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2.
Cancer Sci ; 112(11): 4772-4784, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34490703

RESUMO

Copy number variations (CNVs) in cell-free DNA (cfDNA) are emerging as noninvasive biomarkers for various cancers. However, multiple-level analysis of cfDNA CNVs for hepatocellular carcinoma (HCC) patients with radical treatments remains uninvestigated. Here, CNVs at genome-wide, chromosomal-arm, and bin levels were analyzed in cfDNA from 117 HCC patients receiving radical treatments. Then, the relationship between cfDNA CNVs and clinical outcomes was explored. Our results showed that a concordant profile of CNVs was observed between cfDNA and tumor tissue DNA. Three genome-wide CNV indicators including tumor fraction (TFx), prediction score (P-score), and stability score (S-score) were calculated and demonstrated to exhibit significant correlation with poorer overall survival (OS) and recurrence-free survival (RFS). Furthermore, the high-frequency cfDNA CNVs at chromosomal-arm level including the loss of 4q, 17p, and 19p and the gain of 8q and 1q clearly predicted HCC prognosis. Finally, a bin-level risk score was constructed to improve the ability of CNVs in predicting prognosis. Altogether, our study indicates that the multiple-level cfDNA CNVs are significantly associated with OS and RFS in HCC patients with radical treatments, suggesting that cfDNA CNVs detected by low-coverage whole-genome sequencing (WGS) may be used as potential prognostic biomarkers of HCC patients.


Assuntos
Carcinoma Hepatocelular/genética , Ácidos Nucleicos Livres/genética , Variações do Número de Cópias de DNA , Neoplasias Hepáticas/genética , Biomarcadores Tumorais/genética , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/mortalidade , Cromossomos Humanos Par 17 , Cromossomos Humanos Par 19 , Cromossomos Humanos Par 4 , Cromossomos Humanos Par 6 , Cromossomos Humanos Par 8 , DNA de Neoplasias , Intervalo Livre de Doença , Feminino , Marcadores Genéticos , Humanos , Estimativa de Kaplan-Meier , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/mortalidade , Masculino , Pessoa de Meia-Idade , Prognóstico , Resultado do Tratamento , Sequenciamento Completo do Genoma
3.
Front Oncol ; 11: 708784, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34336695

RESUMO

Purpose: Although the role of tumor-infiltrating T cells in follicular lymphoma (FL) has been reported previously, the prognostic value of peripheral blood T lymphocyte subsets has not been systematically assessed. Thus, we aim to incorporate T-cell subsets with clinical features to develop a predictive model of clinical outcome. Methods: We retrospectively screened a total of 1,008 patients, including 252 newly diagnosed de novo FL patients with available peripheral blood T lymphocyte subsets who were randomized to different sets (177 in the training set and 75 in the internal validation set). A nomogram and a novel immune-clinical prognostic index (ICPI) were established according to multivariate Cox regression analysis for progression-free survival (PFS). The concordance index (C-index), Akaike's information criterion (AIC), and likelihood ratio chi-square were employed to compare the ICPI's discriminatory capability and homogeneity to that of FLIPI, FLIPI2, and PRIMA-PI. Additional external validation was performed using a dataset (n = 157) from other four centers. Results: In the training set, multivariate analysis identified five independent prognostic factors (Stage III/IV disease, elevated lactate dehydrogenase (LDH), Hb <120g/L, CD4+ <30.7% and CD8+ >36.6%) for PFS. A novel ICPI was established according to the number of risk factors and stratify patients into 3 risk groups: high, intermediate, and low-risk with 4-5, 2-3, 0-1 risk factors respectively. The hazard ratios for patients in the high and intermediate-risk groups than those in the low-risk were 27.640 and 2.758. The ICPI could stratify patients into different risk groups both in the training set (P < 0.0001), internal validation set (P = 0.0039) and external validation set (P = 0.04). Moreover, in patients treated with RCHOP-like therapy, the ICPI was also predictive (P < 0.0001). In comparison to FLIPI, FLIPI2, and PRIMA-PI (C-index, 0.613-0.647), the ICPI offered adequate discrimination capability with C-index values of 0.679. Additionally, it exhibits good performance based on the lowest AIC and highest likelihood ratio chi-square score. Conclusions: The ICPI is a novel predictive model with improved prognostic performance for patients with de novo FL treated with R-CHOP/CHOP chemotherapy. It is capable to be used in routine practice and guides individualized precision therapy.

4.
Medicine (Baltimore) ; 100(28): e26597, 2021 Jul 16.
Artigo em Inglês | MEDLINE | ID: mdl-34260541

RESUMO

BACKGROUND: Esophageal cancer is the eighth most frequent and sixth most fatal cancer worldwide. This study aimed to investigate the clinical characteristics and prognostic significance of yes related protein 1 (YAP1) and transcriptional co-activator with PDZ binding motif (TAZ) in patients with esophageal squamous cell carcinoma (ESCC). METHODS: A total of 306 ESCC pathological specimens and adjacent tissues (as control; tissues from the esophageal mucosa >5 cm from the edge of the tumor) were collected between January, 2008 and December, 2018. Immunohistochemical staining was used to assess the expression of YAP1 and TAZ proteins in the ESCC and adjacent tissues, and their relationship with clinicopathological parameters was evaluated using SPSS 21.0 software. RESULTS: YAP1 and TAZ proteins were highly expressed in ESCC, and their expression was closely related to TNM stage and lymph node metastasis. Expression of YAP1 was associated with tumor size (P = .029), differentiation (P = .000), depth of invasion (P = .001), and TNM stage (P = .000). Expression of TAZ was associated with tumor size (P = .034), differentiation (P = .000), depth of invasion (P = .029), lymph node metastasis (P = .006), and ethnicity (P < .001). The expression of YAP1 protein was positively correlated with the expression of TAZ protein (r = 0.257, P < .05). YAP1 and TAZ expression (P = .039 and .000, respectively), tumor size (P = .041), and lymph node metastasis (P = .001) significantly affected the overall survival of patients with ESCC, and represent independent factors for overall survival. CONCLUSION: YAP1 and TAZ proteins are highly expressed in ESCC, and closely related to the clinical and pathological parameters such as the diameter of the tumor, degree of differentiation, and depth of invasion, indicating that YAP1 and TAZ may be involved in the development of ESCC. YAP1 and TAZ may be used as prognostic markers in ESCC.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/biossíntese , Neoplasias Esofágicas/genética , Carcinoma de Células Escamosas do Esôfago/genética , Peptídeos e Proteínas de Sinalização Intracelular/biossíntese , Fatores de Transcrição/biossíntese , Idoso , Biomarcadores Tumorais , Neoplasias Esofágicas/etnologia , Neoplasias Esofágicas/patologia , Carcinoma de Células Escamosas do Esôfago/etnologia , Carcinoma de Células Escamosas do Esôfago/patologia , Grupos Étnicos , Feminino , Humanos , Estimativa de Kaplan-Meier , Metástase Linfática , Masculino , Pessoa de Meia-Idade , Invasividade Neoplásica , Estadiamento de Neoplasias , Prognóstico , Análise de Sobrevida , Carga Tumoral
5.
J Cell Mol Med ; 25(15): 7538-7544, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34288389

RESUMO

Mitochondria are central eukaryotic organelles in cellular metabolism and ATP production. Mitochondrial DNA (mtDNA) alterations have been implicated in the development of colorectal cancer (CRC). However, there are few reports on the association between mtDNA haplogroups or single nucleotide polymorphisms (SNPs) and the risk of CRC. The mtDNA of 286 Northern Han Chinese CRC patients were sequenced by next-generation sequencing technology. MtDNA data from 811 Han Chinese population controls were collected from two public data sets. Then, logistic regression analysis was used to determine the effect of mtDNA haplogroup or SNP on the risk of CRC. We found that patients with haplogroup M7 exhibited a reduced risk of CRC when compared to patients with other haplogroups (odds ratio [OR] = 0.532, 95% confidence interval [CI] = 0.285-0.937, p = 0.036) or haplogroup B (OR = 0.477, 95% CI = 0.238-0.916, p = 0.030). Furthermore, haplogroup M7 was still associated with the risk of CRC when the validation and combined control cohort were used. In addition, several haplogroup M7 specific SNPs, including 199T>C, 4071C>T and 6455C>T, were significantly associated with the risk of CRC. Our results indicate the risk potential of mtDNA haplogroup M7 and SNPs in CRC in Northern China.

6.
J Hematol Oncol ; 14(1): 106, 2021 07 05.
Artigo em Inglês | MEDLINE | ID: mdl-34225766

RESUMO

CD19-directed chimeric antigen receptor T cell (CART19) therapy is efficient and approved for relapsed/refractory diffuse large B cell lymphoma (DLBCL). To increase durable antitumor response, we previously designed tandem CART19/20 cells and shown longer progression-free survival. However, a proportion of CART19/20-treated patients will finally progress and require salvage therapies. In this study, we analyzed data from five patients with relapsed/refractory DLBCL who had disease progression or relapse following CART19/20 therapy and then treated with PD-1-blocking antibodies as salvage therapy. Two of five patients acquired complete remissions after anti-PD-1 therapy, including one patient remained ongoing remission for more than 21 months. One patient achieved a partial remission, and the other two had progressive diseases. No ≥ grade 3 treatment-related adverse events or cytokine release syndrome was observed. Immunohistochemistry of tumor specimens revealed higher PD-1/PD-L1 expression in responsive patients with anti-PD-1 therapy as compared to that in non-responders. After anti-PD-1 treatment, circulating T cells were activated in responders, and no significant expansion of CART19/20 cells was detected. Our data suggest that PD-1 blockade therapy can be active in patients with relapsed/refractory DLBCL after failure of CAR T cell therapy who had PD-L1 expression in tumor cells and high PD-1 level in tumor-infiltrated T cells.


Assuntos
Inibidores de Checkpoint Imunológico/uso terapêutico , Imunoterapia Adotiva , Linfoma Difuso de Grandes Células B/terapia , Recidiva Local de Neoplasia/terapia , Terapia de Salvação , Adulto , Antígenos CD19/imunologia , Antígenos CD20/imunologia , Feminino , Humanos , Imunoterapia Adotiva/métodos , Linfoma Difuso de Grandes Células B/imunologia , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/imunologia , Receptores de Antígenos de Linfócitos T/uso terapêutico , Estudos Retrospectivos , Terapia de Salvação/métodos
7.
Redox Biol ; 46: 102076, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34315112

RESUMO

Acquired resistance to tyrosine kinase inhibitors (TKIs) is the major obstacle to improve clinical efficacy in cancer patients. The epithelial-stromal interaction in tumor microenvironment influences cancer drug response to TKIs. Anlotinib is a novel oral multi-targeted TKI, and has recently been proven to be effective and safe for several tumors. However, if and how the epithelial-stromal interaction in tumor microenvironment affects anlotinib response in gastric cancer (GC) is not known. In this study, we found that anlotinib inhibited GC cells growth by inducing GC cells apoptosis and G2/M phase arrest in a dose- and time-dependent manner. Reactive oxygen species (ROS) mediated anlotinib-induced apoptosis in GC cells, while cancer-associated fibroblasts (CAFs) significantly suppressed anlotinib-induced apoptosis and ROS in GC cells. Increased BDNF that was derived from CAFs activated TrkB-Nrf2 signaling in GC cells, and reduced GC cells response to anlotinib. We identified secreted lactate from GC cells as the key molecule instructing CAFs to produce BDNF in a NF-κB-dependent manner. Additionally, functional targeting BDNF-TrkB pathway with neutralizing antibodies against BDNF and TrkB increased the sensitivity of GC cells towards anlotinib in human patient-derived organoid (PDO) model. Taken together, these results characterize a critical role of the epithelial-stroma interaction mediated by the lactate/BDNF/TrkB signaling in GC anlotinib resistance, and provide a novel option to overcome drug resistance.


Assuntos
Fator Neurotrófico Derivado do Encéfalo , Neoplasias Gástricas , Fator Neurotrófico Derivado do Encéfalo/genética , Fibroblastos , Humanos , Indóis , Ácido Láctico , Quinolinas , Neoplasias Gástricas/tratamento farmacológico , Neoplasias Gástricas/genética , Microambiente Tumoral
8.
Exp Anim ; 70(4): 498-507, 2021 Nov 10.
Artigo em Inglês | MEDLINE | ID: mdl-34135271

RESUMO

Transverse aortic constriction (TAC) has been widely used to study cardiac hypertrophy, fibrosis, diastolic dysfunction, and heart failure in rodents. Few studies have been reported in preclinical animal models. The similar physiology and anatomy between non-human primates (NHPs) and humans make NHPs valuable models for disease modeling and testing of drugs and devices. In the current study, we aimed to establish a TAC model in NHPs and characterize the structural and functional profiles of the heart after TAC. A non-absorbable suture was placed around the aorta between the brachiocephalic artery and left common carotid artery to create TAC. NHPs were divided into 2 groups according to pressure gradient (PG): the Mild Group (PG=31.01 ± 12.40 mmHg, n=3) and the Moderate Group (PG=53.00 ± 9.37 mmHg, n=4). At 4 weeks after TAC, animals in both TAC groups developed cardiac hypertrophy: enlarged myocytes and increased wall thickness of the left ventricular (LV) anterior wall. Although both TAC groups had normal systolic function that was similar to a Sham Group, the Moderate Group showed diastolic dysfunction that was associated with more severe cardiac fibrosis, as evidenced by a reduced A wave velocity, large E wave velocity/A wave velocity ratio, and short isovolumic relaxation time corrected by heart rate. Furthermore, no LV arrhythmia was observed in either animal group after TAC. A diastolic dysfunction model with cardiac hypertrophy and fibrosis was successfully developed in NHPs.


Assuntos
Aorta Torácica/fisiopatologia , Ventrículos do Coração/fisiopatologia , Coração/fisiopatologia , Função Ventricular Esquerda/fisiologia , Animais , Constrição , Modelos Animais de Doenças , Feminino , Macaca fascicularis , Masculino
9.
EBioMedicine ; 69: 103436, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34157484

RESUMO

BACKGROUND: Due to the molecular mechanism complexity and heterogeneity of gastric cancer (GC), mechanistically interpretable biomarkers were required for predicting prognosis and discovering therapeutic targets for GC patients. METHODS: Based on a total of 824 GC-specific fitness genes from the Project Score database, LASSOCox regression was performed in TCGA-STAD cohort to construct a GC Prognostic (GCP) model which was then evaluated on 7 independent GC datasets. Targets prioritization was performed in GC organoids. ARGLU1 was selected to further explore the biological function and molecular mechanism. We evaluated the potential of ARGLU1 serving as a promising therapeutic target for GC using patients derived xenograft (PDX) model. FINDINGS: The 9-gene GCP model showed a statistically significant prognostic performance for GC patients in 7 validation cohorts. Perturbation of SSX4, DDX24, ARGLU1 and TTF2 inhibited GC organoids tumor growth. The results of tissue microarray indicated lower expression of ARGLU1 was correlated with advanced TNM stage and worse overall survival. Over-expression ARGLU1 significantly inhibited GC cells viability in vitro and in vivo. ARGLU1 could enhance the transcriptional level of mismatch repair genes including MLH3, MSH2, MSH3 and MSH6 by potentiating the recruitment of SP1 and YY1 on their promoters. Moreover, inducing ARGLU1 by LNP-formulated saRNA significantly inhibited tumor growth in PDX model. INTERPRETATION: Based on genome-wide functional screening data, we constructed a 9-gene GCP model with satisfactory predictive accuracy and mechanistic interpretability. Out of nine prognostic genes, ARGLU1 was verified to be a potential therapeutic target for GC. FUNDING: National Natural Science Foundation of China.


Assuntos
Biomarcadores Tumorais/genética , Peptídeos e Proteínas de Sinalização Intracelular/genética , Neoplasias Gástricas/genética , Transcriptoma , Adenosina Trifosfatases/genética , Adenosina Trifosfatases/metabolismo , Animais , Biomarcadores Tumorais/metabolismo , Proteínas de Ciclo Celular/genética , Proteínas de Ciclo Celular/metabolismo , Linhagem Celular Tumoral , Proliferação de Células , Células Cultivadas , RNA Helicases DEAD-box/genética , RNA Helicases DEAD-box/metabolismo , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Regulação Neoplásica da Expressão Gênica , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , Organoides/crescimento & desenvolvimento , Organoides/metabolismo , Proteínas Repressoras/genética , Proteínas Repressoras/metabolismo , Neoplasias Gástricas/metabolismo , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Regulação para Cima
10.
Mol Oncol ; 15(9): 2377-2389, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34133846

RESUMO

Circulating cell-free DNA (cfDNA) fragmentomics, which encompasses the measurement of cfDNA length and short nucleotide motifs at the ends of cfDNA molecules, is an emerging field for cancer diagnosis. The utilization of cfDNA fragmentomics for the diagnosis of patients with hepatocellular carcinoma (HCC) caused by hepatitis B virus (HBV) is currently limited. In this study, we utilized whole-genome sequencing data of cfDNA in samples from patients with HCC (n = 197) and HBV (n = 187) to analyze the association of fragment size selection (< 150 bp) with tumor fraction (TF), copy number variation (CNV) alterations and the change in the proportion of 4-mer end motifs in HCC and HBV samples. Our analyses identified five typical CNV markers (i.e. loss in chr1p, chr4q and chr8p, and gain in chr1q and chr8q) in cfDNA with a cumulatively positive rate of ˜ 95% in HCC samples. Size selection (< 150 bp) significantly enhanced TF and CNV signals in HCC samples. Additionally, three 4-mer end motifs (CCCA, CCTG and CCAG) were identified as preferred end motifs in HCC samples. We identified 139 end motifs significantly associated with fragment size that showed similar patterns of associations between patients with HCC and HBV, suggesting that end motifs might be inherently coupled with fragment size by a ubiquitous mechanism. Here we conclude that CNV markers, fragment size selection and end-motif pattern in cfDNA have potential for effective detection of patients with HCC.

11.
Front Cell Dev Biol ; 9: 667252, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34136485

RESUMO

Induced pluripotent stem cells derived cells (iPSCs) not only can be used for personalized cell transfer therapy, but also can be used for modeling diseases for drug screening and discovery in vitro. Although prior studies have characterized the function of rodent iPSCs derived endothelial cells (ECs) in diabetes or metabolic syndrome, feature phenotypes are largely unknown in hiPSC-ECs from patients with diabetes. Here, we used hiPSC lines from patients with type 2 diabetes mellitus (T2DM) and differentiated them into ECs (dia-hiPSC-ECs). We found that dia-hiPSC-ECs had disrupted glycine homeostasis, increased senescence, and impaired mitochondrial function and angiogenic potential as compared with healthy hiPSC-ECs. These signature phenotypes will be helpful to establish dia-hiPSC-ECs as models of endothelial dysfunction for understanding molecular mechanisms of disease and for identifying and testing new targets for the treatment of endothelial dysfunction in diabetes.

12.
Exp Ther Med ; 22(1): 722, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34007331

RESUMO

Esophageal cancer has always been one of the major malignant tumor types affecting the health of the Chinese population. Metastasis-associated protein 1 (MTA1), SOX4 and enhancer of zeste homolog 2 (EZH2) are all potent inducers of invasion and metastasis in esophageal squamous cell carcinoma (ESCC). However, the role of these signaling molecules and their implication in ESCC have remained largely elusive. In the present study, the effects of MTA1, SOX4 and EZH2 on the prognosis of patients with ESCC were explored. Immunohistochemistry was used to examine the expression levels of MTA1, SOX4 and EZH2. The χ2 test was used to analyze the association between protein expression and clinicopathological parameters. Kaplan-Meier curves and Cox proportional hazards model survival analysis was performed to investigate the effects of the three proteins examined on disease prognosis. The results indicated that MTA1 may be used as a prognostic and diagnostic marker for ESCC. To the best of our knowledge, the present study was the first to demonstrate that MTA1-SOX4 signaling is associated with prognosis in ESCC. However, no significant association was noted between SOX4 and EZH2 in the present study, which was inconsistent with previously reported findings. The function of the MTA1-SOX4-EZH2 axis and the interactions of the proteins involved require further investigation.

13.
Cell Death Dis ; 12(4): 368, 2021 04 06.
Artigo em Inglês | MEDLINE | ID: mdl-33824303

RESUMO

Autophagy defection contributes to inflammation dysregulation, which plays an important role in gastric cancer (GC) progression. Various studies have demonstrated that long noncoding RNA could function as novel regulators of autophagy. Previously, long noncoding RNA MALAT1 was reported upregulated in GC cells and could positively regulate autophagy in various cancers. Here, we for the first time found that MALAT1 could promote interleukin-6 (IL-6) secretion in GC cells by blocking autophagic flux. Moreover, IL-6 induced by MALAT1 could activate normal to cancer-associated fibroblast conversion. The interaction between GC cells and cancer-associated fibroblasts in the tumour microenvironment could facilitate cancer progression. Mechanistically, MALAT1 overexpression destabilized the PTEN mRNA in GC cells by competitively interacting with the RNA-binding protein ELAVL1 to activate the AKT/mTOR pathway for impairing autophagic flux. As a consequence of autophagy inhibition, SQSTM1 accumulation promotes NF-κB translocation to elevate IL-6 expression. Overall, these results demonstrated that intercellular interaction between GC cells and fibroblasts was mediated by autophagy inhibition caused by increased MALAT1 that promotes GC progression, providing novel prevention and therapeutic strategies for GC.


Assuntos
Autofagia/genética , Proliferação de Células/genética , Fibroblastos/metabolismo , RNA Longo não Codificante/genética , Neoplasias Gástricas/genética , Linhagem Celular Tumoral , Regulação Neoplásica da Expressão Gênica/genética , Humanos , MicroRNAs/genética , Transdução de Sinais/genética , Estômago/patologia , Neoplasias Gástricas/patologia , Serina-Treonina Quinases TOR/genética , Microambiente Tumoral/genética
14.
FASEB J ; 35(4): e20649, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33715234

RESUMO

Adenosine triphosphate (ATP) in the tumor microenvironment serves a vital role during tumor progression. ATP synthase F1 ß subunit (ATP5B) is one of the most important subunits of ATP synthase and increases cellular ATP levels. ATP5B reportedly participates in carcinogenesis in several tumors. However, the regulatory mechanisms of ATP5B remain poorly understood in gastric cancer (GC). Here, we determined that high ATP5B expression in tumor tissues of GC is positively correlated with age, the tumor size, the TNM stage, lymph node metastasis, and patients' poor prognosis. The overexpression of ATP5B in GC cells elevated the cellular ATP content and promoted migration, invasion and proliferation. The levels of MMP2 expression, phosphorylated FAK, and phosphorylated AKT were increased after ATP5B overexpression in GC cells. Additionally, ATP5B overexpression increased the extracellular ATP level through the secretion of intracellular ATP and activated the FAK/AKT/MMP2 signaling pathway. ATP5B-induced downstream pathway activation was induced through the plasma membrane P2X7 receptor. Inhibitors of P2X7, FAK, AKT, and MMP2 suppressed the proliferative, migratory, and invasive capabilities of GC cells. In conclusion, our experiments indicate that ATP5B contributes to tumor progression of GC via FAK/AKT/MMP2 pathway. ATP5B, therefore, may be a biomarker of poor prognosis and a potential therapeutic target for GC.


Assuntos
Quinase 1 de Adesão Focal/metabolismo , Metaloproteinase 2 da Matriz/metabolismo , ATPases Mitocondriais Próton-Translocadoras/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Neoplasias Gástricas/metabolismo , Animais , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Feminino , Quinase 1 de Adesão Focal/genética , Regulação Neoplásica da Expressão Gênica , Humanos , Masculino , Metaloproteinase 2 da Matriz/genética , Camundongos , Pessoa de Meia-Idade , ATPases Mitocondriais Próton-Translocadoras/genética , Neoplasias Experimentais , Neoplasias Peritoneais/secundário , Proteínas Proto-Oncogênicas c-akt/genética , Transdução de Sinais , Neoplasias Gástricas/patologia , Análise Serial de Tecidos , Regulação para Cima
15.
Cancer Biol Med ; 2021 Mar 23.
Artigo em Inglês | MEDLINE | ID: mdl-33755379

RESUMO

OBJECTIVE: To assess the efficacy and safety of the novel histone deacetylase inhibitor, chidamide, in combination with cyclophosphamide, doxorubicin, vincristine, etoposide, and prednisone (Chi-CHOEP) for untreated peripheral T-cell lymphoma (PTCL). METHODS: A prospective, multicenter, single arm, phase 1b/2 study was conducted. A total of 128 patients with untreated PTCL (18-70 years of age) were enrolled between March 2016 and November 2019, and treated with up to 6 cycles with the Chi-CHOEP regimen. In the phase 1b study, 3 dose levels of chidamide were evaluated and the primary endpoint was determination of the maximum-tolerated dose and recommended phase 2 dose (RP2D). The primary endpoint of the phase 2 study was 2-year progression-free survival (PFS). RESULTS: Fifteen patients were enrolled in the phase 1b study and the RP2D for chidamide was determined to be 20 mg, twice a week. A total of 113 patients were treated at the RP2D in the phase 2 study, and the overall response rate was 60.2%, with a complete response rate of 40.7%. At a median follow-up of 36 months, the median PFS was 10.7 months, with 1-, 2-, and 3-year PFS rates of 49.9%, 38.0%, and 32.8%, respectively. The Chi-CHOEP regimen was well-tolerated, with grade 3/4 neutropenia occurring in approximately two-thirds of the patients. No unexpected adverse events (AEs) were reported and the observed AEs were manageable. CONCLUSIONS: This large cohort phase 1b/2 study showed that Chi-CHOEP was well-tolerated with modest efficacy in previously untreated PTCL patients.

16.
Mol Ther Nucleic Acids ; 23: 1288-1303, 2021 Mar 05.
Artigo em Inglês | MEDLINE | ID: mdl-33717650

RESUMO

Tumor metastasis is a crucial impediment to the treatment of gastric cancer (GC), and the epithelial-to-mesenchymal transition (EMT) program plays a critical role for the initiation of GC metastasis. Thus, the aim of this study is to investigate the regulation of lnc-CTSLP4 in the EMT process during GC progression. We found that lnc-CTSLP4 was significantly downregulated in GC tumor tissues compared with adjacent non-tumor tissues, and its levels in GC tumor tissues were closely correlated with tumor local invasion, TNM stage, lymph node metastasis, and prognosis of GC patients. Loss- and gain-of-function assays indicated that lnc-CTSLP4 inhibited GC cell migration, invasion, and EMT in vitro, as well as peritoneal dissemination in vivo. Mechanistic analysis demonstrated that lnc-CTSLP4 could bind with Hsp90α/heterogeneous nuclear ribonucleoprotein AB (HNRNPAB) complex and recruit E3-ubiquitin ligase ZFP91 to induce the degradation of HNRNPAB, thus suppressing the transcriptional activation of Snail and ultimately reversing EMT of GC cells. Taken together, our results suggest that lnc-CTSLP4 is significantly downregulated in GC tumor tissues and inhibits metastatic potential of GC cells by attenuating HNRNPAB-dependent Snail transcription via interacting with Hsp90α and recruiting E3 ubiquitin ligase ZFP91, which shows that lnc-CTSLP4 could serve as a prognostic biomarker and therapeutic target for metastatic GC.

17.
Mol Med Rep ; 23(5)2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33649847

RESUMO

Diffuse large B­cell lymphoma (DLBCL) is a highly heterogeneous malignant tumor type, and epigenetic modifications such as acetylation or deacetylation serve vital roles in its development. Chidamide, a novel histone deacetylase inhibitor, exerts an anticancer effect against various types of cancer. The present study aimed to evaluate the cellular effect of chidamide on a number of DLBCL cell lines and to investigate its underlying mechanism. The results demonstrated that chidamide induced the death of these cells in a concentration­(0­30 µmol/l) and time­dependent (24­72 h) manner, as determined using the Cell Counting Kit­8 cell viability assay. Moreover, chidamide promoted cellular apoptosis, which was identified via flow cytometry and western blot analysis, with an increase in cleaved caspase­3 expression and a decrease in Bcl­2 expression. Chidamide treatment also decreased the expression level of STAT3 and its phosphorylation, which was accompanied by the downregulation of a class­I histone deacetylase (HDAC) inhibitor, chidamide. Collectively, these data suggested that chidamide can be a potent therapeutic agent to treat DLBCL by inducing the apoptotic death of DLBCL cells by inhibiting the HDACs/STAT3/Bcl­2 pathway.


Assuntos
Aminopiridinas/farmacologia , Apoptose/efeitos dos fármacos , Benzamidas/farmacologia , Histona Desacetilases/metabolismo , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Fator de Transcrição STAT3/metabolismo , Transdução de Sinais/efeitos dos fármacos , Caspase 3/metabolismo , Linhagem Celular Tumoral , Relação Dose-Resposta a Droga , Expressão Gênica/efeitos dos fármacos , Inibidores de Histona Desacetilases/farmacologia , Humanos , Isoenzimas/metabolismo , Linfoma Difuso de Grandes Células B/genética , Linfoma Difuso de Grandes Células B/metabolismo , Linfoma Difuso de Grandes Células B/patologia , Fosforilação/efeitos dos fármacos , Fator de Transcrição STAT3/genética
18.
Mol Ther Nucleic Acids ; 23: 657-666, 2021 Mar 05.
Artigo em Inglês | MEDLINE | ID: mdl-33575112

RESUMO

Mitochondrial DNA (mtDNA) mutations are closely implicated in the pathogenesis of multiple cancers, making circulating cell-free mtDNA (ccf-mtDNA) as a potential non-invasive tumor biomarker. However, an effective approach to comprehensively profile ccf-mtDNA mutations is still lacking. In this study, we first characterized ccf-mtDNA by low-depth whole-genome sequencing (WGS) and found that plasma DNA samples exhibited a dramatic decrease in mtDNA copy number when compared with fresh tumor tissues. Further analysis revealed that plasma ccf-mtDNA had a biased distribution of fragment size with a peak around 90 bp. Based on these insights, we developed a robust captured-based mtDNA deep-sequencing approach that enables accurate and efficient detection of plasma ccf-mtDNA mutations by systematic optimization of probe quantity and length, hybridization temperature, and PCR amplification cycles. Moreover, we found that placement of isolated plasma for 6 h at both 4°C and room temperature (RT) led to a dramatic decrease of ccf-mtDNA stability, highlighting the importance of proper plasma sample processing. We further showed that the optimized approach can successfully detect a substantial fraction of tumor-specific mtDNA mutations in plasma ccf-mtDNA specifically from hepatocellular carcinoma (HCC) patients but not from colorectal cancer (CRC) patients, suggesting the presence of a potential cancer-specific difference in the abundance of tumor-derived mtDNA in plasma.

19.
Zhongguo Shi Yan Xue Ye Xue Za Zhi ; 29(1): 98-103, 2021 Feb.
Artigo em Chinês | MEDLINE | ID: mdl-33554804

RESUMO

OBJECTIVE: To evaluate the prognostic value of GELTAMO-IPI for patients with diffuse large B-cell lymphoma (DLBCL). METHODS: The clinical data of 238 newly diagnosed DLBCL patients treated in Shanxi Cancer Hospital from September 2011 to March 2016 were collected retrospectively, the risk stratification and prognostic evaluation of the patients were analyzed according to GELTAMO-IPI. Progression-free survival (PFS) and overall survival (OS) of the patients were analyzed by the Kaplan-Meier method, COX regression analysis was used to compare the risk of death and progress in each risk group. Harrell's C statistics was used to compare the prognostic stratification ability of each model. RESULTS: The 3-year OS rate statistics showed that both IPI and GELTAMO-IPI could distinguish low risk group and Low-intermediate risk group, but the prognosis stratification ability of IPI was better (IPI: HR=5.085, P<0.05; GELTAMO-IPI; HR=4.639, P>0.05). GELTAMO-IPI could distinguish High-intermediate risk group from high risk group (GELTAMO-IPI: HR=2.966, P<0.05; 3 years OS rate was 34.5%), but the ability of IPI to identify high risk groups was weak (3 years OS>50%). The results of Harrell's C statistics showed the C-index of IPI and GELTAMO-IPI was 0.687 and 0.721 (P<0.001); the C-index of the predicted PFS was 0.672 and 0.700 (P<0.001). It was suggested that the prognostic stratification ability of GELTAM0-IPI be superior to that of IPI, R-IPI, NCCN-IPI. CONCLUSION: GELTAMO-IPI can make a clear distinction between DLBCL patients with different prognosis, especially for high-risk patients, and the prognostic stratification ability of GELTAMO-IPI is significantly better than that of IPI.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica , Linfoma Difuso de Grandes Células B , Humanos , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Prognóstico , Estudos Retrospectivos , Fatores de Risco
20.
Medicine (Baltimore) ; 100(6): e24598, 2021 Feb 12.
Artigo em Inglês | MEDLINE | ID: mdl-33578562

RESUMO

ABSTRACT: Primary thyroid lymphoma (PTL) is a rare malignant disease with the most common histological type of diffuse large B-cell lymphoma (DLBCL). Hashimoto's thyroiditis (HT) is closely related to the pathogenesis of PTL. The present study is to explore the clinical prognosis of PTL and analyze the gene correlations between PTL and HT.Thirty-nine patients diagnosed with PTL between 2010 and 2018 in our institute were retrospectively reviewed and clinical features were evaluated on PTL survival. Then, overlapping differentially expressed genes (DEGs) between PTL and HT were evaluated for gene ontology, pathways enrichment, protein-protein interaction network analysis. Furthermore, we used gene expression profiling interactive analysis to evaluate the differential expression of these hub genes.In this analysis, International Prognostic Index (IPI) score ≥3 and high ß2-MG (>3 mg/L) were associated with worse prognosis in PTL. Notably, a total of 15 both upregulated DEGs in DLBCL and HT were identified and 10 hub genes with a high degree of connectivity were picked out. Among these 10 hub genes, IL6, IL10, CXCL10, and CXCR3 were higher expressed in DLBCL than the normal tissue but have no significant prognosis of DLBCL.High IPI score and high ß2-MG level have a poor prognosis in PTL. Besides, IL6, IL10, CXCL10, and CXCR3 are associated with both DLBCL and HT and may be used for the early diagnosis of PTL.


Assuntos
Biomarcadores Tumorais/metabolismo , Doença de Hashimoto/metabolismo , Linfoma/metabolismo , Neoplasias da Glândula Tireoide/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , China/epidemiologia , Feminino , Perfilação da Expressão Gênica , Humanos , Linfoma/mortalidade , Masculino , Pessoa de Meia-Idade , Mapas de Interação de Proteínas , Estudos Retrospectivos , Neoplasias da Glândula Tireoide/mortalidade
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