Gamma-ray bursts (GRBs) are most probably powered by collimated relativistic outflows (jets) from accreting black holes at cosmological distances. Bright afterglows are produced when the outflow ...collides with the ambient medium. Afterglow polarization directly probes the magnetic properties of the jet when measured minutes after the burst, and it probes the geometric properties of the jet and the ambient medium when measured hours to days after the burst. High values of optical polarization detected minutes after the burst of GRB 120308A indicate the presence of large-scale ordered magnetic fields originating from the central engine (the power source of the GRB). Theoretical models predict low degrees of linear polarization and no circular polarization at late times, when the energy in the original ejecta is quickly transferred to the ambient medium and propagates farther into the medium as a blast wave. Here we report the detection of circularly polarized light in the afterglow of GRB 121024A, measured 0.15 days after the burst. We show that the circular polarization is intrinsic to the afterglow and unlikely to be produced by dust scattering or plasma propagation effects. A possible explanation is to invoke anisotropic (rather than the commonly assumed isotropic) electron pitch-angle distributions, and we suggest that new models are required to produce the complex microphysics of realistic shocks in relativistic jets.
For kinase inhibitors, intracellular target selectivity is fundamental to pharmacological mechanism. Although a number of acellular techniques have been developed to measure kinase binding or ...enzymatic inhibition, such approaches can fail to accurately predict engagement in cells. Here we report the application of an energy transfer technique that enabled the first broad-spectrum, equilibrium-based approach to quantitatively profile target occupancy and compound affinity in live cells. Using this method, we performed a selectivity profiling for clinically relevant kinase inhibitors against 178 full-length kinases, and a mechanistic interrogation of the potency offsets observed between cellular and biochemical analysis. For the multikinase inhibitor crizotinib, our approach accurately predicted cellular potency and revealed improved target selectivity compared with biochemical measurements. Due to cellular ATP, a number of putative crizotinib targets are unexpectedly disengaged in live cells at a clinically relevant drug dose.
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•The approach enables quantitative profiling of 178 full-length kinases•Compared with biochemical approaches, this is a better predictor of cellular potency•An unexpected intracellular selectivity is observed for certain kinase inhibitors•A mechanistic analysis of ATP interference on target engagement is performed
Vasta et al. describe a broad-spectrum approach (BRET) to quantitatively measure target engagement for kinases inside live cells. Compared with biochemical measurements, the analysis revealed an improved intracellular selectivity profile for clinically relevant kinase inhibitors. This serves as a mechanistic tool to determine the effect of cellular ATP on engagement potency.
CDK7 inhibitors as anticancer drugs Sava, Georgina P.; Fan, Hailing; Coombes, R. Charles ...
Cancer and metastasis reviews,
09/2020, Letnik:
39, Številka:
3
Journal Article
Recenzirano
Odprti dostop
Cyclin-dependent kinase 7 (CDK7), along with cyclin H and MAT1, forms the CDK-activating complex (CAK), which directs progression through the cell cycle
via
T-loop phosphorylation of cell cycle CDKs. ...CAK is also a component of the general transcription factor, TFIIH. CDK7-mediated phosphorylation of RNA polymerase II (Pol II) at active gene promoters permits transcription. Cell cycle dysregulation is an established hallmark of cancer, and aberrant control of transcriptional processes, through diverse mechanisms, is also common in many cancers. Furthermore, CDK7 levels are elevated in a number of cancer types and are associated with clinical outcomes, suggestive of greater dependence on CDK7 activity, compared with normal tissues. These findings identify CDK7 as a cancer therapeutic target, and several recent publications report selective CDK7 inhibitors (CDK7i) with activity against diverse cancer types. Preclinical studies have shown that CDK7i cause cell cycle arrest, apoptosis and repression of transcription, particularly of super-enhancer-associated genes in cancer, and have demonstrated their potential for overcoming resistance to cancer treatments. Moreover, combinations of CDK7i with other targeted cancer therapies, including BET inhibitors, BCL2 inhibitors and hormone therapies, have shown efficacy in model systems. Four CDK7i, ICEC0942 (CT7001), SY-1365, SY-5609 and LY3405105, have now progressed to Phase I/II clinical trials. Here we describe the work that has led to the development of selective CDK7i, the current status of the most advanced clinical candidates, and discuss their potential importance as cancer therapeutics, both as monotherapies and in combination settings.
ClinicalTrials.gov
Identifiers: NCT03363893; NCT03134638; NCT04247126; NCT03770494.
Context:
Skeletal deterioration, leading to an increased risk of fracture, is a known complication of type 2 diabetes mellitus (T2D). Yet plausible mechanisms to account for skeletal fragility in T2D ...have not been clearly established.
Objective:
The objective of the study was to determine whether bone material properties, as measured by reference point indentation, and advanced glycation endproducts (AGEs), as determined by skin autofluorescence (SAF), are related in patients with T2D.
Design:
This was a cross-sectional study.
Setting:
The study was conducted at a tertiary medical center.
Patients:
Sixteen postmenopausal women with T2D and 19 matched controls participated in the study.
Main Outcome Measures:
Bone material strength index (BMSi) by in vivo reference point indentation, AGE accumulation by SAF, and circulating bone turnover markers were measured.
Results:
BMSi was reduced by 9.2% in T2D (P = .02) and was inversely associated with the duration of T2D (r = −0.68, P = .004). Increased SAF was associated with reduced BMSi (r = −0.65, P = .006) and lower bone formation marker procollagen type 1 amino-terminal propeptide (r = −0.63, P = .01) in T2D, whereas no associations were seen in controls. SAF accounted for 26% of the age-adjusted variance in BMSi in T2D (P = .03).
Conclusions:
Bone material properties are impaired in postmenopausal women with T2D as determined by reference point indentation. The results suggest a role for the accumulation of AGEs to account for inferior BMSi in T2D.
“Bone material strength is impaired in type 2 diabetes and is lowest in diabetic patients with increased advanced glycation endproducts as determined by skin autofluorescence.”
The COVID-19 pandemic has had growing environmental consequences related to plastic use and follow-up waste, but more urgent health issues have far overshadowed the potential impacts. This paper ...gives a prospective outlook on how the disruption caused by COVID-19 can act as a catalyst for short-term and long-term changes in plastic waste management practices throughout the world. The impact of the pandemic and epidemic following through the life cycles of various plastic products, particularly those needed for personal protection and healthcare, is assessed. The energy and environmental footprints of these product systems have increased rapidly in response to the surge in the number of COVID-19 cases worldwide, while critical hazardous waste management issues are emerging due to the need to ensure destruction of residual pathogens in household and medical waste. The concept of Plastic Waste Footprint (PWF) is proposed to capture the environmental footprint of a plastic product throughout its entire life cycle. Emerging challenges in waste management during and after the pandemic are discussed from the perspective of novel research and environmental policies. The sudden shift in waste composition and quantity highlights the need for a dynamically reponsive waste management system. Six future research directions are suggested to mitigate the potential impacts of the pandemic on waste management systems.
•Expert insight for dealing with COVID-19 plastic use and waste.•Minimising plastic waste during and after the pandemic.•Introduction and benefits of Plastic Waste Footprint.•Considering and reducing Environmental, including GHG, Footprints.
In patients with stable cardiovascular disease, those receiving rivaroxaban plus aspirin had fewer major cardiovascular events but more major bleeding events than those receiving aspirin alone. ...Rivaroxaban alone did not result in fewer major cardiovascular events than aspirin alone.
The University of California Santa Cruz Genome Browser (http://genome.ucsc.edu) offers online public access to a growing database of genomic sequence and annotations for a wide variety of organisms. ...The Browser is an integrated tool set for visualizing, comparing, analyzing and sharing both publicly available and user-generated genomic data sets. In the past year, the local database has been updated with four new species assemblies, and we anticipate another four will be released by the end of 2011. Further, a large number of annotation tracks have been either added, updated by contributors, or remapped to the latest human reference genome. Among these are new phenotype and disease annotations, UCSC genes, and a major dbSNP update, which required new visualization methods. Growing beyond the local database, this year we have introduced 'track data hubs', which allow the Genome Browser to provide access to remotely located sets of annotations. This feature is designed to significantly extend the number and variety of annotation tracks that are publicly available for visualization and analysis from within our site. We have also introduced several usability features including track search and a context-sensitive menu of options available with a right-click anywhere on the Browser's image.
Obliterative bronchiolitis (OB) is the key impediment to the long‐term survival of lung transplant recipients and the lack of a robust preclinical model precludes examining OB immunopathogenesis. In ...the current study, lungs from C57BL/10 H‐2b mice that are MHC compatible, but minor histocompatability antigen incompatible, were transplanted into C57BL/6 mice. Histological features and cytokine profiles of OB were assessed. Moderate rejection (grade A3) developed by day 14, with evidence of OB at that time point. At 21 days, OB was present in 55% of grafts and moderate to severe rejection (grade A3‐A4) was present in all mice. At 28 days, OB was present in 44% of mice and severe rejection (grade A4) was present in all. IL‐17A, but not IL‐17F, splenic mRNA transcripts and serum protein levels were increased only in mice that developed OB, whereas IL‐10 transcripts and protein were increased only in non‐OB mice. Neutralizing IL‐17 prevented OB, down regulated acute rejection, and upregulated systemic IL‐10. Collectively, these data show that transplantation of minor histoincompatible lungs from C57BL/10 mice into C57BL/6 mice results in a highly reproducible preclinical model of OB. In addition, these data indicate that neutralizing IL‐17A or augmenting IL‐10 could be therapeutic interventions to prevent OB.
This article reports on an orthotopic mouse lung transplant that develops obliterative bronchiolitis, and shows that neutralizing IL‐17A prevents this lesion. See editorial by Kreisel et al on page 882.
There is growing recognition and understanding of the entities that cause interstitial lung disease (ILD) in infants. These entities are distinct from those that cause ILD in older children and ...adults.
A multidisciplinary panel was convened to develop evidence-based guidelines on the classification, diagnosis, and management of ILD in children, focusing on neonates and infants under 2 years of age. Recommendations were formulated using a systematic approach. Outcomes considered important included the accuracy of the diagnostic evaluation, complications of delayed or incorrect diagnosis, psychosocial complications affecting the patient's or family's quality of life, and death.
No controlled clinical trials were identified. Therefore, observational evidence and clinical experience informed judgments. These guidelines: (1) describe the clinical characteristics of neonates and infants (<2 yr of age) with diffuse lung disease (DLD); (2) list the common causes of DLD that should be eliminated during the evaluation of neonates and infants with DLD; (3) recommend methods for further clinical investigation of the remaining infants, who are regarded as having "childhood ILD syndrome"; (4) describe a new pathologic classification scheme of DLD in infants; (5) outline supportive and continuing care; and (6) suggest areas for future research.
After common causes of DLD are excluded, neonates and infants with childhood ILD syndrome should be evaluated by a knowledgeable subspecialist. The evaluation may include echocardiography, controlled ventilation high-resolution computed tomography, infant pulmonary function testing, bronchoscopy with bronchoalveolar lavage, genetic testing, and/or lung biopsy. Preventive care, family education, and support are essential.
Bandtail states in disordered semiconductor materials result in losses in open-circuit voltage (V
) and inhibit carrier transport in photovoltaics. For colloidal quantum dot (CQD) films that promise ...low-cost, large-area, air-stable photovoltaics, bandtails are determined by CQD synthetic polydispersity and inhomogeneous aggregation during the ligand-exchange process. Here we introduce a new method for the synthesis of solution-phase ligand-exchanged CQD inks that enable a flat energy landscape and an advantageously high packing density. In the solid state, these materials exhibit a sharper bandtail and reduced energy funnelling compared with the previous best CQD thin films for photovoltaics. Consequently, we demonstrate solar cells with higher V
and more efficient charge injection into the electron acceptor, allowing the use of a closer-to-optimum bandgap to absorb more light. These enable the fabrication of CQD solar cells made via a solution-phase ligand exchange, with a certified power conversion efficiency of 11.28%. The devices are stable when stored in air, unencapsulated, for over 1,000 h.
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