RESUMO
OBJECTIVE: To explore the efficacy and survival of venetoclax based (VEN-based) regimen in the treatment of acute myeloid leukemiaï¼AMLï¼. METHODS: A retrospective study was conducted in patients who received VEN-based regimen and completed at least 1 course of efficacy evaluation at the The First Affiliated Hospital of Nanchang University from July 2019 to July 2022. The incidence of complete remission ï¼CRï¼/CR with incomplete hematologic recovery ï¼CRiï¼ rate, objective remission rateï¼ORRï¼ and survival of patients with different risk strati- fication and gene subtypes were analyzed. RESULTS: A total of 79 patients were enrolled, including 43 patients with newly diagnosed unfit AML ï¼unfit AMLï¼ and 36 relapsed/refractory AML (R/R AML). The median age of the patients was 62(14-83) years old. 36 out of 79 patients achieved CR/CRi and the ORR of the whole cohort was 64.6%. The CR/CRi rate of unfit AML patients was significantly higher than that of R/R AML patients (60.5% vs 27.8%, P=0.004). In unfit AML cohort, the patients with NPM1 and IDH1/2 mutations were benefited, 8 out of 9 patients ahcieved CR/CRi, 7/8 and 5/8 patients achieved minimal residual disease (MRD) negativity, respectively. Six out of 9 patients with TET2 mutation achieved CR/CRi, 3/6 patients achieved MRD negativity. In R/R AML cohort, 2 out of 3 patients with RUNX1 mutation achieved CR/CRi, without MRD negative, while the CR/CRi rate of patients with other gene mutations was lower than 40%. The median follow-up time was 10.1(95%CI: 8.6-11.6) months. In whole cohort, the median overall survival (mOS) time was 9.1 months and the relapse free survival (RFS) time was not reached. The mOS and RFS of unfit AML patients were significantly longer than those of R/R AML patients (14.1 vs 6.8 months, P=0.013; not reached vs 3.3 months, P=0.000). In unfit AML cohort, the mOS of patients with NPM1 or IDH1/2 mutations was not reached, while that of patients without NPM1 or IDH1/2 mutations was 8.0 months (P=0.009; P=0.022). Furthermore, the mOS of patients with TP53 mutaion was significantly shorter than that of patients without TP53 mutation (5.2 vs 14.1 monthsï¼ P=0.049). In R/R AML cohort, there was no significant difference in mOS between patients with mutation in each gene subtype and those without gene mutation (P>0.05). All patients had hematology adverse reactions, 91.1% patients had AE grade≥3. The most common non-hematology adverse reactions was infection, with an incidence of 91.1%. VEN-based regimen was tolerable for AML patients. CONCLUSION: VEN-based regimen can achieve a high response rate, especially in unfit AML with acceptable safety, and some patients can achieve MRD negative. It is also effective in NPM1-, IDH1/2-positive patients with long survival time.
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Leucemia Mieloide Aguda , Nucleofosmina , Humanos , Pessoa de Meia-Idade , Idoso , Idoso de 80 Anos ou mais , Estudos Retrospectivos , Compostos Bicíclicos Heterocíclicos com Pontes/efeitos adversos , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/genética , Recidiva , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêuticoRESUMO
OBJECTIVE: To analyze the efficacy and safety of flumatinib in the treatment of patients with chronic myeloid leukemia (CML). METHODS: The clinical data of 56 CML patients treated with flumatinib from January 2020 to December 2021 in the First Affiliated Hospital of Nanchang University were retrospectively analyzed. Patients were divided into three groups: 35 new diagnosed CML patients treated with flumatinib (group A), 10 patients with imatinib/dasatinib intolerance (group B) and 11 patients with imatinib/dasatinib resistance (group C) switched to flumatinib treatment, respectively. The molecular response and adverse effects of flumatinib treatment were evaluated. RESULTS: In group A, the early molecular response (EMR) at 3 months was 40.0%, and the major molecular response (MMR) at 6 and 12 months was 43.7% and 46.2%, respectively. In group B, the EMR was 50.0% at 3 months, and the MMR was 70.0% and 66.2% at 6 and 12 months, respectively. Among evaluable patients, 6 cases in group B achieved molecular response of 4.5 (MR4.5) at 12 months after switching to flumatinib treatment. In group C, 3 cases who switched from imatinib resistance to flumatinib achieved MR4.5 at 12 months, but 2 cases who switched from dasatinib resistance to flumatinib failed. Subgroup analysis showed significant differences in EUTOS long-term survival (ELTS) scores for patients in the medium-risk/high-risk group compared with those in the low-risk group for 3-month EMR (18.8% vs 57.9%), 6-month MMR (15.4% vs 63.2%) and 12-month MR4.5 (15.4% vs 69.2%) (P =0.036, P =0.012,P =0.015). The most common adverse effect in group A was thrombocytopenia, accounting for 54.5%, and 22.8% (8/35) patients discontinued the drug due to haematological adverse effects. Compared with patients who did not discontinue the drug or whose recovery time from discontinuation due to haematological toxicity was <1 month, patients whose recovery time from discontinuation was ≥1 month had a significantly worse 3-month EMR, 6-month MMR and 12-month MR4.5 (P =0.028, P =0.021, P =0.002). CONCLUSIONS: Flumatinib has better molecular response and tolerance in patients with primary, imatinib/dasatinib-intolerant or resistant CML. Medium-risk/high-risk in ELTS score and time to recovery from discontinuation due to haematological toxicity ≥1 month are important factors influencing achievement of better molecular response in flumatinib treatment.
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Antineoplásicos , Leucemia Mielogênica Crônica BCR-ABL Positiva , Humanos , Mesilato de Imatinib/uso terapêutico , Dasatinibe/uso terapêutico , Inibidores de Proteínas Quinases/uso terapêutico , Estudos Retrospectivos , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Benzamidas/uso terapêutico , Doença Crônica , Resultado do Tratamento , Antineoplásicos/uso terapêuticoRESUMO
BACKGROUND: Spleen tyrosine kinase (Syk) inhibitor is a treatment option for primary immune thrombocytopenia. We aimed to evaluate the safety, tolerability, pharmacokinetics, preliminary activity, and recommended phase 2 dose of sovleplenib in patients with primary immune thrombocytopenia. METHODS: This randomised, double-blind, placebo-controlled, phase 1b/2 study was conducted at nine hospitals in China. Eligible patients were aged 18-75 years, had an ECOG performance score of 0-1, had primary immune thrombocytopenia for more than 6 months, and did not respond or relapsed after previous first-line treatment or had poor response or postoperative relapse after a splenectomy. Dose-escalation (100 mg, 200 mg, or 300 mg given orally once a day) and dose-expansion phases (recommended phase 2 dose) each consisted of an 8-week, double-blind, placebo-controlled period in which patients were randomly assigned (3:1) to receive sovleplenib or placebo with an interactive web response system followed by a 16-week, open-label period with sovleplenib. Patients, investigators, and the sponsor were masked to treatment allocation during the first 8 weeks. The main efficacy endpoint was the proportion of patients whose platelet count reached 30 × 109 platelets per L or higher and was double of the baseline at two consecutive visits during 0-8 weeks without rescue therapy. Efficacy was evaluated by intention-to-treat. This study is registered with ClinicalTrials.gov, NCT03951623. FINDINGS: Between May 30, 2019, and April 22, 2021, 62 patients were assessed for eligibility and 45 (73%) were randomly assigned. Patients received at least one dose of the study drug during the 8-week double-blind period (placebo [n=11] and sovleplenib 100 mg [n=6], 200 mg [n=6], 300 mg [n=16], and 400 mg [n=6]; this group was added following the observation of no protocol-specified safety events at the previous doses). All participants were Asian; 18 (40%) of 45 were male and 27 (60%) were female. The median age was 40·0 years (IQR 33·0-50·0). Ten (29%) of 34 patients in sovleplenib groups versus five (45%) of 11 in the placebo group received concomitant anti-primary immune thrombocytopenia therapy. The recommended phase 2 dose was determined as 300 mg once a day. The proportion of patients who met the main efficacy endpoint were three (50%; 95% CI 12-88) in the 100 mg group, three (50%; 12-88) in the 200 mg group, ten (63%; 35-85) in the 300 mg group, and two (33%; 4-78) in the 400 mg group compared with one (9%; 0-41) in the placebo group. The overall response rate in the 300 mg group was 80% (16 of 20 who received continuous sovleplenib plus those who crossed over from placebo) and the durable response rate was 31% (11-59; five of 16) in the continuous sovleplenib 300 mg and 75% (19-99; three of four) crossed from placebo to sovleplenib during 0-24 weeks. During the 28-day safety evaluation period, two grade 2 or worse treatment-related treatment-emergent adverse events occurred in the sovleplenib groups (hypertriglyceridaemia and anaemia). During 0-8 weeks, the most frequent treatment-emergent adverse events were an increase in blood lactate dehydrogenase, haematuria, and urinary tract infection (seven [21%] of 34 in sovleplenib groups vs one [9%] of 11 in the placebo group); and occult blood-positive and hyperuricaemia (four [12%] vs three [27%] for each). No fatal treatment-emergent adverse events were recorded. INTERPRETATION: Sovleplenib was well tolerated, and the recommended phase 2 dose showed a promising durable response in patients with primary immune thrombocytopenia, which provides evidence for future investigations. A phase 3 trial is ongoing (NCT05029635) to confirm the efficacy and safety of sovleplenib in patients with primary immune thrombocytopenia. FUNDING: HUTCHMED.
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Púrpura Trombocitopênica Idiopática , Humanos , Masculino , Feminino , Adulto , Resultado do Tratamento , Púrpura Trombocitopênica Idiopática/tratamento farmacológico , Contagem de Plaquetas , Doença Crônica , Método Duplo-Cego , Quinase Syk/uso terapêuticoRESUMO
BACKGROUND: Multiple myeloma (MM) is a malignant hematopoietic disease that is usually incurable. However, the ubiquitin-proteasome system (UPS) genes have not yet been established as a prognostic predictor for MM, despite their potential applications in other cancers. METHODS: RNA sequencing data and corresponding clinical information were acquired from Multiple Myeloma Research Foundation (MMRF)-COMMPASS and served as a training set (n=787). Validation of the prediction signature were conducted by the Gene Expression Omnibus (GEO) databases (n=1040). To develop a prognostic signature for overall survival (OS), least absolute shrinkage and selection operator regressions, along with Cox regressions, were used. RESULTS: A six-gene signature, including KCTD12, SIAH1, TRIM58, TRIM47, UBE2S, and UBE2T, was established. Kaplan-Meier survival analysis of the training and validation cohorts revealed that patients with high-risk conditions had a significantly worse prognosis than those with low-risk conditions. Furthermore, UPS-related signature is associated with a positive immune response. For predicting survival, a simple to use nomogram and the corresponding web-based calculator (https://jiangyanxiamm.shinyapps.io/MMprognosis/) were built based on the UPS signature and its clinical features. Analyses of calibration plots and decision curves showed clinical utility for both training and validation datasets. CONCLUSIONS: As a result of these results, we established a genetic signature for MM based on UPS. This genetic signature could contribute to improving individualized survival prediction, thereby facilitating clinical decisions in patients with MM.
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Mieloma Múltiplo , Nomogramas , Humanos , Complexo de Endopeptidases do Proteassoma/genética , Mieloma Múltiplo/genética , Prognóstico , Ubiquitinas , Proteínas de Transporte , Proteínas de Neoplasias , Proteínas Nucleares , Enzimas de Conjugação de UbiquitinaRESUMO
Immune thrombocytopenia (ITP) is an acquired autoimmune hemorrhagic disorder characterized by persistent thrombocytopenia. It may be induced by different pathogenesis due to its heterogeneity, and the therapeutic effects vary on different patients. Bone marrow derived mesenchymal stem cells (BMMSCs) can modulate innate and adaptive immunity, thus resulting in a tolerant microenvironment. Functional defects and immunomodulatory disorders of BMMSCs are significant causes of ITP. Functional effects associated with the activation of the P53 pathway include decreased activity of the phosphatidylinositol 3 kinase/AKT pathway and activation of the TNFAIP3/NF-κB/SMAD7 pathway. Immune dysfunction appears to be correlated with an impaired ability of BMMSCs to induce various types of immune cells in ITP. An in-depth investigation into the pathogenesis of ITP facilitates the treatment of ITP, but larger-scale clinical trials are needed to verify the efficacy of exogenous BMMSCs in the clinical treatment of ITP.
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Células-Tronco Mesenquimais , Púrpura Trombocitopênica Idiopática , Trombocitopenia , Humanos , Células-Tronco Mesenquimais/metabolismo , NF-kappa B/metabolismo , Púrpura Trombocitopênica Idiopática/metabolismo , Púrpura Trombocitopênica Idiopática/terapia , Trombocitopenia/metabolismo , Trombocitopenia/patologiaRESUMO
Immune thrombocytopenia (ITP) is an acquired autoimmune disorder characterized by persistent thrombocytopenia resulting from increased platelet destruction and a loss of autoimmune tolerance. The pathogenesis of ITP is highly complex. Although ITP may be effectively controlled with currently available medications in some patients, a subset of cases remain refractory. The application of mesenchymal stem cells (MSCs) for human hematopoietic stem cell transplantation has increasingly demonstrated that MSCs modulate innate or adaptive immunity, thus resulting in a tolerant microenvironment. Functional defects and immunomodulatory disorders have been observed after the use of bone marrow mesenchymal stem cells (BM-MSCs) from patients with ITP. Here, we summarize the underlying mechanisms and clinical applications of various derived MSCs for ITP treatment, focusing on the main mechanisms underlying the functional defects and immune dysfunction of BM-MSCs from patients with ITP. Functional effects associated with the activation of the p53 pathway include decreased activity of the phosphatidylinositol 3 kinase/Akt pathway and activation of the TNFAIP3/NF-κB/SMAD7 pathway. Immune dysfunction appears to be associated with an impaired ability of BM-MSCs to induce various types of immune cells in ITP. At present, research focusing on MSCs in ITP remains in preliminary stages. The application of autologous or exogenous MSCs in the clinical treatment of ITP has been attempted in only a small case study and must be validated in larger-scale clinical trials.
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Transplante de Células-Tronco Hematopoéticas , Células-Tronco Mesenquimais/imunologia , Púrpura Trombocitopênica Idiopática/imunologia , Púrpura Trombocitopênica Idiopática/terapia , Transdução de Sinais/imunologia , Humanos , NF-kappa B/imunologia , Fosfatidilinositol 3-Quinases/imunologia , Proteínas Proto-Oncogênicas c-akt/imunologia , Proteína 3 Induzida por Fator de Necrose Tumoral alfa/imunologia , Proteína Supressora de Tumor p53/imunologiaRESUMO
Haploidentical hematopoietic stem cell transplantation (haplo-HSCT) produces similar survival outcomes as HLA-matched sibling donor allogeneic HCST in younger patients with acquired severe aplastic anemia (SAA). This study reported a 29-years-old man with SAA and intracranial hemorrhage who underwent haplo-HSCT with a modified BU/CY + ATG conditioning regimen. Neutrophil and platelet engraftment were both achieved on day 14 after HSCT. The patient developed grade IV acute graft-versus-host disease (aGVHD) on day 20 and acquired cytomegalovirus (CMV) and Epstein-Barr virus (EBV) infections on day 47. After the failure of methylprednisolone, basiliximab, ruxolitinib, and antiviral treatment, the patient was diagnosed with steroid-resistant grade IV aGVHD and refractory CMV and EBV infections. We performed fecal microbiota transplantation and infused CMV- and EBV-specific cytotoxic T lymphocytes. After that the stool volume and frequency gradually decreased, and viral DNA was undetectable on day 80. This report provides helpful clinical experience for treating steroid-resistant aGVHD and refractory viral infections.
Assuntos
Infecções por Vírus Epstein-Barr , Doença Enxerto-Hospedeiro , Transplante de Células-Tronco Hematopoéticas , Adulto , Citomegalovirus , Infecções por Vírus Epstein-Barr/complicações , Infecções por Vírus Epstein-Barr/terapia , Transplante de Microbiota Fecal , Doença Enxerto-Hospedeiro/tratamento farmacológico , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Herpesvirus Humano 4 , Humanos , Esteroides/uso terapêuticoRESUMO
Xeroderma Pigmentosum group D (XPD) gene has been shown to suppress hepatocellular carcinoma (HCC) progression, but its mechanism remains not fully understood. ETS-related gene (ERG) is generally known as an oncogenic gene. This study aimed to explore whether XPD regulated HCC cell proliferation, apoptosis and cell cycle by inhibiting ERG expression via the PPARγ pathway. The human hepatoma cells (HepG2) were transfected with the XPD overexpression vector (pEGFP-N2/XPD) or empty vector (pEGFP-N2). The PPARγ inhibitor GW9662 was used to determine whether XPD effects were mediated by activation of PPARγ pathway. Cell cycle and apoptosis were ascertained by flow cytometry, and cell viability was measured by MTT assay. Reverse transcription-polymerase chain reaction and Western blot were performed to determine the mRNA and protein levels. Overexpression of XPD significantly enhanced the expression of PPARγ and p-PPARγ, whereas it downregulated that of ERG and cdk7. Furthermore, XPD overexpression notably inhibited proliferation, promoted apoptosis and decreased the percentage of cells in the S + G2 phase of HepG2 cells. However, these effects of XPD overexpression were abrogated by GW9662. Collectively, XPD suppresses proliferation and promotes apoptosis of HepG2 cells by downregulating ERG expression via activation of the PPARγ pathway.
Assuntos
Carcinoma Hepatocelular/patologia , Neoplasias Hepáticas/patologia , PPAR gama/metabolismo , Proteína Grupo D do Xeroderma Pigmentoso/metabolismo , Apoptose/fisiologia , Carcinoma Hepatocelular/metabolismo , Proliferação de Células/fisiologia , Regulação para Baixo , Células Hep G2 , Humanos , Neoplasias Hepáticas/metabolismo , Transdução de Sinais/fisiologia , Regulador Transcricional ERG/metabolismoRESUMO
Bone marrow mesenchymal stem cells (BMSCs) are associated with immune thrombocytopenia (ITP), the underlying mechanism has not been fully elucidated. Here, we attempted to investigate whether BMSCs can regulate Th17/Treg imbalance in ITP through the exosome pathway. We first assessed the proportions of Th17 cells and Tregs in ITP patients, showing that ITP patients exhibited an evident imbalance of Th17/Treg. BMSCs-exosomes' treatment significantly reduced Th17/Treg ratio in the CD4+ T cells of ITP patients. Moreover, miR-146a-5p was highly expressed in BMSCs-exosomes. The expression of miR-146a-5p was obviously increased in CD4+ T cells following the treatment of BMSCs-exosomes. BMSCs-exosomal miR-146a-5p silencing promoted the proportions of Th17 cells and repressed the proportions of Tregs in CD4+ T cells. In addition, miR-146a-5p directly interacted with IL-1R-associated kinase-1 (IRAK), and repressed IRAK1 expression. IRAK1 overexpression promoted Th17/Treg ratio in CD4+ T cells, which was abolished by BMSCs-exosomal miR-146a-5p. In conclusion, these findings demonstrate that BMSC-derived exosomal miR-146a-5p regulates Th17/Treg imbalance in ITP by repressing IRAK1 expression. Thus, this work suggests that BMSCs-exosomal miR-146a-5p may be a potential therapeutic target for ITP.
Assuntos
Células da Medula Óssea/citologia , Exossomos/genética , Exossomos/fisiologia , Quinases Associadas a Receptores de Interleucina-1/genética , Quinases Associadas a Receptores de Interleucina-1/metabolismo , Células-Tronco Mesenquimais/citologia , MicroRNAs/genética , MicroRNAs/metabolismo , Púrpura Trombocitopênica Idiopática/genética , Púrpura Trombocitopênica Idiopática/imunologia , Linfócitos T Reguladores/imunologia , Células Th17/imunologia , Células Cultivadas , Expressão Gênica/genética , Humanos , Terapia de Alvo Molecular , Púrpura Trombocitopênica Idiopática/terapiaRESUMO
Bone marrow mesenchymal stem cells (BMSCs) in acute myeloid leukemia (AML) microenvironment undergo modification that includes expression of contents in the small-sized extracellular vesicles (EVs) they secrete. This study aims to investigate whether small-sized EVs from BMSCs of AML patients regulate AML progression by modifying the expression of miR-26a-5p. Small-sized EVs from BMSCs of AML patients (AML-BMSC-EVs) or healthy controls (HC-BMSC-EVs) were isolated by ultra-centrifugation and administered to AML cells (OCI/AML-2 and THP-1). Cell proliferation, migration, and invasion were evaluated by CCK-8 assay, Transwell migration and invasion assays, respectively. Compared with HC-BMSC-EVs, AML-BMSC-EVs contained higher expression of miR-26a-5p and promoted AML cell proliferation, migration, and invasion. Inhibition of miR-26a-5p expression in AML-BMSC-EVs could abrogate the promoting effects of AML-BMSC-EVs on AML cell proliferation, migration, and invasion. Furthermore, GSK3ß was a direct target of miR-26a-5p. Moreover, AML-BMSC-EVs inhibited GSK3ß expression and activated Wnt/ß-catenin signaling in AML cells. Additionally, GSK3ß overexpression in THP-1 cells counteracted the promoting effects of AML-BMSCs-EVs on THP-1 cell proliferation, migration, and invasion. AML-BMSC-EVs promoted AML progression by transferring miR-26a-5p to AML cells and subsequently activating the Wnt/ß-catenin pathway.
Assuntos
Movimento Celular/genética , Proliferação de Células/genética , Vesículas Extracelulares/fisiologia , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/patologia , Células-Tronco Mesenquimais/citologia , MicroRNAs/metabolismo , Invasividade Neoplásica/genética , Linhagem Celular Tumoral , Vesículas Extracelulares/metabolismo , Humanos , Células-Tronco Mesenquimais/fisiologiaRESUMO
BACKGROUND: With the advent of rituximab combined with cyclophosphamide, doxorubicin, vincristine, and prednisolone (RCHOP) treatment has become considered the appropriate chemotherapy treatment for aggressive or advanced-stage indolent B-cell non-Hodgkins lymphoma (NHL). In recent years, RCHOP-14 seems to have achieved better outcomes in patients with aggressive or advanced-stage indolent B-cell NHL than RCHOP-21. METHODS: To verify the befitting chemotherapy regimens for patients with B-cell NHL, we searched the electronic databases for relevant English-language literature published in January 2020. The primary outcomes were complete response (CR), progression-free survival (PFS), overall survival (OS), and adverse events (AEs). Six eligible Phase II and III randomized controlled clinical trials (RCTs) and two high-quality observational comparative studies (OCSs) were extracted, with 5,565 patients with B-cell NHL involved in the evaluation. RESULTS: The analysis demonstrated no significant difference in RCHOP-14 and RCHOP-21 CR rates [odds ratio (OR) =0.98, 95% CI: 0.77-1.24, P=0.85]. Compared with RCHOP-21, the merged hazard ratio (HR) after treatment with RCHOP-14 for PFS and OS was 0.94 (95% CI: 0.84-1.06, P=0.32) and 0.91 (95% CI: 0.83-1.01, P=0.08), respectively. A subgroup analysis based on the international prognostic index (IPI) score showed that both chemotherapy regimens were applicable in B-cell NHL patients with different prognoses. The frequency of toxic side-effects was similar between schemes. CONCLUSIONS: The data presented suggest that the efficacy and safety of both regimens are comparable and that RCHOP-14 remains a viable plan in patients with B-cell NHL who prefer a shorter therapy course.
RESUMO
BACKGROUND: Cyclosporine injection is usually applied in allogeneic hematopoietic stem cell transplantation (Allo-HSCT) during induction phase. Anaphylaxis to cyclosporine injection is rare and how to deal with this issue in clinical practice is intractable. METHODS: We report a Chinese male patient with aplastic anemia who underwent allogeneic bone marrow transplantation (BMT) from his brother where HLA totally matched (10/10). Cyclosporine at a dose of 3 mg/kg was started by continuous infusion over 24 hours on day -1 of BMT and the patient showed sever anaphylaxis symptoms. He was then given oral capsules of cyclosporine (Sandimmun) at a conversion ratio 2:1. No further anaphylactic reaction was observed. The BM cells were successfully engrafted without causing severe GVHD. Moreover, frequent TDM monitoring as well as CYP3A4/CYP3A5/MDR1 genotyping were given so as to tailor the oral dosage of cyclosporine individually and prevent the adverse reaction between cyclosporine and posaconazole. RESULTS: The patient carried CYP3A5*3 GG genotype and the concentration of cyclosporine remained steady in the period of conversion and combination of cyclosporine and posaconazole. Consequently, the patient reported no allergy after conversion to oral cyclosporine. CONCLUSIONS: Polyoxyethylated castor oil that is contained in cyclosporine may be the main allergen. Changing to oral capsules that do not contain this medicinal excipient instead of cyclosporine injection would no longer cause an allergic reaction. Rational use of immunosuppressants and prophylaxis antibiotics may need close cooperation between physicians and pharmacists to avoid side effects and harmful interactions.
Assuntos
Anafilaxia/induzido quimicamente , Anemia Aplástica/cirurgia , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Transplante Homólogo/efeitos adversos , Administração Oral , Adulto , Ciclosporina/administração & dosagem , Ciclosporina/efeitos adversos , Ciclosporina/uso terapêutico , Doença Enxerto-Hospedeiro/tratamento farmacológico , Doença Enxerto-Hospedeiro/prevenção & controle , Transplante de Células-Tronco Hematopoéticas/métodos , Humanos , Imunossupressores/efeitos adversos , Imunossupressores/uso terapêutico , Infusões Intravenosas , Masculino , Transplante Homólogo/métodos , Adulto JovemAssuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Leucemia Mieloide Aguda , Proteínas de Fusão Oncogênica , Receptores do Ácido Retinoico , Fatores de Poliadenilação e Clivagem de mRNA , Citarabina/administração & dosagem , Mepesuccinato de Omacetaxina/administração & dosagem , Humanos , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/metabolismo , Leucemia Mieloide Aguda/patologia , Masculino , Pessoa de Meia-Idade , Proteínas de Fusão Oncogênica/genética , Proteínas de Fusão Oncogênica/metabolismo , Receptores do Ácido Retinoico/genética , Receptores do Ácido Retinoico/metabolismo , Fatores de Poliadenilação e Clivagem de mRNA/genética , Fatores de Poliadenilação e Clivagem de mRNA/metabolismo , Receptor gama de Ácido RetinoicoRESUMO
BACKGROUND/AIMS: CyclinG1 (CycG1) is frequently overexpressed in solid tumors and overexpression of CycG1 promotes cell survival upon paclitaxel exposure by inducing polyploidy. Whether and how CycG1 regulates polyploidization caused by small molecular targeted inhibitors remains unclear. METHODS: Immunohistochemistry and immunoblotting were utilized to examine protein expression. Cell proliferation was measured by ATPlite assay, and cell cycle distribution and apoptosis were measured by flow cytometry and/or DNA fragmentation assays. RESULTS: Overexpression of CycG1 in breast cancer cells caused apoptosis-resistant polyploidy upon treatment with Aurora kinase inhibitor, ZM447439 (ZM). Addition of ABT-263, a small-molecule BH3 mimetic, to ZM, produced a synergistic loss of cell viability with greater sustained tumor growth inhibition in breast cancer cell lines. Decrease of Mcl-1 and increase of NOXA caused by ZM treatment, were responsible for the synergy. Furthermore, CycG1 was highly expressed in Triple-Negative-Breast-Cancer patients treated with paclitaxel and was paralleled by decreased cell survival. CONCLUSION: CycG1 is a crucial factor in ZM-induced polyploidy resistance, and ABT-263/ZM combination hold therapeutic utility in the CycG1-amplified subset of breast cancer and CycG1, thus, is a promising target in breast cancer.
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Ciclina G1/metabolismo , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Inibidores de Proteínas Quinases/farmacologia , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Adulto , Compostos de Anilina/toxicidade , Antineoplásicos Fitogênicos/farmacologia , Antineoplásicos Fitogênicos/uso terapêutico , Benzamidas/farmacologia , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Ciclina G1/antagonistas & inibidores , Ciclina G1/genética , Feminino , Humanos , Células MCF-7 , Pessoa de Meia-Idade , Proteína de Sequência 1 de Leucemia de Células Mieloides/metabolismo , Paclitaxel/farmacologia , Paclitaxel/uso terapêutico , Poliploidia , Prognóstico , Quinazolinas/farmacologia , Interferência de RNA , Sulfonamidas/toxicidade , Neoplasias de Mama Triplo Negativas/diagnóstico , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Neoplasias de Mama Triplo Negativas/mortalidade , Proteína bcl-X/metabolismoRESUMO
We investigated the biological functions and mechanism of miRNA301a on apoptosis in chronic myelogenous leukemia (CML). The expression of miRNA301a in patient with CML cells was higher than the expression of normal patients. Overall survival (OS) of chronic granulocytic leukemia cell patient with low miRNA301 expression was superior to that of CML patient with high miRNA301 expression. Moreover, the upregulation of miRNA301a increased cell proliferation, inhibited apoptosis and caspase-3 and -9 activity of K562 cells. Next, the upregulation of miRNA301a suppressed Bax/Bcl-2 rate and TIMP2 protein expression, increased phosphorylation-ERK1/2 and decreased phosphorylation-AKT protein expression of K562 cells. Furthermore, siTIMP2 expression enhanced the upregulation of miRNA301a on the promotion of cell proliferation, inhibition of apoptosis and caspase-3 and -9 activity, suppression of Bax/Bcl-2 rate, increasing phosphorylation-ERK1/2 and decreasing phosphorylation-AKT protein expression of K562 cells. Taken together, our results clearly suggested that miRNA301a induces apoptosis of CML cells by directly targeting the TIMP2/ERK1/2 and AKT pathways.
Assuntos
Biomarcadores Tumorais/metabolismo , Leucemia Mielogênica Crônica BCR-ABL Positiva/patologia , MicroRNAs/genética , Proteína Quinase 1 Ativada por Mitógeno/antagonistas & inibidores , Proteína Quinase 3 Ativada por Mitógeno/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-akt/antagonistas & inibidores , Inibidor Tecidual de Metaloproteinase-2/antagonistas & inibidores , Apoptose , Biomarcadores Tumorais/genética , Western Blotting , Estudos de Casos e Controles , Proliferação de Células , Citometria de Fluxo , Humanos , Leucemia Mielogênica Crônica BCR-ABL Positiva/genética , Leucemia Mielogênica Crônica BCR-ABL Positiva/metabolismo , Proteína Quinase 1 Ativada por Mitógeno/genética , Proteína Quinase 1 Ativada por Mitógeno/metabolismo , Proteína Quinase 3 Ativada por Mitógeno/genética , Proteína Quinase 3 Ativada por Mitógeno/metabolismo , Estadiamento de Neoplasias , Fosforilação , Prognóstico , Proteínas Proto-Oncogênicas c-akt/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo , RNA Mensageiro/genética , Reação em Cadeia da Polimerase em Tempo Real , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Taxa de Sobrevida , Inibidor Tecidual de Metaloproteinase-2/genética , Inibidor Tecidual de Metaloproteinase-2/metabolismo , Células Tumorais CultivadasRESUMO
Pentose phosphate pathway (PPP) is a metabolic pathway that generates NADPH and pentose. PPP genes have been reported to be primarily or secondarily upregulated in many cancers. We aimed to study the general alteration of PPP in acute myelogenous leukemia (AML). We performed data mining and analysis of the Cancer Genome Atlas (TCGA) AML dataset for genetic alteration of the PPP gene set. In vitro studies including proliferation, migration, and invasion assays, together with metabolite consumption and oxidation assays, were performed. PPP genes were upregulated in 61 % of patients with AML. The majority of altered cases were expression changes measured by RNA sequencing. Expressions of critical PPP genes such as G6PD, PFKL, PFKP, and PGLS were consistently upregulated in all altered cases. Altered PPP is not associated with survival or disease relapse. PPP inhibition using 6-aminonicotinamide (6AN) increases glucose oxidative metabolism in AML. 6AN decreased the glucose oxidation and increased fatty acid oxidation. Here, we showed that PPP inhibition increased glucose oxidative metabolism in AML. PPP inhibition suppressed growth, migration, and invasion of AML, but not colony formation. PPP plays an important role in AML. Our results could contribute to the development of novel targeted treatment.
Assuntos
Leucemia Mieloide Aguda/metabolismo , Via de Pentose Fosfato , 6-Aminonicotinamida/farmacologia , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Biologia Computacional/métodos , Perfilação da Expressão Gênica , Regulação Leucêmica da Expressão Gênica , Variação Genética , Glucose/metabolismo , Humanos , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/mortalidade , Oxirredução/efeitos dos fármacos , PrognósticoRESUMO
Multiple myeloma (MM) was characterized by frequent mutations in KRAS/NRAS/BRAF within the EGFR pathway that could induce resistance to EGFR inhibitors. We here report that EGFR inhibition solely exhibited moderate inhibition in KRAS/NRAS/BRAF wildtype (triple-WT) MM cells, whilst had no effect in myeloma cells with any of the mutated genes. The moderate inhibitory effect was conferred by induction of pentose phosphate pathway (PPP) when cells were treated with Gefitinib, the EGFR inhibitor. Combination of Gefitinib with PPP inhibitor 6AN effected synergistically in triple-WT cells. The inhibition could be restored by addition of NADPH. Dual EGFR/ERBB2 inhibitor Afatinib also exhibited similar effects. Further genetic silencing of EGFR, ERBB2 and mTOR indicated that major effect conferred by ERBB2 was via convergence to EGFR pathway in MM. Our results contributed to the individualized targeted therapy with EGFR inhibitors in MM.
Assuntos
Proliferação de Células/efeitos dos fármacos , Receptores ErbB/antagonistas & inibidores , Via de Pentose Fosfato/efeitos dos fármacos , Inibidores de Proteínas Quinases/farmacologia , 6-Aminonicotinamida/farmacologia , Afatinib , Linhagem Celular Tumoral , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Sinergismo Farmacológico , Receptores ErbB/genética , Receptores ErbB/metabolismo , Gefitinibe , Glucose/metabolismo , Humanos , Metaboloma/efeitos dos fármacos , Mieloma Múltiplo/tratamento farmacológico , Mieloma Múltiplo/metabolismo , Mieloma Múltiplo/patologia , Oxigênio/metabolismo , Inibidores de Proteínas Quinases/uso terapêutico , Proteínas Proto-Oncogênicas B-raf/metabolismo , Quinazolinas/farmacologia , Quinazolinas/uso terapêutico , RNA Interferente Pequeno/metabolismo , Receptor ErbB-2/antagonistas & inibidores , Receptor ErbB-2/genética , Receptor ErbB-2/metabolismo , Serina-Treonina Quinases TOR/antagonistas & inibidores , Serina-Treonina Quinases TOR/genética , Serina-Treonina Quinases TOR/metabolismo , Proteínas ras/metabolismoRESUMO
To identify the clinical features of lymphoma-associated hemophagocytic syndrome (LAHS), we retrospectively analyzed the clinical characteristics, laboratory findings and survival data of 16 LAHS patients from 69 adult hemophagocytic syndrome (HPS) patients. The results showed that the most common clinical manifestations and laboratory parameters were fever (100%), ferritin ≥ 500 g/L (100%), peripheral cytopenia in two or more lineages (100%), fibrinogen (Fbg) < 1.5 g/L (93.8%) and splenomegaly (81.3%) in LAHS patients. The percentages of patients with Fbg < 1.5 g/L, PLT < 40 × 10(9)/L and LDH ≥ 1,000 U/L in the LAHS group were significantly higher than those in non-LAHS patients (P = 0.010, 0.000, and 0.001, respectively). Survival analysis showed that HLH patients with rheumatological reasons had better prognosis (OS; median not reached), followed by patients in the infection group (350 days) and those with unexplained causes (140 days). LAHS had the worst prognosis (only 37 days). The symptoms of LAHS patients are usually confused with other HPS. Patients with LAHS had higher probabilities to have Fbg < 1.5 g/L, PLT < 40 × 10(9)/L, LDH ≥ 1,000 U/L and poor prognosis, so early diagnosis and systemic treatments are required.
Assuntos
Linfo-Histiocitose Hemofagocítica/diagnóstico , Linfoma/diagnóstico , Adolescente , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica , Contagem de Células Sanguíneas , China , Feminino , Ferritinas/sangue , Fibrinogênio/metabolismo , Rearranjo Gênico , Geografia , Humanos , Linfo-Histiocitose Hemofagocítica/epidemiologia , Masculino , Pessoa de Meia-Idade , Tomografia por Emissão de Pósitrons , Prognóstico , Esplenomegalia/complicações , Resultado do Tratamento , Adulto JovemRESUMO
Beclin 1, a key regulator of autophagy, has been found to be aberrantly expressed in a variety of human malignancies. Herein, we employed immunohistochemistry (IHC) to detect the protein expression of Beclin 1 in non-small cell lung cancer (NSCLC) and paired normal adjacent lung tissues, and analyzed its clinicopathological/prognostic significance in NSCLC. Receiver operating characteristic (ROC) curve analysis was utilized to determine a cutoff point (>2 VS. ≤ 2) for Beclin 1 expression in a training set (n = 105). For validation, the ROC-derived cutoff value was subjected to analysis of the association of Beclin 1 with patients' clinical characteristics and outcome in a testing set (n = 111) and the overall patient cohort (n = 216). Our data showed that Beclin 1 was significantly lower in NSCLC tissues compared with the adjacent normal tissues, negatively associating with tumor recurrence rate (65.8% VS 32.3%; p < 0.001). In the testing set and the overall patient cohort, low expression of Beclin 1 showed significantly inferior overall survival (OS) (p < 0.001) and progression-free survival (PFS) (p < 0.001) compared to high expression of Beclin 1. In the testing set and the overall patient cohort, the median duration of OS for patients with high and low expression of Beclin 1 was 108 VS. 24.5 months (p < 0.001) and 108 VS. 28 months (p < 0.001), respectively. Furthermore, low expression of Beclin 1 was also a poor prognostic factor within each stage of NSCLC patients. Multivariate analysis identified that Beclin 1 was an independent prognostic factor for NSCLC. Our findings in the present study provided evidence that Beclin 1 may thus emerge as an independent prognostic biomarker in this tumor entity in the future.