4 research outputs found
The worldwide clinical trial research response to the COVID-19 pandemic - the first 100 days
Background: Never before have clinical trials drawn as much public attention as those testing interventions for COVID-19. We aimed to describe the worldwide COVID-19 clinical research response and its evolution over the first 100 days of the pandemic. Methods: Descriptive analysis of planned, ongoing or completed trials by April 9, 2020 testing any intervention to treat or prevent COVID-19, systematically identified in trial registries, preprint servers, and literature databases. A survey was conducted of all trials to assess their recruitment status up to July 6, 2020. Results: Most of the 689 trials (overall target sample size 396,366) were small (median sample size 120; interquartile range [IQR] 60-300) but randomized (75.8%; n=522) and were often conducted in China (51.1%; n=352) or the USA (11%; n=76). 525 trials (76.2%) planned to include 155,571 hospitalized patients, and 25 (3.6%) planned to include 96,821 health-care workers. Treatments were evaluated in 607 trials (88.1%), frequently antivirals (n=144) or antimalarials (n=112); 78 trials (11.3%) focused on prevention, including 14 vaccine trials. No trial investigated social distancing. Interventions tested in 11 trials with >5,000 participants were also tested in 169 smaller trials (median sample size 273; IQR 90-700). Hydroxychloroquine alone was investigated in 110 trials. While 414 trials (60.0%) expected completion in 2020, only 35 trials (4.1%; 3,071 participants) were completed by July 6. Of 112 trials with detailed recruitment information, 55 had recruited <20% of the targeted sample; 27 between 20-50%; and 30 over 50% (median 14.8% [IQR 2.0-62.0%]). Conclusions: The size and speed of the COVID-19 clinical trials agenda is unprecedented. However, most trials were small investigating a small fraction of treatment options. The feasibility of this research agenda is questionable, and many trials may end in futility, wasting research resources. Much better coordination is needed to respond to global health threats
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Investigating the role of select receptors in radiation-induced cellular plasticity events in glioblastoma
All living matter is under constant environmental stress that jeopardizes the genomic integrity of individual cells and the functional integrity of tissues in higher organisms. At the level of non-post-mitotic tissues, stem cells constantly divide to give rise to all lineages of differentiated cells. Once thought to be unidirectional, cellular differentiation can now be reversed and overexpression of developmental transcription factors can turn somatic cells into induced pluripotent stem cells by means of reprogramming. This process is critically dependent on optimal co-stimulation of the innate immune response through activation of pattern recognition receptors (PRRs) by pathogen and/or damage associated molecular patterns (PAMPs/DAMPs). Ionizing radiation (IR) being an extreme form of genotoxic stress, can lead to the release of DAMPs. Our lab has identified that radiation induces the formation of cancer stem cells from non-cancer stem cells, a process termed IR-induced phenotype conversion. Cellular plasticity, an umbrella term encompassing reprogramming and radiation-induced phenotypic conversion events, allows cells to effectively respond to triggers that would otherwise compromise them. The underlying mechanisms driving these processes are incompletely understood but PAMPs and DAMPs are readily involved and employ common pathways downstream of their respective receptors. Glioblastoma (GBM) is a highly aggressive, malignant primary brain tumor for which cancer stem cells play a critical role in therapy resistance, recurrence and overall disease progression. This in combination with the radiation-induced cellular plasticity response could further exacerbate patient outcome if unaccounted for. Thus, to better understand the underlying mechanisms driving IR-induced cellular plasticity events, cancer stem cell maintenance/self-renewal (SFAs, ELDAs) and de novo stem cell induction (reprogramming assays) were studied using patient-derived glioblastoma cells. Several Toll-like receptors (TLRs) as well as components of the free cytosolic DNA sensing machinery, the cGAS/STING pathway, were evaluated. Our main study findings were as follows: 1) stem cell maintenance following irradiation is mediated through cGAS-independent STING signaling, with potential crosstalk with TLR4 and TLR9 and 2) de novo stem cell induction following irradiation implicates TLR3 signaling and potentially other receptors and processes affected by chloroquine. Collectively, these point to a direct link between innate immune signaling and IR-induced cellular plasticity events
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Trichothiodystrophy hair shafts display distinct ultrastructural features
Hair shafts from three trichothiodystrophy (TTD) patients with mutations in the ERCC2 (XPD) gene were examined by transmission electron microscopy. TTD is a rare, recessive disorder with mutations in several genes in the DNA repair/transcription pathway, including ERCC2. Unlike previous studies, the hair shafts were examined after relaxation of their structure by partial disulphide bond reduction in the presence of sodium dodecyl sulphate, permitting improved visualization. Compared with hair shafts of normal phenotype, TTD cuticle cells displayed aberrant marginal bands and exocuticle layers. Clusters of cells stained differently (light versus dark) in the cortex of aberrant shafts, and the keratin macrofibrils appeared much shorter in the cytoplasm. Considerable heterogeneity in these properties was evident among samples and even along the length of single hair shafts. The results are consistent with not only a paucity of high sulphur components, such as keratin-associated proteins, but also a profound imbalance in protein content and organization