Human Trials Research Articles

Multi-omics uncovers immune-modulatory molecules in plasma contributing to resistance exercise-ameliorated locomotor disability after incomplete spinal cord injury

BackgroundExercise rehabilitation therapy has garnered widespread recognition for its beneficial effects on the restoration of locomotor function in individuals with spinal cord injury (SCI). Notably, resistance exercise has demonstrated significant improvements in muscle strength, coordination, and overall functional recovery. However, to optimize clinical management and mimic exercise-like effects, it is imperative to obtain a comprehensive understanding of the molecular alterations that underlie these positive effects.MethodsWe conducted a randomized controlled clinical trial investigating the effects of resistance exercise therapy for incomplete SCI. We integrated the analysis of plasma proteomics and peripheral blood mononuclear cells (PBMC) transcriptomics to explore the molecular and cellular changes induced by resistance exercise. Subsequently, we established a weight-loaded ladder-climbing mouse model to mimic the physiological effects of resistance exercise, and we analyzed the plasma proteome and metabolome, as well as the transcriptomes of PBMC and muscle tissue. Lastly, to confirm the transmissibility of the neuroprotective effects induced by resistance exercise, we intravenously injected plasma obtained from exercised male mice into SCI female mice during the non-acute phase.ResultsPlasma proteomic and PBMC transcriptomic profiling underscored the notable involvement of the complement pathways and humoral immune response in the process of restoring locomotor function following SCI in the human trial. Moreover, it was emphasized that resistance exercise interventions could effectively modulate these pathways. Through employing plasma proteomic profiling and transcriptomic profiling of PBMC and muscle tissues in mice, our study revealed immunomodulatory responses that parallel those observed in human trials. In addition, our analysis of plasma metabolomics revealed an enhancement in lipid metabolism following resistance exercise. We observed that resistance exercise plasma exhibited significant effects in ameliorating locomotor disability after SCI via reducing demyelination and inhibiting neuronal apoptosis.ConclusionsOur investigation elucidates the molecular alterations associated with resistance exercise therapy promoting recovery of locomotor function following incomplete SCI. Moreover, we demonstrate the direct neuroprotective effects delivered via exercise plasma injection, which facilitates spinal cord repair. Mechanistically, the comprehensive multi-omics analysis involving both human and mice reveals that the principal constituents responsible for the observed neuroprotective effects within the plasma are predominantly immunoregulatory factors, warranting further experimental validation.Trial registrationThe study was retrospectively registered on 17 July, 2024, in Chinese Clinical Trial Registry (No.: ChiCTR2400087038) at https://www.chictr.org.cn/.

A new taxonomy of neuroprotective agents for stroke appropriate for the reperfusion era

The advent of the era of highly effective reperfusion therapy for acute ischemic stroke has reawakened interest in neuroprotective treatments as they are far more likely to be efficacious as synergistic complements to reperfusion rather than standalone interventions. However, testing neuroprotective agents combined with reperfusion mandates not only renewed conduct of trials but also a fundamental reconceptualization of the subclasses of neuroprotection therapies. We propose a new taxonomy of neuroprotective treatment agents appropriate for the reperfusion era that recognizes six broad classes of agents, each targeting a distinct process and time epoch of injury: (1) Bridging neuroprotectives slow infarct expansion in the pre-reperfusion period, (2) Blood–brain barrier stabilizers restore the integrity of BBB before and early after reperfusion, (3) Microcirculation lumen preservers protect arteriolar and capillary endothelial cell integrity deterring the no-reflow phenomenon, (4) Reperfusion injury preventors block inflammatory, oxidative, and other processes that start immediately after reperfusion, (5) Edema reducers avert cerebral swelling and secondary injury due to brain tissue compression and herniation, and (6) Delayed neuroprotectives mitigate injury due to apoptosis and mitochondrial dysfunction in the late post-reperfusion period. This approach also broadly distinguishes neuroprotection from other major treatment strategies, including recanalization, collateral enhancement, and neurorepair. By focusing on broad physiologic targets of action rather than granular molecular mechanisms, this six-fold classification of neuroprotection can inform the design of preclinical studies and human clinical trials, including imaging biomarker endpoint selection and treatment timing. This updated taxonomy may accelerate the translation of cerebroprotective agents from bench to bedside.

The therapeutic potential of exercise in post-traumatic stress disorder and its underlying mechanisms: A living systematic review of human and non-human studies

Background Exercise for post-traumatic stress disorder (PTSD) is a potentially effective adjunct to psychotherapy. However, the biopsychosocial mechanisms of exercise are not well understood. This co-produced living systematic review synthesizes evidence from human and non-human studies. Methods We Included controlled human and non-human studies involving searches of multiple electronic databases (until 31.10.23). Records were screened, extracted, assessed for risk of bias, and reconciled by two independent reviewers. The primary outcome for human studies was PTSD symptom severity, while outcomes of interest for non-human studies included freezing behaviour, fear memory, fear generalization, startle response, and locomotion. Data were synthesised with random-effects meta-analysis. Results Eleven human studies met the eligibility criteria. Overall, exercise was not associated with symptom severity improvement compared to control (standardized mean difference [SMD] -0.08, 95% confidence interval [CI] -0.24 to 0.07; 8 studies, one at low risk of bias). High-intensity exercise reduced PTSD symptoms scores more than moderate-intensity exercise. There was insufficient data to examine the effects of exercise on functional impairment, PTSD symptom clusters, and PTSD remission. Only three studies, all at high risk of bias, examined mechanisms of exercise with inconclusive results. Exercise was associated with improvement in all behavioural outcomes, including locomotor activity (SMD 1.30, 95% CI 0.74 to 1.87, 14 studies), and changes in several neurobiological markers, including increase in brain-derived neurotrophic factor (SMD 1.79, 95% CI 0.56 to 3.01). Conclusions While non-human studies provide compelling evidence for the beneficial effects of exercise, human trials do not. Evidence from non-human studies suggest that exercise might increase the levels of brain-derived neurotrophic factor, enhance cognitive appraisal, and improve perceived exertion. Overall, the paucity of data on the effectiveness of exercise in PTSD and mechanisms of action underscore the need for rigorous trials. Registration The protocol was registered with PROSPERO (ID:453615; 22.08.2023).

A Review of Human Studies Assessing the Efficacy of Cannabidiol for Anxiety Disorders

Anxiety disorders are the most commonly diagnosed mental disorders worldwide, and their prevalence continues to rise, leading to significant social and economic burdens. Recent interest has focused on CBD as a potential treatment. This systematic review assesses the current evidence on the efficacy of CBD in treating anxiety and related disorders, including post-traumatic stress disorder (PTSD), social anxiety disorder (SAD), and autism spectrum disorder (ASD). Unlike open-label trials prone to placebo bias, this study reviews randomized, double-blind, placebo-controlled trials. A review of literature was conducted using the Google Scholar database to gather information on "cannabidiol," specifically focusing on its relationship with "anxiety," "social anxiety disorder", "post-traumatic stress disorder” and ,,human trials." Positive outcomes were observed with 300 mg CBD doses, reducing anxiety in SAD patients, tremor in Parkinson’s disease, and anxiety in ASD and opioid-dependent individuals. Minimal improvements were noted in PTSD patients with sexual trauma. Further research is needed to clarify CBD’s therapeutic potential in diverse clinical contexts.

Mechanistic investigation and the optimal dose based on baicalin in the treatment of ulcerative colitis–A preclinical systematic review and meta-analysis

BackgroundUlcerative colitis (UC) is a type of inflammatory bowel disease, and current treatments often fall short, necessitating new therapeutic options. Baicalin shows therapeutic promise in UC animal models, but a systematic review is needed.MethodsA systematic search was conducted across databases including PubMed, EBSCO, Web of Science, and Science Direct, up to March 2024, identifying randomized controlled trials (RCTs) examining baicalin’s impact on UC in animal models. Seventeen studies were selected through manual screening. Meta-analyses and subgroup analyses utilized Rev Man 5.3 and Stata 15.0 software to assess symptom improvement.ResultsFrom 1304 citations, 17 were analyzed. Baicalin significantly modulated various biomarkers: HCS (SMD = -3.91), DAI (MD = -2.75), spleen index (MD = -12.76), MDA (SMD = -3.88), IL-6 (SMD = -10.59), IL-1β (SMD = -3.98), TNF-α (SMD = -8.05), NF-κB (SMD = -5.46), TLR4 (MD = -0.38), RORγ (MD = -0.89), MCP-1 (MD = -153.25), MPO (SMD = -7.34), Caspase-9 (MD = -0.93), Caspase-3 (MD = -0.45), FasL (MD = -1.20)) and enhanced BWC (MD = 0.06), CL (MD = 1.39), ZO-1 (MD = 0.44), SOD (SMD = 3.04), IL-10 mRNA (MD = 3.14), and FOXP3 (MD = 0.45) levels. Baicalin’s actions may involve the PI3K/AKT, TLR4/NF-κB, IKK/IKB, Bcl-2/Bax, Th17/Treg, and TLRs/MyD88 pathways. Optimal therapeutic outcomes were predicted at dosages of 60–150 mg/kg over 10–14 weeks.ConclusionBaicalin demonstrates a multifaceted therapeutic potential in UC, attributed to its anti-inflammatory, antioxidant, anti-apoptotic, and intestinal barrier repair properties. While higher doses and longer treatments appear beneficial, further research, particularly human clinical trials, is necessary to verify its effectiveness and safety in people.

Omega-3 polyunsaturated fatty acids modify glucose metabolism in THP-1 monocytes.

Chronic inflammation is a driving factor in diseases like obesity and type 2 diabetes. Enhanced cellular glucose metabolism may contribute to heightened immune activation. A human supplementation trial showed that the n-3 PUFA α-linolenic acid (ALA) reduced oxidative phosphorylation in monocytes. Our objective here is to assess the direct effects of ALA and docosahexaenoic acid (DHA) on glucose metabolism in a cell culture model and to explore possible mechanisms. THP-1 monocytes were treated with 10-40 μM of ALA or DHA and compared with vehicle and oleic acid controls. The Seahorse XFe24 and Oroboros O2k Oxygraph systems were used to approximate catabolic rates in the presence of glucose. Both ALA and DHA reduced oxidative phosphorylation. We identified pyruvate dehydrogenase kinase 4 (PDK4) as a possible mechanistic candidate explaining the effect of DHA. Additionally, both n-3 PUFAs reduced LPS-induced IL-1β production, while only DHA increased reactive oxygen species to a small but significant extent. Our data suggest that ALA and DHA trigger a re-wiring of bioenergetic pathways in monocytes, possibly via the upregulation of PKD4. Given the close relationship between cell metabolism and immune cell activation, this may represent a novel mechanism by which n-3 PUFAs modulate immune function and inflammation.

Phytoconstituent analysis, bioactivity, and safety evaluation of various colors of Chrysanthemum morifolium flower extracts for cosmetic application

This study evaluated the phytochemical composition, bioactivity, and safety of purple, yellow, and white Chrysanthemum × morifolium (Ramat.) Hemsl. (C. morifolium) flower extracts using a hydroglycolic solvent blend of water and propylene glycol (PG) in a 1:1 ratio as a solvent for extraction. Quantitative analysis revealed that the purple and yellow flower extracts possessed significantly higher total phenolic content (TPC) and total flavonoid content (TFC) compared to the white flower extract (p < 0.05). These extracts also exhibited superior antioxidant activity, as measured by DPPH and ABTS assays. High-performance liquid chromatography (HPLC) analysis indicated that the purple extract had the highest concentration of luteolin (0.2403% w/w, p < 0.05), while the yellow extract contained the highest levels of chlorogenic acid (0.4320% w/w, p < 0.05) and caffeic acid (0.0289% w/w, p < 0.05). In vitro anti-glycation assays demonstrated that the purple extract exhibited the highest anti-glycation activity (p < 0.05). However, there was no significant difference in anti-collagenase activity between the purple and yellow extracts (p > 0.05). Safety evaluations confirmed that the extracts did not induce skin irritation or sensitization. These preliminary findings suggest the potential of C. morifolium flower extracts, particularly from yellow and purple varieties, as a promising ingredient in plant-based formulations. Initial results indicate antioxidant, anti-glycation, and anti-collagenase properties without apparent adverse skin reactions in vitro. However, further studies, including human clinical trials, are needed to confirm these biological activities and safety profiles.

Impact of Olive Oil Components on the Expression of Genes Related to Type 2 Diabetes Mellitus

Type 2 diabetes mellitus (T2DM) is a multifactorial metabolic disorder characterized by insulin resistance and beta cell dysfunction, resulting in hyperglycemia. Olive oil, a cornerstone of the Mediterranean diet, has attracted considerable attention due to its potential health benefits, including reducing the risk of developing T2DM. This literature review aims to critically examine and synthesize existing research regarding the impact of olive oil on the expression of genes relevant to T2DM. This paper also seeks to provide an immunological and genetic perspective on the signaling pathways of the main components of extra virgin olive oil. Key bioactive components of olive oil, such as oleic acid and phenolic compounds, were identified as modulators of insulin signaling. These compounds enhanced the insulin signaling pathway, improved lipid metabolism, and reduced oxidative stress by decreasing reactive oxygen species (ROS) production. Additionally, they were shown to alleviate inflammation by inhibiting the NF-κB pathway and downregulating pro-inflammatory cytokines and enzymes. Furthermore, these bioactive compounds were observed to mitigate endoplasmic reticulum (ER) stress by downregulating stress markers, thereby protecting beta cells from apoptosis and preserving their function. In summary, olive oil, particularly its bioactive constituents, has been demonstrated to enhance insulin sensitivity, protect beta cell function, and reduce inflammation and oxidative stress by modulating key genes involved in these processes. These findings underscore olive oil’s therapeutic potential in managing T2DM. However, further research, including well-designed human clinical trials, is required to fully elucidate the role of olive oil in personalized nutrition strategies for the prevention and treatment of T2DM.

Efficacy and Safety of Stem Cell Therapy in Alzheimer's Disease: A Review

Alzheimer's disease (AD) prevalence is a significant public health concern. Tau tangle buildup and different metabolic abnormalities are the primary neuropathological alterations that lead to this illness. Currently, there is a lack of effective treatment for patients with AD due to the complexity of the disease and the lack of a clear understanding of its aetiology. However, stem cell therapy can potentially be used to replace lost neuronal cells. Although this technology is only in its initial stages, it has the potential to transform the treatment of this condition. AD is amenable to disease-modifying treatment with stem cell therapy. Since the early 2000s, there have been more investigations on stem cells, including Mesenchymal Stem Cells (MSCs) and Neural Stem Cells (NSCs), as a result of the failure to produce new medicines for AD. Numerous animal studies have investigated issues relating to stem cells, such as their origin, ability to differentiate, how they are cultured, how they form tumours, how they are injected, and how mobile they are. Clinical trials to test the use of stem cells for AD have been underway since 2010, primarily in East Asia. Although there were no significant immediate or long-term side effects, two phase I investigations on moderate AD have been completed. Neither of these studies revealed any considerable clinical efficacy. Numerous investigations with more complex study designs, established levels, and biomarkers, such as amyloid positron emission tomography among people with mild to moderate AD, are in the works. Stem cell therapy for AD has the potential to alter the condition. The methods of action, preclinical animal studies, human clinical trials, and challenges stem cell therapy for AD faces are all covered in this article. We will also go over current advancements in stem cell research and the pathophysiology of AD, as well as challenges and solutions for employing cell-based therapeutics for AD and associated conditions.

CLINICAL EXERCISE PHYSIOLOGISTS IN THE INPATIENT SETTING – A CASE STUDY

https://youtu.be/i0pv5V6NKxM INTRODUCTION Preservation of functional capacity for patients admitted to the cardiovascular intensive care unit (CVICU) relies heavily on interventions prescribed by physical therapy. Traditional interventions are bed/chair exercises utilizing only body weight and ambulation around the unit. In this case, the clinical exercise physiologist (CEP) sought to push this standard of care to prepare a subject implanted with a BiVACOR total artificial heart (TAH) for orthotopic heart transplantation (OHT). This serves to present the methods in doing so and the need to further implement the role of clinical exercise physiologists in the inpatient setting. CASE PRESENTATION A 51-year-old male with history of chronic nonischemic cardiomyopathy, hypertension, diabetes mellitus, hyperlipidemia, and obesity presented to the hospital for right heart catheterization (RHC) in the setting of increased heart failure symptoms. Results of RHC led to admission and listing as UNOS status 4 for OHT. Hospital course was complicated by hypotension, ventricular tachycardia, and chronic kidney disease. Cardiothoracic surgery determined the need for mechanical circulatory support, a TAH as bridge to transplant. The patient elected to undergo implantation of BiVACOR, a TAH geared towards individuals with biventricular or univentricular heart failure where left ventricular assist device is not recommended. The patient is part of the BiVACOR Early Feasibility Trial in humans, approved by the FDA – he was the third human implant and would remain in hospital until OHT. The goal of the multi-disciplinary team was to preserve functional capacity during admission. MANAGEMENT Before implant, the patient’s 6-minute walk test (6MWT) distance was 320 meters, 2.52 METs. Post-implant in the ICU, the patient walked 1,800 feet 4 times per day. His 6MWT distance 13 days post-implant was 411 meters, 2.95 METs. By day 22 post-implant the patient progressed to recumbent bike cycling intervals. He was able to tolerate one 3-minutes interval and two 4-minutes intervals, split by 6-minutes rest intervals. His prescription was to cycle at 55-65 RPMs for 10-15 minutes three days per week with progression to 30 minutes continuously, 5-6 days per week. The patient was transplanted prior to completing any further sessions. During the cycling session, his blood lactate was measured at 5.2 mmol and hemoglobin 5.7 g/dL. His blood pressures remained stable, with normal responses to exercise, and pump flow increased from 8.9 L/min at rest to 12.5 L/min at peak exercise. Reported quadriceps muscle fatigue was the reason for session discontinuation. DISCUSSION Inpatient rehab goals of care should evolve to include various modalities of exercise that allow for more physiological adaptations, decreasing the impact of frailty and improving quality of life during admission. This patient’s case is an attestation to the growing need for exercise intervention prescribed by the CEP at all levels of care.

Chitosan and its derivatives: A novel approach to gut microbiota modulation and immune system enhancement.

Chitosan, a biopolymer derived from the deacetylation of chitin found in crustacean shells and certain fungi, has attracted considerable attention for its promising health benefits, particularly in gut microbiota maintenance and immune system modulation. This review critically examines chitosan's multifaceted role in supporting gut health and enhancing immunity, beginning with a comprehensive overview of its sources, chemical structure, and its dual function as a dietary supplement and biomaterial. Chitosan's prebiotic effects are highlighted, with a focus on its ability to selectively stimulate beneficial gut bacteria, such as Bifidobacteria and Lactobacillus, while enhancing gut barrier integrity and inhibiting the growth of pathogenic microorganisms. The review delves deeply into chitosan's immunomodulatory mechanisms, including its impact on antigen-presenting cells, cytokine profiles, and systemic immune responses. A detailed comparative analysis assesses chitosan's efficacy relative to other prebiotics and immunomodulatory agents, examining challenges related to bioavailability and metabolic activity. Beyond its role in gut health, this review explores chitosan's potential as a dual-action agent that not only supports gut microbiota but also fortifies immune resilience. It introduces emerging research on novel chitosan derivatives, such as chitooligosaccharides, and evaluates their enhanced bioactivity for functional food applications. Special attention is given to sustainability, with an exploration of alternative, plant-based sources of chitosan and their implications for both health and environmental stewardship. Also, the review identifies new research avenues, such as the growing interest in chitosan's role in the gut-brain axis and its potential mental health benefits through microbial interactions. By addressing these innovative areas, the review aims to shift the focus from basic health effects to chitosan's broader impact on public health. The findings encourage further exploration, particularly through human trials, and emphasize chitosan's untapped potential in revolutionizing health and disease management.

Moringa oleifera in a modern time: A comprehensive review of its nutritional and bioactive composition as a natural solution for managing diabetes mellitus by reducing oxidative stress and inflammation.

Globally, diabetes mellitus (DM) and its complications are considered among the most significant public health problems. According to numerous scientific studies, Plants and their bioactive compounds may reduce inflammation and oxidative stress (OS), leading to a reduction in the progression of DM. Moringa oleifera (MO), widely used in Ayurvedic and Unani medicine for centuries because of its health-promoting characteristics, particularly its ability to control DM and its related complications. MO is a multi-purpose plant that has an impressive range of nutritional components including proteins, amino acids (Essential and non-essential amino acids), carbs, fats, fiber, vitamins, and phenolic compounds. In the modern era, scientists have paid close attention to the anti-diabetic, anti-oxidative and anti-inflammatory attributes and other medicinal properties, of MO leaves and seeds. MO leaves and seeds have modulatory effects on DM that are likely influenced by multiple mechanisms. Some of these mechanisms include direct effects, but other mechanisms involve inhibition the production of inflammatory markers, modulation of the gut microbiome, reduction of OS, enhancement of glucose metabolism through hexokinase and glucose 6-phosphate dehydrogenase, improve insulin sensitivity and glucose uptake in the liver and muscles. Overall, these findings suggest that MO may play a role in lowering the risk of DM and its related outcomes. The purpose of this review is to provide a comprehensive overview of the nutritional and bioactive profiles of MO leaves and seeds, as well as to investigate their possible anti-diabetic effects by modulating oxidative stress and inflammation. Our results indicate that MO may be a beneficial natural resource for management of DM and related issues by lowering oxidative stress and inflammation. Furthermore, studies on MO has yielded promising findings in diabetic animal models, indicating antioxidant and anti-inflammatory properties. However, human trials have shown less solid results, most likely due to a lack of studies, different techniques, and dosages. More clinical research is needed to fully understand MO's anti-diabetic potential, notably in lowering oxidative stress and inflammation, both of which are critical in controlling diabetes complications.

Abstract TMP115: Technical Feasibility and Protocol Compliance in the Second Stroke Pre-Clinical Assessment Network

Background/Aims: The Stroke Preclinical Assessment Network (SPAN) is a randomized, placebo-controlled, blinded, multi-laboratory preclinical study using a Multi-Arm Multi-Stage statistical design to select one or more putative stroke treatments with an implied high likelihood of success in future human clinical stroke trials. Methods: Through a rigorous NIH-managed peer review process, six independent research laboratories were selected for testing five promising cerebrovascular interventions. A Coordinating Center at the University of Southern California leads the trial. The Interventions, also selected through an NIH peer review process, included NanO2 (NuvOx) an oxygen delivery emulsion, tatCN19o (Neurexis) a CaM-kinase II inhibitor, GSK2256098 (GlaxoSmithKline/ETSU) a focal adhesion kinase inhibitor, GSK2256294 (GlaxoSmithKline/OHSU) a soluble epoxide hydrolase inhibitor, and BPN-27332 (Loxagen/MGH) a lipoxygenase inhibitor. After a pilot trial to evaluate several behavioral measures, we designated the primary endpoint for SPAN 2 to be a multi-item functional test battery, the Simplified SPAN Score. All other procedures, including behavior tests and magnetic resonance imaging were performed as they were in SPAN 1. Per the SPAN 2 pre-specified protocol, an interim analysis was performed after Stage 1, aka, SPAN 2.1. Results: SPAN 2.1 enrolled 774 subjects, divided among 4 animal co-morbid models in whom a transient filament MCAo was performed: young healthy mice (n=193), diet-induced obese mice (n=197), aged mice (n=192), and spontaneously hypertensive rats (192). Nine subjects were found ineligible, leaving an ITT population of 765, of whom 13 were dropped during the stroke procedure—the primary analysis population (mITT) included 751 subjects. Protocol compliance was evaluated: over 99% of subjects received the correct assigned intervention, but dose timing was protocol adherent in only 61%. Animals who did not receive all assigned doses (n=100) were excluded, leaving a Full Treatment population of 651. Mortality after treatment included 158 subjects, 21% of the mITT group. Among the animal comorbid models, mortality was greatest (40%) in aged mice. Conclusions: The feasibility and protocol compliance seen in SPAN 1 have been replicated in stage 1 of the second trial, SPAN 2.1. Mortality resembles previous experience, with an improved survival in aged mice. SPAN 2 has advanced to Stage 2 where improved dose timing is implemented.

Results from GALILEO1, a first in human clinical trial of FLT201 AAV-gene therapy in adult patients with Gaucher disease type 1

Results from GALILEO1, a first in human clinical trial of FLT201 AAV-gene therapy in adult patients with Gaucher disease type 1

Regenerative approaches in alveolar bone augmentation for dental implant placement: Techniques, biomaterials, and clinical decision-making: A comprehensive review.

This review aimed to evaluate the outcomes of ridge augmentation techniques and bio-materials for alveolar bone regeneration, addressing inconsistencies across studies. A decision tree is provided to guide clinicians in selecting optimal approaches for diverse clinical scenarios. An extensive search was conducted across electronic databases, including PubMed, Scopus, and Embase, alongside dental implant and prosthodontics journal portals. Reference lists of relevant articles were also manually reviewed up to October 2024. Inclusion criteria were established to emphasize English-language human clinical trials investigating regenerative techniques and materials utilized for ridge augmentation prior to implant placement. Selecting defect-specific regenerative approaches is crucial for successful outcomes in alveolar bone augmentation. While autografts remain the gold standard, advancements in allografts, xenografts, synthetics, and biological enhancers are transforming the field. Distraction osteogenesis is also gaining prominence as a promising technique. Clinicians should leverage these innovations to tailor treatments to individual patient needs for optimal results. The decision tree developed categorizes alveolar bone anomalies and suggests tailored approaches based on anticipated resorption patterns. Careful patient evaluation and tailored technique selection, combined with advancements in biomaterials and tissue engineering, are essential for achieving optimal outcomes in ridge augmentation, particularly for challenging vertical defects.

Beneficial Effects of Spirulina on Brain Health: A Systematic Review

&lt;p&gt;Background: This review provides a concise overview of existing scientific research concerning the potential advantages of incorporating spirulina, a blue-green algae, into one's diet to promote brain health. The substantial nutritional composition and associated health benefits of algae have drawn significant interest. &lt;/p&gt; &lt;p&gt; Methods: Numerous studies have illuminated the neuroprotective characteristics of spirulina, contributing to its positive influence on brain functionality. Primarily, spirulina boasts antioxidants, like phycocyanin and beta-carotene, that effectively counter oxidative stress and curb inflammation within the brain. This is particularly significant as these factors play roles in the advancement of neurodegenerative conditions like Parkinson's and Alzheimer's disease. Additionally, spirulina has demonstrated the capacity to enhance cognitive capabilities and enrich memory and learning aptitudes. &lt;/p&gt; &lt;p&gt; Results: Animal-based investigations have revealed that introducing spirulina can bolster spatial learning and memory, as well as guard against cognitive decline linked to aging. Research has indicated its potential in shielding against neurotoxins, encompassing heavy metals and specific environmental pollutants. Its potential to neutralize heavy metals and counteract free radicals contributes to these protective effects, potentially thwarting neuronal harm. &lt;/p&gt; &lt;p&gt; Conclusion: In conclusion, the extant scientific literature proposes that spirulina integration can elicit advantageous outcomes for brain health. Its antioxidative, neuroprotective, cognitiveenhancing, and mood-regulating properties present a promising avenue for bolstering brain health and potentially diminishing the susceptibility to neurodegenerative ailments. Nonetheless, further research, notably well-designed human clinical trials, is imperative to ascertain the optimal dosing, duration, and enduring consequences of spirulina supplementation concerning brain health.&lt;/p&gt;

Clinical results of a phase 1 trial evaluating a HER2 directed CAR-T product selective for the tumor microenvironment (TME) in patients with GI and other solid tumor malignancies.

449 Background: A major limitation of CAR-T in solid tumors has been the inability to safely target antigens shared between healthy and malignant tissue. One approach to improving selectivity is to regulate CAR affinity through the unique metabolism of the tumor microenvironment (TME). This first in human trial evaluated an autologous (41BB) CAR-T product encoding a tumor metabolism regulated HER2 CAR. Methods: This Phase 1, dose escalation, basket trial evaluated the safety, tolerability, pharmacokinetics and efficacy in 12 patients (pts) with HER2 IHC 3+ / FISH + Stage IV r/r solid tumor malignancies (gastric, esophageal, colorectal, breast). They had failed multiple lines of therapy (66.7% patients had failed 4~10 lines of therapies previously). Dose cohorts of 3E5 (n=3), 1E6 (n=3), or 1E7 (n=6) CAR-T cells/kg were evaluated with a 28-day in-patient DLT observation period. Cell product was manufactured from whole blood, with a 12-day closed process and release on day 17. Lymphodepletion regimen was 500 mg/m 2 Cy and 30 mg/kg 2 Flu X 3 prior to infusion of CAR-T. Results: Data cutoff 09/16/24. All 12 patients were evaluable for safety and efficacy. No DLTs, ICANS or SAEs were observed. For HER2 positive normal tissues of special concern (e.g. cardiomyocytes), longitudinal functional, biochemical and clinical cardiovascular tests showed no signs of OTOT. One patient experienced Grade 2 CRS and recovered. No AE’s lead to study discontinuation. In one patient, there were two Grade 3 AEs attributed to product (neutropenia and hypoxia); both which resolved. With a median follow-up of 302 days for cohort 3, 12-month survival rate in this cohort is 83.3%, compared to the 12-month survival rate of 33.3% for cohorts 1 and 2 combined. Encouraging signals of efficacy were observed with an ongoing (at 24 wks) deep PR (100% reduction SLD) in a GC patient. The median peak copy number of CAR-T cells in peripheral blood (n=12) was 1,818 copies/µg DNA (range 403 – 10,466). Conclusions: The tumor metabolism regulated HER2 CAR-T product was generally well tolerated, with no DLTs, and evidence of radiologic objective response in patients with gastroesophageal cancer. Combined, the safety and activity observed in this study suggests that a previously challenging solid tumor antigen may be safely targeted by a CAR with affinity regulated by the metabolism of the TME. Enrollment for the study was complete as of 28-Feb-2024 (NCT04511871). Clinical trial information: NCT04511871 .

The potential impact of glycine supplementation on the process of aging

Aging is a multifactorial process characterized by the progressive loss of cellular integrity, metabolic flexibility, mitochondrial function, and the gradual accumulation of oxidative and inflammatory damage. These changes increase vulnerability to age-related disorders, including cardiovascular disease, neurodegenerative conditions, metabolic syndrome, and frailty. Glycine, the simplest amino acid, has recently gained attention as a potential nutritional and therapeutic intervention to modulate various pathways implicated in aging. Beyond its structural role in collagen and other proteins, glycine is a critical precursor for glutathione- an essential intracellular antioxidant- plays a role in neurotransmission, and is involved in the synthesis of heme, creatine, and bile acids. Emerging studies suggest that glycine supplementation may alleviate oxidative stress, dampen chronic low-grade inflammation, improve insulin sensitivity, enhance mitochondrial function, and even mimic aspects of methionine restriction- a dietary approach known to extend lifespan in animal models. These combined effects may help preserve physiological function, slow the onset of age-associated diseases, and promote healthspan. Nevertheless, the evidence base is still evolving; most current data derive from animal models, in vitro experiments, and limited human trials. Rigorous, long-term, randomized controlled studies are needed to identify optimal dosing, determine long-term safety, and clarify whether glycine can be strategically leveraged as an anti-aging nutrient. If confirmed, glycine’s safety, affordability, and accessibility may make it a compelling option for improving the quality of aging worldwide.

Preclinical toxicity evaluation of the novel anti-hypertensive compound KSD179019.

The Secretin receptor (SCTR) presents a promising path for hypertension management, with KSD179019 as identified as a Positive Allosteric Modulator (PAM) of SCTR, demonstrating anti-hypertensive effects in animal models. Our objective was to comprehensively evaluate the potential toxicity of KSD179019 through in vitro and in vivo investigations. Initial in vitro studies showed minimal toxicity in liver and kidney cells and non-mutagenicity in bacterial assays. A 14-day acute toxicity test indicated an LD50 over 5000mg/kg body weight, suggesting a safe profile, yet necessitating further in vivo analysis before progressing to human trials. Following OECD protocols, we conducted sub-chronic (90 days) and chronic (180 days) toxicity studies in male and female C57 mice at various dosages. These included comprehensive hematological, biochemical, macroscopic, urinalysis, and histopathological examinations. The sub-chronic study reported minimal toxicity except at the highest doses (700 and 1000mg/kg), while the chronic study suggested a no-observed-adverse-effect-level (NOAEL) at 250mg/kg with limitations. QSAR analysis supported the non-mutagenic nature of KSD179019. KSD179019 demonstrated a favorable general toxicity profile at a dose of 250mg/kg in a 180-day chronic testing study. However, further preclinical investigations, including assessments of in vivo mutagenicity, reproductive and developmental toxicity, and carcinogenicity, are required to comprehensively establish its safety profile.

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.