Aggregated initiators: defining their role in the ROP of <i>rac</i>-lactide

Reported examples of aggregated initiators for the ring-opening polymerisation (ROP) of lactide often lack detailed investigations as to the nature of the active species, making it difficult to reconcile ligand design with performance.</p

Hydrochlorination of ruthenaphosphaalkenyls: unexpectedly facile access to alkylchlorohydrophosphane complexes

The novel ruthenaphosphaalkenyls [Ru{P═C(H)SiMe2R}Cl- (CO)(PPh3)2] (R = p-C6H4CF3, nBu) have been prepared for the first time, and studied alongside precedent analogues (R = Me, Ph, p-tol) for their reactions with HCl. In contrast to chemistry defined for the tert-butyl congener [Ru{P═C(H)tBu}Cl(CO)(PPh3)2], which initially adds a single equivalent of HCl across the Ru−P linkage, all five silyl derivatives undergo spontaneous addition of a second equivalent to afford [Ru{η1-PHCl−CH2SiMe2R}Cl(CO)(PPh3)2], extremely rare examples of coordinated “PHXR” type ligands. Where R = SiMe3, a distorted octahedral geometry with a conformationally restricted “PHXR” ligand is observed crystallographically; this structure is appreciably retained in solution, as determined from multinuclear NMR spectroscopic features, which include a Karplus-like PPh3−Ru−P−H spin−spin coupling dependence. Computational data suggest a silyl-induced increase in negative charge density at the phosphaalkenic carbon, rather than an intrinsic thermodynamic driver, as the likely origin of the disparate reactivity

Stability of the CpG island methylator phenotype during glioma progression and identification of methylated loci in secondary glioblastomas

BACKGROUND: Grade IV glioblastomas exist in two forms, primary (de novo) glioblastomas (pGBM) that arise without precursor lesions, and the less common secondary glioblastomas (sGBM) which develop from earlier lower grade lesions. Genetic heterogeneity between pGBM and sGBM has been documented as have differences in the methylation of individual genes. A hypermethylator phenotype in grade IV GBMs is now well documented however there has been little comparison between global methylation profiles of pGBM and sGBM samples or of methylation profiles between paired early and late sGBM samples.METHODS: We performed genome-wide methylation profiling of 20 matched pairs of early and late gliomas using the Infinium HumanMethylation450 BeadChips to assess methylation at &gt;485,000 cytosine positions within the human genome.RESULTS: Clustering of our data demonstrated a frequent hypermethylator phenotype that associated with IDH1 mutation in sGBM tumors. In 80% of cases, the hypermethylator status was retained in both the early and late tumor of the same patient, indicating limited alterations to genome-wide methylation during progression and that the CIMP phenotype is an early event. Analysis of hypermethylated loci identified 218 genes frequently methylated across grade II, III and IV tumors indicating a possible role in sGBM tumorigenesis. Comparison of our sGBM data with TCGA pGBM data indicate that IDH1 mutated GBM samples have very similar hypermethylator phenotypes, however the methylation profiles of the majority of samples with WT IDH1 that do not demonstrate a hypermethylator phenotype cluster separately from sGBM samples, indicating underlying differences in methylation profiles. We also identified 180 genes that were methylated only in sGBM. Further analysis of these genes may lead to a better understanding of the pathology of sGBM vs pGBM.CONCLUSION: This is the first study to have documented genome-wide methylation changes within paired early/late astrocytic gliomas on such a large CpG probe set, revealing a number of genes that maybe relevant to secondary gliomagenesis.</p

Structure and mechanism of acetolactate decarboxylase

Acetolactate decarboxylase catalyzes the conversion of both enantiomers of acetolactate to the (R)-enantiomer of acetoin, via a mechanism that has been shown to involve a prior rearrangement of the non-natural (R)-enantiomer substrate to the natural (S)-enantiomer. In this paper, a series of crystal structures of ALDC complex with designed transition state mimics are reported. These structures, coupled with inhibition studies and site-directed mutagenesis provide an improved understanding of the molecular processes involved in the stereoselective decarboxylation/protonation events. A mechanism for the transformation of each enantiomer of acetolactate is proposed

From Program to Policy: Expanding the Role of Community Coalitions

Background Diabetes mortality at the United States–Mexico border is twice the national average. Type 2 diabetes mellitus is increasingly diagnosed among children and adolescents. Fragmented services and scarce resources further restrict access to health care. Increased awareness of the incidence of disease and poor health outcomes became a catalyst for creating community-based coalitions and partnerships with the University of Arizona that focused on diabetes. Context Five partnerships between the communities and the University of Arizona were formed to address these health issues. They began with health promotion as their goal and were challenged to add policy and environmental change to their objectives. Understanding the meaning of policy in the community context is the first step in the transition from program to policy. Policy participation brings different groups together, strengthening ties and building trust among community members and community organizations. Methods Data on progress and outcomes were collected from multiple sources. We used the Centers for Disease Control and Prevention’s Racial and Ethnic Approaches to Community Health (REACH) 2010 Community Change Model as the capacity-building and analytic framework for supporting and documenting the transition of coalitions from program to policy. Consequences Over 5 years, the coalitions made the transition, in varying degrees, from a programmatic focus to a policy planning and advocacy focus. The coalitions raised community awareness, built community capacity, encouraged a process of “change in change agents,” and advocated for community environmental and policy shifts to improve health behaviors. Interpretation The five coalitions made environmental and policy impacts by engaging in policy advocacy. These outcomes indicate the successful, if not consistently sustained, transition from program to policy. Whether and how these “changes in change agents” are transferable to the larger community over the long term remains to be seen

Womens satisfaction with their breast prosthesis: What determines a quality prosthesis

The aim of this study is to determine what factors constitute a quality prosthesis and ascertain which factors affect prosthesis satisfaction. Sixty-four women who received full funding for their prosthesis and 38 women who received their hospital&rsquo;s usual fundingwere recruited. Women rated the information provided about breast prostheses very highly, with 85% reporting that it was &quot;very good&quot; or &quot;excellent.&quot; Satisfaction was significantly associatedwith how well the prosthesis fit (1 week,p=.001; 3 months,p=.01), level of comfort (3 months,p=.005), and appearance of the prosthesis when worn (6 months,p = .001). Quality was significantly associated with how well it fit (1 week,p = .001; 3months,p = .001), how natural it felt (1 week,p = .001; 6months,p=.01), the weight of the prosthesis (3 months,p=.003), and appearance when worn (6 months,p = .03). The results will be used to improve women&rsquo;s access to a quality prosthesis. <br /

Identification of 5 novel genes methylated in breast and other epithelial cancers

<p>Abstract</p> <p>Background</p> <p>There are several high throughput approaches to identify methylated genes in cancer. We utilized one such recently developed approach, MIRA (methylated-CpG island recovery assay) combined with CpG island arrays to identify novel genes that are epigenetically inactivated in breast cancer.</p> <p>Results</p> <p>Using this approach we identified numerous CpG islands that demonstrated aberrant DNA methylation in breast cancer cell lines. Using a combination of COBRA and sequencing of bisulphite modified DNA, we confirmed 5 novel genes frequently methylated in breast tumours; <it>EMILIN2, SALL1</it>, <it>DBC1</it>, <it>FBLN2 </it>and <it>CIDE-A</it>. Methylation frequencies ranged from between 25% and 63% in primary breast tumours, whilst matched normal breast tissue DNA was either unmethylated or demonstrated a much lower frequency of methylation compared to malignant breast tissue DNA. Furthermore expression of the above 5 genes was shown to be restored following treatment with a demethylating agent in methylated breast cancer cell lines. We have expanded this analysis across three other common epithelial cancers (lung, colorectal, prostate). We demonstrate that the above genes show varying levels of methylation in these cancers. Lastly and most importantly methylation of <it>EMILIN2 </it>was associated with poorer clinical outcome in breast cancer and was strongly associated with estrogen receptor as well as progesterone receptor positive breast cancers.</p> <p>Conclusion</p> <p>The combination of the MIRA assay with CpG island arrays is a very useful technique for identifying epigenetically inactivated genes in cancer genomes and can provide molecular markers for early cancer diagnosis, prognosis and epigenetic therapy.</p

Intravenous immunoglobulin treatment for encephalitis in children aged 6 months to 16 years: the IgNiTE RCT

Background: There are data suggesting that intravenous immunoglobulin treatment has some benefit for certain forms of encephalitis but robust evidence from large randomised controlled trials in children with all-cause encephalitis is lacking. Objective: To evaluate whether intravenous immunoglobulin treatment improves neurological outcomes in childhood encephalitis when given early in the illness. Design: Phase 3b, investigator-initiated, randomised, double-blind, placebo-controlled trial of intravenous immunoglobulin for the treatment of encephalitis in children. Setting: Twenty-one NHS Hospitals in the UK. Participants: Children aged 6 months to 16 years with a diagnosis of acute or sub-acute encephalitis. Intervention: Two doses (1 g/kg/dose) of either intravenous immunoglobulin or matching placebo, given 24–36 hours apart, in addition to standard treatment. Main outcome measure: Participants were followed up for 12 months (+/– 4 weeks) after randomisation. The primary outcome measure was a ‘good recovery’ defined as a score of ≤ 2 on the Paediatric Glasgow Outcome Score Extended at 12 months after randomisation. Secondary outcomes: The secondary outcomes were clinical, neurological, neuroimaging and neuropsychological results, identification of the proportion of children with immune-mediated encephalitis, and intravenous immunoglobulin safety data. Results: We planned to recruit 308 children over a 42-month period. After enrolment of 18 participants (8 male; 44%) over 21 months (from December 2015 to September 2017), funding was withdrawn due to slow recruitment and the study was terminated. Ten participants were randomised to the intravenous immunoglobulin group, and eight to the placebo group, and all 18 participants were included in the analysis. At 12 months after randomisation, 9 participants [50%; intravenous immunoglobulin n = 5 (50%), placebo n = 4 (50%)] made good recovery and 5 participants [28%; intravenous immunoglobulin n = 3 (30%), placebo n = 2 (25%)] made a poor recovery. Three participants in the placebo group (43%) experienced a total of 10 serious adverse events compared with none in the intravenous immunoglobulin group but none of the adverse events were judged to be related to the study treatment. No deaths occurred during the study period. Conclusion: ImmunoglobuliN in the Treatment of Encephalitis (IgNiTE) was halted prematurely due to slow recruitment. Given the small sample size, the study was underpowered to evaluate the effect of intravenous immunoglobulin when compared with placebo in childhood encephalitis. The study findings, albeit from a small sample size, support existing evidence that encephalitis results in poor neurological outcomes for many children. Lessons learned from the ImmunoglobuliN in the Treatment of Encephalitis trial would be valuable for the success of future trials set up to address the efficacy of early treatment with intravenous immunoglobulin in all-cause encephalitis in children. Study limitations and future work: The study was underpowered to evaluate the efficacy of intravenous immunoglobulin in the treatment of childhood encephalitis due to the small sample size achieved. Future trials should seek to address this important question. Trial registration: This trial is registered as Clinical Trials.gov (NCT02308982) and ISRCTN15791925. Funding: This award was funded by the National Institute for Health and Care Research (NIHR) Efficacy and Mechanism Evaluation (EME) programme (NIHR award ref: 12/212/15) and is published in full in Efficacy and Mechanism Evaluation; Vol. 11, No. 6. See the NIHR Funding and Awards website for further award information