The antitumour activity of endogenous or adoptively transferred tumour-specific T cells is highly dependent on their differentiation status. It is now apparent that less differentiated T cells ...compared with fully differentiated effector T cells have better antitumour therapeutic effects owing to their enhanced capacity to expand and their long-term persistence. In patients with cancer, the presence of endogenous or adoptively transferred T cells with stem-like memory or precursor phenotype correlates with improved therapeutic outcomes. Advances in our understanding of T cell differentiation states at the epigenetic and transcriptional levels have led to the development of novel methods to generate tumour-specific T cells - namely, chimeric antigen receptor T cells - that are more persistent and resistant to the development of dysfunction. These include the use of novel culture methods before infusion, modulation of transcriptional, metabolic and/or epigenetic programming, and strategies that fine-tune antigen receptor signalling. This Review discusses existing barriers and strategies to overcome them for successful T cell expansion and persistence in the context of adoptive T cell immunotherapy for solid cancers.
•Contact tracing is not that useful if other interventions have been fully deployed.•Students should be prioritized for vaccination.•Home isolation and visiting doctors after symptom onset are the ...most effective.•Fever detection in public areas is useless if fully deployed other interventions.
By the end of February 2021, COVID-19 had spread to over 230 countries, with more than 100 million confirmed cases and 2.5 million deaths. To control infection spread with the least disruption to economic and societal activities, it is crucial to implement the various interventions effectively. In this study, we developed an agent-based SEIR model, using real demographic and geographic data from Hong Kong, to analyse the efficiency of various intervention strategies in preventing infection by the SARS-CoV-2 virus. Close contact route including short-range airborne is considered as the main transmission routes for COVID-19 spread. Contact tracing is not that useful if all other interventions have been fully deployed. The number of infected individuals could be halved if people reduced their close contact rate by 25%. For reducing transmission, students should be prioritized for vaccination rather than retired older people and preschool aged children. Home isolation, and taking the nucleic acid test (NAT) as soon as possible after symptom onset, are much more effective interventions than wearing masks in public places. Temperature screening in public places only disrupted the infection spread by a small amount when other interventions have been fully implemented. Our results may be useful for other highly populated cities, when choosing their intervention strategies to prevent outbreaks of COVID-19 and similar diseases.
Fomites are known to spread infectious diseases, but their role in determining transmission risk remains unclear. The association of surface touch networks (STNs), proposed to explain this risk, with ...real-life surface contamination has not yet been demonstrated. To construct STNs, we collected surface touch data from 23 to 26 scholars through 2 independent experiments conducted in office spaces for 13 h each. In parallel, a tracer bacterium (Lactobacillus bulgaricus) was spread by a designated carrier in each experiment during normal activities; the subsequent extent of surface contamination was assessed using qPCR. The touch data were also analyzed using an agent-based model that predicted the observed contamination. Touching public (door handles) and hidden public (desks, chair seatbacks) surfaces that connected occupants, sparse hand-to-hand contact, and active carriers contributed significantly to contamination spread, which was also correlated with the size of the social group containing carriers. The natural and unsupervised experiments reflected realistic exposure levels of mouths (1–10 ppm of total contamination spread by one root carrier), nostrils (~1 ppm), and eyes (~0.1 ppm). We conclude that the contamination degree of known and hidden public surfaces can indicate fomite exposure risk. The social group effect could trigger superspreading events through fomite transmission.
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•The association between observed surface contamination and touch behaviors was built.•The association was investigated using a surrogate tracer and a surface touch network.•Behavioral factors that contributed to bacterial contamination spread was identified.•Realistic fomite exposure risks through touching mucous membranes was evaluated.•The social group effect may create superspreading events through fomite transmission.
Adoptive cell therapies using genetically engineered T cell receptor or chimeric antigen receptor T cells are emerging forms of immunotherapy that redirect T cells to specifically target cancer. ...However, tumor antigen heterogeneity remains a key challenge limiting their efficacy against solid cancers. Here, we engineered T cells to secrete the dendritic cell (DC) growth factor Fms-like tyrosine kinase 3 ligand (Flt3L). Flt3L-secreting T cells expanded intratumoral conventional type 1 DCs and substantially increased host DC and T cell activation when combined with immune agonists poly (I:C) and anti-4-1BB. Importantly, combination therapy led to enhanced inhibition of tumor growth and the induction of epitope spreading towards antigens beyond those recognized by adoptively transferred T cells in solid tumor models of T cell receptor and chimeric antigen receptor T cell therapy. Our data suggest that augmenting endogenous DCs is a promising strategy to overcome the clinical problem of antigen-negative tumor escape following adoptive cell therapy.
This book teaches you all that's needed to build a fully functional web application from scratch. You'll learn all the necessary tools and modules that are required in the process. Beginning with the ...basics of RESTful API, you'll complete the book by building and deploying an industry-grade web application.
In this issue of Cancer Cell, Gurusamy et al. use a CRISPR-Cas9 screening approach to demonstrate that deletion of p38 increases multiple phenotypic qualities of effective anti-tumor T cells. ...Preconditioning T cells with a p38 inhibitor enhances anti-tumor efficacy of adoptive immunotherapy.
In this issue of Cancer Cell, Gurusamy et al. use a CRISPR-Cas9 screening approach to demonstrate that deletion of p38 increases multiple phenotypic qualities of effective anti-tumor T cells. Preconditioning T cells with a p38 inhibitor enhances anti-tumor efficacy of adoptive immunotherapy.
Field-effect transistors fabricated on graphene grown by chemical vapor deposition (CVD) often exhibit large hysteresis accompanied by low mobility, high positive backgate voltage corresponding to ...the minimum conductivity point (V min), and high intrinsic carrier concentration (n 0). In this report, we show that the mobility reported to date for CVD graphene devices on SiO2 is limited by trapped water between the graphene and SiO2 substrate, impurities introduced during the transfer process and adsorbates acquired from the ambient. We systematically study the origin of the scattering impurities and report on a process which achieves the highest mobility (μ) reported to date on large-area devices for CVD graphene on SiO2: maximum mobility (μmax) of 7800 cm2/(V·s) measured at room temperature and 12 700 cm2/(V·s) at 77 K. These mobility values are close to those reported for exfoliated graphene on SiO2 and can be obtained through the careful control of device fabrication steps including minimizing resist residue and non-aqueous transfer combined with annealing. It is also observed that CVD graphene is prone to adsorption of atmospheric species, and annealing at elevated temperature in vacuum helps remove these species.
Multiomic analyses have shed light upon the molecular heterogeneity and complexity of triple-negative breast cancers (TNBCs). With increasing recognition that TNBC is not a single disease entity but ...encompasses different disease subtypes, a one-size-fits-all treatment paradigm has become obsolete. In this context, the inhibition of phosphatidylinositol 3-kinase/protein kinase B (PI3K/AKT) and androgen receptor (AR) signaling pathways have emerged as potential therapeutic strategies against selected tumors. In this paper, we reviewed the preclinical rationale, predictive biomarkers, efficacy, and safety data from early phase trials, and the future directions for these two biomarker-directed treatment approaches in TNBC.
Conventional treatments for pancreatic cancer are largely ineffective, and the prognosis for the vast majority of patients is poor. Clearly, new treatment options are desperately needed. ...Immunotherapy offers hope for the development of treatments for pancreatic cancer. A central requirement for the efficacy of this approach is the existence of cancer antigen-specific T cells, but these are often not present or difficult to isolate for most pancreatic tumors. Nevertheless, specific T cells can be generated using genetic modification to express chimeric antigen receptors (CAR), which can enable T cell responses against pancreatic tumor cells. CAR T cells can be produced
and expanded
for infusion into patients. Remarkable responses have been documented using CAR T cells against several malignancies, including leukemias and lymphomas. Based on these successes, the extension of CAR T cell therapy for pancreatic cancer holds great promise. However, there are a number of challenges that limit the full potential of CAR T cell therapies for pancreatic cancer, including the highly immunosuppressive tumor microenvironment (TME). In this article, we will review the recent progress in using CAR T cells in pancreatic cancer preclinical and clinical settings, discuss hurdles for utilizing the full potential of CAR T cell therapy and propose research strategies and future perspectives. Research into the use of CAR T cell therapy in pancreatic cancer setting is rapidly gaining momentum and understanding strategies to overcome the current challenges in the pancreatic cancer setting will allow the development of effective CAR T cell therapies, either alone or in combination with other treatments to benefit pancreatic cancer patients.
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