Explore the vast range of titles available.

Computational vaccinology includes epitope mapping, antigen selection, and immunogen design using computational tools. Tools that facilitate the prediction of immune response to biothreats, emerging infectious diseases, and cancers can accelerate the design of novel and next generation vaccines and their delivery to the clinic. Over the past 20 years, vaccinologists, bioinformatics experts, and advanced programmers based in Providence, Rhode Island, USA have advanced the development of an integrated toolkit for vaccine design called iVAX, that is secure and user-accessible by internet. This integrated set of immunoinformatic tools comprises algorithms for scoring and triaging candidate antigens, selecting immunogenic and conserved T cell epitopes, re-engineering or eliminating regulatory T cell epitopes, and re-designing antigens to induce immunogenicity and protection against disease for humans and livestock. Commercial and academic applications of iVAX have included identifying immunogenic T cell epitopes in the development of a T-cell based human multi-epitope Q fever vaccine, designing novel influenza vaccines, identifying cross-conserved T cell epitopes for a malaria vaccine, and analyzing immune responses in clinical vaccine studies. Animal vaccine applications to date have included viral infections of pigs such as swine influenza A, PCV2, and African Swine Fever. \"Rapid-Fire\" applications for biodefense have included a demonstration project for Lassa Fever and Q fever. As recent infectious disease outbreaks underscore the significance of vaccine-driven preparedness, the integrated set of tools available on the iVAX toolkit stand ready to help vaccine developers deliver genome-derived, epitope-driven vaccines.

•There are limited real-world studies of advanced HER2m NSCLC in Europe.•Patients with advanced HER2m NSCLC had a median age of 66 years and 64% were female.•The most common first-line treatment for advanced HER2m NSCLC was chemotherapy.•Median overall survival from advanced HER2m NSCLC diagnosis date was <1.5 years.•Routine HER2 testing and HER2-directed therapies for advanced HER2m NSCLC are needed. Human epidermal growth factor receptor 2 (HER2 [ERBB2]) gene mutations occur in ∼3–5% of non-small cell lung cancer (NSCLC) cases and are associated with poor prognosis. However, real-world data on patients with HER2-mutant (HER2m) NSCLC are needed. This retrospective, observational study evaluated characteristics, treatment patterns, and clinical outcomes of patients with advanced nonsquamous HER2m NSCLC from the Institut Curie (France) and Thoraxklinik Heidelberg (Germany) between 2011 and 2022. Of the 55 patients (Curie: n = 17; Heidelberg: n = 38) included in the study, median age at diagnosis was 66 years (range, 22–90), 63.6% were female, and 50.9% had no history of smoking. Forty-eight (87.3%) patients received ≥1 line of therapy, 29 (52.7%) received ≥2 lines of therapy, and 19 (34.5%) received ≥3 lines of therapy. The most common first-line treatment was platinum-based and non-platinum-based chemotherapy (54.2%, n/n = 26/48); treatment patterns in the second- and third-line settings were more diverse than in the first-line setting. Median overall survival was 14.2 months (95% confidence interval [CI] 11.2, 23.2; n = 55) from the diagnosis of advanced disease and 16.5 months (12.3, 29.8; n = 48) from the start of first-line treatment. Median progression-free survival was 5.1 months (95% CI 3.5, 8.5; n = 48) and 4.0 months (2.4, 6.3; n = 29) from the start of first- and second-line treatment, respectively. Patients with advanced HER2m NSCLC had a poor prognosis despite treatment with standard-of-care regimens available during the study period. These findings highlight the need for novel therapeutic options to improve clinical outcomes for patients with HER2m NSCLC.

Background: Treatment for advanced non-small-cell lung cancer (NSCLC) has evolved substantially over the past decade, necessitating evaluation of real-world treatment patterns and effectiveness before and after the introduction of newer therapies. Methods: This retrospective cohort study included adult patients initiating a non-curative first-line therapy for advanced NSCLC between 2014 and 2021 at the IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST), with follow-up through 2022. Overall survival (OS) and real-world progression-free survival from the start date of the first line of therapy for advanced NSCLC were estimated using Kaplan–Meier methods. Results: Overall, 910 patients were included; at diagnosis, 83% had a de novo diagnosis and 17% had recurrent disease. During the study, 41% of patients received platinum-based chemotherapy alone; 22% received non-platinum-based chemotherapy alone; 21% received anti-programmed death (PD)-(ligand [L])1 immune checkpoint inhibitors (ICIs), alone or with chemotherapy; and 16% received targeted therapy (single-agent tyrosine kinase inhibitors) as first-line therapy for advanced disease. From 2014 to 2021, the proportion of patients receiving first-line anti-PD-(L)1 ICIs increased from 0% to 58% and the proportion of those receiving first-line platinum-based chemotherapy decreased from 65% to 6%. Median (95% CI) OS was 8.2 (7.5–9.2) months; the minimum-to-maximum range of median OS was 6.0–7.4 months from 2014 to 2017 and 8.4–15.9 months from 2018 to 2021. Median OS was numerically longer in patients with recurrent disease versus a de novo diagnosis, first-line targeted versus other therapy, high versus low PD-L1 expression, and non-squamous/other versus squamous histology. Conclusions: This study provides real-world data further supporting (i) the benefits of precision targeted therapy for patients with advanced NSCLC and actionable genomic alterations and (ii) the positive impact of immunotherapy approvals on the treatment paradigm for advanced NSCLC.

The economic burden of blood transfusions (BTs) in transfusion-dependent β-thalassemia (TDT) is not well characterized in adults from Brazil, Thailand, and India. To assess direct and indirect costs of BTs in adults with TDT in three geographically distinct countries: Brazil, Thailand, and India. Healthcare professionals (HCPs) and administrative personnel completed a cross-sectional survey to assess transfusion-associated direct costs and indirect costs among patients with TDT. Direct (blood collection, BTs, iron chelation therapy (ICT), transfusion-related adverse events (AEs)), and indirect costs (blood supply shortages, waiting time, patient, and caregiver time) per patient per year (PPPY) were calculated from survey data, and publicly available cost data. Between February 2, 2024, and March 12, 2024, 54, 104, and 125 participants in Brazil, Thailand, and India, respectively, were included, mostly hematologists or pharmacists. Median number of BTs PPPY was 12 (Brazil), 6 (Thailand), and 20 (India). Physicians and nurses conducted pretransfusion monitoring, whereas nurses monitored during BTs and posttransfusion appointments. AEs were estimated in 15% (Brazil), 5% (Thailand), and 10% (India) of BTs. In the past 12 months, 72%, 50%, and 54% of participants experienced blood supply shortages in Brazil, Thailand, and India, respectively; 40%, 25%, and 70% of patients experienced iron overload due to BTs, and 30%, 20%, and 70% of patients received ICT due to BTs. Total direct costs PPPY (USD) were 4438 in Brazil, 1775 in Thailand, and 1991 in India; total indirect costs PPPY (USD) were 831 in Brazil, 392 in Thailand, and 715 in India. Results showed a significant burden of BTs in TDT on HCPs, patients, and caregivers, along with shortages and delays in blood supplies. These findings underscore the importance of enhancing supportive care for BTs and exploring alternative approaches to alleviate this burden.

The hurdles to effective blood stage malaria vaccine design include immune evasion tactics used by the parasite such as redundant invasion pathways and antigen variation among circulating parasite strains. While blood stage malaria vaccine development primarily focuses on eliciting optimal humoral responses capable of blocking erythrocyte invasion, clinically-tested Plasmodium falciparum (Pf) vaccines have not elicited sterile protection, in part due to the dramatically high levels of antibody needed. Recent development efforts with non-redundant, conserved blood stage antigens suggest both high antibody titer and rapid antibody binding kinetics are important efficacy factors. Based on the central role of helper CD4 T cells in development of strong, protective immune responses, we systematically analyzed the class II epitope content in five leading Pf blood stage antigens (RH5, CyRPA, RIPR, AMA1 and EBA175) using in silico , in vitro , and ex vivo methodologies. We employed in silico T cell epitope analysis to enable identification of 67 HLA-restricted class II epitope clusters predicted to bind a panel of nine HLA-DRB1 alleles. We assessed a subset of these for HLA-DRB1 allele binding in vitro , to verify the in silico predictions. All clusters assessed (40 clusters represented by 46 peptides) bound at least two HLA-DR alleles in vitro . The overall epitope prediction to in vitro HLA-DRB1 allele binding accuracy was 71%. Utilizing the set of RH5 class II epitope clusters (10 clusters represented by 12 peptides), we assessed stimulation of T cells collected from HLA-matched RH5 vaccinees using an IFN-γ T cell recall assay. All clusters demonstrated positive recall responses, with the highest responses – by percentage of responders and response magnitude – associated with clusters located in the N-terminal region of RH5. Finally, a statistically significant correlation between in silico epitope predictions and ex vivo IFN-γ recall response was found when accounting for HLA-DR matches between the epitope predictions and donor HLA phenotypes. This is the first comprehensive analysis of class II epitope content in RH5, CyRPA, RIPR, AMA1 and EBA175 accompanied by in vitro HLA binding validation for all five proteins and ex vivo T cell response confirmation for RH5.

Immunization with radiation-attenuated sporozoites (RAS) has been shown to protect against malaria infection, primarily through CD8 T cell responses, but protection is limited based on parasite strain. Therefore, while CD8 T cells are an ideal effector population target for liver stage malaria vaccine development strategies, such strategies must incorporate conserved epitopes that cover a large range of class I human leukocyte antigen (HLA) supertypes to elicit cross-strain immunity across the target population. This approach requires identifying and characterizing a wide range of CD8 T cell epitopes for incorporation into a vaccine such that coverage across a large range of class I HLA alleles is attained. Accordingly, we devised an experimental framework to identify CD8 T cell epitopes from novel and minimally characterized antigens found at the pre-erythrocytic stage of parasite development. Through in silico analysis we selected conserved P. falciparum proteins, using P. vivax orthologues to establish stringent conservation parameters, predicted to have a high number of T cell epitopes across a set of six class I HLA alleles representative of major supertypes. Using the decision framework, five proteins were selected based on the density and number of predicted epitopes. Selected epitopes were synthesized as peptides and evaluated for binding to the class I HLA alleles in vitro to verify in silico binding predictions, and subsequently for stimulation of human T cells using the Modular IMmune In-vitro Construct (MIMIC ® ) technology to verify immunogenicity. By combining the in silico tools with the ex vivo high throughput MIMIC platform, we identified 15 novel CD8 T cell epitopes capable of stimulating an immune response in alleles across the class I HLA panel. We recommend these epitopes should be evaluated in appropriate in vivo humanized immune system models to determine their protective efficacy for potential inclusion in future vaccines.

An effective malaria vaccine must prevent disease in a range of populations living in regions with vastly different transmission rates and protect against genetically-diverse Plasmodium falciparum (Pf) strains. The protective efficacy afforded by the currently licensed malaria vaccine, Mosquirix™, promotes strong humoral responses to Pf circumsporozoite protein (CSP) 3D7 but protection is limited in duration and by strain variation. Helper CD4 T cells are central to development of protective immune responses, playing roles in B cell activation and maturation processes, cytokine production, and stimulation of effector T cells. Therefore, we took advantage of recent in silico modeling advances to predict and analyze human leukocyte antigen (HLA)-restricted class II epitopes from PfCSP – across the entire PfCSP 3D7 sequence as well as in 539 PfCSP sequence variants – with the goal of improving PfCSP-based malaria vaccines. Specifically, we developed a systematic workflow to identify peptide sequences capable of binding HLA-DR in a context relevant to achieving broad human population coverage utilizing cognate T cell help and with limited T regulatory cell activation triggers. Through this workflow, we identified seven predicted class II epitope clusters in the N- and C-terminal regions of PfCSP 3D7 and an additional eight clusters through comparative analysis of 539 PfCSP sequence variants. A subset of these predicted class II epitope clusters was synthesized as peptides and assessed for HLA-DR binding in vitro . Further, we characterized the functional capacity of these peptides to prime and activate human peripheral blood mononuclear cells (PBMCs), by monitoring cytokine response profiles using MIMIC ® technology (Modular IMmune In vitro Construct). Utilizing this decision framework, we found sufficient differential cellular activation and cytokine profiles among HLA-DR-matched PBMC donors to downselect class II epitope clusters for inclusion in a vaccine targeting PfCSP. Importantly, the downselected clusters are not highly conserved across PfCSP variants but rather, they overlap a hypervariable region (TH2R) in the C-terminus of the protein. We recommend assessing these class II epitope clusters within the context of a PfCSP vaccine, employing a test system capable of measuring immunogenicity across a broad set of HLA-DR alleles.

Abstract Aims Evidence for the use of beta-blockers, angiotensin II receptor blockers (ARB), or angiotensin-converting enzyme inhibitors (ACEi) to mitigate chemotherapy-induced cardiotoxicity is inconclusive. The objectives are to investigate associations between prescription of ARBs, ACEis, and/or beta-blockers in the year following cancer diagnosis and subsequent risk of heart failure/cardiomyopathy (HF/CM) in chemotherapy-treated breast cancer and non-Hodgkin lymphoma (NHL) survivors. Methods and results This cohort study used linked English electronic healthcare records from 9875 adult (≥18 years) breast cancer and NHL survivors who received chemotherapy. Cox regression was used to estimate the association between primary care-prescribed beta-blocker, ARB, and ACEi use in the year following cancer diagnosis, and subsequent HF/CM incidence, adjusting for potential confounders. Likelihood ratio tests were used to assess effect modification. The mean follow-up duration was 4.9 years (maximum 21.4). After adjusting for age, the risk of HF/CM was higher in the exposed group [hazard ratio (HR): 1.69, 95% confidence interval (CI): 1.34–2.14], but further adjustment for gender, comorbidities, and other medications reduced the association to close to null (HR: 1.07, 95% CI: 0.68–1.69). There was no evidence that the association differed by cancer site, age, radiotherapy, prior cardiovascular disease, or years since cancer diagnosis. Conclusion We found no evidence that general practitioner prescribed beta-blocker, ARB, or ACEi use was associated with a reduced incidence of HF/CM in this population of chemotherapy-treated breast cancer and NHL survivors. This might be because the drug dosage and timing were not optimized to prevent chemotherapy-related cardiac damage; residual confounding by indication may also have obscured any treatment benefit. Structured Graphical abstract Graphical Abstract

Poor management of chronic diseases, such as hypertension and diabetes, particularly among the uninsured, places medical and financial burdens on the healthcare system. Clínica Esperanza/Hope Clinic initiated a chronic disease management program for uninsured residents of Rhode Island (RI) called Bridging the [Health Equity] Gap (BTG), which offers continuity of care, quarterly goal-setting appointments, and healthy lifestyle interventions. Outcomes for 549 participants from the initial evaluation period are presented here. Over the first 12 months of enrollment, mean hemoglobin A1c decreased from 10.2% to 8.3% (p<0.001), and mean blood glucose of individuals with diabetes decreased by 51 mg/dL (p<0.01). BTG participants used the local emergency department (ED) 60% less than Medicaid-insured RI residents and had 61% fewer \"potentially preventable\" ED visits. The positive impact of BTG on chronic disease outcomes and ED usage by uninsured patients suggests that programs like BTG may reduce overall healthcare costs in the state.Poor management of chronic diseases, such as hypertension and diabetes, particularly among the uninsured, places medical and financial burdens on the healthcare system. Clínica Esperanza/Hope Clinic initiated a chronic disease management program for uninsured residents of Rhode Island (RI) called Bridging the [Health Equity] Gap (BTG), which offers continuity of care, quarterly goal-setting appointments, and healthy lifestyle interventions. Outcomes for 549 participants from the initial evaluation period are presented here. Over the first 12 months of enrollment, mean hemoglobin A1c decreased from 10.2% to 8.3% (p<0.001), and mean blood glucose of individuals with diabetes decreased by 51 mg/dL (p<0.01). BTG participants used the local emergency department (ED) 60% less than Medicaid-insured RI residents and had 61% fewer \"potentially preventable\" ED visits. The positive impact of BTG on chronic disease outcomes and ED usage by uninsured patients suggests that programs like BTG may reduce overall healthcare costs in the state.

Poor management of chronic diseases, such as hypertension and diabetes, particularly among the uninsured, places medical and financial burdens on the healthcare system. Clínica Esperanza/Hope Clinic initiated a chronic disease management program for uninsured residents of Rhode Island (RI) called Bridging the [Health Equity] Gap (BTG), which offers continuity of care, quarterly goal-setting appointments, and healthy lifestyle interventions. Outcomes for 549 participants from the initial evaluation period are presented here. Over the first 12 months of enrollment, mean hemoglobin A1c decreased from 10.2% to 8.3% (p<0.001), and mean blood glucose of individuals with diabetes decreased by 51 mg/dL (p<0.01). BTG participants used the local emergency department (ED) 60% less than Medicaid-insured RI residents and had 61% fewer “potentially preventable” ED visits. The positive impact of BTG on chronic disease outcomes and ED usage by uninsured patients suggests that programs like BTG may reduce overall healthcare costs in the state.