EXPRESSION OF cAMP AND CREB IN THE HUMAN PENIS

The aim of this study is to investigate the expression of adenosine 3',5'-cyclic monophosphate (cAMP) and cAMP-response element-binding protein (CREB) in the human penis as it is known that luteinizing hormone (LH) regulates cellular function mostly through the cAMP signaling pathway and LH receptors are expressed by the penile endothelium. Penile tissue was obtained from three patients during partial or total penectomy due to a rectal cancer with secondary penile metastasis or squamous cell carcinoma of the penis. Immunohistochemistry was used for the detection of cAMP and CREB. Positive immunoreaction for cAMP was present in most cells of superficial, intermedial, and basal layer of urethral epithelium and in fibroblast-like cells (FLC) of interstitial tissue and endothelial cells (EC) of cavernous spaces in corpus spongiosum penis. Positive staining for cAMP was also visible in EC of cavernous spaces and in FLC of interstitial tissue in corpus cavernosum penis. Positive immunoreaction for CREB was present in the superficial and intermedial layer of urethral epithelium, and some positive immunoreaction was also noticed in EC of cavernous spaces and in FLC of interstitial tissue in corpus spongiosum penis. Positive staining was also visible in the EC of cavernous spaces and in fibroplast-like cells of the interstitial tissue in the corpus cavernosum penis. Our results show the presence of cAMP and CREB in the human penis. While LH exerts its actions through cAMP signaling system and our previous studies have shown the expression of luteinizing hormone/choriogonadotropin (LHCG) receptor in the mouse and human penis, this finding may support the hypothesis that LH could affect the spongious and cavernous tissue of the human penis and thereby influence the development of erectile dysfunction among aging men.Peer reviewe

Eesnäärmevähi levikuulatuse määramine magnetresonantstomograafial

Eesnäärmevähi sagenemise tõttu pööratakse üha suuremat tähelepanu selle diagnoosimisele ja ravile. Operatiivse ravi planeerimisel on äärmiselt oluline võimalikult täpne teave haiguse levikuulatusest. Tänaseni puudub ühtne tegutsemisjuhend selle saavutamiseks, sest senised meetodid pole staadiumi määramisel olnud piisava täpsusega. Artikli autorid on võrrelnud magnetresonatstomograafilist leidu histopatoloogilise leiu ja operatsiooniandmetega ning leidnud, et kuigi MRT-meetod on veel arendamisjärgus, on siiski tegemist praegusel ajal parima kohapeal kättesaadava prostatakartsinoomi staadiumi määramise viisiga. Eesti Arst 2004; 83 (6): 364–37

Randomised double-blind phase 3 clinical study testing impact of atorvastatin on prostate cancer progression after initiation of androgen deprivation therapy : study protocol

Introduction Blood cholesterol is likely a risk factor for prostate cancer prognosis and use of statins is associated with lowered risk of prostate cancer recurrence and progression. Furthermore, use of statins has been associated with prolonged time before development of castration resistance (CR) during androgen deprivation therapy (ADT) for prostate cancer. However, the efficacy of statins on delaying castration-resistance has not been tested in a randomised placebo-controlled setting. This study aims to test statins' efficacy compared to placebo in delaying development of CR during ADT treatment for primary metastatic or recurrent prostate cancer. Secondary aim is to explore effect of statin intervention on prostate cancer mortality and lipid metabolism during ADT. Methods and analysis In this randomised placebo-controlled trial, a total of 400 men with de novo metastatic prostate cancer or recurrent disease after primary treatment and starting ADT will be recruited and randomised 1:1 to use daily 80 mg of atorvastatin or placebo. All researchers, study nurses and patients will be blinded throughout the trial. Patients are followed until disease recurrence or death. Primary outcome is time to formation of CR after initiation of ADT. Serum lipid levels (total cholesterol, high-density lipoprotein (HDL), low-density lipoprotein (LDL) and trigyserides) are analysed to test whether changes in serum cholesterol parameters during ADT predict length of treatment response. Furthermore, the trial will compare quality of life, cardiovascular morbidity, changes in blood glucose and circulating cell-free DNA, and urine lipidome during trial. Ethics and dissemination This study is approved by the Regional ethics committees of the Pirkanrnaa Hospital District, Science centre, Tampere, Finland (R18065M) and Tarto University Hospital, Tarto, Estonia (319/T-6). All participants read and sign informed consent form before study entry. After publication of results for the primary endpoints, anonymised summary metadata and statistical code will be made openly available. The data will not include any information that could make it possible to identify a given participant.Peer reviewe

Randomised double-blind phase 3 clinical study testing impact of atorvastatin on prostate cancer progression after initiation of androgen deprivation therapy: study protocol

Introduction Blood cholesterol is likely a risk factor for prostate cancer prognosis and use of statins is associated with lowered risk of prostate cancer recurrence and progression. Furthermore, use of statins has been associated with prolonged time before development of castration resistance (CR) during androgen deprivation therapy (ADT) for prostate cancer. However, the efficacy of statins on delaying castration-resistance has not been tested in a randomised placebo-controlled setting.This study aims to test statins’ efficacy compared to placebo in delaying development of CR during ADT treatment for primary metastatic or recurrent prostate cancer. Secondary aim is to explore effect of statin intervention on prostate cancer mortality and lipid metabolism during ADT.Methods and analysis In this randomised placebo-controlled trial, a total of 400 men with de novo metastatic prostate cancer or recurrent disease after primary treatment and starting ADT will be recruited and randomised 1:1 to use daily 80 mg of atorvastatin or placebo. All researchers, study nurses and patients will be blinded throughout the trial. Patients are followed until disease recurrence or death. Primary outcome is time to formation of CR after initiation of ADT. Serum lipid levels (total cholesterol, high-density lipoprotein (HDL), low-density lipoprotein (LDL) and trigyserides) are analysed to test whether changes in serum cholesterol parameters during ADT predict length of treatment response. Furthermore, the trial will compare quality of life, cardiovascular morbidity, changes in blood glucose and circulating cell-free DNA, and urine lipidome during trial.Ethics and dissemination This study is approved by the Regional ethics committees of the Pirkanmaa Hospital District, Science centre, Tampere, Finland (R18065M) and Tarto University Hospital, Tarto, Estonia (319/T-6). All participants read and sign informed consent form before study entry. After publication of results for the primary endpoints, anonymised summary metadata and statistical code will be made openly available. The data will not include any information that could make it possible to identify a given participant.</p

A biodegradable urethral stent with new braided configuration and drug-eluting properties

Uusiutuva virtsaputken arpireaktion aiheuttama ahtauma on edelleenkin hoidollinen ongelma, vaikka urologisen kirurgian menetelmät ovat kehittyneet paljon viimeisten vuosikymmenien aikana. Tutkimuksen tarkoituksena oli ensinnäkin tutkia uuden punotun, verkkorakenteisen, biohajoavan virtsaputkistentin (laajentimen) hajoamista ja kudossoveltuvuusominaisuuksia sekä kliinisiä käyttömahdollisuuksia. Toisena tarkoituksena oli kehittää aivan uusi, lääkeainetta luovuttava biohajoava virtsaputkistentti. Stenttimateriaalin vaikutusta tulehdustekijätuottoon tutkittiin monosyytti-makrofagi solumallissa. Stentin hajoamista ja kudossoveltuvuutta selvitettiin vertaamalla punottuja, biohajoavia stenttejä metallistentteihin kanin virtsaputkessa. Kliinisessä pilottitutkimuksessa selvitettiin vastaavanlaisen stentin toimivuutta eturauhasen hyvänlaatuisen liikakasvun aiheuttaman akuutin virtsaummen hoidossa yhdistettynä eturauhasta pienentävään lääkitykseen. Koe-eläinmallissa stentti hajosi hallitusti ja oli kudossoveltuvuudeltaan parempi kuin metallistentti. Kliinisessä pilottitutkimuksessa stentin asennus onnistui hyvin tutkimuksessa kehitetyn asettimen avulla ja asennuksen jälkeen kaikki potilaat kykenivät virtsaamaan. Kuitenkin joillakin potilailla laajennin litistyi, jolloin virtsaaminen huononi uudelleen. Lääkeainetta luovuttavien biohajoavien stenttien kudossoveltuvuus oli verrattavissa puhtaiden biohajoavien stenttien ominaisuuksiin, minkä lisäksi biohajoavat stentit aiheuttivat vähemmän kudosreaktioita kuin kontrollistentit. Soluviljelymallissa stenttimateriaalin havaittiin lisäävän tulehdustekijätuottoa, jota voitiin hillitä tulehduskipulääkkeenä tunnetulla indometasiinilla. Uuden biohajoavan, verkkorakenteisen virtsaputkistentin hajoaminen tapahtui hyvin hallitusti ja sen kudossoveltuvuus oli parempi kuin metallistenteillä. Kliinisessä pilottitutkimuksessa kävi ilmi, että aikaisempiin stentteihin liittyvät liukumisongelmat ja rakenteen nopeasta romahtamisesta johtuvat ongelmat ratkesivat uuden, verkkomaisen rakenteen ansiosta. Kuitenkin stentin kasaanpuristuminen on ongelma, joka pitää pystyä vielä ratkaisemaan. Tutkimustulokset osoittavat, että lääkeluovutusominaisuus on mahdollista liittää biohajoaviin virtsaputkistentteihin ja tutkittujen lääkeaineiden osalta kudossoveltuvuusominaisuudet olivat hyvät. Tulevaisuudessa tätä tietoa voidaan käyttää hyväksi kehitettäessä lääkettä luovuttavia virtsatiestenttejä ja uusia menetelmiä virtsaputken ahtauman hoitoon.The first aim of this study was to evaluate the biocompatibility and degradation as well as potential clinical use of a new biodegradable PLGA (copolymer of L-lactide and glycolide acid) urethral stent with braided mesh configuration. The second and at the same time the main objective of this study was to develop a new drug-eluting biodegradable urethral stent. The biocompatibility profile of this new generation stent was tested and analysed both in vitro and in vivo experimental studies. The degradation and biocompatibility profiles of the new braided stent were investigated in an experimental study in 24 male rabbits. Braided PLGA stents were compared with metallic stents in situ in the rabbit urethra. PLGA stents with the same configuration were evaluated also in a pilot clinical study of 10 patients combining urethral stent and dutasteride in the treatment of acute urinary retention due to benign prostatic hyperplasia. The safety, biocompatibility and efficacy of new biodegradable PLGA urethral stent materials with drug-eluting properties were evaluated preclinically using standardized muscle implantation tests in 18 animals as well as in situ urethral biocompatibility testing in 16 rabbits - indomethacin, dexamethasone and ciprofloxacine being the primary interests. Additional studies were carried through with 24 rabbits in studying particulary indomethacin-eluting stents. The effect of stent material and drug-releasing stent material as well as indomethacin itself on cytokine production was studied in THP-1 macrophages. Cytokine production was measured by protein antibody array. The effect of stent material was measured on inflammatory mediators. ELISA was used to confirm the results detected by the protein antibody array and also the effect of indomethacin-releasing stent material and indomethacin itself on the production of cytokines were studied. In experimental study with rabbits the new braided pattern PLGA stents appeared to be more biocompatible than metallic stents as well as the degradation process of these stents was well controlled. In a pilot clinical study the insertion of the stents was successful with a new insertion device and all the patients were able to void after inserting the stent. When investigating drug-eluting properties of biodegradable stents we found biocompatibility profiles similar to pure biodegradable stents and even decrease in several tissue biological parameters compared to positive controls. Stent material was found to increase production of IL-8, TNF-alfa, TGF-beeta, MCP-1 and RANTES. Interestingly, both indomethacin-releasing stent material and indomethacin itself inhibited the production of inflammatory mediators. The degradation process of the new braided PLGA urethral stents was well controlled and they were more biocompatible compared to metallic stents. In clinical study the new stent overcame the earlier problems of migration and sudden breakage into large particles. However, mechanical properties still need to be improved. Studies with drug-eluting stents revealed their good biocompatibility properties and that drug-eluting capacity can be safely added to urethral stents. In the present study the stent material was found to increase and both indomethacin-releasing stent material and indomethacin to decrease the production of inflammatory mediators. The findings of the present study can be utilized in the development of novel drug releasing biomaterials

Improved renal cancer prognosis among users of drugs targeting renin-angiotensin system

Purpose: We explored renal cell cancer (RCC) survival among users of antihypertensive medication as hypertension is proposed to be a risk factor for RCC and ACE-inhibitors and angiotensin receptor blockers (ARBs) have been associated with improved prognosis of RCC. Methods: Finnish cohort of 13,873 participants with RCC diagnosed between 1995–2012 was formed from three national databases. RCC cases were identified from Finnish Cancer Registry, medication usage from national prescription database and co-morbidities from Care Registry of Healthcare. Logistic regression was used to calculate odds ratios for metastatic tumor extent at the time of diagnosis. Risk of RCC specific death after diagnosis was analyzed using Cox regression adjusted for tumor clinical characteristics. Results: A total of 5,179 participants died of RCC during the follow-up. No risk association was found for metastatic tumor extent for any drug group. ACE-inhibitors, but no other drug group were associated with decreased risk of RCC specific death overall (HR 0.88, 95% CI 0.82–0.95) compared to non-users. In time-dependent analysis high-dose use of ACE-inhibitors (392 Defined Daily Dose (DDD)/year), HR 0.54, 95% CI 0.45–0.66) and ARBs (786.1 DDD/year, HR 0.66, 95% CI 0.50–0.87) associated with improved RCC survival. No information of TNM-classification or tobacco smoking was available. Conclusion: ACE-inhibitors and ARBs in high dose associated with improved RCC specific survival. This may reflect overall benefit of treating hypertension with medication targeting renin-angiotensin system (RAS) system among RCC patients. Further studies are needed to explore the role of RAS in RCC.publishedVersionPeer reviewe