Basic Drug Research Articles

Surface Roughness Examination of Glass Ionomer Restorative Cements Treated with Acidic and Basic Pediatric Medications: An In Vitro Study.

Consumption of different types of beverages and liquid drugs can affect of the surface properties of restorative material. This may lead to an increased probability of dental caries and periodontal inflammation. This study evaluated and compared the effect of amoxicillin suspension (AMS) and azithromycin suspension (AZS) on the surface roughness (SR) of silver-reinforced glass ionomer (SGI) and nano resin-modified glass ionomer (NGI). Thirty disks (2 mm height × 4 mm diameter) of each glass ionomer (GI) type were prepared and subdivided into three groups (n = 10), which were separately exposed to AMS, AZS, and artificial saliva (AS). SR was evaluated by atomic force microscopy before and after three-immersion protocols repeated over a 3-week duration with 2-day intervals. In each protocol, the GI samples were exposed weekly to AMS three times daily, AZS once daily, and a full day to AS. This study demonstrated, for the first time, the effect of a basic drug (AZS) on the SR of GIs. Intra- and inter-group comparisons showed significant changes (P ˂ 0.05) in the SR pattern of the GIs after immersion cycles in AZS, AMS, and AS. However, the acidic medication (AMS) exhibited significantly higher changes in SGI than in NGI. The SR of NGIs and SGIs can be significantly affected by the use of AMS and AZS suspensions. SGI demonstrated higher SR deterioration than NGI after immersion cycles in AMS.

Identification of gemcitabine resistance-related AHNAK2 gene associated with prognosis and immune infiltration in pancreatic cancer

PurposeGemcitabine is a basic chemotherapy drug for pancreatic cancer (PC), but resistance is common and causes tumor recurrence and metastasis. Therefore, it is significant to explore gemcitabine resistance-related molecules for individualized treatment and prognosis assessment of PC. MethodsIn this study, transcriptome sequencing and TCGA database analysis were performed, and a differentiated gene AHNAK2 was screened. MEXPRESS database, tissue microarray analysis, and CIBERSORT and TIMER databases were used to correlate AHNAK2 expression with clinicopathological features and prognosis and immune infiltration of PC. Enrichment analysis was used to investigate the significant biological processes associated with AHNAK2. ResultsAHNAK2 was highly expressed in gemcitabine-resistant cells. High expression of AHNAK2 increased the risk of poor overall survival (OS) and progression-free survival (PFS) in PC. Clinicopathologic analysis revealed that AHNAK2 correlated with KRAS, TP53 mutations, histologic type, short OS, N stage, and elevated CA199 levels in PC. Knockdown of AHNAK2 inhibited the ability of cell proliferation and colony formation and enhanced the toxic effect of gemcitabine in PC. Meanwhile, the knockdown of AHNAK2 expression enhanced cell-ECM adhesion, inhibited cell-cell adhesion, and downregulated the KRAS/p53 signaling pathway in PC. Furthermore, AHNAK2 was correlated with immune infiltration, especially B cells and macrophages. ConclusionsOur study unveils for the first time the pivotal role of AHNAK2 in PC, particularly its association with gemcitabine resistance, clinical prognosis, and immune infiltration. AHNAK2 not only drives the proliferation and drug resistance of PC cells by potentially activating the KRAS/p53 pathway but also significantly impacts cell-cell and cell- ECM adhesion. Additionally, AHNAK2 plays a crucial role in modulating the tumor immune microenvironment. These insights underscore AHNAK2's unique potential as a novel therapeutic target for overcoming gemcitabine resistance, offering new perspectives for PC treatment strategies.

Comparative effects of insulin pump and injection on gestational diabetes mellitus pregnancy outcomes and serum biomarkers

BACKGROUND Insulin injection is the basic daily drug treatment for diabetic patients. AIM To evaluate the comparative impacts of continuous subcutaneous insulin infusion (CSII). METHODS Based on the treatment modality received, the patients were allocated into two cohorts: The CSII group and the multiple daily injections (MDI) group, with each cohort comprising 210 patients. Comparative assessments were made regarding serum levels of serum-secreted frizzled-related protein 5, homocysteine, and C1q/TNF-related protein 9. Furthermore, outcomes such as fasting plasma glucose, 2-hour postprandial glucose levels, pain assessment scores, and the incidence of complications were evaluated post-treatment. RESULTS The CSII group displayed notably lower fasting plasma glucose and 2-h postprandial glucose levels in comparison to the MDI group (P < 0.05). Subsequent analysis post-treatment unveiled a significantly higher percentage of patients reporting no pain in the CSII group (60.00%) in contrast to the MDI group (36.19%) (P < 0.05). Additionally, the CSII group exhibited a markedly reduced occurrence of fetal distress and premature rupture of membranes compared to the MDI group (P < 0.05). However, there were no significant variances observed in other pregnancy outcomes between the two groups (P > 0.05). A statistical analysis revealed a significant difference in the incidence of complications between the groups (χ 2 = 11.631, P = 0.001). CONCLUSION The utilization of CSII via an insulin pump, as opposed to MDI, can significantly enhance the management of insulin administration in patients with GDM by diversifying the sites of insulin delivery. This approach not only promotes optimal glycemic control but also regulates metabolic factors linked to blood sugar, reducing the likelihood of adverse pregnancy outcomes and complications. The clinical relevance and importance of CSII in GDM management highlight its wide-ranging clinical usefulness.

Establishment of an Embryo Implantation Model In Vitro.

Embryo implantation is the first step in the establishment of a successful pregnancy. An in vitro model for embryo implantation is critical for basic biological research, drug development, and screening. This paper presents a simple, rapid, and highly efficient in vitro model for embryo implantation. In this protocol, we first introduce mouse blastocyst acquisition and human endometrial adenocarcinoma cells (Ishikawa)preparation for implantation, followed by the co-culture method for mouse embryos and Ishikawa cells. Finally, we conducted a study to assess the impact of varying concentrations of 17-β-estradiol (E2) and progesterone (P4) on embryo adhesion rates based on this model. Our findings revealed that high concentrations of E2 significantly reduced embryo adhesion, whereas the addition of progesterone could restore the adhesion rate. This model offers a simple and fast platform for evaluating and screening molecules involved in the adhesion process, such as cytokines, drugs, and transcription factors controlling implantation and endometrial receptivity.

Effect of Polymer Architecture and Acidic Group Density on the Degree of Salt Formation in Amorphous Solid Dispersions.

Recent work has shown that an amorphous drug-polymer salt can be highly stable against crystallization under hot and humid storage conditions (e.g., 40 °C/75% RH) and provide fast release and that these advantages depend on the degree of salt formation. Here, we investigate the salt formation between the basic drug lumefantrine (LMF) and several acidic polymers: poly(acrylic acid) (PAA), hypromellose phthalate (HPMCP), hypromellose acetate succinate (HPMCAS), cellulose acetate phthalate (CAP), Eudragit L100, and Eudragit L100-55. Salt formation was performed by "slurry synthesis" where dry components were mixed at room temperature in the presence of a small quantity of an organic solvent, which was subsequently removed. This method achieved more complete salt formation than the conventional methods of hot-melt extrusion and rotary evaporation. The acidic group density of a polymer was determined by nonaqueous titration in the same solvent used for slurry synthesis; the degree of LMF protonation was determined by X-ray photoelectron spectroscopy. The polymers studied show very different abilities to protonate LMF when compared at a common drug loading, following the order PAA > (HPMCP ∼ CAP ∼ L100 ∼ L100-55) > HPMCAS, but the difference largely disappears when the degree of protonation is plotted against the concentration of the available acidic groups for reaction. This indicates that the extent of salt formation is mainly controlled by the acidic group density and is less sensitive to the polymer architecture. Our results are relevant for selecting the optimal polymer to control the degree of ionization in amorphous solid dispersions.

Physiologically Based Biopharmaceutics Modeling for Gefapixant IR Formulation Development and Defining the Bioequivalence Dissolution Safe Space.

Gefapixant is a weakly basic drug which has been formulated as an immediate release tablet for oral administration. A physiologically based biopharmaceutics model (PBBM) was developed based on gefapixant physicochemical properties and clinical pharmacokinetics to aid formulation selection, bioequivalence safe space assessment and dissolution specification settings. In vitro dissolution profiles of different free base and citrate salt formulations were used as an input to the model. The model was validated against the results of independent studies, which included a bioequivalence and a relative bioavailability study, as well as a human ADME study, all meeting acceptance criteria of prediction errors ≤ 20% for both Cmax and AUC. PBBM was also applied to evaluate gastric pH-mediated drug-drug-interaction potential with co-administration of a proton pump inhibitor (PPI), omeprazole. Model results showed good agreement with clinical data in which omeprazole lowered gefapixant exposure for the free base formulation but did not significantly alter gefapixant pharmacokinetics for the citrate based commercial drug product. An extended virtual dissolution bioequivalence safe space was established. Gefapixant drug product batches are anticipated to be bioequivalent with the clinical reference batch when their dissolution is > 80% in 60 minutes. PBBM established a wide dissolution bioequivalence space as part of assuring product quality.

TMEM205 induces TAM/M2 polarization to promote cisplatin resistance in gastric cancer

Cisplatin (DDP) is a basic chemotherapy drug for gastric cancer (GC). With the increase of DDP drug concentration in clinical treatment, cancer cells gradually became resistant. Therefore, it is necessary to find effective therapeutic targets to enhance the sensitivity of GC to DDP. Studies have shown that Transmembrane protein 205 (TMEM205) is overexpressed in DDP-resistant human epidermoid carcinoma cells and correlates with drug resistance, and database analyses show that TMEM 205 is also overexpressed in GC, but its role in cisplatin-resistant gastric cancer remains unclear. In this study, we chose a variety of experiments in vivo and vitro, aiming to investigate the role of TMEM 205 in cisplatin resistance in gastric cancer. The results showed that TMEM 205 promoted proliferation, stemness, epithelial–mesenchymal transition (EMT), migration and angiogenesis of gastric cancer cells through activation of the Wnt/β-catenin signaling pathway. In addition, TMEM205 promotes GC progression by inducing M2 polarization of tumor-associated macrophages (TAMs). These results suggest that TMEM205 may be an effective target to regulate the sensitivity of GC to DDP, providing a new therapeutic direction for clinical treatment.

Influence of Parameters of Mechanochemical Processing on the Efficacy of Complex Solid Dispersion of Anthelmintics

Background: Due to the fact that animal parasitic diseases often occur in the form of mixed infections, it is necessary to use complex drugs with a combination of active substances that act against different classes of helminths. Fenbendazole has a wide spectrum of nematocidal action and is less effective against cestodes. Considering that sheep are often infected with both gastro-intestinal nematodes and cestodes, a complex drug based on fenbendazole, niclosamide with polyvinylpyrrolidone polymer, was developed using mechanochemical technology in order to increase its solubility and bioavailability and reduce the dosages and side effects. Objective: This study aimed to evaluate the influence of mechanochemical technology on the efficacy of complex solid dispersions of anthelmintics against cestodoses and nematodoses. Methods: The influence of different types of mills (roller and planetary mills), levels of energy intensity (20, 40, 60 g), and component ratio (2:20:78; 3:30:67; 4:40:56) during mechanochemical processing was studied on the anthelmintic efficacy of complex solid dispersions of fenbendazole, niclosamide, and polyvinylpyrrolidone in laboratory models of trichinellosis and hymenolepiosis of white mice, and on sheep naturally infected with helminths. Results: The efficacy of complex solid dispersions obtained in the planetary mill was higher than the activity of dispersions obtained in a roller mill. It showed 87.5, 96.36, 83.77, and 99.39% efficacy, respectively, against experimental trichinellosis, hymenolepiosis of white mice, gastrointestinal nematode infection and monieziosis of sheep at a ratio of 2:20:78. The basic drug – fenbendazole demonstrated 31.37 and 22.77% activity against experimental trichinellosis and gastro-intestinal nematode infection of sheep. The basic drug, niclosamide, showed 36.37% efficacy against hymenolepiosis in mice and 28.31% against monieziosis in sheep. It was established that with an increase in the energy intensity level of the planetary mill (20, 40, and 60 g), the decrease in the efficacy of solid dispersion occurred from 73.90 to 59.12% against T. spiralis and from 92.73% to 79.81% against H. nana. Conclusion: The use of mechanochemical technology for the production of solid dispersions of fenbendazole and niclosamide with polyvinylpyrrolidone makes it possible to increase the anthelmintic efficacy by 2.7–3 times compared to the activity of basic substances. It was noted that the complex solid dispersions of anthelmintics obtained in a planetary mill had 7.51–10.17% greater activity in comparison with the samples obtained in a roller mill. The most optimal ratio of active substances was 2:20:78 at a 20 g level of energy intensity of the planetary mill.

The influence of a course of complex application of supravenous laser irradiation of blood and phototherapy on indicators of the neurohormonal status of patients with true eczema

BACKGROUND: In the pathogenesis of true eczema, an important place is occupied by stress, under the influence of which stimulation of the hypothalamus and brain stem occurs, as well as activation of the hypothalamic-pituitary-adrenal axis and the autonomic nervous system. Stress-induced secretion of neurotransmitters impairs the barrier function of the epidermis, slows wound healing, increases itching and inflammation, and suppresses immunity by changing the immune response of T-helper cells. AIM: Assessment of the severity of the corrective effect of a course of application of supravenous laser irradiation of blood and broadband medium-wave phototherapy on the blood levels of adrenocorticotropin, cortisol and beta-endorphin in patients with true eczema with a moderate form of the course. MATERIALS AND METHODS: The study was carried out with the participation of 120 patients with a moderate form of true eczema. Using simple fixed randomization, all patients were divided into 4 groups. The first group (control, n=30) received only basic drug therapy, including the use of detoxification, hyposensitizing, antihistamines and topical glucocorticosteroids. Patients of the second group (comparison group 1, n=30) additionally underwent a course of supravenous laser irradiation of blood. In the third group (comparison group 2, n=30), broadband medium-wave phototherapy was performed against the background of basic therapy. Patients of the fourth group (main group, n=30) in addition to basic therapy received a course of combined exposure to supravenous laser blood irradiation and phototherapy. The concentrations of adrenocorticotropin, cortisol and beta-endorphin were determined in the blood of patients twice (before the start of treatment and 1 month after the start of therapy) using ELISA. The clinical condition of patients in the groups was assessed by changes in the EASI index. Additionally, we studied the dynamics of the level of reactive and personal anxiety using the Spielberger–Khanin questionnaire. RESULTS: Positive dynamics of adrenocorticotropin, cortisol and beta-endorphin were noted only in the comparison groups and the main group, which proves the high efficiency of correction of the neurohumoral status of patients through a course of complex use of supravenous laser blood irradiation and broadband mid-wave phototherapy. Quantitative changes in the assessed parameters during complex therapy with therapeutic physical factors indicate a supra-additive version of their interaction, realized through different modalities, points of application and mechanisms for realizing the biological potential of physiotherapeutic effects. CONCLUSION: The results obtained convincingly prove the effectiveness of an additional course of use of supravenous laser irradiation of blood in combination with broadband medium-wave phototherapy when correcting the neuroendocrine status in patients with true eczema. The close correlation between neurohumoral indicators and clinical and psychological patterns of the disease proves the pathogenetic significance of the studied neuroendocrine indicators, which allows us to consider their dynamics as informative criteria for the effectiveness of the treatment.

Triptolide regulates neutrophil function through the Hippo signaling pathway to alleviate rheumatoid arthritis disease progression

Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by inflammatory changes in the joints, the etiology of which is unclear. It is now well established that regulated cell death (RCD) and migration of neutrophils play an important role in the pathogenesis of RA. Tripterygium wilfordii Hook.f (TwHF) is a total saponin extracted from the root of Tripterygium wilfordii Hook.f, a plant of the family Wesleyanaceae, which has strong anti-inflammatory and immunomodulatory effects and has been used as a basic drug in the clinical treatment of RA. Despite the good efficacy of TwHF treatment, the mechanism of action of TwHF remains unclear. Several studies have demonstrated that the drug tripterygium glycosides, in which TwHF is the main ingredient, has achieved excellent efficacy in the clinical treatment of RA. Investigations have also found that TwHF can affect cellular RCD, cell migration, cell proliferation, and the apoptosis-related Hippo signaling pathway. In this study, we first analyzed the RCD and migration differences of neutrophils in patients with RA through network pharmacology and transcriptome analysis. Subsequently, we used electron microscopy, immunofluorescence, and other methods to identify the RCD phenotype of neutrophils. In collagen-induced arthritis (CIA) model, we demonstrated that Triptolide (the main active ingredient in TwHF) could alleviate the progression of arthritis by reducing the bone destruction and the infiltration of neutrophils. Furthermore, in vitro experiments showed that Triptolide induced neutrophil apoptosis, inhibited the formation of neutrophil extracellular traps (NETs), and impeded the neutrophil migration process in a Hippo pathway-dependent manner. Taken together, these findings indicate that Triptolide has potential for treating RA and provide theoretical support for the clinical application of TwHF, as a traditional Chinese medicine, in RA.

Label-free morphological profiling and isolation of immune cell subsets using VisionSort, a novel, AI-based flow cytometry platform.

Abstract Identification, characterization, and minimally invasive isolation of specific populations of human immune cells are critical for understanding and treating disease. Here we present data on label-free identification of three immune cell subsets by morphological profiling using VisionSort; a label-free, artificial intelligence (AI)-driven cellular analysis and sorting platform. By capturing single-cell digital phenotypes, we characterized mouse T-cells and generated ‘ground truth’ functional profiles for activated and non-activated T cells. A set of machine-learning derived classifiers was generated to identify these phenotypic classes in unlabeled T-cell subsets. The classifier showed an area under the curve (AUC) performance for differentiating between phenotypically defined T cell populations of 0.917. In addition, by using unsupervised machine learning, we were able to resolve activated and non-activated T cell populations label free, using morphological data alone. Using a similar approach, we show label-free differentiation/classification of B cells from plasma cells with an AUC score of 0.941 and M1 and M2 polarized macrophages with an AUC score of 0.878 +/- 0.002 (n=6). Here we report results on the use of a novel, label-free cytometry platform to characterize and isolate human immune cell subsets using morphological profiling and AI with applications for investigators in basic life sciences and drug developers in small molecule, antibody, and cell therapy R&D.

Changing Concepts About Optimal Target Blood Pressure and the Therapeutic Advantages of Azilsartan for Achieving it

The article discusses current issues of the treatment of arterial hypertension. According to presented data, so-called therapeutic nihilism is becoming one of the main barriers to achieving target blood pressure (BP). This nihilism is that despite evidence of the effectiveness of achieving lower BP values, practitioners do not intensify antihypertensive therapy sufficiently to achieve such values. The article specially addresses new criteria for the effectiveness of antihypertensive therapy, which reflect the therapy sustainability. The most commonly used indicator is the duration of the period, during which systolic BP remains in the therapeutic range. The prognostic significance of such indicators is discussed. In these conditions, it is very important to use the most effective antihypertensive drugs for initial antihypertensive therapy, including as a part of combination therapy. This tactic provides more frequent achievement of BP goals without the need for dose adjustment. In this regard, a systematic review was performed, which included sufficiently large randomized studies of the antihypertensive effectiveness of azilsartan medoxomil. This systematic review will provide comprehensive information on a possible role of using the angiotensin II receptor blocker azilsartan as a basic drug for the treatment of a wide range of patients with high BP. Most of the studies included in the systematic review assessed the effectiveness of combination therapy including azilsartan.

Utilizing the allyl-terminated copolymer methoxy(poly(ethylene glycol))-block-poly(jasmine lactone) in the development of amorphous solid dispersions: A comparative study of functionalized and non-functionalized polymer

Molecular interactions are crucial to stabilize amorphous drugs in amorphous solid dispersions (ASDs). Most polymers, however, have only a limited ability to form strong molecular interactions with drugs. Polymers tailored to fit the physicochemical properties of the drug molecule to be incorporated, for instance by allowing the incorporation of specific functional groups, would be highly sought-for in this regard. For this purpose, the novel allyl-terminated polymer methoxy(polyethylene glycol)-block-poly(jasmine lactone) (mPEG-b-PJL) has been synthesized and functionalized to potentially enhance specific drug-polymer interactions. This study investigated the use of mPEG-b-PJL in ASDs, using carvedilol (CAR), a weakly basic model drug. The findings revealed that the acidic functionalized form of the polymer (mPEG-b-PJL-COOH) indeed established stronger molecular interactions with CAR compared to its non-functionalized counterpart mPEG-b-PJL. Evaluations on polymer effectiveness in forming ASDs demonstrated that mPEG-b-PJL-COOH outperformed its non-functionalized counterpart in miscibility, drug loading ability, and stability, inferred from reduced molecular mobility. However, dissolution tests indicated that ASDs with mPEG-b-PJL-COOH did not significantly improve the dissolution behaviour compared to amorphous CAR alone, despite potential solubility enhancement through micelle formation. Overall, this study confirms the potential of functionalized polymers in ASD formulations, while the challenge of improving dissolution performance in these ASDs remains an area of further development.

Open-label observational study of effectiveness and tolerability of ipidacrine in treatment of patients with diabetic polyneuropathy (DIAMANT study)

Diabetic polyneuropathy (DPN) is one of the most common complications of diabetes mellitus, leading to the development of flaccid paresis, neuropathic pain syndrome, sensitive ataxia, as well as trophic disorders in the distal parts of the lower extremities.The purpose of the randomized, open-label, comparative, prospective study was to evaluate the effectiveness and tolerability of ipidacrine in the complex treatment of patients with DPN.Materials and methods. Patients with DPN (n = 60) were randomized into 2 groups. Both groups received basic therapy (alpha-lipoic acid, B vitamins, gabapentin); in the treatment of patients of the main group (n = 30), in addition, ipidacrine was used (Ipidacrine-SZ, North Star Co., Russia). We have analyzed the intensity of pain syndrome (VAS-P), the average daily dosage of gabapentin, and the results of the neuropathic dysfunctional scale (modified version, NDSm), Pittsburgh Sleep Quality Index, PSQI), Global Rating of Change Scale (GROC), the results of electroneuromyography (ENMG). The total duration of the observation and treatment period was 2 months.Results. After 2 months of therapy in the main group of patients, compared with the control group, there was significantly more complete pain control (VAS-P: 3.0 ± 0.9 vs 3.6 ± 0.8), a decrease in the average daily dosage of gabapentin (390 vs 500 mg/day), reduction in the severity of clinical manifestations of polyneuropathic syndrome (NDSm: 4.4 ± 1.0 vs 4.9 ± 1.0 points) and improvement in sleep quality (PSQI: 6.8 ± 1.3 vs 7.9 ± 1.7). According to ENMG data, patients in the main group showed a significant improvement in the neurophysiological parameters of both motor and sensory fibers, which was significantly more pronounced compared to the control group. A significantly larger proportion of patients in the main group assessed the improvement from the therapy as ‘pronounced’ (GROC: 10/33.3 % vs 6/20.0 %).Conclusions. The use of ipidacrine in complex therapy of patients with DPN can significantly reduce the clinical manifestations of disease and improve the neurophysiological parameters of the peripheral nerves of the lower extremities. Ipidacrine can be considered as a basic drug for the treatment of patients with neurological complications of diabetes mellitus.

Standardization of next-generation sequencing for detecting mutations associated with targeted therapy and immunotherapy based on dynamic pattern of expandable detection range

Next-generation sequencing (NGS) has laid the foundation for precision oncology care. NGS technologynot only represents an innovation in the methodology but also brings about a revolution in the concept of detecting gene alterations for targeted therapy and immunotherapy of cancers. As basic biomedical research and drug development progress, the landscape of biomarkers associated with gene alterations continues to evolve. Thus, the standardization of NGS-based gene alterations detection should take into account the characteristics of NGS methods and the gene alteration biomarkers. To be specific, whether employed as in vitro diagnostic products or laboratory-developed tests, the detection range can be expanded in response to changes in the clinical evidence level of biomarkers during the process of assay development and clinical application. Such adjustment needs the analytical validation results for supplemented genes or mutant sites within a predefined detection system, which will maximally fulfill the evolving clinical demands in cancer diagnosis and treatment, simultaneously mitigate potential risks effectively. This article primarily discusses the standardization pathway for NGS testing of gene alterations in cancer by focusing on the characteristics of NGS methods, gene alteration biomarkers, and the current status of the standardization of NGS application.

Correction of peroxidation of lipids with upadacitinib, a Janus kinase 1 inhibitor, in patients with true eczema

Objective. To study the effect of upadacitinib (UPA), a Janus kinase inhibitor 1 kinase, on the status of peroxidation of lipids (POL) and the antioxidant system in patients with true eczema. Subjects and methods. The investigation involved 64 patiens (43 males and 21 females) with true eczema (the mean age was 58.5±3.4 years). The patients were randomized into 2 groups: 1) 33 patients who received basic drug therapy (BDT); 2) 31 patients who received the Janus kinase 1 inhibitor UPA 15 mg/day during 2 months. The components of the antioxidant system and the state of POL were determined by enzyme immunoassay. Results. After 2 months of therapy, Group 1 showed no statistically significant changes in the analyzed parameters from the baseline level (p>0.05). In Group 2, the total oxidative capacity of blood reduced by 1.27 tines; the level of oxidized low-density lipoproteins decreased by 1.28 times; the total antioxidant activity of blood increased by 1.24 times; the level of superoxidase dismutase increased by 1.43 times (p < 0.001 for all values). Conclusion. The combined use of BDT and the JAK1 inhibitor UPA in patients with true eczema contributed to a statistically significant decline in the oxidative capacity of blood and POL products along with the enhanced antioxidant activity of blood.

Abstract 4239: Pancreatic cancer organoids from the Human Cancer Models Initiative biobank reflect disease genotypes, capture patient heterogeneity, and are amenable to therapeutic screening

Abstract Pancreatic cancer is the fourth leading cause of cancer-related death in the United States (~3% of all cancer cases) and has one of the lowest 5-year relative survival rates. There is a lack of clinically representative, easily available, validated, in vitro pancreatic cancer models that reflect the genomic and phenotypic diversity of the disease. The Human Cancer Models Initiative (HCMI) is an international collaborative project devoted to the development and distribution of approximately 1,000 novel human primary tissue-derived tumor models supported with clinical and molecular annotation. These models were manufactured, characterized, and validated at a not-for-profit biobank and made available for academic and commercial use in basic research, compound screening, and drug development. Available pancreatic cancer organoids (PCOs) from the HCMI biobank (n=46 unique models, n=41 unique donors) were acquired and subjected to a targeted next-generation sequencing hybridization capture, pan-cancer panel of 663 genes. Data were compared to publicly available clinical and genotyping results from the patient’s tumor (n=42) that the model was derived from as well as cancer datasets such as The Cancer Genome Atlas (TCGA). A subset of models was cultured following standard procedures and tested for response to chemotherapeutics (cisplatin, nab-paclitaxel), KRAS-targeting inhibitors (MRTX1133, KR-pep-2D), or PARP inhibitors (PJ34, olaparib) at three time points. A luminescent ATP viability assay was used to assess response. PCOs from the HCMI were predominantly derived from primary tumors (75%), had an adenocarcinoma ductal histological type, and were from female patients (56%) with an average age of 65 years at diagnosis. Models had mutations in key disease-relevant driver genes including KRAS, TP53, SMAD4, and/or CDKN2A at frequencies similar to the TGCA cohort. Sequencing revealed mutations in genes less commonly associated with pancreatic cancer, including BRCA, APC, BRAF, TGFBR2, and ARID1A, albeit at lower frequencies. Most models had mutations in KRAS including G12D, G12V, G12C, and G12R variants. Significant but not complete concordance was seen in comparison with the mutation status of the patient’s respective tumor, indicating potential genotypic drift had occurred. Response to acute treatment varied by model, genotype, timepoint, and drug. Chemotherapeutics like Cisplatin were broadly cytotoxic while MRTX1133 exhibited greater toxicity in models with KRAS G12D variants as compared with KRAS wild type. Patient-derived cancer organoids from the HCMI recapitulate genotypes seen in patient populations and respond to therapeutic treatment in vitro. Citation Format: Stephen Friend, Rachel Demerath, Matthew Graziano, James Clinton. Pancreatic cancer organoids from the Human Cancer Models Initiative biobank reflect disease genotypes, capture patient heterogeneity, and are amenable to therapeutic screening [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4239.

The use of belimumab on patients with both systemic lupus erythematosus and immune thrombocytopenia: A retrospective cohort study.

The objective of this study is to provide a description of a group of retrospective cohort outcomes in patients with systemic lupus erythematosus (SLE) complicated with immune thrombocytopenia (ITP) receiving belimumab. This study reports on the treatment of 10 female patients (mean age 34.3 ± 14.0years, mean weight 58.7 ± 18.2kg) with both SLE and ITP who received belimumab in addition to basic drug therapy. The belimumab treatment regimen consisted of a dosage of 10mg/kg, with an initial infusion every 2weeks for the first 3 doses, followed by an infusion every 4weeks. Ten patients were included in the study. The overall response rate of thrombocytopenia was 90% after treatment. The parameters such as platelet count, lymphocyte count, erythrocyte count, hemoglobin, dsDNA, C3, and C4 were significantly improved (p < .05). The SLE Disease Activity Index (SLEDAI), British Islet lupus Assessment Group 2004 (BILAG-2004), and Physician Global assessment (PGA) scores were significantly decreased (p < .05). There were no significant differences in glutamic pyruvic transaminase (ALT), glutamic oxaloacetic transaminase (AST), and serum creatinine (Scr) before and after treatment (p > .05). Belimumab shows promising clinical outcomes in the treatment on patients with both SLE and ITP. Further studies are needed to validate these findings in larger patient populations and compare the efficacy of belimumab with other treatments for SLE complicated with ITP. Long-term response rates and adverse events associated with belimumab treatment also warrant further investigation.

Zebrafish as a Model for Cardiovascular and Metabolic Disease: The Future of Precision Medicine.

The zebrafish (Danio rerio) has emerged as an appreciated and versatile model organism for studying cardiovascular and metabolic diseases, offering unique advantages for both basic research and drug discovery. The genetic conservation between zebrafish and humans and their high fecundity and transparent embryos allow for efficient large-scale genetic and drug-oriented screening studies. Zebrafish possess a simplified cardiovascular system that shares similarities with mammals, making them particularly suitable for modeling various aspects of heart development, function, and disease. The transparency of zebrafish embryos enables the real-time visualization of cardiovascular dynamics, offering insights into early embryonic events and facilitating the study of heart-related anomalies. In metabolic research, zebrafish provide a cost-effective platform for modeling obesity, type 2 diabetes, hyperlipidemia, and other metabolic disorders. Their high reproductive rate allows for the generation of large cohorts for robust statistical analyses, while advanced genetic tools, such as CRISPR/Cas9, enable precise gene editing with which to model specific genetic mutations associated with human diseases. Zebrafish metabolic models have been instrumental in elucidating the molecular mechanisms underlying metabolic diseases, studying the effects of environmental factors, and identifying potential therapeutic targets. Additionally, the permeability of zebrafish embryos to small molecules facilitates drug discovery and screening, offering a rapid and economical approach to identifying compounds with therapeutic potential. In conclusion, zebrafish cardiovascular and metabolic disease models continue to contribute significantly to our perception of disease pathogenesis, providing a platform for translational research and developing novel therapeutic interventions. The versatility, scalability, and genetic manipulability of zebrafish position them as an invaluable asset in unraveling the complexities of cardiovascular and metabolic diseases. This review presents an overview of the zebrafish model's key features and contributions to investigating cardiovascular and metabolic disorders. We discuss the benefits and drawbacks of using zebrafish models to study human disease and the critical findings revealed by the progress in this endeavor to date.

RE-TRABECULECTOMY + 5-FLUOROURACIL IN PRIMARY ANGLE CLOSURE GLAUCOMA PATIENTS AGGRAVATED BY CONSUMPTION OF SCHIZOAFFECTIVE DRUG

Introduction : PACG occurs when the anterior chamber angle is occluded by the iris thus reducing aqueous humor outflow. Most schizoaffective patients use anticholinergic drugs which may result in iridocorneal angle closure through deposition. This article reported a Re-Trabeculectomy + 5 FU surgery in PACG which was aggravated by the use of schizoaffective drugs&#x0D; Case Illustration : A 43 year old woman, underwent Re-Trabeculectomy + 5 FU on LE after increasing IOP and regularly took schizoaffective drugs. Tapering of schizoaffective therapy was done 1 month preoperatively. Patient presented with LE UCVA of 3/60 and LE IOP is 30.9 mmHg with three anti- glaucoma medications. LE examinations revealed VH1 AC, bayonet sign and cupping on funduscope, closed angle on gonioscope, nasal step defect on humphrey and diffuse RNFL thinning on OCT. On the first postoperative day LE IOP is 18.5 mmHg. The schizoaffective therapy was re-initiated from psychiatric and evaluation was done weekly&#x0D; Discussion : Re-trabeculectomy surgery have been done considering the failure of the first trabeculectomy and administration of 5-Fluorouracil as an anti-fibrosis. The benefits of reducing preoperative dose of schizoaffective drugs for a month due to having an anticholinergic effect and reduces IOP by 5 mmHg. Psychiatrists and ophthalmologists work together to try to administer basic schizoaffective drug doses and evaluate IOP to keep it under control.&#x0D; Conclusion : The re-operative action was carried out by adding anti-fibrosis and cooperating with psychiatry for postoperative tapering of schizoaffective drugs. Long-term use of antidepressant drugs and benzodiazepines increases PACG.