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2.
Trials ; 25(1): 324, 2024 May 16.
Article En | MEDLINE | ID: mdl-38755709

BACKGROUND: The optimal antithrombotic strategy early after aortic valve replacement surgery with a biological valve remains controversial due to lack of high-quality evidence. Either oral anticoagulants or acetylsalicylic acid should be considered for the first 3 months. Hypo-attenuated leaflet thickening on cardiac computed tomography has been associated with latent bioprosthetic valve thrombosis and may be prevented with anticoagulation. We hypothesize that anticoagulation with apixaban is superior to single antiplatelet therapy with acetylsalicylic acid in reducing hypo-attenuated leaflet thickening of bioprosthetic aortic valve prostheses. METHODS: In this prospective, open-label, randomized trial, patients undergoing isolated aortic valve replacement surgery with rapid deployment bioprosthetic valves will be randomized. The treatment group will receive 5 mg of apixaban twice a day for the first 3 months and 100 mg of acetylsalicylic acid thereafter. The control group will be administered 100 mg of acetylsalicylic acid once a day, indefinitely. After the 3-month treatment period, a contrast-enhanced electrocardiogram-gated cardiac computed tomography will be performed to identify hypo-attenuated leaflet thickening of the bioprosthetic valve. The primary objective of the study is to assess the impact of apixaban on the prevention of hypo-attenuated leaflet thickening at 3 months. The secondary and exploratory endpoints will be clinical outcomes and safety profiles of the two strategies. DISCUSSION: Antithrombotic therapy after aortic valve replacement is used to prevent valve thrombosis and systemic thromboembolism. Latent bioprosthetic valve thrombosis is a precursor of clinically significant prosthetic valve dysfunction or thromboembolic events. The hallmark feature of latent bioprosthetic valve thrombosis is hypo-attenuated leaflet thickening on cardiac computed tomography. Subclinical leaflet thrombosis occurs frequently in bioprosthetic aortic valves, more commonly in transcatheter than in surgical valves. There is no evidence on the effect of direct oral anticoagulants on the incidence of hypo-attenuated leaflet thickening after surgical aortic valve replacement with rapid deployment bioprostheses. TRIAL REGISTRATION: ClinicalTrials.gov NCT06184113. Registered on December 28, 2023.


Aortic Valve , Aspirin , Bioprosthesis , Factor Xa Inhibitors , Heart Valve Prosthesis Implantation , Heart Valve Prosthesis , Pyrazoles , Pyridones , Randomized Controlled Trials as Topic , Thrombosis , Humans , Aspirin/administration & dosage , Aspirin/therapeutic use , Aspirin/adverse effects , Pyridones/therapeutic use , Pyridones/administration & dosage , Pyridones/adverse effects , Prospective Studies , Heart Valve Prosthesis/adverse effects , Aortic Valve/surgery , Aortic Valve/diagnostic imaging , Thrombosis/prevention & control , Thrombosis/etiology , Pyrazoles/therapeutic use , Pyrazoles/administration & dosage , Pyrazoles/adverse effects , Factor Xa Inhibitors/administration & dosage , Factor Xa Inhibitors/adverse effects , Factor Xa Inhibitors/therapeutic use , Heart Valve Prosthesis Implantation/adverse effects , Heart Valve Prosthesis Implantation/instrumentation , Heart Valve Prosthesis Implantation/methods , Treatment Outcome , Platelet Aggregation Inhibitors/administration & dosage , Platelet Aggregation Inhibitors/therapeutic use , Platelet Aggregation Inhibitors/adverse effects , Female , Male , Middle Aged , Time Factors , Aged , Adult , Fibrinolytic Agents/administration & dosage , Fibrinolytic Agents/adverse effects
3.
Sci Total Environ ; 932: 172811, 2024 Jul 01.
Article En | MEDLINE | ID: mdl-38701918

Fipronil is a persistent insecticide known to transfer into hen eggs from exposure from animal drinking water and feed, but some questions remain regarding its transfer behavior and distribution characteristics. Therefore, the dynamic metabolism, residue distribution and transfer factor (TF) of fipronil were investigated in 11 edible tissues of laying hens and eggs over 21 days. After a continuous low-dose drinking water exposure scenario, the sum of fipronil and all its metabolites (defined as fipronilT) quickly transferred to each edible tissue and gradually increased with exposure time. FipronilT residue in eggs first appeared at 3 days and then gradually increased. After a single high-dose feed exposure scenario, fipronilT residue in edible tissues first appeared after 2 h, quickly peaked at 1 day, and then gradually decreased. In eggs, fipronilT residue first appeared at 2 days, peaked 6-7 days and then gradually decreased. The TF values followed the order of the skin (0.30-0.73) > egg yolk (0.30-0.71) > bottom (0.21-0.59) after drinking water exposure, and the order of the skin (1.01-1.59) > bottom (0.75-1.1) > egg yolk (0.58-1.10) for feed exposure. Fipronil sulfone, a more toxic compound, was the predominant metabolite with higher levels distributed in the skin and bottom for both exposure pathways. FipronilT was distributed in egg yolks rather than in albumen owing to its lipophilicity, and the ratio of egg yolk to albumen may potentially reflect the time of exposure. The distinction is that the residues after feed exposure were much higher than that after drinking water exposure in edible tissues and eggs. The study highlights the residual characteristics of two exposure pathways, which would contribute to the tracing of contamination sources and risk assessment.


Chickens , Eggs , Insecticides , Pyrazoles , Animals , Pyrazoles/analysis , Insecticides/analysis , Eggs/analysis , Risk Assessment , Female , Animal Feed/analysis , Food Contamination/analysis , Water Pollutants, Chemical/analysis , Environmental Monitoring
6.
Dermatol Clin ; 42(3): 357-363, 2024 Jul.
Article En | MEDLINE | ID: mdl-38796267

Oral psoriasis therapies include both older traditional immunosuppressants, such as methotrexate, cyclosporine, and acitretin, as well as newer, more targeted agents, such as apremilast, deucravacitinib, and oral interleukin-23 receptor antagonists. Patients may prefer oral therapies to injectable therapies based on the route of administration. Both older and newer oral psoriasis therapies can be utilized effectively in the treatment of psoriasis. Here, we will review oral agents used in the treatment of psoriasis as well as provide commentary on their role in our current, evolving psoriasis treatment paradigm.


Acitretin , Cyclosporine , Dermatologic Agents , Immunosuppressive Agents , Methotrexate , Psoriasis , Thalidomide , Humans , Psoriasis/drug therapy , Administration, Oral , Thalidomide/analogs & derivatives , Thalidomide/therapeutic use , Acitretin/therapeutic use , Acitretin/administration & dosage , Immunosuppressive Agents/therapeutic use , Methotrexate/therapeutic use , Methotrexate/administration & dosage , Cyclosporine/therapeutic use , Cyclosporine/administration & dosage , Dermatologic Agents/therapeutic use , Dermatologic Agents/administration & dosage , Piperidines/therapeutic use , Piperidines/administration & dosage , Pyrazoles/therapeutic use , Pyrimidines/therapeutic use , Pyrroles/therapeutic use , Pyrroles/administration & dosage , Antibodies, Monoclonal, Humanized/therapeutic use , Keratolytic Agents/therapeutic use , Indoles/therapeutic use , Nicotinic Acids/therapeutic use , Nicotinic Acids/administration & dosage , Antibodies, Monoclonal
7.
BMC Med ; 22(1): 204, 2024 May 20.
Article En | MEDLINE | ID: mdl-38764059

BACKGROUND: Severe fever with thrombocytopenia syndrome (SFTS) is an emerging tick-borne infectious disease, and its morbidity and mortality are increasing. At present, there is no specific therapy available. An exacerbated IFN-I response and cytokine storm are related to the mortality of patients with SFTS. Ruxolitinib is a Janus kinase (JAK) 1/2 inhibitor that can block proinflammatory cytokines and inhibit the type I IFN pathway. We aimed to explore the use of ruxolitinib plus standard of care for severe SFTS. METHODS: We conducted a prospective, single-arm study of severe SFTS. We recruited participants aged 18 years or older who were admitted to the hospital with laboratory-confirmed severe SFTS and whose clinical score exceeded 8 points within 6 days of symptom onset. Participants received oral ruxolitinib (10 mg twice a day) for up to 10 days. The primary endpoint was 28-day overall survival. The secondary endpoints included the proportion of participants who needed intensive care unit (ICU) admission, total cost, changes in neurologic symptoms and clinical laboratory parameters, and adverse events (AEs) within 28 days. A historical control group (HC group, n = 26) who met the upper criteria for inclusion and hospitalized from April 1, 2021, to September 16, 2022, was selected and 1:1 matched for baseline characteristics by propensity score matching. RESULTS: Between Sep 16, 2022, and Sep 16, 2023, 26 participants were recruited into the ruxolitinib treatment group (RUX group). The 28-day overall mortality was 7.7% in the RUX group and 46.2% in the HC group (P = 0.0017). There was a significantly lower proportion of ICU admissions (15.4% vs 65.4%, p < 0.001) and total hospitalization cost in the RUX group. Substantial improvements in neurologic symptoms, platelet counts, hyperferritinemia, and an absolute decrease in the serum SFTS viral load were observed in all surviving participants. Treatment-related adverse events were developed in 6 patients (23.2%) and worsened in 8 patients (30.8%), and no treatment-related serious adverse events were reported. CONCLUSIONS: Our findings indicate that ruxolitinib has the potential to increase the likelihood of survival as well as reduce the proportion of ICU hospitalization and being tolerated in severe SFTS. Further trials are needed. TRAIL REGISTRATION: ChiCTR2200063759, September 16, 2022.


Nitriles , Pyrazoles , Pyrimidines , Severe Fever with Thrombocytopenia Syndrome , Humans , Pyrazoles/therapeutic use , Nitriles/therapeutic use , Male , Female , Pyrimidines/therapeutic use , Middle Aged , Prospective Studies , Aged , Severe Fever with Thrombocytopenia Syndrome/drug therapy , Standard of Care , Adult , Hospitalization , Treatment Outcome
8.
RMD Open ; 10(2)2024 May 30.
Article En | MEDLINE | ID: mdl-38816210

OBJECTIVE: To compare the effectiveness of a strategy administering baricitinib versus one using TNF-inhibitors (TNFi) in patients with rheumatoid arthritis (RA) after conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) failure in a real-life treat-to-target (T2T) setting. METHODS: Patients with biological and targeted synthetic DMARD (b/tsDMARD) naïve RA with disease duration ≤5 years without contraindications to b/tsDMARD were randomised to either TNFi or baricitinib when csDMARD failed to achieve disease control in a T2T setting. Changes in clinical and patient-reported outcome measures (PROMs) were assessed at 12-week intervals for 48 weeks. The primary endpoint was non-inferiority, with testing for superiority if non-inferiority is demonstrated, of baricitinib strategy in the number of patients achieving American College of Rheumatology 50 (ACR50) response at 12 weeks. Secondary endpoints included 28-joint count Disease Activity Score with C reactive protein (DAS28-CRP) <2.6, changes in PROMs and radiographic progression. RESULTS: A total of 199 patients (TNFi, n=102; baricitinib, n=97) were studied. Both study groups were similar. Baricitinib was both non-inferior and superior in achieving ACR50 response at week 12 (42% vs 20%). Moreover, 75% of baricitinib patients achieved DAS28-CRP <2.6 at week 12 compared with 46% of TNFi patients. On secondary outcomes throughout the duration of the study, the baricitinib strategy demonstrated comparable or better outcomes than TNFi strategy. Although not powered for safety, no unexpected safety signals were seen in this relatively small group of patients. CONCLUSION: Up to present, in a T2T setting, patients with RA failing csDMARDs have two main strategies to consider, Janus Kinases inhibitor versus bDMARDs (in clinical practice, predominantly TNFi). The PERFECTRA study suggested that starting with baricitinib was superior over TNFi in achieving response at 12 weeks and resulted in improved outcomes across all studied clinical measures and PROMs throughout the study duration in these patients.


Antirheumatic Agents , Arthritis, Rheumatoid , Azetidines , Purines , Pyrazoles , Sulfonamides , Humans , Purines/administration & dosage , Purines/therapeutic use , Sulfonamides/therapeutic use , Sulfonamides/administration & dosage , Arthritis, Rheumatoid/drug therapy , Arthritis, Rheumatoid/complications , Pyrazoles/therapeutic use , Pyrazoles/administration & dosage , Pyrazoles/adverse effects , Azetidines/therapeutic use , Azetidines/administration & dosage , Azetidines/adverse effects , Male , Female , Middle Aged , Antirheumatic Agents/therapeutic use , Antirheumatic Agents/administration & dosage , Aged , Treatment Outcome , Tumor Necrosis Factor Inhibitors/therapeutic use , Tumor Necrosis Factor Inhibitors/administration & dosage , Tumor Necrosis Factor Inhibitors/adverse effects , Treatment Failure , Adult , Patient Reported Outcome Measures , Severity of Illness Index
9.
Cell Death Dis ; 15(5): 381, 2024 May 30.
Article En | MEDLINE | ID: mdl-38816365

Osteosarcoma (OS) therapy presents numerous challenges, due largely to a low survival rate following metastasis onset. Nerve growth factor (NGF) has been implicated in the metastasis and progression of various cancers; however, the mechanism by which NGF promotes metastasis in osteosarcoma has yet to be elucidated. This study investigated the influence of NGF on the migration and metastasis of osteosarcoma patients (88 cases) as well as the underlying molecular mechanisms, based on RNA-sequencing and gene expression data from a public database (TARGET-OS). In osteosarcoma patients, the expression of NGF was significantly higher than that of other growth factors. This observation was confirmed in bone tissue arrays from 91 osteosarcoma patients, in which the expression levels of NGF and matrix metallopeptidase-2 (MMP-2) protein were significantly higher than in normal bone, and strongly correlated with tumor stage. In summary, NGF is positively correlated with MMP-2 in human osteosarcoma tissue and NGF promotes osteosarcoma cell metastasis by upregulating MMP-2 expression. In cellular experiments using human osteosarcoma cells (143B and MG63), NGF upregulated MMP-2 expression and promoted wound healing, cell migration, and cell invasion. Pre-treatment with MEK and ERK inhibitors or siRNA attenuated the effects of NGF on cell migration and invasion. Stimulation with NGF was shown to promote phosphorylation along the MEK/ERK signaling pathway and decrease the expression of microRNA-92a-1-5p (miR-92a-1-5p). In in vivo experiments involving an orthotopic mouse model, the overexpression of NGF enhanced the effects of NGF on lung metastasis. Note that larotrectinib (a tropomyosin kinase receptor) strongly inhibited the effect of NGF on lung metastasis. In conclusion, it appears that NGF promotes MMP-2-dependent cell migration by inhibiting the effects of miR-92a-1-5p via the MEK/ERK signaling cascade. Larotrectinib emerged as a potential drug for the treatment of NGF-mediated metastasis in osteosarcoma.


Bone Neoplasms , Cell Movement , Matrix Metalloproteinase 2 , Nerve Growth Factor , Osteosarcoma , Pyrazoles , Pyrimidines , Humans , Osteosarcoma/drug therapy , Osteosarcoma/pathology , Osteosarcoma/metabolism , Osteosarcoma/genetics , Nerve Growth Factor/metabolism , Animals , Pyrimidines/pharmacology , Pyrimidines/therapeutic use , Cell Line, Tumor , Cell Movement/drug effects , Pyrazoles/pharmacology , Pyrazoles/therapeutic use , Mice , Matrix Metalloproteinase 2/metabolism , Matrix Metalloproteinase 2/genetics , Bone Neoplasms/metabolism , Bone Neoplasms/drug therapy , Bone Neoplasms/pathology , Bone Neoplasms/genetics , Mice, Nude , Male , Neoplasm Metastasis , Female , Gene Expression Regulation, Neoplastic/drug effects , Mice, Inbred BALB C
10.
Expert Rev Hematol ; 17(6): 201-210, 2024 Jun.
Article En | MEDLINE | ID: mdl-38784995

INTRODUCTION: This review evaluates zanubrutinib as a treatment option for adults with chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL). Zanubrutinib, a covalent BTK (Bruton's tyrosine kinase) inhibitor, was recently approved by the US FDA based in part on head-to-head data demonstrating improved efficacy and safety compared to ibrutinib. AREAS COVERED: The review discusses the efficacy, safety, and comparative advantages of zanubrutinib, highlighting its safety profile compared to other BTK inhibitors. It also addresses the unmet needs of current therapies in CLL/SLL and provides an overview of competitor compounds and ongoing research in BTK inhibition. EXPERT OPINION: Zanubrutinib, the first BTK inhibitor to demonstrate superior efficacy and safety compared to another BTK inhibitor in CLL, is likely to be widely adopted due to its high-quality data and ease of use. Looking ahead, pirtobrutinib, a novel non-covalent BTK inhibitor, has shown promise in heavily pretreated CLL patients, including those unresponsive to covalent inhibitors, with ongoing phase 3 trials comparing it against ibrutinib. The field is also exploring time-limited therapies like the combination of ibrutinib and venetoclax, with ongoing trials evaluating different combinations to optimize efficacy and minimize toxicity, indicating a promising future for combination therapies in CLL treatment.


Agammaglobulinaemia Tyrosine Kinase , Leukemia, Lymphocytic, Chronic, B-Cell , Piperidines , Protein Kinase Inhibitors , Pyrazoles , Pyrimidines , Humans , Leukemia, Lymphocytic, Chronic, B-Cell/drug therapy , Pyrimidines/therapeutic use , Pyrazoles/therapeutic use , Piperidines/therapeutic use , Agammaglobulinaemia Tyrosine Kinase/antagonists & inhibitors , Protein Kinase Inhibitors/therapeutic use , Protein Kinase Inhibitors/adverse effects , Adult , Sulfonamides/therapeutic use , Antineoplastic Agents/therapeutic use , Adenine/analogs & derivatives , Adenine/therapeutic use , Treatment Outcome , Clinical Trials as Topic
11.
Cell Death Dis ; 15(5): 369, 2024 May 28.
Article En | MEDLINE | ID: mdl-38806478

Signal transducer and activator of transcription 3 (STAT3) is frequently overexpressed in patients with acute myeloid leukemia (AML). STAT3 exists in two distinct alternatively spliced isoforms, the full-length isoform STAT3α and the C-terminally truncated isoform STAT3ß. While STAT3α is predominantly described as an oncogenic driver, STAT3ß has been suggested to act as a tumor suppressor. To elucidate the role of STAT3ß in AML, we established a mouse model of STAT3ß-deficient, MLL-AF9-driven AML. STAT3ß deficiency significantly shortened survival of leukemic mice confirming its role as a tumor suppressor. Furthermore, RNA sequencing revealed enhanced STAT1 expression and interferon (IFN) signaling upon loss of STAT3ß. Accordingly, STAT3ß-deficient leukemia cells displayed enhanced sensitivity to blockade of IFN signaling through both an IFNAR1 blocking antibody and the JAK1/2 inhibitor Ruxolitinib. Analysis of human AML patient samples confirmed that elevated expression of IFN-inducible genes correlated with poor overall survival and low STAT3ß expression. Together, our data corroborate the tumor suppressive role of STAT3ß in a mouse model in vivo. Moreover, they provide evidence that its tumor suppressive function is linked to repression of the STAT1-mediated IFN response. These findings suggest that the STAT3ß/α mRNA ratio is a significant prognostic marker in AML and holds crucial information for targeted treatment approaches. Patients displaying a low STAT3ß/α mRNA ratio and unfavorable prognosis could benefit from therapeutic interventions directed at STAT1/IFN signaling.


Leukemia, Myeloid, Acute , STAT3 Transcription Factor , Animals , Leukemia, Myeloid, Acute/genetics , Leukemia, Myeloid, Acute/pathology , Leukemia, Myeloid, Acute/metabolism , Humans , STAT3 Transcription Factor/metabolism , Mice , Signal Transduction , Interferons/metabolism , STAT1 Transcription Factor/metabolism , STAT1 Transcription Factor/genetics , Mice, Inbred C57BL , Receptor, Interferon alpha-beta/metabolism , Receptor, Interferon alpha-beta/genetics , Cell Line, Tumor , Nitriles , Pyrazoles , Pyrimidines
12.
BMC Pulm Med ; 24(1): 260, 2024 May 28.
Article En | MEDLINE | ID: mdl-38807122

BACKGROUND: Physical activity is a crucial demand on cystic fibrosis treatment management. The highest value of oxygen uptake (VO2peak) is an appropriate tool to evaluate the physical activity in these patients. However, there are several other valuable CPET parameters describing exercise tolerance (Wpeak, VO2VT1, VO2VT2, VO2/HRpeak, etc.), and helping to better understand the effect of specific treatment (VE, VT, VD/VT etc.). Limited data showed ambiguous results of this improvement after CFTR modulator treatment. Elexacaftor/tezacaftor/ivacaftor medication improves pulmonary function and quality of life, whereas its effect on CPET has yet to be sufficiently demonstrated. METHODS: We performed a single group prospective observational study of 10 adolescent patients with cystic fibrosis who completed two CPET measurements between January 2019 and February 2023. During this period, elexacaftor/tezacaftor/ivacaftor treatment was initiated in all of them. The first CPET at the baseline was followed by controlled CPET at least one year after medication commencement. We focused on interpreting the data on their influence by the novel therapy. We hypothesized improvements in cardiorespiratory fitness following treatment. We applied the Wilcoxon signed-rank test. The data were adjusted for age at the time of CPET to eliminate bias of aging in adolescent patients. RESULTS: We observed significant improvement in peak workload, VO2 peak, VO2VT1, VO2VT2, VE/VCO2 slope, VE, VT, RQ, VO2/HR peak and RR peak. The mean change in VO2 peak was 5.7 mL/kg/min, or 15.9% of the reference value (SD ± 16.6; p= 0.014). VO2VT1 improved by 15% of the reference value (SD ± 0.1; p= 0.014), VO2VT2 improved by 0.5 (SD ± 0.4; p= 0.01). There were no differences in other parameters. CONCLUSION: Exercise tolerance improved after elexacaftor/tezacaftor/ivacaftor treatment initiation. We suggest that the CFTR modulator alone is not enough for recovering physical decondition, but should be supplemented with physical activity and respiratory physiotherapy. Further studies are needed to examine the effect of CFTR modulators and physical therapy on cardiopulmonary exercise tolerance.


Aminophenols , Benzodioxoles , Cystic Fibrosis , Drug Combinations , Indoles , Pyrazoles , Pyridines , Quinolones , Humans , Cystic Fibrosis/drug therapy , Cystic Fibrosis/physiopathology , Adolescent , Male , Female , Prospective Studies , Pilot Projects , Indoles/therapeutic use , Benzodioxoles/therapeutic use , Quinolones/therapeutic use , Aminophenols/therapeutic use , Pyrazoles/therapeutic use , Pyridines/therapeutic use , Cardiorespiratory Fitness , Exercise Test , Pyrroles/therapeutic use , Exercise Tolerance/drug effects , Oxygen Consumption , Child , Pyrrolidines
13.
Zhonghua Xue Ye Xue Za Zhi ; 45(3): 271-276, 2024 Mar 14.
Article Zh | MEDLINE | ID: mdl-38716599

Objective: This study aimed at investigating the efficacy and safety of eltrombopag in the treatment of adult primary immune thrombocytopenia (ITP) and evaluated the factors influencing its efficacy and side effects. Methods: A total of 198 patients with adult ITP who were admitted to Tianjin Medical University General Hospital between January 2018 and March 2022 were retrospectively analyzed. The efficacy of each starting dose of eltrombopag was evaluated, and adverse events were analyzed. The factors influencing efficacy were investigated, including sex, age, adult ITP type, platelet antibodies, and combined drug treatments. Results: Of the 198 patients, 70 males and 128 females with a median age of 45 years (18-88 years) were included; 130 (65.7%) had newly diagnosed adult ITP, 25 (12.6%) had persistent adult ITP, and 43 (21.7%) had chronic adult ITP. The bleeding event scores at baseline were assessed; 84.3% had scores of<4 and 15.7% had scores of ≥4. The eltrombopag response rate (initial response) at 6 weeks was 78.8% (complete response [CR]: 49.0%; CR1: 14.6%; CR2: 15.2%). The median response time to eltrombopag was 7 (7, 14) days. The initial response rates to 25, 50, and 75 mg eltrombopag were 74.1%, 85.9%, and 60.0%, respectively (P=0.031). The initial response rate to the 50 mg dose was significantly higher than that of the 25-mg and 75-mg doses. Two patients received 100 mg as the starting dose, and their initial response was 0. Regarding dose adjustment, 70.7% of the patients remained on the starting dose, 8.6% underwent dose adjustment to 50 mg, and 6.1% underwent dose adjustment to 75 mg. Another two patients underwent dose adjustment to 100 mg. After dose adjustment, the persistent response rates were 83.6%, 85.3%, and 85.7% for the 25-, 50-, and 75-mg doses, respectively, with no significant difference. After dose adjustment, the sustained efficacy rate for the 100-mg dose (4 patients) was 100.0%. After 6 weeks of treatment with eltrombopag, the overall bleeding score of patients with ITP decreased. The number of patients with a score of ≥4 decreased to 0, the number of patients with a score of<4 decreased, and there was no significant change in the number of patients with a score of 1-2. The most common adverse event associated with eltrombopag was impaired liver function (7.7%). No thrombosis events or other adverse events were observed. ITP type and number of megakaryocytes significantly affected the initial response to eltrombopag. The initial response rates to eltrombopag for newly diagnosed adult ITP, persistent adult ITP, and chronic adult ITP were 85.3%, 56.0%, and 76.2%, respectively (P=0.003). For megakaryocytes, the initial response rates were 61.8%, 87.1%, and 84.3% (P=0.009) for the decreased, normal, and increased megakaryocyte groups, respectively. Conclusion: Eltrombopag, as a second-line or higher treatment for adult ITP, has a rapid onset of action and good safety. The initial response rate is significantly higher with a dose of 50 mg than with a dose of 25 mg. Patients with newly diagnosed ITP and those with normal or increased megakaryocyte numbers have a higher initial response rate to eltrombopag.


Benzoates , Hydrazines , Purpura, Thrombocytopenic, Idiopathic , Pyrazoles , Humans , Male , Female , Middle Aged , Retrospective Studies , Purpura, Thrombocytopenic, Idiopathic/drug therapy , Adult , Aged , Pyrazoles/administration & dosage , Pyrazoles/therapeutic use , Benzoates/administration & dosage , Benzoates/therapeutic use , Benzoates/adverse effects , Hydrazines/therapeutic use , Hydrazines/administration & dosage , Adolescent , Aged, 80 and over , Treatment Outcome , Child , Young Adult , Hemorrhage
15.
Med Oncol ; 41(6): 142, 2024 May 07.
Article En | MEDLINE | ID: mdl-38714583

The development of BCR::ABL1-targeting tyrosine kinase inhibitors (TKIs) has improved the prognosis of patients with chronic myeloid leukemia (CML). However, resistance to ABL TKIs can develop in CML patients due to BCR::ABL1 point mutations and CML leukemia stem cell (LSC). Aurora kinases are essential kinases for cell division and regulate mitosis, especially the process of chromosomal segregation. Aurora kinase members also promote cancer cell survival and proliferation. This study analyzed whether aurora kinases were regulated in the progression of CML. It also evaluated the efficacy of the ABL TKI asciminib and the aurora kinase inhibitor LY3295668. The expressions of AURKA and AURKB were higher in the CML cells compared with normal cells using a public database (GSE100026). Asciminib or LY3295668 alone inhibited CML cells after 72 h, and cellular cytotoxicity was increased. The combined use of Asciminib and LY3295668 increased superior efficacy compared with either drug alone. Colony formation was reduced by cotreatment with asciminib and LY3295668. In the cell-cycle analyses, LY3295668 induced G2/M arrest. Cell populations in the sub-G1 phase were observed when cotreating with asciminib and LY3295668. The combination treatment also changed the mitochondrial membrane potential. In addition, AURKA shRNA transfectant cells had increased asciminib sensitivity. Combining asciminib and aurora kinase inhibition enhanced the efficacy and is proposed as a new therapeutic option for patients with CML. These findings have clinical implications for a potential novel therapeutic strategy for CML patients.


Drug Resistance, Neoplasm , Leukemia, Myelogenous, Chronic, BCR-ABL Positive , Niacinamide/analogs & derivatives , Protein Kinase Inhibitors , Humans , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/drug therapy , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/pathology , Drug Resistance, Neoplasm/drug effects , Protein Kinase Inhibitors/pharmacology , Aurora Kinase A/antagonists & inhibitors , Cell Line, Tumor , Fusion Proteins, bcr-abl/antagonists & inhibitors , Fusion Proteins, bcr-abl/genetics , Aurora Kinase B/antagonists & inhibitors , Apoptosis/drug effects , Antineoplastic Combined Chemotherapy Protocols/pharmacology , Cell Proliferation/drug effects , Pyrazoles
16.
Biotechnol J ; 19(5): e2300672, 2024 May.
Article En | MEDLINE | ID: mdl-38719621

The production of recombinant adeno-associated virus (rAAV) for gene therapy applications relies on the use of various host cell lines, with suspension-grown HEK293 cells being the preferred expression system due to their satisfactory rAAV yields in transient transfections. As the field of gene therapy continues to expand, there is a growing demand for efficient rAAV production, which has prompted efforts to optimize HEK293 cell line productivity through engineering. In contrast to other cell lines like CHO cells, the transcriptome of HEK293 cells during rAAV production has remained largely unexplored in terms of identifying molecular components that can enhance yields. In our previous research, we analyzed global regulatory pathways and mRNA expression patterns associated with increased rAAV production in HEK293 cells. Our data revealed substantial variations in the expression patterns between cell lines with low (LP) and high-production (HP) rates. Moving to a deeper layer for a more detailed analysis of inflammation-related transcriptome data, we detected an increased expression of interferon-related genes in low-producing cell lines. Following upon these results, we investigated the use of Ruxolitinib, an interferon pathway inhibitor, during the transient production of rAAV in HEK293 cells as potential media additive to boost rAAV titers. Indeed, we find a two-fold increase in rAAV titers compared to the control when the interferon pathways were inhibited. In essence, this work offers a rational design approach for optimization of HEK293 cell line productivity and potential engineering targets, ultimately paving the way for more cost-efficient and readily available gene therapies for patients.


Dependovirus , Interferons , Signal Transduction , Humans , HEK293 Cells , Dependovirus/genetics , Interferons/metabolism , Interferons/genetics , Nitriles/pharmacology , Pyrimidines/pharmacology , Transfection , Pyrazoles/pharmacology
17.
JAMA Netw Open ; 7(5): e249465, 2024 May 01.
Article En | MEDLINE | ID: mdl-38709533

Importance: The influence of race and ethnicity on initiation of direct oral anticoagulants (DOACs) is relatively understudied in Medicare data. Objective: To investigate disparities in the initiation of DOACs compared with warfarin by race, ethnicity, and social vulnerability. Design, Setting, and Participants: This retrospective cohort study used a 50% sample of Medicare fee-for-service data from January 1, 2010, to December 31, 2019 (mean patient enrollment duration, 7.7 years). Analysis took place between January 2023 and February 2024. A cohort of older adults (aged ≥65 years) with atrial fibrillation who newly initiated warfarin or DOACs (dabigatran, rivaroxaban, apixaban, and edoxaban) was identified. Exposure: Patients were classified as non-Hispanic White, non-Hispanic Black, and Hispanic. Main Outcomes and Measures: The likelihood of starting use of DOACs compared with warfarin was modeled, adjusting for race, ethnicity, age, sex, county-level social vulnerability, and other clinical factors. Results: Among 950 698 anticoagulation initiations, consisting of 680 974 DOAC users and 269 724 warfarin users (mean [SD] age, 78.5 [7.6] years; 52.6% female), 5.2% were Black, 4.3% were Hispanic, and 86.7% were White. During the 10-year study period, DOAC use increased for all demographic groups. After adjustment, compared with White patients, Black patients were 23% less likely (adjusted odds ratio [AOR, 0.77; 95% CI, 0.75-0.79) and Hispanic patients were 13% less likely (AOR, 0.87; 95% CI, 0.85-0.89) to initiate DOAC use. Disparities in DOAC initiation were greatest among Black patients in the earlier years but attenuated during the study period. For instance, in 2010, the OR of Black patients initiating DOACs was 0.54 (95% CI, 0.50-0.57), attenuating linearly over time to 0.69 by 2013 (95% CI, 0.65-0.74) and 0.83 (95% CI, 0.78-0.89) by 2017. By 2019, these differences became nonsignificant (OR, 1.08; 95% CI, 0.99-1.18). Conclusions and Relevance: In this cohort study of Medicare patients with atrial fibrillation, Black and Hispanic patients were less likely to initiate DOACs for atrial fibrillation, although these differences diminished over time. Identifying the factors behind these early disparities is crucial for ensuring equitable access to novel therapies as they emerge for Black and Hispanic populations.


Anticoagulants , Atrial Fibrillation , Healthcare Disparities , Medicare , Warfarin , Humans , Aged , Female , United States , Male , Medicare/statistics & numerical data , Retrospective Studies , Aged, 80 and over , Anticoagulants/therapeutic use , Warfarin/therapeutic use , Atrial Fibrillation/drug therapy , Atrial Fibrillation/ethnology , Healthcare Disparities/ethnology , Healthcare Disparities/statistics & numerical data , Pyridones/therapeutic use , Dabigatran/therapeutic use , Pyrazoles/therapeutic use , Administration, Oral , Hispanic or Latino/statistics & numerical data , Rivaroxaban/therapeutic use , Ethnicity/statistics & numerical data , Thiazoles/therapeutic use , White People/statistics & numerical data , Cohort Studies , Pyridines/therapeutic use
20.
Luminescence ; 39(5): e4760, 2024 May.
Article En | MEDLINE | ID: mdl-38738510

The present communication reports on the synthesis of a novel methyl-pyridone azo fluorescent tag (MPAFT) were proven through 1H (NMR), FT-IR, UV-vis, and high-resolution mass spectrometry. The quantum chemical parameters of MPAFT were evaluated using density functional theory (DFT) analysis. It was further investigated for its latent fingerprint (LFPs) in various surfaces and anticounterfeiting applications. By exposing Level I-Level III, ridge features to UV light with a wavelength of 365 nm, a bioimaging investigation has also demonstrated the potential of MPAFT's emission behaviour. The cyclic voltammetry (CV) and linear sweep voltammetry (LSV) at MPAFT/MGCE (modified glassy carbon electrode) were used to explore the electrochemical sensitivity and reliable detection of dopamine (DA) in neutral PBS (pH 7) electrolyte solution, and the results show good sensitivity and detection. The lower detection limit for LSV was 0.81 µM under optimum conditions.


Dopamine , Electrochemical Techniques , Fluorescent Dyes , Pyrazoles , Pyridones , Pyridones/chemistry , Dopamine/analysis , Dopamine/chemistry , Fluorescent Dyes/chemistry , Fluorescent Dyes/chemical synthesis , Pyrazoles/chemistry , Humans , Molecular Structure , Density Functional Theory , Optical Imaging , Photochemical Processes
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