Human Trials Research Articles

Preclinical evaluation of an anchored immunotherapy strategy with aluminum hydroxide-tethered interleukin-12 in dogs with advanced malignant melanoma.

Melanoma is an aggressive cancer in dogs involving skin and mucosa similar to people. Anchored immunotherapeutics offer a novel approach to increase intratumoral retention of therapeutic payloads while decreasing systemic exposure, and this strategy can be critically evaluated through a comparative oncology approach. JEN-101 is an anchored canine interleukin-12 (IL-12) tethered to aluminum hydroxide administered by local injection. A Phase I study was conducted to determine the tolerability, activity, and immune responses of JEN-101 in dogs with advanced melanoma. A 3+3 dose escalation design was used to evaluate intratumoral injection of JEN-101 at 1, 3, 10, or 20 μg/kg every three weeks for four cycles. A second course was allowable in the absence of disease progression or toxicity. Peripheral blood, serum, and tumor biopsies were collected at baseline and at pre-specified timepoints for pharmacokinetic and immune analyses, which included serum cytokines, immunohistochemistry, and gene expression assessment. JEN-101 was well tolerated with adverse events being fever, lethargy, and isolated elevated liver enzymes. Five dogs experienced grade 3 events and no grade 4 events were observed. Pharmacokinetic analysis showed a trend towards dose-related Cmax within 8 hours of injection. Responding dogs demonstrated increased systemic interferon-γ and IL-10 AUC levels and local recruitment of CD3+ T cells. Increased pro-inflammatory and antigen processing gene expressions were identified in responding lesions. JEN-101 was well tolerated with evidence of biologic and therapeutic activities. Anchored IL-12 immunotherapy merits further investigation in dogs with melanoma and our approach represents an immune competent model to inform human clinical trials.

Describing randomization in trials included in systematic reviews in orthopaedic surgery.

Systematic reviews of randomized controlled trials (RCTs) are the highest level of evidence used to inform patient care. However, it has been suggested that the quality of randomization in RCTs in orthopaedic surgery may be low. This study aims to describe the quality of randomization in trials included in systematic reviews in orthopaedic surgery. Systematic reviews of RCTs testing orthopaedic procedures published in 2022 were extracted from PubMed, Embase, and the Cochrane Library. A random sample of 100 systematic reviews was selected, and all included RCTs were retrieved. To be eligible for inclusion, systematic reviews must have tested an orthopaedic procedure as the primary intervention, included at least one study identified as a RCT, been published in 2022 in English, and included human clinical trials. The Cochrane Risk of Bias-2 Tool was used to assess random sequence generation as 'adequate', 'inadequate', or 'no information'; we then calculated the proportion of trials in each category. We also collected data to test the association between these categories and characteristics of the RCTs and systematic reviews. We included 917 unique RCTs. We found that 374 RCTs (40.8%) reported adequate sequence generation, 61 (6.7%) were inadequate, 410 (44.7%) lacked information, and 72 (7.9%) were observational studies incorrectly included as RCTs within the systematic review. Publication year, an author with statistical or epidemiological qualifications, and journal impact factor were each associated with adequate randomization. We found that 45 systematic reviews (45%) included at least one inadequately randomized RCT or an observational study incorrectly treated as a RCT. There is evidence of a lack of random allocation in RCTs included in systematic reviews in orthopaedic surgery. The conduct of RCTs and systematic reviews should be improved to minimize the risk of bias from inadequate randomization in RCTs and mislabelling of non-randomized studies as RCTs.

Empathetic solicitude attenuates the affective and sensory dimensions of CO2-induced dyspnea: A randomized parallel arm experimental trial in healthy humans.

Dyspnea testifies to profound suffering in patients and its relief is a priority for caregivers. This can be achieved by correcting causative disorders ("etiopathogenic" approach) or targeting the dyspnea itself ("symptomatic" approach), as is done for pain. Empathetic solicitude from caregivers has an intrinsic analgesic effect, but its effects on dyspnea have not been formally documented. This study tests the hypothesis that the empathetic solicitude behavior of a caregiver during experimental induction of acute and intense dyspnea would have a mitigating effect. In a double-blind, randomized, controlled experimental trial, 80 healthy participants were assigned to a neutral behavior arm or a solicitude behavior arm. During two successive visits (V1 and V2), dyspnea was induced through CO2-rebreathing and (i) assessed in an immediate manner using 10 cm affective and sensory visual analog scales (A-VAS and S-VAS) and (ii) post hoc using the Multidimensional Dyspnea Profile (MDP). A-VAS ratings at the end of the dyspnea challenge were significantly lower at V2 in the "solicitude behavior" arm than in the "neutral behavior" arm (6.69 [3.825-9.67] vs. 8.05 [6.43-10], p = 0.039). There were no significant differences between arms regarding S-VAS. MDP analysis showed that CO2-rebreathing induced dyspnea of the air hunger type, with statistically significant reductions in its intensity and both the sensory and affective dimensions of dyspnea. This study shows that empathetic solicitude can reduce the affective and sensory dimensions of experimentally induced dyspnea in healthy volunteers. Future studies should evaluate the impact of empathetic solicitude on clinical dyspnea.

Safety Evaluation for Acute and Chronic Oral Toxicity of Maha Pigut Triphala Contains Three Medicinal Fruits in Sprague-Dawley Rats

Maha Pigut Triphala is the herbal mixture of three fruits consisting of T. bellirica, T. chebula, and E. officinalis also known as P. emblica. Humans regularly eat the fresh fruits of these plants on a daily basis. Maha Pigut Triphala is one of the widely known herbal medicinal formulas used in traditional Thai medicine. Besides studying pharmacological properties, attention should also be paid to the safety and toxicity studies of herbal medicines. The objective of the present study was to evaluate the acute and chronic oral toxicity of Maha Pigut Triphala (2:1:3) in Sprague-Dawley rats. A single dose of Maha Pigut Triphala at a concentration of 5000 mg/kg body weight was administered orally to female rats in the acute oral toxicity study. In the chronic oral toxicity study, male and female rats were treated with various concentrations of Maha Pigut Triphala (600, 1200, and 2400 mg/kg body weight) once daily for 270 consecutive days. The presence of abnormalities in the symptoms and behavior of the rats were observed and recorded throughout the experiment. Additionally, body weight, organ weight, and mortality were recorded. At the end of the study, blood samples were collected for hematological and blood chemistry analysis, while the internal organs were evaluated for gross pathological and histopathological changes. The acute oral toxicity study revealed no mortality and abnormal symptoms or behavior in Maha Pigut Triphala-treated rats. Moreover, gross pathological and histopathological findings did not reveal any abnormalities in the internal organs. In the chronic oral toxicity evaluation, although there were negligible changes in body weight, organ weight, and hematological and blood chemistry parameters in rats treated with Maha Pigut Triphala for 270 days, no behavioral or gross pathological and histopathological abnormalities were observed. Overall, the results of this study demonstrate that Maha Pigut Triphala (2:1:3) neither causes acute nor chronic oral toxicity in rats, proposing the safety of this herbal formula in animals prior to human trials and use.

Effects of intermittent fasting on body composition, clinical health markers and memory status in the adult population: a single-blind randomised controlled trial

IntroductionDespite the popularity and potential protective effects of intermittent fasting (IF) against metabolic disorders, more human trials must be conducted to highlight its effects on human health. Therefore, the present trial aimed to investigate the effect of IF on the body composition, health markers, and memory status of obese and overweight adults.MethodsA parallel randomised controlled trial was conducted in Lahore, Pakistan, with 30 participants recruited from each of the three arms (regular diet, customised diet, and IF group) with a follow-up period of 12 weeks.ResultsThere was no significant difference in the mean percentage change in BMI at the end of the study period (p = 0.55). The IF group exhibited a negative median change (-4.41%) in systolic blood pressure compared with the other two groups (p = 0.014), with no difference among the groups in diastolic blood pressure or blood sugar levels (p > 0.05). The percentage change in waist circumference was more significant in the IF group than in the control group, with a significant improvement in the median percentage change in total cholesterol, LDL, triglyceride, and HDL levels (p < 0.05) as well as in the memory score (p < 0.05).ConclusionThis study revealed that IF helps improve participants’ lipid parameters, systolic blood pressure, and memory status.Trial RegistrationThe present study is registered at the registry of Clinicaltrials.gov with identity number NCT05521945 and registration date 30/08/22.

Dietary Phytic Acid, Dephytinization, and Phytase Supplementation Alter Trace Element Bioavailability—A Narrative Review of Human Interventions

Background: Phytic acid is abundant in plant-based diets and acts as a micronutrient inhibitor for humans and non-ruminant animals. Phytases are enzymes that break down phytic acid, releasing micronutrients and enhancing their bioavailability, particularly iron and zinc. Deficiencies in iron and zinc are significant public health problems, especially among populations with disease-associated malnutrition or those in developing countries consuming phytic acid-rich diets. This narrative review aimed to summarize findings from human intervention studies on the interactions between phytic acid, phytase, and micronutrient bioavailability. Methods: An extensive PubMed search (1 January 1990 to 8 February 2024) was conducted using MeSH terms (phytic acid, phytase, IP6, “inositol hexaphosphate,” micronutrient, magnesium, calcium, iron, zinc). Eligible studies included human intervention trials investigating the bioavailability of micronutrients following (a) phytase supplementation, (b) consumption of phytic acid-rich foods, or (c) consumption of dephytinized foods. In vitro, animal, cross-sectional, and non-English studies were excluded. Results: 3055 articles were identified. After the title and full-text review, 40 articles were eligible. Another 2 were identified after cross-checking reference lists from included papers, resulting in 42 included articles. Most studies exploring the efficacy of exogenous phytase (9 of 11, 82%) or the efficacy of food dephytinization (11 of 14, 79%) demonstrated augmented iron and zinc bioavailability. Most phytic acid-rich food-feeding studies (13 of 17, 77%) showed compromised iron and zinc bioavailability. Conclusions: Strong evidence supports decreased iron and zinc bioavailability in phytic acid-rich diets and significant improvements with phytase interventions. Studies of longer periods and within larger populations are needed.

The Pros and Cons of Dental Laser Therapy in Conservative Dentistry and Endodontics—A Systematic Review

ABSTRACT The objective of this systematic review was to investigate the clinical evidence on the utilization of lasers in endodontics and evaluate the advantages and disadvantages associated with its use. The search engines, such as PubMed, Cochrane, and Scopus, were utilized to locate human clinical trials pertaining to the application of lasers in endodontic therapy. By utilizing keywords, additional filters, and inclusion and exclusion criteria, the initial pool of 387 articles was narrowed down to 12. Laser reduces endodontic postoperative discomfort and improves patient satisfaction, according to research.

Pathological role of RAGE underlying progression of various diseases: its potential as biomarker and therapeutic target.

The receptor for advanced glycation end products (RAGE) is a multi-ligand receptor with several structural types, performing a myriad of molecular mechanisms. The RAGE-ligand interactions play important roles in maintaining latent chronic inflammation, and oxidative damage underlying various pathological conditions like metabolic syndrome (MetS), neurodegenerative diseases, stroke, cardiovascular disorders, pulmonary disorders,cancer and infections. RAGE is thoroughly explored in knockout animals and human trials, targeted by small molecule inhibitors, peptides, diet, and natural compounds. But it is yet to be incorporated in the mainstream managementof anyailment. This review performs an appraisal of the pathological mechanisms influenced by RAGE to uncover its prospects as a biomarker while also assessing its power to become a promising therapeutic target.

Dual therapy with corticosteroid ablates the beneficial effect of DP2 antagonism in chronic experimental asthma

Prostaglandin D2 (PGD2) signals via the DP1 and DP2 receptors. In Phase II trials, DP2 antagonism decreased airway inflammation and airway smooth muscle (ASM) area in moderate-to-severe asthma patients. However, in Phase III, DP2 antagonism failed to lower the rate of exacerbations, and DP2 as a target was shelved. Here, using a preclinical model of chronic experimental asthma, we demonstrate that rhinovirus-induced exacerbations increase PGD2 release, mucus production, transforming growth factor (TGF)-β1 and type-2 inflammation. DP2 antagonism or DP1 agonism ablates these phenotypes, increases epithelial EGF expression and decreases ASM area via increased IFN-γ. In contrast, dual DP1-DP2 antagonism or dual corticosteroid/DP2 antagonism, which attenuates endogenous PGD2, prevented ASM resolution. We demonstrate that DP2 antagonism resolves ASM remodelling via PGD2/DP1-mediated upregulation of IFN-γ expression, and that dual DP2 antagonism/corticosteroid therapy, as often occurred in the human trials, impairs the efficacy of DP2 antagonism by suppressing endogenous PGD2 and IFN-γ production.

Lifestyle and the Gut-Brain Axis Insights into Mental Health and Microbiome Interactions

Introduction: The intricate relationship between lifestyle factors and gut health has become a focus of recent research, emphasizing the significant role of the gut-brain axis (GBA) in regulating both physical and emotional well- being. Unhealthy lifestyle choices, including a diet high in ultra-processed foods, irregular sleep patterns, physical inactivity, and substance abuse, have been closely associated with gut dysbiosis, leading to gastrointestinal (GI) symptoms and mood disturbances such as anxiety and depression. The gut microbiota, through the production of neurotransmitters like serotonin and dopamine, as well as short-chain fatty acids (SCFAs), influences mood and mental health via the GBA. Maintaining a healthy lifestyle, characterized by balanced nutrition, regular physical activity, and good sleep quality, is critical in fostering a diverse and stable gut microbiome, which in turn supports emotional stability.  Aim: This review aims to examine the existing literature on the impact of lifestyle factors, such as diet, physical activity, sleep, smoking, alcohol consumption, and stress management, on gut health and emotional well-being. The goal is to highlight the importance of gut microbiota in mental health and the potential therapeutic strategies to enhance gut health for improved emotional outcomes.  Methodology: A comprehensive search of peer-reviewed journal articles was conducted using databases such as PubMed, Google Scholar, and Web of Science. Keywords like "lifestyle," "gut health," "emotional well-being," "dietary habits," "physical activity," "sleep patterns," and "gut-brain axis" were used to identify relevant studies. Inclusion criteria focused on human clinical trials and observational studies published within the last 16 years. Studies involving animal subjects, non-peer- reviewed articles, and outdated research were excluded.  Results: The literature shows that diets high in fiber and low in processed foods support a healthier gut microbiome, while high consumption of ultra-processed foods disrupts gut bacteria, leading to GI symptoms and mood disorders. Regular physical activity was found to enhance gut microbiota diversity, contributing to better emotional well-being. Conversely, poor sleep quality and chronic stress were linked to gut dysbiosis, which exacerbated mood disturbances. Smoking and excessive alcohol consumption further damaged gut health, contributing to mood dysregulation. Probiotic and prebiotic interventions, particularly synbiotics, were found to restore gut balance and improve both GI and mental health outcomes.  Conclusion: This review underscores the pivotal role of lifestyle choices in shaping gut health and emotional well-being. A balanced diet, regular exercise, sufficient sleep, and stress management are essential for maintaining a healthy gut microbiome, which, in turn, supports emotional stability. Therapeutic strategies involving prebiotics, probiotics, and synbiotics offer promising avenues for improving both gut health and mood. Addressing lifestyle factors and promoting gut health can potentially serve as an effective approach for enhancing overall well-being and preventing mood disorders.

Rapid Development of Modified Vaccinia Virus Ankara (MVA)-Based Vaccine Candidates Against Marburg Virus Suitable for Clinical Use in Humans

Background/Objectives: Marburg virus (MARV) is the etiological agent of Marburg Virus Disease (MVD), a rare but severe hemorrhagic fever disease with high case fatality rates in humans. Smaller outbreaks have frequently been reported in countries in Africa over the last few years, and confirmed human cases outside Africa are, so far, exclusively imported by returning travelers. Over the previous years, MARV has also spread to non-endemic African countries, demonstrating its potential to cause epidemics. Although MARV-specific vaccines are evaluated in preclinical and clinical research, none have been approved for human use. Modified Vaccinia virus Ankara (MVA), a well-established viral vector used to generate vaccines against emerging pathogens, can deliver multiple antigens and has a remarkable clinical safety and immunogenicity record, further supporting its evaluation as a vaccine against MARV. The rapid availability of safe and effective MVA-MARV vaccine candidates would expand the possibilities of multi-factored intervention strategies in endemic countries. Methods: We have used an optimized methodology to rapidly generate and characterize recombinant MVA candidate vaccines that meet the quality requirements to proceed to human clinical trials. As a proof-of-concept for the optimized methodology, we generated two recombinant MVAs that deliver either the MARV glycoprotein (MVA-MARV-GP) or the MARV nucleoprotein (MVA-MARV-NP). Results: Infections of human cell cultures with recombinant MVA-MARV-GP and MVA-MARV-NP confirmed the efficient synthesis of MARV-GP and MARV-NP proteins in mammalian cells, which are non-permissive for MVA replication. Prime-boost immunizations in C57BL/6J mice readily induced circulating serum antibodies binding to recombinant MARV-GP and MARV-NP proteins. Moreover, the MVA-MARV-candidate vaccines elicited MARV-specific T-cell responses in C57BL/6J mice. Conclusions: We confirmed the suitability of our two backbone viruses MVA-mCherry and MVA-GFP in a proof-of-concept study to rapidly generate candidate vaccines against MARV. However, further studies are warranted to characterize the protective efficacy of these recombinant MVA-MARV vaccines in other preclinical models and to evaluate them as vaccine candidates in humans.

Exploring acenocoumarol and silodosin as allosteric EGFR inhibitors for the treatment of non-small cell lung cancer

Background Non-small-cell lung cancer (NSCLC) is a highly morbid disease. Chemotherapy for NSCLC lacks specificity and efficacy mainly because of drug resistance. The current study aimed to explore computational tools to target allosteric epidermal growth factor receptor (EGFR) sites and screen for the top molecules in vitro and in vivo xenograft models. Methods Molecular docking, virtual screening, and molecular dynamic studies revealed that acenocoumarol and silodosin are the top two allosteric EGFR inhibitors. They were further tested for cytotoxicity, apoptosis, cell cycle, and gene expression by qPCR, western blotting, A549 cell xenograft anti-proliferative activity, and tumor regression efficacy analysis. Results Acenocoumarol and silodosin exhibited cytotoxicity in A549 and IMR-90 cells at concentrations below 50 and 80 μM, respectively. Acenocoumarol and silodosin induced S-phase and G2/M-phase arrest in A549 cells in the cell cycle analysis. Both drugs showed early apoptosis at their IC50 doses (acenocoumarol 50 μM and silodosin 25 μM). KRAS (Kirsten rat sarcoma viral oncogene homolog) and ERK2 (extracellular signal-regulated kinase 2) gene regulation in A549 cells was confirmed using qPCR. KRAS and ERK2 activities were quantified by western blot analysis. In the xenograft study, tumor size, body weight, and organ weight were significantly attenuated by the test drugs compared with the standard cisplatin. Immunoblotting and western blot results of the A549-xenograft tissue indicated downregulation of KRAS and ERK2. Furthermore, the test drugs have upregulated caspase-3 gene expression. Conclusion The drugs acenocoumarol and silodosin downregulate KRAS and ERK2 both in cell line and in Xenograft model. KRAS and ERK2 are associated with EGFR inhibition. Hence, acenocoumarol and silodosin can be further explored for repurposing studies in human trials.

A randomized clinical trial evaluating Hydralazine’s efficacy in early-stage Alzheimer’s disease: The EHSAN Study

Alzheimer’s Disease (AD), a neurodegenerative disorder escalating worldwide, remains incurable with existing interventions merely mitigating symptoms. Hydralazine, an antihypertensive agent, has displayed neuroprotective potential in AD animal models via amplification of mitochondrial functionality and stimulation of stress management and repair pathways. Nevertheless, its effectiveness and tolerability in human AD cohorts are yet to be confirmed. This study protocol describes the design of an ongoing, single-center, randomized, triple-blind, placebo-controlled trial to assess hydralazine’s effects on cognitive function in mild to moderate -stage AD patients. We will enroll 424 patients aged 50 and older, meeting NINCDS-ADRDA criteria for probable AD with Mini-Mental State Examination scores from 12–26. They’ll be randomly assigned to receive either hydralazine HCL (25 mg, thrice daily) or a placebo for 12 months. The primary outcome is the Alzheimer’s Disease Assessment Scale change from baseline to 12 months. Secondary outcomes include various measures using Lawton instrumental activities of daily living scale, neuropsychiatry inventory, and caregiver activity survey. This trial will explore the potential benefits and risks of hydralazine in mild to moderate AD treatment. It’s the first trial examining hydralazine’s impact on mild to moderate -stage AD in human and is registered at the Iranian Registry of Clinical Trials (IRCT20200711048075N1, registered 29/07/2020) and ClinicalTrials.gov (NCT 04,842,552AQ, registered 13/04/2021). Ethics approval was granted by the Research Ethics Committee of the National Institute for Medical Research Development (IR.NIMAD.REC.1398.424), following the SPIRIT Statement guidelines. Findings will be disseminated via peer-reviewed publications and conferences. This inaugural human clinical trial evaluates hydralazine’s impact on patients in the mild to moderate AD. Executed with a randomized, triple-blind, placebo-controlled methodology, this study incorporates a significant sample size and an extended monitoring duration. Multiple parameters, including cognitive capabilities, will be assessed. Potential limitations include the inherent homogeneity of the AD cohort, the lack of biomarker assays, and the unpredictable progression of the disease. Notably, the study might not elucidate the protracted effects of hydralazine beyond a 12-month period. Another limitation of our clinical trial is that patients were diagnosed with Alzheimer’s disease based solely on clinical evaluation and MRI findings, without the inclusion of specific biomarkers, which may impact the accuracy and specificity of the diagnosis. Trial registration: Iranian Registry of Clinical Trials (IRCT20200711048075N1, registered 29/07/2020) and ClinicalTrials.gov (NCT 04,842,552, registered 13/04/2021).

Aloe vera and the Proliferative Phase of Cutaneous Wound Healing: Status Quo Report on Active Principles, Mechanisms, and Applications.

Aloe vera is commonly used as traditional medicine for cutaneous wound healing. Nonetheless, the wound healing mechanisms of Aloe vera remain unclear. This review aims to provide insight into the molecular mechanisms of Aloe vera in promoting cutaneous wound healing, with particular emphasis on the mechanisms that stimulate cell proliferation and migration. Aloe vera has been shown to upregulate growth factors such as keratinocyte growth factor-1 (KGF-1), transforming growth factor-β (TGF-β), cyclin D1, insulin-like growth factor 1 (IGF-1), vascular endothelial growth factor (VEGF), basic fibroblastic growth factor (bFGF), and microfibril-associated glycoprotein 4 (MFAP4), as well as collagen, fibrillin, elastin, α-smooth muscle actin (α-SMA), integrins, and platelet endothelial cell adhesion molecule 1 (PECAM-1, also known as CD31), while downregulating the expression of matrix metalloproteinases (MMPs). In addition, Aloe vera was also found to upregulate PI3K/Akt and MAPK pathways, as well as the TGF-β signalling pathway via Smad proteins. Furthermore, molecular docking studies revealed that certain chemical constituents of Aloe vera bind to some of the forementioned growth factors or signalling molecules. With regards to current applications, although human clinical trials have reported positive results from using Aloe vera in healing open wounds and burns and alleviating some inflammatory skin diseases, the current commercial uses of Aloe vera remain largely focused on cosmetic products. Thus, greater advances are required to promote the use of Aloe vera products in clinical settings.

Development and Characterization of an Oncolytic Human Adenovirus-Based Vector Co-Expressing the Adenovirus Death Protein and p14 Fusion-Associated Small Transmembrane Fusogenic Protein.

Human adenovirus (HAdV)-based oncolytic vectors, which are designed to preferentially replicate in and kill cancer cells, have shown modest efficacy in human clinical trials in part due to poor viral distribution throughout the tumor mass. Previously, we showed that expression of the p14 fusion-associated small transmembrane (FAST) fusogenic protein could enhance oncolytic HAdV efficacy and reduce tumor growth rate in a human xenograft mouse model of cancer. We now explore whether co-expression of the adenovirus death protein (ADP) with p14 FAST protein could synergize to further enhance oncolytic vector efficacy. ADP is naturally encoded within the early region 3 (E3) of HAdV, a region which is frequently removed from HAdV-based vectors, and functions to enhance cell lysis and progeny release. We evaluated a variety of approaches to achieve optimal expression of the two proteins, the most efficient method being insertion of an expression cassette within the E3 deletion, consisting of the coding sequences for p14 FAST protein and ADP separated by a self-cleaving peptide derived from the porcine teschovirus-1 (P2A). However, the quantities of p14 FAST protein and ADP produced from this vector were reduced approximately 10-fold compared to a similar vector-expressing only p14 FAST protein and wildtype HAdV, respectively. Compared to our original oncolytic vector-expressing p14 FAST protein alone, reduced expression of p14 FAST protein and ADP from the P2A construct reduced cell-cell fusion, vector spread, and cell-killing activity in human A549 adenocarcinoma cells in culture. These studies show that a self-cleaving peptide can be used to express two different transgenes in an armed oncolytic HAdV vector, but also highlight the challenges in maintaining adequate transgene expression when modifying vector design.

Effects of resveratrol supplementation on inflammatory markers, fatigue scale, fasting blood sugar and lipid profile in relapsing-remitting multiple sclerosis patients: a double-blind, randomized placebo-controlled trial

ABSTRACT Objectives: Resveratrol, a polyphenol found in grapes, has been studied extensively for its potential benefits on metabolic markers and inflammation. While promising results have been observed in animal studies and some human trials, the overall evidence is mixed. Moreover, elevated inflammatory markers have been closely linked to more severe symptoms of Multiple Sclerosis (MS). Therefore, strategies to reduce systemic inflammation could potentially improve outcomes for MS patients. So we aimed to examine the effectiveness of resveratrol supplementation on inflammatory markers in patients with Multiple sclerosis (MS), in a randomized placebo-controlled double-blinded parallel clinical trial. Methods: A total of 55 subjects with MS were enrolled in this study and randomly assigned to the two groups who were supplemented with resveratrol at a dose of 500 mg/day or received placebo capsules for 8 weeks. Tumor necrosis factor-alpha (TNF-α), Malondialdehyde (MDA), fasting blood sugar (FBS), triglycerides, total cholesterol, low-density lipoprotein – cholesterol (LDL-C), high-density lipoprotein – cholesterol (HDL-C), and the degree of fatigue were measured at baseline and after the intervention. Results: Resveratrol treatment significantly decreased TNF-α (P < 0.001), and MDA (P < 0.001) compared to the placebo. The respective increase and decrease in FBS and HDL levels were seen in both groups, while the change in participants receiving resveratrol was significantly less pronounced. Changes in the levels of TG and fatigue scale remained unchanged. Conclusion: This study showed that resveratrol supplementation exerted anti-inflammatory and anti-oxidant effects in patients with MS. Trial registration: Iranian Registry of Clinical Trials identifier: IRCT20230315057731N1.

Ethical issues in vaccine trial participation by adolescents: qualitative insights on family decision making from a human papillomavirus vaccine trial in Tanzania

BackgroundResearch in children is essential for them to benefit from the outcomes of research but involvement must be weighed against potential harms. In many countries and circumstances, medical research legally requires parental consent until the age of 18 years, with poorly defined recommendations for assent prior to this. However, there is little research exploring how these decisions are made by families and the ethical implications of this.AimTo explore key ethical debates in decision-making for participation of children and adolescents in a human papillomavirus (HPV) vaccine trial.MethodsSemi-structured interviews were undertaken with Tanzanian girls (aged 9–16 years) who had participated in an HPV vaccine trial (n = 13), their parents or guardians (n = 12), and girls together with their parents (in paired parent-child interviews) (n = 6). The interviews were analysed using thematic analysis. Interview data came from a qualitative acceptability study undertaken as part of the Dose Reduction Immunobridging and Safety Study of Two Human Papillomavirus (HPV) Vaccines in Tanzanian Girls (DoRIS) trial.ResultsGirls and parents desired collaborative decision-making, with parents ultimately making the decision to consent. However, girls wanted a larger part in decision-making. Decisions to consent involved many people, including extended social networks, the trial team, media outlets and healthcare professionals and this resulted in conflicts to be negotiated. Deciding where to place trust was central in participants and parents considering decisions to consent and overcoming rumours about trial involvement.ConclusionsExisting models of decision-making help to understand dynamics between parents, adolescents and researchers but neglect the important wider social impacts and the fundamental nature of trust. Children’s roles in discussions can be evaluated using the principles of consent: autonomy, freedom and information. Concepts such as relational autonomy help to explain mechanisms families use to negotiate complex consent decisions. Whilst interviewees supported the maintenance of legal parental consent, researchers must design consent processes centring the child to ensure that whole family decision-making processes are supported.

Profiling Human iPSC-Derived Sensory Neurons for Analgesic Drug Screening Using a Multi-Electrode Array.

Chronic pain affects approximately 1.5 billion people worldwide, yet effective treatments remain elusive. A significant barrier to progress in analgesic drug discovery is the limited translation of preclinical findings to human clinical outcomes. Traditional rodent models, although widely used, often fail to accurately predict human responses, while human primary tissues are limited by scarcity, technical difficulties, and ethical concerns. Recent advancements have identified human induced pluripotent stem cell (hiPSC)-derived nociceptors as promising alternatives; however, current differentiation protocols produce cells with inconsistent and physiologically questionable phenotypes.To address these challenges, our study introduces a novel high-content screening (HCS) platform using hiPSC-derived nociceptors cultured on multi-well micro-electrode arrays (MEAs). The "Anatomic" protocol, used to generate these nociceptors, ensures cells with transcriptomic profiles closely matching human primary sensory neurons. Our platform achieves nearly 100% active electrode yield within two weeks and demonstrates sustained, stable activity over time. Additionally, robust Z' factor analysis (exceeding 0.5) confirms the platform's reliability, while pharmacological validation establishes the functional expression of critical analgesic targets. This innovative approach improves both the efficiency and clinical relevance of analgesic drug screening, potentially bridging the translational gap between preclinical studies and human clinical trials, and offering new hope for effective pain management.

Tissue-Engineered Skin Substitutes for Use in Clinical Dermatological Practice

Skin replacements are essential in dermatology as they serve to connect the gap between conventional wound care and surgical procedures. Due to pioneering innovations from the last century, tissue-engineered skin substitutes have significantly advanced in the field of dermatology, offering new hope for patients with complex wound healing needs. Whilst before, skin grafting was performed to act as an intermediary to promote skin healing, it has now evolved to also mimic skin structure and function. To our knowledge, there have not been any summaries on the use of tissue-engineered in dermatology. Therefore, we conducted a scoping review to summarize research papers which performed human clinical trials and follow-up work using synthetic lab-made skin with a clear clinical application from the last 30 years.

Chemical Composition, Bioactivities, and Applications of Spirulina (Limnospira platensis) in Food, Feed, and Medicine.

Spirulina (Limnospira platensis) is a microalga recognised for its rich nutritional composition and diverse bioactive compounds, making it a valuable functional food, feed, and therapeutic agent. This review examines spirulina's chemical composition, including its high levels of protein, essential fatty acids, vitamins, minerals, and bioactive compounds, such as the phycocyanin pigment, polysaccharides, and carotenoids, in food, feed, and medicine. These compounds exhibit various biological activities, including antioxidant, anti-inflammatory, immunomodulatory, antiviral, anticancer, antidiabetic and lipid-lowering effects. Spirulina's potential to mitigate oxidative stress, enhance immune function, and inhibit tumour growth positions it as a promising candidate for preventing chronic diseases. Additionally, spirulina is gaining interest in the animal feed sector as a promotor of growth performance, improving immune responses and increasing resistance to diseases in livestock, poultry, and aquaculture. Despite its well-documented health benefits, future research is needed to optimize production/cultivation methods, improve its bioavailability, and validate its efficacy (dose-effect relationship) and safety through clinical trials and large-scale human trials. This review underscores the potential of spirulina to address global health and nutrition challenges, supporting its continued application in food, feed, and medicine.