Phosphoproteomic Analysis of Cell-Based Resistance to BRAF Inhibitor Therapy in Melanoma

The treatment of melanoma by targeted inhibition of the mutated kinase BRAF with small molecules only temporarily suppresses metastatic disease. In the face of chemical inhibition tumor plasticity, both innate and adaptive, promotes survival through the biochemical and genetic reconfiguration of cellular pathways that can engage proliferative and migratory systems. To investigate this process, high-resolution mass spectrometry was used to characterize the phosphoproteome of this transition in vitro. A simple and accurate, label-free quantitative method was used to localize and quantitate thousands of phosphorylation events. We also correlated changes in the phosphoproteome with the proteome to more accurately determine changes in the activity of regulatory kinases determined by kinase landscape profiling. The abundance of phosphopeptides with sites that function in cytoskeletal regulation, GTP/GDP exchange, protein kinase C, IGF signaling, and melanosome maturation were highly divergent after transition to a drug resistant phenotype

Morphology and hemodynamics in isolated common iliac artery aneurysms impacts proximal aortic remodeling

Objective- Isolated common iliac artery aneurysms (CIAA) are rare. Their prognosis and influence on aortoiliac blood flow and remodeling are unclear. We evaluated the hypotheses that morphology at and distal to the aortic bifurcation, together with the associated hemodynamic changes, influence both the natural history of CIAA and proximal aortic remodeling. Approach and Results- Twenty-five isolated CIAAs (15 intact, 10 ruptured), in 23 patients were reconstructed and analyzed with computational fluid dynamics: all showed abnormal flow. Then we studied a series of 24 hypothetical aortoiliac geometries in silico with varying abdominal aortic deflection and aortic bifurcation angles: key findings were assessed in an independent validation cohort of 162 patients. Wall shear stress in isolated unilateral CIAAs was lower than the contralateral common iliac artery, 0.38±0.33 Pa versus 0.61±0.24 Pa, inversely associated with CIAA diameter ( P<0.001) and morphology (high shear stress in variants distal to a sharp kink). Rupture usually occurred in regions of elevated low and oscillatory shear with a wide aortic bifurcation angle. Abdominal aortas deflected towards the CIAA for most unilateral isolated CIAAs (14/21). In silico, wider bifurcation angles created high focal regions of low and oscillatory shear in the common iliac artery. The associations of unilateral CIAA with aortic deflection and common iliac artery diameter with bifurcation angle were confirmed in the validation cohort. Conclusions- Decreasing wall shear stress is strongly associated with CIAA progression (larger aneurysms and rupture), whereas abnormal blood flow in the CIAA seems to promote proximal aortic remodeling, with adaptive lateral deflection of the abdominal aorta towards the aneurysmal side

Multi-Regge kinematics and the moduli space of Riemann spheres with marked points

We show that scattering amplitudes in planar N = 4 Super Yang-Mills in multi-Regge kinematics can naturally be expressed in terms of single-valued iterated integrals on the moduli space of Riemann spheres with marked points. As a consequence, scattering amplitudes in this limit can be expressed as convolutions that can easily be computed using Stokes' theorem. We apply this framework to MHV amplitudes to leading-logarithmic accuracy (LLA), and we prove that at L loops all MHV amplitudes are determined by amplitudes with up to L + 4 external legs. We also investigate non-MHV amplitudes, and we show that they can be obtained by convoluting the MHV results with a certain helicity flip kernel. We classify all leading singularities that appear at LLA in the Regge limit for arbitrary helicity configurations and any number of external legs. Finally, we use our new framework to obtain explicit analytic results at LLA for all MHV amplitudes up to five loops and all non-MHV amplitudes with up to eight external legs and four loops.Comment: 104 pages, six awesome figures and ancillary files containing the results in Mathematica forma

High-Temperature Transport Properties of Yb4−xSmxSb3

Polycrystalline L4Sb3 (L = La, Ce, Sm, and Yb) and Yb4−x Sm x Sb3, which crystallizes in the anti-Th3P4 structure type (I-43d no. 220), were synthesized via high-temperature reaction. Structural and chemical characterization were performed by x-ray diffraction and electronic microscopy with energy-dispersive x-ray analysis. Pucks were densified by spark plasma sintering. Transport property measurements showed that these compounds are n-type with low Seebeck coefficients, except for Yb4Sb3, which shows semimetallic behavior with hole conduction above 523 K. By partially substituting Yb by a trivalent rare earth we successfully improved the thermoelectric figure of merit of Yb4Sb3 up to 0.7 at 1273 K

Happiness matters : exploring the linkages between personality, personal happiness, and work-related psychological health among priests and sisters in Italy

This study responds to the challenge posed by Rossetti’s work to explore the antecedents and consequences of individual differences in happiness among priests and religious sisters. The Oxford Happiness Questionnaire was completed together with measures of personality and work-related psychological health by 95 priests and 61 religious sisters. Overall the data demonstrated high levels of personal happiness among priests and religious sisters, but also significant signs of vulnerability. Personality provided significant prediction of individual differences in both personal happiness and work-related psychological health. However, personal happiness provided additional protection against work-related emotional exhaustion and additional enhancement of work-related satisfaction. These findings suggest that acknowledging and affirming personal happiness may enhance the work-related psychological health of Catholic priests and religious sisters

Quantifying the effect of population mixing on childhood leukaemia risk: the Seascale cluster

A statistical model was developed based on Poisson regression of incidence of childhood leukaemia and non-Hodgkin’s lymphoma (NHL) in relation to population mixing among all 119 539 children born 1969–1989 to mothers living in Cumbria, north-west England, (excluding Seascale). This model was used to predict the number of cases in Seascale (the village adjacent to the Sellafield nuclear installation) children, born 1950–1989 and diagnosed before 1993. After allowing for age, the incidence of acute lymphoblastic leukaemia (ALL) and NHL was significantly higher among children born in areas with the highest levels of population mixing, relative risk (RR) = 11.7 (95% confidence interval (CI) 3.2–43) and was highest among children of incomers. The model predicted up to 3.0 (95% CI 1.3–6.0) cases of ALL/NHL in children born in Seascale compared to six observed and 2.0 (95% CI 1.0–3.4) cases in children resident, but not born, in Seascale compared to two observed. Population mixing is a significant risk factor for ALL/NHL, especially in young children, accounting for over 50% of cases in Cumbria and most cases in Seascale. © 1999 Cancer Research Campaig

Childhood solid tumours in relation to population mixing around the time of birth

In a retrospective cohort study of 673 787 live births in the Northern Region of England, 1975 - 1994, we investigated whether a higher level of population mixing around birth was a risk factor for solid tumours, by diagnostic group (Hodgkin's disease, brain and spinal tumours, neuroblastoma, other solid tumours), diagnosed during 1975-2001 under age 15 years. Logistic regression was used to relate risk to population mixing, based on (i) all movers and (ii) incomers from outside the region. Both ward and county district level analyses were performed. There was a decreased risk of brain and spinal tumours with increasing population mixing based on incomers from outside the region (OR for trend across three categories = 0.79, 95% CI: 0.66-0.95, P = 0.01 in the ward level analysis). Although this may be because of chance, it is consistent with a role of exposure to infection and immunological response in the aetiology of these tumours. For other tumour groups, there was no consistent evidence of an association between risk and population mixing

Preventing ethics dumping: the challenges for Kenyan research ethics committees

Ethics dumping is the practice of undertaking research in a low- or middle-income setting which would not be permitted, or would be severely restricted, in a high-income setting. Whilst Kenya operates a sophisticated research governance system, resource constraints and the relatively low number of accredited research ethics committees limit the capacity for ensuring ethical compliance. As a result, Kenya has been experiencing cases of ethics dumping. This article presents 11 challenges in the context of preventing ethics dumping in Kenya, namely variations in governance standards, resistance to double ethics review, resource constraints, unresolved issues in the management of biological samples, unresolved issues in the management of primary data, unsuitable informed consent procedures, cultural insensitivity, differing standards of care, reluctance to provide feedback to research communities, power differentials which facilitate the exploitation of local researchers and lack of local relevance and/or affordability of the resultant products. A reflective approach for researchers, built around the values of fairness, respect, care and honesty, is presented as a means of taking shared responsibility for preventing ethics dumping

Alexithymia, emotion processing and social anxiety in adults with ADHD

<p>Abstract</p> <p>Objective</p> <p>Given sparse research on the issue, this study sought to shed light upon the interactions of alexithymia, emotion processing, and social anxiety in adults with attention-deficit hyperactivity disorder (ADHD).</p> <p>Subjects and methods</p> <p>73 German adults with ADHD according to DSM-IV diagnostic criteria participated. We used the Toronto Alexithymia Scale (TAS-20) to assess alexithymia, the Social Phobia Scale (SPS) and the Social Interaction Anxiety Scale (SIAS) to assess different features of social anxiety, and we applied the German 'Experience of Emotions Scale' (SEE) to measure emotion processing.</p> <p>Results</p> <p>40% of the sample were found to meet the DSM-IV criteria of social anxiety disorder, and about 22% were highly alexithymic according to a TAS-20 total score ≥ 61; however, the mean TAS-20 total score of 50.94 ± 9.3 was not much higher than in community samples. Alexithymic traits emerged to be closely linked to emotion processing problems, particularly 'difficulty accepting own emotions', and to social anxiety features.</p> <p>Discussion/conclusion</p> <p>Our findings suggest interactions of alexithymia, emotion processing dysfunction, and social anxiety in adults with ADHD, which may entail the therapeutic implication to thoroughly instruct these patients to identify, accept, communicate, and regulate their emotions to aid reducing interaction anxiety.</p

Measuring quality of life in patients with abdominal wall hernias: a systematic review of available tools

Introduction Abdominal wall herniation (AWH) is an increasing problem for patients, surgeons, and healthcare providers. Surgical-site specific outcomes, such as infection, recurrence, and mesh explantation, are improving; however, successful repair still exposes the patient to what is often a complex major operation aimed at improving quality of life. Quality-of-life (QOL) outcomes, such as aesthetics, pain, and physical and emotional functioning, are less often and less well reported. We reviewed QOL tools currently available to evaluate their suitability. Methods A systematic review of the literature in compliance with PRISMA guidelines was performed between 1st January 1990 and 1st May 2019. English language studies using validated quality-of-life assessment tool, whereby outcomes using this tool could be assessed were included. Results Heterogeneity in the QOL tool used for reporting outcome was evident throughout the articles reviewed. AWH disease-specific tools, hernia-specific tools, and generic tools were used throughout the literature with no obviously preferred or dominant method identified. Conclusion Despite increasing acknowledgement of the need to evaluate QOL in patients with AWH, no tool has become dominant in this field. Assessment, therefore, of the impact of certain interventions or techniques on quality of life remains difficult and will continue to do so until an adequate standardised outcome measurement tool is available