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1.
Exp Cell Res ; 416(2): 113180, 2022 07 15.
Artículo en Inglés | MEDLINE | ID: mdl-35489384

RESUMEN

T-cell lymphoma (TCL) is a highly heterogeneous group of invasive non-Hodgkin lymphoma with adverse prognosis and limited treatment options. The relationship between TCL and Exportin-1 (XPO1), a major nuclear export receptor, has not been established yet. We here investigated the prognostic role and therapeutic implication of XPO1 in TCL. We analyzed XPO1 expression in a cohort of 69 TCL tumors and found that XPO1 was over-expressed in 76.8% of TCL and correlated with decreased progression-free survival (PFS) and overall survival (OS). In vitro treatment of TCL cell lines with KPT-8602, the second-generation selective inhibitor of nuclear export (SINE), inhibited XPO1 expression and showed significant anti-proliferative, cell-cycle arrest and pro-apoptotic efficacy. In mechanism, KPT-8602 restored the localization of cytoplasmic FOXO3A, p27, p21, IκBα and PP2A into the nucleus, leading to AKT and NF-κB deactivation. Our data demonstrate for the first time that XPO1 could be an unfavorable prognostic factor for TCL, and provide a rationale for further investigation of the efficacy of KPT-8602 in TCL patients.


Asunto(s)
Hidrazinas , Linfoma de Células T , Transporte Activo de Núcleo Celular , Apoptosis , Línea Celular Tumoral , Humanos , Hidrazinas/farmacología , Carioferinas/genética , Carioferinas/metabolismo , Pronóstico , Receptores Citoplasmáticos y Nucleares , Proteína Exportina 1
2.
BMC Ophthalmol ; 23(1): 28, 2023 Jan 23.
Artículo en Inglés | MEDLINE | ID: mdl-36690959

RESUMEN

OBJECTIVE: To develop and validate a nomogram model for predicting chronic ocular graft-versus-host disease (coGVHD) in patients after allogenic haematopoietic stem cell transplantation (allo-HSCT). METHODS: This study included 61 patients who survived at least 100 days after allo-HSCT. Risk factors for coGVHD were screened using LASSO regression, then the variables selected were subjected to logistic regression. Nomogram was established to further confirm the risk factors for coGVHD. Receiver operating characteristic (ROC) curves were constructed to assess the performance of the predictive model with the training and test sets. Odds ratios and 95% confidence intervals (95% CIs) were calculated by using logistic regression analysis. RESULTS: Among the 61 patients, 38 were diagnosed with coGVHD. We selected five texture features: lymphocytes (LYM) (OR = 2.26), plasma thromboplastin antecedent (PTA) (OR = 1.19), CD3 + CD25 + cells (OR = 1.38), CD3 + HLA-DR + cells (OR = 0.95), and the ocular surface disease index (OSDI) (OR = 1.44). The areas under the ROC curve (AUCs) of the nomogram with the training and test sets were 0.979 (95% CI, 0.895-1.000) and 0.969 (95% CI, 0.846-1.000), respectively.And the Hosmer-Lemeshow test was nonsignificant with the training (p = 0.9949) and test sets (p = 0.9691). CONCLUSION: We constructed a nomogram that can assess the risk of coGVHD in patients after allo-HSCT and help minimize the irreversible loss of vision caused by the disease in high-risk populations.


Asunto(s)
Enfermedad Injerto contra Huésped , Trasplante de Células Madre Hematopoyéticas , Humanos , Nomogramas , Trasplante Homólogo/efectos adversos , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Enfermedad Injerto contra Huésped/etiología , Factores de Riesgo
3.
Ann Hematol ; 101(7): 1509-1522, 2022 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-35445843

RESUMEN

The optimal induction chemotherapy regimens for young adult patients with newly diagnosed acute myeloid leukemia (AML) are not well-defined since the lack of direct comparisons between emerging treatments. Network meta-analysis (NMA) is a statistical tool to integrate direct and indirect evidence to evaluate the effect of multiple interventions. Thus, we conducted an NMA to systematically assess the efficacy and safety of different inductions for these patients. PubMed, Embase, Cochrane Library, and Web of Science were searched from establishment to 2020-03-11. Randomized controlled trials (RCTs) using different inductions were included. We deemed 11 trials eligible, including 11 inductions with 5052 participants. Relative risk (RR) and 95% confidence intervals (CIs) were calculated. In terms of complete remission (CR) rate, DAC ranked highest and was significantly higher than IA (RR = 1.27, 95% CI (1.09-1.48)) and DA (RR = 1.28, 95% CI (1.13-1.46)) (p < 0.05). The ranking of DA + Pioglitazone was second only to that of DAC, followed by HAA. For early mortality, HAD, HAA, and DA + GO were significantly higher than DA/IA (p < 0.05). DAC and DA + Pioglitazone showed similar early mortality compared to DA/IA (p > 0.05). Regarding incidence of early grade 3-4 infection, no significant differences between interventions were observed. To conclude, among the included 11 induction regimens, DAC was potentially the top choice for young adult patients with newly diagnosed AML, with highest CR rate, low early mortality, and incidence of early infection. DA + Pioglitazone and HAA also showed a superiority over the others to achieve higher CR rate, while caution should be kept in mind due to the higher early mortality of HAA.


Asunto(s)
Quimioterapia de Inducción , Leucemia Mieloide Aguda , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Humanos , Leucemia Mieloide Aguda/tratamiento farmacológico , Metaanálisis en Red , Pioglitazona/uso terapéutico , Inducción de Remisión , Adulto Joven
4.
Acta Biochim Biophys Sin (Shanghai) ; 54(9): 1244-1256, 2022 Sep 25.
Artículo en Inglés | MEDLINE | ID: mdl-36148953

RESUMEN

Acute myeloid leukemia (AML) is one of the most common malignancies of the hematopoietic progenitor cell in adults. Quercetin has gained recognition over the years because of its anti-cancer effect with minimal toxicity. Herein, we aim to investigate the anti-leukemia mechanism of quercetin and to decipher the signaling pathway of quercetin in HL-60 leukemic cells. We observed that quercetin induces apoptosis and autophagic cell death, in which both pathways play an important role in suppressing the viability of leukemia cells. Phosphorylated AMPK (p-AMPK) protein expressions are lower in primary AML cells, HL-60 cells, KG-1 and THP-1 cells than in peripheral blood monocular cells. After quercetin treatment, the expression of p-AMPK is increased while the expression of p-mTOR is decreased in a dose-dependent manner. Mechanistically, compound C, an AMPK phosphorylation inhibitor, upregulates the phosphorylation of mTOR and inhibits autophagy and apoptosis in quercetin-induced HL-60 cells, while silencing of CaMKKß inhibits the quercetin-induced phosphorylation of AMPK, resulting in increased mTOR phosphorylation. Furthermore, silencing of CaMKKß inhibits the autophagy in HL-60 cells. Taken together, our data delineate that quercetin plays its anti-leukemia role by inhibiting cell viability and inducing apoptosis and autophagy in leukemia cells. Quercetin inhibits the phosphorylation of mTOR by regulating the activity of AMPK, thus playing a role in the regulation of autophagy and apoptosis. CaMKKß is a potential upstream molecule for AMPK/mTOR signaling pathway, through which quercetin induces autophagy in HL-60 cells.


Asunto(s)
Muerte Celular Autofágica , Humanos , Células HL-60 , Quercetina/farmacología , Quinasa de la Proteína Quinasa Dependiente de Calcio-Calmodulina/metabolismo , Proteínas Quinasas Activadas por AMP/genética , Proteínas Quinasas Activadas por AMP/metabolismo , Fosforilación , Transducción de Señal , Serina-Treonina Quinasas TOR/metabolismo , Apoptosis , Autofagia
5.
BMC Med Inform Decis Mak ; 22(1): 276, 2022 10 22.
Artículo en Inglés | MEDLINE | ID: mdl-36273130

RESUMEN

BACKGROUND: Early prediction of patients' deterioration is helpful in early intervention for patients at greater risk of deterioration in Intensive Care Unit (ICU). This study aims to apply machine learning approaches to heterogeneous clinical data for predicting life-threatening events of patients in ICU. METHODS: We collected clinical data from a total of 3151 patients admitted to the Medical Intensive Care Unit of Peking Union Medical College Hospital in China from January 1st, 2014, to October 1st, 2019. After excluding the patients who were under 18 years old or stayed less than 24 h at the ICU, a total of 2170 patients were enrolled in this study. Multiple machine learning approaches were utilized to predict life-threatening events (i.e., death) in seven 24-h windows (day 1 to day 7) and their performance was compared. RESULTS: Light Gradient Boosting Machine showed the best performance. We found that life-threatening events during the short-term windows can be better predicted than those in the medium-term windows. For example, death in 24 h can be predicted with an Area Under Curve of 0.905. Features like infusion pump related fluid input were highly related to life-threatening events. Furthermore, the prediction power of static features such as age and cardio-pulmonary function increased with the extended prediction window. CONCLUSION: This study demonstrates that the integration of machine learning approaches and large-scale high-quality clinical data in ICU could accurately predict life-threatening events for ICU patients for early intervention.


Asunto(s)
Unidades de Cuidados Intensivos , Aprendizaje Automático , Humanos , Adolescente , Hospitalización , China
7.
Ann Hematol ; 95(5): 783-91, 2016 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-26891877

RESUMEN

The novel FMS-like tyrosine kinase 3 (FLT3)-N676K point mutation within the FLT3 kinase domain-1 was recently identified in 6 % of de novo acute myeloid leukemia (AML) patients with inv(16). Because FLT3-N676K was encountered almost exclusively in inv(16) AML, we investigated the transforming potential of FLT3-N676K, the cooperation between FLT3-N676K and core binding factor ß-smooth muscle myosin heavy chain (CBFß-SMMHC) (encoded by the inv(16) chimeric gene CBFB-MYH11) in inducing acute leukemia, and tested the sensitivity of FLT3-N676K-positive leukemic cells to FLT3 inhibitors. Retroviral expression of FLT3-N676K in myeloid 32D cells induced AML in syngeneic C3H/HeJ mice (n = 11/13, median latency 58 days), with a transforming activity similar to FLT3-internal tandem duplication (ITD) (n = 8/8), FLT3-TKD D835Y (n = 8/9), and FLT3-ITD-N676K (n = 9/9) mutations. Three out of 14 (21.4 %) C57BL/6J mice transplanted with FLT3-N676K-transduced primary hematopoietic progenitor cells developed acute leukemia (latency of 68, 77, and 273 days), while no hematological malignancy was observed in the control groups including FLT3-ITD. Moreover, co-expression of FLT3-N676K/CBFß-SMMHC did not promote acute leukemia in three independent experiments (n = 16). In comparison with FLT3-ITD, FLT3-N676K induced much higher activation of FLT3 and tended to trigger stronger phosphorylation of MAPK and AKT. Importantly, leukemic cells carrying the FLT3-N676K mutant in the absence of an ITD mutation were highly sensitive to FLT3 inhibitors AC220 and crenolanib, and crenolanib even retained activity against the AC220-resistant FLT3-ITD-N676K mutant. Taken together, the FLT3-N676K mutant is potent to transform murine hematopoietic stem/progenitor cells in vivo. This is the first report of acute leukemia induced by an activating FLT3 mutation in C57BL/6J mice. Moreover, further experiments investigating molecular mechanisms for leukemogenesis induced by FLT3-N676K mutation and clinical evaluation of FLT3 inhibitors in FLT3-N676K-positive AML seem warranted.


Asunto(s)
Leucemia Experimental/genética , Mutación Missense , Mutación Puntual , Tirosina Quinasa 3 Similar a fms/genética , Sustitución de Aminoácidos , Animales , Antineoplásicos/uso terapéutico , Bencimidazoles/uso terapéutico , Benzotiazoles/uso terapéutico , Trasplante de Médula Ósea , Transformación Celular Neoplásica/genética , Regulación Leucémica de la Expresión Génica , Predisposición Genética a la Enfermedad , Vectores Genéticos , Humanos , Leucemia Experimental/tratamiento farmacológico , Leucemia Experimental/enzimología , Ratones , Ratones Endogámicos C3H , Ratones Endogámicos C57BL , Trasplante de Neoplasias , Células Madre Neoplásicas/trasplante , Proteínas de Fusión Oncogénica/genética , Proteínas de Fusión Oncogénica/fisiología , Compuestos de Fenilurea/uso terapéutico , Piperidinas/uso terapéutico , Inhibidores de Proteínas Quinasas/uso terapéutico , Procesamiento Proteico-Postraduccional/genética , Quimera por Radiación , Retroviridae , Secuencias Repetidas en Tándem , Transgenes , Ensayo de Tumor de Célula Madre , Tirosina Quinasa 3 Similar a fms/antagonistas & inhibidores , Tirosina Quinasa 3 Similar a fms/fisiología
8.
J Cancer ; 15(9): 2538-2548, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-38577610

RESUMEN

As a rate-limiting enzyme for the serine biosynthesis pathway (SSP) in the initial step, phosphoglycerate dehydrogenase (PHGDH) is overexpressed in many different tumors, and pharmacological or genetic inhibition of PHGDH promotes antitumor effects. In the present research, by analyzing several acute myeloid leukemia (AML) datasets in the Gene Expression Omnibus (GEO), we identified prognosis-related genes and constructed a multigene signature by univariate, multivariate Cox regression and LASSO regression. Subsequently, the multigene signature was confirmed through Cox, Kaplan-Meier, and ROC analyses in the validation cohort. Moreover, PHGDH acted as a risk factor and was correlated with inferior overall survival. We further analysed other datasets and found that PHGDH was overexpressed in AML. Importantly, the expression of PHGDH was higher in drug-resistant AML compared to drug-sensitive ones. In vitro experiments showed that inhibition of PHGDH induced apoptosis and reduced proliferation in AML cells, and these antitumor effects could be related to the Bcl-2/Bax signaling pathway by the noncanonical or nonmetabolic functions of PHGDH. In summary, we constructed a twenty-gene signature that could predicate prognosis of AML patients and found that PHGDH may be a potential target for AML treatment.

9.
Hematology ; 28(1): 2219554, 2023 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-37288810

RESUMEN

BACKGROUND: T cells' function and activation and the immunosuppressive effect of regulatory T cells (Tregs) play a pivotal role in the occurrence and progression of acute myeloid leukemia (AML). In this study, we investigate the expression of T cell activation markers and quantity of Tregs in bone marrow (BM) and peripheral blood (PB) from AML patients and further characterized their correlation with BM leukemic blasts. METHODS: Expression of CD25, CD38, CD69, and HLA-DR on the surfaces of CD4+ and CD8+ T cells and the quantity of Tregs in BM and PB from new diagnosed (ND), relapsed-refractory (RR), complete remission (CR) AML patients were measured via flow cytometry. RESULTS: Compared to normal controls (NC), we found higher proportion of CD4+ CD69+ T cells, CD8+ CD69+ T cells and Tregs in PB. CD8+ CD38+ T cells and CD8+ HLA-DR+ T cells in RR were significantly higher than ND, CR and NC). Tregs were normalized when AML patients achieved CR. Moreover, there was a minor positive correlation between AML blasts and CD8+ CD25+ T cells or Tregs, while AML blasts had a minor negative correlation with CD4+ CD69+ T cells. CONCLUSION: Abnormal activation markers of T cells and Tregs may be involved in the pathological mechanism of ND and RR AML. Our results indicated that CD8+ CD38+ T cells and CD8+ HLA-DR+ T cells might be RR markers of AML patients. Furthermore, Tregs could be used as clinical indicators to evaluate prognosis for AML patients.


Asunto(s)
Médula Ósea , Leucemia Mieloide Aguda , Humanos , Médula Ósea/patología , Linfocitos T CD8-positivos/patología , Regulación hacia Arriba , Leucemia Mieloide Aguda/patología , Antígenos HLA-DR/metabolismo
10.
Int J Ophthalmol ; 16(7): 1138-1144, 2023.
Artículo en Inglés | MEDLINE | ID: mdl-37465516

RESUMEN

AIM: To explore the relationship between ocular and systemic conditions and the impact of ocular complications on the quality of life (QOL) in patients after allogeneic hematopoietic stem cell transplantation (ALLO-HSCT). METHODS: Forty-four patients with severe hematopoietic disease were enrolled after ALLO-HSCT at our center from July 2018 to October 2020. They completed two questionnaires: the Ocular Surface Disease Index (OSDI) and the quality-of-life scale for Chinese patients with visual impairment (SQOL-DV1). Ocular conditions and systemic conditions were also assessed. RESULTS: Eye damage was correlated with total bilirubin (P=0.005), and gamma-glutamyl transferase (GGT) (P=0.021). There was no significant correlation between the overall QOL score and OSDI (P=0.8226) or SQOL-DV1 (P=0.9526) scores. The OSDI and the overall QOL score were not correlated with ocular conditions, including best-corrected visual acuity (BCVA), intraocular pressure, Schirmer tear test II, sodium fluorescein staining, tear film breakup time, and tear meniscus height. SQOL-DV1 was correlated with BCVA (P=0.0007), sodium fluorescein staining (P=0.007), and tear film breakup time (P=0.0146). CONCLUSION: In some patients, early ocular symptoms are not evident after ALLO-HSCT, while ocular surface complications can be observed after a comprehensive ophthalmological examination. Especially for those with elevated total bilirubin or GGT, regular ophthalmic follow-up visits are essential to diagnose and treat ocular graft versus host disease (oGVHD), especially for patients with elevated total bilirubin or GGT.

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