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Chemogenetics for sensing antigens
Get PDFAntigen-based systems offer highly specific binding and customizability, broadening their application to various fields of cell biology. In a recent issue of Nature, Kalogriopoulos et al. design antigen-sensing G-protein-coupled receptors that exhibit programmable responses spanning exogenous gene expression, G-protein signaling, and receptor activation
Combinatorial treatment of glioblastoma with temozolomide (TMZ) plus 5-ethynyl-2'-deoxyuridine (EdU).
Get PDFGlioblastoma (GBM) is the most aggressive malignant primary brain tumor in adults, with incidence peaking in later life. It is commonly treated with surgery followed by administration of ionizing radiation and the DNA-alkylating agent temozolomide (TMZ). Even though this regimen confers some progression-free survival, there is essentially no cure with the median survival with the standard of care being about 12 mo. Currently, several alternative approaches are being developed to improve upon this outcome. We have already shown EdU alone effectively treats GBM, and we now study the efficacy of TMZ+EdU combination therapy. TMZ+EdU significantly improves antitumor efficacy compared to either single-agent therapy against GBM cell lines in vitro, against three different orthotopic GBM xenograft models, and against passage-zero GBM patient tumor tissues engrafted within an organotypic brain slice culture-based platform. Together, our results suggest that EdU could be effective alongside standard-of-care TMZ in patients with GBM
Transition of Perovskite Solar Technologies to Being Flexible
Get PDFPerovskite technologies has taken giant steps on its advances in only a decade time, from fundamental science to device engineering. The possibility to exploit this technology on a thin flexible substrate gives an unbeatable power to weight ratio compares to similar photovoltaic systems, opening new possibilities and new integration concepts, going from building integrated and applied photovoltaics (BIPV, BAPV) to internet of things (IoT). In this perspective, the recent progress of perovskite solar technologies on flexible substrates are summarized, focusing on the challenges that researchers face upon using flexible substrates. A dig into material science is necessary to understand what kind of mechanisms are limiting its efficiency compare to rigid substrates, and which physical mechanism limits the upscaling on flexible substrate. Furthermore, an overview of stability test on flexible modules will be described, suggesting common standard procedure and guidelines to follow, showing additional issues that flexible modules face upon bending, and how to prevent device degradation providing an ad-hoc encapsulation. Finally, the recent advances of flexible devices in the perovskite market will be shown, giving an outline of how this technology is exploited on flexible substrates, and what are still missing that need stakeholders' attention
Protective envelope dimer epitope–like antibodies are elicited against dengue virus in children after infection and vaccination
Get PDFCross-reactive antibodies to epitopes that span envelope proteins on the virion surface are hypothesized to protect against dengue virus (DENV) infection and disease. Here, we measured antibodies targeting a quaternary epitope called the envelope dimer epitope (EDE) as well as neutralizing and binding antibodies and evaluated their association with DENV infection, vaccine response, and disease outcome in dengue-vaccinated (n = 164) and dengue-unvaccinated children (n = 88) within a longitudinal cohort in Cebu, Philippines (n = 2996). Antibodies targeting EDE were prevalent and associated with broad neutralization of mature DENV1 to DENV4 virions in those with evidence of at least two prior DENV infections but were mostly absent in those with only one prior infection. Subsequent infection and vaccination boosted titers of EDE-like antibodies, neutralizing antibodies, and DENV-binding antibodies. EDE-like antibodies were associated with reduced risk of symptomatic dengue and more severe dengue and statistically explained the protective effect of binding and neutralizing antibodies on dengue. Thus, antibodies targeting quaternary epitopes help explain the broad cross-protection observed in those with multiple prior DENV exposures, making them useful for evaluation and development of future vaccines and therapeutics
Exogenous Hormones, Tumor Intrinsic Subtypes, and Breast Cancer
Get PDFEtiologic heterogeneity in breast carcinogenesis needs to be well characterized for targeted prevention. Associations between menopausal hormonal therapy (MHT) and oral contraceptive (OC) use and breast cancer intrinsic-like subtypes are not well understood. To examine whether exogenous hormone use is differentially associated with breast cancer subtypes and to evaluate heterogeneity by intrinsic-like subtypes. This study pooled data from 31 nested and population-based case-control studies involved in the Breast Cancer Association Consortium. The study population included individuals with breast cancer and control participants from 13 case-control studies nested in prospective cohorts (recruited between 1982 and 2011) and 18 population-based case-control studies (recruited between 1990 and 2013). Data analysis was performed in June 2024. MHT use (estrogen-progestin therapy [EPT] or estrogen-only therapy [ET]) in postmenopausal women and OC use in premenopausal women (never, past use, or current use). Breast cancer intrinsic-like subtypes (luminal A–like, luminal B–like, luminal B–ERBB2 [formerly HER2 or HER2/neu]-like, ERBB2 enriched–like, or triple-negative) were determined by immunohistochemistry of tumor sections. Polytomous logistic regression was performed to estimate the association between exogenous hormones and risk of breast cancer by intrinsic-like subtypes. Analyses by subtypes were stratified by body mass index (BMI [calculated as weight in kilograms divided by height in meters squared]; healthy weight, 18.5-<25; overweight, 25-<30; or obesity, ≥30). This study included 42 269 individuals with breast cancer (11 901 [28.2%] premenopausal and 30 368 [71.8%] postmenopausal; 23 353 [55.2%] had a known intrinsic-like subtype) and 71 072 control participants. The mean (SD) age of all participants was 57.9 (10.9) years. In postmenopausal women, associations between current MHT use (EPT or ET) and breast cancer differed by subtype. Current EPT users with healthy weight were more likely to be diagnosed with luminal A–like (odds ratio [OR], 2.51 [95% CI, 2.26-2.80]) or luminal B–ERBB2-like (OR, 1.95 [95% CI, 1.61-2.37]) subtypes. These associations were attenuated but remained for individuals with overweight (OR, 1.40 [95% CI, 1.02-1.92]) or obesity (OR, 1.68 [95% CI, 1.01-2.78]). EPT use increased the odds of being diagnosed with luminal B–like tumors solely in women with healthy weight (OR, 1.47 [95% CI, 1.17-1.86]). Current ET use was positively associated with luminal A–like disease in women with healthy weight only (OR, 1.16 [95% CI, 1.01-1.32]), showing inverse associations with higher BMI (obesity: OR, 0.65 [95% CI, 0.50-0.85]). In premenopausal women, recent OC use was associated with luminal B–ERBB2-like (OR, 1.50 [95% CI, 1.09-2.08]), ERBB2 enriched–like (OR, 2.33 [95% CI, 1.55-3.51]), and triple-negative (OR, 1.75 [95% CI, 1.33-2.29]; P < .04 for heterogeneity) tumors. In this study, clear differences were observed in associations between current EPT use and luminal-like breast cancer subtypes and other subtypes. EPT users with healthy weight were more likely to be diagnosed with luminal-like breast cancer compared with nonusers. Subtype heterogeneity was less apparent in associations of OC and ET use. Future studies on contemporary formulations, patterns of use, and routes of administration of exogenous hormone usage are warranted
Poor Oral HIV Pre-Exposure Prophylaxis (PrEP) Persistence in an Integrated PrEP/STI Program in Malawi
Get PDFThe integration of HIV pre-exposure prophylaxis (PrEP) into STI services can improve PrEP uptake among a population at elevated risk of acquiring HIV. The effectiveness of PrEP relies on ongoing coverage during periods of HIV risk, however, and little is known about longitudinal PrEP use among people accessing PrEP through STI clinics in sub-Saharan Africa. In this study, we analyzed routine records data from people who newly initiated PrEP at an STI clinic in Lilongwe, Malawi in March-December 2022. We assessed PrEP persistence among clients who received Malawi’s standard-of-care PrEP services (n = 662) and reweighted the data to reflect the baseline distribution of age, sex, and PrEP indication among the full study population (n = 835). We used weighted generalized estimating equations to estimate the proportion of clients expected to persist on PrEP if all clients had received Malawi’s standard-of-care services. We also assessed predictors of persistence and described re-engagement in PrEP among clients who did not persist. We estimated that, had all clients received standard-of-care services, 17% (95% CI: 14%, 20%), 7% (95% CI: 6%, 10%), and 4% (95% CI: 3%, 5%) would have persisted on PrEP at 1, 3, and 6 months, respectively, and that 8% (95% CI: 5%, 11%) of those who did not persist on PrEP at 1 month would have re-engaged in PrEP services by 12 months. Persistence varied by age and PrEP indication. Our findings indicate very low PrEP persistence in this population and suggest opportunities to support ongoing PrEP use in settings with integrated PrEP/STI services
Genomic Evaluation of Canine Prostatic Carcinomas as a Model for the Human Disease
Get PDFSpontaneous canine prostate cancer (PC) is widely considered a pertinent clinical model for the human disease. While over 95% of PC in men are adenocarcinomas, arising from prostatic glandular epithelium, it is increasingly recognised that many canine PC are of urothelial origin, arising within the prostatic urethra or ducts, or through invasion from a primary urinary bladder tumour. At diagnosis, canine prostatic tumours are often poorly differentiated and widely disseminated, masking the primary site and limiting the sensitivity of cellular biomarkers. Consequently, published studies of canine PC show varying representation of glandular versus urothelial tumours, yielding conflicting observations regarding their molecular pathogenesis and clinical behaviour. We characterised DNA sequence mutations and copy number aberrations in 31 canine PC, seeking evidence supporting relevance as a disease model. Only three tumours resembled adenocarcinomas. The remainder were either histologically consistent with urothelial carcinoma (n = 15), showed mixed glandular and urothelial morphology (n = 4), or were carcinomas of undetermined cell type (n = 9). BRAF V588E mutation was detected in 87% of tumours, including all three adenocarcinomas. Urinary bladder involvement was evident in 46% of cases, but none of the adenocarcinomas. Genome-wide DNA copy number instability was apparent throughout the cohort, with chromosome 36 gain significantly associated with urothelial tumours. Hallmark alterations of human PC, such as defects within PI3K and androgen receptor signalling pathways, were not detected. Improved molecular subclassification of canine PC is needed to direct selection of relevant cases for modelling the human disease and to ensure appropriate extrapolation between canine and human studies
Methods for implementing and reporting the Patient‐Reported Outcomes version of the Common Terminology Criteria for Adverse Events to measure patient‐reported adverse events in cancer clinical trials
Get PDFThe Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE) was developed by the US National Cancer Institute to allow patients to directly report their side effects, enhancing the accuracy and patient-centeredness of cancer clinical trial adverse event reporting. Clinician-based reporting often misses the full range of patient symptoms, resulting in underreporting of side effects. The selection of adverse events for patient reporting must be defined in advance and consistently applied across all study arms. Investigators can use core symptom sets, including diarrhea, fatigue, and nausea, alongside tailored items specific to the treatments being studied. PRO-CTCAE has demonstrated similar scores across electronic, paper-based, and automated telephone administration methods. PRO-CTCAE administration typically occurs before start of treatment and regularly throughout treatment, with the administration frequency tailored to the expected trajectory of side effects. Ensuring high survey completion rates is essential for PRO-CTCAE success. Standard reporting can include tabular reporting of the proportion of patients with any (score ≥1) and high (score ≥3) levels of symptoms at the individual item level. A baseline-adjustment approach should be applied to account for symptoms before start of treatment to isolate treatment-emergent adverse events. The distribution of PRO-CTCAE scores at each time point can be visualized using stacked bar charts. PRO-CTCAE integration into cancer clinical trials is crucial for capturing a comprehensive range of treatment-related symptomatic adverse events and improving the evaluation of therapy tolerability. Ongoing research continues to refine its implementation, supported by regulatory guidance
Dual role of circulating and mucosal Vδ1 T cells in the control of and contribution to persistent HIV-1 infection
Get PDFCurative strategies for human immunodeficiency virus (HIV-1) infection are hindered by incomplete characterization of the latent reservoir and limited enhancement of anti-HIV immune responses. In this study, we identify a dual role for peripheral and tissue-resident Vδ1 T cells within the gastrointestinal mucosa of virally suppressed people with HIV. Phenotypic analyses identify an increased frequency of highly differentiated, cytotoxic effector Vδ1 T cells that inhibit HIV-1 replication in vitro coinciding with increased degranulation and IFN-γ production. Conversely, we detect an enrichment of HIV-1 DNA in tissue-resident CD4 + Vδ1 T cells in situ. Despite low CD4 expression, we find circulating Vδ1 T cells also contain HIV-1 DNA which is replication-competent. We show that T cell receptor-mediated activation of peripheral Vδ1 T cells induces de novo upregulation of CD4 providing a plausible mechanism for increased permissibility to infection. These findings highlight juxtaposing roles for Vδ1 T cells in HIV-1 persistence including contribution to tissue reservoirs
Understanding Opioid Use from Retrospective Accounts of Young Adults in Recovery: Motives, Experiences, and Implications for Prevention
Get PDFOpioid use disorder is a public health problem with disastrous effects for young people and their families. Opioid use shares risk factors with other substances; there may be additional unique motives and experiences associated with opioid use with potential implications for improving prevention. The present study used surveys and interviews to elicit retrospective accounts of 30 young adults (19 female) in recovery from opioid use disorder to examine (1) self-reported motives for opioid use, and (2) experiences and factors that participants associate with opioid use as compared to other substances. Motives reported for past opioid use on surveys were enhancement (i.e., fun or excitement) and coping (i.e., to forget worries or cheer up when in a bad mood), followed by conformity and social motives. Through analysis of interview data, we found that: experiences of opioid use differed from experiences associated with other substances, with effects described in terms of escape and numbing (theme 1); and the ability (early in use) to remain/appear functional (theme 2). Participants reported perceptions of lower risk of harm compared to other substances (theme 3). For some, access was the main factor reported to contribute to opioid use (theme 4). Evidence-based prevention approaches focused on environmental strategies (such as prescription regulation policies) and individual strategies (such as coping skills and prevention education) are relevant for opioid use prevention. Additional supplemental approaches are needed to focus on misperceptions among young people that prescription medications confer lower risk than other substances