The Many Faces of Interleukin-6: The Role of IL-6 in Inflammation, Vasculopathy, and Fibrosis in Systemic Sclerosis

Interleukin-6 is currently attracting significant interest as a potential therapeutic target in systemic sclerosis (SSc). In this paper, the biology of interleukin-6 is reviewed, and the evidence for interleukin-6 dysregulation in SSc is explored. The role of inteleukin-6 classical and trans signalling pathways in SSc relevant phenomena such as chronic inflammation, autoimmunity, endothelial cell dysfunction, and fibrogenesis is discussed. The existing evidence that interventions designed to block interleukin-6 signalling are of therapeutic relevance in SSc is evaluated

Regulation of p27Kip1 Protein Levels Contributes to Mitogenic Effects of the RET/PTC Kinase in Thyroid Carcinoma Cells

Abstract We show that treatment of a panel of thyroid carcinoma cell lines naturally harboring the RET/PTC1 oncogene, with the RET kinase inhibitors PP1 and ZD6474, results in reversible G1 arrest. This is accompanied by interruption of Shc and mitogen-activated protein kinase (MAPK) phosphorylation, reduced levels of G1 cyclins, and increased levels of the cyclin-dependent kinase inhibitor p27Kip1 because of a reduced protein turnover. MAP/extracellular signal-regulated kinase 1/2 inhibition by U0126 caused G1 cyclins down-regulation and p27Kip1 up-regulation as well. Forced expression of RET/PTC in normal thyroid follicular cells caused a MAPK- and proteasome-dependent down-regulation of p27Kip1. Reduction of p27Kip1 protein levels by antisense oligonucleotides abrogated the G1 arrest induced by RET/PTC blockade. Therefore, in thyroid cancer, RET/PTC-mediated MAPK activation contributes to p27Kip1 deregulation. This pathway is implicated in cell cycle progression and in response to small molecule kinase inhibitors

Patient-reported outcome instruments for assessing Raynaud’s phenomenon in systemic sclerosis:A SCTC vascular working group report

The episodic nature of Raynaud’s phenomenon in systemic sclerosis has led to a reliance on patient-reported outcome instruments such as the Raynaud’s Condition Score diary. Little is known about the utilization in routine clinical practice and health professional attitudes toward existing patient-reported outcome instruments for assessing systemic sclerosis- Raynaud’s phenomenon. Members of the Scleroderma Clinical Trials Consortium Vascular Working Group (n = 28) were invited to participate in a survey gauging attitudes toward the Raynaud’s Condition Score diary and the perceived need for novel patient-reported outcome instruments for assessing patient-reported outcome. Nineteen Scleroderma Clinical Trials Consortium Vascular Working Group members (68% response rate) from academic units based in North America (n = 9), Europe (n = 8), South America (n = 1) and Australasia (n = 1) took part in the survey. There was broad consensus that Raynaud’s Condition Score diary returns could be influenced by factors including seasonal variation in weather, efforts made by patients to avoid or ameliorate attacks of Raynaud’s phenomenon, habituation to Raynaud’s phenomenon symptoms, evolution of Raynaud’s phenomenon symptom characteristics with progressive obliterative microangiopathy, patient-coping strategies, respondent burden and placebo effect. There was consensus that limitations of the Raynaud’s Condition Score diary might be a barrier to drug development (79% of respondents agree/strongly agree) and that a novel patient-reported outcome instrument for assessing systemic sclerosis-Raynaud’s phenomenon should be developed with the input of both clinicians and patients (84% agree/strongly agree). Perceived potential limitations of the Raynaud’s Condition Score diary have been identified along with concerns that such factors might impede drug development programs for systemic sclerosis-Raynaud’s phenomenon. There is support within the systemic sclerosis community for the development of a novel patient-reported outcome instrument for assessing systemic sclerosis-Raynaud’s phenomenon.</p

Landau Damping and Coherent Structures in Narrow-Banded 1+1 Deep Water Gravity Waves

We study the nonlinear energy transfer around the peak of the spectrum of surface gravity waves by taking into account nonhomogeneous effects. In the narrow-banded approximation the kinetic equation resulting from a nonhomogeneous wave field is a Vlasov-Poisson type equation which includes at the same time the random version of the Benjamin-Feir instability and the Landau damping phenomenon. We analytically derive the values of the Phillips' constant $\alpha$ and the enhancement factor $\gamma$ for which the narrow-banded approximation of the JONSWAP spectrum is unstable. By performing numerical simulations of the nonlinear Schr\"{o}dinger equation we check the validity of the prediction of the related kinetic equation. We find that the effect of Landau damping is to suppress the formation of coherent structures. The problem of predicting freak waves is briefly discussed.Comment: 4 pages, 3 figure

Framing referendum campaigns: the 2014 Scottish independence referendum in the press

This article explores the framing of referendum campaigns in the press and its relationship to the framing of elections. Drawing from an empirical analysis of the newspaper coverage of the 2014 Scottish referendum and from previous research on campaigns in different contexts, it finds that frames associated with elections, like the strategic game and policy frames, were also dominant in the framing of the referendum. It argues that by framing the independence debate in similar terms to other electoral contests, the press promoted an understanding of this event as being about pragmatic decision-making on policy and political competition, rather than purely a decision about constitutional matters of self-determination

Prior elicitation of the efficacy and tolerability of Methotrexate and Mycophenolate Mofetil in Juvenile Localised Scleroderma [version 1; peer review: 2 approved]

Background: Evidence is lacking for safe and effective treatments for juvenile localised scleroderma (JLS). Methotrexate (MTX) is commonly used first line and mycophenolate mofetil (MMF) second line, despite a limited evidence base. A head to head trial of these two medications would provide data on relative efficacy and tolerability. However, a frequentist approach is difficult to deliver in JLS, because of the numbers needed to sufficiently power a trial. A Bayesian approach could be considered. // Methods: An international consensus meeting was convened including an elicitation exercise where opinion was sought on the relative efficacy and tolerability of MTX compared to MMF to produce prior distributions for a future Bayesian trial. Secondary aims were to achieve consensus agreement on critical aspects of a future trial. // Results: An international group of 12 clinical experts participated. Opinion suggested superior efficacy and tolerability of MMF compared to MTX; where most likely value of efficacy of MMF was 0.70 (95% confidence interval (CI) 0.34-0.90) and of MTX was 0.68 (95% CI 0.41-0.8). The most likely value of tolerability of MMF was 0.77 (95% CI 0.3-0.94) and of MTX was 0.62 (95% CI 0.32-0.84). The wider CI for MMF highlights that experts were less sure about relative efficacy and tolerability of MMF compared to MTX. Despite using a Bayesian approach, power calculations still produced a total sample size of 240 participants, reflecting the uncertainty amongst experts about the performance of MMF. // Conclusions: Key factors have been defined regarding the design of a future Bayesian approach clinical trial including elicitation of prior opinion of the efficacy and tolerability of MTX and MMF in JLS. Combining further efficacy data on MTX and MMF with prior opinion could potentially reduce the pre-trial uncertainty so that, when combined with smaller trial sample sizes a compelling evidence base is available

The Differentiation and Stress Response Factor XBP-1 Drives Multiple Myeloma Pathogenesis

Multiple myeloma (MM) evolves from a highly prevalent premalignant condition termed MGUS. The factors underlying the malignant transformation of MGUS are unknown. We report a MGUS/MM phenotype in transgenic mice with Eμ-directed expression of the XBP-1 spliced isoform (XBP-1s), a factor governing unfolded protein/ER stress response and plasma-cell development. Eμ-XBP-1s elicited elevated serum Ig and skin alterations. With age, Eμ-xbp-1s transgenics develop features diagnostic of human MM, including bone lytic lesions and subendothelial Ig deposition. Furthermore, transcriptional profiles of Eμ-xbp-1s lymphoid and MM cells show aberrant expression of known human MM dysregulated genes. The similarities of this model with the human disease, coupled with documented frequent XBP-1s overexpression in human MM, serve to implicate XBP-1s dysregulation in MM pathogenesis

Correlates of verbal and physical violence experienced and perpetrated among cisgender college women: serial cross-sections during one year of the COVID-19 pandemic

IntroductionViolence against women is a prevalent, preventable public health crisis. COVID-19 stressors and pandemic countermeasures may have exacerbated violence against women. Cisgender college women are particularly vulnerable to violence. Thus, we examined the prevalence and correlates of verbal/physical violence experienced and perpetrated among cisgender women enrolled at a New York City college over one year during the COVID-19 pandemic.MethodsFrom a prospective cohort study, we analyzed data self-reported quarterly (T1, T2, T3, T4) between December 2020 and December 2021. Using generalized estimated equations (GEE) and logistic regression, we identified correlates of experienced and perpetrated violence among respondents who were partnered or cohabitating longitudinally and at each quarter, respectively. Multivariable models included all variables with unadjusted parameters X2p-value ≤0.05.ResultsThe prevalence of experienced violence was 52% (T1: N = 513), 30% (T2: N = 305), 33% (T3: N = 238), and 17% (T4: N = 180); prevalence of perpetrated violence was 38%, 17%, 21%, and 9%. Baseline correlates of experienced violence averaged over time (GEE) included race, living situation, loneliness, and condom use; correlates of perpetrated violence were school year, living situation, and perceived social support. Quarter-specific associations corroborated population averages: living with family members and low social support were associated with experienced violence at all timepoints except T4. Low social support was associated with higher odds of perpetrated violence at T1/T3. Other/Multiracial identity was associated with higher odds of violence experience at T3.ConclusionsLiving situation was associated with experienced and perpetrated violence in all analyses, necessitating further exploration of household conditions, family dynamics, and interpersonal factors. The protective association of social support with experienced and perpetrated violence also warrants investigation into forms of social engagement and cohesion. Racial differences in violence also require examination. Our findings can inform university policy development on violence and future violence research. Within or beyond epidemic conditions, universities should assess and strengthen violence prevention and support systems for young women by developing programming to promote social cohesion