Long-term Safety Assessment Research Articles

Samelisant (SUVN-G3031), A Histamine 3 Receptor Inverse Agonist: Results from The Phase 2 Double-Blind Randomized Placebo-Controlled Study for The Treatment of Excessive Daytime Sleepiness in Adult Patients with Narcolepsy

Narcolepsy is a rare, chronic neurological disorder characterized by a dysregulated sleep-wake cycle, with core clinical features including excessive daytime sleepiness (EDS), cataplexy, hypnopompic/hypnagogic hallucinations, and sleep paralysis. Several treatment options are available for the symptomatic management of narcolepsy, but they have limitations. Comorbidities of narcolepsy further limit the treatment choices. Blocking of histamine 3 (H3) receptors has been demonstrated to be a viable approach for the management of symptoms of narcolepsy. Samelisant (SUVN-G3031) is a new H3 receptor inverse agonist. The efficacy, safety, tolerability, and pharmacokinetics of Samelisant in narcolepsy patients were evaluated in a phase 2, double-blind, placebo-controlled study (ClinicalTrials.gov identifier: NCT04072380). Patients diagnosed with narcolepsy according to the International Classification of Sleep Disorders criteria and having an Epworth Sleepiness Scale (ESS) score of ≥12 and a mean Maintenance of Wakefulness Test (MWT) time of <12min across the 4 sessions at baseline were enrolled. The total study duration was up to 7 weeks, which included a screening period of 4 weeks, a treatment period of 2 weeks, and a safety follow-up 1 week after the last study drug administration. The primary efficacy measure was the change in total ESS score compared to placebo. Secondary and exploratory assessments included the Clinical Global Impression of Severity, MWT, Clinical Global Impression of Change, Patient Global Impression of Change and cataplexy rate. Safety assessments included monitoring adverse events (AEs) and laboratory assessments. Of the 426 patients screened, 190 were randomized. The safety and intention-to-treat population included 188 and 164 patients, respectively. A statistically significant treatment effect of Samelisant was observed on the primary endpoint, indicating improvements in EDS. The treatment's impact on EDS was also evident on the other patients' and clinicians' perspectives scales. The AEs reported in ≥5% patients in any treatment groups were insomnia, abnormal dreams, nausea, and hot flush. Global phase 3 studies and long-term safety and efficacy assessments of Samelisant are planned to reaffirm the current findings.

Belimumab safety in adult and paediatric Chinese patients with systemic lupus erythematosus: A Phase 4, multicentre, observational study.

Although belimumab has been widely used in patients with systemic lupus erythematosus (SLE) globally, real-world safety data among Chinese patients are limited, particularly for children. This study assessed the safety and tolerability of belimumab in adult and paediatric patients with SLE in China in real-world clinical practice. This Phase 4, multicentre, prospective, observational study enrolled patients prescribed intravenous belimumab by their physicians in tertiary hospitals, independent of a clinical study, during routine clinical visits between May 2021 and May 2022. Patients could have been receiving belimumab prior to enrolment. The primary objective was to describe the incidence of adverse events (AEs), serious AEs (SAEs), adverse drug reactions (ADRs) and AEs of special interest (AESIs) over the 24-week follow-up period. Data were collected at enrolment and approximately 4, 12 and 24weeks post-enrolment, during routine clinical visits. AEs, ADRs and SAEs were collected as independent events. The safety population comprised patients who received ≥1 dose of belimumab and completed ≥1 follow-up visit. Overall, 417 patients were included in the analysis (safety population); 89.2% were female and mean (standard deviation) age was 35.5 (11.9) years. AEs were reported in 158 patients (37.9%) and were mostly mild (79.1%). The most common AEs were upper respiratory tract infections (n = 19, 4.6%) and hypokalaemia (n = 18, 4.3%; all mild). Among 22 patients (5.3%) with SAEs, four patients (1.0%) had drug-related SAEs (pneumonia, respiratory tract infection, gingivitis and decreased white blood cell and neutrophil count). ADRs were experienced by 25 patients (6.0%), most commonly urinary tract infections (n = 5, 1.2%). There were no fatal SAEs. AESIs occurred in 14 patients (3.4%), including infections of interest (n = 5, 1.2% all herpes zoster), serious selected psychiatric events (n = 3, 0.7%) and infusion-related systemic and anaphylactic reactions (n = 7, 1.7%). Of 14 paediatric patients enrolled, six experienced AEs, zero ADRs, two SAEs and one AESI. Belimumab was generally well tolerated in adult and paediatric patients with SLE in this real-world setting in China, with no new safety signals identified. Future assessment of long-term belimumab safety in China beyond 24weeks will extend this current body of evidence.

Sensitive imaging of actinide materials in shielded radioactive waste

This paper reports on the development of a method for enhanced non-destructive assay (NDA) of radioactive waste using the novel technique neutron-gamma emission tomography (NGET). The technique relies on the detection of correlated fast neutrons and gamma rays emitted in spontaneous or induced fission. It is based on fast organic scintillators and enables sensitive detection and three-dimensional (3D) localization of the fission events. The technique is passive and does not require moving components. In this work, we apply the NGET technique to the category of radioactive waste which is often referred to as historic or legacy waste. This can include mixed wastes encased in shielded containers many decades ago, before the advent of detailed waste description criteria. These low or intermediate level wastes are often associated with lacking, limited or conflicting documentation. This poses a challenge when assigning the waste to the proper disposal route as well as in deciding whether the waste needs to undergo sorting and conditioning to fulfil waste acceptance criteria both with regards to safe interim storage and to its ultimate disposal. Actinides, such as isotopes of uranium and plutonium, with their typically long half-lives and decay chains are of special interest in this regard since they may challenge the long-term safety assessment in repositories predicated on mainly shorter half-life radionuclides if undetected. Accurate identification and localisation of actinides is also important from a safeguards perspective, especially since they are generally difficult to detect and localise by established passive means due to their relatively weak radiation emissions, in particular in shielded containments and in the presence of strong radiation fields from other radioactive materials. In this paper we present findings of measurements on shielded containments of long-lived radioactive waste performed at the Studsvik site in Sweden, as well as measurements on a laboratory assembly simulating a grouted waste drum. Similarities and differences between the novel NGET technique and a commercially available gamma imaging system are also briefly discussed.

FDA Approval Summary: Olutasidenib for Adult Patients with Relapsed or Refractory Acute Myeloid Leukemia with an Isocitrate Dehydrogenase-1 Mutation.

On December 1st, 2022, the FDA approved the new molecular entity olutasidenib (Rezlidhia: Rigel Pharmaceuticals), a small-molecule inhibitor of isocitrate dehydrogenase-1 (IDH1), for the treatment of adult patients with relapsed or refractory acute myeloid leukemia (R/R AML) with a susceptible IDH1 mutation as detected by an FDA-approved test. The efficacy of olutasidenib was established based on complete remission (CR) + CR with partial hematological recovery (CRh) rate, duration of CR + CRh, and conversion of transfusion dependence (TD) to transfusion independence (TI) in Study 2102-HEM-101. In the pivotal trial, 147 adult patients treated with 150mg twice daily (BID) of olutasidenib were evaluable for efficacy. With a median follow-up of 10.2 months, the CR/CRh rate was 35% (95% CI: 27-43%), with a median duration of response of 25.9 months (95% CI: 13.5 months, not reached [NR]). Of the 86 patients that were TD at baseline, 29 became TI (34%). The most common (≥20%) adverse reactions were nausea, fatigue, arthralgia, leukocytosis, dyspnea, pyrexia, rash, mucositis, diarrhea, and transaminitis. An assessment of long-term safety of olutasidenib is a condition of this approval.

Advancing Osteoarthritis Treatment: The Therapeutic Potential of Mesenchymal Stem Cell-Derived Exosomes and Biomaterial Integration

Background/Objectives: Osteoarthritis (OA) is a prevalent and debilitating joint disorder characterized by progressive cartilage degradation and inflammation, for which traditional treatments offer only symptomatic relief without halting disease progression. Exosomes, cell-free vesicles derived from mesenchymal stem cells, have emerged as a promising alternative therapy owing to their regenerative and anti-inflammatory properties. Methods: This review synthesizes findings from recent studies (2017–2023) on the therapeutic potential of exosomes in OA treatment, highlighting their ability to modulate the joint microenvironment, reduce inflammation, and promote cartilage repair by delivering bioactive molecules such as cytokines, growth factors, and regulatory ribonucleic acids. Results: We explore the integration of exosomes with biomaterials, such as hydrogels and scaffolds, to enhance their delivery and therapeutic efficacy, and we address the critical challenges associated with their clinical application, including standardization of isolation and characterization methods, scalability of production, mechanistic understanding, and long-term safety. Despite these challenges, exosome-based therapies offer several advantages over traditional and cell-based treatments, including lower immunogenicity, ease of handling, and targeted delivery of therapeutic agents to damaged tissues. Conclusions: We provide an analytical perspective on the current state of exosome research in OA, emphasizing the need for standardized production methods, deeper mechanistic insights, and rigorous long-term safety assessments. Future directions should focus on optimizing delivery systems, exploring personalized medicine approaches, and conducting comparative effectiveness studies to fully realize the potential of exosome therapies for OA treatment. Addressing these gaps will be crucial for translating exosome therapies from bench to bedside and achieving a transformative impact on OA management.

Assessment of long-term safety and efficacy of Dupilumab therapy in patients with moderate-to-severe atopic dermatitis in the UAE: A real-life observational study

Assessment of long-term safety and efficacy of Dupilumab therapy in patients with moderate-to-severe atopic dermatitis in the UAE: A real-life observational study

Research and application of ice force monitoring technology for upright structures based on distributed fiber optic sensors

A ice force monitoring system based on fiber optic sensing technology is proposed to address the limitations of traditional ice force monitoring methods in harsh marine environments. The design requirements of the ice force sensor, the design calculations of the elastic element, and the selection and arrangement of fiber optic sensors are elaborated. The sensitivity coefficient of the designed sensor is determined to be 0.044 nm/KN, with an R2 value of 0.999. The performance and reliability of the sensor are validated through calibration tests and indoor loading experiments. Field measurements of ice force are conducted, with ice force amplitudes measured to be around 2KN. Additionally, Temporal Convolutional Network (TCN) is introduced for sequential prediction of extreme static ice force data, aiming to provide more comprehensive support for long-term safety assessment and risk warning of marine platforms.

Enhancing therapy with nano-based delivery systems: exploring the bioactive properties and effects of apigenin.

Apigenin, a potent natural flavonoid, has emerged as a key therapeutic agent due to its multifaceted medicinal properties in combating various diseases. However, apigenin's clinical utility is greatly limited by its poor water solubility, low bioavailability and stability issues. To address these challenges, this review paper explores the innovative field of nanotechnology-based delivery systems, which have shown significant promise in improving the delivery and effectiveness of apigenin. This paper also explores the synergistic potential of co-delivering apigenin with conventional therapeutic agents. Despite the advantageous properties of these nanoformulations, critical challenges such as scalable production, regulatory approvals and comprehensive long-term safety assessments remain key hurdles in their clinical adoption which must be addressed for commercialization of apigenin-based formulations.

Mesenchymal stem cell therapy in veterinary ophthalmology: clinical evidence and prospects.

Mesenchymal stem cell (MSC) therapy presents a promising strategy for treating various ocular conditions in veterinary medicine. This review explores the therapeutic potential of MSCs in managing corneal ulcers, immune-mediated keratitis, chronic superficial keratitis, keratoconjunctivitis sicca, retinal degeneration, and ocular burns in feline, equine, and canine patients. Studies have demonstrated the immunomodulatory and regenerative properties of MSCs, highlighting their ability to mitigate inflammation and promote tissue regeneration. Experimental studies have shown the potential of MSC therapy in reducing corneal opacity and vascularization, indicating significant therapeutic advantages. Delivery methods play a crucial role in optimizing the therapeutic efficacy of MSCs in ocular diseases. Various delivery methods, such as intravitreal injection, subconjunctival injection, topical administration, and scaffold-mediated delivery, are being explored to optimize MSC delivery to the target ocular tissues. Clinical trials have shown significant improvements in clinical signs following MSC therapy, underscoring its efficacy in treating ocular diseases. Additionally, tissue engineering approaches incorporating MSCs, growth factors, and scaffolds offer innovative strategies for corneal regeneration and tissue repair. Despite challenges such as standardization of protocols and long-term safety assessment, ongoing research endeavours seek to unlock the full therapeutic potential of MSC therapy in ocular diseases. Future prospects in MSC therapy involve exploring scaffold and hydrogel-based approaches and cell-free therapies leveraging the bioactive molecules released by MSCs. Continued research and development efforts are essential to unlock the full therapeutic potential of MSCs and realize their transformative impact on ocular diseases in veterinary patients.

Long-Term Stability Analysis and Structural Safety Assessment of Tunnel Surrounding Rock in Carbonaceous Slate Formation

Long-Term Stability Analysis and Structural Safety Assessment of Tunnel Surrounding Rock in Carbonaceous Slate Formation

Thermal effects on the strain rate-dependent behavior of highly compacted GMZ01 bentonite

Investigation of thermal effects on the strain rate-dependent properties of compacted bentonite is crucial for the long-term safety assessment of deep geological repository for disposal of high-level radioactive waste. In the present work, cylindrical GMZ01 bentonite specimens were compacted with suction-controlled by the vapor equilibrium technique. Then, a series of temperature- and suction-controlled stepwise constant rate strain (CRS) tests was performed and the rate-dependent compressibility behavior of the highly compacted GMZ01 bentonite was investigated. The plastic compressibility parameter λ, the elastic compressibility parameter κ, the yield stress p0, as well as the viscous parameter α were determined. Results indicate that λ, κ and α decrease and p0 increases as suction increases. Upon heating, parameters λ, α and p0 decrease. It is also found that p0 increases linearly with increasing CRS in a double-logarithm coordinate. Based on the experimental results, a viscosity parameter α(s, T) was fitted to capture the effects of suction s and temperature T on the relationship between yield stress and strain rate. Then, an elastic-thermo-viscoplastic model for unsaturated soils was developed to describe the thermal effects on the rate-dependent behavior of highly compacted GMZ01 bentonite. Validation showed that the calculated results agreed well to the measured ones.

Revolutionizing Brain Tumor Therapy: Unleashing the Potential of Phytosomal Nanoparticles

Unleashing the potential of phytosomal nanoparticles in brain tumor therapy. This article discusses the transforming potential of phytosomal nanoparticles in the fight against brain tumors, delving into this novel field. When the complex problems of traditional medicine are considered, the special qualities of phytosomal nanoparticles show great potential. Because of the nanoparticles’ ability to cross the blood-brain barrier, it is possible to transport drugs specifically to the brain, which solves a long-standing issue with current treatments. This accuracy reduces off-target effects, providing a crucial therapeutic benefit in a sensitive brain environment. Phytosomal formulations are further distinguished by their lower toxicity and biocompatibility, which establishes them as a safer substitute for several traditional medicines. These natural compound-based nanoparticles fit in with the medical paradigm shift towards personalized and integrative care. The versatility of phytosomal formulations opens up new avenues for personalized medicine in the treatment of brain tumors by enabling customized approaches based on the molecular profiles of individual tumors.Phytosomal nanoparticles provide a unique combination of natural pharmacopeia and state-of-the-art nanotechnology, which presents opportunities for novel therapeutic approaches beyond their clinical usefulness. The consequences could change the way brain tumors are treated as research and clinical trials are conducted. In order to overcome obstacles related to scalability, legal frameworks, and long-term safety assessments, cooperation between researchers, physicians, and legislators is essential. The full potential of phytosomal nanoparticles in the fight against brain tumors will be realized through ongoing research into how they might work in concert with current therapies and the creation of evidence-based guidelines. This article essentially presents a paradigm shift that will have a significant impact on cancer therapy in the future. It is the result of the convergence of innovative ideas inspired by nature with state-of-the-art nanotechnology.

Structurally-controlled failure and damage around an opening in faulted Opalinus Clay shale at the Mont Terri Rock Laboratory: In-situ experimental observation and 3D numerical simulation

We present a combined experimental and numerical study of failure and damage in faulted Opalinus Clay shale around an opening at the Mont Terri Rock Laboratory, Switzerland. An experiment borehole with a diameter of 0.6 m and a length of 12.9 m intersecting a major fault zone at an acute angle of ∼40° was drilled, with subsequent overbreaks closely monitored. To investigate the underlying mechanisms that lead to the observed overbreaks, we developed a 3D geomechanics model to simulate the deformation and failure behaviour of faulted Opalinus Clay shale. To represent geological structures including the major fault zone and secondary fracture sets, a site-specific fracture network was constructed. Our model captured many important geomechanical properties and responses of the faulted Opalinus Clay shale, such as anisotropy of the shale matrix, deformation of the fault zone, dislocation of secondary fractures, and growth of new cracks as well as generation of overbreaks around the opening. We compared our simulation results with in-situ experimental observation of short-term overbreak patterns along the borehole and found that the overbreak occurrence is strongly controlled by both stress conditions and geological structures. Our results indicate that the damaged zone is characterised by an inner shell and an outer shell, where the former (dominated by extensive tensile/shear cracks) has a thickness of about one quarter of the borehole diameter and the latter (dominated by sparse shear cracks) extends by half to one borehole diameter into the surrounding rock. We further elucidated the impacts of the major fault zone and secondary fracture sets as well as the borehole–fault intersection angle on the deformation, damage, and failure characteristics. The findings and insights obtained in this study have important implications for the stability evaluation of waste emplacement drifts and long-term safety assessments of nuclear waste galleries in faulted argillaceous rocks.

Exploring molecular mechanisms, therapeutic strategies, and clinical manifestations of Huntington's disease.

Huntington's disease (HD) is a paradigm of a genetic neurodegenerative disorder characterized by the expansion of CAG repeats in the HTT gene. This extensive review investigates the molecular complexities of HD by highlighting the pathogenic mechanisms initiated by the mutant huntingtin protein. Adverse outcomes of HD include mitochondrial dysfunction, compromised protein clearance, and disruption of intracellular signaling, consequently contributing to the gradual deterioration of neurons. Numerous therapeutic strategies, particularly precision medicine, are currently used for HD management. Antisense oligonucleotides, such as Tominersen, play a leading role in targeting and modulating the expression of mutant huntingtin. Despite the promise of these therapies, challenges persist, particularly in improving delivery systems and the necessity for long-term safety assessments. Considering the future landscape, the review delineates promising directions for HD research and treatment. Innovations such as Clustered regularly interspaced short palindromic repeats associated system therapies (CRISPR)-based genome editing and emerging neuroprotective approaches present unprecedented opportunities for intervention. Collaborative interdisciplinary endeavors and a more insightful understanding of HD pathogenesis are on the verge of reshaping the therapeutic landscape. As we navigate the intricate landscape of HD, this review serves as a guide for unraveling the intricacies of this disease and progressing toward transformative treatments.

The adsorption of U(VI) on chlorite: batch, modeling and XPS study

Abstract A mechanistic modelling of the adsorption processes onto individual minerals presenting in the near- and far-fields can greatly enhance the credibility of long-term safety assessments of granite-based geological repositories. In this study, the titration and U(VI) adsorption characteristics of chlorite, one of the major minerals of rock fractures, have been studied. Potentiometric titration curves at two ionic strengths (0.1 and 0.4 mol/L NaCl) are successfully interpreted by considering protonation/deprotonation reactions on generic edge sites (≡SOH) in the framework of a non-electrostatic surface complexation model (SCM). The adsorption of U(VI) on chlorite was reached after 24 h, the adsorption kinetics can be described by a pseudo-second-order model. A non-electrostatic SCM with three surface complexes (≡SOUO2 +, ≡SO(UO2)3(OH)5 and ≡SO(UO2)3(OH)7 2−) was set up based on pH edges of U(VI) at adsorption equilibrium in the absence of CO2. Additional, experimental data measured as a function of U(VI) concentration, solid-to-liquid ratio and carbonate concentration were well reproduced by the proposed model. Finally, parallel experiments were conducted using X-ray photoelectron spectroscopy (XPS) to analyze the variation of U(VI) surface species speciation at different pH values. The good agreement between SCM prediction and XPS analysis demonstrates the reliability of the model in predicting and quantifying the radionuclides retention by chlorite.

Fracture smectites in bedrock at the Kivetty and Romuvaara sites, Finland, as natural analogues for radioactive waste repository buffers

Bentonite is used in various geological repository designs for highly radioactive and low- and intermediate-level waste. Stability of such materials has been evaluated in long-term safety assessments, with recent emphasis on potential chemical erosion of these clays in fresh groundwater conditions. The fracture-filling mineralogy at two investigation sites, Kivetty and Romuvaara, in Finland shows the existence of different types of smectites characterized by their respective dominant elements, such as Mg-, Fe- and Na–Ca-rich smectites. Of these, Ca- and Na-smectites are likely to be montmorillonites that provide potential natural analogues for the bentonite buffers and their long-term performance in fractured bedrock environments. The smectite minerals observed reflect the local parent rock mineral composition, suggesting in situ formation during hydrothermal alteration, well predating the current freshwater conditions in the fractured bedrock. These observations support the stability of smectites, including Na- and Ca-montmorillonites, in the fractured bedrock of glaciated terrain with fresh continental groundwater extending to repository-relevant depths. Further, no erosion or sedimentation processes have been observed to have taken place in the fracture systems studied. However, uncertainties remain related to detailed exchangeable cation compositions of the smectite. Current groundwater systems at both sites would alter the composition of montmorillonite towards the Ca-rich form, and more detailed investigations are required to assess the stability of Na-montmorillonite in connection to open fractures. In general, bentonite alteration in fractures to Ca-montmorillonite would be beneficial in repository scenarios that consider potential chemical erosion by dilute groundwater. Supplementary material: Supplementary material 1 (XCT data for fracture smectite samples from Kivetty and Romuvaara) are available at https://doi.org/10.23729/1ce75faa-d52a-43cd-af40-3961b3081f70 [last accessed 5 July 2023] and Supplementary material 2 (XRD diffractogram data) and Supplementary material 3 (SEM-EDS data) are available at https://doi.org/10.6084/m9.figshare.c.7126477 Thematic collection: This article is part of the Sustainable geological disposal and containment of radioactive waste collection available at: https://www.lyellcollection.org/topic/collections/radioactive

Abstract LB023: A novel oral Paclitaxel delivery strategy and softgel capsule product for improving cancer therapeutics

Abstract The therapeutic efficacy of a novel oral Paclitaxel formulation was evaluated and compared in Balb/c nude mice bearing PDX NSCLC, gastric cancer, liver cancer, breast cancer, and ovarian cancer treated with Abraxane, Taxol, Lenvatinib and Sorafenib. Therapeutic parameters including tumor volume, tumor growth inhibition (TGI), and treatment-to-control ratio (T/C) were compared among different treatment groups. The drug tolerance, cytotoxicity and safety profile of the oral Paclitaxel formulations were evaluated in Balb/c nude mice and beagle dogs. The tumor distribution of Paclitaxel in NCI-N87 gastric cancer-bearing mice after administration of oral Paclitaxel formulation and Paclitaxel Injection was investigated. The oral Paclitaxel formulation administrated at 100 mg/Kg demonstrated significant better therapeutic efficacy than Albumin-bound Paclitaxel for Injectable Suspension at 30 mg/Kg and Paclitaxel Injection at 15 mg/Kg for NCI-N87 gastric cancer-bearing mice, while the same 100 mg/Kg dose demonstrated noninferior therapeutic efficacy to Abraxane and significant better therapeutic efficacy than Taxol in Hs467T gastric cancer-bearing mice. The oral Paclitaxel formulation administrated at 180 mg/Kg demonstrated noninferior therapeutic efficacy compared with Lenvatinib at 40 mg/Kg, and significant better therapeutic efficacy than Sorafenib at 30 mg/Kg for Hep G2 liver cancer-bearing mice, while the oral paclitaxel at 180 mg/Kg showed inferior therapeutic efficacy than Lenvatinib at 30 mg/Kg but noninferior therapeutic efficacy to Sorafenib at 30 mg/Kg for Huh-7 liver cancer-bearing mice. The oral Paclitaxel formulation administrated at 100 mg/Kg demonstrated significant better therapeutic efficacy than Abraxane for Injectable Suspension at 30 mg/Kg and Taxol at 15 mg/Kg for NCI-H358 NSCLC-bearing mice. The oral Paclitaxel formulation administrated at 100 mg/Kg demonstrated noninferior therapeutic efficacy to Abraxane for Injectable Suspension at 30 mg/Kg and significant better therapeutic efficacy than Taxol at 15 mg/Kg for MDA-MB-231 breast cancer-bearing mice. The oral Paclitaxel formulation administrated at 100 mg/Kg demonstrated noninferior therapeutic efficacy to Abraxane at 30 mg/Kg and significant better therapeutic efficacy than Taxol at 15 mg/Kg for SK-OV-3 ovarian cancer-bearing mice. The gastric tumor distribution of Paclitaxel between 6-24 hour was similar after oral and intravenous administration. The Maximum Tolerated Dose (MTD) of the oral Paclitaxel was determined to be ≥ 200 mg/Kg in mice and ≥ 8.0 mg/Kg in beagle dogs when dosing at Q3DX3Weeks, there were no significant body weight losses, tissue damages and animal death observed during the long-term safety assessment study. The oral Paclitaxel formulation demonstrated better or noninferior therapeutic efficacy in five different PDX tumor-bearing mice compared with standard treatment drugs, good safety and low cytotoxicity at high doses in long-term safety and toxicity studies were observed in both mice and beagle dogs. The oral Paclitaxel formulation showed promising therapeutic potential for various cancer treatment and conducting “chemotherapy at home” with lower medical costs. Citation Format: Hui Yu Huang, Richard Jun Huang. A novel oral Paclitaxel delivery strategy and softgel capsule product for improving cancer therapeutics [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB023.

Dysbiosis in Multiple Sclerosis: Can Immunoglobulin Y Supplements Help?

The role of gut microbiota in autoimmune disorders like multiple sclerosis is gaining attention. Multiple sclerosis is characterized by inflammation, demyelination, and neurodegeneration in the central nervous system. Alterations in gut microbiota have been linked to multiple sclerosis development, with decreased beneficial bacteria and increased harmful species. The gut-brain axis is a complex interface influencing bidirectional interactions between the gut and the brain. Dysbiosis, an imbalance in gut microbiota, has been associated with autoimmune diseases. The influence of gut microbiota in multiple sclerosis is reversible, making it a potential therapeutic target. Probiotics, prebiotics, and fecal microbiota transplantation have shown promise in multiple sclerosis treatment, with positive effects on inflammation and immune regulation. Immunoglobulin Y (IgY) supplements derived from chicken egg yolk have potential as nutraceuticals or dietary supplements. IgY technology has been effective against various infections, and studies have highlighted its role in modulating gut microbiota and immune responses. Clinical trials using IgY supplements in multiple sclerosis are limited but have shown positive outcomes, including reduced symptoms, and altered immune responses. Future research directions involve understanding the mechanisms of IgY's interaction with gut microbiota, optimal dosage determination, and long-term safety assessments. Combining IgY therapy with other interventions and investigating correlations between microbiota changes and clinical outcomes are potential avenues for advancing multiple sclerosis treatment with IgY supplements.

What are filling (volumizing) threads?

Facial aging prompts a shift in the demands for lifting procedures, transitioning from targeted improvements in younger individuals to overall facial contour enhancements as skin elasticity declines in later years. This paper examines the evolution of PDO volumizing threads, delineating their development from initial limitations to contemporary innovations aimed at addressing tissue deformation and maintaining thread integrity post-insertion. Categorizing these threads based on elasticity, shape, and functionality underscores their versatility and application nuances, catering to specific wrinkle correction, contour sculpting, and facial volume restoration. The discussion emphasizes the pivotal role of thread characteristics in achieving optimal outcomes while minimizing potential complications. By delving into historical contexts, mechanisms, effectiveness, and thread classification, this paper equips practitioners with a comprehensive understanding to make informed decisions in selecting threads for volumizing thread procedures. Recommendations for future research directions, including long-term safety assessments and patient-specific outcomes, seek to enhance the clinical utility and applicability of this analysis.

Speciation simulation and sorption mechanism of 238Pu in radioactive waste repository lithosphere

Abstract The assessment of the migratory and environmental behavior of radioactive nuclides escaping from waste treatment facilities heavily relies on the use of numerical models capable of simulating and characterizing all significant processes of nuclides in complex geological environments. Adsorption models typically encompass the chemical properties of the nuclides themselves and their chemical reactions with the surrounding environment, as well as processes such as ion exchange or physical adsorption. These processes must be taken into consideration in the long-term safety assessment of radioactive waste repositories. The redox-sensitive nuclide 238Pu, a critical member among transuranic elements, exhibits a diverse range of aqueous forms, and concurrently, it possesses high toxicity. The chemical behavior of 238Pu shows strong spatial variability with changes in environmental conditions. In this study, we constructed a theoretical model for the migration of nuclides in soil and groundwater environments through indoor static batch experiments and hydrogeochemical simulations. Experimental methods were employed to dissect the micro-scale, irreversible adsorption reaction processes of nuclides and identify their primary existing forms. According to field measurements, the pH of groundwater was recorded as 7.48, with an Eh of 125.7 mV. Introducing a solid-to-liquid ratio of 1:10 g/mL in centrifuge tubes, we measured the radioactive nuclide concentration after achieving adsorption and desorption equilibrium, obtaining adsorption and desorption isotherms. The PHREEQC software was employed to investigate the changes in 238Pu forms under varying conditions of pH and redox potential. Field measurements provided groundwater pH and Eh values. The activity concentration of the nuclide was measured after reaching adsorption and desorption equilibrium. The results show that the adsorption isotherms of 238Pu differ from its desorption isotherms, indicating an irreversible adsorption-desorption process. Ion exchange and surface complexation were identified as the main modes of adsorption. PHREEQC simulations revealed that 238Pu primarily existed in forms such as tetravalent Pu(OH)4 and trivalent Pu(SO4)2 −, PuSO4 +. Pu(OH)4 accounted for the largest proportion (97%) in the groundwater solution system, while a minimal amount of pentavalent PuO2 + was present. Environmental factors, such as pH and the presence of ions like SO4 2− and HCO3 −, influenced the forms of 238Pu.