Search

Purpose: The goal of this study was to characterize the activity of the covalent CDK7 inhibitor THZ1 in multiple myeloma models. Experimental Design: Multiple myeloma lines were exposed to varying THZ1 concentrations alone or with carfilzomib or ABT-199, after which apoptosis was monitored by flow cytometry, protein expression by Western blot analysis, mRNA by RT-PCR. Analogous studies were performed in cells ectopically expressing c-MYC, MCL-1, or BCL-XL, or CRISPER-Cas CDK7 sgRNA knockout. Primary multiple myeloma cells were exposed to THZ1 ± carfilzomib or ABT-199. In vivo effects of THZ1 were examined in a systemic U266 xenograft model. Results: THZ1 markedly diminished multiple myeloma cell proliferation and survival despite bortezomib or stromal cell resistance in association with G2–M arrest, inactivation of CTD RNA Pol II, dephosphorylation of CDKs 7 as well as 1, 2, and 9, and MCL-1, BCL-xL, and c-MYC mRNA or protein downregulation. Ectopic MCL-1, c-MYC, or BCL-XL expression significantly protected cells from THZ1 lethality. Both THZ1 and CRISPR-Cas CDK7 knockout sharply diminished multiple myeloma cell proliferation and significantly increased carfilzomib and ABT-199 lethality. Parallel effects and interactions were observed in primary CD138+ (N = 22) or primitive multiple myeloma cells (CD138−/CD19+/CD20+/CD27+; N = 16). THZ1 administration [10 mg/kg i.p. twice daily (BID), 5 days/week] significantly improved survival in a systemic multiple myeloma xenograft model with minimal toxicity and induced similar events observed in vitro, for example, MCL-1 and c-MYC downregulation. Conclusions: THZ1 potently reduces multiple myeloma cell proliferation through transcriptional downregulation of MCL-1, BCL-XL, and c-MYC in vitro and in vivo. It warrants further attention as a therapeutic agent in multiple myeloma.

ObjectiveThe aim of this paper is to describe evolution, epidemiology and clinical outcomes of COVID-19 in subjects tested at or admitted to hospitals in North West London.DesignObservational cohort study.SettingLondon North West Healthcare NHS Trust (LNWH).ParticipantsPatients tested and/or admitted for COVID-19 at LNWH during March and April 2020Main outcome measuresDescriptive and analytical epidemiology of demographic and clinical outcomes (intensive care unit (ICU) admission, mechanical ventilation and mortality) of those who tested positive for COVID-19.ResultsThe outbreak began in the first week of March 2020 and reached a peak by the end of March and first week of April. In the study period, 6183 tests were performed in on 4981 people. Of the 2086 laboratory confirmed COVID-19 cases, 1901 were admitted to hospital. Older age group, men and those of black or Asian minority ethnic (BAME) group were predominantly affected (pConclusionThe findings confirm that men, BAME and older population were most commonly and severely affected groups. Only older age was independently associated with mortality.

Intimal sarcoma (IS) is a rare malignancy arising in the great vessels or heart, most commonly in the pulmonary artery, primarily treated with surgical intervention. We report a case of IS of the pulmonary artery diagnosed after an endarterectomy to remove a suspected pulmonary embolism. The tumor could not be entirely resected and showed interval growth at post-operative follow up. Neoadjuvant radiotherapy was then delivered to improve resectability. Imaging confirmed decreased tumor size, and a surgical resection with pulmonary artery reconstruction and right upper lobectomy was then successfully performed. Adjuvant gemcitabine and docetaxel was later initiated. Four months post-operatively, the patient is alive without disease recurrence. While prior reports in the literature document use of adjuvant chemotherapy and radiotherapy for treatment of IS of the pulmonary artery, no prior experience has documented utility of neoadjuvant radiotherapy for improvement of resectability. Our experience suggests that neoadjuvant radiation should be considered to improve resectability in cases of borderline resectable IS of the pulmonary artery.

The aim of this guideline is to provide an update on evidence-based recommendations for treatment of adult patients with PsA. The previous BSR guidelines for PsA were published in 2012 and since that time, there have been many new advanced therapies licensed for PsA. This update will provide practical guidance for clinicians on the optimal selection of advanced therapies taking into account different domains of PsA (arthritis, enthesitis, dactylitis, axial disease and psoriasis) and key associated comorbidities. It will also update guidance on treatment strategy including the use of a treat-to-target approach. The guideline will be developed using the methods and processes outlined in Creating Clinical Guidelines: Our Protocol. (1) This development process to produce guidance, advice and recommendations for practice has National Institute for Health and Care Excellence (NICE) accreditation.

The presented report is part of WP4 of the FANBEST (Funding Atlantic Network for Blue Economy Technology Transfer; www.fanbest.eu) Project and is addressing Action 4.1. aimed at analysing the stakeholder and agent landscape in the Blue Economy (BE) in the Atlantic Area. The report is meant as a conclusion report presenting an Atlantic wide methodology for the collection and analysis of spatial and non-spatial information of stakeholders supporting BE and the evaluation of results on the distribution and type of stakeholders present in the five countries of the Atlantic area (United Kingdom, Ireland, France, Spain and Portugal). The method was based on a structured BE Stakeholder Directory and comprises over 600 stakeholder of local, regional, national and international (EU wide and global) level, playing a potential role (financier, service providers, research/innovators, regulators/policy makers in the Atlantic BE landscape. Results from the analysis were presented in terms of geospatial distribution of stakeholders and in terms of quantitative representation of the stakeholder type(e.g. public institutions, private companies, investment banks, clusters, crowed funding organizations, etc...). The report draws attention on a set of conclusions and recommendations on the current opportunities and challenges of mapping BE stakeholders across the Atlantic Area, the financial instruments available at sectoral and at territorial level.

Introduction: Intravenous alteplase improves functional outcome in patients with acute ischemic stroke. While patients often have better outcomes, other patients may experience recurrent or worsening symptoms. We sought to determine the association between stroke subtype and neurologic deterioration in this study cohort. Methods: Data were abstracted from a prospective quality improvement registry at a comprehensive stroke center. Patients with symptomatic intracranial hemorrhage, no follow-up imaging, code status change to comfort measures only in the first 24 hours, or stroke mimics were excluded. Recurrent cerebrovascular events (RCVE) were defined as any new or worsening symptoms due to cerebral ischemia in the absence of intracranial hemorrhage or an alternative etiology such as infection or seizure. We compared demographic factors, vascular comorbidities, admission blood pressure, medications, use and timing of antithrombotics during hospitalization, admission NIH stroke scale, endovascular intervention, stroke subtype [Cardioembolic, large artery atherosclerosis, small vessel disease, cryptogenic, and other defined (such as dissection, hypercoagulability, cancer related, illicit drug use)], and good 90-day outcome (mRS 0-1) between the two groups using Fisher’s exact test and t-test as indicated. We then performed multivariable logistic regression analyses to determine associations between stroke subtypes and RCVE. Results: We identified 705 patients treated with tPA, and 606 met the inclusion criteria. The rate of RCVE was 5.8% (35/606). In multivariable analyses, when compared to cardioembolic/cryptogenic stroke, RCVE was more common in small vessel disease (adjusted OR 9.51 p=0.029), large vessel disease (adjusted OR 5.60, p=0.033), and other stroke mechanisms (adjusted OR 11.29, p=0.019). RCVE was associated with more disability at 90 days when compared to non-RCVE (median mRS 4, IQR 3 vs. median mRS 3, IQR 2, p = 0.016). Conclusions: Non-cryptogenic/Non-cardioembolic stroke subtypes are associated with early RCVE, and RCVE is associated with long term disability. Studies are needed to confirm our findings and test interventions optimizing stroke prevention strategies in these subtypes.

Supplemental material, sj-pdf-2-jcb-10.1177_0271678X20961854 for Large-scale characterization of the microvascular geometry in development and disease by tissue clearing and quantitative ultramicroscopy by Artur Hahn, Julia Bode, Allen Alexander, Kianush Karimian-Jazi, Katharina Schregel, Daniel Schwarz, Alexander C Sommerkamp, Thomas Krüwel, Amir Abdollahi, Wolfgang Wick, Michael Platten, Martin Bendszus, Björn Tews, Felix T Kurz and Michael O Breckwoldt in Journal of Cerebral Blood Flow & Metabolism

Supplemental material, sj-pdf-1-jcb-10.1177_0271678X20961854 for Large-scale characterization of the microvascular geometry in development and disease by tissue clearing and quantitative ultramicroscopy by Artur Hahn, Julia Bode, Allen Alexander, Kianush Karimian-Jazi, Katharina Schregel, Daniel Schwarz, Alexander C Sommerkamp, Thomas Krüwel, Amir Abdollahi, Wolfgang Wick, Michael Platten, Martin Bendszus, Björn Tews, Felix T Kurz and Michael O Breckwoldt in Journal of Cerebral Blood Flow & Metabolism

Systems biology has experienced dramatic growth in the number, size, and complexity of computational models. To reproduce simulation results and reuse models, researchers must exchange unambiguous model descriptions. We review the latest edition of the Systems Biology Markup Language (SBML), a format designed for this purpose. A community of modelers and software authors developed SBML Level 3 over the past decade. Its modular form consists of a core suited to representing reaction‐based models and packages that extend the core with features suited to other model types including constraint‐based models, reaction‐diffusion models, logical network models, and rule‐based models. The format leverages two decades of SBML and a rich software ecosystem that transformed how systems biologists build and interact with models. More recently, the rise of multiscale models of whole cells and organs, and new data sources such as single‐cell measurements and live imaging, has precipitated new ways of integrating data with models. We provide our perspectives on the challenges presented by these developments and how SBML Level 3 provides the foundation needed to support this evolution., Over the past two decades, scientists from different fields have been developing SBML, a standard format for encoding computational models in biology and medicine. This article summarizes recent progress and gives perspectives on emerging challenges.

Supplemental material, sj-pdf-8-jcb-10.1177_0271678X20961854 for Large-scale characterization of the microvascular geometry in development and disease by tissue clearing and quantitative ultramicroscopy by Artur Hahn, Julia Bode, Allen Alexander, Kianush Karimian-Jazi, Katharina Schregel, Daniel Schwarz, Alexander C Sommerkamp, Thomas Krüwel, Amir Abdollahi, Wolfgang Wick, Michael Platten, Martin Bendszus, Björn Tews, Felix T Kurz and Michael O Breckwoldt in Journal of Cerebral Blood Flow & Metabolism

Autoimmune glial fibrillary acidic protein (GFAP) astrocytopathy is an autoimmune neurological disorder associated with the presence of anti-GFAP IgG. Meningoencephalitis is the predominant clinical presentation of autoimmune GFAP astrocytopathy in published case series. We report a case of autoimmune GFAP astrocytopathy with the unusual feature of radiculoneuritis in addition to encephalomyelitis, resulting in flaccid paralysis unresponsive to immunotherapy. Imaging data confirmed involvement of brain, spinal cord and nerve roots. Electrodiagnostic testing showed changes consistent with a severe sensorimotor neuropathy with active denervation. The results of this case suggest the need for future studies to assess the impact of peripheral nerve involvement on the outcome of autoimmune GFAP astrocytopathy.

We report targeted sequencing of 63 known prostate cancer risk regions in a multi-ancestry study of 9,237 men and use the data to explore the contribution of low-frequency variation to disease risk. We show that SNPs with minor allele frequencies (MAFs) of 0.1-1% explain a substantial fraction of prostate cancer risk in men of African ancestry. We estimate that these SNPs account for 0.12 (standard error (s.e.) = 0.05) of variance in risk (∼42% of the variance contributed by SNPs with MAF of 0.1-50%). This contribution is much larger than the fraction of neutral variation due to SNPs in this class, implying that natural selection has driven down the frequency of many prostate cancer risk alleles; we estimate the coupling between selection and allelic effects at 0.48 (95% confidence interval [0.19, 0.78]) under the Eyre-Walker model. Our results indicate that rare variants make a disproportionate contribution to genetic risk for prostate cancer and suggest the possibility that rare variants may also have an outsize effect on other common traits.

Uterine fibroids are benign tumors of the uterus affecting up to 77% of women by menopause. They are the leading indication for hysterectomy, and account for $34 billion annually in the United States. Race/ethnicity and age are the strongest known risk factors. African American (AA) women have higher prevalence, earlier onset, and larger and more numerous fibroids than European American women. We conducted a multi-stage genome-wide association study (GWAS) of fibroid risk among AA women followed by in silico genetically predicted gene expression profiling of top hits. In Stage 1, cases and controls were confirmed by pelvic imaging, genotyped and imputed to 1000 Genomes. Stage 2 used self-reported fibroid and GWAS data from 23andMe, Inc. and the Black Women’s Health Study. Associations with fibroid risk were modeled using logistic regression adjusted for principal components, followed by meta-analysis of results. We observed a significant association among 3399 AA cases and 4764 AA controls at rs739187 (risk-allele frequency = 0.27) in CYTH4 (OR (95% confidence interval) = 1.23 (1.16–1.30), p value = 7.82 × 10−9). Evaluation of the genetic association results with MetaXcan identified lower predicted gene expression of CYTH4 in thyroid tissue as significantly associated with fibroid risk (p value = 5.86 × 10−8). In this first multi-stage GWAS for fibroids among AA women, we identified a novel risk locus for fibroids within CYTH4 that impacts gene expression in thyroid and has potential biological relevance for fibroids.

Introduction: Despite advances in stroke care, readmission rates for patients with ischemic stroke remain high. Although factors such as age, diabetes, and continuous use of antiplatelet agents have been found to predict readmission rates, the impact of after-hospital care has not been examined. Methods: The present study reviewed the charts of 416 patients with acute ischemic stroke and recorded stroke-related comorbidities, neurology follow-up within 21 days, readmission at 0 to 30 days, readmission at 31 to 90 days, and any reasons for readmission. Results: For those readmitted within 0 to 30 days, reasons for readmission were other medical conditions (62.5%), recurrent stroke (30.4%), and elective procedure (7.1%). For those readmitted within 31 to 90 days, reasons for readmission were other medical conditions (62.3%), recurrent stroke (15.1%), and elective procedure (22.6%). There was no significant relationship between being evaluated within 21 days and readmission at 0 to 30 or 31 to 90 days. However, those who did have a neurology follow-up at any point in time had a lower readmission rate of 10.6% compared to those who never came back (19.2%, P = .017). Patients with coronary artery disease and diabetes had a significantly higher likelihood of readmission within 0 to 30 days. Conclusion: The present study suggests that neurology follow-up at any point in time for patients with acute ischemic stroke may reduce short-term readmissions, but special attention to optimizing management of other underlying medical conditions, coronary artery disease, or diabetes may also help reduce overall readmissions. Patients with stroke, therefore, may benefit from a follow-up with both the primary care and neurology in a coordinated fashion to prevent early readmissions at 30 days.

Whilst knowledge and technology transfer unarguably present an important source of wealth for a nation and an important component of a modern University’s offering to society, the management of this activity is complex and as a result many economies struggle to realise their expectations. According to extensive, policy-driven surveys academics and commercial organisations are quick to blame inflexible and bureaucratic university transfer offices and administrators for this shortfall. However this research identifies interdependent and complex management practices coupled with equally complex organisational architectures which lead to issues of conflicting pressures and ambiguous governance. The research also goes on to illustrate a number of ‘structural’ solutions that universities have adopted to try to side-step some of the problems. The findings presented within this paper result from a snap shot survey, undertaken as part of a wider more in-depth study, spanning a 10 year period and focussing on universities and public research organisation’s knowledge and technology transfer capability in Europe and from other key areas around the world. The purpose of the paper is to begin allow senior managers in research-centred organisations to visualise their respective organisational structures and to reference them against their governance, service offering and management competences.

Increased understanding of knowledge transfer (KT) from universities to the wider regional knowledge ecosystem offers opportunities for increased regional innovation and commercialisation. The aim of this article is to improve the understanding of the KT phenomena in an open innovation context where multiple diverse quadruple helix stakeholders are interacting. An absorptive capacity-based conceptual framework is proposed, using a priori constructs which portrays the multidimensional process of KT between universities and its constituent stakeholders in pursuit of open innovation and commercialisation. Given the lack of overarching theory in the field, an exploratory, inductive theory building methodology was adopted using semi-structured interviews, document analysis and longitudinal observation data over a three-year period. The findings identify five factors, namely human centric factors, organisational factors, knowledge characteristics, power relationships and network characteristics, which mediate both the ability of stakeholders to engage in KT and the effectiveness of knowledge acquisition, assimilation, transformation and exploitation. This research has implications for policy makers and practitioners by identifying the need to implement interventions to overcome the barriers to KT effectiveness between regional quadruple helix stakeholders within an open innovation ecosystem.

Uterine fibroids are benign tumors of the uterus affecting up to 77% of women by menopause. They are the leading indication for hysterectomy, and account for $34 billion annually in the United States. Race/ethnicity and age are the strongest known risk factors. African American (AA) women have higher prevalence, earlier onset, and larger and more numerous fibroids than European American women. We conducted a multi-stage genome-wide association study (GWAS) of fibroid risk among AA women followed by in silico genetically predicted gene expression profiling of top hits. In Stage 1, cases and controls were confirmed by pelvic imaging, genotyped and imputed to 1000 Genomes. Stage 2 used self-reported fibroid and GWAS data from 23andMe, Inc. and the Black Women's Health Study. Associations with fibroid risk were modeled using logistic regression adjusted for principal components, followed by meta-analysis of results. We observed a significant association among 3399 AA cases and 4764 AA controls at rs739187 (risk-allele frequency = 0.27) in CYTH4 (OR (95% confidence interval) = 1.23 (1.16-1.30), p value = 7.82 × 10

An experimental investigation on the wake vortex formation and evolution of a four vortex system of a generic model in the near field and extended near field as well as the behaviour and decay in the far field region has been conducted by means of hot-wire anemometry in a wind tunnel. The results were obtained during an experimental campaign as part of the EC project “FAR-Wake”. The model used consists of a wing–tail plane configuration with the wing producing positive lift and the tail plane negative lift. The circulation ratio of tail plane to wing is −0.3 and the span ratio is 0.3. Thus, a four vortex system with counter-rotating neighboured vortices exists. The model set-up was chosen on the condition to create a most promising four vortex system with respect to accelerate wake vortex decay by optimal perturbations enhancing inherent instability mechanisms. The flow field has been investigated for a half plane of the entire wake up to a distance of 48 span dimensions downstream of the model. The results obtained at 1, 12, 24 and 48 span distances are shown as non-dimensional axial vorticity and vertical turbulence intensities. A significant decay in peak vorticity, swirl velocity and circulation is observable during the downward motion of the vortices. Spectral analysis of the unsteady velocity data reveals a peak in the power spectral density distributions indicating the presence of a dominating instability. Using two hot-wire probes cross spectral density distributions have also been evaluated, which highlight the co-operative instability leading to a rapid wake vortex decay within 30 span dimensions downstream.

The wake vortex development in the near field and extended near field behind a four engined large transport aircraft model fitted with an active winglet is presented. A detailed wind-tunnel investigation is conducted using a half-model focusing on the high-lift case of a typical approach configuration at a Reynolds number of 0.5 x 10 6 based on the wing mean aerodynamic chord and an angle of attack of 6.5 deg. The flowfield is observed using advanced hot-wire anemometry mainly focusing on the crossflow plane at 5.6 spans downstream of the model. Based on the time-dependent velocity components the wake flowfield is analyzed by distributions of mean vorticity, turbulence intensities, and spectral densities. Seven main vortical structures dominating the near-field wing vortex sheet roll up and merge to form the remaining trailing vortex in the extended near field. By the use of oscillating winglet flaps the velocity fluctuations at the core region of the remaining vortex are significantly influenced. Distinct narrowband concentrations of turbulent kinetic energy can be found for the farthest downstream plane documenting the presence of the disturbances generated by the winglet flaps which may result in an amplification of inherent far-field instabilities. The frequencies at which these narrowband energy concentrations occur are, on the one hand, dependent on the oscillation frequency of the winglet flaps; on the other hand, there are also independent energy concentrations within the frequency bands associated with wake instabilities.

An experimental investigation on the wake vortex formation and evolution of a four-engine large transport aircraft model in the near field and extended near field has been conducted by means of hot-wire anemometry in a wind tunnel. The half-model used has a scale of 1:19.25 and the tests focus on the high-lift case of a typical landing configuration at a Reynolds number of 0.52 x 10 6 based on the wing mean aerodynamic chord. The flowfield is investigated up to 4.7 spans downstream of the model, which is investigated with and without landing gear. Based on the measured time-dependent velocity components, the wake flowfield is analyzed by distributions of vorticity, turbulence intensities, and spectral densities. The landing gear consists of a stay and four wheels, which create a bluff-body wake that interferes with the shear layer caused by the wing and wing junction. The landing gear creates a low-energy vortex system and a highly turbulent wake. Due to the landing gear, the main vortex centers are located slightly further outboard and the roll-up process is retarded, especially the inboard movement of the horizontal tail plane vortex. The velocity spectra of the landing gear wake show broadband characteristics with some moderate narrowband energy concentrations in the close near field, which do not enhance inherent wake instabilities. Although the turbulence caused by the landing gear is still present in the extended near field, only a small influence on the overall vortex system of the entire aircraft can be found. The landing gear influence is therefore negligible in the context of reducing minimum aircraft separation distances.

Detailed flowfields of a wind-tunnel investigation are discussed presenting the wake vortex development and evolution in the near field and extended near field behind a four-engined large transport aircraft model fitted with a large winglet. The tests use a half-model of 1:32 scale focusing on the high-lift case of a typical approach configuration at a Reynolds number of 0.5 x 10 6 based on the wing mean aerodynamic chord and at an angle of attack of 7 deg. Flowfields are carefully inspected by advanced hot-wire anemometry at seven crossflow planes up to 5.6 spans downstream of the model. Based on the measured time-dependent velocity components, the wake flowfield is analyzed by distributions of mean velocity and vorticity, turbulence intensities, and spectral densities. The near-field wing vortex sheet is dominated by seven main vortical structures, namely the winglet vortex, the wing tip vortex, the outboard flap vortex, the outboard and inboard nacelle vortices, and the vortices shed at the wing-body junction and the horizontal tail plane. In the extended near field, these vortices roll up and merge to form the remaining rolled-up vortex. The deflection of winglet flaps produce additional vortices influencing the wing tip near field and enhancing the overall merging process. Especially for the cases with asymmetrical flap deflection, the remaining rolled-up vortex shows a significant narrowband concentration of turbulent kinetic energy which may result in an amplification of inherent far-field instabilities.

Although genome-wide association studies (GWAS) have found more than a hundred common susceptibility alleles for prostate cancer, the GWAS reported variants jointly explain only 33% of risk to siblings, leaving the majority of the familial risk unexplained. We use targeted sequencing of 63 known GWAS risk regions in 9,237 men from four ancestries (African, Latino, Japanese, and European) to explore the role of low-frequency variation in risk for prostate cancer. We find that the sequenced variants explain significantly more of the variance in the trait than the known GWAS variants, thus showing that part of the missing familial risk lies in poorly tagged causal variants at known risk regions. We report evidence for genetic heterogeneity in SNP effect sizes across different ancestries. We also partition heritability by minor allele frequency (MAF) spectrum using variance components methods, and find that a large fraction of heritability (0.12, s.e. 0.05; 95% CI [0.03, 0.21]) is explained by rare variants (MAF

In keeping with efforts to expand universal health care (UHC) throughout the Americas, Peru established a UHC programme in 2009. Although it was a tremendous achievement, Peru must continue to address non-communicable chronic diseases in upcoming health-care reforms. For instance, the 2009 reforms established a fund to support high-cost therapies for certain chronic conditions; however, the coverage is not universal throughout the country and essential services for other chronic conditions remain uncovered...