Identification of Epigenetic Targets in Prostate Cancer for Therapeutic Development

Recurrent castration resistant prostate cancer remains a challenge for cancer therapies and novel treatment options in addition to current anti-androgen and mitosis inhibitors are needed. Aberrations in epigenetic enzymes and chromatin binding proteins have been linked to prostate cancer and they may form a novel class of drug targets in the future. In this thesis we systematically evaluated the epigenenome as a prostate cancer drug target. We functionally silenced 615 known and putative epigenetically active protein coding genes in prostate cancer cell lines using high throughput RNAi screening and evaluated the effects on cell proliferation, androgen receptor (AR) expression and histone patterns. Histone deacetylases (HDACs) were found to regulate AR expression. Furthermore, HDAC inhibitors reduced AR signaling and inhibited synergistically with androgen deprivation prostate cancer cell proliferation. In particular, TMPRSS2- EGR fusion gene positive prostate cancer cell lines were sensitive to combined HDAC and AR inhibition, which may partly be related to the dependency of a fusion gene induced epigenetic pathway. Histone demethylases (HDMs) were identified to regulate prostate cancer cell line proliferation. We discovered a novel histone JmjC-domain histone demethylase PHF8 to be highly expressed in high grade prostate cancers and mediate cell proliferation, migration and invasion in in vitro models. Additionally, we explored novel HDM inhibitor chemical structures using virtual screening methods. The structures best fitting to the active pocket of KDM4A were tested for enzyme inhibition and prostate cancer cell proliferation activity in vitro. In conclusion, our results show that prostate cancer may efficiently be targeted with combined AR and HDAC inhibition which is also currently being tested in clinical trials. HDMs were identified as another feasible novel drug target class. Future studies in representative animal models and development of specific inhibitors may reveal HDMs full potential in prostate cancer therapySiirretty Doriast

Fibre-optic endoscopic evaluation of swallowing as a second-stage diagnostic tool in 117 patients with dysphagia

Peer reviewe

A randomised, double-blinded, placebocontrolled clinical study on intra-articular hyaluronan treatment in equine lameness originating from the metacarpophalangeal joint

Background: Intra-articular inflammation resulting in lameness is a common health problem in horses. Exogenous intra-articular hyaluronic acid has been shown to provide an analgesic effect and reduce pain in equine and human osteoarthritis. High molecular weight non-animal stabilized hyaluronic acid (NASHA) has gained popularity in the treatment of human arthritic conditions due to its long-acting pain-relieving effects. The aim of this study was to compare the response to treatment of lameness localized in the equine metacarpophalangeal joint injected with non-animal stabilized hyaluronic acid (NASHA) and placebo (saline). Twenty-seven clinically lame horses with a positive response to diagnostic intra-articular anaesthesia of the metacarpophalangeal joint and with no, or at most mild, radiographic changes in this joint were included in the study. Horses in the treatment group (n = 14) received 3 mL of a NASHA product intra-articularly, and those in the placebo group (n = 13) received an equivalent volume of sterile 0.9 % saline solution. Results: The change in the lameness score did not significantly differ between NASHA and placebo groups (P = 0.94). Scores in the flexion test improved more in the NASHA group compared with placebo (P = 0.01). The changes in effusion and pain in flexion were similar (P = 0.94 and P = 0.27, respectively) when NASHA and placebo groups were compared. A telephone interview follow-up of the owners three months post-treatment revealed that 14 of the 21 horses (67 %) were able to perform at their previous level of exercise. Conclusions: In the present study, a single IA NASHA injection was not better than a single saline injection for reducing lameness in horses with synovitis or mild osteoarthritis. However, the results of this study indicate that IA NASHA may have some beneficial effects in modifying mild clinical signs but more research is needed to evaluate whether the positive effect documented ie. reduced response in the flexion test is a true treatment effect.Peer reviewe

Activating transcription factor 3 is a positive regulator of human IFNG gene expression

IL-12 and IL-18 are essential for Th1 differentiation, whereas the role of IFN-α in Th1 development is less understood. In this microarray-based study, we searched for genes that are regulated by IFN-α, IL-12, or the combination of IL-12 plus IL-18 during the early differentiation of human umbilical cord blood CD4+ Th cells. Twenty-six genes were similarly regulated in response to treatment with IL-12, IFN-α, or the combination of IL-12 plus IL-18. These genes could therefore play a role in Th1 lineage decision. Transcription factor activating transcription factor (ATF) 3 was upregulated by these cytokines and selected for further study. Ectopic expression of ATF3 in CD4+ T cells enhanced the production of IFN-α, the hallmark cytokine of Th1 cells, whereas small interfering RNA knockdown of ATF3 reduced IFN-γ production. Furthermore, ATF3 formed an endogenous complex with JUN in CD4+ T cells induced to Th1. Chromatin immunoprecipitation and luciferase reporter assays showed that both ATF3 and JUN are recruited to and transactivate the IFNG promoter during early Th1 differentiation. Collectively, these data indicate that ATF3 promotes human Th1 differentiation

Evaluating Complementary Therapies for Canine Osteoarthritis—Part II: A Homeopathic Combination Preparation (Zeel®)

A homeopathic combination preparation (HCP) for canine osteoarthritic pain was evaluated in a randomized, double-controlled and double-blinded clinical trial. Forty-four dogs with osteoarthritis (OA) that were randomly allocated into one of three groups completed the study. All dogs were fed test products or placebo for 8 weeks. The dogs were evaluated at the clinic four times, with 4-week intervals. Six different variables were assessed: veterinary-assessed mobility, two force plate variables, an owner-evaluated chronic pain index and pain and locomotion visual analogue scales (VASs). Intake of extra non-steroidal anti-inflammatory drugs was also evaluated. A Chi-squared test and a Mann–Whitney test were used to determine significant improvement between groups. When changed into dichotomous responses of ‘improved’ or ‘not improved’ three out of the six variables showed a significant difference (P = 0.016, P = 0.008, P = 0.039) in improved dogs per group, between the HCP group and the placebo group. The odds ratios were over one for the same variables. As extent of improvement in the variables from start to end of treatment, the HCP product was significantly more improved in four (P = 0.015, P = 0.028, P = 0.049, P = 0.020) of the six variables, compared with the placebo. Our results indicated that the HCP Zeel® was beneficial in alleviating chronic orthopedic pain in dogs although it was not as effective as carprofen

Bemötandefrågor : politikers och tjänstemäns syn på bemötande och lagar som gäller för personer med funktionsnedsättningar i kommunal regi

Validerat; 20101217 (root

Jokaiselle lapselle isovanhempi

TIIVISTELMÄ Tia Björkman jaSanna-Mari Vaarna Jokaiselle lapselle isovanhempi –Varamummotoiminta 42s., 6 liitettä Kevät2019 Diakonia-ammattikorkeakoulu Hoitotyön koulutusohjelma Sairaanhoitaja (AMK), Terveydenhoitaja (AMK) Opinnäytetyössä selvitettiin millainen merkitys isovanhemmilla ja isovanhempi suhteella on sekä vanhemmille että lapsille. Lisäksi tavoiteltiin varamummotoiminnan näkyvyyttä, jotta toiminnalla olisi mahdollisuus laajentua maanlaajuiseksi. Opinnäytetyö toteutettiin yhdessä työelämän edustajan kanssa. Varkauden SPR:lle suunniteltiin esite, joka toimii innoittajana uusille varamummotoiminnasta kiinnostuneille. Opinnäytetyön pohjalle hankittiin tietoa käyttäen osallistuvaa havainnointia, avoimia haastattelu sekä puolistrukturoituja kysymyksiä. Kysymysten avulla selvitettiin, pitävätkö helsinkiläisen päiväkodin vanhemmat sekä lapset isovanhempien läsnäoloa tärkeänä ja millainen isovanhempien vaikutus on perheen toimintaan ja lapsen kehitykseen. Varkauden SPR:n varamummotoiminnan jäseniltä saimme tiedon, kuinka varamummotoiminta toimii, kuinka varamummoksi voi päästä, miten varamummoja perhe valitaan sekä mitkä ovat perheiden ja varamummojen ja varapappojen kokemukset toiminnasta. Isovanhemmat tuovat lasten elämään asioita, joihin vanhemmilla ei välttämättä ole aikaa. He pystyvät antamaan lapsille jakamattoman huomion, läsnäolon sekä auttamaan perhettä erilaisissa arjen asioissa. Vanhemmat saavat tukea ja apua lapsensa kasvatuksessa. Opinnäytetyön perusteella voidaan todeta isovanhemmuuden olevan erittäin tärkeä osa lapsen ja perheen elämää. Jokaisella lapsella ja perheellä tulisi olla halutessaanmahdollisuus saada tukea ja läsnäoloa isovanhemmilta tai silloin, kun heitä ei ole, tulisi perheillä olla mahdollisuus varamummoon tai varapap-paan. Asiasanat: Isovanhemmat, Lapsuus, Perh

Changes in biomarkers in equine synovial fluid two weeks after intra-articular hyaluronan treatment : a randomised double-blind clinical trial

Background: Inflammatory and degenerative activity inside the joint can be studied in vivo via analysis of synovial fluid (SF) biomarkers, which are molecular markers of inflammatory processes and tissue turnover. The aim of this study was to investigate the response of selected biomarkers in the SF after an intra-articular (IA) high-molecular-weight non-animal stabilized hyaluronic acid (NASHA) treatment. Our hypothesis was that prostaglandin E-2 (PGE(2)), substance P, aggrecan chondroitin sulfate 846 epitope (CS846), and carboxypeptide of type II collagen (CPII) concentrations in SF would decrease more in the NASHA than in the placebo group. Twenty-eight clinically lame horses with positive responses to diagnostic IA anaesthesia of the metacarpophalangeal or metatarsophalangeal joints were randomized into treatment (n = 15) and control (n = 13) groups. After collection of baseline SF samples followed by IA diagnostic anaesthesia, horses in the treatment group received 3 ml of a NASHA product IA. Those in the placebo group received an equivalent volume of sterile 0.9% saline solution. The horses were re-evaluated and a second SF sample was obtained after a 2-week period. Results: CS846 concentration decreased in the NASHA group only (P = 0.010). Both PGE(2) and CPII concentrations decreased within the groups (PGE(2), P = 0.010 for the NASHA group; P = 0.027 for the placebo group; CPII, P <0.001 for NASHA group; P = 0.009 for placebo group). No significant treatment effect for any biomarker was found between groups. NASHA induced an increase in white blood cell count; this was significant compared with baseline (P = 0.021) and the placebo group (P = 0.045). Conclusions: Although the SF concentration of the cartilage-derived biomarker CS846 decreased in the NASHA group, no statistically significant treatment effect of any of the biomarkers were observed between treatment groups. The significant increase in SF white blood cell count after IA NASHA may indicate a mild inflammatory response. However, as no clinical adverse effects were observed, we conclude that IA NASHA was well tolerated.Peer reviewe