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Therapeutic antibodies targeting the CTLA4/PD-1 pathways have revolutionized cancer immunotherapy by eliciting durable remission in patients with cancer. However, relapse following early response, attributable to primary and adaptive resistance, is frequently observed. Additional immunomodulatory pathways are being studied in patients with primary or acquired resistance to CTLA4 or PD-1 blockade. The DNAM1 axis is a potent coregulator of innate and adaptive immunity whose other components include the immunoglobulin receptors TIGIT, PVRIG, and CD96, and their nectin and nectin-like ligands. We review the basic biology and therapeutic relevance of this family, which has begun to show promise in cancer clinical trials. SIGNIFICANCE Recent studies have outlined the immuno-oncologic ascendancy of coinhibitory receptors in the DNAM1 axis such as TIGIT and PVRIG and, to a lesser extent, CD96. Biological elucidation backed by ongoing clinical trials of single-agent therapy directed against TIGIT or PVRIG is beginning to provide the rationale for testing combination regimens of DNAM1 axis blockers in conjunction with anti-PD-1/PD-L1 agents.Recently, the phase II HUDSON trial demonstrated the feasibility of testing multiple immunotherapy-based combinations simultaneously, with biomarker-driven treatment matching where possible, in patients with non-small cell lung cancer. The study provides an example of how novel trial designs can improve the efficiency of drug testing.Epigenetic regulators are a class of promising targets in the combination with immune checkpoint inhibitors for cancer treatment, but the impact of the broad effects of perturbing epigenetic regulators on tumor immunotherapy remains to be fully explored. Here we show that ablation of the histone demethylase LSD1 in multiple tumor cells induces TGF-B expression, which exerts an inhibitory effect on T cell immunity through suppressing the cytotoxicity of intratumoral CD8+ T cells and consequently dampens the antitumor effect of LSD1 ablation-induced T cell infiltration. Importantly, concurrent depletion of LSD1 and TGF-B in combination with PD-1 blockade significantly increases both CD8+ T cell infiltration and cytotoxicity, leading to eradication of poorly immunogenic tumors and a long-term protection from tumor re-challenge. Thus, combining LSD1 inhibition with blockade of TGF-B and PD-1 may represent a promising triple combination therapy for treating certain refractory tumors.An effective vaccine is considered the best method to achieve herd immunity. As of February 2021, 12 vaccines were in late-stage clinical trials worldwide, with many more in development. Of those, 8 have received emergency use authorization from at least one country's governing body. These vaccines use various platforms to deliver the vaccines, each with pros and cons. Published data show these vaccines are effective in preventing the severe symptoms associated with COVID-19 in adults with few side effects, but challenges remain with storage and delivery and treating virus variants.
Antimicrobial resistance (AMR) is a global health priority. Acne vulgaris is a common skin condition for which antibiotic use ranges from a few months to years of daily exposure.
To systemically search for and synthesise evidence on the risk of treatment-resistant infections, and other evidence of AMR, following long-term oral antibiotic use for acne.
In this systematic review, a literature search was carried out using the databases Embase, MEDLINE, Cochrane, and Web of Science. They were searched using MeSH, Emtree, or other relevant terms, and followed a pre-registered protocol.
Search strategies were developed with a librarian and undertaken in July 2019. All searches date from database inception. The primary outcome was antibiotic treatment failure or infection caused by a resistant organism. Secondary outcomes included detection of resistant organisms without an infection, rate of infection, or changes to flora.
A total of 6996 records were identified. Seventy-three full-text articles were shortlisted for full review, of which five were included. selleck kinase inhibitor Two investigated rates of infection, and three resistance or changes to microbial flora. Three studies had 35 or fewer participants (range 20-118 496). Three studies had a serious or high risk of bias, one moderate, and one a low risk of bias. Weak evidence was found for an association between antibiotic use for acne and subsequent increased rates of upper respiratory tract infections and pharyngitis.
There is a lack of high quality evidence on the relationship between oral antibiotics for acne treatment and subsequent AMR sequelae. This needs to be urgently addressed with rigorously conducted studies.
There is a lack of high quality evidence on the relationship between oral antibiotics for acne treatment and subsequent AMR sequelae. This needs to be urgently addressed with rigorously conducted studies.
Increasing access to general practice work experience placements for school students is a strategy for improving general practice recruitment, despite limited evidence and concerns surrounding equity of access to general practice experiences.
To examine the association between undertaking general practice experience and the perceptions of general practice as an appealing future career among prospective medical applicants. To identify socioeconomic factors associated with obtaining general practice experience.
Cross-sectional questionnaire study in the UK.
Participants were UK residents aged ≥16 years and seriously considering applying to study medicine in 2019/2020. They were invited to take part via the University Clinical Aptitude Test (UCAT). Questionnaire data were analysed using a linear regression of general practice appeal on general practice experience, adjusting for career motivations and demographics, and a logistic regression of general practice experience on measures of social capital and hool was associated with finding general practice appealing, which supports its utility in recruitment. Applicants from more deprived backgrounds were less likely to have had a general practice experience, possibly through lack of accessible opportunities.