Inhibitor of DNA binding/differentiation protein 4 (ID4) is a dominant negative regulator of basic helix loop helix (bHLH) family of transcription factors. ID4 shares the homology of HLH domain with other ID proteins (ID1, ID2, and ID3) and lack the basic DNA binding region. Evidence suggested that unlike ID1, ID2 and ID3, ID4 acts as a tumor suppressor in prostate cancer by attenuating cell proliferation and promoting apoptosis. Consistent with these observations ID4 is epigenetically silenced in DU145 prostate cancer cell line. In this study we investigated whether ID4 is also epigenetically silenced in prostate cancer. We also examined association between ID4 promoter hyper-methylation and its expression in prostate cancer cell lines. ID4 protein expression was analyzed in human prostate adenocarcinoma samples by Immunohistochemistry (IHC). ID4 promoter methylation pattern on prostate cancer cell lines was examined by methylation specific PCR. In addition, we performed methylation specific PCR on the human prostate tissues and genomic DNA to correlate cell line studies with clinical studies. IHC demonstrated decreased ID4 protein expression in human prostate tissue samples, whereas higher nuclear ID4 expression was found in normal prostate tissues. ID4 methylation specific PCR (MSP) on prostate cancer cell lines, showed ID4 methylation in DU145, but not in LNCaP and C33 cells. C81 and PC3 cells showed partial methylation. Increased ID4 methylation in C81 as compared to LNCaP suggests its epigenetic silencing as cells acquire androgen independence. Tumors with ID4 promoter hyper-methylation showed distinct loss of ID4 expression. However, the underlying mechanism involved in epigenetic silencing of ID4 is currently unknown. We hypothesized that ID4 promoter methylation is initiated by an EZH2 dependent tri-methylation of histone 3 at lysine 27 (H3K27Me3). ID4 expressing (LNCaP) and non-expressing (DU145 and C81) prostate cancer cell lines were used to investigate EZH2, H3K27Me3 and DNMT1 enrichment on ID4 promoter by Chromatin immuno-precipitation (ChIP). Increased enrichment of EZH2, H3K27Me3 and DNMT1 in DU145 and C81 cell lines was compared to ID4 expressing LNCaP cell line. Knockdown of EZH2 in DU145 cell line led to re-expression of ID4 and decrease in enrichment of EZH2, H3K27Me3 and DNMT1 demonstrating that ID4 is regulated in an EZH2 dependent manner. ChIP on prostate cancer tissue specimens and cell lines suggested EZH2 occupancy and H3K27Me3 marks on the ID4 promoter. Collectively, our data indicate a PRC2 dependent mechanism in ID4 promoter silencing in prostate cancer through recruitment of EZH2 and a corresponding increase in H3K27Me3. Increased EZH2, but decreased ID4 expression in prostate cancer strongly supports this model.

Να διερευνηθεί η επίδρασης μίας τροποποιημένης τεχνικής ριζικής προστατεκτομής, με διατήρηση της ουρήθρας μέχρι το επίπεδο του σπερματικού λοφιδίου, στα μετεγχειρητικά ογκολογικά και λειτουργικά αποτελέσματα. Ασθενείς και μέθοδοι: Στην προοπτική αυτή μελέτη, 360 ασθενείς που υποβλήθηκαν σε ανοικτή οπισθοηβική ριζική προστατεκτομή από τον Ιανουάριο του 2008 μέχρι τον Απρίλιο του 2012 χωρίστηκαν σε δύο ομάδες. Στους ασθενείς της ομάδας Α πραγματοποιήθηκε η κλασσική ριζική προστατεκτομή ενώ οι ασθενείς της ομάδας Β υποβλήθηκαν στην τροποποιημένη χειρουργική επέμβαση. Τα ογκολογικά αποτελέσματα αξιολογήθηκαν με την παρακολούθηση του PSA και τον έλεγχο βιοχημικής υποτροπής καθώς και με την ύπαρξη θετικών χειρουργικών ορίων. Η μετεγχειρητική ακράτεια εκτιμήθηκε με τον αριθμό πανών/ημέρα καθώς και με τη συμπλήρωση των ερωτηματολογίων ICIQ-SF και IIQ-SF. Η μετεγχειρητική στυτική δυσλειτουργία εκτιμήθηκε με τη συμπλήρωση των ερωτηματολογίων IIEF και SEAR. Επίσης καταγράφηκε και αναλύθηκε η επίδραση της χειρουργικής τροποποίησης στην εμφάνιση μετεγχειρητικών συμπτωμάτων αποθήκευσης των ούρων. Αποτελέσματα: Ογδόντα πέντε ασθενείς εξαιρέθηκαν από τη μελέτη. Από τους 244 ασθενείς που πληρώσουν τα κριτήρια εισόδου, στην ομάδα Α και Β συμπεριλήφθηκαν 115 (47,1%) και 129 (52,9%) ασθενείς, αντίστοιχα. Δεν παρατηρήθηκαν στατιστικά σημαντικές διαφορές στα ποσοστά εμφάνισης θετικών χειρουργικών ορίων (p=0,562) και βιοχημικής υποτροπής (p=0,321). Παρατηρήθηκαν σημαντικά υψηλότερα ποσοστά ακράτειας (p=0,026), επιτακτικότητας (p<0,001) και νυκτουρίας (p<0,001) στους ασθενείς της ομάδας Α στον 1ο μήνα μετεγχειρητικά. Επίσης, υπήρξε στατιστικά σημαντική διαφορά στον αριθμό πανών/ημέρα υπέρ της ομάδας Β στον 1ο (p=0,037), 3ο (p=0,003) και 6ο (p=0,032) μήνα μετά το χειρουργείο. Η διαφορά αυτή, ωστόσο, εξαλείφθηκε στους 12 μήνες μετεγχειρητικά. Παρόμοια αποτελέσματα παρατηρήθηκαν με τις βαθμολογίες των ερωτηματολογίων ICIQ-SF και IIQ-SF, αναδεικνύοντας βελτιωμένα αποτελέσματα στους ασθενείς της ομάδας Β για τους πρώτους 6 μήνες. Δεν παρατηρήθηκαν διαφορές στα ποσοστά εμφάνισης μετεγχειρητικής στυτικής δυσλειτουργίας καθώς και στις βαθμολογίες των ερωτηματολογίων IIEF και SEAR. Συμπεράσματα: Η τροποποιημένη χειρουργική τεχνική με διατήρηση της ουρήθρας μέχρι το επίπεδο του σπερματικού λοφιδίου αποτελεί μία νέα τροποποίηση της κλασσικής τεχνικής, η οποία μπορεί να μειώσει το χρόνο ανάκτησης της εγκράτειας των ούρων σε ασθενείς που υποβάλλονται σε ριζική προστατεκτομή, χωρίς να μειώνει το ογκολογικό αποτέλεσμα και την πρόγνωση της νόσου. / To investigate the effect of a modified surgical technique of open retropubic radical prostatectomy, with preservation of maximal urethral length to the level of verumontanum, in postoperative oncological and functional outcomes. Patients and methods: In this study, 360 patients who underwent open retropubic radical prostatectomy from January 2008 until April 2012 were divided into two groups. Patients of group A underwent the classical procedure of radical prostatectomy as it has been described by Walsh and Donker, while patients of group B underwent the modified technique. The oncological outcomes were evaluated by monitoring PSA value for biochemical failure and by recording the incidence of positive surgical margins. Postoperative incontinence was evaluated by the number of pads/day and through ICIQ-SF and IIQ-SF questionnaires. Postoperative erectile dysfunction was assessed by completing IIEF and SEAR questionnaires. We also recorded and analyzed the effect of the surgical modification in postoperative irritative urinary symptoms. Results: Eighty five patients were excluded from the study. Of the 244 patients who fulfill the inclusion criteria, 115 (47.1%) and 129 (52.9%) patients were included in group A and B, respectively. There was no statistically significant difference in the incidence rates of positive surgical margins (p=0.562) and biochemical recurrence (p=0.321) between the groups. There were significantly higher rates of incontinence (p=0.026), urgency (p<0.001) and nocturia (p<0.001) in patients of group A within the first postoperative month. There was also statistically significant difference in the number of pads/day in favor of group B in 1st (p=0.037), 3rd (p=0.003) and 6th (p=0.032) month after the operation. However, this difference disappeared at 12 months postoperatively. Similar results were observed in the scores of ICIQ-SF and IIQ-SF questionnaires, demonstrating improved outcomes in patients of group B within the first 6 months. There were no differences in the incidence rates of postoperative erectile dysfunction and in the scores of IIEF and SEAR questionnaires, as well. Conclusions: We proposed a modified surgical technique with preservation of maximal urethral length until the anatomical landmark of verumontanum. This technique may reduce the time continence recovery in patients undergoing radical prostatectomy, without compromising the oncological outcome and disease prognosis.

Prostate and breast cancer are among the most commonly diagnosed cancers and leading causes of cancer-related deaths in men and women worldwide. It is therefore evident that enhanced understanding of tumorigenesis is required to improve diagnostic tools, improve prognostics and identify novel therapeutic targets. The goal of this dissertation was to elucidate the role of primary cilia in prostate and breast cancer. Little is known about the role primary cilia may play in these cancers. Primary cilia are microtubule-based organelles which aid in sensing the extracellular environment and participate in signal transduction. Important developmental signaling pathways, such as Hedgehog (Hh) and Wnt signaling pathways, involve cilia. These pathways have also been implicated in prostate and breast cancer. In this work, we demonstrate that cilia are lost through prostate cancer progression. The few remaining cilia on prostate cancers appeared to be dysfunctional, as assessed by quantifying cilia lengths, an indirect measure of functionality. We also investigated a link between the observed cilia loss and canonical Wnt signaling in prostate cancers. Primary cilia have been determined to have a suppressive role in Wnt signaling, therefore we predicted loss of cilia to correlate with increased Wnt signaling. A link between cilia loss or shortened cilia and activated Wnt signaling was suggested in a subset of prostate cancers. Our lab has established that cilia are similarly lost in breast cancer. These data suggested the hypothesis that cilia may act as tumor suppressor organelles in the prostate and breast. To test this hypothesis, we knocked down cilia in an oncogenic mammary mouse model and assessed changes in tumor growth and characteristics. We observed enhanced tumor growth with cilia loss. The data supports the hypothesis that primary cilia may be playing a tumor suppressor role in the prostate and breast, and provides promising avenues for identifying novel therapeutic approaches for cancer patients.

Prostate-specific antigen (PSA) testing has caused a steep increase in the incidence of prostate cancer, especially the incidence of localised low risk disease. In order to decrease the overdiagnosis accompanied by PSA testing, analysis of inherited genetic variants have been suggested as potential tools for clinical assessment of disease risk. With the aim of minimizing overtreatment and postpone side-effects of curative treatment for low risk prostate cancer, active surveillance, a treatment strategy with initial surveillance and deferred radical prostatectomy at the time of progression has evolved.  The aim of this thesis was to study the validity of PSA (paper I) and inherited genetic variants (paper II) for early diagnosis of prostate cancer, to assess the extent of PSA testing in Sweden (paper III), and to study the safety of deferred radical prostatectomy in localised low to intermediate risk prostate cancer (paper IV). The study designs were i) case-control studies nested within the Västerbotten intervention project (paper I and II), ii) observational study in the Cancer Register of Sweden (paper III), and iii) observational study in the NPCR Follow-up study (paper IV). PSA had a high validity in predicting a prostate cancer diagnosis with an area under the receiver operating characteristics (ROC) curve of 0.86 (95% CI, 0.84 to 0.88). A combined test, including PSA, the ratio of free to total PSA, and 33 single nucleotide polymorphisms (SNPs) in a genetic risk score, increased the area under curve to 0.87 (95% CI, 0.85 to 0.89). The estimated uptake of PSA testing among men aged 55 to 69 years increased from zero to 56% between 1997 and 2007 and there were large variations in the uptake of PSA testing between counties in Sweden. After a median follow-up time of eight years there was no significant difference in presence of any one or more adverse pathology features or prostate cancer specific mortality after primary compared to deferred radical prostatectomy in localised low to intermediate risk prostate cancer. Results from these studies indicate that PSA and the hitherto identified SNPs are not suitable biomarkers in single-test prostate cancer screening. It is possible to estimate the uptake of PSA testing on a population level. Initial surveillance and deferred radical prostatectomy represent a feasible treatment strategy in localised low to intermediate risk prostate cancer.

No description available.

När människan befinner sig i svåra situationer kan hoppet utgöra en viktig resurs. Trots detta har hoppet en förmåga att svikta i de stunder då det behövs som mest. Hopplöshet kan ses som en börda och kan skapa lidande för patienten, därför är det viktigt att hopplösheten synliggörs så att hoppet kan främjas. För patienter som lider av cancer är stöd från omgivningen en viktig del i att främja hoppet. Genom att ha ett hälsofrämjande och individanpassat vårdande kan sjuksköterskan bidra till att ge hoppet näring. Syftet med litteraturstudien var att belysa hopp i omvårdnaden av patienter med bröst- och prostatacancer. Metoden utgjordes av en systematisk litteraturstudie med induktiv ansats. I resultatet framträder tre olika teman som hoppet påverkas av- individens, relationens och omvårdnadens betydelse för hopp. I resultatet beskrivs hur hoppet kan ta sig i uttryck i de olika kategorierna. Familj och vänners stöd är betydelsefullt för förmågan att känna hopp liksom att känna meningsfullhet samt en förtroendefull relation med sjuksköterskan. Även den egna inställningen till sjukdomen och självkänslan är av stor betydelse för förmågan att känna hopp. Vidare forskning behövs för att undersöka hoppets betydelse hos äldre män. / When humans find themselves in difficult situations, hope can be an important resource. Despite this, hope has the ability to fail you in those crucial moments when it is most needed. The feeling of hopelessness can be a heavy burden and can create immense suffering for the patient. Therefore, it is crucial that the feeling of hopelessness is understood and revealed when prominent so that hope can be encouraged. For patients suffering cancer, support from the community is an important factor to boost hope. By providing personalized and health-promoting care the nurse can contribute towards giving hope nourishment. The purpose of this study is to elucidate hope in caring in patients with breast- or prostate cancer. The method consists of a systematic literature review with an inductive approach. The result shows three different areas that hope is influenced by: the individual, their relationships, and the importance that the caregiver puts on hope. It illustrates how hope can be expressed in these three different categories. The support of friends and family was crucial for the ability to feel hope, developing a sense of meaning, and having a trusting relationship with the nurse. The attitude towards the disease and the self-esteem are also of great importance for the ability to feel hope. Further research is needed to investigate the meaning of hope for elder men.

This thesis consists of three main parts. An introduction to diode-pumped solid-state lasers, thermal modelling of solid-state lasers and rate-equation modelling of solid-state lasers. The first part explains the basic components and operation principles of a typical diode-end-pumped solid-state laser. The stimulated emission process, solid-state laser gain media, various pump geometries and a basic end-pumped laser resonator configuration are among the topics that are explained. Since thermal effects are one of the main limiting factors in the power-scaling of diode-pumped solid-state lasers, the second part of this thesis describes numerical and analytical thermal models that determine the thermal lens and thermally induced stresses in a laser crystal. As a first step, a time-independent numerical thermal model which calculates the three-dimensional temperature distribution in the laser crystal is implemented. In order to calculate the time dependent thermally induced stresses in a laser crystal, a coupled thermal-stress finite element analysis model was implemented. Even though some steady-state analytical solutions for simple crystal geometries do exist, the finite element analysis approach was taken so that the time dependent thermally induced stresses could be calculated for birefringent crystals of various geometries. In order to validate the numerical results, they are compared to experimental data and analytical solutions where possible. In the last part, the population dynamics inside the laser gain medium are described and modelled with a quasi-three-level rate-equation model. A comprehensive spatially resolved rate-equation model is developed and discussed. In order to simplify the implementation of the rate-equation model as a computer simulation, the spatial dependence of the laser parameters is ignored so that the model reduces to a singleelement plane-wave model. The simplified rate-equation model is implemented and solved numerically. The model is applied to a four-level CW and Q-switched Nd:YLF laser as well as a quasi-three-level QCW Tm:GdV04 laser. The models' predictions are thoroughly verified with experimental results and also with analytical solutions where possible. / Thesis (M.Med.Sc.)-University of KwaZulu-Natal, Durban, 2007.

Prostate cancer is frequently diagnosed in elderly men and, despite the largely unproven survival benefits of treatment, the majority receive treatment. Treatment options include surgery, radiation, and/or androgen deprivation therapy (ADT). Risks associated with treatment include hip fracture. Current understanding suggests that hip fracture is a frequent cause of morbidity and mortality in the elderly, and both radiation treatment and ADT can increase the risk of hip fracture. It is important to understand these risks so they can be minimized and the morbidity of treatment reduced. The objectives of this study were to estimate the risk of hip fracture as a major adverse outcome of treatment for prostate cancer among elderly men. The specific objectives include estimating: 1) the risk of hip fracture and the dose-risk relationship among patients receiving curative radiation treatment, and 2) the risk of hip fracture associated with palliative ADT and relapsed ADT compared to curative ADT. The cancer diagnosis and treatment records of 32,673 men were linked to their hospital discharge abstracts. The risk of hip fracture was estimated using Cox regression and the estimates were adjusted for age, comorbidity, income, and year of diagnosis. The risk of hip fracture was 59% higher among men who received curative radiation when compared to men who received curative surgery. The risk of hip fracture fell by 6% with each one Gy increase in radiation dose between 55 and 81 Gy Biological Equivalent Dose to the hip-bone. The risk of hip fracture for subjects in the palliative ADT and relapsed ADT categories was 5.98 and 5.77 times the risk in comparison to men who received curative ADT treatment. Curative radiation treatment is associated with an increased risk of hip fracture when compared to curative surgery. The risk of hip fracture is greater with ADT for palliation and relapsed cancer than with curative treatment. Current treatments for prostate cancer contain significant risk of hip fracture for elderly men and these risks should be considered as part of the treatment decision.

Advanced prostate cancer (PCa) patients are offered androgen deprivation therapy (ADT) to control their cancer’s growth. ADT impairs sexual function and the sleep patterns of ADT patients. Since ADT deprives patients of estrogen, and supplemental estrogen reduces such problems in menopausal women, I studied whether administering estrogen reduces these problems for castrated male rats as a model for PCa patients on ADT. First, I tested how early versus late estradiol treatment after castration influenced rats’ sexual behaviour. Estradiol increases mounting behaviour to comparable levels regardless of when the treatment was started after castration, suggesting that estrogen’s ability to restore male sexual interest is insensitive to a delay since castration. Secondly, to understand the biological basis of these behavioural effects, I examined brain and muscle tissues from the same animals. Specifically, I compared changes in 1) estrogen receptors (ERs) and c-Fos protein (a neuronal activation marker) levels in brain areas controlling sex behavior; 2) ERs levels in pelvic floor muscles, important for erection; and 3) ERs levels in the hippocampus and prefrontal cortex. Prolonged castration increases ER? levels in the preoptic area (POA), a key brain area that regulates mating behaviour, and estradiol treatment reduced these effects. In the POA, mating-induced c-Fos expression was not affected by estradiol regardless of when the treatment began post-castration. Estrogen may upregulate ERs in pelvic floor muscles, and downregulate ERs in the hippocampus and prefrontal cortex, depending on administration time after castration. These findings suggest that mating activates POA neurons, and this activation induces mounting only in the presence of estrogen. Additionally, the duration after castration influences ER autoregulation in the pelvic floor muscles, hippocampus, and prefrontal cortex in response to estradiol. Lastly, I studied how estrogen modulates the sleep-wake behaviour of orchiectomized rats. Estradiol promotes baseline wakefulness during the dark period and prevents castration-induced impairment in sleep recovery after sleep deprivation. These findings suggest that estradiol may positively influence the sleep-wake behaviour of castrated males. Collectively, I demonstrate that estrogen administered to castrated rats improves sexual and sleep functions. It may similarly improve the quality of life of PCa patients on ADT.

Prostatos, vėžys. yra pati dažniausia ir antra pagal mirtingumą vyrų onkologinė liga Lietuvoje. Prostatos specifinio antigeno (PSA) testo naudojimas ankstyvai patikrai leidžia tikėtis šios ligos užleistumo ir mirtingumo mažėjimo. Mažos rizikos prostatos vėžio gydymas radikaliais metodais yra tapęs neatsiejamu ankstyvos patikros palydovu. Nėra žinoma ar bendros praktikos gydytojų (BPG) siūloma informuoto paciento PSA patikra realioje populiacijoje turės tokį patį poveikį kaip klinikiniuose tyrimuose. Šis tyrimas yra pirmas nacionaliniu mastu atliekamos PSA tyrimu pagrįstos patikros programos poveikio sergamumui prostatos vėžiu vertinimas. Išanalizuota organizuotos patikros skvarba populiacijoje pagal skirtingas amžiaus grupes ir BPG teikiamos paslaugos galimybės mažinant skirtingo amžiaus vyrų prostatos vėžio užleistumą. Sukurta duomenų bazė jungianti PSA patikros ir sergamumo prostatos vėžiu duomenis leidžia nagrinėti organizuotos patikros efektyvumą. Nustatyta, kad ankstyvos patikros skvarba ypač maža 50-54 metų vyrų grupėje, tačiau jau po dvejų metų BPG teikiama informavimo ir PSA patikros paslauga lėmė ne tik lokalaus, bet vietiškai išplitusio prostatos vėžio atvejų mažėjimą visoje 50–75 metų vyrų grupėje. Remiantis tyrimo rezultatais rekomenduojama naudoti papildomas informavimo priemones, įtraukiant jaunesnius nei 60 metų vyrus į ankstyvos patikros programą, bei plačiai naudoti mažos rizikos prostatos vėžio aktyvią stebėseną. / Prostate cancer is most common and second deadliest tumour diagnosed in Lithuanian men. Prostate specific antigen (PSA) test in early detection of prostate cancer could result in decreased morbidity and mortality. Radical treatment of low-risk prostate emerged as an inevitable satellite of early detection. It is unknown if PSA testing offered to informed men by general practitioners (GP) could have the same results as in clinical trials. This study is the first evaluation of the nation wide prostate cancer detection program based on PSA testing. GP based early detection program is analysed according to the penetration of PSA testing in different age groups and the potential to decrease prostate cancer morbidity. The created database integrating data of PSA testing and incidence of prostate cancer permits in analysis of the effectiveness of early detection. Penetration of PSA testing was determined to be the lowest in 50-54 years men. After two years GP based PSA testing service resulted in decreased incidence of localized and locally advanced prostate cancer across 50-75 years men group. Results of the study suggest that men younger than 60 years need to be involved in early detection program by additional means of information. The active surveillance should be widely used for management of the low-risk prostate cancer.