Previous analysis of COMBI-d (NCT01584648) demonstrated improved progression-free survival (PFS) and overall survival (OS) with combination dabrafenib and trametinib versus dabrafenib monotherapy in ...BRAF V600E/K-mutant metastatic melanoma. This study was continued to assess 3-year landmark efficacy and safety after≥36-month follow-up for all living patients.
This double-blind, phase 3 study enrolled previously untreated patients with BRAF V600E/K-mutant unresectable stage IIIC or stage IV melanoma. Patients were randomized to receive dabrafenib (150mg twice daily) plus trametinib (2mg once daily) or dabrafenib plus placebo. The primary endpoint was PFS; secondary endpoints were OS, overall response, duration of response, safety, and pharmacokinetics.
Between 4 May and 30 November 2012, a total of 423 of 947 screened patients were randomly assigned to receive dabrafenib plus trametinib (n= 211) or dabrafenib monotherapy (n = 212). At data cut-off (15 February 2016), outcomes remained superior with the combination: 3-year PFS was 22% with dabrafenib plus trametinib versus 12% with monotherapy, and 3-year OS was 44% versus 32%, respectively. Twenty-five patients receiving monotherapy crossed over to combination therapy, with continued follow-up under the monotherapy arm (per intent-to-treat principle). Of combination-arm patients alive at 3 years, 58% remained on dabrafenib plus trametinib. Three-year OS with the combination reached 62% in the most favourable subgroup (normal lactate dehydrogenase and<3 organ sites with metastasis) versus only 25% in the unfavourable subgroup (elevated lactate dehydrogenase). The dabrafenib plus trametinib safety profile was consistent with previous clinical trial observations, and no new safety signals were detected with long-term use.
These data demonstrate that durable (≥3 years) survival is achievable with dabrafenib plus trametinib in patients with BRAF V600-mutant metastatic melanoma and support long-term first-line use of the combination in this setting.
In men with prostate cancer on PSA screening, radical treatments led to half the incidence of metastasis and local progression as active monitoring without affecting disease-specific or overall ...survival.
The atomic nucleus and its electrons are often thought of as independent systems that are held together in the atom by their mutual attraction. Their interaction, however, leads to other important ...effects, such as providing an additional decay mode for excited nuclear states, whereby the nucleus releases energy by ejecting an atomic electron instead of by emitting a γ-ray. This 'internal conversion' has been known for about a hundred years and can be used to study nuclei and their interaction with their electrons. In the inverse process-nuclear excitation by electron capture (NEEC)-a free electron is captured into an atomic vacancy and can excite the nucleus to a higher-energy state, provided that the kinetic energy of the free electron plus the magnitude of its binding energy once captured matches the nuclear energy difference between the two states. NEEC was predicted in 1976 and has not hitherto been observed. Here we report evidence of NEEC in molybdenum-93 and determine the probability and cross-section for the process in a beam-based experimental scenario. Our results provide a standard for the assessment of theoretical models relevant to NEEC, which predict cross-sections that span many orders of magnitude. The greatest practical effect of the NEEC process may be on the survival of nuclei in stellar environments, in which it could excite isomers (that is, long-lived nuclear states) to shorter-lived states. Such excitations may reduce the abundance of the isotope after its production. This is an example of 'isomer depletion', which has been investigated previously through other reactions, but is used here to obtain evidence for NEEC.
We have carried out a cell-based screen aimed at discovering small molecules that activate p53 and have the potential to decrease tumor growth. Here, we describe one of our hit compounds, tenovin-1, ...along with a more water-soluble analog, tenovin-6. Via a yeast genetic screen, biochemical assays, and target validation studies in mammalian cells, we show that tenovins act through inhibition of the protein-deacetylating activities of SirT1 and SirT2, two important members of the sirtuin family. Tenovins are active on mammalian cells at one-digit micromolar concentrations and decrease tumor growth in vivo as single agents. This underscores the utility of these compounds as biological tools for the study of sirtuin function as well as their potential therapeutic interest.
In the ProtecT trial, over 1600 men with PSA-detected localized prostate cancer were assigned to active monitoring, prostatectomy, or radiotherapy. Although more patients assigned to active ...monitoring had disease progression, overall survival was similar in the three groups.
The management of clinically localized prostate cancer that is detected on the basis of prostate-specific antigen (PSA) levels remains controversial. In the United States alone, an estimated 180,890 cases will be diagnosed in 2016, and 26,120 men will die from the disease.
1
The widespread use of PSA testing has resulted in a dramatic increase in the diagnosis and treatment of prostate cancer, but many men do not benefit from intervention because the disease is either indolent or disseminated at diagnosis. Prostate cancer often progresses slowly, and many men die of competing causes. In addition, interventions for prostate cancer can have . . .
Purpose
To conduct a review of the current state of the evidence for rehabilitation strategies post-fragility fracture.
Methods
Narrative review conducted by the Rehabilitation Working Group of the ...International Osteoporosis Foundation Committee of Scientific Advisors characterizing the range of rehabilitation modalities instrumental for the management of fragility fractures.
Results
Multi-modal exercise post-fragility fracture to the spine and hip is strongly recommended to reduce pain, improve physical function, and improve quality of life. Outpatient physiotherapy post-hip fracture has a stronger evidence base than outpatient physiotherapy post-vertebral fracture. Appropriate nutritional care after fragility fracture provides a large range of improvement in morbidity and mortality. Education increases understanding of osteoporosis which in turn increases utilization of other rehabilitation services. Education may improve other health outcomes such as pain and increase a patient’s ability for self-advocacy.
Conclusion
Rehabilitation interventions are inter-reliant, and research investigating the interaction of exercise, nutrition, and other multi-modal therapies may increase the relevance of rehabilitation research to clinical care.
OX40, OX40L and Autoimmunity: a Comprehensive Review Webb, Gwilym J.; Hirschfield, Gideon M.; Lane, Peter J. L.
Clinical Reviews in Allergy & Immunology,
06/2016, Letnik:
50, Številka:
3
Journal Article, Book Review
Recenzirano
The tumour necrosis factor receptor OX40 (CD134) is activated by its cognate ligand OX40L (CD134L, CD252) and functions as a T cell co-stimulatory molecule. OX40-OX40L interactions have been proposed ...as a potential therapeutic target for treating autoimmunity. OX40 is expressed on activated T cells, and in the mouse at rest on regulatory T cells (Treg). OX40L is found on antigen-presenting cells, activated T cells and others including lymphoid tissue inducer cells, some endothelia and mast cells. Expression of both molecules is increased after antigen presentation occurs and also in response to multiple other pro-inflammatory factors including CD28 ligation, CD40L ligation and interferon-gamma signaling. Their interactions promote T cell survival, promote an effector T cell phenotype, promote T cell memory, tend to reduce regulatory function, increase effector cytokine production and enhance cell mobility. In some circumstances, OX40 agonism may be associated with increased tolerance, although timing with respect to antigenic stimulus is important. Further, recent work has suggested that OX40L blockade may be more effective than OX40 blockade in reducing autoimmunity. This article reviews the expression of OX40 and OX40L in health, the effects of their interactions and insights from their under- or over-expression. We then review OX40 and OX40L expression in human autoimmune disease, identified associations of variations in their genes (
TNFRSF4
and
TNFSF4
, respectively) with autoimmunity, and data from animal models of human diseases. A rationale for blocking OX40-OX40L interaction in human autoimmunity is then presented along with commentary on the one trial of OX40L blockade in human disease conducted to date. Finally, we discuss potential problems with clinical use of OX40-OX40L directed pharmacotherapy.
Benchmarking model performance across large samples of
catchments is useful to guide model selection and future model development.
Given uncertainties in the observational data we use to drive and ...evaluate
hydrological models, and uncertainties in the structure and parameterisation
of models we use to produce hydrological simulations and predictions, it is
essential that model evaluation is undertaken within an uncertainty analysis
framework. Here, we benchmark the capability of several lumped hydrological
models across Great Britain by focusing on daily flow and peak flow
simulation. Four hydrological model structures from the Framework for
Understanding Structural Errors (FUSE) were applied to over 1000 catchments
in England, Wales and Scotland. Model performance was then evaluated using
standard performance metrics for daily flows and novel performance metrics
for peak flows considering parameter uncertainty. Our results show that lumped hydrological models were able to produce
adequate simulations across most of Great Britain, with each model producing
simulations exceeding a 0.5 Nash–Sutcliffe efficiency for at least 80 % of
catchments. All four models showed a similar spatial pattern of performance,
producing better simulations in the wetter catchments to the west and poor
model performance in central Scotland and south-eastern England. Poor model performance
was often linked to the catchment water balance, with models unable to
capture the catchment hydrology where the water balance did not close.
Overall, performance was similar between model structures, but different
models performed better for different catchment characteristics and metrics,
as well as for assessing daily or peak flows, leading to the ensemble of
model structures outperforming any single structure, thus demonstrating the
value of using multi-model structures across a large sample of different
catchment behaviours. This research evaluates what conceptual lumped models can achieve as a
performance benchmark and provides interesting insights into where
and why these simple models may fail. The large number of river catchments
included in this study makes it an appropriate benchmark for any future
developments of a national model of Great Britain.
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