Abstract Background Atorvastatin and metformin are known energy restricting mimetic agents that act synergistically to produce molecular and metabolic changes in advanced prostate cancer (PCa). This ...trial seeks to determine whether these drugs favourably alter selected parameters in men with clinically-localized, aggressive PCa. Methods/design This prospective phase II randomized, controlled window trial is recruiting men with clinically significant PCa, confirmed by biopsy following multiparametric MRI and intending to undergo radical prostatectomy. Ethical approval was granted by the Royal Brisbane and Women's Hospital Human and The University of Queensland Medical Research Ethics Committees. Participants are being randomized into four groups: metformin with placebo; atorvastatin with placebo; metformin with atorvastatin; or placebo alone. Capsules are consumed for 8 weeks, a duration selected as the most appropriate period in which histological and biochemical changes may be observed while allowing prompt treatment with curative intent of clinically significant PCa. At recruitment and prior to RP, participants provide blood, urine and seminal fluid. A subset of participants will undergo 7Tesla magnetic resonance spectroscopy to compare metabolites in-vivo with those in seminal fluid and biopsied tissue. The primary end point is biochemical evolution, defined using biomarkers (serum prostate specific antigen; PCA3 and citrate in seminal fluid and prostatic tissue). Standard pathological assessment will be undertaken. Discussion This study is designed to assess the potential synergistic action of metformin and atorvastatin on PCa tumour biology. The results may determine simple methods of tumour modulation to reduce disease progression.
Access to treatment for pediatric insomnia is limited by a number of factors. Recently, the Internet has started to be used as a means of increasing access to evidence-based behavioral treatment. The ...current article describes the results of 2 studies focused on evaluating potential factors that could influence parents' use of an Internet intervention for pediatric insomnia. In Study 1, health professionals were asked to report on their perceptions of potential barriers and facilitators to their use of an Internet intervention for pediatric insomnia with their patients. Study 2 was a usability study in which participants (parents and health professionals) were asked to evaluate the usability of a beta version of an Internet intervention for pediatric insomnia (Better Nights, Better Days) that is currently under development. Results from both studies suggest that factors related to the website, as well as factors external to the website, may impact parents' use of an Internet intervention for pediatric insomnia, as well as perceptions of usability and satisfaction. The results of the current research have implications for the development of both the intervention under investigation and of future e-health interventions.
Tau is a family of microtubule-associated phosphoproteins in which isoform variation is produced by alternative splicing of a single gene and posttranslational modifications. Tau isoforms that ...include exon 10 are overexpressed in frontotemporal dementia and progressive supranuclear palsy. Therefore, we examined the expression of tau mRNA splice variants during axonal regeneration and abortive regeneration. Previous work in our laboratory demonstrated that expression of exon 10 tau isoforms during regeneration and abortive regeneration was altered and partially recapitulated the developmental patterns of tau isoform expression. Using RT-PCR, we examined the alternative splicing of exons 2 and 3 in tau during early postnatal development and regeneration in the rat spinal cord. The levels of tau lacking exons 2 and 3 were high on the day of birth and rapidly declined. Conversely, tau isoforms containing exon 2 or exons 2 and 3 first appeared at low levels and steadily increased. During axonal regeneration, the levels of all three tau mRNA isoforms were significantly lower 7 days after injury. In a model of abortive regeneration, all of the tau isoforms were elevated 14 and 42 days postinjury. The relative levels of exon 2 and 3 tau splice variants were not altered during regeneration or abortive regeneration as occurred during development. These results suggest that tau isoform expression following neuronal injury does not recapitulate the developmental pattern and is not independently regulated as in development. Our previous results together with these data suggest that alterations in tau mRNA isoform expression that occur in neurodegeneration are not secondary to axonal injury but may be a more primary event underlying cytoskeletal derangement.
Intravenous (IV) ascorbic acid (AA) improves organ function and reduces inflammation in sepsis, an inflammatory state similar to post-hematopoietic cell transplant (HCT) milieu. This salutary effect ...is mediated by antioxidant activity as well transcriptional modulation by AA. We evaluated the safety and efficacy of IV AA in ameliorating the inflammatory milieu following myeloablative conditioning and allogeneic HCT.
Methods: Patients with advanced hematologic malignancies (CML, AML, ALL, MDS) were enrolled in an IRB approved prospective phase 2 clinical trial (NCT03613727). IV AA 50mg/kg/d divided in 3 doses was given on days 1-14 after HCT followed by oral AA 500mg bid from day 15 until 6 months post HCT (IND 138924). The treatment regimens included myeloablative fludarabine & melphalan, or cyclophosphamide with either busulfan or total body irradiation. GVHD prophylaxis included ATG. FDA mandated safety lead-in cohort enrollment for the trial is complete with ongoing accrual to target primary end point of reducing 1-year non-relapse mortality. Cytokines were measured at various time points following HCT.
Results: As of October 2019 21 patients have received IV AA: these include HLA-MRD (n=5), and 10/10 or 9/10 HLA-MUD (12 & 4 respectively) recipients. Graft source was either peripheral blood (19) or bone marrow (2). Median age was 56 years; males (11). All patients enrolled were deficient in AA at day 0, median 0.3 mg/dL (range: 0.1-0.5), day 14, post AA infusion level was normal at 1.6 (1.2-5.7). Neutrophil recovery was by 11 days (9-15 days) and platelets by 12 (9-19) with sustained donor engraftment. Median absolute CD3+ cell count at day 30 was 390/mL (55-2288) with 100% donor chimerism. Pro-inflammatory cytokines IL-1b, IL-2, IL-6, IL-12, TNF-α, IFN-γ, as well as soluble thrombomodulin remained unchanged between day 0 and day 14 & day 30 after HCT (P=NS for all comparisons Figure 1). At a median follow up of 201 days (13-335) there is a 95% survival observed (Figure 2). There was no VOD and no attributable grade 3 and 4 toxicities to AA. Mucositis was mild and TPN was required in only 43% of patients. The cumulative incidences of grades II–IV and grades III–IV acute GVHD were 33% and 9% respectively, and moderate chronic GVHD 21%. No severe cGVHD has been observed, only one relapse has occurred.
Conclusions: In patients undergoing myeloablative allogeneic HCT the administration of IV ascorbic acid is safe and does not negatively impact myeloid engraftment or immune reconstitution. Pro-inflammatory cytokines and endothelial injury markers remain around baseline levels, with no VOD and low rates of GVHD observed. IV AA requires further investigation in HCT given its safety, and low cost (∼$450 for 14 day infusion in a 80 KG recipient) and potential for worldwide use.
Increasing age, numbers, and complexity of care are potentially impacting physiotherapy service delivery for adults with cystic fibrosis (CF).
This study aimed to describe physiotherapy service ...provision, scope of practice, and skill mix in a large tertiary adult CF center, and determine if services were meeting clinical practice recommendations.
A prospective cross-sectional study examined inpatient and outpatient physiotherapy care across a three-month period in a tertiary adult CF center. Physiotherapy services were described by number and skill level of physiotherapists, total hours of activity, and number, type, and duration of each physiotherapy activity.
Twenty-two physiotherapists provided care. Respiratory (n = 1058, 38%), and exercise treatments (n = 338, 12%) were the most frequent. Exercise testing (n = 20, 1%), and detailed treatment reviews (n = 79, 3%) occurred infrequently. Time for research was limited. Junior physiotherapists undertook more exercise treatments per day (p < .01), with senior physiotherapists attending outpatient clinics (p < .01).
A large number of physiotherapists were involved in the delivery of services. Recommended respiratory and exercise treatments were frequently provided; however, other recommended activities occurred infrequently. The impact of increasing age, numbers of patients, and complexity of care may be contributing to demand exceeding supply for physiotherapy services. Future studies are required to determine innovative approaches to address the gaps in clinical practice recommendations.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, OILJ, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK, VSZLJ
36.
Not all wine yeast are equal Bartowsky, Eveline; Bellon, Jenny; Borneman, Anthony ...
Microbiology Australia,
05/2007, Letnik:
28, Številka:
2
Journal Article
Recenzirano
Odprti dostop
It may come as a surprise to learn that there are over 200 commercial strains of Saccharomyces cerevisiae available for winemakers to work their magic on grape juice. Why so many? Surely one or two ...reliable workhorse strains should suffice; after all, don?t they just make ethanol from sugar? The answer to this is an emphatic no; the more we look at the role(s) of yeast in winemaking, the more we are learning about their influences on appearance, aroma, flavour, mouthfeel and final ethanol concentration. And different yeast are more or less robust and efficient in converting the hostile environment of grape juice into wine. Indeed, not all wine yeasts are equal.
Herpes simplex virus thymidine kinase (HSV-TK) and ganciclovir (GCV) gene therapy can induce apoptosis in tumor cells that are normally resistant to this type of cell death, although the cellular ...mechanisms by which this occurs remain to be elucidated. Human colon tumor cell lines expressing HSV-TK were treated with GCV or four other inducers of apoptosis: butyrate, camptothecin (CPT), Taxol (paclitaxel), or 7-hydroxystaurosporine (UCN-01). Over a 2-4 day treatment period with GCV or the other four drugs, protein levels of the apoptosis agonist Bak increased 1.5- to 3-fold, whereas a corresponding decrease in the levels of the apoptosis antagonist, Bcl-X(L), was observed in butyrate-, CPT-, and 7-hydroxystaurosporine (UCN-01)-treated cells. GCV and paclitaxel treatments resulted in increased levels of Bcl-X(L). In two-drug combinations with GCV plus one of the four other drugs, increased tumor cell killing was found with GCV plus UCN-01 or with some GCV/butyrate combinations; the other two tested combinations were largely antagonistic. The GCV/UCN-01 and GCV/butyrate combinations resulted in increased Bak and decreased Bcl-X(L) protein levels, while the GCV/CPT and GCV/paclitaxel combinations resulted in increased levels of both proteins. The results highlight the potential for new combination therapies of HSV-TK/GCV and chemotherapeutic drugs that result in increased tumor cell apoptosis for future treatments of colon cancer.
Herpes simplex virus thymidine kinase (HSV-TK) and ganciclovir (GCV) gene therapy can induce apoptosis in tumor cells that are normally resistant to this type of cell death, although the cellular ...mechanisms by which this occurs remain to be elucidated. Human colon tumor cell lines expressing HSV-TK were treated with GCV or four other inducers of apoptosis: butyrate, camptothecin (CPT), Taxol (paclitaxel), or 7-hydroxystaurosporine (UCN-01). Over a 2-4 day treatment period with GCV or the other four drugs, protein levels of the apoptosis agonist Bak increased 1.5- to 3-fold, whereas a corresponding decrease in the levels of the apoptosis antagonist, Bcl-X(L), was observed in butyrate-, CPT-, and 7-hydroxystaurosporine (UCN-01)-treated cells. GCV and paclitaxel treatments resulted in increased levels of Bcl-X(L). In two-drug combinations with GCV plus one of the four other drugs, increased tumor cell killing was found with GCV plus UCN-01 or with some GCV/butyrate combinations; the other two tested combinations were largely antagonistic. The GCV/UCN-01 and GCV/butyrate combinations resulted in increased Bak and decreased Bcl-X(L) protein levels, while the GCV/CPT and GCV/paclitaxel combinations resulted in increased levels of both proteins. The results highlight the potential for new combination therapies of HSV-TK/GCV and chemotherapeutic drugs that result in increased tumor cell apoptosis for future treatments of colon cancer.
This document provides the final two appendixes for "Improving Teaching Effectiveness: Implementation. The Intensive Partnerships for Effective Teaching through 2013-2014" (ED580306). Appendix D ...provides detailed discussions of lever implementation for each site along with the detailed coded lever tables. Appendix E summarizes the responses of teachers and school leaders to survey questions about the allocation of their work time.
To improve the U.S. education system through more-effective classroom teaching, in school year 2009-2010, the Bill and Melinda Gates Foundation announced four Intensive Partnership for Effective ...Teaching sites. The Intensive Partnerships Initiative is based on the premise that efforts to improve instruction can benefit from high-quality measures of teaching effectiveness. The initiative seeks to determine whether a school can implement a high-quality measure of teaching effectiveness and use it to support and manage teachers in ways that improve student outcomes. This approach is consistent with broader national trends in which performance-based teacher evaluation is increasingly being mandated at state and local levels. To test the theory in practice, the foundation sought partnership sites. It selected three school districts--Hillsborough County Public Schools in Florida, Shelby County Schools in Tennessee, and Pittsburgh Public Schools in Pennsylvania. The foundation also selected four charter management organizations--Alliance College-Ready Public Schools, Aspire Public Schools, Green Dot Public Schools, and the Partnerships to Uplift Communities, all in California. To evaluate Intensive Partnership implementation, researchers from the RAND Corporation and the American Institutes for Research interviewed annually central office staff at each site and teachers and other staff in a sample of schools for each site. They also used data from annual teacher and school-leader surveys and documents that the sites and the foundation provided. This report summarizes the implementation status of key reform elements at each site when the Intensive Partnerships initiative launched and five years later in the spring of 2014. For the executive summary, see ED580307. For Appendixes D and E, see ED580322.
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