FKBPL:a marker of good prognosis in breast cancer

FK506-binding protein-like (FKBPL) has established roles as an anti-tumor protein, with a therapeutic peptide based on this protein, ALM201, shortly entering phase I/II clinical trials. Here, we evaluated FKBPL’s prognostic ability in primary breast cancer tissue, represented on tissue microarrays (TMA) from 3277 women recruited into five independent retrospective studies, using immunohistochemistry (IHC). In a meta-analysis, FKBPL levels were a significant predictor of BCSS; low FKBPL levels indicated poorer breast cancer specific survival (BCSS) (hazard ratio (HR) = 1.30, 95% confidence interval (CI) 1.14–1.49, p < 0.001). The prognostic impact of FKBPL remained significant after adjusting for other known prognostic factors (HR = 1.25, 95% CI 1.07–1.45, p = 0.004). For the sub-groups of 2365 estrogen receptor (ER) positive patients and 1649 tamoxifen treated patients, FKBPL was significantly associated with BCSS (HR = 1.34, 95% CI 1.13–1.58, p < 0.001, and HR = 1.25, 95% CI 1.04–1.49, p = 0.02, respectively). A univariate analysis revealed that FKBPL was also a significant predictor of relapse free interval (RFI) within the ER positive patient group, but it was only borderline significant within the smaller tamoxifen treated patient group (HR = 1.32 95% CI 1.05–1.65, p = 0.02 and HR = 1.23 95% CI 0.99–1.54, p = 0.06, respectively). The data suggests a role for FKBPL as a prognostic factor for BCSS, with the potential to be routinely evaluated within the clinic

A novel human stress response gene with a potential role in induced radioprotection and cell cycle control

EThOS - Electronic Theses Online ServiceGBUnited Kingdo

Degradation models for polyesters and their composites

Intensive studies are being carried out to use devices made of bioresorbable polymers inside the human body to provide various temporary functions. Typical examples include scaffolds for tissue engineering, fixation screws for broken bones and drug-loaded matrices for controlled-release. The development is entirely based on trial and error. The degradation rate strongly depends on the shape and size of the devices, making it difficult to transfer experience from one device to another. The degradation time ranges from weeks to years; animal and ultimately human trials have to be carried out, making the trial and error approach time-consuming and expensive. The entire field would benefit enormously from mathematical models capable of predicting the degradation and property change of the devices. This PhD project will develop such models as following: a) A multi-scale model for degradation of bioresorbable polyesters was developed. Events that occur at the molecular scale are modelled at the molecular scale using the kinetic Monte Carlo schemes while events that occur at the device scale are modelled using macroscopic diffusion model. b) A phenomenological model for simultaneous crystallisation and biodegradation of biodegradable polymers was developed. This model completed the degradation theory developed by Wang et al. at University of Leicester. c) The model in (b) was improved and applied to the analysis of accelerated degradation data. Temperature effects were taking into account by using Arrhenius relations. d) A model for the biodegradation of composite materials made of polyesters and calcium phosphates was developed. A calcium phosphate effectiveness map is established to show the conditions under which incorporating calcium phosphates into polyesters is effective, saturated or ineffective. f) A phase field model was developed for drug release from a swelling Hydroxypropyl methylcellulose matrix. This model can be readily extended to full three dimensional problems

The emerging role of FK506-binding proteins as cancer biomarkers: a focus on FKBPL

FKBPs (FK506-binding proteins) have long been recognized as key regulators of the response to immunosuppressant drugs and as co-chaperones of steroid receptor complexes. More recently, evidence has emerged suggesting that this diverse protein family may also represent cancer biomarkers owing to their roles in cancer progression and response to treatment. FKBPL (FKBP-like) is a novel FKBP with roles in GR (glucocorticoid receptor), AR (androgen receptor) and ER (oestrogen receptor) signalling. FKBPL binds Hsp90 (heat-shock protein 90) and modulates translocation, transcriptional activation and phosphorylation of these steroid receptors. It has been proposed as a novel prognostic and predictive biomarker, where high levels predict for increased recurrence-free survival in breast cancer patients and enhanced sensitivity to endocrine therapy. Since this protein family has roles in a plethora of signalling pathways, its members represent novel prognostic markers and therapeutic targets for cancer diagnosis and treatment

RALA-mediated delivery of FKBPL nucleic acid therapeutics

AIMS: RALA is a novel 30 mer bioinspired amphipathic peptide that is showing promise for gene delivery. Here, we used RALA to deliver the FK506-binding protein like – FKBPL gene (pFKBPL) – a novel member of the immunophilin protein family. FKBPL is a secreted protein, with overexpression shown to inhibit angiogenesis, tumor growth and stemness, through a variety of intra- and extracellular signaling mechanisms. We also elucidated proangiogenic activity and stemness after utilizing RALA to deliver siRNA (siFKBPL). MATERIALS & METHODS: The RALA/pFKBPL and RALA/siFKBPL nanoparticles were characterized in terms of size, charge, stability and toxicity. Overexpression and knockdown of FKBPL was assessed in vitro and in vivo. RESULTS: RALA delivered both pFKBPL and siFKBPL with less cytotoxicity than commercially available counterparts. In vivo, RALA/pFKBPL delivery retarded tumor growth, and prolonged survival with an associated decrease in angiogenesis, while RALA/siFKBPL had no effect on tumor growth rate or survival, but resulted in an increase in angiogenesis and stemness. CONCLUSION: RALA is an effective delivery system for both FKBPL DNA and RNAi and highlights an alternative therapeutic approach to harnessing FKBPL's antiangiogenic and antistemness activity

Kasvattajien kokemuksia vanhempien kanssa tehtävästä yhteistyöstä varhaiskasvatuksessa : "Kunniatyö mulle, se, että ne on ottanu mukaan heidän lapsensa kasvatukseen"

Opinnäytetyön tavoitteena oli selvittää varhaiskasvattajien kokemuksia yhteistyöstä vanhempien kanssa. Lisäksi selvitettiin, millaiset toimintamallit ja käytänteet koetaan edistävinä, sekä mitkä tekijät ovat esteenä yhteistyön sujumiselle. Opinnäytetyö oli laadullinen. Tutkimusaineisto kerättiin kahdella eri ryhmäkeskustelukerralla, joihin osallistui yhteensä 10 kasvattajaa. Aineisto analysointiin soveltaen sisällönanalyysia. Varhaiskasvattajat kokivat yhteistyön luontevaksi osaksi varhaiskasvatustyötä. Vanhemmuuden ja lapsen kehityksen tukeminen nousivat vahvasti esille varhaiskasvattajien puheessa. Luottamus, avoimuus ja kunnioitus sekä niiden merkitys korostuivat avainsanoina tuloksissa. Haasteiksi varhaiskasvattajat nimesivät sekä vanhempien että varhaiskasvattajien kiireen, henkilökuntaresurssit, rauhallisen tilan löytämisen, työskentelytavat ja lasten osa-aikaisen hoidon. Kulttuurilliset ja kielelliset erot koetaan tulevaisuuden haasteiksi. Opinnäytetyötä voidaan käyttää osana varhaiskasvatuksen kehittämistä. Opinnäytetyön tuloksia voidaan käyttää myös työyhteisön kehittämisessä. Jatkotutkimuksena voisi kartoittaa vanhempien kokemuksia osallisuudesta ja yhteistyöstä varhaiskasvatuksessa.The purpose of this thesis was to study how day care educators experience the coopera-tion with parents. In addition, procedures that are considered either to promote or hinder the collaboration were examined. The thesis is a qualitative research. The data were collected during two group discussions in which altogether 10 day-care educators participated. The data were analysed using con-tent data analysis. Day-care educators considered the cooperation to be a natural part of early education. Supporting both parenthood and a child's development was highlighted in the educators' narrative. Trust, openness and respect appeared to be essential in this research whereas staff resources, ways of working, part-time day care, finding a calm space and educators' and parents' constant hurry were regarded as challenging by day care educators. Future challenges may include cultural and language-related differences. The results of this research can be utilised in developing early education. In addition, the results can be applied to developing work communities in early education. Further studies could be conducted on parents' experiences of cooperation and participation in day care

FKBPL regulates estrogen receptor signaling and determines response to endocrine therapy

The HSP90 chaperone and immunophilin FKBPL is an estrogen-responsive gene that interacts with estogen receptor alpha (ER alpha) and regulates its levels. In this study, we explored the effects of FKBPL on breast cancer proliferation. Breast cancer cells stably overexpressing FKBPL became dependent on estrogen for their growth and were dramatically more sensitive to the antiestrogens tamoxifen and fulvestrant, whereas FKBPL knockdown reverses this phenotype. FKBPL knockdown also decreased the levels of the cell cycle inhibitor p21WAF1 and increased ERa phosphorylation on Ser(118) in response to 17 beta-estradiol and tamoxifen. In support of the likelihood that these effects explained FKBPL-mediated cell growth inhibition and sensitivity to endocrine therapies, FKBPL expression was correlated with increased overall survival and distant metastasis-free survival in breast cancer patients. Our findings suggest that FKBPL may have prognostic value based on its impact on tumor proliferative capacity and sensitivity to endocrine therapies, which improve outcome. Cancer Res; 70(3); 1090-100. (C)2010 AACR