Human Trials Research Articles

The role of exercise intensity and duration on cardiac angiogenesis

Abstract Numerous studies showed the exercise intensity and exercise duration involved in the pathways of angiogenesis biomarkers expression. The aim of this systematic review was to analyse the effects of different exercise intensities and exercise duration in cardiac angiogenesis regulation between healthy animal studies and human studies. The research databases used in this systematic review, including MEDLINE and Cochrane Library, within the last 6 years from 2018 to 2023 and published in English. Before the study selection, the study duplication was detected by Zotero Reference Manager® and then removed. The related studies examined and selected with rayyan.ai® website using a ‘blind-on’ mode to ensure eligibility. The eligible studies were assessed by the SYRCLE’s risk of bias tool and Risk of Bias Tool 2.0. A total of 16 studies were included, consisting of 5 animal studies or in vivo or experimental studies and 11 human studies or clinical trials. The studies then grouped in 3 durations of exercise, that was short-term, long-term term-intermittent, and long-term-continuous exercise. The most significant duration and intensity were found in long-term-continuous exercise and moderate to vigorous intensity exercise. Further research needs to explain the other factors of exercise that influence cardiac angiogenesis, such as the frequency and the type of exercise both in humans and animals to determine the most effective exercise program for a healthy population, as a potential prevention from the cardiovascular disease.

Effects of starter cultures on the metabolite profile, antioxidant activities, and anti-aging properties of tapuy lees

The Philippine rice wine (tapuy) and tapuy lees making process utilizes bubod, the traditional starter culture. The bubod contains variable number and species of microorganisms and influences the physical and chemical properties of tapuy and tapuy lees, resulting in inconsistent quality products. Hence, improvement and standardization of local starter culture are significant. Here, we examined the effects of well-defined starter cultures (Rhizopus oryzae (RO), Mucor indicus (MI), and Saccharomyces cerevisiae (SC)) and bubod on the metabolite profile, antioxidant, and anti-aging activities of tapuy lees. Our results showed the presence of polyphenols (102.36 ± 2.84 to 173.92 ± 3.88 μg GAE/g dry matter) in the tapuy lees, which are known for their bioactivities such as antioxidant, cellular protection, anti-inflammatory, and anti-aging. Additionally, the tapuy lees produced by RO + MI + SC starter exhibited the strongest scavenging activities against DPPH, hydroxyl, and superoxide radicals compared to bubod. The RO + MI + SC-produced tapuy lees extract significantly improved the lifespan, motility, and reproductive health of Caenorhabditis elegans, while boosting superoxide dismutase activity in vivo. These findings suggest that the use of well-defined starter cultures significantly enhances the health-promoting properties of tapuy lees. This research underscores the potential of tapuy lees as a functional food with antioxidant and anti-aging properties, suggesting its valuable role in promoting public health and preventing age-related diseases. Future studies should focus on clinical trials in humans to validate these findings and further explore the potential of tapuy lees as a natural, sustainable source of bioactive compounds.

Nutritional, phytochemical composition and antioxidant activities of the red and white Malakwang (hibiscus species) leaves

Malakwang (Hibiscus species) is a common vegetable in Uganda diets. This study established the nutritional, phytochemical composition, and antioxidant activities of the red and white malakwang leaves. Malakwang leaves were harvested six weeks after germination. Nutrients and phytochemicals were quantified and qualified using the methods of Association of Official Analytical Chemists (AOAC) and High-Performance Liquid Chromatography (HPLC). The antioxidant activity was determined using the 2, 2- Diphenyl-1-picrylhydrazyl (DPPH) scavenging method. The quantity of crude fat was significantly higher (p<0.05) in the white malakwang leaf samples (6.9 %) than the red (3.3%). The red had significantly higher (p<0.05) quantities of calcium (1753.6 mg), magnesium (1814.4 mg), iron (233.4 mg), vitamin A (RE) (952.7 µg) and vitamin E (22.8) per 100 g when compared to the 1522.2 mg, 1297.9 mg, 179.7 mg, 857.6 µg, and 16.8 µg, respectively for the white malakwang leaves. The white malakwang leaf samples had higher (p<0.05) quantities of flavonoids (25.7 %) and alkaloids (5.5) than the 20.7 % and 2.1 %, respectively for the red malakwang leaves. The red malakwang leaf extract had more mucilage and coumarin contents than the white malakwang leaves. The white and red leaf extracts scavenged 61.3% and 52.7% of DPPH radicals, respectively, which are similar to the 62.2% scavenged by vitamin C. Malakwang leaves could significantly contribute to dietary intake of crude fibre, essential oil, calcium, magnesium, zinc, vitamin A (RE), C and E and phytochemicals hence suggesting a correlation with the cultural health claims for improving breast milk production, appetite, immunity and healing of sores and wounds. Further studies on the evaluation of nutrients and phytochemicals in malakwang leaves are recommended to approve the results of this study. Experimental trials in humans could be performed to evidence the effect of malakwang leaves on breast milk production and healing of sores and wounds. Also, the determination of essential fatty acids and the effect of preparation and post-harvest methods are recommended for further studies. Key words: Nutritional, antioxidant activities, health benefits, indigenous, malakwang (Hibiscus) species

P-594. Temperature Stability of BPL-1357, a BPL-Inactivated, Whole-Virus, Universal Influenza Vaccine

Abstract Background Influenza A viruses (IAV) present a constant public health threat from seasonal epidemics to potential pandemics. Currently approved vaccines perform poorly against mismatched seasonal influenza strains and are unlikely to provide any protection against a pandemic potential influenza such as avian influenza. We have developed a vaccine composed of four β-propiolactone-inactivated (BPL-inactivated) low-pathogenicity avian IAV subtypes (H1N9, H3N8, H5N1 and H7N3) which demonstrated protection against lethal challenge with a wide variety of influenza subtypes in mice and ferrets. Human trials are ongoing but even with a promising vaccine, thermal stability can still be an issue that could limit use in resource-poor settings. Methods The four components of BPL-inactivated vaccine were stored individually at four different conditions, -80°C, -20°C, 4°C, and room temperature. Hemagglutination (HA), neuraminidase activity (NA), and protein assays were done for each temperature condition after 7 and 28 days of storage. Results Baseline protein concentrations were similar across vaccine components. After 28 day incubation, protein concentrations remained stable at room temperature and at 4°C for H1N9 and H7N3, but decreased for H3N8 and H5N1, more at room temperature to 52.1% and 56.1% of Day 0 concentration respectively. At 4°C there was less loss of protein for those components. Activity of NA and HA varied at baseline; for example H3 and H5 had much higher activity (1280) than H1 (160) and H7 (320) and NA activity was highest for N1 (482.22 mU/ml) and lowest for N9 (33.65 mU/ml). HA and NA activity was stable for 28 days at room temperature and 4°C. At -20°C, HA activity showed marked declines within 7 days. Overall, our data shows stability of protein and HA and NA activity at 4°C for up to 28 days, and some short-term stability at room temperature. Conclusion Developing a universal flu vaccine would contribute greatly to preventing future pandemics. However, for global use, this vaccine would need to be stable and distributable. Here we show that we may potentially have a vaccine that is both efficacious and shelf stable at 4°C. Further evaluation of immunogenicity at different temperature conditions should be performed, especially to resolve discordance between protein and activity assays. Disclosures All Authors: No reported disclosures

Effects of Oral Xylitol, Sucrose, and Acesulfame Potassium on Total Energy Intake During a Subsequent ad libitum Test Meal: A Randomized, Controlled, Crossover Trial in Healthy Humans

Background/Objectives: Xylitol, a natural low-caloric bulk sweetener, is increasingly used as a sugar alternative due to its low-glycemic and low-insulinemic properties. The aim was to investigate the effect of orally administered xylitol, sucrose, and acesulfame potassium (ace-K) on energy intake during a subsequent ad libitum test meal. Methods: In this randomized, controlled, double-blind, crossover trial (ClinicalTrials.gov NCT05671965, 20 December 2022), we included 20 healthy participants with normal body weight. Over four study visits, participants consumed an oral preload containing 33.5 g xylitol, 33.5 g sucrose, or 0.1675 g ace-K dissolved in 300 mL water, or 300 mL pure water as control. Participants were provided with an ad libitum test meal 15 min after the preload consumption, and both energy intake and total energy intake (= preload + ad libitum test meal) were assessed. Blood samples were collected to quantify cholecystokinin (CCK), glucagon-like peptide-1 (GLP-1), glucose, and insulin concentrations. Results: Total energy intake was lower in response to xylitol and ace-K compared to sucrose (pTukey < 0.03), with no differences between xylitol and ace-K or water. Plasma CCK concentrations were higher in response to xylitol compared to sucrose, ace-K, and water (pHolm < 0.01), whereas GLP-1 concentrations did not differ between the preloads. Plasma glucose and insulin concentrations were lower in response to xylitol compared to sucrose (pHolm < 0.01), but xylitol led to an increase in insulin compared to ace-K and water (pHolm < 0.01). Conclusions: The consumption of oral preloads sweetened with xylitol or ace-K prior to an ad libitum test meal result in a lower total energy intake compared to a preload with sucrose.

Therapeutic Potential of Experimental Stereotactic Hippocampal Cell Transplant in the Management of Alzheimer’s Disease

Due to a continuous increase in life expectancy and the progress made in specialized healthcare, the incidence of Alzheimer’s disease (AD) has dramatically increased to the point that it has become one of the main challenges of contemporary medicine. Despite a huge scientific and clinical effort, current treatments manage just a temporary alleviation of symptomatology but offer no cure. Modern trials involving cell transplantation in experimental animals require the involvement of neurosurgeons in the treatment protocol. CSF shunting, intraventricular infusions, or DBS for symptoms relief have been an integral part of the therapeutic arsenal from the very beginning. The development of stereotactic surgery has facilitated the experimental potential of cell transplantation in the hippocampus for Alzheimer’s disease. We conducted a narrative review of the literature in the top three medical databases (PubMed, Science Direct, and Google Scholar) using the keywords “Alzheimer’s disease”, “hippocampus”, and “transplant”. After eliminating duplicates, 241 papers were selected and screened by title and abstract. Two reviewers independently analyzed the 88 papers and chose 32 experiments that involved stereotactic hippocampal transplantation of cells in experimental animals with AD. The stereotactic transplantation of cells such as mesenchymal stem cells (MSCs), neuronal stem cells (NSCs), induced pluripotent cells (iPSCs), astrocytes, and derivates from stem cells was analyzed. The experiments used either a chemically induced or transgenic AD model and observed the impact of the stereotactic transplantation with behavioral testing, MRS spectroscopy, and biochemical analysis. The stereotaxic method delivers minimal invasive treatment option by cell transplantation at the hippocampus. The results showed that amyloid deposits were lower after transplantation, showing a positive impact. Other impactful results involve proliferation of neurogenesis, downregulation of anti-inflammatory response, and increased neuronal plasticity. The increased precision with which the stereotaxic method manages to target deep structures of the brain and the results of the reviewed papers could represent an argument for future human trials. More studies are needed to confirm the viability of the transplanted cells and the long-term effects.

Activation of KATP channels in pain modulation: a systematic review of preclinical studies

ObjectiveTo systematically review the involvement of KATP channel activation in pain modulation in preclinical studies.BackgroundKATP channels are expressed at several levels in the spinal and trigeminal pain pathways, where they seem to modulate nociceptive transmission.MethodsPubMed and Embase databases were searched until 29 January 2024, using the following search string: [(pain) OR (nociception) OR (antinociception) AND (KATP channel) OR (ATP sensitive potassium channel)]. Non-English and unavailable records, as well as records with non-experimental methodology, were excluded. Inclusion criteria were preclinical studies measuring pain in vivo upon activation of the KATP channel by administering a stimulator or positive modulator. Records were screened based on title and abstract, and those that met the study inclusion criteria were reviewed based on study design, measurements, intervention, and outcomes.ResultsThe search resulted in 569 records. In total, 126 duplicates were detected. Subsequently, 438 records were screened by title and abstract, resulting in the exclusion of 396. Based on inclusion criteria, 42 studies were included. The main findings of the present systematic review were that KATP channel openers can attenuate induced pain in various animal models and potentiate the effects of analgesics.ConclusionLocal, systemic, spinal, and supraspinal activation of KATP channels can attenuate pain and potentiate the efficacy of analgesic drugs. One exception was levcromakalim, as the systemic levcromakalim administration, but not a local application, induced pain. This finding is consistent with those of recent human trials. Future studies should investigate the differences in KATP channel activation between rodents and humans, as well as the differences in activation sites between levcromakalim and other KATP channel openers.

A Pentavalent HIV-1 Subtype C Vaccine Containing Computationally Selected gp120 Strains Improves the Breadth of V1V2 Region Responses

Background: HIV-1 envelope (Env) variable loops 1 and 2 (V1V2) directed non-neutralizing antibodies were a correlate of decreased transmission risk in the RV144 vaccine trial. Thus, the elicitation and breadth of antibody responses against the V1V2 of HIV-1 Env are important considerations for HIV-1 vaccine candidates. The V1V2 region’s highly variable nature and the extensive diversity of subtype C HIV-1 Envelopes (Envs) make the V1V2 response breadth a high priority for HIV-1 vaccine regimens aiming for V1V2-mediated protection in Southern Africa. Here, we determined whether the breadth of the anti-V1V2 vaccine response can be broadened by including HIV-1 Env strains computationally designed to enhance the coverage of subtype C V1V2 sequence diversity. Methods: Three subtype C Env strains were selected to maximize antibody binding coverage while complementing subtype C vaccine gp120s that were given in human clinical trials in South Africa, as well as to improve epitope accessibility. Humoral immunogenicity of a novel trivalent gp120 vaccine immunogen, a bivalent gp120 boost already in clinical trials (1086C and TV1), and a pentavalent (all five gp120s combined) were evaluated in a preclinical immunization study in guinea pigs. The pentavalent combination was further evaluated with alum versus glucopyranosyl lipid adjuvants formulated in squalene-in-water emulsion (GLA-SE) adjuvants in non-human primates. The breadth of the anti-V1V2 response was assessed using an array of cross-subtype variable loops 1&2 (V1V2) scaffold proteins and linear V2 peptides. Results: The breadth of the IgG response against V1V2 antigens of the trivalent and pentavalent groups was comparable, and both were greater than the breadth of the bivalent group. Linear epitope mapping showed that two linear epitopes in V2 were targeted by the vaccinated animals: the V2 hotspot focused at 169K that potentially correlated with decreased HIV-1 risk in RV144 and the V2.2 site (179LDV/I181) that is part of the integrin α4β7 binding site. The bivalent vaccine elicited a significantly higher magnitude of binding to the V2 hotspot compared to the trivalent vaccine whereas the trivalent vaccine elicited significantly higher binding to the V2.2 epitope compared to the bivalent vaccine, while the pentavalent recognized both regions. Conclusions: These results demonstrate that the three new computationally selected subtype C Envs successfully complemented 1086C and TV1 for broader V1V2 antibody responses, and, in concert with adjuvants that stimulate V1V2 responses, can be considered as part of a rationale immunogen design to improve V1V2 IgG coverage in future vaccine trials in South Africa.

Efficacy of an Autologous Dermal Fibroblast Injection in Reducing the Retear Rate After Arthroscopic Rotator Cuff Repair: A Prospective Randomized Controlled Trial.

Interest in biological augmentation for improving bone-tendon interface (BTI) healing after arthroscopic rotator cuff repair (ARCR) is growing. Dermal fibroblasts, known for collagen synthesis similar to tenocytes, have shown effectiveness in BTI healing in chronic rotator cuff tear (RCT) models in rabbits. However, no human clinical trials have been conducted. To evaluate the clinical efficacy of autologous dermal fibroblasts (ADFs) for BTI healing after ARCR in patients with full-thickness RCTs >2 cm. Randomized controlled trial; Level of evidence, 2. A total of 86 patients were prospectively enrolled and randomized into 2 groups: an additional ADF injection between the bone and tendon during ARCR (ADF group) or ARCR alone (control group). A skin biopsy from the buttock was performed to obtain ADFs, which were cultured for approximately 4 weeks before surgery. ARCR was standardized to the double-row suture bridge technique to reduce the heterogeneity in different repair methods. The primary variable for evaluating ADF efficacy was the retear rate using magnetic resonance imaging at 6 months postoperatively. Secondary variables included range of motion, the American Shoulder and Elbow Surgeons score, the Constant score, and the Simple Shoulder Test score at baseline and at 6 and 12 months postoperatively. Overall, 13 patients dropped out because of a subscapularis tendon tear, loss to follow-up, or the withdrawal of consent (7 in the ADF group and 6 in the control group). The retear rate was significantly lower in the ADF group (5.6% [2/36]) than in the control group (24.3% [9/37]) (P = .025). The American Shoulder and Elbow Surgeons, Constant, and Simple Shoulder Test scores showed significant improvement after surgery in both groups (all P values <.001). Functional scores and range of motion did not significantly differ between the 2 groups at 6 and 12 months (all P values >.05). ADF application into the BTI during ARCR significantly decreased the retear rate in patients with full-thickness RCTs >2 cm. Therefore, an ADF injection could be a promising biological supplement to enhance BTI healing in these patients. However, clinical outcomes showed no significant difference between the 2 groups at 6 months and 1 year postoperatively.

A current review on animal models of anti-asthmatic drugs screening

Asthma is a chronic inflammatory respiratory condition characterised by airway constriction, smooth muscle spasm, and severe morbidity. It affects around 300 million people globally, with children being especially vulnerable. Despite its worldwide effect, the invention of innovative asthma medicines has been slow over the last 5 decades, leaving significant unmet requirements in asthma care. Although intriguing medicines have demonstrated efficacy in animal models, many fail to fulfil safety and effectiveness requirements in human trials, highlighting the critical need for more predictive models that better transfer to human results. This comprehensive review investigates the mechanisms and efficacy of anti-asthmatic drugs using both genetic and conventional animal models. Both genetic and traditional models of anti-asthmatic agents, their characteristics, and their significance are summarized as: In-Vitro Animal Models: Histamine receptor assay, Cell Culture Method, WST Assay, Spasmolytic Activity of the Lungs of Guinea Pigs, Airway and Vascular Responses to an Isolated Lung, The Isolated Perfused Guinea Pig Trachea’s Reactivity. In-Vivo Models: In vivo small animal models, Broncho Spasmolytic Activity in anaesthetized Guinea Pigs, Guinea Pigs Respiratory and Vascular Dysfunction Caused by Arachidonic Acid or platelet-activated factor (PAF), Guinea Pig Asphyxia Induced by Serotonin Aerosol and Anaphylactic Microshock, Guinea Pigs Under Anaesthesia: Histamine-Induced Bronchoconstriction, Microshock in Rabbits and Pneumotachography in Guinea Pigs, Guinea Pig Bronchial Hyperactivity, Guinea Pig Airway Microvascular Leakage, Mice With Inflammatory Airways. Conclusion: This review focusses on the benefits and limitations of current animal models in asthma research, emphasising the need for more sophisticated, predictive models to decrease translational failures. By critically evaluating these models, the review emphasises their importance in directing anti-asthmatic drug development and highlights the urgent need for innovation to bridge the gap between preclinical success and clinical efficacy.

Feasibility and accuracy of continuous intraabdominal pressure monitoring with a capsular device in human pilot trial

BackgroundIntrabdominal pressure (IAP) is an important parameter. Elevated IAP can reduce visceral perfusion, lead to intraabdominal hypertension, and result in life-threatening abdominal compartment syndrome. While ingestible capsular devices have been used for various abdominal diagnoses, their application in continuous IAP monitoring remains unproven.MethodWe conducted a prospective clinical trial to evaluate the feasibility of IAP measurement using a digital capsule PressureDOT, an ingestible capsule equipped with wireless transmission capability and a pressure sensor, then compared its reliability with conventional intravesical method. Patients undergoing laparoscopic or robotic surgeries were recruited. During surgery, we created pneumoperitoneum by inflating CO2 into the peritoneal cavity and IAP was simultaneously monitored using both the ingestible capsules and intravesical measurements from Foley catheter. We assessed the feasibility of signal transmission and the accuracy of pressure measurements.ResultsSix patients were enrolled in this pilot study. No adverse events were reported, and the average first-intake time was within 24 h. All capsules were successfully expelled, with an average excretion time of 81 h. In the summarized data, the mean IAPdot is 0.6 mmHg lower than the IAPivp, with a standard deviation of 1.68 mmHg. However, capsule measurements showed excellent correlation with intravesical IAP measurements, with an intraclass correlation coefficient of 0.916 (95% CI: 0.8821–0.9320).ConclusionOur study demonstrates the feasibility and safety of using digital capsules for continuous IAP monitoring, providing the agreement between IAP measurements from digital capsules and conventional intravesical measurement within a near-normal pressure.

Time to broaden pharmacological treatment of cardiovascular disorders with physiological dimensions of Adropin

Adropin, an emerging substance hailed for its heart-protective potential, presents a promising avenue for combating cardiovascular ailments. The current narrative review was planned to underscore its link with metabolic syndrome and its role in preventing ischemic heart disease, accentuating its multifaceted impact on metabolism and cardiac wellbeing. Mechanistically, it operates through diverse pathways, including modulation of endothelial nitric oxide synthase, anti-apoptotic properties, and regulation of pyruvate dehydrogenase phosphorylation to boost cellular energy production and mitochondrial function. Furthermore, its interactions with cellular receptors, signalling cascades and metabolic regulators unveil its prowess in mitigating cardiovascular risks and enhancing glycaemic control. To transition adropin from bench to bedside, rigorous human trials are imperative, encompassing dose optimisation, long-term safety assessments, and exploration of genetic influences. Inclusive research targeting diverse populations, especially high-risk cohorts, is advocated to unravel its full therapeutic potential. Interdisciplinary collaboration is pivotal for unravelling its mechanisms as a targeted therapy for cardiovascular disorders. Key Words: Adropin, ENHO protein, Human protein, Rat protein, Myocardial ischemia, Coronary artery disease, Pyruvates, Pyruvic acid, Nitric oxide, Mitochondria, Apoptosis, Therapeutic, Risk factors, Collateral circulation, Homeostasis.

Derivation of human toxicokinetic parameters and internal threshold of toxicological concern for tenuazonic acid through a human intervention trial and hierarchical Bayesian population modeling.

Tenuazonic acid (TeA), a mycotoxin produced by Alternaria alternata, contaminates various food commodities and is known to cause acute and chronic health effects. However, the lack of human toxicokinetic (TK) data and the reliance on external exposure estimates have stalled a comprehensive risk assessment for TeA. To bridge this gap, a human TK trial and population-based TK (PopTK) modeling were applied to determine human TK parameters of TeA, and the results were applied for risk screening using population biomonitoring data and threshold of toxicological concern (TTC)-based approaches. Ten healthy volunteers participated in the TK trial during which the volunteers ingested a bolus dose of TeA at the (external) TTC (1500 ng/kg bw). Blood, urine, and fecal samples were collected over 48 h and analyzed using UPLC-MS/MS. Concentration-time profiles were fit with a multi-compartmental PopTK model using a hierarchical Bayesian population structure. Utilizing a probabilistic framework, fitted TK parameters were used to derive internal TTC (iTTC) values for comparison to blood and urine biomonitoring data. Risk screening with data from five diverse biomonitoring cohorts was performed using Hazard Quotient (HQ) and probabilistic individual margin of exposure (IMOE) approaches. TeA was estimated to have a population median half-life of 1.9 [90% CI: 1.4-2.7] hours and volume of distribution of 4.4 [3.1-6.1] L/kg, with inter-individual variability geometric standard deviations of 2.4- and 1.7-fold, respectively. Probabilistic lower confidence bound iTTCs were derived of 0.5 nmol/L in blood and 2.53 nmol/kg-d urinary excretion. Risk screening HQs were mostly >1 for the three blood biomonitoring cohorts and < 1 for the two urinary biomonitoring cohorts; results from probabilistic IMOE calculations were qualitatively consistent. A comprehensive human TK study was performed for TeA for the first time, demonstrating the importance of integrating TK and population variability for a more comprehensive risk evaluation, particularly for interpreting biomonitoring data. The results for TeA point to the critical need for toxicity data to move beyond TTC-based risk screening. A critical gap in food safety research was addressed studying the toxicokinetics of tenuazonic acid (TeA) in humans and using these data to derive an internal threshold of toxicological concern (iTTC) for comparison to human biomonitoring data. The innovative approach-combining a human intervention trial with population-based toxicokinetic modeling-accounts for inter-individual variability and provides a more comprehensive understanding of population exposure to TeA. The resulting probabilistic iTTC and risk screening methodologies offer improved tools for interpretation of biomonitoring data. These findings have significant implications for food safety regulations and public health protection, potentially influencing future mycotoxin risk assessment strategies.

A Review of the Clinical Application of Endovascular Electrodes and Its Future Prospects

Brain-computer interface (BCI) has been used to treat neurological diseases. Traditional BCI technologies are usually invasive and may damage neural tissue during implantation. However, endovascular electrodes (EE) are a promising solution to the above problem. They represent a minimally invasive neural technique that can reduce the risks associated with surgery and its complications. In this review, we summarized the research progress on EE technology in animal models and human clinical trials. In addition, we reviewed the development of devices that can enhance EE applications, focusing on the representative product StentrodeTM. Finally, we discussed the prospects of EE technology based on current experimental results. Early animal experiments have demonstrated the safety and viability of EE, while recent human trials have shown its potential in treating diseases such as paralysis. Besides, with the development of technology, EE may be applied in a broader range of areas. In conclusion, existing studies indicate that EE can overcome the limitations of traditional BCIs and suggest a wider use of EE in the future.

Human Neural Stem Cell Therapy for Traumatic Brain Injury-A Systematic Review of Pre-Clinical Studies.

Human neural stem cells (hNSCs) possess significant therapeutic potential for the treatment of traumatic brain injury (TBI), a leading cause of global death and disability. Recent pre-clinical studies have shown that hNSCs reduce tissue damage and promote functional recovery through neuroprotective and regenerative signaling and cell replacement. Yet the overall efficacy of hNSCs for TBI indications remains unclear. Therefore, this systematic review aims to evaluate hNSC interventions compared with controls in pre-clinical TBI models. Through this process, variations in hNSC administration protocols were consolidated, and key knowledge gaps were identified. Meta-analysis was applied to primary outcomes of lesion volume, Morris Water Maze (MWM) performance, modified Neurological Severity Scores (mNSS), and the rotarod task. Narrative review of secondary outcomes included hNSC survival and differentiation, endogenous neuron survival, axonal injury, and inflammation. Overall, hNSC intervention reduced lesion volume, enhanced MWM performance, and led to trending decreases in acute and chronic neurological deficits at acute and chronic time points. These results suggest hNSCs demonstrate clear efficacy in pre-clinical TBI models. However, further studies are needed to address key questions regarding optimal hNSC administration (e.g., dosing, treatment window) and underlying mechanisms of action prior to progressing to human clinical trials.

Utilising single‐cell sequencing in clinical nutraceutical research: Recent progress and perspectives

AbstractBackgroundSingle‐cell sequencing technologies have revolutionised pharmaceutical research by providing in‐depth insights into human biology at the single‐cell level. These tools enable researchers to identify rare cell types and analyse cellular diversity within tissues, facilitating the discovery of new therapeutic targets and biomarkers. However, their application in nutraceutical research is still in its early stages.Main BodyUnlike pharmaceuticals, which have well‐defined chemical structures and mechanisms, nutraceuticals are food‐based materials intended for specific medical purposes and often contain complex and diverse food chemicals. These molecules can work synergistically, producing multi‐targeted effects in various tissues. Traditional bulk profiling methods for tissues and tumours do not adequately capture cellular heterogeneity or specific cellular responses to treatments. Therefore, advanced single‐cell sequencing is crucial for dissecting tissues into distinct cell types, helping to clarify the underlying mechanisms at the cellular level. Many derivatives of functional foods have been marketed or assessed, demonstrating health benefits. However, mechanistic insights are lacking, with most current data derived from observational studies or traditional in vitro and in vivo models. Human clinical trials are needed to validate these nutraceutical effects and determine effective and safe dosages. Edible mushrooms have gained attention as nutraceuticals due to their medicinal properties. They have been observed to enhance immunity, reduce inflammation, and combat cancer. These effects have been attributed to their unique bioactive components and historical uses in traditional medicine. Epidemiological studies show that higher consumption of edible mushrooms is linked to a reduced risk of certain cancers.ConclusionIn this review, we share important lessons learned in the design and execution of clinical trials focusing on white button mushrooms as anti‐cancer nutraceuticals. We demonstrate the use of single‐cell RNA sequencing (scRNA‐seq) in nutraceutical research to capture the nuanced biological responses and health effects of dietary foods and their constituents.

P0961 Establishing a new cellular therapy for patients with Ulcerative Colitis

Abstract Background Inflammatory Bowel Diseases (IBD), which include Crohn’s Disease and Ulcerative Colitis (UC), show an accelerated incidence rate, affecting up to 1% in Western countries, and an increased burden in healthcare costs, reaching up to 5.6 billion euros per year. Although there are several treatment options, the remission rates are around 30-60%, with primary non-response and loss of response to be the main reasons for changing treatment plans. Thus, there is a need for new therapeutic strategies targeting these groups of non-responding patients. Towards this, we are developing a novel cellular therapy for UC, using autologous transplantation of intestinal epithelial organoids. Methods Here, colonic epithelial cells will be isolated, expanded under GMP conditions, and transplanted into ulcerated colonic regions of patients with UC, to promote and accelerate mucosal healing. This initial strategy targets patients with localized ulceration unresponsive to first- and second-lines of treatments. Results We have established a robust protocol for expanding intestinal epithelial organoids. These organoids contain all major cell type populations that orchestrate the intestinal epithelium. We have successfully transplanted both murine and human colonic organoids into NOG mice. After successful engraftment onto the damaged intestinal mucosa, they promote and accelerate mucosal healing. Currently, we are establishing scale-up culturing methodologies, in order to expand our cell cultures to a number of cells that would be enough to promote mucosal healing during transplantation in humans. Finally, we are refining the cell culture conditions to be GMP-approved, and thus, registering our final product as acceptable to be used during human clinical trials. Conclusion Our approach could offer a new therapeutic option for patients with UC that do not respond to current drug regimens and are in need for an effective treatment.

P0637 Ebrasodebart (Ent001) First in Human trial in healthy volunteers: pharmacokinetic results and predicted therapeutic concentrations to preserve mucosal healing in patients with Ulcerative Colitis

Abstract Background Ebrasodebart (Ent001) is a human IgG4 monoclonal antibody that antagonizes the binding of IGFBP3 to the novel cell death receptor TMEM219, expressed on Intestinal Stem Cells (ISCs) and well conserved across human and animal species. Ebrasodebart is thus expected to inhibit TMEM219-mediated activation of Caspase-8 and the exaggerated apoptosis of ISCs observed in patients with Ulcerative Colitis (UC). Ebrasodebart is currently in clinical development as a novel first-in class investigational treatment in patients with UC. A FIH single ascending dose (SAD) study in healthy volunteers (HVs) was conducted to define the safety, tolerability and pharmacokinetics (PK) of ebrasodebart at the concentrations anticipated to be required to elicit pharmacological and therapeutic activity in patients. Methods Thirty (30) HVs were enrolled in the monocentric, randomized, double-blind, placebo-controlled SAD study, 29 subjects completed the study. In vitro and in vivo concentration-response preclinical experiments defined the pharmacologically active concentrations, measuring the inhibition of IGFBP3-induced Caspase-8 activation in human intestinal epithelial cell lines and organoids, and the exposure-response in DSS-induced chronic colitic mice, while modeling and simulation (M&amp;S) predicted effective concentrations. Results After single intravenous (IV) doses of ebrasodebart in HVs, maximum exposure (Cmax) and systemic exposure (AUCinf) increased in an approximately dose proportional manner with a low intersubject variability at all dose levels (CV% &amp;lt; 20% for Cmax and AUCinf). Geometric mean t1/2 was between 17 to 19 days at the predicted therapeutic doses. Ebrasodebart achieved a Cmax of 296 µg/mL and AUC0-inf of 37646 µg/mL*h well below the No Observed Adverse Effect Level (NOAEL) from the 26-week chronic toxicity study in monkeys, but significantly higher than the minimal pharmacologically active concentration in vitro. The concentrations achieved in the FIH trial were also higher than those that significantly reduced the Disease Activity Index and both histological and endoscopic scores in mice, exceeding M&amp;S predictions for pharmacological effectiveness in patients. Conclusion These data indicate that ebrasodebart concentrations with predictable PK and expected therapeutic efficacy can be safely reached in humans, and remained significantly below the NOAEL in monkeys, suggesting a potential for a wide therapeutic window in patients. A multicentric Phase 1b, randomized, double-blind, placebo-controlled trial is ongoing to evaluate safety, tolerability, PK, immunogenicity and preliminary efficacy of multiple ascending doses of ebrasodebart in patients with moderately to severely active UC.

Winery By-Products In Vitro and In Vivo Effects on Atherothrombotic Markers: Focus on Platelet-Activating Factor.

Platelet aggregation and inflammation play a crucial role in atherothrombosis. Wine contains micro-constituents of proper quality and quantity that exert cardioprotective actions, partly through inhibiting platelet-activating factor (PAF), a potent inflammatory and thrombotic lipid mediator. However, wine cannot be consumed extensively due to the presence of ethanol. Alternatively, winery by-products are abundant in similar-to-wine micro-constituents that could be used in food fortification and dietary supplements. Also, the vinification process produces millions of tons of by-products worldwide, posing an environmental matter of waste management. Therefore, the purpose of this literature review is to update the existing data concerning the in vitro anti-platelet and anti-inflammatory properties of winery by-product extracts and their possible health effects through controlled clinical trials in humans, specifically focused on their effects on PAF's actions. Data from in vitro studies report that winery by-product compounds are able to inhibit platelet aggregation against several aggregation factors, as well as to downregulate inflammatory markers. Among their actions, extracts or phenolic compounds present in winery by-products inhibit PAF's actions, a potent inflammatory and thrombotic mediator. Similar conclusions have been drawn from human supplementation studies, which suggest that winery by-product extracts may have beneficial biological effects on the cardiovascular system. Evidence from long-term studies shows that consumption may lower total and low density lipoprotein (LDL) cholesterol, improve insulin sensitivity, decrease lipid and protein oxidative damage, enhance antioxidant capacity, and have mild anti-inflammatory action toward reducing cytokine expression and levels. Data from the limited postprandial studies report that the acute consumption of winery by-product extracts improves glycemic response and reduces platelet reactivity to aggregatory stimuli. Although wine extracts and phenolic compounds have been reported to inhibit PAF's actions and reduce the activity of its biosynthetic enzymes, no data exist concerning the influence of winery by-product extracts. In the future, additional long-term randomized controlled trials or postprandial studies are needed to draw definitive conclusions and establish a viable cardioprotective strategy that incorporates the sustainable use of winery by-products.

Continuous Core Body Temperature Monitoring for Heatstroke Alert via a Wearable In-Ear Thermometer.

Heatstroke, a global concern exacerbated by climate change, poses significant health risks, potentially leading to multiorgan damage and fatalities. Core body temperature (CBT) is a critical and precise indicator of heatstroke, and its continuous monitoring could serve as a pivotal tool for early detection. Traditional CBT measurements, often invasive (e.g., surgical intubation, rectal or oral placement), and disrupt daily activities, whereas existing wearable devices predominantly measure skin temperatures which is susceptible to ambient environment, thus unreliable for heatstroke alert. To overcome these limitations, this study introduces an innovative in-ear wearable device to measure CBT via the cochlea, which allows for accurate CBT monitoring and timely heatstroke alerts during activities in high-temperature and high-humidity environments. The device comprises a negative temperature coefficient (NTC) thermometer integrated into a flexible precision circuit (FPC), a compact Bluetooth module, an 8 mA h micro battery, and a biocompatible, low-stimulus silica gel casing. With dimensions of 27 mm × 18 mm and a maximum in-ear diameter of 5 mm, weighing just 1.3 g, the device offers high portability and comfort, with a continuous operational lifespan of at least 24 h postcharging. A complementary software system facilitates continuous CBT monitoring, heatstroke alerts, and device management. Preliminary human trials demonstrate the device's accuracy in CBT measurement, rivaling that of rectal thermometry, and superior to the performance of surface body temperature measurement at different body parts. Long-term experiments affirm the device's efficacy in detecting rapid CBT escalations, enabling timely preventive measures against heatstroke.