Germline variants in the melanocortin 1 receptor gene (MC1R) might increase the risk of childhood and adolescent melanoma, but a clear conclusion is challenging because of the low number of studies ...and cases. We assessed the association of MC1R variants with childhood and adolescent melanoma in a large study comparing the prevalence of MC1R variants in child or adolescent patients with melanoma to that in adult patients with melanoma and in healthy adult controls.
In this retrospective pooled analysis, we used the M-SKIP Project, the Italian Melanoma Intergroup, and other European groups (with participants from Australia, Canada, France, Greece, Italy, the Netherlands, Serbia, Spain, Sweden, Turkey, and the USA) to assemble an international multicentre cohort. We gathered phenotypic and genetic data from children or adolescents diagnosed with sporadic single-primary cutaneous melanoma at age 20 years or younger, adult patients with sporadic single-primary cutaneous melanoma diagnosed at age 35 years or older, and healthy adult individuals as controls. We calculated odds ratios (ORs) for childhood and adolescent melanoma associated with MC1R variants by multivariable logistic regression. Subgroup analysis was done for children aged 18 or younger and 14 years or younger.
We analysed data from 233 young patients, 932 adult patients, and 932 healthy adult controls. Children and adolescents had higher odds of carrying MC1R r variants than did adult patients (OR 1·54, 95% CI 1·02-2·33), including when analysis was restricted to patients aged 18 years or younger (1·80, 1·06-3·07). All investigated variants, except Arg160Trp, tended, to varying degrees, to have higher frequencies in young patients than in adult patients, with significantly higher frequencies found for Val60Leu (OR 1·60, 95% CI 1·05-2·44; p=0·04) and Asp294His (2·15, 1·05-4·40; p=0·04). Compared with those of healthy controls, young patients with melanoma had significantly higher frequencies of any MC1R variants.
Our pooled analysis of MC1R genetic data of young patients with melanoma showed that MC1R r variants were more prevalent in childhood and adolescent melanoma than in adult melanoma, especially in patients aged 18 years or younger. Our findings support the role of MC1R in childhood and adolescent melanoma susceptibility, with a potential clinical relevance for developing early melanoma detection and preventive strategies.
SPD-Pilot/Project-Award-2015; AIRC-MFAG-11831.
The use of personal monitors for the assessment of exposure to radiofrequency fields and radiation in potential future epidemiological studies of occupationally exposed populations has been ...investigated. Data loggers have been developed for use with a commercially available personal monitor and these allowed personal exposure records consisting of time-tagged measurements of electric and magnetic field strength to be accrued over extended periods of the working day. The instrumentation was worn by workers carrying out tasks representative of some of their typical daily activities at a variety of radio sites. The results indicated significant differences in the exposures of workers in various RF environments. A number of measures of exposure have been examined with a view to assessing possible exposure metrics for epidemiological studies. There was generally a good correlation between a given measure of electric field strength and the same measure of magnetic field strength.
Abemaciclib, an inhibitor of cyclin dependent kinases 4 and 6 (CDK4/6), has recently been approved for the treatment of hormone receptor-positive breast cancer. In this study, we use murine syngeneic ...tumor models and in vitro assays to investigate the impact of abemaciclib on T cells, the tumor immune microenvironment and the ability to combine with anti-PD-L1 blockade. Abemaciclib monotherapy resulted in tumor growth delay that was associated with an increased T cell inflammatory signature in tumors. Combination with anti-PD-L1 therapy led to complete tumor regressions and immunological memory, accompanied by enhanced antigen presentation, a T cell inflamed phenotype, and enhanced cell cycle control. In vitro, treatment with abemaciclib resulted in increased activation of human T cells and upregulated expression of antigen presentation genes in MCF-7 breast cancer cells. These data collectively support the clinical investigation of the combination of abemaciclib with agents such as anti-PD-L1 that modulate T cell anti-tumor immunity.
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•Abemaciclib monotherapy induces intra-tumor T cell inflammatory signature•Treatment causes MHC class I and II upregulation in tumor cells and increased NFAT signaling in T cells•Synergy with PD-L1 checkpoint blockade enhances adaptive and innate immune activation•Combination therapy leads to complete tumor rejection and immunological memory
Schaer, Beckmann et al. describe unique immune-modulating properties of abemaciclib that include upregulation of antigen presentation on tumor cells and increased T cell activation. These activities synergize with anti-PD-L1 therapy to further enhance immune activation, including macrophage and DC antigen presentation, and also lead to a reciprocal increase in abemaciclib-dependent cell cycle gene regulation.
We develop a kinematic model for the transition from subduction beneath the North Island, New Zealand, to strike‐slip in the South Island, constrained by GPS velocities and active fault slip data. To ...interpret these data, we use an approach that inverts the kinematic data for poles of rotation of tectonic blocks and the degree of interseismic coupling on faults in the region. Convergence related to the Hikurangi subduction margin becomes very low offshore of the northern South Island, indicating that in this region the majority of the relative plate motion has been transferred onto faults within the upper plate, as suggested by previous studies. This result has implications for understanding the likely extent of subduction interface earthquake rupture in central New Zealand. Easterly trending strike slip faults (such as the Boo Boo fault) are the key features that facilitate the transfer of strike‐slip motion from the northern South Island faults further north into the southern North Island and onto the Hikurangi subduction thrust. Our results also indicate that the transition from rapid forearc rotation adjacent to the Hikurangi subduction margin to a strike‐slip dominated plate boundary (with negligible vertical‐axis rotation) in the South Island occurs via a crustal‐scale hinge or kink in the upper plate, compatible with paleomagnetic and structural geological data. Despite the ongoing tectonic evolution of the central New Zealand region, our study highlights a remarkable consistency between data sets spanning decades (GPS), thousands of years (active faulting data), and millions of years (paleomagnetic data and bedrock structure).
Key Points
Active fault and GPS data used to constrain strike‐slip to subduction in NZ
Excellent agreement between short‐term (GPS) and longer‐term (active fault) data
New model for subduction interface coupling at Hikurangi margin
I describe the new generation of muon-to-electron conversion experiments, COMET and Mu2e, being constructed to make use of new high power pulsed muon beams a J-PARC and Fermilab respectively. A brief ...overview of the physics explored by the muon to electron conversion is given, followed by a description of the experimental challenges and resulting features common to the new experiments. The differences in approach between Mu2e and COMET are then highlighted, and the current schedules given.
A model of active faulting in New Zealand Litchfield, NJ; Van Dissen, R; Sutherland, R ...
New Zealand journal of geology and geophysics,
01/2014, Letnik:
57, Številka:
1
Journal Article
Recenzirano
Odprti dostop
Active fault traces are a surface expression of permanent deformation that accommodates the motion within and between adjacent tectonic plates. We present an updated national-scale model for active ...faulting in New Zealand, summarize the current understanding of fault kinematics in 15 tectonic domains, and undertake some brief kinematic analysis including comparison of fault slip rates with GPS velocities. The model contains 635 simplified faults with tabulated parameters of their attitude (dip and dip-direction) and kinematics (sense of movement and rake of slip vector), net slip rate and a quality code. Fault density and slip rates are, as expected, highest along the central plate boundary zone, but the model is undoubtedly incomplete, particularly in rapidly eroding mountainous areas and submarine areas with limited data. The active fault data presented are of value to a range of kinematic, active fault and seismic hazard studies.
The New Zealand Active Faults Database Langridge, RM; Ries, WF; Litchfield, NJ ...
New Zealand journal of geology and geophysics,
01/2016, Letnik:
59, Številka:
1
Journal Article
Recenzirano
The New Zealand Active Faults Database (NZAFD) is a national geospatial database of active faults - including their locations, names and degrees of activity - that have deformed the ground surface of ...New Zealand within the last 125,000 years. The NZAFD is used for geological research, hazard modelling and infrastructure planning and is an underlying dataset for other nationally significant hazard applications such as the National Seismic Hazard Model. Recent refinements to the data structure have improved the accuracy of active fault locations and characteristics. A subset of active fault information from the NZAFD, generalised for portrayal and use at a scale of 1:250,000 (and referred to as NZAFD250), is freely available online and can be downloaded in several different formats to suit the needs of a range of users including scientists, governmental authorities and the general public. To achieve a uniform spatial scale of 1:250,000 a simplification of detailed fault locational data was required in some areas, while in other areas new mapping was necessary to provide a consistent level of coverage. Future improvements to the NZAFD will include the incorporation of data on active folds and offshore active faults.
Searches for a light sterile neutrino have been performed independently by the MINOS and the Daya Bay experiments using the muon (anti)neutrino and electron antineutrino disappearance channels, ...respectively. In this Letter, results from both experiments are combined with those from the Bugey-3 reactor neutrino experiment to constrain oscillations into light sterile neutrinos. The three experiments are sensitive to complementary regions of parameter space, enabling the combined analysis to probe regions allowed by the Liquid Scintillator Neutrino Detector (LSND) and MiniBooNE experiments in a minimally extended four-neutrino flavor framework. Stringent limits on sin^{2}2θ_{μe} are set over 6 orders of magnitude in the sterile mass-squared splitting Δm_{41}^{2}. The sterile-neutrino mixing phase space allowed by the LSND and MiniBooNE experiments is excluded for Δm_{41}^{2}<0.8 eV^{2} at 95% CL_{s}.
Coseismic coastal deformation is often used to understand slip on offshore faults in large earthquakes but in the 2016 MW7.8 Kaikōura earthquake multiple faults ruptured across and sub-parallel to ...the coastline. Along ∼110 km of coastline, a rich dataset of coastal deformation comprising airborne lidar differencing, field surveying and satellite geodesy reveals highly variable vertical displacements, ranging from −2.5 to 6.5 m. These inform a refined slip model for the Kaikōura earthquake which incorporates changes to the slip on offshore faults and inclusion of an offshore reverse crustal fault that accounts for broad, low-amplitude uplift centered on Kaikōura Peninsula. The exceptional detail afforded by differential lidar and the high variability in coastal deformation combine to form the highest-resolution and most complex record of coseismic coastal deformation yet documented. This should prompt reassessment of coastal paleoseismic records that may not have considered multi-fault ruptures and high complexity deformation fields.
•Coseismic coastal deformation was highly variable in the 2016 Kaikōura earthquake.•Coastal deformation varied from −2.5 m to 6.5 m along 110 km of coastline.•Coastal deformation constrains the location and slip on offshore reverse fault.•High complexity coseismic coastal deformation has implications for paleoseismology.
Mechanisms driving resistance to cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) in hormone receptor-positive (HR
) breast cancer have not been clearly defined. Whole-exome sequencing of 59 tumors ...with CDK4/6i exposure revealed multiple candidate resistance mechanisms including
loss, activating alterations in
, and
, and loss of estrogen receptor expression.
experiments confirmed that these alterations conferred CDK4/6i resistance. Cancer cells cultured to resistance with CDK4/6i also acquired
, or
alterations, which conferred sensitivity to AURKA, ERK, or CHEK1 inhibition. Three of these activating alterations-in
, and
-have not, to our knowledge, been previously demonstrated as mechanisms of resistance to CDK4/6i in breast cancer preclinically or in patient samples. Together, these eight mechanisms were present in 66% of resistant tumors profiled and may define therapeutic opportunities in patients. SIGNIFICANCE: We identified eight distinct mechanisms of resistance to CDK4/6i present in 66% of resistant tumors profiled. Most of these have a therapeutic strategy to overcome or prevent resistance in these tumors. Taken together, these findings have critical implications related to the potential utility of precision-based approaches to overcome resistance in many patients with HR
metastatic breast cancer.
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