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1.
Analyst ; 146(18): 5474-5495, 2021 Sep 13.
Artigo em Inglês | MEDLINE | ID: mdl-34515706

RESUMO

Acute myocardial infarction (AMI) is the main cause of death from cardiovascular diseases. Thus, early diagnosis of AMI is essential for the treatment of irreversible damage from myocardial infarction. Traditional electrocardiograms (ECG) cannot meet the specific detection of AMI. Cardiac troponin I (cTnI) is the main biomarker for the diagnosis of myocardial infarction, and the detection of cTnI content has become particularly important. In this review, we introduced and compared the advantages and disadvantages of various cTnI detection methods. We focused on the analysis and comparison of the main indicators and limitations of various cTnI biosensors, including the detection range, detection limit, specificity, repeatability, and stability. In particular, we pay more attention to the application and development of electrochemical biosensors in the diagnosis of cardiovascular diseases based on different biological components. The application of electrochemical microfluidic chips for cTnI was also briefly introduced in this review. Finally, this review also briefly discusses the unresolved challenges of electrochemical detection and the expectations for improvement in the detection of cTnI biosensing in the future.


Assuntos
Técnicas Biossensoriais , Infarto do Miocárdio , Biomarcadores , Diagnóstico Precoce , Humanos , Infarto do Miocárdio/diagnóstico , Troponina I
2.
J Hematol Oncol ; 14(1): 125, 2021 08 17.
Artigo em Inglês | MEDLINE | ID: mdl-34404434

RESUMO

B-cell lymphoma is a group of hematological malignancies with high clinical and biological heterogeneity. The pathogenesis of B-cell lymphoma involves a complex interaction between tumor cells and the tumor microenvironment (TME), which is composed of stromal cells and extracellular matrix. Although the roles of the TME have not been fully elucidated, accumulating evidence implies that TME is closely relevant to the origination, invasion and metastasis of B-cell lymphoma. Explorations of the TME provide distinctive insights for cancer therapy. Here, we epitomize the recent advances of TME in B-cell lymphoma and discuss its function in tumor progression and immune escape. In addition, the potential clinical value of targeting TME in B-cell lymphoma is highlighted, which is expected to pave the way for novel therapeutic strategies.

3.
Cell Death Dis ; 12(7): 640, 2021 06 23.
Artigo em Inglês | MEDLINE | ID: mdl-34162828

RESUMO

Polo-like kinase 4 (PLK4), a key regulator of centriole biogenesis, has recently been shown to play key roles in tumorigenesis. Blocking PLK4 expression by interference or targeted drugs exhibits attractive potential in improving the efficacy of chemotherapy. Nevertheless, the role of PLK4 in diffuse large B-cell lymphoma (DLBCL) is still undefined. In this study, we discover that PLK4 is a potential target for the treatment of DLBCL, and demonstrate the efficacy of a PLK4 inhibitor when used in combination with doxorubicin. Pharmaceutical inhibition of PLK4 with CFI-400945 inhibited DLBCL cell proliferation and induced apoptotic cell death. The anti-tumor effects were accompanied by mitotic defects, including polyploidy and cytokinesis failure. Activation of p53 and Hippo/YAP tumor suppressor signaling pathway was identified as the potential mechanisms driving CFI-400945 activity. Moreover, CFI-400945 treatment resulted in activation of DNA damage response. Combining CFI-400945 with doxorubicin markedly delayed tumor progression in DLBCL xenografts. Finally, PLK4 was increased in primary DLBCL tissues and cell lines. High levels of PLK4 expression were associated with poor survival in the patients receiving CHOP-based treatment, implicating PLK4 as a predictive biomarker of DLBCL chemosensitivity. These results provide the therapeutic potential of CFI-400945 both as monotherapy or in combination with doxorubicin for the treatment of DLBCL.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Dano ao DNA , Doxorrubicina/farmacologia , Indazóis/farmacologia , Indóis/farmacologia , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Mitose/efeitos dos fármacos , Inibidores de Proteínas Quinases/farmacologia , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Animais , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Linfoma Difuso de Grandes Células B/enzimologia , Linfoma Difuso de Grandes Células B/genética , Linfoma Difuso de Grandes Células B/patologia , Camundongos SCID , Proteínas Serina-Treonina Quinases/metabolismo , Transdução de Sinais , Carga Tumoral/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto
4.
J Hematol Oncol ; 14(1): 88, 2021 06 05.
Artigo em Inglês | MEDLINE | ID: mdl-34090506

RESUMO

Antibody-drug conjugates (ADCs) are a promising class of immunotherapies with the potential to specifically target tumor cells and ameliorate the therapeutic index of cytotoxic drugs. ADCs comprise monoclonal antibodies, cytotoxic payloads with inherent antitumor activity, and specialized linkers connecting the two. In recent years, three ADCs, brentuximab vedotin, polatuzumab vedotin, and loncastuximab tesirine, have been approved and are already establishing their place in lymphoma treatment. As the efficacy and safety of ADCs have moved in synchrony with advances in their design, a plethora of novel ADCs have garnered growing interest as treatments. In this review, we provide an overview of the essential elements of ADC strategies in lymphoma and elucidate the up-to-date progress, current challenges, and novel targets of ADCs in this rapidly evolving field.


Assuntos
Antineoplásicos Imunológicos/uso terapêutico , Imunoconjugados/uso terapêutico , Linfoma/tratamento farmacológico , Animais , Antineoplásicos Imunológicos/efeitos adversos , Ensaios Clínicos como Assunto , Desenvolvimento de Medicamentos , Humanos , Imunoconjugados/efeitos adversos
5.
Biochem Pharmacol ; 188: 114576, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33930347

RESUMO

Diffuse large B-cell lymphoma (DLBCL) is the most common subtype of non-Hodgkin lymphoma (NHL) with high clinical heterogeneity and poor prognosis. Immune escape mediated by CD47 overexpression contributes to the limited efficacy of rituximab, an anti-CD20 antibody, which indicates a target to improve the efficacy of DLBCL treatment. Here, we validated berberine, a natural compound, as a suppressor of CD47 and revealed the involved mechanism and biological function in DLBCL. Berberine downregulated the expression of CD47 in DLBCL at the transcriptional level by suppressing c-myc expression. Berberine-induced CD47 inhibition enhanced the phagocytosis of macrophages, thereby eliminating DLBCL cells in vitro and in vivo. Interestingly, berberine enhanced the efficiency of anti-CD47 antibody and rituximab-mediated phagocytosis. Moreover, a novel prognostic model based on the combination of CD47 and CD68, a biomarker of macrophages, was established in DLBCL. Our results highlighted for the first time that berberine could restore macrophage function in the tumor microenvironment, enhance rituximab-mediated phagocytosis and promote anti-CD47 antibody function via suppressing CD47 expression, which revealed a new anti-tumor mechanism of berberine and provided novel insights into the rituximab-based immunochemotherapy and CD47-targeted immunotherapy in DLBCL.


Assuntos
Antineoplásicos/uso terapêutico , Berberina/uso terapêutico , Antígeno CD47/antagonistas & inibidores , Antígeno CD47/biossíntese , Genes myb/efeitos dos fármacos , Linfoma Difuso de Grandes Células B/metabolismo , Adulto , Idoso , Animais , Antineoplásicos/farmacologia , Berberina/farmacologia , Antígeno CD47/genética , Genes myb/fisiologia , Humanos , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Linfoma Difuso de Grandes Células B/genética , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Pessoa de Meia-Idade
6.
Cancer Gene Ther ; 2021 Jan 07.
Artigo em Inglês | MEDLINE | ID: mdl-33414519

RESUMO

Angiomotin (AMOT) is a membrane protein that is aberrantly expressed in a variety of solid tumors. Accumulating evidence support that AMOT is involved in the pathological processes of tumor proliferation, apoptosis, and invasion. However, the potential role of AMOT in the pathogenesis of diffuse large B-cell lymphoma (DLBCL) remains elusive. In the present study, we investigated the expression level and biological function of AMOT in DLBCL. AMOT expression was significantly reduced in DLBCL biopsy section, and low AMOT expression was associated with poor clinical prognosis. Overexpression of AMOT by lentivirus in human DLBCL cells induced cell viability inhibition concomitant with an increased percentage of cells in G1 phase and decreased percentage in S phase. Moreover, AMOT upregulation increased the sensitivity of DLBCL cells to doxorubicin. Furthermore, overexpression of AMOT led to reduced activation of key kinases for the DNA damage response (DDR). The above results indicated that AMOT acts as a tumor suppressor via inhibition of the DDR, thus reducing the viability while increasing the chemosensitivity in DLBCL. In summary, AMOT may be a novel potential target for DLBCL therapeutic intervention.

7.
Leuk Lymphoma ; 62(6): 1335-1343, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33399486

RESUMO

Diffuse large B-cell lymphoma (DLBCL) has been correlated with virus infection and immunity status. We retrospectively analyzed the association between HBV antibody and DLBCL development in HBsAg- patients. Compared with HBeAb- patients, HBeAb+ patients displayed unique clinical features. HBV antibody-negative patients had better therapeutic efficiency (p < .05). The media progression-free survival (PFS) and overall survival (OS) of HBV antibody-positive group were shorter than the negative group (p < .05). Furthermore, we found positive association between CD21 and HBsAb and their synergistic effect for prognostic predication. Interestingly, the effect of Rituximab in prognostic improvement was more significant in HBV antibody-positive group than negative group. Univariate analysis showed that HBV antibody was independent risk factor for disease prognosis. Altogether, our investigations identified for the first time the close association between HBV antibody and clinical prognosis in DLBCL patients. These findings provide potential biomarker to predict the effect of Rituximab and prognosis in DLBCL patients.


Assuntos
Hepatite B , Linfoma Difuso de Grandes Células B , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Ciclofosfamida/uso terapêutico , Hepatite B/complicações , Hepatite B/diagnóstico , Hepatite B/tratamento farmacológico , Vírus da Hepatite B , Humanos , Linfoma Difuso de Grandes Células B/diagnóstico , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Prognóstico , Estudos Retrospectivos , Rituximab/uso terapêutico
8.
J Hematol Oncol ; 13(1): 138, 2020 10 17.
Artigo em Inglês | MEDLINE | ID: mdl-33069241

RESUMO

With covalently closed circular structures, circular RNAs (circRNAs) were once misinterpreted as by-products of mRNA splicing. Being abundant, stable, highly conserved, and tissue-specific, circRNAs are recently identified as a type of regulatory RNAs. CircRNAs bind to certain miRNAs or proteins to participate in gene transcription and translation. Emerging evidence has indicated that the dysregulation of circRNAs is closely linked to the tumorigenesis and treatment response of hematological malignancies. CircRNAs play critical roles in various biological processes, including tumorigenesis, drug resistance, tumor metabolism, autophagy, pyroptosis, and ferroptosis. The N6-methyladenosine modification of circRNAs and discovery of fusion-circRNAs provide novel insights into the functions of circRNAs. Targeting circRNAs in hematological malignancies will be an attractive treatment strategy. In this review, we systematically summarize recent advances toward the novel functions and molecular mechanisms of circRNAs in hematological malignancies, and highlight the potential clinical applications of circRNAs as novel biomarkers and therapeutic targets for future exploration.


Assuntos
Carcinogênese/genética , Neoplasias Hematológicas/genética , RNA Circular/genética , Animais , Biomarcadores Tumorais/genética , Regulação Neoplásica da Expressão Gênica , Humanos , MicroRNAs/genética
9.
J Exp Clin Cancer Res ; 39(1): 142, 2020 Jul 25.
Artigo em Inglês | MEDLINE | ID: mdl-32711549

RESUMO

BACKGROUND: Sirtuin 6 (Sirt6) is a highly conserved ADP-ribosylase and NAD+ dependent deacylase, involved in broad cellular processes. This molecule possesses contradictory roles in carcinogenesis, as it has been documented to both suppressing and augmenting tumor growth. This project aimed to explore the expression and functions of Sirt6 in diffuse large B-cell lymphoma (DLBCL), especially with regards to the regulatory role of OSS_128167, a novel small molecular inhibitor targeting Sirt6. METHODS: Immunohistochemistry (IHC) was conducted to assess the expression of Sirt6 on paraffin-embedded tissues. Microarray dataset GSE32918 and GSE83632 were obtained from Gene Expression Omnibus and survival analysis was performed. Lentivirus vectors either encoding shSirt6, lvSirt6 or empty lentiviral vector were stably transfected into DLBCL cells. LY1 cell transfected with shSirt6 were performed RNA-sequencing (RNA-seq) analysis, functional enrichment analyses of gene ontology (GO) and gene set enrichment analysis (GSEA). DLBCL cells were subcutaneously injected to SCID beige mice to establish xenograft models. RESULTS: Sirt6 is found to be overexpressed in DLBCL, and is related to poor prognosis. Sirt6-deprived DLBCL cells displayed augmented sensitivity towards chemotherapy, higher rates of apoptosis, dysfunctional cell proliferation, and arrested cell cycle progression between the G2 and M phases. Selective OSS_128167-mediated Sirt6 blockage resulted in similar anti-lymphoma effects when compared to Sirt6 knocked-down DLBCL cells. PI3K signaling along with phosphorylation of its downstream targets was reduced upon Sirt6 downregulation. Xenograft models subjected to either OSS_128167 treatment or Sirt6-knockdown showed suppressed tumor growth and lower Ki-67 level. CONCLUSIONS: These findings provide mechanistic insights into the oncogenic activity of Sirt6 in DLBCL for the first time and highlighted the potency of OSS_128167 for novel therapeutic strategies in DLBCL.


Assuntos
Biomarcadores Tumorais/metabolismo , Resistencia a Medicamentos Antineoplásicos , Regulação Neoplásica da Expressão Gênica , Linfoma Difuso de Grandes Células B/patologia , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Sirtuínas/metabolismo , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Animais , Apoptose , Biomarcadores Tumorais/genética , Movimento Celular , Proliferação de Células , Feminino , Humanos , Linfoma Difuso de Grandes Células B/genética , Linfoma Difuso de Grandes Células B/metabolismo , Masculino , Camundongos , Camundongos SCID , Pessoa de Meia-Idade , Fosfatidilinositol 3-Quinases/genética , Prognóstico , Proteínas Proto-Oncogênicas c-akt/genética , Sirtuínas/genética , Taxa de Sobrevida , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de Xenoenxerto , Adulto Jovem
10.
J Hematol Oncol ; 13(1): 77, 2020 06 16.
Artigo em Inglês | MEDLINE | ID: mdl-32546241

RESUMO

BACKGROUND: Hippo-Yes-associated protein (YAP) signaling is a key regulator of organ size and tumorigenesis, yet the underlying molecular mechanism is still poorly understood. At present, the significance of the Hippo-YAP pathway in diffuse large B-cell lymphoma (DLBCL) is ill-defined. METHODS: The expression of YAP in DLBCL was determined in public database and clinical specimens. The effects of YAP knockdown, CRISPR/Cas9-mediated YAP deletion, and YAP inhibitor treatment on cell proliferation and the cell cycle were evaluated both in vitro and in vivo. RNA sequencing was conducted to detect dysregulated RNAs in YAP-knockout DLBCL cells. The regulatory effects of insulin-like growth factor-1 receptor (IGF-1R) on Hippo-YAP signaling were explored by targeted inhibition and rescue experiments. RESULTS: High expression of YAP was significantly correlated with disease progression and poor prognosis. Knockdown of YAP expression suppressed cell proliferation and induced cell cycle arrest in DLBCL cells. Verteporfin (VP), a benzoporphyrin derivative, exerted an anti-tumor effect by regulating the expression of YAP and the downstream target genes, CTGF and CYR61. In vitro and in vivo studies revealed that deletion of YAP expression with a CRISPR/Cas9 genome editing system significantly restrained tumor growth. Moreover, downregulation of IGF-1R expression led to a remarkable decrease in YAP expression. In contrast, exposure to IGF-1 promoted YAP expression and reversed the inhibition of YAP expression induced by IGF-1R inhibitors. CONCLUSIONS: Our study highlights the critical role of YAP in the pathogenesis of DLBCL and uncovers the regulatory effect of IGF-1R on Hippo-YAP signaling, suggesting a novel therapeutic strategy for DLBCL.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/fisiologia , Linfoma Difuso de Grandes Células B/metabolismo , Proteínas de Neoplasias/fisiologia , Proteínas Serina-Treonina Quinases/fisiologia , Receptor IGF Tipo 1/fisiologia , Transdução de Sinais/fisiologia , Fatores de Transcrição/fisiologia , Proteínas Adaptadoras de Transdução de Sinal/antagonistas & inibidores , Proteínas Adaptadoras de Transdução de Sinal/deficiência , Idoso , Animais , Apoptose/efeitos dos fármacos , Linfócitos B/metabolismo , Sistemas CRISPR-Cas , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Transformação Celular Neoplásica , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Fator de Crescimento Insulin-Like I/farmacologia , Linfoma Difuso de Grandes Células B/etiologia , Linfoma Difuso de Grandes Células B/patologia , Masculino , Camundongos , Camundongos SCID , Pessoa de Meia-Idade , Proteínas de Neoplasias/antagonistas & inibidores , Podofilotoxina/análogos & derivados , Podofilotoxina/farmacologia , Pseudolinfoma/metabolismo , Interferência de RNA , RNA Interferente Pequeno/genética , RNA Interferente Pequeno/farmacologia , Distribuição Aleatória , Receptor IGF Tipo 1/antagonistas & inibidores , Receptor IGF Tipo 1/biossíntese , Receptor IGF Tipo 1/genética , Fatores de Transcrição/antagonistas & inibidores , Fatores de Transcrição/deficiência , Tirfostinas/farmacologia , Tirfostinas/uso terapêutico , Verteporfina/farmacologia , Ensaios Antitumorais Modelo de Xenoenxerto
11.
Medicine (Baltimore) ; 98(44): e17684, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31689789

RESUMO

RATIONALE: Pulmonary mucoepidermoid carcinomas (PMECs) of the lung are rare malignant tumors. Despite progresses in examinations, the tumor represents a diagnostic challenge for pathologists and clinical physicians. Here, we present a patient who was eventually diagnosed with PMEC by the bronchoscopic examinations conducted three times. PATIENT CONCERNS: We present the case of a 41-year-old female who was initially diagnosed with pulmonary pleomorphic adenoma (PPA) with a 68 × 82 mm mass and nodules in her lung and eventually diagnosed with PMEC. DIAGNOSES: Based on histopathology, immunohistology, and imaging studies, the patient was diagnosed with PMEC (pT4N2M1). INTERVENTIONS: The patient received first-line systemic chemotherapy regime (gemcitabine combined with carboplatin). OUTCOMES: The patient received 2 cycles of chemotherapy. Based on the response evaluation criteria in solid tumor, she achieved partial response, and the mass was distinctly decreased from 68 × 22 mm to 41 × 17 mm. LESSONS: This case presents a rare PMEC overlapping with PPA, based on histological findings, suggesting that besides imaging studies and laboratory examinations, multiple biopsies and ThinPrep cytology tests are necessary to obtain an accurate diagnosis. The patient showed positive response to chemotherapy.


Assuntos
Carcinoma Mucoepidermoide/diagnóstico , Carcinoma Mucoepidermoide/patologia , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/patologia , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Broncoscopia , Carcinoma Mucoepidermoide/tratamento farmacológico , Feminino , Humanos , Neoplasias Pulmonares/tratamento farmacológico
12.
Cancer Manag Res ; 11: 4243-4254, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31190991

RESUMO

Background: Accumulating evidence suggested that tumor microenvironment and host immune system played important roles in determining the clinical course and outcome of human malignancies. The derived neutrophil to lymphocyte ratio (dNLR) and absolute lymphocyte count (ALC) were demonstrated to act as a prognostic factor in several malignancies. Nevertheless, the prognostic significance of them in extranodal natural killer/T-cell lymphoma (ENKTL) patients has never been explored. Patients and methods: A total of 33 newly diagnosed patients with ENKTL were included in this study. Clinicopathological characteristics were collected and prognostic significance of dNLR and ALC were evaluated. Results: Elevated dNLR and low ALC were both associated with poor survival rates. Patients with dNLR ≥3.6 revealed significantly shorter overall survival (OS) (P=0.001) and progression-free survival (PFS) (P=0.008) than those with dNLR <3.6. Patients with ALC <0.8×109/L had worse OS (P=0.008) and PFS (P<0.001) than those with ALC ≥0.8×109/L. An independent significant association between low ALC and poor clinical outcome in multivariate analysis for OS (HR, 36.023; 95% CI, 2.438-532.243; P=0.009) as well as PFS (HR, 7.698; 95%CI, 1.573-37.679; P=0.012) was identified. Conclusion: In this study, we validated for the first time the prognostic value of dNLR and ALC in ENKTL patients. Elevated dNLR and low ALC were both associated with aggressive tumor process and poor survival.ALC value at diagnosis represented an independent favorable prognostic factor for the clinical outcome of ENKTL patients.

13.
Oncol Lett ; 17(4): 3719-3726, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30881494

RESUMO

Proteasome inhibitors represent a novel class of drugs that have clinical efficacy against hematological and solid cancer types, including acute myeloid leukaemia, myelodysplastic syndrome an non-small cell lung cancer. It has been demonstrated that the anti-apoptotic protein B-cell lymphoma-2-associated athanogene 3 (BAG3) is induced by proteasome inhibitors in various cancer cells and serves an important role in chemotherapy resistance. The phosphatidylinositol 3-kinase (PI3K)/RAC-α serine/threonine-protein kinase (AKT) pathway is constitutively activated in a number of lymphoid malignancy types, including diffuse large B-cell lymphoma (DLBCL) and Burkitt lymphoma. In the present study, the aim was to elucidate the role of the PI3K/AKT signaling pathway in the induction of BAG3, following exposure to a proteasome inhibitor in DLBCL cell lines. Bortezomib and MG132 were used as proteasome inhibitors. Western blotting was used to evaluate the roles of proteasome inhibitors and the PI3K/AKT pathway in BAG3 induction in DLBCL cells (LY1 and LY8), and LY294002 was used to block the PI3K/AKT pathway. Cell viability was detected using a Cell Counting Kit-8 assay. Apoptosis of LY1 and LY8 cells was quantified by Annexin V/7-amino-actinomycin D flow cytometry. The BAG3 protein was markedly induced upon exposure to bortezomib and MG132 in a dose-dependent manner. The PI3K/AKT inhibitor LY294002 significantly suppressed the induction of BAG3 by proteasome inhibitors. Inhibition of the PI3K/AKT pathway decreased the proliferation and increased the apoptosis induced by proteasome inhibitors. The present results indicated that the PI3K/AKT pathway is associated with the activation of BAG3 expression in DLBCL cells, and is involved in the protective response against proteasome inhibition.

14.
Leuk Lymphoma ; 60(5): 1266-1274, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30714848

RESUMO

Chronic lymphocytic leukemia (CLL) constitutes the largest percentage of adult leukemia cases in Western countries. Classically, fludarabine (Flu) is an effective drug used as a first-line therapy for CLL; however, Flu resistance limits its clinical effect. Minichromosome maintenance (MCM) complex components 2-7 exert important functions in maintaining genomic stability. Replication stress occurs upon dysregulation of MCM7, which potentiates malignant phenotypes. In this study, primary CLL cells and CLL-derived cell lines displayed elevated MCM7 expression. In CD40-stimulated primary CLL cells, MCM7 inhibition resulted in increased Flu-induced apoptosis and delayed repair of DNA damage. In the MEC-1 and EHEB cell lines, knockdown of MCM7 with lentivirus significantly inhibited cell proliferation and promoted cell cycle arrest at S phase. Moreover, MCM7 silencing sensitized both cell lines to Flu by increasing replication stress. The combination of Flu administration with MCM7 inhibition represents a novel approach to reverse Flu resistance in CLL.


Assuntos
Antineoplásicos/farmacologia , Regulação Leucêmica da Expressão Gênica/efeitos dos fármacos , Leucemia Linfocítica Crônica de Células B/genética , Componente 7 do Complexo de Manutenção de Minicromossomo/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/uso terapêutico , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Dano ao DNA , Feminino , Humanos , Influenza Humana/imunologia , Leucemia Linfocítica Crônica de Células B/diagnóstico , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Masculino , Pessoa de Meia-Idade , Componente 7 do Complexo de Manutenção de Minicromossomo/metabolismo , RNA Mensageiro/genética , Regulação para Cima , Vidarabina/análogos & derivados , Vidarabina/farmacologia , Vidarabina/uso terapêutico , Replicação Viral/imunologia
15.
Cell Cycle ; 18(4): 379-394, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30612524

RESUMO

Aberrant expression of CUL4B was identified in various types of solid cancers. Cumulative evidences support the oncogenic role of CUL4B in cancers, including regulation of cell proliferation and signal transduction. However, its clinical value and potential pathogenic mechanism in diffuse large B-cell lymphoma (DLBCL) have not been described previously. Therefore, we hypothesize that overexpressed CUL4B may contribute to the pathogenesis of DLBCL. The aim of this study is to assess the expression and the biological function of CUL4B in DLBCL progression. In our study, CUL4B overexpression was observed in DLBCL tissues, and its upregulation was closely associated with poor prognosis in patients. Furthermore, the functional roles of CUL4B was detected both in vitro and in vivo. We demonstrated that silencing CUL4B could not only induce cell proliferation inhibition, cell cycle arrest, and motility attenuation of DLBCL cells in vitro, but also decrease tumor growth in DLBCL xenografts mice. In addition, we identified that CUL4B may act as a potent inductor of JNK phosphorylation in regulation of autophagy. Our findings demonstrated a significant role of CUL4B in the development and progression of DLBCL. CUL4B may act as a useful biomarker and a novel therapeutic target in DLBCL.


Assuntos
Autofagia/genética , Proteínas Culina/genética , Proteínas Culina/metabolismo , Linfoma Difuso de Grandes Células B/metabolismo , Sistema de Sinalização das MAP Quinases , Adulto , Idoso , Idoso de 80 Anos ou mais , Animais , Apoptose/genética , Linhagem Celular Tumoral , Movimento Celular/genética , Proliferação de Células/genética , Feminino , Inativação Gênica , Xenoenxertos , Humanos , Estimativa de Kaplan-Meier , Linfoma Difuso de Grandes Células B/patologia , Masculino , Camundongos , Camundongos SCID , Pessoa de Meia-Idade , Transfecção , Carga Tumoral/genética , Adulto Jovem
16.
Onco Targets Ther ; 11: 8623-8632, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30584321

RESUMO

Background: PD1/PDL1 blockade is a promising treatment for patients with non-small-cell lung cancer (NSCLC). Here, we employed meta-analysis to evaluate the efficacy and safety of PD1/PDL1 blockades for previously treated NSCLC patients. Methods: Randomized clinical trials were retrieved by searching electronic databases. Data for HRs, 95% CIs for overall survival (OS), progression-free survival (PFS), and adverse events (AEs) were extracted and pooled. Results: A total of five randomized controlled trials including 2,910 patients were included in this meta-analysis. Pooled HRs (95% CI) were 0.71 (0.63-0.79, P<0.0001) for OS and 0.86 (0.73-1.02) for PFS. In the subgroup analysis, the pooled HR (95% CI) for PFS was 0.82 (0.75-0.91, P<0.0001) in patients with high PDL1 expression, but no significant difference was seen in patients with low expression (0.97 [0.76-1.24], P=0.82). The pooled RR for treatment-related AEs of all grades was 0.32 (0.27-0.38, P<0.00001) compared with the docetaxel arm, while that for grade 3-5 treatment-related AEs in the PD1/PDL1-blockade arm was 0.16 (0.10-0.27, P<0.00001). Conclusion: PD1/PDL1 blockades enhanced OS and PFS and led to lower risk of AEs in NSCLC patients. Smoking history and wild-type EGFR were associated with extended OS.

17.
Oncol Lett ; 16(5): 5838-5846, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30333864

RESUMO

T-cell lymphoma (TCL) is a group of heterogeneous disorders with a poor response to conventional treatment. In order to identify novel therapeutic targets, the present study investigated the effect of leptin and its receptor on glucose metabolism in TCL. The expression of the leptin receptor (ObR), and glucose transporter (Glut)1 and 4 was detected in TCL and reactive lymphoid hyperplasia (RLH) tissues by immunohistochemical analysis. A higher level of ObR expression was observed in the TCL tissues than in the RLH tissues (58.3 vs. 22.2%; P=0.012), and ObR overexpression was associated with high expression of Glut1 (P=0.007). In vitro analysis using the human TCL MOLT-3 cell line demonstrated that leptin stimulated cell glucose uptake via promoting recruitment and expression of Glut1, effects which were abolished by ObR-specific small interfering RNA (siRNA). Additionally, MOLT-3 cell viability was also increased following leptin treatment. ObR-specific siRNA abolished these responses. In conclusion, these results suggested that leptin serves a critical role in TCL glucose uptake via the ObR.

18.
Oncogene ; 37(41): 5520-5533, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-29895969

RESUMO

TP53 pathway defects contributed to therapy resistance and adverse clinical outcome in chronic lymphocytic leukemia (CLL), which represents an unmet clinical need with few therapeutic options. Maternal embryonic leucine zipper kinase (MELK) is a novel oncogene, which plays crucial roles in mitotic progression and stem cell maintenance. OTSSP167, an orally administrated inhibitor targeting MELK, is currently in a phase I/II clinical trial in patients with advanced breast cancer and acute myeloid leukemia. Yet, no investigation has been elucidated to date regarding the oncogenic role of MELK and effects of OTSSP167 in chronic lymphocytic leukemia (CLL). Previous studies confirmed MELK inhibition abrogated cancer cell survival via p53 signaling pathway. Thus, we aimed to determine the biological function of MELK and therapeutic potential of OTSSP167 in CLL. Herein, MELK over-expression was observed in CLL cells, and correlated with higher WBC count, advanced stage, elevated LDH, increased ß2-MG level, unmutated IGHV, positive ZAP-70, deletion of 17p13 and inferior prognosis of CLL patients. In accordance with functional enrichment analyses in gene expression profiling, CLL cells with depletion or inhibition of MELK exhibited impaired cell proliferation, enhanced fast-onset apoptosis, induced G2/M arrest, attenuated cell chemotaxis and promoted sensitivity to fludarabine and ibrutinib. However, gain-of-function assay showed increased cell proliferation and cell chemotaxis. In addition, OTSSP167 treatment reduced phosphorylation of AKT and ERK1/2. It decreased FoxM1 phosphorylation, expression of FoxM1, cyclin B1 and CDK1, while up-regulating p53 and p21 expression. Taken together, MELK served as a candidate of therapeutic target in CLL. OTSSP167 exhibits potent anti-tumor activities in CLL cells, highlighting a novel molecule-based strategy for leukemic interventions.


Assuntos
Antineoplásicos/farmacologia , Leucemia Linfocítica Crônica de Células B/metabolismo , Naftiridinas/farmacologia , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Adulto , Idoso , Idoso de 80 Anos ou mais , Apoptose/efeitos dos fármacos , Apoptose/fisiologia , Movimento Celular/efeitos dos fármacos , Movimento Celular/fisiologia , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/fisiologia , Feminino , Humanos , Leucemia Linfocítica Crônica de Células B/patologia , Masculino , Pessoa de Meia-Idade , Inibidores de Proteínas Quinases/farmacologia
19.
J Cancer Res Ther ; 14(1): 94-98, 2018 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-29516967

RESUMO

Context: T-cell lymphomas (TCLs) have been heterogeneous lymphoid malignancies with aggressive clinical phenotype and poor prognosis. Centrosomal protein 55 (CEP55) played a critical role in cytokinesis and served as a centrosome- and midbody-associated protein. Previous studies have reported the overexpression and clinical significance of CEP55 in various human malignancies, but the exact biological roles of CEP55 in TCLs remained unclear. Aims: In this study, we aimed to evaluate the CEP55 expression in patients with TCL and reactive hyperplasia of lymph nodes. The correlation between CEP55 levels and clinical characteristics was also explored for TCL patients. For further investigation, the cell viability of TCL cell lines after CEP55 inhibition was also assessed. Subjects and Methods: Immunohistochemistry was applied to assess the elevated level of CEP55 in TCLs. After siRNA treatment, cell viability and apoptotic rate of TCL cell lines were observed with CCK-8 assay and flow cytometry, respectively. Statistical Analysis: The Pearson's Chi-square test or Fisher's exact test was applied to analyze the correlations between CEP55 overexpression and clinical characteristics. All statistical tests were two-sided, and P < 0.05 was considered to be statistically significant. Results: CEP55 was upregulated in TCL patients and significantly correlated with Ki-67 label index. Consistently, cell viability was decreased, and apoptosis was increased after the suppression of CEP55 in TCL cell lines. Conclusions: These results suggested that target CEP55 would be a novel therapeutic strategy for the TCL.


Assuntos
Biomarcadores Tumorais , Proteínas de Ciclo Celular/metabolismo , Linfoma de Células T/metabolismo , Linfoma de Células T/mortalidade , Proteínas Nucleares/metabolismo , Apoptose/genética , Proteínas de Ciclo Celular/genética , Linhagem Celular Tumoral , Feminino , Expressão Gênica , Humanos , Imuno-Histoquímica , Linfoma de Células T/diagnóstico , Linfoma de Células T/terapia , Masculino , Proteínas Nucleares/genética , Prognóstico
20.
J Hazard Mater ; 346: 113-123, 2018 03 15.
Artigo em Inglês | MEDLINE | ID: mdl-29253750

RESUMO

A novel water-compatible surface molecularly imprinted thiol-functionalized titanium dioxide (TiO2) material (CMIP-coated TiO2) was prepared in water, using 2, 4-dinitrophenol (2, 4-DNP) as template molecule and o-phenylenediamine (OPDA) as both functional monomer and cross-linker. The as-synthesized materials were characterized by FESEM, FTIR, XRD, BET and UV-vis DRS. Moreover, we have investigated the adsorption capacity, adsorption selectivity and photodegradation activity of the CMIP-coated TiO2 and non-molecular imprinted materials (CNIP-coated TiO2). Additionally, the effects of pH and concentration of 2, 4-DNP on the degradation rate of 2, 4-DNP were also investigated. Results showed that CMIP-coated TiO2 exhibited higher adsorption capacity, greater selectivity and faster photodegradation activity for 2, 4-DNP compared with the CNIP-coated TiO2. Meanwhile, the specific selectivity to 2, 4-DNP over its structural analogue 4-nitrophenol (4-NP) and the enhanced photodegradation capacity were mainly attributed to the imprinted cavities on the surface of CMIP-coated TiO2. Taking advantage of efficient removal capacity, high reusability and no-additional chemicals in imprinted process, the prepared materials can be potentially applied to "green" removal of 2, 4-DNP in wastewater.

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