Allosteric p97 inhibitors can overcome resistance to ATP-competitive p97 inhibitors for potential anti-cancer therapy

A major challenge of targeted cancer therapy is the selection for drug‐resistant mutations in tumor cells leading to loss of treatment effectiveness. p97/VCP is a central regulator of protein homeostasis and a promising anti‐cancer target because of its vital role in cell growth and survival. One ATP‐competitive p97 inhibitor, CB‐5083, has entered clinical trials. Selective pressure on HCT116 cells treated with CB‐5083 identified 5 different resistant mutants. Identification of p97 inhibitors with different mechanisms of action would offer the potential to overcome this class of resistance mutations. Our results demonstrate that two CB‐5083 resistant p97 mutants, N660K and T688A, were also resistant to several other ATP‐competitive p97 inhibitors, whereas inhibition by two allosteric p97 inhibitors NMS‐873 and UPCDC‐30245 were unaffected by these mutations. We also established a CB‐5083 resistant cell line that harbors a new p97 double mutation (D649A/T688A). While CB‐5083, NMS‐873, and UPCDC‐30245 all effectively inhibited proliferation of the parental HCT116 cell line, NMS‐873 and UPCDC‐30245 were 30‐fold more potent than CB‐5083 in inhibiting the CB‐5083 resistant D649A/T688A double mutant. Our results suggest that allosteric p97 inhibitors are promising alternatives when resistance to ATP‐competitive p97 inhibitors arises during anti‐cancer treatment

Allosteric p97 inhibitors can overcome resistance to ATP-competitive p97 inhibitors for potential anti-cancer therapy

A major challenge of targeted cancer therapy is the selection for drug‐resistant mutations in tumor cells leading to loss of treatment effectiveness. p97/VCP is a central regulator of protein homeostasis and a promising anti‐cancer target because of its vital role in cell growth and survival. One ATP‐competitive p97 inhibitor, CB‐5083, has entered clinical trials. Selective pressure on HCT116 cells treated with CB‐5083 identified 5 different resistant mutants. Identification of p97 inhibitors with different mechanisms of action would offer the potential to overcome this class of resistance mutations. Our results demonstrate that two CB‐5083 resistant p97 mutants, N660K and T688A, were also resistant to several other ATP‐competitive p97 inhibitors, whereas inhibition by two allosteric p97 inhibitors NMS‐873 and UPCDC‐30245 were unaffected by these mutations. We also established a CB‐5083 resistant cell line that harbors a new p97 double mutation (D649A/T688A). While CB‐5083, NMS‐873, and UPCDC‐30245 all effectively inhibited proliferation of the parental HCT116 cell line, NMS‐873 and UPCDC‐30245 were 30‐fold more potent than CB‐5083 in inhibiting the CB‐5083 resistant D649A/T688A double mutant. Our results suggest that allosteric p97 inhibitors are promising alternatives when resistance to ATP‐competitive p97 inhibitors arises during anti‐cancer treatment

An evaluation of Independent Child Trafficking Guardians – early adopter sites

This publication is licensed under the terms of the Open Government Licence v3.0 except where otherwise stated. To view this licence, visit nationalarchives.gov.uk/doc/open-government-licence/version/3This evaluation, conducted by the Home Office and the University of Bedfordshire has assessed the ICTG service in the three original early adopter sites (Greater Manchester, Hampshire, and Wales). The evaluation, conducted across a two-year period from February 2017 – January 2019, considers the original model for the ICTG service which provided one-to-one ICTG support for all children. The overall aim of the evaluation is to answer the question: What is the ‘added value’ of the ICTG service, and is this different for different groups of children and in different early adopter sites

Incident venous thromboembolic events in the Prospective Study of Pravastatin in the Elderly at Risk (PROSPER)

<p>Background: Venous thromboembolic events (VTE), including deep venous thrombosis and pulmonary embolism, are common in older age. It has been suggested that statins might reduce the risk of VTE however positive results from studies of middle aged subjects may not be generalisable to elderly people. We aimed to determine the effect of pravastatin on incident VTE in older people; we also studied the impact of clinical and plasma risk variables.</p> <p>Methods: This study was an analysis of incident VTE using data from the Prospective Study of Pravastatin in the Elderly at Risk (PROSPER), a randomized, double-blind, placebo-controlled trial of pravastatin in men and women aged 70-82. Mean follow-up was 3.2 years. Risk for VTE was examined in non-warfarin treated pravastatin (n = 2834) and placebo (n = 2865) patients using a Cox's proportional hazard model, and the impact of other risk factors assessed in a multivariate forward stepwise regression analysis. Baseline clinical characteristics, blood biochemistry and hematology variables, plasma levels of lipids and lipoproteins, and plasma markers of inflammation and adiposity were compared. Plasma markers of thrombosis and hemostasis were assessed in a nested case (n = 48) control (n = 93) study where the cohort was those participants, not on warfarin, for whom data were available.</p> <p>Results: There were 28 definite cases (1.0%) of incident VTE in the pravastatin group recipients and 20 cases (0.70%) in placebo recipients. Pravastatin did not reduce VTE in PROSPER compared to placebo [unadjusted hazard ratio (95% confidence interval) 1.42 (0.80, 2.52) p = 0.23]. Higher body mass index (BMI) [1.09 (1.02, 1.15) p = 0.0075], country [Scotland vs Netherlands 4.26 (1.00, 18.21) p = 0.050 and Ireland vs Netherlands 6.16 (1.46, 26.00) p = 0.013], lower systolic blood pressure [1.35 (1.03, 1.75) p = 0.027] and lower baseline Mini Mental State Examination (MMSE) score [1.19 (1.01, 1.41) p = 0.034] were associated with an increased risk of VTE, however only BMI, country and systolic blood pressure remained significant on multivariate analysis. In a nested case control study of definite VTE, plasma Factor VIII levels were associated with VTE [1.52 (1.01, 2.28), p = 0.044]. However no other measure of thrombosis and haemostasis was associated with increased risk of VTE.</p> <p>Conclusions: Pravastatin does not prevent VTE in elderly people at risk of vascular disease. Blood markers of haemostasis and inflammation are not strongly predictive of VTE in older age however BMI, country and lower systolic blood pressure are independently associated with VTE risk.</p&gt

New horizons: the management of hypertension in people with dementia

The optimal management of hypertension in people with dementia is uncertain. This review explores if people with dementia experience greater adverse effects from antihypertensive medications, if cognitive function is protected or worsened by controlling blood pressure (BP) and if there are subgroups of people with dementia for whom antihypertensive therapy is more likely to be harmful. Robust evidence is scant, trials of antihypertensive medications have generally excluded those with dementia. Observational data show changes in risk association over the life course, with high BP being a risk factor for cognitive decline in mid-life, while low BP is predictive in later life. It is therefore possible that excessive BP lowering in older people with dementia might harm cognition. From the existing literature, there is no direct evidence of benefit or harm from treating hypertension in people with dementia. So what practical steps can the clinician take? Assess capacity, establish patient preferences when making treatment decisions, use ambulatory monitoring to thoroughly assess BP, individualise and consider deprescribing where side effects (e.g. hypotension) outweigh the benefits. Future research might include pragmatic randomised trials of targeted deprescribing, which include patient-centred outcome measures to help support decision-making and studies to address mechanistic uncertainties

Progress in paleoclimate modeling

International audienceThis paper briefly surveys areas of paleoclimate modeling notable for recent progress. New ideas, including hypotheses giving a pivotal role to sea ice, have revitalized the low-order models used to simulate the time evolution of glacial cycles through the Pleistocene, a prohibitive length of time for comprehensive general circulation models (GCMs). In a recent breakthrough, however, GCMs have succeeded in simulating the onset of glaciations. This occurs at times (most recently, 115 kyr B.P.) when high northern latitudes are cold enough to maintain a snow cover and tropical latitudes are warm, enhancing the moisture source. More generally, the improvement in models has allowed simulations of key periods such as the Last Glacial Maximum and the mid-Holocene that compare more favorably and in more detail with paleoproxy data. These models now simulate ENSO cycles, and some of them have been shown to reproduce the reduction of ENSO activity observed in the early to middle Holocene. Modeling studies have demonstrated that the reduction is a response to the altered orbital configuration at that time. An urgent challenge for paleoclimate modeling is to explain and to simulate the abrupt changes observed during glacial epochs (i.e., Dansgaard-Oescher cycles, Heinrich events, and the Younger Dryas). Efforts have begun to simulate the last millennium. Over this time the forcing due to orbital variations is less important than the radiance changes due to volcanic eruptions and variations in solar output. Simulations of these natural variations test the models relied on for future climate change projections. They provide better estimates of the internal and naturally forced variability at centennial time scales, elucidating how unusual the recent global temperature trends are