Current Candidates Research Articles

The barriers and enablers to completing the RPS core advanced pharmacist credentialing programme via the CPPE/RPS pilot programme

Abstract Introduction The RPS and CPPE launched a pilot programme in March 2023 to support 300 pharmacists to evidence their advanced practice via an e-portfolio aligned to the RPS Core Advanced curriculum1 in a 12-week period. Successful pharmacists are credentialed as Advanced Pharmacists. The pilot involved CPPE education supervisors (ESs) support, an online learning platform and small group learning and support. Aim To ascertain barriers and enablers to completing an advanced e-portfolio and to identify how to improve the on-going programme. Methods The invitation to complete the anonymous survey in May 2024 was administered via www.onlinesurveys.ac.uk and developed linking to key performance indicators around education supervision support, to understand why candidates were deferring cohorts and to ascertain additional support accessed by candidates. Ethical approval was not required as study is service evaluation. Candidates who responded included those who successfully submitted their e-portfolio ‘submitted candidates’ n=10, candidates who are resubmitting their portfolio after not passing ‘resubmission candidates’ n=8, pharmacists currently completing their portfolio ‘current candidates’ n=44 and those who started but left without submitting ‘attrition candidates’ n=13. Results All submitted candidates scored ES support as very good/excellent; 60% agreed strongly they would not have submitted their portfolio without this support. Each cohort had two small-group tutorials where candidates accessed peer support and joined WhatsApp groups. Only 38% of resubmission candidates, compared to 80% of portfolio submitted candidates attended both group tutorials. Resubmission candidates were less likely to access additional peer support (38% for resubmission candidates vs 60% for submitted candidates) or to join the cohort WhatsApp group (75% for resubmission candidates vs 90% for submitted candidates). Resubmission candidates rated the remedial SMART action planning support highly. Submitted candidates would have found it easier to complete their portfolio with more comprehensive (60%) and timely responses (70%) from their collaborators. This compares to 55% and 59% of current candidates recognising the same issues. Submitted candidates wanted more allocated time during working hours to support completion of the portfolio (60% rising to 80% for current candidates). There is a notable increase for current candidates wanting a longer period to complete their portfolio (75% compared to 40% of submitted candidates). Half of submitted candidates (50%) reported spending more than 5 hours (average) each week on their portfolio compared to 18% of current candidates. Top reasons for attrition include too busy with work, family responsibilities, personal health challenges and no support from the workplace. Candidates across all groups suggested programme improvement ideas including more evidence examples, making the RPS platform less difficult to navigate and use, and more education supervisor support. Motivating factors for completion include recognition of advanced level working and preparation for the consultant portfolio. Conclusion Enablers include education supervision, CPPE resources/facilitated support events, peer support, WhatsApp groups, recognition and career progression. Key barriers include needing more time and lack of dedicated time at work to complete e-portfolio, lack of timely and comprehensive support from collaborators and finding the RPS e-portfolio platform difficult to navigate. Limitations – low numbers and response rate. Data collection is on-going. Reference 1. Royal Pharmaceutical Society, Core Advanced Pharmacist Curriculum, 2022 https://www.rpharms.com/Portals/0/Credentialing/RPS%20-%20Core%20Advanced%20curriculumFINAL.pdf?ver=8gc3s2aE9t1nZN37CSU7Lw%3d%3d (Accessed 28 May 2024)

A cervical cancer control strategy for lower-resource settings: interventions to complement one-dose HPV vaccination.

One-dose prophylactic HPV vaccination of pre-adolescents may reduce cervical cancer deaths dramatically in lower-resource settings, but the benefits of achieving immediate high coverage among pre-adolescents would not be realized for 20 to 40 years. Prophylactic vaccine efficacy is reduced after sexual debut, and current therapeutic intervention candidates designed to treat existing HPV infections or precancerous lesions have yielded insufficient evidence to warrant widespread use. However, we are developing a feasible, scalable, high-quality cervical screening approach that could prevent hundreds of thousands of deaths, while we work to achieve high coverage of one-dose vaccination for adolescent cohorts. A time-limited "one screen" campaign approach for lower-resource settings could complement parallel efforts to achieve high coverage with one-dose vaccination. This screen-triage-treat strategy would target the highest risk groups of screening age (ie, 25 to 49 years) for once-in-a-lifetime HPV testing of self-collected samples using a low-cost accurate HPV test; subsequent triage relying on extended genotyping and a validated deep-learning algorithm for automated visual evaluation (AVE) would stratify management based on risk to provide treatment for those most likely to develop cancer without overburdening health care systems. Early efficacy of this approach has been demonstrated in 9 countries within the HPV-AVE (PAVE) Study Consortium. We estimate that the cost per death averted of a screen-triage-treat campaign is of similar magnitude to prophylactic vaccination. We do not envision perpetual investment in ubiquitous brick-and-mortar screening programs if "one dose, one screen" is implemented with high coverage and targets the highest-risk populations. In collaboration with in-country stakeholders, efforts to ensure acceptability, risk communication, and cost-effectiveness are underway.

Perspectives on program duration and research: A survey of graduates of a 3-year medical physics residency program.

The goal of this manuscript is to evaluate strengths and weaknesses of a 3-year medical physics residency program with the first year dedicated to research and the remaining 2 years dedicated to clinical training. An anonymous survey was distributed to graduates of a 3-year medical physics residency program with a dedicated year of research. Questions focused on several categories: (1) in retrospect, factors graduates considered at the time of application, (2) aspects of respondents' career and life after graduating from residency, (3) respondents' opinions on the residency duration, and (4) research productivity during residency. Of 22 graduates who were contacted, 17 filled out the survey. In retrospect, the most impactful consideration at the time of application was quality of clinical training. Extra time for research was reported as the factor with the most positive career impact and financial considerations as the most negative impact of completing a 3-year residency. Preference for a 3-year residency at the time of application and in retrospect was expressed by 47% and 88% of respondents, respectively. 71% of respondents would recommend applying to a 3-year program to current residency candidates, and 29% respondents said their recommendation on entering a 3-year program would depend on the candidate's interests. 76% of respondents preferred dedicated time for research during residency. The optimal duration of medical physics residency depends on the goals and career objectives of the incoming residents. Two years may be an optimal duration for clinical training. For candidates interested in a career with a substantial research component, a 3-year program may be a good option, and graduates express favorable opinions after completing such a program. A 4-year residency duration is not viewed favorably by the graduates.

Preclinical Evaluation of STI-8811, a Novel Antibody-Drug Conjugate Targeting BCMA for the Treatment of Multiple Myeloma.

Treatment for patients with multiple myeloma has experienced rapid development and improvement in recent years; however, patients continue to experience relapse, and multiple myeloma remains largely incurable. B-cell maturation antigen (BCMA) has been widely recognized as a promising target for treatment of multiple myeloma due to its exclusive expression in B-cell linage cells and its critical role in the growth and survival of malignant plasma cells. Here, we introduce STI-8811, a BCMA-targeting antibody-drug conjugate (ADC) linked to an auristatin-derived duostatin payload via an enzymatically cleavable peptide linker, using our proprietary C-lock technology. STI-8811 exhibits target-specific binding activity and rapid internalization, leading to G2/M cell-cycle arrest, caspase 3/7 activation, and apoptosis in BCMA-expressing tumor cells in vitro. Soluble BCMA (sBCMA) is shed by multiple myeloma cells into the blood and increases with disease progression, competing for ADC binding and reducing its efficacy. We report enhanced cytotoxic activity in the presence of high levels of sBCMA compared with a belantamab mafodotin biosimilar (J6M0-mcMMAF). STI-8811 demonstrated greater in vivo activity than J6M0-mcMMAF in solid and disseminated multiple myeloma models, including tumor models with low BCMA expression and/or in large solid tumors representing soft-tissue plasmacytomas. In cynomolgus monkeys, STI-8811 was well tolerated, with toxicities consistent with other BCMA-targeting ADCs with auristatin payloads in clinical studies. STI-8811 has the potential to outperform current clinical candidates with lower toxicity and higher activity under conditions found in patients with advanced disease. Significance: STI-8811 is a BCMA-targeting ADC carrying a potent auristatin derivative. We report unique binding properties which maintain potent cytotoxic activity under sBCMA-high conditions that hinder the clinical efficacy of current BCMA-targeting ADC candidates. Beyond disseminated models of multiple myeloma, we observed efficacy in solid tumor models of plasmacytomas with low and heterogenous BCMA expressions at a magnitude and duration of response exceeding that of clinical comparators.

Experimental Success in Marburg Virus Vaccination

The Marburg virus (MRV), classified within the Filoviridae family, was initially identified in 1967, precipitating Marburg virus disease (MARV), a severe and often fatal hemorrhagic fever. With its pronounced infectiousness, high mortality rate, and proclivity for epidemic outbreaks, MARV stands as a formidable public health menace. Despite extensive sporadic outbreaks and its designation as a priority disease, the quest for efficacious drugs or vaccines against MRV remains an ongoing challenge. Nonetheless, the relentless pursuit of scientific inquiry, augmented by the innovative application of immunoinformatics, is propelling forward vaccine development endeavors. Current vaccine candidates, spanning from VSV-based formulations to virus-like particle vaccines, exhibit encouraging outcomes in preclinical and clinical evaluations, boasting notable efficacy and safety profiles. Furthermore, the exploration of multivalent vaccine strategies, designed to target a spectrum of hemorrhagic fever viruses, holds promise in fortifying pandemic preparedness efforts. Immunoinformatics assumes a pivotal role in this context, offering predictive insights into vaccine candidate selection and optimization, thereby facilitating expedited development tailored to diverse demographic cohorts. The integration of computational modeling techniques into vaccine development paradigms represents a transformative avenue for effectively controlling MRV outbreaks on a global scale. Sustained collaboration and continued research endeavors are imperative to fully harness the potential of these advancements in confronting the formidable challenge posed by the lethal Marburg virus and safeguarding global public health.

Trabecular meshwork cell differentiation in response to collagen and TGFβ-2 spatial interactions

Primary open-angle glaucoma (POAG) is currently the most prevalent cause of irreversible blindness globally. To date, few in vitro models that can faithfully recapitulate the complex architecture of the trabecular meshwork (TM) and the specialised trabecular meshwork cell (TMC) characteristics that are local to the structurally opposing regions. This study aimed to investigate the parameters that govern TMC phenotype by adapting the extracellular matrix structure to mimic the juxtacanalicular tissue (JCT) region of the TM. Initially, TMC phenotypic characteristics were investigated within type I collagen matrices of controlled fiber density and anisotropy, generated through confined plastic compression (PC). Notably, PC-collagen presented biophysical cues that induced JCT cellular characteristics (elastin, α-β-Crystallin protein expression, cytoskeletal remodelling, increased mesenchymal markers and JCT-specific genetic markers). In parallel, a pathological mesenchymal phenotype associated with POAG was induced through localised transforming growth factor -beta 2 (TGFβ-2) exposure. This resulted in a profile of alternative mesenchymal states (fibroblast/smooth muscle or myofibroblast) displayed by the TMC in vitro. Overall, the study provides an advanced insight into the biophysical cues that modulate TMC fate, inducing a JCT-specific phenotype and transient mesenchymal characteristics that reflect healthy and pathological scenarios. Statement of significanceGlaucoma is a leading cause of blindness, with a lack of long-term efficacy within current drug candidates. Reliable trabecular meshwork (TM) in vitro models will be critical for enhancing the fields understanding of healthy and disease states for pre-clinical testing.Trabecular meshwork cells (TMCs) display heterogeneity throughout the hierarchical TM, however our understanding into recapitulating these phenotypes in vitro, remains elusive. This study hypothesizes the importance of specific matrix/growth factor spatial stimuli in governing TMCs phenotype. By emulating certain biophysical/biochemical in vivo parameters, we introduce an advanced profile of distinct TMC phenotypic states, reflecting healthy and disease scenarios. A notion that has not be stated prior and a fundamental consideration for future 3D TM in vitro modelling.

Nomination of a novel plasma protein biomarker panel capable of classifying Alzheimer's disease dementia with high accuracy in an African American cohort.

African Americans (AA) are widely underrepresented in plasma biomarker studies for Alzheimer's disease (AD) and current diagnostic biomarker candidates do not reflect the heterogeneity of AD. Untargeted proteome measurements were obtained using the SomaScan 7k platform to identify novel plasma biomarkers for AD in a cohort of AA clinically diagnosed as AD dementia (n=183) or cognitively unimpaired (CU, n=145). Machine learning approaches were implemented to identify the set of plasma proteins that yields the best classification accuracy. A plasma protein panel achieved an area under the curve (AUC) of 0.91 to classify AD dementia vs CU. The reproducibility of this finding was observed in the ANMerge plasma and AMP-AD Diversity brain datasets (AUC=0.83; AUC=0.94). This study demonstrates the potential of biomarker discovery through untargeted plasma proteomics and machine learning approaches. Our findings also highlight the potential importance of the matrisome and cerebrovascular dysfunction in AD pathophysiology.

A Local Search Algorithm with Vertex Weighting Strategy and Two-Level Configuration Checking for the Minimum Connected Dominating Set Problem.

The minimum connected dominating set problem is a combinatorial optimization problem with a wide range of applications in many fields. We propose an efficient local search algorithm to solve this problem. In this work, first, we adopt a new initial solution construction method based on three simplification rules. This method can reduce the size of the original graph and thus obtain a high-quality initial solution. Second, we propose an approach based on a two-level configuration checking strategy and a tabu strategy to reduce the cycling problem. Third, we introduce a perturbation strategy and a vertex weighting strategy to help the algorithm be able to jump out of the local optimum effectively. Fourth, we combine the scoring functions Cscore and Mscore with the aforementioned strategies to propose effective methods for selecting vertices. These methods assist the algorithm in selecting vertices that are suitable for addition to or removal from the current candidate solution. Finally, we verify the performance advantages of the local search algorithm by comparing it with existing optimal heuristic algorithms on two sets of instances. The experimental results show that the algorithm exhibits better performance on two sets of classical instances.

Strengthening the Attachment to Local Brands through Consumer Ethnocentrism and Impactful Entrepreneurship Education

This study investigates whether consumer ethnocentrism, a concept that refers to the tendency of consumers to favor domestic products over foreign ones, and entrepreneurship education are variables that can be used to strengthen attachment to local brands. Brand attachment is a well-researched concept in marketing literature. Many variables have been found to have different impacts on brand attachment across the globe. However, studies linking consumer ethnocentrism and entrepreneurship education to brand attachment are scarce, and this study contributes in that regard. Furthermore, the study examines whether entrepreneurship education mediates the association between consumer ethnocentrism and brand attachment. The study adopted a quantitative research methodology. Primary data were gathered through a survey. Past and current entrepreneurship education candidates were targeted. Factor analysis, simple linear regression, and hierarchical regression analyses using PROCESS were performed to make sense of the data. The study’s findings reveal that consumer ethnocentrism and entrepreneurship education can be used to strengthen attachment to local brands. The study recommends that marketing practitioners, scholars, and policymakers collaborate to design an impactful entrepreneurship education curriculum with the goal of enhancing consumer ethnocentrism, leading to increased interaction between consumers and local brands.

Performance Evaluation of mm-Wave Based System in GFDM- 5G and Beyond Channel Model with Dust Storm Scenario

Telecommunication has made tremendous improvements in terms of bandwidth, requiring good frequency location, high data rates, and wideband spectrum availability. One solution to these requirements is the millimeter wave frequency band of 30 GHz. However, communication in this band is facing new challenges due to climate effects such as humidity, dust storms, and temperature. For fifth-generation (5G) mobile networks and beyond, Generalized Frequency Division Multiplexing (GFDM) has been proposed as a compelling candidate to substitute Orthogonal Frequency Division Multiplexing (OFDM). The GFDM's ability to adapt the block size and type of pulse shaping filters enables it to meet various crucial requirements, including low latency, low Out-Of-Band(OOB) radiation, and high data rates. This paper evaluated the overall GFDM performance and investigated the Bit Error Rate (BER) across a Rayleigh channel under various weather conditions. The simulation results show that GFDM outperforms the current OFDM candidate system. Also, GFDM offers better resistance to the Rayleigh channel with moderate and heavy dust storms in terms of BER.

Establishing a mass-loss rate relation for red supergiants in the Large Magellanic Cloud

Context. The high mass-loss rates of red supergiants (RSGs) drastically affect their evolution and final fate, but their mass-loss mechanism remains poorly understood. Various empirical prescriptions scaled with luminosity have been derived in the literature, yielding results with a dispersion of two to three orders of magnitude. Aims. We determine an accurate mass-loss rate relation with luminosity and other parameters using a large, clean sample of RSGs. In this way, we shed light into the underlying physical mechanism and explain the discrepancy between previous works. Methods. We assembled a sample of 2219 RSG candidates in the Large Magellanic Cloud, with ultraviolet to mid-infrared photometry in up to 49 filters. We determined the luminosity of each RSG by integrating the spectral energy distribution and the mass-loss rate using the radiative transfer code DUSTY. Results. Our derived RSG mass-loss rates range from approximately 10−9 M⊙ yr−1 to 10−5 M⊙ yr−1, mainly depending on the luminosity. The average mass-loss rate is 9.3 × 10−7 M⊙ yr−1 for log(L/L⊙) > 4, corresponding to a dust-production rate of ∼3.6 × 10−9 M⊙ yr−1. We established a mass-loss rate relation as a function of luminosity and effective temperature. Furthermore, we found a turning point in the relation of mass-loss rate versus luminosity at approximately log(L/L⊙) = 4.4, indicating enhanced rates beyond this limit. We show that this enhancement correlates with photometric variability. We compared our results with prescriptions from the literature, finding an agreement with works assuming steady-state winds. Additionally, we examined the effect of different assumptions on our models and found that radiatively driven winds result in mass-loss rates higher by two to three orders of magnitude, which is unrealistically high for RSGs. For grain sizes < 0.1 μm, the predicted mass-loss rates are higher by a factor of 25−30 than larger grain sizes. Finally, we found that 21% of our sample constitute current binary candidates. This has a minor effect on our mass-loss relation.

Identification of superior haplotypes for flowering time in pigeonpea through candidate gene-based association study of a diverse minicore collection.

In current study candidate gene (261 genes) based association mapping on 144 pigeonpea accessions for flowering time and related traits and 29 MTAs producing eight superior haplotypes were identified. In the current study, we have conducted an association analysis for flowering-associated traits in a diverse pigeonpea mini-core collection comprising 144 accessions using the SNP data of 261 flowering-related genes. In total, 13,449 SNPs were detected in the current study, which ranged from 743 (ICP10228) to 1469 (ICP6668) among the individuals. The nucleotide diversity (0.28) and Watterson estimates (0.34) reflected substantial diversity, while Tajima's D (-0.70) indicated the abundance of rare alleles in the collection. A total of 29 marker trait associations (MTAs) were identified, among which 19 were unique to days to first flowering (DOF) and/or days to fifty percent flowering (DFF), 9 to plant height (PH), and 1 to determinate (Det) growth habit using 3years of phenotypic data. Among these MTAs, six were common to DOF and/or DFF, and four were common to DOF/DFF along with the PH, reflecting their pleiotropic action. These 29 MTAs spanned 25 genes, among which 10 genes clustered in the protein-protein network analysis, indicating their concerted involvement in floral induction. Furthermore, we identified eight haplotypes, four of which regulate late flowering, while the remaining four regulate early flowering using the MTAs. Interestingly, haplotypes conferring late flowering (H001, H002, and H008) were found to be taller, while those involved in early flowering (H003) were shorter in height. The expression pattern of these genes, as inferred from the transcriptome data, also underpinned their involvement in floral induction. The haplotypes identified will be highly useful to the pigeonpea breeding community for haplotype-based breeding.

Lack of evidence for GWAS signals of exfoliation glaucoma working via monogenic loss-of-function mutation in the nearest gene.

Exfoliation syndrome (XFS) is a systemic disease of elastin-rich tissues involving a deposition of fibrillar exfoliative material (XFM) in the anterior chamber of the eye, which can promote glaucoma. The purpose of this study was to create mice with CRISPR/Cas9-induced variations in candidate genes identified from human genome-wide association studies (GWAS) and screen them for indices of XFS. Variants predicted to be deleterious were sought in the Agpat1, Cacna1a, Loxl1, Pomp, Rbms3, Sema6a, and Tlcd5 genes of C57BL/6J mice using CRISPR/Cas9-based gene editing. Strains were phenotyped by slit-lamp, SD-OCT imaging, and fundus exams at 1-5 mos of age. Smaller cohorts of 12-mos-old mice were also studied. Deleterious variants were identified in six targets; Pomp was recalcitrant to targeting. Multiple alleles of some targets were isolated, yielding 12 strains. Across all genotypes and ages, 277 mice were assessed by 902 slit-lamp exams, 928 SD-OCT exams, and 358 fundus exams. Homozygosity for Agpat1 or Cacna1a mutations led to early lethality; homozygosity for Loxl1 mutations led to pelvic organ prolapse, preventing aging. Loxl1 homozygotes exhibited a conjunctival phenotype of potential relevance to XFS. Multiple other genotype-specific phenotypes were variously identified. XFM was not observed in any mice. This study did not detect XFM in any of the strains. This may have been due to species-specific differences, background dependence, or insufficient aging. Alternatively, it is possible that the current candidates, selected based on proximity to GWAS signals, are not effectors acting via monogenic loss-of-function mechanisms.

Coming of age within ‘implosion’

AbstractIn a recent article, Maria Eriksson Baaz and Swati Parashar1 trace the continued salience of Eurocentrism in critical International Relations (IR), demonstrating how the ‘master’s outlook’ continues to stifle the study of global politics; they ultimately encourage an unsettling and even implosion of the discipline. Starting from this proposed ‘implosion’ of critical IR, this article reflects on our hopes, as two current PhD candidates and one early career researcher in global politics, for teaching and learning in this future world. We begin by reflecting on our own complicity in reproducing the Western-centrism of the discipline and consider how this discomfort can be used productively. The article then considers the radical potential of the classroom and the necessity of empathetic, collaborative inquiry to the future of the discipline of global politics. We advocate for an IR which is imaginative, relational, messy, and vulnerable – and are hopeful about how this may animate a meaningful and sustainable implosion. Embracing our discomfort and the possibility of failure, we hope to contribute to the ongoing ‘unsettling’ of academia from the standpoint of incipient feminist scholars and hopeful early-career teachers.

A new adaptive Kriging-based optimization (AKBO) framework for constrained optimization problems: A case study on shared autonomous electric vehicle system design

Adaptive Kriging-based optimization (AKBO) efficiently performs optimization by employing adaptive sampling methods that sequentially update Kriging model. To solve constrained optimization problems, existing adaptive sampling methods add samples based on probability of feasibility (PoF) representing the probability that all constraints are satisfied. However, these methods have the limitation that samples are added inefficiently when the PoF is inaccurate. Therefore, this study proposes a new AKBO framework that is robust to instability of PoF in adaptive sampling. To this end, a near constraint boundary region that is expected to be close to the constraint boundary is defined based on a probability measure. Then, a near constraint boundary search (NCBS) algorithm, which explores the sample point that minimizes the objective function within the near constraint boundary region, is developed for global search, whereas a near optimum search (NOS) algorithm, which searches for better solutions that may exist near the current optimum candidate, is developed for local search. To alleviate the distortions of the Kriging model that may occur due to the highly nonlinear response, a truncated constraint function (TCF) method that limits the extremely violated constraint values used in the design of experiment (DoE) of the Kriging model is also proposed. This study verifies the performance of the proposed AKBO framework through the shared autonomous electric vehicle (SAEV) system design optimization problem. Comparison of optimum designs derived from various optimization methods shows that the proposed AKBO framework derives the feasible global optimum with high accuracy and efficiency.

Targeting Plasmodium Life Cycle with Novel Parasite Ligands as Vaccine Antigens.

The WHO reported an estimated 249 million malaria cases and 608,000 malaria deaths in 85 countries in 2022. A total of 94% of malaria deaths occurred in Africa, 80% of which were children under 5. In other words, one child dies every minute from malaria. The RTS,S/AS01 malaria vaccine, which uses the Plasmodium falciparum circumsporozoite protein (CSP) to target sporozoite infection of the liver, achieved modest efficacy. The Malaria Vaccine Implementation Program (MVIP), coordinated by the WHO and completed at the end of 2023, found that immunization reduced mortality by only 13%. To further reduce malaria death, the development of a more effective malaria vaccine is a high priority. Three malaria vaccine targets being considered are the sporozoite liver infection (pre-erythrocytic stage), the merozoite red blood cell infection (asexual erythrocytic stage), and the gamete/zygote mosquito infection (sexual/transmission stage). These targets involve specific ligand-receptor interactions. However, most current malaria vaccine candidates that target two major parasite population bottlenecks, liver infection, and mosquito midgut infection, do not focus on such parasite ligands. Here, we evaluate the potential of newly identified parasite ligands with a phage peptide-display technique as novel malaria vaccine antigens.

Nanocarriers for natural polyphenol senotherapeutics.

Senescence is a heterogenous and dynamic process in which various cell types undergo cell-cycle arrest due to cellular stressors. While senescence has been implicated in aging and many human pathologies, therapeutic interventions remain inadequate due to the absence of a comprehensive set of biomarkers in a context-dependent manner. Polyphenols have been investigated as senotherapeutics in both preclinical and clinical settings. However, their use is hindered by limited stability, toxicity, modest bioavailability, and often inadequate concentration at target sites. To address these limitations, nanocarriers such as polymer nanoparticles and lipid vesicles can be utilized to enhance the efficacy of senolytic polyphenols. Focusing on widely studied senolytic agents-specifically fisetin, quercetin, and resveratrol-we provide concise summaries of their physical and chemical properties, along with an overview of preclinical and clinical findings. We also highlight common signaling pathways and potential toxicities associated with these agents. Addressing challenges linked to nanocarriers, we present examples of senotherapeutic delivery to various cell types, both with and without nanocarriers. Finally, continued research and development of senolytic agents and nanocarriers are encouraged to reduce the undesirable effects of senescence on different cell types and organs. This review underscores the need for establishing reliable sets of senescence biomarkers that could assist in evaluating the effectiveness of current and future senotherapeutic candidates and nanocarriers.

Gene polymorphisms of TACR1 serve as the potential pharmacogenetic predictors of response to the neurokinin-1 receptor antagonist-based antiemetic regimens: a candidate-gene association study in breast cancer patients.

The current candidate gene association study aims to investigate tag SNPs from the TACR1 gene as pharmacogenetic predictors of response to the antiemetic guidelines-recommended, NK-1 receptor antagonist-based, triple antiemetic regimens. A set of eighteen tag SNPs of TACR1 were genotyped in breast cancer patients receiving anthracycline and cyclophosphamide (with/without docetaxel) applying real-time PCR-HRMA. Data analysis for 121 ultimately enrolled patients was initiated by defining haplotype blocks using PHASE v.2.1. The association of each tag SNP and haplotype alleles with failure to achieve the defined antiemetic regimen efficacy endpoints was tested using PLINK (v.1.9 and v.1.07, respectively) based on the logistic regression, adjusting for the previously known chemotherapy-induced nausea and vomiting (CINV) prognostic factors. All reported p-values were corrected using the permutation test (n = 100,000). Four variants of rs881, rs17010730, rs727156, and rs3755462, as well as haplotypes containing the mentioned variants, were significantly associated with failure to achieve at least one of the defined efficacy endpoints. Variant annotation via in-silico studies revealed that the non-seed sequence variant, rs881, is located in the miRNA (hsa-miR-613) binding site. The other three variants or a variant in complete linkage disequilibrium with them overlap a region of high H3K9ac-promoter-like signature or regions of high enhancer-like signature in the brain or gastrointestinal tissue. Playing an essential role in regulating TACR1 expression, gene polymorphisms of TACR1 serve as the potential pharmacogenetic predictors of response to the NK-1 receptor antagonist-based, triple antiemetic regimens. If clinically approved, modifying the NK-1 receptor antagonist dose leads to better management of CINV in risk-allele carriers.

Overall haemostatic potential assay for prediction of outcomes in venous and arterial thrombosis and thrombo-inflammatory diseases.

Thromboembolic diseases including arterial and venous thrombosis are common causes of morbidity and mortality globally. Thrombosis frequently recurs and can also complicate many inflammatory conditions through the process of 'thrombo-inflammation,' as evidenced during the COVID-19 pandemic. Current candidate biomarkers for thrombosis prediction, such as D-dimer, have poor predictive efficacy. This limits our capacity to tailor anticoagulation duration individually and may expose lower risk individuals to undue bleeding risk. Global coagulation assays, such as the Overall Haemostatic Potential (OHP) assay, that investigate fibrin generation and fibrinolysis, may provide a more accurate and functional assessment of hypercoagulability. We present a review of fibrin's critical role as a central modulator of thrombotic risk. The results of our studies demonstrating the OHP assay as a predictive biomarker in venous thromboembolism, chronic renal disease, diabetes mellitus, post-thrombotic syndrome, and COVID-19 are discussed. As a comprehensive and global measurement of fibrin generation and fibrinolytic capacity, the OHP assay may be a valuable addition to future multi-modal predictive tools in thrombosis.

Identification of 1,3,8-Triazaspiro[4.5]Decane-2,4-Dione Derivatives as a Novel δ Opioid Receptor-Selective Agonist Chemotype.

δ opioid receptors (DORs) hold potential as a target for neurologic and psychiatric disorders, yet no DOR agonist has proven efficacious in critical phase II clinical trials. The exact reasons for the failure to produce quality drug candidates for the DOR are unclear. However, it is known that certain DOR agonists can induce seizures and exhibit tachyphylaxis. Several studies have suggested that those adverse effects are more prevalent in delta agonists that share the (+)-4-[(αR)-α-((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-methoxybenzyl]-N,N-diethylbenzamide (SNC80)/4-[(αR*)-α-((2S*,5R*)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl]-N,N-diethylbenzamide chemotype. There is a need to find novel lead candidates for drug development that have improved pharmacological properties to differentiate them from the current failed delta agonists. Our objective in this study was to identify novel DOR agonists. We used a β-arrestin assay to screen a small G-protein coupled receptors (GPCR)-focused chemical library. We identified a novel chemotype of DOR agonists that appears to bind to the orthosteric site based of docking and molecular dynamic simulation. The most potent agonist hit compound is selective for the DOR over a panel of 167 other GPCRs, is slightly biased toward G-protein signaling and has anti-allodynic efficacy in a complete Freund's adjuvant model of inflammatory pain in C57BL/6 male and female mice. The newly discovered chemotype contrasts with molecules like SNC80 that are highly efficacious β-arrestin recruiters and may suggest this novel class of DOR agonists could be expanded on to develop a clinical candidate drug. SIGNIFICANCE STATEMENT: δ opioid receptors are a clinical target for various neurological disorders, including migraine and chronic pain. Many of the clinically tested delta opioid agonists share a single chemotype, which carries risks during drug development. Through a small-scale high-throughput screening assay, this study identified a novel δ opioid receptor agonist chemotype, which may serve as alternative for the current analgesic clinical candidates.