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Previous evidence supports androgen deprivation therapy (ADT) with primary radiotherapy as initial treatment for intermediate-risk and high-risk localised prostate cancer. However, the use and optimal duration of ADT with postoperative radiotherapy after radical prostatectomy remains uncertain. RADICALS-HD was a randomised controlled trial of ADT duration within the RADICALS protocol. Here, we report on the comparison of short-course versus long-course ADT. Key eligibility criteria were indication for radiotherapy after previous radical prostatectomy for prostate cancer, prostate-specific antigen less than 5 ng/mL, absence of metastatic disease, and written consent. Participants were randomly assigned (1:1) to add 6 months of ADT (short-course ADT) or 24 months of ADT (long-course ADT) to radiotherapy, using subcutaneous gonadotrophin-releasing hormone analogue (monthly in the short-course ADT group and 3-monthly in the long-course ADT group), daily oral bicalutamide monotherapy 150 mg, or monthly subcutaneous degarelix. Randomisation was done centrally through minimisation with a random element, stratified by Gleason score, positive margins, radiotherapy timing, planned radiotherapy schedule, and planned type of ADT, in a computerised system. The allocated treatment was not masked. The primary outcome measure was metastasis-free survival, defined as metastasis arising from prostate cancer or death from any cause. The comparison had more than 80% power with two-sided α of 5% to detect an absolute increase in 10-year metastasis-free survival from 75% to 81% (hazard ratio [HR] 0·72). Standard time-to-event analyses were used. Analyses followed intention-to-treat principle. The trial is registered with the ISRCTN registry, ISRCTN40814031, and ClinicalTrials.gov, NCT00541047. Between Jan 30, 2008, and July 7, 2015, 1523 patients (median age 65 years, IQR 60–69) were randomly assigned to receive short-course ADT (n=761) or long-course ADT (n=762) in addition to postoperative radiotherapy at 138 centres in Canada, Denmark, Ireland, and the UK. With a median follow-up of 8·9 years (7·0–10·0), 313 metastasis-free survival events were reported overall (174 in the short-course ADT group and 139 in the long-course ADT group; HR 0·773 [95% CI 0·612–0·975]; p=0·029). 10-year metastasis-free survival was 71·9% (95% CI 67·6–75·7) in the short-course ADT group and 78·1% (74·2–81·5) in the long-course ADT group. Toxicity of grade 3 or higher was reported for 105 (14%) of 753 participants in the short-course ADT group and 142 (19%) of 757 participants in the long-course ADT group (p=0·025), with no treatment-related deaths. Compared with adding 6 months of ADT, adding 24 months of ADT improved metastasis-free survival in people receiving postoperative radiotherapy. For individuals who can accept the additional duration of adverse effects, long-course ADT should be offered with postoperative radiotherapy. Cancer Research UK, UK Research and Innovation (formerly Medical Research Council), and Canadian Cancer Society.

Previous evidence indicates that adjuvant, short-course androgen deprivation therapy (ADT) improves metastasis-free survival when given with primary radiotherapy for intermediate-risk and high-risk localised prostate cancer. However, the value of ADT with postoperative radiotherapy after radical prostatectomy is unclear. RADICALS-HD was an international randomised controlled trial to test the efficacy of ADT used in combination with postoperative radiotherapy for prostate cancer. Key eligibility criteria were indication for radiotherapy after radical prostatectomy for prostate cancer, prostate-specific antigen less than 5 ng/mL, absence of metastatic disease, and written consent. Participants were randomly assigned (1:1) to radiotherapy alone (no ADT) or radiotherapy with 6 months of ADT (short-course ADT), using monthly subcutaneous gonadotropin-releasing hormone analogue injections, daily oral bicalutamide monotherapy 150 mg, or monthly subcutaneous degarelix. Randomisation was done centrally through minimisation with a random element, stratified by Gleason score, positive margins, radiotherapy timing, planned radiotherapy schedule, and planned type of ADT, in a computerised system. The allocated treatment was not masked. The primary outcome measure was metastasis-free survival, defined as distant metastasis arising from prostate cancer or death from any cause. Standard survival analysis methods were used, accounting for randomisation stratification factors. The trial had 80% power with two-sided α of 5% to detect an absolute increase in 10-year metastasis-free survival from 80% to 86% (hazard ratio [HR] 0·67). Analyses followed the intention-to-treat principle. The trial is registered with the ISRCTN registry, ISRCTN40814031, and ClinicalTrials.gov, NCT00541047. Between Nov 22, 2007, and June 29, 2015, 1480 patients (median age 66 years [IQR 61–69]) were randomly assigned to receive no ADT (n=737) or short-course ADT (n=743) in addition to postoperative radiotherapy at 121 centres in Canada, Denmark, Ireland, and the UK. With a median follow-up of 9·0 years (IQR 7·1–10·1), metastasis-free survival events were reported for 268 participants (142 in the no ADT group and 126 in the short-course ADT group; HR 0·886 [95% CI 0·688–1·140], p=0·35). 10-year metastasis-free survival was 79·2% (95% CI 75·4–82·5) in the no ADT group and 80·4% (76·6–83·6) in the short-course ADT group. Toxicity of grade 3 or higher was reported for 121 (17%) of 737 participants in the no ADT group and 100 (14%) of 743 in the short-course ADT group (p=0·15), with no treatment-related deaths. Metastatic disease is uncommon following postoperative bed radiotherapy after radical prostatectomy. Adding 6 months of ADT to this radiotherapy did not improve metastasis-free survival compared with no ADT. These findings do not support the use of short-course ADT with postoperative radiotherapy in this patient population. Cancer Research UK, UK Research and Innovation (formerly Medical Research Council), and Canadian Cancer Society.

Metformin is a widely used anti-diabetic drug. Several studies have suggested that metformin has anticancer activity in some malignancies, including prostate cancer. Metformin might also mitigate the adverse metabolic effects of androgen-deprivation therapy (ADT). We hypothesised that metformin might improve survival in patients with metastatic hormone-sensitive prostate cancer and reduce metabolic complications associated with ADT. The STAMPEDE multi-arm, multi-stage, randomised phase 3 trial recruited patients with high-risk locally advanced or metastatic adenocarcinoma of the prostate staged by conventional imaging with isotope bone and CT scanning. This publication reports findings for the most recent STAMPEDE research question, testing the addition of metformin to standard of care for non-diabetic (glycated haemoglobin [HbA1c] <48 mmol/mol [equivalent to <6·5%]) patients with metastatic disease with adequate renal function (glomerular filtration rate ≥45 ml/min/1·73 m2) and WHO performance status 0–2. This trial recruited from 112 hospitals in the UK and Switzerland to the STAMPEDE protocol. Patients were randomly allocated (1:1) to standard of care or standard of care plus metformin 850 mg twice daily. Random assignment was by telephone using minimisation with a random element of 20% (developed and maintained by the MRC Clinical Trials Unit at UCL), stratified for randomising hospital, age (<70 years vs ≥70 years), WHO performance status (0 vs 1 or 2), type of ADT, regular long-term use of aspirin or non-steroidal anti-inflammatory drugs (NSAIDs; yes vs no), pelvic nodal status (positive vs negative), planned radiotherapy (yes vs no), and planned docetaxel or androgen receptor pathway inhibitor (ARPI) use (docetaxel vs abiraterone, enzalutamide, or apalutamide vs none). Standard of care comprised ADT with or without radiotherapy and with or without docetaxel or ARPI. The primary outcome measure was overall survival, defined as the time to death from any cause, assessed in the intention-to-treat population. Safety was assessed in patients who started treatment. The trial is registered with ClinicalTrials.gov, NCT00268476 and ISRCTN, ISRCTN78818544. Between Sep 5, 2016, and Mar 31, 2023, 1874 patients with metastatic disease were randomly allocated to standard of care (n=938) or standard of care plus metformin (n=936). The median patient age was 69 years (IQR 63-73) and the median PSA was 84 ng/mL (24–352). 1758 (94%) of 1874 patients were newly diagnosed with metastatic disease and 116 (6%) were diagnosed with metachronous relapsing disease. 1543 (82%) of 1874 patients received ADT plus docetaxel and 52 (3%) received abiraterone, enzalutamide, or apalutamide. The median time to most recent case report form follow-up was 60 months (IQR 49–72). 473 deaths were reported in the standard of care group; median survival was 61·8 months (IQR 29·7 to not reached). There were 453 deaths in the metformin group; median survival was 67·4 months (32·5 to not reached; HR 0·91, 95% CI 0·80–1·03; p=0·15). Grade 3 or worse adverse events were reported in 487 (52%) of 938 patients in the standard of care group and 523 (57%) of 921 patients in the standard of care plus metformin group. 61 (7%) patients in the standard of care group and 84 (9%) patients in the standard of care plus metformin group reported at least one grade 3 or worse gastrointestinal adverse event; all other body systems showed no difference in grade 3 adverse events. There were six drug-related deaths in the standard of care group and one in the standard of care plus metformin group. We did not find significant evidence of an overall survival benefit of adding metformin to standard of care in the overall population of patients with metastatic hormone-sensitive prostate cancer. The side-effect profile of metformin was as expected and consisted mainly of diarrhoea. Adverse metabolic side-effects of ADT were significantly reduced in the metformin group compared with the standard of care group. Cancer Research UK, Prostate Cancer UK, and UK Research and Innovation Medical Research Council.

Recreational drug use and the emerging phenomenon of chemsex (the use of mephedrone, crystal methamphetamine and γ -hydroxybutyrate/γ -butryolactone (GHB/GBL) to enable, enhance and prolong sexual interactions), are of significant concern in men who have sex with men (MSM), particularly in the context of HIV and STI transmission. Prevalence data from the UK and Europe are lacking and no studies have examined changes in chemsex over time within a cohort of MSM. In this thesis I use data from two studies that recruited HIV negative MSM from sexual health clinics in England; the cross-sectional AURAH study (Attitudes to and Understanding Risk of Acquisition of HIV), 2013-2014, (n=1484), and the prospective cohort study, AURAH2 study (Attitudes to and Understanding Risk of Acquisition of HIV over Time) (n=1167), which collected online questionnaire data from 2015 to 2018. I investigate the prevalence of recreational drug use including chemsex, and associations with sexual behaviours, and examine whether prevalence of chemsex and sexual behaviour changed over time. Over half (54.7% AURAH, 60.4% AURAH2) of HIV negative MSM attending sexual health clinics self-reported recreational drug use, and whilst the proportion engaged in chemsex was less (21.8% AURAH, 32.3% AURAH2), it is significant in terms of vulnerability to HIV and STI infections. Prevalence of chemsex significantly declined during online follow-up of AURAH2 participants (n=622) from 31.8% (198/622) at first online questionnaire, to 11.1% (8/72; p < 0.001) at the 9th. Most measures of sexual behaviour also declined over the follow-up period. MSM engaged in recreational drug use, and in particular chemsex, are at significant risk of both STI and HIV infection, as well as other harms, and should be a focus for targeted prevention interventions such as regular HIV and STI testing and treatment, PrEP initiation and chemsex support, which is potentially only necessary for select, and relatively short periods of time.

Glaucoma leads to millions of cases of visual impairment and blindness around the world. Its susceptibility is shaped by both environmental and genetic risk factors. Although over 120 risk loci have been identified for glaucoma, a large portion of its heritability is still unexplained. Here we describe the foundation of the Genetics of GLaucoma Evaluation in the AMish (GGLEAM) study to investigate the genetic architecture of glaucoma in the Ohio Amish, which exhibits lower genetic and environmental heterogeneity compared to the general population. To date, we have enrolled 81 Amish individuals in our study from Holmes County, Ohio. As a part of our enrollment process, 62 GGLEAM study participants (42 glaucoma-affected and 20 unaffected individuals) received comprehensive eye examinations and glaucoma evaluations. Using the data from the Anabaptist Genealogy Database, we found that 80 of the GGLEAM study participants were related to one another through a large, multigenerational pedigree containing 1586 people. We plan to integrate the health and kinship data obtained for the GGLEAM study to interrogate glaucoma genetics and pathophysiology in this unique population.

This thesis details the synthesis of novel Rh(I) and Rh(III) bis-phosphine fragments, and their use, along with other known rhodium species, to investigate the reactivity of amine-boranes, with a particular focus on the dehydrocoupling of the secondary amine-borane H3B.NMe2H (DMAB). Chapter 2 utilises the new mixed phosphine, PtBuiBu2, to investigate the role of the phosphine with regard to the corresponding low-coordinate organometallic species isolated. Their coordination and reactivity with amine-boranes is studied, leading to the development of a mechanism for an alkene hydroboration catalyst that employs H3B.NMe3 (TMAB). The final section of the chapter studies several fluxional processes pertinent to rhodium and iridium complexes of the model amine-borane TMAB using H/D exchange and low temperature NMR experiments. In Chapter 3, the mechanism of dehydrocoupling of DMAB is investigated in detail, employing catalysts based on the cationic bis¬-phosphine Rh fragment, {Rh(PCy3)2Ln}+. A series of stoichiometric and catalytic reactions are probed using NMR spectroscopy and mass spectrometry, revealing a complex mechanistic landscape. Subtleties include: the product of dehydrocoupling, [H2BNMe2]2, acting in an autocatalytic role; and parallel dehydrogenation of DMAB by a neutral catalyst present in a low but constant concentration. The mechanism was additionally interrogated through kinetic simulations conducted by Prof. Guy C. Lloyd-Jones (University of Bristol). From this, a generic mechanistic scheme has been suggested, aspects of which can be applied to transition metal and main group systems reported to catalyse the dehydrocoupling of DMAB. The final chapter moves on from cationic rhodium fragments to investigate the reactivity of the neutral rhodium species, Rh(H)2(PCy3)2Cl and [Rh(PCy3)2Cl]2, with amine-boranes. The mechanism by which Rh(H)2(PCy3)2Cl catalyses the dehydrogenation of DMAB has been investigated through initial rate and H/D exchange experiments, leading to the proposal of a reaction scheme. Additionally, the formation and characterisation of a base-stabilised boryl species has been reported resulting from the reactivity of an amino-borane with [Rh(PCy3)2Cl]2.

The erbB family consists of four structurally related, transmembrane, receptors - the epidermal growth factor receptor (EGFr; erbBl), erbB2, erbB3 and erbB4. In association with the EGF-like growth factors, they create a potent and complex ligandreceptor network, which has been associated with a number of cell phenotypes, including proliferation and motility. The ERK kinase, PI-3 kinase and PLCy pathways have been widely implicated as downstream mediators of these effects. Deregulation of the network is common in human cancers, including ovarian tumours, and is frequently associated with poor patient survival. These observations have generated interest in the underlying mechanisms of the network, and how its disruption manifests as oncogenic malignancy. This project investigates the roles of different erbB receptors and their downstream signalling pathways in ovarian cancer systems. A panel of six cell lines (SKOV-3, PEOl, OVCAR5, A2780, 41M and PE01cddp) were chosen to represent a range of erbB receptor expression levels, and these were characterised within growth and migration assays. Growth assays were based upon cell counts, whereas migration assays were developed using transwell inserts coated with collagen IV, fibronectin and laminin. To assess the contribution of individual erbB family members to cell growth and migration, specific ligand-receptor interactions were exploited within functional assays; transforming growth factor-alpha (TGFa) binds and activates the EGFr, while neuregulin (NRG) growth factors activate erbB3 and erbB4. Such growth factor stimulation induces receptor homo- or heterodimerisation within the family, which initiates intracellular signalling. At equal concentrations (InM), NRGip was a more potent mitogen than TGFa, although both significantly increased cell growth in a number of cell lines; NRG la effects however were trivial. Although the neuregulin growth factors both associate with the same receptors, the a-isoform is known to be less potent. Therefore these data suggest that erbB3 and/or erbB4 receptors have the most significant influences upon cell proliferation and increased cell survival. Correlative analysis revealed some association between erbB3 expression levels cell growth rates (TGFa stimulated growth p=0.0069; NRGp stimulated growth p=0.0456). This is consistent with the suggestion that erbB3, probably in combination with erbB2, is the most potently mitogenic receptor complex. In migration assays, growth factor iii concentrations were varied to equalise mitogenic effects, TGFa was used at InM, whereas NRG1β was used at 0.lnM. TGFa demonstrated the most potent effects in these experiments, and a strong correlation was found between migration on collagen and cell line expression levels of erbB2 (p=0.004), suggesting an association between EGFr-erbB2 dimers and cell motility. Blockade of the EGFr, using the small molecule inhibitor Iressa (lμM), significantly reduced cell growth (in SKOV-3, PEO1 and OVCAR5 lines) and migration (in SKOV-3 and PEO1 cells). Herceptin downregulation of erbB2 was ineffective and thus had minimal impact on cell function. A subset of four cell lines (SKOV-3, PEO1, OVCAR5 and A2780) was used to analyse TGFa and NRGlp signalling effects within the ERK, PI-3 kinase and PLCy pathways. Three cell lines (SKOV-3, PEO1 and OVCAR5) showed pathway induction in response to either one or both ligands, whereas A2780 cells showed no response, but appeared to have some constitutive pathway activation. Growth factor activation of the ERK and PI- 3 kinase cascades was observed only in the lines that showed growth stimulation. Ligand activation of all three pathways occurred where cells were stimulated to migrate, possibly in a signal duration dependant manner. Specific inhibitors of MEK (PD98059 and U0126), PI-3 kinase (LY294002) and PLCy (U73122) were utilised within functional assays. Blockade of the ERK and PI-3 kinase pathways decreased cell growth in all of the cell lines. However, only blockade of PLCy was capable of inhibiting migration in all of the lines. These results are consistent with findings in other cell systems. These studies have demonstrated that the erbB3 receptor has a potent effect on cell mitogenesis and/or increased cell survival, probably through activation of the ERK and PI-3 kinase pathways. They have also shown that the EGFr in combination with erbB2 is an important drive to cell migration, predominantly utilising the PLCy pathway. These finding are relevant to ovarian cancers expressing erbB receptors, particularly those which have established an autocrine loop with stimulating ligands, and may be important for determination of patient treatment strategies in the future.

At a glance Premier 1 final: Kereru 47 (Julianna Naoupu GS 28/35, Tyler Rollo GA1 13/17, Erin McDuff GA2 6/9) beat Technical 39 (Maddy Lloyd GS1 19/26, Gemma Hazeldine GA1...

At a glance Kereru A 54 (Julianna Naoupu GS 32/37, Tyler Rollo GA1 18/21, Erin McDuff GA2 4/5) beat Lincoln University 51 (Ellie Bird GS 39/45, Bella James GA 12/13).

At a glance Technical 56 (Maddy Lloyd GS 17/29, Gemma Hazeldine GA 39/47) beat Kereru 43 (Julianna Naoupu GS 33/39, Claudia Lewis GA1 3/7, Erin McDuff GA2 6/11, Tyler Rollo...