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ABSTRACT: This study aimed to compare the efficacy and safety of eltrombopag plus diacerein vs eltrombopag alone in patients with primary immune thrombocytopenia (ITP) who were previously unresponsive to 14 days of eltrombopag treatment at the full dose. Recruited patients were randomly assigned 1:1 to receive either eltrombopag plus diacerein (n = 50) or eltrombopag monotherapy (n = 52). Overall response rate, defined as a platelet count of ≥30 × 109/L, at least doubling of the baseline platelet count, and no bleeding, was reached in 44% of patients in the eltrombopag plus diacerein group compared with 13% in the eltrombopag group at day 15 (P = .0009), and reached in 42% of patients in the combination group compared with 12% in the monotherapy group at day 28 (P = .0006). The addition of diacerein to eltrombopag also led to a longer duration of response (P = .0004). The 2 most common treatment-emergent adverse events were respiratory infection and gastrointestinal reactions in the combination group, and fatigue and respiratory infection in the eltrombopag group. In conclusion, eltrombopag plus diacerein was well tolerated, and induced higher overall response rates and longer duration of response than eltrombopag alone, offering a rejuvenating salvage therapy for patients with ITP unresponsive to 14 days of full dosage eltrombopag. Our work has the potential to enhance the care of patients treated with thrombopoietin receptor agonists, reducing the need for rapid transitions to less-preferable therapies. This study is registered at ClinicalTrials.gov as #NCT04917679.
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Antraquinonas , Benzoatos , Quimioterapia Combinada , Hidrazinas , Púrpura Trombocitopênica Idiopática , Pirazóis , Humanos , Hidrazinas/uso terapêutico , Hidrazinas/efeitos adversos , Hidrazinas/administração & dosagem , Pirazóis/uso terapêutico , Pirazóis/efeitos adversos , Pirazóis/administração & dosagem , Benzoatos/uso terapêutico , Benzoatos/administração & dosagem , Benzoatos/efeitos adversos , Masculino , Feminino , Pessoa de Meia-Idade , Púrpura Trombocitopênica Idiopática/tratamento farmacológico , Adulto , Idoso , Antraquinonas/uso terapêutico , Antraquinonas/administração & dosagem , Antraquinonas/efeitos adversos , Contagem de Plaquetas , Resultado do TratamentoRESUMO
Thin-film polarizing beam splitters (PBSs) fulfill a pivotal role in laser beam splitting, modulation, shaping and isolation. In this study, a high-reliability infrared broadband thin-film PBS was developed. To correct for tensile stress in Ge/YbF3 multilayer coatings, ZnSe compensation layers were incorporated in the multilayer design. The effects of different symmetrical periods on the spectral properties of the infrared PBS were systematically discussed. The infrared PBS operated at 45° and in the long-wave infrared (LWIR) band. Using the percent of optical extrema monitoring (POEM) strategy combined with the high-temperature optical constants (HTOC) of Ge film, the infrared PBS was precisely fabricated on ZnSe substrates. Subsequently, the spectral performance and film reliability of the infrared PBS were carefully characterized. Specifically, the transmittance of p-polarization surpassed 96%, while the extinction ratio exceeded 100:1 within the 10.6 ± 0.15â µm band. The infrared PBS demonstrated commendable environmental reliability, in addition to exhibiting excellent spectral characteristics.
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Sovleplenib (HMPL-523) is a selective spleen tyrosine kinase (Syk) inhibitor with anti-tumor activity in preclinical models of B-cell malignancy. We conducted a dose-escalation and dose-expansion phase I study of sovleplenib in patients with relapsed/ refractory mature B-cell tumors. Dose escalation followed a 3+3 design; patients received oral sovleplenib (200-800 mg once daily [q.d.] or 200 mg twice daily [b.i.d.], 28-day cycles). During dose expansion, patients were enrolled into four cohorts per lymphoma classification and treated at the recommended phase II dose (RP2D) (clinicaltrials gov. Identifier: NCT02857998). Overall, 134 Chinese patients were enrolled (dose escalation, N=27; dose expansion, N=107). Five patients experienced dose-limiting toxicities: one each of amylase increased (200 mg q.d.), febrile neutropenia (800 mg q.d.), renal failure (800 mg q.d.), hyperuricemia and blood creatine phosphokinase increased (200 mg b.i.d.) and blood bilirubin increased and pneumonia (200 mg b.i.d.). RP2D was determined as 600 mg (>65 kg) or 400 mg (≤65 kg) q.d.. The primary efficacy end point of independent review committee-assessed objective response rate in indolent B-cell lymphoma was 50.8% (95% confidence interval: 37.5- 64.1) in 59 evaluable patients at RP2D (follicular lymphoma: 60.5%, marginal zone lymphoma: 28.6%, lymphoplasmacytic lymphoma/Waldenström macroglobulinemia, 0%). The most common (≥10% patients) grade ≥3 treatment-related adverse events in the dose-expansion phase were decreased neutrophil count (29.9%), pneumonia (12.1%) and decreased white blood cell count (11.2%). Pharmacokinetic exposures increased dose-proportionally with ascending dose levels from 200-800 mg, without observed saturation. Sovleplenib showed anti-tumor activity in relapsed/refractory B-cell lymphoma with acceptable safety. Further studies are warranted.
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Linfoma de Células B , Inibidores de Proteínas Quinases , Quinase Syk , Humanos , Pessoa de Meia-Idade , Masculino , Feminino , Quinase Syk/antagonistas & inibidores , Idoso , Adulto , Linfoma de Células B/tratamento farmacológico , Linfoma de Células B/patologia , Inibidores de Proteínas Quinases/uso terapêutico , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/farmacocinética , Inibidores de Proteínas Quinases/efeitos adversos , Adulto Jovem , Idoso de 80 Anos ou mais , Resultado do Tratamento , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Dose Máxima Tolerável , Pirazinas/administração & dosagem , Pirazinas/uso terapêutico , Pirazinas/farmacocinética , Pirazinas/efeitos adversos , Recidiva , Antineoplásicos/uso terapêutico , Antineoplásicos/farmacocinética , Antineoplásicos/administração & dosagem , Antineoplásicos/efeitos adversos , Indazóis , MorfolinasRESUMO
OBJECTIVE: To evaluate the frequency and prognostic significance of DTA (DNMT3AãTET2ãASXL1) gene mutation and co-occurring mutations in patients with myelodysplastic syndrome (MDS). METHODS: The clinical data of 102 newly diagnosed MDS patients who accepted Next Generation Sequencing (NGS) was retrospectively analyzed. According to whether the patients had DTA gene mutation, the patients were divided into DTA mutated (DTA-mut) group and wild type (DTA-wt) group, and the relationship between gene mutation and clinical characteristics and prognosis was analyzed. RESULTS: Among the 102 MDS patients, 96% (98/102) presented with mutation, while the mean number of mutations was 3.04 mutations/patient. DTA-mut was detected in 56.9% (58/102) patients. The most frequent co-mutated genes in DTA-mut group were SF3B1 (25.8%), RUNX1 (24.1%), U2AF1 (18.9%), SRSF2, EZH2, SETBP1 (17.2%), STAG2 (15.5%), IDH2 (12.1%) and BCOR, CBL (10.3%). The two groups showed no significant differences in ages, blood parameters, bone marrow blasts, WHO 2022 classification, IPSS-R risk category and rate of conversion to leukemia. Compared with the DTA-wt group, the mutation frequency of RUNX1 was higher (P = 0.02), while mutation frequency of TP53 was lower (P = 0.001) and the mutation frequency of ≥ 3 co-mutated genes was higher in DTA-mut group (P = 0.00). Survival analysis showed that the overall survivals (OS) of DTA-mut patients was significantly inferior to that of DTA-wt patients (P = 0.0332). According to IPSS-R classification, a statistically significant difference in OS was only observed in higher risk (IPSS-R > 3.5) group (P = 0.0058). In the context of DTA mutation, the OS of patients with RUNX1 mutation was shorter than that of patients without RUNX1 mutation significantly (P = 0.0074). The OS of patients with SF3B1 mutation was longer than that of patients without SF3B1 mutation, but there was no statistical difference (P = 0.0827). DTA mutations were not independent prognostic factors when DTA and co-mutated genes with frequency > 10% were considered in Cox regression model (P = 0.329). However, multivariate analysis confirmed an independently adverse prognosis of RUNX1 co-mutation (P = 0.042, HR = 2.426, 95% CI:1.031-5.711) in DTA-mut cohort. Moreover, our multivariable analysis suggests that SRSF2-mut was an independent poor prognostic factor for all MDS patients (P = 0.047), but lost significance (P = 0.103) for DTA-mut patients. CONCLUSIONS: DTA mutations are frequently observed in patients with MDS, often accompanied by genes involved in RNA splicing and transcription factors like SF3B1 and RUNX1. DTA and concomitant mutations affect prognosis in MDS patients and RUNX1 was identified as an independent poor prognostic factor in patients with DTA mutations.
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DNA (Citosina-5-)-Metiltransferases , DNA Metiltransferase 3A , Proteínas de Ligação a DNA , Dioxigenases , Mutação , Síndromes Mielodisplásicas , Proteínas Proto-Oncogênicas , Proteínas Repressoras , Humanos , Síndromes Mielodisplásicas/genética , Síndromes Mielodisplásicas/mortalidade , Masculino , Feminino , Mutação/genética , Pessoa de Meia-Idade , Prognóstico , Idoso , Adulto , Proteínas Proto-Oncogênicas/genética , DNA (Citosina-5-)-Metiltransferases/genética , Proteínas Repressoras/genética , Proteínas de Ligação a DNA/genética , Estudos Retrospectivos , Idoso de 80 Anos ou mais , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Adolescente , Adulto JovemRESUMO
BACKGROUND: Major depressive disorder is characterized by a high risk of relapse. We aimed to compare the prophylactic effects of different antidepressant medicines (ADMs). METHODS: PubMed, Cochrane Central Register of Controlled Trials, Embase and the Web of Science were searched on 4 July 2019. A pooled analysis of parametric survival curves was performed using a Bayesian framework. The main outcomes were hazard ratios (HRs), relapse-free survival and mean relapse-free months. RESULTS: Forty randomized controlled trials were included. The 1-year relapse-free survival for ADM (76%) was significantly better than that for placebo (56%). Most of the relapse difference (86.5%) occurred in the first 6 months. Most HRs were not constant over time. Proof of benefit after 6 months of follow-up was not established partially because of small differences between the drug and placebo after 6 months. Almost all studies used an 'enriched' randomized discontinuation design, which may explain the high relapse rates in the first 6 months after randomization. CONCLUSIONS: The superiority of ADM v. placebo was mainly attributed to the difference in relapse rates that occurred in the first 6 months. Our analysis provided evidence that the prophylactic efficacy was not constant over time. A beneficial effect was observed, but the prevention of new episodes after 6 months was questionable. These findings may have implications for clinical practice.
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Transtorno Depressivo Maior , Humanos , Transtorno Depressivo Maior/tratamento farmacológico , Transtorno Depressivo Maior/prevenção & controle , Teorema de Bayes , Antidepressivos/uso terapêutico , Recidiva , Doença CrônicaRESUMO
Primary immune thrombocytopenia (ITP) is an autoimmune bleeding disorder, in which rituximab (RTX) induces the best long-term effect among recommended second-line treatments. Nevertheless, the optimal regimen of RTX remains unclear. We herein conducted a prospective, multicenter, open-label, randomized controlled trial to compare the efficacy and safety of RTX at two different dosage regimens in patients with corticosteroid-resistant or relapsed ITP. Recruited patients were randomly assigned (1:1) to receive either RTX at a repeated low dose (100 mg weekly for 4 weeks, LD-RTX) or at a single dose (375 mg/m2 , S-RTX). Overall response was achieved in 64.3% of patients who received LD-RTX versus 67.4% of those receiving S-RTX (p = .759). The complete response (CR) rate was 23.8% after LD-RTX and 28.3% after S-RTX (p = .635). In health-related quality of life, S-RTX improved patients' psychological status, quality of life, social activities, and work compared with LD-RTX. Furthermore, S-RTX significantly reduced physician visits without compromising efficacy. Our findings demonstrate that a S-RTX is comparable to LD-RTX in effectiveness and safety for treatment of corticosteroid-resistant or relapsed ITP. The single-dosage regimen optimizes the use of medical resources, improves the cost-effectiveness of RTX, and represents a promising and more convenient replacement for LD-RTX in ITP. This study has been completed and is registered with ClinicalTrials.gov, number NCT03258866.
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Corticosteroides , Qualidade de Vida , Corticosteroides/uso terapêutico , Humanos , Estudos Prospectivos , Indução de Remissão , Rituximab/efeitos adversos , Resultado do TratamentoRESUMO
The insect-specific epsilon class of glutathione S-transferases (GSTEs) plays important roles in insecticide detoxification in insects. In our previous work, five GSTEs were identified in Locusta migratoria, and two recombinant GSTEs, rLmGSTE1 and rLmGSTE4, showed high catalytic activity when 1-chloro-2,4-dinitrobenzene (CDNB) was used as a substrate. In this work, we further investigated whether these two GSTEs could metabolize three insecticides including malathion, deltamethrin and DDT. Using ultra-high-performance liquid chromatography tandem mass spectrometry (UHPLC/MS) method, we found that rLmGSTE4, but not rLmGSTE1, can metabolize malathion and DDT. Malathion bioassays of L.migratoria after the expression of LmGSTE4 was suppressed by RNA interference (RNAi) showed increased insect mortality from 33.8% to 68.9%. However, no changes in mortality were observed in deltamethrin- or DDT-treated L.migratoria after the expression of LmGSTE4 was suppressed by RNAi. Our results provided direct evidences that LmGSTE4 participates in malathion detoxification in L.migratoria. These findings are important for understanding the mechanisms of insecticide resistance in L.migratoria and developing new strategies for managing the insect populations in the field.
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Inseticidas , Locusta migratoria , Animais , DDT/metabolismo , DDT/farmacologia , Glutationa Transferase/genética , Glutationa Transferase/metabolismo , Inativação Metabólica/genética , Resistência a Inseticidas/genética , Inseticidas/metabolismo , Inseticidas/farmacologia , Locusta migratoria/genética , Locusta migratoria/metabolismo , Malation/metabolismo , Malation/farmacologiaRESUMO
Increased macrophage phagocytosis of antibody-coated platelets, as well as decreased numbers and/or impaired function of CD4+CD25+Foxp3+ regulatory T (Treg) cells, has been shown to participate in the pathogenesis of immune thrombocytopenia (ITP). Low-dose histone deacetylase inhibitors (HDACi's) are anti-inflammatory and immunomodulatory agents that can enhance immunosuppression in graft-versus-host disease by increasing the number and function of Foxp3+ Treg cells, but it is unclear whether they have the potential to promote immune tolerance and platelet release in ITP. In this study, we performed in vitro and in vivo experiments and found that a low-dose HDACi (chidamide) alleviated thrombocytopenia in passive and active murine models of ITP. Further, low-dose HDACi's attenuated macrophage phagocytosis of antibody-coated platelets, stimulated the production of natural Foxp3+ Treg cells, promoted the peripheral conversion of T cells into Treg cells, and restored Treg cell suppression in vivo and in vitro. Finally, we confirmed that low-dose HDACi's could regulate CTLA4 expression in peripheral blood mononuclear cells through modulation of histone H3K27 acetylation. Low-dose HDACi treatment in ITP could be offset by blocking the effect of CTLA4. Therefore, we propose that low-dose chidamide administration has potential as a novel treatment for ITP in the clinic.
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Aminopiridinas/administração & dosagem , Benzamidas/administração & dosagem , Tolerância Imunológica/imunologia , Leucócitos Mononucleares/imunologia , Púrpura Trombocitopênica Idiopática/imunologia , Linfócitos T Reguladores/imunologia , Acetilação , Adulto , Idoso , Animais , Antígeno CTLA-4/metabolismo , Relação Dose-Resposta a Droga , Feminino , Fatores de Transcrição Forkhead/metabolismo , Humanos , Tolerância Imunológica/efeitos dos fármacos , Leucócitos Mononucleares/efeitos dos fármacos , Leucócitos Mononucleares/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Pessoa de Meia-Idade , Prognóstico , Púrpura Trombocitopênica Idiopática/tratamento farmacológico , Púrpura Trombocitopênica Idiopática/metabolismo , Linfócitos T Reguladores/efeitos dos fármacos , Adulto JovemRESUMO
OBJECTIVE: To investigate the biochemical characterization of the carboxylesterase LmCesA1 from Locusta migratoria. RESULTS: We expressed recombinant LmCesA1 in Sf9 cells by using the Bac-to-bac baculovirus expression system. Enzyme kinetic assays showed that the Km values of LmCesA1 for α-naphthyl acetate (α-NA) and ß-naphthyl acetate (ß-NA) were 0.08 ± 0.01 mM and 0.22 ± 0.03 mM, respectively, suggesting that LmCesA1 has a higher affinity for α-NA. LmCesA1 retained its enzymatic activity during incubations at pH 7-10 and at 10-30 °C. In an inhibition experiment, two organophosphate pesticides (malaoxon and malathion) and one pyrethroid pesticide (deltamethrin) showed different inhibition profiles against purified LmCesA1. Recombinant LmCesA1 activity was significantly inhibited by malaoxon in vitro. UPLC analysis showed that no metabolites were detected. CONCLUSIONS: These results suggest that overexpression of LmCesA1 enhances malathion sequestration to confer malathion tolerance in L. migratoria.
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Carboxilesterase/metabolismo , Proteínas de Insetos/metabolismo , Locusta migratoria/enzimologia , Animais , Carboxilesterase/genética , Carboxilesterase/isolamento & purificação , Expressão Gênica , Concentração de Íons de Hidrogênio , Proteínas de Insetos/genética , Proteínas de Insetos/isolamento & purificação , Inseticidas/metabolismo , Inseticidas/farmacologia , Cinética , Naftóis/metabolismo , Proteínas Recombinantes/genética , Proteínas Recombinantes/isolamento & purificação , Proteínas Recombinantes/metabolismo , Células Sf9 , TemperaturaRESUMO
We conducted a prospective, multicenter, randomized, controlled clinical trial to compare the efficacy and safety of high-dose dexamethasone (HD-DXM) plus recombinant human thrombopoietin (rhTPO), vs HD-DXM alone in newly diagnosed adult immune thrombocytopenia (ITP) patients. Enrolled patients were randomly assigned to receive DXM plus rhTPO or DXM monotherapy. Another 4-day course of DXM was repeated if response was not achieved by day 10 in both arms. One hundred patients in the HD-DXM plus rhTPO arm and 96 patients in the HD-DXM monotherapy arm were included in the full analysis set. So, HD-DXM plus rhTPO resulted in a higher incidence of initial response (89.0% vs 66.7%, P < .001) and complete response (CR, 75.0% vs 42.7%, P < .001) compared with HD-DXM monotherapy. Response rate at 6 months was also higher in the HD-DXM plus rhTPO arm than that in the HD-DXM monotherapy arm (51.0% vs 36.5%, P = .02; sustained CR: 46.0% vs 32.3%, P = .043). Throughout the follow-up period, the overall duration of response was greater in the HD-DXM plus rhTPO arm compared to the HD-DXM monotherapy arm (P = .04), as estimated by the Kaplan-Meier analysis. The study drugs were generally well tolerated. In conclusion, the combination of HD-DXM with rhTPO significantly improved the initial response and yielded favorable SR in newly diagnosed ITP patients, thus could be further validated as a frontline treatment for ITP. This study is registered as clinicaltrials.gov identifier: NCT01734044.
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Dexametasona/administração & dosagem , Púrpura Trombocitopênica Idiopática , Trombopoetina/administração & dosagem , Adulto , Idoso , Dexametasona/efeitos adversos , Intervalo Livre de Doença , Quimioterapia Combinada , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Púrpura Trombocitopênica Idiopática/tratamento farmacológico , Púrpura Trombocitopênica Idiopática/mortalidade , Taxa de Sobrevida , Trombopoetina/efeitos adversosRESUMO
Overexpression of leucine aminopeptidase 3 (LAP3) is involved in proliferation, migration, and invasion of several tumor cells and plays a crucial role in tumor metastasis. However, the related mechanism remains unknown. In this study, we used MDA-MB-231 and MCF7 breast cancer cell lines to explore the role of LAP3 in the regulation of cancer cell migration and invasion by employing the natural LAP3 inhibitor bestatin and a lentivirus vector that overexpresses or knocks down LAP3. Bestatin inhibited tumor cell migration and invasion in a dose-dependent manner. Western blot assay showed that bestatin and knockdown of LAP3 upregulated phosphorylation of Hsp27 and downregulated expression of fascin. Phosphorylation of Akt and expression of matrix metalloproteinase-2/9 can also be downregulated. LAP3 overexpression showed the opposite results. Immunohistochemistry analysis was conducted to detect expression levels of LAP3 in breast cancer tissues. High LAP3 expression was correlated with the grade of malignancy. Findings of this study uncovered the molecular mechanism of LAP3 on breast cancer metastasis and indicated that LAP3 may act as a potential antimetastasis therapeutic target.
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Neoplasias da Mama/metabolismo , Proteínas de Transporte/sangue , Movimento Celular , Regulação Neoplásica da Expressão Gênica , Leucil Aminopeptidase/metabolismo , Metaloproteinase 2 da Matriz/biossíntese , Metaloproteinase 9 da Matriz/biossíntese , Proteínas dos Microfilamentos/sangue , Proteínas de Neoplasias/metabolismo , Regulação para Cima , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Proteínas de Transporte/genética , Feminino , Humanos , Leucil Aminopeptidase/genética , Células MCF-7 , Metaloproteinase 2 da Matriz/genética , Metaloproteinase 9 da Matriz/genética , Proteínas dos Microfilamentos/genética , Invasividade Neoplásica , Proteínas de Neoplasias/genéticaRESUMO
In the three-dimensional extracellular matrix of the insect cuticle, horizontally aligned microfibrils composed of the polysaccharide chitin and associated proteins are stacked either parallel to each other or helicoidally. The underlying molecular mechanisms that implement differential chitin organization are largely unknown. To learn more about cuticle organization, we sought to study the role of chitin deacetylases (CDA) in this process. In the body cuticle of nymphs of the migratory locust Locusta migratoria, helicoidal chitin organization is changed to an organization with unidirectional microfibril orientation when LmCDA2 expression is knocked down by RNA interference. In addition, the LmCDA2-deficient cuticle is less compact suggesting that LmCDA2 is needed for chitin packaging. Animals with reduced LmCDA2 activity die at molting, underlining that correct chitin organization is essential for survival. Interestingly, we find that LmCDA2 localizes only to the initially produced chitin microfibrils that constitute the apical site of the chitin stack. Based on our data, we hypothesize that LmCDA2-mediated chitin deacetylation at the beginning of chitin production is a decisive reaction that triggers helicoidal arrangement of subsequently assembled chitin-protein microfibrils.
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Amidoidrolases/biossíntese , Quitina/metabolismo , Regulação Enzimológica da Expressão Gênica/fisiologia , Proteínas de Insetos/biossíntese , Locusta migratoria/enzimologia , Muda/fisiologia , Amidoidrolases/genética , Animais , Quitina/genética , Proteínas de Insetos/genética , Locusta migratoria/genéticaRESUMO
This study aimed to compare the efficacy and safety of rituximab (RTX) plus recombinant human thrombopoietin (rhTPO) with RTX alone in patients with immune thrombocytopenia (ITP) who had failed to respond to corticosteroids or relapsed. Recruited patients were randomized at a ratio of 2:1 into 2 groups: the combination group (RTX + rhTPO, n = 77) and the monotherapy group (RTX, n = 38). Overall response was achieved in 79.2% of patients in the combination group vs 71.1% in the monotherapy group (P = .36), and the complete response (CR) rate was 45.4% in the combination group compared with 23.7% in the monotherapy group (P = .026). The combination group had significantly shorter time to response (TTR; median and range, 7 and 4-28 days) compared with the monotherapy group (28 and 4-90 days) (P < .01). There was no difference between these 2 groups in terms of the long-term response (P = .12). Our findings demonstrated that the combination of RTX and rhTPO significantly increased the CR rate and shortened TTR compared with RTX monotherapy in the treatment of corticosteroid-resistant or relapsed ITP but failed to show a beneficial effect on the long-lasting response. This study is registered at www.clinicaltrials.gov as #NCT01525836.
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Anticorpos Monoclonais Murinos/administração & dosagem , Púrpura Trombocitopênica Idiopática/tratamento farmacológico , Púrpura Trombocitopênica Idiopática/terapia , Trombopoetina/administração & dosagem , Adolescente , Corticosteroides/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais Murinos/efeitos adversos , Autoanticorpos/sangue , Criança , Terapia Combinada , Resistência a Medicamentos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Contagem de Plaquetas , Púrpura Trombocitopênica Idiopática/sangue , Proteínas Recombinantes/administração & dosagem , Proteínas Recombinantes/efeitos adversos , Recidiva , Rituximab , Trombopoetina/efeitos adversos , Resultado do Tratamento , Adulto JovemRESUMO
AIMS: To investigate the safety and efficacy of the triple therapy of decitabine, idarubicin, and cytarabine in the treatment of refractory or recurrent acute myeloid leukemia (R/R AML). METHODS: We conducted a single-center retrospective study in which decitabine treatment was administered prior to full-dose idarubicin and cytarabine (D-IA) for 21 R/R AML patients. RESULTS: After 1 cycle of D-IA, 10/21 (47.6%) patients experienced a complete remission (CR) and 2/21 (9.5%) showed a partial response. There was a 1-month response rate (RR) in 12/21 patients (57.14%); these patients achieved CR after 2 cycles of D-IA. Five of these 12 (40%) patients then received sequential allogeneic stem cell transplantation. At the last follow-up date, 9/21 (42.8%) patients had survived, and 7/21 (33.3%) were in continuous CR. Hematological toxicity and infections were the most prominent toxicities of this regimen. Other toxicities included nausea, vomiting, bleeding, and liver enzyme abnormalities. No mortalities were recorded due to treatment-related toxicity during remission. CONCLUSIONS: The combination was well tolerated, and the RR was encouraging. Our study suggests that D-IA may offer a novel and potentially effective treatment regimen for R/R AML patients.
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Azacitidina/análogos & derivados , Citarabina/administração & dosagem , Idarubicina/administração & dosagem , Leucemia Mieloide Aguda/tratamento farmacológico , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Azacitidina/administração & dosagem , Terapia Combinada , Decitabina , Feminino , Humanos , Leucemia Mieloide Aguda/terapia , Masculino , Pessoa de Meia-Idade , Recidiva , Indução de Remissão , Estudos Retrospectivos , Transplante de Células-Tronco , Transplante HomólogoRESUMO
CONTEXT: Diabetic nephropathy (DN) is the main cause of end-stage kidney disease in developed countries. Current therapy can slow the rate of progression of DN, but eventually end-stage renal failure will occur in a proportion of patients. Identification of new strategies and additional complementary and alternative therapies for treating DN are important. OBJECTIVE: The research team wanted to assess the beneficial and harmful effects of using puerarin plus angiotensin converting enzyme inhibitor (ACEI) compared with using only ACEI for treatment of individuals with stage III DN. DESIGN: The research team performed a meta-analysis of randomized, controlled trials (RCTs) by searching the following electronic databases: (1) the Cochrane Database of Systematic Reviews, (2) the Cochrane Central Register of Controlled Trials (CENTRAL), (3) PubMed, (4) EMBASE (Elsevier), (5) the Allied and Complementary Medicine Database (AMED), (6) the Chinese Biomedicine Database (CBM), (7) the China National Knowledge Infrastructure (CNKI), and (8) the Chinese Biomedical Journals (VIP), with no language restrictions, as well as databases of clinical trials. OUTCOME MEASURES: Measured outcomes included (1) urinary protein measured as urinary albumin excretion rate (UAER) (µg/min) and 24-h urine protein (24-h UP) (mg/24 h); (2) renal function measured as blood urea nitrogen (BUN) (mmol/L) and serum creatinine (SCr) (µmol/L); (3) α1-microglobulin (α1-MG) (mg/24 h) and endothelin-1 (ET-1) (ng/24 h); (4) end points (EPs); and (5) adverse events (AEs). RESULTS: Ten RCTs involving 669 participants were included. All trials were conducted and published in China. Treatment of DN with puerarin plus ACEI significantly decreased the UAER-P < .0001, MD = -23.43 (95% CI, -33.95 to -12.91), and had no effect on 24-h UP-P = .09, MD = -56.76 (95% CI, -122.65 to 9.12); BUN-P = .17, MD = -0.51 (95% CI, -1.24 to 0.21); and SCr-P = .26, MD = -4.43 (95% CI, -12.05 to 3.20). One trial reported abdominal discomfort and nausea (2 cases) in the treatment group. CONCLUSIONS: Puerarin may be a beneficial therapy for treating DN; however, this hypothesis needs to be proven by additional high-quality studies using large samples and multicenter evidence.
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Nefropatias Diabéticas/tratamento farmacológico , Isoflavonas/efeitos adversos , Isoflavonas/uso terapêutico , Vasodilatadores/efeitos adversos , Vasodilatadores/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Albuminúria , Nitrogênio da Ureia Sanguínea , Creatinina/sangue , Nefropatias Diabéticas/epidemiologia , Nefropatias Diabéticas/fisiopatologia , Humanos , Pessoa de Meia-IdadeRESUMO
The development of micro cracks in shale formations can easily lead to wellbore instability caused by liquid phase invasion. In order to effectively seal the shale micropores, the surface treatment of nano-SiO2 particles was developed using the silicane coupling agent A-1891. Then, the temperature-sensitive polypenic acrylamide polymer was modified onto the surface of the nanoprocal particle through reaction to obtain the nanosomal blocking agent ASN. The infrared spectrum shows that there are chemical bonds between the generated polymer chains, rather than simple physical composites, indicating the successful synthesis of the temperature-responsive nanosealing agent ASN. The particle size analysis showed that the synthesized nanoparticles in ASN have a uniform particle size distribution and display no agglomeration phenomenon. Applying ASN as a sealing agent in drilling fluid effectively fills the nanoscale micropores and microcracks in shale, making shale denser and significantly improving the wellbore stability of shale formations. In addition, it has good temperature resistance, can adapt to reservoirs at different temperatures, is non-toxic and environmentally friendly, and has good prospects for stable applications in shale formation wellbore.
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OBJECTIVE: To analyze the DTA (DNMT3A, TET2, ASXL1) mutations in patients with myeloproliferative neoplasms (MPN), and preliminarily explore their correlation with thromboembolism. METHODS: Clinical characteristics of 62 patients diagnosed de novo MPN at Central Hospital Affiliated to Shandong First Medical University from September 2016 to September 2022 were retrospectively analyzed. Next-generation sequencing was used to detect 35 MPN-related genes, and the DTA mutations in MPN patients and their relationship with thromboembolic events were analyzed. RESULTS: 75.8% (47/62) of the patients presented pathogenic non-driver mutations, and the mean number of pathogenic non-driver mutations per patient was 1.08. Among them, the most frequently mutated non-driver genes were TET2 (38.7%, 24/62), DNMT3A (9.7%, 6/62) and ASXL1 (6.5%, 4/62). The presence of DTA gene mutations was 50% (31/62) in the total MPN patients, and mainly accompanied by driver mutations. The mutation rate of DTA in patients aged ≥60 years was significantly higher than that in patients <60 years old (P =0.039). The incidence of thromboembolism in patients with DTA mutation was 58.1% (18/31), which was significantly higher than that in patients without DTA mutation (19.4%, 6/31) (P =0.002). The TET2 gene mutation rate in MPN patients with thromboembolism was 66.7% (16/24), which was significantly higher than that in patients without thromboembolism (21.1%, 8/38) (P =0.00). CONCLUSION: Patients with MPN have a higher incidence of DTA mutations, which are mainly accompanied by driver gene mutations. The incidence of thromboembolism in MPN patients with DTA mutations is higher than that in patients without DTA mutations. Especially, the elderly (≥60 years) essential thrombocythemia(ET) and polycythemia vera(PV) patients with TET2 mutation should be vigilant for thromboembolic events.
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DNA Metiltransferase 3A , Proteínas de Ligação a DNA , Dioxigenases , Mutação , Transtornos Mieloproliferativos , Proteínas Proto-Oncogênicas , Proteínas Repressoras , Tromboembolia , Humanos , Pessoa de Meia-Idade , Transtornos Mieloproliferativos/genética , Transtornos Mieloproliferativos/complicações , Tromboembolia/genética , Estudos Retrospectivos , Proteínas Proto-Oncogênicas/genética , Proteínas de Ligação a DNA/genética , Proteínas Repressoras/genética , DNA (Citosina-5-)-Metiltransferases/genética , Masculino , Feminino , Sequenciamento de Nucleotídeos em Larga EscalaRESUMO
Traditional granular hydrogels showed excellent injectivity, thermal integrity, and efficient remediation of heterogeneous reservoirs. However, granular hydrogels have demonstrated their inability to adapt to fractures due to the lack of sufficient interactions. Herein, we present new nanocomposite hydrogels consisting of cationic nanogelators and anionic granular hydrogels that can chemically in situ reform bulk hydrogels in the fractures. Interestingly, our granular hydrogels showed recross-linking independence on carrying fluids, contrary to prior reported fluid-dependent recross-linking granular hydrogels. The recross-linking of nanogelators and granular hydrogels can be accomplished from room temperature to 130 °C. The nanocomposite hydrogels displayed increased shear elastic moduli compared to pristine anionic granular hydrogels, probably due to the increased covalent cross-links formed by the homogeneous regenerative approach. We found that the granular hydrogels had high salinity tolerance even in the presence of 1000 ppm divalent ions of calcium (Ca2+) since Ca2+ ions often act as the cross-linker for partially hydrolyzed acrylamide-based hydrogels. Overall, we obtained new regenerative nanocomposite hydrogels based on cationic nanogelators and anionic granular hydrogels for fracture treatments.
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BACKGROUND: Stressors across the lifespan are associated with the onset of major depressive disorder (MDD) and increased severity of depressive symptoms. However, it is unclear how lifetime stressors are related to specific MDD subtypes. The present study aims to examine the relationships between MDD subtypes and stressors experienced across the lifespan while considering potential confounders. METHODS: Data analyzed were from the Zone d'Épidémiologie Psychiatrique du Sud-Ouest de Montréal (N = 1351). Lifetime stressors included childhood maltreatment, child-parent bonding, and stressful life events. Person-centered analyses were used to identify the clusters/profiles of the studied variables and multinomial logistic regression analyses were performed to examine the relationships between stressors and identified MDD subtypes. Intersectional analysis was applied to further examine how distal stressors interact with proximal stressors to impact the development of MDD subtypes. RESULTS: There was a significant association between proximal stressors and melancholic depression, whereas severe atypical depression and moderate depression were only associated with some domains of stressful life events. Additionally, those with severe atypical depression and melancholic depression were more likely to be exposed to distal stressors such as childhood maltreatment. The combinations of distal and proximal stressors predicted a greater risk of all MDD subtypes except for moderate atypical depression. CONCLUSIONS: MDD was characterized into four subtypes based on depressive symptoms and severity. Different stressor profiles were linked with various MDD subtypes. More specific interventions and clinical management are called to provide precision treatment for MDD patients with unique stressor profiles and MDD subtypes.
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Transtorno Depressivo Maior , Estresse Psicológico , Humanos , Transtorno Depressivo Maior/psicologia , Transtorno Depressivo Maior/epidemiologia , Feminino , Masculino , Adulto , Estudos Longitudinais , Estresse Psicológico/psicologia , Pessoa de Meia-Idade , Acontecimentos que Mudam a Vida , Índice de Gravidade de Doença , Sobreviventes Adultos de Maus-Tratos Infantis/psicologia , Sobreviventes Adultos de Maus-Tratos Infantis/estatística & dados numéricos , Experiências Adversas da Infância/estatística & dados numéricos , Adulto JovemRESUMO
Purpose: The aim of our study was to explore the relation between serum levels of non-enzymatic antioxidants, thyroid function with the risk of non-suicidal self-injury (NSSI) in depressed adolescents. Patients and Methods: We retrospected the electronic records of 454 hospitalized patients aged 13-17 years old with a diagnosis of major depressive disorder (239 patients with NSSI and 215 subjects without NSSI), and collected their demographic and clinical information, including serum levels of total bilirubin (Tbil), uric acid (UA), free triiodothyronine (FT3), free thyroxine (FT4) and thyroid stimulating hormone (TSH). Results: The incidence of NSSI was 52.6% among depressed adolescents aged 13-17, 57.1% in female and 38.5% in male. After using the propensity scoring method to exclude the influence of age between the two groups, it was found that patients with NSSI showed lower levels of Tbil (P=0.046) and UA (P=0.015) compared with those without NSSI. Logistic regression results showed that serum UA was associated with NSSI behavior in female patients (OR=0.995, 95% CI: 0.991-0.999, P=0.014), and TSH was associated with NSSI in male participants (OR=0.499, 95% CI: 0.267-0.932, P=0.029). Conclusion: Female and male may have different pathological mechanisms of NSSI. NSSI is more likely to be related to antioxidant reaction in female adolescent patients, while more likely to be related to thyroid function in male depressed adolescent patients.