Activation of the Wnt pathway through use ,a glycogen synthase kinase 3beta inhibitor, promotes pca.

    

News  12.October.2013

Molecular Cancer Researchmcr.aacrjournals.org

Yuan Jiang1, Jinlu Dai1, Honglai Zhang1, Joe L. Sottnik1, Jill M. Keller1, Katherine J. Escott2,

Hitesh J. Sanganee2, Zhi Yao3, Laurie K. McCauley4, and Evan T. Keller5,*

¹Department of Urology, University of Michigan ²Emerging Innovations Unit, AstraZeneca R&D

³Department of Immunology, Tianjin Medical University ⁴Department of Pathology, University of Michigan ⁵Department of Periodontics and Oral Medicine, University of Michigan

 Due to its bone anabolic activity, methods to increase Wnt activity, such as inhibitors of dickkopf-1 and sclerostin, are being clinically explored.

Glycogen synthase kinase (GSK3β) inhibits Wnt signaling through inducing beta-catenin degradation. Therefore, AR79, an inhibitor of GSK3β, is being evaluated as a bone anabolic agent. However, Wnt activation has potential to promote tumor growth.

The goal of this study was to determine if AR79 impacted progression of prostate cancer (PCa). PCa tumors were established in subcutaneous and bone sites of mice followed by AR79 administration. Tumor growth, beta-catenin activation, proliferation (Ki67 expression) and apoptosis (caspase 3 activity) were measured.

 Additionally, PCa and osteoblast cell lines were treated with AR79 and beta-catenin status, proliferation (with beta-catenin knocked down in some cases) and proportion of the ALDH+CD133+ stem-like cells was determined. AR79 promoted PCa growth, decreased phospho-beta-catenin expression and increased total and nuclear beta-catenin expression in tumors and increased tumor-induced bone remodeling.

Additionally, it decreased caspase 3 and increased Ki67 expression. In addition, AR79 increased bone formation in normal mouse tibiae. AR79 inhibited beta-catenin phosphorylation, increased nuclear β-catenin accumulation in PCa and osteoblast cell lines and increased proliferation of PCa cells in vitro through beta-catenin. Furthermore, AR79 increased the ALDH+CD133+ cancer stem cell-like proportion of the PCa cell lines.

We conclude that AR79, while being bone anabolic, promotes PCa cell growth through Wnt pathway activation. Implications: These data suggest that clinical application of pharmaceuticals that promote Wnt pathway activation should be used with caution as they may enhance tumor growth.

Copyright © 2013, American Association for Cancer Research.

IL-6 and Oncostatin-M Synergize with the PI3K/AKT Pathway/Promote Aggressive Pca.

News  12.October.2013

Molecular Cancer Research 

Daniel A. Smith1, Atsushi Kiba5, Yang Zong4, and Owen N. Witte2,3,4

 ¹Molecular Biology Interdepartmental Program, ²Department of Microbiology, Immunology, and Molecular Genetics, ³Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Research, ⁴Howard Hughes Medical Institute, David Geffen School of Medicine, University of California, Los Angeles, California; and ⁵Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, Kanagawa, Japan

Chronic inflammation has been proposed as an etiological and progression factor in prostate cancer. In this study, we used a dissociated prostate tissue recombination system to interrogate the role of interleukin 6 (IL6) and the related cytokine oncostatin-M (OSM) in the initiation and progression of prostate cancer.

We identified that prostatic intraepithelial neoplasia (PIN) lesions induced by PTEN loss of function (PTEN^LOF) progress to invasive adenocarcinoma following paracrine expression of either cytokine.

Increased expression of OSM was also able to drive progression of benign human epithelium when combined with constitutively activated AKT. Malignant progression in the mouse was associated with invasion into the surrounding mesenchyme and increased activation of STAT3 in PTEN^LOF grafts expressing IL6 or OSM. Collectively, our work indicates that pro-inflammatory cytokines such as IL6 or OSM could activate pathways associated with prostate cancer progression and synergize with cell-autonomous oncogenic events to promote aggressive malignancy.

Implications: Increased expression of IL6 or OSM synergizes with loss of PTEN to promote invasive prostate cancer.

Mol Cancer Res; 1–7. ©2013 AACR.

©2013 American Association for Cancer Research. 

Pca. Telomere Length Variability and Stromal Cell Telomere Length as Prognostic Markers for Metastas

 News  12.October.2013 

Christopher M. Heaphy1, Ghil Suk Yoon1,8, Sarah B. Peskoe3, Corinne E. Joshu3, Thomas K. Lee1,

Edward Giovannucci5,6,7, Lorelei A. Mucci6,7, Stacey A. Kenfield6,7, Meir J. Stampfer5,6,7,

Jessica L. Hicks1, Angelo M. De Marzo1,2,4, Elizabeth A. Platz2,3,4 and Alan K. Meeker1,2,4

Authors' Affiliations:¹Department of Pathology; ²James Buchanan Brady Urological Institute, Johns Hopkins University School of Medicine; ³Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health; ⁴Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, Maryland; Departments of ⁵Nutrition and ⁶Epidemiology, Harvard School of Public Health; and ⁷Department of Medicine, Channing Division of Network Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts; ⁸Department of Pathology, Kyungpook National University School of Medicine, Daegu, Republic of Korea

 

Current prognostic indicators are imperfect predictors of outcome in men with clinically localized prostate cancer. Thus, tissue-based markers are urgently needed to improve treatment and surveillance decision-making. Given that shortened telomeres enhance chromosomal instability and such instability is a hallmark of metastatic lesions, we hypothesized that alterations in telomere length in the primary cancer would predict risk of progression to metastasis and prostate cancer death.

To test this hypothesis, we conducted a prospective cohort study of 596 surgically treated men who participated in the ongoing Health Professionals Follow-up Study. Men who had the combination of more variable telomere length among prostate cancer cells (cell-to-cell) and shorter telomere length in prostate cancer–associated stromal (CAS) cells were substantially more likely to progress to metastasis or die of their prostate cancer. These findings point to the translational potential of this telomere biomarker for prognostication and risk stratification for individualized therapeutic and surveillance strategies.

Significance: In this prospective study, the combination of more variable telomere length among cancer cells and shorter telomere length in CAS cells was strongly associated with progression to metastasis and prostate cancer death, pointing to the translational potential for prognostication and risk stratification for individualized therapeutic and surveillance strategies.

Cancer Discov; 3(10); 1130–41. ©2013 AACR.

©2013 American Association for Cancer Research.

Selection of figure by:Dr.M.Hezarkhani

Urine biomarkers reveal mitochondrial dysfunction in diabetic kidney disease

 

News  12.October.2013

Researchers at the University of California, San Diego School of Medicine have identified 13 metabolites – small molecules produced by cellular metabolism – that are significantly different in patients with diabetes and chronic kidney disease compared to healthy controls.

Twelve of the 13 metabolites are linked to mitochondrial function, suggesting that suppression of mitochondria – the powerhouses of cells – is a fundamental characteristic of diabetic kidney disease. The findings are published in the November edition of the Journal of the American Society of Nephrology.

"This work provides strong evidence that reduced mitochondrial function is a dominant feature of human diabetic kidney disease," said first author Kumar Sharma, MD, professor of medicine and director of the Center for Renal Translational Medicine at UC San Diego. "We found that a specific cellular pathway, AMPK-PGC1a, likely plays a key role to reduce mitochondrial function and content, which means that new therapeutic approaches that restore and increase mitochondrial function and content could ameliorate or perhaps even arrest chronic kidney disease."

 

This is an X-ray of human kidneys. Credit: UC San Diego School of Medicine

Diabetic kidney disease is the leading cause of end-stage kidney disease, which is the eighth leading cause of death in the United States and a major risk factor for cardiovascular disease, the nation's leading killer. An estimated 26 million American adults have chronic kidney disease (CKD), with millions more at increased risk. These patients often require dialysis or an organ transplant.

The primary causes of CKD are high blood pressure and diabetes. Rates of both CKD and diabetes have risen dramatically in the last decade, particularly among people aged 65 and older. According to the National Kidney and Urologic Diseases Information Clearinghouse, the annual mortality rate for end-stage renal disease rose from 10,478 in 1980 to 90,118 in 2009, though it has declined somewhat in recent years.

After analyzing a total of 193 urine samples from patients with diabetes and CKD, diabetes but no CKD and healthy controls with neither condition, Sharma and colleagues quantified 94 metabolites in the samples. Thirteen metabolites were significantly different between patients with diabetes and CKD versus controls. Twelve remained significant when compared to patients with diabetes but not CKD. Twelve metabolites play a role in mitochondrial metabolism and were present in lower levels in patients with diabetes and CKD, suggesting that this major diabetic complication is at least partly the consequence of suppressed mitochondrial activity.

Sharma said measuring urine metabolites to detect and assess diabetic kidney disease is a major diagnostic step forward. "The urine metabolites can indicate the underlying function of the kidney at a biochemical and intracellular level," he said, "and are well-conserved compared to many cell-based and protein measurements. Urine metabolomics also offers an opportunity to gauge effects of new treatments which will be an advantage to guide precision medicine."

Explore further: Healthy diet, moderate alcohol linked with decreased risk of kidney disease in patient with diabetes

Journal reference: Journal of the American Society of Nephrology

Provided by University of California - San Diego  

The effects of Ketamine on Urinary Bladder

 

Edited by:Mohammad  Hezarkhani  MD,Urologist

Board-Certified of Urology,Tehran  University ,The Member  of  Iranian  Urological  Association

Madaen Hospital  Tehran Iran

Tehran clinic Hospital  Tehran  Iran

[e-mail]

www.Hezarkhani.blogfa.com  hosted in Washington DC, United States

11,October, 2013

Background

Ketamine is a drug used in human and veterinary medicine, primarily for the induction and maintenance of general anesthesia, usually in combination with a sedative. Other uses include sedation in intensive care, analgesia (particularly in emergency medicine), and treatment of bronchospasm. Ketamine has a wide range of effects in humans, including analgesia, anesthesia, hallucinations, elevated blood pressure, and bronchodilation. Like other drugs of its class, such as tiletamine and phencyclidine (PCP), ketamine induces a state referred to as "dissociative anesthesia" and is used as a recreational drug.

Ketamine is effective in treating depression in patients with depression and bipolar disorder who have not responded to antidepressants. It produces a rapid antidepressant effect, acting within two hours as opposed to the several weeks taken by typical antidepressants to work.

Its hydrochloride salt is sold as Ketanest, Ketaset, and Ketalar. Pharmacologically, ketamine is classified as an NMDA receptor antagonist. At high, fully anesthetic level doses, ketamine has also been found to bind to μ-opioid receptors type 2 in cultured human neuroblastoma cells – however, without agonist activity – and to sigma receptors in rats. Also, ketamine interacts with muscarinic receptors, descending monoaminergic pain pathways and voltage-gated calcium channels.

Ketamine is a chiral compound. Most pharmaceutical preparations of ketamine are racemic; however, some brands reportedly have (mostly undocumented) differences in their enantiomeric proportions. The more active enantiomer, (S)-ketamine, is also available for medical use under the brand name Ketanest S.

According to a recent systematic review, 110 documented reports of irritative urinary tract symptoms from ketamine dependence exist. Urinary tract symptoms have been collectively referred as "ketamine-induced ulcerative cystitis" or "ketamine-induced vesicopathy", and they include urge incontinence, decreased bladder compliance, decreased bladder volume, detrusor overactivity, and painful haematuria (blood in urine). Bilateral hydronephrosis and renal papillary necrosis have also been reported in some cases. The pathogenesis of papillary necrosis has been investigated in mice, and mononuclear inflammatory infiltration in the renal papilla resulting from ketamine dependence has been suggested as a possible mechanism.

The time of onset of lower urinary tract symptoms varies depending, in part, on the severity and chronicity of ketamine use; however, it is unclear whether the severity and chronicity of ketamine use corresponds linearly to the presentation of these symptoms. All reported cases where the user consumed greater than 5 grams per day reported symptoms of the lower urinary tract. Urinary tract symptoms appear to be most common in daily ketamine abusers who have abused the drug for an extended period of time. These symptoms have presented in only one case of medical use of ketamine. However, following dose reduction, the symptoms remitted.

Management of these symptoms primarily involves ketamine cessation, for which compliance is low. Other treatments have been used, including antibiotics, NSAIDs, steroids, anticholinergics, and cystodistension.

Both hyaluronic acid instillation and combined pentosan polysulfate and ketamine cessation have been shown to provide relief in some patients, but in the latter case, it is unclear whether relief resulted from ketamine cessation, administration of pentosan polysulfate, or both. Further follow-up is required to fully assess the efficacy of these treatments.

In addition, extreme cases are associated with severe unresolving bladder pain in conjunction with a thickened, contracted bladder and an ulcerated/absent urothelium. Reseachers report on unusual neuropathological features seen by immunohistology in ketamine cystitis. In all cases, the lamina propria was replete with fine neurofilament protein (NFP⁺) nerve fibres and in most patients (20/21), there was prominent peripheral nerve fascicle hyperplasia that showed particular resemblance to Morton’s neuroma.

The nerve fascicles, which were positive for NFP, S100 and the p75 low-affinity nerve growth factor receptor (NGFR), were generally associated with a well-developed and in places, prominent, epithelial membrane antigen⁺/NGFR⁺ perineurium. This peripheral nerve fascicle hyperplasia is likely to account for the extreme pain experienced by ketamine cystitis patients.

Urothelial damage was a notable feature of all ketamine cystitis specimens and where urothelium remained, increased NGFR expression was observed, with expansion from a basal-restricted normal pattern of expression into the suprabasal urothelium.

The histological findings were distinguishing features of ketamine cystitis and were not present in other painful bladder conditions. Ketamine cystitis afflicts predominantly young patients, with unknown long-term consequences, and requires a strategy to control severe bladder pain in order to remove a dependency on the causative agent. Our study indicates that the development of pain in ketamine cystitis is mediated through a specific neurogenic mechanism that may also implicate the urothelium.

References:

1-Nerve hyperplasia: a unique feature of ketamine cystitis

Simon C Baker^1*, Jens Stahlschmidt², Jon Oxley³, Jennifer Hinley¹, Ian Eardley², Fiona Marsh², David Gillatt³, Simon Fulford⁴ and Jennifer Southgate^1* /Acta Neuropathologica Communications 2013, 1:64 doi:10.1186/2051-5960-1-64/Published: 8 October 2013

2- Ketamine  Wikipedia,The Free Encyclopedia  10.October.2013

Recruiting E. coli to combat hard-to-treat bacterial infections

 

October 10, 2013

The notorious bacteria E. coli is best known for making people sick, but scientists have reprogrammed the microbe -- which also comes in harmless varieties -- to make it seek out and fight other disease-causing pathogens.

The researchers' report appears in the journal ACS Synthetic Biology and describes development of this new type of E. coli that can even kill off slimy groups of bacteria called biofilms that are responsible for many hard-to-treat infections, such as those that take hold in the lungs, the bladder and on implanted medical devices. Matthew Wook Chang and colleagues explain that biofilm infections are difficult to treat because the bacteria hide away under a protective barrier of sugars, DNA and proteins. That shield makes them very resistant to conventional therapies.

 In addition, overuse of antibiotics in medicine and agriculture also have made some bacteria, such as MRSA, shrug off most known treatments, making at least 2 million Americans sick every year. This growing public health threat has motivated scientists to look for new antibiotics and alternative treatments to beat infections. In the past, researchers made bacteria that fight off other microbes, but they had limitations. Chang's team addressed those limitations by making a new kind of bacterial "gun-for-hire" that can sense an infection, swim toward it and kill off the disease-causing microbes.

They reprogrammed E. coli to sense Pseudomonas aeruginosa -- a bacteria that can form biofilms and causes hospital-acquired infections in the lungs and the gut. The new E. coli then swims directly toward P. aeruginosa and launches an attack with an antimicrobial peptide and an enzyme that breaks down biofilms. Though the researchers successfully tested their engineered microbe on P. aeruginosa, they say that their engineering strategy could be used to combat other pathogens as well.

The authors acknowledge funding from the National Medical Research Council of Singapore and the U.S. Defense Threat Reduction Agency.

Source: American Chemical Society

Compound developed that may treat erectile dysfunction priapism

 

Medical news today  02.october.2013

It's not the little blue pill famous for helping men get big results, but for those who need it, the outcome might be even more significant. A new research report published online in The FASEB Journal, offers hope to men who experience priapism. This condition, which is often seen in men with sickle cell disease, causes erections lasting so long that they cause permanent damage to the penis.

Specifically, a compound, called "C6'" offered mice -- with and without sickle cell disease -- relief by normalizing nitric oxide levels in penile blood. In addition to helping men with priapism, this action of this compound also provides insight for future research related to vascular and circulatory disorders such as hypertension.

"This study has implications for quality of life by suggesting the possible role of a drug therapy for controlled, physiologic release of nitric oxide that may treat conditions of altered nitric oxide signaling or function," said Gwen Lagoda, M.S., a researcher involved in the work from the Department of Urology at Johns Hopkins Medical Institutions, in Baltimore, Maryland. "Its application may extend beyond erection disorders and include other health conditions involving abnormal circulation and blood flow."

Scientists analyzed two groups of experimental mice. The first group had both endothelial and neuronal nitric oxide synthase knocked out. The second group of mice had sickle cell disease. In both groups of mice, nitric oxide signaling was known to be abnormal and resulted in abnormal erections. When these mice were given C6' treatment, their molecular abnormalities were reduced and erectile functioning returned to levels similar to normal mice.

Prognostic Factors of Patients/Metastatic RCC With Removed Metastases: A Multicenter Study of 556 Pa

 

UrologyVolume 82, Issue 4 , Pages 846-851, October 2013

·Department of Urology, Yamagata University Faculty of Medicine, Yamagata, Japan

Hidefumi Kinoshita ,Tsunenori Kondo,Nobuo Shinohara,Takashi Kasahara and colleaguesAffiliations

·Department of Urology and Andrology, Kansai Medical University, Osaka, Japan

·Department of Urology, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan

Objective:To investigate the prognosis and prognostic factors of patients with metastatic renal cell carcinoma who underwent metastasectomy. 

Methods:We sent questionnaires to Japanese hospitals. The questionnaires included data of patients with metastatic renal cell carcinoma who had their metastatic lesions removed between January 1988 and December 2009. We collected them and retrospectively analyzed these data and calculated the overall survival from the first metastasectomy until death or last follow-up. We also analyzed the relationship between survival and clinico-pathologic features and determined adverse prognostic factors. Furthermore, we identified a poor prognostic group by counting the number of prognostic factors.

Results:A sample size of 556 patients from 48 institutions was studied. The median overall survival was 80 months. Four adverse prognostic factors were detected: incomplete resection by metastasectomy (hazard ratio [HR], 2.15), brain metastasis (HR, 3.73), >1.0 mg/dL C-reactive protein (HR, 2.45), and the highest histologic grade in Japanese classification (nuclei of tumor cells are larger than nuclei of normal tubular cells; HR, 1.88). The median overall survivals of patients with 3 or 4 prognostic factors, 2 factors, and 0 and 1 factors were 10 months, 42 months, and 105 months, respectively.

Conclusion:Four adverse prognostic factors for predicting the survival of patients with removed metastases were identified. Patients with 3 or 4 of these adverse prognostic factors had a worse prognosis. 

Serum level of follicle-stimulating hormone is associatedwith extraprostatic extension of Pca.

News  10.october.2013 

Hisamitsu Ide, Yuichi Terado1, Kentaro Sakamaki2, Masahiro Inoue, Akiko Nakajima, Yan Lu, Schinichi Hisasue3,Raizo Yamaguchi, Satoru Muto, Shigeo Horie3 

Department of Urology, Teikyo University School of Medicine, Tokyo, Japan1Department of Pathology, Kyorin University School of Medicine, Tokyo, Japan2Department of Biostatistics and Epidemiology, Yokohama City University School of Medicine, Yokohama, Japan3Department of Urology, Juntendo University Graduate School of Medicine, Tokyo, Japan

Purpose: To determine whether serum follicle-stimulating hormone (FSH) can be used to predict the aggressiveness of prostatecancer prior to radical prostatectomy. 

Methods: Ninety-six patients who underwent radical prostatectomy for biopsy proved cT1c-T2N0M0 prostate cancer between 2003and 2008 were identified for retrospective analysis. Using univariate regression analysis, potential variables of extraprostatic tumorextension were identified, including prostate-specific antigen (PSA), luteinizing hormone, FSH, testosterone, biopsy findings, and age.

These variables of interest were analyzed by logistic and linear regression analysis to determine if serum FSH is predictive of extraprostaticextension.

Results: Extraprostatic extension was pathologically confirmed in 18 of 96 patients (18.8%). Statistical analysis confirmed that serumFSH was significantly associated with extraprostatic extension (P=0.04). However, age, PSA level, Gleason score, number of tumors,and serum testosterone level were not found to be independent predictors of extraprostatic extension. 

Conclusions: Selective expression of FSH receptor on the surface of blood vessels of prostate cancers has recently been reported.Measuring serum FSH preoperatively in patients with prostate cancer may provide clinically relevant information about extraprostaticspread of tumor.

Prostate Int 2013;1(3):109-112 • http://dx.doi.org/10.12954/PI.13019

Autophagy proteins in Pca.: Relation with anaerobic metabolism and Gleason score

News

Urologic Oncology: Seminars and Original Investigations

10/08/2013  

Giatromanolaki A et al. – Up–regulation of autophagy provides an important survival mechanism to normal and malignant cells residing in a hypoxic and unfavorable nutritional environment. Yet, its role in the biology of prostate cancer remains poorly understood. Immunohistochemical detection of autophagy proteins may potentially prove to be useful as prognostic markers and a tool for the stratification of patients in therapeutic trials targeting autophagy in prostate cancer.

Methods

·In this study authors investigated the expression of four major autophagy proteins, namely the microtubule–associated protein 1 light chain 3A (LC3A), LC3B, Beclin 1, and p62, together with an enzyme of anaerobic metabolism, the lactate dehydrogenase 5 (LDH5), in relation to Gleason score and extraprostatic invasion.

·A series of 96 prostate adenocarcinomas was examined using immunohistochemical techniques and appropriate antibodies.

Results

·The LC3A protein was expressed in the form of “stone–like” structures, and diffuse cytoplasmic staining, the LC3B reactivity was solely cytoplasmic, whereas that of p62 and LDH5 was both cytoplasmic and nuclear.

·A median count of 0.90 “stone–like” structures per 200×optical field (range 0–3.6) was highly associated with a high Gleason score.

·Similarly, a strong cytoplasmic LC3A, LC3B, and p62 expression, when extensive (present in>50% tumor cells per section), was significantly associated with LDH5 and a high Gleason score.

·In addition, extensive cytoplasmic p62 expression was related with LC3A and B reactivity and also with extraprostatic invasion.

·Extensive Beclin–1 expression was significantly linked with extraprostatic invasion and also with p62 and LDH5 expression.