIH-CPSI to be associated with the Quick score. The relation between the Quick score and each domain score of the NIH-CPSI showed only the subscore of urinary symptoms to be an associated factor. We found a correlation only between histological prostatitis and LUTS, but not erectile dysfunction. Especially, the subscore of urinary symptoms (residual feeling and urinary frequency) was associated with histological prostatitis.

Expression of Pleiotrophin in the Prostate is Androgen Regulated and it Functions as an Autocrine Regulator of Mesenchyme and Cancer Associated Fibroblasts and as a Paracrine Regulator of Epithelia

PubMed Central

Orr, Brigid; Vanpoucke, Griet; Grace, O Cathal; Smith, Lee; Anderson, Richard A; Riddick, Antony CP; Franco, Omar E; Hayward, Simon W; Thomson, Axel A

2011-01-01

BACKGROUND Androgens and paracrine signaling from mesenchyme/stroma regulate development and disease of the prostate, and gene profiling studies of inductive prostate mesenchyme have identified candidate molecules such as pleiotrophin (Ptn). METHODS Ptn transcripts and protein were localized by in situ and immunohistochemistry and Ptn mRNA was quantitated by Northern blot and qRT-PCR. Ptn function was examined by addition of hPTN protein to rat ventral prostate organ cultures, primary human fetal prostate fibroblasts, prostate cancer associated fibroblasts, and BPH1 epithelia. RESULTS During development, Ptn transcripts and protein were expressed in ventral mesenchymal pad (VMP) and prostatic mesenchyme. Ptn was localized to mesenchyme surrounding ductal epithelial tips undergoing branching morphogenesis, and was located on the surface of epithelia. hPTN protein stimulated branching morphogenesis and stromal and epithelial proliferation, when added to rat VP cultures, and also stimulated growth of fetal human prostate fibroblasts, prostate cancer associated fibroblasts, and BPH1 epithelia. PTN mRNA was enriched in patient-matched normal prostate fibroblasts versus prostate cancer associated fibroblasts. PTN also showed male enriched expression in fetal human male urethra versus female, and between wt male and ARKO male mice. Transcripts for PTN were upregulated by testosterone in fetal human prostate fibroblasts and organ cultures of female rat VMP. Ptn protein was increased by testosterone in organ cultures of female rat VMP and in rat male urethra compared to female. CONCLUSIONS Our data suggest that in the prostate Ptn functions as a regulator of both mesenchymal and epithelial proliferation, and that androgens regulate Ptn levels. Prostate 71:305–317, 2011. © 2010 Wiley-Liss, Inc. PMID:20812209

De novo loss-of-function mutations in WAC cause a recognizable intellectual disability syndrome and learning deficits in Drosophila

PubMed Central

Lugtenberg, Dorien; Reijnders, Margot R F; Fenckova, Michaela; Bijlsma, Emilia K; Bernier, Raphael; van Bon, Bregje W M; Smeets, Eric; Vulto-van Silfhout, Anneke T; Bosch, Danielle; Eichler, Evan E; Mefford, Heather C; Carvill, Gemma L; Bongers, Ernie M H F; Schuurs-Hoeijmakers, Janneke HM; Ruivenkamp, Claudia A; Santen, Gijs W E; van den Maagdenberg, Arn M J M; Peeters-Scholte, Cacha M P C D; Kuenen, Sabine; Verstreken, Patrik; Pfundt, Rolph; Yntema, Helger G; de Vries, Petra F; Veltman, Joris A; Hoischen, Alexander; Gilissen, Christian; de Vries, Bert B A; Schenck, Annette; Kleefstra, Tjitske; Vissers, Lisenka E L M

2016-01-01

Recently WAC was reported as a candidate gene for intellectual disability (ID) based on the identification of a de novo mutation in an individual with severe ID. WAC regulates transcription-coupled histone H2B ubiquitination and has previously been implicated in the 10p12p11 contiguous gene deletion syndrome. In this study, we report on 10 individuals with de novo WAC mutations which we identified through routine (diagnostic) exome sequencing and targeted resequencing of WAC in 2326 individuals with unexplained ID. All but one mutation was expected to lead to a loss-of-function of WAC. Clinical evaluation of all individuals revealed phenotypic overlap for mild ID, hypotonia, behavioral problems and distinctive facial dysmorphisms, including a square-shaped face, deep set eyes, long palpebral fissures, and a broad mouth and chin. These clinical features were also previously reported in individuals with 10p12p11 microdeletion syndrome. To investigate the role of WAC in ID, we studied the importance of the Drosophila WAC orthologue (CG8949) in habituation, a non-associative learning paradigm. Neuronal knockdown of Drosophila CG8949 resulted in impaired learning, suggesting that WAC is required in neurons for normal cognitive performance. In conclusion, we defined a clinically recognizable ID syndrome, caused by de novo loss-of-function mutations in WAC. Independent functional evidence in Drosophila further supported the role of WAC in ID. On the basis of our data WAC can be added to the list of ID genes with a role in transcription regulation through histone modification. PMID:26757981

De novo loss-of-function mutations in WAC cause a recognizable intellectual disability syndrome and learning deficits in Drosophila.

PubMed

Lugtenberg, Dorien; Reijnders, Margot R F; Fenckova, Michaela; Bijlsma, Emilia K; Bernier, Raphael; van Bon, Bregje W M; Smeets, Eric; Vulto-van Silfhout, Anneke T; Bosch, Danielle; Eichler, Evan E; Mefford, Heather C; Carvill, Gemma L; Bongers, Ernie M H F; Schuurs-Hoeijmakers, Janneke Hm; Ruivenkamp, Claudia A; Santen, Gijs W E; van den Maagdenberg, Arn M J M; Peeters-Scholte, Cacha M P C D; Kuenen, Sabine; Verstreken, Patrik; Pfundt, Rolph; Yntema, Helger G; de Vries, Petra F; Veltman, Joris A; Hoischen, Alexander; Gilissen, Christian; de Vries, Bert B A; Schenck, Annette; Kleefstra, Tjitske; Vissers, Lisenka E L M

2016-08-01

Recently WAC was reported as a candidate gene for intellectual disability (ID) based on the identification of a de novo mutation in an individual with severe ID. WAC regulates transcription-coupled histone H2B ubiquitination and has previously been implicated in the 10p12p11 contiguous gene deletion syndrome. In this study, we report on 10 individuals with de novo WAC mutations which we identified through routine (diagnostic) exome sequencing and targeted resequencing of WAC in 2326 individuals with unexplained ID. All but one mutation was expected to lead to a loss-of-function of WAC. Clinical evaluation of all individuals revealed phenotypic overlap for mild ID, hypotonia, behavioral problems and distinctive facial dysmorphisms, including a square-shaped face, deep set eyes, long palpebral fissures, and a broad mouth and chin. These clinical features were also previously reported in individuals with 10p12p11 microdeletion syndrome. To investigate the role of WAC in ID, we studied the importance of the Drosophila WAC orthologue (CG8949) in habituation, a non-associative learning paradigm. Neuronal knockdown of Drosophila CG8949 resulted in impaired learning, suggesting that WAC is required in neurons for normal cognitive performance. In conclusion, we defined a clinically recognizable ID syndrome, caused by de novo loss-of-function mutations in WAC. Independent functional evidence in Drosophila further supported the role of WAC in ID. On the basis of our data WAC can be added to the list of ID genes with a role in transcription regulation through histone modification.

DE-Cadherin regulates unconventional Myosin ID and Myosin IC in Drosophila left-right asymmetry establishment.

PubMed

Petzoldt, Astrid G; Coutelis, Jean-Baptiste; Géminard, Charles; Spéder, Pauline; Suzanne, Magali; Cerezo, Delphine; Noselli, Stéphane

2012-05-01

In bilateria, positioning and looping of visceral organs requires proper left-right (L/R) asymmetry establishment. Recent work in Drosophila has identified a novel situs inversus gene encoding the unconventional type ID myosin (MyoID). In myoID mutant flies, the L/R axis is inverted, causing reversed looping of organs, such as the gut, spermiduct and genitalia. We have previously shown that MyoID interacts physically with β-Catenin, suggesting a role of the adherens junction in Drosophila L/R asymmetry. Here, we show that DE-Cadherin co-immunoprecipitates with MyoID and is required for MyoID L/R activity. We further demonstrate that MyoIC, a closely related unconventional type I myosin, can antagonize MyoID L/R activity by preventing its binding to adherens junction components, both in vitro and in vivo. Interestingly, DE-Cadherin inhibits MyoIC, providing a protective mechanism to MyoID function. Conditional genetic experiments indicate that DE-Cadherin, MyoIC and MyoID show temporal synchronicity for their function in L/R asymmetry. These data suggest that following MyoID recruitment by β-Catenin at the adherens junction, DE-Cadherin has a twofold effect on Drosophila L/R asymmetry by promoting MyoID activity and repressing that of MyoIC. Interestingly, the product of the vertebrate situs inversus gene inversin also physically interacts with β-Catenin, suggesting that the adherens junction might serve as a conserved platform for determinants to establish L/R asymmetry both in vertebrates and invertebrates.

Midkine-A functions upstream of Id2a to regulate cell cycle kinetics in the developing vertebrate retina

PubMed Central

2012-01-01

Background Midkine is a small heparin binding growth factor expressed in numerous tissues during development. The unique midkine gene in mammals has two paralogs in zebrafish: midkine-a (mdka) and midkine-b (mdkb). In the zebrafish retina, during both larval development and adult photoreceptor regeneration, mdka is expressed in retinal stem and progenitor cells and functions as a molecular component of the retina’s stem cell niche. In this study, loss-of-function and conditional overexpression were used to investigate the function of Mdka in the retina of the embryonic zebrafish. Results The results show that during early retinal development Mdka functions to regulate cell cycle kinetics. Following targeted knockdown of Mdka synthesis, retinal progenitors cycle more slowly, and this results in microphthalmia, a diminished rate of cell cycle exit and a temporal delay of cell cycle exit and neuronal differentiation. In contrast, Mdka overexpression results in acceleration of the cell cycle and retinal overgrowth. Mdka gain-of-function, however, does not temporally advance cell cycle exit. Experiments to identify a potential Mdka signaling pathway show that Mdka functions upstream of the HLH regulatory protein, Id2a. Gene expression analysis shows Mdka regulates id2a expression, and co-injection of Mdka morpholinos and id2a mRNA rescues the Mdka loss-of-function phenotype. Conclusions These data show that in zebrafish, Mdka resides in a shared Id2a pathway to regulate cell cycle kinetics in retinal progenitors. This is the first study to demonstrate the function of Midkine during retinal development and adds Midkine to the list of growth factors that transcriptionally regulate Id proteins. PMID:23111152

Midkine-A functions upstream of Id2a to regulate cell cycle kinetics in the developing vertebrate retina.

PubMed

Luo, Jing; Uribe, Rosa A; Hayton, Sarah; Calinescu, Anda-Alexandra; Gross, Jeffrey M; Hitchcock, Peter F

2012-10-30

Midkine is a small heparin binding growth factor expressed in numerous tissues during development. The unique midkine gene in mammals has two paralogs in zebrafish: midkine-a (mdka) and midkine-b (mdkb). In the zebrafish retina, during both larval development and adult photoreceptor regeneration, mdka is expressed in retinal stem and progenitor cells and functions as a molecular component of the retina's stem cell niche. In this study, loss-of-function and conditional overexpression were used to investigate the function of Mdka in the retina of the embryonic zebrafish. The results show that during early retinal development Mdka functions to regulate cell cycle kinetics. Following targeted knockdown of Mdka synthesis, retinal progenitors cycle more slowly, and this results in microphthalmia, a diminished rate of cell cycle exit and a temporal delay of cell cycle exit and neuronal differentiation. In contrast, Mdka overexpression results in acceleration of the cell cycle and retinal overgrowth. Mdka gain-of-function, however, does not temporally advance cell cycle exit. Experiments to identify a potential Mdka signaling pathway show that Mdka functions upstream of the HLH regulatory protein, Id2a. Gene expression analysis shows Mdka regulates id2a expression, and co-injection of Mdka morpholinos and id2a mRNA rescues the Mdka loss-of-function phenotype. These data show that in zebrafish, Mdka resides in a shared Id2a pathway to regulate cell cycle kinetics in retinal progenitors. This is the first study to demonstrate the function of Midkine during retinal development and adds Midkine to the list of growth factors that transcriptionally regulate Id proteins.

Association between penile dynamic contrast-enhanced MRI-derived quantitative parameters and self-reported sexual function in patients with newly diagnosed prostate cancer.

PubMed

Vargas, Hebert Alberto; Donati, Olivio F; Wibmer, Andreas; Goldman, Debra A; Mulhall, John P; Sala, Evis; Hricak, Hedvig

2014-10-01

The high incidence of prostate cancer, coupled with excellent prostate cancer control rates, has resulted in growing interest in nononcological survivorship issues such as sexual function. Multiparametric magnetic resonance imaging (MRI) is increasingly being performed for local staging of prostate cancer, and due to the close anatomical relationship to the prostate, penile enhancement is often depicted in prostate MRI. To evaluate the associations between quantitative perfusion-related parameters derived from dynamic contrast-enhanced (DCE)-MRI of the penis and self-reported sexual function in patients with newly diagnosed prostate cancer. This retrospective study included 50 patients who underwent DCE-MRI for prostate cancer staging before prostatectomy. The following perfusion-related parameters were calculated: volume transfer constant (K(trans)), rate constant (k(ep)), extracellular-extravascular volume fraction (v(e)), contrast enhancement ratio (CER), area under the gadolinium curve after 180 seconds (AUC180), and slope of the time/signal intensity curve of the corpora cavernosa. Associations between perfusion-related parameters and self-reported sexual function were evaluated using the Wilcoxon Rank-Sum test. Patient responses to the sexual function domain of the Prostate Quality of Life survey. Five of the six DCE-MRI parameters (K(trans), v(e), CER, AUC180, and slope) were significantly associated with the overall score from the sexual domain of the survey (P = 0.0020-0.0252). CER, AUC180, and slope were significantly associated with the answers to all six questions (P = 0.0020-0.0483), ve was significantly associated with the answers to five of six questions (P = 0.0036-0.1029), and K(trans) was significantly associated with the answers to three of six questions (P = 0.0252-0.1023). k(ep) was not significantly associated with the overall survey score (P = 0.7665) or the answers to any individual questions (P = 0.4885-0.8073). Penile DCE-MRI parameters were significantly associated with self-reported sexual function in patients with prostate cancer. These parameters are readily available when performing prostate MRI for staging and may be relevant to the management of patients considering prostate cancer therapies. © 2014 International Society for Sexual Medicine.

Analysis of the Human Prostate-Specific Proteome Defined by Transcriptomics and Antibody-Based Profiling Identifies TMEM79 and ACOXL as Two Putative, Diagnostic Markers in Prostate Cancer

PubMed Central

O'Hurley, Gillian; Busch, Christer; Fagerberg, Linn; Hallström, Björn M.; Stadler, Charlotte; Tolf, Anna; Lundberg, Emma; Schwenk, Jochen M.; Jirström, Karin; Bjartell, Anders; Gallagher, William M.; Uhlén, Mathias; Pontén, Fredrik

2015-01-01

To better understand prostate function and disease, it is important to define and explore the molecular constituents that signify the prostate gland. The aim of this study was to define the prostate specific transcriptome and proteome, in comparison to 26 other human tissues. Deep sequencing of mRNA (RNA-seq) and immunohistochemistry-based protein profiling were combined to identify prostate specific gene expression patterns and to explore tissue biomarkers for potential clinical use in prostate cancer diagnostics. We identified 203 genes with elevated expression in the prostate, 22 of which showed more than five-fold higher expression levels compared to all other tissue types. In addition to previously well-known proteins we identified two poorly characterized proteins, TMEM79 and ACOXL, with potential to differentiate between benign and cancerous prostatic glands in tissue biopsies. In conclusion, we have applied a genome-wide analysis to identify the prostate specific proteome using transcriptomics and antibody-based protein profiling to identify genes with elevated expression in the prostate. Our data provides a starting point for further functional studies to explore the molecular repertoire of normal and diseased prostate including potential prostate cancer markers such as TMEM79 and ACOXL. PMID:26237329

The perspective of prostate cancer patients and patients' partners on the psychological burden of androgen deprivation and the dyadic adjustment of prostate cancer couples.

PubMed

Hamilton, Lisa Dawn; Van Dam, Dexter; Wassersug, Richard J

2016-07-01

Prostate cancer and its treatments, particularly androgen deprivation therapy (ADT), affect both patients and partners. This study assessed how prostate cancer treatment type, patient mood, and sexual function related to dyadic adjustment from patient and partner perspectives. Men with prostate cancer (n = 206) and partners of men with prostate cancer (n = 66) completed an online survey assessing the patients' mood (profile of mood states short form), their dyadic adjustment (dyadic adjustment scale), and sexual function (expanded prostate cancer index composite). Analyses of covariance found that men on ADT reported better dyadic adjustment compared with men not on ADT. Erectile dysfunction was high for all patients, but a multivariate analysis of variance found that those on ADT experienced greater bother at loss of sexual function than patients not on ADT, suggesting that loss of libido when on ADT does not mitigate the psychological distress associated with loss of erections. In a multiple linear regression, patients' mood predicted their dyadic adjustment, such that worse mood was related to worse dyadic adjustment. However, more bother with patients' overall sexual function predicted lower relationship scores for the patients, while the patients' lack of sexual desire predicted lower dyadic adjustment for partners. Both patients and partners are impacted by the prostate cancer treatment effects on patients' psychological and sexual function. Our data help clarify the way that prostate cancer treatments can affect relationships and that loss of libido on ADT does not attenuate distress about erectile dysfunction. Understanding these changes may help patients and partners maintain a co-supportive relationship. Copyright © 2015 John Wiley & Sons, Ltd. Copyright © 2015 John Wiley & Sons, Ltd. Copyright © 2015 John Wiley & Sons, Ltd.

Intrinsic disorder in scaffold proteins: Getting more from less

PubMed Central

Cortese, Marc S.; Uversky, Vladimir N.; Dunker, A. Keith

2008-01-01

Regulation, recognition and cell signaling involve the coordinated actions of many players. Signaling scaffolds, with their ability to bring together proteins belonging to common and/or interlinked pathways, play crucial roles in orchestrating numerous events by coordinating specific interactions among signaling proteins. This review examines the roles of intrinsic disorder (ID) in signaling scaffold protein function. Several well-characterized scaffold proteins with structurally and functionally characterized ID regions are used here to illustrate the importance of ID for scaffolding function. These examples include scaffolds that are mostly disordered, only partially disordered or those in which the ID resides in a scaffold partner. Specific scaffolds discussed include RNase, voltage-activated potassium channels, axin, BRCA1, GSK-3β, p53, Ste5, titin, Fus3, BRCA1, Titin, MAP2, D-AKAP2 and AKAP250. Among the mechanisms discussed are: molecular recognition features, fly-casting, ease of encounter complex formation, structural isolation of partners, modulation of interactions between bound partners, masking of intramolecular interaction sites, maximized interaction surface per residue, toleration of high evolutionary rates, binding site overlap, allosteric modification, palindromic binding, reduced constraints for alternative splicing, efficient regulation via posttranslational modification, efficient regulation via rapid degradation, protection of normally solvent-exposed sites, enhancing the plasticity of interaction and molecular crowding. We conclude that ID can enhance scaffold function by a diverse array of mechanisms. In other words, scaffold proteins utilize several ID-facilitated mechanisms to enhance function, and by doing so, get more functionality from less structure. PMID:18619997

The D allele of the angiotensin-converting enzyme (ACE) insertion/deletion (I/D) polymorphism is associated with worse functional outcome of ischaemic stroke.

PubMed

Malueka, Rusdy Ghazali; Dwianingsih, Ery Kus; Sutarni, Sri; Bawono, Rheza Gandi; Bayuangga, Halwan Fuad; Gofir, Abdul; Setyopranoto, Ismail

2017-12-29

Insertion/deletion polymorphism in ACE gene (ACE I/D) is known to be associated with the occurrence of ischaemic stroke through its effect on pathogenesis of atherosclerosis and hypertension. This study was aimed to examine the association between this polymorphism with functional outcome of ischaemic stroke. This was a cross-sectional study. The subjects were patients with ischaemic stroke in a reference hospital in Yogyakarta, Indonesia. Data on demographic characteristics, stroke risk factors, comorbidities and stroke severity were assessed on admission. The functional outcome, Barthel index (BI), was assessed when the patients were discharged from the hospital. ACE I/D genotypes of the patients were identified by polymerase chain reaction (PCR). In total, 61 patients were included. Of these, 38 patients (62.3%) had II polymorphism, 22 patients (36.1%) had ID polymorphism and 1 patient (1.6%) had DD polymorphism in the ACE gene. There were significant differences in the functional outcomes between patients without D allele (II polymorphisms) and patients with D allele (ID and DD polymorphism) (mean BI on discharge: 75 ± 23.57 and 60.65 ± 27.15, respectively; p = 0.034). Multiple linear regression model showed that the availability of D allele is an independent variable negatively associated with functional outcome as assessed by BI (β = -0.232, p = 0.024). This study showed that the D allele in ACE I/D polymorphism is associated with worse functional outcomes. This highlights the possibility of further research to improve functional outcomes of ischaemic stroke by inhibiting the ACE system.

Brush border enzyme-cleavable linkers: Evaluation for reducing renal uptake of radiolabeled prostate-specific membrane antigen inhibitors.

PubMed

Vaidyanathan, Ganesan; Kang, Choong Mo; McDougald, Darryl; Minn, Il; Brummet, Mary; Pomper, Martin G; Zalutsky, Michael R

2018-05-05

Radiolabeled, low-molecular-weight prostate-specific membrane antigen (PSMA) inhibitors based on the Glu-ureido pharmacophore show promise for the detection and treatment of castration-resistant prostate cancer; however, high renal retention of activity, related in part to overexpression of PSMA in kidneys can be problematic. The goal of the current study was to investigate the use of brush border enzyme-cleavable linkers as a strategy for reducing kidney activity levels from radiolabeled PSMA inhibitors. PSMA-769 (6), a derivative of the prototypical PSMA inhibitor (((S)‑1‑carboxy‑5‑(4‑iodobenzamido)pentyl)carbamoyl)glutamate (12) modified to contain a Gly-Tyr linker, and its protected tin precursor (11) were synthesized starting from the basic pharmacophore molecule Lys-urea-Glu. An analogue of 6 containing d‑tyrosine in lieu of l‑tyrosine (PSMA-769-d-tyrosine) and the corresponding tin precursor (d-11) also were synthesized. Both radioiodinated and 211 At-labeled 6 were synthesized by radiohalogenation of 11 and deprotection in situ. Similarly, radioiodinated d-6 was synthesized from d-11. Paired label biodistribution of [ 125 I]12 and [ 131 I]6 was performed in normal mice and in SCID mice bearing both PC3 PIP (PSMA+) and PC3 flu (PSMA-) subcutaneous prostate carcinoma xenografts. The biodistribution of [ 131 I]6 and [ 211 At]6 was also evaluated in this tumor model. Biodistribution of the two radioiodinated diastereomers of 6 was evaluated in normal mice and urine samples were analyzed for the presence of 4‑iodohippuric acid. Compounds [ 131 I]6 and [ 211 At]6 were synthesized from 11 in overall radiochemical yields of 32.5 ± 0.1% (n = 4) and 22% (n = 1), respectively; radiochemical purity was >95%. In normal mice, renal uptake of [ 131 I]6 was 1.4-, 2.8- and 161-fold lower than that seen for co-injected [ 125 I]12 at 1 h, 4 h and 21 h, respectively. In tumor-bearing mice, kidney uptake of [ 131 I]6 was similar to that for [ 125 I]12 (P > 0.05) at 1 h and 4 h but was 6- to 7-fold lower at 21 h; however, [ 131 I]6 uptake in PC3 PIP tumors was also lower than that seen for [ 125 I]12 at 21 h (12.6 ± 3.4%ID/g vs. 36.8 ± 12.4%ID/g). Uptake of [ 211 At]PSMA-769 in PC3 PIP tumors was slightly higher than that seen for [ 131 I]PSMA-769 at 4 h (9.6 ± 1.6%ID/g versus 7.8 ± 1.6%ID/g; P = 0.002); its uptake in a number of normal tissues also was higher. In normal mice, kidney uptake of [ 125 I]PSMA-769 at 4 h was about 73% of that seen for [ 131 I]PSMA-769-d-tyrosine. Activity in the urine of mice receiving [ 125 I]PSMA-769 contained mainly 4‑[ 125 I]iodohippuric acid while unmetabolized intact molecule was present in the case of [ 125 I]PSMA-769-d-tyrosine. Use of this brush border enzyme-cleavable linker reduced kidney uptake and resulted in improved tumor:kidney uptake ratios. Although further structural improvements are needed, this linker approach might be useful as a component in strategies for reducing renal uptake of radiolabeled PSMA inhibitors. Copyright © 2018 Elsevier Inc. All rights reserved.

Androgen receptor: structure, role in prostate cancer and drug discovery

PubMed Central

Tan, MH Eileen; Li, Jun; Xu, H Eric; Melcher, Karsten; Yong, Eu-leong

2015-01-01

Androgens and androgen receptors (AR) play a pivotal role in expression of the male phenotype. Several diseases, such as androgen insensitivity syndrome (AIS) and prostate cancer, are associated with alterations in AR functions. Indeed, androgen blockade by drugs that prevent the production of androgens and/or block the action of the AR inhibits prostate cancer growth. However, resistance to these drugs often occurs after 2–3 years as the patients develop castration-resistant prostate cancer (CRPC). In CRPC, a functional AR remains a key regulator. Early studies focused on the functional domains of the AR and its crucial role in the pathology. The elucidation of the structures of the AR DNA binding domain (DBD) and ligand binding domain (LBD) provides a new framework for understanding the functions of this receptor and leads to the development of rational drug design for the treatment of prostate cancer. An overview of androgen receptor structure and activity, its actions in prostate cancer, and how structural information and high-throughput screening have been or can be used for drug discovery are provided herein. PMID:24909511

Detecting microRNAs of high influence on protein functional interaction networks: a prostate cancer case study

PubMed Central

2012-01-01

Background The use of biological molecular network information for diagnostic and prognostic purposes and elucidation of molecular disease mechanism is a key objective in systems biomedicine. The network of regulatory miRNA-target and functional protein interactions is a rich source of information to elucidate the function and the prognostic value of miRNAs in cancer. The objective of this study is to identify miRNAs that have high influence on target protein complexes in prostate cancer as a case study. This could provide biomarkers or therapeutic targets relevant for prostate cancer treatment. Results Our findings demonstrate that a miRNA’s functional role can be explained by its target protein connectivity within a physical and functional interaction network. To detect miRNAs with high influence on target protein modules, we integrated miRNA and mRNA expression profiles with a sequence based miRNA-target network and human functional and physical protein interactions (FPI). miRNAs with high influence on target protein complexes play a role in prostate cancer progression and are promising diagnostic or prognostic biomarkers. We uncovered several miRNA-regulated protein modules which were enriched in focal adhesion and prostate cancer genes. Several miRNAs such as miR-96, miR-182, and miR-143 demonstrated high influence on their target protein complexes and could explain most of the gene expression changes in our analyzed prostate cancer data set. Conclusions We describe a novel method to identify active miRNA-target modules relevant to prostate cancer progression and outcome. miRNAs with high influence on protein networks are valuable biomarkers that can be used in clinical investigations for prostate cancer treatment. PMID:22929553

Id4 functions downstream of Bmp signaling to restrict TCF function in endocardial cells during atrioventricular valve development.

PubMed

Ahuja, Suchit; Dogra, Deepika; Stainier, Didier Y R; Reischauer, Sven

2016-04-01

The atrioventricular canal (AVC) connects the atrial and ventricular chambers of the heart and its formation is critical for the development of the cardiac valves, chamber septation and formation of the cardiac conduction system. Consequently, problems in AVC formation can lead to congenital defects ranging from cardiac arrhythmia to incomplete cardiac septation. While our knowledge about early heart tube formation is relatively comprehensive, much remains to be investigated about the genes that regulate AVC formation. Here we identify a new role for the basic helix-loop-helix factor Id4 in zebrafish AVC valve development and function. id4 is first expressed in the AVC endocardium and later becomes more highly expressed in the atrial chamber. TALEN induced inactivation of id4 causes retrograde blood flow at the AV canal under heat induced stress conditions, indicating defects in AV valve function. At the molecular level, we found that id4 inactivation causes misexpression of several genes important for AVC and AV valve formation including bmp4 and spp1. We further show that id4 appears to control the number of endocardial cells that contribute to the AV valves by regulating Wnt signaling in the developing AVC endocardium. Copyright © 2016 Elsevier Inc. All rights reserved.

Large-scale analysis of intrinsic disorder flavors and associated functions in the protein sequence universe.

PubMed

Necci, Marco; Piovesan, Damiano; Tosatto, Silvio C E

2016-12-01

Intrinsic disorder (ID) in proteins has been extensively described for the last decade; a large-scale classification of ID in proteins is mostly missing. Here, we provide an extensive analysis of ID in the protein universe on the UniProt database derived from sequence-based predictions in MobiDB. Almost half the sequences contain an ID region of at least five residues. About 9% of proteins have a long ID region of over 20 residues which are more abundant in Eukaryotic organisms and most frequently cover less than 20% of the sequence. A small subset of about 67,000 (out of over 80 million) proteins is fully disordered and mostly found in Viruses. Most proteins have only one ID, with short ID evenly distributed along the sequence and long ID overrepresented in the center. The charged residue composition of Das and Pappu was used to classify ID proteins by structural propensities and corresponding functional enrichment. Swollen Coils seem to be used mainly as structural components and in biosynthesis in both Prokaryotes and Eukaryotes. In Bacteria, they are confined in the nucleoid and in Viruses provide DNA binding function. Coils & Hairpins seem to be specialized in ribosome binding and methylation activities. Globules & Tadpoles bind antigens in Eukaryotes but are involved in killing other organisms and cytolysis in Bacteria. The Undefined class is used by Bacteria to bind toxic substances and mediate transport and movement between and within organisms in Viruses. Fully disordered proteins behave similarly, but are enriched for glycine residues and extracellular structures. © 2016 The Protein Society.

Large‐scale analysis of intrinsic disorder flavors and associated functions in the protein sequence universe

PubMed Central

Necci, Marco; Piovesan, Damiano

2016-01-01

Abstract Intrinsic disorder (ID) in proteins has been extensively described for the last decade; a large‐scale classification of ID in proteins is mostly missing. Here, we provide an extensive analysis of ID in the protein universe on the UniProt database derived from sequence‐based predictions in MobiDB. Almost half the sequences contain an ID region of at least five residues. About 9% of proteins have a long ID region of over 20 residues which are more abundant in Eukaryotic organisms and most frequently cover less than 20% of the sequence. A small subset of about 67,000 (out of over 80 million) proteins is fully disordered and mostly found in Viruses. Most proteins have only one ID, with short ID evenly distributed along the sequence and long ID overrepresented in the center. The charged residue composition of Das and Pappu was used to classify ID proteins by structural propensities and corresponding functional enrichment. Swollen Coils seem to be used mainly as structural components and in biosynthesis in both Prokaryotes and Eukaryotes. In Bacteria, they are confined in the nucleoid and in Viruses provide DNA binding function. Coils & Hairpins seem to be specialized in ribosome binding and methylation activities. Globules & Tadpoles bind antigens in Eukaryotes but are involved in killing other organisms and cytolysis in Bacteria. The Undefined class is used by Bacteria to bind toxic substances and mediate transport and movement between and within organisms in Viruses. Fully disordered proteins behave similarly, but are enriched for glycine residues and extracellular structures. PMID:27636733

MRI-Derived Cellularity Index as a Potential Noninvasive Imaging Biomarker of Prostate Cancer

DTIC Science & Technology

2014-10-01

previously diagnosed with prostate cancer via standard transrectal ultrasound guided prostate biopsy after prostate specific antigen (PSA) elevation or...around 70% and specificity of 55% (72). Functional MR techniques enhance detection, grading, and staging of prostate cancer through the use of dynamic...and specificity in the diagnosis of prostate cancer by increasing tumor conspicuity on DWI or quantitative ADC maps. How- ever, hemorrhage, inflammatory

Dual-Modality PET/Ultrasound imaging of the Prostate

DOE Office of Scientific and Technical Information (OSTI.GOV)

Huber, Jennifer S.; Moses, William W.; Pouliot, Jean

2005-11-11

Functional imaging with positron emission tomography (PET)will detect malignant tumors in the prostate and/or prostate bed, as well as possibly help determine tumor ''aggressiveness''. However, the relative uptake in a prostate tumor can be so great that few other anatomical landmarks are visible in a PET image. Ultrasound imaging with a transrectal probe provides anatomical detail in the prostate region that can be co-registered with the sensitive functional information from the PET imaging. Imaging the prostate with both PET and transrectal ultrasound (TRUS) will help determine the location of any cancer within the prostate region. This dual-modality imaging should helpmore » provide better detection and treatment of prostate cancer. LBNL has built a high performance positron emission tomograph optimized to image the prostate.Compared to a standard whole-body PET camera, our prostate-optimized PET camera has the same sensitivity and resolution, less backgrounds and lower cost. We plan to develop the hardware and software tools needed for a validated dual PET/TRUS prostate imaging system. We also plan to develop dual prostate imaging with PET and external transabdominal ultrasound, in case the TRUS system is too uncomfortable for some patients. We present the design and intended clinical uses for these dual imaging systems.« less

Expression and Function of the Progesterone Receptor in Human Prostate Stroma Provide Novel Insights to Cell Proliferation Control

PubMed Central

Yu, Yue; Liu, Liangliang; Xie, Ning; Xue, Hui; Fazli, Ladan; Buttyan, Ralph; Wang, Yuzhuo; Gleave, Martin

2013-01-01

Context: Like other tissues, the prostate is an admixture of many different cell types that can be segregated into components of the epithelium or stroma. Reciprocal interactions between these 2 types of cells are critical for maintaining prostate homeostasis, whereas aberrant stromal cell proliferation can disrupt this balance and result in diseases such as benign prostatic hyperplasia. Although the androgen and estrogen receptors are relatively well studied for their functions in controlling stromal cell proliferation and differentiation, the role of the progesterone receptor (PR) remains unclear. Objective: The aim of the study was to investigate the expression and function of the PR in the prostate. Design and Setting: Human prostate biopsies, renal capsule xenografts, and prostate stromal cells were used. Immunohistochemistry, Western blotting, real-time quantitative PCR, cell proliferation, flow cytometry, and gene microarray analyses were performed. Results: Two PR isoforms, PRA and PRB, are expressed in prostate stromal fibroblasts and smooth muscle cells, but not in epithelial cells. Both PR isoforms suppress prostate stromal cell proliferation through inhibition of the expression of cyclinA, cyclinB, and cdc25c, thus delaying cell cycling through S and M phases. Gene microarray analyses further demonstrated that PRA and PRB regulated different transcriptomes. However, one of the major gene groups commonly regulated by both PR isoforms was the one associated with regulation of cell proliferation. Conclusion: PR plays an inhibitory role in prostate stromal cell proliferation. PMID:23666965

Adaptation and validation of the Tower of London test of planning and problem solving in people with intellectual disabilities.

PubMed

Masson, J D; Dagnan, D; Evans, J

2010-05-01

There is a need for validated, standardised tools for the assessment of executive functions in adults with intellectual disabilities (ID). This study examines the validity of a test of planning and problem solving (Tower of London) with adults with ID. Participants completed an adapted version of the Tower of London (ToL) while day-centre staff completed adaptive function (Adaptive Behaviour Scale - Residential and Community: Second Edition, modified version) and dysexecutive function (DEX-Independent Rater) questionnaires for each participant. Correlation analyses of test and questionnaire variables were undertaken. The adapted ToL has a robust structure and shows significant associations with independent living skills, challenging behaviour and behaviours related to dysexecutive function. The adapted ToL is a valid test for use with people with ID. However, there is also a need to develop other ecologically valid tools based on everyday planning tasks undertaken by people with ID.

Frontal Brain Electrical Activity (EEG) and Heart Rate in Response to Affective Infant-Directed (ID) Speech in 9-Month-Old Infants

ERIC Educational Resources Information Center

Santesso, Diane L.; Schmidt, Louis A.; Trainor, Laurel J.

2007-01-01

Many studies have shown that infants prefer infant-directed (ID) speech to adult-directed (AD) speech. ID speech functions to aid language learning, obtain and/or maintain an infant's attention, and create emotional communication between the infant and caregiver. We examined psychophysiological responses to ID speech that varied in affective…

Functional properties of behaviour problems depending on level of intellectual disability.

PubMed

Medeiros, K; Rojahn, J; Moore, L L; van Ingen, D J

2014-02-01

Behaviour problems are common among individuals with intellectual disabilities (ID) especially in those with more severe forms. The determination of the functional profile of a targeted behaviour has important implications for the design of customised behavioural interventions. We investigated the relationship between the level of ID and the functional profile of aggression, stereotypy and self-injurious behaviour (SIB) using the Questions about Behavioural Function (QABF). Two staff members at two time points completed the QABF for each of 115 adults with varying levels of ID participating in a day training and habilitation programme. Our results suggest that there is a differential relationship between the functions of behaviour problems and level of ID. While SIB is more often seen by raters to be maintained by escape of social demands and by attaining access to tangible items with the decline of the intellectual level, aggressive and stereotypic behaviours were identified more often as serving multiple functions equally across functioning level. © 2013 The Authors. Journal of Intellectual Disability Research © 2013 John Wiley & Sons Ltd, MENCAP & IASSIDD.

Executive Functioning in Individuals with Intellectual Disabilities and Autism Spectrum Disorders

ERIC Educational Resources Information Center

Roelofs, R. L.; Visser, E. M.; Berger, H. J. C.; Prins, J. B.; Van Schrojenstein Lantman-De Valk, H. M. J.; Teunisse, J. P.

2015-01-01

Background: Executive functioning (EF) is important for adequate behavioural functioning and crucial for explaining symptoms of autism spectrum disorders (ASD) in individuals with normal intelligence, but is scarcely studied in individuals with ASD and intellectual disabilities (ID). We therefore study EF in an ID population by comparing…

Differential requirements of androgen receptor in luminal progenitors during prostate regeneration and tumor initiation

PubMed Central

Chua, Chee Wai; Epsi, Nusrat J; Leung, Eva Y; Xuan, Shouhong; Lei, Ming; Li, Bo I; Bergren, Sarah K; Hibshoosh, Hanina; Mitrofanova, Antonina

2018-01-01

Master regulatory genes of tissue specification play key roles in stem/progenitor cells and are often important in cancer. In the prostate, androgen receptor (AR) is a master regulator essential for development and tumorigenesis, but its specific functions in prostate stem/progenitor cells have not been elucidated. We have investigated AR function in CARNs (CAstration-Resistant Nkx3.1-expressing cells), a luminal stem/progenitor cell that functions in prostate regeneration. Using genetically--engineered mouse models and novel prostate epithelial cell lines, we find that progenitor properties of CARNs are largely unaffected by AR deletion, apart from decreased proliferation in vivo. Furthermore, AR loss suppresses tumor formation after deletion of the Pten tumor suppressor in CARNs; however, combined Pten deletion and activation of oncogenic Kras in AR-deleted CARNs result in tumors with focal neuroendocrine differentiation. Our findings show that AR modulates specific progenitor properties of CARNs, including their ability to serve as a cell of origin for prostate cancer. PMID:29334357

Effect of Prostate Cancer Severity on Functional Outcomes After Localized Treatment: Comparative Effectiveness Analysis of Surgery and Radiation Study Results.

PubMed

Tyson, Mark Douglas; Koyama, Tatsuki; Lee, Dan; Hoffman, Karen E; Resnick, Matthew J; Wu, Xiao-Cheng; Cooperberg, Matthew R; Goodman, Michael; Greenfield, Sheldon; Hamilton, Ann S; Hashibe, Mia; Paddock, Lisa E; Stroup, Antoinette; Chen, Vivien; Conwill, Ralph; McCollum, Dan; Penson, David F; Barocas, Daniel A

2018-07-01

Whether prostate cancer severity modifies patient-reported functional outcomes after radical prostatectomy (RP) or external beam radiotherapy (EBRT) for localized cancer is unknown. The purpose of this study was to determine whether differences in predicted function over time between RP and EBRT varied by risk group. The Comparative Effectiveness Analysis of Surgery and Radiation (CEASAR) study is a prospective, population-based, observational study that enrolled men with localized prostate cancer in 2011-2012. Among 2117 CEASAR participants who underwent RP or EBRT, 817 had low-risk, 902 intermediate-risk, and 398 high-risk disease. Patient-reported, disease-specific function was measured using the 26-item Expanded Prostate Index Composite (at baseline and 6, 12, and 36 mo). Predicted function was estimated using regression models and compared by disease risk. Low-risk EBRT patients reported 3-yr sexual function scores 12 points higher than those of low-risk RP patients (RP, 39 points [95% confidence interval {CI}, 37-42] vs EBRT, 52 points [95% CI, 47-56]; p<0.001). The difference in 3-yr scores for high-risk patients was not clinically significant (RP, 32 points [95% CI, 28-35] vs EBRT, 38 points [95% CI, 33-42]; p=0.03). However, when using a commonly used binary definition of sexual function (erections firm enough for intercourse), no major differences were noted between RP and EBRT at 3 yr across low-, intermediate-, and high-risk disease strata. No clinically significant interactive effects between treatment and cancer severity were observed for incontinence, bowel, irritative voiding, and hormone domains. The primary limitation is the lack of firmly established thresholds for clinically significant differences in Expanded Prostate Index Composite domain scores. For men with low-risk prostate cancer, EBRT was associated with higher sexual function scores at 3 yr than RP; however, for men with high-risk prostate cancer, no clinically significant difference was noted. Men with high-risk prostate cancer should be counseled that EBRT and RP carry similar sexual function outcomes at 3 yr. In this report, we studied the urinary, sexual, bowel, and hormonal functions of patients 3 yr after undergoing prostate cancer surgery or radiation. We found that for patients with high-risk disease, sexual function was similar between surgery and radiation. We conclude that high-risk patients undergoing radiation therapy should be counseled that sexual function may not be as good as low-risk patients undergoing radiation. Copyright © 2018 European Association of Urology. Published by Elsevier B.V. All rights reserved.

A supervoxel-based segmentation method for prostate MR images

NASA Astrophysics Data System (ADS)

Tian, Zhiqiang; Liu, LiZhi; Fei, Baowei

2015-03-01

Accurate segmentation of the prostate has many applications in prostate cancer diagnosis and therapy. In this paper, we propose a "Supervoxel" based method for prostate segmentation. The prostate segmentation problem is considered as assigning a label to each supervoxel. An energy function with data and smoothness terms is used to model the labeling process. The data term estimates the likelihood of a supervoxel belongs to the prostate according to a shape feature. The geometric relationship between two neighboring supervoxels is used to construct a smoothness term. A threedimensional (3D) graph cut method is used to minimize the energy function in order to segment the prostate. A 3D level set is then used to get a smooth surface based on the output of the graph cut. The performance of the proposed segmentation algorithm was evaluated with respect to the manual segmentation ground truth. The experimental results on 12 prostate volumes showed that the proposed algorithm yields a mean Dice similarity coefficient of 86.9%+/-3.2%. The segmentation method can be used not only for the prostate but also for other organs.

Lower urinary tract symptoms/benign prostatic hypertrophy and vascular function: Role of the nitric oxide-phosphodiesterase type 5-cyclic guanosine 3',5'-monophosphate pathway.

PubMed

Higashi, Yukihito

2017-06-01

It is well known that there is an association of lower urinary tract symptoms/benign prostatic hypertrophy with cardiovascular disease, suggesting that lower urinary tract symptoms/benign prostatic hypertrophy is a risk factor for cardiovascular events. Vascular function, including endothelial function and vascular smooth muscle function, is involved in the pathogenesis, maintenance and development of atherosclerosis, leading to cardiovascular events. Vascular dysfunction per se should also contribute to lower urinary tract symptoms/benign prostatic hypertrophy. Both lower urinary tract symptoms/benign prostatic hypertrophy and vascular dysfunction have cardiovascular risk factors, such as hypertension, dyslipidemia, diabetes mellitus, aging, obesity and smoking. Inactivation of the phosphodiesterase type 5-cyclic guanosine 3',5'-monophosphate-nitric oxide pathway causes lower urinary tract symptoms/benign prostatic hypertrophy through an enhancement of sympathetic nervous activity, endothelial dysfunction, increase in Rho-associated kinase activity and vasoconstriction, and decrease in blood flow of pelvic viscera. Both endogenous nitric oxide and exogenous nitric oxide act as vasodilators on vascular smooth muscle cells through an increase in the content of cyclic guanosine 3',5'-monophosphate, which is inactivated by phosphodiesterase type 5. In a clinical setting, phosphodiesterase type 5 inhibitors are widely used in patients with lower urinary tract symptoms/benign prostatic hypertrophy. Phosphodiesterase type 5 inhibitors might have beneficial effects on vascular function through not only inhibition of cyclic guanosine 3',5'-monophosphate degradation, but also increases in testosterone levels and nitric oxide bioavailability, increase in the number and improvement of the function of endothelial progenitor cells, and decrease in insulin resistance. In the present review, the relationships between lower urinary tract symptoms/benign prostatic hypertrophy, the phosphodiesterase type 5-nitric oxide-cyclic guanosine 3',5'-monophosphate pathway, vascular function and cardiovascular outcomes are examined. © 2017 The Japanese Urological Association.

Progesterone receptor in the prostate: A potential suppressor for benign prostatic hyperplasia and prostate cancer.

PubMed

Chen, RuiQi; Yu, Yue; Dong, Xuesen

2017-02-01

Advanced prostate cancer undergoing androgen receptor pathway inhibition (ARPI) eventually progresses to castrate-resistant prostate cancer (CRPC), suggesting that (i) androgen receptor (AR) blockage is incomplete, and (ii) there are other critical molecular pathways contributing to prostate cancer (PCa) progression. Although most PCa occurs in the epithelium, prostate stroma is increasingly believed to play a crucial role in promoting tumorigenesis and facilitating tumor progression. In the stroma, sex steroid hormone receptors such as AR and estrogen receptor-α are implicated to have important functions, whereas the progesterone receptor (PR) remains largely under-investigated despite the high sequence and structural similarities between PR and AR. Stromal progesterone/PR signaling may play a critical role in PCa development and progression because not only progesterone is a critical precursor for de novo androgen steroidogenesis and an activator of mutant androgen receptors, but also PR functions in a ligand-independent manner in various important pathways. In fact, recent progress in our understanding of stromal PR function suggests that this receptor may exert an inhibitory effect on benign prostatic hyperplasia (BPH), reactive stroma development, and PCa progression. These early findings of stromal PR warrant further investigations as this receptor could be a potential biomarker and therapeutic target in PCa management. Copyright © 2016 Elsevier Ltd. All rights reserved.

Induction at high incidence of ductal prostate adenocarcinomas in NBL/Cr and Sprague-Dawley Hsd:SD rats treated with a combination of testosterone and estradiol-17 beta or diethylstilbestrol.

PubMed

Bosland, M C; Ford, H; Horton, L

1995-06-01

This study determined the incidence of prostate adenocarcinoma following long-term treatment of NBL and Sprague-Dawley rats with estradiol-17 beta or diethylstilbestrol (DES) plus testosterone and it defined the origin of these tumors. NBL and Sprague-Dawley rats were treated with two Silastic tubing implants (i.d. 1.6 mm, o.d. 3.2 mm) containing a 2 cm long filling of testosterone and one implant containing a 1 cm long filling of estradiol-17 beta or DES. Control animals received empty implants. Treated animals were killed when moribund and controls were killed at 91 (NBL) or 75 (Sprague-Dawley) weeks after initiation of treatment and accessory sex glands were sampled for histopathological examination of multiple step sections. Prostatic adenocarcinoma occurred in 100% of NBL rats after treatment with estradiol-17 beta or DES plus testosterone for 44 and 59 weeks (group means) respectively. Adenocarcinoma incidences were lower in Sprague-Dawley rats. The adenocarcinomas were small, microscopic, invasive tumors and they were spatially closely associated with the periurethral ducts of the dorsal, lateral and/or anterior (= coagulating gland) prostate, but never with the ducts of the ventral lobe and seminal vesicles. One adenocarcinoma was of uncertain origin. Duct-acinar dysplastic lesions occurred in the periphery of the dorsal and lateral prostate of all hormone-treated NBL and many Sprague-Dawley rats, but did not appear to give rise to carcinoma. Although some adenocarcinomas were contiguous with dysplastic ducts of the peripheral dorsolateral prostate, the main mass of these neoplasms was located in the periurethral area. Also, most adenocarcinomas were only connected with the periurethral ducts, in which atypical hyperplasia occurred following hormone treatment for 36 weeks or longer. Thus atypical hyperplasia of the periurethral prostate ducts, but not peripheral duct-acinar dysplasia, appeared to be the likely precursor of the induced carcinomas. Testosterone plus DES, but not estradiol-17 beta, induced marked dysplasia-like lesions in the acini of the ventral prostate of all NBL and many Sprague-Dawley rats. These lesions had progressed to carcinoma in situ (or adenoma) in 46% of NBL rats.

Clinical translation of a PSMA inhibitor for 99mTc-based SPECT.

PubMed

Ferro-Flores, Guillermina; Luna-Gutiérrez, Myrna; Ocampo-García, Blanca; Santos-Cuevas, Clara; Azorín-Vega, Erika; Jiménez-Mancilla, Nallely; Orocio-Rodríguez, Emmanuel; Davanzo, Jenny; García-Pérez, Francisco O

2017-05-01

Prostate-specific membrane antigen (PSMA) is highly over-expressed in advanced prostate cancers. 68 Ga-labeled PSMA inhibitors (iPSMA) are currently used for prostate cancer detection by PET imaging. The availability of simple, efficient and reproducible radiolabeling procedures is essential for developing new SPECT radiopharmaceuticals for clinical translation. The aim of this research was to prepare 99m Tc-EDDA/HYNIC-Lys(Nal)-Urea-Glu ( 99m Tc-EDDA/HYNIC-iPSMA) obtained from lyophilized kit formulations and evaluate the in vitro and in vivo radiopharmaceutical binding to prostate cancer cells over-expressing PSMA, as well as the 99m Tc-EDDA/HYNIC-iPSMA normal biodistribution in humans and the preliminary uptake in patients with prostate cancer. 99m Tc labeling was performed by adding sodium pertechnetate solution and a 0.2M phosphate buffer (pH 7.0) to a lyophilized formulation containing HYNIC-iPSMA, EDDA, tricine, mannitol and stannous chloride. The radiochemical purity was evaluated by reversed-phase HPLC and ITLC-SG analyses. Stability studies in human serum were performed by size-exclusion HPLC. In vitro cell uptake was tested using prostate cancer cells (LNCaP) with blocked and non-blocked receptors. Biodistribution and tumor uptake were determined in LNCaP tumor-bearing nude mice with blocked and non-blocked receptors, and images were obtained using a micro-SPECT/CT. Whole-body images from three healthy men and two patients with histologically-confirmed prostate cancer (one of them with a previous 68 Ga-PSMA-617scan) were acquired at 1h and 3h after 99m Tc-EDDA/HYNIC-iPSMA administration with radiochemical purities of >98%. In vitro and in vivo studies showed high radiopharmaceutical stability in human serum, specific recognition for PSMA, high tumor uptake (10.22±2.96% ID/g at 1h) with rapid blood clearance and mainly kidney elimination. Preliminary images in patients demonstrated the ability of 99m Tc-EDDA/HYNIC-iPSMA to detect tumors and metastases of prostate cancer as well as 68 Ga-PSMA-617 does. The results obtained in this study warrant further dosimetry and clinical studies to determine the specificity and sensitivity of 99m Tc-EDDA/HYNIC-iPSMA. Copyright © 2017 Elsevier Inc. All rights reserved.

Involvement of the kinesin family members KIF4A and KIF5C in intellectual disability and synaptic function.

PubMed

Willemsen, Marjolein H; Ba, Wei; Wissink-Lindhout, Willemijn M; de Brouwer, Arjan P M; Haas, Stefan A; Bienek, Melanie; Hu, Hao; Vissers, Lisenka E L M; van Bokhoven, Hans; Kalscheuer, Vera; Nadif Kasri, Nael; Kleefstra, Tjitske

2014-07-01

Kinesin superfamily (KIF) genes encode motor proteins that have fundamental roles in brain functioning, development, survival and plasticity by regulating the transport of cargo along microtubules within axons, dendrites and synapses. Mouse knockout studies support these important functions in the nervous system. The role of KIF genes in intellectual disability (ID) has so far received limited attention, although previous studies have suggested that many ID genes impinge on synaptic function. By applying next-generation sequencing (NGS) in ID patients, we identified likely pathogenic mutations in KIF4A and KIF5C. To further confirm the pathogenicity of these mutations, we performed functional studies at the level of synaptic function in primary rat hippocampal neurons. Four males from a single family with a disruptive mutation in the X-linked KIF4A (c.1489-8_1490delins10; p.?- exon skipping) showed mild to moderate ID and epilepsy. A female patient with a de novo missense mutation in KIF5C (c.11465A>C; p.(Glu237Lys)) presented with severe ID, epilepsy, microcephaly and cortical malformation. Knock-down of Kif4a in rat primary hippocampal neurons altered the balance between excitatory and inhibitory synaptic transmission, whereas the mutation in Kif5c affected its protein function at excitatory synapses. Our results suggest that mutations in KIF4A and KIF5C cause ID by tipping the balance between excitatory and inhibitory synaptic excitability. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.

IRON DEFICIENCY AND INFANT MOTOR DEVELOPMENT

PubMed Central

Shafir, Tal; Angulo-Barroso, Rosa; Jing, Yuezhou; Lu Angelilli, Mary; Jacobson, Sandra W.; Lozoff, Betsy

2011-01-01

Background Iron deficiency (ID) during early development impairs myelination and basal ganglia function in animal models. Aims To examine the effects of iron deficiency anemia (IDA) and iron deficiency (ID) without anemia on infant motor skills that are likely related to myelination and basal ganglia function. Study design Observational study. Subjects Full-term inner-city African-American 9- to 10-month-old infants who were free of acute or chronic health problems with iron status indicators ranging from IDA to iron sufficiency (n = 106). Criteria for final iron status classification were met by 77 of these infants: 28 IDA, 28 non-anemic iron-deficient (NA ID), and 21 iron-sufficient (IS). Outcome measures Gross motor developmental milestones, Peabody Developmental Motor Scale, Infant Neurological International Battery (INFANIB), motor quality factor of the Bayley Behavioral Rating Scale, and a sequential/bi-manual coordination toy retrieval task. General linear model analyses tested for linear effects of iron status group and thresholds for effects. Results There were linear effects of iron status on developmental milestones, Peabody gross motor (suggestive trend), INFANIB standing item, motor quality, and toy retrieval. The threshold for effects was ID with or without anemia for developmental milestones, INFANIB standing item, and motor quality and IDA for toy retrieval. Conclusions Using a comprehensive and sensitive assessment of motor development, this study found poorer motor function in ID infants with and without anemia. Poorer motor function among non-anemic ID infants is particularly concerning, since ID without anemia is not detected by common screening procedures and is more widespread than IDA. PMID:18272298

Croton membranaceus Improves Some Biomarkers of Cardiovascular Disease and Diabetes in Genetic Animal Models.

PubMed

Asare, George Awuku; Adjei, Samuel; Afriyie, Daniel; Appiah-Danquah, Akua Bempomaa; Asia, Jonas; Asiedu, Bernice; Santa, Sheila; Doku, Derek

2015-12-01

Cardiovascular disease (CVD) accounts for 17.3 million deaths per year globally. In Ghana, CVD accounts for 22.2% of deaths. Croton membranaceus (CM) Mull. Arg. (Euphorbiaceae), a medicinal plant in Ghana is mainly used traditionally for the treatment of benign prostatic hyperplasia and measles. However, some hypoglycaemic and hypotensive effects have recently been reported but not scientifically examined. The study aimed at establishing whether Croton membranaceus (CM) used for prostatitis had any effect on CVD markers. In experiment 1, lipid profile changes were determined. Twenty four male Spontaneously Hypertensive Rats (SHR) were divided into 4 groups. Low (LD), intermediate (ID) and high dose (HD) groups received 25, 50 and 100 mg/kg b.wt. CM aqueous root extracts (CMARE) for 60 days, respectively, the controls received distilled water. In experiment 2, blood glucose levels (BGL) were determined. 21 db/db mice were divided into 3 groups of 7 mice each alongside db/+ mice (7) (negative control). Groups 1 and 2 received 250 mg/kg b.wt CMARE and metformin, respectively. Group 3 (positive control) and db/+ mice (negative control) received distilled water. Mice were monitored for 15 hours. Data collected were analysed using SPSS version 20. Hypotriglyceridaemic effect was observed (p=0.005). High Density Lipoprotein cholesterol (HDL) and Low Density Lipoprotein cholesterol (LDL) showed significant increases (p=0.013) and decreases (p=0.003), respectively. A significant CRP reduction was observed for ID and HD groups (p = 0.010, p = 0.011, respectively). BGL was reduced in Metformin and Croton groups (p=0.000; p= 0.006, respectively) after 3 hours. In conclusion, CMARE has positive effects on some CVD biomarkers and a hypoglycaemic effect.

Croton membranaceus Improves Some Biomarkers of Cardiovascular Disease and Diabetes in Genetic Animal Models

PubMed Central

Adjei, Samuel; Afriyie, Daniel; Appiah-Danquah, Akua Bempomaa; Asia, Jonas; Asiedu, Bernice; Santa, Sheila; Doku, Derek

2015-01-01

Introduction Cardiovascular disease (CVD) accounts for 17.3 million deaths per year globally. In Ghana, CVD accounts for 22.2% of deaths. Croton membranaceus (CM) Mull. Arg. (Euphorbiaceae), a medicinal plant in Ghana is mainly used traditionally for the treatment of benign prostatic hyperplasia and measles. However, some hypoglycaemic and hypotensive effects have recently been reported but not scientifically examined. Aim The study aimed at establishing whether Croton membranaceus (CM) used for prostatitis had any effect on CVD markers. Materials and Methods In experiment 1, lipid profile changes were determined. Twenty four male Spontaneously Hypertensive Rats (SHR) were divided into 4 groups. Low (LD), intermediate (ID) and high dose (HD) groups received 25, 50 and 100 mg/kg b.wt. CM aqueous root extracts (CMARE) for 60 days, respectively, the controls received distilled water. In experiment 2, blood glucose levels (BGL) were determined. 21 db/db mice were divided into 3 groups of 7 mice each alongside db/+ mice (7) (negative control). Groups 1 and 2 received 250 mg/kg b.wt CMARE and metformin, respectively. Group 3 (positive control) and db/+ mice (negative control) received distilled water. Mice were monitored for 15 hours. Data collected were analysed using SPSS version 20. Results Hypotriglyceridaemic effect was observed (p=0.005). High Density Lipoprotein cholesterol (HDL) and Low Density Lipoprotein cholesterol (LDL) showed significant increases (p=0.013) and decreases (p=0.003), respectively. A significant CRP reduction was observed for ID and HD groups (p = 0.010, p = 0.011, respectively). BGL was reduced in Metformin and Croton groups (p=0.000; p= 0.006, respectively) after 3 hours. Conclusion In conclusion, CMARE has positive effects on some CVD biomarkers and a hypoglycaemic effect. PMID:26816938

Utility Estimates of Disease-Specific Health States in Prostate Cancer from Three Different Perspectives.

PubMed

Gries, Katharine S; Regier, Dean A; Ramsey, Scott D; Patrick, Donald L

2017-06-01

To develop a statistical model generating utility estimates for prostate cancer specific health states, using preference weights derived from the perspectives of prostate cancer patients, men at risk for prostate cancer, and society. Utility estimate values were calculated using standard gamble (SG) methodology. Study participants valued 18 prostate-specific health states with the five attributes: sexual function, urinary function, bowel function, pain, and emotional well-being. Appropriateness of model (linear regression, mixed effects, or generalized estimating equation) to generate prostate cancer utility estimates was determined by paired t-tests to compare observed and predicted values. Mixed-corrected standard SG utility estimates to account for loss aversion were calculated based on prospect theory. 132 study participants assigned values to the health states (n = 40 men at risk for prostate cancer; n = 43 men with prostate cancer; n = 49 general population). In total, 792 valuations were elicited (six health states for each 132 participants). The most appropriate model for the classification system was a mixed effects model; correlations between the mean observed and predicted utility estimates were greater than 0.80 for each perspective. Developing a health-state classification system with preference weights for three different perspectives demonstrates the relative importance of main effects between populations. The predicted values for men with prostate cancer support the hypothesis that patients experiencing the disease state assign higher utility estimates to health states and there is a difference in valuations made by patients and the general population.

Clinical outcomes of a specialised inpatient unit for adults with mild to severe intellectual disability and mental illness.

PubMed

Lunsky, Y; White, S E; Palucka, A M; Weiss, J; Bockus, S; Gofine, T

2010-01-01

Limitations of general psychiatric services have led to the development of specialised psychiatric programmes for patients with intellectual disability (ID) and mental health needs. Few studies have examined treatment outcomes of specialised inpatient units, and no studies have explored how the effects of intervention may differ for individuals at varying levels of cognitive ability. The present study examined clinical outcomes of inpatients with mild ID in contrast to inpatients with moderate to severe ID within the same service. Thirty-three patients (17 with mild ID and 16 with moderate to severe ID) discharged between 2006 and 2008 from a specialised inpatient unit in Canada for adults with ID and mental illness were studied. In addition to examining change in scores on clinical measures, outcomes with regard to length of stay, diagnostic change, residential change and re-admission to hospital were explored. Both groups demonstrated clinical improvement from admission to discharge. However, only patients with mild ID demonstrated improvements on the Global Assessment of Functioning. This study is one of the first to consider outcomes of higher and lower functioning individuals with ID on a specialised inpatient unit. Results suggest that outcomes may be different for these groups, and some clinical measures may be more sensitive to changes in patients with more severe disabilities.

A critical analysis of the current knowledge of surgical anatomy related to optimization of cancer control and preservation of continence and erection in candidates for radical prostatectomy.

PubMed

Walz, Jochen; Burnett, Arthur L; Costello, Anthony J; Eastham, James A; Graefen, Markus; Guillonneau, Bertrand; Menon, Mani; Montorsi, Francesco; Myers, Robert P; Rocco, Bernardo; Villers, Arnauld

2010-02-01

Detailed knowledge of the anatomy of the prostate and adjacent tissues is mandatory during radical prostatectomy to ensure reliable oncologic and functional outcomes. To review critically and to summarize the available literature on surgical anatomy of the prostate and adjacent structures involved in cancer control, erectile function, and urinary continence. A search of the PubMed database was performed using the keywords radical prostatectomy, anatomy, neurovascular bundle, fascia, pelvis, and sphincter. Relevant articles and textbook chapters were reviewed, analyzed, and summarized. Anatomy of the prostate and the adjacent tissues varies substantially. The fascia surrounding the prostate is multilayered, sometimes either fused with the prostate capsule or clearly separated from the capsule as a reflection of interindividual variations. The neurovascular bundle (NVB) is situated between the fascial layers covering the prostate. The NVB is composed of numerous nerve fibers superimposed on a scaffold of veins, arteries, and variable amounts of adipose tissue surrounding almost the entire lateral and posterior surfaces of the prostate. The NVB is also in close, cage-like contact to the seminal vesicles. The external urethral sphincter is a complex structure in close anatomic and functional relationship to the pelvic floor, and its fragile innervation is in close association to the prostate apex. Finally, the shape and size of the prostate can significantly modify the anatomy of the NVB, the urethral sphincter, the dorsal vascular complex, and the pubovesical/puboprostatic ligaments. The surgical anatomy of the prostate and adjacent tissues involved in radical prostatectomy is complex. Precise knowledge of all relevant anatomic structures facilitates surgical orientation and dissection during radical prostatectomy and ideally translates into both superior rates of cancer control and improved functional outcomes postoperatively. Copyright 2009 European Association of Urology. All rights reserved.

Orphan nuclear receptor TLX functions as a potent suppressor of oncogene-induced senescence in prostate cancer via its transcriptional co-regulation of the CDKN1A (p21(WAF1) (/) (CIP1) ) and SIRT1 genes.

PubMed

Wu, Dinglan; Yu, Shan; Jia, Lin; Zou, Chang; Xu, Zhenyu; Xiao, Lijia; Wong, Kam-Bo; Ng, Chi-Fai; Chan, Franky L

2015-05-01

Oncogene-induced senescence is an important tumour-suppressing mechanism to prevent both premalignant transformation and cancer progression. Overcoming this process is a critical step in early cancer development. The druggable orphan nuclear receptor TLX (NR2E1) is characterized as an important regulator of neural stem cells and is also implicated in the development of some brain tumours. However, its exact functional roles in cancer growth regulation still remain unclear. Here we report that TLX can act as a promoter of tumourigenesis in prostate cancer by suppressing oncogene-induced senescence. We determined that TLX exhibited an increased expression in high-grade prostate cancer tissues and many prostate cancer cell lines. Functional studies revealed that TLX could perform an oncogenic function in prostate cancer cells, as its knockdown triggered cellular senescence and cell growth arrest in vitro and in vivo, whereas its over-expression promoted the malignant growth of prostate cancer cells. Furthermore, enhancement of TLX activity, by either ectopic expression or ligand stimulation, could potently prevent doxorubicin-induced senescence in prostate cancer cells and also allow prostatic epithelial cells to escape oncogene-induced senescence induced either by activated oncogene H-Ras(G12V) or knockdown of tumour suppressor PTEN, via a mechanism of direct but differential transcriptional regulation of two senescence-associated genes, repression of CDKN1A and transactivation of SIRT1. Together, our present study shows, for the first time, that TLX may play an important role in prostate carcinogenesis through its suppression of oncogene-induced senescence, and also suggests that targeting the senescence-regulatory TLX is of potential therapeutic significance in prostate cancer. Copyright © 2015 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

[Anatomo-functional changes in the prostate and seminal vesicles with aging].

PubMed

Mantovani, F; Mastromarino, G; Colombo, F; Canclini, L; Fenice, O

1993-10-01

The anatomo-functional modifications of the prostate and the seminal pathways during the genital apparatus aging, (prostatic hyperplasia and hypotrophy of the seminal pathways and testis), are caused by hormonal modifications (inconstant increase of the gonadotropins LH-FSH, decrease of the peripheric utilization of testosterone, alterations of the adrenal secretion), by anatomical involutions (degenerations of the glandular, stromal and vascular components).

Psychometric Comparison of the Motivation Assessment Scale (MAS) and the Questions about Behavioral Function (QABF)

ERIC Educational Resources Information Center

Koritsas, S.; Iacono, T.

2013-01-01

Background: The Motivation Assessment Scale (MAS) and the Questions About Behavioral Function (QABF) are frequently used to assess the learned function of challenging behaviour in people with intellectual disability (ID). The aim was to explore and compare the psychometric properties of the MAS and the QABF. Method: Seventy adults with ID and…

Stem cell and neurogenic gene-expression profiles link prostate basal cells to aggressive prostate cancer

PubMed Central

Zhang, Dingxiao; Park, Daechan; Zhong, Yi; Lu, Yue; Rycaj, Kiera; Gong, Shuai; Chen, Xin; Liu, Xin; Chao, Hsueh-Ping; Whitney, Pamela; Calhoun-Davis, Tammy; Takata, Yoko; Shen, Jianjun; Iyer, Vishwanath R.; Tang, Dean G.

2016-01-01

The prostate gland mainly contains basal and luminal cells constructed as a pseudostratified epithelium. Annotation of prostate epithelial transcriptomes provides a foundation for discoveries that can impact disease understanding and treatment. Here we describe a genome-wide transcriptome analysis of human benign prostatic basal and luminal epithelial populations using deep RNA sequencing. Through molecular and biological characterizations, we show that the differential gene-expression profiles account for their distinct functional properties. Strikingly, basal cells preferentially express gene categories associated with stem cells, neurogenesis and ribosomal RNA (rRNA) biogenesis. Consistent with this profile, basal cells functionally exhibit intrinsic stem-like and neurogenic properties with enhanced rRNA transcription activity. Of clinical relevance, the basal cell gene-expression profile is enriched in advanced, anaplastic, castration-resistant and metastatic prostate cancers. Therefore, we link the cell-type-specific gene signatures to aggressive subtypes of prostate cancer and identify gene signatures associated with adverse clinical features. PMID:26924072

Stem cell and neurogenic gene-expression profiles link prostate basal cells to aggressive prostate cancer.

PubMed

Zhang, Dingxiao; Park, Daechan; Zhong, Yi; Lu, Yue; Rycaj, Kiera; Gong, Shuai; Chen, Xin; Liu, Xin; Chao, Hsueh-Ping; Whitney, Pamela; Calhoun-Davis, Tammy; Takata, Yoko; Shen, Jianjun; Iyer, Vishwanath R; Tang, Dean G

2016-02-29

The prostate gland mainly contains basal and luminal cells constructed as a pseudostratified epithelium. Annotation of prostate epithelial transcriptomes provides a foundation for discoveries that can impact disease understanding and treatment. Here we describe a genome-wide transcriptome analysis of human benign prostatic basal and luminal epithelial populations using deep RNA sequencing. Through molecular and biological characterizations, we show that the differential gene-expression profiles account for their distinct functional properties. Strikingly, basal cells preferentially express gene categories associated with stem cells, neurogenesis and ribosomal RNA (rRNA) biogenesis. Consistent with this profile, basal cells functionally exhibit intrinsic stem-like and neurogenic properties with enhanced rRNA transcription activity. Of clinical relevance, the basal cell gene-expression profile is enriched in advanced, anaplastic, castration-resistant and metastatic prostate cancers. Therefore, we link the cell-type-specific gene signatures to aggressive subtypes of prostate cancer and identify gene signatures associated with adverse clinical features.

Psychosocial issues related to sexual functioning among African-American prostate cancer survivors and their spouses†

PubMed Central

Rivers, Brian M.; August, Euna M.; Gwede, Clement K.; Hart, Alton; Donovan, Kristine A.; Pow-Sang, Julio M.; Quinn, Gwendolyn P.

2015-01-01

Objective Focus on cancer survivorship and quality of life (QOL) is a growing priority. The aim of this study was to identify and describe the most salient psychosocial concerns related to sexual functioning among African-American (AA) prostate cancer survivors and their spouses. Methods Twelve AA prostate cancer survivors and their spouses participated in semi-structured individual interviews. The interviews assessed couples’ experiences with psychosocial adjustment and sexual functioning posttreatment for localized prostate cancer. The data were analyzed using the constant comparison method and content analysis. Results In this qualitative study of couples surviving prostate cancer, there were divergent views between the male prostate cancer survivors and their female partners, particularly regarding sexual functioning. For the males, QOL issues emerged as the primary area of concern, whereas survival of their husbands was considered most important among the female spouses. The male respondents expressed unease with the sexual side effects of their cancer treatment, such as erectile dysfunction and decreased sexual desire and satisfaction. Female spouses recognized decreased sexual desire in their partners following treatment, but this was not considered a primary concern. Conclusions Patients and their spouses may have differing perceptions regarding QOL and the impact of sexual functioning on survivorship. This study points to the need for further research and intervention development to address these domains with a goal to improve QOL. PMID:20187071

PHF21B overexpression promotes cancer stem cell-like traits in prostate cancer cells by activating the Wnt/β-catenin signaling pathway.

PubMed

Li, Qiji; Ye, Liping; Guo, Wei; Wang, Min; Huang, Shuai; Peng, Xinsheng

2017-06-23

PHF21B is newly identified to be involved in the tumor progression; however, its biological role and molecular mechanism in prostate cancer have not been defined. This study is aimed to study the role of PHF21B in the progression of prostate cancer. Real-time PCR, immunohistochemistry and western blotting analysis were used to determine PHF21B expression in prostate cancer cell lines and clinical specimens. The role of PHF21B in maintaining prostate cancer stem cell-like phenotype was examined by tumor-sphere formation assay and expression levels of stem cell markers. Luciferase reporter assay, western blot analysis, enzyme-linked immunosorbent assay and ChIP assay were used to determine whether PHF21B activates the Wnt/β-catenin signaling by transcriptionally downregulating SFRP1 and SFRP2. Our results revealed that PHF21B was markedly upregulated in prostate cancer cell lines and tissues. High PHF21B levels predicted poorer recurrence-free survival in prostate cancer patients. Gain-of-function and loss-of-function studies showed that overexpression of PHF21B enhanced, while downregulation suppressed, the cancer stem cell-like phenotype in prostate cancer cells. Xenograft tumor model showed that silencing PHF21B decreased the ability of tumorigenicity in vivo. Notably, Wnt/β-catenin signaling was hyperactivated in prostate cancer cells overexpressing PHF21B, and mediated PHF21B-induced cancer stem cell-like phenotype. Furthermore, PHF21B suppressed repressors of the Wnt/β-catenin signaling cascade, including SFRP1 and SFRP2. These results demonstrated that PHF21B constitutively activated wnt/β-catenin signaling by transcriptionally downregulating SFRP1 and SFRP2, which promotes prostate cancer stem cell-like phenotype. Our results revealed that PHF21B functions as an oncogene in prostate cancer, and may represent a promising prognostic biomarker and an attractive candidate for target therapy of prostate cancer.

Regulation of TCF ETS-domain transcription factors by helix-loop-helix motifs.

PubMed

Stinson, Julie; Inoue, Toshiaki; Yates, Paula; Clancy, Anne; Norton, John D; Sharrocks, Andrew D

2003-08-15

DNA binding by the ternary complex factor (TCF) subfamily of ETS-domain transcription factors is tightly regulated by intramolecular and intermolecular interactions. The helix-loop-helix (HLH)-containing Id proteins are trans-acting negative regulators of DNA binding by the TCFs. In the TCF, SAP-2/Net/ERP, intramolecular inhibition of DNA binding is promoted by the cis-acting NID region that also contains an HLH-like motif. The NID also acts as a transcriptional repression domain. Here, we have studied the role of HLH motifs in regulating DNA binding and transcription by the TCF protein SAP-1 and how Cdk-mediated phosphorylation affects the inhibitory activity of the Id proteins towards the TCFs. We demonstrate that the NID region of SAP-1 is an autoinhibitory motif that acts to inhibit DNA binding and also functions as a transcription repression domain. This region can be functionally replaced by fusion of Id proteins to SAP-1, whereby the Id moiety then acts to repress DNA binding in cis. Phosphorylation of the Ids by cyclin-Cdk complexes results in reduction in protein-protein interactions between the Ids and TCFs and relief of their DNA-binding inhibitory activity. In revealing distinct mechanisms through which HLH motifs modulate the activity of TCFs, our results therefore provide further insight into the role of HLH motifs in regulating TCF function and how the inhibitory properties of the trans-acting Id HLH proteins are themselves regulated by phosphorylation.

Androgen-responsive circular RNA circSMARCA5 is up-regulated and promotes cell proliferation in prostate cancer.

PubMed

Kong, Zhe; Wan, Xuechao; Zhang, Yalong; Zhang, Pu; Zhang, Yingyi; Zhang, Xiaona; Qi, Xiaoxiang; Wu, Hai; Huang, Jianfeng; Li, Yao

2017-11-25

Prostate cancer (PCa) is one of the most commonly diagnosed cancers in males worldwide. Circular RNA (circRNA) is a unique class of RNA transcribed by RNA polymerase II characterized by jointing 3' and 5' ends together via exon or intron circularization. However, the molecular functions of circRNAs in prostate cancer have rarely been explored. In present study, we found circ-SMARCA5 was up-regulated in prostate cancer samples compared to match normal tissues. We also observed circ-SMARCA5 expression was significantly induced after DHT treatment. Functional experiments showed circ-SMARCA5 acted as an oncogene in prostate cancer by promoting cell cycle and inhibiting cell apoptosis. We thought this study provided useful information for exploring circRNAs as potential therapeutic and prognostic targets for prostate cancer. Copyright © 2017. Published by Elsevier Inc.

[Laservaporization of the prostate: current status of the greenlight and diode laser].

PubMed

Rieken, M; Bachmann, A; Gratzke, C

2013-03-01

In the last decade laser vaporization of the prostate has emerged as a safe and effective alternative to transurethral resection of the prostate (TURP). This was facilitated in particular by the introduction of photoselective vaporization of the prostate (PVP) with a 532 nm 80 W KTP laser in 2002. Prospective randomized trials comparing PVP and TURP with a maximum follow-up of 3 years mostly demonstrated comparable functional results. Cohort studies showed a safe application of PVP in patients under oral anticoagulation and with large prostates. Systems from various manufacturers with different maximum power output and wavelengths are now available for diode laser vaporization of the prostate. Prospective randomized trials comparing diode lasers and TURP are not yet available. In cohort studies and comparative studies PVP diode lasers are characterized by excellent hemostatic properties but functional results vary greatly with some studies reporting high reoperation rates.

Overexpression and knock-down studies highlight that a disintegrin and metalloproteinase 28 controls proliferation and migration in human prostate cancer.

PubMed

Rudnicka, Caroline; Mochizuki, Satsuki; Okada, Yasunori; McLaughlin, Claire; Leedman, Peter J; Stuart, Lisa; Epis, Michael; Hoyne, Gerard; Boulos, Sherif; Johnson, Liam; Schlaich, Markus; Matthews, Vance

2016-10-01

Prostate cancer is one of the most prevalent cancers in men. It is critical to identify and characterize oncogenes that drive the pathogenesis of human prostate cancer. The current study builds upon previous research showing that a disintegrin and metallproteinase (ADAM)28 is involved in the pathogenesis of numerous cancers. Our novel study used overexpression, pharmacological, and molecular approaches to investigate the biological function of ADAM28 in human prostate cancer cells, with a focus on cell proliferation and migration. The results of this study provide important insights into the role of metalloproteinases in human prostate cancer.The expression of ADAM28 protein levels was assessed within human prostate tumors and normal adjacent tissue by immunohistochemistry. Immunocytochemistry and western blotting were used to assess ADAM28 protein expression in human prostate cancer cell lines. Functional assays were conducted to assess proliferation and migration in human prostate cancer cells in which ADAM28 protein expression or activity had been altered by overexpression, pharmacological inhibition, or by siRNA gene knockdown.The membrane bound ADAM28 was increased in human tumor biopsies and prostate cancer cell lines. Pharmacological inhibition of ADAM28 activity and/or knockdown of ADAM28 significantly reduced proliferation and migration of human prostate cancer cells, while overexpression of ADAM28 significantly increased proliferation and migration.ADAM28 is overexpressed in primary human prostate tumor biopsies, and it promotes human prostate cancer cell proliferation and migration. This study supports the notion that inhibition of ADAM28 may be a potential novel therapeutic strategy for human prostate cancer.

An Interaction with Ewing's Sarcoma Breakpoint Protein EWS Defines a Specific Oncogenic Mechanism of ETS Factors Rearranged in Prostate Cancer.

PubMed

Kedage, Vivekananda; Selvaraj, Nagarathinam; Nicholas, Taylor R; Budka, Justin A; Plotnik, Joshua P; Jerde, Travis J; Hollenhorst, Peter C

2016-10-25

More than 50% of prostate tumors have a chromosomal rearrangement resulting in aberrant expression of an oncogenic ETS family transcription factor. However, mechanisms that differentiate the function of oncogenic ETS factors expressed in prostate tumors from non-oncogenic ETS factors expressed in normal prostate are unknown. Here, we find that four oncogenic ETS (ERG, ETV1, ETV4, and ETV5), and no other ETS, interact with the Ewing's sarcoma breakpoint protein, EWS. This EWS interaction was necessary and sufficient for oncogenic ETS functions including gene activation, cell migration, clonogenic survival, and transformation. Significantly, the EWS interacting region of ERG has no homology with that of ETV1, ETV4, and ETV5. Therefore, this finding may explain how divergent ETS factors have a common oncogenic function. Strikingly, EWS is fused to various ETS factors by the chromosome translocations that cause Ewing's sarcoma. Therefore, these findings link oncogenic ETS function in both prostate cancer and Ewing's sarcoma. Copyright © 2016 The Author(s). Published by Elsevier Inc. All rights reserved.

Aspects of Cognitive Functioning in Adults with Intellectual Disabilities

ERIC Educational Resources Information Center

Perkins, Elizabeth A.; Small, Brent J.

2006-01-01

Recently, more attention is being given to identifying aging-related and dementia-related pathological changes in performance and cognition among persons with intellectual disabilities (ID). This literature review examines age-related differences in specific aspects of cognitive functioning and cognitive performance of people with ID and…

Functional anatomy of the prostate: implications for treatment planning.

PubMed

McLaughlin, Patrick W; Troyer, Sara; Berri, Sally; Narayana, Vrinda; Meirowitz, Amichay; Roberson, Peter L; Montie, James

2005-10-01

To summarize the functional anatomy relevant to prostate cancer treatment planning. Coronal, axial, and sagittal T2 magnetic resonance imaging (MRI) and MRI angiography were fused by mutual information and registered with computed tomography (CT) scan data sets to improve definition of zonal anatomy of the prostate and critical adjacent structures. The three major prostate zones (inner, outer, and anterior fibromuscular) are visible by T2 MRI imaging. The bladder, bladder neck, and internal (preprostatic) sphincter are a continuous muscular structure and clear definition of the preprostatic sphincter is difficult by MRI. Transition zone hypertrophy may efface the bladder neck and internal sphincter. The external "lower" sphincter is clearly visible by T2 MRI with wide variations in length. The critical erectile structures are the internal pudendal artery (defined by MRI angiogram or T2 MRI), corpus cavernosum, and neurovascular bundle. The neurovascular bundle is visible along the posterior lateral surface of the prostate on CT and MRI, but its terminal branches (cavernosal nerves) are not visible and must be defined by their relationship to the urethra within the genitourinary diaphragm. Visualization of the ejaculatory ducts within the prostate is possible on sagittal MRI. The anatomy of the prostate-rectum interface is clarified by MRI, as is the potentially important distinction of rectal muscle and rectal mucosa. Improved understanding of functional anatomy and imaging of the prostate and critical adjacent structures will improve prostate radiation therapy by improvement of dose and toxicity correlation, limitation of dose to critical structures, and potential improvement in post therapy quality of life.

Profiles and Cognitive Predictors of Motor Functions among Early School-Age Children with Mild Intellectual Disabilities

ERIC Educational Resources Information Center

Wuang, Y.-P.; Wang, C.-C.; Huang, M.-H.; Su, C.-Y.

2008-01-01

Background: The purpose of the study was to describe sensorimotor profile in children with mild intellectual disability (ID), and to examine the association between cognitive and motor function. Methods: A total of 233 children with mild ID aged 7 to 8 years were evaluated with measures of cognitive, motor and sensory integrative functioning.…

Roles for the Stem Cell–Associated Intermediate Filament Nestin in Prostate Cancer Migration and Metastasis

PubMed Central

Kleeberger, Wolfram; Bova, G. Steven; Nielsen, Matthew E.; Herawi, Mehsati; Chuang, Ai-Ying; Epstein, Jonathan I.; Berman, David M.

2011-01-01

The intermediate filament protein Nestin identifies stem/progenitor cells in adult tissues, but the function of Nestin is poorly understood. We investigated Nestin expression and function in common lethal cancers. Nestin mRNA was detected in cell lines from small cell lung, and breast cancers, and particularly elevated in cell lines derived from prostate cancer metastases. Whereas the androgen-independent lines PC3, 22RV1, and DU145 all expressed Nestin transcripts under standard culture conditions, the androgen-dependent line LnCaP expressed Nestin only on androgen withdrawal. We confirmed associations of Nestin expression, androgen withdrawal, and metastatic potential by immunohistochemical analysis of samples from 254 prostate cancer patients. Cytoplasmic Nestin protein was readily identifiable in prostate cancer cells from 75% of patients with lethal androgen-independent disease, even in cancer sampled from the prostate itself. However, Nestin expression was undetectable in localized androgen-deprived tumors and in metastases without prior androgen deprivation. To address its function, we reduced Nestin levels with short hairpin RNAs, markedly inhibiting in vitro migration and invasion in prostate cancer cells but leaving cell growth intact. Nestin knockdown also diminished metastases 5-fold compared with controls despite uncompromised tumorigenicity at the site of inoculation. These results specify a function for Nestin in cell motility and identify a novel pathway for prostate cancer metastasis. Activity of this pathway may be selected by the extraprostatic environment or, as supported by our data, may originate within the prostate after androgen deprivation. Further dissection of this novel Nestin migration pathway may lead to strategies to prevent and neutralize metastatic spread. PMID:17909025

[Concomitant oncopathological changes in the prostate of urinary bladder cancer patients undergoing radical cystoprostateectomy].

PubMed

Komyakov, B K; Sergeev, A V; Fadeev, V A; Ismailov, K I; Ulyanov, A Yu; Shmelev, A Yu; Onoshko, M V

2017-09-01

To determine the incidence of spreading bladder transitional cell carcinoma and primary adenocarcinoma to the prostate in patients with bladder cancer undergoing radical cystectomy. From 1995 to 2016, 283 men underwent radical cystectomy with removal of the bladder, perivesical tissue, prostate, seminal vesicles and pelvic lymph nodes. Prostate sparing cystectomy was performed in 45 (13.7%) patients. The whole prostate and the apex of the prostate were preserved in 21 (6.4%) and 24 (7.3%) patients, respectively. The spread of transitional cell cancer of the bladder to the prostate occurred in 50 (15.2%) patients. Twelve (3.6%) patients were found to have primary prostate adenocarcinoma. Clinically significant prostate cancer was diagnosed in 4 (33.3%) patients. We believe that the high oncological risk of prostate sparing cystectomy, despite some functional advantages, dictates the need for complete removal of the prostate in the surgical treatment of bladder cancer.

XSIM Final Report: Modelling the Past and Future of Identity Management for Scientific Collaborations

DOE Office of Scientific and Technical Information (OSTI.GOV)

Cowles, Robert; Jackson, Craig; Welch, Von

The eXtreme Science Identity Management (XSIM1) research project: collected and analyzed real world data on virtual organization (VO) identity management (IdM) representing the last 15+ years of collaborative DOE science; constructed a descriptive VO IdM model based on that data; used the model and existing trends to project the direction for IdM in the 2020 timeframe; and provided guidance to scientific collaborations and resource providers that are implementing or seeking to improve IdM functionality. XSIM conducted over 20 semi­structured interviews of representatives from scientific collaborations and resource providers, both in the US and Europe; the interviewees supported diverse set ofmore » scientific collaborations and disciplines. We developed a definition of “trust,” a key concept in IdM, to understand how varying trust models affect where IdM functions are performed. The model identifies how key IdM data elements are utilized in collaborative scientific workflows, and it has the flexibility to describe past, present and future trust relationships and IdM implementations. During the funding period, we gave more than two dozen presentations to socialize our work, encourage feedback, and improve the model; we also published four refereed papers. Additionally, we developed, presented, and received favorable feedback on three white papers providing practical advice to collaborations and/or resource providers.« less

Psychiatric Disorders in Outpatients With Borderline Intellectual Functioning: Comparison With Both Outpatients From Regular Mental Health Care and Outpatients With Mild Intellectual Disabilities

PubMed Central

Wieland, Jannelien; Haan, Sara Kapitein-de; Zitman, Frans G

2014-01-01

Objective: In the Netherlands, patients with borderline intellectual functioning are eligible for specialized mental health care. This offers the unique possibility to examine the mix of psychiatric disorders in patients who, in other countries, are treated in regular outpatient mental health care clinics. Our study sought to examine the rates of all main Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision, Axis I psychiatric diagnoses in outpatients with borderline intellectual functioning of 2 specialized regional psychiatric outpatient departments and to compare these with rates of the same disorders in outpatients from regular mental health care (RMHC) and outpatients with mild intellectual disabilities (IDs). Method: Our study was a cross-sectional, anonymized medical chart review. All participants were patients from the Dutch regional mental health care provider Rivierduinen. Diagnoses of patients with borderline intellectual functioning (borderline intellectual functioning group; n = 235) were compared with diagnoses of patients from RMHC (RMHC group; n = 1026) and patients with mild ID (mild ID group; n = 152). Results: Compared with the RMHC group, psychotic and major depressive disorders were less common in the borderline intellectual functioning group, while posttraumatic stress disorder and V codes were more common. Compared with the mild ID group, psychotic disorders were significantly less common. Conclusion: Mental health problems in people with borderline intellectual functioning may not be well addressed in general psychiatry, or by standard psychiatry for patients with ID. Specific attention to this group in clinical practice and research may be warranted lest they fall between 2 stools. PMID:25007114

Psychiatric disorders in outpatients with borderline intellectual functioning: comparison with both outpatients from regular mental health care and outpatients with mild intellectual disabilities.

PubMed

Wieland, Jannelien; Kapitein-de Haan, Sara; Zitman, Frans G

2014-04-01

In the Netherlands, patients with borderline intellectual functioning are eligible for specialized mental health care. This offers the unique possibility to examine the mix of psychiatric disorders in patients who, in other countries, are treated in regular outpatient mental health care clinics. Our study sought to examine the rates of all main Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision, Axis I psychiatric diagnoses in outpatients with borderline intellectual functioning of 2 specialized regional psychiatric outpatient departments and to compare these with rates of the same disorders in outpatients from regular mental health care (RMHC) and outpatients with mild intellectual disabilities (IDs). Our study was a cross-sectional, anonymized medical chart review. All participants were patients from the Dutch regional mental health care provider Rivierduinen. Diagnoses of patients with borderline intellectual functioning (borderline intellectual functioning group; n = 235) were compared with diagnoses of patients from RMHC (RMHC group; n = 1026) and patients with mild ID (mild ID group; n = 152). Compared with the RMHC group, psychotic and major depressive disorders were less common in the borderline intellectual functioning group, while posttraumatic stress disorder and V codes were more common. Compared with the mild ID group, psychotic disorders were significantly less common. Mental health problems in people with borderline intellectual functioning may not be well addressed in general psychiatry, or by standard psychiatry for patients with ID. Specific attention to this group in clinical practice and research may be warranted lest they fall between 2 stools.

Transcriptional regulation of core autophagy and lysosomal genes by the androgen receptor promotes prostate cancer progression

PubMed Central

Blessing, Alicia M.; Rajapakshe, Kimal; Reddy Bollu, Lakshmi; Shi, Yan; White, Mark A.; Pham, Alexander H.; Lin, Chenchu; Jonsson, Philip; Cortes, Constanza J.; Cheung, Edwin; La Spada, Albert R.; Bast, Robert C.; Merchant, Fatima A.; Coarfa, Cristian; Frigo, Daniel E.

2017-01-01

ABSTRACT AR (androgen receptor) signaling is crucial for the development and maintenance of the prostate as well as the initiation and progression of prostate cancer. Despite the AR's central role in prostate cancer progression, it is still unclear which AR-mediated processes drive the disease. Here, we identified 4 core autophagy genes: ATG4B, ATG4D, ULK1, and ULK2, in addition to the transcription factor TFEB, a master regulator of lysosomal biogenesis and function, as transcriptional targets of AR in prostate cancer. These findings were significant in light of our recent observation that androgens promoted prostate cancer cell growth in part through the induction of autophagy. Expression of these 5 genes was essential for maximal androgen-mediated autophagy and cell proliferation. In addition, expression of each of these 5 genes alone or in combination was sufficient to increase prostate cancer cell growth independent of AR activity. Further, bioinformatic analysis demonstrated that the expression of these genes correlated with disease progression in 3 separate clinical cohorts. Collectively, these findings demonstrate a functional role for increased autophagy in prostate cancer progression, provide a mechanism for how autophagy is augmented, and highlight the potential of targeting this process for the treatment of advanced prostate cancer. PMID:27977328

Transcriptional regulation of core autophagy and lysosomal genes by the androgen receptor promotes prostate cancer progression.

PubMed

Blessing, Alicia M; Rajapakshe, Kimal; Reddy Bollu, Lakshmi; Shi, Yan; White, Mark A; Pham, Alexander H; Lin, Chenchu; Jonsson, Philip; Cortes, Constanza J; Cheung, Edwin; La Spada, Albert R; Bast, Robert C; Merchant, Fatima A; Coarfa, Cristian; Frigo, Daniel E

2017-03-04

AR (androgen receptor) signaling is crucial for the development and maintenance of the prostate as well as the initiation and progression of prostate cancer. Despite the AR's central role in prostate cancer progression, it is still unclear which AR-mediated processes drive the disease. Here, we identified 4 core autophagy genes: ATG4B, ATG4D, ULK1, and ULK2, in addition to the transcription factor TFEB, a master regulator of lysosomal biogenesis and function, as transcriptional targets of AR in prostate cancer. These findings were significant in light of our recent observation that androgens promoted prostate cancer cell growth in part through the induction of autophagy. Expression of these 5 genes was essential for maximal androgen-mediated autophagy and cell proliferation. In addition, expression of each of these 5 genes alone or in combination was sufficient to increase prostate cancer cell growth independent of AR activity. Further, bioinformatic analysis demonstrated that the expression of these genes correlated with disease progression in 3 separate clinical cohorts. Collectively, these findings demonstrate a functional role for increased autophagy in prostate cancer progression, provide a mechanism for how autophagy is augmented, and highlight the potential of targeting this process for the treatment of advanced prostate cancer.

Distinct function of estrogen receptor α in smooth muscle and fibroblast cells in prostate development.

PubMed

Vitkus, Spencer; Yeh, Chiuan-Ren; Lin, Hsiu-Hsia; Hsu, Iawen; Yu, Jiangzhou; Chen, Ming; Yeh, Shuyuan

2013-01-01

Estrogen signaling, through estrogen receptor (ER)α, has been shown to cause hypertrophy in the prostate. Our recent report has shown that epithelial ERα knockout (KO) will not affect the normal prostate development or homeostasis. However, it remains unclear whether ERα in different types of stromal cells has distinct roles in prostate development. This study proposed to elucidate how KO of ERα in the stromal smooth muscle or fibroblast cells may interrupt cross talk between prostate stromal and epithelial cells. Smooth muscle ERαKO (smERαKO) mice showed decreased glandular infolding with the proximal area exhibiting a significant decrease. Fibroblast ERαKO mouse prostates did not exhibit this phenotype but showed a decrease in the number of ductal tips. Additionally, the amount of collagen observed in the basement membrane was reduced in smERαKO prostates. Interestingly, these phenotypes were found to be mutually exclusive among smERαKO or fibroblast ERαKO mice. Compound KO of ERα in both fibroblast and smooth muscle showed combined phenotypes from each of the single KO. Further mechanistic studies showed that IGF-I and epidermal growth factor were down-regulated in prostate smooth muscle PS-1 cells lacking ERα. Together, our results indicate the distinct functions of fibroblast vs. smERα in prostate development.

Motor competency and social communication skills in preschool children with autism spectrum disorder.

PubMed

Craig, Francesco; Lorenzo, Alessandro; Lucarelli, Elisabetta; Russo, Luigi; Fanizza, Isabella; Trabacca, Antonio

2018-06-01

This study aimed to investigate the association between motor competency and social communication in children with Autism Spectrum Disorder (ASD) compared with children with Intellectual Disabilities (ID) and typically developing (TD) children. Motor competency, ASD symptoms, and nonverbal Intelligent Quotient (IQ) were investigated through the following tests: Movement Assessment Battery for Children, second edition (MABC-2), Social Communication Questionnaire (SCQ), Autism Classification System of Functioning: Social Communication (ACSF:SC) and Leiter International Performances Scale Revised (Leiter-R). The ASD + ID and ID groups had lower MABC-2-manual dexterity mean scores, MABC-2-aiming and catching mean scores, MABC-2-static and dynamic balance mean scores and MABC-2-TTS compared with the TD group (P < 0.05). In addition, the ASD + ID group had lower MABC-2-aiming and catching mean scores compared with the ID group. In the ASD + ID group, we found a significant negative correlation (P < 0.001) between MABC-2-aiming and catching scores with SCQ scores, nonverbal IQ and ACSF:SC levels. Our findings provide new insight into the common neuropsychological mechanisms underlying social communication and motor deficits in ASD. Multiple deficits in motor functioning may be present in ASD and ID, however deficits involving the ability to integrate motor and social cues are somewhat specific to ASD. Autism Res 2018, 11: 893-902. © 2018 International Society for Autism Research, Wiley Periodicals, Inc. This study highlighted the specificity of motor impairment in ASD comparing performances on a frequently used measure of motor impairment between clinical groups (ASD + ID and ID) and a non-clinical group. While previous research has suggested that multiple deficits in motor functioning may be present in ASD, our findings suggest that deficits in tasks involving the ability to integrate visual and motor cues (aiming and catching task) are somewhat specific to ASD. © 2018 International Society for Autism Research, Wiley Periodicals, Inc.

ERG signaling in prostate cancer is driven through PRMT5-dependent methylation of the Androgen Receptor.

PubMed

Mounir, Zineb; Korn, Joshua M; Westerling, Thomas; Lin, Fallon; Kirby, Christina A; Schirle, Markus; McAllister, Gregg; Hoffman, Greg; Ramadan, Nadire; Hartung, Anke; Feng, Yan; Kipp, David Randal; Quinn, Christopher; Fodor, Michelle; Baird, Jason; Schoumacher, Marie; Meyer, Ronald; Deeds, James; Buchwalter, Gilles; Stams, Travis; Keen, Nicholas; Sellers, William R; Brown, Myles; Pagliarini, Raymond A

2016-05-16

The TMPRSS2:ERG gene fusion is common in androgen receptor (AR) positive prostate cancers, yet its function remains poorly understood. From a screen for functionally relevant ERG interactors, we identify the arginine methyltransferase PRMT5. ERG recruits PRMT5 to AR-target genes, where PRMT5 methylates AR on arginine 761. This attenuates AR recruitment and transcription of genes expressed in differentiated prostate epithelium. The AR-inhibitory function of PRMT5 is restricted to TMPRSS2:ERG-positive prostate cancer cells. Mutation of this methylation site on AR results in a transcriptionally hyperactive AR, suggesting that the proliferative effects of ERG and PRMT5 are mediated through attenuating AR's ability to induce genes normally involved in lineage differentiation. This provides a rationale for targeting PRMT5 in TMPRSS2:ERG positive prostate cancers. Moreover, methylation of AR at arginine 761 highlights a mechanism for how the ERG oncogene may coax AR towards inducing proliferation versus differentiation.

Low Testosterone Alters the Activity of Mouse Prostate Stem Cells.

PubMed

Zhou, Ye; Copeland, Ben; Otto-Duessel, Maya; He, Miaoling; Markel, Susan; Synold, Tim W; Jones, Jeremy O

2017-04-01

Low serum testosterone (low T) has been repeatedly linked to worse outcomes in men with newly diagnosed prostate cancer (PC). How low T contributes to these outcomes is unknown. Here we demonstrate that exposure to low T causes significant changes in the mouse prostate and prostate stem cells. Mice were castrated and implanted with capsules to achieve castrate, normal, or sub-physiological levels of T. After 6 weeks of treatment, LC-MS/MS was used to quantify the levels of T and dihydrotestosterone (DHT) in serum and prostate tissue. FACS was used to quantify the percentages of purported prostate stem and transit amplifying (TA) cells in mouse prostates. Prostate tissues were also stained for the presence of CD68+ cells and RNA was extracted from prostate tissue or specific cell populations to measure changes in transcript levels with low T treatment. Despite having significantly different levels of T and DHT in the serum, T and DHT concentrations in prostate tissue from different T treatment groups were similar. Low T treatment resulted in significant alterations in the expression of androgen biosynthesis genes, which may be related to maintaining prostate androgen levels. Furthermore, the expression of androgen-regulated genes in the prostate was similar among all T treatment groups, demonstrating that the mouse prostate can maintain functional levels of androgens despite low serum T levels. Low T increased the frequency of prostate stem and TA cells in adult prostate tissue and caused major transcriptional changes in those cells. Gene ontology analysis suggested that low T caused inflammatory responses and immunofluorescent staining indicated that low T treatment led to the increased presence of CD68+ macrophages in prostate tissue. Low T alters the AR signaling axis which likely leads to maintenance of functional levels of prostate androgens. Low T also induces quantitative and qualitative changes in prostate stem cells which appear to lead to inflammatory macrophage infiltration. These changes are proposed to lead to an aggressive phenotype once cancers develop and may contribute to the poor outcomes in men with low T. Prostate 77:530-541, 2017. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

Patient-reported outcome (PRO) questionnaires for men who have radical surgery for prostate cancer: a conceptual review of existing instruments.

PubMed

Protopapa, Evangelia; van der Meulen, Jan; Moore, Caroline M; Smith, Sarah C

2017-10-01

To critically review conceptual frameworks for available patient-reported outcome (PRO) questionnaires in men having radical prostatectomy (RP), psychometrically evaluate each questionnaire, and identify whether each is appropriate for use at the level of the individual patient. We searched PubMed, the Reports and Publications database of the University of Oxford Patient-Reported Outcomes Measurement Group and the website of the International Consortium for Health Outcomes Measurement (ICHOM) for psychometric reviews of prostate cancer-specific PRO questionnaires. From these we identified relevant questionnaires and critically appraised the conceptual content, guided by the Wilson and Cleary framework and psychometric properties, using well established criteria. The searches found four reviews and one recommendation paper. We identified seven prostate cancer-specific PROs: the Expanded Prostate Cancer Index Composite-26 (EPIC-26), Expanded Prostate Cancer Index Composite-50 (EPIC-50), University of California-Los Angeles Prostate Cancer Index (UCLA-PCI), Functional Assessment of Cancer Therapy - Prostate Cancer Subscale (FACT-P PCS), European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire - prostate specific 25-item (EORTC QLQ-PR25), Prostate Cancer - Quality of Life (PC-QoL), and Symptom Tracking and Reporting (STAR). Six out of seven measures purported to measure health-related quality of life (HRQL), but items focused strongly on urinary and sexual symptoms/functioning. The remaining questionnaire (STAR) claimed to assess functional recovery after RP. The psychometric evidence for these questionnaires was incomplete and variable in quality; none had evidence that they were appropriate for use with individual patients. Several questionnaires provide the basis of measures of urinary and/or sexual symptoms/functioning. Further work should explore other aspects of HRQL that are important for men having RP. Further psychometric work is also needed to determine whether they can be used at the individual level. © 2017 The Authors BJU International © 2017 BJU International Published by John Wiley & Sons Ltd.

MicroRNAs and intellectual disability (ID) in Down syndrome, X-linked ID, and Fragile X syndrome

PubMed Central

Siew, Wei-Hong; Tan, Kai-Leng; Babaei, Maryam Abbaspour; Cheah, Pike-See; Ling, King-Hwa

2013-01-01

Intellectual disability (ID) is one of the many features manifested in various genetic syndromes leading to deficits in cognitive function among affected individuals. ID is a feature affected by polygenes and multiple environmental factors. It leads to a broad spectrum of affected clinical and behavioral characteristics among patients. Until now, the causative mechanism of ID is unknown and the progression of the condition is poorly understood. Advancement in technology and research had identified various genetic abnormalities and defects as the potential cause of ID. However, the link between these abnormalities with ID is remained inconclusive and the roles of many newly discovered genetic components such as non-coding RNAs have not been thoroughly investigated. In this review, we aim to consolidate and assimilate the latest development and findings on a class of small non-coding RNAs known as microRNAs (miRNAs) involvement in ID development and progression with special focus on Down syndrome (DS) and X-linked ID (XLID) [including Fragile X syndrome (FXS)]. PMID:23596395

Micrornas in prostate cancer: an overview.

PubMed

Vanacore, Daniela; Boccellino, Mariarosaria; Rossetti, Sabrina; Cavaliere, Carla; D'Aniello, Carmine; Di Franco, Rossella; Romano, Francesco Jacopo; Montanari, Micaela; La Mantia, Elvira; Piscitelli, Raffaele; Nocerino, Flavia; Cappuccio, Francesca; Grimaldi, Giovanni; Izzo, Alessandro; Castaldo, Luigi; Pepe, Maria Filomena; Malzone, Maria Gabriella; Iovane, Gelsomina; Ametrano, Gianluca; Stiuso, Paola; Quagliuolo, Lucio; Barberio, Daniela; Perdonà, Sisto; Muto, Paolo; Montella, Maurizio; Maiolino, Piera; Veneziani, Bianca Maria; Botti, Gerardo; Caraglia, Michele; Facchini, Gaetano

2017-07-25

Prostate cancer is the second highest cause of cancer mortality after lung tumours. In USA it affects about 2.8 million men and the incidence increases with age in many countries. Therefore, early diagnosis is a very important step for patient clinical evaluation and for a selective and efficient therapy. The study of miRNAs' functions and molecular mechanisms has brought new knowledge in biological processes of cancer. In prostate cancer there is a deregulation of several miRNAs that may function as tumour suppressors or oncogenes. The aim of this review is to analyze the progress made to our understanding of the role of miRNA dysregulation in prostate cancer tumourigenesis.

[Neuroendocrine differentiation in prostate adenocarcinoma].

PubMed

Ramírez-Balderrama, Lázaro; López-Briones, Sergio; Daza-Benítez, Leonel; Macías, Maciste H; López-Gaytán, Teresa; Pérez-Vázquez, Victoriano

2013-01-01

The human prostate is a gland composed of many types of cells and extracellular components with specific functions. The stromal compartment includes nerve tissue, fibroblasts, lymphocytes, macrophages, endothelial cells, and smooth muscular cells. The epithelial compartment is composed of luminal epithelial cells, basal cells, and a lesser number of neuroendocrine cells, which are transcendental in growth regulation, differentiation, and secretory function. In prostate cancer, neuroendocrine cells replicate especially in high grade and advanced stage, and hormonally treated tumoral cells adopt characteristics that make them resistant to hormonal deprivation. Androgen receptors have a crucial role in tumorigenesis of prostate adenocarcinoma. Deprivation hormone therapy blocks the expression of androgen receptors in the prostatic epithelial cells. Neuroendocrine cells lack androgen receptors; their growth is hormonally independent and that is why deprivation hormonal therapy does not eliminate the neoplasic neuroendocrine cells. In contrast, these types of cells proliferate after therapy and make a paracrine network, stimulating the proliferation of androgen-independent neoplastic cells, which finally lead to tumoral recurrence. In this work we describe the neuroendocrine function in normal tissue and in prostatic adenocarcinoma, including neoplasic proliferation stimulation, invasion, apoptosis resistance, and angiogenesis, and describe some molecular pathways involved in this neuroendocrine differentiation.

A review of cognitive impairments in children with intellectual disabilities: Implications for cognitive behaviour therapy.

PubMed

Hronis, Anastasia; Roberts, Lynette; Kneebone, Ian I

2017-06-01

Nearly half of children with intellectual disability (ID) have comorbid affective disorders. These problems are chronic if left untreated and can significantly impact upon future vocational, educational, and social opportunities. Despite this, there is a paucity of research into effective treatments for this population. Notably, one of the most supported of psychological therapies, cognitive behaviour therapy (CBT), remains largely uninvestigated in children with ID. The current review considers the neuropsychological profile of children and adolescents with mild to moderate ID, with a view to informing how CBT might best be adapted for children and adolescents with ID. Narrative review of literature considering the neuropsychological profiles of children and adolescents with ID, with specific focus upon attention, memory, learning, executive functioning, and communication. Studies were identified through SCOPUS, PsycINFO, and PubMed databases, using combinations of the key words 'intellectual disability', 'learning disability', 'neuropsychology', 'attention', 'learning', 'memory', 'executive function', 'language', and 'reading'. Children with ID have significant deficits in attention, learning, memory, executive functions, and language. These deficits are likely to have a negative impact upon engagement in CBT. Suggestions for adapting therapy to accommodate these wide ranging deficits are proposed. There are multiple cognitive factors which need to be considered when modifying CBT for children who have ID. Furthermore, research is required to test whether CBT so modified is effective in this population. Clinical implications Effective ways of providing cognitive behavioural therapy (CBT) to children with intellectual disability (ID) is unclear. This study provides a framework of potential adaptations for clinical practice As rates of mental illness for children with intellectual disability are high, and rates of treatment provision low, it is hoped that the recommendations provided in this study will encourage more mental health practitioners to provide CBT to children with ID. Limitations These recommendations are based only upon neuropsychological literature. Trialling the effectiveness of an adapted form of CBT for children and adolescents with ID is required. There are varying causes of intellectual disability, with differences in cognitive profiles. The utility of the recommendations made here may vary according to specific aetiologies. © 2017 The British Psychological Society.

Prostate Cancer Patient Characteristics Associated With a Strong Preference to Preserve Sexual Function and Receipt of Active Surveillance.

PubMed

Broughman, James R; Basak, Ramsankar; Nielsen, Matthew E; Reeve, Bryce B; Usinger, Deborah S; Spearman, Kiayni C; Godley, Paul A; Chen, Ronald C

2018-04-01

Men with early-stage prostate cancer have multiple options that have similar oncologic efficacy but vary in terms of their impact on quality of life. In low-risk cancer, active surveillance is the option that best preserves patients' sexual function, but it is unknown if patient preference affects treatment selection. Our objectives were to identify patient characteristics associated with a strong preference to preserve sexual function and to determine whether patient preference and baseline sexual function level are associated with receipt of active surveillance in low-risk cancer. In this population-based cohort of men with localized prostate cancer, baseline patient-reported sexual function was assessed using a validated instrument. Patients were also asked whether preservation of sexual function was very, somewhat, or not important. Prostate cancer disease characteristics and treatments received were abstracted from medical records. A modified Poisson regression model with robust standard errors was used to compute adjusted risk ratio (aRR) estimates. All statistical tests were two-sided. Among 1194 men, 52.6% indicated a strong preference for preserving sexual function. Older men were less likely to have a strong preference (aRR = 0.98 per year, 95% confidence interval [CI] = 0.97 to 0.99), while men with normal sexual function were more likely (vs poor function, aRR = 1.59, 95% CI = 1.39 to 1.82). Among 568 men with low-risk cancer, there was no clear association between baseline sexual function or strong preference to preserve function with receipt of active surveillance. However, strong preference may differnetially impact those with intermediate baseline function vs poor function (Pinteraction = .02). Treatment choice may not always align with patients' preferences. These findings demonstrate opportunities to improve delivery of patient-centered care in early prostate cancer.

A novel selective androgen receptor modulator (SARM) MK-4541 exerts anti-androgenic activity in the prostate cancer xenograft R-3327G and anabolic activity on skeletal muscle mass & function in castrated mice.

PubMed

Chisamore, Michael J; Gentile, Michael A; Dillon, Gregory Michael; Baran, Matthew; Gambone, Carlo; Riley, Sean; Schmidt, Azriel; Flores, Osvaldo; Wilkinson, Hilary; Alves, Stephen E

2016-10-01

The androgen receptor (AR) is a member of the nuclear hormone receptor super family of transcription factors. Androgens play an essential role in the development, growth, and maintenance of male sex organs, as well as the musculoskeletal and central nervous systems. Yet with advancing age, androgens can drive the onset of prostate cancer, the second leading cause of cancer death in males within the United States. Androgen deprivation therapy (ADT) by pharmacologic and/or surgical castration induces apoptosis of prostate cells and subsequent shrinkage of the prostate and prostate tumors. However, ADT is associated with significant musculoskeletal and behavioral adverse effects. The unique pharmacological activity of selective androgen receptor modulator (SARM) MK-4541 recently has been reported as an AR antagonist with 5α-reductase inhibitor function. The molecule inhibits proliferation and induces apoptosis in AR positive, androgen dependent prostate cancer cells. Importantly, MK-4541 inhibited androgen-dependent prostate growth in male rats yet maintained lean body mass and bone formation following ovariectomy in female rats. In the present study, we evaluated the effects of SARM MK-4541 in the androgen-dependent Dunning R3327-G prostate carcinoma xenograft mouse model as well as on skeletal muscle mass and function, and AR-regulated behavior in mice. MK-4541 significantly inhibited the growth of R3327-G prostate tumors, exhibited anti-androgen effects on the seminal vesicles, reduced plasma testosterone concentrations in intact males, and inhibited Ki67 expression. MK-4541 treated xenografts appeared similar to xenografts in castrated mice. Importantly, we demonstrate that MK-4541 exhibited anabolic activity in androgen deficient conditions, increasing lean body mass and muscle function in adult castrated mice. Moreover, MK-4541 treatment restored general activity levels in castrated mice. Thus, MK-4541 exhibits an optimum profile as an adjuvant therapy to ADT which may provide potent anti-androgenic activity at the prostate yet protective activity on skeletal muscle and behavior in patients. Copyright © 2016 Elsevier Ltd. All rights reserved.

Prenatal Iron Deficiency, Neonatal Ferritin, and Infant Cognitive Function

PubMed Central

Davidson, Leslie L.; Boivin, Michael J.; Zoumenou, Romeo; Massougbodji, Achille; Cot, Michel; Bodeau-Livinec, Florence

2016-01-01

OBJECTIVE: To investigate the impact of prenatal maternal iron deficiency (ID) on cord blood serum ferritin (CBSF) concentration and infant cognitive and motor development. METHODS: Our prospective cohort study included 636 mother-singleton child pairs from 828 eligible pregnant women who were enrolled during their first antenatal care (ANC) visit in Allada, Benin, into a clinical trial comparing the efficacy of mefloquine and sulfadoxine-pyrimethamine. Venous blood samples of women were assessed for ferritin and hemoglobin concentrations at the first and second ANC visits (occurring at least 1-month apart) and at delivery. Women were prescribed daily iron and folic acid supplements throughout pregnancy. Hematologic examinations were repeated for cord blood at birth. At age 1 year, cognitive and motor functions of children were assessed by using the Mullen Scales of Early Learning. RESULTS: The prevalence of prenatal ID at first and second ANC visits, and at delivery was 30.5%, 34.0%, and 28.4%, respectively. CBSF concentrations were similar between ID and non-ID pregnant women. Neither prenatal ID nor CBSF concentration was associated with poor cognitive or gross motor function of children at age 1 year. CBSF concentrations were lower among mothers who had ID anemia (IDA) at delivery compared with non-IDA pregnant women (adjusted mean difference: –0.2 [95% confidence interval: –0.4 to –0.0]). CONCLUSIONS: In a malaria-endemic region, ID in pregnancy in the context of iron supplementation is neither associated with CBSF concentration nor with infant cognitive and motor development. Prenatal IDA around the time of delivery is associated with lower CBSF concentrations. PMID:27940685

Absolute and functional iron deficiency in professional athletes during training and recovery.

PubMed

Reinke, Simon; Taylor, William R; Duda, Georg N; von Haehling, Stephan; Reinke, Petra; Volk, Hans-Dieter; Anker, Stefan D; Doehner, Wolfram

2012-04-19

Iron deficiency (ID) is one of the most important metabolic dysfunctions. Athletic performance depends on oxygen transport and mitochondrial efficiency, thus on optimal iron balance. We hypothesised that physical extremes result in ID in elite athletes and that the short recovery period may be insufficient to allow a lasting replenishment of iron reserves. Iron metabolism was examined in 20 elite rowing athletes and 10 professional soccer players at the end of a competitive season, after recuperation and during pre-season training. Absolute ID values were defined as ferritin <30 μg/L, functional ID as ferritin 30-99 μg/L or 100-299 μg/L+transferrin saturation <20%. At the end of season, 27% of all athletes had absolute ID and 70% showed functional ID. Absolute iron depletion was not generally restored after recuperation and observed at all time points in 14% of the athletes. Although athletes with initially low ferritin levels showed a slight increase during recuperation (p<0.09), these increases remained within borderline levels. Furthermore, 10% showed borderline haemoglobin levels, suggestive of mild anaemia, as defined by the World Health Organisation. A significant proportion of professional athletes have ID, independent of the training mode. Although recuperation seems to allow a certain recovery of iron storage, particularly in athletes with initially low ferritin levels, this retrieval was insufficient to fully normalise reduced iron levels. Therefore, iron status should be carefully monitored during the various training and competitive periods in elite athletes. An adequate iron supplementation may be needed to maintain balanced iron stores. Copyright © 2010 Elsevier Ireland Ltd. All rights reserved.

Sleep and Daytime Functioning: A Short-Term Longitudinal Study of Three Preschool-Age Comparison Groups

ERIC Educational Resources Information Center

Anders, Thomas; Iosif, Ana-Maria; Schwichtenberg, A. J.; Tang, Karen; Goodlin-Jones, Beth

2012-01-01

This study examined sleep, sleepiness, and daytime performance in 68 children with autism, 57 children with intellectual disability (ID), and 69 typically developing preschool children. Children in the autism and ID groups had poorer daytime performance and behaviors than the typically developing children. Children in the ID group also were…

Parents' Perceptions of the Supports Received for Their Children's Problem Behaviors

ERIC Educational Resources Information Center

Schofield, Dean Alexander

2012-01-01

Individuals with significant intellectual disabilities (ID) are more likely to engage in problem behaviors than are people with milder disabilities or with no disability. It is widely considered that behavior problems serve a communicative function for individuals with severe ID and limited communication skills. Among people with significant ID,…

Anatomy and Histology of the Human and Murine Prostate.

PubMed

Ittmann, Michael

2018-05-01

The human and murine prostate glands have similar functional roles in the generation of seminal fluid to assist in reproduction. There are significant differences in the anatomy and histology of murine and human prostate and knowledge of the normal anatomy and histology of the murine prostate is essential to interpreting changes in genetically engineered mouse models. In this review, the normal anatomy and histology of both human and mouse prostate will be described. Copyright © 2018 Cold Spring Harbor Laboratory Press; all rights reserved.

Investigating the Functional Role of Prostate-Specific Membrane Antigen and its Enzymatic Activity in Prostate Cancer Metastasis

DTIC Science & Technology

2007-02-01

saponin (Calbiochem, San Diego, CA) in PBS. Results, Significance, Obstacles and Alternative Approaches: We have generated several different fluorescent...1 integrin antibody P4C10 (Life technologies ). We will conjugate the fluorescent probes to these functional blocking antibodies for live cell...characterization of the prostate-specific membrane antigen (PSMA) in tissue extracts and body fluids. Int. J. Cancer. 62:552-558. 1995. 9. Wright GL Jr

Dental care among young adults with intellectual disability

PubMed Central

Kancherla, Vijaya; Van Naarden Braun, Kim; Yeargin-Allsopp, Marshalyn

2015-01-01

Dental care among young adults with intellectual disability (ID) is poorly documented and largely unmet. By using population-based data from the Metropolitan Atlanta Developmental Disabilities Follow-Up Study, we assessed factors associated with at least one or two dental visits per year among young adults with and without ID. Significantly fewer young adults with ID (45%) visited a dentist at least once per year, compared with those without ID (58%). ID severity and the presence of co-occurring developmental disabilities predicted dental care use. Sociodemographics, daily functioning, societal participation, dental services, and dental health factors were examined as predictors of dental care frequency. Our findings can help focus efforts toward improving the frequency of dental care visits among young adults with ID. PMID:23501584

Health perceptions in patients who undergo screening and workup for prostate cancer.

PubMed

Katz, David A; Jarrard, David F; McHorney, Colleen A; Hillis, Stephen L; Wiebe, Donald A; Fryback, Dennis G

2007-02-01

False-positive screening tests may induce persistent psychological distress. This study was designed to determine whether a positive screening test with negative biopsy findings for prostate cancer is associated with worsened mental health during short-term follow-up. We conducted a cross-sectional telephone survey of two groups of men approximately 2 months after testing: group 1, 109 men with an abnormal prostate-specific antigen level or digital rectal examination findings but with negative biopsy findings for prostate cancer; and group 2, 101 age-matched primary care patients with PSA screening levels in the reference range (less than 4 ng/mL). Primary outcomes included state anxiety and prostate cancer-related worry. Secondary outcomes included Medical Outcomes Study Short Form 36-item Health Survey subscales and sexual function items. Multivariate regression techniques were used to adjust for differences in baseline covariates. Group 1 patients were more worried than group 2 patients about getting prostate cancer (mean worry 3.9 versus 4.5, P = 0.0001, using a 5-point scale, with 1 indicating extreme worry and 5 no worry). Group 1 patients also perceived their risk of prostate cancer to be significantly greater than that of controls (P = 0.001). No significant differences were found across state anxiety or Medical Outcomes Study Short Form 36-item Health Survey subscales. Sexual bother was greater for group 1 patients, with 19% reporting that sexual function was a moderate to big problem compared with 10% of group 2 patients (P = 0.0001). Men with abnormal prostate cancer screening tests report increased cancer-related worry and more problems with sexual function, despite having a negative biopsy result. Effective counseling interventions are needed before prostate cancer screening and during follow-up.

Ubiquitin ligase CHIP functions as an oncogene and activates the AKT signaling pathway in prostate cancer.

PubMed

Cheng, Li; Zang, Jin; Dai, Han-Jue; Li, Feng; Guo, Feng

2018-07-01

Carboxyl terminus of Hsc-70-interacting protein (CHIP) is an E3 ubiquitin ligase that induces the ubiquitination and degradation of numerous tumor-associated proteins and serves as a suppressor or promoter in tumor progression. To date, the molecular mechanism of CHIP in prostate cancer remains unknown. Therefore, the present study investigated the biological function of CHIP in prostate cancer cells and obtained evidence that CHIP expression is upregulated in prostate cancer tissues. The CHIP vector was introduced into DU145 cancer cells and the cell biological behaviour was examined through a series of experiments, including cell growth, cell apoptosis and migration and invasion assays. The results indicated that the overexpression of CHIP in DU145 prostatic cancer cells promoted cell proliferation through activation of the protein kinase B (AKT) signaling pathway, which subsequently increased cyclin D1 protein levels and decreased p21 and p27 protein levels. The overexpression of CHIP significantly increased the migration and invasion of the DU145 cells, which is possible due to activation of the AKT signaling pathway and upregulation of vimentin. The expression level of CHIP was observed to be increased in human prostate cancer tissues compared with the adjacent normal tissue. Furthermore, the CHIP expression level exhibited a positively association with the Gleason score of the patents. These findings indicate that CHIP functions as an oncogene in prostate cancer.

Marginal Iodine Deficiency Affects Dendritic Spine Development by Disturbing the Function of Rac1 Signaling Pathway on Cytoskeleton.

PubMed

Min, Hui; Dong, Jing; Wang, Yi; Wang, Yuan; Yu, Ye; Shan, Zhongyan; Xi, Qi; Teng, Weiping; Chen, Jie

2017-01-01

Iodine deficiency (ID)-induced thyroid hormone (TH) insufficient during development leads to impairments of brain function, such as learning and memory. Marginal ID has been defined as subtle insufficiency of TH, characterized as low thyroxine (T 4 ) levels, whether marginal ID potentially had adverse effects on the development of hippocampus and the underlying mechanisms remain unclear. Thus, in the present study, we established Wistar rat models with ID diet during pregnancy and lactation. The effects of marginal ID on long-term potentiation (LTP) were investigated in the hippocampal CA1 region. To study the development of dendritic spines in pyramidal cells, Golgi-Cox staining was conducted on postnatal day (PN) 7, PN14, PN21, and PN28. The activation of Rac1 signaling pathway, which is essential for dendritic spine development by regulating actin cytoskeleton, was also investigated. Our results showed that marginal ID slightly reduced the field-excitatory postsynaptic potential (f-EPSP) slope and the population spike (PS) amplitude. Besides, the density of dendritic spines during the critical period of rat postnatal development was mildly decreased, and we found no significant change of spine morphology in marginal ID group. We also observed decreased activation of the Rac1 signaling pathway in pups subjected to maternal marginal ID. Our study may support the hypothesis that decreased T 4 induced by marginal ID results in slight impairments of LTP and leads to mild damage of dendritic spine development, which may be due to abnormal regulation of Rac1 signaling pathway on cytoskeleton.

A prospective study on association of prostatic calcifications with sexual dysfunction in men with chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS).

PubMed

Zhao, Zhigang; Xuan, Xujun; Zhang, Jingwei; He, Jun; Zeng, Guohua

2014-10-01

Chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) is a common debilitating condition of unclear etiology. Sexual dysfunction is an important component of the clinical phenotype of CP/CPPS. Patients often have prostatic calcifications, but a link to sexual dysfunction is unknown. The aim of this study was to evaluate the association of prostatic calcifications with sexual dysfunction in this condition. A total of 358 males with CP/CPPS were consecutively enrolled, and a prospectively maintained database of these patients was analyzed. Calcifications were diagnosed using ultrasound imaging of the prostate. Symptom severity was measured using the National Institutes of Health Chronic Prostatitis Symptom Index (CPSI). Sexual dysfunction was evaluated using the validated 15-item International Index of Erectile Function (IIEF-15) questionnaire and 5-item Premature Ejaculation Diagnostic Tool scales. The variables were compared between patients with prostatic calcifications and those without using the Student's t-test, Wilcoxon unpaired test, or chi-square test. Logistic regression models were developed to explore a possible association between prostatic calcifications and sexual dysfunction. Measurable calcifications in the prostate were found in 175 (48.9%) of the 358 patients. Patients with calcifications were more likely to have higher white blood cell counts or positive bacteria cultures in their prostatic fluid, longer symptoms duration, and lower scores for the total IIEF-15, IIEF-erectile function, and IIEF-intercourse satisfaction domains (P < 0.001 for each). However, the scores for CPSI, premature ejaculation, and IIEF-orgasmic function, IIEF-sexual desire, and IIEF-overall satisfaction domains were identical between men with and without calcifications (P > 0.05 for each). Furthermore, logistic regression analyses revealed that intraprostatic calcification is significantly associated with self-assessed erectile dysfunction (ED) (odds ratio:3.632, 95% confidence interval: 2.405-5.822, P < 0.001). Our results showed that prostatic calcifications are significantly associated with the presence of ED in CP/CPPS males. © 2014 International Society for Sexual Medicine.

Carbohydrate degrading polypeptide and uses thereof

DOEpatents

Sagt, Cornelis Maria Jacobus; Schooneveld-Bergmans, Margot Elisabeth Francoise; Roubos, Johannes Andries; Los, Alrik Pieter

2015-10-20

The invention relates to a polypeptide having carbohydrate material degrading activity which comprises the amino acid sequence set out in SEQ ID NO: 2 or an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 1 or SEQ ID NO: 4, or a variant polypeptide or variant polynucleotide thereof, wherein the variant polypeptide has at least 96% sequence identity with the sequence set out in SEQ ID NO: 2 or the variant polynucleotide encodes a polypeptide that has at least 96% sequence identity with the sequence set out in SEQ ID NO: 2. The invention features the full length coding sequence of the novel gene as well as the amino acid sequence of the full-length functional protein and functional equivalents of the gene or the amino acid sequence. The invention also relates to methods for using the polypeptide in industrial processes. Also included in the invention are cells transformed with a polynucleotide according to the invention suitable for producing these proteins.

A supervoxel-based segmentation method for prostate MR images.

PubMed

Tian, Zhiqiang; Liu, Lizhi; Zhang, Zhenfeng; Xue, Jianru; Fei, Baowei

2017-02-01

Segmentation of the prostate on MR images has many applications in prostate cancer management. In this work, we propose a supervoxel-based segmentation method for prostate MR images. A supervoxel is a set of pixels that have similar intensities, locations, and textures in a 3D image volume. The prostate segmentation problem is considered as assigning a binary label to each supervoxel, which is either the prostate or background. A supervoxel-based energy function with data and smoothness terms is used to model the label. The data term estimates the likelihood of a supervoxel belonging to the prostate by using a supervoxel-based shape feature. The geometric relationship between two neighboring supervoxels is used to build the smoothness term. The 3D graph cut is used to minimize the energy function to get the labels of the supervoxels, which yields the prostate segmentation. A 3D active contour model is then used to get a smooth surface by using the output of the graph cut as an initialization. The performance of the proposed algorithm was evaluated on 30 in-house MR image data and PROMISE12 dataset. The mean Dice similarity coefficients are 87.2 ± 2.3% and 88.2 ± 2.8% for our 30 in-house MR volumes and the PROMISE12 dataset, respectively. The proposed segmentation method yields a satisfactory result for prostate MR images. The proposed supervoxel-based method can accurately segment prostate MR images and can have a variety of application in prostate cancer diagnosis and therapy. © 2016 American Association of Physicists in Medicine.

Id-1 promotes osteosarcoma cell growth and inhibits cell apoptosis via PI3K/AKT signaling pathway

DOE Office of Scientific and Technical Information (OSTI.GOV)

Hao, Liang; Liao, Qi; Tang, Qiang

2016-02-12

Accumulating evidence reveals that Id-1 is upregulated and functions as a potential tumor promoter in several human cancer types. However, the role of Id-1 in osteosarcoma (OS) is unknown. In present study, we found that Id-1 expression was elevated in OS tissues than adjacent normal bone tissues. More importantly, we demonstrated that overexpression of Id-1 is significantly correlated with tumor progression and poor survival in OS patients. Furthermore, increased expression of Id-1 was observed in OS cell lines and ectopic expression of Id-1 significantly enhanced in vitro cell proliferation and promoted in vivo tumor growth, whereas knockdown of Id-1 suppressed OS cellsmore » growth. Moreover, our experimental data revealed that Id-1 promotes cell proliferation by facilitating cell cycle progression and inhibits cell apoptosis. Mechanistically, the effects of Id-1 in OS cells is at least partly through activation of PI3K/Akt signaling pathway. Therefore, we identified a tumorigenic role of Id-1 in OS and suggested a potential therapeutic target for OS patients. - Highlights: • Id-1 expression is positively correlated in OS patients with poor prognosis. • Overexpression of Id-1 promotes OS cell growth in vitro and in vivo. • Id-1induces cell cycle progression and inhibits cell apoptosis. • PI3K/Akt signaling pathway contributed to the oncogenic effects of Id-1 in OS cells.« less

Sexual function and bother after radical prostatectomy or radiation for prostate cancer: multivariate quality-of-life analysis from CaPSURE. Cancer of the Prostate Strategic Urologic Research Endeavor.

PubMed

Litwin, M S; Flanders, S C; Pasta, D J; Stoddard, M L; Lubeck, D P; Henning, J M

1999-09-01

To measure the effect of treatment choice (pelvic irradiation [XRT] versus radical prostatectomy [RP] with or without nerve sparing) on sexual function and sexual bother during the first 2 years after treatment. We studied sexual function and sexual bother in 438 men recently diagnosed with early-stage prostate cancer and treated with XRT or RP with or without nerve sparing. Outcomes were assessed with the University of California, Los Angeles Prostate Cancer Index, a validated health-related quality-of-life instrument that includes these two domains. To minimize the influence of other factors, we adjusted for age, comorbidity, general health, and previous treatment for erectile dysfunction. All subjects were drawn from CaPSURE, a national, longitudinal data base. Sexual function improved over time during the first year in all treatment groups; however, during the second year, sexual function began to decline in the XRT group. Older patients who received XRT showed substantial declines in sexual function throughout the 2 years, and older patients who underwent RP experienced a return of very low baseline sexual function. Sexual function was improved by the use of nerve-sparing procedures or erectile aids. Alterations in sexual bother were ameliorated by many factors, including age, general health perceptions, and sexual function. Patients undergoing XRT or RP with or without nerve sparing all showed comparable rates of improvement in sexual function during the first year after treatment for early-stage prostate cancer. However, in the second year after treatment, patients treated with XRT began to show declining sexual function; patients treated with RP did not.

Prostate-Specific G-Protein Coupled Receptor, an Emerging Biomarker Regulating Inflammation and Prostate Cancer Invasion.

PubMed

Rodriguez, M; Siwko, S; Liu, M

2016-01-01

Prostate cancer is highly prevalent among men in developed countries, but a significant proportion of detected cancers remain indolent, never progressing into aggressive carcinomas. This highlights the need to develop refined biomarkers that can distinguish between indolent and potentially dangerous cases. The prostate-specific G-protein coupled receptor (PSGR, or OR51E2) is an olfactory receptor family member with highly specific expression in human prostate epithelium that is highly overexpressed in PIN and prostate cancer. PSGR has been functionally implicated in prostate cancer cell invasiveness, suggesting a potential role in the transition to metastatic PCa. Recently, transgenic mice overexpressing PSGR in the prostate were reported to develop an acute inflammatory response followed by emergence of low grade PIN, whereas mice with compound PSGR overexpression and loss of PTEN exhibited accelerated formation of invasive prostate adenocarcinoma. This article will review recent PSGR findings with a focus on its role as a potential prostate cancer biomarker and regulator of prostate cancer invasion and inflammation.

Sca-1 Identifies a Distinct Androgen-Independent Murine Prostatic Luminal Cell Lineage with Bipotent Potential

PubMed Central

Kwon, Oh-Joon; Zhang, Li; Xin, Li

2016-01-01

Recent lineage tracing studies support the existence of prostate luminal progenitors that possess extensive regenerative capacity, but their identity remains unknown. We show that Sca-1 (Stem Cell Antigen-1) identifies a small population of murine prostate luminal cells that reside in the proximal prostatic ducts adjacent to the urethra. Sca-1+ luminal cells do not express Nkx3.1. They do not carry the secretory function, although they express the androgen receptor. These cells are enriched in the prostates of castrated mice. In the in vitro prostate organoid assay, a small fraction of the Sca-1+ luminal cells are capable of generating budding organoids that are morphologically distinct from those derived from other cell lineages. Histologically, this type of organoid is composed of multiple inner layers of luminal cells surrounded by multiple outer layers of basal cells. When passaged, these organoids retain their morphological and histological features. Finally, the Sca-1+ luminal cells are capable of forming small prostate glands containing both basal and luminal cells in an in vivo prostate regeneration assay. Collectively, our study establishes the androgen-independent and bipotent organoid-forming Sca-1+ luminal cells as a functionally distinct cellular entity. These cells may represent a putative luminal progenitor population and serve as a cellular origin for castration resistant prostate cancer. PMID:26418304

Impact of Radiotherapy When Added to Androgen-Deprivation Therapy for Locally Advanced Prostate Cancer: Long-Term Quality-of-Life Outcomes From the NCIC CTG PR3/MRC PR07 Randomized Trial

PubMed Central

Brundage, Michael; Sydes, Matthew R.; Parulekar, Wendy R.; Warde, Padraig; Cowan, Richard; Bezjak, Andrea; Kirkbride, Peter; Parliament, Matthew; Moynihan, Clare; Bahary, Jean-Paul; Parmar, Mahesh K.B.; Sanders, Karen; Chen, Bingshu E.; Mason, Malcolm D.

2015-01-01

Purpose The NCIC CTG PR3/MRC PR07 randomized phase III trial compared androgen-deprivation therapy (ADT) alone versus ADT with radiotherapy (RT) for patients with locally advanced prostate cancer. This article reports the health-related quality-of-life (HRQOL) outcomes of this trial. Patients and Methods A total of 1,205 patients were randomly allocated to either ADT alone or ADT with RT. HRQOL was assessed at baseline and every 6 months thereafter using the European Organisation for Research and Treatment of Cancer Core Questionnaire and a prostate cancer–specific checklist or the Functional Assessment of Cancer Therapy–Prostate questionnaire. Mean changes from baseline scores for five function domains and nine symptom domains were analyzed as those most relevant to ADT and RT. The proportions of patients with improved, stable, or worsened HRQOL scores according to instrument-specific minimal important differences were calculated. Results Baseline questionnaires were completed by 1,028 patients (88%). At 6 months, RT had a statistically significant impact on mean score for bowel symptoms (P = .02), diarrhea (P < .001), urinary function (P = .003), and erectile dysfunction (P = .008); by 3 years, however, there were no significant between-group differences in any domain. Generalized linear mixed modeling revealed no significant between-arm differences in any of the function scales but showed significant deterioration in both arms over time for Functional Assessment of Cancer Therapy–Prostate total score, treatment outcome index, and physical and functional well-being. Conclusion The addition of RT to ADT for patients with locally advanced prostate cancer significantly improved overall survival and had only modest and transient negative impact on relevant domains of HRQOL. PMID:26014295

R&D100: IC ID

ScienceCinema

Hamlet, Jason; Pierson, Lyndon; Bauer, Todd

2018-06-25

Supply chain security to detect, deter, and prevent the counterfeiting of networked and stand-alone integrated circuits (ICs) is critical to cyber security. Sandia National Laboratory researchers have developed IC ID to leverage Physically Unclonable Functions (PUFs) and strong cryptographic authentication to create a unique fingerprint for each integrated circuit. IC ID assures the authenticity of ICs to prevent tampering or malicious substitution.

SU-E-J-164: Estimation of DVH Variation for PTV Due to Interfraction Organ Motion in Prostate VMAT Using Gaussian Error Function

DOE Office of Scientific and Technical Information (OSTI.GOV)

Lewis, C; Jiang, R; Chow, J

2015-06-15

Purpose: We developed a method to predict the change of DVH for PTV due to interfraction organ motion in prostate VMAT without repeating the CT scan and treatment planning. The method is based on a pre-calculated patient database with DVH curves of PTV modelled by the Gaussian error function (GEF). Methods: For a group of 30 patients with different prostate sizes, their VMAT plans were recalculated by shifting their PTVs 1 cm with 10 increments in the anterior-posterior, left-right and superior-inferior directions. The DVH curve of PTV in each replan was then fitted by the GEF to determine parameters describingmore » the shape of curve. Information of parameters, varying with the DVH change due to prostate motion for different prostate sizes, was analyzed and stored in a database of a program written by MATLAB. Results: To predict a new DVH for PTV due to prostate interfraction motion, prostate size and shift distance with direction were input to the program. Parameters modelling the DVH for PTV were determined based on the pre-calculated patient dataset. From the new parameters, DVH curves of PTVs with and without considering the prostate motion were plotted for comparison. The program was verified with different prostate cases involving interfraction prostate shifts and replans. Conclusion: Variation of DVH for PTV in prostate VMAT can be predicted using a pre-calculated patient database with DVH curve fitting. The computing time is fast because CT rescan and replan are not required. This quick DVH estimation can help radiation staff to determine if the changed PTV coverage due to prostate shift is tolerable in the treatment. However, it should be noted that the program can only consider prostate interfraction motions along three axes, and is restricted to prostate VMAT plan using the same plan script in the treatment planning system.« less

Micrornas in prostate cancer: an overview

PubMed Central

Rossetti, Sabrina; Cavaliere, Carla; D'Aniello, Carmine; Di Franco, Rossella; Romano, Francesco Jacopo; Montanari, Micaela; La Mantia, Elvira; Piscitelli, Raffaele; Nocerino, Flavia; Cappuccio, Francesca; Grimaldi, Giovanni; Izzo, Alessandro; Castaldo, Luigi; Pepe, Maria Filomena; Malzone, Maria Gabriella; Iovane, Gelsomina; Ametrano, Gianluca; Stiuso, Paola; Quagliuolo, Lucio; Barberio, Daniela; Perdonà, Sisto; Muto, Paolo; Montella, Maurizio; Maiolino, Piera; Veneziani, Bianca Maria; Botti, Gerardo; Caraglia, Michele; Facchini, Gaetano

2017-01-01

Prostate cancer is the second highest cause of cancer mortality after lung tumours. In USA it affects about 2.8 million men and the incidence increases with age in many countries. Therefore, early diagnosis is a very important step for patient clinical evaluation and for a selective and efficient therapy. The study of miRNAs' functions and molecular mechanisms has brought new knowledge in biological processes of cancer. In prostate cancer there is a deregulation of several miRNAs that may function as tumour suppressors or oncogenes. The aim of this review is to analyze the progress made to our understanding of the role of miRNA dysregulation in prostate cancer tumourigenesis. PMID:28445135

Timing, duration, and severity of iron deficiency in early development and motor outcomes at 9 months

PubMed Central

Santos, Denise CC; Angulo-Barroso, Rosa M; Li, Ming; Bian, Yang; Sturza, Julie; Richards, Blair; Lozoff, Betsy

2017-01-01

BACKGROUND/OBJECTIVES Poorer motor development is reported in infants with iron deficiency (ID). The role of timing, duration and severity is unclear. We assessed relations between ID timing, duration, and severity and gross motor scores, neurological integrity, and motor behavior quality at 9 months. METHODS Iron status was determined at birth and 9 months in otherwise healthy term Chinese infants. The 9-month motor evaluation included the Peabody Developmental Motor Scale (PDMS-2), Infant Neurological International Battery (INFANIB), and motor quality factor. Motor outcomes were analyzed by ID timing (fetal-neonatal, infancy), duration, and severity. For severity, we also considered maternal iron status. RESULTS Data were available for 1194 infants. Iron status was classified as fetal-neonatal and infancy ID (n=253), fetal-neonatal ID (n=256), infancy ID (n=288), and not ID (n=397). Compared with not ID, infants with fetal-neonatal or infancy ID had lower locomotion scores (effect size ds=0.19, 0.18) and those with ID in both periods (longer duration) had lower locomotion and overall PDMS-2 gross motor scores (ds=0.20, 0.18); ID groups did not differ. More severe ID in late pregnancy was associated with lower INFANIB Vestibular function (p=0.01), and total score (p=0.03). More severe ID in infancy was associated with lower scores for locomotion (p=0.03), overall gross motor (p=0.05). CONCLUSIONS Fetal-neonatal and/or infancy ID was associated with lower overall gross motor development and locomotion test scores at 9 months. Associations with ID severity varied by ID timing: more severe ID in late pregnancy, poorer neurological integrity; more severe ID in infancy, poorer gross motor development. PMID:29235557

On the relationship between motor performance and executive functioning in children with intellectual disabilities.

PubMed

Hartman, E; Houwen, S; Scherder, E; Visscher, C

2010-05-01

It has been suggested that children with intellectual disabilities (ID) have motor problems and higher-order cognitive deficits. The aim of this study was to examine the motor skills and executive functions in school-age children with borderline and mild ID. The second aim was to investigate the relationship between the two performance domains. Sixty-one children aged between 7 and 12 years diagnosed with borderline ID (33 boys and 28 girls; 71 < IQ < 79) and 36 age peers with mild ID (24 boys and 12 girls; 54 < IQ < 70) were assessed. Their abilities were compared with those of 97 age- and gender-matched typically developing children. Qualitative motor skills, i.e. locomotor ability and object control, were evaluated with the Test of Gross Motor Development (TGMD-2). Executive functioning (EF), in terms of planning ability, strategic decision-making and problem solving, was gauged with the Tower of London (TOL) task. Compared with the reference group, the full ID cohort scored significantly lower on all assessments. For the locomotor skills, the children with mild ID scored significantly lower than the children with borderline ID, but for the object control skills and the TOL score, no significant differences between the two groups were found. Motor performance and EF correlated positively. At the most complex level, the TOL showed decision time to be a mediator between motor performance and EF: the children with the lower motor scores had significantly shorter decision times and lower EF scores. Analogously, the children with the lower object control scores had longer execution times and lower EF scores. The current results support the notion that besides being impaired in qualitative motor skills intellectually challenged children are also impaired in higher-order executive functions. The deficits in the two domains are interrelated, so early interventions boosting their motor and cognitive development are recommended.

Single Nucleotide Polymorphisms of Stemness Genes Predicted to Regulate RNA Splicing, microRNA and Oncogenic Signaling are Associated with Prostate Cancer Survival.

PubMed

Freedman, Jennifer A; Wang, Yanru; Li, Xuechan; Liu, Hongliang; Moorman, Patricia G; George, Daniel J; Lee, Norman H; Hyslop, Terry; Wei, Qingyi; Patierno, Steven R

2018-05-03

Prostate cancer is a clinically and molecularly heterogeneous disease, with variation in outcomes only partially predicted by grade and stage. Additional tools to distinguish indolent from aggressive disease are needed. Phenotypic characteristics of stemness correlate with poor cancer prognosis. Given this correlation, we identified single nucleotide polymorphisms (SNPs) of stemness-related genes and examined their associations with prostate cancer survival. SNPs within stemness-related genes were analyzed for association with overall survival of prostate cancer in the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial. Significant SNPs predicted to be functional were selected for linkage disequilibrium analysis and combined and stratified analyses. Identified SNPs were evaluated for association with gene expression. SNPs of CD44 (rs9666607), ABCC1 (rs35605 and rs212091) and GDF15 (rs1058587) were associated with prostate cancer survival and predicted to be functional. A role for rs9666607 of CD44 and rs35605 of ABCC1 in RNA splicing regulation, rs212091 of ABCC1 in miRNA binding site activity and rs1058587 of GDF15 in causing an amino acid change was predicted. These SNPs represent potential novel prognostic markers for overall survival of prostate cancer and support a contribution of the stemness pathway to prostate cancer patient outcome.

A comprehensive review of the role of zinc in normal prostate function and metabolism; and its implications in prostate cancer☆

PubMed Central

Costello, Leslie C.; Franklin, Renty B.

2016-01-01

The human prostate gland contains extremely high zinc levels; which is due to the specialized zinc-accumulating acinar epithelial of the peripheral zone. These cells evolved for their unique capability to produce and secrete extremely levels of citrate, which is achieved by the high cellular zinc level effects on the cell metabolism. This review highlights the specific functional and metabolic alterations that result from the accumulation of the high zinc levels, especially its effects on mitochondrial citrate metabolism and terminal oxidation. The implications of zinc in the development and progression of prostate cancer are described, which is the most consistent hallmark characteristic of prostate cancer. The requirement for decreased zinc resulting from down regulation of ZIP1 to prevent zinc cytotoxicity in the malignant cells is described as an essential early event in prostate oncogenesis. This provides the basis for the concept that an agent (such as the zinc ionophore, clioquinol) that facilitates zinc uptake and accumulation in ZIP1-deficient prostate tumors cells will markedly inhibit tumor growth. In the current absence of an efficacious chemotherapy for advanced prostate cancer, and for prevention of early development of malignancy; a zinc treatment regimen is a plausible approach that should be pursued. PMID:27132038

OCT image segmentation of the prostate nerves

NASA Astrophysics Data System (ADS)

Chitchian, Shahab; Weldon, Thomas P.; Fried, Nathaniel M.

2009-08-01

The cavernous nerves course along the surface of the prostate and are responsible for erectile function. Improvements in identification, imaging, and visualization of the cavernous nerves during prostate cancer surgery may improve nerve preservation and postoperative sexual potency. In this study, 2-D OCT images of the rat prostate were segmented to differentiate the cavernous nerves from the prostate gland. Three image features were employed: Gabor filter, Daubechies wavelet, and Laws filter. The features were segmented using a nearestneighbor classifier. N-ary morphological post-processing was used to remove small voids. The cavernous nerves were differentiated from the prostate gland with a segmentation error rate of only 0.058 +/- 0.019.

Wavelet denoising during optical coherence tomography of the prostate nerves using the complex wavelet transform.

PubMed

Chitchian, Shahab; Fiddy, Michael; Fried, Nathaniel M

2008-01-01

Preservation of the cavernous nerves during prostate cancer surgery is critical in preserving sexual function after surgery. Optical coherence tomography (OCT) of the prostate nerves has recently been studied for potential use in nerve-sparing prostate surgery. In this study, the discrete wavelet transform and complex dual-tree wavelet transform are implemented for wavelet shrinkage denoising in OCT images of the rat prostate. Applying the complex dual-tree wavelet transform provides improved results for speckle noise reduction in the OCT prostate image. Image quality metrics of the cavernous nerves and signal-to-noise ratio (SNR) were improved significantly using this complex wavelet denoising technique.

Mutations in DDX3X Are a Common Cause of Unexplained Intellectual Disability with Gender-Specific Effects on Wnt Signaling.

PubMed

Snijders Blok, Lot; Madsen, Erik; Juusola, Jane; Gilissen, Christian; Baralle, Diana; Reijnders, Margot R F; Venselaar, Hanka; Helsmoortel, Céline; Cho, Megan T; Hoischen, Alexander; Vissers, Lisenka E L M; Koemans, Tom S; Wissink-Lindhout, Willemijn; Eichler, Evan E; Romano, Corrado; Van Esch, Hilde; Stumpel, Connie; Vreeburg, Maaike; Smeets, Eric; Oberndorff, Karin; van Bon, Bregje W M; Shaw, Marie; Gecz, Jozef; Haan, Eric; Bienek, Melanie; Jensen, Corinna; Loeys, Bart L; Van Dijck, Anke; Innes, A Micheil; Racher, Hilary; Vermeer, Sascha; Di Donato, Nataliya; Rump, Andreas; Tatton-Brown, Katrina; Parker, Michael J; Henderson, Alex; Lynch, Sally A; Fryer, Alan; Ross, Alison; Vasudevan, Pradeep; Kini, Usha; Newbury-Ecob, Ruth; Chandler, Kate; Male, Alison; Dijkstra, Sybe; Schieving, Jolanda; Giltay, Jacques; van Gassen, Koen L I; Schuurs-Hoeijmakers, Janneke; Tan, Perciliz L; Pediaditakis, Igor; Haas, Stefan A; Retterer, Kyle; Reed, Patrick; Monaghan, Kristin G; Haverfield, Eden; Natowicz, Marvin; Myers, Angela; Kruer, Michael C; Stein, Quinn; Strauss, Kevin A; Brigatti, Karlla W; Keating, Katherine; Burton, Barbara K; Kim, Katherine H; Charrow, Joel; Norman, Jennifer; Foster-Barber, Audrey; Kline, Antonie D; Kimball, Amy; Zackai, Elaine; Harr, Margaret; Fox, Joyce; McLaughlin, Julie; Lindstrom, Kristin; Haude, Katrina M; van Roozendaal, Kees; Brunner, Han; Chung, Wendy K; Kooy, R Frank; Pfundt, Rolph; Kalscheuer, Vera; Mehta, Sarju G; Katsanis, Nicholas; Kleefstra, Tjitske

2015-08-06

Intellectual disability (ID) affects approximately 1%-3% of humans with a gender bias toward males. Previous studies have identified mutations in more than 100 genes on the X chromosome in males with ID, but there is less evidence for de novo mutations on the X chromosome causing ID in females. In this study we present 35 unique deleterious de novo mutations in DDX3X identified by whole exome sequencing in 38 females with ID and various other features including hypotonia, movement disorders, behavior problems, corpus callosum hypoplasia, and epilepsy. Based on our findings, mutations in DDX3X are one of the more common causes of ID, accounting for 1%-3% of unexplained ID in females. Although no de novo DDX3X mutations were identified in males, we present three families with segregating missense mutations in DDX3X, suggestive of an X-linked recessive inheritance pattern. In these families, all males with the DDX3X variant had ID, whereas carrier females were unaffected. To explore the pathogenic mechanisms accounting for the differences in disease transmission and phenotype between affected females and affected males with DDX3X missense variants, we used canonical Wnt defects in zebrafish as a surrogate measure of DDX3X function in vivo. We demonstrate a consistent loss-of-function effect of all tested de novo mutations on the Wnt pathway, and we further show a differential effect by gender. The differential activity possibly reflects a dose-dependent effect of DDX3X expression in the context of functional mosaic females versus one-copy males, which reflects the complex biological nature of DDX3X mutations. Copyright © 2015 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.

Rest but busy: Aberrant resting-state functional connectivity of triple network model in insomnia.

PubMed

Dong, Xiaojuan; Qin, Haixia; Wu, Taoyu; Hu, Hua; Liao, Keren; Cheng, Fei; Gao, Dong; Lei, Xu

2018-02-01

One classical hypothesis among many models to explain the etiology and maintenance of insomnia disorder (ID) is hyperarousal. Aberrant functional connectivity among resting-state large-scale brain networks may be the underlying neurological mechanisms of this hypothesis. The aim of current study was to investigate the functional network connectivity (FNC) among large-scale brain networks in patients with insomnia disorder (ID) during resting state. In the present study, the resting-state fMRI was used to evaluate whether patients with ID showed aberrant FNC among dorsal attention network (DAN), frontoparietal control network (FPC), anterior default mode network (aDMN), and posterior default mode network (pDMN) compared with healthy good sleepers (HGSs). The Pearson's correlation analysis was employed to explore whether the abnormal FNC observed in patients with ID was associated with sleep parameters, cognitive and emotional scores, and behavioral performance assessed by questionnaires and tasks. Patients with ID had worse subjective thought control ability measured by Thought Control Ability Questionnaire (TCAQ) and more negative affect than HGSs. Intriguingly, relative to HGSs, patients with ID showed a significant increase in FNC between DAN and FPC, but a significant decrease in FNC between aDMN and pDMN. Exploratory analysis in patients with ID revealed a significantly positive correlation between the DAN-FPC FNC and reaction time (RT) of psychomotor vigilance task (PVT). The current study demonstrated that even during the resting state, the task-activated and task-deactivated large-scale brain networks in insomniacs may still maintain a hyperarousal state, looking quite similar to the pattern in a task condition with external stimuli. Those results support the hyperarousal model of insomnia.

Dissecting the roles of the androgen receptor in prostate cancer from molecular perspectives.

PubMed

Hu, Jieping; Wang, Gongxian; Sun, Ting

2017-05-01

Androgen receptor plays a pivotal role in prostate cancer progression, and androgen deprivation therapy to intercept androgen receptor signal pathway is an indispensable treatment for most advanced prostate cancer patients to delay cancer progression. However, the emerging of castration-resistant prostate cancer reminds us the alteration of androgen receptor, which includes androgen receptor mutation, the formation of androgen receptor variants, and androgen receptor distribution in cancer cells. In this review, we introduce the process of androgen receptor and also its variants' formation, translocation, and function alteration by protein modification or interaction with other pathways. We dissect the roles of androgen receptor in prostate cancer from molecular perspective to provide clues for battling prostate cancer, especially castration-resistant prostate cancer.

Visual-Motor Integration in Children With Mild Intellectual Disability: A Meta-Analysis.

PubMed

Memisevic, Haris; Djordjevic, Mirjana

2018-01-01

Visual-motor integration (VMI) skills, defined as the coordination of fine motor and visual perceptual abilities, are a very good indicator of a child's overall level of functioning. Research has clearly established that children with intellectual disability (ID) have deficits in VMI skills. This article presents a meta-analytic review of 10 research studies involving 652 children with mild ID for which a VMI skills assessment was also available. We measured the standardized mean difference (Hedges' g) between scores on VMI tests of these children with mild ID and either typically developing children's VMI test scores in these studies or normative mean values on VMI tests used by the studies. While mild ID is defined in part by intelligence scores that are two to three standard deviations below those of typically developing children, the standardized mean difference of VMI differences between typically developing children and children with mild ID in this meta-analysis was 1.75 (95% CI [1.11, 2.38]). Thus, the intellectual and adaptive skill deficits of children with mild ID may be greater (perhaps especially due to their abstract and conceptual reasoning deficits) than their relative VMI deficits. We discuss the possible meaning of this relative VMI strength among children with mild ID and suggest that their stronger VMI skills may be a target for intensive academic interventions as a means of attenuating problems in adaptive functioning.

Prostatic arterial embolization: post-procedural follow-up.

PubMed

Fernandes, Lucia; Rio Tinto, Hugo; Pereira, Jose; Duarte, Marisa; Bilhim, Tiago; Martins Pisco, João

2012-12-01

Prostatic arterial embolization (PAE) gained special attention in the past years as a potential minimally invasive technique for benign prostatic hyperplasia. Treatment decisions are based on morbidity and quality-of-life issues and the patient has a central role in decision-making. Medical therapy is a first-line treatment option and surgery is usually performed to improve symptoms and decrease the progression of disease in patients who develop complications or who have inadequately controlled symptoms on medical treatment. The use of validated questionnaires to assess disease severity and sexual function, uroflowmetry studies, prostate-specific antigen and prostate volume measurements are essential when evaluating patients before PAE and to evaluate response to treatment. PAE may be performed safely with minimal morbidity and without associated mortality. The minimally invasive nature of the technique inducing a significant improvement in symptom severity associated with prostate volume reduction and a slight improvement in the sexual function are major advantages. However, as with other surgical therapies for benign prostatic hyperplasia, up to 15% of patients fail to show improvement significantly after PAE, and there is a modest improvement of the peak urinary flow. Copyright © 2012 Elsevier Inc. All rights reserved.

The role of sialomucin CD164 (MGC-24v or endolyn) in prostate cancer metastasis

PubMed Central

Havens, AM; Jung, Y; Sun, YX; Wang, J; Shah, RB; Bühring, HJ; Pienta, KJ; Taichman, RS

2006-01-01

Background The chemokine stromal derived factor-1 (SDF-1 or CXCL12) and its receptor CXCR4 have been demonstrated to be crucial for the homing of stem cells and prostate cancers to the marrow. While screening prostate cancers for CXCL12-responsive adhesion molecules, we identified CD164 (MGC-24) as a potential regulator of homing. CD164 is known to function as a receptor that regulates stem cell localization to the bone marrow. Results Using prostate cancer cell lines, it was demonstrated that CXCL12 induced both the expression of CD164 mRNA and protein. Functional studies demonstrated that blocking CD164 on prostate cancer cell lines reduced the ability of these cells to adhere to human bone marrow endothelial cells, and invade into extracellular matrices. Human tissue microarrays stained for CD164 demonstrated a positive correlation with prostate-specific antigen levels, while its expression was negatively correlated with the expression of androgen receptor. Conclusion Our findings suggest that CD164 may participate in the localization of prostate cancer cells to the marrow and is further evidence that tumor metastasis and hematopoietic stem cell trafficking may involve similar processes. PMID:16859559

TUSC3 Loss Alters the ER Stress Response and Accelerates Prostate Cancer Growth in vivo

NASA Astrophysics Data System (ADS)

Horak, Peter; Tomasich, Erwin; Vaňhara, Petr; Kratochvílová, Kateřina; Anees, Mariam; Marhold, Maximilian; Lemberger, Christof E.; Gerschpacher, Marion; Horvat, Reinhard; Sibilia, Maria; Pils, Dietmar; Krainer, Michael

2014-01-01

Prostate cancer is the most prevalent cancer in males in developed countries. Tumor suppressor candidate 3 (TUSC3) has been identified as a putative tumor suppressor gene in prostate cancer, though its function has not been characterized. TUSC3 shares homologies with the yeast oligosaccharyltransferase (OST) complex subunit Ost3p, suggesting a role in protein glycosylation. We provide evidence that TUSC3 is part of the OST complex and affects N-linked glycosylation in mammalian cells. Loss of TUSC3 expression in DU145 and PC3 prostate cancer cell lines leads to increased proliferation, migration and invasion as well as accelerated xenograft growth in a PTEN negative background. TUSC3 downregulation also affects endoplasmic reticulum (ER) structure and stress response, which results in increased Akt signaling. Together, our findings provide first mechanistic insight in TUSC3 function in prostate carcinogenesis in general and N-glycosylation in particular.

Epigenetics in Prostate Cancer

PubMed Central

Albany, Costantine; Alva, Ajjai S.; Aparicio, Ana M.; Singal, Rakesh; Yellapragada, Sarvari; Sonpavde, Guru; Hahn, Noah M.

2011-01-01

Prostate cancer (PC) is the most commonly diagnosed nonskin malignancy and the second most common cause of cancer death among men in the United States. Epigenetics is the study of heritable changes in gene expression caused by mechanisms other than changes in the underlying DNA sequences. Two common epigenetic mechanisms, DNA methylation and histone modification, have demonstrated critical roles in prostate cancer growth and metastasis. DNA hypermethylation of cytosine-guanine (CpG) rich sequence islands within gene promoter regions is widespread during neoplastic transformation of prostate cells, suggesting that treatment-induced restoration of a “normal” epigenome could be clinically beneficial. Histone modification leads to altered tumor gene function by changing chromosome structure and the level of gene transcription. The reversibility of epigenetic aberrations and restoration of tumor suppression gene function have made them attractive targets for prostate cancer treatment with modulators that demethylate DNA and inhibit histone deacetylases. PMID:22191037

Epigenetics in prostate cancer.

PubMed

Albany, Costantine; Alva, Ajjai S; Aparicio, Ana M; Singal, Rakesh; Yellapragada, Sarvari; Sonpavde, Guru; Hahn, Noah M

2011-01-01

Prostate cancer (PC) is the most commonly diagnosed nonskin malignancy and the second most common cause of cancer death among men in the United States. Epigenetics is the study of heritable changes in gene expression caused by mechanisms other than changes in the underlying DNA sequences. Two common epigenetic mechanisms, DNA methylation and histone modification, have demonstrated critical roles in prostate cancer growth and metastasis. DNA hypermethylation of cytosine-guanine (CpG) rich sequence islands within gene promoter regions is widespread during neoplastic transformation of prostate cells, suggesting that treatment-induced restoration of a "normal" epigenome could be clinically beneficial. Histone modification leads to altered tumor gene function by changing chromosome structure and the level of gene transcription. The reversibility of epigenetic aberrations and restoration of tumor suppression gene function have made them attractive targets for prostate cancer treatment with modulators that demethylate DNA and inhibit histone deacetylases.

Correlation of thermocouple data with voiding function after prostate cryoablation.

PubMed

Levy, David A

2010-02-01

To identify possible correlations of thermocouple recorded data with altered postoperative voiding function after prostate cryosurgery. A retrospective analysis of the records of 58 patients treated with prostate cryoablation from October 2005 through April 2009 was conducted. Multivariate analysis of patient age, presenting prostate-specific antigen level, Gleason score, clinical T stage, prostate volume, maximum low temperature thermocouple recordings, history of radiation and or hormonal therapy, were studied as possible correlative factors for altered postoperative voiding function. Of 58 patients, 22 (37.9%) manifested postcryoablation urgency and frequency (n = 13) requiring medical therapy or retention (n = 9). On multivariate analysis, age (P = .037) and an external sphincter temperature < or = 23 degrees C (P = .012) were associated with voiding frequency, urgency, or retention (odds ratio = 6.26, 95% CI: 1.62-24.16), whereas anterior rectal wall temperature (Denon) was weakly associated (P = .079). Thermocouple data provide an objective means of assessing cryosurgical outcomes. This is the first report of a correlation of such data to post-treatment voiding function. A total of 37.9% of patients experienced urgency and/or frequency or urinary retention after cryoablation of the prostate for localized disease. Older age and external sphincter temperature < or = 23 degrees C were statistically significant predictors of these events. The data suggest that limiting the degree of freezing at the external sphincter may decrease procedure related morbidity. Further study is warranted to better delineate temperature-related data on treatment outcomes. 2010 Elsevier Inc. All rights reserved.

Open radical prostatectomy after transurethral resection: perioperative, functional, oncologic outcomes.

PubMed

Fragkoulis, Charalampos; Pappas, Athanasios; Theocharis, Georgios; Papadopoulos, Georgios; Stathouros, Georgios; Ntoumas, Konstantinos

2018-04-01

To demonstrate any differences in the perioperative, functional and oncologic outcomes after radical retropubic prostatectomy (RRP) among those patients having previously performed transurethral resection of prostate (TURP) and those not. A total of 35 patients were diagnosed with prostate cancer (T1a and T1b) after TURP, underwent RRP and completed a 1 year follow up (group A). They were matched with a cohort of another 35 men (group B) in terms of age, body mass index (BMI), prostatic specific antigen (PSA), Gleason score, prostate volume (before surgery), pathological stage and neurovascular bundle-sparing technique. That was a retrospective study completed between September 2011 and March 2014. Not a significant difference was demonstrated among the two groups of patients concerning the functional and oncologic results. On the other hand, previous prostate surgery made the operation procedure more demanding. Besides, operative time and blood loss (though not translated in transfusion rates) were higher among patients in group A. Besides, catheter removal in group A patients was performed later than their counterparts of group B. RRP after TURP is a relatively safe procedure and in the hands of experienced surgeons, a previously performed TURP, does not seem to compromise oncologic outcomes of the operation. Continence is preserved, though erectile function seems to be compromised compared with patients undergoing RRP without prior TURP. Moreover, defining the prostate and bladder neck margins can be challenging and the surgeon has to be aware of the difficulties that might confront.

Bowel, Urinary, and Sexual Problems Among Long-Term Prostate Cancer Survivors: A Population-Based Study

DOE Office of Scientific and Technical Information (OSTI.GOV)

Mols, Floortje; Comprehensive Cancer Centre South; Korfage, Ida J.

Purpose: To obtain insight into the long-term (5- to 10-year) effects of prostate cancer and treatment on bowel, urinary, and sexual function, we performed a population-based study. Prostate-specific function was compared with an age-matched normative population without prostate cancer. Methods and Materials: Through the population-based Eindhoven Cancer Registry, we selected all men diagnosed with prostate cancer between 1994 and 1998 in the southern Netherlands. In total, 964 patients, alive in November 2004, received questionnaire; 780 (81%) responded. Results: Urinary problems were most common after a prostatectomy; bowel problems were most common after radiotherapy. Compared with an age-matched normative population bothmore » urinary and bowel functioning and bother were significantly worse among survivors. Urinary incontinence was reported by 23-48% of survivors compared with 4% of the normative population. Bowel leakage occurred in 5-14% of patients compared with 2% of norms. Erection problems occurred in 40-74% of patients compared with 18% of norms. Conclusions: These results form an important contribution to the limited information available on prostate-specific problems in the growing group of long-term prostate cancer survivors. Bowel, urinary, and sexual problems occur more often among long-term survivors compared with a reference group and cannot be explained merely by age. Because these problems persist for many years, urologists should provide patients with adequate information before treatment. After treatment, there should be an appropriate focus on these problems.« less

The role of BPH, lower urinary tract symptoms, and PSA levels on erectile function of Brazilian men who undergo prostate cancer screening.

PubMed

Antunes, Alberto A; Srougi, Miguel; Dall'oglio, Marcos F; Vicentini, Fabio; Paranhos, Mario; Freire, Geraldo C

2008-07-01

Lower urinary tract symptoms (LUTS) and erectile dysfunction (ED) are common problems in middle-aged and older men. Recently, epidemiologic studies have shown significant associations between severity of LUTS and male sexual dysfunction. We analyzed the role of prostate enlargement, LUTS, and prostate specific antigen (PSA) levels in the erectile function of Brazilian men who underwent prostate cancer (PCa) screening. We analyzed data from 1,008 consecutive patients enrolled in a PCa screening program. Benign prostatic hyperplasia (BPH) was defined as a prostate weight greater than 30 g as defined by digital rectal examination. For statistical analysis, we used the chi-squared and analysis of variance tests. The odds ratios (OR) for correlation of ED with prostate volume LUTS and PSA were estimated using logistic regression models. The American Urological Association (AUA) symptom score for LUTS and the International Index of Erectile Function. Mean patient age was 61.2 years (45-87) and median PSA value was 1.9 ng/mL. BPH was identified in 48.5% of patients. Mild, moderate, and severe LUTS were found in 52.3%, 30.9%, and 16.8% of cases, respectively. ED was classified as absent, mild, mild to moderate, moderate, and severe in 18.6%, 23.1%, 18.6%, 15.2%, and 24.5%, respectively. While only 5.4% of the patients with no ED presented severe LUTS, this finding was observed in 27.1% of patients with severe ED (P < 0.001). Univariate logistic regression analysis demonstrated that age, prostate volume, AUA symptom score, and PSA levels were significant predictors of ED. However, when controlled for patient age, only LUTS remained as an independent predictor of ED. Controlling for patient age, LUTS are independent risk factors for the development of ED among Brazilian men who undergo PCa screening. Antunes AA, Srougi M, Dall'Oglio MF, Vicentini F, Paranhos M, and Freire GC. The role of BPH, lower urinary tract symptoms, and PSA levels on erectile function of Brazilian men who undergo prostate cancer screening.

Needs among persons with human immunodeficiency virus and intellectual and developmental disabilities in community mental health care: a cross-sectional study.

PubMed

Durbin, A; Sirotich, F; Lunsky, Y; Roesslein, K; Durbin, J

2017-03-01

The experience of having human immunodeficiency virus (HIV) is often associated with co-occurring mental health issues. Community mental health services are an important source of support for persons with HIV living in the community. Persons with intellectual disability (ID) are vulnerable to HIV and may have unique support needs beyond those without ID receiving community care. This study compared support needs of men with HIV in community mental health programmes, with and without ID. The sample was composed of 138 HIV-positive men with and without ID receiving mental health case management from one community organisation in Ontario, Canada, on 31 March 2013. Staff-rated needs across 16 domains grouped into four clusters were measured using the Camberwell Assessment of Need: Basic needs (accommodation, food, public transportation, money and benefits); self-care/functional needs (looking after the home, self-care and daytime activities); health/safety needs (physical health, psychological distress, psychotic symptoms, safety to self and safety to others); and social needs (company, intimate relationships and sexual expression). Adjusted logistic regression models examined the association between ID and each need domain. One-quarter of the sample (n = 34/138, 24.6%) had co-occurring ID. Those with ID were more likely to have needs in the basic cluster [odds ratios: food 4.05 (1.14, 14.44), P:0.031; benefits 2.58 (1.05, 6.32), P:0.038)] and self-care/functional cluster [looking after the home (2.75 (1.17, 6.49), P:0.021); self-care (2.72 (1.18, 6.27), P:0.019)], but were less likely to have need for sexual expression: 0.35 (0.14,0.90), P:0.030) (social cluster). There were no differences in the domains in the health/safety cluster. Despite elevated cognitive needs in the basic and self-care/functional clusters for the ID group, limited other differences suggest that with moderate additional targeting, community mental health programmes for persons with HIV may be appropriate for men with ID. © 2016 MENCAP and International Association of the Scientific Study of Intellectual and Developmental Disabilities and John Wiley & Sons Ltd.

Clinical context and mechanism of functional tricuspid regurgitation in patients with and without pulmonary hypertension.

PubMed

Topilsky, Yan; Khanna, Amber; Le Tourneau, Thierry; Park, Soon; Michelena, Hector; Suri, Rakesh; Mahoney, Douglas W; Enriquez-Sarano, Maurice

2012-05-01

Functional tricuspid regurgitation (FTR) with structurally normal valve is of poorly defined mechanisms. Prevalence and clinical context of idiopathic FTR (Id-FTR) (without overt TR cause) are unknown. To investigate prevalence, clinical context, and mechanisms specific to FTR types, Id-FTR versus pulmonary hypertension-related (PHTN-FTR, systolic pulmonary pressure ≥50 mm Hg), we analyzed 1161 patients with prospectively quantified TR. Id-FTR (prevalence 12%) was associated with aging and atrial fibrillation. For mechanistic purposes, we measured valvular and right ventricular (RV) remodeling in 141 Id-FTR matched to 140 PHTN-FTR and to 99 controls with trivial TR for age, sex, atrial fibrillation, and ejection fraction. PHTN-FTR and Id-FTR were also matched for TR effective-regurgitant-orifice (ERO). Id-FTR valvular alterations (versus controls) were largest annular area (3.53±0.6 versus 2.74±0.4 cm(2), P<0.0001) and lowest valvular/annular coverage ratio (1.06±0.1 versus 1.45±0.2, P<0.0001) but normal valve tenting height. PHTN-FTR had mild annular enlargement but excessive valve tenting height (0.8±0.3 versus 0.35±0.1 cm, P<0.0001). Valvular changes were linked to specific RV changes, largest basal dilatation, and normal length (RV conical deformation) in Id-FTR versus longest RV with elliptical/spherical deformation in PHTN-FTR. With increasing FTR severity (ERO ≥40 mm(2)), changes specific to each FTR type were accentuated, and RV function (index of myocardial performance) was consistently reduced. Id-FTR is frequent, linked to aging and atrial fibrillation, can be severe, and is of unique mechanism. In Id-FTR, excess annular and RV-basal enlargement exhausts valvular/annular coverage reserve, and RV conical deformation does not cause notable valvular tenting. Conversely, PHTN-FTR is determined by valvular tethering with tenting linked to RV elongation and elliptical/spherical deformation. These specific FTR-mechanisms may be important in considering surgical correction in FTR.

Biofortification of riboflavin and folate in idli batter, based on fermented cereal and pulse, by Lactococcus lactis N8 and Saccharomyces boulardii SAA655.

PubMed

Chandrasekar Rajendran, S C; Chamlagain, B; Kariluoto, S; Piironen, V; Saris, P E J

2017-06-01

Lactococcus lactis N8 and Saccharomyces boulardii SAA655 were investigated for their ability to synthesize B-vitamins (riboflavin and folate) and their functional role as microbial starters in idli fermentation. In this study, ultra-high performance liquid chromatography and microbiological assay were used to determine the total riboflavin and folate content respectively. Increased levels of folate were evident in both L. lactis N8 and S. boulardii SAA655 cultivated medium. Enhanced riboflavin levels were found only in S. boulardii SAA655 grown medium, whereas decreased riboflavin level was found in L. lactis N8 cultivated medium. To evaluate the functional role of microbial starter strains, L. lactis N8 and S. boulardii SAA655 were incorporated individually and in combination into idli batter, composed of wet grounded rice and black gram. For the experiments, naturally fermented idli batter was considered as control. The results indicated that natural idli fermentation did not enhance the riboflavin level and depleted folate levels by half. In comparison with control, L. lactis N8 and S. boulardii SAA655 incorporated idli batter (individually and in combination) increased riboflavin and folate levels by 40-90%. Apart from compensating the folate loss caused by natural fermentation, S. boulardii SAA655 fermented idli batter individually and in combination with L. lactis N8 also showed the highest leavening character. Moreover, the microbial starter incorporation did not significantly influence the pH of idli batter. Incorporation of L. lactis N8 and S. boulardii SAA655 can evidently enhance the functional and technological characteristics of idli batter. UN General Assembly declared 2016 the International Year of pulses emphasizing the importance of legumes as staple food. Furthermore, this is the first experimental report of in situ biofortifcation of riboflavin and folate using microbes in pulse based fermented staple food. The current study suggests possible avenues for research towards an economical strategy to reduce B-vitamin deficiency among the consuming population. © 2017 The Society for Applied Microbiology.

Overcoming Drug Resistant Prostate Cancer with APE1/Ref 1 Blockade

DTIC Science & Technology

2016-10-01

prostate cancer specimens. Genetic knockdown of APE1/Ref-1 disrupts prostate cancer cell growth and survival in cell culture. In addition...inhibition of the redox function selectively of Ref-1 results in cell growth inhibition, with this therapy preferentially inhibiting prostate cancer cell... growth above that in non-cancerous cells. Specific blockade of Ref-1 redox activity in tumors is a novel concept in tumor therapy. If we are successful

Irreversible Electroporation for Prostate Cancer as Salvage Treatment Following Prior Radiation and Cryotherapy.

PubMed

Murray, Katie S; Akin, Oguz; Coleman, Jonathan A

2017-01-01

Salvage treatment options after localized primary treatment failure of prostate cancer are limited and associated with risk for serious complications. We report on the management details of a 57-year-old African American man treated with partial-gland ablation using irreversible electroporation following local recurrence after brachytherapy and prior salvage cryoablation. Therapeutic and functional outcomes were assessed by conventional means, including serum prostate-specific antigen values and prostate biopsy results.

SMILE upregulated by metformin inhibits the function of androgen receptor in prostate cancer cells.

PubMed

Lee, Seung-Yon; Song, Chin-Hee; Xie, Yuan-Bin; Jung, Chaeyong; Choi, Hueng-Sik; Lee, Keesook

2014-11-28

Metformin, a diabetes drug, has been reported to inhibit the growth of prostate cancer cells. In this study, we investigated the effect and action mechanism of metformin on the function of androgen receptor (AR), a key molecule in the proliferation of prostate cancer cells. Metformin was found to reduce androgen-dependent cell growth and the expression of AR target genes by inhibiting AR function in prostate cancer cells such as LNCaP and C4-2 cells. Interestingly, metformin upregulated the protein level of small heterodimer partner-interacting leucine zipper (SMILE), a coregulator of nuclear receptors, and knockdown of SMILE expression with shRNA abolished the inhibitory effect of metformin on AR function. Further studies revealed that SMILE protein itself suppressed the transactivation of AR, and its ectopic expression resulted in the repressed expression of endogenous AR target genes, PSA and NKX3.1, in LNCaP cells. In addition, SMILE protein physically interacted with AR and competed with the AR coactivator SRC-1 to modulate AR transactivation. As expected, SMILE repressed androgen-dependent growth of LNCaP and C4-2 cells. Taken together, these results suggest that SMILE, which is induced by metformin, functions as a novel AR corepressor and may mediate the inhibitory effect of metformin on androgen-dependent growth of prostate cancer cells. Copyright © 2014. Published by Elsevier Ireland Ltd.

Initial value problem of space dynamics in universal Stumpff anomaly

NASA Astrophysics Data System (ADS)

Sharaf, M. A.; Dwidar, H. R.

2018-05-01

In this paper, the initial value problem of space dynamics in universal Stumpff anomaly ψ is set up and developed in analytical and computational approach. For the analytical expansions, the linear independence of the functions U_{j} (ψ;σ); {j=0,1,2,3} are proved. The differential and recurrence equations satisfied by them and their relations with the elementary functions are given. The universal Kepler equation and its validations for different conic orbits are established together with the Lagrangian coefficients. Efficient representations of these functions are developed in terms of the continued fractions. For the computational developments we consider the following items: 1. Top-down algorithm for continued fraction evaluation. 2. One-point iteration formulae. 3. Determination of the coefficients of Kepler's equation. 4. Derivatives of Kepler's equation of any integer order. 5. Determination of the initial guess for the solution of the universal Kepler equation. Finally we give summary on the computational design for the initial value problem of space dynamics in universal Stumpff anomaly. This design based on the solution of the universal Kepler's equation by an iterative schemes of quadratic up to any desired order ℓ.

The molecular biology of prostate cancer: current understanding and clinical implications.

PubMed

Gandhi, Jason; Afridi, Adil; Vatsia, Sohrab; Joshi, Gargi; Joshi, Gunjan; Kaplan, Steven A; Smith, Noel L; Khan, Sardar Ali

2018-04-01

With continuous progress over the past few decades in understanding diagnosis, treatment, and genetics, much has been learned about the prostate cancer-diagnosed genome. A comprehensive MEDLINE® and Google scholar literature search was conducted using keyword variations relating to the genetics of prostate cancer such as chromosomal alterations, androgen receptor, castration-resistant, inheritance, polymorphisms, oncogenes, metastasis, biomarkers, and immunotherapy. Traditionally, androgen receptors (AR) have been the focus of research. Recently, identification of recurrent chromosomal alterations that lead to either multiplication of regions (gain-of-function) or deletion of regions (loss-of-function) has opened the door to greater genetic accessibility. These chromosomal aberrations lead to variation in copy number and gene expression. Some of these chromosomal alterations are inherited, while others undergo somatic mutations during disease progression. Inherited gene mutations that make one susceptible to prostate cancer have been identified with familial-linked studies. Somatic genes that progress tumorigenesis have also been identified. Research on the molecular biology of prostate cancer has characterized these genes into tumor suppressor genes or oncogenes. Additionally, genome-wide assay studies have identified many high-risk single-nucleotide polymorphisms recurrent throughout the prostate cancer-diagnosed genome. Castration-resistant prostate cancer is the most aggressive form of prostate cancer, and its research has elucidated many types of mutations associated with AR itself, including enhanced expression and amplification, point mutations, and alternative splicing. Understanding the molecular biology of prostate cancer has permitted more accurate identification using advanced biomarkers and therapy for aggressive forms using immunotherapy. An age-related disease, prostate cancer commands profound attention. With increasing life expectancy and the continuous pursuit of it, prostate cancer is a powerful obstacle best defeated using targeted therapies specifically designed for the unique molecular profile of the malignancy.

Parental social support, coping strategies, resilience factors, stress, anxiety and depression levels in parents of children with MPS III (Sanfilippo syndrome) or children with intellectual disabilities (ID).

PubMed

Grant, Sheena; Cross, Elaine; Wraith, James Edmond; Jones, Simon; Mahon, Louise; Lomax, Michelle; Bigger, Brian; Hare, Dougal

2013-03-01

Mucopolysaccharidosis type III (MPS III, Sanfilippo syndrome) is a lysosomal storage disorder, caused by a deficiency in one of four enzymes involved in the catabolism of the glycosaminoglycan heparan sulphate. It is a degenerative disorder, with a progressive decline in children's intellectual and physical functioning. There is currently no cure for the disorder. To date there is a paucity of research on how this disorder impacts parents psychological functioning. Specifically, research in the area has failed to employ adequate control groups to assess if the impact of this disorder on parents psychological functioning differs from parenting a child with intellectual disability (ID). The current study examined child behaviour and parental psychological functioning in 23 parents of children with MPS III and 23 parents of children with ID. Parents completed postal questionnaires about their child's behaviour and abilities and their own psychological functioning. Parents of children with MPS III reported fewer behavioural difficulties as their child aged, more severe level of intellectual disability, and similar levels of perceived social support, coping techniques, stress, anxiety and depression levels as parents of children with ID. Both groups of parents scored above the clinical cut off for anxiety and depression. Parents of children with MPS III rated themselves as significantly less future-orientated and goal directed than parents of children with ID. Services should develop support packages for parents of children with MPS III that incorporate an understanding of the unique stressors and current-difficulty approach of this population. Future research should examine gender differences between parental psychological functioning, using mixed qualitative and quantitative approaches, and utilise matched developmental level and typically developing control groups.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Zhang, Long; Shi, Songting; Zhang, Juan

Highlights: Black-Right-Pointing-Pointer Expression of Id3 but not Id1 is induced by Wnt3a stimulation in C2C12 cells. Black-Right-Pointing-Pointer Wnt3a induces Id3 expression via canonical Wnt/{beta}-catenin pathway. Black-Right-Pointing-Pointer Wnt3a-induced Id3 expression does not depend on BMP signaling activation. Black-Right-Pointing-Pointer Induction of Id3 expression is critical determinant in Wnt3a-induced cell proliferation and differentiation. -- Abstract: Canonical Wnt signaling plays important roles in regulating cell proliferation and differentiation. In this study, we report that inhibitor of differentiation (Id)3 is a Wnt-inducible gene in mouse C2C12 myoblasts. Wnt3a induced Id3 expression in a {beta}-catenin-dependent manner. Bone morphogenetic protein (BMP) also potently induced Id3 expression. However,more » Wnt-induced Id3 expression occurred independent of the BMP/Smad pathway. Functional studies showed that Id3 depletion in C2C12 cells impaired Wnt3a-induced cell proliferation and alkaline phosphatase activity, an early marker of osteoblast cells. Id3 depletion elevated myogenin induction during myogenic differentiation and partially impaired Wnt3a suppressed myogenin expression in C2C12 cells. These results suggest that Id3 is an important Wnt/{beta}-catenin induced gene in myoblast cell fate determination.« less

STEAP: A prostate-specific cell-surface antigen highly expressed in human prostate tumors

PubMed Central

Hubert, Rene S.; Vivanco, Igor; Chen, Emily; Rastegar, Shiva; Leong, Kahan; Mitchell, Steve C.; Madraswala, Rashida; Zhou, Yanhong; Kuo, James; Raitano, Arthur B.; Jakobovits, Aya; Saffran, Douglas C.; Afar, Daniel E. H.

1999-01-01

In search of novel genes expressed in metastatic prostate cancer, we subtracted cDNA isolated from benign prostatic hypertrophic tissue from cDNA isolated from a prostate cancer xenograft model that mimics advanced disease. One novel gene that is highly expressed in advanced prostate cancer encodes a 339-amino acid protein with six potential membrane-spanning regions flanked by hydrophilic amino- and carboxyl-terminal domains. This structure suggests a potential function as a channel or transporter protein. This gene, named STEAP for six-transmembrane epithelial antigen of the prostate, is expressed predominantly in human prostate tissue and is up-regulated in multiple cancer cell lines, including prostate, bladder, colon, ovarian, and Ewing sarcoma. Immunohistochemical analysis of clinical specimens demonstrates significant STEAP expression at the cell–cell junctions of the secretory epithelium of prostate and prostate cancer cells. Little to no staining was detected at the plasma membranes of normal, nonprostate human tissues, except for bladder tissue, which expressed low levels of STEAP at the cell membrane. Protein analysis located STEAP at the cell surface of prostate-cancer cell lines. Our results support STEAP as a cell-surface tumor-antigen target for prostate cancer therapy and diagnostic imaging. PMID:10588738

Assessment of energy density usage during 180W lithium triborate laser photoselective vaporization of the prostate for benign prostatic hyperplasia. Is there an optimum amount of kilo-Joules per gram of prostate?

PubMed

Valdivieso, Roger; Meyer, Christian P; Hueber, Pierre-Alain; Meskawi, Malek; Alenizi, Abdullah M; Azizi, Mounsif; Trinh, Quoc-Dien; Misrai, Vincent; Rutman, Matthew; Te, Alexis E; Chughtai, Bilal; Barber, Neil J; Emara, Amr M; Munver, Ravi; Zorn, Kevin C

2016-10-01

To assess the effect of energy density (kJ/mL) applied on adenoma during photoselective vaporization of the prostate (PVP) treatment for benign prostate hyperplasia (BPH) on functional outcomes, prostate-specific antigen (PSA) reduction and complications. After exclusions, a total of 440 patients who underwent GreenLight (tm) laser XPS-180W lithium triborate PVP for the treatment of BPH were retrospectively reviewed. Data were collected from seven different international centres (Canada, USA, UK and France). Patients were stratified into four energy density groups (kJ/mL) according to intra-operative energy delivered and prostate volume as determined by preoperative transrectal ultrasonography (TRUS): group 1: <3 kJ/mL; group 2: 3-5 kJ/mL; group 3: 5-7 kJ/mL; and group 4: ≥7 kJ/mL. Energy density groups were chosen arbitrarily. PSA reduction and functional outcomes (International Prostate Symptom Score, quality of life, post-void residual urine volume, maximum urinary flow rate) were compared at 6, 12 and 24 months. Peri-operative complications and retreatment rates were also compared among the groups. The PSA reduction rates at 24 months after the procedure were 51, 61, 79 and 83% for the energy density groups <3, 3-5, 5-7 and ≥7 kJ/mL, respectively (P ≤ 0.01). This held true after accounting for baseline confounders. Energy density was not associated with higher complication rates, including haematuria, stricture formation, incontinence, refractory urinary retention, urinary tract infection and conversion to transurethral resection of the prostate. Functional outcomes at 2 years of follow-up were equivalent among the groups (P > 0.05 for all) and similar retreatment rates were observed (P = 0.36). Higher energy usage per cc of prostate was associated with a more significant reduction in PSA level (>50%) at 6, 12 and 24 months, suggesting increased vaporization of adenoma tissue; however, this did not translate into differences in functional outcomes at 2-year follow-up. © 2016 The Authors BJU International © 2016 BJU International Published by John Wiley & Sons Ltd.

Health-related quality of life, psychological well-being, and sexual function in patients with benign prostatic hyperplasia after prostatic surgery.

PubMed

Yim, Pierre W C; Wang, Wenru; Jiang, Ying; Zakir, Hussain Abdul Salam; Toh, Poh Choo; Lopez, Violeta; He, Hong-Gu

2015-11-01

Patients with benign prostatic hyperplasia (BPH) may receive prostatic surgery due to severe lower urinary tract symptoms (LUTS). This study aimed to investigate the health-related quality of life (HRQoL), psychological well-being, and sexual function of patients with BPH after prostatic surgery and identify the predictors of HRQoL among this group of patients. This was a cross-sectional, descriptive, correlational study. A convenience sample of 94 participants was recruited from a urology center in a tertiary public hospital in Singapore. The 12-item Short Form Health Survey version 2 (SF-12v2), International Prostate Symptom Score (IPSS), Hospital Anxiety and Depression Scale (HADS), and 5-item International Index of Erectile Function (IIEF-5) were used to measure the study variables. Compared to the general population norms and the findings of similar studies conducted in western countries, this group of patients reported poorer physical health but better mental health as assessed by SF-12v2. Despite the prostatic surgery, over a quarter of the patients experienced moderate LUTS, and 13.8% experienced severe erectile dysfunction. Multiple linear regression analysis identified that LUTS (B=-0.51, p=0.02) and maximum flow rate (B=-0.23, p=0.02) predicted poor physical health, accounting for 45.9% of variance, while HADS-Anxiety (B=-1.07, p<0.01) and LUTS (B=-0.32, p=0.03) predicted poor mental health, accounting for 57.2% of variance. The physical health of BPH patients with prostatic surgery was poor, with many suffering moderate LUTS and sexual dysfunction. Special attention should be given to those patients with severe LUTS who have a low maximum flow rate or have anxiety symptoms. Copyright © 2015 Elsevier Inc. All rights reserved.

Health-Related Quality of Life up to Six Years After {sup 125}I Brachytherapy for Early-Stage Prostate Cancer

DOE Office of Scientific and Technical Information (OSTI.GOV)

Roeloffzen, Ellen M.A., E-mail: E.M.A.Roeloffzen@UMCUtrecht.n; Lips, Irene M.; Gellekom, Marion P.R. van

2010-03-15

Purpose: Health-related quality of life (HRQOL) after prostate brachytherapy has been extensively described in published reports but hardly any long-term data are available. The aim of the present study was to prospectively assess long-term HRQOL 6 years after {sup 125}I prostate brachytherapy. Methods and Materials: A total of 127 patients treated with {sup 125}I brachytherapy for early-stage prostate cancer between December 2000 and June 2003 completed a HRQOL questionnaire at five time-points: before treatment and 1 month, 6 months, 1 year, and 6 years after treatment. The questionnaire included the RAND-36 generic health survey, the cancer-specific European Organization for Researchmore » and Treatment of Cancer core questionnaire (EORTCQLQ-C30), and the tumor-specific EORTC prostate cancer module (EORTC-PR25). A change in a score of >=10 points was considered clinically relevant. Results: Overall, the HRQOL at 6 years after {sup 125}I prostate brachytherapy did not significantly differ from baseline. Although a statistically significant deterioration in HRQOL at 6 years was seen for urinary symptoms, bowel symptoms, pain, physical functioning, and sexual activity (p <.01), most changes were not clinically relevant. A statistically significant improvement at 6 years was seen for mental health, emotional functioning, and insomnia (p <.01). The only clinically relevant changes were seen for emotional functioning and sexual activity. Conclusion: This is the first study presenting prospective HRQOL data up to 6 years after {sup 125}I prostate brachytherapy. HRQOL scores returned to approximately baseline values at 1 year and remained stable up to 6 years after treatment. {sup 125}I prostate brachytherapy did not adversely affect patients' long-term HRQOL.« less

Investigation of parameters affecting treatment time in MRI-guided transurethral ultrasound therapy

NASA Astrophysics Data System (ADS)

N'Djin, W. A.; Burtnyk, M.; Chopra, R.; Bronskill, M. J.

2010-03-01

MRI-guided transurethral ultrasound therapy shows promise for minimally invasive treatment of localized prostate cancer. Real-time MR temperature feedback enables the 3D control of thermal therapy to define an accurate region within the prostate. Previous in-vivo canine studies showed the feasibility of this method using transurethral planar transducers. The aim of this simulation study was to reduce the procedure time, while maintaining treatment accuracy by investigating new combinations of treatment parameters. A numerical model was used to simulate a multi-element heating applicator rotating inside the urethra in 10 human prostates. Acoustic power and rotation rate were varied based on the feedback of the temperature in the prostate. Several parameters were investigated for improving the treatment time. Maximum acoustic power and rotation rate were optimized interdependently as a function of prostate radius and transducer operating frequency, while avoiding temperatures >90° C in the prostate. Other trials were performed on each parameter separately, with the other parameter fixed. The concept of using dual-frequency transducers was studied, using the fundamental frequency or the 3rd harmonic component depending on the prostate radius. The maximum acoustic power which could be used decreased as a function of the prostate radius and the frequency. Decreasing the frequency (9.7-3.0 MHz) or increasing the power (10-20 W.cm-2) led to treatment times shorter by up to 50% under appropriate conditions. Dual-frequency configurations, while helpful, tended to have less impact on treatment times. Treatment accuracy was maintained and critical adjacent tissues like the rectal wall remained protected. The interdependence between power and frequency may require integrating multi-parametric functions inside the controller for future optimizations. As a first approach, however, even slight modifications of key parameters can be sufficient to reduce treatment time.

On the Relationship between Motor Performance and Executive Functioning in Children with Intellectual Disabilities

ERIC Educational Resources Information Center

Hartman, E.; Houwen, S.; Scherder, E.; Visscher, C.

2010-01-01

Background: It has been suggested that children with intellectual disabilities (ID) have motor problems and higher-order cognitive deficits. The aim of this study was to examine the motor skills and executive functions in school-age children with borderline and mild ID. The second aim was to investigate the relationship between the two performance…

A Pilot Study of a Test for Visual Recognition Memory in Adults with Moderate to Severe Intellectual Disability

ERIC Educational Resources Information Center

Pyo, Geunyeong; Ala, Tom; Kyrouac, Gregory A.; Verhulst, Steven J.

2010-01-01

Objective assessment of memory functioning is an important part of evaluation for Dementia of Alzheimer Type (DAT). The revised Picture Recognition Memory Test (r-PRMT) is a test for visual recognition memory to assess memory functioning of persons with intellectual disabilities (ID), specifically targeting moderate to severe ID. A pilot study was…

A Preliminary Study of the Validity of Memory Tests Recommended by the Working Group for Individuals with Moderate to Severe Intellectual Disability

ERIC Educational Resources Information Center

Pyo, G.; Kripakaran, K.; Curtis, K.; Curtis, R.; Markwell, S.

2007-01-01

Background: Normal aging and Dementia of Alzheimer's Type (DAT) among higher functioning individuals with intellectual disability (ID) have been relatively well studied using a variety of cognitive tests. However, cognitive studies for lower functioning individuals with ID are scarce in the literature. The Working Group recommended the Test…

A matter of life and death: knowledge about the body and concept of death in adults with intellectual disabilities.

PubMed

McEvoy, J; Treacy, B; Quigley, J

2017-01-01

An increased awareness of how people with intellectual disabilities (ID) understand death and dying is necessary in supporting life-long learning, post-bereavement support and planning end-of-life care. Previous research suggests that adults with ID have a limited or 'patchy' understanding of the basic biological components of death. However, the relationship between biological understanding of how the body works and conceptualisation of death remains unexplored in this population. Thirty adults with ID were interviewed to assess their knowledge of human body function and their understanding of the concept of death. Using pictures, participants were asked if they recognised certain organs, asked to explain the function of various body parts and what would happen if certain body parts were missing or did not work. Participants who referred to 'life' or 'not dying' as the goal of body function were categorised as 'Life Theorisers'. In addition, participants were asked about the causes of death, whether all things die and the status of the body after death. The results support previous studies suggesting that understanding of death in adults with ID varies from partial to full comprehension and is associated with level of ID. Also, death comprehension was positively correlated with total body interview scores and 'Life Theorisers' who understood that body parts maintain life and who spontaneously appealed to 'vitalistic' concepts when reasoning about the human body were also more sophisticated in their understanding of death. The study highlights the relationship between knowledge about the goal of human body functioning and death comprehension in adults with ID. The potential that learning to adopt a 'vitalistic' approach to human functioning may have on the acquisition of a greater understanding of death and dying, understanding illness and supporting end-of-life planning is discussed. © 2016 MENCAP and International Association of the Scientific Study of Intellectual and Developmental Disabilities and John Wiley & Sons Ltd.

The androgen receptor malignancy shift in prostate cancer.

PubMed

Copeland, Ben T; Pal, Sumanta K; Bolton, Eric C; Jones, Jeremy O

2018-05-01

Androgens and the androgen receptor (AR) are necessary for the development, function, and homeostatic growth regulation of the prostate gland. However, once prostate cells are transformed, the AR is necessary for the proliferation and survival of the malignant cells. This change in AR function appears to occur in nearly every prostate cancer. We have termed this the AR malignancy shift. In this review, we summarize the current knowledge of the AR malignancy shift, including the DNA-binding patterns that define the shift, the transcriptome changes associated with the shift, the putative drivers of the shift, and its clinical implications. In benign prostate epithelial cells, the AR primarily binds consensus AR binding sites. In carcinoma cells, the AR cistrome is dramatically altered, as the AR associates with FOXA1 and HOXB13 motifs, among others. This shift leads to the transcription of genes associated with a malignant phenotype. In model systems, some mutations commonly found in localized prostate cancer can alter the AR cistrome, consistent with the AR malignancy shift. Current evidence suggests that the AR malignancy shift is necessary but not sufficient for transformation of prostate epithelial cells. Reinterpretation of prostate cancer genomic classification systems in light of the AR malignancy shift may improve our ability to predict clinical outcomes and treat patients appropriately. Identifying and targeting the molecular factors that contribute to the AR malignancy shift is not trivial but by doing so, we may be able to develop new strategies for the treatment or prevention of prostate cancer. © 2018 Wiley Periodicals, Inc.

Medical Therapy for Benign Prostatic Hyperplasia: New Terminology, New Concepts, Better Choices

PubMed Central

Kaplan, Steven A

2006-01-01

This article discusses 3 areas of medical therapy for benign prostatic hyperplasia (BPH) that are undergoing extensive research and evaluation: 1) the use of muscarinic receptor antagonists to treat lower urinary tract symptoms (LUTS) in men with BPH; 2) the definition of an “enlarged prostate”; and 3) sexual function and LUTS. Fears of worsening obstructive symptoms or causing acute urinary retention often keep practitioners from prescribing muscarinic receptor antagonists to men who might have concomitant bladder outlet obstruction; a multicenter, multinational, double-blind study showed that tolterodine is safe for men with low postvoid residual volumes. Most urologists accept that a prostate volume of more than 40 mL is consistent with an enlarged prostate; there is more debate regarding prostate volumes of 30 to 40 mL. Recently presented data suggest that combination medical therapy might be effective for men having prostates with volumes of more than 25 mL. The association between voiding and sexual function has been increasingly recognized and investigated, and there seem to be common pathophysiologic mechanisms governing both conditions. Targeted treatment algorithms addressing both conditions seem warranted. PMID:16985556

Physical fitness is predictive for a decline in daily functioning in older adults with intellectual disabilities: results of the HA-ID study.

PubMed

Oppewal, Alyt; Hilgenkamp, Thessa I M; van Wijck, Ruud; Schoufour, Josje D; Evenhuis, Heleen M

2014-10-01

A high incidence of limitations in daily functioning is seen in older adults with intellectual disabilities (ID), along with poor physical fitness levels. The aim of this study was to assess the predictive value of physical fitness for daily functioning after 3 years, in 602 older adults with borderline to profound ID (≥ 50 years). At baseline, physical fitness levels and daily functioning (operationalized as basic activities of daily living [ADL] and mobility) were assessed. After 3 years, the measurements of daily functioning were repeated. At follow-up, 12.6% of the participants were completely independent in ADL and 48.5% had no mobility limitations. More than half of the participants (54.8%) declined in their ability to perform ADL and 37.5% declined in their mobility. Manual dexterity, visual reaction time, balance, comfortable and fast gait speed, muscular endurance, and cardiorespiratory fitness were significant predictors for a decline in ADL. For a decline in mobility, manual dexterity, balance, comfortable and fast walking speed, grip strength, muscular endurance, and cardiorespiratory fitness were all significant predictors. This proves the predictive validity of these physical fitness tests for daily functioning and stresses the importance of using physical fitness tests and implementing physical fitness enhancing programs in the care for older adults with ID. Copyright © 2014 Elsevier Ltd. All rights reserved.

hsa-miR-135a-1 inhibits prostate cancer cell growth and migration by targeting EGFR.

PubMed

Xu, Bin; Tao, Tao; Wang, Yiduo; Fang, Fang; Huang, Yeqing; Chen, Shuqiu; Zhu, Weidong; Chen, Ming

2016-10-01

Prostate cancer is one of the leading causes of death in men worldwide. Differentially expressed microRNAs (miRNAs) are associated with metastatic prostate cancer. However, their potential roles for affecting prostate cancer initiation and progression remain largely unknown. Here, we examined the aberrant expression profiles of miRNAs in human metastatic prostate cancer tissues. We further validated our miRNA expression data using two large, independent clinical prostate cancer datasets from the Memorial Sloan Kettering Cancer Center (MSKCC) and The Cancer Genome Atlas (TCGA). Our data support a model in which hsa-miR-135-1 acts as a potential tumor suppressor in metastatic prostate cancer. First, its downregulation was positively correlated with late TNM stage, high Gleason score, and adverse prognosis. Second, cell growth, cell cycle progression, cell migration and invasion, and xenograft tumor formation were dramatically inhibited by miR-135a overexpression. Third, in the microarray gene expression data analysis using Gene Set Enrichment Analysis (GSEA), Database for Annotation, Visualization and Integrated Discovery (DAVID) analysis, Ingenuity Pathway Analysis (IPA), and Oncomine concept analysis, we showed that miR-135a targets multiple oncogenic pathways including epidermal growth factor receptor (EGFR), which we verified using functional experimental assays. These results help advance our understanding of the function of miRNAs in metastatic prostate cancer and provide a basis for further clinical investigation.

Influence of the neural microenvironment on prostate cancer.

PubMed

Coarfa, Christian; Florentin, Diego; Putluri, NagiReddy; Ding, Yi; Au, Jason; He, Dandan; Ragheb, Ahmed; Frolov, Anna; Michailidis, George; Lee, MinJae; Kadmon, Dov; Miles, Brian; Smith, Christopher; Ittmann, Michael; Rowley, David; Sreekumar, Arun; Creighton, Chad J; Ayala, Gustavo

2018-02-01

Nerves are key factors in prostate cancer (PCa), but the functional role of innervation in prostate cancer is poorly understood. PCa induced neurogenesis and perineural invasion (PNI), are associated with aggressive disease. We denervated rodent prostates chemically and physically, before orthotopically implanting cancer cells. We also performed a human neoadjuvant clinical trial using botulinum toxin type A (Botox) and saline in the same patient, before prostatectomy. Bilateral denervation resulted in reduced tumor incidence and size in mice. Botox treatment in humans resulted in increased apoptosis of cancer cells in the Botox treated side. A similar denervation gene array profile was identified in tumors arising in denervated rodent prostates, in spinal cord injury patients and in the Botox treated side of patients. Denervation induced exhibited a signature gene profile, indicating translation and bioenergetic shutdown. Nerves also regulate basic cellular functions of non-neoplastic epithelial cells. Nerves play a role in the homeostasis of normal epithelial tissues and are involved in prostate cancer tumor survival. This study confirms that interactions between human cancer and nerves are essential to disease progression. This work may make a major impact in general cancer treatment strategies, as nerve/cancer interactions are likely important in other cancers as well. Targeting the neural microenvironment may represent a therapeutic approach for the treatment of human prostate cancer. © 2017 The Authors. The Prostate Published by Wiley Periodicals, Inc.

Polypeptide having or assisting in carbohydrate material degrading activity and uses thereof

DOEpatents

Schooneveld-Bergmans, Margot Elisabeth Francoise; Heijne, Wilbert Herman Marie; Los, Alrik Pieter

2016-02-16

The invention relates to a polypeptide which comprises the amino acid sequence set out in SEQ ID NO: 2 or an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 1, or a variant polypeptide or variant polynucleotide thereof, wherein the variant polypeptide has at least 76% sequence identity with the sequence set out in SEQ ID NO: 2 or the variant polynucleotide encodes a polypeptide that has at least 76% sequence identity with the sequence set out in SEQ ID NO: 2. The invention features the full length coding sequence of the novel gene as well as the amino acid sequence of the full-length functional polypeptide and functional equivalents of the gene or the amino acid sequence. The invention also relates to methods for using the polypeptide in industrial processes. Also included in the invention are cells transformed with a polynucleotide according to the invention suitable for producing these proteins.

Polypeptide having beta-glucosidase activity and uses thereof

DOE Office of Scientific and Technical Information (OSTI.GOV)

Schoonneveld-Bergmans, Margot Elisabeth Francoise; Heijne, Wilbert Herman Marie; De Jong, Rene Marcel

The invention relates to a polypeptide comprising the amino acid sequence set out in SEQ ID NO: 2 or an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 1, or a variant polypeptide or variant polynucleotide thereof, wherein the variant polypeptide has at least 96% sequence identity with the sequence set out in SEQ ID NO: 2 or the variant polynucleotide encodes a polypeptide that has at least 96% sequence identity with the sequence set out in SEQ ID NO: 2. The invention features the full length coding sequence of the novel gene as well asmore » the amino acid sequence of the full-length functional polypeptide and functional equivalents of the gene or the amino acid sequence. The invention also relates to methods for using the polypeptide in industrial processes. Also included in the invention are cells transformed with a polynucleotide according to the invention suitable for producing these proteins.« less

Polypeptide having swollenin activity and uses thereof

DOEpatents

Schoonneveld-Bergmans, Margot Elizabeth Francoise; Heijne, Wilbert Herman Marie; Vlasie, Monica D; Damveld, Robbertus Antonius

2015-11-04

The invention relates to a polypeptide comprising the amino acid sequence set out in SEQ ID NO: 2 or an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 1, or a variant polypeptide or variant polynucleotide thereof, wherein the variant polypeptide has at least 73% sequence identity with the sequence set out in SEQ ID NO: 2 or the variant polynucleotide encodes a polypeptide that has at least 73% sequence identity with the sequence set out in SEQ ID NO: 2. The invention features the full length coding sequence of the novel gene as well as the amino acid sequence of the full-length functional polypeptide and functional equivalents of the gene or the amino acid sequence. The invention also relates to methods for using the polypeptide in industrial processes. Also included in the invention are cells transformed with a polynucleotide according to the invention suitable for producing these proteins.

Polypeptide having beta-glucosidase activity and uses thereof

DOEpatents

Schooneveld-Bergmans, Margot Elisabeth Francoise; Heijne, Wilbert Herman Marie; De Jong, Rene Marcel; Damveld, Robbertus Antonius

2015-09-01

The invention relates to a polypeptide comprising the amino acid sequence set out in SEQ ID NO: 2 or an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 1, or a variant polypeptide or variant polynucleotide thereof, wherein the variant polypeptide has at least 70% sequence identity with the sequence set out in SEQ ID NO: 2 or the variant polynucleotide encodes a polypeptide that has at least 70% sequence identity with the sequence set out in SEQ ID NO: 2. The invention features the full length coding sequence of the novel gene as well as the amino acid sequence of the full-length functional polypeptide and functional equivalents of the gene or the amino acid sequence. The invention also relates to methods for using the polypeptide in industrial processes. Also included in the invention are cells transformed with a polynucleotide according to the invention suitable for producing these proteins.

Polypeptide having cellobiohydrolase activity and uses thereof

DOEpatents

Sagt, Cornelis Maria Jacobus; Schooneveld-Bergmans, Margot Elisabeth Francoise; Roubos, Johannes Andries; Los, Alrik Pieter

2015-09-15

The invention relates to a polypeptide comprising the amino acid sequence set out in SEQ ID NO: 2 or an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 1, or a variant polypeptide or variant polynucleotide thereof, wherein the variant polypeptide has at least 93% sequence identity with the sequence set out in SEQ ID NO: 2 or the variant polynucleotide encodes a polypeptide that has at least 93% sequence identity with the sequence set out in SEQ ID NO: 2. The invention features the full length coding sequence of the novel gene as well as the amino acid sequence of the full-length functional polypeptide and functional equivalents of the gene or the amino acid sequence. The invention also relates to methods for using the polypeptide in industrial processes. Also included in the invention are cells transformed with a polynucleotide according to the invention suitable for producing these proteins.

Polypeptide having acetyl xylan esterase activity and uses thereof

DOEpatents

Schoonneveld-Bergmans, Margot Elisabeth Francoise; Heijne, Wilbert Herman Marie; Los, Alrik Pieter

2015-10-20

The invention relates to a polypeptide comprising the amino acid sequence set out in SEQ ID NO: 2 or an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 1, or a variant polypeptide or variant polynucleotide thereof, wherein the variant polypeptide has at least 82% sequence identity with the sequence set out in SEQ ID NO: 2 or the variant polynucleotide encodes a polypeptide that has at least 82% sequence identity with the sequence set out in SEQ ID NO: 2. The invention features the full length coding sequence of the novel gene as well as the amino acid sequence of the full-length functional polypeptide and functional equivalents of the gene or the amino acid sequence. The invention also relates to methods for using the polypeptide in industrial processes. Also included in the invention are cells transformed with a polynucleotide according to the invention suitable for producing these proteins.

Polypeptide having carbohydrate degrading activity and uses thereof

DOEpatents

Schooneveld-Bergmans, Margot Elisabeth Francoise; Heijne, Wilbert Herman Marie; Vlasie, Monica Diana; Damveld, Robbertus Antonius

2015-08-18

The invention relates to a polypeptide comprising the amino acid sequence set out in SEQ ID NO: 2 or an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 1, or a variant polypeptide or variant polynucleotide thereof, wherein the variant polypeptide has at least 73% sequence identity with the sequence set out in SEQ ID NO: 2 or the variant polynucleotide encodes a polypeptide that has at least 73% sequence identity with the sequence set out in SEQ ID NO: 2. The invention features the full length coding sequence of the novel gene as well as the amino acid sequence of the full-length functional polypeptide and functional equivalents of the gene or the amino acid sequence. The invention also relates to methods for using the polypeptide in industrial processes. Also included in the invention are cells transformed with a polynucleotide according to the invention suitable for producing these proteins.

Characterization of the seminal plasma proteome in men with prostatitis by mass spectrometry

PubMed Central

2012-01-01

Background Prostatitis is an inflammation of the prostate gland which affects approximately 10% of men. Despite its frequency, diagnosing prostatitis and monitoring patient response to treatment remains frustrating. As the prostate contributes a substantial percentage of proteins to seminal plasma, we hypothesized that a protein biomarker of prostatitis might be found by comparing the seminal plasma proteome of patients with and without prostatitis. Results Using mass spectrometry, we identified 1708 proteins in the pooled seminal plasma of 5 prostatitis patients. Comparing this list to a previously published list of seminal plasma proteins in the pooled seminal plasma of 5 healthy, fertile controls yielded 1464 proteins in common, 413 found only in the control group, and 254 found only in the prostatitis group. Applying a set of criteria to this dataset, we generated a high-confidence list of 59 candidate prostatitis biomarkers, 33 of which were significantly increased in prostatitis as compared to control, and 26 of which were decreased. The candidates were analyzed using Gene Ontology and Ingenuity Pathway analysis to delineate their subcellular localizations and functions. Conclusions Thus, in this study, we identified 59 putative biomarkers in seminal plasma that need further validation for diagnosis and monitoring of prostatitis. PMID:22309592

Array-CGH in children with mild intellectual disability: a population-based study.

PubMed

Coutton, Charles; Dieterich, Klaus; Satre, Véronique; Vieville, Gaëlle; Amblard, Florence; David, Marie; Cans, Christine; Jouk, Pierre-Simon; Devillard, Francoise

2015-01-01

Intellectual disability (ID) is characterized by limitation in intellectual function and adaptive behavior, with onset in childhood. Frequent identifiable causes of ID originate from chromosomal imbalances. During the last years, array-CGH has successfully contributed to improve the diagnostic detection rate of genetic abnormalities in patients with ID. Most array-CGH studies focused on patients with moderate or severe intellectual disability. Studies on genetic etiology in children with mild intellectual disability (ID) are very rare. We performed array-CGH analysis in 66 children with mild intellectual disability assessed in a population-based study and for whom no genetic etiology was identified. We found one or more copy number variations (CNVs) in 20 out of 66 (~30 %) patients with a mild ID. In eight of them (~12 %), the CNVs were certainly responsible for the phenotype and in six they were potentially pathogenic for ID. Altogether, array-CGH helped to determine the etiology of ID in 14 patients (~21 %). Our results underscore the clinical relevance of array-CGH to investigate the etiology of isolated idiopathic mild ID in patients or associated with even subtle dysmorphic features or congenital malformations.

A human GRPr-transfected Ace-1 canine prostate cancer model in mice.

PubMed

Ding, Haiming; Kothandaraman, Shankaran; Gong, Li; Williams, Michelle M; Dirksen, Wessel P; Rosol, Thomas J; Tweedle, Michael F

2016-06-01

A versatile drug screening system was developed to simplify early targeted drug discovery in mice and then translate readily from mice to a dog prostate cancer model that more fully replicates the features of human prostate cancer. We stably transfected human cDNA of the GRPr bombesin (BBN) receptor subtype to canine Ace-1 prostate cancer cells (Ace-1(huGRPr) ). Expression was examined by (125) I-Tyr(4) -BBN competition, calcium stimulation assay, and fluorescent microscopy. A dual tumor nude mouse xenograft model was developed from Ace-1(CMV) (vector transfected Ace-1) and Ace-1(huGRPr) cells. The model was used to explore the in vivo behavior of two new IRDye800-labeled GRPr binding optical imaging agents: 800-G-Abz4-t-BBN, from a GRPr agonist peptide, and 800-G-Abz4-STAT, from a GRPr antagonist peptide, by imaging the tumor mice and dissected organs. Both agents bound Ace-1(huGRPr) and PC-3, a known GRPr-expressing human prostate cancer cell line, with 4-13 nM IC50 against (125) I-Tyr(4) -BBN, but did not bind Ace-1(CMV) cells (vector transfected). Binding was blocked by bombesin. Ca(2+) activation assays demonstrated that Ace-1(huGPRr) expressed biologically active GRPr. Both Ace-1 cell lines grew in the flanks of 100% of the nude mice and formed tumors of ∼0.5 cm diameter in 1 week. In vivo imaging of the mice at 800 nm emission showed GRPr+: GRPr- tumor signal brighter by a factor of two at 24 h post IV administration of 10 nmol of the imaging agents. Blood retention (4-8% ID at 1 h) was greater by a factor >10 and cumulative urine accumulation (28-30% at 4 h) was less by a factor 2 compared to a radioactive analog of the t-BBN containing agent, (177) LuAMBA, probably due to binding to blood albumin, which we confirmed in a mouse serum assay. The dual tumor Ace-1(CMV) /Ace-1(huGRPr) model system provides a rapid test of specific to nonspecific binding of new GRPr avid agents in a model that will extend logically to the known Ace-1 orthotopic canine prostate cancer model. Prostate 76:783-795, 2016. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

The helix-loop-helix protein id1 controls stem cell proliferation during regenerative neurogenesis in the adult zebrafish telencephalon.

PubMed

Rodriguez Viales, Rebecca; Diotel, Nicolas; Ferg, Marco; Armant, Olivier; Eich, Julia; Alunni, Alessandro; März, Martin; Bally-Cuif, Laure; Rastegar, Sepand; Strähle, Uwe

2015-03-01

The teleost brain has the remarkable ability to generate new neurons and to repair injuries during adult life stages. Maintaining life-long neurogenesis requires careful management of neural stem cell pools. In a genome-wide expression screen for transcription regulators, the id1 gene, encoding a negative regulator of E-proteins, was found to be upregulated in response to injury. id1 expression was mapped to quiescent type I neural stem cells in the adult telencephalic stem cell niche. Gain and loss of id1 function in vivo demonstrated that Id1 promotes stem cell quiescence. The increased id1 expression observed in neural stem cells in response to injury appeared independent of inflammatory signals, suggesting multiple antagonistic pathways in the regulation of reactive neurogenesis. Together, we propose that Id1 acts to maintain the neural stem cell pool by counteracting neurogenesis-promoting signals. © 2014 AlphaMed Press.

Prostate volume did not affect voiding function improvements in diode laser enucleation of the prostate.

PubMed

Yang, Stephen Shei-Dei; Hsieh, Cheng-Hsing; Chiang, I-Ni; Lin, Chia-Da; Chang, Shang-Jen

2013-03-01

We compared safety and surgical outcomes in patients with different prostate sizes treated with diode laser enucleation of the prostate. From 2008 to 2012 consecutive patients with benign prostatic obstruction undergoing diode laser prostate enucleation at our institution were enrolled for analysis. A single surgeon performed diode laser prostate enucleation with an end firing, continuous wave diode laser (980 nm). Based on preoperative prostate volume on transrectal ultrasound, patients were stratified into 2 groups, including group 1-65 with less than 60 ml and group 2-55 with 60 ml or greater. Baseline and perioperative characteristics, and postoperative surgical outcomes were compared between the 2 groups. A total of 120 men with a mean ± SD age of 70.2 ± 9.0 years were enrolled for analysis. Compared with group 1 patients, those in group 2 had larger mean total prostate volume (85.0 ± 24.6 vs 40.9 ± 10.8 ml), longer mean operative time (117.7 ± 48.2 vs 60.7 ± 25.0 minutes), higher mean retrieved prostate weight (37.3 ± 16.1 vs 12.5 ± 7.3 gm) and a higher mean tissue retrieval ratio (74.4% ± 22.2% vs 58.8% ± 23.2%, p <0.01). There was no significant difference in the postoperative hemoglobin decrease in the 2 groups (median 0.5 vs 0.9 mg/dl, p = 0.11). The rate of temporary postoperative urinary retention after Foley catheter removal was significantly lower in group 2 (15.4% vs 3.6%, p = 0.04). Postoperative improvements in the peak flow rate, post-void residual urine volume and International Prostate Symptom Score were comparable in the 2 groups. Although patients with a larger prostate required significantly longer operative time and laser energy, voiding function improvements and surgical complication rates of diode laser prostate enucleation were comparable in patients with a larger vs smaller prostate. Copyright © 2013 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.

Image-derived and arterial blood sampled input functions for quantitative PET imaging of the angiotensin II subtype 1 receptor in the kidney

DOE Office of Scientific and Technical Information (OSTI.GOV)

Feng, Tao; Tsui, Benjamin M. W.; Li, Xin

Purpose: The radioligand {sup 11}C-KR31173 has been introduced for positron emission tomography (PET) imaging of the angiotensin II subtype 1 receptor in the kidney in vivo. To study the biokinetics of {sup 11}C-KR31173 with a compartmental model, the input function is needed. Collection and analysis of arterial blood samples are the established approach to obtain the input function but they are not feasible in patients with renal diseases. The goal of this study was to develop a quantitative technique that can provide an accurate image-derived input function (ID-IF) to replace the conventional invasive arterial sampling and test the method inmore » pigs with the goal of translation into human studies. Methods: The experimental animals were injected with [{sup 11}C]KR31173 and scanned up to 90 min with dynamic PET. Arterial blood samples were collected for the artery derived input function (AD-IF) and used as a gold standard for ID-IF. Before PET, magnetic resonance angiography of the kidneys was obtained to provide the anatomical information required for derivation of the recovery coefficients in the abdominal aorta, a requirement for partial volume correction of the ID-IF. Different image reconstruction methods, filtered back projection (FBP) and ordered subset expectation maximization (OS-EM), were investigated for the best trade-off between bias and variance of the ID-IF. The effects of kidney uptakes on the quantitative accuracy of ID-IF were also studied. Biological variables such as red blood cell binding and radioligand metabolism were also taken into consideration. A single blood sample was used for calibration in the later phase of the input function. Results: In the first 2 min after injection, the OS-EM based ID-IF was found to be biased, and the bias was found to be induced by the kidney uptake. No such bias was found with the FBP based image reconstruction method. However, the OS-EM based image reconstruction was found to reduce variance in the subsequent phase of the ID-IF. The combined use of FBP and OS-EM resulted in reduced bias and noise. After performing all the necessary corrections, the areas under the curves (AUCs) of the AD-IF were close to that of the AD-IF (average AUC ratio =1 ± 0.08) during the early phase. When applied in a two-tissue-compartmental kinetic model, the average difference between the estimated model parameters from ID-IF and AD-IF was 10% which was within the error of the estimation method. Conclusions: The bias of radioligand concentration in the aorta from the OS-EM image reconstruction is significantly affected by radioligand uptake in the adjacent kidney and cannot be neglected for quantitative evaluation. With careful calibrations and corrections, the ID-IF derived from quantitative dynamic PET images can be used as the input function of the compartmental model to quantify the renal kinetics of {sup 11}C-KR31173 in experimental animals and the authors intend to evaluate this method in future human studies.« less

Navy Information Dominance Corps: Human Capital Strategy 2012-2017

DTIC Science & Technology

2012-01-01

Information Dominance (ID) is the operational advantage gained from fully integrating information functions, capabilities, resources and people to...and information domains. The human component of ID is the Information Dominance Corps (IDC) and it has three core functions in this mission. First, it...processes, delivery of a Corps-wide learning continuum, and cultivation of an identifiable, inclusive Information Dominance culture and ethos. This

Health Status and ADL Functioning of Older Persons with Intellectual Disability: Community Residence versus Residential Care Centers

ERIC Educational Resources Information Center

Lifshitz, Hefziba; Merrick, Joav; Morad, Mohammed

2008-01-01

The objective of the study was to study differences in aging phenomena among adults with intellectual disability (ID), who live in community residence versus their peers in residential care centers and to determine the contribution of health status, age, gender, etiology and level of ID to the decline in ADL function with age. Our study was based…

The effect of asymptomatic histological prostatitis on sexual function and lower urinary tract symptoms.

PubMed

Urkmez, Ahmet; Yuksel, Ozgur Haki; Uruc, Fatih; Akan, Serkan; Yildirim, Caglar; Sahin, Aytac; Verit, Ayhan

2016-05-01

Prostatitis affects 10-14% of men of all ages and ethnicities. More than 50% of the men experience episodes of prostatitis at one time of their lives. Patients with CP typically have longlasting genitourinary/pelvic pain and obstructive and/or irritative voiding symptoms. Sexual dysfunction and psychological symptoms are frequently added to these symptoms. We also investigated the relationship between sexual functions, and lower urinary system symptoms, and asymptomatic histological prostatitis detected on transrectal ultrasound-guided (TRUS) biopsy performed with the indication of high PSA levels. Sixty cases compliant with the study criteria among patients who underwent prostate biopsies between September 2014 and June 2015 with the indication of higher PSA levels were included in the study. All patients were requested to complete IIEF-5 and IPSS forms one day previously. Based on histological analysis of biopsy materials, the patients were allocated into groups of BPH (simple BPH without histological prostatitis) (n:30) and histological chronic prostatitis (combination of BPH and histological prostatitis) (n:30). Mean age of the cases was 65.73±5.01 (range, 56-75 yrs) years. PSA levels ranged between 4-15 ng/ml. A statistically significant intergroup difference was not found regarding mean age, BMIs, PSA levels, incidence rates of hypertension and coronary artery disease (p>0.05). Prostate volumes of the HCP group were higher than those of the BPH group , with statistically significant differences (p:0.001; p<0.01). Questionnaire forms of the patients included in the study were statistically evaluated, and mean IPSS score of the HCP group was found to be higher when compared with that of the BPH group, with statistically significant differences. (p:0.016; p<0.05). However mean IIEF score of the BPH group was higher than that of the HCP group, with statistically significant differences (p:0.039; p<0.05). These findings suggested the presence of a correlation between chronic inflammation and lower urinary tract symptoms (LUTS). In addition, statistically significant lower IIEF values in patients with histological chronic prostatitis relative to those without suggested negative effects of even asymptomatic inflammation on sexual functions and mechanism of erection.

A dual yet opposite growth-regulating function of miR-204 and its target XRN1 in prostate adenocarcinoma cells and neuroendocrine-like prostate cancer cells

PubMed Central

Ding, Miao; Lin, Biaoyang; Li, Tao; Liu, Yuanyuan; Li, Yuhua; Zhou, Xiaoyu; Miao, Maohua; Gu, Jinfa; Pan, Hongjie; Yang, Fen; Li, Tianqi; Liu, Xin Yuan; Li, Runsheng

2015-01-01

Androgen deprivation therapy in prostate cancer (PCa) causes neuroendocrine differentiation (NED) of prostatic adenocarcinomas (PAC) cells, leading to recurrence of PCa. Androgen-responsive genes involved in PCa progression including NED remain largely unknown. Here we demonstrated the importance of androgen receptor (AR)-microRNA-204 (miR-204)-XRN1 axis in PCa cell lines and the rat ventral prostate. Androgens downregulate miR-204, resulting in induction of XRN1 (5′-3′ exoribonuclease 1), which we identified as a miR-204 target. miR-204 acts as a tumor suppressor in two PAC cell lines (LNCaP and 22Rv1) and as an oncomiR in two neuroendocrine-like prostate cancer (NEPC) cell lines (PC-3 and CL1). Importantly, overexpression of miR-204 and knockdown of XRN1 inhibited AR expression in PCa cells. Repression of miR-34a, a known AR-targeting miRNA, contributes AR expression by XRN1. Thus we revealed the AR-miR-204-XRN1-miR-34a positive feedback loop and a dual function of miR-204/XRN1 axis in prostate cancer. PMID:25797256

Deep Learning Role in Early Diagnosis of Prostate Cancer

PubMed Central

Reda, Islam; Khalil, Ashraf; Elmogy, Mohammed; Abou El-Fetouh, Ahmed; Shalaby, Ahmed; Abou El-Ghar, Mohamed; Elmaghraby, Adel; Ghazal, Mohammed; El-Baz, Ayman

2018-01-01

The objective of this work is to develop a computer-aided diagnostic system for early diagnosis of prostate cancer. The presented system integrates both clinical biomarkers (prostate-specific antigen) and extracted features from diffusion-weighted magnetic resonance imaging collected at multiple b values. The presented system performs 3 major processing steps. First, prostate delineation using a hybrid approach that combines a level-set model with nonnegative matrix factorization. Second, estimation and normalization of diffusion parameters, which are the apparent diffusion coefficients of the delineated prostate volumes at different b values followed by refinement of those apparent diffusion coefficients using a generalized Gaussian Markov random field model. Then, construction of the cumulative distribution functions of the processed apparent diffusion coefficients at multiple b values. In parallel, a K-nearest neighbor classifier is employed to transform the prostate-specific antigen results into diagnostic probabilities. Finally, those prostate-specific antigen–based probabilities are integrated with the initial diagnostic probabilities obtained using stacked nonnegativity constraint sparse autoencoders that employ apparent diffusion coefficient–cumulative distribution functions for better diagnostic accuracy. Experiments conducted on 18 diffusion-weighted magnetic resonance imaging data sets achieved 94.4% diagnosis accuracy (sensitivity = 88.9% and specificity = 100%), which indicate the promising results of the presented computer-aided diagnostic system. PMID:29804518

Sexual (dys)function after radiotherapy for prostate cancer: a review.

PubMed

Incrocci, Luca; Slob, A Koos; Levendag, Peter C

2002-03-01

Prostate cancer has become the most common nonskin malignant neoplasm in older men in Western countries. As treatment efficacy has improved, issues related to posttherapy quality of life and sexual functioning have become more important. We discuss the various methods used to evaluate erectile and sexual dysfunction and the definition of potency. The etiologies of erectile dysfunction after external beam radiotherapy and brachytherapy for prostate cancer are also reviewed. The literature is summarized, and comparative studies of radiation and surgery are surveyed briefly. Rates of erectile dysfunction vary from 6 to 84% after external beam radiotherapy and from 0 to 51% after brachytherapy. In most of the studies, the analysis is retrospective, the definition of erectile dysfunction is not clear, only one question about sexual functioning is asked, and nonvalidated instruments are used. The etiology of erectile dysfunction after radiation for prostate cancer is not completely understood. Because erectile function is only one component of sexual function, it is necessary to assess sexual desire, satisfaction, frequency of intercourse, and other such factors when evaluating the effects of therapy. Patients should be offered sexual counseling and informed about the availability of effective treatments for erectile dysfunction, such as sildenafil, intracavernosal injection, and vacuum devices.

Targeted Elimination of PCDH-PC Expressing Prostate Cancer Cells for Control of Hormone-Resistant Prostate Cancer

DTIC Science & Technology

2008-11-01

or antisense oligonucleotides ( ASOs ) might be useful in preventing the development of castration- recurrent prostate cancer in prostate cancer...patients. To this end, we have created functional shRNA vectors and ASOs capable of suppressing PCDH-PC expression and we have also created a monoclonal...electrophoresed on an SDS-PAGE gel and blotted onto a filter. The filter was probed with an anti-myc antibody. The levels of myc-tagged PCDH-PC protein

Targeted Elimination of PCDH-PC Expressing Prostate Cancer Cells for Control of Hormone-Resistant Prostate Cancer

DTIC Science & Technology

2009-11-01

expression knockout by shRNAs or antisense oligonucleotides ( ASOs ) might be useful in preventing the development of castration-recurrent prostate...cancer in prostate cancer patients. To this end, we have created functional shRNA vectors and ASOs capable of suppressing PCDH-PC expression and we have...containing PCDH-PC cDNA. Cell extracts were prepared 48 hrs after co-transfection and were electrophoresed on an SDS-PAGE gel and blotted onto a

Regulation of Prostate Development and Benign Prostatic Hyperplasia by Autocrine Cholinergic Signaling via Maintaining the Epithelial Progenitor Cells in Proliferating Status.

PubMed

Wang, Naitao; Dong, Bai-Jun; Quan, Yizhou; Chen, Qianqian; Chu, Mingliang; Xu, Jin; Xue, Wei; Huang, Yi-Ran; Yang, Ru; Gao, Wei-Qiang

2016-05-10

Regulation of prostate epithelial progenitor cells is important in prostate development and prostate diseases. Our previous study demonstrated a function of autocrine cholinergic signaling (ACS) in promoting prostate cancer growth and castration resistance. However, whether or not such ACS also plays a role in prostate development is unknown. Here, we report that ACS promoted the proliferation and inhibited the differentiation of prostate epithelial progenitor cells in organotypic cultures. These results were confirmed by ex vivo lineage tracing assays and in vivo renal capsule recombination assays. Moreover, we found that M3 cholinergic receptor (CHRM3) was upregulated in a large subset of benign prostatic hyperplasia (BPH) tissues compared with normal tissues. Activation of CHRM3 also promoted the proliferation of BPH cells. Together, our findings identify a role of ACS in maintaining prostate epithelial progenitor cells in the proliferating state, and blockade of ACS may have clinical implications for the management of BPH. Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.

Clinicopathological, functional, and immediate oncologic outcome assessment in men aged≤50 years with prostate cancer after robotic prostatectomy.

PubMed

Samadi, David B; Sebrow, Dov; Hobbs, Adele R; Bernstein, Adrien N; Brajtbord, Jonathan; Lavery, Hugh J; Jazayeri, Seyed Behzad

2017-01-01

To define the pathologic and functional outcomes of men 50 years of age and younger with prostate cancer in a contemporary robotic cohort, this study was designed. Patients undergoing robotic-assisted laparoscopic prostatectomy from April 2002 to April 2012 (n = 2,495) formed the base population for the current analyses. The patients were dichotomized according to their age≤50 (n = 271) and>50-year-old (n = 2,224). Clinicopathological and health-related quality-of-life outcomes were recorded and analyzed for differences. Propensity score matching was used when assessing urinary and sexual function outcome. Baseline prostate-specific antigen and clinical stage were similar between men older than 50 years and those younger. Younger patients had less severe disease (D׳Amico risk and Gleason scores) and smaller prostates. Young men had higher rates of erectile function at all time points, including baseline (94% vs. 83% at 12mo, P <0.01). Continence was similar at all time points except for 6 months, where younger patients experienced a faster return than older patients and then remained constant, while older patients continued to improve (96% vs. 89%, P<0.01). After matching process, the difference in erectile function at 6-month follow-up was lost. Most men aged 50 years and younger who received robotic-assisted laparoscopic prostatectomy had clinically significant prostate cancer. Although histopathologic and short-term oncologic outcomes were nearly identical when compared to older patients, younger men had a more rapid and superior return of erectile function. Copyright © 2017 Elsevier Inc. All rights reserved.

The impact of minimally invasive surgeries for the treatment of symptomatic benign prostatic hyperplasia on male sexual function: a systematic review.

PubMed

Frieben, Ryan W; Lin, Hao-Cheng; Hinh, Peter P; Berardinelli, Francesco; Canfield, Steven E; Wang, Run

2010-07-01

A systematic review of randomized controlled trials and cohort studies was conducted to evaluate data for the effects of minimally invasive procedures for treatment of symptomatic benign prostatic hyperplasia (BPH) on male sexual function. The studies searched were trials that enrolled men with symptomatic BPH who were treated with laser surgeries, transurethral microwave therapy (TUMT), transurethral needle ablation of the prostate (TUNA), transurethral ethanol ablation of the prostate (TEAP) and high-intensity frequency ultrasound (HIFU), in comparison with traditional transurethral resection of the prostate (TURP) or sham operations. A total of 72 studies were identified, of which 33 met the inclusion criteria. Of the 33 studies, 21 were concerned with laser surgeries, six with TUMT, four with TUNA and two with TEAP containing information regarding male sexual function. No study is available regarding the effect of HIFU for BPH on male sexual function. Our analysis shows that minimally invasive surgeries for BPH have comparable effects to those of TURP on male erectile function. Collectively, less than 15.4% or 15.2% of patients will have either decrease or increase, respectively, of erectile function after laser procedures, TUMT and TUNA. As observed with TURP, a high incidence of ejaculatory dysfunction (EjD) is common after treatment of BPH with holmium, potassium-titanyl-phosphate and thulium laser therapies (> 33.6%). TUMT, TUNA and neodymium:yttrium aluminum garnet visual laser ablation or interstitial laser coagulation for BPH has less incidence of EjD, but these procedures are considered less effective for BPH treatment when compared with TURP.

The impact of minimally invasive surgeries for the treatment of symptomatic benign prostatic hyperplasia on male sexual function: a systematic review

PubMed Central

Frieben, Ryan W.; Lin, Hao-Cheng; Hinh, Peter P.; Berardinelli, Francesco; Canfield, Steven E.; Wang, Run

2010-01-01

A systematic review of randomized controlled trials and cohort studies was conducted to evaluate data for the effects of minimally invasive procedures for treatment of symptomatic benign prostatic hyperplasia (BPH) on male sexual function. The studies searched were trials that enrolled men with symptomatic BPH who were treated with laser surgeries, transurethral microwave therapy (TUMT), transurethral needle ablation of the prostate (TUNA), transurethral ethanol ablation of the prostate (TEAP) and high-intensity frequency ultrasound (HIFU), in comparison with traditional transurethral resection of the prostate (TURP) or sham operations. A total of 72 studies were identified, of which 33 met the inclusion criteria. Of the 33 studies, 21 were concerned with laser surgeries, six with TUMT, four with TUNA and two with TEAP containing information regarding male sexual function. No study is available regarding the effect of HIFU for BPH on male sexual function. Our analysis shows that minimally invasive surgeries for BPH have comparable effects to those of TURP on male erectile function. Collectively, less than 15.4% or 15.2% of patients will have either decrease or increase, respectively, of erectile function after laser procedures, TUMT and TUNA. As observed with TURP, a high incidence of ejaculatory dysfunction (EjD) is common after treatment of BPH with holmium, potassium-titanyl-phosphate and thulium laser therapies (> 33.6%). TUMT, TUNA and neodymium:yttrium aluminum garnet visual laser ablation or interstitial laser coagulation for BPH has less incidence of EjD, but these procedures are considered less effective for BPH treatment when compared with TURP. PMID:20473318

Amide-to-triazole switch vs. in vivo NEP-inhibition approaches to promote radiopeptide targeting of GRPR-positive tumors.

PubMed

Maina, Theodosia; Kaloudi, Aikaterini; Valverde, Ibai E; Mindt, Thomas L; Nock, Berthold A

2017-09-01

Radiolabeled bombesin (BBN)-analogs have been proposed for diagnosis and therapy of gastrin-releasing peptide receptor (GRPR)-expressing tumors, such as prostate, breast and lung cancer. Metabolic stability represents a crucial factor for the success of this approach by ensuring sufficient delivery of circulating radioligand to tumor sites. The amide-to-triazole switch on the backbone of DOTA-PEG 4 -[Nle 14 ]BBN(7-14) (1) was reported to improve the in vitro stability of resulting 177 Lu-radioligands. On the other hand, in-situ inhibition of neutral endopeptidase (NEP) by coinjection of phosphoramidon (PA) was shown to significantly improve the in vivo stability and tumor uptake of biodegradable radiopeptides. We herein compare the impact of the two methods on the bioavailability and localization of 177 Lu-DOTA-PEG 4 -[Nle 14 ]BBN(7-14) analogs in GRPR-positive tumors in mice. The 1,4-disubstituted [1-3]-triazole was used to replace one (2: Gly 11 -His 12 ; 3: Ala 9 -Val 10 ) or two (4: Ala 9 -Val 10 and Gly 11 -His 12 ) peptide bonds in 1 (reference) and all compounds were labeled with 177 Lu. Each of [ 177 Lu]1-[ 177 Lu]4 was injected without (control) or with PA in healthy mice. Blood samples collected 5min post-injection (pi) were analyzed by HPLC. Biodistribution of [ 177 Lu]1-[ 177 Lu]4 was conducted in SCID mice bearing human prostate adenocarcinoma PC-3 xenografts at 4h pi. Groups of 4 animals were injected with radioligand, alone (controls), or with coinjection of PA, or of a mixture of PA and excess and [Tyr 4 ]BBN to determine GRPR-specificity of uptake (Block). The in vivo stability of the radioligands was: [ 177 Lu]1 (25% intact), [ 177 Lu]2 (45% intact), [ 177 Lu]3 (30% intact) and [ 177 Lu]4 (40% intact). By PA-coinjection these values notably increased to 90%-93%. Moreover, treatment with PA induced an impressive and GRPR-specific uptake of all radioligands in the PC-3 xenografts at 4h pi: [ 177 Lu]1: 4.7±0.4 to 24.8±4.9%ID/g; [ 177 Lu]2: 8.3±1.2 to 26.0±1.1%ID/g; [ 177 Lu]3: 6.6±0.4 to 21.3±4.4%ID/g; and [ 177 Lu]4: 4.8±1.6 to 13.7±3.8%ID/g. This study has shown that amide-to-triazole substitutions in 177 Lu-DOTA-PEG 4 -[Nle 14 ]BBN(7-14) induced minor effects on bioavailability and tumor uptake in mice models, whereas in-situ NEP-inhibition(s) by PA impressively improved in vivo profiles. Copyright © 2017 Elsevier Inc. All rights reserved.

Imaging of Prostate Cancer Using Gallium-68-Labeled Bombesin.

PubMed

Sonni, Ida; Baratto, Lucia; Iagaru, Andrei

2017-04-01

Nuclear medicine can play an important role in evaluating prostate cancer combining anatomical and functional information with hybrid techniques. Various PET radiopharmaceuticals have been used for targeting specific biological markers in prostate cancer. Research is ideally oriented towards the development of radiopharmaceuticals targeting antigens overexpressed in prostate cancer, as opposed to normal prostate tissue. In this regard, gastrin-releasing peptide receptors (GRPR) are excellent candidates. Bombesin analogues targeting the GRPR have been investigated. Gallium-68 ( 68 Ga) is an interesting PET radioisotope due to several advantages, such as availability, ease of radiochemistry, half-life, and costs. The focus of this review is on 68 Ga-labeled bombesin analogues in prostate cancer. Copyright © 2016 Elsevier Inc. All rights reserved.

Questions and answers on prostate multiparameter magnetic resonance imaging: Everything a urologist should know.

PubMed

Catalá, V; Salas, D; Esquena, S; Mateu, S; Algaba, F; Palou, J; de la Torre, P

2016-01-01

For many years, the detection of prostate cancer (PC) and the management of its therapy have been based primarily on prostate-specific antigen, rectal examination and prostate biopsy. However, these parameters have known limitations. Multiparametric magnetic resonance imaging (mpMRI) for prostate cancer has undergone extensive development in recent years, providing morphological and functional information. The aim of this study is to present an updated review of the scope and limitations of prostatic mpMRI for PC, in the framework of a multidisciplinary vision. We conducted a literature review (in PubMed) of articles referencing "mpMRI/staging/ PC/detection/active surveillance/therapy planning/post-therapy". We included 4 systematic reviews and other articles published in high impact-factor journals within the field of radiology and urology. MpMRI provides morphological and functional information concerning PC. This information is integrated into the Prostate Imaging Report and Date System, classifying the probability of clinically significant carcinoma on a scale from 1 to 5. The usefulness of mpMRI is currently being established for patients with high prostate-specific antigen levels and prior negative prostate biopsy; tumour staging in selected cases; assessment of patients who are candidates for active surveillance; the planning of focal treatments; and the assessment of tumour persistence and recurrence. MpMRI currently fills a relevant role in the diagnosis and therapeutic decision-making of PC. More widespread use of the technique requires a cost/benefit analysis. Copyright © 2015 AEU. Publicado por Elsevier España, S.L.U. All rights reserved.

Estrogenic Environmental Chemicals and Drugs: Mechanisms for Effects on the Developing Male Urogenital System

PubMed Central

Taylor, Julia A.; Richter, Catherine A.; Ruhlen, Rachel L.; vom Saal, Frederick S.

2011-01-01

Development and differentiation of the prostate from the fetal urogenital sinus (UGS) is dependent on androgen action via androgen receptors (AR) in the UGS mesenchyme. Estrogens are not required for prostate differentiation but do act to modulate androgen action. In mice exposure to exogenous estrogen during development results in permanent effects on adult prostate size and function, which is mediated through mesenchymal estrogen receptor (ER) alpha. For many years estrogens were thought to inhibit prostate growth because estrogenic drugs studied were administered at very high concentrations that interfered with normal prostate development. There is now extensive evidence that exposure to estrogen at very low concentrations during the early stages of prostate differentiation can stimulate fetal/neonatal prostate growth and lead to prostate disease in adulthood. Bisphenol A (BPA) is an environmental endocrine disrupting chemical that binds to both ER receptor subtypes as well as to AR. Interest in BPA has increased because of its prevalence in the environment and its detection in over 90% of people in the USA. In tissue culture of fetal mouse UGS mesenchymal cells, BPA and estradiol stimulated changes in the expression of several genes. We discuss here the potential involvement of estrogen in regulating signaling pathways affecting cellular functions relevant to steroid hormone signaling and metabolism and to inter- and intra-cellular communications that promote cell growth. The findings presented here provide additional evidence that BPA and the estrogenic drug ethinylestradiol disrupt prostate development in male mice at administered doses relevant to human exposures. PMID:21827855

Telocytes play a key role in prostate tissue organisation during the gland morphogenesis.

PubMed

Sanches, Bruno D A; Maldarine, Juliana S; Zani, Bruno C; Tamarindo, Guilherme H; Biancardi, Manoel F; Santos, Fernanda C A; Rahal, Paula; Góes, Rejane M; Felisbino, Sérgio L; Vilamaior, Patricia S L; Taboga, Sebastião R

2017-12-01

Telocytes are CD34-positive interstitial cells, known to exert several functions, one of which is a role in tissue organisation, previously demonstrated by telocytes in the myocardium. The existence of telocytes in the prostate has recently been reported, however, there is a lack of information regarding the function of these cells in prostate tissue, and information regarding the possible role of these cells in prostatic development. This study used immunofluorescence techniques in prostate tissue and prostatic telocytes in culture to determine the relationship between telocytes and prostate morphogenesis. Furthermore, immunofluorescent labelling of telocytes was performed on prostate tissue at different stages of early postnatal development. Initially, CD34-positive cells are found at the periphery of the developing alveoli, later in the same region, c-kit-positive cells and cells positive for both factors are verified and CD34-positive cells were predominantly observed in the interalveolar stroma and the region surrounding the periductal smooth muscle. Fluorescence assays also demonstrated that telocytes secrete TGF-β1 and are ER-Beta (ERβ) positive. The results suggest that telocytes play a changing role during development, initially supporting the differentiation of periductal and perialveolar smooth muscle, and later, producing dense networks that separate alveoli groups and form a barrier between the interalveolar region and periurethral smooth muscle. We conclude that telocytes play a relevant role in prostate tissue organisation during postnatal development. © 2017 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.

Serial Changes in Sexual Function Following Holmium Laser Enucleation of the Prostate: A Short-term Follow-up Study.

PubMed

Jeong, Min Su; Ha, Seung Beom; Lee, Chang Ju; Cho, Min Chul; Kim, Soo Woong; Paick, Jae-Seung

2012-02-01

To evaluate the serial changes in sexual function in the short-term period after holmium laser enucleation of the prostate (HoLEP) for benign prostatic hyperplasia (BPH) and to investigate whether a change in each domain of the International Index of Erectile Function (IIEF) is associated with improvement of micturition. Thirty-eight potent men who underwent HoLEP and in whom complete 12-month follow-up data on the IIEF were available were included in this retrospective study. All patients underwent a baseline evaluation for BPH. The surgical outcome was evaluated at 1, 3, 6, and 12 months postoperatively by use of the International Prostate Symptom Score, IIEF, and uroflowmetry. The mean age and body mass index of the patients was 64.5±6.2 years and 24.2±2.6 kg/m(2), respectively. Mean total prostate volume and transitional zone volume were 48.8±18.8 ml and 24.2±16.1 ml, respectively. Most IIEF domain scores showed a slight decrease at 1, 3, and 6 months after surgery but recovered to the baseline or showed a marginal but nonsignificant increase at 12 months postoperatively compared with baseline. Orgasmic function and the overall sexual satisfaction domain score remained slightly reduced up to 12 months postoperatively. There was no significant correlation between improvement of micturition and change in sexual function throughout the follow-up period after surgery. Although HoLEP achieves significant improvements in micturition, overall sexual function decreases slightly in the early postoperative period, but recovers to the baseline at 12 months postoperatively. Our data suggest that changes in sexual function after HoLEP are not associated with improvement of micturition.

Prostasomes--their effects on human male reproduction and fertility.

PubMed

Burden, H P; Holmes, C H; Persad, R; Whittington, K

2006-01-01

The prostate is a glandular male accessory sex organ vital for normal fertility. It provides the prostatic component of seminal plasma which nourishes and protects sperm following ejaculation. Prostasomes are small (40-500 nm) membrane-bound vesicles produced by epithelial cells lining the prostate acini and are a component of prostatic secretions. Although the existence of these particles has been known for many years, their full function and relevance to reproductive health are largely unknown. Proteomic studies have shown a wide range of proteins (enzymes, structural proteins and novel, unannotated proteins) present in or on the surface of prostasomes providing them with a diverse nature. Interestingly prostasomes are able to fuse with sperm, this event and the associated transfer of proteins lies at the heart of many of their proposed functions. Sperm motility is increased by the presence of prostasomes and their fusion prevents premature acrosome reactions. Prostasomes have been shown to aid protection of sperm within the female reproductive tract because of immunosuppressive, antioxidant and antibacterial properties. Clinically these functions imply a role for prostasomes in male factor infertility. However, the very functions that promote fertility may have negative connotations in later life; recent work has suggested that prostasomes are involved in prostate cancer. Clearly more work is needed to clarify the role of these novel particles and their impact on men's health.

Androgen receptor and chemokine receptors 4 and 7 form a signaling axis to regulate CXCL12-dependent cellular motility.

PubMed

Hsiao, Jordy J; Ng, Brandon H; Smits, Melinda M; Wang, Jiahui; Jasavala, Rohini J; Martinez, Harryl D; Lee, Jinhee; Alston, Jhullian J; Misonou, Hiroaki; Trimmer, James S; Wright, Michael E

2015-03-31

Identifying cellular signaling pathways that become corrupted in the presence of androgens that increase the metastatic potential of organ-confined tumor cells is critical to devising strategies capable of attenuating the metastatic progression of hormone-naïve, organ-confined tumors. In localized prostate cancers, gene fusions that place ETS-family transcription factors under the control of androgens drive gene expression programs that increase the invasiveness of organ-confined tumor cells. C-X-C chemokine receptor type 4 (CXCR4) is a downstream target of ERG, whose upregulation in prostate-tumor cells contributes to their migration from the prostate gland. Recent evidence suggests that CXCR4-mediated proliferation and metastasis of tumor cells is regulated by CXCR7 through its scavenging of chemokine CXCL12. However, the role of androgens in regulating CXCR4-mediated motility with respect to CXCR7 function in prostate-cancer cells remains unclear. Immunocytochemistry, western blot, and affinity-purification analyses were used to study how androgens influenced the expression, subcellular localization, and function of CXCR7, CXCR4, and androgen receptor (AR) in LNCaP prostate-tumor cells. Moreover, luciferase assays and quantitative polymerase chain reaction (qPCR) were used to study how chemokines CXCL11 and CXCL12 regulate androgen-regulated genes (ARGs) in LNCaP prostate-tumor cells. Lastly, cell motility assays were carried out to determine how androgens influenced CXCR4-dependent motility through CXCL12. Here we show that, in the LNCaP prostate-tumor cell line, androgens coordinate the expression of CXCR4 and CXCR7, thereby promoting CXCL12/CXCR4-mediated cell motility. RNA interference experiments revealed functional interactions between AR and CXCR7 in these cells. Co-localization and affinity-purification experiments support a physical interaction between AR and CXCR7 in LNCaP cells. Unexpectedly, CXCR7 resided in the nuclear compartment and modulated AR-mediated transcription. Moreover, androgen-mediated cell motility correlated positively with the co-localization of CXCR4 and CXCR7 receptors, suggesting that cell migration may be linked to functional CXCR4/CXCR7 heterodimers. Lastly, CXCL12-mediated cell motility was CXCR7-dependent, with CXCR7 expression required for optimal expression of CXCR4 protein. Overall, our results suggest that inhibition of CXCR7 function might decrease the metastatic potential of organ-confined prostate cancers.

New and Emerging Technologies in Treatment of Lower Urinary Tract Symptoms From Benign Prostatic Hyperplasia.

PubMed

Gupta, Nikhil K; Gange, Steven N; McVary, Kevin T

2018-03-29

Lower urinary tract symptoms (LUTS) from bladder outlet obstruction from benign prostatic hyperplasia (BPH) occur in a large percentage of urologic patients. Treatment of this condition with medical and surgical therapy provides symptom relief but has serious adverse effects and causes sexual dysfunction. New technologies to treat BPH-associated LUTS aim to effectively treat urinary symptoms and minimize side effects and sexual dysfunction. To review the efficacy of new and emerging therapies for treatment of LUTS from BPH. A literature search was performed to identify therapies for LUTS from BPH with early outcomes data within the past 5 years. Improvement in International Prostate Symptom Score (IPSS) and effect on sexual functions such as erectile and ejaculatory functions as measured on the International Index of Erectile Function and the Male Sexual Health Questionnaire. Technologies introduced within the past 5 years include techniques using intraprostatic injectables, mechanical devices, and prostatic tissue ablation. Most technologies remain in the development phase and have only phase I and II studies available that show promising alleviation of urinary symptoms. Injectables have not typically surpassed placebo or sham effects, although special cohorts could be exceptions. Thus far, convective water vapor ablation therapy and prostatic urethral lift have shown the most promise, with short- and medium-term data available on phase III studies demonstrating significant improvement in IPSS with minimal impact on sexual function. Many of these technologies are limited in their potential treatment population by prostate size and conformation, whereas other therapies might be more generalizable. Many new technologies aim to treat LUTS from BPH and minimize sexual side effects. Most therapies remain experimental, although prostatic urethral lift and water vapor ablation therapy have been brought to market and show promise. Long-term durability of symptom relief remains to be demonstrated. Gupta NK, Gange SN, McVary KT. New and Emerging Technologies in Treatment of Lower Urinary Tract Symptoms From Benign Prostatic Hyperplasia. Sex Med Rev 2018;XX:XXX-XXX. Copyright © 2018. Published by Elsevier Inc.

Lectin-Like Oxidized LDL Receptor-1 Is an Enhancer of Tumor Angiogenesis in Human Prostate Cancer Cells

PubMed Central

González-Chavarría, Iván; Cerro, Rita P.; Parra, Natalie P.; Sandoval, Felipe A.; Zuñiga, Felipe A.; Omazábal, Valeska A.; Lamperti, Liliana I.; Jiménez, Silvana P.; Fernandez, Edelmira A.; Gutiérrez, Nicolas A.; Rodriguez, Federico S.; Onate, Sergio A.; Sánchez, Oliberto; Vera, Juan C.; Toledo, Jorge R.

2014-01-01

Altered expression and function of lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) has been associated with several diseases such as endothelial dysfunction, atherosclerosis and obesity. In these pathologies, oxLDL/LOX-1 activates signaling pathways that promote cell proliferation, cell motility and angiogenesis. Recent studies have indicated that olr1 mRNA is over-expressed in stage III and IV of human prostatic adenocarcinomas. However, the function of LOX-1 in prostate cancer angiogenesis remains to be determined. Our aim was to analyze the contribution of oxLDL and LOX-1 to tumor angiogenesis using C4-2 prostate cancer cells. We analyzed the expression of pro-angiogenic molecules and angiogenesis on prostate cancer tumor xenografts, using prostate cancer cell models with overexpression or knockdown of LOX-1 receptor. Our results demonstrate that the activation of LOX-1 using oxLDL increases cell proliferation, and the expression of the pro-angiogenic molecules VEGF, MMP-2, and MMP-9 in a dose-dependent manner. Noticeably, these effects were prevented in the C4-2 prostate cancer model when LOX-1 expression was knocked down. The angiogenic effect of LOX-1 activated with oxLDL was further demonstrated using the aortic ring assay and the xenograft model of tumor growth on chorioallantoic membrane of chicken embryos. Consequently, we propose that LOX-1 activation by oxLDL is an important event that enhances tumor angiogenesis in human prostate cancer cells. PMID:25170920

Molecular Innovations Toward Theranostics of Aggressive Prostate Cancer

DTIC Science & Technology

2013-09-01

objective is to develop dendrimer -based theranostic agent with prostate cancer specificity and positron emission tomography imaging capability that...The goal of this project is to construct dendrimer nanoconjuate containing a prostate specific cell permeation peptide, peptide therapeutic(s) and...bifunctional chelator for PET imaging. Dr. Simanek’s laboratory will make dendrimers that bear functional handles for conjugation with imaging

Role of PSMA in Aberrant Cell Cycle Progression in Prostate Cancer

DTIC Science & Technology

2004-12-01

playing a role in nutrient uptake, and a peptidase involved in signal transduction in prostate epithelial cells. Insights into possible functions of PSMA...should improve the diagnostic and therapeutic values of this clinically important molecule. prostate cancer; receptor; peptidase ; endocytosis 2 OVERVIEW... peptidase activities hydrolyze gamma-peptide bonds between N-acetylaspartate and glutamate in the abundant neuropeptide N-acetylaspartylglutamate

Health-related quality-of-life in low-income, uninsured men with prostate cancer.

PubMed

Krupski, Tracey L; Fink, Arlene; Kwan, Lorna; Maliski, Sally; Connor, Sarah E; Clerkin, Barbara; Litwin, Mark S

2005-05-01

The objective was to describe health-related quality-of-life (HRQOL) in low-income men with prostate cancer. Subjects were drawn from a statewide public assistance prostate cancer program. Telephone and mail surveys included the RAND 12-item Health Survey and UCLA Prostate Cancer Index Short Form and were compared with normative age-matched men without cancer from the general population reported on in the literature. Of 286 eligible men, 233 (81%) agreed to participate and completed the necessary items. The sample consisted of 51% Hispanics, 23% non-Hispanic whites, and 17% African Americans. The low-income men had worse scores in every domain of prostate-specific and general HRQOL than had the age-matched general population controls. The degree of disparity indicated substantial clinical differences in almost every domain of physical and emotional functioning between the sample group and the control group. Linear regression modeling determined that among the low-income men, Hispanic race, and income level were predictive of worse physical functioning, whereas only comorbidities predicted mental health. Low-income patients with prostate cancer appear to have quality-of-life profiles that are meaningfully worse than age-matched men from the general population without cancer reported on in the literature.

Surgical anatomy of the prostate in the era of radical robotic prostatectomy.

PubMed

Walz, Jochen; Graefen, Markus; Huland, Hartwig

2011-05-01

New insights in the anatomy of the prostate and the surrounding tissue evolve the technique of radical prostatectomy for the treatment of prostate cancer. Regarding the course of the erectile nerves along the prostate, recent studies confirmed the presence of parasympathetic pro-erectile nerve fibers at the anterolateral aspect of the prostate. Another study of intraoperative electrostimulation of those nerves confirmed an increase in intracavernosal pressure by stimulations between the 1 and 3 o'clock position. Therefore, it is very likely that these anterior nerve fibers have an effect on erectile function. Regarding the urethral sphincter in the male, a study showed no attachment of the external sphincter to the levator ani muscle, probably resulting in an absence of a levator ani support to the continence mechanism. The male urinary sphincter seems to be in isolation responsible for urinary continence. The nerve fibers at the anterolateral aspect of the prostate seem to participate in erectile function, which renders the concept of a high anterior release during nerve sparing beneficial. The isolated urinary sphincter mechanism results in the need to conserve as much urethral length as possible during radical prostatectomy to avoid urinary incontinence.

Epidermal growth factor receptor signaling promotes metastatic prostate cancer through microRNA-96-mediated downregulation of the tumor suppressor ETV6.

PubMed

Tsai, Yuan-Chin; Chen, Wei-Yu; Siu, Man Kit; Tsai, Hong-Yuan; Yin, Juan Juan; Huang, Jiaoti; Liu, Yen-Nien

2017-01-01

It has been suggested that ETV6 serves as a tumor suppressor; however, its molecular regulation and cellular functions remain unclear. We used prostate cancer as a model system and demonstrated a molecular mechanism in which ETV6 can be regulated by epidermal growth factor receptor (EGFR) signaling through microRNA-96 (miR-96)-mediated downregulation. In addition, EGFR acts as a transcriptional coactivator that binds to the promoter of primary miR-96 and transcriptionally regulates miR-96 levels. We analyzed two sets of clinical prostate cancer samples, confirmed association patterns that were consistent with the EGFR-miR-96-ETV6 signaling model and demonstrated that the reduced ETV6 levels were associated with malignant prostate cancer. Based on results derived from multiple approaches, we identified the biological functions of ETV6 as a tumor suppressor that inhibits proliferation and metastasis in prostate cancer. We present a molecular mechanism in which EGFR activation leads to the induction of miR-96 expression and suppression of ETV6, which contributes to prostate cancer progression. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Recent advances in prostate development and links to prostatic diseases

PubMed Central

Powers, Ginny L.

2013-01-01

The prostate is a branched ductal-acinar gland that is part of the male reproductive tract. Prostate development depends upon the integration of steroid hormone signals, paracrine interactions between the stromal and epithelial tissue layers, and the actions of cell autonomous factors. Several genes and signalling pathways are known to be required for one or more steps of prostate development including epithelial budding, duct elongation, branching morphogenesis, and/or cellular differentiation. Recent progress in the field of prostate development has included the application of genome-wide technologies including serial analysis of gene expression (SAGE), expression profiling microarrays, and other large scale approaches to identify new genes and pathways that are essential for prostate development. The aggregation of experimental results into online databases by organized multi-lab projects including the Genitourinary Developmental Molecular Atlas Project (GUDMAP) has also accelerated the understanding of molecular pathways that function during prostate development and identified links between prostate anatomy and molecular signaling. Rapid progress has also recently been made in understanding the nature and role of candidate stem cells in the developing and adult prostate. This has included the identification of putative prostate stem cell markers, lineage tracing, and organ reconstitution studies. However, several issues regarding their origin, precise nature, and possible role(s) in disease remain unresolved. Nevertheless, several links between prostatic developmental mechanisms and the pathogenesis of prostatic diseases including benign prostatic hyperplasia and prostate cancer have led to recent progress on targeting developmental pathways as therapeutic strategies for these diseases. PMID:23335485

MicroRNA-613 represses prostate cancer cell proliferation and invasion through targeting Frizzled7

DOE Office of Scientific and Technical Information (OSTI.GOV)

Ren, Wei; Department of Urology, Shaanxi Provincial People's Hospital, The Third Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710068; Li, Chan

A growing number of studies have indicated that microRNAs (miRNAs) are critical regulators of carcinogenesis and cancer progression and may serve as potential therapeutic tools for cancer therapy. Frizzled7 (Fzd7), the most important receptor of the Wnt signaling pathway, is extensively involved in cancer development and progression. However, the role of Fzd7 in prostate cancer remains unclear. In this study, we aimed to explore the expression of Fzd7 in prostate cancer and test whether modulating Fzd7 expression by miR-613 would have an impact on prostate cancer cell proliferation and invasion. We found that Fzd7 was highly expressed in prostate cancermore » cell lines. Through bioinformatics analysis, Fzd7 was predicted as a target gene of miR-613, which was validated by dual-luciferase reporter assays, real-time quantitative polymerase chain reaction and Western blot analysis. By gain of function experiments, we showed that overexpression of miR-613 significantly suppressed prostate cancer cell proliferation and invasion. Furthermore, miR-613 overexpression markedly downregulated the Wnt signaling pathway. Through a rescue experiment, we showed that overexpression of Fzd7 could abrogate the inhibitory effect of miR-613 on cell proliferation and invasion as well as Wnt signaling. Additionally, these results were further strengthened by data showing that miR-613 was significantly downregulated in prostate cancer tissues, exhibiting an inverse correlation with Fzd7 expression. In conclusion, our study suggests that miR-613 functions as a tumor suppressor, partially through targeting Fzd7, and is a potential therapeutic target for prostate cancer. - Highlights: • Fzd7 was highly expressed in prostate cancer. • Fzd7 was predicted as a target gene of miR-613. • MiR-613 negatively regulated prostate cancer by Fzd7. • MiR-613 inversely correlated with Fzd7 in prostate cancer.« less

Managing Weight: What Do People with an Intellectual Disability Want from Mobile Technology?

PubMed

Smyth, Phil; McDowell, Claire; Leslie, Julian C; Leader, Geraldine; Donnelly, Mark; Simpson, Elizabeth; Skelly, Laura

2017-01-01

Obesity is a significant health challenge. People with Intellectual Disability (ID) are particularly vulnerable to developing obesity. Mobile technology has been developed to support the management of weight and obesity in the form of apps, although not with people with an ID in mind. As a result existing off-the-shelf weight management apps currently available may not be functional in supporting weight reduction within this population. This paper presents the results of consultations with people with ID regarding weight management, comfort with mobile technology and desired characteristics in apps designed for people with ID that target weight management.

Working memory impairment and recovery in iron deficient children.

PubMed

Otero, Gloria A; Pliego-Rivero, F Bernardo; Porcayo-Mercado, Rosario; Mendieta-Alcántara, Gustavo

2008-08-01

Iron is an important oligoelement participating in multiple metabolic processes, including the synthesis of catecholamines, and its deficiency (ID) throughout development is particularly insidious on brain maturation and the emergence of cognitive functions during school age. A working memory (WM) study in 8-10-year-old ID children is presented. It is hypothesized that an impairment in WM exists in ID school-age children and a substantial restoration of this mental ability should occur after iron supplementation. Event-related potentials (ERPs) were recorded during the completion of a Sternberg-type task in control, ID and ID-iron supplemented children. ID children showed less correct answers and diminished ERP amplitude in frontal, central, parietal and temporal regions compared to control children. After iron supplementation and normalizing bodily iron stores, behavioral and ERP differences disappeared between ID and control children. Considering that WM is fundamentally related to attention ability, the results presented here confirm and reinforce previous observations: ID severely diminishes attention [Otero GA, Pliego-Rivero FB, Contreras G, Ricardo J, Fernandez T. Iron supplementation brings up a lacking P300 in iron deficient children. Clin Neurophysiol 2004;115:2259-66] and WM while iron supplementation substantially restores the cognitive capabilities tested. This is one of very few reports using ERP showing a diminished WM capability in ID school-age children.

ACE I/D and ACTN3 R/X polymorphisms as potential factors in modulating exercise-related phenotypes in older women in response to a muscle power training stimuli.

PubMed

Pereira, Ana; Costa, Aldo M; Izquierdo, Mikel; Silva, António J; Bastos, Estela; Marques, Mário C

2013-10-01

Genetic variation of the human ACE I/D and ACTN3 R577X polymorphisms subsequent to 12 weeks of high-speed power training on maximal strength (1RM) of the arm and leg muscles, muscle power performance (counter-movement jump), and functional capacity (sit-to-stand test) was examined in older Caucasian women [n = 139; mean age 65.5 (8.2) years; 67.0 (10.0) kg and 1.57 (0.06) m]. Chelex 100 was used for DNA extraction, and genotype was determined by PCR-RFLP methods. Muscular strength, power, and functional testing were conducted at baseline (T1) and after 12 weeks (T2) of high-speed power training. At baseline, the ACE I/D and ACTN3 R/X polymorphisms were not associated with muscle function or muscularity phenotypes in older Caucasian women. After the 12-week high-speed training program, subjects significantly increased their muscular and functional capacity performance (p < 0.05). For both polymorphisms, significant genotype-training interaction (p < 0.05) was found in all muscular performance indices, except for 1RM leg extension in the ACE I/D (p = 0.187). Analyses of the combined effects between genotypes showed significant differences in all parameters (p < 0.05) in response to high-speed power training between the power (ACTN3 RR + RX & ACE DD) versus "non-power" muscularity-oriented genotypes (ACTN3 XX & ACE II + ID)]. Our data suggest that the ACE and ACTN3 genotypes (single or combined) exert a significant influence in the muscle phenotypes of older Caucasian women in response to high-speed power training. Thus, the ACE I/D and ACTN3 R/X polymorphisms are likely factors in modulating exercise-related phenotypes in older women, particularly in response to a resistance training stimuli.

Exome sequencing of Pakistani consanguineous families identifies 30 novel candidate genes for recessive intellectual disability

PubMed Central

Riazuddin, S; Hussain, M; Razzaq, A; Iqbal, Z; Shahzad, M; Polla, D L; Song, Y; van Beusekom, E; Khan, A A; Tomas-Roca, L; Rashid, M; Zahoor, M Y; Wissink-Lindhout, W M; Basra, M A R; Ansar, M; Agha, Z; van Heeswijk, K; Rasheed, F; Van de Vorst, M; Veltman, J A; Gilissen, C; Akram, J; Kleefstra, T; Assir, M Z; Grozeva, D; Carss, K; Raymond, F L; O'Connor, T D; Riazuddin, S A; Khan, S N; Ahmed, Z M; de Brouwer, A P M; van Bokhoven, H; Riazuddin, S

2017-01-01

Intellectual disability (ID) is a clinically and genetically heterogeneous disorder, affecting 1–3% of the general population. Although research into the genetic causes of ID has recently gained momentum, identification of pathogenic mutations that cause autosomal recessive ID (ARID) has lagged behind, predominantly due to non-availability of sizeable families. Here we present the results of exome sequencing in 121 large consanguineous Pakistani ID families. In 60 families, we identified homozygous or compound heterozygous DNA variants in a single gene, 30 affecting reported ID genes and 30 affecting novel candidate ID genes. Potential pathogenicity of these alleles was supported by co-segregation with the phenotype, low frequency in control populations and the application of stringent bioinformatics analyses. In another eight families segregation of multiple pathogenic variants was observed, affecting 19 genes that were either known or are novel candidates for ID. Transcriptome profiles of normal human brain tissues showed that the novel candidate ID genes formed a network significantly enriched for transcriptional co-expression (P<0.0001) in the frontal cortex during fetal development and in the temporal–parietal and sub-cortex during infancy through adulthood. In addition, proteins encoded by 12 novel ID genes directly interact with previously reported ID proteins in six known pathways essential for cognitive function (P<0.0001). These results suggest that disruptions of temporal parietal and sub-cortical neurogenesis during infancy are critical to the pathophysiology of ID. These findings further expand the existing repertoire of genes involved in ARID, and provide new insights into the molecular mechanisms and the transcriptome map of ID. PMID:27457812

Exome sequencing of Pakistani consanguineous families identifies 30 novel candidate genes for recessive intellectual disability.

PubMed

Riazuddin, S; Hussain, M; Razzaq, A; Iqbal, Z; Shahzad, M; Polla, D L; Song, Y; van Beusekom, E; Khan, A A; Tomas-Roca, L; Rashid, M; Zahoor, M Y; Wissink-Lindhout, W M; Basra, M A R; Ansar, M; Agha, Z; van Heeswijk, K; Rasheed, F; Van de Vorst, M; Veltman, J A; Gilissen, C; Akram, J; Kleefstra, T; Assir, M Z; Grozeva, D; Carss, K; Raymond, F L; O'Connor, T D; Riazuddin, S A; Khan, S N; Ahmed, Z M; de Brouwer, A P M; van Bokhoven, H; Riazuddin, S

2017-11-01

Intellectual disability (ID) is a clinically and genetically heterogeneous disorder, affecting 1-3% of the general population. Although research into the genetic causes of ID has recently gained momentum, identification of pathogenic mutations that cause autosomal recessive ID (ARID) has lagged behind, predominantly due to non-availability of sizeable families. Here we present the results of exome sequencing in 121 large consanguineous Pakistani ID families. In 60 families, we identified homozygous or compound heterozygous DNA variants in a single gene, 30 affecting reported ID genes and 30 affecting novel candidate ID genes. Potential pathogenicity of these alleles was supported by co-segregation with the phenotype, low frequency in control populations and the application of stringent bioinformatics analyses. In another eight families segregation of multiple pathogenic variants was observed, affecting 19 genes that were either known or are novel candidates for ID. Transcriptome profiles of normal human brain tissues showed that the novel candidate ID genes formed a network significantly enriched for transcriptional co-expression (P<0.0001) in the frontal cortex during fetal development and in the temporal-parietal and sub-cortex during infancy through adulthood. In addition, proteins encoded by 12 novel ID genes directly interact with previously reported ID proteins in six known pathways essential for cognitive function (P<0.0001). These results suggest that disruptions of temporal parietal and sub-cortical neurogenesis during infancy are critical to the pathophysiology of ID. These findings further expand the existing repertoire of genes involved in ARID, and provide new insights into the molecular mechanisms and the transcriptome map of ID.

Idea density measured in late life predicts subsequent cognitive trajectories: implications for the measurement of cognitive reserve.

PubMed

Farias, Sarah Tomaszewski; Chand, Vineeta; Bonnici, Lisa; Baynes, Kathleen; Harvey, Danielle; Mungas, Dan; Simon, Christa; Reed, Bruce

2012-11-01

The Nun Study showed that lower linguistic ability in young adulthood, measured by idea density (ID), increased the risk of dementia in late life. The present study examined whether ID measured in late life continues to predict the trajectory of cognitive change. ID was measured in 81 older adults who were followed longitudinally for an average of 4.3 years. Changes in global cognition and 4 specific neuropsychological domains (episodic memory, semantic memory, spatial abilities, and executive function) were examined as outcomes. Separate random effects models tested the effect of ID on longitudinal change in outcomes, adjusted for age and education. Lower ID was associated with greater subsequent decline in global cognition, semantic memory, episodic memory, and spatial abilities. When analysis was restricted to only participants without dementia at the time ID was collected, results were similar. Linguistic ability in young adulthood, as measured by ID, has been previously proposed as an index of neurocognitive development and/or cognitive reserve. The present study provides evidence that even when ID is measured in old age, it continues to be associated with subsequent cognitive decline and as such may continue to provide a marker of cognitive reserve.

Comparison of DOTA and NODAGA as chelators for (64)Cu-labeled immunoconjugates.

PubMed

Ghosh, Sukhen C; Pinkston, Kenneth L; Robinson, Holly; Harvey, Barrett R; Wilganowski, Nathaniel; Gore, Karen; Sevick-Muraca, Eva M; Azhdarinia, Ali

2015-02-01

Bifunctional chelators have been shown to impact the biodistribution of monoclonal antibody (mAb)-based imaging agents. Recently, radiolabeled 1,4,7-triazacyclononane,1-glutaric acid-4,7-acetic acid (NODAGA)-peptide complexes have demonstrated improved in vivo stability and performance compared to their 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) counterparts. Here, we investigated if similar utility could be achieved with mAbs and compared (64)Cu-labeled DOTA and NODAGA-immunoconjugates for the detection of epithelial cell adhesion molecule (EpCAM) in a prostate cancer model. DOTA and NODAGA-immunoconjugates of an EpCAM targeting mAb (mAb7) were synthesized and radiolabeled with (64)Cu (DOTA: 40°C for 1hr; NODAGA: 25°C for 1hr). The average number of chelators per mAb was quantified by isotopic dilution, and the biological activity of the immunoconjugates was evaluated by flow cytometry and ELISA. Radioligand assays were performed to compare cellular uptake and determine the dissociation constant (Kd) and maximum number of binding sites (Bmax) for the immunoconjugates using DsRed-transfected PC3-cells. A PC3-DsRed xenograft tumor model was established in nude mice and used to perform biodistribution studies to compare organ uptake and pharmacokinetics. (64)Cu-DOTA-mAb7 and (64)Cu-NODAGA-mAb7 were prepared with chelator/protein ratios of 2-3 and obtained in comparable radiochemical yields ranging from 59 to 71%. Similar immunoreactivity was observed with both agents, and mock labeling studies indicated that incubation at room temperature or 40°C did not affect potency. (64)Cu-NODAGA-mAb7 demonstrated higher in vitro cellular uptake while (64)Cu-DOTA-mAb7 had higher Kd and Bmax values. From the biodistribution data, we found similar tumor uptake (13.44±1.21%ID/g and 13.24±4.86%ID/g for (64)Cu-DOTA-mAb7 and (64)Cu-NODAGA-mAb7, respectively) for both agents at 24hr, although normal prostate tissue was significantly lower for (64)Cu-NODAGA-mAb7. (64)Cu-NODAGA-mAb7 also had less accumulation in the liver, suggesting excellent retention of the chelation complex in vivo. This was further confirmed by the higher blood activity of (64)Cu-NODAGA-mAb7, which corresponds to increased bioavailability afforded by the enhanced in vivo stability of the agent. Although tumor/muscle ratios were comparable, tumor/prostate ratios were >2-fold and 1.5-fold higher for (64)Cu-NODAGA-mAb7 at 24 and 48hr, respectively, and suggest better ability to discriminate tumor tissue with (64)Cu-NODAGA-mAb7 in our prostate cancer model. To the best of our knowledge, this study represents the first comparison of (64)Cu-labeled DOTA and NODAGA immunoconjugates in vivo. Our results show favorable in vivo performance for (64)Cu-NODAGA-mAb7 which builds upon previous data on our hybrid mAb7 imaging agent by increasing the detection sensitivity for metastatic prostate tumors, as well as for other types of cancer that express EpCAM. Copyright © 2014 Elsevier Inc. All rights reserved.

The effect of chronic prostatitis on zinc concentration of prostatic fluid and seminal plasma: a systematic review and meta-analysis.

PubMed

Cui, Dong; Han, GuangWei; Shang, YongGang; Mu, LiJun; Long, QingZhi; Du, YueFeng

2015-01-01

Prostatitis is a common disease in urology departments. Prostatic zinc accumulation is connected with the secretory function of the prostate, and zinc concentrations present in prostatic diseases differ greatly from the normal level. Studies have investigated the effect of chronic prostatitis on zinc concentration of prostatic fluid and seminal plasma, but have shown inconsistent results. Hence, we performed a systematic literature review and meta-analysis to assess the effect of chronic prostatitis on the zinc concentration of prostatic fluid and seminal plasma. Systematic literature searches were conducted with PubMed, Embase, Science Direct/Elsevier, CNKI and the Cochrane Library up to March 2015 for case-control studies that involved the relationship between chronic prostatitis and zinc concentration of prostatic fluid and seminal plasma. Meta-analysis was performed with Review Manager and Stata software. Standard mean differences (SMDs) of zinc concentration were identified with 95% confidence intervals (95% CIs) in a random- or fixed-effects model. Our results illustrated that the zinc concentrations in prostatic fluid and seminal plasma from chronic prostatitis patients were significantly lower than normal controls (SMD [95% CI] -246.71 [-347.97, -145.44], -20.74 [-35.11, -6.37], respectively). The sample size of each study was relatively small, and a total of 731 chronic prostatitis patients and 574 normal controls were investigated in all fourteen studies. Several studies related to the subject were excluded due to lack of control data or means and standard deviations. The present study illustrates that there was a significant negative effect of chronic prostatitis on zinc concentrations of prostatic fluid and seminal plasma. Further studies with larger sample sizes are needed to better illuminate the negative impact of chronic prostatitis on zinc concentrations.

Combined prostatic urethral lift and remodeling of the prostate and bladder neck: a modified transurethral approach in the treatment of symptomatic lower urinary tract obstruction.

PubMed

Schoenthaler, Martin; Sievert, Karl-Dietrich; Schoeb, Dominik Stefan; Miernik, Arkadiusz; Kunit, Thomas; Hein, Simon; Herrmann, Thomas R W; Wilhelm, Konrad

2018-02-15

The aim of the study was to evaluate the feasibility and safety of combining prostatic urethral lift (PUL) and a limited resection of the prostatic middle lobe or bladder neck incision in the treatment of lower urinary tract symptoms (LUTS) secondary to benign prostatic hyperplasia (BPH). Twenty-eight patients were treated at two tertiary centers and followed prospectively. Patient evaluations included patient characteristics, relief of LUTS symptoms, erectile and ejaculatory function, continence, operative time and adverse events. Patients were followed for a mean of 10.9 months. Patient characteristics were as follows: age 66 years (46-85), prostate volume 39.6 cc (22-66), preoperative IPSS/AUASI 20 (6-35)/QoL 3.9 (1-6)/peak flow 10.5 mL/s (4.0-19)/post-void residual volume (PVR) 123 mL (0-500). Mean operating time was 31 min (9-55). Postoperative complications were minor except for the surgical retreatment of one patient for blood clot retention (Clavien 3b). One patient required catheterization due to urinary retention. Reduction of symptoms (IPSS - 59.6%), increase in QoL (+ 49.0%), increase in flow (+ 111.5%), and reduction of PVR (- 66.8%) were significant. Antegrade ejaculation was always maintained. Our data suggest that a combination of PUL and transurethral surgical techniques is feasible, safe, and effective. This approach may be offered to patients with moderate size prostates including those with unfavorable anatomic conditions for PUL. This procedure is still 'minimally invasive' and preserves sexual function. In addition, it may add to a higher functional efficacy compared to PUL alone. DRKS00008970.

Investigative clinical study on prostate cancer part IV: exploring functional relationships of total testosterone predicting free testosterone and total prostate-specific antigen in operated prostate cancer patients.

PubMed

Porcaro, Antonio B; Petrozziello, Aldo; Migliorini, Filippo; Lacola, Vincenzo; Romano, Mario; Sava, Teodoro; Ghimenton, Claudio; Caruso, Beatrice; Zecchini Antoniolli, Stefano; Rubilotta, Emanuele; Monaco, Carmelo; Comunale, Luigi

2011-01-01

To explore, in operated prostate cancer patients, functional relationships of total testosterone (tt) predicting free testosterone (ft) and total PSA. 128 operated prostate cancer patients were simultaneously investigated for tt, ft and PSA before surgery. Patients were not receiving 5α-reductase inhibitors, LH-releasing hormone analogues and testosterone replacement treatment. Scatter plots including ft and PSA versus tt were computed in order to assess the functional relationship of the variables. Linear regression analysis of tt predicting ft and PSA was computed. tt was a significant predictor of the response variable (ft) and different subsets of the patient population were assessed according to the ft to tt ratio. PSA was related to tt according to a nonlinear law. tt was a significant predictor of PSA according to an inversely nonlinear law and different significant clusters of the patient population were assessed according to the different constant of proportionality computed from experimental data. In our prostate cancer population, ft was significantly predicted by tt according to a linear law, and the ft/tt ratio was a significant parameter for assessing the different clusters. Also, tt was a significant variable predicting PSA by a nonlinear law and different clusters of the patient population were assessed by the different constants of proportionality. As a theory, we explain the nonlinear relation of tt in predicting PSA as follows: (a) the number of androgen-independent prostate cancer cells increases as tumor volume and PSA serum levels rise, (b) the prevalence of androgen-independent cells producing a substance which inhibits serum LH, and (c) as a result lower levels of serum tt are detected. Copyright © 2011 S. Karger AG, Basel.

Initial brazilian experience in the treatment of localized prostate cancer using a new generation cryotechnology: feasibility study.

PubMed

Kim, Fernando J; Cerqueira, Michael A; Almeida, Jose C; Pompeo, Alexandre; Sehrt, David; Calheiros, Jose M; Martins, Fernando A; Molina, Wilson R

2012-01-01

The objective of our study is to present the first Brazilian cryoablation experience in the treatment of low and intermediate risk localized prostate cancer using 3rd generation cryoablation and real-time biplanar transrectal ultrasonography. Ten Brazilian patients underwent primary cryoablation for localized prostate cancer between October 2010 and June 2011. All patients consented for whole gland primary cryotherapy. The procedures were performed by 3rd generation cryoablation with the Cryocare System ® (Endocare, Irvine, California). Preoperative data collection included patient demographics along with prostate gland size, Gleason score, serum prostate specific antigen, and erectile function status. Operative and post--operative assessment involved estimated blood loss, operative time, complications, serum PSA level, erectile function status, urinary incontinence, biochemical disease free survival (BDFS), and follow-up time. All patients in the study successfully underwent whole gland cryoablation. The mean of: age, prostate size, PSA level, and Gleason score, was 66.2 years old; 40.7 g; 7.8 ng/mL; and 6 respectively. All patients were classified as low or moderate D' Amico risk (5 low and 5 moderate). Erectile dysfunction was present in 50% of patients. The estimated blood loss was minimal, operative time was 46.1 minutes. All patients that developed erectile dysfunction post-treatment responded to oral or intracavernosal medications with early penile rehabilitation. All patients maintained urinary continence by the end of a 10 months evaluation period and none had biochemical relapse within the mean follow-up of 13 months (7-15 months). Our initial experience shows that cryoablation is a minimally invasive option for the treatment of localized prostate cancer. Short term data seems to be promising but longer follow-up is necessary to verify oncological and functional results.

Splicing Factor Prp8 Interacts With NES(AR) and Regulates Androgen Receptor in Prostate Cancer Cells.

PubMed

Wang, Dan; Nguyen, Minh M; Masoodi, Khalid Z; Singh, Prabhpreet; Jing, Yifeng; O'Malley, Katherine; Dar, Javid A; Dhir, Rajiv; Wang, Zhou

2015-12-01

Androgen receptor (AR) plays a pivotal role in the development of primary as well as advanced castration-resistant prostate cancer. Previous work in our lab identified a novel nuclear export signal (NES) (NES(AR)) in AR ligand-binding domain essential for AR nucleocytoplasmic trafficking. By characterizing the localization of green fluorescence protein (GFP)-tagged NES(AR), we designed and executed a yeast mutagenesis screen and isolated 7 yeast mutants that failed to display the NES(AR) export function. One of those mutants was identified as the splicing factor pre-mRNA processing factor 8 (Prp8). We further showed that Prp8 could regulate NES(AR) function using short hairpin RNA knockdown of Prp8 coupled with a rapamycin export assay in mammalian cells and knockdown of Prp8 could induce nuclear accumulation of GFP-tagged AR in PC3 cells. Prp8 expression was decreased in castration-resistant LuCaP35 xenograft tumors as compared with androgen-sensitive xenografts. Laser capture microdissection and quantitative PCR showed Prp8 mRNA levels were decreased in human prostate cancer specimens with high Gleason scores. In prostate cancer cells, coimmunoprecipitation and deletion mutagenesis revealed a physical interaction between Prp8 and AR mainly mediated by NES(AR). Luciferase assay with prostate specific antigen promoter-driven reporter demonstrated that Prp8 regulated AR transcription activity in prostate cancer cells. Interestingly, Prp8 knockdown also increased polyubiquitination of endogenous AR. This may be 1 possible mechanism by which it modulates AR activity. These results show that Prp8 is a novel AR cofactor that interacts with NES(AR) and regulates AR function in prostate cancer cells.

Reactivation of Embryonic Nodal Signaling is Associated with Tumor Progression and Promotes the Growth of Prostate Cancer Cells

PubMed Central

Lawrence, Mitchell G.; Margaryan, Naira V.; Loessner, Daniela; Collins, Angus; Kerr, Kris M.; Turner, Megan; Seftor, Elisabeth A.; Stephens, Carson R.; Lai, John; BioResource, APC; Postovit, Lynne-Marie; Clements, Judith A.; Hendrix, Mary J.C.

2011-01-01

Background Nodal is a member of the Transforming Growth Factor β (TGFβ) superfamily that directs embryonic patterning and promotes the plasticity and tumorigenicity of tumor cells, but its role in the prostate is unknown. The goal of this study was to characterize the expression and function of Nodal in prostate cancer and determine whether, like other TGFβ ligands, it modulates androgen receptor (AR) activity. Methods Nodal expression was investigated using immunohistochemistry of tissue microarrays and Western blots of prostate cell lines. The functional role of Nodal was examined using Matrigel and soft agar growth assays. Cross-talk between Nodal and AR signaling was assessed with luciferase reporter assays and expression of endogenous androgen regulated genes. Results Significantly increased Nodal expression was observed in cancer compared with benign prostate specimens. Nodal was only expressed by DU145 and PC3 cells. All cell lines expressed Nodal’s co-receptor, Cripto-1, but lacked Lefty, a critical negative regulator of Nodal signaling. Recombinant human Nodal triggered downstream Smad2 phosphorylation in DU145 and LNCaP cells, and stable transfection of pre-pro-Nodal enhanced the growth of LNCaP cells in Matrigel and soft agar. Finally, Nodal attenuated AR signaling, reducing the activity of a PSA promoter construct in luciferase assays and down-regulating the endogenous expression of androgen regulated genes. Conclusions An aberrant Nodal signaling pathway is re-expressed and functionally active in prostate cancer cells. PMID:21656830

The Androgen-Regulated Calcium-Activated Nucleotidase 1 (CANT1) Is Commonly Overexpressed in Prostate Cancer and Is Tumor-Biologically Relevant in Vitro

PubMed Central

Gerhardt, Josefine; Steinbrech, Corinna; Büchi, Oralea; Behnke, Silvia; Bohnert, Annette; Fritzsche, Florian; Liewen, Heike; Stenner, Frank; Wild, Peter; Hermanns, Thomas; Müntener, Michael; Dietel, Manfred; Jung, Klaus; Stephan, Carsten; Kristiansen, Glen

2011-01-01

Previously, we identified the calcium-activated nucleotidase 1 (CANT1) transcript as up-regulated in prostate cancer. Now, we studied CANT1 protein expression in a large cohort of nearly 1000 prostatic tissue samples including normal tissue, prostatic intraepithelial neoplasia (PIN), primary carcinomas, metastases, and castrate-resistant carcinomas, and further investigated its functional relevance. CANT1 displayed predominantly a Golgi-type immunoreactivity with additional and variable cytoplasmic staining. In comparison to normal tissues, the staining intensity was significantly increased in PIN lesions and cancer. In cancer, high CANT1 levels were associated with a better prognosis, and castrate-resistant carcinomas commonly showed lower CANT1 levels than primary carcinomas. The functional role of CANT1 was investigated using RNA interference in two prostate cancer cell lines with abundant endogenous CANT1 protein. On CANT1 knockdown, a significantly diminished cell number and DNA synthesis rate, a cell cycle arrest in G1 phase, and a strong decrease of cell transmigration rate and wound healing capacity of CANT1 knockdown cells was found. However, on forced CANT1 overexpression, cell proliferation and migration remained unchanged. In summary, CANT1 is commonly overexpressed in the vast majority of primary prostate carcinomas and in the precursor lesion PIN and may represent a novel prognostic biomarker. Moreover, this is the first study to demonstrate a functional involvement of CANT1 in tumor biology. PMID:21435463

Trajectories of quality of life, life satisfaction, and psychological adjustment after prostate cancer.

PubMed

Chambers, Suzanne K; Ng, Shu Kay; Baade, Peter; Aitken, Joanne F; Hyde, Melissa K; Wittert, Gary; Frydenberg, Mark; Dunn, Jeff

2017-10-01

To describe trajectories of health-related quality of life (QoL), life satisfaction, and psychological adjustment for men with prostate cancer over the medium to long term and identify predictors of poorer outcomes using growth mixture models. One-thousand sixty-four (82.4% response) men diagnosed with prostate cancer were recruited close to diagnosis and assessed over a 72-month (6-year) period with self-report assessment of health-related QoL, life satisfaction, cancer-related distress, and prostate specific antigen anxiety. Urinary, bowel, and sexual function were also assessed using validated questionnaires. Poorer physical QOL was predicted by older age, lower education, lower income, comorbidities, and receiving hormone therapy. Lower life satisfaction was related to younger age, lower income, not being partnered, and comorbidities. Poorer psychological trajectories were predicted by younger age, lower income, comorbidities, and receiving radical prostatectomy or brachytherapy. Better urinary, bowel, and sexual function were related to better global outcomes over time. Anxiety about prostate specific antigen testing was rare. Distinct trajectories exist for medium- to long-term QoL, life satisfaction, and psychological adjustment after prostate cancer; with age and socioeconomic deprivation playing a differential role in men's survivorship profile and the impact of functional status on outcomes increasing over time. These results reinforce the need for an appraisal of men's life course in addition to treatment side effects when planning survivorship care after cancer. © 2016 The Authors. Psycho-Oncology Published by John Wiley & Sons Ltd.

Disease-specific and general health-related quality of life in newly diagnosed prostate cancer patients: the Pros-IT CNR study.

PubMed

Porreca, Angelo; Noale, Marianna; Artibani, Walter; Bassi, Pier Francesco; Bertoni, Filippo; Bracarda, Sergio; Conti, Giario Natale; Corvò, Renzo; Gacci, Mauro; Graziotti, Pierpaolo; Magrini, Stefano Maria; Mirone, Vincenzo; Montironi, Rodolfo; Muto, Giovanni; Pecoraro, Stefano; Ricardi, Umberto; Russi, Elvio; Tubaro, Andrea; Zagonel, Vittorina; Crepaldi, Gaetano; Maggi, Stefania

2018-06-13

The National Research Council (CNR) prostate cancer monitoring project in Italy (Pros-IT CNR) is an observational, prospective, ongoing, multicentre study aiming to monitor a sample of Italian males diagnosed as new cases of prostate cancer. The present study aims to present data on the quality of life at time prostate cancer is diagnosed. One thousand seven hundred five patients were enrolled. Quality of life is evaluated at the time cancer was diagnosed and at subsequent assessments via the Italian version of the University of California Los Angeles-Prostate Cancer Index (UCLA-PCI) and the Short Form Health Survey (SF-12). At diagnosis, lower scores on the physical component of the SF-12 were associated to older ages, obesity and the presence of 3+ moderate/severe comorbidities. Lower scores on the mental component were associated to younger ages, the presence of 3+ moderate/severe comorbidities and a T-score higher than one. Urinary and bowel functions according to UCLA-PCI were generally good. Almost 5% of the sample reported using at least one safety pad daily to control urinary loss; less than 3% reported moderate/severe problems attributable to bowel functions, and sexual function was a moderate/severe problem for 26.7%. Diabetes, 3+ moderate/severe comorbidities, T2 or T3-T4 categories and a Gleason score of eight or more were significantly associated with lower sexual function scores at diagnosis. Data collected by the Pros-IT CNR study have clarified the baseline status of newly diagnosed prostate cancer patients. A comprehensive assessment of quality of life will allow to objectively evaluate outcomes of different profile of care.

[Transrectal magnetotherapy of the prostate from Intramag device in prophylaxis of postoperative complications of transurethral resection of prostatic adenoma].

PubMed

Neĭmark, A I; Snegirev, I V; Neĭmark, B A

2006-01-01

The authors analyse preoperative preparation of 91 patients with benign prostatic hyperplasia (BPH). Two groups of patients received conventional preparation (group 1) and magnetotherapy (group 2) before TUR of the prostate. The examination covered immune system, bacteriological indices of urine and prostatic tissue. Infection of the urinary tract is a main risk factor of complications after TUR. Conventional preoperative preparation fails to correct immunity, to change bacterial urine flora, to improve hemodynamics in the prostate. Transrectal magnetotherapy with running magnetic field eliminates deficiency of T- and B-cell immunity, raises functional activity of B-lymphocytes and phagocytic ability of neutrophils, reduces endogenic intoxication, tissue edema, bacterial contamination, number of thrombohemorrhagic complications. This leads to a decrease in the number of postoperative complications.

Impact of Androgen Deprivation Therapy on Self-Reported Cognitive Function in Men with Prostate Cancer.

PubMed

Marzouk, Shireen; Naglie, Gary; Tomlinson, George; Duff Canning, Sarah; Breunis, Henriette; Timilshina, Narhari; Alibhai, Shabbir M H

2018-03-01

Although androgen deprivation therapy is widely used to treat prostate cancer, its effects on cognitive function are unclear. To our knowledge no prior report has examined the impact of androgen deprivation therapy on self-reported cognitive function. Three groups of men 50 years old or older who were matched on age and education were enrolled in the study, including 81 with prostate cancer starting on continuous androgen deprivation therapy, 84 controls with prostate cancer not receiving androgen deprivation therapy and 85 healthy controls. Two scales from the FACT-Cog (Functional Assessment of Cancer Therapy-Cognitive subscale) version 3 were used to assess self-reported cognitive function. Changes in cognitive scores with time were analyzed by 2 approaches, including 1) multivariable regression and 2) calculation of the proportion of subjects per group with a decrease of 1 SD or more. Multivariable regression was applied to assess predictors of a decline in self-reported cognitive function. We also examined relationships between the FACT-Cog and a neuropsychological battery of 15 tests. Mean participant age was 69 years (range 50 to 87). The mean educational level was 15 years (range 8 to 24). FACT-Cog scores were similar at baseline across the cohorts. Neither analytical approach revealed that androgen deprivation therapy was associated with changes in self-reported cognitive function on either FACT-Cog scale. Mood and fatigue correlated with changes in self-reported cognitive function. The relationship between self-reported and objective cognitive measures was weak (maximum Spearman correlation coefficient 0.14) and only 2 of 30 correlations were statistically significant. A total of 12 months of androgen deprivation therapy were not associated with self-reported cognitive function changes in older men with nonmetastatic prostate cancer. Copyright © 2018 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.

Essential Roles of Epithelial Bone Morphogenetic Protein Signaling During Prostatic Development

PubMed Central

Omori, Akiko; Miyagawa, Shinichi; Ogino, Yukiko; Harada, Masayo; Ishii, Kenichiro; Sugimura, Yoshiki; Ogino, Hajime; Nakagata, Naomi

2014-01-01

Prostate is a male sex-accessory organ. The prostatic epithelia consist primarily of basal and luminal cells that differentiate from embryonic urogenital sinus epithelia. Prostate tumors are believed to originate in the basal and luminal cells. However, factors that promote normal epithelial differentiation have not been well elucidated, particularly for bone morphogenetic protein (Bmp) signaling. This study shows that Bmp signaling prominently increases during prostatic differentiation in the luminal epithelia, which is monitored by the expression of phosphorylated Smad1/5/8. To elucidate the mechanism of epithelial differentiation and the function of Bmp signaling during prostatic development, conditional male mutant mouse analysis for the epithelial-specific Bmp receptor 1a (Bmpr1a) was performed. We demonstrate that Bmp signaling is indispensable for luminal cell maturation, which regulates basal cell proliferation. Expression of the prostatic epithelial regulatory gene Nkx3.1 was significantly reduced in the Bmpr1a mutants. These results indicate that Bmp signaling is a key factor for prostatic epithelial differentiation, possibly by controlling the prostatic regulatory gene Nkx3.1. PMID:24731097

GSTP1 Loss results in accumulation of oxidative DNA base damage and promotes prostate cancer cell survival following exposure to protracted oxidative stress.

PubMed

Mian, Omar Y; Khattab, Mohamed H; Hedayati, Mohammad; Coulter, Jonathan; Abubaker-Sharif, Budri; Schwaninger, Julie M; Veeraswamy, Ravi K; Brooks, James D; Hopkins, Lisa; Shinohara, Debika Biswal; Cornblatt, Brian; Nelson, William G; Yegnasubramanian, Srinivasan; DeWeese, Theodore L

2016-02-01

Epigenetic silencing of glutathione S-transferase π (GSTP1) is a hallmark of transformation from normal prostatic epithelium to adenocarcinoma of the prostate. The functional significance of this loss is incompletely understood. The present study explores the effects of restored GSTP1 expression on glutathione levels, accumulation of oxidative DNA damage, and prostate cancer cell survival following oxidative stress induced by protracted, low dose rate ionizing radiation (LDR). GSTP1 protein expression was stably restored in LNCaP prostate cancer cells. The effect of GSTP1 restoration on protracted LDR-induced oxidative DNA damage was measured by GC-MS quantitation of modified bases. Reduced and oxidized glutathione levels were measured in control and GSTP1 expressing populations. Clonogenic survival studies of GSTP1- transfected LNCaP cells after exposure to protracted LDR were performed. Global gene expression profiling and pathway analysis were performed. GSTP1 expressing cells accumulated less oxidized DNA base damage and exhibited decreased survival compared to control LNCaP-Neo cells following oxidative injury induced by protracted LDR. Restoration of GSTP1 expression resulted in changes in modified glutathione levels that correlated with GSTP1 protein levels in response to protracted LDR-induced oxidative stress. Survival differences were not attributable to depletion of cellular glutathione stores. Gene expression profiling and pathway analysis following GSTP1 restoration suggests this protein plays a key role in regulating prostate cancer cell survival. The ubiquitous epigenetic silencing of GSTP1 in prostate cancer results in enhanced survival and accumulation of potentially promutagenic DNA adducts following exposure of cells to protracted oxidative injury suggesting a protective, anti-neoplastic function of GSTP1. The present work provides mechanistic backing to the tumor suppressor function of GSTP1 and its role in prostate carcinogenesis. © 2015 Wiley Periodicals, Inc.

GSTP1 Loss Results in Accumulation of Oxidative DNA Base Damage and Promotes Prostate Cancer Cell Survival Following Exposure to Protracted Oxidative Stress

PubMed Central

Mian, Omar Y.; Khattab, Mohamed H.; Hedayati, Mohammad; Coulter, Jonathan; Abubaker-Sharif, Budri; Schwaninger, Julie M.; Veeraswamy, Ravi K.; Brooks, James D.; Hopkins, Lisa; Shinohara, Debika Biswal; Cornblatt, Brian; Nelson, William G.; Yegnasubramanian, Srinivasan; DeWeese, Theodore L.

2016-01-01

BACKGROUND Epigenetic silencing of glutathione S-transferase π (GSTP1) is a hallmark of transformation from normal prostatic epithelium to adenocarcinoma of the prostate. The functional significance of this loss is incompletely understood. The present study explores the effects of restored GSTP1 expression on glutathione levels, accumulation of oxidative DNA damage, and prostate cancer cell survival following oxidative stress induced by protracted, low dose rate ionizing radiation (LDR). METHODS GSTP1 protein expression was stably restored in LNCaP prostate cancer cells. The effect of GSTP1 restoration on protracted LDR-induced oxidative DNA damage was measured by GC-MS quantitation of modified bases. Reduced and oxidized glutathione levels were measured in control and GSTP1 expressing populations. Clonogenic survival studies of GSTP1-transfected LNCaP cells after exposure to protracted LDR were performed. Global gene expression profiling and pathway analysis were performed. RESULTS GSTP1 expressing cells accumulated less oxidized DNA base damage and exhibited decreased survival compared to control LNCaP-Neo cells following oxidative injury induced by protracted LDR. Restoration of GSTP1 expression resulted in changes in modified glutathione levels that correlated with GSTP1 protein levels in response to protracted LDR-induced oxidative stress. Survival differences were not attributable to depletion of cellular glutathione stores. Gene expression profiling and pathway analysis following GSTP1 restoration suggests this protein plays a key role in regulating prostate cancer cell survival. CONCLUSIONS The ubiquitous epigenetic silencing of GSTP1 in prostate cancer results in enhanced survival and accumulation of potentially promutagenic DNA adducts following exposure of cells to protracted oxidative injury suggesting a protective, anti-neoplastic function of GSTP1. The present work provides mechanistic backing to the tumor suppressor function of GSTP1 and its role in prostate carcinogenesis. PMID:26447830

Protective effect of tadalafil on the functional and structural changes of the rat ventral prostate caused by chronic pelvic ischemia.

PubMed

Zarifpour, Mona; Nomiya, Masanori; Sawada, Norifumi; Andersson, Karl-Erik

2015-02-15

The etiology of Benign Prostatic Hyperplasia (BPH), a common among aged men, is not fully understood, however, in addition to androgens and aging, chronic ischemia has been proposed to contribute. Using an established rat model, we investigated whether chronic ischemia alters the structural and functional properties of the ventral rat prostate, and whether phosphodiesterase type 5 (PDE5) inhibitor (tadalafil) may have a protective action. Adult male Sprague-Dawley rats were divided into control, arterial endothelial injury (AI), and AI with tadalafil treatment (AI-tadalafil) groups. AI and AI-tadalafil groups underwent endothelial injury of the iliac arteries and received a 2% cholesterol diet following AI. AI-tadalafil rats were treated with tadalafil (2 mg/kg/day) orally for 8 weeks after AI. The control group received a regular diet. After 8 weeks, animals were sacrificed, and pharmacological and morphological studies on prostate tissues were performed. Iliac arteries from AI rats displayed neo-intimal formation and luminal occlusion, an effect that was not prevented by tadalafil treatment. In the AI group, there was an obvious epithelial atrophy and a statistically significant increase in collagen fibers compared with the controls. Immunohistochemically, there was an up-regulation of smooth muscle α-actin (SMA). Contractile responses of prostate strips to KCl, electrical field stimulation (EFS), and phenylephrine (PE) were significantly higher after AI than in controls. Chronic treatment with tadalafil prevented the increase in contractile responses in ischemic tissue, and decreased the collagen deposition compared with the AI group. In this rat model, chronic pelvic ischemia caused distinct functional and morphological changes in the prostate. Prostatic tissue from ischemic animals showed an increased contractile response to electrical and pharmacological stimulation, an increase in SMA, and an increased deposition of collagen. All these changes could be prevented by treatment with the PDE5 inhibitor, tadalafil, suggesting an involvement of cyclic guanosine monophosphate (cGMP). © 2014 The Authors. The Prostate Published by Wiley Periodicals, Inc.

Stem cells in prostate cancer initiation and progression

PubMed Central

Lawson, Devon A.; Witte, Owen N.

2007-01-01

Peter Nowell and David Hungerford’s discovery of the Philadelphia chromosome facilitated many critical studies that have led to a paradigm shift in our understanding of cancer as a disease of stem cells. This Review focuses on the application of these concepts to investigation of the role of stem cells in prostate cancer initiation and progression. Major strides in the development of in vitro and in vivo assays have enabled identification and characterization of prostate stem cells as well as functional evaluation of the tumorigenic effects of prostate cancer–related genetic alterations. PMID:17671638

Influence of the neural microenvironment on prostate cancer

PubMed Central

Coarfa, Christian; Florentin, Diego; Putluri, NagiReddy; Ding, Yi; Au, Jason; He, Dandan; Ragheb, Ahmed; Frolov, Anna; Michailidis, George; Lee, MinJae; Kadmon, Dov; Miles, Brian; Smith, Christopher; Ittmann, Michael; Rowley, David; Sreekumar, Arun; Creighton, Chad J.

2017-01-01

Background Nerves are key factors in prostate cancer (PCa), but the functional role of innervation in prostate cancer is poorly understood. PCa induced neurogenesis and perineural invasion (PNI), are associated with aggressive disease. Method We denervated rodent prostates chemically and physically, before orthotopically implanting cancer cells. We also performed a human neoadjuvant clinical trial using botulinum toxin type A (Botox) and saline in the same patient, before prostatectomy. Result Bilateral denervation resulted in reduced tumor incidence and size in mice. Botox treatment in humans resulted in increased apoptosis of cancer cells in the Botox treated side. A similar denervation gene array profile was identified in tumors arising in denervated rodent prostates, in spinal cord injury patients and in the Botox treated side of patients. Denervation induced exhibited a signature gene profile, indicating translation and bioenergetic shutdown. Nerves also regulate basic cellular functions of non‐neoplastic epithelial cells. Conclusion Nerves play a role in the homeostasis of normal epithelial tissues and are involved in prostate cancer tumor survival. This study confirms that interactions between human cancer and nerves are essential to disease progression. This work may make a major impact in general cancer treatment strategies, as nerve/cancer interactions are likely important in other cancers as well. Targeting the neural microenvironment may represent a therapeutic approach for the treatment of human prostate cancer. PMID:29131367

Investigation of scattering coefficients and anisotropy factors of human cancerous and normal prostate tissues using Mie theory

NASA Astrophysics Data System (ADS)

Pu, Yang; Chen, Jun; Wang, Wubao

2014-02-01

The scattering coefficient, μs, the anisotropy factor, g, the scattering phase function, p(θ), and the angular dependence of scattering intensity distributions of human cancerous and normal prostate tissues were systematically investigated as a function of wavelength, scattering angle and scattering particle size using Mie theory and experimental parameters. The Matlab-based codes using Mie theory for both spherical and cylindrical models were developed and applied for studying the light propagation and the key scattering properties of the prostate tissues. The optical and structural parameters of tissue such as the index of refraction of cytoplasm, size of nuclei, and the diameter of the nucleoli for cancerous and normal human prostate tissues obtained from the previous biological, biomedical and bio-optic studies were used for Mie theory simulation and calculation. The wavelength dependence of scattering coefficient and anisotropy factor were investigated in the wide spectral range from 300 nm to 1200 nm. The scattering particle size dependence of μs, g, and scattering angular distributions were studied for cancerous and normal prostate tissues. The results show that cancerous prostate tissue containing larger size scattering particles has more contribution to the forward scattering in comparison with the normal prostate tissue. In addition to the conventional simulation model that approximately considers the scattering particle as sphere, the cylinder model which is more suitable for fiber-like tissue frame components such as collagen and elastin was used for developing a computation code to study angular dependence of scattering in prostate tissues. To the best of our knowledge, this is the first study to deal with both spherical and cylindrical scattering particles in prostate tissues.

Human Prostate Side Population Cells Demonstrate Stem Cell Properties in Recombination with Urogenital Sinus Mesenchyme

PubMed Central

Foster, Barbara A.; Gangavarapu, Kalyan J.; Mathew, Grinu; Azabdaftari, Gissou; Morrison, Carl D.; Miller, Austin; Huss, Wendy J.

2013-01-01

Stem cell enrichment provides a tool to examine prostate stem cells obtained from benign and malignant tissue. Functional assays can enrich stem cells based on common stem cell phenotypes, such as high ATP binding cassette (ABC) transporter mediated efflux of Hoechst substrates (side population assay). This functional assay is based upon mechanisms that protect cells from environmental insult thus contributing to the survival and protection of the stem cell population. We have isolated and analyzed cells digested from twelve clinical prostate specimens based on the side population assay. Prostate stem cell properties of the isolated cells were tested by serial recombination with rat urogenital mesenchyme. Recombinants with side population cells demonstrate an increase in the frequency of human ductal growth and the number of glands per recombinant when compared to recombinants with non-side population cells. Isolated cells were capable of prostatic growth for up to three generations in the recombination assay with as little as 125 sorted prostate cells. The ability to reproducibly use cells isolated by fluorescence activated cell sorting from human prostate tissue is an essential step to a better understanding of human prostate stem cell biology. ABC transporter G2 (ABCG2) was expressed in recombinants from side population cells indicating the side population cells have self-renewal properties. Epithelial cell differentiation of recombinants was determined by immunohistochemical analysis for expression of the basal, luminal, and neuroendocrine markers, p63, androgen receptor, prostate specific antigen, and chromogranin A, respectively. Thus, the ABCG2 expressing side population demonstrates multipotency and self-renewal properties indicating stem cells are within this population. PMID:23383057

Implications of pleiotrophin in human PC3 prostate cancer cell growth in vivo.

PubMed

Tsirmoula, Sotiria; Dimas, Kostas; Hatziapostolou, Maria; Lamprou, Margarita; Ravazoula, Panagiota; Papadimitriou, Evangelia

2012-10-01

Pleiotrophin (PTN) is a heparin-binding growth factor with diverse functions related to tumor growth, angiogenesis, and metastasis. Pleiotrophin seems to have a significant role in prostate cancer cell growth and to mediate the stimulatory actions of other factors that affect prostate cancer cell functions. However, all studies carried out up to date are in vitro, using different types of human prostate cancer cell lines. The aim of the present work was to study the role of endogenous PTN in human prostate cancer growth in vivo. For this purpose, human prostate cancer PC3 cells were stably transfected with a plasmid vector, bearing the antisense PTN sequence, in order to inhibit PTN expression (AS-PC3). Migration, apoptosis, and adhesion on osteoblastic cells were measured in vitro. In vivo, PC3 cells were s.c. injected into male NOD/SCID mice, and tumor growth, survival rates, angiogenesis, apoptosis, and the number of metastasis were estimated. Pleiotrophin depletion resulted in a decreased migration capability of AS-PC3 cells compared with the corresponding mock-transfected or the non-transfected PC3 cells, as well as increased apoptosis and decreased adhesiveness to osteoblastic cells in vitro. In prostate cancer NOD/SCID mouse xenografts, PTN depletion significantly suppressed tumor growth and angiogenesis and induced apoptosis of cancer cells. In addition, PTN depletion decreased the number of metastases, providing a survival benefit for the animals bearing AS-PC3 xenografts. Our data suggest that PTN is implicated in human prostate cancer growth in vivo and could be considered a potential target for the development of new therapeutic approaches for prostate cancer. © 2012 Japanese Cancer Association.

Comprehensive quality-of-life outcomes in the setting of a multidisciplinary, equal access prostate cancer clinic.

PubMed

Rice, Kevin; Hudak, Jane; Peay, Kimberly; Elsamanoudi, Sally; Travis, Judith; Lockhart, Robbin; Cullen, Jennifer; Black, Libby; Houge, Susan; Brassell, Stephen

2010-11-01

To identify racial and demographic factors that influence treatment choice and its resulting impact on health-related quality of life (HRQoL) for prostate cancer patients. Patients presenting to an equal access, military, multidisciplinary prostate cancer clinic composed the study group. The Expanded Prostate Cancer Index Composite (EPIC), EPIC Demographic, and Medical Outcomes Study Short Form 36 were the instruments used. Evaluation was performed before treatment and every 3 months after treatment. The study group comprised 665 patients. Caucasians were 3-fold more likely to choose surgery (radical prostatectomy [RP]) over external beam radiation therapy (EBRT). Patients who earned more than $100,000 annually disproportionately chose RP (P < .0001). Similarly, those having a graduate school degree disproportionally chose RP (P < .0001). Patients undergoing RP had the greatest risk of urinary function decline (P < .0001) and sexual bother (P = .0003). African Americans (AA) had a greater risk of urinary function decline irrespective of treatment choice. Patients undergoing EBRT had equivalent urinary function to expectant management (EM) at 12 months (P < .0001). Brachytherapy was the only treatment that posed an increased risk of urinary bother decline when compared with EM (P = .0217). EBRT alone did not show significant decrement in sexual function when compared with EM. RP was chosen by patients of Caucasian ethnicity and patients with higher income and education level, despite providing the greatest risk of HRQoL decline. EBRT had no significant impact on urinary function, sexual function, or sexual bother scores at 12 months. EBRT may be offered to older patients with minimal HRQoL impact. Pretreatment counseling of HRQoL outcomes is essential to overall prostate cancer management. Published by Elsevier Inc.

Sexual outcome of patients undergoing thulium laser enucleation of the prostate for benign prostatic hyperplasia.

PubMed

Carmignani, Luca; Bozzini, Giorgio; Macchi, Alberto; Maruccia, Serena; Picozzi, Stefano; Casellato, Stefano

2015-01-01

Treatment of patients with lower urinary tract symptoms (LUTS) secondary to benign prostatic hyperplasia (BPH) may affect the quality of sexual function and ejaculation. The effect of new surgical procedures, which are currently available to treat BPH, on erection and ejaculation, has been poorly studied. This study aimed to assess the effect of thulium laser enucleation of the prostate (ThuLEP) on sexual function and retrograde ejaculation in patients with LUTS secondary to BPH. We performed a prospective study in 110 consecutive patients who had undergone ThuLEP to analyze changes in sexual function and urinary symptoms. To evaluate changes in erection and ejaculation, and the effect of urinary symptoms on the quality of life (QoL), five validated questionnaires were used: the ICIQ-MLUTSsex, MSHQ-EjD, International Index of Erectile Function 5, International Prognostic Scoring System (IPSS) questionnaire, and QoL index of the intraclass correlation coefficients. Patients also underwent IPSS and flowmetry to assess the outcome of flow. Patients were evaluated before surgery and 3-6 months after ThuLEP, whereas those with previous abdominal surgery were excluded. The patients' mean age was 67.83 years. Postoperative urinary symptoms improved after surgery. No significant differences in erectile function before and after surgery were observed. As compared with other techniques described in the literature, the percentage of patients with conserved ejaculation increased by 52.7% after ThuLEP. ThuLEP positively affects urinary symptoms and their effect on the QoL of patients as assessed by questionnaire scores. While endoscopic management of BPH (e.g. transurethral resection of the prostate) causes retrograde ejaculation in most patients, those who undergo ThuLEP have conserved ejaculation and erectile function.

[Bacterial prostatitis and prostatic fibrosis: modern view on the treatment and prophylaxis].

PubMed

Zaitsev, A V; Pushkar, D Yu; Khodyreva, L A; Dudareva, A A

2016-08-01

Treatments of chronic bacterial prostatitis (CP) remain difficult problem. Bacterial prostatitis is a disease entity diagnosed clinically and by evidence of inflammation and infection localized to the prostate. Risk factors for UTI in men include urological interventions, such as transrectal prostate biopsy. Ensuing infections after prostate biopsy, such as UTI and bacterial prostatitis, are increasing due to increasing rates of fluoroquinolone resistance. The increasing global antibiotic resistance also significantly affects management of UTI in men, and therefore calls for alternative strategies. Prostatic inflammation has been suggested to contribute to the etiology of lower urinary tract symptoms (LUTS) by inducing fibrosis. Several studies have shown that prostatic fibrosis is strongly associated with impaired urethral function and LUTS severity. Fibrosis resulting from excessive deposition of collagen is traditionally recognized as a progressive irreversible condition and an end stage of inflammatory diseases; however, there is compelling evidence in both animal and human studies to support that the development of fibrosis could potentially be a reversible process. Prostate inflammation may induce fibrotic changes in periurethral prostatic tissues, promote urethral stiffness and LUTS. Patients experiencing CP and prostate-related LUTS could benefit from anti-inflammatory therapies, especially used in combination with the currently prescribed enzyme treatment with Longidase. Treatment results showed that longidase is highly effective in bacterial and abacterial CP. Longidase addition to standard therapeutic methods significantly reduced the disease symptoms and regression of inflammatory-proliferative alterations in the prostate.

Characterization and evaluation of DOTA-conjugated Bombesin/RGD-antagonists for prostate cancer tumor imaging and therapy.

PubMed

Stott Reynolds, Tamila J; Schehr, Rebecca; Liu, Dijie; Xu, Jingli; Miao, Yubin; Hoffman, Timothy J; Rold, Tammy L; Lewis, Michael R; Smith, Charles J

2015-02-01

Here we present the metallation, characterization, in vivo and in vitro evaluations of dual-targeting, peptide-based radiopharmaceuticals with utility for imaging and potentially treating prostate tumors by virtue of their ability to target the αVβ3 integrin or the gastrin releasing peptide receptor (GRPr). [RGD-Glu-6Ahx-RM2] (RGD: Arg-Gly-Asp; Glu: glutamic acid; 6-Ahx: 6-amino hexanoic acid; RM2: (D-Phe-Gln-Trp-Ala-Val-Gly-His-Sta-Leu-NH2)) was conjugated to a DOTA (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid) bifunctional chelator (BFCA) purified via reversed-phase high-performance liquid chromatography (RP-HPLC), characterized by electrospray ionization-mass spectrometry (ESI-MS), and radiolabeled with (111)In or (177)Lu. Natural-metallated compounds were assessed for binding affinity for the αVβ3 integrin or GRPr in human glioblastoma U87-MG and prostate PC-3 cell lines and stability prior to in vivo evaluation in normal CF-1 mice and SCID mice xenografted with PC-3 cells. Competitive displacement binding assays with PC-3 and U87-MG cells revealed high to moderate binding affinity for the GRPr or the αVβ3 integrin (IC50 range of 5.39±1.37 nM to 9.26±0.00 nM in PC-3 cells, and a range of 255±47 nM to 321±85 nM in U87-MG cells). Biodistribution studies indicated high tumor uptake in PC-3 tumor-bearing mice (average of 7.40±0.53% ID/g at 1h post-intravenous injection) and prolonged retention of tracer (mean of 4.41±0.91% ID/g at 24h post-intravenous injection). Blocking assays corroborated the specificity of radioconjugates for each target. Micro-single photon emission computed tomography (microSPECT) confirmed favorable radiouptake profiles in xenografted mice at 20h post-injection. [RGD-Glu-[(111)In-DO3A]-6-Ahx-RM2] and [RGD-Glu-[(177)Lu- DO3A]-6-Ahx-RM2] show favorable pharmacokinetic and radiouptake profiles, meriting continued evaluation for molecular imaging in murine U87-MG/PC-3 xenograft models and radiotherapy studies with (177)Lu and (90)Y conjugates. These heterovalent, peptide-targeting ligands perform comparably with many mono- and multivalent conjugates with the potential benefit of increased sensitivity for detecting cancer cells exhibiting differential expression of target receptors. Published by Elsevier Inc.

The Atypical Cadherin Dachsous Controls Left-Right Asymmetry in Drosophila.

PubMed

González-Morales, Nicanor; Géminard, Charles; Lebreton, Gaëlle; Cerezo, Delphine; Coutelis, Jean-Baptiste; Noselli, Stéphane

2015-06-22

Left-right (LR) asymmetry is essential for organ development and function in metazoans, but how initial LR cue is relayed to tissues still remains unclear. Here, we propose a mechanism by which the Drosophila LR determinant Myosin ID (MyoID) transfers LR information to neighboring cells through the planar cell polarity (PCP) atypical cadherin Dachsous (Ds). Molecular interaction between MyoID and Ds in a specific LR organizer controls dextral cell polarity of adjoining hindgut progenitors and is required for organ looping in adults. Loss of Ds blocks hindgut tissue polarization and looping, indicating that Ds is a crucial factor for both LR cue transmission and asymmetric morphogenesis. We further show that the Ds/Fat and Frizzled PCP pathways are required for the spreading of LR asymmetry throughout the hindgut progenitor tissue. These results identify a direct functional coupling between the LR determinant MyoID and PCP, essential for non-autonomous propagation of early LR asymmetry. Copyright © 2015 Elsevier Inc. All rights reserved.

The Function of Neuroendocrine Cells in Prostate Cancer

DTIC Science & Technology

2015-06-20

Comprehensive Cancer Center and 4Broad Center for Regenerative Medicine and Stem Cell Biology, David Geffen School of Medicine at UCLA, 10833 Le Conte... Regenerative Medicine and Stem Cell Research, UCLA David Geffen School of Medicine , Los Angeles, California. 2Department of Urology, The First...progress in prostate cancer. Soochou University Annual Translational Medicine Meeting, Suzhou, China, November 2013 21. Prostate Cancer Stem Cells

[Physical factors in the treatment and rehabilitation of patients with chronic prostatitis complicated by impotence].

PubMed

Karpukhin, I V; Bogomol'nyĭ, V A

1999-01-01

103 patients with chronic prostatitis complicated by erectile impotence were given combined treatment including shock-wave massage, mud applications, local vacuum magnetotherapy. This combination was found to stimulate copulative function, urodynamics of the lower urinary tracts, to produce an antiinflammatory effect. These benefits allow to recommend the above physical factors for management of chronic prostatitis patients with copulative dysfunction.

Seminal Plasma Proteins as Androgen Receptor Corregulators Promote Prostate Cancer Growth

DTIC Science & Technology

2015-10-01

functional analyses of semenogelins in pathological conditions have been reported and their roles in prostate cancer outgrowth remain uncertain. In...1Departments of Pathology and Urology, Johns Hopkins University School of Medicine, Baltimore, MD, USA; 2Department of Pathology and Laboratory... pathological conditions have been reported and their roles in prostate cancer growth remain uncertain. In the current study, we aim to determine the

Acute bacterial prostatitis and abscess formation.

PubMed

Lee, Dong Sup; Choe, Hyun-Sop; Kim, Hee Youn; Kim, Sun Wook; Bae, Sang Rak; Yoon, Byung Il; Lee, Seung-Ju

2016-07-07

The purpose of this study was to identify risk factors for abscess formation in acute bacterial prostatitis, and to compare treatment outcomes between abscess group and non-abscess group. This is a multicenter, retrospective cohort study. All patients suspected of having an acute prostatic infection underwent computed tomography or transrectal ultrasonography to discriminate acute prostatic abscesses from acute prostatitis without abscess formation. A total of 31 prostate abscesses were reviewed among 142 patients with acute prostatitis. Univariate analysis revealed that symptom duration, diabetes mellitus and voiding disturbance were predisposing factors for abscess formation in acute prostatitis. However, diabetes mellitus was not related to prostate abscess in multivariate analysis. Patients with abscesses <20 mm in size did not undergo surgery and were cured without any complications. In contrast, patients with abscesses >20 mm who underwent transurethral resection had a shorter duration of antibiotic treatment than did those who did not have surgery. Regardless of surgical treatment, both the length of hospital stay and antibiotic treatment were longer in patients with prostatic abscesses than they were in those without abscesses. However, the incidence of septic shock was not different between the two groups. A wide spectrum of microorganisms was responsible for prostate abscesses. In contrast, Escherichia coli was the predominant organism responsible for acute prostatitis without abscess. Imaging studies should be considered when patients with acute prostatitis have delayed treatment and signs of voiding disturbance. Early diagnosis is beneficial because prostatic abscesses require prolonged treatment protocols, or even require surgical drainage. Surgical drainage procedures such as transurethral resection of the prostate were not necessary in all patients with prostate abscesses. However, surgical intervention may have potential merits that reduce the antibiotic exposure period and enhance voiding function in patients with prostatic abscess.

GPRC6A regulates prostate cancer progression

PubMed Central

Pi, Min; Quarles, L. Darryl

2011-01-01

BACKGROUND GPRC6A is a nutrient sensing GPCR that is activated in vitro by a variety of ligands, including amino acids, calcium, zinc, osteocalcin (OC) and testosterone. The association between nutritional factors and risk of prostate cancer, the finding of increased expression of OC in prostate cancer cells and the association between GPRC6A and risk of prostate cancer in Japanese men implicates a role of GPRC6A in prostate cancer. METHODS We examined if GPRC6A is expressed in human prostate cancer cell lines and used siRNA-mediated knockdown GPRC6A expression in prostate cancer cells to explore the function of GPRC6A in vitro. To assess the role GPRC6A in prostate cancer progression in vivo we intercrossed Gprc6a−/− mice onto the TRAMP mouse prostate cancer model. RESULTS GPRC6A transcripts were markedly increased in prostate cancer cell lines 22Rv1, PC-3 and LNCaP, compared to the normal prostate RWPE-1 cell line. In addition, a panel of GPRC6A ligands, including calcium, OC, and arginine, exhibited in prostate cancer cell lines a dose-dependent stimulation of ERK activity, cell proliferation, chemotaxis, and prostate specific antigen and Runx 2 gene expression. These responses were inhibited by siRNA-mediated knockdown of GPRC6A. Finally, transfer of Gprc6a deficiency onto a TRAMP mouse model of prostate cancer significantly retarded prostate cancer progression and improved survival of compound Gprc6a−/−/TRAMP mice. CONCLUSIONS GPRC6A is a novel molecular target for regulating prostate growth and cancer progression. Increments in GPRC6A may augment the ability of prostate cancer cells to proliferate in response to dietary and bone derived ligands. PMID:21681779

Function of PTP1B in Neuroendocrine Differentiation of Prostate Cancer

DTIC Science & Technology

2008-01-01

Annual 3. DATES COVERED 1 JAN 2007 - 31 DEC 2007 4. TITLE AND SUBTITLE Function of PTP1B in Neuroendocrine Differentiation of Prostate Cancer 5a...particularly the relationship of PTP1B to IL-8 signaling through its receptors CXCR1 and CXCR2, to IGF-1 receptor signaling through PI3 kinase/AKT/mTOR pathway

Prostate cancer stem cells: from theory to practice.

PubMed

Adamowicz, Jan; Pakravan, Katayoon; Bakhshinejad, Babak; Drewa, Tomasz; Babashah, Sadegh

2017-04-01

None of the generally accepted theories on prostate cancer development can fully explain many distinguishing features of the disease, such as intratumoral heterogeneity, metastatic growth, drug resistance and tumor relapse. Prostate stem cells are a heterogeneous and small subpopulation of self-renewing cells which can actively proliferate in response to changes in the androgen level and give rise to all the cell lineages that build the prostate epithelium. According to the cancer stem cell hypothesis, prostate cancer could be a stem cell disease. Prostate cancer stem cells, which represent only a minimal percentage of the tumor mass, are characterized by a markedly increased clonogenicity and therapeutic resistance. These tumor-initiating cells reside in dynamic niches distributed within the prostate but at a higher concentration in proximal regions of the prostatic ducts. Several markers have been used to identify prostate cancer stem cells. Nevertheless, a definitive profile has not yet been established owing to specificity issues. As cancer stem cells play determining roles in the birth and burst of prostate malignancy, strategies that selectively target them have gained huge clinical attention. Unraveling the mechanisms underlying the physiological functions of cancer stem cells and gaining fundamental insights into their putative involvement in the pathogenesis of prostate tumors provide novel opportunities for the development of efficient and sophisticated therapeutic strategies in the future.

Estrogen and estrogen receptor alpha promotes malignancy and osteoblastic tumorigenesis in prostate cancer.

PubMed

Mishra, Sweta; Tai, Qin; Gu, Xiang; Schmitz, James; Poullard, Ashley; Fajardo, Roberto J; Mahalingam, Devalingam; Chen, Xiaodong; Zhu, Xueqiong; Sun, Lu-Zhe

2015-12-29

The role of estrogen signaling in regulating prostate tumorigenesis is relatively underexplored. Although, an increasing body of evidence has linked estrogen receptor beta (ERß) to prostate cancer, the function of estrogen receptor alpha (ERα) in prostate cancer is not very well studied. We have discovered a novel role of ERα in the pathogenesis of prostate tumors. Here, we show that prostate cancer cells express ERα and estrogen induces oncogenic properties in prostate cancer cells through ERα. Importantly, ERα knockdown in the human prostate cancer PacMetUT1 cells as well as pharmacological inhibition of ERα with ICI 182,780 inhibited osteoblastic lesion formation and lung metastasis in vivo. Co-culture of pre-osteoblasts with cancer cells showed a significant induction of osteogenic markers in the pre-osteoblasts, which was attenuated by knockdown of ERα in cancer cells suggesting that estrogen/ERα signaling promotes crosstalk between cancer and osteoblastic progenitors to stimulate osteoblastic tumorigenesis. These results suggest that ERα expression in prostate cancer cells is essential for osteoblastic lesion formation and lung metastasis. Thus, inhibition of ERα signaling in prostate cancer cells may be a novel therapeutic strategy to inhibit the osteoblastic lesion development as well as lung metastasis in patients with advanced prostate cancer.

Role of Stromal Paracrine Signals in Proliferative Diseases of the Aging Human Prostate

PubMed Central

Takahashi, Sanai; Sugimura, Yoshiki

2018-01-01

Androgens are essential for the development, differentiation, growth, and function of the prostate through epithelial–stromal interactions. However, androgen concentrations in the hypertrophic human prostate decrease significantly with age, suggesting an inverse correlation between androgen levels and proliferative diseases of the aging prostate. In elderly males, age- and/or androgen-related stromal remodeling is spontaneously induced, i.e., increased fibroblast and myofibroblast numbers, but decreased smooth muscle cell numbers in the prostatic stroma. These fibroblasts produce not only growth factors, cytokines, and extracellular matrix proteins, but also microRNAs as stromal paracrine signals that stimulate prostate epithelial cell proliferation. Surgical or chemical castration is the standard systemic therapy for patients with advanced prostate cancer. Androgen deprivation therapy induces temporary remission, but the majority of patients eventually progress to castration-resistant prostate cancer, which is associated with a high mortality rate. Androgen deprivation therapy-induced stromal remodeling may be involved in the development and progression of castration-resistant prostate cancer. In the tumor microenvironment, activated fibroblasts stimulating prostate cancer cell proliferation are called carcinoma-associated fibroblasts. In this review, we summarize the role of stromal paracrine signals in proliferative diseases of the aging human prostate and discuss the potential clinical applications of carcinoma-associated fibroblast-derived exosomal microRNAs as promising biomarkers. PMID:29614830

ADHD and Challenging behaviour in People with Intellectual Disability: should we screen for ADHD?

PubMed

Perera, Bhathika; Courtenay, Ken

2017-09-01

People with Intellectual Disability (ID) have cognitive impairments that affect their level of functioning the causes of which are multiple and often unknown. Behavioural difficulties are common among people with ID. Attention Deficit Hyperactivity Disorder (ADHD) is recognised more among people with Intellectual Disability and could be a cause of problem behaviours. Screening and assessing for ADHD in people with ID is difficult because of the paucity of robust assessment tools and diagnostic criteria.

MicroRNAs in prostate cancer: Functional role as biomarkers.

PubMed

Kanwal, Rajnee; Plaga, Alexis R; Liu, Xiaoqi; Shukla, Girish C; Gupta, Sanjay

2017-10-28

MicroRNAs (miRNAs) are small endogenous non-coding molecules that alters gene expression through post-transcriptional regulation of messenger RNA. Compelling evidence suggest the role of miRNA in cancer biology having potential as diagnostic, prognostic and predictive biomarkers. This review summarizes the current knowledge on miRNA deregulated in prostate cancer and their role as oncogene, tumor suppressor and metastasis regulators. The emerging information elucidating the biological function of miRNA is promising and may lead to their potential usefulness as diagnostic/prognostic markers and development as effective therapeutic tools for management of prostate cancer. Copyright © 2017 Elsevier B.V. All rights reserved.

Monoamine Oxidase Deficiency Causes Prostate Atrophy and Reduces Prostate Progenitor Cell Activity.

PubMed

Yin, Lijuan; Li, Jingjing; Liao, Chun-Peng; Jason Wu, Boyang

2018-04-10

Monoamine oxidases (MAOs) degrade a number of biogenic and dietary amines, including monoamine neurotransmitters, and play an essential role in many biological processes. Neurotransmitters and related neural events have been shown to participate in the development, differentiation, and maintenance of diverse tissues and organs by regulating the specialized cellular function and morphological structures of innervated organs such as the prostate. Here we show that mice lacking both MAO isoforms, MAOA and MAOB, exhibit smaller prostate mass and develop epithelial atrophy in the ventral and dorsolateral prostates. The cellular composition of prostate epithelium showed reduced CK5 + or p63 + basal cells, accompanied by lower Sca-1 expression in p63 + basal cells, but intact differentiated CK8 + luminal cells in MAOA/B-deficient mouse prostates. MAOA/B ablation also decreased epithelial cell proliferation without affecting cell apoptosis in mouse prostates. Using a human prostate epithelial cell line, we found that stable knockdown of MAOA and MAOB impaired the capacity of prostate stem cells to form spheres, coinciding with a reduced CD133 + /CD44 + /CD24 - stem cell population and less expression of CK5 and select stem cell markers, including ALDH1A1, TROP2, and CD166. Alternative pharmacological inhibition of MAOs also repressed prostate cell stemness. In addition, we found elevated expression of MAOA and MAOB in epithelial and/or stromal components of human prostate hyperplasia samples compared with normal prostate tissues. Taken together, our findings reveal critical roles for MAOs in the regulation of prostate basal progenitor cells and prostate maintenance. Stem Cells 2018. © AlphaMed Press 2018.

Epigenetics of prostate cancer and the prospect of identification of novel drug targets by RNAi screening of epigenetic enzymes.

PubMed

Björkman, Mari; Rantala, Juha; Nees, Matthias; Kallioniemi, Olli

2010-10-01

Alterations in epigenetic processes probably underlie most human malignancies. Novel genome-wide techniques, such as chromatin immunoprecipitation and high-throughput sequencing, have become state-of-the-art methods to map the epigenomic landscape of development and disease, such as in cancers. Despite these advances, the functional significance of epigenetic enzymes in cancer progression, such as prostate cancer, remain incompletely understood. A comprehensive mapping and functional understanding of the cancer epigenome will hopefully help to facilitate development of novel cancer therapy targets and improve future diagnostics. The authors have developed a novel cell microarray-based high-content siRNA screening technique suitable to address the putative functional role and impact of all known putative and novel epigenetic enzymes in cancer, including prostate cancer.

Prophylactic sildenafil citrate improves select aspects of sexual function in men treated with radiotherapy for prostate cancer.

PubMed

Zelefsky, Michael J; Shasha, Daniel; Branco, Rebekah Dunn; Kollmeier, Marisa; Baser, Raymond E; Pei, Xin; Ennis, Ronald; Stock, Richard; Bar-Chama, Natan; Mulhall, John P

2014-09-01

We studied adjuvant daily sildenafil citrate during and after radiotherapy for prostate cancer for erectile function preservation. We performed a randomized, prospective trial of 279 patients with localized prostate cancer treated with radiotherapy who received sildenafil citrate (50 mg daily) or placebo (2:1 randomization). Medication/placebo was initiated 3 days before treatment and continued daily for 6 months. Before therapy and 3, 6, 9, 12, 18 and 24 months after radiotherapy patients completed the IIEF questionnaire, including the erectile function domain, the I-PSS questionnaire and the RAND SF-36®. All IIEF domains were scored. At 12 months erectile function scores were better for sildenafil citrate than placebo (p = 0.018), 73% of patients on sildenafil citrate vs 50% on placebo had mild/no erectile dysfunction (p = 0.024) and the sildenafil citrate arm had superior overall satisfaction (p = 0.027) and IIEF total scores (p = 0.043). At 24 months erectile function and IIEF scores were no longer significantly better for sildenafil citrate (p = 0.172 and 0.09, respectively) and yet overall satisfaction scores were higher (p = 0.033). Sexual desire scores in patients who received sildenafil citrate were higher at 24 months although they had completed drug therapy 18 months previously (p = 0.049). At 24 months 81.6% of patients on sildenafil citrate and 56.0% of those on placebo achieved functional erection with or without erectile dysfunction medication (p = 0.045). Daily sildenafil citrate during and after radiotherapy for prostate cancer was associated with improved overall sexual function compared with placebo for various sexual function domains. To our knowledge this is the largest randomized, prospective, controlled trial to show the usefulness of a phosphodiesterase-5 inhibitor as a rehabilitation strategy in patients with prostate cancer who received radiation therapy. Copyright © 2014 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.

Pharmacologic inhibition of Pim kinases alters prostate cancer cell growth and resensitizes chemoresistant cells to taxanes.

PubMed

Mumenthaler, Shannon M; Ng, Patricia Y B; Hodge, Amanda; Bearss, David; Berk, Gregory; Kanekal, Sarath; Redkar, Sanjeev; Taverna, Pietro; Agus, David B; Jain, Anjali

2009-10-01

The serine/threonine family of Pim kinases function as oncogenes and have been implicated in prostate cancer progression, particularly in hormone-refractory prostate disease, as a result of their antiapoptotic function. In this study, we used a pharmacologic inhibitor targeting the Pim family members, SGI-1776, to determine whether modulation of Pim kinase activity could alter prostate cancer cell survival and modulate chemotherapy resistance. Extensive biochemical characterization of SGI-1776 confirmed its specificity for the three isoforms of the Pim family. Treatment of prostate cancer cells with SGI-1776 resulted in a dose-dependent reduction in phosphorylation of known Pim kinase substrates that are involved in cell cycle progression and apoptosis (p21(Cip1/WAF1) and Bad). Consequently, SGI-1776 compromised overall cell viability by inducing G(1) cell cycle arrest and triggering apoptosis. Overexpression of recombinant Pim-1 markedly increased sensitivity of SGI-1776-mediated prostate cancer cell apoptosis and p21(Cip1/WAF1) phosphorylation inhibition, reinforcing the specificity of SGI-1776. An additional cytotoxic effect was observed when SGI-1776 was combined with taxane-based chemotherapy agents. SGI-1776 was able to reduce cell viability in a multidrug resistance 1 protein-based taxane-refractory prostate cancer cell line. In addition, SGI-1776 treatment was able to resensitize chemoresistant cells to taxane-based therapies by inhibiting multidrug resistance 1 activity and inducing apoptosis. These findings support the idea that inhibiting Pim kinases, in combination with a chemotherapeutic agent, could play an important role in prostate cancer treatment by targeting the clinical problem of chemoresistance.

Analysis of the gene coding for the BRCA2-interacting protein PALB2 in hereditary prostate cancer.

PubMed

Tischkowitz, Marc; Sabbaghian, Nelly; Ray, Anna M; Lange, Ethan M; Foulkes, William D; Cooney, Kathleen A

2008-05-01

The genetic basis of susceptibility to prostate cancer (PRCA) remains elusive. Mutations in BRCA2 have been associated with increased prostate cancer risk and account for around 2% of young onset (<56 years) prostate cancer cases. PALB2 is a recently identified breast cancer susceptibility gene whose protein is closely associated with BRCA2 and is essential for BRCA2 anchorage to nuclear structures. This functional relationship made PALB2 a candidate PRCA susceptibility gene. We sequenced PALB2 in probands from 95 PRCA families, 77 of which had two or more cases of early onset PRCA (age at diagnosis <55 years), and the remaining 18 had one case of early onset PRCA and five or more total cases of PRCA. Two previously unreported variants, K18R and V925L were identified, neither of which is in a known PALB2 functional domain and both of which are unlikely to be pathogenic. No truncating mutations were identified. These results indicate that deleterious PALB2 mutations are unlikely to play a significant role in hereditary prostate cancer.

Iron assessment to protect the developing brain.

PubMed

Georgieff, Michael K

2017-12-01

Iron deficiency (ID) before the age of 3 y can lead to long-term neurological deficits despite prompt diagnosis of ID anemia (IDA) by screening of hemoglobin concentrations followed by iron treatment. Furthermore, pre- or nonanemic ID alters neurobehavioral function and is 3 times more common than IDA in toddlers. Given the global prevalence of ID and the enormous societal cost of developmental disabilities across the life span, better methods are needed to detect the risk of inadequate concentrations of iron for brain development (i.e., brain tissue ID) before dysfunction occurs and to monitor its amelioration after diagnosis and treatment. The current screening and treatment strategy for IDA fails to achieve this goal for 3 reasons. First, anemia is the final state in iron depletion. Thus, the developing brain is already iron deficient when IDA is diagnosed owing to the prioritization of available iron to red blood cells over all other tissues during negative iron balance in development. Second, brain ID, independently of IDA, is responsible for long-term neurological deficits. Thus, starting iron treatment after the onset of IDA is less effective than prevention. Multiple studies in humans and animal models show that post hoc treatment strategies do not reliably prevent ID-induced neurological deficits. Third, most currently used indexes of ID are population statistical cutoffs for either hematologic or iron status but are not bioindicators of brain ID and brain dysfunction in children. Furthermore, their relation to brain iron status is not known. To protect the developing brain, there is a need to generate serum measures that index brain dysfunction in the preanemic stage of ID, assess the ability of standard iron indicators to detect ID-induced brain dysfunction, and evaluate the efficacy of early iron treatment in preventing ID-induced brain dysfunction. © 2017 American Society for Nutrition.

ID2 collaborates with ID3 to suppress iNKT and innate-like tumors1

PubMed Central

Li, Jia; Roy, Sumedha; Kim, Young-Mi; Li, Shibo; Zhang, Baojun; Love, Cassandra; Reddy, Anupama; Rajagopalan, Deepthi; Dave, Sandeep; Diehl, Anna Mae; Zhuang, Yuan

2017-01-01

Inhibitor of DNA binding (ID) proteins, including ID1-4, are transcriptional regulators involved in promoting cell proliferation and survival in various cell types. Although upregulation of Id proteins has been associated with a broad spectrum of tumors, recent studies have identified that ID3 plays a tumor suppressor role in the development of Burkitt’s lymphoma in humans and Hepatosplenic T cell lymphomas in mice. Here, we report rapid lymphoma development in Id2/Id3 double knockout (L-DKO) mice caused by unchecked expansion of either invariant Natural Killer T (iNKT) cells, or a unique subset of innate-like, CD1d-independent T cells. These populations started expansion in neonatal mice and, upon malignant transformation, caused fatality at age between 3–11 months. The malignant cells also gave rise to lymphomas upon transfer to Rag-deficient and wild-type hosts, reaffirming their inherent tumorigenic potential. Microarray analysis revealed a significantly modified program in these neonatal iNKT cells that ultimately led to their malignant transformation. The lymphoma cells demonstrated chromosome instability, along with upregulation of several different signaling pathways, including the cytokine-cytokine receptor interaction pathway, which can promote their expansion and migration. Dysregulation of genes with reported driver mutations and the NF-kB pathway were found to be shared between L-DKO lymphomas and human NKT tumors. Our work identifies a distinct premalignant state and multiple tumoriogenic pathways caused by loss function of ID2 and ID3. Thus, conditional deletion of Id2 and Id3 in developing T cells establishes a unique animal model for iNKT and relevant innate-like lymphomas. PMID:28258199

Notch signaling dynamics in the adult healthy prostate and in prostatic tumor development.

PubMed

Pedrosa, Ana-Rita; Graça, José L; Carvalho, Sandra; Peleteiro, Maria C; Duarte, António; Trindade, Alexandre

2016-01-01

The Notch signaling pathway has been implicated in prostate development, maintenance and tumorigenesis by its key role in cell-fate determination, differentiation and proliferation. Therefore, we proposed to analyze Notch family members transcription and expression, including ligands (Dll1, 3, 4 and Jagged1 and 2), receptors (Notch1-4) and effectors (Hes1, 2, 5 and Hey1, 2, L), in both normal and tumor bearing mouse prostates to better understand the dynamics of Notch signaling in prostate tumorigenesis. Wild type mice and transgenic adenocarcinoma of the mouse prostate model (TRAMP) mice were sacrificed at 18, 24 or 30 weeks of age and the prostates collected and processed for either whole prostate or prostate cell specific populations mRNA analysis and for protein expression analysis by immunohistochemistry and immunofluorescence. We observed that Dll1 and Dll4 are expressed in the luminal compartment of the mouse healthy prostate, whereas Jagged2 expression is restricted to the basal and stromal compartment. Additionally, Notch2 and Notch4 are normally expressed in the prostate luminal compartment while Notch2 and Notch3 are also expressed in the stromal layer of the healthy prostate. As prostate tumor development takes place, there is up-regulation of Notch components. Particularly, the prostate tumor lesions have increased expression of Jagged1 and 2, of Notch3 and of Hey1. We have also detected the presence of activated Notch3 in prostatic tumors that co-express Jagged1 and ultimately the Hey1 effector. Taken together our results point out the Notch axis Jagged1-2/Notch3/Hey1 to be important for prostate tumor development and worthy of additional functional studies and validation in human clinical disease. © 2015 Wiley Periodicals, Inc.

Red maca (Lepidium meyenii) reduced prostate size in rats

PubMed Central

Gonzales, Gustavo F; Miranda, Sara; Nieto, Jessica; Fernández, Gilma; Yucra, Sandra; Rubio, Julio; Yi, Pedro; Gasco, Manuel

2005-01-01

Background Epidemiological studies have found that consumption of cruciferous vegetables is associated with a reduced risk of prostate cancer. This effect seems to be due to aromatic glucosinolate content. Glucosinolates are known for have both antiproliferative and proapoptotic actions. Maca is a cruciferous cultivated in the highlands of Peru. The absolute content of glucosinolates in Maca hypocotyls is relatively higher than that reported in other cruciferous crops. Therefore, Maca may have proapoptotic and anti-proliferative effects in the prostate. Methods Male rats treated with or without aqueous extracts of three ecotypes of Maca (Yellow, Black and Red) were analyzed to determine the effect on ventral prostate weight, epithelial height and duct luminal area. Effects on serum testosterone (T) and estradiol (E2) levels were also assessed. Besides, the effect of Red Maca on prostate was analyzed in rats treated with testosterone enanthate (TE). Results Red Maca but neither Yellow nor Black Maca reduced significantly ventral prostate size in rats. Serum T or E2 levels were not affected by any of the ecotypes of Maca assessed. Red Maca also prevented the prostate weight increase induced by TE treatment. Red Maca administered for 42 days reduced ventral prostatic epithelial height. TE increased ventral prostatic epithelial height and duct luminal area. These increases by TE were reduced after treatment with Red Maca for 42 days. Histology pictures in rats treated with Red Maca plus TE were similar to controls. Phytochemical screening showed that aqueous extract of Red Maca has alkaloids, steroids, tannins, saponins, and cardiotonic glycosides. The IR spectra of the three ecotypes of Maca in 3800-650 cm (-1) region had 7 peaks representing 7 functional chemical groups. Highest peak values were observed for Red Maca, intermediate values for Yellow Maca and low values for Black Maca. These functional groups correspond among others to benzyl glucosinolate. Conclusions Red Maca, a cruciferous plant from the highland of Peru, reduced ventral prostate size in normal and TE treated rats. PMID:15661081

Targeting Androgen Receptor to Suppress Macrophage-induced EMT and Benign Prostatic Hyperplasia (BPH) Development

PubMed Central

Lu, Tianjing; Lin, Wen-Jye; Izumi, Kouji; Wang, Xiaohai; Xu, Defeng; Fang, Lei-Ya; Li, Lei; Jiang, Qi

2012-01-01

Early studies suggested macrophages might play roles in inflammation-associated benign prostatic hyperplasia (BPH) development, yet the underlying mechanisms remain unclear. Here we first showed that CD68+ macrophages were identified in both epithelium and the stromal area of human BPH tissues. We then established an in vitro co-culture model with prostate epithelial and macrophage cell lines to study the potential impacts of infiltrating macrophages in the BPH development and found that co-culturing prostate epithelial cells with macrophages promoted migration of macrophages. In a three-dimensional culture system, the sphere diameter of BPH-1 prostate cells was significantly increased during coculture with THP-1 macrophage cells. Mechanism dissection suggested that expression levels of epithelial-mesenchymal transition (EMT) markers, such as N-cadherin, Snail, and TGF-β2, were increased, and administration of anti-TGF-β2 neutralizing antibody during co-culture suppressed the EMT and THP-1-mediated growth of BPH-1 cells, suggesting THP-1 might go through EMT to influence the BPH development and progression. Importantly, we found that modulation of androgen receptor (AR) in BPH-1 and mPrE cells significantly increased THP-1 and RAW264.7 cell migration, respectively, and enhanced expression levels of EMT markers, suggesting that AR in prostate epithelial cells might play a role in promoting macrophage-mediated EMT in prostate epithelial cells. Silencing AR function via an AR degradation enhancer, ASC-J9, decreased the macrophage migration to BPH-1 cells and suppressed EMT marker expression. Together, these results provide the first evidence to demonstrate that prostate epithelial AR function is important for macrophage-mediated EMT and proliferation of prostate epithelial cells, which represents a previously unrecognized role of AR in the cross-talk between macrophages and prostate epithelial cells. These results may provide new insights for a new therapeutic approach to battle BPH via targeting AR and AR-mediated inflammatory signaling pathways. PMID:22915828

Targeting androgen receptor to suppress macrophage-induced EMT and benign prostatic hyperplasia (BPH) development.

PubMed

Lu, Tianjing; Lin, Wen-Jye; Izumi, Kouji; Wang, Xiaohai; Xu, Defeng; Fang, Lei-Ya; Li, Lei; Jiang, Qi; Jin, Jie; Chang, Chawnshang

2012-10-01

Early studies suggested macrophages might play roles in inflammation-associated benign prostatic hyperplasia (BPH) development, yet the underlying mechanisms remain unclear. Here we first showed that CD68(+) macrophages were identified in both epithelium and the stromal area of human BPH tissues. We then established an in vitro co-culture model with prostate epithelial and macrophage cell lines to study the potential impacts of infiltrating macrophages in the BPH development and found that co-culturing prostate epithelial cells with macrophages promoted migration of macrophages. In a three-dimensional culture system, the sphere diameter of BPH-1 prostate cells was significantly increased during coculture with THP-1 macrophage cells. Mechanism dissection suggested that expression levels of epithelial-mesenchymal transition (EMT) markers, such as N-cadherin, Snail, and TGF-β2, were increased, and administration of anti-TGF-β2 neutralizing antibody during co-culture suppressed the EMT and THP-1-mediated growth of BPH-1 cells, suggesting THP-1 might go through EMT to influence the BPH development and progression. Importantly, we found that modulation of androgen receptor (AR) in BPH-1 and mPrE cells significantly increased THP-1 and RAW264.7 cell migration, respectively, and enhanced expression levels of EMT markers, suggesting that AR in prostate epithelial cells might play a role in promoting macrophage-mediated EMT in prostate epithelial cells. Silencing AR function via an AR degradation enhancer, ASC-J9, decreased the macrophage migration to BPH-1 cells and suppressed EMT marker expression. Together, these results provide the first evidence to demonstrate that prostate epithelial AR function is important for macrophage-mediated EMT and proliferation of prostate epithelial cells, which represents a previously unrecognized role of AR in the cross-talk between macrophages and prostate epithelial cells. These results may provide new insights for a new therapeutic approach to battle BPH via targeting AR and AR-mediated inflammatory signaling pathways.

Intellectual disabilities, neuronal posttranscriptional RNA metabolism, and RNA-binding proteins: three actors for a complex scenario.

PubMed

Bardoni, Barbara; Abekhoukh, Sabiha; Zongaro, Samantha; Melko, Mireille

2012-01-01

Intellectual disability (ID) is the most frequent cause of serious handicap in children and young adults and interests 2-3% of worldwide population, representing a serious problem from the medical, social, and economic points of view. The causes are very heterogeneous. Genes involved in ID have various functions altering different pathways important in neuronal function. Regulation of mRNA metabolism is particularly important in neurons for synaptic structure and function. Here, we review ID due to alteration of mRNA metabolism. Functional absence of some RNA-binding proteins--namely, FMRP, FMR2P, PQBP1, UFP3B, VCX-A--causes different forms of ID. These proteins are involved in different steps of RNA metabolism and, even if a detailed analysis of their RNA targets has been performed so far only for FMRP, it appears clear that they modulate some aspects (translation, stability, transport, and sublocalization) of a subset of RNAs coding for proteins, whose function must be relevant for neurons. Two other proteins, DYRK1A and CDKL5, involved in Down syndrome and Rett syndrome, respectively, have been shown to have an impact on splicing efficiency of specific mRNAs. Both proteins are kinases and their effect is indirect. Interestingly, both are localized in nuclear speckles, the nuclear domains where splicing factors are assembled, stocked, and recycled and influence their biogenesis and/or their organization. Copyright © 2012 Elsevier B.V. All rights reserved.

Id1 expression promotes peripheral CD4{sup +} T cell proliferation and survival upon TCR activation without co-stimulation

DOE Office of Scientific and Technical Information (OSTI.GOV)

Liu, Chen; Jin, Rong; Wang, Hong-Cheng

2013-06-21

Highlights: •Id1 expression enables naïve T cell proliferation without anti-CD28 co-stimulation. •Id1 expression facilitates T cells survival when stimulated with anti-CD3. •Elevation of IL-2 production by Id1 contributes increased proliferation and survival. •Id1 potentiates NF-κB activation by anti-CD3 stimulation. -- Abstract: Although the role of E proteins in the thymocyte development is well documented, much less is known about their function in peripheral T cells. Here we demonstrated that CD4 promoter-driven transgenic expression of Id1, a naturally occurring dominant-negative inhibitor of E proteins, can substitute for the co-stimulatory signal delivered by CD28 to facilitate the proliferation and survival of naïvemore » CD4{sup +} cells upon anti-CD3 stimulation. We next discovered that IL-2 production and NF-κB activity after anti-CD3 stimulation were significantly elevated in Id1-expressing cells, which may be, at least in part, responsible for the augmentation of their proliferation and survival. Taken together, results from this study suggest an important role of E and Id proteins in peripheral T cell activation. The ability of Id proteins to by-pass co-stimulatory signals to enable T cell activation has significant implications in regulating T cell immunity.« less

miRNA let-7b modulates macrophage polarization and enhances tumor-associated macrophages to promote angiogenesis and mobility in prostate cancer.

PubMed

Wang, Zhigang; Xu, Lu; Hu, Yinying; Huang, Yanqin; Zhang, Yujuan; Zheng, Xiufen; Wang, Shanshan; Wang, Yifan; Yu, Yanrong; Zhang, Meng; Yuan, Keng; Min, Weiping

2016-05-09

Macrophage polarization is a highly plastic physiological process that responds to a variety of environmental factors by changing macrophage phenotype and function. Tumor-associated macrophages (TAMs) are generally recognized as promoting tumor progression. As universal regulators, microRNAs (miRNAs) are functionally involved in numerous critical cellular processes including macrophage polarization. Let-7b, a miRNA, has differential expression patterns in inflamed tissues compared with healthy controls. However, whether and how miRNA let-7b regulates macrophage phenotype and function is unclear. In this report, we find that up-regulation of let-7b is characteristic of prostatic TAMs, and down-regulation of let-7b in TAMs leads to changes in expression profiles of inflammatory cytokines, such as IL-12, IL-23, IL-10 and TNF-α. As a result, TAMs treated with let-7b inhibitors reduce angiogenesis and prostate carcinoma (PCa) cell mobility. Let-7b may play a vital role in regulating macrophage polarization, thus modulating the prognosis of prostate cancer.

Multivalent Peptidomimetic Conjugates as Inhibitors of Androgen Receptor Function in Therapy Resistant Prostate Cancer

DTIC Science & Technology

2016-10-01

hormones that play a critical role in stimulating prostate cancer growth . Androgens activate a protein called the androgen receptor (AR), which...5-15 3 1. INTRODUCTION: Androgens are hormones that play a critical role in stimulating prostate cancer growth . Androgens...regulates genes involved in cell growth . Although powerful anti-androgen drugs can be administered to block AR action and have been used successfully to

Novel Fatty Acid Lipoxygenases in the Development of Human and Murine Prostate Cancer

DTIC Science & Technology

1999-10-01

with Dr. Matthew Breyer on a study utilizing bladder biopsy and cystectomy specimens and in situ hybridization and immunohistochemistry which...Reduced in Prostate Adenocarcinoma Scott B. Shappell,* William E. Boeglin,t prostate adenocarcinomas. (Am J Patbol 1999, Sandy J. Olson,* Susan Kasper...this novel enzyme in secretory function. 33157-33160 5. Samuelsson B. Dahlen SE, Lindgren JA, Rouzer CA, Serhan CN: Reduced expression in atrophic

Overcoming Drug Resistant Prostate Cancer with APE1/Ref-1 Blockade

DTIC Science & Technology

2015-10-01

cells avoid being killed by chemotherapy: Apurinic/apyrimidinic endonuclease/ redox -factor 1, or simply, Ref-1, for short. In this report, we...survivin signaling in human prostate cancer specimens. Genetic knockdown of APE1/Ref-1 disrupts prostate cancer cell growth and survival in cell culture...In addition, inhibition of the redox function selectively of Ref-1 results in cell growth inhibition, with this therapy preferentially inhibiting

Overcoming Drug Resistant Prostate Cancer with APE1/Ref 1 Blockade

DTIC Science & Technology

2015-10-01

cells avoid being killed by chemotherapy: Apurinic/apyrimidinic endonuclease/ redox -factor 1, or simply, Ref-1, for short. In this report, we...survivin signaling in human prostate cancer specimens. Genetic knockdown of APE1/Ref-1 disrupts prostate cancer cell growth and survival in cell culture...In addition, inhibition of the redox function selectively of Ref-1 results in cell growth inhibition, with this therapy preferentially inhibiting

New advances in focal therapy for early stage prostate cancer.

PubMed

Tay, Kae Jack; Schulman, Ariel A; Sze, Christina; Tsivian, Efrat; Polascik, Thomas J

2017-08-01

Prostate focal therapy offers men the opportunity to achieve oncological control while preserving sexual and urinary function. The prerequisites for successful focal therapy are to accurately identify, localize and completely ablate the clinically significant cancer(s) within the prostate. We aim to evaluate the evidence for current and upcoming technologies that could shape the future of prostate cancer focal therapy in the next five years. Areas covered: Current literature on advances in patient selection using imaging, biopsy and biomarkers, ablation techniques and adjuvant treatments for focal therapy are summarized. A literature search of major databases was performed using the search terms 'focal therapy', 'focal ablation', 'partial ablation', 'targeted ablation', 'image guided therapy' and 'prostate cancer'. Expert commentary: Advanced radiological tools such as multiparametric magnetic resonance imaging (mpMRI), multiparametric ultrasound (mpUS), prostate-specific-membrane-antigen positron emission tomography (PSMA-PET) represent a revolution in the ability to understand cancer function and biology. Advances in ablative technologies now provide a menu of modalities that can be rationalized based on lesion location, size and perhaps in the near future, pre-determined resistance to therapy. However, these need to be carefully studied to establish their safety and efficacy parameters. Adjuvant strategies to enhance focal ablation are under development.

Intellectual disability in young people in custody in New South Wales, Australia - prevalence and markers.

PubMed

Haysom, L; Indig, D; Moore, E; Gaskin, C

2014-11-01

Intellectual disability (ID) is known to be more common in incarcerated groups, especially incarcerated youth. Aboriginal young people have higher rates of ID, and make up half of all youth in juvenile custody in New South Wales (NSW), Australia. We aimed to describe the prevalence of possible ID and borderline intellectual functioning (BIF) in young people in NSW custody, and to describe the association between possible ID and Aboriginality after adjusting for the inequalities in social disadvantage. Baseline study of all youth in NSW Custodial Centres between August and October 2009, with 18-month follow-up. Using Wechsler Intelligence Scale for Children - Fourth Edition (WISC-IV) and Wechsler Adult Intelligence Scale - Fourth Edition (WAIS-IV) cognitive assessments, possible ID was defined as Extremely Low Intellectual Quotient range (Full Scale Intellectual Quotient, FSIQ < 70), and possible BIF was defined as Borderline IQ range (FSIQ < 80). Risk factors for possible ID and BIF included age, gender, Aboriginality, socio-economic disadvantage, offending history and psychological disorders. N = 295 (65%) of all young people in NSW custody completed cognitive and psychological assessments (87% male, 50% Aboriginal, average age 17 years). Almost one half (45.8%) of young people had borderline or lower intellectual functioning (by IQ assessment), and 14% had an IQ in the extremely low range (FSIQ < 70), indicating a possible ID. Aboriginal participants were three times more likely than non-Aboriginal participants to have a possible ID, but after accounting for the excess disadvantage in the Aboriginal group, Aboriginality was no longer a marker of ID. Incarceration from a young age and psychosis were significantly associated with possible ID in Aboriginal participants, compared with Aboriginal participants first incarcerated at a later age, and Aboriginal participants without psychosis. The inequalities in criminal justice between Aboriginal and non-Aboriginal youth may exacerbate or contribute to the intellectual impairment of those incarcerated from a young age. Aboriginal young people with psychosis are also at high risk of cognitive impairments that might indicate a possible co-morbid ID, and these patients should be diverted at court into community assessment services, rather than incarcerated. These results highlight a need for better and earlier identification of young people (particularly Aboriginal youth) at risk of ID and other co-morbidities in the juvenile justice system. © 2014 MENCAP and International Association of the Scientific Study of Intellectual and Developmental Disabilities and John Wiley & Sons Ltd.

The expanding role of epigenetics in the development, diagnosis and treatment of prostate cancer and benign prostatic hyperplasia.

PubMed

Dobosy, Joseph R; Roberts, J Lea W; Fu, Vivian X; Jarrard, David F

2007-03-01

Prostate cancer research has focused significant attention on the mutation, deletion or amplification of the DNA base sequence that encodes critical growth or suppressor genes. However, these changes have left significant gaps in our understanding of the development and progression of disease. It has become clear that epigenetic changes or modifications that influence phenotype without altering the genotype present a new and entirely different mechanism for gene regulation. Several interrelated epigenetic modifications that are altered in abnormal growth states are DNA methylation changes, histone modifications and genomic imprinting. We discuss the status of epigenetic alterations in prostate cancer and benign prostatic hyperplasia progression. In addition, the rationale and status of ongoing clinical trials altering epigenetic processes in urological diseases are reviewed. An online search of current and past peer reviewed literature on DNA methylation, histone acetylation and methylation, imprinting and epigenetics in prostate cancer and benign prostatic hyperplasia was performed. Relevant articles and reviews were examined and a synopsis of reproducible data was generated with the goal of informing the practicing urologist of these advances and their implications. Only 20 years ago the first study was published demonstrating global changes in DNA methylation patterns in tumors. Accumulating data have now identified specific genes that are commonly hypermethylated and inactivated during prostate cancer progression, including GSTpi, APC, MDR1, GPX3 and 14-3-3sigma. Altered histone modifications, including acetylation and methylation, were also recently described that may modify gene function, including androgen receptor function. These epigenetic changes are now being used to assist in prostate cancer diagnosis and cancer outcome prediction. Epigenetic changes appear to have a role in benign prostatic hyperplasia development as well as in the susceptibility of the prostate to developing cancer. Treatments involving 5-aza-deoxycytosine and other, more selective DNA methyltransferase inhibitors remove methyl residues from silenced genes, generating re-expression, and are currently being used in therapeutic trials. Histone deacetylase inhibitors have shown promise, not only by directly reactivating silenced genes, but also as regulators of apoptosis and sensitizers to radiation therapy. Evolving data support a significant role for epigenetic processes in the development of prostate cancer and benign prostatic hyperplasia. Epigenetic changes can predict tumor behavior and often distinguish between genetically identical tumors. Targeted drugs that alter epigenetic modifications hold promise as a tool for curing and preventing these diseases.

Operational Art and the Sustainment Warfighting Function

DTIC Science & Technology

2011-12-01

Infantry Division (ID) a continuous sustainment line of operation. The leap- frogging of Forward Logisitics Bases provided 3rd Infantry Division (ID...victims. A C-17 Globemaster III departed North Carolina and delivered 14,000 Meals Ready-to- Eat , or MREs, and 14,000 quarts of water in a 7-hour round

Intellectual disability and homelessness.

PubMed

Mercier, C; Picard, S

2011-04-01

The association between poverty and intellectual disability (ID) has been well documented. However, little is known about persons with ID who face circumstances of extreme poverty, such as homelessness. This paper describes the situation of persons with ID who were or are homeless in Montreal and are currently receiving services from a team dedicated to homeless persons. (1) To describe the characteristics, history and current situation of these persons; and (2) to report within-group differences as a function of gender and current residential status. The data were collected from files using an anonymous chart summary. Descriptive statistics on the whole sample (n = 68) and inferential statistics on cross-tabulations by gender and residential status were performed. Persons with ID exhibited several related problems. Some of these persons, primarily women, experienced relatively short periods of homelessness and their situations stabilised once they were identified and followed up. Other persons with ID experienced chronic homelessness that appeared to parallel the number and severity of their other problems. When compared with a previous epidemiological study of the homeless in Montreal, the population of homeless persons with ID differed from the overall homeless population in a number of respects. The results suggest prevention and intervention targets. The need for epidemiological research appears particularly clear in light of the fact that below-average intellectual functioning has been identified as a risk factor for homelessness and a predisposing factor for vulnerability among street people. © 2011 The Authors. Journal of Intellectual Disability Research © 2011 Blackwell Publishing Ltd.

Idea Density Measured in Late Life Predicts Subsequent Cognitive Trajectories: Implications for the Measurement of Cognitive Reserve

PubMed Central

Chand, Vineeta; Bonnici, Lisa; Baynes, Kathleen; Harvey, Danielle; Mungas, Dan; Simon, Christa; Reed, Bruce

2012-01-01

Objective. The Nun Study showed that lower linguistic ability in young adulthood, measured by idea density (ID), increased the risk of dementia in late life. The present study examined whether ID measured in late life continues to predict the trajectory of cognitive change. Method. ID was measured in 81 older adults who were followed longitudinally for an average of 4.3 years. Changes in global cognition and 4 specific neuropsychological domains (episodic memory, semantic memory, spatial abilities, and executive function) were examined as outcomes. Separate random effects models tested the effect of ID on longitudinal change in outcomes, adjusted for age and education. Results. Lower ID was associated with greater subsequent decline in global cognition, semantic memory, episodic memory, and spatial abilities. When analysis was restricted to only participants without dementia at the time ID was collected, results were similar. Discussion. Linguistic ability in young adulthood, as measured by ID, has been previously proposed as an index of neurocognitive development and/or cognitive reserve. The present study provides evidence that even when ID is measured in old age, it continues to be associated with subsequent cognitive decline and as such may continue to provide a marker of cognitive reserve. PMID:22357642

Androgen Ablation Augments Prostate Cancer Vaccine Immunogenicity Only When Applied After Immunization

PubMed Central

Koh, Yi T.; Gray, Andrew; Higgins, Sean A.; Hubby, Bolyn; Kast, W. Martin

2009-01-01

Background Androgen ablation (AA) causes apoptosis of normal and neoplastic prostate cells. It is a standard treatment for advanced prostate cancer. Androgen ablation-mediated immunological effects include bone marrow hyperplasia, thymic regeneration, T and B cell lymphopoeisis and restoration of age-related peripheral T cell dysfunction. Androgens also regulate the transcription of several cytokines. Dendritic cells (DC) are the most potent antigen presenting cells that can activate antigen-specific naïve T cells. Despite myriad clinical trials involving DC-based prostate cancer immunotherapies, the effects of AA on DC function remain largely uncharacterized. Therefore, we investigated the effects of AA on DC and whether it could improve the efficacy of prostate cancer immunotherapy. Methods Cytokine expression changes due to AA were quantified by multiplex ELISA. Flow cytometry was used to assess AA-mediated effects on DC maturation and expression of costimulatory markers. Mixed leukocyte reactions and cell-mediated lysis assays elucidated the role of androgens in DC function. The effect of AA on the efficacy of vaccination against a prostate tumor-associated antigen was tested using Elispot assays. Results Androgen ablation increased dendritic cell maturation and costimulatory marker expression, but had no effect on DC costimulatory function. However, DC isolated from castrated mice increased the expression of key cytokines by antigen-experienced T cells while decreasing their expression in naïve cells. Finally, androgen ablation improved immune responses to vaccination only when applied after immunization. Conclusion Androgen ablation causes differential effects of DC on primary and secondary T cell responses, thus augmenting vaccine immunogenicity only when applied after immunization. PMID:19143030

Iron supplementation until 6 months protects marginally low-birth-weight infants from iron deficiency during their first year of life.

PubMed

Berglund, Staffan K; Westrup, Björn; Domellöf, Magnus

2015-03-01

Low-birth-weight (LBW) infants (<2500 g) have an increased risk of iron deficiency (ID) during their first 6 months of life. The optimal dose and duration of iron supplementation to LBW infants are, however, unknown. The objective of the present study was to investigate the long-term effect on iron status and growth in marginally LBW (2000-2500 g) infants, of iron supplements given until 6 months of life. In a randomized controlled trial, 285 healthy marginally LBW infants received 0, 1, or 2 mg · kg(-1) · day(-1) of iron supplements from 6 weeks to 6 months of age. At 12 months and 3.5 years of life we measured length, weight, head circumference, and indicators of iron status (hemoglobin, ferritin, mean corpuscular volume, and transferrin saturation) and assessed the prevalence of iron depletion, functional ID, and ID anemia. At 12 months of age, there was a significant difference in ferritin between the groups (P = 0.006). Furthermore, there was a significant difference in the prevalence of iron depletion (23.7%, 10.6%, and 6.8%, respectively, in the placebo, 1-mg, and 2-mg groups, P = 0.009) and similar nonsignificant trends for functional ID and ID anemia. At 3.5 years of life there were no significant differences in iron status and the mean prevalence of iron depletion was 3.2%. Anthropometric data were not affected by the intervention. Iron supplements with 2 mg · kg(-1) · day(-1) until 6 months of life effectively reduces the risk of ID during the first 12 months of life and is an effective intervention for preventing early ID in marginally LBW infants.

State-of-the-art: prostate LDR brachytherapy.

PubMed

Voulgaris, S; Nobes, J P; Laing, R W; Langley, S E M

2008-01-01

This article on low dose rate (LDR) prostate brachytherapy reviews long-term results, patient selection and quality of life issues. Mature results from the United States and United Kingdom are reported and issues regarding definitions of biochemical failure are discussed. Latest data comparing brachytherapy with radical prostatectomy or no definitive treatment and also the risk of secondary malignancies after prostate brachytherapy are presented. Urological parameters of patient selection and quality of life issues concerning urinary, sexual and bowel function are reviewed. The position of prostate brachytherapy next to surgery as a first-line treatment modality is demonstrated.

A 3D isodose manipulation tool for interactive dose shaping

NASA Astrophysics Data System (ADS)

Kamerling, C. P.; Ziegenhein, P.; Heinrich, H.; Oelfke, U.

2014-03-01

The interactive dose shaping (IDS) planning paradigm aims to perform interactive local dose adaptations of an IMRT plan without compromising already established valuable dose features in real-time. In this work we introduce an interactive 3D isodose manipulation tool which enables local modifications of a dose distribution intuitively by direct manipulation of an isodose surface. We developed an in-house IMRT TPS framework employing an IDS engine as well as a 3D GUI for dose manipulation and visualization. In our software an initial dose distribution can be interactively modified through an isodose surface manipulation tool by intuitively clicking on an isodose surface. To guide the user interaction, the position of the modification is indicated by a sphere while the mouse cursor hovers the isodose surface. The sphere's radius controls the locality of the modification. The tool induces a dose modification as a direct change of dose in one or more voxels, which is incrementally obtained by fluence adjustments. A subsequent recovery step identifies voxels with violated dose features and aims to recover their original dose. We showed a proof of concept study for the proposed tool by adapting the dose distribution of a prostate case (9 beams, coplanar). Single dose modifications take less than 2 seconds on an actual desktop PC.

Boosting antitumor responses of T lymphocytes infiltrating human prostate cancers.

PubMed

Bronte, Vincenzo; Kasic, Tihana; Gri, Giorgia; Gallana, Keti; Borsellino, Giovanna; Marigo, Ilaria; Battistini, Luca; Iafrate, Massimo; Prayer-Galetti, Tommaso; Pagano, Francesco; Viola, Antonella

2005-04-18

Immunotherapy may provide valid alternative therapy for patients with hormone-refractory metastatic prostate cancer. However, if the tumor environment exerts a suppressive action on antigen-specific tumor-infiltrating lymphocytes (TIL), immunotherapy will achieve little, if any, success. In this study, we analyzed the modulation of TIL responses by the tumor environment using collagen gel matrix-supported organ cultures of human prostate carcinomas. Our results indicate that human prostatic adenocarcinomas are infiltrated by terminally differentiated cytotoxic T lymphocytes that are, however, in an unresponsive status. We demonstrate the presence of high levels of nitrotyrosines in prostatic TIL, suggesting a local production of peroxynitrites. By inhibiting the activity of arginase and nitric oxide synthase, key enzymes of L-arginine metabolism that are highly expressed in malignant but not in normal prostates, reduced tyrosine nitration and restoration of TIL responsiveness to tumor were achieved. The metabolic control exerted by the tumor on TIL function was confirmed in a transgenic mouse prostate model, which exhibits similarities with human prostate cancer. These results identify a novel and dominant mechanism by which cancers induce immunosuppression in situ and suggest novel strategies for tumor immunotherapy.

EphA2 enhances the proliferation and invasion ability of LNCaP prostate cancer cells.

PubMed

Chen, Peijie; Huang, Yan; Zhang, Bo; Wang, Qiuquan; Bai, Peiming

2014-07-01

EphA2 is persistently overexpressed and functionally changed in numerous human cancers. However, to the best of our knowledge, the role that EphA2 plays in prostate cancer is not entirely clear. To investigate the roles of EphA2 in the development and progression of prostate cancer, the present study initially evaluated the roles of the EphA2 protein in LNCaP prostate cancer cells using recombinant plasmid, western blot analysis, flow cytometry, Matrigel invasion chamber and the cell counting kit-8 assay. An immunohistochemistry assay was also conducted to observe the effects of EphA2 in prostate cancer tissues. The results demonstrated that the LNCaP human prostate cancer cells that were transfected with pcDNA3.1(+) plasmid-mediated pcDNA3.1(+)-EphA2, markedly enhanced the cell growth and invasion in vitro . Additionally, EphA2 was overexpressed in prostate cancer specimens and the expression of EphA2 was significantly associated with Gleason grade, total prostate-specific antigen, advanced clinical stage and lymph node metastasis. Collectively, these results demonstrate that EphA2 is involved in malignant cell behavior and is a potential therapeutic target in human prostate cancer.

Combining immunotherapies for the treatment of prostate cancer.

PubMed

Redman, Jason M; Gulley, James L; Madan, Ravi A

2017-12-01

Sipuleucel-T, a therapeutic dendritic-cell vaccine, was Food and Drug Administration-approved for prostate cancer in 2010. No new immunotherapies for prostate cancer have been approved since. However, novel agents and combination approaches offer great promise for improving outcomes for prostate cancer patients. Here we review the latest developments in immunotherapy for prostate cancer. Sipuleucel-T has demonstrated a survival advantage of 4.1 months in metastatic castration-resistant prostate cancer. PSA-TRICOM (PROSTVAC), a prostate-specific antigen-targeted vaccine platform, showed evidence of clinical and immunologic efficacy in early-phase clinical trials, and results from a phase III trial in advanced disease are pending. While immune checkpoint inhibitors appear to have modest activity as monotherapy, preclinical and clinical data suggest that they may synergize with vaccines, poly [ADP-ribose] polymerase inhibitors, and other agents. Several clinical studies that combine these therapies are underway. Combining prostate cancer vaccines with immune checkpoint inhibitors has great potential for improving clinical outcomes in prostate cancer. Such combination approaches may create and then recruit tumor-specific T cells to tumor while also increasing their effector function. Other emerging agents may also enhance immune-mediated tumor destruction. Copyright © 2017. Published by Elsevier Inc.

Prostate-specific antigen (PSA) as a possible biomarker in non-prostatic cancer: A review.

PubMed

Pérez-Ibave, Diana Cristina; Burciaga-Flores, Carlos Horacio; Elizondo-Riojas, Miguel-Ángel

2018-06-01

Prostate-specific antigen (PSA) is a serine protease produced by epithelial prostatic cells and its main function is to liquefy seminal coagulum. Currently, PSA is a biomarker for the diagnosis and screening of prostate cancer and it was the first cancer biomarker approved by the FDA. The quantity and serum isoforms of male PSA, allows distinguishing between carcinoma and benign inflammatory disease of the prostate. Initially, it was thought that PSA was produced only by the prostate, and thus, a protein that was expressed exclusively in men. However, several authors report that PSA is a protein that is expressed by multiple non-prostatic tissues not only in men but also in women. Some authors also report that in women, the expression of this protein is highly related to breast and colon cancer and therefore can act as a possible biomarker for early detection, diagnosis and prognosis of these cancers in women. In this review, we will focus on the characteristics of the PSA at a molecular level, its current clinical implications, the expression of this protein in non-prostatic tissues, and its relationship with cancer, especially in women. Copyright © 2018 Elsevier Ltd. All rights reserved.

Targeting Stromal Androgen Receptor Suppresses Prolactin-Driven Benign Prostatic Hyperplasia (BPH)

PubMed Central

Lai, Kuo-Pao; Huang, Chiung-Kuei; Fang, Lei-Ya; Izumi, Kouji; Lo, Chi-Wen; Wood, Ronald; Kindblom, Jon; Yeh, Shuyuan

2013-01-01

Stromal-epithelial interaction plays a pivotal role to mediate the normal prostate growth, the pathogenesis of benign prostatic hyperplasia (BPH), and prostate cancer development. Until now, the stromal androgen receptor (AR) functions in the BPH development, and the underlying mechanisms remain largely unknown. Here we used a genetic knockout approach to ablate stromal fibromuscular (fibroblasts and smooth muscle cells) AR in a probasin promoter-driven prolactin transgenic mouse model (Pb-PRL tg mice) that could spontaneously develop prostate hyperplasia to partially mimic human BPH development. We found Pb-PRL tg mice lacking stromal fibromuscular AR developed smaller prostates, with more marked changes in the dorsolateral prostate lobes with less proliferation index. Mechanistically, prolactin mediated hyperplastic prostate growth involved epithelial-stromal interaction through epithelial prolactin/prolactin receptor signals to regulate granulocyte macrophage-colony stimulating factor expression to facilitate stromal cell growth via sustaining signal transducer and activator of transcription-3 activity. Importantly, the stromal fibromuscular AR could modulate such epithelial-stromal interacting signals. Targeting stromal fibromuscular AR with the AR degradation enhancer, ASC-J9®, led to the reduction of prostate size, which could be used in future therapy. PMID:23893956

A Quantitative Model for the Dynamics of Serum Prostate-Specific Antigen as a Marker for Cancerous Growth

PubMed Central

Swanson, Kristin R.; True, Lawrence D.; Lin, Daniel W.; Buhler, Kent R.; Vessella, Robert; Murray, James D.

2001-01-01

Prostate-specific antigen (PSA) is an enzyme produced by both normal and cancerous prostate epithelial cells. Although PSA is the most widely used serum marker to detect and follow patients with prostatic adenocarcinoma, there are certain anomalies in the values of serum levels of PSA that are not understood. We developed a mathematical model for the dynamics of serum levels of PSA as a function of the tumor volume. Our model results show good agreement with experimental observations and provide an explanation for the existence of significant prostatic tumor mass despite a low-serum PSA. This result can be very useful in enhancing the use of serum PSA levels as a marker for cancer growth. PMID:11395397

A large scale analysis of genetic variants within putative miRNA binding sites in prostate cancer

PubMed Central

Stegeman, Shane; Amankwah, Ernest; Klein, Kerenaftali; O’Mara, Tracy A.; Kim, Donghwa; Lin, Hui-Yi; Permuth-Wey, Jennifer; Sellers, Thomas A.; Srinivasan, Srilakshmi; Eeles, Rosalind; Easton, Doug; Kote-Jarai, Zsofia; Olama, Ali Amin Al; Benlloch, Sara; Muir, Kenneth; Giles, Graham G.; Wiklund, Fredrik; Gronberg, Henrik; Haiman, Christopher A.; Schleutker, Johanna; Nordestgaard, Børge G.; Travis, Ruth C.; Neal, David; Pharoah, Paul; Khaw, Kay-Tee; Stanford, Janet L.; Blot, William J.; Thibodeau, Stephen; Maier, Christiane; Kibel, Adam S.; Cybulski, Cezary; Cannon-Albright, Lisa; Brenner, Hermann; Kaneva, Radka; Teixeira, Manuel R.; Consortium, PRACTICAL; Spurdle, Amanda B.; Clements, Judith A.; Park, Jong Y.; Batra, Jyotsna

2015-01-01

Prostate cancer is the second most common malignancy among men worldwide. Genome-wide association studies (GWAS) have identified 100 risk variants for prostate cancer, which can explain ~33% of the familial risk of the disease. We hypothesized that a comprehensive analysis of genetic variations found within the 3′ UTR of genes predicted to affect miRNA binding (miRSNPs) can identify additional prostate cancer risk variants. We investigated the association between 2,169 miRSNPs and prostate cancer risk in a large-scale analysis of 22,301 cases and 22,320 controls of European ancestry from 23 participating studies. Twenty-two miRSNPs were associated (p<2.3×10−5) with risk of prostate cancer, 10 of which were within the 7 genes previously not mapped by GWASs. Further, using miRNA mimics and reporter gene assays, we showed that miR-3162-5p has specific affinity for the KLK3 rs1058205 miRSNP T-allele whilst miR-370 has greater affinity for the VAMP8 rs1010 miRSNP A-allele, validating their functional role. Significance Findings from this large association study suggest that a focus on miRSNPs, including functional evaluation, can identify candidate risk loci below currently accepted statistical levels of genome-wide significance. Studies of miRNAs and their interactions with SNPs could provide further insights into the mechanisms of prostate cancer risk. PMID:25691096

The emerging roles of orphan nuclear receptors in prostate cancer.

PubMed

Wu, Dinglan; Cheung, Alyson; Wang, Yuliang; Yu, Shan; Chan, Franky L

2016-08-01

Orphan nuclear receptors are members of the nuclear receptor (NR) superfamily and are so named because their endogenous physiological ligands are either unknown or may not exist. Because of their important regulatory roles in many key physiological processes, dysregulation of signalings controlled by these receptors is associated with many diseases including cancer. Over years, studies of orphan NRs have become an area of great interest because their specific physiological and pathological roles have not been well-defined, and some of them are promising drug targets for diseases. The recently identified synthetic small molecule ligands, acting as agonists or antagonists, to these orphan NRs not only help to understand better their functional roles but also highlight that the signalings mediated by these ligand-independent NRs in diseases could be therapeutically intervened. This review is a summary of the recent advances in elucidating the emerging functional roles of orphan NRs in cancers, especially prostate cancer. In particular, some orphan NRs, RORγ, TR2, TR4, COUP-IFII, ERRα, DAX1 and SHP, exhibit crosstalk or interference with androgen receptor (AR) signaling in either normal or malignant prostatic cells, highlighting their involvement in prostate cancer progression as androgen and AR signaling pathway play critical roles in this process. We also propose that a better understanding of the mechanism of actions of these orphan NRs in prostate gland or prostate cancer could help to evaluate their potential value as therapeutic targets for prostate cancer. Copyright © 2016 Elsevier B.V. All rights reserved.

EMMPRIN Regulates Cytoskeleton Reorganization and Cell Adhesion in Prostate Cancer

PubMed Central

Zhu, Haining; Zhao, Jun; Zhu, Beibei; Collazo, Joanne; Gal, Jozsef; Shi, Ping; Liu, Li; Ström, Anna-Lena; Lu, Xiaoning; McCann, Richard O.; Toborek, Michal; Kyprianou, Natasha

2011-01-01

Background Proteins on cell surface play important roles during cancer progression and metastasis via their ability to mediate cell-to-cell interactions and navigate the communication between cells and the microenvironment. Methods In this study a targeted proteomic analysis was conducted to identify the differential expression of cell surface proteins in human benign (BPH-1) vs. malignant (LNCaP and PC-3) prostate epithelial cells. We identified EMMPRIN (extracellular matrix metalloproteinase inducer) as a key candidate and shRNA functional approaches were subsequently applied to determine the role of EMMPRIN in prostate cancer cell adhesion, migration, invasion as well as cytoskeleton organization. Results EMMPRIN was found to be highly expressed on the surface of prostate cancer cells compared to BPH-1 cells, consistent with a correlation between elevated EMMPRIN and metastasis found in other tumors. No significant changes in cell proliferation, cell cycle progression or apoptosis were detected in EMMPRIN knockdown cells compared to the scramble controls. Furthermore, EMMPRIN silencing markedly decreased the ability of PC-3 cells to form filopodia, a critical feature of invasive behavior, while it increased expression of cell-cell adhesion and gap junction proteins. Conclusions Our results suggest that EMMPRIN regulates cell adhesion, invasion and cytoskeleton reorganization in prostate cancer cells. This study identifies a new function for EMMPRIN as a contributor to prostate cancer cell-cell communication and cytoskeleton changes towards metastatic spread, and suggests its potential value as a marker of prostate cancer progression to metastasis. PMID:21563192

EMMPRIN regulates cytoskeleton reorganization and cell adhesion in prostate cancer.

PubMed

Zhu, Haining; Zhao, Jun; Zhu, Beibei; Collazo, Joanne; Gal, Jozsef; Shi, Ping; Liu, Li; Ström, Anna-Lena; Lu, Xiaoning; McCann, Richard O; Toborek, Michal; Kyprianou, Natasha

2012-01-01

Proteins on cell surface play important roles during cancer progression and metastasis via their ability to mediate cell-to-cell interactions and navigate the communication between cells and the microenvironment. In this study a targeted proteomic analysis was conducted to identify the differential expression of cell surface proteins in human benign (BPH-1) versus malignant (LNCaP and PC-3) prostate epithelial cells. We identified EMMPRIN (extracellular matrix metalloproteinase inducer) as a key candidate and shRNA functional approaches were subsequently applied to determine the role of EMMPRIN in prostate cancer cell adhesion, migration, invasion as well as cytoskeleton organization. EMMPRIN was found to be highly expressed on the surface of prostate cancer cells compared to BPH-1 cells, consistent with a correlation between elevated EMMPRIN and metastasis found in other tumors. No significant changes in cell proliferation, cell cycle progression, or apoptosis were detected in EMMPRIN knockdown cells compared to the scramble controls. Furthermore, EMMPRIN silencing markedly decreased the ability of PC-3 cells to form filopodia, a critical feature of invasive behavior, while it increased expression of cell-cell adhesion and gap junction proteins. Our results suggest that EMMPRIN regulates cell adhesion, invasion, and cytoskeleton reorganization in prostate cancer cells. This study identifies a new function for EMMPRIN as a contributor to prostate cancer cell-cell communication and cytoskeleton changes towards metastatic spread, and suggests its potential value as a marker of prostate cancer progression to metastasis. Copyright © 2011 Wiley Periodicals, Inc.

Identifying molecular features for prostate cancer with Gleason 7 based on microarray gene expression profiles.

PubMed

Bălăcescu, Loredana; Bălăcescu, O; Crişan, N; Fetica, B; Petruţ, B; Bungărdean, Cătălina; Rus, Meda; Tudoran, Oana; Meurice, G; Irimie, Al; Dragoş, N; Berindan-Neagoe, Ioana

2011-01-01

Prostate cancer represents the first leading cause of cancer among western male population, with different clinical behavior ranging from indolent to metastatic disease. Although many molecules and deregulated pathways are known, the molecular mechanisms involved in the development of prostate cancer are not fully understood. The aim of this study was to explore the molecular variation underlying the prostate cancer, based on microarray analysis and bioinformatics approaches. Normal and prostate cancer tissues were collected by macrodissection from prostatectomy pieces. All prostate cancer specimens used in our study were Gleason score 7. Gene expression microarray (Agilent Technologies) was used for Whole Human Genome evaluation. The bioinformatics and functional analysis were based on Limma and Ingenuity software. The microarray analysis identified 1119 differentially expressed genes between prostate cancer and normal prostate, which were up- or down-regulated at least 2-fold. P-values were adjusted for multiple testing using Benjamini-Hochberg method with a false discovery rate of 0.01. These genes were analyzed with Ingenuity Pathway Analysis software and were established 23 genetic networks. Our microarray results provide new information regarding the molecular networks in prostate cancer stratified as Gleason 7. These data highlighted gene expression profiles for better understanding of prostate cancer progression.

SYSTEMS MODELING OF PROSTATE REGULATION AND ...

EPA Pesticide Factsheets

The prostate is an androgen-dependent tissue that is an important site of disease in human males as well as an important indicator of androgen status in animals. The rat prostate is used for studying antiandrogenic drugs as well as for evaluation of endocrine disruption (e.g., Hershberger Assay). Pubertal changes in the prostate have been observed to be as sensitive to environmental antiandrogens as in utero effects. The goal of this research is to model the biology of prostate androgen function on a systems level to determine the factors responsible for the dose-response observable with androgens and antiandrogens in the male rat. This includes investigation of the roles of positive and negative feedback loops in prostatic response following castration and dosing with testosterone and/or antiandrogens. A biologically-based, systems-level model will be developed describing the regulation of the prostate by androgens. The model will extend an existing model for the male rat central axis, which describes feedback between luteinizing hormone and testosterone production in the testes, to include the prostate and conversion of testosterone to dihydrotestosterone (DHT). The prostate model will describe binding of androgens to the androgen receptor, 5α-reductase catalyzed production of DHT, and gene regulation affecting cell proliferation, apoptosis, and prostatic fluid production. The model will combine pharmacokinetic models for endogenous hormones (i.e., testost

Genetic influence on exercise-induced changes in physical function among mobility-limited older adults

PubMed Central

Hsu, Fang-Chi; Brinkley, Tina E.; Carter, Christy S.; Church, Timothy S.; Dodson, John A.; Goodpaster, Bret H.; McDermott, Mary M.; Nicklas, Barbara J.; Yank, Veronica; Johnson, Julie A.; Pahor, Marco

2014-01-01

To date, physical exercise is the only intervention consistently demonstrated to attenuate age-related declines in physical function. However, variability exists in seniors' responsiveness to training. One potential source of variability is the insertion (I allele) or deletion (D allele) of a 287 bp fragment in intron 16 of the angiotensin-converting enzyme (ACE) gene. This polymorphism is known to influence a variety of physiological adaptions to exercise. However, evidence is inconclusive regarding the influence of this polymorphism on older adults' functional responses to exercise. This study aimed to evaluate the association of ACE I/D genotypes with changes in physical function among Caucasian older adults (n = 283) following 12 mo of either structured, multimodal physical activity or health education. Measures of physical function included usual-paced gait speed and performance on the Short Physical Performance Battery (SPPB). After checking Hardy-Weinberg equilibrium, we used using linear regression to evaluate the genotype*treatment interaction for each outcome. Covariates included clinic site, body mass index, age, sex, baseline score, comorbidity, and use of angiotensin receptor blockers or ACE inhibitors. Genotype frequencies [II (19.4%), ID (42.4%), DD (38.2%)] were in Hardy-Weinberg equilibrium (P > 0.05). The genotype*treatment interaction was statistically significant for both gait speed (P = 0.002) and SPPB (P = 0.020). Exercise improved gait speed by 0.06 ± 0.01 m/sec and SPPB score by 0.72 ± 0.16 points among those with at least one D allele (ID/DD carriers), but function was not improved among II carriers. Thus, ACE I/D genotype appears to play a role in modulating functional responses to exercise training in seniors. PMID:24423970

Non-coding RNAs in Prostate Cancer: From Discovery to Clinical Applications.

PubMed

Ceder, Yvonne

2016-01-01

Prostate cancer is a heterogeneous disease for which the molecular mechanisms are still not fully elucidated. Prostate cancer research has traditionally focused on genomic and epigenetic alterations affecting the proteome, but over the last decade non-coding RNAs, especially microRNAs, have been recognized to play a key role in prostate cancer progression. A considerable number of individual microRNAs have been found to be deregulated in prostate cancer and their biological significance elucidated in functional studies. This review will delineate the current advances regarding the involvement of microRNAs and their targets in prostate cancer biology as well as their potential usage in the clinical management of the disease. The main focus will be on microRNAs contributing to initiation and progression of prostate cancer, including androgen signalling, cellular plasticity, stem cells biology and metastatic processes. To conclude, implications on potential future microRNA-based therapeutics based on the recent advances regarding the interplay between microRNAs and their targets are discussed.

Quantitative Proteomic Profiling of Prostate Cancer Reveals a Role for miR-128 in Prostate Cancer*

PubMed Central

Khan, Amjad P.; Poisson, Laila M.; Bhat, Vadiraja B.; Fermin, Damian; Zhao, Rong; Kalyana-Sundaram, Shanker; Michailidis, George; Nesvizhskii, Alexey I.; Omenn, Gilbert S.; Chinnaiyan, Arul M.; Sreekumar, Arun

2010-01-01

Multiple, complex molecular events characterize cancer development and progression. Deciphering the molecular networks that distinguish organ-confined disease from metastatic disease may lead to the identification of biomarkers of cancer invasion and disease aggressiveness. Although alterations in gene expression have been extensively quantified during neoplastic progression, complementary analyses of proteomic changes have been limited. Here we interrogate the proteomic alterations in a cohort of 15 prostate-derived tissues that included five each from adjacent benign prostate, clinically localized prostate cancer, and metastatic disease from distant sites. The experimental strategy couples isobaric tags for relative and absolute quantitation with multidimensional liquid phase peptide fractionation followed by tandem mass spectrometry. Over 1000 proteins were quantified across the specimens and delineated into clinically localized and metastatic prostate cancer-specific signatures. Included in these class-specific profiles were both proteins that were known to be dysregulated during prostate cancer progression and new ones defined by this study. Enrichment analysis of the prostate cancer-specific proteomic signature, to gain insight into the functional consequences of these alterations, revealed involvement of miR-128-a/b regulation during prostate cancer progression. This finding was validated using real time PCR analysis for microRNA transcript levels in an independent set of 15 clinical specimens. miR-128 levels were elevated in benign prostate epithelial cell lines compared with invasive prostate cancer cells. Knockdown of miR-128 induced invasion in benign prostate epithelial cells, whereas its overexpression attenuated invasion in prostate cancer cells. Taken together, our profiles of the proteomic alterations of prostate cancer progression revealed miR-128 as a potentially important negative regulator of prostate cancer cell invasion. PMID:19955085

Antigen specific T-cell responses against tumor antigens are controlled by regulatory T cells in patients with prostate cancer.

PubMed

Hadaschik, Boris; Su, Yun; Huter, Eva; Ge, Yingzi; Hohenfellner, Markus; Beckhove, Philipp

2012-04-01

Immunotherapy is a promising approach in an effort to control castration resistant prostate cancer. We characterized tumor antigen reactive T cells in patients with prostate cancer and analyzed the suppression of antitumor responses by regulatory T cells. Peripheral blood samples were collected from 57 patients with histologically confirmed prostate cancer, 8 patients with benign prostatic hyperplasia and 16 healthy donors. Peripheral blood mononuclear cells were isolated and antigen specific interferon-γ secretion of isolated T cells was analyzed by enzyme-linked immunospot assay. T cells were functionally characterized and T-cell responses before and after regulatory T-cell depletion were compared. As test tumor antigens, a panel of 11 long synthetic peptides derived from a total of 8 tumor antigens was used, including prostate specific antigen and prostatic acid phosphatase. In patients with prostate cancer we noted a 74.5% effector T-cell response rate compared with only 25% in patients with benign prostatic hyperplasia and 31% in healthy donors. In most patients 2 or 3 tumor antigens were recognized. Comparing various disease stages there was a clear increase in the immune response against prostate specific antigens from intermediate to high risk tumors and castration resistant disease. Regulatory T-cell depletion led to a significant boost in effector T-cell responses against prostate specific antigen and prostatic acid phosphatase. Tumor specific effector T cells were detected in most patients with prostate cancer, especially those with castration resistant prostate cancer. Since effector T-cell responses against prostate specific antigens strongly increased after regulatory T-cell depletion, our results indicate that immunotherapy efficacy could be enhanced by decreasing regulatory T cells. Copyright © 2012 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.

Synaptic dysfunction and intellectual disability.

PubMed

Valnegri, Pamela; Sala, Carlo; Passafaro, Maria

2012-01-01

Intellectual disability (ID) is a common and highly heterogeneous paediatric disorder with a very severe social impact. Intellectual disability can be caused by environmental and/or genetic factors. Although in the last two decades a number of genes have been discovered whose mutations cause mental retardation, we are still far from identifying the impact of these mutations on brain functions. Many of the genes mutated in ID code for several proteins with a variety of functions: chromatin remodelling, pre-/post-synaptic activity, and intracellular trafficking. The prevailing hypothesis suggests that the ID phenotype could emerge from abnormal cellular processing leading to pre- and/or post-synaptic dysfunction. In this chapter, we focus on the role of small GTPases and adhesion molecules, and we discuss the mechanisms through which they lead to synaptic network dysfunction.

Extraperitoneoscopic transcapsular adenomectomy: complications and functional results after at least 1 year of followup.

PubMed

Porpiglia, Francesco; Fiori, Cristian; Cavallone, Barbara; Morra, Ivano; Bertolo, Riccardo; Scarpa, Roberto Mario

2011-05-01

Laparoscopic simple prostatectomy has been proposed to treat large glands. To date groups have investigated the feasibility and perioperative results of laparoscopic simple prostatectomy but to our knowledge no study has focused on its complications and functional results at longer followup. We investigated complications and functional results in patients with a large prostate who were treated with laparoscopic simple prostatectomy and had at least 1 year of followup. From our prospectively maintained database we extracted data on 78 patients treated with laparoscopic simple prostatectomy at our institution who had at least 1 year of reported followup. Demographics, perioperative results, early and late complications, and functional results were evaluated. Followup was planned at 1, 3, 6 and 12 months, and every 6 months thereafter. Mean followup was 30 months. Grade III complications were recorded in 2 cases and late complications were reported in 4 (5%). Statistically significant differences were observed in the International Prostate Symptom Score, the International Prostate Symptom Score quality of life index and maximum urine flow when comparing preoperative and postoperative results. No significant differences were recorded in maximum urine flow or the International Prostate Symptom Score quality of life index during followup. Results suggest that laparoscopic simple prostatectomy is safe and effective even after a significant period, as indicated by the low complication rate and positive, stable functional results found during followup. In our opinion laparoscopic simple prostatectomy can be offered to patients as a valid treatment option for a large prostate at advanced laparoscopic centers. Copyright © 2011 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.

Comparison of health-related quality of life and prostate-associated symptoms after primary and salvage cryotherapy for prostate cancer.

PubMed

Anastasiadis, Aristotelis G; Sachdev, Reena; Salomon, Laurent; Ghafar, Mohamed A; Stisser, Brian C; Shabsigh, Ridwan; Katz, Aaron E

2003-12-01

Recent advances in cryosurgery of the prostate have led to the ability to treat tumors successfully with decreased morbidity. The patients' perspectives of this relatively new technique, however, have not yet been addressed. The purpose of this study was to compare health related quality of life (QoL) as well as prostate-associated symptoms in patients after primary and salvage cryoablation for clinically localized prostate cancer using a self-administered questionnaire. A total of 131 consecutive patients who underwent cryoablation of the prostate between 1997 and 2001 were included in this confidential mailing study. The patients were either (a) patients with localized prostate cancer with contraindications for radical surgery, including patients refusing other forms of therapy, or (b) had locally recurrent prostate cancer after failure of radiation therapy. All patients received 3 months of neoadjuvant androgen deprivation therapy prior to cryosurgery and were surgically treated by the same surgeon using an argon-based system. We used the EORTC QLQ-C30, a commonly used, multidimensional instrument together with a supplementing, prostate-cancer-specific module. Eighty-one of the 131 patients (response rate 62%) returned the questionnaires. The two groups were comparable regarding age (mean age 72.8 vs 70.1 for the primary and the salvage group, respectively; p=0.22). The overall QoL scores were high in both groups. Primary cryotherapy patients fared significantly better regarding physical (p=0.005) and social (p=0.024) functioning compared with salvage cryotherapy patients. The most prominent prostate-related symptom in both patient groups was sexual dysfunction, followed by urinary symptoms, which were significantly more severe in the salvage group (p=0.001). Incontinence rates were 5.9 and 10% in the primary and the salvage group, respectively. Severe erectile dysfunction was reported in 86 and 90% of the primary and the salvage group, respectively. The present study demonstrates that, in selected patients, cryotherapy is a treatment option which has a functional outcome comparable to traditionally used prostate cancer treatments. More information regarding QoL is necessary for appropriate patient counseling and individual decision-making in the presence of various treatment alternatives.

Metabolic syndrome and prostate abnormalities in male subjects of infertile couples

PubMed Central

Lotti, Francesco; Corona, Giovanni; Vignozzi, Linda; Rossi, Matteo; Maseroli, Elisa; Cipriani, Sarah; Gacci, Mauro; Forti, Gianni; Maggi, Mario

2014-01-01

No previous study has evaluated systematically the relationship between metabolic syndrome (MetS) and prostate-related symptoms and signs in young infertile men. We studied 171 (36.5 ± 8.3-years-old) males of infertile couples. MetS was defined based on the National Cholesterol Education Program Third Adult Treatment Panel. All men underwent hormonal (including total testosterone (TT) and insulin), seminal (including interleukin-8 (IL-8), seminal plasma IL-8 (sIL-8)), scrotal and transrectal ultrasound evaluations. Because we have previously assessed correlations between MetS and scrotal parameters in a larger cohort of infertile men, here, we focused on transrectal features. Prostate-related symptoms were assessed using the National Institutes of Health Chronic Prostatitis Symptom Index (NIH-CPSI) and the International Prostate Symptom Score (IPSS). Twenty-two subjects fulfilled MetS criteria. In an age-adjusted logistic ordinal model, insulin levels increased as a function of MetS components (Wald = 29.5, P < 0.0001) and showed an inverse correlation with TT (adjusted r = -0.359, P< 0.0001). No association between MetS and NIH-CPSI or IPSS scores was observed. In an age-, TT-, insulin-adjusted logistic ordinal model, an increase in number of MetS components correlated negatively with normal sperm morphology (Wald = 5.59, P< 0.02) and positively with sIL-8 levels (Wald = 4.32, P < 0.05), which is a marker of prostate inflammation, with prostate total and transitional zone volume assessed using ultrasound (Wald = 17.6 and 12.5, both P < 0.0001), with arterial peak systolic velocity (Wald = 9.57, P = 0.002), with texture nonhomogeneity (hazard ratio (HR) = 1.87 (1.05–3.33), P < 0.05), with calcification size (Wald = 3.11, P < 0.05), but not with parameters of seminal vesicle size or function. In conclusion, in males of infertile couples, MetS is positively associated with prostate enlargement, biochemical (sIL8) and ultrasound-derived signs of prostate inflammation but not with prostate-related symptoms, which suggests that MetS is a trigger for a subclinical, early-onset form of benign prostatic hyperplasia. PMID:24435050

Protein profile of basal prostate epithelial progenitor cells--stage-specific embryonal antigen 4 expressing cells have enhanced regenerative potential in vivo.

PubMed

Höfner, Thomas; Klein, Corinna; Eisen, Christian; Rigo-Watermeier, Teresa; Haferkamp, Axel; Sprick, Martin R

2016-04-01

The long-term propagation of basal prostate progenitor cells ex vivo has been very difficult in the past. The development of novel methods to expand prostate progenitor cells in vitro allows determining their cell surface phenotype in greater detail. Mouse (Lin(-)Sca-1(+) CD49f(+) Trop2(high)-phenotype) and human (Lin(-) CD49f(+) TROP2(high)) basal prostate progenitor cells were expanded in vitro. Human and mouse cells were screened using 242 anti-human or 176 antimouse monoclonal antibodies recognizing the cell surface protein profile. Quantitative expression was evaluated at the single-cell level using flow cytometry. Differentially expressed cell surface proteins were evaluated in conjunction with the known CD49f(+)/TROP2(high) phenotype of basal prostate progenitor cells and characterized by in vivo sandwich-transplantation experiments using nude mice. The phenotype of basal prostate progenitor cells was determined as CD9(+)/CD24(+)/CD29(+)/CD44(+)/CD47(+)/CD49f(+)/CD104(+)/CD147(+)/CD326(+)/Trop2(high) of mouse as well as human origin. Our analysis revealed several proteins, such as CD13, Syndecan-1 and stage-specific embryonal antigens (SSEAs), as being differentially expressed on murine and human CD49f(+) TROP2(+) basal prostate progenitor cells. Transplantation experiments suggest that CD49f(+) TROP2(high) SSEA-4(high) human prostate basal progenitor cells to be more potent to regenerate prostate tubules in vivo as compared with CD49f(+) TROP2(high) or CD49f(+) TROP2(high) SSEA-4(low) cells. Determination of the cell surface protein profile of functionally defined murine and human basal prostate progenitor cells reveals differentially expressed proteins that may change the potency and regenerative function of epithelial progenitor cells within the prostate. SSEA-4 is a candidate cell surface marker that putatively enables a more accurate identification of the basal PESC lineage. © 2016 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.

High-throughput sequencing technology to reveal the composition and function of cecal microbiota in Dagu chicken.

PubMed

Xu, Yunhe; Yang, Huixin; Zhang, Lili; Su, Yuhong; Shi, Donghui; Xiao, Haidi; Tian, Yumin

2016-11-04

The chicken gut microbiota is an important and complicated ecosystem for the host. They play an important role in converting food into nutrient and energy. The coding capacity of microbiome vastly surpasses that of the host's genome, encoding biochemical pathways that the host has not developed. An optimal gut microbiota can increase agricultural productivity. This study aims to explore the composition and function of cecal microbiota in Dagu chicken under two feeding modes, free-range (outdoor, OD) and cage (indoor, ID) raising. Cecal samples were collected from 24 chickens across 4 groups (12-w OD, 12-w ID, 18-w OD, and 18-w ID). We performed high-throughput sequencing of the 16S rRNA genes V4 hypervariable regions to characterize the cecal microbiota of Dagu chicken and compare the difference of cecal microbiota between free-range and cage raising chickens. It was found that 34 special operational taxonomic units (OTUs) in OD groups and 4 special OTUs in ID groups. 24 phyla were shared by the 24 samples. Bacteroidetes was the most abundant phylum with the largest proportion, followed by Firmicutes and Proteobacteria. The OD groups showed a higher proportion of Bacteroidetes (>50 %) in cecum, but a lower Firmicutes/Bacteroidetes ratio in both 12-w old (0.42, 0.62) and 18-w old groups (0.37, 0.49) compared with the ID groups. Cecal microbiota in the OD groups have higher abundance of functions involved in amino acids and glycan metabolic pathway. The composition and function of cecal microbiota in Dagu chicken under two feeding modes, free-range and cage raising are different. The cage raising mode showed a lower proportion of Bacteroidetes in cecum, but a higher Firmicutes/Bacteroidetes ratio compared with free-range mode. Cecal microbiota in free-range mode have higher abundance of functions involved in amino acids and glycan metabolic pathway.

Effect of red maca (Lepidium meyenii) on prostate zinc levels in rats with testosterone-induced prostatic hyperplasia.

PubMed

Gonzales, C; Leiva-Revilla, J; Rubio, J; Gasco, M; Gonzales, G F

2012-05-01

Lepidium meyenii (maca) is a plant that grows exclusively above 4000 m in the Peruvian central Andes. Red maca (RM) extract significantly reduced prostate size in rats with benign prostatic hyperplasia (BPH) induced by testosterone enanthate (TE). Zinc is an important regulator of prostate function. This study aimed to determine the effect of RM on prostate zinc levels in rats with BPH induced by TE. Also, the study attempted to determine the best marker for the effect of RM on sex accessory glands. Rats treated with RM extract from day 1 to day 14 reversed the effect of TE administration on prostate weight and zinc levels. However, RM administered from day 7 to day 14 did not reduce the effect of TE on all studied variables. Finasteride (FN) reduced prostate, seminal vesicle and preputial gland weights in rats treated with TE. Although RM and FN reduced prostate zinc levels, the greatest effect was observed in TE-treated rats with RM from day 1 to day 14. In addition, prostate weight and zinc levels showed the higher diagnosis values than preputial and seminal vesicle weights. In conclusion, RM administered from day 1 to day 14 reduced prostate size and zinc levels in rats where prostatic hyperplasia was induced with TE. Also, this experimental model could be used as accurately assay to determine the effect of maca obtained under different conditions and/or the effect of different products based on maca. © 2011 Blackwell Verlag GmbH.

Androgen receptor-related diseases: what do we know?

PubMed

Shukla, G C; Plaga, A R; Shankar, E; Gupta, S

2016-05-01

The androgen receptor (AR) and the androgen-AR signaling pathway play a significant role in male sexual differentiation and the development and function of male reproductive and non-reproductive organs. Because of AR's widely varied and important roles, its abnormalities have been identified in various diseases such as androgen insensitivity syndrome, spinal bulbar muscular atrophy, benign prostatic hyperplasia, and prostate cancer. This review provides an overview of the function of androgens and androgen-AR mediated diseases. In addition, the diseases delineated above are discussed with respect to their association with mutations and other post-transcriptional modifications in the AR. Finally, we present an introduction to the potential therapeutic application of most recent pharmaceuticals including miRNAs in prostate cancer that specifically target the transactivation function of the AR at post-transcriptional stages. © 2016 American Society of Andrology and European Academy of Andrology.

Anoctamin 1 (TMEM16A) is essential for testosterone-induced prostate hyperplasia.

PubMed

Cha, Joo Young; Wee, Jungwon; Jung, Jooyoung; Jang, Yongwoo; Lee, Byeongjun; Hong, Gyu-Sang; Chang, Beom Chul; Choi, Yoon-La; Shin, Young Kee; Min, Hye-Young; Lee, Ho-Young; Na, Tae-Young; Lee, Mi-Ock; Oh, Uhtaek

2015-08-04

Benign prostatic hyperplasia (BPH) is characterized by an enlargement of the prostate, causing lower urinary tract symptoms in elderly men worldwide. However, the molecular mechanism underlying the pathogenesis of BPH is unclear. Anoctamin1 (ANO1) encodes a Ca(2+)-activated chloride channel (CaCC) that mediates various physiological functions. Here, we demonstrate that it is essential for testosterone-induced BPH. ANO1 was highly amplified in dihydrotestosterone (DHT)-treated prostate epithelial cells, whereas the selective knockdown of ANO1 inhibited DHT-induced cell proliferation. Three androgen-response elements were found in the ANO1 promoter region, which is relevant for the DHT-dependent induction of ANO1. Administration of the ANO1 blocker or Ano1 small interfering RNA, inhibited prostate enlargement and reduced histological abnormalities in vivo. We therefore concluded that ANO1 is essential for the development of prostate hyperplasia and is a potential target for the treatment of BPH.

Anoctamin 1 (TMEM16A) is essential for testosterone-induced prostate hyperplasia

PubMed Central

Cha, Joo Young; Wee, Jungwon; Jung, Jooyoung; Jang, Yongwoo; Lee, Byeongjun; Hong, Gyu-Sang; Chang, Beom Chul; Choi, Yoon-La; Shin, Young Kee; Min, Hye-Young; Lee, Ho-Young; Na, Tae-Young; Lee, Mi-Ock; Oh, Uhtaek

2015-01-01

Benign prostatic hyperplasia (BPH) is characterized by an enlargement of the prostate, causing lower urinary tract symptoms in elderly men worldwide. However, the molecular mechanism underlying the pathogenesis of BPH is unclear. Anoctamin1 (ANO1) encodes a Ca2+-activated chloride channel (CaCC) that mediates various physiological functions. Here, we demonstrate that it is essential for testosterone-induced BPH. ANO1 was highly amplified in dihydrotestosterone (DHT)-treated prostate epithelial cells, whereas the selective knockdown of ANO1 inhibited DHT-induced cell proliferation. Three androgen-response elements were found in the ANO1 promoter region, which is relevant for the DHT-dependent induction of ANO1. Administration of the ANO1 blocker or Ano1 small interfering RNA, inhibited prostate enlargement and reduced histological abnormalities in vivo. We therefore concluded that ANO1 is essential for the development of prostate hyperplasia and is a potential target for the treatment of BPH. PMID:26153424

Clinical and Functional Analyses of p73R1 Mutations in Prostate Cancer

DTIC Science & Technology

2005-02-01

mutations in several genes (BRCA 1, BRCA2, and CHEK2) whose products are involved in this pathway have been associated with increased risk for this...screened this gene for mutations in prostate cancer. Two germline truncating mutations were identified. Genotyping of 403 men with sporadic prostate...based on mutation screening of candidate genes involved in the DNA damage- signaling pathway. Genomic instability is a common feature of all human

Iron deficiency in a tertiary gastroenterology center in Romania: prevalence and significancy.

PubMed

Preda, Carmen Monica; Proca, Doina; Sandra, Irina; Horeanga, Boroka Claudia; Fulger, Larisa Elena; Manuc, Teodora; Bancila, Ion; Balas, Oana Elena; Manuc, Mircea; Diculescu, Mircea; Baicus, Cristian; Tieranu, Cristian; Constantinescu, Ileana

2018-01-01

Introduction: Iron deficiency has been known to cause significant functional impairment, lower quality of life and higher morbidity and mortality. The aim of this study was to estimate the prevalence and significance of iron deficiency in our patients and medical staff. Material and methods: We performed a prospective cross-sectional study: In July 2016, 383 persons were screened for the presence of iron deficiency (ID): 325 patients and 58 people from the medical staff. Transferrin saturation (TSAT), serum ferritin (SF) and complete blood count were performed. Absolute ID was diagnosed if SF <100 ng/ml and TSAT <20%. Relative ID was defined by SF >100 ng/ml and TSAT <20%. Results: The group of medical staff was younger and had a greater proportion of women. The prevalence of absolute ID was 22.5% in patients and 43.1% in medical staff; relative ID was present in 15% of patients and 1.7% of medical staff. Among patients, the absolute ID was significantly correlated with the female sex (p=0.002) and pre-menopausal status (p=0.01) but did not correlate with diagnosis, age, BMI, nonsteroidal anti-inflammatory drug (NSAID), aspirin or acenocoumarol consumption. The relative ID is associated with advanced age (p=0.03) and diagnosis of cancer and liver cirrhosis (p=0.01). Conclusions: Absolute ID had a high prevalence among patients (22.5%), but there was even a bigger issue among the medical staff (43.1%). Absolute ID was correlated with female sex and pre-menopausal status. Relative ID was related to advanced age, cancer and liver cirrhosis. Abbreviations: serum ferritine- SF, transferrin saturation coefficient- TSAT, iron deficiency- ID, inflammatory bowel diseases- IBD, quality of life- QoL, GI- gastrointestinal.

Iron deficiency in a tertiary gastroenterology center in Romania: prevalence and significancy

PubMed Central

Preda, Carmen Monica; Proca, Doina; Sandra, Irina; Horeanga, Boroka Claudia; Fulger, Larisa Elena; Manuc, Teodora; Bancila, Ion; Balas, Oana Elena; Manuc, Mircea; Diculescu, Mircea; Baicus, Cristian; Tieranu, Cristian; Constantinescu, Ileana

2018-01-01

Introduction:Iron deficiency has been known to cause significant functional impairment, lower quality of life and higher morbidity and mortality. The aim of this study was to estimate the prevalence and significance of iron deficiency in our patients and medical staff. Material and methods:We performed a prospective cross-sectional study: In July 2016, 383 persons were screened for the presence of iron deficiency (ID): 325 patients and 58 people from the medical staff. Transferrin saturation (TSAT), serum ferritin (SF) and complete blood count were performed. Absolute ID was diagnosed if SF <100 ng/ml and TSAT <20%. Relative ID was defined by SF >100 ng/ml and TSAT <20%. Results:The group of medical staff was younger and had a greater proportion of women. The prevalence of absolute ID was 22.5% in patients and 43.1% in medical staff; relative ID was present in 15% of patients and 1.7% of medical staff. Among patients, the absolute ID was significantly correlated with the female sex (p=0.002) and pre-menopausal status (p=0.01) but did not correlate with diagnosis, age, BMI, nonsteroidal anti-inflammatory drug (NSAID), aspirin or acenocoumarol consumption. The relative ID is associated with advanced age (p=0.03) and diagnosis of cancer and liver cirrhosis (p=0.01). Conclusions:Absolute ID had a high prevalence among patients (22.5%), but there was even a bigger issue among the medical staff (43.1%). Absolute ID was correlated with female sex and pre-menopausal status. Relative ID was related to advanced age, cancer and liver cirrhosis. Abbreviations: serum ferritine- SF, transferrin saturation coefficient- TSAT, iron deficiency- ID, inflammatory bowel diseases- IBD, quality of life- QoL, GI- gastrointestinal PMID:29696062

Saw Palmetto for Symptom Management During Radiation Therapy for Prostate Cancer.

PubMed

Wyatt, Gwen K; Sikorskii, Alla; Safikhani, Abolfazl; McVary, Kevin T; Herman, James

2016-06-01

Lower urinary tract symptoms (LUTSs) affect 75%-80% of men undergoing radiation therapy (RT) for prostate cancer. To determine the safety, maximum tolerated dose (MTD), and preliminary efficacy of Serenoa repens commonly known as saw palmetto (SP) for management of LUTS during RT for prostate cancer. The dose finding phase used the time-to-event continual reassessment method to evaluate safety of three doses (320, 640, and 960 mg) of SP. Dose-limiting toxicities were assessed for 22 weeks using the Common Terminology Criteria for Adverse Events for nausea, gastritis, and anorexia. The exploratory randomized controlled trial phase assessed preliminary efficacy of the MTD against placebo. The primary outcome of LUTS was measured over 22 weeks using the International Prostate Symptom Score. Additional longitudinal assessments included quality of life measured with the Functional Assessment of Cancer Therapy-Prostate. The dose finding phase was completed by 27 men who reported no dose-limiting toxicities and with 20 participants at the MTD of 960 mg daily. The exploratory randomized controlled trial phase included 21 men, and no statistically significant differences in the International Prostate Symptom Score were observed. The prostate-specific concerns score of the Functional Assessment of Cancer Therapy-Prostate improved in the SP group (P = 0.03). Of 11 men in the placebo group, two received physician-prescribed medications to manage LUTS compared with none of the 10 men in the SP group. SP at 960 mg may be a safe herbal supplement, but its efficacy in managing LUTS during RT needs further investigation. Copyright © 2016 American Academy of Hospice and Palliative Medicine. Published by Elsevier Inc. All rights reserved.

POWERS forID: Personalized Online Weight and Exercise Response System for Individuals with Intellectual Disability: study protocol for a randomized controlled trial.

PubMed

Neumeier, William H; Guerra, Nichole; Thirumalai, Mohanraj; Geer, Betty; Ervin, David; Rimmer, James H

2017-10-23

Intellectual disability (ID) is characterized by limitations in intellectual functioning and adaptive behavior. Adults with ID exhibit higher rates of obesity and poorer health status compared to the general population. Continuity of care and barriers to health-related activities may contribute to the poorer health status observed in this population. To address this problem, a tailored weight management online health information and communication technology platform, known as POWERS forID , was developed and is being tested to determine if this delivery mechanism can improve weight maintenance/weight loss in adults with ID. Obese adults with mild-to-moderate ID (n = 70) are randomized to the POWERS forID intervention or control group for a 24-week trial. Each group undergoes an assessment that includes body weight, waist circumference, and percent body fat at baseline and at weeks 6, 12, and 24. Physical activity barriers, healthy eating barriers, food frequency, and psychosocial wellbeing are measured at baseline and at weeks 12 and 24. Blood lipids are assessed at baseline and 24 weeks. Participants randomized to POWERS forID receive access to the POWERS forID website and calls from a health coach (weekly during weeks 1-12, biweekly during weeks 13-24). The health coach employs motivational interviewing techniques adapted for individuals with ID to promote behavior change. Participants randomized to the control group receive standard clinical weight-loss care. Differences in weight, waist circumference, blood lipids, percent body fat, and psychosocial self-report will be assessed. Barriers and facilitators of implementation as well as perception of study outcomes will be conducted via qualitative analysis. POWERS forID is a novel information and communication technology platform designed to address health needs for adults with ID. This article describes the development and components of POWERS forID . The overall aim is to assess usability and feasibility of POWERS forID for promoting weight loss for obese adults with ID over the course of a 24-week randomized control trial. Clinicaltrials.gov, NCT03139760 . Registered on XXX.

The co-occurrence of mental disorders in children and adolescents with intellectual disability/intellectual developmental disorder

PubMed Central

Munir, Kerim M.

2016-01-01

Purpose of review The study summarizes supportive epidemiological data regarding the true co-occurrence (comorbidity) and course of mental disorders in children with intellectual disability/intellectual developmental disorders (ID/IDD) across the lifespan. Recent findings Published studies involving representative populations of children and adolescents with ID/IDD have demonstrated a three to four-fold increase in prevalence of co-occurring mental disorders. The effect of age, sex, and severity (mild, moderate, severe, and profound) and socioeconomic status on prevalence is currently not clearly understood. To date there are no prevalence estimates of co-occurring mental disorders in youth identified using the new DSM-5 (and proposed ICD-11) definition of ID/IDD using measures of intellectual functions and deficits in adaptive functioning with various severity levels defined on the basis of adaptive functioning, and not intellectual quotient scores. Summary The true relationship between two forms of morbidity remains complex and causal relationships that may be true for one disorder may not apply to another. The new conceptualization of ID/IDD offers a developmentally better informed psychobiological approach that can help distinguish co-occurrence of mental disorders within the neurodevelopmental section with onset during the developmental period as well as the later onset of other mental disorders. PMID:26779862

The co-occurrence of mental disorders in children and adolescents with intellectual disability/intellectual developmental disorder.

PubMed

Munir, Kerim M

2016-03-01

The study summarizes supportive epidemiological data regarding the true co-occurrence (comorbidity) and course of mental disorders in children with intellectual disability/intellectual developmental disorders (ID/IDD) across the lifespan. Published studies involving representative populations of children and adolescents with ID/IDD have demonstrated a three to four-fold increase in prevalence of co-occurring mental disorders. The effect of age, sex, and severity (mild, moderate, severe, and profound) and socioeconomic status on prevalence is currently not clearly understood. To date there are no prevalence estimates of co-occurring mental disorders in youth identified using the new DSM-5 (and proposed ICD-11) definition of ID/IDD using measures of intellectual functions and deficits in adaptive functioning with various severity levels defined on the basis of adaptive functioning, and not intellectual quotient scores. The true relationship between two forms of morbidity remains complex and causal relationships that may be true for one disorder may not apply to another. The new conceptualization of ID/IDD offers a developmentally better informed psychobiological approach that can help distinguish co-occurrence of mental disorders within the neurodevelopmental section with onset during the developmental period as well as the later onset of other mental disorders.

Metabolomic signatures of aggressive prostate cancer.

PubMed

McDunn, Jonathan E; Li, Zhen; Adam, Klaus-Peter; Neri, Bruce P; Wolfert, Robert L; Milburn, Michael V; Lotan, Yair; Wheeler, Thomas M

2013-10-01

Current diagnostic techniques have increased the detection of prostate cancer; however, these tools inadequately stratify patients to minimize mortality. Recent studies have identified a biochemical signature of prostate cancer metastasis, including increased sarcosine abundance. This study examined the association of tissue metabolites with other clinically significant findings. A state of the art metabolomics platform analyzed prostatectomy tissues (331 prostate tumor, 178 cancer-free prostate tissues) from two independent sites. Biochemicals were analyzed by gas chromatography-mass spectrometry and ultrahigh performance liquid chromatography-tandem mass spectrometry. Statistical analyses identified metabolites associated with cancer aggressiveness: Gleason score, extracapsular extension, and seminal vesicle and lymph node involvement. Prostate tumors had significantly altered metabolite profiles compared to cancer-free prostate tissues, including biochemicals associated with cell growth, energetics, stress, and loss of prostate-specific biochemistry. Many metabolites were further associated with clinical findings of aggressive disease. Aggressiveness-associated metabolites stratified prostate tumor tissues with high abundances of compounds associated with normal prostate function (e.g., citrate and polyamines) from more clinically advanced prostate tumors. These aggressive prostate tumors were further subdivided by abundance profiles of metabolites including NAD+ and kynurenine. When added to multiparametric nomograms, metabolites improved prediction of organ confinement (AUROC from 0.53 to 0.62) and 5-year recurrence (AUROC from 0.53 to 0.64). These findings support and extend earlier metabolomic studies in prostate cancer and studies where metabolic enzymes have been associated with carcinogenesis and/or outcome. Furthermore, these data suggest that panels of analytes may be valuable to translate metabolomic findings to clinically useful diagnostic tests. Copyright © 2013 Wiley Periodicals, Inc.

Connexins in Prostate Cancer Initiation and Progression

DTIC Science & Technology

2013-11-01

the Golgi Apparatus for Cargo Transport Prior to Complete Assembly. Mol.Biol.Cell, 17, 4105-4117. 79. Hunziker,W. and Geuze,H. (2011...tumor growth by inducing the assembly of other junctional and signaling complexes? Wild type connexins which form functional gap junctions and mutant...and influences the function of two other important proteins that have been shown to prevent the spread of cancer cells from prostate to distant organs

Holographic calculation for large interval Rényi entropy at high temperature

NASA Astrophysics Data System (ADS)

Chen, Bin; Wu, Jie-qiang

2015-11-01

In this paper, we study the holographic Rényi entropy of a large interval on a circle at high temperature for the two-dimensional conformal field theory (CFT) dual to pure AdS3 gravity. In the field theory, the Rényi entropy is encoded in the CFT partition function on n -sheeted torus connected with each other by a large branch cut. As proposed by Chen and Wu [Large interval limit of Rényi entropy at high temperature, arXiv:1412.0763], the effective way to read the entropy in the large interval limit is to insert a complete set of state bases of the twist sector at the branch cut. Then the calculation transforms into an expansion of four-point functions in the twist sector with respect to e-2/π T R n . By using the operator product expansion of the twist operators at the branch points, we read the first few terms of the Rényi entropy, including the leading and next-to-leading contributions in the large central charge limit. Moreover, we show that the leading contribution is actually captured by the twist vacuum module. In this case by the Ward identity the four-point functions can be derived from the correlation function of four twist operators, which is related to double interval entanglement entropy. Holographically, we apply the recipe in [T. Faulkner, The entanglement Rényi entropies of disjoint intervals in AdS/CFT, arXiv:1303.7221] and [T. Barrella et al., Holographic entanglement beyond classical gravity, J. High Energy Phys. 09 (2013) 109] to compute the classical Rényi entropy and its one-loop quantum correction, after imposing a new set of monodromy conditions. The holographic classical result matches exactly with the leading contribution in the field theory up to e-4 π T R and l6, while the holographical one-loop contribution is in exact agreement with next-to-leading results in field theory up to e-6/π T R n and l4 as well.

ACE-Inhibition Benefit on Lung Function in Heart Failure is Modulated by ACE Insertion/Deletion Polymorphism.

PubMed

Contini, Mauro; Compagnino, Elisa; Cattadori, Gaia; Magrì, Damiano; Camera, Marina; Apostolo, Anna; Farina, Stefania; Palermo, Pietro; Gertow, Karl; Tremoli, Elena; Fiorentini, Cesare; Agostoni, Piergiuseppe

2016-04-01

The benefit of angiotensin converting enzyme (ACE) inhibition in chronic heart failure (HF) is partially due to its effects on pulmonary function and particularly on lung diffusion, the latter being counteracted by acetylsalicylic acid (ASA). Tissue ACE activity is largely determined by an insertion/deletion (I/D) polymorphism resulting in three possible genotypes (DD, ID and II). It is not clear if ACE inhibitor therapy could exert different effects in these genotypes. The aim of the study was to understand whether I/D polymorphism interferes with ACE inhibitor's protection of the lungs in HF during acute fluid overload. 100 HF patients (left ventricular ejection fraction ≤40 %) in stable clinical conditions, treated with enalapril but without ASA performed pulmonary function tests including lung diffusion (DLco) and its subcomponents, membrane diffusion (Dm) and capillary volume (Vcap), and a cardiopulmonary exercise test before and immediately after rapid infusion of 500 cc saline. ACE I/D genotype prevalence was: DD = 28, ID =55 and II = 17 cases. No significant differences in major pulmonary function and exercise parameters were observed before saline infusion among ACE genotypes. After fluid challenge, DD patients presented a higher DLco and Dm reduction than ID and II (DLco -2.3 ± 1.3 vs. -0.8 ± 1.9 and -0.6 ± 1 mL/mmHg/min, p < 0.0001 and p < 0.01; Dm -7 ± 5 vs. -3.2 ± 7.4 and -1.3 ± 5 mL/mmHg/min, p < 0.05, respectively) and a higher increase in VE/VCO2 slope than II (1.8 ± 1.9 vs. -0.8 ± 2.3, p = 0.01). ACE DD genotype is associated with higher vulnerability of the alveolar-capillary membrane to acute fluid overload in HF patients treated with ACE inhibitors.

Decreased serum hepcidin, inflammation, and improved functional iron status six-months post-restrictive bariatric surgery.

USDA-ARS?s Scientific Manuscript database

Excess adiposity is associated with low-grade inflammation and decreased iron status. Iron depletion (ID) in obesity is thought to be mediated by an inflammation-induced increase in the body’s main regulator of iron homeostasis, hepcidin. Elevated hepcidin can result in ID as it prevents the release...

DOE Office of Scientific and Technical Information (OSTI.GOV)

Hamlet, Jason; Pierson, Lyndon; Bauer, Todd

Supply chain security to detect, deter, and prevent the counterfeiting of networked and stand-alone integrated circuits (ICs) is critical to cyber security. Sandia National Laboratory researchers have developed IC ID to leverage Physically Unclonable Functions (PUFs) and strong cryptographic authentication to create a unique fingerprint for each integrated circuit. IC ID assures the authenticity of ICs to prevent tampering or malicious substitution.

Executive Functions and Adaptive Behaviour in Autism Spectrum Disorders with and without Intellectual Disability

PubMed Central

Panerai, Simonetta; Tasca, Domenica; Ferri, Raffaele; Genitori D'Arrigo, Valentina; Elia, Maurizio

2014-01-01

Executive functions (EF) in autism spectrum disorders (ASD) have been often investigated, although results seem to be rather inconsistent. The first aim of this study was to detect which EF components are common to the ASD continuum (from high- to low-functioning ASD) and identify a possible EF profile for ASD people. Planning, mental flexibility, inhibition of response, generativity, and ecologic EF were investigated. This study was extended not only to high-functioning ASD, but also to ASD with intellectual disability (ID). The second aim was to find EF aspects correlating with adaptive skills in ASD. A total of 61 children participated in the study (27 ASD with and without ID and 34 controls). Results highlight an executive profile characterised by impaired flexibility and deficient planning; these deficits are associated with decreased adaptive ability, particularly socialization, and a deficient shifting in ecologic conditions. These features are present in all ASD subgroups with and without ID; for this reason, they might be assumed as being specific features in ASD. PMID:24829905

The role of CD133 in normal human prostate stem cells and malignant cancer-initiating cells.

PubMed

Vander Griend, Donald J; Karthaus, Wouter L; Dalrymple, Susan; Meeker, Alan; DeMarzo, Angelo M; Isaacs, John T

2008-12-01

Resolving the specific cell of origin for prostate cancer is critical to define rational targets for therapeutic intervention and requires the isolation and characterization of both normal human prostate stem cells and prostate cancer-initiating cells (CIC). Single epithelial cells from fresh normal human prostate tissue and prostate epithelial cell (PrEC) cultures derived from them were evaluated for the presence of subpopulations expressing stem cell markers and exhibiting stem-like growth characteristics. When epithelial cell suspensions containing cells expressing the stem cell marker CD133+ are inoculated in vivo, regeneration of stratified human prostate glands requires inductive prostate stromal cells. PrEC cultures contain a small subpopulation of CD133+ cells, and fluorescence-activated cell sorting-purified CD133+ PrECs self-renew and regenerate cell populations expressing markers of transit-amplifying cells (DeltaNp63), intermediate cells (prostate stem cell antigen), and neuroendocrine cells (CD56). Using a series of CD133 monoclonal antibodies, attachment and growth of CD133+ PrECs requires surface expression of full-length glycosylated CD133 protein. Within a series of androgen receptor-positive (AR+) human prostate cancer cell lines, CD133+ cells are present at a low frequency, self-renew, express AR, generate phenotypically heterogeneous progeny negative for CD133, and possess an unlimited proliferative capacity, consistent with CD133+ cells being CICs. Unlike normal adult prostate stem cells, prostate CICs are AR+ and do not require functional CD133. This suggests that (a) AR-expressing prostate CICs are derived from a malignantly transformed intermediate cell that acquires "stem-like activity" and not from a malignantly transformed normal stem cell and (b) AR signaling pathways are a therapeutic target for prostate CICs.

The expression of β3-adrenoceptors and their function in the human prostate.

PubMed

Suzuki, Takahisa; Otsuka, Atsushi; Matsumoto, Rikiya; Furuse, Hiroshi; Ozono, Seiichiro

2016-02-01

Little is known about β3-adrenoceptor (AR) expression and function in human prostate. We examined the expression and distribution of β-AR subtypes in normal prostate and benign prostatic hyperplasia (BPH) tissues, and investigated which selective β-AR subtype agonist was most involved in the relaxation of isolated human prostate strips. Messenger RNA (mRNA) expression for β1-, β2-, and β3 -ARs was investigated using reverse transcriptase-polymerase chain reactions (RT-PCR). Quantitative analysis of mRNA expression of β-AR subtypes between normal prostate and BPH tissues was performed using quantitative RT-PCR (qPCR). Distributions were examined by immunohistochemistry (IHC). Strips of human normal prostate or BPH were suspended in organ baths and exposed to isoproterenol, dobutamine, procaterol, and TRK-380 to investigate their relaxant effects on KCl-induced contractions, and their inhibitory effects on electrical field stimulation (EFS)-induced contractions. We confirmed the presence of mRNA for β1-, β2-, and β3-ARs both in normal prostate and in BPH tissues. For β3-AR, mRNA expression in BPH tissues was significantly higher than in normal prostate tissues, but there was no significant difference in β1- and β2-AR expression between normal and BPH tissues. IHC revealed differences in staining intensity between smooth muscle cells and glandular cells, with different proportions for different β-AR subtypes. Staining of β3-AR was particularly intense in smooth muscle cells as opposed to glandular cells. Isoproterenol and TRK-380 significantly decreased the tone of KCl-induced contractions of the normal prostate strips. The rank order of relaxant effects was isoproterenol > TRK-380 > procaterol > dobutamine. All selective β-AR agonists significantly decreased the amplitude of EFS-induced contractions of the normal prostate strips. The rank order of inhibitory effects was isoproterenol > dobutamine >TRK-380 > procaterol. In BPH strips, all selective β-AR agonists showed no significant relaxant or inhibitory effects on KCl- or EFS-induced contractions. β3 -AR is abundant in human prostate smooth muscle, whose relaxation is mediated by β1- and β3-AR stimulation. β3-AR agonists may have clinical use in the treatment of male non-BPH patients or neurogenic bladder patients with voiding dysfunction. © 2015 Wiley Periodicals, Inc.

Effects of recreational soccer in men with prostate cancer undergoing androgen deprivation therapy: study protocol for the ‘FC Prostate’ randomized controlled trial

PubMed Central

2013-01-01

Background Androgen deprivation therapy (ADT) is a cornerstone in the treatment of advanced prostate cancer. Adverse musculoskeletal and cardiovascular effects of ADT are widely reported and investigations into the potential of exercise to ameliorate the effects of treatment are warranted. The ‘Football Club (FC) Prostate’ study is a randomized trial comparing the effects of soccer training with standard treatment approaches on body composition, cardiovascular function, physical function parameters, glucose tolerance, bone health, and patient-reported outcomes in men undergoing ADT for prostate cancer. Methods/Design Using a single-center randomized controlled design, 80 men with histologically confirmed locally advanced or disseminated prostate cancer undergoing ADT for 6 months or more at The Copenhagen University Hospital will be enrolled on this trial. After baseline assessments eligible participants will be randomly assigned to a soccer training group or a control group receiving usual care. The soccer intervention will consist of 12 weeks of training 2–3 times/week for 45–60 min after which the assessment protocol will be repeated. Soccer training will then continue bi-weekly for an additional 20 weeks at the end of which all measures will be repeated to allow for additional analyses of long-term effects. The primary endpoint is changes in lean body mass from baseline to 12 weeks assessed by dual X-ray absorptiometry scan. Secondary endpoints include changes of cardiovascular, metabolic, and physical function parameters, as well as markers of bone metabolism and patient-reported outcomes. Discussion The FC Prostate trial will assess the safety and efficacy of a novel soccer-training approach to cancer rehabilitation on a number of clinically important health outcomes in men with advanced prostate cancer during ADT. The results may pave the way for innovative, community-based interventions in the approach to treating prostate cancer. Trial registration ClinicalTrials.gov: NCT01711892 PMID:24330570

Cohort study comparing prostate photovaporisation with XPS 180W and HPS 120W laser.

PubMed

López, B; Capitán, C; Hernández, V; de la Peña, E; Jiménez-Valladolid, I; Guijarro, A; Pérez-Fernández, E; Llorente, C

2016-01-01

Prostate photovaporisation with Greenlight laser for the surgical treatment of benign prostate hyperplasia has rapidly evolve to the new XPS 180W. We have previously demonstrated the safety and efficacy of the HPS 120W. The aim of this study was to assess the functional and safety results, with a year of follow-up, of photovaporisation using the XPS 180W laser compared with its predecessor. A cohort study was conducted with a series of 191 consecutive patients who underwent photovaporisation between 1/2008 and 5/2013. The inclusion criteria were an international prostate symptom score (IPSS) >15 after medical failure, a prostate volume <80 cm(3) and a maximum flow <15 mL/s. We assessed preoperative and intraoperative variables (energy used, laser time and total surgical time), complications, catheter hours, length of stay and functional results (maximum flow, IPSS, prostate-specific antigen and prostate volume) at 3, 6 and 12 months. We analysed the homogeneity in preoperative characteristics of the 2 groups through univariate analysis techniques. The postoperative functional results were assessed through an analysis of variance of repeated measures with mixed models. A total of 109 (57.1%) procedures were performed using HPS 120W, and 82 (42.9%) were performed using XPS. There were no differences between the preoperative characteristics. We observed significant differences both in the surgical time and effective laser time in favour of the XPS system. This advantage was 11% (48 ± 15.7 vs. 53.8 ± 16.2, p<.05) and 9% (32.8 ± 11.7 vs. 36 ± 11.6, p<.05), respectively. There were no statistically significant differences in the rest of the analysed parameters. The technical improvements in the XPS 180W system help reduce surgical time, maintaining the safety and efficacy profile offered by the HPS 120W system, with completely superimposable results at 1 year of follow-up. Copyright © 2015 AEU. Publicado por Elsevier España, S.L.U. All rights reserved.

Problem solving ability in children with intellectual disability as measured by the Raven's colored progressive matrices.

PubMed

Goharpey, Nahal; Crewther, David P; Crewther, Sheila G

2013-12-01

This study investigated the developmental trajectory of problem solving ability in children with intellectual disability (ID) of different etiologies (Down Syndrome, Idiopathic ID or low functioning Autism) as measured on the Raven's Colored Progressive Matrices test (RCPM). Children with typical development (TD) and children with ID were matched on total correct performance (i.e., non-verbal mental age) on the RCPM. RCPM total correct performance and the sophistication of error types were found to be associated with receptive vocabulary in all participants, suggesting that verbal ability plays a role in more sophisticated problem solving tasks. Children with ID made similar errors on the RCPM as younger children with TD as well as more positional error types. This result suggests that children with ID who are deficient in their cognitive processing resort to developmentally immature problem solving strategies when unable to determine the correct answer. Overall, the findings support the use of RCPM as a valid means of matching intellectual capacity of children with TD and ID. Copyright © 2013 Elsevier Ltd. All rights reserved.

Grief and its Complications in Individuals with Intellectual Disability

PubMed Central

Brickell, Claire; Munir, Kerim

2011-01-01

Bereavement and loss have significant impact on the lives of individuals with intellectual disability (ID). Although there is a growing impetus to define the symptoms of grief that predict long-term functional impairment, little is known about maladaptive grieving among individuals with ID. We examine the literature concerning the phenomenology of traumatic grief (TG) in the general population, along with what is known about the manifestations of grief in individuals with ID. We then apply modern theories of grief and grief resolution to individuals with ID in order to highlight potential areas of vulnerability in this population and to lay the groundwork for interventions that will facilitate their adaptation to loss. We provide a theoretical framework for the proposition that individuals (including children and adults) with ID are more susceptible to TG, based on an increased risk of secondary loss, barriers to communicating about the loss, and difficulty finding meaning in the loss. We conclude that individuals with ID should be considered as potential candidates for targeted bereavement interventions. Further research is required, however, in order to develop population-appropriate measurement scales for testing these hypotheses. PMID:18306095

A high-affinity [ 18F]-labeled phosphoramidate peptidomimetic PSMA-targeted inhibitor for PET imaging of prostate cancer

DOE PAGES

Ganguly, Tanushree; Dannoon, Shorouk; Hopkins, Mark R.; ...

2015-06-09

Here in this study, a structurally modified phosphoramidate scaffold, with improved prostate-specific membrane antigen (PSMA) avidity, stability and in vivo characteristics, as a PET imaging agent for prostate cancer (PCa), was prepared and evaluated. p-Fluorobenzoyl-aminohexanoate and 2-(3-hydroxypropyl)glycine were introduced into the PSMA-targeting scaffold yielding phosphoramidate 5. X-ray crystallography was performed on the PSMA/5 complex. [ 18F]5 was synthesized, and cell uptake and internalization studies were conducted in PSMA(+) LNCaP and CWR22Rv1 cells and PSMA(-) PC-3 cells. In vivo PET imaging and biodistribution studies were performed at 1 and 4 h post injection in mice bearing CWR22Rv1 tumor, with or withoutmore » blocking agent. The crystallographic data showed interaction of the p-fluorobenzoyl group with an arene-binding cleft on the PSMA surface. In vitro studies revealed elevated uptake of [ 18F]5 in PSMA(+) cells (2.2% in CWR22Rv1 and 12.1% in LNCaP) compared to PSMA(-) cells (0.08%) at 4 h. In vivo tumor uptake of 2.33% ID/g and tumor-to-blood ratio of 265:1 was observed at 4 h. In conclusion, we have successfully synthesized, radiolabeled and evaluated a new PSMA-targeted PET agent. The crystal structure of the PSMA/5 complex highlighted the interactions within the arene-binding cleft contributing to the overall complex stability. The high target uptake and rapid non-target clearance exhibited by [ 18F]5 in PSMA(+) xenografts substantiates its potential use for PET imaging of PCa.« less

Focal Cryotherapy for Localized Prostate Cancer.

PubMed

Tay, K J; Polascik, T J

2016-07-01

To systematically review the oncological and functional outcomes of contemporary primary prostate focal cryotherapy for localized prostate cancer in the context of current developments in prostate focal therapy. We performed a systematic search of the Pubmed, Cochrane and Embase databases to identify studies where primary prostate focal cryotherapy was performed to treat prostate cancer. These included reports on focal/ lesion/ sector ablation, hemi-ablation and partial prostate ablation. We excluded salvage focal therapy studies. Where multiple reports were published over time from a single cohort, the latest one was used. Our search yielded 290 publications, including 17 primary reports on eight single-center cohort studies and one multi-center registry report. Of 1,595 men identified, mean age was 60.5-69.5 years and mean PSA 5.1-7.8 ng/ml. When stratified by D'Amico risk criteria, 52% of the aggregate total number of men were low-risk, 38% intermediate-risk and 10% high-risk. Besides 12-core TRUS biopsy, 3 cohorts reported using TTMB and one included mpMRI to select men for focal treatment. Median follow-up ranged from 13-63 months. BPFS ranged from 71-98%. The overall post-treatment positive biopsy rate was 8-25%. Among 5 cohorts with a mandatory 6-12 month posttreatment biopsy, 216 of 272 men (79%) did undergo biopsy, with 47 positive (21.8%). Of these, 15 were infield, 26 outfield, 2 bilateral and 4 undeclared. Ten upgraded to Gleason≥7. Overall, two men had metastatic disease and none died of prostate cancer. Post-treatment continence rates were 96-100% and rates of erectile dysfunction ranged from 0-42%. The rate of post-treatment urinary retention ranged from 0-15%. The rate of recto-urethral fistula was 0-0.1%. Focal cryotherapy for localized prostate cancer is a safe and provides good preservation of sexual and urinary function. Accurate cancer localization and risk stratification is key to patient selection. In highly selected patients, focal therapy has good short to medium term oncological efficacy.

A novel vaporization-enucleation technique for benign prostate hyperplasia using 120-W HPS GreenLight™ laser: Seoul technique II in comparison with vaporization and previously reported modified vaporization-resection technique.

PubMed

Yoo, Sangjun; Park, Juhyun; Cho, Sung Yong; Cho, Min Chul; Jeong, Hyeon; Son, Hwancheol

2017-12-01

We developed a novel vaporization-enucleation technique (Seoul II), which consists of vaporization-enucleation of the prostate using 120-W HPS GreenLight laser, and enucleated prostate resection using bipolar devices for tissue removal. We compared the outcomes of the Seoul II with vaporization and a previously reported modified vaporization-resection technique (Seoul I). Among patients with benign prostate hyperplasia who underwent transurethral surgery using GreenLight laser at our institute, 347 patients with prostate volume ≥ 40 ml were included. The impact of surgical techniques on efficacy and postoperative functional outcomes was compared. No difference was found in baseline characteristics, although the prostate volume was marginally greater in Seoul II (p = 0.051). Prostate volume reduction per operation time (p < 0.001) and lasing time (p = 0.016) were greater in Seoul II. At postoperative 12 months, the International Prostate Symptom Score (I-PSS) was lower (p = 0.011), and the decrement in I-PSS was greater in Seoul II (p = 0.001) than other techniques. In multivariate analysis, postoperative 12-month I-PSS for Seoul II was significantly superior to vaporization (p < 0.001), although it was similar to Seoul I. The maintenance of immediate postoperative I-PSS decrement, until postoperative 12 months was superior in Seoul II compared with vaporization (p = 0.014) and Seoul I (p = 0.048). Seoul II showed improved efficacy and voiding functional maintenance over postoperative 12 months in patients with prostate volume ≥ 40 ml compared with vaporization and Seoul I. This technique could be easily accepted by clinicians who are familiar with GreenLight lasers and add flexibility to surgery without additional equipment.

SU-E-T-385: Evaluation of DVH Change for PTV Due to Patient Weight Loss in Prostate VMAT Using Gaussian Error Function

DOE Office of Scientific and Technical Information (OSTI.GOV)

Viraganathan, H; Jiang, R; Chow, J

Purpose: We proposed a method to predict the change of dose-volume histogram (DVH) for PTV due to patient weight loss in prostate volumetric modulated arc therapy (VMAT). This method is based on a pre-calculated patient dataset and DVH curve fitting using the Gaussian error function (GEF). Methods: Pre-calculated dose-volume data from patients having weight loss in prostate VMAT was employed to predict the change of PTV coverage due to reduced depth in external contour. The effect of patient weight loss in treatment was described by a prostate dose-volume factor (PDVF), which was evaluated by the prostate PTV. Along with themore » PDVF, the GEF was used to fit into the DVH curve for the PTV. To predict a new DVH due to weight loss, parameters from the GEF describing the shape of DVH curve were determined. Since the parameters were related to the PDVF as per the specific reduced depth, we could first predict the PDVF at a reduced depth based on the prostate size from the pre-calculated dataset. Then parameters of the GEF could be determined from the PDVF to plot the new DVH for the PTV corresponding to the reduced depth. Results: A MATLAB program was built basing on the patient dataset with different prostate sizes. We input data of the prostate size and reduced depth of the patient into the program. The program then calculated the PDVF and DVH for the PTV considering the patient weight loss. The program was verified by different patient cases with various reduced depths. Conclusion: Our method can estimate the change of DVH for the PTV due to patient weight loss quickly without CT rescan and replan. This would help the radiation staff to predict the change of PTV coverage, when patient’s external contour reduced in prostate VMAT.« less

TRPM8 ion channels differentially modulate proliferation and cell cycle distribution of normal and cancer prostate cells.

PubMed

Valero, María Ll; Mello de Queiroz, Fernanda; Stühmer, Walter; Viana, Félix; Pardo, Luis A

2012-01-01

Overexpression of the cation-permeable channel TRPM8 in prostate cancers might represent a novel opportunity for their treatment. Inhibitors of TRPM8 reduce the growth of prostate cancer cells. We have used two recently described and highly specific blockers, AMTB and JNJ41876666, and RNAi to determine the relevance of TRPM8 expression in the proliferation of non-tumor and tumor cells. Inhibition of the expression or function of the channel reduces proliferation rates and proliferative fraction in all tumor cells tested, but not of non-tumor prostate cells. We observed no consistent acceleration of growth after stimulation of the channel with menthol or icilin, indicating that basal TRPM8 expression is enough to sustain growth of prostate cancer cells.

Regulation of prostate cancer by hormone-responsive G protein-coupled receptors.

PubMed

Wang, Wei; Chen, Zhao-Xia; Guo, Dong-Yu; Tao, Ya-Xiong

2018-06-15

Regulation of prostate cancer by androgen and androgen receptor (AR), and blockade of AR signaling by AR antagonists and steroidogenic enzyme inhibitors have been extensively studied. G protein-coupled receptors (GPCRs) are a family of membrane receptors that regulate almost all physiological processes. Nearly 40% of FDA-approved drugs in the market target GPCRs. A variety of GPCRs that mediate reproductive function have been demonstrated to be involved in the regulation of prostate cancer. These GPCRs include gonadotropin-releasing hormone receptor, luteinizing hormone receptor, follicle-stimulating hormone receptor, relaxin receptor, ghrelin receptor, and kisspeptin receptor. We highlight here GPCR regulation of prostate cancer by these GPCRs. Further therapeutic approaches targeting these GPCRs for the treatment of prostate cancer are summarized. Copyright © 2018. Published by Elsevier Inc.

"A plea for the prostate": doctors, prostate dysfunction, and male sexuality in late 19th- and early 20th-century Canada.

PubMed

O'Shea, Christopher D

2012-01-01

Historical examinations of medical discourse concerning male sexuality have focused on the perceived linkage between masturbation and sexual neurasthenia. However, more tangible conditions such as prostatic hypertrophy were also linked to the sexual misconduct of young and old men. This paper examines both the medical discourse concerning prostatic hypertrophy and how the development of treatment was influenced by contemporary concerns with both sexuality and masculinity. It argues that mainstream doctors moved away from the Victorian preoccupation with the dangers of illicit sexuality and increasingly regarded the restoration of sexual function as being in the best interests of their patients. This view was particularly evident in their quest for an operative method that would cure prostatic hypertrophy while preserving potency.

[The treatment of benign prostatic hyperplasia using the Mumie-Vitas preparation].

PubMed

Andriukhova, N N

1997-01-01

Overall thirty-eight patients presenting with stage I-II benign prostate hyperplasia received treatment with a new local drug preparation Mumiyo-Vitas, 0.2 g on a once- or twice-daily basis over six months. Effects were studied of the drug on the urologic symptomatology and quality of life of patients presenting with ongoing micturitional disturbances, functional state of detrusor vesicae, prostate volume and urethral resistance. Efficiency of the treatment given was assessed by the International system, uroflowmetry, ultrasonic investigation. Mumiyo-Vitas appeared to be of therapeutic benefit in those patients with subjective and objective symptoms of the urinary bladder obstruction who had innocent prostate hyperplasia.

Gender differences in functional connectivities between insular subdivisions and selective pain-related brain structures.

PubMed

Dai, Yu-Jie; Zhang, Xin; Yang, Yang; Nan, Hai-Yan; Yu, Ying; Sun, Qian; Yan, Lin-Feng; Hu, Bo; Zhang, Jin; Qiu, Zi-Yu; Gao, Yi; Cui, Guang-Bin; Chen, Bi-Liang; Wang, Wen

2018-03-14

The incidence of pain disorders in women is higher than in men, making gender differences in pain a research focus. The human insular cortex is an important brain hub structure for pain processing and is divided into several subdivisions, serving different functions in pain perception. Here we aimed to examine the gender differences of the functional connectivities (FCs) between the twelve insular subdivisions and selected pain-related brain structures in healthy adults. Twenty-six healthy males and 11 age-matched healthy females were recruited in this cross-sectional study. FCs between the 12 insular subdivisions (as 12 regions of interest (ROIs)) and the whole brain (ROI-whole brain level) or 64 selected pain-related brain regions (64 ROIs, ROI-ROI level) were measured between the males and females. Significant gender differences in the FCs of the insular subdivisions were revealed: (1) The FCs between the dorsal dysgranular insula (dId) and other brain regions were significantly increased in males using two different techniques (ROI-whole brain and ROI-ROI analyses); (2) Based on the ROI-whole brain analysis, the FC increases in 4 FC-pairs were observed in males, including the left dId - the right median cingulate and paracingulate/ right posterior cingulate gyrus/ right precuneus, the left dId - the right median cingulate and paracingulate, the left dId - the left angular as well as the left dId - the left middle frontal gyrus; (3) According to the ROI-ROI analysis, increased FC between the left dId and the right rostral anterior cingulate cortex was investigated in males. In summary, the gender differences in the FCs of the insular subdivisions with pain-related brain regions were revealed in the current study, offering neuroimaging evidence for gender differences in pain processing. ClinicalTrials.gov, NCT02820974 . Registered 28 June 2016.

Phosphoproteomic Assessment of Therapeutic Kinases for Personalized Therapy in Castration-Resistant Prostate Cancer

DTIC Science & Technology

2016-10-01

Huang J , Witte ON (2016) Functional Screen Identifies Kinases Driving Prostate Cancer Visceral and Bone Metastasis. PNAS. 113(2):E172-E181. PMCID...Faltermeier CM, Carlin DE, Flemming DT, Wong CK, Newton Y, Sudha S, Vashisht AA, Huang J , Wohlschlegel JA, Graeber TG, Witte ON#, Stuart JM# (2016...Pitteri S, Huang J , Witte ON (2016) Activation of Notch1 Synergizes with Multiple Pathways in Promoting Castration Resistant Prostate Cancer. PNAS. In

Human PIRH2 Enhances Androgen Receptor Signaling through Inhibition of Histone Deacetylase 1 and Is Overexpressed in Prostate Cancer

PubMed Central

Logan, Ian R.; Gaughan, Luke; McCracken, Stuart R. C.; Sapountzi, Vasileia; Leung, Hing Y.; Robson, Craig N.

2006-01-01

The androgen receptor (AR) is a hormone-dependent transcription factor critically involved in human prostate carcinogenesis. Optimal transcriptional control of androgen-responsive genes by AR may require complex interaction among multiple coregulatory proteins. We have previously shown that the AR coregulator TIP60 can interact with human PIRH2 (hPIRH2). In this study, we uncover important new functional role(s) for hPIRH2 in AR signaling: (i) hPIRH2 interacts with AR and enhances AR-mediated transcription with a dynamic pattern of recruitment to androgen response elements in the prostate-specific antigen (PSA) gene; (ii) hPIRH2 interacts with the AR corepressor HDAC1, leading to reduced HDAC1 protein levels and inhibition of transcriptional repression; (iii) hPIRH2 is required for optimal PSA expression; and (iv) hPIRH2 is involved in prostate cancer cell proliferation. In addition, overexpression of hPIRH2 protein was detected in 73 of 82 (89%) resected prostate cancers, with a strong correlation between increased hPIRH2 expression and aggressive disease, as signified by high Gleason sum scores and the presence of metastatic disease (P = <0.0001 and 0.0004, respectively). Collectively, our data establish hPIRH2 as a key modulator of AR function, opening a new direction for targeted therapy in aggressive human prostate cancer. PMID:16914734

Human PIRH2 enhances androgen receptor signaling through inhibition of histone deacetylase 1 and is overexpressed in prostate cancer.

PubMed

Logan, Ian R; Gaughan, Luke; McCracken, Stuart R C; Sapountzi, Vasileia; Leung, Hing Y; Robson, Craig N

2006-09-01

The androgen receptor (AR) is a hormone-dependent transcription factor critically involved in human prostate carcinogenesis. Optimal transcriptional control of androgen-responsive genes by AR may require complex interaction among multiple coregulatory proteins. We have previously shown that the AR coregulator TIP60 can interact with human PIRH2 (hPIRH2). In this study, we uncover important new functional role(s) for hPIRH2 in AR signaling: (i) hPIRH2 interacts with AR and enhances AR-mediated transcription with a dynamic pattern of recruitment to androgen response elements in the prostate-specific antigen (PSA) gene; (ii) hPIRH2 interacts with the AR corepressor HDAC1, leading to reduced HDAC1 protein levels and inhibition of transcriptional repression; (iii) hPIRH2 is required for optimal PSA expression; and (iv) hPIRH2 is involved in prostate cancer cell proliferation. In addition, overexpression of hPIRH2 protein was detected in 73 of 82 (89%) resected prostate cancers, with a strong correlation between increased hPIRH2 expression and aggressive disease, as signified by high Gleason sum scores and the presence of metastatic disease (P = <0.0001 and 0.0004, respectively). Collectively, our data establish hPIRH2 as a key modulator of AR function, opening a new direction for targeted therapy in aggressive human prostate cancer.

In Vitro Evaluation of Gd(3+)-Anionic Linear Globular Dendrimer-Monoclonal Antibody: Potential Magnetic Resonance Imaging Contrast Agents for Prostate Cancer Cell Imaging.

PubMed

Mirzaei, Mehdi; Mehravi, Bita; Ardestani, Mehdi Shafiee; Ziaee, Seyed Amir Mohsen; Pourghasem, Peyman

2015-12-01

Early stage prostate cancer diagnosis is of high global interest. Magnetic resonance imaging (MRI) is a non-invasive modality for early cancer diagnosis, in particular for prostate cancer detection. The research aim is to synthesize a nanodendrimer and its conjugate with C595 monoclonal antibody (mAb C595), against prostate cancer, followed by its chelating with Gd(3+). Anti-MUC-1 mAb C595 was conjugated to an anionic linear globular dendrimer (ALGDG2). The polyethylene glycol core and citric acid shell were synthesized followed by loading with Gd(3+) to make novel contrast agents for functional MRI. The in vitro behavior and MRI parameters of the nanoconjugate were investigated performing several studies such as cell toxicity and TNF-alpha evaluations. The investigation of magnetic resonance imaging parameters indicated how well nanoconjugate performs in (1)H-NMR and (17)O-NMR in vitro. Results showed a potential specific MRI activity by improving the swelling responses cell binding. The MTT (2-(4,5-dimethyl-2-thiazolyl)-3,5-diphenyl-2H-tetrazolium bromide) assay demonstrated that this contrast agent had significant cytotoxicity on prostate cancer cells. These results showed that Gd(3+)-ALGDG2-C595 is a potential prostate molecular imaging agent and could be considered as an ideal functional nanoprobe. Additionally, further investigations by clinical trials are in the pipeline.

CIP2A is a candidate therapeutic target in clinically challenging prostate cancer cell populations.

PubMed

Khanna, Anchit; Rane, Jayant K; Kivinummi, Kati K; Urbanucci, Alfonso; Helenius, Merja A; Tolonen, Teemu T; Saramäki, Outi R; Latonen, Leena; Manni, Visa; Pimanda, John E; Maitland, Norman J; Westermarck, Jukka; Visakorpi, Tapio

2015-08-14

Residual androgen receptor (AR)-signaling and presence of cancer stem-like cells (SCs) are the two emerging paradigms for clinically challenging castration-resistant prostate cancer (CRPC). Therefore, identification of AR-target proteins that are also overexpressed in the cancer SC population would be an attractive therapeutic approach.Our analysis of over three hundred clinical samples and patient-derived prostate epithelial cultures (PPECs), revealed Cancerous inhibitor of protein phosphatase 2A (CIP2A) as one such target. CIP2A is significantly overexpressed in both hormone-naïve prostate cancer (HN-PC) and CRPC patients . CIP2A is also overexpressed, by 3- and 30-fold, in HN-PC and CRPC SCs respectively. In vivo binding of the AR to the intronic region of CIP2A and its functionality in the AR-moderate and AR-high expressing LNCaP cell-model systems is also demonstrated. Further, we show that AR positively regulates CIP2A expression, both at the mRNA and protein level. Finally, CIP2A depletion reduced cell viability and colony forming efficiency of AR-independent PPECs as well as AR-responsive LNCaP cells, in which anchorage-independent growth is also impaired.These findings identify CIP2A as a common denominator for AR-signaling and cancer SC functionality, highlighting its potential therapeutic significance in the most clinically challenging prostate pathology: castration-resistant prostate cancer.

Association between radiation therapy, surgery, or observation for localized prostate cancer and patient-reported outcomes after 3 years

PubMed Central

Barocas, Daniel A.; Alvarez, JoAnn; Resnick, Matthew J.; Koyama, Tatsuki; Hoffman, Karen E.; Tyson, Mark D.; Conwill, Ralph; McCollum, Dan; Cooperberg, Matthew R.; Goodman, Michael; Greenfield, Sheldon; Hamilton, Ann S.; Hashibe, Mia; Kaplan, Sherrie H.; Paddock, Lisa E.; Stroup, Antoinette M.; Wu, Xiao-Cheng; Penson, David F.

2017-01-01

Importance Prostate cancer treatments are associated with side effects. Understanding the side effects of contemporary approaches to management of localized prostate could inform shared decision-making. Objective To compare the harms of radical prostatectomy (RP), radiation (EBRT) and active surveillance (AS). Design The Comparative Effectiveness Analysis of Surgery and Radiation (CEASAR) study is a prospective, population-based, cohort study of men diagnosed with localized prostate cancer in 2011–2012. This study reports follow up through August 2015. Setting Patients accrued from five Surveillance Epidemiology, and End Results registry sites and the Cancer of the Prostate Strategic Urologic Research Endeavor. Participants Men < 80 years old with clinical stage cT1-2 disease, prostate specific antigen < 50 ng/mL, enrolled within six months of diagnosis, who completed a baseline survey and at least 1 follow-up survey. Exposure Treatment with RP, EBRT or AS was ascertained within one year of diagnosis. Main Outcome and Measures Patient-reported function in sexual, urinary incontinence, urinary irritative, bowel, and hormonal domains on the 26-item Expanded Prostate Cancer Index Composite (EPIC) 36 months after enrollment. Domain scores range from 0–100. Higher score indicates better function. Minimum clinically important difference defined as 10–12, 6, 5, 5, and 4, respectively. Results The cohort included 2550 men (mean age 63.8 years, 74% white, 55% intermediate or high risk), of whom 1523 (59.7%) underwent RP, 598 (23.5%) EBRT, and 429 (16.8%) AS. Men undergoing EBRT were older (mean age 68.1 vs. 61.5, p<0.001), and had worse baseline sexual function (mean EPIC domain score 52.3 vs. 65.2, p<0.001) than men undergoing RP. At 3 years, adjusted mean sexual domain score for men undergoing RP had declined more than for men undergoing EBRT (mean difference −11.9 points, 95% CI [−15.1, −8.7]). The difference in decline in sexual domain scores between EBRT and AS was not clinically significant (−4.3 points, 95% CI [−9.2, 0.7]). RP was associated with worse urinary incontinence than EBRT (−18.0 points, 95% CI [−20.5, −15.4]) or AS (−12.7 points, 95% CI [−16.0, −9.3]) and better urinary irritative symptoms compared to AS (5.2 points, 95% CI [3.2, 7.2]). No clinically significant differences for bowel or hormone function were noted beyond 12 months. No differences in global quality of life or disease-specific survival (3 deaths) were noted (99.7–100%). Conclusion and Relevance In this cohort of men with localized prostate cancer, RP was associated with a larger decline in sexual function and urinary incontinence than EBRT or AS after 3 years, and lesser urinary irritative symptoms compared to AS; however, there were no meaningful differences in bowel or hormonal function beyond 12 months and no meaningful differences in global quality of life measures. These findings may facilitate counseling regarding the comparative harms of contemporary treatments for prostate cancer. PMID:28324093

Ethnic variation in localized prostate cancer: a pilot study of preferences, optimism, and quality of life among black and white veterans.

PubMed

Knight, Sara J; Siston, Amy K; Chmiel, Joan S; Slimack, Nicholas; Elstein, Arthur S; Chapman, Gretchen B; Nadler, Robert B; Bennett, Charles L

2004-06-01

Ethnic variations that may influence the preferences and outcomes associated with prostate cancer treatment are not well delineated. Our objective was to evaluate prospectively preferences, optimism, involvement in care, and quality of life (QOL) in black and white veterans newly diagnosed with localized prostate cancer. A total of 95 men who identified themselves as black/African-American or white who had newly diagnosed, localized prostate cancer completed a "time trade-off" task to assess utilities for current health and mild, moderate, and severe functional impairment; importance rankings for attributes associated with prostate cancer (eg, urinary function); and baseline and follow-up measures of optimism, involvement in care, and QOL. Interviews were scheduled before treatment, and at 3 and 12 months after treatment. At baseline, both blacks and whites ranked pain, bowel, and bladder function as their most important concerns. Optimism, involvement in care, and QOL were similar. Utilities for mild impairment were lower for blacks than whites, but were similar for moderate and severe problems. Decline in QOL at 3 and 12 months compared to baseline occurred for both groups. However, even with adjustment for marital status, education level, and treatment, blacks had less increase in nausea and vomiting and more increase in difficulty with sexual interest and weight gain compared with whites. Black and white veterans entered localized prostate cancer treatment with similar priorities, optimism, and involvement in care. Quality-of-life declines were common to both groups during the first year after diagnosis, but ethnic variation occurred with respect to nausea and vomiting, sexual interest, and weight gain.

A reference set of health utilities for long-term survivors of prostate cancer: population-based data from Ontario, Canada.

PubMed

Krahn, Murray D; Bremner, Karen E; Alibhai, Shabbir M H; Ni, Andy; Tomlinson, George; Laporte, Audrey; Naglie, Gary

2013-12-01

To measure quality of life (QOL) and utilities for prostate cancer (PC) patients and determine their predictors. A population-based, community-dwelling, geographically diverse sample of long-term PC survivors in Ontario, Canada, was identified from the Ontario Cancer Registry and contacted through their referring physician. Consenting patients completed questionnaires by mail: Health Utilities Index (HUI 2/3), Patient Oriented Prostate Utility Scale PORPUS-U (utility), PORPUS-P (health profile), Functional Assessment of Cancer Therapy-Prostate (FACT-P), and Prostate Cancer Index (PCI). Clinical data were obtained from chart reviews. Regression models determined the effects of a series of variables on QOL and utility. We received questionnaires and reviewed charts for 585 patients (mean age 72.6, 2-13 years postdiagnosis). Mean utility scores were as follows: PORPUS-U = 0.92, HUI2 = 0.85, and HUI3 = 0.78. Mean health profile scores were as follows: PORPUS-P = 71.7, PCI sexual, urinary, and bowel function = 23.7, 79.1, and 84.6, respectively (0 = worst, 100 = best), and FACT-P = 125.1 (0 = worst, 156 = best). In multiple regression analyses, comorbidity and PCI urinary, sexual, and bowel function were significant predictors of other QOL measures. With all variables, 32-50 % of the variance in utilities was explained. Many variables affect global QOL of PC survivors; only prostate symptoms and comorbidity have independent effects. Our model allows estimation of the effects of multiple factors on utilities. These utilities for long-term outcomes of PC and its treatment are valuable for decision/cost-effectiveness models of PC treatment.

Physical Activity, Sedentary Behavior and Health Related Quality of Life in Prostate Cancer Survivors in the Health Professionals Follow-up Study

PubMed Central

Phillips, Siobhan M.; Stampfer, Meir J.; Chan, June M.; Giovannucci, Edward L.; Kenfield, Stacey A.

2015-01-01

Purpose Many prostate cancer survivors experience compromised health-related quality of life (HRQOL) as a result of prostate cancer. We examined relationships between types and intensities of activity and sedentary behavior and prostate cancer-related HRQOL, overall, and by demographic, disease, and treatment characteristics. Methods Associations between post-diagnosis activity and sedentary behavior and HRQOL domains (urinary incontinence, urinary irritation/obstruction, bowel, sexual and vitality/hormonal) were prospectively examined in men diagnosed with non-metastatic prostate cancer in the Health Professionals Follow-up Study (n=1917) using generalized linear models. Results After adjusting for potential confounders, higher duration of total, non-vigorous, and walking activity was associated with higher vitality/hormonal functioning scores (p-trends,< 0.0001). Effects were small (d= 0.16–0.20), but approached clinical significance for men in the highest versus lowest activity categories. Survivors who walked ≥90 minutes/week at a normal pace, or faster, reported higher hormone/vitality scores (p=0.001) than men walking <90 minutes at an easy pace. Weight lifting was associated with increased urinary incontinence (p-trend,0.02). Total activity was associated with higher hormone/vitality functioning in men who were ≥5 years post-treatment, had more advanced disease (Gleason score ≥7), and had ≥1 comorbid condition. No relationships were observed between vigorous activity or sedentary behavior and HRQOL. Conclusions Increased duration of non-vigorous activity and walking post-diagnosis was positively associated with better hormone/vitality functioning. Specifically, engaging in ≥5 hours of non-vigorous activity or ≥3 hours of walking per week may be beneficial. Implications for Cancer Survivors Encouraging men to engage in non-vigorous activity and walking may be helpful for managing prostate cancer-related HRQOL. PMID:25876555

Health related quality of life patterns in patients treated with interstitial prostate brachytherapy for localized prostate cancer--data from CaPSURE.

PubMed

Downs, Tracy M; Sadetsky, Natalia; Pasta, David J; Grossfeld, Gary D; Kane, Christopher J; Mehta, Shilpa S; Carroll, Peter R; Lubeck, Deborah P

2003-11-01

We measured the impact brachytherapy monotherapy (BMT) has on general and disease specific health related quality of life (HRQOL) compared to patients treated with radical prostatectomy (RP). We studied 419 men with newly diagnosed prostate cancer who enrolled in CaPSURE (Cancer of the Prostate Strategic Urological Research Endeavor) data base whose primary treatment was brachytherapy monotherapy (92) or radical prostatectomy (327). The validated RAND 36-Item Health Survey and the UCLA Prostate Cancer Index were used to measure HRQOL before treatment and at 6-month intervals during the first 2 years after treatment. Patients treated with BMT or RP did not differ greatly in general HRQOL after treatment. Both treatment groups showed early functional impairment in most general domains with scores returning to or approaching baseline in most domains 18 to 24 months after treatment. Patients treated with BMT had significantly higher urinary function scores at 0 to 6 months after treatment (84.5, SD 18.7) than patients treated with RP (63.3, SD 26.6). Urinary bother scores at 0 to 6 months after treatment were not significantly different between patients treated with BMT (67.7, SD 31.2) and those treated with RP (67.4, SD 29.1). Both treatment groups had decreases in sexual function that did not return to pretreatment levels. Overall BMT and RP are well tolerated procedures that cause mild changes in general HRQOL. Disease specific HRQOL patterns are different in patients treated with BMT or RP. Baseline and serial HRQOL measurements after treatment can provide valuable information regarding expected quality of life outcome after treatment for localized prostate cancer.

Physical function is weakly associated with angiotensin-converting enzyme gene I/D polymorphism in elderly Japanese subjects.

PubMed

Yoshihara, A; Tobina, T; Yamaga, T; Ayabe, M; Yoshitake, Y; Kimura, Y; Shimada, M; Nishimuta, M; Nakagawa, N; Ohashi, M; Hanada, N; Tanaka, H; Kiyonaga, A; Miyazaki, H

2009-01-01

The turning point in the deterioration of physical function seems to occur between the ages of 70 and 80 years. In particular, muscle strength may decline even more in subjects older than 75. A recent study found that the angiotensin-converting enzyme (ACE) genotype also affects physiological left ventricular hypertrophy. A very limited number of papers have examined genetic differences in resistance and endurance forms of a single sporting discipline. The purpose of this study was to evaluate the relationship between ACE genotype and physical function by controlling the known confounding factors including dental status. We selected 431 subjects who were aged 76 years and did not require special care for their daily activities. We conducted a medical examination, followed by 5 physical function tests, as follows: (1) maximum hand grip strength, (2) maximal isometric knee extensor strength, (3) maximal stepping rate for 10 s, (4) one-leg standing time with eyes open and (5) 10-meter maximum walking speed. Subjects were genotyped for the ACE intron 16 Alu insertion. In addition, serum concentrations of total cholesterol, total protein, IgA and IgG were measured at a commercial laboratory. The Eichner index was used as an indicator of occlusal condition. Multiple linear regression analysis was performed to evaluate the relationship between the ACE gene insertion/deletion (I/D) polymorphism and physical function considering confounding factors. The ACE gene I/D polymorphism was positively associated with hand grip strength and 10-meter maximum walking speed. Betas of hand grip strength were 0.09 for I/D (p = 0.022) and 0.12 for insertion/insertion (I/I; p = 0.004). Betas of 10-meter walking speed were -0.11 for I/D (p = 0.093) and -0.14 for I/I (p = 0.039). Dental status such as Eichner index class C was significantly associated with one-leg standing time with eyes open (beta -0.11; p = 0.028). This study suggests that there is a significant relationship between ACE genotype and physical function. In particular, subjects with the ACE deletion/deletion genotype were associated with upper extremities. Copyright 2009 S. Karger AG, Basel.

Targeting Btk/Etk of prostate cancer cells by a novel dual inhibitor

PubMed Central

Guo, W; Liu, R; Bhardwaj, G; Yang, J C; Changou, C; Ma, A-H; Mazloom, A; Chintapalli, S; Xiao, K; Xiao, W; Kumaresan, P; Sanchez, E; Yeh, C-T; Evans, C P; Patterson, R; Lam, K S; Kung, H-J

2014-01-01

Btk and Etk/BMX are Tec-family non-receptor tyrosine kinases. Btk has previously been reported to be expressed primarily in B cells and has an important role in immune responses and B-cell malignancies. Etk has been shown previously to provide a strong survival and metastasis signal in human prostate cancer cells, and to confer androgen independence and drug resistance. While the role of Etk in prostate carcinogenesis is well established, the functions of Btk in prostate cancer have never been investigated, likely due to the perception that Btk is a hematopoietic, but not epithelial, kinase. Herein, we found that Btk is overexpressed in prostate cancer tissues and prostate cancer cells. The level of Btk in prostate cancer tissues correlates with cancer grades. Knockdown of Btk expression selectively inhibits the growth of prostate cancer cells, but not that of the normal prostate epithelial cells, which express very little Btk. Dual inhibition of Btk and Etk has an additive inhibitory effect on prostate cancer cell growth. To explore Btk and Etk as targets for prostate cancer, we developed a small molecule dual inhibitor of Btk and Etk, CTN06. Treatment of PC3 and other prostate cancer cells, but not immortalized prostate epithelial cells with CTN06 resulted in effective cell killing, accompanied by the attenuation of Btk/Etk signals. The killing effect of CTN06 is more potent than that of commonly used inhibitors against Src, Raf/VEGFR and EGFR. CTN06 induces apoptosis as well as autophagy in human prostate cancer cells, and is a chemo-sensitizer for docetaxel (DTX), a standard of care for metastatic prostate cancer patients. CTN06 also impeded the migration of human prostate cancer cells based on a ‘wound healing' assay. The anti-cancer effect of CTN06 was further validated in vivo in a PC3 xenograft mouse model. PMID:25188519

Targeting Btk/Etk of prostate cancer cells by a novel dual inhibitor.

PubMed

Guo, W; Liu, R; Bhardwaj, G; Yang, J C; Changou, C; Ma, A-H; Mazloom, A; Chintapalli, S; Xiao, K; Xiao, W; Kumaresan, P; Sanchez, E; Yeh, C-T; Evans, C P; Patterson, R; Lam, K S; Kung, H-J

2014-09-04

Btk and Etk/BMX are Tec-family non-receptor tyrosine kinases. Btk has previously been reported to be expressed primarily in B cells and has an important role in immune responses and B-cell malignancies. Etk has been shown previously to provide a strong survival and metastasis signal in human prostate cancer cells, and to confer androgen independence and drug resistance. While the role of Etk in prostate carcinogenesis is well established, the functions of Btk in prostate cancer have never been investigated, likely due to the perception that Btk is a hematopoietic, but not epithelial, kinase. Herein, we found that Btk is overexpressed in prostate cancer tissues and prostate cancer cells. The level of Btk in prostate cancer tissues correlates with cancer grades. Knockdown of Btk expression selectively inhibits the growth of prostate cancer cells, but not that of the normal prostate epithelial cells, which express very little Btk. Dual inhibition of Btk and Etk has an additive inhibitory effect on prostate cancer cell growth. To explore Btk and Etk as targets for prostate cancer, we developed a small molecule dual inhibitor of Btk and Etk, CTN06. Treatment of PC3 and other prostate cancer cells, but not immortalized prostate epithelial cells with CTN06 resulted in effective cell killing, accompanied by the attenuation of Btk/Etk signals. The killing effect of CTN06 is more potent than that of commonly used inhibitors against Src, Raf/VEGFR and EGFR. CTN06 induces apoptosis as well as autophagy in human prostate cancer cells, and is a chemo-sensitizer for docetaxel (DTX), a standard of care for metastatic prostate cancer patients. CTN06 also impeded the migration of human prostate cancer cells based on a 'wound healing' assay. The anti-cancer effect of CTN06 was further validated in vivo in a PC3 xenograft mouse model.

Ornithine Decarboxylase Activity Is Required for Prostatic Budding in the Developing Mouse Prostate

PubMed Central

Gamat, Melissa; Malinowski, Rita L.; Parkhurst, Linnea J.; Steinke, Laura M.; Marker, Paul C.

2015-01-01

The prostate is a male accessory sex gland that produces secretions in seminal fluid to facilitate fertilization. Prostate secretory function is dependent on androgens, although the mechanism by which androgens exert their effects is still unclear. Polyamines are small cationic molecules that play pivotal roles in DNA transcription, translation and gene regulation. The rate-limiting enzyme in polyamine biosynthesis is ornithine decarboxylase, which is encoded by the gene Odc1. Ornithine decarboxylase mRNA decreases in the prostate upon castration and increases upon administration of androgens. Furthermore, testosterone administered to castrated male mice restores prostate secretory activity, whereas administering testosterone and the ornithine decarboxylase inhibitor D,L-α-difluromethylornithine (DFMO) to castrated males does not restore prostate secretory activity, suggesting that polyamines are required for androgens to exert their effects. To date, no one has examined polyamines in prostate development, which is also androgen dependent. In this study, we showed that ornithine decarboxylase protein was expressed in the epithelium of the ventral, dorsolateral and anterior lobes of the adult mouse prostate. Ornithine decarboxylase protein was also expressed in the urogenital sinus (UGS) epithelium of the male and female embryo prior to prostate development, and expression continued in prostatic epithelial buds as they emerged from the UGS. Inhibiting ornithine decarboxylase using DFMO in UGS organ culture blocked the induction of prostatic buds by androgens, and significantly decreased expression of key prostate transcription factor, Nkx3.1, by androgens. DFMO also significantly decreased the expression of developmental regulatory gene Notch1. Other genes implicated in prostatic development including Sox9, Wif1 and Srd5a2 were unaffected by DFMO. Together these results indicate that Odc1 and polyamines are required for androgens to exert their effect in mediating prostatic bud induction, and are required for the expression of a subset of prostatic developmental regulatory genes including Notch1 and Nkx3.1. PMID:26426536

Bruton's tyrosine kinase is a potential therapeutic target in prostate cancer

PubMed Central

Kokabee, Leila; Wang, Xianhui; Sevinsky, Christopher J; Wang, Wei Lin Winnie; Cheu, Lindsay; Chittur, Sridar V; Karimipoor, Morteza; Tenniswood, Martin; Conklin, Douglas S

2015-01-01

Bruton's tyrosine kinase (BTK) is a non-receptor tyrosine kinase that has mainly been studied in haematopoietic cells. We have investigated whether BTK is a potential therapeutic target in prostate cancer. We find that BTK is expressed in prostate cells, with the alternate BTK-C isoform predominantly expressed in prostate cancer cells and tumors. This isoform is transcribed from an alternative promoter and results in a protein with an amino-terminal extension. Prostate cancer cell lines and prostate tumors express more BTK-C transcript than the malignant NAMALWA B-cell line or human lymphomas. BTK protein expression is also observed in tumor tissue from prostate cancer patients. Down regulation of this protein with RNAi or inhibition with BTK-specific inhibitors, Ibrutinib, AVL-292 or CGI-1746 decrease cell survival and induce apoptosis in prostate cancer cells. Microarray results show that inhibiting BTK under these conditions increases expression of apoptosis related genes, while overexpression of BTK-C is associated with elevated expression of genes with functions related to cell adhesion, cytoskeletal structure and the extracellular matrix. These results are consistent with studies that show that BTK signaling is important for adhesion and migration of B cells and suggest that BTK-C may confer similar properties to prostate cancer cells. Since BTK-C is a survival factor for these cells, it represents both a potential biomarker and novel therapeutic target for prostate cancer. PMID:26383180

Bruton's tyrosine kinase is a potential therapeutic target in prostate cancer.

PubMed

Kokabee, Leila; Wang, Xianhui; Sevinsky, Christopher J; Wang, Wei Lin Winnie; Cheu, Lindsay; Chittur, Sridar V; Karimipoor, Morteza; Tenniswood, Martin; Conklin, Douglas S

2015-01-01

Bruton's tyrosine kinase (BTK) is a non-receptor tyrosine kinase that has mainly been studied in haematopoietic cells. We have investigated whether BTK is a potential therapeutic target in prostate cancer. We find that BTK is expressed in prostate cells, with the alternate BTK-C isoform predominantly expressed in prostate cancer cells and tumors. This isoform is transcribed from an alternative promoter and results in a protein with an amino-terminal extension. Prostate cancer cell lines and prostate tumors express more BTK-C transcript than the malignant NAMALWA B-cell line or human lymphomas. BTK protein expression is also observed in tumor tissue from prostate cancer patients. Down regulation of this protein with RNAi or inhibition with BTK-specific inhibitors, Ibrutinib, AVL-292 or CGI-1746 decrease cell survival and induce apoptosis in prostate cancer cells. Microarray results show that inhibiting BTK under these conditions increases expression of apoptosis related genes, while overexpression of BTK-C is associated with elevated expression of genes with functions related to cell adhesion, cytoskeletal structure and the extracellular matrix. These results are consistent with studies that show that BTK signaling is important for adhesion and migration of B cells and suggest that BTK-C may confer similar properties to prostate cancer cells. Since BTK-C is a survival factor for these cells, it represents both a potential biomarker and novel therapeutic target for prostate cancer.

Feasibility and outcomes of the Berg Balance Scale in older adults with intellectual disabilities.

PubMed

Oppewal, Alyt; Hilgenkamp, Thessa I M; van Wijck, Ruud; Evenhuis, Heleen M

2013-09-01

High incidence of falls and increased risk of fall-related injuries are seen in individuals with intellectual disabilities (ID). The Berg Balance Scale (BBS) is a reliable instrument for balance assessment in the population of (older) adults with ID. The aims of this study were to assess the balance capacities of a large group of older adults with ID with the BBS and look for gender and age effects, as well as reasons for drop-out on separate items, and to identify feasible subtests for subgroups in which the complete BBS is not feasible. The balance capacities of 1050 older clients with borderline to profound ID of three Dutch care-provider services (mean age 61.6 [sd=8.0]) were assessed with the BBS. The participants who completed all items of the BBS (n=508) were the functionally more able part of the study sample. Results showed that even this functionally more able part had poor balance capacities, with a mean BBS score of 47.2, 95% CI [46.3, 48.0], similar to adults in the general population aged around 20 years older. Balance capacities decreased with increasing age and females had poorer balance capacities than males. Difficulties understanding the task and physical limitations were most often the reasons for drop-out. Feasible subtests were identified for the subgroups with very low cognitive levels and wheelchair users. Low balance capacities of older adults with ID show the need for regular screening and the urge for fall prevention programs for individuals with ID. Copyright © 2013 Elsevier Ltd. All rights reserved.

Drug burden index to define the burden of medicines in older adults with intellectual disabilities: An observational cross-sectional study.

PubMed

O'Connell, Juliette; Burke, Éilish; Mulryan, Niamh; O'Dwyer, Claire; Donegan, Clare; McCallion, Philip; McCarron, Mary; Henman, Martin C; O'Dwyer, Máire

2018-03-01

The drug burden index (DBI) is a dose-related measure of anticholinergic and sedative drug exposure. This cross-sectional study described DBI in older adults with intellectual disabilities (ID) and the most frequently reported therapeutic classes contributing to DBI and examined associations between higher DBI scores and potential adverse effects as well as physical function. This study analysed data from Wave 2 (2013/2014) of the Intellectual Disability Supplement to the Irish Longitudinal Study on Ageing (IDS-TILDA), a representative study on the ageing of people with ID in Ireland. Self- and objectively-reported data were collected on medication use and physical health, including health conditions. The Barthel index was the physical function measure. The study examined 677 individuals with ID, of whom 644 (95.1%) reported taking medication and 78.6% (n = 532) were exposed to medication with anticholinergic and/or sedative activity. 54.2% (n = 367) were exposed to high DBI score (≥1). Adjusted multivariate regression analysis revealed no significant association between DBI score and daytime dozing, constipation or falls. After adjusting for confounders (sex, age, level of ID, comorbidities, behaviours that challenge, history of falls), DBI was associated with significantly higher dependence in the Barthel index (P = 0.002). This is the first time DBI has been described in older adults with ID. Scores were much higher than those observed in the general population and higher scores were associated with higher dependence in Barthel index activities of daily living. © 2017 The British Pharmacological Society.

EphA2 enhances the proliferation and invasion ability of LNCaP prostate cancer cells

PubMed Central

CHEN, PEIJIE; HUANG, YAN; ZHANG, BO; WANG, QIUQUAN; BAI, PEIMING

2014-01-01

EphA2 is persistently overexpressed and functionally changed in numerous human cancers. However, to the best of our knowledge, the role that EphA2 plays in prostate cancer is not entirely clear. To investigate the roles of EphA2 in the development and progression of prostate cancer, the present study initially evaluated the roles of the EphA2 protein in LNCaP prostate cancer cells using recombinant plasmid, western blot analysis, flow cytometry, Matrigel invasion chamber and the cell counting kit-8 assay. An immunohistochemistry assay was also conducted to observe the effects of EphA2 in prostate cancer tissues. The results demonstrated that the LNCaP human prostate cancer cells that were transfected with pcDNA3.1(+) plasmid-mediated pcDNA3.1(+)-EphA2, markedly enhanced the cell growth and invasion in vitro. Additionally, EphA2 was overexpressed in prostate cancer specimens and the expression of EphA2 was significantly associated with Gleason grade, total prostate-specific antigen, advanced clinical stage and lymph node metastasis. Collectively, these results demonstrate that EphA2 is involved in malignant cell behavior and is a potential therapeutic target in human prostate cancer. PMID:24959216

PTK6 activation at the membrane regulates epithelial-mesenchymal transition in prostate cancer.

PubMed

Zheng, Yu; Wang, Zebin; Bie, Wenjun; Brauer, Patrick M; Perez White, Bethany E; Li, Jing; Nogueira, Veronique; Raychaudhuri, Pradip; Hay, Nissim; Tonetti, Debra A; Macias, Virgilia; Kajdacsy-Balla, André; Tyner, Angela L

2013-09-01

The intracellular tyrosine kinase protein tyrosine kinase 6 (PTK6) lacks a membrane-targeting SH4 domain and localizes to the nuclei of normal prostate epithelial cells. However, PTK6 translocates from the nucleus to the cytoplasm in human prostate tumor cells. Here, we show that while PTK6 is located primarily within the cytoplasm, the pool of active PTK6 in prostate cancer cells localizes to membranes. Ectopic expression of membrane-targeted active PTK6 promoted epithelial-mesenchymal transition in part by enhancing activation of AKT, thereby stimulating cancer cell migration and metastases in xenograft models of prostate cancer. Conversely, siRNA-mediated silencing of endogenous PTK6 promoted an epithelial phenotype and impaired tumor xenograft growth. In mice, PTEN deficiency caused endogenous active PTK6 to localize at membranes in association with decreased E-cadherin expression. Active PTK6 was detected at membranes in some high-grade human prostate tumors, and PTK6 and E-cadherin expression levels were inversely correlated in human prostate cancers. In addition, high levels of PTK6 expression predicted poor prognosis in patients with prostate cancer. Our findings reveal novel functions for PTK6 in the pathophysiology of prostate cancer, and they define this kinase as a candidate therapeutic target. Cancer Res; 73(17); 5426-37. ©2013 AACR.

Serum antibodies to huntingtin interacting protein-1: a new blood test for prostate cancer.

PubMed

Bradley, Sarah V; Oravecz-Wilson, Katherine I; Bougeard, Gaelle; Mizukami, Ikuko; Li, Lina; Munaco, Anthony J; Sreekumar, Arun; Corradetti, Michael N; Chinnaiyan, Arul M; Sanda, Martin G; Ross, Theodora S

2005-05-15

Huntingtin-interacting protein 1 (HIP1) is frequently overexpressed in prostate cancer. HIP1 is a clathrin-binding protein involved in growth factor receptor trafficking that transforms fibroblasts by prolonging the half-life of growth factor receptors. In addition to human cancers, HIP1 is also overexpressed in prostate tumors from the transgenic adenocarcinoma of the mouse prostate (TRAMP) mouse model. Here we provide evidence that HIP1 plays an important role in mouse tumor development, as tumor formation in the TRAMP mice was impaired in the Hip1null/null background. In addition, we report that autoantibodies to HIP1 developed in the sera of TRAMP mice with prostate cancer as well as in the sera from human prostate cancer patients. This led to the development of an anti-HIP1 serum test in humans that had a similar sensitivity and specificity to the anti-alpha-methylacyl CoA racemase (AMACR) and prostate-specific antigen tests for prostate cancer and when combined with the anti-AMACR test yielded a specificity of 97%. These data suggest that HIP1 plays a functional role in tumorigenesis and that a positive HIP1 autoantibody test may be an important serum marker of prostate cancer.

Impact of a walking intervention on cardiorespiratory fitness, self-reported physical function, and pain in patients undergoing treatment for solid tumors.

PubMed

Griffith, Kathleen; Wenzel, Jennifer; Shang, JingJing; Thompson, Carol; Stewart, Kerry; Mock, Victoria

2009-10-15

Cancer treatment is associated with decline in measured and self-reported physical function and increased pain. In the current study, the authors evaluated the impact of a walking intervention on these outcomes during chemotherapy/radiation. Patients with breast, prostate, and other cancers (N=126) were randomized to a home-based walking intervention (exercise) or usual care (control). Exercise dose during the intervention was assessed using a 5-item Physical Activity Questionnaire. Outcome measures were cardiorespiratory fitness, expressed as peak oxygen uptake (VO2) measured during treadmill testing (n=85) or estimated by 12-minute walk (n=27), and self-reported physical function, role limitations, and pain derived from Medical Outcomes Study Short Form 36. Linear regression was used to evaluate pre-to-post intervention change outcomes between groups. The mean (standard deviation) age of the patients was 60.2 (10.6) years. Diagnoses included prostate (55.6%) and breast (32.5%) cancer. Treatment included external beam radiotherapy (52.3%) and chemotherapy (34.9%). Exercise patients reported worsening Medical Outcomes Study physical function role limitations by the end of cancer treatment (P=.037). Younger age was associated with improved Medical Outcomes Study physical function (P=.048). In all patients, increased exercise dose was associated with decreased Medical Outcomes Study pain (P=.046), regardless of diagnosis. The percent change of VO2 between prostate and nonprostate cancer patients when adjusted for baseline VO2 and Physical Activity Questionnaire values was 17.45% (P=.008), with better VO2 maintenance in the prostate group. Exercise during cancer treatment improves cardiorespiratory fitness and self-reported physical function in prostate cancer patients and in younger patients, regardless of diagnosis, and may attenuate loss of those capacities in patients undergoing chemotherapy. Exercise also reduces the pain experience. Copyright (c) 2009 American Cancer Society.

Gap junctional communication in the male reproductive system.

PubMed

Pointis, Georges; Fiorini, Céline; Defamie, Norah; Segretain, Dominique

2005-12-20

Male fertility is a highly controlled process that allows proliferation, meiosis and differentiation of male germ cells in the testis, final maturation in the epididymis and also requires functional male accessory glands: seminal vesicles, prostate and corpus cavernosum. In addition to classical endocrine and paracrine controls, mainly by gonadotropins LH and FSH and steroids, there is now strong evidence that all these processes are dependent upon the presence of homocellular or heterocellular junctions, including gap junctions and their specific connexins (Cxs), between the different cell types that structure the male reproductive tract. The present review is focused on the identification of Cxs, their distribution in the testis and in different structures of the male genital tract (epididymis, seminal vesicle, prostate, corpus cavernosum), their crucial role in the control of spermatogenesis and their implication in the function of the male accessory glands, including functional smooth muscle tone. Their potential dysfunctions in some testis (spermatogenic arrest, seminoma) and prostate (benign hyperplasia, adenocarcinoma) diseases and in the physiopathology of the human erectile function are also discussed.

Evolutionary conservation of the polyproline II conformation surrounding intrinsically disordered phosphorylation sites.

PubMed

Elam, W Austin; Schrank, Travis P; Campagnolo, Andrew J; Hilser, Vincent J

2013-04-01

Intrinsically disordered (ID) proteins function in the absence of a unique stable structure and appear to challenge the classic structure-function paradigm. The extent to which ID proteins take advantage of subtle conformational biases to perform functions, and whether signals for such mechanism can be identified in proteome-wide studies is not well understood. Of particular interest is the polyproline II (PII) conformation, suggested to be highly populated in unfolded proteins. We experimentally determine a complete calorimetric propensity scale for the PII conformation. Projection of the scale into representative eukaryotic proteomes reveals significant PII bias in regions coding for ID proteins. Importantly, enrichment of PII in ID proteins, or protein segments, is also captured by other PII scales, indicating that this enrichment is robustly encoded and universally detectable regardless of the method of PII propensity determination. Gene ontology (GO) terms obtained using our PII scale and other scales demonstrate a consensus for molecular functions performed by high PII proteins across the proteome. Perhaps the most striking result of the GO analysis is conserved enrichment (P < 10(-8) ) of phosphorylation sites in high PII regions found by all PII scales. Subsequent conformational analysis reveals a phosphorylation-dependent modulation of PII, suggestive of a conserved "tunability" within these regions. In summary, the application of an experimentally determined polyproline II (PII) propensity scale to proteome-wide sequence analysis and gene ontology reveals an enrichment of PII bias near disordered phosphorylation sites that is conserved throughout eukaryotes. Copyright © 2013 The Protein Society.

[Giant prostatic calculus with neurogenic bladder disease and prostate diverticulum: a case report and review of the literature].

PubMed

Li, Xiao-Shi; Quan, Chang-Yi; Li, Gang; Cai, Qi-Liang; Hu, Bin; Wang, Jiu-Wei; Niu, Yuan-Jie

2013-02-01

To study the etiology, clinical manifestation, diagnosis and treatment of giant prostatic calculus with neurogenic bladder disease and prostate diverticulum. We retrospectively analyzed the clinical data of a case of giant prostatic calculus with neurogenic bladder disease and prostate diverticulum and reviewed the relevant literature. The patient was a 37-year-old man, with urinary incontinence for 22 years and intermittent dysuria with frequent micturition for 9 years, aggravated in the past 3 months. He had received surgery for spina bifida and giant vesico-prostatic calculus. The results of preoperative routine urinary examination were as follows: WBC 17 -20/HPF, RBC 12 - 15/HPF. KUB, IVU and pelvic CT revealed spina bifida occulta, neurogenic bladder and giant prostatic calculus. The patient underwent TURP and transurethral lithotripsy with holmium-YAG laser. The prostatic calculus was carbonate apatite in composition. Urinary dynamic images at 2 weeks after surgery exhibited significant improvement in the highest urine flow rate and residual urine volume. Seventeen months of postoperative follow-up showed dramatically improved urinary incontinence and thicker urine stream. Prostate diverticulum with prostatic giant calculus is very rare, and neurogenic bladder may play a role in its etiology. Cystoscopy is an accurate screening method for its diagnosis. For the young patients and those who wish to retain sexual function, TURP combined with holmium laser lithotripsy can be employed, and intraoperative rectal examination should be taken to ensure complete removal of calculi.

Combined deficiency of iron and (n-3) fatty acids in male rats disrupts brain monoamine metabolism and produces greater memory deficits than iron deficiency or (n-3) fatty acid deficiency alone.

PubMed

Baumgartner, Jeannine; Smuts, Cornelius M; Malan, Linda; Arnold, Myrtha; Yee, Benjamin K; Bianco, Laura E; Boekschoten, Mark V; Müller, Michael; Langhans, Wolfgang; Hurrell, Richard F; Zimmermann, Michael B

2012-08-01

Deficiencies of iron (Fe) (ID) and (n-3) fatty acids (FA) [(n-3)FAD] may impair brain development and function through shared mechanisms. However, little is known about the potential interactions between these 2 common deficiencies. We studied the effects of ID and (n-3)FAD, alone and in combination, on brain monoamine pathways (by measuring monoamines and related gene expression) and spatial working and reference memory (by Morris water maze testing). Using a 2 × 2 design, male rats were fed an ID, (n-3)FAD, ID+(n-3)FAD, or control diet for 5 wk postweaning (postnatal d 21-56) after (n-3)FAD had been induced over 2 generations. The (n-3)FAD and ID diets decreased brain (n-3) FA by 70-76% and Fe by 20-32%, respectively. ID and (n-3)FAD significantly increased dopamine (DA) concentrations in the olfactory bulb (OB) and striatum, with an additive 1- to 2-fold increase in ID+(n-3)FAD rats compared with controls (P < 0.05). ID decreased serotonin (5-HT) levels in OB, with a significant decrease in ID+(n-3)FAD rats. Furthermore, norepinephrine concentrations were increased 2-fold in the frontal cortex (FC) of (n-3)FAD rats (P < 0.05). Dopa decarboxylase was downregulated in the hippocampus of ID and ID+(n-3)FAD rats (fold-change = -1.33; P < 0.05). ID and (n-3)FAD significantly impaired working memory performance and the impairment positively correlated with DA concentrations in FC (r = 0.39; P = 0.026). Reference memory was impaired in the ID+(n-3)FAD rats (P < 0.05) and was negatively associated with 5-HT in FC (r = -0.42; P = 0.018). These results suggest that the combined deficiencies of Fe and (n-3) FA disrupt brain monoamine metabolism and produce greater deficits in reference memory than ID or (n-3)FAD alone.

Infectious Disease Stigmas: Maladaptive in Modern Society

PubMed Central

Smith, Rachel A.; Hughes, David

2014-01-01

At multiple times in human history people have asked if there are good stigmas. Is there some useful function stigmas serve in the context of our evolutionary history; is stigma adaptive? This essay discusses stigmas as a group-selection strategy and the human context in which stigmas likely appeared. The next section explores how human patterns have changed in modern society and the consequences for infectious disease (ID) stigmas in the modern age. The concluding section suggests that while social-living species may be particularly apt to create and communicate ID stigmas and enact ID-related stigmatization, such stigma-related processes no longer function to protect human communities. Stigmas do not increase the ability of modern societies to survive infectious diseases, but in fact may be important drivers of problematic disease dynamics and act as catalysts for failures in protecting public health. PMID:25477728

Cysteine-rich secretory protein 3 plays a role in prostate cancer cell invasion and affects expression of PSA and ANXA1.

PubMed

Pathak, Bhakti R; Breed, Ananya A; Apte, Snehal; Acharya, Kshitish; Mahale, Smita D

2016-01-01

Cysteine-rich secretory protein 3 (CRISP-3) is upregulated in prostate cancer as compared to the normal prostate tissue. Higher expression of CRISP-3 has been linked to poor prognosis and hence it has been thought to act as a prognostic marker for prostate cancer. It is proposed to have a role in innate immunity but its role in prostate cancer is still unknown. In order to understand its function, its expression was stably knocked down in LNCaP cells. CRISP-3 knockdown did not affect cell viability but resulted in reduced invasiveness. Global gene expression changes upon CRISP-3 knockdown were identified by microarray analysis. Microarray data were quantitatively validated by evaluating the expression of seven candidate genes in three independent stable clones. Functional annotation of the differentially expressed genes identified cell adhesion, cell motility, and ion transport to be affected among other biological processes. Prostate-specific antigen (PSA, also known as Kallikrein 3) was the top most downregulated gene whose expression was also validated at protein level. Interestingly, expression of Annexin A1 (ANXA1), a known anti-inflammatory protein, was upregulated upon CRISP-3 knockdown. Re-introduction of CRISP-3 into the knockdown clone reversed the effect on invasiveness and also led to increased PSA expression. These results suggest that overexpression of CRISP-3 in prostate tumor may maintain higher PSA expression and lower ANXA1 expression. Our data also indicate that poor prognosis associated with higher CRISP-3 expression could be due to its role in cell invasion.

NPM1 Silencing Reduces Tumour Growth and MAPK Signalling in Prostate Cancer Cells

PubMed Central

Loubeau, Gaëlle; Boudra, Rafik; Maquaire, Sabrina; Lours-Calet, Corinne; Beaudoin, Claude; Verrelle, Pierre; Morel, Laurent

2014-01-01

The chaperone nucleophosmin (NPM1) is over-expressed in the epithelial compartment of prostate tumours compared to adjacent healthy epithelium and may represent one of the key actors that support the neoplastic phenotype of prostate adenocarcinoma cells. Yet, the mechanisms that underlie NPM1 mediated phenotype remain elusive in the prostate. To better understand NPM1 functions in prostate cancer cells, we sought to characterize its impact on prostate cancer cells behaviour and decipher the mechanisms by which it may act. Here we show that NPM1 favors prostate tumour cell migration, invasion and colony forming. Furthermore, knockdown of NPM1 leads to a decrease in the growth of LNCaP-derived tumours grafted in Nude mice in vivo. Such oncogenic-like properties are found in conjunction with a positive regulation of NPM1 on the ERK1/2 (Extracellular signal-Regulated Kinases 1/2) kinase phosphorylation in response to EGF (Epidermal Growth Factor) stimulus, which is critical for prostate cancer progression following the setting of an autonomous production of the growth factor. NPM1 could then be a target to switch off specifically ERK1/2 pathway activation in order to decrease or inhibit cancer cell growth and migration. PMID:24796332

Boosting antitumor responses of T lymphocytes infiltrating human prostate cancers

PubMed Central

Bronte, Vincenzo; Kasic, Tihana; Gri, Giorgia; Gallana, Keti; Borsellino, Giovanna; Marigo, Ilaria; Battistini, Luca; Iafrate, Massimo; Prayer-Galetti, Tommaso; Pagano, Francesco; Viola, Antonella

2005-01-01

Immunotherapy may provide valid alternative therapy for patients with hormone-refractory metastatic prostate cancer. However, if the tumor environment exerts a suppressive action on antigen-specific tumor-infiltrating lymphocytes (TIL), immunotherapy will achieve little, if any, success. In this study, we analyzed the modulation of TIL responses by the tumor environment using collagen gel matrix–supported organ cultures of human prostate carcinomas. Our results indicate that human prostatic adenocarcinomas are infiltrated by terminally differentiated cytotoxic T lymphocytes that are, however, in an unresponsive status. We demonstrate the presence of high levels of nitrotyrosines in prostatic TIL, suggesting a local production of peroxynitrites. By inhibiting the activity of arginase and nitric oxide synthase, key enzymes of L-arginine metabolism that are highly expressed in malignant but not in normal prostates, reduced tyrosine nitration and restoration of TIL responsiveness to tumor were achieved. The metabolic control exerted by the tumor on TIL function was confirmed in a transgenic mouse prostate model, which exhibits similarities with human prostate cancer. These results identify a novel and dominant mechanism by which cancers induce immunosuppression in situ and suggest novel strategies for tumor immunotherapy. PMID:15824085

Non-Coding RNAs in Castration-Resistant Prostate Cancer: Regulation of Androgen Receptor Signaling and Cancer Metabolism.

PubMed

Shih, Jing-Wen; Wang, Ling-Yu; Hung, Chiu-Lien; Kung, Hsing-Jien; Hsieh, Chia-Ling

2015-12-04

Hormone-refractory prostate cancer frequently relapses from therapy and inevitably progresses to a bone-metastatic status with no cure. Understanding of the molecular mechanisms conferring resistance to androgen deprivation therapy has the potential to lead to the discovery of novel therapeutic targets for type of prostate cancer with poor prognosis. Progression to castration-resistant prostate cancer (CRPC) is characterized by aberrant androgen receptor (AR) expression and persistent AR signaling activity. Alterations in metabolic activity regulated by oncogenic pathways, such as c-Myc, were found to promote prostate cancer growth during the development of CRPC. Non-coding RNAs represent a diverse family of regulatory transcripts that drive tumorigenesis of prostate cancer and various other cancers by their hyperactivity or diminished function. A number of studies have examined differentially expressed non-coding RNAs in each stage of prostate cancer. Herein, we highlight the emerging impacts of microRNAs and long non-coding RNAs linked to reactivation of the AR signaling axis and reprogramming of the cellular metabolism in prostate cancer. The translational implications of non-coding RNA research for developing new biomarkers and therapeutic strategies for CRPC are also discussed.

Non-Coding RNAs in Castration-Resistant Prostate Cancer: Regulation of Androgen Receptor Signaling and Cancer Metabolism

PubMed Central

Shih, Jing-Wen; Wang, Ling-Yu; Hung, Chiu-Lien; Kung, Hsing-Jien; Hsieh, Chia-Ling

2015-01-01

Hormone-refractory prostate cancer frequently relapses from therapy and inevitably progresses to a bone-metastatic status with no cure. Understanding of the molecular mechanisms conferring resistance to androgen deprivation therapy has the potential to lead to the discovery of novel therapeutic targets for type of prostate cancer with poor prognosis. Progression to castration-resistant prostate cancer (CRPC) is characterized by aberrant androgen receptor (AR) expression and persistent AR signaling activity. Alterations in metabolic activity regulated by oncogenic pathways, such as c-Myc, were found to promote prostate cancer growth during the development of CRPC. Non-coding RNAs represent a diverse family of regulatory transcripts that drive tumorigenesis of prostate cancer and various other cancers by their hyperactivity or diminished function. A number of studies have examined differentially expressed non-coding RNAs in each stage of prostate cancer. Herein, we highlight the emerging impacts of microRNAs and long non-coding RNAs linked to reactivation of the AR signaling axis and reprogramming of the cellular metabolism in prostate cancer. The translational implications of non-coding RNA research for developing new biomarkers and therapeutic strategies for CRPC are also discussed. PMID:26690121

Glutathione Peroxidase 3 Inhibits Prostate Tumorigenesis in TRAMP Mice.

PubMed

Chang, Seo-Na; Lee, Ji Min; Oh, Hanseul; Park, Jae-Hak

2016-11-01

Glutathione peroxidase 3 (GPx3) is involved in protecting cells from oxidative damage, and down-regulated levels of expression have been found in prostate cancer samples. We hypothesize that loss of the GPx3 increases the rate of prostate carcinogenesis and generated GPx3-deficient transgenic adenocarcinoma of the mouse prostate (TRAMP) mice. Prostate cancer incidence and progression were determined in TRAMP, TRAMP/GPx3 (+/-) HET, and TRAMP/GPx3 (-/-) KO mice at 8, 16, and 20 weeks of age. We found that GPx3 expression was decreased in TRAMP mice and not detected in GPx3 KO mice both in mRNA and protein levels. Disruption of GPx3 expression in TRAMP mice increased the GU tract weights and the histopathological scores in each lobes with increased proliferation rates. Moreover, inactivation of one (+/-) or both (-/-) alleles of GPx3 resulted in increase in prostate cancer incidence with activated Wnt/β-catenin pathway. Our results provide the first in vivo molecular genetic evidence that GPx3 does indeed function as a tumor suppressor during prostate carcinogenesis. Prostate 76:1387-1398, 2016. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

MicroRNAs Are Mediators of Androgen Action in Prostate and Muscle

PubMed Central

Narayanan, Ramesh; Jiang, Jinmai; Gusev, Yuriy; Jones, Amanda; Kearbey, Jeffrey D.; Miller, Duane D.; Schmittgen, Thomas D.; Dalton, James T.

2010-01-01

Androgen receptor (AR) function is critical for the development of male reproductive organs, muscle, bone and other tissues. Functionally impaired AR results in androgen insensitivity syndrome (AIS). The interaction between AR and microRNA (miR) signaling pathways was examined to understand the role of miRs in AR function. Reduction of androgen levels in Sprague-Dawley rats by castration inhibited the expression of a large set of miRs in prostate and muscle, which was reversed by treatment of castrated rats with 3 mg/day dihydrotestosterone (DHT) or selective androgen receptor modulators. Knockout of the miR processing enzyme, DICER, in LNCaP prostate cancer cells or tissue specifically in mice inhibited AR function leading to AIS. Since the only function of miRs is to bind to 3′ UTR and inhibit translation of target genes, androgens might induce miRs to inhibit repressors of AR function. In concordance, knock-down of DICER in LNCaP cells and in tissues in mice induced the expression of corepressors, NCoR and SMRT. These studies demonstrate a feedback loop between miRs, corepressors and AR and the imperative role of miRs in AR function in non-cancerous androgen-responsive tissues. PMID:21048966

Quality of life outcomes following treatment for localized prostate cancer: is there a clear winner?

PubMed

Parker, Walter R; Montgomery, Jeffery S; Wood, David P

2009-05-01

The majority of men treated for localized prostate cancer are cured of their disease. As a result, it is important to discuss long-term quality of life (QoL) expectations when counseling patients regarding treatment options. The varying QoL outcomes for radical prostatectomy, external beam radiotherapy, brachytherapy, and cryotherapy will be reviewed. Robotic and radical prostatectomy has similar outcomes with significant initial worsening of urinary continence and sexual function. External beam radiation has less impact on continence and sexual function but noteworthy bowel toxicity. Brachytherapy results in the most irritative urinary symptoms, with decreased sexual and bowel QoL as well. Cryotherapy greatly reduces sexual function. Every patient has unique pretreatment variables, priorities, and preferences. It is crucial to fully explain the range of oncologic and QoL implications when counseling patients regarding treatment for localized prostate cancer.

Human Prostatic Acid Phosphatase: Structure, Function and Regulation

PubMed Central

Muniyan, Sakthivel; Chaturvedi, Nagendra K.; Dwyer, Jennifer G.; LaGrange, Chad A.; Chaney, William G.; Lin, Ming-Fong

2013-01-01

Human prostatic acid phosphatase (PAcP) is a 100 kDa glycoprotein composed of two subunits. Recent advances demonstrate that cellular PAcP (cPAcP) functions as a protein tyrosine phosphatase by dephosphorylating ErbB-2/Neu/HER-2 at the phosphotyrosine residues in prostate cancer (PCa) cells, which results in reduced tumorigenicity. Further, the interaction of cPAcP and ErbB-2 regulates androgen sensitivity of PCa cells. Knockdown of cPAcP expression allows androgen-sensitive PCa cells to develop the castration-resistant phenotype, where cells proliferate under an androgen-reduced condition. Thus, cPAcP has a significant influence on PCa cell growth. Interestingly, promoter analysis suggests that PAcP expression can be regulated by NF-κB, via a novel binding sequence in an androgen-independent manner. Further understanding of PAcP function and regulation of expression will have a significant impact on understanding PCa progression and therapy. PMID:23698773

Fluorescence guided surgery and tracer-dose, fact or fiction?

PubMed

KleinJan, Gijs H; Bunschoten, Anton; van den Berg, Nynke S; Olmos, Renato A Valdès; Klop, W Martin C; Horenblas, Simon; van der Poel, Henk G; Wester, Hans-Jürgen; van Leeuwen, Fijs W B

2016-09-01

Fluorescence guidance is an upcoming methodology to improve surgical accuracy. Challenging herein is the identification of the minimum dose at which the tracer can be detected with a clinical-grade fluorescence camera. Using a hybrid tracer such as indocyanine green (ICG)-(99m)Tc-nanocolloid, it has become possible to determine the accumulation of tracer and correlate this to intraoperative fluorescence-based identification rates. In the current study, we determined the lower detection limit of tracer at which intraoperative fluorescence guidance was still feasible. Size exclusion chromatography (SEC) provided a laboratory set-up to analyze the chemical content and to simulate the migratory behavior of ICG-nanocolloid in tissue. Tracer accumulation and intraoperative fluorescence detection findings were derived from a retrospective analysis of 20 head-and-neck melanoma patients, 40 penile and 20 prostate cancer patients scheduled for sentinel node (SN) biopsy using ICG-(99m)Tc-nanocolloid. In these patients, following tracer injection, single photon emission computed tomography fused with computed tomography (SPECT/CT) was used to identify the SN(s). The percentage injected dose (% ID), the amount of ICG (in nmol), and the concentration of ICG in the SNs (in μM) was assessed for SNs detected on SPECT/CT and correlated with the intraoperative fluorescence imaging findings. SEC determined that in the hybrid tracer formulation, 41 % (standard deviation: 12 %) of ICG was present in nanocolloid-bound form. In the SNs detected using fluorescence guidance a median of 0.88 % ID was present, compared to a median of 0.25 % ID in the non-fluorescent SNs (p-value < 0.001). The % ID values could be correlated to the amount ICG in a SN (range: 0.003-10.8 nmol) and the concentration of ICG in a SN (range: 0.006-64.6 μM). The ability to provide intraoperative fluorescence guidance is dependent on the amount and concentration of the fluorescent dye accumulated in the lesion(s) of interest. Our findings indicate that intraoperative fluorescence detection with ICG is possible above a μM concentration.

Defined Conditions for the Isolation and Expansion of Basal Prostate Progenitor Cells of Mouse and Human Origin

PubMed Central

Höfner, Thomas; Eisen, Christian; Klein, Corinna; Rigo-Watermeier, Teresa; Goeppinger, Stephan M.; Jauch, Anna; Schoell, Brigitte; Vogel, Vanessa; Noll, Elisa; Weichert, Wilko; Baccelli, Irène; Schillert, Anja; Wagner, Steve; Pahernik, Sascha; Sprick, Martin R.; Trumpp, Andreas

2015-01-01

Summary Methods to isolate and culture primary prostate epithelial stem/progenitor cells (PESCs) have proven difficult and ineffective. Here, we present a method to grow and expand both murine and human basal PESCs long term in serum- and feeder-free conditions. The method enriches for adherent mouse basal PESCs with a Lin−SCA-1+CD49f+TROP2high phenotype. Progesterone and sodium selenite are additionally required for the growth of human Lin−CD49f+TROP2high PESCs. The gene-expression profiles of expanded basal PESCs show similarities to ESCs, and NF-kB function is critical for epithelial differentiation of sphere-cultured PESCs. When transplanted in combination with urogenital sinus mesenchyme, expanded mouse and human PESCs generate ectopic prostatic tubules, demonstrating their stem cell activity in vivo. This novel method will facilitate the molecular, genomic, and functional characterization of normal and pathologic prostate glands of mouse and human origin. PMID:25702639

Early-Onset Endocrine Disruptor–Induced Prostatitis in the Rat

PubMed Central

Cowin, Prue A.; Foster, Paul; Pedersen, John; Hedwards, Shelley; McPherson, Stephen J.; Risbridger, Gail P.

2008-01-01

Background Androgens are critical for specifying prostate development, with the fetal prostate sensitive to altered hormone levels and endocrine-disrupting chemicals (EDCs) that exhibit estrogenic or antiandrogenic properties. Prostatic inflammation (prostatitis) affects 9% of men of all ages, and > 90% of cases are of unknown etiology. Objectives In this study we aimed to evaluate effects of in utero exposure to the antiandrogenic EDC vinclozolin, during the period of male reproductive tract development, on neonatal, prepubertal, and postpubertal prostate gland function of male offspring. Methods Fetal rats were exposed to vinclozolin (100 mg/kg body weight) or vehicle control (2.5 mL/kg body weight) in utero from gestational day 14 (GD14) to GD19 via oral administration to pregnant dams. Tissue analysis was carried out when male offspring were 0, 4, or 8 weeks of age. Results In utero exposure to vinclozolin was insufficient to perturb prostatic development and branching, although expression of androgen receptor and mesenchymal fibroblast growth factor-10 was down-regulated. Prostate histology remained normal until puberty, but 100% of animals displayed prostatitis postpubertally (56 days of age). Prostatic inflammation was associated with phosphorylation and nuclear translocation of nuclear factor-kappa B (NFκB) and postpubertal activation of proinflammatory NFκB-dependent genes, including the chemokine interleukin-8 and the cytokine transforming growth factor-β1. Significantly, inflammation arising from vinclozolin exposure was not associated with the emergence of premalignant lesions, such as prostatic intra-epithelial neoplasia or proliferative inflammatory atrophy, and hence mimics nonbacterial early-onset prostatitis that commonly occurs in young men. Conclusions These data are the first to unequivocally implicate EDCs as a causative factor and fill an important knowledge gap on the etiology of prostatitis. PMID:18629315

miR-888 is an expressed prostatic secretions-derived microRNA that promotes prostate cell growth and migration

PubMed Central

Lewis, Holly; Lance, Raymond; Troyer, Dean; Beydoun, Hind; Hadley, Melissa; Orians, Joseph; Benzine, Tiffany; Madric, Kenya; Semmes, O John; Drake, Richard; Esquela-Kerscher, Aurora

2014-01-01

microRNAs (miRNAs) are a growing class of small non-coding RNAs that exhibit widespread dysregulation in prostate cancer. We profiled miRNA expression in syngeneic human prostate cancer cell lines that differed in their metastatic potential in order to determine their role in aggressive prostate cancer. miR-888 was the most differentially expressed miRNA observed in human metastatic PC3-ML cells relative to non-invasive PC3-N cells, and its levels were higher in primary prostate tumors from cancer patients, particularly those with seminal vesicle invasion. We also examined a novel miRNA-based biomarker source called expressed prostatic secretions in urine (EPS urine) for miR-888 expression and found that its levels were preferentially elevated in prostate cancer patients with high-grade disease. These expression studies indicated a correlation for miR-888 in disease progression. We next tested how miR-888 regulated cancer-related pathways in vitro using human prostate cancer cell lines. Overexpression of miR-888 increased proliferation and migration, and conversely inhibition of miR-888 activity blocked these processes. miR-888 also increased colony formation in PC3-N and LNCaP cells, supporting an oncogenic role for this miRNA in the prostate. Our data indicates that miR-888 functions to promote prostate cancer progression and can suppress protein levels of the tumor suppressor genes RBL1 and SMAD4. This miRNA holds promise as a diagnostic tool using an innovative prostatic fluid source as well as a therapeutic target for aggressive prostate cancer. PMID:24200968

Molecular classification of benign prostatic hyperplasia: A gene expression profiling study in a rat model.

PubMed

Hata, Junya; Satoh, Yuichi; Akaihata, Hidenori; Hiraki, Hiroyuki; Ogawa, Soichiro; Haga, Nobuhiro; Ishibashi, Kei; Aikawa, Ken; Kojima, Yoshiyuki

2016-07-01

To characterize the molecular features of benign prostatic hyperplasia by carrying out a gene expression profiling analysis in a rat model. Fetal urogenital sinus isolated from 20-day-old male rat embryo was implanted into a pubertal male rat ventral prostate. The implanted urogenital sinus grew time-dependently, and the pathological findings at 3 weeks after implantation showed epithelial hyperplasia as well as stromal hyperplasia. Whole-genome oligonucleotide microarray analysis utilizing approximately 30 000 oligonucleotide probes was carried out using prostate specimens during the prostate growth process (3 weeks after implantation). Microarray analyses showed 926 upregulated (>2-fold change, P < 0.01) and 3217 downregulated genes (<0.5-fold change, P < 0.01) in benign prostatic hyperplasia specimens compared with normal prostate. Gene ontology analyses of upregulated genes showed predominant genetic themes of involvement in development (162 genes, P = 2.01 × 10(-4) ), response to stimulus (163 genes, P = 7.37 × 10(-13) ) and growth (32 genes, P = 1.93 × 10(-5) ). When we used both normal prostate and non-transplanted urogenital sinuses as controls to identify benign prostatic hyperplasia-specific genes, 507 and 406 genes were upregulated and downregulated, respectively. Functional network and pathway analyses showed that genes associated with apoptosis modulation by heat shock protein 70, interleukin-1, interleukin-2 and interleukin-5 signaling pathways, KIT signaling pathway, and secretin-like G-protein-coupled receptors, class B, were relatively activated during the growth process in the benign prostatic hyperplasia specimens. In contrast, genes associated with cholesterol biosynthesis were relatively inactivated. Our microarray analyses of the benign prostatic hyperplasia model rat might aid in clarifying the molecular mechanism of benign prostatic hyperplasia progression, and identifying molecular targets for benign prostatic hyperplasia treatment. © 2016 The Japanese Urological Association.

Bombesin functionalized 64Cu-copper sulfide nanoparticles for targeted imaging of orthotopic prostate cancer.

PubMed

Cai, Huawei; Xie, Fang; Mulgaonkar, Aditi; Chen, Lihong; Sun, Xiankai; Hsieh, Jer-Tsong; Peng, Fangyu; Tian, Rong; Li, Lin; Wu, Changqiang; Ai, Hua

2018-05-22

To synthesize and evaluate the imaging potential of Bom-PEG-[ 64 Cu]CuS nanoparticles (NPs) in orothotopic prostate tumor. [ 64 Cu]CuS NPs were synthesized in aqueous solution by 64 CuCl 2 and Na 2 S reaction. Then PEG linker with or without bombesin peptide were conjugated to the surface of [ 64 Cu]CuS NPs to produce Bom-PEG-[ 64 Cu]CuS and PEG-[ 64 Cu]CuS NPs. These two kinds of NPs were used for testing specific uptake in prostate cancer cells in vitro and imaging of orthotopic prostate tumor in vivo. Bom-PEG-[ 64 Cu]CuS and PEG-[ 64 Cu]CuS NPs were successfully synthesized with core diameter of approximately 5 nm. Radioactive cellular uptake revealed that Bom-PEG-[ 64 Cu]CuS was able to specifically bind to prostate cancer cells, and the microPET-CT imaging indicated clear visualization of orthotopic prostate tumors. Radiolabeled Bom-PEG-[ 64 Cu]CuS NPs have potential as an ideal agent for orthotopic prostate tumor imaging by microPET-CT.

Impact of 120-W 2-μm continuous wave laser vapoenucleation of the prostate on sexual function.

PubMed

Wang, Yubin; Shao, Jinkai; Lu, Yongning; Lü, Yongan; Li, Xiaodong

2014-03-01

The objective of this work is to evaluate the impact of 120-W 2-μm continuous wave (cw) laser vapoenucleation of the prostate in patients with benign prostatic hyperplasia (BPH) on sexual function. One hundred twenty-two consecutive patients with BPH were retrospectively collected in this study and were classified into two groups for surgical treatment with 2-μm cw laser vapoenucleation or transurethral resection of the prostate (TURP). International Index of Erectile Function (IIEF) and general assessment questions were completed before and 12 months after treatment to determine the impact on sexual function. A total of 33 patients (52.4%) in group 1 and 31 (52.5%) in group 2 reported various degrees of erectile dysfunction before surgery. Interestingly, an increase in IIEF-EF score by 2 points was reported by 16 (25.4%) and 14 (23.7%) patients, respectively, and mean EF score did show a marginal but not significant increase postoperatively in both group. Differences about orgasmic intercourse satisfaction, sexual desire domain, and overall satisfaction scores in each group were not significant between preoperative and postoperative, but there was a significant decrease in the orgasmic function domain score at 12 months postoperation in both groups (p < 0.001). The prevalence of postoperative retrograde ejaculation was significantly higher than at baseline assessment in two groups. This study demonstrates that there is no difference between 2 μm laser vapoenucleation and TURP in terms of impact on sexual function. No significant erectile function improvement was observed after surgery, but these two techniques significantly lowered the IIEF orgasmic function domain and this was mainly caused by retrograde ejaculation.

Physical Fitness Profile in Adults with Intellectual Disabilities: Differences between Levels of Sport Practice

ERIC Educational Resources Information Center

Cuesta-Vargas, Antonio Ignacio; Paz-Lourido, Berta; Rodriguez, Alejandro

2011-01-01

Neuromuscular and aerobic capacity can be reduced in people with intellectual disabilities (ID). Previous studies suggest these individuals might be particularly susceptible to losing basic functions because of poor physical fitness. The aim of this study is to describe the physical fitness profile of adult athletes with ID and identify whether…

Schizophrenia-Spectrum Psychoses in People With and Without Intellectual Disability

ERIC Educational Resources Information Center

Bouras, N.; Martin, G.; Leese, M.; Vanstraelen, M.; Holt, G.; Thomas, C.; Hindler, C.; Boardman, J.

2004-01-01

Although there is an increased risk of schizophrenia-spectrum psychoses (SSP) in people with intellectual disability (ID), there is a paucity of research evidence into clinical presentation of the disorder in comparison with research into SSP in people without ID. Aims The aims of the study were to compare clinical, functional, and social factors…

The Diagnosis of Depression in People with Severe Limitations in Intellectual Functioning

ERIC Educational Resources Information Center

Scott, Haleigh; Havercamp, Susan M.

2015-01-01

People with intellectual disability (ID) were once considered immune to developing psychopathology, including affective disorders such as depression. Now research has shown that people with ID do suffer from depression, and the focus is on understanding how to best diagnose and provide treatment. Research has come a long way in adapting the…

Frontal brain electrical activity (EEG) and heart rate in response to affective infant-directed (ID) speech in 9-month-old infants.

PubMed

Santesso, Diane L; Schmidt, Louis A; Trainor, Laurel J

2007-10-01

Many studies have shown that infants prefer infant-directed (ID) speech to adult-directed (AD) speech. ID speech functions to aid language learning, obtain and/or maintain an infant's attention, and create emotional communication between the infant and caregiver. We examined psychophysiological responses to ID speech that varied in affective content (i.e., love/comfort, surprise, fear) in a group of typically developing 9-month-old infants. Regional EEG and heart rate were collected continuously during stimulus presentation. We found the pattern of overall frontal EEG power was linearly related to affective intensity of the ID speech, such that EEG power was greatest in response to fear, than surprise than love/comfort; this linear pattern was specific to the frontal region. We also noted that heart rate decelerated to ID speech independent of affective content. As well, infants who were reported by their mothers as temperamentally distressed tended to exhibit greater relative right frontal EEG activity during baseline and in response to affective ID speech, consistent with previous work with visual stimuli and extending it to the auditory modality. Findings are discussed in terms of how increases in frontal EEG power in response to different affective intensity may reflect the cognitive aspects of emotional processing across sensory domains in infancy.

Novel Fatty Acid Lipoxygenases in the Development of Human and Murine Prostate Cancer

DTIC Science & Technology

2000-10-01

expression of COX-2 mRNA in benign and malignant prostate samples by RNase protection assays in collaboration with Dr. Matthew Breyer at Vanderbilt. COX-2...Shappell,* William E. Boeglin,t prostate adenocarcinomas. (Am J Pathol 1999, Sandy J. Olson,* Susan Kasper,f and 155:235-245) Alan R. Brasht From the...possible role of this novel enzyme in secretory function, 33157-331605. Samuelssor,- B. Dahlen SE, Lindgren JA, Rouzer CA, Serhan CN: Reduced expression in

Nuclear Imaging for Assessment of Prostate Cancer Gene Therapy

DTIC Science & Technology

2007-03-01

thymidine kinase transfected EL4 cells . Further exploration of Tc-99m conjugated potential HSV1-TK substrates is still undergoing in our laboratory...prostate cancer cells , has been demonstrated the utility for tissue-specific toxic gene therapy for prostate cancer[10, 11]. Therefore, an adenovirus...BJ5183 together with pAdeasy-1, the viral DNA plasmid. The pAdeasy-1 is E1 and E3 deleted, its E1 function can be complemented in 293A cells . The

Bone Morphogenetic Proteins, Antagonists and Receptors in Prostate Cancer

DTIC Science & Technology

2005-01-01

expressed in prostate. This work investigates BMP receptors and BMP antagonists to understand the basic mechanisms to inhibit the BMP signaling in...during embryoge- nesis, and prostate cancer metastases to bone. BMP functions can be inhibited by antagonists such as Noggin or DAN. DAN is a protein...protein along with a constant 0-6 -1 10 100 1000 1O0ng/ml of BMP-6, we were able to show a ng/ml BMP-6 dose-dependent inhibition of BMP-6 activity in DU

Inhibition of microRNA-500 has anti-cancer effect through its conditional downstream target of TFPI in human prostate cancer.

PubMed

Cai, Bing; Chen, Wei; Pan, Yue; Chen, Hongde; Zhang, Yirong; Weng, Zhiliang; Li, Yeping

2017-07-01

We investigated the prognostic potential and regulatory mechanism of microRNA-500 (miR-500), and human gene of tissue factor pathway inhibitor (TFPI) in prostate cancer. MiR-500 expression was assessed by qRT-PCR in prostate cancer cell lines and primary tumors. Cancer patients' clinicopathological factors and overall survival were analyzed according to endogenous miR-500 level. MiR-500 was downregulated in DU145 and VCaP cells. Its effect on prostate cancer proliferation, invasion in vitro, and tumorigenicity in vivo, were probed. Possible downstream target of miR-500, TFPI was assessed by luciferase assay and qRT-PCR in prostate cancer cells. In miR-500-downregulated DU145 and VCaP cells, TFPI was silenced to see whether it was directly involved in the regulation of miR-500 in prostate cancer. TFPI alone was either upregulated or downregulated in DU145 and VCaP cells. Their effect on prostate cancer development was further evaluated. MiR-500 is upregulated in both prostate cancer cells and primary tumors. In prostate cancer patients, high miR-500 expression is associated with poor prognosis and overall survival. In DU145 and VCaP cells, miR-500 downregulation inhibited cancer proliferation, invasion in vitro, and explant growth in vivo. TFPI was verified to be associated with miR-500 in prostate cancer. Downregulation of TFPI reversed anti-cancer effects of miR-500 downregulation in prostate cancer cells. However, neither TFPI upregulation nor downregulation alone had any functional impact on prostate cancer development. MiR-500 may be a potential biomarker and molecular target in prostate cancer. TFPI may conditionally regulate prostate cancer in miR-500-downregualted prostate cancer cells. © 2017 Wiley Periodicals, Inc.

[Elucidating the molecular mechanism of prostate cancer progression under chronic hypoxia and development of the novel therapeutic approach].

PubMed

Nomura, Takeo; Yamasaki, Mutsushi; Mimata, Hiromitsu

2014-12-01

Cancer cells encounter a hypoxic microenvironment during tumor growth and progression. In addition, androgen-deprivation therapy against prostate cancer can develop secondary to a hypoxic condition caused by drastic blood supply reduction because androgen drives angiogenic inducers including vascular endothelial growth factor (VEGF) and inhibits angiogenesis inhibitor prostatic pigment epithelium-derived factor (PEDF). Extreme hypoxic conditions are not suitable for cancer survival, however, cancer cells soon adapt to a hypoxic environment and survive. We established a prostate cancer cell line cultured under chronic hypoxia and analyzed a castration-resistant phenotype. Here, the Vav3 was identified as a key oncogenic molecule associated with castration-resistance under chronic hypoxia. We analyzed the functions of Vav3 and Vav3-mediated signaling to establish a novel therapeutic target for castration-resistant prostate cancer.

Epigenetics of prostate cancer.

PubMed

Li, Long-Cheng

2007-05-01

Prostate cancer is the most common type of cancer other than skin cancer and the second leading cause of cancer death in men in the United States. Its exact causes are unknown. Several risk factors have been associated with prostate cancer including age, race, family history and diet. Epigenetic mechanisms including DNA methylation and histone modifications are important means of gene regulation and play essential roles in diverse biological and disease processes. Recently, frequent epigenetic aberrations such as DNA hypo- and hypermethylation and altered histone acetylation and methylation have been observed in prostate cancer affecting the expression and function of a large array of genes, leading to tumorigenesis, tumor progression and metastasis. In this chapter, we examined the current literature regarding epigenetic changes in prostate cancer and discuss the clinical potential of cancer epigenetics for the diagnosis and treatment of this disease.

FANCI-FANCD2 stabilizes the RAD51-DNA complex by binding RAD51 and protects the 5′-DNA end

PubMed Central

Sato, Koichi; Shimomuki, Mayo; Katsuki, Yoko; Takahashi, Daisuke; Kobayashi, Wataru; Ishiai, Masamichi; Miyoshi, Hiroyuki; Takata, Minoru; Kurumizaka, Hitoshi

2016-01-01

The FANCI-FANCD2 (I-D) complex is considered to work with RAD51 to protect the damaged DNA in the stalled replication fork. However, the means by which this DNA protection is accomplished have remained elusive. In the present study, we found that the I-D complex directly binds to RAD51, and stabilizes the RAD51-DNA filament. Unexpectedly, the DNA binding activity of FANCI, but not FANCD2, is explicitly required for the I-D complex-mediated RAD51-DNA filament stabilization. The RAD51 filament stabilized by the I-D complex actually protects the DNA end from nucleolytic degradation by an FA-associated nuclease, FAN1. This DNA end protection is not observed with the RAD51 mutant from FANCR patient cells. These results clearly answer the currently enigmatic question of how RAD51 functions with the I-D complex to prevent genomic instability at the stalled replication fork. PMID:27694619

Inhibitor of differentiation 1 transcription factor promotes metabolic reprogramming in hepatocellular carcinoma cells

PubMed Central

Sharma, Bal Krishan; Kolhe, Ravindra; Black, Stephen M.; Keller, Jonathan R.; Mivechi, Nahid F.; Satyanarayana, Ande

2016-01-01

Reprograming of metabolism is one of the central hallmarks of cancer. The majority of cancer cells depend on high rates of glycolysis and glutaminolysis for their growth and survival. A number of oncogenes and tumor suppressors have been connected to the regulation of altered glucose and glutamine metabolism in cancer cells. For example, the oncogene c-Myc plays vital roles in cancer cell metabolic adaptation by directly regulating various genes that participate in aerobic glycolysis and glutaminolysis. Inhibitor of differentiation 1 (Id1) is a helix-loop-helix transcription factor that plays important roles in cell proliferation, differentiation, and cell fate determination. Overexpression of Id1 causes intestinal adenomas and thymic lymphomas in mice, suggesting that Id1 could function as an oncogene. Despite it being an oncogene, whether Id1 plays any prominent role in cancer cell metabolic reprograming is unknown. Here, we demonstrate that Id1 is strongly expressed in human and mouse liver tumors and in hepatocellular carcinoma (HCC) cell lines, whereas its expression is very low or undetectable in normal liver tissues. In HCC cells, Id1 expression is regulated by the MAPK/ERK pathway at the transcriptional level. Knockdown of Id1 suppressed aerobic glycolysis and glutaminolysis, suggesting that Id1 promotes a metabolic shift toward aerobic glycolysis. At the molecular level, Id1 mediates its metabolic effects by regulating the expression levels of c-Myc. Knockdown of Id1 resulted in down-regulation (∼75%) of c-Myc, whereas overexpression of Id1 strongly induced (3-fold) c-Myc levels. Interestingly, knockdown of c-Myc resulted in down-regulation (∼60%) of Id1, suggesting a positive feedback-loop regulatory mechanism between Id1 and c-Myc. Under anaerobic conditions, both Id1 and c-Myc are down-regulated (50–70%), and overexpression of oxygen-insensitive hypoxia-inducible factor 1α (Hif1α) or its downstream target Mxi1 resulted in a significant reduction of c-Myc and Id1 (∼70%), suggesting that Hif1α suppresses Id1 and c-Myc under anaerobic conditions via Mxi1. Together, our findings indicate a prominent novel role for Id1 in liver cancer cell metabolic adaptation.—Sharma, B. K., Kolhe, R., Black, S. M., Keller, J. R., Mivechi, N. F., Satyanarayana, A. Inhibitor of differentiation 1 transcription factor promotes metabolic reprogramming in hepatocellular carcinoma cells. PMID:26330493

Genome-wide CRISPR screen identifies HNRNPL as a prostate cancer dependency regulating RNA splicing.

PubMed

Fei, Teng; Chen, Yiwen; Xiao, Tengfei; Li, Wei; Cato, Laura; Zhang, Peng; Cotter, Maura B; Bowden, Michaela; Lis, Rosina T; Zhao, Shuang G; Wu, Qiu; Feng, Felix Y; Loda, Massimo; He, Housheng Hansen; Liu, X Shirley; Brown, Myles

2017-06-27

Alternative RNA splicing plays an important role in cancer. To determine which factors involved in RNA processing are essential in prostate cancer, we performed a genome-wide CRISPR/Cas9 knockout screen to identify the genes that are required for prostate cancer growth. Functional annotation defined a set of essential spliceosome and RNA binding protein (RBP) genes, including most notably heterogeneous nuclear ribonucleoprotein L (HNRNPL). We defined the HNRNPL-bound RNA landscape by RNA immunoprecipitation coupled with next-generation sequencing and linked these RBP-RNA interactions to changes in RNA processing. HNRNPL directly regulates the alternative splicing of a set of RNAs, including those encoding the androgen receptor, the key lineage-specific prostate cancer oncogene. HNRNPL also regulates circular RNA formation via back splicing. Importantly, both HNRNPL and its RNA targets are aberrantly expressed in human prostate tumors, supporting their clinical relevance. Collectively, our data reveal HNRNPL and its RNA clients as players in prostate cancer growth and potential therapeutic targets.

Current Insights into Long Non-Coding RNAs (LncRNAs) in Prostate Cancer

PubMed Central

Smolle, Maria A.; Bauernhofer, Thomas; Pummer, Karl; Calin, George A.; Pichler, Martin

2017-01-01

The importance of long non-coding RNAs (lncRNAs) in the pathogenesis of various malignancies has been uncovered over the last few years. Their dysregulation often contributes to or is a result of tumour progression. In prostate cancer, the most common malignancy in men, lncRNAs can promote castration resistance, cell proliferation, invasion, and metastatic spread. Expression patterns of lncRNAs often change during tumour progression; their expression levels may constantly rise (e.g., HOX transcript antisense RNA, HOTAIR), or steadily decrease (e.g., downregulated RNA in cancer, DRAIC). In prostate cancer, lncRNAs likewise have diagnostic (e.g., prostate cancer antigen 3, PCA3), prognostic (e.g., second chromosome locus associated with prostate-1, SChLAP1), and predictive (e.g., metastasis-associated lung adenocarcinoma transcript-1, MALAT-1) functions. Considering their dynamic role in prostate cancer, lncRNAs may also serve as therapeutic targets, helping to prevent development of castration resistance, maintain stable disease, and prohibit metastatic spread. PMID:28241429

Sexual self-schema and depressive symptoms after prostate cancer.

PubMed

Hoyt, Michael A; Carpenter, Kristen M

2015-04-01

The years following prostate cancer treatment are characterized by changes in sexual functioning and risk for depressive symptoms. Sexual self-schema (SSS) is a cognitive generalization about sexual aspects of the self that are associated with sexual behavior, affect, and the processing of sexually relevant information. This study tested if men's SSS moderates the impact of sexual morbidity on depressive symptoms. Men (N = 66) treated for localized prostate cancer in the preceding 2 years were assessed at T1 and 4 months later (T2). Questionnaires included the Center for Epidemiologic Studies Depression Scale, Sexual Self-schema Scale for Men, Sexual Experience Scale, and Expanded Prostate Cancer Index Composite. Regressions controlled for age, sexual activity, and T1 depressive symptoms revealed no significant effect of SSS on depressive symptoms; however, better sexual functioning was related to fewer depressive symptoms (B = -0.25, p < 0.05). Results showed significant interactions between SSS and sexual outcomes. Among men with high SSS, poor sexual functioning was associated with increased depressive symptoms; loss of sexual function was particularly distressing. There was no significant effect of sexual functioning. Among men with high SSS, there was an inverse relationship between sexual engagement and depressive symptoms. Among men with lower SSS, greater frequency of sexual behavior was associated with increased depressive symptoms. SSS may be an important individual difference in determining the impact of sexual morbidity on psychological adjustment. Men high on SSS are more vulnerable to psychological consequences of lower sexual functioning and less engagement in sexual activities. Copyright © 2014 John Wiley & Sons, Ltd.

Iron deficiency impairs developing hippocampal neuron gene expression, energy metabolism and dendrite complexity

PubMed Central

Bastian, Thomas W.; von Hohenberg, William C.; Mickelson, Daniel J.; Lanier, Lorene M.; Georgieff, Michael K.

2016-01-01

Iron deficiency (ID), with and without anemia, affects an estimated 2 billion people worldwide. ID is particularly deleterious during early-life brain development, leading to long-term neurological impairments, including deficits in hippocampus-mediated learning and memory. Neonatal rats with fetal/neonatal ID anemia (IDA) have shorter hippocampal CA1 apical dendrites with disorganized branching. ID-induced dendritic structural abnormalities persist into adulthood despite normalization of iron status. However, the specific developmental effects of neuronal iron loss on hippocampal neuron dendrite growth and branching are unknown. Embryonic hippocampal neuron cultures were chronically treated with deferoxamine (DFO, an iron chelator) beginning at 3 days in vitro (DIV). Levels of mRNA for Tfr1 and Slc11a2, iron-responsive genes involved in iron uptake, were significantly elevated in DFO-treated cultures at 11DIV and 18DIV, indicating a similar degree of neuronal ID as seen in rodent ID models. DFO treatment decreased mRNA levels for genes indexing dendritic and synaptic development (i.e., BdnfVI, Camk2a, Vamp1, Psd95, Cfl1, Pfn1, Pfn2, and Gda) and mitochondrial function (i.e., Ucp2, Pink1, and Cox6a1). At 18DIV, DFO reduced key aspects of energy metabolism including basal respiration, maximal respiration, spare respiratory capacity, ATP production, and glycolytic rate, capacity, and reserve. Sholl analysis revealed a significant decrease in distal dendritic complexity in DFO-treated neurons at both 11DIV and 18DIV. At 11DIV, the length of primary dendrites and the number and length of branches in DFO-treated neurons was reduced. By 18DIV, a partial recovery of dendritic branch number in DFO-treated neurons was counteracted by a significant reduction in the number and length of primary dendrites and length of branches. Our findings suggest that early neuronal iron loss, at least partially driven through altered mitochondrial function and neuronal energy metabolism, is responsible for the effects of fetal/neonatal ID and IDA on hippocampal neuron dendritic and synaptic maturation. Impairments in these neurodevelopmental processes likely underlie the negative impact of early life ID and IDA on hippocampus-mediated learning and memory. PMID:27669335

Are Non-intellectually Disabled Black Youth with ASD Less Impaired on Parent Report than Their White Peers?

PubMed Central

Anthony, Bruno J.; Kenworthy, Lauren; Armour, Anna Chelsea; Dudley, Katerina; Anthony, Laura Gutermuth

2016-01-01

There is a lack of research examining differences in functioning in autism spectrum disorder (ASD) across ethnicity, particularly among those without intellectual disability (ID). This study investigated ethnic differences in parent-reported impairment in executive function, adaptive behavior, and social–emotional functioning. White and Black youth (n = 64; ages 6–17) with ASD without ID were compared on each of these domains. Black youth had significantly lower levels of impairment on all three domains. Findings may reflect better daily functioning among Black youth with ASD and/or cultural differences in parent response to questionnaires. Regardless, these findings raise concern about the sensitivity of commonly used measures for Black children with ASD and the impact of culture on daily functioning and symptom manifestation. PMID:26439481

Are Non-intellectually Disabled Black Youth with ASD Less Impaired on Parent Report than Their White Peers?

PubMed

Ratto, Allison B; Anthony, Bruno J; Kenworthy, Lauren; Armour, Anna Chelsea; Dudley, Katerina; Anthony, Laura Gutermuth

2016-03-01

There is a lack of research examining differences in functioning in autism spectrum disorder (ASD) across ethnicity, particularly among those without intellectual disability (ID). This study investigated ethnic differences in parent-reported impairment in executive function, adaptive behavior, and social-emotional functioning. White and Black youth (n = 64; ages 6-17) with ASD without ID were compared on each of these domains. Black youth had significantly lower levels of impairment on all three domains. Findings may reflect better daily functioning among Black youth with ASD and/or cultural differences in parent response to questionnaires. Regardless, these findings raise concern about the sensitivity of commonly used measures for Black children with ASD and the impact of culture on daily functioning and symptom manifestation.

Preliminary findings of serum creatinine and estimated glomerular filtration rate (eGFR) in adolescents with intellectual disabilities.

PubMed

Lin, Jin-Ding; Lin, Lan-Ping; Hsieh, Molly; Lin, Pei-Ying

2010-01-01

The present study aimed to describe the kidney function profile - serum creatinine and estimated glomerular filtration rate (eGFR), and to examine the relationships of predisposing factors to abnormal serum creatinine in people with intellectual disabilities (ID). Data were collected by a cross-sectional study of 827 aged 15-18 years adolescents with ID who participated in annual health examinations as they enrolled into special education schools in Taiwan. We used serum samples to determine participants' creatinine profiles, and the Cockcroft-Gault formula to calculate the data of eGFR to present the chronic kidney disease. The results found 22% of the participants have abnormal serum creatinine value (creatinine>1.0mg/dl) and 59.6%, 36.4% and 4.0% at chronic kidney disease (CKD) stage 1, 2 and 3 cases accordingly based on the Cockcroft-Gault formula. No CKD stage 4 and 5 cases in this study. That is, there were 4% CKD cases (eGFR <60 mL/min/1.73 m(2); CKD stage 3, 4 and 5) in adolescents with ID in this study. The results also indicated that gender and BMI could significantly predict abnormal creatinine condition in multivariate logistic regression analysis. Those boys with ID were more likely to have abnormal creatinine value than girls with ID (OR=10.13, 95% CI=5.96-17.23). In term of BMI, those underweight adolescents with ID were less likely to have high creatinine value compared to normal weight group (OR=0.45, 95% CI=0.28-0.72). In summary, this study provides the preliminary information of creatinine and estimated GFR in people with ID; we suggest the public health policy should initiate appropriate management strategies to monitor kidney function and to improve treatment outcomes of chronic kidney disease for this vulnerable population. Copyright © 2010 Elsevier Ltd. All rights reserved.

A heterodimeric [RGD-Glu-[(64)Cu-NO2A]-6-Ahx-RM2] αvβ3/GRPr-targeting antagonist radiotracer for PET imaging of prostate tumors.

PubMed

Durkan, Kubra; Jiang, Zongrun; Rold, Tammy L; Sieckman, Gary L; Hoffman, Timothy J; Bandari, Rajendra Prasad; Szczodroski, Ashley F; Liu, Liqin; Miao, Yubin; Reynolds, Tamila Stott; Smith, Charles J

2014-02-01

In the present study, we describe a (64)Cu-radiolabeled heterodimeric peptide conjugate for dual αvβ3/GRPr (αvβ3 integrin/gastrin releasing peptide receptor) targeting of the form [RGD-Glu-[(64)Cu-NO2A]-6-Ahx-RM2] (RGD: the amino acid sequence [Arg-Gly-Asp], a nonregulatory peptide used for αvβ3 integrin receptor targeting; Glu: glutamic acid; NO2A: 1,4,7-triazacyclononane-1,4-diacetic acid; 6-Ahx: 6-amino hexanoic acid; and RM2: (D-Phe-Gln-Trp-Ala-Val-Gly-His-Sta-Leu-NH2), an antagonist analogue of bombesin (BBN) peptide used for GRPr targeting). RGD-Glu-6Ahx-RM2] was conjugated to a NOTA (1,4,7-triazacyclononane-1,4,7-triacetic acid) complexing agent to produce [RGD-Glu-[NO2A]-6-Ahx-RM2], which was purified by reversed-phase high-performance liquid chromatography (RP-HPLC) and characterized by electrospray ionization-mass spectrometry (ESI-MS). Radiolabeling of the conjugate with (64)Cu produced [RGD-Glu-[(64)Cu-NO2A]-6-Ahx-RM2 in high radiochemical yield (≥95%). In vivo behavior of the radiolabeled peptide conjugate was investigated in normal CF-1 mice and in the PC-3 human prostate cancer experimental model. A competitive displacement receptor binding assay in human prostate PC-3 cells using (125)I-[Tyr(4)]BBN as the radioligand showed high binding affinity of [RGD-Glu-[(nat)Cu-NO2A]-6-Ahx-RM2] conjugate for the GRPr (3.09±0.34 nM). A similar assay in human, glioblastoma U87-MG cells using (125)I-Echistatin as the radioligand indicated a moderate receptor-binding affinity for the αvβ3 integrin (518±37.5 nM). In vivo studies of [RGD-Glu-[(64)Cu-NO2A]-6-Ahx-RM2] showed high accumulation (4.86±1.01 %ID/g, 1h post-intravenous injection (p.i.)) and prolonged retention (4.26±1.23 %ID/g, 24h p.i.) of tracer in PC-3 tumor-bearing mice. Micro-positron emission tomography (microPET) molecular imaging studies produced high-quality, high contrast images in PC-3 tumor-bearing mice at 4h p.i. The favorable pharmacokinetics and enhanced tumor uptake of (64)Cu-NOTA-RGD-Glu-6Ahx-RM2 warrant further investigations for dual integrin and GRPr-positive tumor imaging and possible radiotherapy. Copyright © 2014 Elsevier Inc. All rights reserved.

Simple, mild, one-step labelling of proteins with gallium-68 using a tris(hydroxypyridinone) bifunctional chelator: a 68Ga-THP-scFv targeting the prostate-specific membrane antigen.

PubMed

Nawaz, Saima; Mullen, Gregory E D; Sunassee, Kavitha; Bordoloi, Jayanta; Blower, Philip J; Ballinger, James R

2017-10-25

Labelling proteins with gallium-68 using bifunctional chelators is often problematic because of unsuitably harsh labelling conditions such as low pH or high temperature and may entail post-labelling purification. To determine whether tris(hydroxypyridinone) (THP) bifunctional chelators offer a potential solution to this problem, we have evaluated the labelling and biodistribution of a THP conjugate with a new single-chain antibody against the prostate-specific membrane antigen (PSMA), an attractive target for staging prostate cancer (PCa). A single-chain variable fragment (scFv) of J591, a monoclonal antibody that recognises an external epitope of PSMA, was prepared in order to achieve biokinetics matched to the half-life of gallium-68. The scFv, J591c-scFv, was engineered with a C-terminal cysteine. J591c-scFv was produced in HEK293T cells and purified by size-exclusion chromatography. A maleimide THP derivative (THP-mal) was coupled site-specifically to the C-terminal cysteine residue. The THP-mal-J591c-scFv conjugate was labelled with ammonium acetate-buffered gallium-68 from a 68 Ge/ 68 Ga generator at room temperature and neutral pH. The labelled conjugate was evaluated in the PCa cell line DU145 and its PSMA-overexpressing variant in vitro and xenografted in SCID mice. J591c-scFv was produced in yields of 4-6 mg/l culture supernatant and efficiently coupled with the THP-mal bifunctional chelator. Labelling yields > 95% were achieved at room temperature following incubation of 5 μg conjugate with gallium-68 for 5 min without post-labelling purification. 68 Ga-THP-mal-J591c-scFv was stable in serum and showed selective binding to the DU145-PSMA cell line, allowing an IC50 value of 31.5 nM to be determined for unmodified J591c-scFv. Serial PET/CT imaging showed rapid, specific tumour uptake and clearance via renal elimination. Accumulation in DU145-PSMA xenografts at 90 min post-injection was 5.4 ± 0.5%ID/g compared with 0.5 ± 0.2%ID/g in DU145 tumours (n = 4). The bifunctional chelator THP-mal enabled simple, rapid, quantitative, one-step room temperature radiolabelling of a protein with gallium-68 at neutral pH without a need for post-labelling purification. The resultant gallium-68 complex shows high affinity for PSMA and favourable in vivo targeting properties in a xenograft model of PCa.

RNA splicing and splicing regulator changes in prostate cancer pathology.

PubMed

Munkley, Jennifer; Livermore, Karen; Rajan, Prabhakar; Elliott, David J

2017-09-01

Changes in mRNA splice patterns have been associated with key pathological mechanisms in prostate cancer progression. The androgen receptor (abbreviated AR) transcription factor is a major driver of prostate cancer pathology and activated by androgen steroid hormones. Selection of alternative promoters by the activated AR can critically alter gene function by switching mRNA isoform production, including creating a pro-oncogenic isoform of the normally tumour suppressor gene TSC2. A number of androgen-regulated genes generate alternatively spliced mRNA isoforms, including a prostate-specific splice isoform of ST6GALNAC1 mRNA. ST6GALNAC1 encodes a sialyltransferase that catalyses the synthesis of the cancer-associated sTn antigen important for cell mobility. Genetic rearrangements occurring early in prostate cancer development place ERG oncogene expression under the control of the androgen-regulated TMPRSS2 promoter to hijack cell behaviour. This TMPRSS2-ERG fusion gene shows different patterns of alternative splicing in invasive versus localised prostate cancer. Alternative AR mRNA isoforms play a key role in the generation of prostate cancer drug resistance, by providing a mechanism through which prostate cancer cells can grow in limited serum androgen concentrations. A number of splicing regulator proteins change expression patterns in prostate cancer and may help drive key stages of disease progression. Up-regulation of SRRM4 establishes neuronal splicing patterns in neuroendocrine prostate cancer. The splicing regulators Sam68 and Tra2β increase expression in prostate cancer. The SR protein kinase SRPK1 that modulates the activity of SR proteins is up-regulated in prostate cancer and has already given encouraging results as a potential therapeutic target in mouse models.

Overexpression of HepaCAM inhibits cell viability and motility through suppressing nucleus translocation of androgen receptor and ERK signaling in prostate cancer.

PubMed

Song, Xuedong; Wang, Yin; Du, Hongfei; Fan, Yanru; Yang, Xue; Wang, Xiaorong; Wu, Xiaohou; Luo, Chunli

2014-07-01

HepaCAM is suppressed in a variety of human cancers, and involved in cell adhesion, growth, migration, invasion, and survival. However, the expression and function of HepaCAM in prostate cancer are still unknown. HepaCAM expression has been detected by RT-PCR, Western blotting and immunohistochemistry staining in prostate cell lines RWPE-1, LNCap, DU145, PC3, and in 75 human prostate tissue specimens, respectively. Meanwhile, the cell proliferation ability was detected by WST-8 assay. The role of HepaCAM in prostate cancer cell migration and invasion was examined by wound healing and transwell assay. And flow cytometry was used to observe the apoptosis of prostate cancer cells. Then we detected changes of Androgen Receptor translocation and ERK signaling using immunofluorescence staining and western blot after overexpression of HepaCAM. The HepaCAM expression was significantly down-regulated in prostate cancer tissues and undetected in prostate cancer cells. However, the low HepaCAM expression was not statistically associated with clinicopathological characteristics of prostate cancer. Overexpression of HepaCAM in prostate cancer cells decreased the cell proliferation, migration and invasion, and induced the cell apoptosis. Meanwhile, HepaCAM prevented the androgen receptor translocation from the cytoplasm to the nucleus and down-regulated the MAPK/ERK signaling. Our results suggested that HepaCAM acted as a tumor suppressor in prostate cancer. HepaCAM inhibited cell viability and motility which might be through suppressing the nuclear translocation of Androgen Receptor and down-regulating the ERK signaling. Therefore, it was indicated that HepaCAM may be a potential therapeutic target for prostate cancer. © 2014 Wiley Periodicals, Inc.

Estrogen receptor signaling in prostate cancer: Implications for carcinogenesis and tumor progression.

PubMed

Bonkhoff, Helmut

2018-01-01

The androgen receptor (AR) is the classical target for prostate cancer prevention and treatment, but more recently estrogens and their receptors have also been implicated in prostate cancer development and tumor progression. Recent experimental and clinical data were reviewed to elucidate pathogenetic mechanisms how estrogens and their receptors may affect prostate carcinogenesis and tumor progression. The estrogen receptor beta (ERβ) is the most prevalent ER in the human prostate, while the estrogen receptor alpha (ERα) is restricted to basal cells of the prostatic epithelium and stromal cells. In high grade prostatic intraepithelial neoplasia (HGPIN), the ERα is up-regulated and most likely mediates carcinogenic effects of estradiol as demonstrated in animal models. The partial loss of the ERβ in HGPIN indicates that the ERβ acts as a tumor suppressor. The tumor promoting function of the TMPRSS2-ERG fusion, a major driver of prostate carcinogenesis, is triggered by the ERα and repressed by the ERβ. The ERβ is generally retained in hormone naïve and metastatic prostate cancer, but is partially lost in castration resistant disease. The progressive emergence of the ERα and ERα-regulated genes (eg, progesterone receptor (PR), PS2, TMPRSS2-ERG fusion, and NEAT1) during prostate cancer progression and hormone refractory disease suggests that these tumors can bypass the AR by using estrogens and progestins for their growth. In addition, nongenomic estrogen signaling pathways mediated by orphan receptors (eg, GPR30 and ERRα) has also been implicated in prostate cancer progression. Increasing evidences demonstrate that local estrogen signaling mechanisms are required for prostate carcinogenesis and tumor progression. Despite the recent progress in this research topic, the translation of the current information into potential therapeutic applications remains highly challenging and clearly warrants further investigation. © 2017 Wiley Periodicals, Inc.

Risk assessment models to evaluate the necessity of prostate biopsies in North Chinese patients with 4-50 ng/mL PSA.

PubMed

Zhao, Jing; Liu, Shuai; Gao, Dexuan; Ding, Sentai; Niu, Zhihong; Zhang, Hui; Huang, Zhilong; Qiu, Juhui; Li, Qing; Li, Ning; Xie, Fang; Cui, Jilei; Lu, Jiaju

2017-02-07

Prostate-specific antigen (PSA) is widely used for prostate cancer screening, but low specificity results in high false positive rates of prostate biopsies. To develop new risk assessment models to overcome the diagnostic limitation of PSA and reduce unnecessary prostate biopsies in North Chinese patients with 4-50 ng/mL PSA. A total of 702 patients in seven hospitals with 4-10 and 10-50 ng/mL PSA, respectively, who had undergone transrectal ultrasound-guided prostate biopsies, were assessed. Analysis-modeling stage for several clinical indexes related to prostate cancer and renal function was carried out. Multiple logistic regression analyses were used to develop new risk assessment models of prostate cancer for both PSA level ranges 4-10 and 10-50 ng/mL. External validation stage of the new models was performed to assess the necessity of biopsy. The new models for both PSA ranges performed significantly better than PSA for detecting prostate cancers. Both models showed higher areas under the curves (0.937 and 0.873, respectively) compared with PSA alone (0.624 and 0.595), at pre-determined cut-off values of 0.1067 and 0.6183, respectively. Patients above the cut-off values were recommended for immediate biopsy, while the others were actively observed. External validation of the models showed significantly increased detection rates for prostate cancer (4-10 ng/mL group, 39.29% vs 17.79%, p=0.006; 10-50 ng/mL group, 71.83% vs 50.0%, p=0.015). We developed risk assessment models for North Chinese patients with 4-50 ng/mL PSA to reduce unnecessary prostate biopsies and increase the detection rate of prostate cancer.

Virus Delivery of CRISPR Guides to the Murine Prostate for Gene Alteration.

PubMed

Riedel, Maria; Berthelsen, Martin F; Bakiri, Latifa; Wagner, Erwin F; Thomsen, Martin K

2018-04-27

With an increasing incidence of prostate cancer, identification of new tumor drivers or modulators is crucial. Genetically engineered mouse models (GEMM) for prostate cancer are hampered by tumor heterogeneity and its complex microevolution dynamics. Traditional prostate cancer mouse models include, amongst others, germline and conditional knockouts, transgenic expression of oncogenes, and xenograft models. Generation of de novo mutations in these models is complex, time-consuming, and costly. In addition, most of traditional models target the majority of the prostate epithelium, whereas human prostate cancer is well known to evolve as an isolated event in only a small subset of cells. Valuable models need to simulate not only prostate cancer initiation, but also progression to advanced disease. Here we describe a method to target a few cells in the prostate epithelium by transducing cells by viral particles. The delivery of an engineered virus to the murine prostate allows alteration of gene expression in the prostate epithelia. Virus type and quantity will hereby define the number of targeted cells for gene alteration by transducing a few cells for cancer initiation and many cells for gene therapy. Through surgery-based injection in the anterior lobe, distal from the urinary track, the tumor in this model can expand without impairing the urinary function of the animal. Furthermore, by targeting only a subset of prostate epithelial cells the technique enables clonal expansion of the tumor, and therefore mimics human tumor initiation, progression, as well as invasion through the basal membrane. This novel technique provides a powerful prostate cancer model with improved physiological relevance. Animal suffering is limited, and since no additional breeding is required, overall animal count is reduced. At the same time, analysis of new candidate genes and pathways is accelerated, which in turn is more cost efficient.

The adaptive immune system promotes initiation of prostate carcinogenesis in a human c-Myc transgenic mouse model.

PubMed

Melis, Monique H M; Nevedomskaya, Ekaterina; van Burgsteden, Johan; Cioni, Bianca; van Zeeburg, Hester J T; Song, Ji-Ying; Zevenhoven, John; Hawinkels, Lukas J A C; de Visser, Karin E; Bergman, Andries M

2017-11-07

Increasing evidence from epidemiological and pathological studies suggests a role of the immune system in the initiation and progression of multiple cancers, including prostate cancer. Reports on the contribution of the adaptive immune system are contradictive, since both suppression and acceleration of disease development have been reported. This study addresses the functional role of lymphocytes in prostate cancer development using a genetically engineered mouse model (GEMM) of human c-Myc driven prostate cancer (Hi-Myc mice) combined with B and T cell deficiency (RAG1 -/- mice). From a pre-cancerous stage on, Hi-Myc mice showed higher accumulation of immune cells in their prostates then wild-type mice, of which macrophages were the most abundant. The onset of invasive adenocarcinoma was delayed in Hi-MycRAG1 -/- compared to Hi-Myc mice and associated with decreased infiltration of leukocytes into the prostate. In addition, lower levels of the cytokines CXCL2, CCL5 and TGF-β1 were detected in Hi-MycRAG1 -/- compared to Hi-Myc mouse prostates. These results from a GEMM of prostate cancer provide new insights into the promoting role of the adaptive immune system in prostate cancer development. Our findings indicate that the endogenous adaptive immune system does not protect against de novo prostate carcinogenesis in Hi-Myc transgenic mice, but rather accelerates the formation of invasive adenocarcinomas. This may have implications for the development of novel treatment strategies.

Integrative analysis identifies targetable CREB1/FoxA1 transcriptional co-regulation as a predictor of prostate cancer recurrence.

PubMed

Sunkel, Benjamin; Wu, Dayong; Chen, Zhong; Wang, Chiou-Miin; Liu, Xiangtao; Ye, Zhenqing; Horning, Aaron M; Liu, Joseph; Mahalingam, Devalingam; Lopez-Nicora, Horacio; Lin, Chun-Lin; Goodfellow, Paul J; Clinton, Steven K; Jin, Victor X; Chen, Chun-Liang; Huang, Tim H-M; Wang, Qianben

2016-05-19

Identifying prostate cancer-driving transcription factors (TFs) in addition to the androgen receptor promises to improve our ability to effectively diagnose and treat this disease. We employed an integrative genomics analysis of master TFs CREB1 and FoxA1 in androgen-dependent prostate cancer (ADPC) and castration-resistant prostate cancer (CRPC) cell lines, primary prostate cancer tissues and circulating tumor cells (CTCs) to investigate their role in defining prostate cancer gene expression profiles. Combining genome-wide binding site and gene expression profiles we define CREB1 as a critical driver of pro-survival, cell cycle and metabolic transcription programs. We show that CREB1 and FoxA1 co-localize and mutually influence each other's binding to define disease-driving transcription profiles associated with advanced prostate cancer. Gene expression analysis in human prostate cancer samples found that CREB1/FoxA1 target gene panels predict prostate cancer recurrence. Finally, we showed that this signaling pathway is sensitive to compounds that inhibit the transcription co-regulatory factor MED1. These findings not only reveal a novel, global transcriptional co-regulatory function of CREB1 and FoxA1, but also suggest CREB1/FoxA1 signaling is a targetable driver of prostate cancer progression and serves as a biomarker of poor clinical outcomes. © The Author(s) 2016. Published by Oxford University Press on behalf of Nucleic Acids Research.

MiR-141-3p promotes prostate cancer cell proliferation through inhibiting kruppel-like factor-9 expression

DOE Office of Scientific and Technical Information (OSTI.GOV)

Li, Jiu-zhi; Department of Urology, People's Hospital of Xinjiang Uygur Autonomous Region, Urumqi, Xinjiang, 830001; Li, Jia

Evidence has revealed that some microRNAs play a critical role in tumor proliferation. We demonstrated that miR-141-3p appears to be a novel oncogene miRNA, which promotes prostate tumorigenesis and facilitates the stemness of prostate cancer cells via suppressing a key transcription factor kruppel-like factor-9 (KLF9). KLF9 is the core effector protein that might suppress tumor growth. MiR-141-3p is upregulated in prostate cancer cells and tissues compared to non-tumorigenic prostate epithelial cells and prostate tissues. MiR-141-3p positively regulated proliferation, spheroid formation, and expression of the stemness factors OCT-4, Nanog, SOX-9, Bmil, CCND1, and CD44 in PC-3 cells. Restoration of miR-141-3p suppresses themore » expression of the transcription factor KLF9 in PC-3 and accelerates prostate tumorigenesis via targeted binding with its 3′-UTR. Downregulation of KLF9 enhances spheres formation of prostate cancer cells. Our results suggest that miR-141-3p/KLF9 may play an important role in regulating the growth of prostate cancer and is a potential target of prevention and therapy. - Highlights: • MiR-141-3p is upregulated in human prostate cancer. • MiR-141-3p induces cell proliferation and apoptosis resistance. • KLF9 is a direct and functional target of miR-141-3p.« less

The Function of PTP1B in Neuroendocrine Differentation of Prostate Cancer

DTIC Science & Technology

2009-01-01

TCTGTGGCTTCACCACTT TTCTC-30; for b-actin, 50-GCGGGAAATCGTGCGT GACATT-30 and 50-GATGGAGTTGAAGGTAGTTTC GTG -30. Real time PCR was performed with iQ...regenerating cell subpopulation that can initiate prostate tumorigenesis. Proc Natl Acad Sci USA 2005; 102(19):6942–6947. 16. Huss WJ, Gray DR

Novel Insights into p63 Expression and Function in Prostate

DTIC Science & Technology

2004-07-15

Gene Family, In Metastatic Prostate Cancer Cells (1999) 49. Kononen, J., Bubendorf, L., Kallioniemi, A., Barlund, M., Schraml, P., Leighton , S... Christiansen -Weber, T., and Haas, M. Independent induction of senescence by p16INK4a and p21CIP1 in spontaneously immortalized human fibroblasts. Cell

Evaluation of Androgen Receptor Function in Prostate Cancer Prognosis and Therapeutic Stratification

DTIC Science & Technology

2012-10-01

Miettinen, Wang et al. 2011) (Braun, Goltz et al. 2011) (Rosen, Sesterhenn et al. 2012), rabbit polyclonal anti-PSA antibody (DAKO, A056201-2... Goltz , et al. (2011). "ERG protein expression and genomic rearrangement status in primary and metastatic prostate cancer - a comparative study of two

Caregivers' reported functional limitations in activities of daily living among middle-aged adults with intellectual disabilities.

PubMed

Lin, Lan-Ping; Hsia, Yi-Chen; Hsu, Shang-Wei; Loh, Ching-Hui; Wu, Chia-Ling; Lin, Jin-Ding

2013-12-01

This study was conducted to describe the functioning of Activities of Daily Living (ADL) and to examine socio-economic effects on ADL functioning among adults with intellectual disabilities (ID) aged 45 years and older (N=480) in Taiwan. The Barthel Index (BI) was used to determine a baseline level of ADL functioning in the study participants. There are five categories of functional impairment using the following cut-off values in Taiwan: total dependence (BI score 0-20), severe (BI score 21-60), moderate (BI score 61-90), mild (BI score 91-99), and total independence (BI score 100) (Taiwan Department of Health, 2012). The results revealed that 2.3% of adults with ID were in total dependence, 11.9% were in severe dependence, 27.9% were in moderate dependence, 8.1% had a mild dependence, and 49.8% were totally independent. In the multiple linear regression model of the ADL score, we determined that educational level, comorbid Down's syndrome, and disability level are the variables able to significantly predict ADL score (R(2)=0.190) after controlling for the factors of age, marital status, and other comorbidity conditions. Those ID adults with a lower education level (primary vs. literate, β=4.780, p=0.031; intermediate vs. literate, β=6.642, p=0.030), with comorbid Down's syndrome (β=-7.135, p=0.063), and with a more severe disability condition (severe vs. mild, β=-7.650, p=0.007; profound vs. mild, β=-19.169, p<0.001) had significantly lower ADL scores. The present study highlights the need to support mobility in older adults with ID as much as possible to optimize independence in this group. Copyright © 2013 Elsevier Ltd. All rights reserved.

Insomnia Disorder and Brain's Default-Mode Network.

PubMed

Marques, Daniel Ruivo; Gomes, Ana Allen; Caetano, Gina; Castelo-Branco, Miguel

2018-06-09

Insomnia disorder (ID) is a prevalent sleep disorder that significantly compromises the physical and mental health of individuals. This article reviews novel approaches in the study of brain networks and impaired function in ID through the application of modern neuroimaging techniques such as functional magnetic resonance imaging (fMRI). The default-mode network (DMN) is presumed to be correlated with self-referential information processing, and it appears to be altered or unbalanced in insomnia. A growing body of evidence suggests the lack of deactivation of brain regions comprising the DMN when insomnia patients are at rest. Moreover, core areas of the DMN demonstrate greater activation in insomnia patients when compared to healthy controls in self-referential related tasks. Despite the few studies on the topic, underpinning the correlation between abnormal DMN activity and ID deserves further attention in the future. Implications for therapeutics are briefly outlined.

Defense system shortcuts and limits of scope.

PubMed

Rewald, E; Francischetti, M M

2000-10-01

Defense, as a key factor of life, shares the biological tendencies of simplicity and energy saving. We propose that, like the mind, defense tends to rely on shortcuts via immune memes. Also, response repetition may induce the formation of virtual 'modules' [toolkits] to simplify and perfect performance. Engaged modules may expand by proliferating or by capturing immune components from the 'dormant' and even perhaps from active ones. With regard to recovery and/or survival, complexity of the integrated defense system (IDS) (1) requires to be inside of what we call the 'functional window'. In contrast to the physiological and common disease repair, energy is squandered when IDS perceives real danger. Our concern is the uncertain transition to conditions that do not fit into the IDS routine and, even worse, that are outside the functional window where the system is lacking. Copyright 2000 Harcourt Publishers Ltd.

Social Skills Training for Adolescents With Intellectual Disabilities: A School-Based Evaluation.

PubMed

O'Handley, Roderick D; Ford, W Blake; Radley, Keith C; Helbig, Kate A; Wimberly, Joy K

2016-07-01

Individuals with intellectual disabilities (ID) often demonstrate impairments in social functioning, with deficits becoming more apparent during adolescence. This study evaluated the effects of the Superheroes Social Skills program, a program that combines behavioral skills training and video modeling to teach target social skills, on accurate demonstration of three target social skills in adolescents with ID. Skills taught in the present study include Expressing Wants and Needs, Conversation, and Turn Taking. Four adolescents with ID participated in a 3-week social skills intervention, with the intervention occurring twice per week. A multiple baseline across skills design was used to determine the effect of the intervention on social skill accuracy in both a training and generalization setting. All participants demonstrated substantial improvements in skill accuracy in both settings, with teacher ratings of social functioning further suggesting generalization of social skills to nontraining settings. © The Author(s) 2016.

Immune function, mitogenicity, and angiogenic growth factor concentrations in lean and obese rodent sera: implications in obesity-related prostate tumor biology.

PubMed

Mydlo, J H; Gerstein, M I; Harris, C F; Braverman, A S

2003-01-01

Some studies suggest that several tumors have a greater incidence in those patients with a high fat diet, such as colon, breast, and prostate. However, we wanted to determine the effects of obesity alone, independent of diet, on the progression of prostate tumor growth. Using a genetic model of obese and lean Zucker rats, we wanted to demonstrate any sera differences in the concentration of basic fibroblast growth factor (FGF-2) and vascular endothelial cell growth factor (VEGF), two important factors involved in the growth and progression of prostate cancer. We also wanted to investigate if there were any differences in immune function between the two sera, which could also account for uninhibited tumor growth, as well as differences in mitogenic stimulation. Female Zucker rat obese and lean sera were analyzed using ELISA assays for FGF-2, VEGF, and macrophage inflammatory protein-1 alpha (MIP-1a), as a measure of macrophage function. In addition, the sera of lean and obese sera were plated on wells growing LNCaP prostate cancer cells to determine differences in mitogenicity. We found a greater concentration of FGF-2 in the sera from obese Zucker rats compared to lean Zucker rats: 6.32+/-0.56 vs 3.48+/-0.34 pg/ml, respectively, P<0.05). We also demonstrated a greater concentration of VEGF in obese rat sera compared to lean sera: 54.4+/-4.1 vs 38.0+/-2.9 pg/mL, respectively, P<0.05). We detected a trend in mitogenic stimulation among LNCaP cells along the higher concentrations of the dose-response curve (0.72+/-0.06 vs 0.51+/-0.5). However, this was not statistically significant. In addition, we did not find a significant difference in MIP-1a macrophage activity levels between sera. To conclude, we speculate that the greater concentrations of VEGF and FGF-2 in the sera of obese rodents vs lean rodents may account for some of the differences seen in obesity-related tumor growth seen in the human condition. However, the lack of any sera differences of immune function, as measured by macrophage activity, as well as no significant differences on mitogenic proliferation on LNCaP prostate cancer cells, suggests that other mechanisms may exist to explain differences seen in obesity-related prostate tumor biology.

Cox-2-derived PGE2 induces Id1-dependent radiation resistance and self-renewal in experimental glioblastoma.

PubMed

Cook, Peter J; Thomas, Rozario; Kingsley, Philip J; Shimizu, Fumiko; Montrose, David C; Marnett, Lawrence J; Tabar, Viviane S; Dannenberg, Andrew J; Benezra, Robert

2016-10-01

In glioblastoma (GBM), Id1 serves as a functional marker for self-renewing cancer stem-like cells. We investigated the mechanism by which cyclooxygenase-2 (Cox-2)-derived prostaglandin E2 (PGE2) induces Id1 and increases GBM self-renewal and radiation resistance. Mouse and human GBM cells were stimulated with dimethyl-PGE2 (dmPGE2), a stabilized form of PGE2, to test for Id1 induction. To elucidate the signal transduction pathway governing the increase in Id1, a combination of short interfering RNA knockdown and small molecule inhibitors and activators of PGE2 signaling were used. Western blotting, quantitative real-time (qRT)-PCR, and chromatin immunoprecipitation assays were employed. Sphere formation and radiation resistance were measured in cultured primary cells. Immunohistochemical analyses were carried out to evaluate the Cox-2-Id1 axis in experimental GBM. In GBM cells, dmPGE2 stimulates the EP4 receptor leading to activation of ERK1/2 MAPK. This leads, in turn, to upregulation of the early growth response1 (Egr1) transcription factor and enhanced Id1 expression. Activation of this pathway increases self-renewal capacity and resistance to radiation-induced DNA damage, which are dependent on Id1. In GBM, Cox-2-derived PGE2 induces Id1 via EP4-dependent activation of MAPK signaling and the Egr1 transcription factor. PGE2-mediated induction of Id1 is required for optimal tumor cell self-renewal and radiation resistance. Collectively, these findings identify Id1 as a key mediator of PGE2-dependent modulation of radiation response and lend insight into the mechanisms underlying radiation resistance in GBM patients. © The Author(s) 2016. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

A 3D Faraday Shield for Interdigitated Dielectrometry Sensors and Its Effect on Capacitance

PubMed Central

Risos, Alex; Long, Nicholas; Hunze, Arvid; Gouws, Gideon

2016-01-01

Interdigitated dielectrometry sensors (IDS) are capacitive sensors investigated to precisely measure the relative permittivity (ϵr) of insulating liquids. Such liquids used in the power industry exhibit a change in ϵr as they degrade. The IDS ability to measure ϵr in-situ can potentially reduce maintenance, increase grid stability and improve safety. Noise from external electric field sources is a prominent issue with IDS. This paper investigates the novelty of applying a Faraday cage onto an IDS as a 3D shield to reduce this noise. This alters the spatially distributed electric field of an IDS affecting its sensing properties. Therefore, dependency of the sensor’s signal with the distance to a shield above the IDS electrodes has been investigated experimentally and theoretically via a Green’s function calculation and FEM. A criteria of the shield’s distance s = s0 has been defined as the distance which gives a capacitance for the IDS equal to 1 − e−2=86.5% of its unshielded value. Theoretical calculations using a simplified geometry gave a constant value for s0/λ = 1.65, where λ is the IDS wavelength. In the experiment, values for s0 were found to be lower than predicted as from theory and the ratio s0/λ variable. This was analyzed in detail and it was found to be resulting from the specific spatial structure of the IDS. A subsequent measurement of a common insulating liquid with a nearby noise source demonstrates a considerable reduction in the standard deviation of the relative permittivity from σunshielded=±9.5% to σshielded=±0.6%. The presented findings enhance our understanding of IDS in respect to the influence of a Faraday shield on the capacitance, parasitic capacitances of the IDS and external noise impact on the measurement of ϵr. PMID:28042868

A 3D Faraday Shield for Interdigitated Dielectrometry Sensors and Its Effect on Capacitance.

PubMed

Risos, Alex; Long, Nicholas; Hunze, Arvid; Gouws, Gideon

2016-12-31

Interdigitated dielectrometry sensors (IDS) are capacitive sensors investigated to precisely measure the relative permittivity ( ϵ r ) of insulating liquids. Such liquids used in the power industry exhibit a change in ϵ r as they degrade. The IDS ability to measure ϵ r in-situ can potentially reduce maintenance, increase grid stability and improve safety. Noise from external electric field sources is a prominent issue with IDS. This paper investigates the novelty of applying a Faraday cage onto an IDS as a 3D shield to reduce this noise. This alters the spatially distributed electric field of an IDS affecting its sensing properties. Therefore, dependency of the sensor's signal with the distance to a shield above the IDS electrodes has been investigated experimentally and theoretically via a Green's function calculation and FEM. A criteria of the shield's distance s = s 0 has been defined as the distance which gives a capacitance for the IDS equal to 1 - e - 2 = 86.5 % of its unshielded value. Theoretical calculations using a simplified geometry gave a constant value for s 0 / λ = 1.65, where λ is the IDS wavelength. In the experiment, values for s 0 were found to be lower than predicted as from theory and the ratio s 0 / λ variable. This was analyzed in detail and it was found to be resulting from the specific spatial structure of the IDS. A subsequent measurement of a common insulating liquid with a nearby noise source demonstrates a considerable reduction in the standard deviation of the relative permittivity from σ unshielded = ± 9.5% to σ shielded = ± 0.6%. The presented findings enhance our understanding of IDS in respect to the influence of a Faraday shield on the capacitance, parasitic capacitances of the IDS and external noise impact on the measurement of ϵ r .

Activation of β-catenin signaling in androgen receptor-negative prostate cancer cells.

PubMed

Wan, Xinhai; Liu, Jie; Lu, Jing-Fang; Tzelepi, Vassiliki; Yang, Jun; Starbuck, Michael W; Diao, Lixia; Wang, Jing; Efstathiou, Eleni; Vazquez, Elba S; Troncoso, Patricia; Maity, Sankar N; Navone, Nora M

2012-02-01

To study Wnt/β-catenin in castrate-resistant prostate cancer (CRPC) and understand its function independently of the β-catenin-androgen receptor (AR) interaction. We carried out β-catenin immunocytochemical analysis, evaluated TOP-flash reporter activity (a reporter of β-catenin-mediated transcription), and sequenced the β-catenin gene in MDA prostate cancer 118a, MDA prostate cancer 118b, MDA prostate cancer 2b, and PC-3 prostate cancer cells. We knocked down β-catenin in AR-negative MDA prostate cancer 118b cells and carried out comparative gene-array analysis. We also immunohistochemically analyzed β-catenin and AR in 27 bone metastases of human CRPCs. β-Catenin nuclear accumulation and TOP-flash reporter activity were high in MDA prostate cancer 118b but not in MDA prostate cancer 2b or PC-3 cells. MDA prostate cancer 118a and MDA prostate cancer 118b cells carry a mutated β-catenin at codon 32 (D32G). Ten genes were expressed differently (false discovery rate, 0.05) in MDA prostate cancer 118b cells with downregulated β-catenin. One such gene, hyaluronan synthase 2 (HAS2), synthesizes hyaluronan, a core component of the extracellular matrix. We confirmed HAS2 upregulation in PC-3 cells transfected with D32G-mutant β-catenin. Finally, we found nuclear localization of β-catenin in 10 of 27 human tissue specimens; this localization was inversely associated with AR expression (P = 0.056, Fisher's exact test), suggesting that reduced AR expression enables Wnt/β-catenin signaling. We identified a previously unknown downstream target of β-catenin, HAS2, in prostate cancer, and found that high β-catenin nuclear localization and low or no AR expression may define a subpopulation of men with bone metastatic prostate cancer. These findings may guide physicians in managing these patients.

Long non-coding RNA lnc-MX1-1 is associated with poor clinical features and promotes cellular proliferation and invasiveness in prostate cancer

DOE Office of Scientific and Technical Information (OSTI.GOV)

Jiang, Chen-Yi; Gao, Yuan; Wang, Xing-Jie

Long non-coding RNAs (lncRNAs) are emerging as key molecules in human cancer genesis and progression, including prostate cancer. Large amount of lncRNAs have been found that differentially expressed between prostate cancer tissues and normal prostate tissues. Whether these lncRNAs could serve as a novel biomarker for prostate cancer diagnosis or prognosis, and their biological functions in prostate cancer need further investigation. In the present study, we identified that lncRNA lnc-MX1-1 is over-expressed in prostate cancer tissues compared with their adjacent normal prostate tissues by gene expression array profiling. The expression of lnc-MX1-1 in 60 prostate cancer cases was determined bymore » real-time quantitative PCR and the correlations between lnc-MX1-1 expression and patients' clinical features were further analyzed. Next, we impaired lnc-MX1-1 expression using RNAi in LNCaP and 22Rv1 prostate cancer cells to explore the effects of lnc-MX1-1 on proliferation and invasiveness of the cells. Our results showed that there was a significant association between over-expression of lnc-MX1-1 and patients' clinical features such as PSA, Gleason score, metastasis, and recurrence free survival. Moreover, knockdown of lnc-MX1-1 reduced both proliferation and invasiveness of LNCaP and 22Rv1 cells. In conclusion, the results suggest that lnc-MX1-1 may serve as a potential biomarker and therapeutic target for prostate cancer. - Highlights: • LncRNA lnc-MX1-1 is up-regulated in prostate cancer. • Overexpression of lnc-MX1-1 is correlated with poor prostate cancer clinical features. • Knockdown of lnc-MX1-1 reduces proliferation and invasiveness of prostate cancer cells.« less

Alterations in CDH15 and KIRREL3 in Patients with Mild to Severe Intellectual Disability

PubMed Central

Bhalla, Kavita; Luo, Yue; Buchan, Tim; Beachem, Michael A.; Guzauskas, Gregory F.; Ladd, Sydney; Bratcher, Shelly J.; Schroer, Richard J.; Balsamo, Janne; DuPont, Barbara R.; Lilien, Jack; Srivastava, Anand K.

2008-01-01

Cell-adhesion molecules play critical roles in brain development, as well as maintaining synaptic structure, function, and plasticity. Here we have found the disruption of two genes encoding putative cell-adhesion molecules, CDH15 (cadherin superfamily) and KIRREL3 (immunoglobulin superfamily), by a chromosomal translocation t(11;16) in a female patient with intellectual disability (ID). We screened coding regions of these two genes in a cohort of patients with ID and controls and identified four nonsynonymous CDH15 variants and three nonsynonymous KIRREL3 variants that appear rare and unique to ID. These variations altered highly conserved residues and were absent in more than 600 unrelated patients with ID and 800 control individuals. Furthermore, in vivo expression studies showed that three of the CDH15 variations adversely altered its ability to mediate cell-cell adhesion. We also show that in neuronal cells, human KIRREL3 colocalizes and interacts with the synaptic scaffolding protein, CASK, recently implicated in X-linked brain malformation and ID. Taken together, our data suggest that alterations in CDH15 and KIRREL3, either alone or in combination with other factors, could play a role in phenotypic expression of ID in some patients. PMID:19012874

Mutations in two large pedigrees highlight the role of ZNF711 in X-linked intellectual disability.

PubMed

van der Werf, Ilse M; Van Dijck, Anke; Reyniers, Edwin; Helsmoortel, Céline; Kumar, Ajay Anand; Kalscheuer, Vera M; de Brouwer, Arjan Pm; Kleefstra, Tjitske; van Bokhoven, Hans; Mortier, Geert; Janssens, Sandra; Vandeweyer, Geert; Kooy, R Frank

2017-03-20

Intellectual disability (ID) affects approximately 1-2% of the general population and is characterized by impaired cognitive abilities. ID is both clinically as well as genetically heterogeneous, up to 2000 genes are estimated to be involved in the emergence of the disease with various clinical presentations. For many genes, only a few patients have been reported and causality of some genes has been questioned upon the discovery of apparent loss-of-function mutations in healthy controls. Description of additional patients strengthens the evidence for the involvement of a gene in the disease and can clarify the clinical phenotype associated with mutations in a particular gene. Here, we present two large four-generation families with a total of 11 males affected with ID caused by mutations in ZNF711, thereby expanding the total number of families with ID and a ZNF711 mutation to four. Patients with mutations in ZNF711 all present with mild to moderate ID and poor speech accompanied by additional features in some patients, including autistic features and mild facial dysmorphisms, suggesting that ZNF711 mutations cause non-syndromic ID. Copyright © 2016 Elsevier B.V. All rights reserved.

Secreted factors from metastatic prostate cancer cells stimulate mesenchymal stem cell transition to a pro-tumourigenic 'activated' state that enhances prostate cancer cell migration.

PubMed

Ridge, Sarah M; Bhattacharyya, Dibyangana; Dervan, Eoin; Naicker, Serika D; Burke, Amy J; Murphy, J M; O'leary, Karen; Greene, John; Ryan, Aideen E; Sullivan, Francis J; Glynn, Sharon A

2018-05-15

Mesenchymal stem cells (MSCs) are a heterogeneous population of multipotent cells that are capable of differentiating into osteocytes, chondrocytes and adipocytes. Recently, MSCs have been found to home to the tumour site and engraft in the tumour stroma. However, it is not yet known whether they have a tumour promoting or suppressive function. We investigated the interaction between prostate cancer cell lines 22Rv1, DU145 and PC3, and bone marrow-derived MSCs. MSCs were 'educated' for extended periods in prostate cancer cell conditioned media and PC3-educated MSCs were found to be the most responsive with a secretory profile rich in pro-inflammatory cytokines. PC3-educated MSCs secreted increased osteopontin (OPN), interleukin-8 (IL-8) and fibroblast growth factor-2 (FGF-2) and decreased soluble fms-like tyrosine kinase-1 (sFlt-1) compared to untreated MSCs. PC3-educated MSCs showed a reduced migration and proliferation capacity that was dependent on exposure to PC3-conditioned medium. Vimentin and α-smooth muscle actin (αSMA) expression was decreased in PC3-educated MSCs compared to untreated MSCs. PC3 and DU145 education of healthy donor and prostate cancer patient-derived MSCs led to a reduced proportion of FAP+ αSMA+ cells contrary to characteristics commonly associated with cancer associated fibroblasts (CAFs). The migration of PC3 cells was increased toward both PC3-educated and DU145-educated MSCs compared to untreated MSCs, while DU145 migration was only enhanced toward patient-derived MSCs. In summary, MSCs developed an altered phenotype in response to prostate cancer conditioned medium which resulted in increased secretion of pro-inflammatory cytokines, modified functional activity and the chemoattraction of prostate cancer cells. © 2017 UICC.

Abhydrolase domain containing 2, an androgen target gene, promotes prostate cancer cell proliferation and migration.

PubMed

Obinata, Daisuke; Takada, Shogo; Takayama, Ken-ichi; Urano, Tomohiko; Ito, Akiko; Ashikari, Daisaku; Fujiwara, Kyoko; Yamada, Yuta; Murata, Taro; Kumagai, Jinpei; Fujimura, Tetsuya; Ikeda, Kazuhiro; Horie-Inoue, Kuniko; Homma, Yukio; Takahashi, Satoru; Inoue, Satoshi

2016-04-01

The androgen receptor (AR) plays a key role in the development of prostate cancer. AR signalling mediates the expression of androgen-responsive genes, which are involved in prostate cancer development and progression. Our previous chromatin immunoprecipitation study showed that the region of abhydrolase domain containing 2 (ABHD2) includes a functional androgen receptor binding site. In this study, we demonstrated that ABHD2 is a novel androgen-responsive gene that is overexpressed in human prostate cancer tissues. The expression levels of ABHD2 in androgen-sensitive cells were evaluated by quantitative reverse transcription polymerase chain reaction and western-blot analyses. LNCaP and VCaP cells with ABHD2 overexpression or short interfering RNA (siRNA) knockdown were used for functional analyses. ABHD2 expression was examined in clinical samples of prostate cancer by immunohistochemistry. We showed that ABHD2 expression is increased by androgen in LNCaP and VCaP cells. This androgen-induced ABHD2 expression was diminished by bicalutamide. While stable expression of ABHD2 affected the enhancement of LNCaP cell proliferation and migration, siRNA-mediated ABHD2 knockdown suppressed cell proliferation and migration. In addition, the siRNA treatment significantly repressed the tumour growth derived from LNCaP cells in athymic mice. Immunohistochemical analysis of ABHD2 expression in tumour specimens showed a positive correlation of ABHD2 immunoreactivity with high Gleason score and pathological N stage. Moreover, patients with high immunoreactivity of ABHD2 showed low cancer-specific survival rates and a resistance to docetaxel-based chemotherapy. ABHD2 is a novel androgen-regulated gene that can promote prostate cancer growth and resistance to chemotherapy, and is a novel target for diagnosis and treatment of prostate cancer. Copyright © 2016 Elsevier Ltd. All rights reserved.

Investigation of power and frequency for 3D conformal MRI-controlled transurethral ultrasound therapy with a dual frequency multi-element transducer.

PubMed

N'djin, William Apoutou; Burtnyk, Mathieu; Bronskill, Michael; Chopra, Rajiv

2012-01-01

Transurethral ultrasound therapy uses real-time magnetic resonance (MR) temperature feedback to enable the 3D control of thermal therapy accurately in a region within the prostate. Previous canine studies showed the feasibility of this method in vivo. The aim of this study was to reduce the procedure time, while maintaining targeting accuracy, by investigating new combinations of treatment parameters. Simulations and validation experiments in gel phantoms were used, with a collection of nine 3D realistic target prostate boundaries obtained from previous preclinical studies, where multi-slice MR images were acquired with the transurethral device in place. Acoustic power and rotation rate were varied based on temperature feedback at the prostate boundary. Maximum acoustic power and rotation rate were optimised interdependently, as a function of prostate radius and transducer operating frequency. The concept of dual frequency transducers was studied, using the fundamental frequency or the third harmonic component depending on the prostate radius. Numerical modelling enabled assessment of the effects of several acoustic parameters on treatment outcomes. The range of treatable prostate radii extended with increasing power, and tended to narrow with decreasing frequency. Reducing the frequency from 8 MHz to 4 MHz or increasing the surface acoustic power from 10 to 20 W/cm(2) led to treatment times shorter by up to 50% under appropriate conditions. A dual frequency configuration of 4/12 MHz with 20 W/cm(2) ultrasound intensity exposure can treat entire prostates up to 40 cm(3) in volume within 30 min. The interdependence between power and frequency may, however, require integrating multi-parametric functions in the controller for future optimisations.

The Individualized Diet and Exercise Adherence Pilot Trial (IDEA-P) in prostate cancer patients undergoing androgen deprivation therapy: study protocol for a randomized controlled trial.

PubMed

Focht, Brian C; Lucas, Alexander R; Grainger, Elizabeth; Simpson, Christina; Thomas-Ahner, Jennifer M; Clinton, Steven K

2014-09-09

Androgen deprivation therapy (ADT) is the foundation of treatment for men with metastatic prostate cancer and is now frequently incorporated into multimodality strategies for the curative treatment of locally advanced prostate cancer. Nevertheless, the catabolic effects of ADT result in meaningful adverse effects on physiological and quality of life outcomes, which may, in turn, increase the risk of functional decline, frailty, cardiovascular disease, and metabolic syndrome. Recent evidence demonstrates that lifestyle intervention promoting change in exercise and dietary behaviors is a promising approach, and may offset, or even reverse, the adverse effects accompanying ADT. Unfortunately, the limited existing studies of the effects of exercise and dietary interventions targeting patients with prostate cancer on ADT are characterized by high attrition rates and poor postintervention maintenance of treatment effects. Consequently, the Individualized Diet and Exercise Adherence Pilot Trial (IDEA-P) is designed to contrast the effects of a lifestyle intervention designed to promote independent self-management of exercise and dietary behavior with those of standard care disease management approach in the treatment of prostate cancer. A total of 40 patients with prostate cancer undergoing ADT will be randomly assigned to lifestyle intervention or standard care. Outcomes of interest in IDEA-P include changes in self-reported and objectively assessed physical function and physical activity, dietary behavior, body composition, muscular strength, and quality of life. Outcomes will be obtained at baseline, 2-month, and 3-month assessments by trial personnel blinded to participants' randomization assignment. Findings from this study will establish the feasibility and preliminary efficacy of an innovative lifestyle intervention designed to promote progressively independent self-regulated exercise and dietary behavior change in the treatment of patients with prostate cancer undergoing ADT. ClinicalTrials.gov NCT02050906.

MEF2‑activated long non‑coding RNA PCGEM1 promotes cell proliferation in hormone‑refractory prostate cancer through downregulation of miR‑148a.

PubMed

Zhang, Shibao; Li, Zongwu; Zhang, Longyang; Xu, Zhonghua

2018-05-04

Prostate cancer gene expression marker 1 (PCGEM1) is a prostate‑specific gene overexpressed in prostate cancer cells that promotes cell proliferation. To study the molecular mechanism of PCGEM1 function in hormone‑refractory prostate cancer, the interaction between myocyte enhancer factor 2 (MEF2) and PCGEM1 was assessed by a luciferase reporter assay and chromatin immunoprecipitation (ChIP) assay. In addition, the underlying mechanism of PCGEM1 regulating expression of microRNA (miR)‑148a in PC3 prostate cancer cells was evaluated. Relative expression levels were measured by reverse transcription‑quantitative polymerase chain reaction, and early apoptosis was measured by flow cytometry. PCGEM1 was demonstrated to be overexpressed in prostate cancer tissues compared with noncancerous tissues. Expression levels of PCGEM1 in PC3 cancer cells were demonstrated to be regulated by MEF2, as PCGME1 mRNA was increased by MEF2 overexpression but decreased by MEF2 silencing. MEF2 was also demonstrated to enhance the activity of PCGEM1 promoter and thus promote PCGEM1 transcription. In addition, downregulation of PCGEM1 expression in PC3 cells increased expression of miR‑148a. By contrast, overexpression of PCGEM1 decreased miR‑148a expression. Finally, PCGME1 silencing by small interfering RNA significantly induced early cell apoptosis but this effect was reduced by a miR‑148a inhibitor. In conclusion, the present study demonstrated a positive regulatory association between MEF2 and PCGEM1, and a reciprocal negative regulatory association between PCGEM1 and miR‑148a that controls cell apoptosis. The present study, therefore, provides new insights into the mechanism of PCGEM1 function in prostate cancer development.

Visual Local and Global Processing in Low-Functioning Deaf Individuals with and without Autism Spectrum Disorder

ERIC Educational Resources Information Center

Maljaars, J. P. W.; Noens, I. L. J.; Scholte, E. M.; Verpoorten, R. A. W.; van Berckelaer-Onnes, I. A.

2011-01-01

Background: The ComFor study has indicated that individuals with intellectual disability (ID) and autism spectrum disorder (ASD) show enhanced visual local processing compared with individuals with ID only. Items of the ComFor with meaningless materials provided the best discrimination between the two samples. These results can be explained by the…

Iron Deficiency Is a Determinant of Functional Capacity and Health-related Quality of Life 30 Days After an Acute Coronary Syndrome.

PubMed

Meroño, Oona; Cladellas, Mercè; Ribas-Barquet, Núria; Poveda, Paula; Recasens, Lluis; Bazán, Víctor; García-García, Cosme; Ivern, Consol; Enjuanes, Cristina; Orient, Salvador; Vila, Joan; Comín-Colet, Josep

2017-05-01

Iron deficiency (ID) is a prevalent condition in patients with ischemic heart disease and heart failure. Little is known about the impact of ID on exercise capacity and quality of life (QoL) in the recovery phase after an acute coronary syndrome (ACS). Iron status and its impact on exercise capacity and QoL were prospectively evaluated in 244 patients 30 days after the ACS. QoL was assessed by the standard EuroQoL-5 dimensions, EuroQoL visual analogue scale, and Heart-QoL questionnaires. Exercise capacity was analyzed by treadmill/6-minute walk tests. The effect of ID on cardiovascular mortality and readmission rate was also investigated. A total of 46% of the patients had ID. These patients had lower exercise times (366±162 vs 462±155seconds; P<.001), metabolic consumption rates (7.9±2.9 vs 9.3±2.6 METS; P=.003), and EuroQoL-5 dimensions (0.76±0.25 vs 0.84±0.16), visual analogue scale (66±16 vs 72±17), and Heart-QoL (1.9±0.6 vs 2.2±0.6) scores (P<.05). ID independently predicted lower exercise times (OR, 2.9; 95%CI, 1.1-7.6; P=.023) and worse QoL (OR, 1.9; 95%CI, 1.1-3.3; P<.001) but had no effect on cardiovascular morbidity or mortality. ID, a prevalent condition in ACS patients, results in a poorer mid-term functional recovery, as measured by exercise capacity and QoL. Copyright © 2016 Sociedad Española de Cardiología. Published by Elsevier España, S.L.U. All rights reserved.

Mechanosensitive Gene Regulation by Myocardin-Related Transcription Factors is Required for Cardiomyocyte Integrity in Load-Induced Ventricular Hypertrophy.

PubMed

Trembley, Michael A; Quijada, Pearl; Agullo-Pascual, Esperanza; Tylock, Kevin M; Colpan, Mert; Dirkx, Ronald A; Myers, Jason R; Mickelsen, Deanne M; de Mesy Bentley, Karen; Rothenberg, Eli; Moravec, Christine S; Alexis, Jeffrey D; Gregorio, Carol C; Dirksen, Robert T; Delmar, Mario; Small, Eric M

2018-05-01

Background -Hypertrophic cardiomyocyte (CM) growth and dysfunction accompanies various forms of heart disease. The mechanisms responsible for transcriptional changes that impact cardiac physiology and the transition to heart failure (HF) are not well understood. The intercalated disc (ID) is a specialized intercellular junction coupling CM electrical activity and force transmission, and is gaining attention as a mechanosensitive signaling hub and hotspot for causative mutations in cardiomyopathy. Methods -Transmission electron microscopy, confocal microscopy, and single-molecule localization microscopy (SMLM) were used to examine changes in ID structure and protein localization in the murine and human heart. We conducted detailed cardiac functional assessment and transcriptional profiling of mice lacking myocardin-related transcription factor-A (MRTF-A) and -B specifically in adult CMs to evaluate the role of mechanosensitive regulation of gene expression in load-induced ventricular remodeling. Results -We found that MRTFs localize to IDs in the healthy human heart and accumulate in the nucleus in heart failure (HF). Although mice lacking MRTFs in adult CMs display normal cardiac physiology at baseline, pressure overload leads to rapid HF characterized by sarcomere disarray, ID disintegration, chamber dilation and wall thinning, cardiac functional decline, and partially penetrant acute lethality. Transcriptional profiling reveals a program of actin cytoskeleton and CM adhesion genes driven by MRTFs during pressure overload. Indeed, conspicuous remodeling of gap junctions at IDs identified by SMLM may partially stem from a reduction in Mapre1 expression, which we show is a direct mechanosensitive MRTF target. Conclusions -Taken together, our study describes a novel paradigm in which MRTFs control an acute mechanosensitive signaling circuit that coordinates crosstalk between the actin and microtubule cytoskeleton and maintains ID integrity and CM homeostasis in heart disease.

Id2 Complexes with the SNAG Domain of Snai1 Inhibiting Snai1-Mediated Repression of Integrin β4

PubMed Central

Chang, Cheng; Yang, Xiaofang; Pursell, Bryan

2013-01-01

The epithelial-mesenchymal transition (EMT) is a fundamental process that underlies development and cancer. Although the EMT involves alterations in the expression of specific integrins that mediate stable adhesion to the basement membrane, such as α6β4, the mechanisms involved are poorly understood. Here, we report that Snai1 inhibits β4 transcription by increasing repressive histone modification (trimethylation of histone H3 at K27 [H3K27Me3]). Surprisingly, Snai1 is expressed and localized in the nucleus in epithelial cells, but it does not repress β4. We resolved this paradox by discovering that Id2 complexes with the SNAG domain of Snai1 on the β4 promoter and constrains the repressive function of Snai1. Disruption of the complex by depleting Id2 resulted in Snai1-mediated β4 repression with a concomitant increase in H3K27Me3 modification on the β4 promoter. These findings establish a novel function for Id2 in regulating Snai1 that has significant implications for the regulation of epithelial gene expression. PMID:23878399

Effects of the natural flavonoid delphinidin on diabetic microangiopathy.

PubMed

Bertuglia, S; Malandrino, S; Colantuoni, A

1995-04-01

The purpose of the present study was to investigate the effects of the flavonoid delphinidin chloride (CAS 528-53-0, IdB 1056) on diabetic microangiopathy. Hamsters were injected with alloxan and cheek pouch microcirculation was observed by a fluorescent microscopy technique 90 days from alloxan. The increase in permeability, the number of adhering leukocytes to venular vessel wall and vasodilatory responses to acetylcholine (Ach) and sodium nitroprusside (SNP) were measured. In diabetic group microvascular permeability and the number of sticking leukocytes to the venular endothelium were increased. Vasoconstriction by Ach was observed while the vasodilation by SNP was significantly attenuated in diabetic animals. These results are consistent for a decreased relaxation and suggest also an impairment in the smooth muscle cell function in diabetic arterioles. IdB 1056 exhibited an inhibitory effect on increased microvascular permeability and on leukocytes adhering to the venular vessels. Indeed, the treatment with IdB 1056 in diabetic hamsters pretreated or not with indometacin, a cyclooxygenase inhibitor, restored the relaxant responses to Ach and SNP. In conclusion, the effects of IdB 1056 observed in vivo at the microcirculatory level prevent the injury to endothelial cell function associated with diabetes and/or oxidative stress.

Inductive learning of thyroid functional states using the ID3 algorithm. The effect of poor examples on the learning result.

PubMed

Forsström, J

1992-01-01

The ID3 algorithm for inductive learning was tested using preclassified material for patients suspected to have a thyroid illness. Classification followed a rule-based expert system for the diagnosis of thyroid function. Thus, the knowledge to be learned was limited to the rules existing in the knowledge base of that expert system. The learning capability of the ID3 algorithm was tested with an unselected learning material (with some inherent missing data) and with a selected learning material (no missing data). The selected learning material was a subgroup which formed a part of the unselected learning material. When the number of learning cases was increased, the accuracy of the program improved. When the learning material was large enough, an increase in the learning material did not improve the results further. A better learning result was achieved with the selected learning material not including missing data as compared to unselected learning material. With this material we demonstrate a weakness in the ID3 algorithm: it can not find available information from good example cases if we add poor examples to the data.

Mobile Phone Apps for Quality of Life and Well-Being Assessment in Breast and Prostate Cancer Patients: Systematic Review

PubMed Central

Rivera-Romero, Octavio; Dorronzoro-Zubiete, Enrique; Sanchez-Bocanegra, Carlos Luis; Gabarron, Elia

2017-01-01

Background Mobile phone health apps are increasingly gaining attention in oncological care as potential tools for supporting cancer patients. Although the number of publications and health apps focusing on cancer is increasing, there are still few specifically designed for the most prevalent cancers diagnosed: breast and prostate cancers. There is a need to review the effect of these apps on breast and prostate cancer patients’ quality of life (QoL) and well-being. Objective The purposes of this study were to review the scientific literature on mobile phone apps targeting breast or prostate cancer patients and involving QoL and well-being (anxiety and depression symptoms) and analyze the clinical and technological characteristics, strengths, and weaknesses of these apps, as well as patients’ user experience with them. Methods We conducted a systematic review of peer-reviewed literature from The Cochrane Library, Excerpta Medica Database, PsycINFO, PubMed, Scopus, and MEDLINE to identify studies involving apps focused on breast and/or prostate cancer patients and QoL and/or well-being published between January 1, 2000, and July 12, 2017. Only trial studies which met the inclusion criteria were selected. The systematic review was completed with a critical analysis of the apps previously identified in the health literature research that were available from the official app stores. Results The systematic review of the literature yielded 3862 articles. After removal of duplicates, 3229 remained and were evaluated on the basis of title and abstract. Of these, 3211 were discarded as not meeting the inclusion criteria, and 18 records were selected for full text screening. Finally, 5 citations were included in this review, with a total of 644 patients, mean age 52.16 years. Four studies targeted breast cancer patients and 1 focused on prostate cancer patients. Four studies referred to apps that assessed QoL. Only 1 among the 5 analyzed apps was available from the official app store. In 3 studies, an app-related intervention was carried out, and 2 of them reported an improvement on QoL. The lengths of the app-related interventions varied from 4 to 12 weeks. Because 2 of the studies only tracked use of the app, no effect on QoL or well-being was found. Conclusions Despite the existence of hundreds of studies involving cancer-focused mobile phone apps, there is a lack of rigorous trials regarding the QoL and/or well-being assessment in breast and/or prostate cancer patients. A strong and collective effort should be made by all health care providers to determine those cancer-focused apps that effectively represent useful, accurate, and reliable tools for cancer patients’ disease management. Trial Registration PROSPERO CRD42017073069; https://www.crd.york.ac.uk/PROSPERO/display_record.asp?ID= CRD42017073069 (Archived by WebCite at http://www.webcitation.org/6v38Clb9T) PMID:29203459

Long-term efficacy of Serenoa repens treatment in patients with mild and moderate symptomatic benign prostatic hyperplasia.

PubMed

Sinescu, Ioanel; Geavlete, Petrisor; Multescu, Razvan; Gangu, Constantin; Miclea, Florin; Coman, Ioan; Ioiart, Ioan; Ambert, Valentin; Constantin, Traian; Petrut, Bogdan; Feciche, Bogdan

2011-01-01

The study aimed to evaluate the long-term efficacy of treatment with extract of Serenoa repens (Prostamol Uno) in patients with lower urinary tract symptoms (LUTS) induced by benign prostatic hyperplasia (BPH). We studied 120 patients with mild or moderate LUTS induced by BPH, maximal urinary flow (Q(max)) <15 ml with a voided volume ≥150 ml, prostate-specific antigen <4 ng/ml, and residual urinary volume <150 ml, treated daily for 24 months with one capsule of 320 mg ethanolic extract of Serenoa repens. Statistically significant improvements in the International Prostate Symptom Score (5.5 points), quality of life (QoL; 1.8 points), Q(max) (5.6 ml/s), International Index of Erectile Function (IIEF; 6.4 points) and reduction in residual urinary volume were observed during the study period. The mean prostate volume at 24 months was 36 ml, compared to 39.8 ml at baseline. Long-term treatment with 320 mg ethanolic extract of Serenoa repens proved to be efficient in reducing urinary obstruction, improving symptomatology and QoL of BPH patients. It also had a positive effect on sexual function, demonstrated by the statistically significant increase in the IIEF. Copyright © 2011 S. Karger AG, Basel.

Estrogen related receptor alpha in castration-resistant prostate cancer cells promotes tumor progression in bone

PubMed Central

Delliaux, Carine; Gervais, Manon; Kan, Casina; Benetollo, Claire; Pantano, Francesco; Vargas, Geoffrey; Bouazza, Lamia; Croset, Martine; Bala, Yohann; Leroy, Xavier; Rosol, Thomas J; Rieusset, Jennifer; Bellahcène, Akeila; Castronovo, Vincent; Aubin, Jane E; Clézardin, Philippe; Duterque-Coquillaud, Martine; Bonnelye, Edith

2016-01-01

Bone metastases are one of the main complications of prostate cancer and they are incurable. We investigated whether and how estrogen receptor-related receptor alpha (ERRα) is involved in bone tumor progression associated with advanced prostate cancer. By meta-analysis, we first found that ERRα expression is correlated with castration-resistant prostate cancer (CRPC), the hallmark of progressive disease. We then analyzed tumor cell progression and the associated signaling pathways in gain-of-function/loss-of-function CRPC models in vivo and in vitro. Increased levels of ERRα in tumor cells led to rapid tumor progression, with both bone destruction and formation, and direct impacts on osteoclasts and osteoblasts. VEGF-A, WNT5A and TGFβ1 were upregulated by ERRα in tumor cells and all of these factors also significantly and positively correlated with ERRα expression in CRPC patient specimens. Finally, high levels of ERRα in tumor cells stimulated the pro-metastatic factor periostin expression in the stroma, suggesting that ERRα regulates the tumor stromal cell microenvironment to enhance tumor progression. Taken together, our data demonstrate that ERRα is a regulator of CRPC cell progression in bone. Therefore, inhibiting ERRα may constitute a new therapeutic strategy for prostate cancer skeletal-related events. PMID:27776343

Bone marrow adipocytes promote tumor growth in bone via FABP4-dependent mechanisms.

PubMed

Herroon, Mackenzie K; Rajagurubandara, Erandi; Hardaway, Aimalie L; Powell, Katelyn; Turchick, Audrey; Feldmann, Daniel; Podgorski, Izabela

2013-11-01

Incidence of skeletal metastases and death from prostate cancer greatly increases with age and obesity, conditions which increase marrow adiposity. Bone marrow adipocytes are metabolically active components of bone metastatic niche that modulate the function of neighboring cells; yet the mechanisms of their involvement in tumor behavior in bone have not been explored. In this study, using experimental models of intraosseous tumor growth and diet-induced obesity, we demonstrate the promoting effects of marrow fat on growth and progression of skeletal prostate tumors. We reveal that exposure to lipids supplied by marrow adipocytes induces expression of lipid chaperone FABP4, pro-inflammatory interleukin IL-1β, and oxidative stress protein HMOX-1 in metastatic tumor cells and stimulates their growth and invasiveness. We show that FABP4 is highly overexpressed in prostate skeletal tumors from obese mice and in bone metastasis samples from prostate cancer patients. In addition, we provide results suggestive of bi-directional interaction between FABP4 and PPARγ pathways that may be driving aggressive tumor cell behavior in bone. Together, our data provide evidence for functional relationship between bone marrow adiposity and metastatic prostate cancers and unravel the FABP4/IL-1β axis as a potential therapeutic target for this presently incurable disease.

Bone marrow adipocytes promote tumor growth in bone via FABP4-dependent mechanisms

PubMed Central

Herroon, Mackenzie K.; Rajagurubandara, Erandi; Hardaway, Aimalie L.; Powell, Katelyn; Turchick, Audrey; Feldmann, Daniel; Podgorski, Izabela

2013-01-01

Incidence of skeletal metastases and death from prostate cancer greatly increases with age and obesity, conditions which increase marrow adiposity. Bone marrow adipocytes are metabolically active components of bone metastatic niche that modulate the function of neighboring cells; yet the mechanisms of their involvement in tumor behavior in bone have not been explored. In this study, using experimental models of intraosseous tumor growth and diet-induced obesity, we demonstrate the promoting effects of marrow fat on growth and progression of skeletal prostate tumors. We reveal that exposure to lipids supplied by marrow adipocytes induces expression of lipid chaperone FABP4, pro-inflammatory interleukin IL-1β, and oxidative stress protein HMOX-1 in metastatic tumor cells and stimulates their growth and invasiveness. We show that FABP4 is highly overexpressed in prostate skeletal tumors from obese mice and in bone metastasis samples from prostate cancer patients. In addition, we provide results suggestive of bi-directional interaction between FABP4 and PPARγ pathways that may be driving aggressive tumor cell behavior in bone. Together, our data provide evidence for functional relationship between bone marrow adiposity and metastatic prostate cancers and unravel the FABP4/IL-1β axis as a potential therapeutic target for this presently incurable disease. PMID:24240026

DD angiotensin-converting enzyme gene polymorphism is associated with endothelial dysfunction in normal humans.

PubMed

Butler, R; Morris, A D; Burchell, B; Struthers, A D

1999-05-01

A polymorphism within the angiotensin-converting enzyme (ACE) gene may increase the risk of myocardial infarction in individuals previously thought to be at low cardiovascular risk. The mechanism through which it exerts this effect is unknown but may be due to increased angiotensin II-induced nitric oxide (NO) breakdown and/or reduced bradykinin-mediated NO release. We investigated whether endothelial function was different between different ACE genotypes. We performed a cross-sectional study comparing the endothelial function of the 3 genotypes (II: n=25; ID: n=31; DD: n=12). Mean+/-SD ages of the subjects were 24+/-4 (II), 25+/-6 (ID), and 25+/-6 (DD) years. We assessed the impact of the genotypes on endothelial function and found that the DD genotype was associated with a significant blunting in endothelial-dependent vasodilatation (forearm blood flow data are presented as mean+/-SD ratio of blood flow in response to 3 incrementally increasing doses of each vasoactive agent in the test arm to blood flow in the control arm; the comparison is between DD versus ID versus II; the P value is an expression of an overall difference by ANOVA, and the 95% CIs are of a pairwise comparison between genotypes): acetylcholine, 2.88+/-1.45 versus 3.81+/-1.93 versus 4.23+/-2.37 (P=0.002; 95% CI [II versus ID], -0.19 to 0.91; 95% CI [II versus DD], 0.36 to 1.80; 95% CI [ID versus DD], 0.02 to 1.42). There was also a significant difference with the endothelial-independent vasodilator sodium nitroprusside, with values of 2.11+/-1.00 versus 2.55+/-1.36 versus 2.75+/-1.18 (P<0.05; 95% CI [II versus ID], -0.15 to 0.51; 95% CI [II versus DD], 0.03 to 0.89; 95% CI [ID versus DD], -0.13 to 0.71), but not with verapamil. There was no effect of the ACE genotype on endothelial-dependent or -independent vasoconstrictors NG-monomethyl-L-arginine or norepinephrine. Investigating the effects of cigarette smoking on each genotype demonstrated that for II and DD genotypes, acetylcholine responses were further blunted if subjects smoked. These data demonstrate that the DD ACE genotype in a young population is associated with a blunting of stimulated endothelial NO and donated NO responses but not to non-NO vasodilators or vasoconstrictors.

14-3-3 Proteins Modulate the ETS Transcription Factor ETV1 in Prostate Cancer

PubMed Central

Oh, Sangphil; Shin, Sook; Lightfoot, Stan A.; Janknecht, Ralf

2013-01-01

Overexpression of the ETS-related transcription factor ETV1 can initiate neoplastic transformation of the prostate. ETV1 activity is highly regulated by phosphorylation, but the underlying mechanisms are unknown. Here we report that all 14-3-3 proteins, with the exception of the tumor suppressor 14-3-3σ, can bind to ETV1 in a condition manner dictated by its prominent phosphorylation site S216. All non-σ 14-3-3 proteins synergized with ETV1 to activate transcription of its target genes MMP-1 and MMP-7, which regulate extracellular matrix in the prostate tumor microenvironment. S216 mutation or 14-3-3τ downregulation was sufficient to reduce ETV1 protein levels in prostate cancer cells, indicating that non-σ 14-3-3 proteins protect ETV1 from degradation. Notably, S216 mutation also decreased ETV1-dependent migration and invasion in benign prostate cells. Downregulation of 14-3-3τ reduced prostate cancer cell invasion and growth in the same manner as ETV1 attenuation. Lastly, we showed that 14-3-3τ and 14-3-3ε were overexpressed in human prostate tumors. Taken together, our results demonstrated that non-σ 14-3-3 proteins are important modulators of ETV1 function that promote prostate tumorigenesis. PMID:23774214

Adenomatous-Dominant Benign Prostatic Hyperplasia (AdBPH) as a Predictor for Clinical Success Following Prostate Artery Embolization: An Age-Matched Case–Control Study

DOE Office of Scientific and Technical Information (OSTI.GOV)

Little, M. W., E-mail: m.little@doctors.org.uk; Boardman, P.; Macdonald, A. C.

PurposeTo investigate the clinical impact of performing prostate artery embolization (PAE) on patients with adenomatous-dominant benign prostatic hyperplasia (AdBPH).Materials and MethodsTwelve patients from the ongoing proSTatic aRtery EmbolizAtion for the treatMent of benign prostatic hyperplasia (STREAM) trial were identified as having AdBPH; defined as two or more adenomas within the central gland of ≥1 cm diameter on multi-parametric MRI (MP-MRI). These patients were age-matched with patients from the STREAM cohort, without AdBPH. Patients were followed up with repeat MP-MRI at 3 months and 1 year. International prostate symptom score (IPSS), international index for erectile function (IIEF), and quality of life assessment from themore » IPSS and EQ-5D-5S questionnaires were recorded pre-PAE and at 6 weeks, 3 months, and 1 year.ResultsThe mean age of patients was 68 (61–76). All patients had PAE as a day-case procedure. The technical success in the cohort was 23/24 (96%). There was a significant reduction in prostate volume following embolization with a median reduction of 34% (30–55) in the AdBPH group, compared to a mean volume reduction of 22% (9–44) in the non-AdBPH group (p = 0.04). There was a significant reduction in IPSS in the AdBPH group following PAE when compared with the control group [AdBPH median IPSS 8 (3–15) vs. non-AdBPH median IPSS 13 (8–18), p = 0.01]. IPSS QOL scores significantly improved in the AdBPH group (p = 0.007). There was no deterioration in sexual function in either group post-PAE.ConclusionsThis is the first time that AdBPH has been identified as being a predictor of clinical success following PAE.« less

Optimization and comprehensive characterization of a faithful tissue culture model of the benign and malignant human prostate.

PubMed

Maund, Sophia Lisette; Nolley, Rosalie; Peehl, Donna Mae

2014-02-01

Few preclinical models accurately depict normal human prostate tissue or primary prostate cancer (PCa). In vitro systems typically lack complex cellular interactions among structured prostatic epithelia and a stromal microenvironment, and genetic and molecular fidelity are concerns in both in vitro and in vivo models. 'Tissue slice cultures' (TSCs) provide realistic preclinical models of diverse tissues and organs, but have not been fully developed or widely utilized for prostate studies. Problems encountered include degeneration of differentiated secretory cells, basal cell hyperplasia, and poor survival of PCa. Here, we optimized, characterized, and applied a TSC model of primary human PCa and benign prostate tissue that overcomes many deficiencies of current in vitro models. Tissue cores from fresh prostatectomy specimens were precision-cut at 300 μm and incubated in a rotary culture apparatus. The ability of varied culture conditions to faithfully maintain benign and cancer cell and tissue structure and function over time was evaluated by immunohistological and biochemical assays. After optimization of the culture system, molecular and cellular responses to androgen ablation and to piperlongumine (PL), purported to specifically reduce androgen signaling in PCa, were investigated. Optimized culture conditions successfully maintained the structural and functional fidelity of both benign and PCa TSCs for 5 days. TSCs exhibited androgen dependence, appropriately undergoing ductal degeneration, reduced proliferation, and decreased prostate-specific antigen expression upon androgen ablation. Further, TSCs revealed cancer-specific reduction of androgen receptor and increased apoptosis upon treatment with PL, validating data from cell lines. We demonstrate a TSC model that authentically recapitulates the structural, cellular, and genetic characteristics of the benign and malignant human prostate, androgen dependence of the native tissue, and cancer-specific response to a potentially new therapeutic for PCa. The work described herein provides a basis for advancing the experimental utility of the TSC model.

Diode laser (980 nm) vaporization in comparison with transurethral resection of the prostate for benign prostatic hyperplasia: randomized clinical trial with 2-year follow-up.

PubMed

Razzaghi, Mohammad Reza; Mazloomfard, Mohammad Mohsen; Mokhtarpour, Hooman; Moeini, Aida

2014-09-01

To compare outcomes of diode laser vaporization of prostate with transurethral resection of the prostate (TURP) as a gold-standard treatment. A total number of 115 patients with benign prostatic hyperplasia underwent TURP and 980-nm diode vaporization of prostate in a balanced randomization (1:1) from 2010 to 2012 and were followed up for 24 months. Baseline characteristics of the patients, perioperative data, and postoperative outcomes were compared. The primary end point of the study was assessing the values of International Prostate Symptom Score (IPSS), and maximum flow rate (Qmax) to predict the functional improvement of each group. The trial is registered at http://www.irct.ir (number IRCT201202138146N3). The mean age (± standard deviation) of the patients was 68.2 ± 7.8 years in TURP and 68.5 ± 8.8 in diode groups. In TURP and diode groups, the operation time was 54.9 ± 15.3 vs 60.6 ± 22.6 minutes (P = .14), Foley catheterization time was 88.9 ± 22.5 vs 20.1 ± 4.6 hours (P = .0001) and postoperative hospital stay was 59.9 ± 14.4 vs 25.8 ± 9.2 hours (P = .0001) respectively. Outcome with regard to increase in Qmax, decrease in IPSS, and decrease in postvoid residual urine volume showed a dramatic improvement in both groups during the first 6 months. In the TURP group, the values of IPSS and Qmax were respectively lower and higher than diode patients at 12 and 24 months of follow-up. According to our study, diode laser vaporization (980 nm) offers a safe and feasible procedure in the management of patients with symptomatic benign prostatic hypertrophy; however, at longer follow-up the functional outcome of diode laser vaporization has been less efficient than TURP. Copyright © 2014 Elsevier Inc. All rights reserved.

Compact CdZnTe-based gamma camera for prostate cancer imaging

NASA Astrophysics Data System (ADS)

Cui, Yonggang; Lall, Terry; Tsui, Benjamin; Yu, Jianhua; Mahler, George; Bolotnikov, Aleksey; Vaska, Paul; De Geronimo, Gianluigi; O'Connor, Paul; Meinken, George; Joyal, John; Barrett, John; Camarda, Giuseppe; Hossain, Anwar; Kim, Ki Hyun; Yang, Ge; Pomper, Marty; Cho, Steve; Weisman, Ken; Seo, Youngho; Babich, John; LaFrance, Norman; James, Ralph B.

2011-06-01

In this paper, we discuss the design of a compact gamma camera for high-resolution prostate cancer imaging using Cadmium Zinc Telluride (CdZnTe or CZT) radiation detectors. Prostate cancer is a common disease in men. Nowadays, a blood test measuring the level of prostate specific antigen (PSA) is widely used for screening for the disease in males over 50, followed by (ultrasound) imaging-guided biopsy. However, PSA tests have a high falsepositive rate and ultrasound-guided biopsy has a high likelihood of missing small cancerous tissues. Commercial methods of nuclear medical imaging, e.g. PET and SPECT, can functionally image the organs, and potentially find cancer tissues at early stages, but their applications in diagnosing prostate cancer has been limited by the smallness of the prostate gland and the long working distance between the organ and the detectors comprising these imaging systems. CZT is a semiconductor material with wide band-gap and relatively high electron mobility, and thus can operate at room temperature without additional cooling. CZT detectors are photon-electron direct-conversion devices, thus offering high energy-resolution in detecting gamma rays, enabling energy-resolved imaging, and reducing the background of Compton-scattering events. In addition, CZT material has high stopping power for gamma rays; for medical imaging, a few-mm-thick CZT material provides adequate detection efficiency for many SPECT radiotracers. Because of these advantages, CZT detectors are becoming popular for several SPECT medical-imaging applications. Most recently, we designed a compact gamma camera using CZT detectors coupled to an application-specific-integratedcircuit (ASIC). This camera functions as a trans-rectal probe to image the prostate gland from a distance of only 1-5 cm, thus offering higher detection efficiency and higher spatial resolution. Hence, it potentially can detect prostate cancers at their early stages. The performance tests of this camera have been completed. The results show better than 6-mm resolution at a distance of 1 cm. Details of the test results are discussed in this paper.

Protein arginine methyltransferase 5 functions as an epigenetic activator of the androgen receptor to promote prostate cancer cell growth.

PubMed

Deng, X; Shao, G; Zhang, H-T; Li, C; Zhang, D; Cheng, L; Elzey, B D; Pili, R; Ratliff, T L; Huang, J; Hu, C-D

2017-03-02

Protein arginine methyltransferase 5 (PRMT5) is an emerging epigenetic enzyme that mainly represses transcription of target genes via symmetric dimethylation of arginine residues on histones H4R3, H3R8 and H2AR3. Accumulating evidence suggests that PRMT5 may function as an oncogene to drive cancer cell growth by epigenetic inactivation of several tumor suppressors. Here, we provide evidence that PRMT5 promotes prostate cancer cell growth by epigenetically activating transcription of the androgen receptor (AR) in prostate cancer cells. Knockdown of PRMT5 or inhibition of PRMT5 by a specific inhibitor reduces the expression of AR and suppresses the growth of multiple AR-positive, but not AR-negative, prostate cancer cells. Significantly, knockdown of PRMT5 in AR-positive LNCaP cells completely suppresses the growth of xenograft tumors in mice. Molecular analysis reveals that PRMT5 binds to the proximal promoter region of the AR gene and contributes mainly to the enriched symmetric dimethylation of H4R3 in the same region. Mechanistically, PRMT5 is recruited to the AR promoter by its interaction with Sp1, the major transcription factor responsible for AR transcription, and forms a complex with Brg1, an ATP-dependent chromatin remodeler, on the proximal promoter region of the AR gene. Furthermore, PRMT5 expression in prostate cancer tissues is significantly higher than that in benign prostatic hyperplasia tissues, and PRMT5 expression correlates positively with AR expression at both the protein and mRNA levels. Taken together, our results identify PRMT5 as a novel epigenetic activator of AR in prostate cancer. Given that inhibiting AR transcriptional activity or androgen synthesis remains the major mechanism of action for most existing anti-androgen agents, our findings also raise an interesting possibility that targeting PRMT5 may represent a novel approach for prostate cancer treatment by eliminating AR expression.