Investigators and participants were masked to treatment assignment. The primary endpoint was change in NT-proBNP, a marker of left ventricular wall stress, from baseline to 12 weeks; analysis included all patients randomly assigned to treatment groups who had a baseline and at least one postbaseline assessment.

This trial is registered at Clinicaltrials.gov, number NCT00887588.

Findings 149 patients were randomly assigned to LCZ696 and 152 to valsartan; 134 in the LCZ696 group and 132 in the valsartan group were included in analysis of the primary endpoint. NT-proBNP was significantly reduced at 12 weeks in the LCZ696 group compared with the valsartan group (LCZ696: baseline, 783 Daporinad pg/mL [95% CI 670-914], 12 weeks, 605 pg/mL [512-714]; valsartan: baseline, 862 pg/mL [733-1012], 12 weeks, 3-deazaneplanocin A price 835 [710-981]; ratio LCZ696/valsartan, 0.77, 95% CI 0.64-0.92, p=0.005). LCZ696 was well tolerated with adverse effects similar to those of valsartan; 22 patients (15%) on LCZ696 and 30 (20%) on valsartan had one or more serious adverse event.

Interpretation In patients with heart failure with preserved ejection fraction, LCZ696 reduced NT-proBNP to a greater extent than did valsartan at 12

weeks and was well tolerated. Whether these effects would translate into improved outcomes needs to be tested prospectively.”
“Reactive oxygen species (ROS) are believed to be involved in many forms of neurodegeneration, including ischaemic infarct damage and Alzheimer’s disease. Despite the known involvement of p38 and JNK MAP kinases in mediating apoptosis and cell death in a variety of cell types, the details of the signalling pathways activated in neuronal cells by ROS are poorly characterised. Recently TAK1 (MAP3K7), a kinase upstream of JNK and p38, has attracted attention as a possible mediator of ischaemic cell death. This study tested the hypothesis that hydrogen

peroxide (H2O2), which produces ROS, induces apoptosis in the NG108-15 neuronal cell line via activation of either TAXI or the related kinase ASK1 (MAP3K5). H2O2 caused a concentration-dependent reduction in cell viability associated with caspase 3 activation. Loss of cell viability was inhibited by a selective caspase 3 inhibitor, and by the p38 inhibitor SB203580, this website but was not affected by the JNK inhibitor SP600125. The selective TAK1 inhibitor 5Z-7-oxozeaenol (5Z-7) exacerbated the loss of cell viability, whereas the ASK1 inhibitor NQDI-1 completely prevented caspase activation and cell death. These results show that pharmacological inhibition of ASK1 is neuroprotective, implicating an ASK1-p38 signalling pathway in ROS-induced apoptosis in neurones. The results also imply that the role of TAK1 may be neuroprotective rather than pro-degenerative. (C) 2013 Elsevier Ireland Ltd. All rights reserved.”
“Objectives Several studies have suggested insulin resistance related to dyslipidemia and body weight in drug treated schizophrenia patients.

In addition, a history of chronic or traumatic stress exposure is a predisposing risk factor. We have developed a Chronic plus Acute Prolonged

Stress (CAPS) treatment for rats that models some of the characteristics of stressful events that can lead to PTSD in humans. We have previously shown that CAPS enhances acute fear responses and impairs selleck kinase inhibitor extinction of conditioned fear. Further, CAPS reduced the expression of glucocorticoid receptors in the medial prefrontal cortex. In this study we examined the effects of CAPS exposure on behavioral stress coping style, anxiety-like behaviors, and acute stress reactivity of the hypothalamic pituitary adrenal (HPA) axis. Male Sprague-Dawley rats were exposed to CAPS treatment, consisting of chronic intermittent cold stress (4 degrees C, 6 h/day, 14,days) followed on day 15 by a single 1-h session of sequential acute stressors (social defeat, immobilization, swim). After

CAPS or control treatment, different groups were tested for shock probe defensive burying, novelty Selleckchem Copanlisib suppressed feeding, or evoked activation of adrenocorticotropic hormone (ACTH) and corticosterone release by an acute immobilization stress. CAPS resulted in a decrease in active burying behavior and an increase in immobility in the shock probe test. Further. CAPS-treated rats displayed increases in the latency to feed in the novelty suppressed feeding test, despite an increase in food intake in the home cage. CAPS treatment also reduced the HPA response to a subsequent acute immobilization stress. These results further validate CAPS treatment as a rat model of relevance to PTSD, and together with results reported previously, suggest that CAPS impairs fear extinction, shifts coping behavior from an active to a more passive strategy, increases anxiety, and alters HPA reactivity, resembling many aspects of human PTSD. (C) 2012 Elsevier PCI-34051 research buy Ltd. All rights reserved.”
“A medication error is a failure in the treatment process that

leads to, or has the potential to lead to, harm to the patient. Medication errors can occur in deciding which medicine and dosage regimen to use (prescribing faults-irrational, inappropriate, and ineffective prescribing, underprescribing, overprescribing); writing the prescription (prescription errors); manufacturing the formulation (wrong strength, contaminants or adulterants, wrong or misleading packaging); dispensing the formulation (wrong drug, wrong formulation, wrong label); administering or taking the medicine (wrong dose, wrong route, wrong frequency, wrong duration); monitoring therapy (failing to alter therapy when required, erroneous alteration). They can be classified, using a psychological classification of errors, as knowledge-, rule-, action- and memory-based errors. Although medication errors can occasionally be serious, they are not commonly so and are often trivial.

Conclusions: In hemodialysis patients, the fragments NT-proBNP and MR-pro-ANP are largely elevated compared to BNP which is explained by accumulation. The prognostic performance of MR-pro-ANP is similar to that of NT-proBNP or BNP. Copyright (c) 2012 S. Karger AG, Basel”
“Advancements in human genetics now poise the field to illuminate the pathophysiology of complex genetic disease. In particular, genome-wide association studies (GWAS) have generated insights into the mechanisms driving inflammatory bowel disease (IBD) and implicated genes shared by multiple autoimmune and autoinflammatory diseases. Thus, emerging evidence suggests a central

Selleckchem MK-8931 role for the mucosal immune system

in mediating immune homeostasis and highlights the complexity of genetic and environmental interactions that collectively modulate the risk of disease. Nevertheless, the challenge remains to determine how genetic variation can precipitate and sustain the inappropriate inflammatory response to commensals that is observed in IBD. Here, we highlight recent advancements in immunogenetics and provide a forward-looking view of the innovations that will deliver mechanistic insights from human genetics.”
“Methamphetamine (METH) is a new type of drug with strong tolerance and addiction. However, the molecular mechanisms underlying the processes of METH addiction are still not fully understood. DAPT concentration To determine possible biomarkers and mechanisms that are responsible for METH addiction, a 2-DE based proteomics approach was used to evaluate the changes in protein expression of the serum in Chinese patients addicted to METH, which to the best of our knowledge is the first study of its kind. We identified five proteins that were markedly altered and complement factor H (CFH), the most stably up-expressed protein in each 2-DE experiment, was further studied using the rat conditioned place preference (CPP) model to detect any changes

to its expression in the sera and six brain C1GALT1 regions of interest. We report, for the first time, that CFH was positive related to METH addiction. (c) 2012 Elsevier Ireland Ltd. All rights reserved.”
“Ultrasound vocalizations (USVs) at approximately 22 kHz are usual components of the defensive response of rats. However, depending on the neural substrate that is activated, such as the dorsal periaqueductal gray (dPAG), USV emissions may be reduced. Activation of neurokinin-1 (NK-1)-mediated mechanisms of the dPAG causes analgesia, reduced 22 kHz USVs, and anxiogenic-like effects in rats exposed to the elevated plus maze (EPM). Involvement of other types of neurokinin receptors in this activation has not yet been evaluated.

The present study examined whether local injections of the selective NK-3 agonist senktide (1-100 pmol/0.

It is not known, however, if noradrenergic modulatory function is compromised by chronic stress, perhaps contributing to the stress-induced cognitive deficit. Thus, the first study investigated whether acutely elevating noradrenergic activity in mPFC still enhances cognitive function after chronic stress. As previously demonstrated, CUS impaired cognitive set-shifting on the AST.

This deficit was abolished by acute systemic administration of the alpha(2)-adrenergic autoreceptor antagonist, atipamezole. Microdialysis revealed no differences in extracellular norepinephrine (NE) levels in mPFC of CUS-exposed and unstressed control rats at baseline or during behavioral testing, and comparable increases after atipamezole. In the second experiment, rats were treated chronically with the selective NE reuptake MDV3100 ic50 blocker, desipramine, during the CUS treatment through behavioral testing. Again. CUS impaired cognitive set-shifting Verubecestat in vehicle-treated rats, and chronic desipramine treatment prevented

such deficits. Acute blockade of post-synaptic alpha(1)-adrenergic receptors in mPFC prior to testing blocked the beneficial effect of desipramine on cognitive set-shifting. These results suggest that desipramine restores cognitive set-shifting capability that has been compromised by chronic stress by activating alpha(1)-adrenergic receptors in the mPFC. Thus, noradrenergic modulatory capability in mPFC remains intact after CUS, and this represents one possible substrate by which antidepressants may exert their beneficial effects in the treatment

of depression. (C) 2010 Elsevier Inc. All rights reserved.”
“Chronic psychosocial isolation stress (CPSI) modulates glucocorticoid receptor else (GR) functioning in Wistar male rat hippocampus (HIPPO) through alteration of nuclear GR phosphorylation and its upstream kinases signaling, which parallels animal depressive-like behavior. The current study investigated potential gender specificities regarding the effect of chronic therapy by an antidepressant fluoxetine (FLU) on GR signaling in HIPPO and depressive-like behavior in CPSI animals.

FLU was administrated to female and male naive or CPSI rats for 21 days and GR protein, its phosphorylation status and upstream kinases, as well as GR and BDNF mRNA were followed in HIPPO together with animal serum corticosterone (CORT) and depressive-like behavior.

The results showed that CPSI increased immobility in males versus hyperactivity in females and disrupted nuclear pGR232-Cdk5 pathway and JNK signaling in a gender-specific way. In contrast, in both genders CPSI increased the nuclear levels of GR and pGR246 but decreased CORT and mRNA levels of GR and BDNF.

Depression is a common psychiatric disorder affecting individuals across the life span. Although the “”monoamine hypothesis”" of depression has long been proposed, the pathologies and mechanisms for depressive disorders remain only partially understood. Pharmacotherapies targeting the monoaminergic pathways have been the mainstay in treating depression. Additional therapeutic approaches focusing other pathological mechanisms of depression are currently being explored.

Interestingly, a number of proposed mechanisms for depression appear to be similar to those implicated in neurodegenerative diseases, including AD. For example,

diminishing neurotrophic factors and neuroinflammation observed in depression are found to be associated with the development of AD. This article first provides a concise review of AD and depression, PD0332991 cost then discusses the putative links between the two neuropsychiatric conditions. (C) 2010 Elsevier Ltd. All rights

reserved.”
“Purpose: We evaluated the association of the resistive index of the https://www.selleckchem.com/products/XAV-939.html prostate capsular arteries and bladder outlet obstruction severity in men with benign prostatic hyperplasia.

Materials and Methods: A total of 74 patients histologically diagnosed with benign prostatic hyperplasia were ultimately enrolled in this prospective study. Urodynamics were performed by a urologist to determine bladder Plasmin outlet obstruction. Baseline parameters measured in patients with benign prostatic hyperplasia were the prostate capsular artery resistive index, International Prostate Symptom Score, quality of life score, total prostate and transition zone volume, and the transition zone index. ROC curves were produced to

calculate the ROC AUC and evaluate the diagnostic performance of the prostate capsular artery resistive index, International Prostate Symptom Score, obstructive symptoms, total prostate and transition zone volume, and the transition zone index for bladder outlet obstruction.

Results: Significant difference between patients with and without bladder outlet obstruction was observed in the resistive index, which showed the highest coefficient with the degree of obstruction (r = 0.712, p <0.0001). At a cutoff of 0.69 the resistive index distinguished patients with and without bladder outlet obstruction with 78% sensitivity and 86.4% specificity. The prostate capsular artery resistive index had the maximum AUC of 0.823.

Conclusions: The prostate capsular artery resistive index is significantly higher in patients with benign prostatic hyperplasia related bladder outlet obstruction than in those without such obstruction. The resistive index might serve as a novel indicator to diagnose and assess bladder outlet obstruction in patients with benign prostatic hyperplasia.

Methods: SVS-VR on-line provider-reported data include baseline through follow-up visits to better understand long-term risks and benefits associated

with CAS and CEA. The primary outcomes are combined death, stroke, and myocardial infarction (MI). An independent data coordinating center maintains the database, which is Health Insurance Portability and Accountability Act (HIPAA)-compliant and auditable.

Results: As of December 26, 2007, 6403 procedures with discharge data were entered by 287 providers at 56 centers oil 2763 CAS patients ZD1839 ic50 (1450 with 30-day outcomes, 52.5%) and 3259 CEA patients (1368 with 30-day outcomes, 42%). Of the total cohort, 98% of CEA and 70.7% of CAS (P < .001) were performed for atherosclerotic disease. Restenosis accounted for 22.3% and post-radiation induced stenosis in 4.5% of CAS patients. Preprocedure lateralizing neurologic symptoms were present in a greater proportion of CAS patients (49.2%) than CEA patients (42.4%, P < .001). CAS patients also had higher preprocedure prevalence of coronary artery disease (CAD), MI, congestive heart failure (CHF), chronic obstructive pulmonary disease (COPD), and cardiac arrhythmia. For

CAS, death/stroke/MI at 30 days was 7.13% for symptomatic https://www.selleckchem.com/products/Temsirolimus.html patients and 4.60% for asymptomatic patients (P = .04). For CEA, death/stroke/MI at 30 days was 3.75% in symptomatic patients and 1.97% in asymptomatic patients (P = .05). After risk-adjustment for age, history of stroke, diabetes, and American Society of Anesthesiologists (ASA) grade lie, factors found to be significant confounders in outcomes using backwards elimination), logistic regression analysis suggested better outcomes following CEA. There were no statistically significant differences when examining CAS outcomes based on center volume. CAS in atherosclerotic disease had significantly worse outcomes than in nonatherosclerotic stenosis. NADPH-cytochrome-c2 reductase When CAS and CEA were compared in the treatment of atherosclerotic disease

only, the difference in outcomes between the two procedures was more pronounced, with death/stroke/MI 6.42% after CAS vs; 2.62% following CEA, P < .0001.

Conclusion: Following best possible risk adjustment of these unmatched groups, symptomatic and asymptomatic CAS patients had significantly higher 30-day postprocedure incidence of death/stroke/MI when compared with CEA patients. The initial 1.5 years of data collection provide proof of concept that a specialty society based VR can succeed in meeting regulatory and scientific goats. With continued enrollment and follow-up, analysis of SVS-VR will supplement randomized trials by providing real-world comparisons of CAS and CEA with sufficient numbers to serve as an outcome assessment tool of important patient subsets and across the spectrum of peripheral vascular procedures.

A body of work suggests that the

sweat gland plays an important role to determine the cholinergic phenotype at this target site. A key issue is whether neurons destined to innervate the sweat glands express cholinergic markers before or only after their terminals make target contact. We employed cholinergic-specific over-expression of the vesicular acetylcholine transporter (VAChT) in transgenic mice to overcome sensitivity limits in the detection of initial cholinergic sweat gland innervation. We found that VAChT immunoreactive nerve terminals were present around the sweat gland anlage already from the earliest postnatal stages on, coincident selectively at this sympathetic target with tyrosine hydroxylase-positive fibers. Our results provide a new mechanistic model for LB-100 nmr sympathetic neuron-target interaction during development, CUDC-907 with initial selection by the target of pioneering nerve terminals expressing a

cholinergic phenotype, and subsequent stabilization of this phenotype during development. (C) 2008 IBRO. Published by Elsevier Ltd. All rights reserved.”
“Studies of DNA tumor viruses have provided important insights into fundamental cellular processes and oncogenic transformation. They have revealed, for example, that upon expression of virally encoded proteins, cellular pathways involved in DNA repair and cell cycle control are disrupted. Herein, evidence is presented that BRCT-related regions are present in the helicase domains of the viral initiators encoded by the Polyomaviridae and Papillomaviridae MSDC-0160 viral families. Of interest, BRCT domains in cellular proteins recruit factors involved in diverse pathways, including DNA repair and the regulation of cell cycle progression. Therefore, the viral BRCT-related regions may compete with host BRCT domains for particular cellular ligands, a process that would help to explain the pleiotropic effects associated with infections

with many DNA tumor viruses.”
“Leucine-rich repeat-containing G-protein-coupled receptor 8 (LGR8; also classified as relaxin family peptide 2 receptor; RXFP2) has been identified as a cognate receptor for the peptide hormone, insulin-like peptide 3 (INSL3) and INSL3-LGR8 signaling plays an essential role in testis descent and germ cell development in human and rodents. Lgr8 mRNA has been detected in human tissues including testis, kidney and brain, but its regional and cellular distribution in these tissues in human or other species is largely unknown. In an initial step to elucidate the physiological function of a putative INSL3-LGR8 system in rat brain, the localization of Lgr8 mRNA was investigated using in situ hybridization histochemistry, revealing a discrete distribution in forebrain, with expression highly enriched in the thalamus.

In comparison to infection with parental virus or mock infection, latent infection with a virus in which the gene encoding viral IL-10 has been deleted upregulated cytokines associated with dendritic cell (DC) formation and increased the proportion of myeloid DCs. These data demonstrate that viral IL-10 restricts the ability of latently infected myeloid progenitors to differentiate into DCs and identifies an immunomodulatory

role for viral IL-10 which may limit the host’s ability to clear latent virus.”
“Eyeblink conditioning has been used for assessing cognitive performance in cases of human neurodegenerative diseases including Alzheimer’s disease (AD). Here, we tested and compared the delay and long-trace interval (TI = 500 ms) eyeblink conditionings in a Tg2576 mouse model of AD, at the age of 3, 6, AG14699 and 12 months. Tg2576 mice exhibited significant impairment in trace conditioning at 6 months of age. In contrast, delay conditioning was not impaired in Tg2576 mice even at 12 months.

These findings indicate that the long-TI eyeblink conditioning is more susceptible to age-related cognitive deterioration than delay conditioning in Tg2576 mice. The long-trace eyeblink conditioning could be a potential tool for detecting early cognitive deficits in AD mouse model. (C) 2011 Elsevier Ireland Ltd. All rights reserved.”
“Safe and effective contraception is an international public health priority. The long-acting progestogen-only contraceptives are used by over 20 million women worldwide but their main drawback is abnormal BIBF1120 uterine bleeding. Such bleeding arises owing to structural and inflammatory changes which compromise endometrial microvascular and epithelial integrity.

The molecular and structural changes that lead to the vessel and surface epithelial fragility, and hence the side effect of abnormal uterine bleeding commonly seen with exogenous progestogen use, might be lessened by short-term treatments shown to shorten bleeding episodes.”
“Few data are available to address whether the use of ERP-based deception detection alternatives have sufficient validity for applied use. The present study was designed to replicate 5-carboxymethyl-2-hydroxymuconate Delta-isomerase and extend J. P. Rosenfeld, M. Soskins, G. Bosh, and A. Ryan’s (2004) study by utilizing a virtual reality crime scenario to determine whether ERP-based procedures, including brain fingerprinting, can be rendered less effective by participant manipulation by employing a virtual reality crime scenario and multiple countermeasures. Bayesian and bootstrapping analytic approaches were used to classify individuals as guilty or innocent. Guilty subjects were detected significantly less frequently compared to previous studies; countermeasures further reduced the overall hit rates. Innocent participants remained protected from being falsely accused. Reaction times did not prove suitable for accurate classification.

These results suggest that an increase in catecholamine production occurs in inflamed joints of CIA. The catecholamines are, at least in part, from Th1 and Th2 cells, and they may be related to joint inflammatory alleviation in CIA progression.”
“To evaluate clinical outcomes and effects of non-surgical periodontal therapy on serum, gingival crevicular fluid (GCF) interleukin-1beta

(IL-1 beta) and tumor necrosis factor-alpha (TNF-alpha) levels in chronic periodontitis patients with/without rheumatoid arthritis (RA), fifteen RA patients with chronic periodontitis (RA-P) and 15 systemically healthy non-RA chronic periodontitis patients (H-P) were recruited. LXH254 cell line Clinical periodontal recordings, GCF, and blood samples were obtained at baseline, 1, 3, and 6 months after periodontal treatment. GCF, serum IL-1 beta, TNF-alpha levels were analyzed by ELISA. Disease activity score 28 (DAS28) was used to assess RA selleck products clinical morbidity. Study groups were compared by Mann-Whitney U test. Wilcoxon test was used to compare the data at baseline, 1, 3, and 6 months after periodontal therapy

within the same group. DAS28 decreased significantly after periodontal therapy in RA-P group (p < 0.01). Serum TNF-alpha concentrations of H-P group were significantly higher than those of RA-P group (p < 0.01), whereas IL-1 beta levels were similar. No significant change was observed in serum levels of these cytokines after periodontal therapy. GCF IL-1 beta amounts decreased significantly in both groups following treatment (p < 0.01). At 6-months, H-P GCF IL-1 beta concentrations

were significantly lower than baseline. DAS28 and GCF IL-1 beta correlated with clinical periodontal indices (p < 0.01). Significant decreases in DAS28 and GCF IL-1 beta amounts after periodontal treatment suggest that periodontal therapy synergizes with systemic RA therapy to improve Aldehyde_oxidase RA status.”
“The aim of this study was to compare the performance characteristics of two answer modalities for BASDAI and BASFI in patients with AS and to show validity and reliability of NRS in Turkish version. BASDAI and BASFI were simultaneously employed with a 10-cm VAS and an 11-point NRS. Internal consistency was assessed by using Cronbach’s alpha coefficients. Testing was performed on baseline and next day under standardized conditions. Construct validity was determined by association of these measures with ASDAS, DFI, global disease activity, pain scores, ASQOL, HAQ, and SF-36. We also tested the ability of NRS version of BASDAI and BASFI to detect changes. A total 114 patients with AS according to the modified New York criteria were included. There was a good agreement between the total scores of each instrument on day 0 (ICC values were 0.894-0.934).

5% vs 14.8%, p < 0.01). Serum ferritin, proliferating cell nuclear antigen expression and interstitial fibrosis correlated with the generation of 4-HNE modified proteins (p < 0.05).

Conclusions: Testicular volume, which is a parameter of spermatogenesis, is impaired in patients on hemodialysis and oxidative stress is considered to CH5183284 order be involved in the process. Serum ferritin is a useful parameter for predicting oxidative stress in the testis.”
“Deep cerebellar dentate nuclei are in a key position to control motor planning as a result of an integration of cerebropontine inputs and hemispheric

Purkinje neurons signals, and their influence through synaptic outputs onto extracerebellar hubs. GABAergic dentate neurons exhibit broader action potentials and slower afterhyperpolarization than non-GABAergic (presumably glutamatergic) neurons. Specific potassium channels may be involved in these distinct firing profiles, Alisertib cell line particularly, Kv3.1 and Kv3.3 subunits which rapidly activate at relatively positive potentials to support the generation of fast action potentials.

To investigate the subcellular localization of Kv3.1b and Kv3.3 in GAD- and GAD+ dentate neurons of glutamic acid decarboxylase 67-green fluorescent protein (GAD67-GFP) knock-in mice a

preembedding immunocytochemical method for electron microscopy was used. Kv3.1b and Kv3.3 were in membranes of cell somata, dendrites, axons and synaptic terminals of both GAD- and GAD+ dontate neurons. The vast majority of GAD- somatodendritic membrane segments domains labeled for Kv3.1b and Kv3.3 (96.1% and 84.7%, respectively) whereas 56.2% and 69.8% of GAD- axonal membrane segments were immunopositive for these subunits. Furthermore, density of Kv3.1b immunoparticles was much higher in GAD- somatodendritic than axonal domains. As to GAD+ neurons, only 70.6% and 50% of somatodendritic membrane segments, and 53.3% and 59.5% of axonal membranes exhibited Kv3.1b and Kv3.3 labelling, respectively. In contrast to GAD- cells, GAD+ cells exhibited a higher density labeling for both Kv3 subunits PLEKHO1 at their axonal than at their

somatodendritic membranes.

Taken together, Kv3.1b and Kv3.3 potassium subunits are expressed in both GAD- and GAD+ cells, albeit at different densities and distribution. They likely contribute to the distinct biophysical properties of both GAD- and GAD+ neurons in the dentate nucleus. (C) 2008 IBRO. Published by Elsevier Ltd. All rights reserved.”
“Purpose: Differences in prostate specific antigen awareness may contribute to differences in the frequency of prostate specific antigen testing. We investigated the association of health risk behaviors, including smoking, physical inactivity, obesity and excessive alcohol consumption, with awareness of the prostate specific antigen test in men in California at risk for prostate cancer.