Search

The editorial discusses the concept of turning "cold" tumors into "hot" tumors through immunogenic cell death (ICD) to enhance cancer therapy effectiveness. It explores various therapies inducing ICD, traditional and innovative, to boost anti-tumor immune responses. The authors also delve into the biological mechanisms of ICD and its clinical applications, suggesting potential improvements in treating immune "cold" tumors. Additionally, the document highlights research on different ablation temperatures inducing distinct types of ICD in hepatocellular carcinoma cells, potentially paving the way for personalized cancer therapies. [Extracted from the article]

Abstract The COVID-19 pandemic has highlighted the importance of efficient drug discovery in respiratory disease. The traditional set up of clinical trials is expensive and allows for significant attrition of new drugs, many of which undergo extensive safety testing before being abandoned for lack of efficacy. Phase 0 trials, named as they sit between pre-clinical research and phase I, allow for the testing of sub-clinical microdoses in humans to gather early pharmacokinetic (PK), pharmacodynamic (PD) and mechanistic data, before deciding on which drugs to advance further. This early data can improve the efficiency and cost effectiveness of drug development and reduce the extent of animal testing. Phase 0 trials traditionally have utilised sub-therapeutic microdoses of compounds administered intravenously with readouts focusing on PK - measured using highly sensitive methods such as accelerator mass spectrometry (AMS) and liquid chromatography tandem mass spectrometry (LC-MS/MS) of peripheral blood, as well as whole-body positron emission tomography (PET). Mathematical models allow for extrapolation of this PK data to support the further testing of larger, systemically effective doses. However, this extrapolation method is limited at providing robust PD or target engagement/ mode of action data. Using an Intra-Target Microdosing (ITM) approach, a small compartment of the body (about 1% or less) is exposed to potentially clinically active local concentrations. This allows for the collection of PD data, evidence of target cell engagement, as well as the opportunity to extrapolate systemic PK and PD data. This approach has the potential within the pulmonary system for the study and rapid and cost-effective development of new and repurposed drugs.

The COVID-19 pandemic has highlighted the importance of efficient drug discovery in respiratory disease. The traditional set up of clinical trials is expensive and allows for significant attrition of new drugs, many of which undergo extensive safety testing before being abandoned for lack of efficacy. Phase 0 trials, named as they sit between pre-clinical research and phase I, allow for the testing of sub-clinical microdoses in humans to gather early pharmacokinetic (PK), pharmacodynamic (PD) and mechanistic data, before deciding on which drugs to advance further. This early data can improve the efficiency and cost effectiveness of drug development and reduce the extent of animal testing. Phase 0 trials traditionally have utilised sub-therapeutic microdoses of compounds administered intravenously with readouts focusing on PK - measured using highly sensitive methods such as accelerator mass spectrometry (AMS) and liquid chromatography tandem mass spectrometry (LC-MS/MS) of peripheral blood, as well as whole-body positron emission tomography (PET). Mathematical models allow for extrapolation of this PK data to support the further testing of larger, systemically effective doses. However, this extrapolation method is limited at providing robust PD or target engagement/ mode of action data. Using an Intra-Target Microdosing (ITM) approach, a small compartment of the body (about 1% or less) is exposed to potentially clinically active local concentrations. This allows for the collection of PD data, evidence of target cell engagement, as well as the opportunity to extrapolate systemic PK and PD data. This approach has the potential within the pulmonary system for the study and rapid and cost-effective development of new and repurposed drugs. [ABSTRACT FROM AUTHOR]

Parkinson's disease (PD) is the second most common neurodegenerative disease globally. Current drugs only alleviate symptoms without halting disease progression, making rodent models essential for researching new therapies and understanding the disease better. However, selecting the right model is challenging due to the numerous models and protocols available. Key factors in model selection include construct, face, and predictive validity. Construct validity ensures the model replicates pathological changes seen in human PD, focusing on dopaminergic neurodegeneration and a-synuclein aggregation. Face validity ensures the model's symptoms mirror those in humans, primarily reproducing motor and non-motor symptoms. Predictive validity assesses if treatment responses in animals will reflect those in humans, typically involving classical pharmacotherapies and surgical procedures. This review highlights the primary characteristics of PD and how these characteristics are validated experimentally according to the three criteria. Additionally, it serves as a valuable tool for researchers in selecting the most appropriate animal model based on established validation criteria. [ABSTRACT FROM AUTHOR]

This year marks the 35th anniversary of Professor Walter Wahli's discovery of the PPARs (Peroxisome Proliferator-Activated Receptors) family of nuclear hormone receptors. To mark the occasion, the editors of the scientific periodical Biomolecules decided to publish a special issue in his honor. This paper summarizes what is known about PPARs and shows how trends have changed and how research on PPARs has evolved. The article also highlights the importance of PPARs and what role they play in various diseases and ailments. The paper is in a mixed form; essentially it is a review article, but it has been enriched with the results of our experiments. The selection of works was subjective, as there are more than 200,000 publications in the PubMed database alone. First, all papers done on an animal model were discarded at the outset. What remained was still far too large to describe directly. Therefore, only papers that were outstanding, groundbreaking, or simply interesting were described and briefly commented on. [ABSTRACT FROM AUTHOR]

Aims: The influence of human factors on safety in healthcare settings is well established, with targeted interventions reducing risk and enhancing team performance. In experimental and early phase clinical research participant safety is paramount and safeguarded by guidelines, protocolized care and staff training; however, the real‐world interaction and implementation of these risk‐mitigating measures has never been subjected to formal system‐based assessment. Methods: Independent structured observations, systematic review of study documents, and interviews and focus groups were used to collate data on three key tasks undertaken in a clinical research facility (CRF) during a SARS CoV‐2 controlled human infection model (CHIM) study. The Systems Engineering Initiative for Patient Safety (SEIPS) was employed to analyse and categorize findings, and develop recommendations for safety interventions. Results: High levels of team functioning and a clear focus on participant safety were evident throughout the study. Despite this, latent risks in both study‐specific and CRF work systems were identified in all four SEIPS domains (people, environment, tasks and tools). Fourteen actionable recommendations were generated collaboratively. These included inter‐organization and inter‐study standardization, optimized checklists for safety critical tasks, and use of simulation for team training and exploration of work systems. Conclusions: This pioneering application of human factors techniques to analyse work systems during the conduct of research in a CRF revealed risks unidentified by routine review and appraisal, and despite international guideline adherence. SEIPS may aid categorization of system problems and the formulation of recommendations that reduce risk and mitigate potential harm applicable across a trials portfolio. [ABSTRACT FROM AUTHOR]

Clinical trials are crucial in experimental medicine as they assess the safety and efficiency of new treatments. Due to its unstructured and plain language nature, clinical text data often presents challenges in understanding the relationships between various elements like disease, symptoms, diagnosis, and treatment. This task is challenging as the Multi-evidence Natural Language Inference for Clinical Trial Data (NLI4CT) requires intricate reasoning involving textual and numerical elements. It involves integrating information from one or two Clinical Trial Reports (CTRs) to validate hypotheses, demanding a multi-faceted approach. To address these problems, we use BERT-base models' ability to predict entailment or contradiction labels and compare the use of transformer-based feature extraction and pre-trained models. We utilize seven pre-trained models, including six BERT-based and one T5-based model: BERT-base uncased, BioBERT-base-cased-v1.1-mnli, DeBERTa-v3-base-mnli-fever-anli, DeBERTa-v3-base-mnli-fever-docnli-ling-2c, DeBERTa-large-mnli, BioLinkBERT-base, and Flan-T5-base. We achieve an F1-score of 61% on both DeBERTa-v3-base-mnli-fever-anli and DeBERTa-large-mnli models and 95% faithfulness on the BioLinkBERT-base model. [ABSTRACT FROM AUTHOR]

Purpose: There is a lack of evidence regarding how patients with malignant brain tumor and their relatives experience participation in neurooncological clinical trials. Similarly, insights from the perspective of trial staff caring for this group of patients are missing. This study aims to investigate patient, relative and trial staff experiences regarding participation in clinical neurooncological trials. Methods: Within a qualitative exploratory study, 29 semi-structured interviews with brain tumor patients, relatives and trial staff were conducted and analyzed using reflexive thematic analysis (RTA) by Braun and Clarke. A patient researcher and patient council were involved in data analysis and interpretation. Results: Four themes were developed reflecting significant aspects of the trial experience: 1. "It all revolves around hope"; 2. "Trial participation: experiencing unique medical care"; 3. "Everyone's roles are changing"; 4. "Communication as a possible area of conflict". Experiencing trial participation and general medical treatment were found to be interconnected to such a degree that they were often not meaningfully distinguished by patients and relatives. Conclusion: In addition to assessing traditional endpoints for patient outcomes, we recommend increased emphasis on investigating the impact of the "soft" components constituting trial participation. Due to the interconnectedness of medical treatment and trial participation, we recommend further investigation in comparison to experiences in regular care. A deeper understanding of trial participation is needed to inform improvements for patient experiences and staff satisfaction alongside medical and scientific progress. Plain Language Summary: The treatment options available to patients with (malignant) brain tumors are currently very limited. Therefore, patients are sometimes offered to participate in a clinical trial. This means that they receive an experimental treatment (eg new medicine) for which it is not yet clear whether it works better than regular medical care. Currently, little is known about how this group of patients, their relatives and the hospital staff who care for them experience the participation in these clinical trials – which is what we aimed to explore in our study reported here. Based on interviews with patients, relatives and staff, we found that:trial participation mainly revolves around hope;trial participation entails experiencing unique medical care;trial participation significantly changes the previous roles of patients, relatives and staff;trial participation intensifies communication as a possible area of conflict. By providing information on how patients, relatives and staff make sense of their trial experiences, this study constitutes an important addition to the traditional focus of clinical trials on medical and scientific endpoints (eg progression-free survival). This may help clinicians and researchers involved in cancer research and treatment to understand why "unsuccessful" trials can still be perceived as positive by patients or how hopeful communication may support their patients even when perceived as "unrealistic" from the clinicians' perspective. An in depth understanding of trial participation from the perspective of those affected is needed for improved care experiences alongside medical and scientific progress for cancer treatment. [ABSTRACT FROM AUTHOR]

This document is a corrigendum published in the journal Frontiers in Pharmacology. It corrects errors in Figures 1, 4, and 5 of the article titled "Long-term efficacy and reduced side-effects of buprenorphine in patients with moderate and severe chronic pain." The corrected figures are provided in the document. The authors apologize for the errors and state that they do not affect the scientific conclusions of the article. The document also includes information about the authors, keywords related to the topic, and copyright information. [Extracted from the article]

This article, titled "Editorial: Women in cancer immunity and immunotherapy," discusses the contributions and challenges faced by women scientists in the field of cancer immunity and immunotherapy. It highlights the achievements of women scientists throughout history and acknowledges the gender gap that still exists in the field. The article also presents several original research articles and reviews that focus on various aspects of cancer immunity and immunotherapy. Overall, the article aims to encourage more women to pursue careers in scientific research and contribute to the advancement of the field. [Extracted from the article]

Alcoholic liver disease (ALD) is characterized by high morbidity and mortality, and mainly results from prolonged and excessive alcohol use. Amomum villosum Lour. (A. villosum), a well‐known traditional Chinese medicine (TCM), has hepatoprotective properties. However, its ability to combat alcohol‐induced liver injury has not been fully explored. The objective of this study was to investigate the hepatoprotective effects of A. villosum in a rat model of alcohol‐induced liver disease, thereby establishing a scientific foundation for the potential preventive use of A. villosum in ALD. We established a Chinese liquor (Baijiu)‐induced liver injury model in rats. Hematoxylin and eosin (HE) staining, in combination with biochemical tests, was used to evaluate the protective effects of A. villosum on the liver. The integration of network medicine analysis with experimental validation was used to explore the hepatoprotective effects and potential mechanisms of A. villosum in rats. Our findings showed that A. villosum ameliorated alcohol‐induced changes in body weight, liver index, hepatic steatosis, inflammation, blood lipid metabolism, and liver function in rats. Network proximity analysis was employed to identify 18 potentially active ingredients of A. villosum for ALD treatment. These potentially active ingredients in the blood were further identified using mass spectrometry (MS). Our results showed that A. villosum plays a hepatoprotective role by modulating the protein levels of estrogen receptor 1 (ESR1), anti‐nuclear receptor subfamily 3 group C member 1 (NR3C1), interleukin 6 (IL‐6), and tumor necrosis factor‐α (TNF‐α). In conclusion, the results of the current study suggested that A. villosum potentially exerts hepatoprotective effects on ALD in rats, possibly through regulating the protein levels of ESR1, NR3C1, IL‐6, and TNF‐α. [ABSTRACT FROM AUTHOR]

Background: Our aim was to develop a validated Patient Reported Experience Measure (PREM) to capture patient and carer experience during participation in experimental cancer medicine trials (ECM): called PREM-ECM. Methods: Mixed method design, consisting of four stages. Questionnaire items were produced for both patients and carers using interviews, focus groups, and cognitive interviews with patients and carers separately. For both patient and carer PREMs, a cross-sectional questionnaire study was conducted to identify final items for inclusion using hierarchical item reduction and Rasch analysis. Questionnaire validity and reliability were assessed, including administration feasibility. Results: Initial interview participants suggested the need for three PREMs, two specific to patients: (i) a 'prior' questionnaire that captured experiences of trial introduction, screening, consenting, and early trial experience (< 6 weeks post consent); and (ii) 'on-trial' that captured experiences of ongoing consent and trial participation; and (iii) a PREM specific for carers. The draft 25-item 'prior' questionnaire was completed by 162 patients and 162 patients completed the draft 35-item 'on-trial' questionnaire. Hierarchical and Rasch analysis produced a 14-item 'prior' list and a 15-item list for 'on-trial'. Both patient PREM's demonstrated a good fit to the Rasch model following Bonferroni correction (X2p = 0.008). The carer 34-draft item questionnaire was completed by 102 participants. Hierarchical and Rasch analysis produced a 13-item list for PREM-ECM-Carer, with good fit to the Rasch model (X2p = 0.62). The pilot testing demonstrated the feasibility of all the PREMs in capturing patient and caregiver experiences in routine clinical settings. Conclusions: The three PREM-ECM questionnaires will be the first validated experience measures for ECM trial patients and their carers. These questionnaires may be used to assess patients' and their carers' experiences of ECM and enable robust comparisons across cancer trial units highlighting areas for service improvement. [ABSTRACT FROM AUTHOR]

Background: Accidental hypothermia is common in all trauma patients and contributes to the lethal diamond, increasing both morbidity and mortality. In hypotensive shock, fluid resuscitation is recommended using fluids with a temperature of 37–42°, as fluid temperature can decrease the patient's body temperature. In Sweden, virtually all prehospital services use preheated fluids. The aim of the present study was to investigate how the temperature of preheated infusion fluids is affected by the ambient temperatures and flow rates relevant for prehospital emergency care. Methods: In this experimental simulation study, temperature changes in crystalloids preheated to 39 °C were evaluated. The fluid temperature changes were measured both in the infusion bag and at the patient end of the infusion system. Measurements were conducted in conditions relevant to prehospital emergency care, with ambient temperatures varying between − 4 and 28 °C and flow rates of 1000 ml/h and 6000 ml/h, through an uninsulated infusion set at a length of 175 cm. Results: The flow rate and ambient temperature affected the temperature in the infusion fluid both in the infusion bag and at the patient end of the system. A lower ambient temperature and lower flow rate were both associated with a greater temperature loss in the infusion fluid. Conclusion: This study shows that both a high infusion rate and a high ambient temperature are needed if an infusion fluid preheated to 39 °C is to remain above 37 °C when it reaches the patient using a 175-cm-long uninsulated infusion set. It is apparent that the lower the ambient temperature, the higher the flow rate needs to be to limit temperature loss of the fluid. [ABSTRACT FROM AUTHOR]

Hyaluronic acid (HA), a major glycosaminoglycan of the brain extracellular matrix, modulates cell behaviors through binding its receptor, Cd44. In this study, we assessed the influence of HA on high-grade brain tumors in vitro. The model comprised cell cultures derived from six rodent carcinogen-induced brain tumors, forming 3D spheroids prone to spontaneous fusion. Supplementation of the standard culture medium with 0.25% HA significantly inhibited the fusion rates, preserving the shape and size uniformity of spheroids. The 3D cultures were assigned to two groups; a Cd44lo group had a tenfold decreased relative expression of Cd44 than another (Cd44hi) group. In addition, these two groups differed by expression levels of Sox2 transcription factor; the correlation analysis revealed a tight negative association for Cd44 and Sox2. Transcriptomic responses of spheroids to HA exposure also depended on Cd44 expression levels, from subtle in Cd44lo to more pronounced and specific in Cd44hi, involving cell cycle progression, PI3K/AKT/mTOR pathway activation, and multidrug resistance genes. The potential HA-induced increase in brain tumor 3D models' resistance to anticancer drug therapy should be taken into account when designing preclinical studies using HA scaffold-based models. The property of HA to prevent the fusion of brain-derived spheroids can be employed in CNS regenerative medicine and experimental oncology to ensure the production of uniform, controllably fusing neurospheres when creating more accurate in vitro brain models. [ABSTRACT FROM AUTHOR]

On 15–16 June 2023, healthcare professionals and breast cancer patients and advocates from across Canada met in Toronto, Ontario, for the 2023 Canadian Breast Cancer Symposium (CBSC.). The CBSC. is a national, multidisciplinary event that occurs every 2 years with the goal of developing a personalized approach to the management of breast cancer in Canada. Experts provided state-of-the-art information to help optimally manage breast cancer patients, including etiology, prevention, diagnosis, experimental biology, and therapy of breast cancer and premalignant breast disease. The symposium also had the objectives of increasing communication and collaboration among breast cancer healthcare providers nationwide and providing a comprehensive and real-life review of the many facets of breast cancer. The sessions covered the patient voice, the top breast cancer papers from different disciplines in 2022, artificial intelligence in breast cancer, systemic therapy updates, the management of central nervous system metastases, multidisciplinary management of ductal carcinoma in situ, special populations, optimization-based individual prognostic factors, toxicity management of novel therapeutics, survivorship, and updates in surgical oncology. The key takeaways of these sessions have been summarized in this conference report. [ABSTRACT FROM AUTHOR]

Nasopharyngeal carcinoma (NPC) is a type of cancer that originates from the mucosal lining of the nasopharynx and can invade and spread. Although contemporary chemoradiotherapy effectively manages the disease locally, there are still challenges with locoregional recurrence and distant failure. Therefore, it is crucial to have a deeper understanding of the molecular basis of NPC cell movement in order to develop a more effective treatment and to improve patient survival rates. Cancer cell line models are invaluable in studying health and disease and it is not surprising that they play a critical role in NPC research. Consequently, scientists have established around 80 immortalized human NPC lines that are commonly used as in vitro models. However, over the years, it has been observed that many cell lines are misidentified or contaminated by other cells. This cross-contamination leads to the creation of false cell lines that no longer match the original donor. In this commentary, we discuss the impact of misidentified NPC cell lines on the scientific literature. We found 1159 articles from 2000 to 2023 that used NPC cell lines contaminated with HeLa cells. Alarmingly, the number of publications and citations using these contaminated cell lines continued to increase, even after information about the contamination was officially published. These articles were most commonly published in the fields of oncology, pharmacology, and experimental medicine research. These findings highlight the importance of science policy and support the need for journals to require authentication testing before publication. [ABSTRACT FROM AUTHOR]

In line with recent proposals for experimental philosophy and philosophy of science in practice, we propose that the philosophy of medicine could benefit from incorporating empirical research, just as bioethics has. In this paper, we therefore take first steps towards the development of an empirical philosophy of medicine, that includes investigating practical and moral dimensions. This qualitative study gives insight into the views and experiences of a group of various medical professionals and patient representatives regarding the conceptualization of health and disease concepts in practice and the possible problems that surround them. This includes clinical, epistemological, and ethical issues. We have conducted qualitative interviews with a broad range of participants (n = 17), working in various health-related disciplines, fields and organizations. From the interviews, we highlight several different practical functions of definitions of health and disease. Furthermore, we discuss 5 types of problematic situations that emerged from the interviews and analyze the underlying conceptual issues. By providing theoretical frameworks and conceptual tools, and by suggesting conceptual changes or adaptations, philosophers might be able to help solve some of these problems. This empirical-philosophical study contributes to a more pragmatic way of understanding the relevance of conceptualizing health and disease by connecting the participants' views and experiences to the theoretical debate. Going back and forth between theory and practice will likely result in a more complex but hopefully also better and more fruitful understanding of health and disease concepts. [ABSTRACT FROM AUTHOR]

Experimental studies devoted to the study of the mechanisms of the pathogenesis of acute peritonitis and the development of new methods of medical and surgical treatment are becoming increasingly relevant. Today, experimental medicine knows many different ways to modeling septic peritonitis and eliminate it, but the role of the local immune system is underestimated, whereas it takes a direct part in inflammation. The objective of our work to study morphological features of results of experimental modeling of septic peritonitis in white rats. The study included 15 sexually mature white male rats weighing 276.75±6.56 grams. A simulation of septic peritonitis was performed by perforating the upper part of the cecum with four punctures with a G16 injection needle. As a result of the experiment, after examination of the peritoneal cavity, all 15 animals were diagnosed with omentum tamponade of perforated damage to the caecum. In 11 cases, the perforated wall of the caecum was covered by the greater omentum (73.34 %), and in the other 4 animals, tamponade was performed by one of the epididymal omentum (26.66 %). The initial stage of tamponade with the greater or epididymal omentums of a perforated caecum begins on the first day of the experiment and consists of tight interstitial consolidation between them, as well as in the invasion of blood vessels from the omentum side to the focus of infection, which ensure the delivery of the appropriate immunocompetent cells. As a result of this process, intensive lymphoid infiltrates are formed in this area, as well as the growth of adipose tissue, which isolates the inflammatory focus from the peritoneal cavity with a thick layer. [ABSTRACT FROM AUTHOR]

This article provides an overview of recent research on prostate cancer, which is the second most common cancer among men worldwide. It covers various topics such as new biomarkers for diagnosis, drug resistance mechanisms, the effects of curcumin on prostate cancer cells, and the role of insulin growth factor signaling. The article also discusses the association between immune cells and prostate cancer risk, as well as the importance of positive surgical margins in treatment decisions. The document includes references to two scientific articles that provide further information on predicting biochemical recurrence and the treatment of metastatic hormone-sensitive prostate cancer. Overall, this article is a valuable resource for researchers and individuals interested in understanding and treating prostate cancer. [Extracted from the article]

Strategies to separately manufacture arterial-scale tissue engineered vascular grafts and microvascular networks have been well-established, but efforts to bridge these two length scales to create hierarchical vasculature capable of supporting parenchymal cell functions or restoring perfusion to ischemic tissues have been limited. This work aimed to create multiscale vascular constructs by assessing the capability of macroscopic vessels isolated from mice to form functional connections to engineered capillary networks ex vivo. Vessels of venous and arterial origins from both thoracic and femoral locations were isolated from mice, and then evaluated for their abilities to sprout endothelial cells (EC) capable of inosculating with surrounding human cell-derived microvasculature within bulk fibrin hydrogels. Comparing aortae, vena cavae, and femoral vessel bundles, we identified the thoracic aorta as the rodent macrovessel that yielded the greatest degree of sprouting and interconnection to surrounding capillaries. The presence of cells undergoing vascular morphogenesis in the surrounding hydrogel attenuated EC sprouting from the macrovessel compared to sprouting into acellular hydrogels, but ultimately sprouted mouse EC interacted with human cell-derived capillary networks in the bulk, yielding chimeric vessels. We then integrated micromolded mesovessels into the constructs to engineer a primitive 3-scale vascular hierarchy comprising capillaries, mesovessels, and macrovessels. Overall, this study yielded a primitive hierarchical vasculature suitable as proof-of-concept for regenerative medicine applications and as an experimental model to better understand the spontaneous formation of host-graft vessel anastomoses. [ABSTRACT FROM AUTHOR]

Introduction: Receptor-interacting protein kinase 1 (RIPK1), a key mediator of inflammation through necroptosis and proinflammatory cytokine production, may play a role in the pathogenesis of immune-mediated inflammatory diseases such as chronic plaque psoriasis. An experimental medicine study of RIPK1 inhibition with GSK2982772 immediate-release formulation at doses up to 60 mg three times daily in mild to moderate plaque psoriasis indicated that efficacy may be improved with higher trough concentrations of GSK2982772. Methods: This multicenter, randomized, double-blind, placebo-controlled, repeat-dose study (NCT04316585) assessed the efficacy, safety, pharmacokinetics, and pharmacodynamics of 960 mg GSK2982772 (once-daily modified-release formulation) in patients with moderate to severe plaque psoriasis. Twenty-nine patients were randomized 2:1 to GSK2982772 (N = 19) or placebo (N = 10) for 12 weeks. Results: GSK2982772 was well tolerated with trough concentrations greater than tenfold higher than the previous phase 1 study with immediate release. Despite near complete RIPK1 target engagement in blood and modest reduction in circulating inflammatory cytokines, the proportion of patients achieving 75% improvement from baseline in Psoriasis Area Severity Index score at week 12 was similar between GSK2982772 and placebo (posterior median 1.8% vs 4.9%, respectively), with an estimated median treatment difference of − 2.3%. This analysis incorporated historical placebo data through the use of an informative prior distribution on the placebo arm. Week 4 changes in skin biopsy gene expression suggested sufficient local drug exposure to elicit a pharmacodynamic response. Conclusion: Administration of the RIPK1 inhibitor GSK2982772 to patients with moderate to severe plaque psoriasis did not translate into meaningful clinical improvements. Plain Language Summary: Psoriasis is thought to be caused by problems with the immune system, including possibly receptor-interacting protein kinase 1 (RIPK1), which plays an important role in the development of inflammation. A previous study suggested that the drug, GSK2982772, which interferes with RIPK1, might improve symptoms in patients with psoriasis. This study examined whether higher doses of GSK2982772 than previously studied would be beneficial for patients with psoriasis. The study found that the severity of psoriasis was similar in patients treated with GSK2982772 for 12 weeks as in those who did not receive the drug, indicating that GSK298772 did not improve psoriasis. [ABSTRACT FROM AUTHOR]

BACKGROUND. Phase 1 study of ATR inhibition alone or with radiation therapy (PATRIOT) was a first-in-human phase I study of the oral ATR (ataxia telangiectasia and Rad3-related) inhibitor ceralasertib (AZD6738) in advanced solid tumors. METHODS. The primary objective was safety. Secondary objectives included assessment of antitumor responses and pharmacokinetic (PK) and pharmacodynamic (PD) studies. Sixty-seven patients received 20--240 mg ceralasertib BD continuously or intermittently (14 of a 28-day cycle). RESULTS. Intermittent dosing was better tolerated than continuous, which was associated with dose-limiting hematological toxicity. The recommended phase 2 dose of ceralasertib was 160 mg twice daily for 2 weeks in a 4-weekly cycle. Modulation of target and increased DNA damage were identified in tumor and surrogate PD. There were 5 (8%) confirmed partial responses (PRs) (40--240 mg BD), 34 (52%) stable disease (SD), including 1 unconfirmed PR, and 27 (41%) progressive disease. Durable responses were seen in tumors with loss of AT-rich interactive domain-containing protein 1A (ARID1A) and DNA damage-- response defects. Treatment-modulated tumor and systemic immune markers and responding tumors were more immune inflamed than nonresponding. CONCLUSION. Ceralasertib monotherapy was tolerated at 160 mg BD intermittently and associated with antitumor activity. TRIAL REGISTRATION. Clinicaltrials.gov: NCT02223923, EudraCT: 2013-003994-84. FUNDING. Cancer Research UK, AstraZeneca, UK Department of Health (National Institute for Health Research), Rosetrees Trust, Experimental Cancer Medicine Centre. [ABSTRACT FROM AUTHOR]

Objectives: Bee venom is used for medicinal purposes, including the treatment of neurological and liver diseases, but its use as a primary health care approach for preventive purposes requires further exploration. The aim of this study was to provide the first investigation into the possible protective effects of bee venom against hepatic encephalopathy, a serious neurodegenerative disease. Materials and Methods: An experimental animal study was conducted in which healthy albino Sprague–Dawley rats were randomized into three groups: healthy, control and bee venom groups. All rats were tested for locomotor activity at the beginning and end of the study. No intervention was made in the healthy group, whereas hepatic encephalopathy was induced in the control and bee venom groups by the administration of thioacetamide (TAA) (200 mg/kg/day). The bee venom group also received bee venom (5 mg/kg/day) subcutaneously every day for 14 days prior to the TAA administration. Results: The results for the final locomotor activity tests were statistically better in the bee venom group than in the control group, supporting a beneficial effect of prophylactic bee venom application. Blood ammonia levels and liver weights, determined as indicators of inflammation, were lower in the bee venom group than in the control group and were close to levels in the healthy group, but not statistically significant. Conclusions: Bee venom administration has protective effects against the development of hepatic encephalopathy and offers a promising therapeutic opportunity in preventive medicine. [ABSTRACT FROM AUTHOR]

The present editorial summarizes the last 2 calendar years of Advances in Clinical and Experimental Medicine (ACEM) publication (2021 and 2022). The specific aims were: 1) To clarify the classification of papers published in ACEM; 2) To present motivations behind choosing this classification; 3) To show how this classification is reflected in citations. Six categories of papers published in ACEM are presented: editorials, meta-analyses, reviews (including systematic reviews), multicenter studies, research-in-progress studies, and research letters; lack of clear definitions for editorials, research letters and research-in-progress studies is discussed. Thematic fields covered by all categories in 2021 and 2022 are presented and differences in this regard between 2021 and 2022 are highlighted. Reasons for not publishing case reports (CRs) are discussed, with some of the debate on this issue in medical literature summarized. The article type classification used in ACEM in only one of many possible solutions and may be modified in the future -- it should be both clear for the authors and allow for orientation in the journal's content. The motivation for choosing the employed categories stem both from their position on the accepted levels of evidence in evidence-based medicine (EBM) and their potential to be cited. [ABSTRACT FROM AUTHOR]

This document is an editorial published in Frontiers in Veterinary Science. It discusses the application of biomedical engineering to veterinary medicine and animal healthcare. The editorial highlights the potential benefits of using biomedical engineering techniques, such as computational modeling, artificial intelligence, and experimental tests, in veterinary medicine. It also provides a summary of 14 research papers included in the journal issue that explore various aspects of animal biomechanics and its applications in veterinary science. The editorial emphasizes the need for further investigation and collaboration between biomedical engineering and veterinary medicine. [Extracted from the article]

This article explores the interactions between tumor cells and immune cells in the development of organ-specific metastasis, a critical stage in cancer progression. It identifies five types of cell-cell interactions that contribute to this process and emphasizes the importance of understanding these interactions for the development of new therapeutic strategies. Additionally, a study discussed in the article suggests that targeting Kupffer cells could be a potential therapeutic approach for preventing the spread of pancreatic ductal adenocarcinoma to the liver. However, more research is needed to confirm these findings and determine their applicability to human patients. [Extracted from the article]

Parkinson’s disease (PD) is the second most common neurodegenerative disease globally. Current drugs only alleviate symptoms without halting disease progression, making rodent models essential for researching new therapies and understanding the disease better. However, selecting the right model is challenging due to the numerous models and protocols available. Key factors in model selection include construct, face, and predictive validity. Construct validity ensures the model replicates pathological changes seen in human PD, focusing on dopaminergic neurodegeneration and a-synuclein aggregation. Face validity ensures the model’s symptoms mirror those in humans, primarily reproducing motor and non-motor symptoms. Predictive validity assesses if treatment responses in animals will reflect those in humans, typically involving classical pharmacotherapies and surgical procedures. This review highlights the primary characteristics of PD and how these characteristics are validated experimentally according to the three criteria. Additionally, it serves as a valuable tool for researchers in selecting the most appropriate animal model based on established validation criteria.

The number of retracted papers from Chinese university-affiliated hospitals is increasing, which has raised much concern. The aim of this study is to analyze the retracted papers from university-affiliated hospitals in mainland China from 2000 to 2021. Data for 1,031 retracted papers were identified from the Web of Science Core collection database. The information of the hospitals involved was obtained from their official websites. We analyzed the chronological changes, journal distribution, discipline distribution and retraction reasons for the retracted papers. The grade and geographic locations of the hospitals involved were explored as well. We found a rapid increase in the number of retracted papers, while the retraction time interval is decreasing. The main reasons for retraction are plagiarism/self-plagiarism (n=255), invalid data/images/conclusions (n=212), fake peer review (n=175) and honesty error(n=163). The disciplines are mainly distributed in oncology (n=320), pharmacology & pharmacy (n=198) and research & experimental medicine (n=166). About 43.8% of the retracted papers were from hospitals affiliated with prestigious universities. This study fails to differentiate between retractions due to honest error and retractions due to research misconduct. We believe that there is a fundamental difference between honest error retractions and misconduct retractions. Another limitation is that authors of the retracted papers have not been analyzed in this study. This study provides a reference for addressing research misconduct in Chinese university-affiliated hospitals. It is our recommendation that universities and hospitals should educate all their staff about the basic norms of research integrity, punish authors of scientific misconduct retracted papers, and reform the unreasonable evaluation system. Based on the analysis of retracted papers, this study further analyzes the characteristics of institutions of retracted papers, which may deepen the research on retracted papers and provide a new perspective to understand the retraction phenomenon. [ABSTRACT FROM AUTHOR]

Some people experience pleasure during physical activity, whereas it can be unpleasant for others. Modifying affective responses during physical activity in real-world situations may be an intervention strategy for increasing physical activity. This article follows an experimental medicine framework to summarize evidence identifying, assessing, and influencing affective response during real-world physical activity to inform interventions targeting this mediating mechanism. [ABSTRACT FROM AUTHOR]

This editorial discusses graphical abstracts (GAs) as a relatively new tool used to concisely summarize a scientific paper and promote it on social media to boost the visibility of research and the number of citations. This article attempts to define GA as clearly as possible and to explain the role of GAs as scientific communication tools in medical journals. A clear definition of a GA is lacking. Several definitions from the literature are presented, which illustrates that the terms "visual abstract" and "graphical abstract" can be used interchangeably. The role of GAs can be described in 3 aspects: 1) time required for communication (GAs are meant to convey the key contents of a scientific paper in a time much shorter than required for reading the full text), 2) means of communication (social media), and 3) mechanism of communication (research results in many fields of medicine can be better conveyed through visual or at least more visual means rather than plain text). A review of the existing literature concerning the effectiveness of GAs presents studies regarding the use of GAs in promoting scientific papers on Twitter - visual abstracts attracted significantly more engagement than plain English ones, especially from medical professionals. Visual abstract tweets were associated with a significantly higher number of impressions, retweets, and link clicks compared to text abstract tweets. Journals that have introduced GAs demonstrated significantly higher impact factor (IF) increases for the past 3 years than those of journals without GAs. The longer GAs have been utilized in a journal, the higher the IF the journal had. The experience of the editors of Advances in Clinical and Experimental Medicine (ACEM) concerning GAs are discussed, divided by types of papers published in this journal (original papers, meta-analyses, reviews, research-in-progress articles, and editorials), illustrated with examples of well-prepared GAs, and supplemented with a brief description of the feedback from authors and readers amassed following the introduction of GAs in ACEM. Finally, the authors offer the readership of ACEM 8 practical tips on how to prepare a useful GA, and list 8 common mistakes and misconceptions regarding GAs - both in text form and summarized in tables. The conclusion of the paper is that there is currently no universal standard for GAs, which can lead to inconsistencies in their formats and content; therefore, more detailed guidelines to standardize GAs for scientific research are warranted. [ABSTRACT FROM AUTHOR]

BackgroundThe pursuit of a cure for HIV is a high priority for researchers, funding agencies, governments and people living with HIV (PLWH). To date, over 250 biomedical studies worldwide are or have been related to discovering a safe, effective, and scalable HIV cure, most of which are early translational research and experimental medicine. As HIV cure research increases, it is critical to identify and address the ethical challenges posed by this research.MethodsWe conducted a scoping review of the growing HIV cure research ethics literature, focusing on articles published in English peer-reviewed journals from 2013 to 2021. We extracted and summarized key developments in the ethics of HIV cure research. Twelve community advocates actively engaged in HIV cure research provided input on this summary and suggested areas warranting further ethical inquiry and foresight via email exchange and video conferencing.DiscussionDespite substantial scholarship related to the ethics of HIV cure research, additional attention should focus on emerging issues in six categories of ethical issues: (1) social value (ongoing and emerging biomedical research and scalability considerations); (2) scientific validity (study design issues, such as the use of analytical treatment interruptions and placebos); (3) fair selection of participants (equity and justice considerations); (4) favorable benefit/risk balance (early phase research, benefit-risk balance, risk perception, psychological risks, and pediatric research); (5) informed consent (attention to language, decision-making, informed consent processes and scientific uncertainty); and (6) respect for enrolled participants and community (perspectives of people living with HIV and affected communities and representation).ConclusionHIV cure research ethics has an unfinished agenda. Scientific research and bioethics should work in tandem to advance ethical HIV cure research. Because the science of HIV cure research will continue to rapidly advance, ethical considerations of the major themes we identified will need to be revisited and refined over time.

The editorial discusses immunological non-responders in HIV infection, where some patients do not show an increase in CD4+ T-cell count despite a decrease in HIV viral load after starting antiretroviral therapy (ART). Studies have found that 10 to 40% of HIV-positive individuals who start treatment at a low CD4+ T-cell count are immunological non-responders (INRs). Various research articles included in the Frontiers in Immunology Research Topic explore the mechanisms of immunological non-response using classical and omics approaches, providing insights into the complex immunological profile of INRs and potential therapeutic targets for improving clinical outcomes for individuals living with HIV. [Extracted from the article]

The editorial in "Frontiers in Pharmacology" discusses the role of the gut-brain axis in neurodegenerative diseases like Alzheimer's and Parkinson's. The gut microbiota influences brain function through the gut-brain axis, with potential therapeutic implications. Various reviews in the article explore topics such as the impact of monosodium glutamate on Alzheimer's disease, the global research status of enteric glia, and the therapeutic potential of probiotics in cognitive development. The articles emphasize the need for further research to deepen our understanding of microbiota, the gut-brain axis, and their role in managing neurodegenerative diseases. [Extracted from the article]

This document is a corrigendum for an article titled "Evidence for a genetic contribution to the ossification of spinal ligaments in ossification of posterior longitudinal ligament and diffuse idiopathic skeletal hyperostosis: a narrative review." The corrigendum acknowledges errors in the affiliation and funding statements of the original article. The errors have been corrected, and the authors state that these corrections do not affect the scientific conclusions of the article. The corrigendum also includes a note from the publisher clarifying that the views expressed in the article are solely those of the authors and do not necessarily represent the views of their affiliated organizations or the publisher. [Extracted from the article]

The global burden of respiratory diseases is very high and still on the rise, prompting the need for accurate models for basic and translational research. Several model systems are currently available ranging from simple airway cell cultures to complex tissue-engineered lungs. In recent years, human lung organoids have been established as highly transferrable three-dimensional in vitro model systems for lung research. For acute infectious and chronic inflammatory diseases as well as lung cancer, human lung organoids have opened possibilities for precise in vitro research and a deeper understanding of mechanisms underlying lung injury and regeneration. Human lung organoids from induced pluripotent stem cells or from adult stem cells of patients' samples introduce tools for understanding developmental processes and personalized medicine approaches. When further state-of-the-art technologies and protocols come into use, the full potential of human lung organoids can be harnessed. High-throughput assays in drug development, gene therapy, and organoid transplantation are current applications of organoids in translational research. In this review, we emphasize novel approaches in translational and personalized medicine in lung research focusing on the use of human lung organoids. [ABSTRACT FROM AUTHOR]

BACKGROUND. The stomach-derived hormone ghrelin stimulates appetite, but the ghrelin receptor is also expressed in brain circuits involved in motivation and reward. We examined ghrelin effects on decision making beyond food or drug reward using monetary rewards. METHODS. Thirty participants (50% women and 50% men) underwent 2 fMRI scans while receiving i.v. ghrelin or saline in a randomized counterbalanced order. RESULTS. Striatal representations of reward anticipation were unaffected by ghrelin, while activity during anticipation of losses was attenuated. Temporal discounting rates of monetary reward were lower overall in the ghrelin condition, an effect driven by women. Discounting rates were inversely correlated with neural activity in a large cluster within the left parietal lobule that included the angular gyrus. Activity in an overlapping cluster was related to behavioral choices and was suppressed by ghrelin. CONCLUSION. This is, to our knowledge, the first human study to extend the understanding of ghrelin's significance beyond the canonical feeding domain or in relation to addictive substances. Contrary to our hypothesis, we found that ghrelin did not affect sensitivity to monetary reward anticipation, but rather resulted in attenuated loss aversion and lower discounting rates for these rewards. Ghrelin may cause a motivational shift toward caloric reward rather than globally promoting the value of reward. TRIAL REGISTRATION. EudraCT 2018-004829-82. FUNDING. Swedish Research Council (2013-07434), Marcus and Marianne Wallenberg foundation (2014.0187) and National Institute on Drug Abuse/National Institute on Alcohol Abuse and Alcoholism Intramural Research Program. [ABSTRACT FROM AUTHOR]

Synaptic loss occurs early in many neurodegenerative diseases and contributes to cognitive impairment even in the absence of gross atrophy. Currently, for human disease there are few formal models to explain how cortical networks underlying cognition are affected by synaptic loss. We advocate that biophysical models of neurophysiology offer both a bridge from preclinical to clinical models of pathology and quantitative assays for experimental medicine. Such biophysical models can also disclose hidden neuronal dynamics generating neurophysiological observations such as EEG and magnetoencephalography. Here, we augment a biophysically informed mesoscale model of human cortical function by inclusion of synaptic density estimates as captured by 11C-UCB-J PET, and provide insights into how regional synapse loss affects neurophysiology. We use the primary tauopathy of progressive supranuclear palsy (Richardson's syndrome) as an exemplar condition, with high clinicopathological correlations. Progressive supranuclear palsy causes a marked change in cortical neurophysiology in the presence of mild cortical atrophy and is associated with a decline in cognitive functions associated with the frontal lobe. Using parametric empirical Bayesian inversion of a conductance-based canonical microcircuit model of magnetoencephalography data, we show that the inclusion of regional synaptic density—as a subject-specific prior on laminar-specific neuronal populations—markedly increases model evidence. Specifically, model comparison suggests that a reduction in synaptic density in inferior frontal cortex affects superficial and granular layer glutamatergic excitation. This predicted individual differences in behaviour, demonstrating the link between synaptic loss, neurophysiology and cognitive deficits. The method we demonstrate is not restricted to progressive supranuclear palsy or the effects of synaptic loss: such pathology-enriched dynamic causal models can be used to assess the mechanisms of other neurological disorders, with diverse non-invasive measures of pathology, and is suitable to test the effects of experimental pharmacology. [ABSTRACT FROM AUTHOR]

Laboratory rats are often used in experimental research of concern to human and veterinary medicine. There are several advantages of using rats as a scientific medium. In this study rats will be used as the scientific model as, previously discussed, they have proven their effectiveness in cardiovascular studies. The aim is to give a description of the cranial region, the head and neck of the rat as well as imaging of the vasculature of these regions to support the planning of surgical therapeutic methods to be applied to human and veterinary medical research. The research of the blood vessels morphology in anatomical studies is key to the prevention of ischemia during organ surgery. In recent times the laboratory rat has become one of the most popular models for experiments in medical research. Corrosion casts were prepared on the cranial arteries of the body of 20 adult Wistar rats using Duracryl Dental® and PUR SP as the casting medium. We found the absence of the brachiocephalic trunk in some cases. Thyroid arteries originated independently or by the short common trunk from the right and left common carotid artery. The facial artery originated by the short trunk with the maxillary artery, or by the linguofacial trunk with the lingual artery from the common carotid artery. The results of this study revealed that, the functional anatomical relationship between the rat neck and head structures are important for the development of medical research of concern to human and veterinary experimental medicine.

Background: Biomedicine, i.e. the application of basic sciences to medicine, has become the cornerstone for the study of etiopathogenesis and treatment of diseases. Biomedicine has enormously contributed to the progress of medicine and healthcare and has become the preferred approach to medical problems in the West. The developments in statistical inference and machine learning techniques have provided the foundation for personalised medicine where clinical management can be fully informed by biomedicine. The deployment of precision medicine may impact the autonomy and self-normativity of the patients. Understanding the relationship between biomedicine and medical practice can help navigate the benefits and challenges offered by precision medicine. Methods: Conventional content analysis was applied to "Le Normal and le Pathologique" (Canguilhem G. The Normal and the Pathological. Princeton: Princeton University Press; 1991) and further investigated with respect to its relationship with techne and precision medicine using PubMed and Google Scholar and the Standford Encyclopedia of Philosophy to search for the following keywords singularly or in combination: "Canguilhem", "techne", "episteme", "precision medicine", "machine learning AND medicine". Results: The Hippocratic concept of techne accounts for many characteristics of medical knowledge and practice. The advances of biomedicine, experimental medicine and, more recently, machine learning offer, in contrast, the model of a medicine based purely on episteme. I argue that Canguilhem medical epistemology establishes a framework where episteme and data-driven medicine is compatible with the promotion of patient's autonomy and self-normativity. Conclusions: Canguilhem's medical epistemology orders the relationship of applied medicine with experimental sciences, ethics and social sciences. It provides guidance to define the scope of medicine and the boundaries of medicalization of healthy life. Finally, it sets an agenda for a safe implementation of machine learning in medicine. [ABSTRACT FROM AUTHOR]

The development of safe and effective HIV vaccines has been a scientific challenge for more than 40 years. Despite disappointing results from efficacy clinical trials, much has been learnt from years of research and development. In a rapidly evolving HIV prevention landscape, swift evaluation of multiple vaccine approaches eliciting cross-reactive humoral and cellular responses is needed to ensure the development of efficacious vaccine candidates. To contain increasing costs, innovative clinical research methods are required. Experimental medicine has the potential to accelerate vaccine discovery by iterating early stages of clinical testing faster and by selecting the most promising immunogen combinations for further clinical evaluation. As part of its mission to unite diverse stakeholders involved in the response to the HIV epidemic, the Global HIV Vaccine Enterprise at IAS—the International AIDS Society—hosted a series of online events between January and September 2022 to discuss the merits and challenges of experimental medicine studies to accelerate the development of safe and effective HIV vaccines. This report summarizes key questions and discussions across the series of events, which brought together scientists, policy makers, community stakeholders, advocates, bioethicists, and funders. [ABSTRACT FROM AUTHOR]

COVID-19 causes significant thrombosis and coagulopathy, with elevated D-dimer a predictor of adverse outcome. The precise mechanism of this coagulopathy remains unclear; one hypothesis is that loss of angiotensin-converting enzyme 2 activity during viral endocytosis leads to pro-inflammatory angiotensin-II accumulation, loss of angiotensin-1-7 and subsequent vascular endothelial activation. We undertook a double-blind randomized, placebo-controlled experimental medicine study to assess the effect of TRV027, a synthetic angiotensin-1-7 analogue on D-dimer in 30 patients admitted to hospital with COVID-19. The study showed a similar rate of adverse events in TRV027 and control groups. There was a numerical decrease in D-dimer in the TRV027 group and increase in D-dimer in the placebo group; however, this did not reach statistical significance (P = .15). A Bayesian analysis demonstrated that there was a 92% probability that this change represented a true drug effect. [ABSTRACT FROM AUTHOR]

Background: Sequential B cell-targeted immunotherapy with BAFF antagonism (belimumab) and B cell depletion (rituximab) may enhance B cell targeting in ANCA-associated vasculitis (AAV) through several mechanisms. Methods: Study design: COMBIVAS is a randomised, double-blind, placebo-controlled trial designed to assess the mechanistic effects of sequential therapy of belimumab and rituximab in patients with active PR3 AAV. The recruitment target is 30 patients who meet the criteria for inclusion in the per-protocol analysis. Thirty-six participants have been randomised to one of the two treatment groups in a 1:1 ratio: either rituximab plus belimumab or rituximab plus placebo (both groups with the same tapering corticosteroid regimen), and recruitment is now closed (final patient enrolled April 2021). For each patient, the trial will last for 2 years comprising a 12-month treatment period followed by a 12-month follow-up period. Participants: Participants have been recruited from five of seven UK trial sites. Eligibility criteria were age ≥ 18 years and a diagnosis of AAV with active disease (newly diagnosed or relapsing disease), along with a concurrent positive test for PR3 ANCA by ELISA. Interventions: Rituximab 1000 mg was administered by intravenous infusions on day 8 and day 22. Weekly subcutaneous injections of 200 mg belimumab or placebo were initiated a week before rituximab on day 1 and then weekly through to week 51. All participants received a relatively low prednisolone (20 mg/day) starting dose from day 1 followed by a protocol-specified corticosteroid taper aiming for complete cessation by 3 months. Outcomes: The primary endpoint of this study is time to PR3 ANCA negativity. Key secondary outcomes include change from baseline in naïve, transitional, memory, plasmablast B cell subsets (by flow cytometry) in the blood at months 3, 12, 18 and 24; time to clinical remission; time to relapse; and incidence of serious adverse events. Exploratory biomarker assessments include assessment of B cell receptor clonality, B cell and T cell functional assays, whole blood transcriptomic analysis and urinary lymphocyte and proteomic analysis. Inguinal lymph node and nasal mucosal biopsies have been performed on a subgroup of patients at baseline and month 3. Discussion: This experimental medicine study provides a unique opportunity to gain detailed insights into the immunological mechanisms of belimumab-rituximab sequential therapy across multiple body compartments in the setting of AAV. Trial registration: ClinicalTrials.gov NCT03967925. Registered on May 30, 2019. [ABSTRACT FROM AUTHOR]

Vaccination induces an adaptive immune response that protects against infectious diseases. A defined magnitude of adaptive immune response that correlates with protection from the disease of interest, or correlates of protection (CoP), is useful for guiding vaccine development. Despite mounting evidence for the protective role of cellular immunity against viral diseases, studies on CoP have almost exclusively focused on humoral immune responses. Moreover, although studies have measured cellular immunity following vaccination, no study has defined if a "threshold" of T cells, both in frequency and functionality, is needed to reduce infection burden. We will thus conduct a double-blind, randomized clinical trial in 56 healthy adult volunteers, using the licensed live-attenuated yellow fever (YF17D) and chimeric Japanese encephalitis-YF17D (JE-YF17D) vaccines. These vaccines share the entire nonstructural and capsid proteome where the majority of the T cell epitopes reside. The neutralizing antibody epitopes, in contrast, are found on the structural proteins which are not shared between the two vaccines and are thus distinct from one another. Study participants will receive JE-YF17D vaccination followed by YF17D challenge, or YF17D vaccination followed by JE-YF17D challenge. A separate cohort of 14 healthy adults will receive the inactivated Japanese Encephalitis virus (JEV) vaccine followed by YF17D challenge that controls for the effect of cross-reactive flaviviral antibodies. We hypothesize that a strong T cell response induced by YF17D vaccination will reduce JE-YF17D RNAemia upon challenge, as compared to JE-YF17D vaccination followed by YF17D challenge. The expected gradient of YF17D-specific T cell abundance and functionality would also allow us to gain insight into a T cell threshold for controlling acute viral infections. The knowledge gleaned from this study could guide the assessment of cellular immunity and vaccine development. Clinical trial registration: Clinicaltrials.gov, NCT05568953. [ABSTRACT FROM AUTHOR]