Barriers to cancer clinical trial participation have been the subject of frequent study, but the rate of trial participation has not changed substantially over time. Studies often emphasize ...patient-related barriers, but other types of barriers may have greater impact on trial participation. Our goal was to examine the magnitude of different domains of trial barriers by synthesizing prior research.
We conducted a systematic review and meta-analysis of studies that examined the trial decision-making pathway using a uniform framework to characterize and quantify structural (trial availability), clinical (eligibility), and patient/physician barrier domains. The systematic review utilized the PubMed, Google Scholar, Web of Science, and Ovid Medline search engines. We used random effects to estimate rates of different domains across studies, adjusting for academic vs community care settings.
We identified 13 studies (nine in academic and four in community settings) with 8883 patients. A trial was unavailable for patients at their institution 55.6% of the time (95% confidence interval CI = 43.7% to 67.3%). Further, 21.5% (95% CI = 10.9% to 34.6%) of patients were ineligible for an available trial, 14.8% (95% CI = 9.0% to 21.7%) did not enroll, and 8.1% (95% CI = 6.3% to 10.0%) enrolled. Rates of trial enrollment in academic (15.9% 95% CI = 13.8% to 18.2%) vs community (7.0% 95% CI = 5.1% to 9.1%) settings differed, but not rates of trial unavailability, ineligibility, or non-enrollment.
These findings emphasize the enormous need to address structural and clinical barriers to trial participation, which combined make trial participation unachievable for more than three of four cancer patients.
Undoubtedly, neuroinflammation is a major contributor to Alzheimer's disease (AD) progression. Neuroinflammation is characterized by the activity of brain resident glial cells, in particular ...microglia, but also by peripheral immune cells, which infiltrate the brain at certain stages of disease progression. The specific role of microglia in shaping AD pathology is still controversially discussed. Moreover, a possible role of microglia in the interaction and recruitment of peripheral immune cells has so far been completely ignored.
We ablated microglia cells in 12-month-old WT and APP-PS1 transgenic mice for 4 weeks using the CSF1R inhibitor PLX5622 and analyzed its consequences to AD pathology and in particular to peripheral immune cell infiltration.
PLX5622 treatment successfully reduced microglia numbers. Interestingly, it uncovered a treatment-resistant macrophage population (Iba1
/TMEM119
). These cells strongly expressed the phagocytosis marker CD68 and the lymphocyte activation, homing, and adhesion molecule CD44, specifically at sites of amyloid-beta plaques in the brains of APP-PS1 mice. In consequence, ablation of microglia significantly raised the number of CD3
/CD8
T-cells and reduced the expression of anti-inflammatory genes in the brains of APP-PS1 mice.
We conclude that in neurodegenerative conditions, chronically activated microglia might limit CD3
/CD8
T-cell recruitment to the brain and that local macrophages connect innate with adaptive immune responses. Investigating the role of peripheral immune cells, their interaction with microglia, and understanding the link between innate and adaptive immune responses in the brain might be a future directive in treating AD pathology.
Functioning as key players in cellular regulation of membrane curvature, BAR domain proteins bend bilayers and recruit interaction partners through poorly understood mechanisms. Using electron ...cryomicroscopy, we present reconstructions of full-length endophilin and its N-terminal N-BAR domain in their membrane-bound state. Endophilin lattices expose large areas of membrane surface and are held together by promiscuous interactions between endophilin's amphipathic N-terminal helices. Coarse-grained molecular dynamics simulations reveal that endophilin lattices are highly dynamic and that the N-terminal helices are required for formation of a stable and regular scaffold. Furthermore, endophilin accommodates different curvatures through a quantized addition or removal of endophilin dimers, which in some cases causes dimerization of endophilin's SH3 domains, suggesting that the spatial presentation of SH3 domains, rather than affinity, governs the recruitment of downstream interaction partners.
Display omitted
► CryoEM structure of membrane-bound full-length N-BAR protein endophilin ► N-BAR lattices are fundamentally different than F-BAR lattices ► Nonspecific, weak, and antiparallel interaction between H0 helices stabilize lattice ► Some lattice geometries allow SH3-domain dimerization between adjacent N-BAR dimers
Unlike other proteins in the membrane-remodeling BAR family, endophilin forms lattices that are held together by surprisingly nonspecific interactions, in which membrane curvature depends on the number of bound endophilin dimers rather than their orientation or conformation.
Membrane-shaping proteins of the BAR domain superfamily are determinants of organelle biogenesis, membrane trafficking, cell division, and cell migration. An upsurge of research now reveals new ...principles of BAR domain-mediated membrane remodeling, enhancing our understanding of membrane curvature-mediated information processing.
The COVID-19 pandemic has caused severe disruptions in care for many patients. A key question is whether the landscape of clinical research has also changed.
In a retrospective cohort study, we ...examined the association of the COVID-19 outbreak with new clinical trial activations. Trial data for all interventional and observational oncology, cardiovascular, and mental health studies from January 2015 through September 2020 were obtained from ClinicalTrials.gov . An interrupted time-series analysis with Poisson regression was used.
We examined 62,252 trial activations. During the initial COVID-19 outbreak (February 2020 through May 2020), model-estimated monthly trial activations for US-based studies were only 57% of the expected estimate had the pandemic not occurred (relative risk = 0.57, 95% CI 0.52 to 0.61, p < .001). For non-US-based studies, the impact of the pandemic was less dramatic (relative risk = 0.77, 95% CI 0.73 to 0.82, p < .001), resulting in an overall 27% reduction in the relative risk of new trial activations for US-based trials compared to non-US-based trials (relative risk ratio = 0.73, 95% CI 0.67 to 0.81, p < .001). Although a rebound occurred in the initial reopening phase (June 2020 through September 2020), the rebound was weaker for US-based studies compared to non-US-based studies (relative risk ratio = 0.87, 95% CI 0.80 to 0.95, p < .001).
These findings are consistent with the disproportionate burden of COVID-19 diagnoses and deaths during the initial phase of the pandemic in the USA. Reduced activation of cancer clinical trials will likely slow the pace of clinical research and new drug discovery, with long-term negative consequences for cancer patients. An important question is whether the renewed outbreak period of winter 2020/2021 will have a similarly negative impact on the initiation of new clinical research studies for non-COVID-19 diseases.
Women have more adverse events (AEs) from chemotherapy than men, but few studies have investigated sex differences in immune or targeted therapies. We examined AEs by sex across different treatment ...domains.
We analyzed treatment-related AEs by sex in SWOG phase II and III clinical trials conducted between 1980 and 2019, excluding sex-specific cancers. AE codes and grade were categorized using the Common Terminology Criteria for Adverse Events. Symptomatic AEs were defined as those aligned with the National Cancer Institute's Patient-Reported Outcome-Common Terminology Criteria for Adverse Events; laboratory-based or observable/measurable AEs were designated as objective (hematologic
nonhematologic). Multivariable logistic regression was used, adjusting for age, race, and disease prognosis. Thirteen symptomatic and 14 objective AE categories were examined.
In total, N = 23,296 patients (women, 8,838 37.9%; men, 14,458 62.1%) from 202 trials experiencing 274,688 AEs were analyzed; 17,417 received chemotherapy, 2,319 received immunotherapy, and 3,560 received targeted therapy. Overall, 64.6% (n = 15,051) experienced one or more severe (grade ≥ 3) AEs. Women had a 34% increased risk of severe AEs compared with men (odds ratio OR = 1.34; 95% CI, 1.27 to 1.42;
< .001), including a 49% increased risk among those receiving immunotherapy (OR = 1.49; 95% CI, 1.24 to 1.78;
< .001). Women experienced an increased risk of severe symptomatic AEs among all treatments, especially immunotherapy (OR = 1.66; 95% CI, 1.37 to 2.01;
< .001). Women receiving chemotherapy or immunotherapy experienced increased severe hematologic AE. No statistically significant sex differences in risk of nonhematologic AEs were found.
The greater severity of both symptomatic AEs and hematologic AEs in women across multiple treatment modalities indicates that broad-based sex differences exist. This could be due to differences in AE reported, pharmacogenomics of drug metabolism/disposition, total dose received, and/or adherence to therapy. Particularly large sex differences were observed for patients receiving immunotherapy, suggesting that studying AEs from these agents is a priority.
•CD8+ T-cells infiltrate the brain in aging and human AD pathology.•CD8+ T-cells can successfully be ablated from blood and brain using an anti-CD8 antibody approach.•AD transgenic mice lacking CD8+ ...T-cells show altered neuronal- and synapse-related gene expression in the hippocampus.
Neuroinflammation is a major contributor to disease progression in Alzheimer’s disease (AD) and is characterized by the activity of brain resident glial cells, in particular microglia cells. However, there is increasing evidence that peripheral immune cells infiltrate the brain at certain stages of AD progression and shape disease pathology. We recently identified CD8+ T-cells in the brain parenchyma of APP-PS1 transgenic mice being tightly associated with microglia as well as with neuronal structures. The functional role of CD8+ T-cells in the AD brain is however completely unexplored. Here, we demonstrate increased numbers of intra-parenchymal CD8+ T-cells in human AD post-mortem hippocampus, which was replicated in APP-PS1 mice. Also, aged WT mice show a remarkable infiltration of CD8+ T-cells, which was more pronounced and had an earlier onset in APP-PS1 mice. To address their functional relevance in AD, we successfully ablated the pool of CD8+ T-cells in the blood, spleen and brain from 12 months-old APP-PS1 and WT mice for a total of 4 weeks using an anti-CD8 antibody treatment. While the treatment at this time of disease stage did neither affect the cognitive outcome nor plaque pathology, RNAseq analysis of the hippocampal transcriptome from APP-PS1 mice lacking CD8+ T-cells revealed highly altered neuronal- and synapse-related gene expression including an up-regulation for neuronal immediate early genes (IEGs) such as the Activity Regulated Cytoskeleton Associated Protein (Arc) and the Neuronal PAS Domain Protein 4 (Npas4). Gene ontology enrichment analysis illustrated that the biological processes “regulation of neuronal synaptic plasticity” and the cellular components “postsynapses” were over-represented upon CD8+ T-cell ablation. Additionally, Kegg pathway analysis showed up-regulated pathways for “calcium signaling”, “long-term potentiation”, “glutamatergic synapse” and “axon guidance”. Therefore, we conclude that CD8+ T-cells infiltrate the aged and AD brain and that brain CD8+ T-cells might directly contribute to neuronal dysfunction in modulating synaptic plasticity. Further analysis will be essential to uncover the exact mechanism of how CD8+ T-cells modulate the neuronal landscape and thereby contribute to AD pathology.
Recent Results From NA61/SHINE Unger, M.
Nuclear and particle physics proceedings,
10/2016, Letnik:
279-281
Journal Article
Recenzirano
We present preliminary measurements of the production spectra of identified charged pions and ρ0 production in π−+C interactions at 158 and 350 GeV/c with the NA61/SHINE detector. The results are ...compared to predictions of hadronic interaction models used for the interpretation of extensive air showers.
PDF
