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Journal of Cellular and Molecular... Apr 2024Acute myelogenous leukaemia (AML) originates and is maintained by leukaemic stem cells (LSCs) that are inherently resistant to antiproliferative therapies, indicating...
Acute myelogenous leukaemia (AML) originates and is maintained by leukaemic stem cells (LSCs) that are inherently resistant to antiproliferative therapies, indicating that a critical strategy for overcoming chemoresistance in AML therapy is to eradicate LSCs. In this work, we investigated the anti-AML activity of bortezomib (BTZ), emphasizing its anti-LSC potential, using KG-1a cells, an AML cell line with stem-like properties. BTZ presented potent cytotoxicity to both solid and haematological malignancy cells and reduced the stem-like features of KG-1a cells, as observed by the reduction in CD34- and CD123-positive cells. A reduction in NF-κB p65 nuclear staining was observed in BTZ-treated KG-1a cells, in addition to upregulation of the NF-κB inhibitor gene NFΚBIB. BTZ-induced DNA fragmentation, nuclear condensation, cell shrinkage and loss of transmembrane mitochondrial potential along with an increase in active caspase-3 and cleaved PARP-(Asp 214) level in KG-1a cells. Furthermore, BTZ-induced cell death was partially prevented by pretreatment with the pancaspase inhibitor Z-VAD-(OMe)-FMK, indicating that BTZ induces caspase-mediated apoptosis. BTZ also increased mitochondrial superoxide levels in KG-1a cells, and BTZ-induced apoptosis was partially prevented by pretreatment with the antioxidant N-acetylcysteine, indicating that BTZ induces oxidative stress-mediated apoptosis in KG-1a cells. At a dosage of 0.1 mg/kg every other day for 2 weeks, BTZ significantly reduced the percentage of hCD45-positive cells in the bone marrow and peripheral blood of NSG mice engrafted with KG-1a cells with tolerable toxicity. Taken together, these data indicate that the anti-LSC potential of BTZ appears to be an important strategy for AML treatment.
Topics: Bortezomib; Oxidative Stress; Humans; Leukemia, Myeloid, Acute; Animals; NF-kappa B; Cell Line, Tumor; Mice; Neoplastic Stem Cells; Apoptosis; Antineoplastic Agents; Xenograft Model Antitumor Assays; Mice, SCID
PubMed: 38652192
DOI: 10.1111/jcmm.18333 -
Frontiers in Immunology 2024Sepsis is a systemic inflammatory response to a severe, life-threatening infection with organ dysfunction. Although there is no effective treatment for this fatal...
Sepsis is a systemic inflammatory response to a severe, life-threatening infection with organ dysfunction. Although there is no effective treatment for this fatal illness, a deeper understanding of the pathophysiological basis of sepsis and its underlying mechanisms could lead to the development of new treatment approaches. Here, we demonstrate that the selective Bruton's tyrosine kinase (Btk) inhibitor acalabrutinib augments survival rates in a lipopolysaccharide (LPS)-induced septic model. Our and findings both indicate that acalabrutinib reduces IL-6 production specifically in marginal zone B (MZ B) cells rather than in macrophages. Furthermore, Btk-deficient MZ B cells exhibited suppressed LPS-induced IL-6 production . Nuclear factor-kappa B (NF-κB) signaling, which is the downstream signaling cascade of Toll-like receptor 4 (TLR4), was also severely attenuated in Btk-deficient MZ B cells. These findings suggest that Btk blockade may prevent sepsis by inhibiting IL-6 production in MZ B cells. In addition, although Btk inhibition may adversely affect B cell maturation and humoral immunity, antibody responses were not impaired when acalabrutinib was administered for a short period after immunization with T-cell-independent (TI) and T-cell-dependent (TD) antigens. In contrast, long-term administration of acalabrutinib slightly impaired humoral immunity. Therefore, these findings suggest that Btk inhibitors may be a potential option for alleviating endotoxic shock without compromising humoral immunity and emphasize the importance of maintaining a delicate balance between immunomodulation and inflammation suppression.
Topics: Animals; Mice; Agammaglobulinaemia Tyrosine Kinase; Benzamides; Interleukin-6; Lipopolysaccharides; NF-kappa B; Pyrazines; Shock, Septic; B-Lymphocytes
PubMed: 38638439
DOI: 10.3389/fimmu.2024.1388947 -
Frontiers in Endocrinology 2024Blood glycosylated hemoglobin level can be affected by various factors in patients with type 2 diabetes and cardiovascular diseases. Frequent measurements are expensive,...
UNLABELLED
Blood glycosylated hemoglobin level can be affected by various factors in patients with type 2 diabetes and cardiovascular diseases. Frequent measurements are expensive, and a suitable estimation method could improve treatment outcomes.
PATIENTS AND METHODS
93 patients were recruited in this research. We analyzed a number of parameters such as age, glucose level, blood pressure, Body Mass Index, cholesterol level, echocardiography et al. Patients were prescribed metformin. One group (n=60) additionally was taking sitagliptin. We applied eight machine learning methods (k nearest neighbors, Random Forest, Support Vector Machine, Extra Trees, XGBoost, Linear Regression including Lasso, and ElasticNet) to predict exact values of glycosylated hemoglobin in two years.
RESULTS
We applied a feature selection approach using step-by-step removal of them, Linear Regression on remaining features, and Pearson's correlation coefficient on the validation set. As a result, we got four different subsets for each group. We compared all eight Machine Learning methods using different hyperparameters on validation sets and chose the best models. We tested the best models on the external testing set and got R = 0.88, C Index = 0.857, Accuracy = 0.846, and MAE (Mean Absolute Error) = 0.65 for the first group, R = 0.86, C Index = 0.80, Accuracy = 0.75, and MAE = 0.41 for the second group.
CONCLUSION
The resulting algorithms could be used to assist clinical decision-making on prescribing anti-diabetic medications in pursuit of achieving glycemic control.
Topics: Humans; Diabetes Mellitus, Type 2; Glycated Hemoglobin; Cardiovascular Diseases; Metformin; Sitagliptin Phosphate
PubMed: 38638138
DOI: 10.3389/fendo.2024.1305640 -
Scientific Reports Apr 2024For the majority of cytotoxic drug preparations, such as bortezomib, the unit dose information is not available. In addition, there is a lack of information on the...
For the majority of cytotoxic drug preparations, such as bortezomib, the unit dose information is not available. In addition, there is a lack of information on the physicochemical stability of the pharmaceutical preparation after opening; this information is crucial for its administration to patients in successive visits, and the per-patient cost can be affected. The purpose of our proposed physicochemical stability study is to determine the shelf life of the reconstituted liquid product under refrigeration and clinical practice conditions. This evaluation was extended to both vials and ready-to-use syringes prefilled with the contents of the open vial. The stability test design includes the specified storage conditions and the critical physicochemical parameters of reconstituted injectable bortezomib. Furthermore, this approach includes the determination of impurities, the monitoring of the purity of the mean peak using a photodiode array, the control of the mass balance, the monitoring of subvisible particles using a laser diffraction analyser, and the setting of stability specifications. For the chemical stability study, the amount of bortezomib and its degradation products were determined using a stability-indicating HPLC method. The physical inspection of the samples was performed throughout the stability study, and their pH values were also monitored. Bortezomib (2.5 mg/mL) in 0.9% sodium chloride remained stable for 7 days when stored in both polypropylene syringes and vials at 5 ± 3 °C (refrigeration) and shielded from light. Additionally, it exhibits stability for 24 h under storage conditions simulating clinical use (20-30 °C and protected from light). The proposed protocol provides the stability in the vials once reconstituted and in prefilled refrigerated syringes; this protocol can be used to reduce waste and increase cost savings.
Topics: Humans; Bortezomib; Drug Packaging; Antineoplastic Agents; Polypropylenes; Drug Stability; Syringes; Chromatography, High Pressure Liquid; Pharmaceutical Solutions
PubMed: 38637597
DOI: 10.1038/s41598-024-58473-1 -
JCO Precision Oncology Apr 2024The multicenter, open-label, randomized phase 2 NCI-9944 study (NCT02595892) demonstrated that addition of ATR inhibitor (ATRi) berzosertib to gemcitabine increased... (Randomized Controlled Trial)
Randomized Controlled Trial
PURPOSE
The multicenter, open-label, randomized phase 2 NCI-9944 study (NCT02595892) demonstrated that addition of ATR inhibitor (ATRi) berzosertib to gemcitabine increased progression-free survival (PFS) compared to gemcitabine alone (hazard ratio [HR]=0.57, one-sided log-rank = .044, which met the one-sided significance level of 0.1 used for sample size calculation).
METHODS
We report here the final overall survival (OS) analysis and biomarker correlations (ATM expression by immunohistochemistry, mutational signature 3 and a genomic biomarker of replication stress) along with post-hoc exploratory analyses to adjust for crossover from gemcitabine to gemcitabine/berzosertib.
RESULTS
At the data cutoff of January 27, 2023 (>30 months of additional follow-up from the primary analysis), median OS was 59.4 weeks with gemcitabine/berzosertib versus 43.0 weeks with gemcitabine alone (HR 0.79, 90% CI 0.52 to 1.2, one-sided log-rank = .18). An OS benefit with addition of berzosertib to gemcitabine was suggested in patients stratified into the platinum-free interval ≤3 months (N = 26) subgroup (HR, 0.48, 90% CI 0.22 to 1.01, one-sided log-rank =.04) and in patients with ATM-negative/low (N = 24) tumors (HR, 0.50, 90% CI 0.23 to 1.08, one-sided log-rank = .06).
CONCLUSION
The results of this follow-up analysis continue to support the promise of combined gemcitabine/ATRi therapy in platinum resistant ovarian cancer, an active area of investigation with several ongoing clinical trials.
Topics: Humans; Female; Gemcitabine; Deoxycytidine; Carcinoma, Ovarian Epithelial; Protein Kinase Inhibitors; Ovarian Neoplasms; Ataxia Telangiectasia Mutated Proteins; Isoxazoles; Pyrazines
PubMed: 38635934
DOI: 10.1200/PO.23.00635 -
Journal of Cellular and Molecular... Apr 2024The rise of pyrazinamide (PZA)-resistant strains of Mycobacterium tuberculosis (MTB) poses a major challenge to conventional tuberculosis (TB) treatments. PZA, a...
The rise of pyrazinamide (PZA)-resistant strains of Mycobacterium tuberculosis (MTB) poses a major challenge to conventional tuberculosis (TB) treatments. PZA, a cornerstone of TB therapy, must be activated by the mycobacterial enzyme pyrazinamidase (PZase) to convert its active form, pyrazinoic acid, which targets the ribosomal protein S1. Resistance, often associated with mutations in the RpsA protein, complicates treatment and highlights a critical gap in the understanding of structural dynamics and mechanisms of resistance, particularly in the context of the G97D mutation. This study utilizes a novel integration of computational techniques, including multiscale biomolecular and molecular dynamics simulations, physicochemical and medicinal chemistry predictions, quantum computations and virtual screening from the ZINC and Chembridge databases, to elucidate the resistance mechanism and identify lead compounds that have the potential to improve treatment outcomes for PZA-resistant MTB, namely ZINC15913786, ZINC20735155, Chem10269711, Chem10279789 and Chem10295790. These computational methods offer a cost-effective, rapid alternative to traditional drug trials by bypassing the need for organic subjects while providing highly accurate insight into the binding sites and efficacy of new drug candidates. The need for rapid and appropriate drug development emphasizes the need for robust computational analysis to justify further validation through in vitro and in vivo experiments.
Topics: Humans; Pyrazinamide; Mycobacterium tuberculosis; Antitubercular Agents; Tuberculosis; Tuberculosis, Multidrug-Resistant; Mutation; Microbial Sensitivity Tests
PubMed: 38634203
DOI: 10.1111/jcmm.18279 -
JAMA Network Open Apr 2024Although insomnia guidelines recommend the use of several individual hypnotics, the most useful hypnotic for treating insomnia in a clinical setting remains unclear. (Observational Study)
Observational Study
IMPORTANCE
Although insomnia guidelines recommend the use of several individual hypnotics, the most useful hypnotic for treating insomnia in a clinical setting remains unclear.
OBJECTIVE
To determine which guideline-recommended hypnotics have lower risks of monotherapy failure and which hypnotics have a higher risk of long-term prescription for insomnia treatment.
DESIGN, SETTING, AND PARTICIPANTS
This retrospective observational cohort study used data from the Japan Medical Data Center Claims Database from April 1, 2005, to March 31, 2021. Participants included adults whose first prescribed pharmaceutical treatment for insomnia was guideline-recommended hypnotic monotherapy. Data were analyzed from December 24, 2022, to September 26, 2023.
EXPOSURES
Suvorexant, ramelteon, eszopiclone, zolpidem, and triazolam monotherapy.
MAIN OUTCOMES AND MEASURES
The primary outcome was monotherapy failure, defined as a change in hypnotic or having an additional hypnotic prescribed for insomnia within 6 months of the first prescription of a guideline-recommended hypnotic monotherapy. The secondary outcome was monotherapy discontinuation, defined as no prescription of any hypnotic for 2 consecutive months within 6 months after prescribing a guideline-recommended hypnotic in patients for whom monotherapy did not fail. Monotherapy failure and discontinuation were compared using Cox proportional hazards and logistic regression models, respectively.
RESULTS
The study included 239 568 adults (median age, 45 [IQR, 34-55] years; 50.2% women) whose first prescription for insomnia was guideline-recommended hypnotic monotherapy. During the 6-month follow-up period, 24 778 patients (10.3%) experienced failure of monotherapy with a guideline-recommended hypnotic. In comparison with eszopiclone, there were more cases of monotherapy failure for ramelteon (adjusted hazard ratio [AHR], 1.23 [95% CI], 1.17-1.30; P < .001), fewer cases for zolpidem (AHR, 0.84 [95% CI, 0.81-0.87]; P < .001) and triazolam (AHR, 0.82 [95% CI, 0.78-0.87]; P < .001), and no significant difference between suvorexant and eszopiclone. Among those without monotherapy failure, monotherapy was discontinued in 84.6% of patients, with more discontinuations for ramelteon (adjusted odds ratio [AOR], 1.31 [95% CI, 1.24-1.40]; P < .001) and suvorexant (AOR, 1.20 [95% CI, 1.15-1.26]; P < .001) than for eszopiclone and no significant difference between zolpidem or triazolam and eszopiclone.
CONCLUSIONS AND RELEVANCE
Due to uncontrolled confounding factors in this cohort study, no conclusions regarding the pharmacologic properties of guideline-recommended hypnotics can be drawn based on these results. Further studies accounting for confounding factors, including diagnoses of chronic vs acute insomnia disorder, insomnia and psychiatric symptom severity, and physician attitudes toward hypnotic prescription, are needed.
Topics: Adult; Female; Humans; Male; Middle Aged; Cohort Studies; Eszopiclone; Hypnotics and Sedatives; Indenes; Japan; Retrospective Studies; Sleep Initiation and Maintenance Disorders; Treatment Failure; Triazolam; Zolpidem
PubMed: 38630476
DOI: 10.1001/jamanetworkopen.2024.6865 -
Peptides Jul 2024G-protein coupled receptor-120 (GPR120; FFAR4) is a free fatty acid receptor, widely researched for its glucoregulatory and insulin release activities. This study aimed...
G-protein coupled receptor-120 (GPR120; FFAR4) is a free fatty acid receptor, widely researched for its glucoregulatory and insulin release activities. This study aimed to investigate the metabolic advantage of FFAR4/GPR120 activation using combination therapy. C57BL/6 mice, fed a High Fat Diet (HFD) for 120 days to induce obesity-diabetes, were subsequently treated with a single daily oral dose of FFAR4/GPR120 agonist Compound A (CpdA) (0.1μmol/kg) alone or in combination with sitagliptin (50 mg/kg) for 21 days. After 21-days, glucose homeostasis, islet morphology, plasma hormones and lipids, tissue genes (qPCR) and protein expression (immunocytochemistry) were assessed. Oral administration of CpdA improved glucose tolerance (34% p<0.001) and increased circulating insulin (38% p<0.001). Addition of CpdA with the dipeptidyl peptidase-IV (DPP-IV) inhibitor, sitagliptin, further improved insulin release (44%) compared to sitagliptin alone and reduced fat mass (p<0.05). CpdA alone (50%) and in combination with sitagliptin (89%) induced marked reductions in LDL-cholesterol, with greater effects in combination (p<0.05). All treatment regimens restored pancreatic islet and beta-cell area and mass, complemented with significantly elevated beta-cell proliferation rates. A marked increase in circulating GLP-1 (53%) was observed, with further increases in combination (38%). With treatment, mice presented with increased Gcg (proglucagon) gene expression in the jejunum (130% increase) and ileum (120% increase), indicative of GLP-1 synthesis and secretion. These data highlight the therapeutic promise of FFAR4/GPR120 activation and the potential for combined benefit with incretin enhancing DPP-IV inhibitors in the regulation of beta cell proliferation and diabetes.
Topics: Animals; Glucagon-Like Peptide 1; Receptors, G-Protein-Coupled; Mice; Insulin-Secreting Cells; Diet, High-Fat; Dipeptidyl-Peptidase IV Inhibitors; Sitagliptin Phosphate; Cell Proliferation; Obesity; Male; Dipeptidyl Peptidase 4; Mice, Inbred C57BL; Homeostasis; Insulin; Glucose; Mice, Obese
PubMed: 38621590
DOI: 10.1016/j.peptides.2024.171218 -
Blood Advances Apr 2024
Jian Y, Chang L, Shi M-X, et al. Pomalidomide, bortezomib, and dexamethasone for newly diagnosed multiple myeloma patients with renal impairment. Blood Adv. 2023;7(24):7581-7584.
Topics: Humans; Multiple Myeloma; Bortezomib; Thalidomide; Renal Insufficiency; Dexamethasone
PubMed: 38619856
DOI: 10.1182/bloodadvances.2024013036 -
ACS Omega Apr 2024Although cigar tobacco leaves (CTLs) have a high economic value, research regarding the flavor characteristics of CTLs is currently limited. A comprehensive study of the...
Characterization of Flavor Profiles of Cigar Tobacco Leaves Grown in China via Headspace-Gas Chromatography-Ion Mobility Spectrometry Coupled with Multivariate Analysis and Sensory Evaluation.
Although cigar tobacco leaves (CTLs) have a high economic value, research regarding the flavor characteristics of CTLs is currently limited. A comprehensive study of the flavor characteristics of CTLs from different regions of China was conducted by identifying their volatile-flavor-containing compounds (VFCs) and flavors. The samples were analyzed via gas chromatography-ion mobility spectrometry (GC-IMS) and sensory evaluation. Results revealed considerable differences in the VFC contents of CTLs from different regions of China, suggesting that the VFLs of CTLs could be influenced by geographical origin. Mainly, phenols, pyrazines, and aldehydes were present in the CTLs from Sichuan. High contents of esters and pyrazines were present in the CTLs from Hubei, while esters were the major components of the CTLs from Hainan. Multivariate analysis results showed the effective differentiation of samples from different geographical origins based on the GC-IMS results. Sensory evaluation revealed that the flavors of CTLs from different geographical origins were different. 1,8-Pinene, 3-methyl-3-butene-1-ol, 2,3-dimethyl-5-ethylpyrazine, 4-methyl-3-penten-2-one, and ()-2-pentenal might serve as geographical marker compounds, indicating the geographical origin of CTLs based on the results of GC-IMS and sensory evaluation. This study may be beneficial for the trade of CTLs and the development of cigar products.
PubMed: 38617669
DOI: 10.1021/acsomega.3c09499