Patient freedom to choose a weight loss diet in the treatment of overweight and obesity: a randomized dietary intervention in type 2 diabetes and pre-diabetes

BackgroundOffering the overweight or obese patient the option of choosing from a selection of weight loss diets has not been investigated in type 2 diabetes. The aim of the study was to investigate if the option to choose from, and interchange between a selection of diets (&ldquo;Choice&rdquo;), as opposed to being prescribed one set diet (&ldquo;No Choice&rdquo;), improves drop out rates and leads to improved weight loss and cardio-metabolic outcomes.MethodsThe study was a 12 month, randomized parallel intervention. A total of 144 volunteers with type 2 diabetes or pre-diabetes and a BMI &gt;27 were randomized to &ldquo;No Choice&rdquo; or &ldquo;Choice&rdquo;. Those in the No Choice group were placed on a set weight loss diet (CSIRO) with no change permitted. Those in the Choice group could choose from, and interchange between, the CSIRO, South Beach or Mediterranean diets.ResultsThere were no differences in attrition rates or weight loss between the &ldquo;Choice&rdquo; and &ldquo;No Choice&rdquo;. In a secondary analysis of the intention-to-treat weight loss data with last measured weight carried forward gave a highly significant diet group by time by gender interaction (p&thinsp;=&thinsp;0.002) with men doing better in the No Choice group overall (maximum difference &ldquo;No Choice &ldquo;-2.9&thinsp;&plusmn;&thinsp;4.6 kg vs. &ldquo;Choice&rdquo;-6.2 kg&thinsp;&plusmn;&thinsp;5.3 kg at 6 months) and women doing better in the Choice group overall (maximum difference Choice -3.1&thinsp;&plusmn;&thinsp;3.7 kg vs. &ldquo;No Choice&rdquo; -2.0 kg&thinsp;&plusmn;&thinsp;2.6 kg at 6 months).ConclusionsMen prefer direction in their weight loss advice and do less well with choice. A gender-specific approach is recommended when prescribing weight loss diets.Trial registrationanzctr.org.au ACTRN12612000310864.<br /

Targeting DNA Damage Response and Replication Stress in Pancreatic Cancer

Background and aims: Continuing recalcitrance to therapy cements pancreatic cancer (PC) as the most lethal malignancy, which is set to become the second leading cause of cancer death in our society. The study aim was to investigate the association between DNA damage response (DDR), replication stress and novel therapeutic response in PC to develop a biomarker driven therapeutic strategy targeting DDR and replication stress in PC. Methods: We interrogated the transcriptome, genome, proteome and functional characteristics of 61 novel PC patient-derived cell lines to define novel therapeutic strategies targeting DDR and replication stress. Validation was done in patient derived xenografts and human PC organoids. Results: Patient-derived cell lines faithfully recapitulate the epithelial component of pancreatic tumors including previously described molecular subtypes. Biomarkers of DDR deficiency, including a novel signature of homologous recombination deficiency, co-segregates with response to platinum (P &lt; 0.001) and PARP inhibitor therapy (P &lt; 0.001) in vitro and in vivo. We generated a novel signature of replication stress with which predicts response to ATR (P &lt; 0.018) and WEE1 inhibitor (P &lt; 0.029) treatment in both cell lines and human PC organoids. Replication stress was enriched in the squamous subtype of PC (P &lt; 0.001) but not associated with DDR deficiency. Conclusions: Replication stress and DDR deficiency are independent of each other, creating opportunities for therapy in DDR proficient PC, and post-platinum therapy

The Eyes Absent family members EYA4 and EYA1 promote PLK1 activation and successful mitosis through tyrosine dephosphorylation

Abstract The Eyes Absent proteins (EYA1-4) are a biochemically unique group of tyrosine phosphatases known to be tumour-promoting across a range of cancer types. To date, the targets of EYA phosphatase activity remain largely uncharacterised. Here, we identify Polo-like kinase 1 (PLK1) as an interactor and phosphatase substrate of EYA4 and EYA1, with pY445 on PLK1 being the primary target site. Dephosphorylation of pY445 in the G2 phase of the cell cycle is required for centrosome maturation, PLK1 localization to centrosomes, and polo-box domain (PBD) dependent interactions between PLK1 and PLK1-activation complexes. Molecular dynamics simulations support the rationale that pY445 confers a structural impairment to PBD-substrate interactions that is relieved by EYA-mediated dephosphorylation. Depletion of EYA4 or EYA1, or chemical inhibition of EYA phosphatase activity, dramatically reduces PLK1 activation, causing mitotic defects and cell death. Overall, we have characterized a phosphotyrosine signalling network governing PLK1 and mitosis

Azithromycin in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial

Background: Azithromycin has been proposed as a treatment for COVID-19 on the basis of its immunomodulatory actions. We aimed to evaluate the safety and efficacy of azithromycin in patients admitted to hospital with COVID-19. Methods: In this randomised, controlled, open-label, adaptive platform trial (Randomised Evaluation of COVID-19 Therapy [RECOVERY]), several possible treatments were compared with usual care in patients admitted to hospital with COVID-19 in the UK. The trial is underway at 176 hospitals in the UK. Eligible and consenting patients were randomly allocated to either usual standard of care alone or usual standard of care plus azithromycin 500 mg once per day by mouth or intravenously for 10 days or until discharge (or allocation to one of the other RECOVERY treatment groups). Patients were assigned via web-based simple (unstratified) randomisation with allocation concealment and were twice as likely to be randomly assigned to usual care than to any of the active treatment groups. Participants and local study staff were not masked to the allocated treatment, but all others involved in the trial were masked to the outcome data during the trial. The primary outcome was 28-day all-cause mortality, assessed in the intention-to-treat population. The trial is registered with ISRCTN, 50189673, and ClinicalTrials.gov, NCT04381936. Findings: Between April 7 and Nov 27, 2020, of 16 442 patients enrolled in the RECOVERY trial, 9433 (57%) were eligible and 7763 were included in the assessment of azithromycin. The mean age of these study participants was 65·3 years (SD 15·7) and approximately a third were women (2944 [38%] of 7763). 2582 patients were randomly allocated to receive azithromycin and 5181 patients were randomly allocated to usual care alone. Overall, 561 (22%) patients allocated to azithromycin and 1162 (22%) patients allocated to usual care died within 28 days (rate ratio 0·97, 95% CI 0·87–1·07; p=0·50). No significant difference was seen in duration of hospital stay (median 10 days [IQR 5 to &gt;28] vs 11 days [5 to &gt;28]) or the proportion of patients discharged from hospital alive within 28 days (rate ratio 1·04, 95% CI 0·98–1·10; p=0·19). Among those not on invasive mechanical ventilation at baseline, no significant difference was seen in the proportion meeting the composite endpoint of invasive mechanical ventilation or death (risk ratio 0·95, 95% CI 0·87–1·03; p=0·24). Interpretation: In patients admitted to hospital with COVID-19, azithromycin did not improve survival or other prespecified clinical outcomes. Azithromycin use in patients admitted to hospital with COVID-19 should be restricted to patients in whom there is a clear antimicrobial indication. Funding: UK Research and Innovation (Medical Research Council) and National Institute of Health Research