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1.
Science ; 384(6695): eadj4857, 2024 May 03.
Artigo em Inglês | MEDLINE | ID: mdl-38696569

RESUMO

B lymphocytes are essential mediators of humoral immunity and play multiple roles in human cancer. To decode the functions of tumor-infiltrating B cells, we generated a B cell blueprint encompassing single-cell transcriptome, B cell-receptor repertoire, and chromatin accessibility data across 20 different cancer types (477 samples, 269 patients). B cells harbored extraordinary heterogeneity and comprised 15 subsets, which could be grouped into two independent developmental paths (extrafollicular versus germinal center). Tumor types grouped into the extrafollicular pathway were linked with worse clinical outcomes and resistance to immunotherapy. The dysfunctional extrafollicular program was associated with glutamine-derived metabolites through epigenetic-metabolic cross-talk, which promoted a T cell-driven immunosuppressive program. These data suggest an intratumor B cell balance between extrafollicular and germinal-center responses and suggest that humoral immunity could possibly be harnessed for B cell-targeting immunotherapy.


Assuntos
Linfócitos B , Centro Germinativo , Linfócitos do Interstício Tumoral , Neoplasias , Humanos , Neoplasias/imunologia , Neoplasias/terapia , Neoplasias/genética , Linfócitos do Interstício Tumoral/imunologia , Linfócitos B/imunologia , Centro Germinativo/imunologia , Imunoterapia , Transcriptoma , Análise de Célula Única , Epigênese Genética , Imunidade Humoral , Linfócitos T/imunologia , Receptores de Antígenos de Linfócitos B/genética , Receptores de Antígenos de Linfócitos B/metabolismo , Receptores de Antígenos de Linfócitos B/imunologia
2.
Cell ; 187(6): 1422-1439.e24, 2024 Mar 14.
Artigo em Inglês | MEDLINE | ID: mdl-38447573

RESUMO

Neutrophils, the most abundant and efficient defenders against pathogens, exert opposing functions across cancer types. However, given their short half-life, it remains challenging to explore how neutrophils adopt specific fates in cancer. Here, we generated and integrated single-cell neutrophil transcriptomes from 17 cancer types (225 samples from 143 patients). Neutrophils exhibited extraordinary complexity, with 10 distinct states including inflammation, angiogenesis, and antigen presentation. Notably, the antigen-presenting program was associated with favorable survival in most cancers and could be evoked by leucine metabolism and subsequent histone H3K27ac modification. These neutrophils could further invoke both (neo)antigen-specific and antigen-independent T cell responses. Neutrophil delivery or a leucine diet fine-tuned the immune balance to enhance anti-PD-1 therapy in various murine cancer models. In summary, these data not only indicate the neutrophil divergence across cancers but also suggest therapeutic opportunities such as antigen-presenting neutrophil delivery.


Assuntos
Apresentação de Antígeno , Neoplasias , Neutrófilos , Animais , Humanos , Camundongos , Antígenos de Neoplasias , Leucina/metabolismo , Neoplasias/imunologia , Neoplasias/patologia , Neutrófilos/metabolismo , Linfócitos T , Análise da Expressão Gênica de Célula Única
3.
Front Oncol ; 14: 1283008, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38357203

RESUMO

Lung cancer treatment has transitioned fully into the era of immunotherapy, yielding substantial improvements in survival rate for patients with advanced non-small cell lung cancer (NSCLC). In this report, we present a case featuring a rare epidermal growth factor receptor (EGFR) mutation accompanied by high programmed death-ligand 1 (PD-L1) expression, demonstrating remarkable therapeutic efficacy through a combination of immunotherapy and chemotherapy. A 77-year-old male with no family history of cancer suffered from upper abdominal pain for more than half months in August 2020 and was diagnosed with stage IV (cT3N3M1c) lung squamous cell carcinoma (LUSC) harboring both a rare EGFR p.G719C mutation and high expression of PD-L1 (tumor proportion score [TPS] = 90%). Treatment with the second-generation targeted therapy drug Afatinib was initiated on September 25, 2020. However, resistance ensued after 1.5 months of treatment. On November 17, 2020, immunotherapy was combined with chemotherapy (Sintilimab + Albumin-bound paclitaxel + Cisplatin), and a CT scan conducted three months later revealed significant tumor regression with a favorable therapeutic effect. Subsequently, the patient received one year of maintenance therapy with Sintilimab, with follow-up CT scans demonstrating subtle tumor shrinkage (stable disease). This case provides evidence for the feasibility and efficacy of immunotherapy combined with chemotherapy in the treatment of EGFR-mutated and PD-L1 highly expressed LUSC.

4.
Arthritis Rheumatol ; 76(4): 599-613, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-37946666

RESUMO

OBJECTIVE: The peripheral B cell compartment is heavily disturbed in systemic lupus erythematosus (SLE), but whether B cells develop aberrantly in the bone marrow (BM) is largely unknown. METHODS: We performed single-cell RNA/B cell receptor (BCR) sequencing and immune profiling of BM B cells and classified patients with SLE into two groups: early B cell (Pro-B and Pre-B) normal (EBnor) and EB defective/low (EBlo) groups. RESULTS: The SLE-EBlo group exhibited more severe disease activity and proinflammatory status, overaction of type I interferon signaling and metabolic pathways within the B cell compartment, and aberrant BCR repertoires compared with the SLE-EBnor group. Moreover, in one patient with SLE who was initially classified in the SLE-EBlo group, early B cell deficiency and associated abnormalities were largely rectified in a second BM sample at the remission phase. CONCLUSION: In summary, this study suggests that early B cell loss in BM defines a unique pathological state in a subset of patients with SLE that may play an active role in the dysregulated autoimmune responses.


Assuntos
Medula Óssea , Lúpus Eritematoso Sistêmico , Humanos , Criança , Medula Óssea/patologia , Deficiências do Desenvolvimento/metabolismo , Deficiências do Desenvolvimento/patologia , Linfócitos B , Transdução de Sinais
5.
Front Neurol ; 14: 1260230, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37840919

RESUMO

Background: Ischemic stroke (IS) represents a major cause of morbidity and mortality across the globe. The aberrant expression of miR-365 has been found to be implicated in a wide array of human diseases, including atherosclerosis and cancer. Studies on single-nucleotide polymorphisms (SNPs) in miRNA genes can help gain insight into the susceptibility to the condition. This study aimed to examine the relationship between miR-365 SNPs and the risk of IS. Methods: The study recruited 215 IS patients and 220 controls. The SNPscans genotyping was employed to genotype three polymorphic loci (rs121224, rs30230, and rs178553) of miR-365. The relative expression of miR-365 in peripheral blood mononuclear cells of the patients and controls was determined by using real-time quantitative PCR. Results: The miR-365 rs30230 polymorphism exhibited a significant association with the risk of developing IS (TC vs. CC: adjusted OR = 0.55, 95% CI: 0.33-0.92, P = 0.022; TT vs. CC: adjusted OR = 0.34, 95% CI: 0.14-0.85, P = 0.021; TC +TT vs. CC: adjusted OR = 0.51, 95% CI: 0.31-0.83, P = 0.007; T vs. C: adjusted OR = 0.57, 95% CI: 0.39-0.83, P = 0.004). Haplotype analysis revealed that the C-T-G haplotype was associated with a decreased risk of IS (OR = 0.68, 95% CI: 0.46-1.00, P = 0.047). Furthermore, miR-365 expression was significantly higher in IS patients than in controls (P < 0.001). Interestingly, patients with rs30230 TC or TT genotypes had lower miR-365 levels compared to their counterparts with CC genotypes (P < 0.001). Conclusions: The miR-365 rs30230 polymorphism might bear an association with IS susceptibility in the Chinese population, and the rs30230 TC/TT genotype might be a protective factor against IS.

6.
Neuropsychol Rehabil ; 33(9): 1564-1581, 2023 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-36059235

RESUMO

OBJECTIVE: The purpose of this study was to explore the prevalence, severity, and factors associated with multidimensional fatigue in Chinese patients with newly diagnosed meningiomas. METHODS: This cross-sectional study included 120 Chinese meningioma patients. Data were collected before surgery, including demographic, clinical, psychological, and sleep characteristics, as well as fatigue scores based on completion of the Multidimensional Fatigue Inventory (MFI-20). Mann-Whitney U tests, Kruskal-Wallis H tests, Spearman correlation and multiple linear regression were used to analyze the data. RESULTS: The results showed there was a high prevalence of severe fatigue for each dimension: general fatigue (33.3%), physical fatigue (27.5%), reduced activity (28.3%), reduced motivation (12.5%), mental fatigue (11.7%), and total fatigue (23.3%). Headache and anxiety were found to be associated with general fatigue. Depression was related with physical fatigue. The Karnofsky Performance Status (KPS) score and depression were associated with reduced activity. Depression and the Epworth Sleepiness Scale (ESS) score were correlated with reduced motivation, while the KPS score and anxiety were associated with mental fatigue. Importantly, comorbidity, the KPS score, headache, depression, sleep disturbances, and the ESS score remained strong correlates of total fatigue. CONCLUSIONS: Our findings indicate that newly diagnosed meningioma patients are affected by multidimensional fatigue. For patients with risk factors of fatigue, targeted interventions are advised to decrease fatigue and improve HRQoL.


Assuntos
Neoplasias Meníngeas , Meningioma , Humanos , Meningioma/complicações , Meningioma/epidemiologia , Prevalência , Estudos Transversais , População do Leste Asiático , Qualidade de Vida , Neoplasias Meníngeas/complicações , Neoplasias Meníngeas/epidemiologia , Cefaleia , Fadiga Mental , Depressão/diagnóstico , Depressão/epidemiologia , Depressão/etiologia
7.
Adv Sci (Weinh) ; 9(36): e2204849, 2022 12.
Artigo em Inglês | MEDLINE | ID: mdl-36354175

RESUMO

Centenarians, who show mild infections and low incidence of tumors, are the optimal model to investigate healthy aging. However, longevity related immune characteristics has not been fully revealed largely due to lack of appropriate controls. In this study, single-cell transcriptomic analysis of peripheral blood mononuclear cells (PBMCs) derived from seven centenarians (CEN), six centenarians' offspring (CO), and nine offspring spouses or neighbors (Control, age-matched to CO) are performed to investigate the shared immune features between CEN and CO. The results indicate that among all 12 T cell clusters, the cytotoxic-phenotype-clusters (CPC) and the naïve-phenotype-clusters (NPC) significantly change between CEN and ontrol. Compared to Control, both CEN and CO are characterized by depleted NPC and increased CPC, which is dominated by CD8+ T cells. Furthermore, CPC from CEN and CO share enhanced signaling pathways and transcriptional factors associated with immune response, and possesse similar T-cell-receptor features, such as high clonal expansion. Interestingly, rather than a significant increase in GZMK+ CD8 cells during aging, centenarians show accumulation of GZMB+ and CMC1+ CD8 T cells. Collectively, this study unveils an immune remodeling pattern reflected by both quantitative increase and functional reinforcement of cytotoxic T cells which are essential for healthy aging.


Assuntos
Centenários , Leucócitos Mononucleares , Humanos , Transcriptoma/genética , Linfócitos T CD8-Positivos , Longevidade/genética
8.
Hum Cell ; 35(6): 1797-1812, 2022 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-35941326

RESUMO

Mesenchymal stromal cells (MSCs) play an important role in the development of human cancer. Meanwhile, exosomes released by MSCs can mediate cell-cell communication by delivering microRNAs (miRNAs/miRs). Hence, this study aimed to explore the role of bone marrow mesenchymal stromal cell (BMSC)-derived exosomal miR-551b-3p in breast cancer. In this study, we found that upregulation of miR-551b-5p suppressed the proliferation and migration and induced the apoptosis of breast cancer cells via downregulating tripartite motif-containing protein 31 (TRIM31). In addition, miR-551b-5p could be transferred from BMSCs to breast cancer cells via exosomes; BMSC-derived exosomal miR-551b-3p suppressed the proliferation and migration and promoted the apoptosis and oxidative stress of MDA-MB-231 cells via inhibiting TRIM31. Furthermore, a xenograft mouse model was used to explore the role of BMSC-derived exosomal miR-551b-3p in vivo. We found that BMSC-derived exosomal miR-551b-3p inhibited tumor growth in a mouse xenograft model of breast cancer in vivo. Collectively, these findings indicated that BMSC-derived exosomal miR-551b-3p could suppress the development of breast cancer via downregulating TRIM31. Thus, miR-551b-3p could serve as a potential target for the treatment of breast cancer.


Assuntos
Neoplasias da Mama , Células-Tronco Mesenquimais , MicroRNAs , Animais , Medula Óssea/metabolismo , Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Neoplasias da Mama/terapia , Proliferação de Células/genética , Feminino , Humanos , Células-Tronco Mesenquimais/metabolismo , Camundongos , MicroRNAs/genética , MicroRNAs/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Proteínas com Motivo Tripartido/genética , Proteínas com Motivo Tripartido/metabolismo , Ubiquitina-Proteína Ligases/metabolismo
9.
Support Care Cancer ; 30(2): 1231-1241, 2022 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-34458943

RESUMO

PURPOSE: Sleep disturbance is common in meningioma patients and may lead to disease aggravation and decreases health-related quality of life (HRQoL). However, the sleep quality of meningioma patients newly diagnosed and ready for surgery has not been well clarified in China. This study aims to evaluate the prevalence, correlates, and impact of sleep disturbance among Chinese meningioma patients. METHODS: In this cross-sectional study, meningioma patients were recruited from the Affiliated Hospital of Nantong University from January 2020 to November 2020. A series of questionnaires were applied: the 0-10 Numerical Rating Scale (NRS), the Hospital Anxiety and Depression Scale (HADS), the Multidimensional Fatigue Inventory (MFI-20), the Epworth Sleepiness Scale (ESS), the Short-Form 36 (SF-36), the Pittsburgh Sleep Quality Index (PSQI). Independent samples t test, Mann-Whitney U test, chi-square analysis, Pearson/Spearman correlation, and binary logistic regression were used to analyze the data. RESULTS: One hundred meningioma patients completed the questionnaires. Sleep disturbance affected 43% of the meningioma patients and was linked to many concomitant symptoms, such as headache, fatigue, anxiety, and depression. Binary logistic regression indicated that fatigue and headache were independently associated with sleep disturbance of meningioma patients. Meanwhile, severe sleep disturbance led to lower quality of life. CONCLUSIONS: These findings demonstrated that a considerable number of meningioma patients newly diagnosed and ready for surgery suffered from sleep disturbance, potentially contributing to impair HRQoL. Medical personnel should pay more attention to meningioma patients with sleep disturbance and take effective measures to improve sleep quality, with the ultimate goal to improve their HRQoL.


Assuntos
Neoplasias Meníngeas , Meningioma , Transtornos do Sono-Vigília , China/epidemiologia , Estudos Transversais , Depressão/epidemiologia , Depressão/etiologia , Humanos , Neoplasias Meníngeas/epidemiologia , Meningioma/epidemiologia , Prevalência , Qualidade de Vida , Sono , Qualidade do Sono , Transtornos do Sono-Vigília/epidemiologia , Transtornos do Sono-Vigília/etiologia , Inquéritos e Questionários
10.
Medicine (Baltimore) ; 100(30): e26547, 2021 Jul 30.
Artigo em Inglês | MEDLINE | ID: mdl-34397686

RESUMO

ABSTRACT: The main purpose of this study was to investigate current state of constipation for lung cancer (LC) patients receiving platinum-based chemotherapy. The relationships between social demography, clinical variables, psychological status, and constipation were analyzed. In addition, quality of life (QoL) in LC patients with constipation was also analyzed. One hundred LC patients participated in this cross-sectional study. Under the guidance of the researchers, Functional Living Index-Emesis, Piper Fatigue Scale, Patient Health Questionnaire, Generalized Anxiety Disorder-7, European Organization for Research and Treatment of Cancer (EORTC) QLQ-C30 (version 3.0), Pittsburgh Sleep Quality Index, General Well-being Scale, Social Support Rate Scale, General Self-Efficacy Scale, and other related questionnaires were completed. The result showed the symptom of constipation was observed in 41 (41%) LC patients. The occurrence and development of constipation were associated with gender, food intake, exercise, nausea, fatigue, anxiety, depression, sleep disorders, and happiness. The study also found patients with constipation had significant lower QoL scores, especially the score in the general state. Constipation was very common in LC patients undergoing platinum-based chemotherapy. Reduced food intake and fatigue were the independent factors. Constipation significantly affects the QoL of the patients. Therefore, more attention should be paid to the risk factors of constipation in LC patients undergoing platinum-based chemotherapy, the earlier intervention was done to these patients, the better to improve their QoL.


Assuntos
Constipação Intestinal/complicações , Platina/farmacologia , Qualidade de Vida/psicologia , Idoso , Constipação Intestinal/etiologia , Constipação Intestinal/psicologia , Estudos Transversais , Tratamento Farmacológico/métodos , Tratamento Farmacológico/estatística & dados numéricos , Humanos , Neoplasias Pulmonares/complicações , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/psicologia , Masculino , Pessoa de Meia-Idade , Questionário de Saúde do Paciente/estatística & dados numéricos , Platina/uso terapêutico
11.
Lipids Health Dis ; 19(1): 57, 2020 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-32238151

RESUMO

BACKGROUND: Metastasis-associated lung adenocarcinoma transcript-1 (MALAT1) was aberrantly expressed in diverse diseases. Particularly in ischemic stroke (IS), the abnormal expression of MALAT1 played important roles including promotion of angiogenesis, inhibition of apoptosis and inflammation and regulation of autophagy. However, the effects of genetic variation (single nucleotide polymorphisms, SNPs) of MALAT1 on IS have rarely been explored. This study aimed to investigate whether SNPs in promoter of MALAT1 were associated with the susceptibility to IS. METHODS: A total of 316 IS patients and 320 age-, gender-, and ethnicity-matched controls were enrolled in this study. Four polymorphisms in the promoter of MALAT1 (i.e., rs600231, rs1194338, rs4102217, and rs591291) were genotyped by using a custom-by-design 48-Plex SNPscan kit. RESULTS: The rs1194338 C > A variant in the promoter of MALAT1 was associated with the risk of IS (AC vs. CC: adjusted OR = 0.623, 95% CI, 0.417-0.932, P = 0.021; AA vs. CC: adjusted OR = 0.474, 95% CI, 0.226-0.991, P = 0.047; Dominant model: adjusted OR = 0.596, 95% CI, 0.406-0.874, P = 0.008; A vs. C adjusted OR = 0.658, 95% CI, 0.487-0.890, P = 0.007). The haplotype analysis showed that rs600231-rs1194338-rs4102217-rs591291 (A-C-G-C) had a 1.3-fold increased risk of IS (95% CI, 1.029-1.644, P = 0.027). Logistic regression analysis identified some independent impact factors for IS including rs1194338 AC/AA, TC, TG, HDL-C, LDL-C, Apo-A1, Apo-B and NEFA (P < 0.05). CONCLUSIONS: These results suggest that the rs1194338 AC/AA genotypes may be a protective factor for IS.


Assuntos
Isquemia Encefálica/genética , Polimorfismo de Nucleotídeo Único/genética , Regiões Promotoras Genéticas/genética , RNA Longo não Codificante/genética , Acidente Vascular Cerebral/genética , Idoso , Feminino , Predisposição Genética para Doença/genética , Genótipo , Haplótipos/genética , Humanos , Masculino , Pessoa de Meia-Idade
12.
Aging (Albany NY) ; 11(5): 1501-1509, 2019 03 07.
Artigo em Inglês | MEDLINE | ID: mdl-30844765

RESUMO

Primary gastric cancer (PGC) is the fourth most common malignant human cancer and the second leading cause of death worldwide. The majority of the subjects of PGC is diagnosed at a late stage, resulting in poor prognosis and therapeutic outcome, largely attributable to dissemination of tumor cells into circulation as circulating tumor cells (CTCs) and their formation of distal tumor. Curcumin is an active ingredient from the rhizome of the plant Curcuma longa. Here, we assessed whether treatment with Curcumin may reduce the incidence of metastatic tumor formation in liver in mice carrying PGC. We found that Curcumin treatment significantly reduced the presence of CTCs and formation of liver tumor. Mechanistically, Curcumin reduced CXCR4 expression in PGCs in vitro and in vivo, and thus likely inhibited metastasis of PGC through suppression of stromal cell -derived factor-1/CXCR4 signaling. Thus, our study suggests that Curcumin may inhibit liver metastasis of PGC through reducing CTCs.


Assuntos
Antineoplásicos/uso terapêutico , Curcumina/uso terapêutico , Neoplasias Hepáticas/prevenção & controle , Neoplasias Hepáticas/secundário , Células Neoplásicas Circulantes , Neoplasias Gástricas/tratamento farmacológico , Neoplasias Gástricas/patologia , Animais , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos NOD , Camundongos Transgênicos , Receptores CXCR4/genética , Receptores CXCR4/metabolismo
13.
J Exp Clin Cancer Res ; 34: 35, 2015 Apr 17.
Artigo em Inglês | MEDLINE | ID: mdl-25927670

RESUMO

Gastric cancer (GC) remains one of the most common types of malignant cancer, and the molecular mechanism underlying its metastasis is still largely unclear. MicroRNAs have emerged as important regulators of metastasis because of their ability to act on multiple signaling pathways. In our study, we found that miR-144 is significantly downregulated in both highly metastatic GC cell lines and tissues. Results from both gain-of-function and loss-of-function experiments demonstrate that increased miR-144 expression significantly reduced GC cell migration, whereas decreased miR-144 expression dramatically enhanced GC cell migration. The met proto-oncogene (MET), which is often amplified in human cancers and functions as an important regulator of cell growth and tumor invasion, was identified as a direct target of miR-144. Moreover, silencing of MET using small interfering RNA (siRNA) recapitulated the anti-metastatic function of miR-144, whereas restoring MET expression attenuated the function of miR-144 in GC cells. Furthermore, we found that miR-144, by targeting MET, suppresses phosphorylation of Akt. Finally, we observed an inverse correlation between the expression of miR-144 and MET mRNA in GC metastatic tissues. In summary, miR-144 suppresses GC progression by directly downregulating MET expression, which subsequently prevents activation of the pro-oncogenic Akt pathway. Reintroduction of miR-144 expression in GC cells presents an attractive therapeutic approach to block the metastasis of gastric cancer.


Assuntos
MicroRNAs/genética , Proteínas Proto-Oncogênicas c-met/genética , Interferência de RNA , Neoplasias Gástricas/genética , Neoplasias Gástricas/patologia , Animais , Linhagem Celular Tumoral , Movimento Celular/genética , Análise por Conglomerados , Modelos Animais de Doenças , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Humanos , Metástase Neoplásica , Proto-Oncogene Mas , Transdução de Sinais , Neoplasias Gástricas/metabolismo , Transcriptoma
14.
Zhonghua Yi Xue Za Zhi ; 94(24): 1889-93, 2014 Jun 24.
Artigo em Chinês | MEDLINE | ID: mdl-25154996

RESUMO

OBJECTIVE: To evaluate the mechanism of interleukin-1 (IL-1) in tumorigenesis. METHODS: The miRNA expression was profiled with the Exiqon miRCURY(TM) LNA Array System. And the miRecords algorithm and luciferase reporter assays were employed for identifying the targets of miR-425. Cell proliferation assay was performed with CCK8. Cell apoptosis assay was performed with flow cytometry. RESULTS: IL-1ß induced the up-regulation of miR-425, a negative expression regulator of phosphatase and tensin homolog (PTEN). An increase in miR-425 depended upon IL-1ß-induced NF-kappaB activation.Repression of PTEN by miR-425 promoted gastric cancer cell proliferation. CONCLUSION: There is a critical role for NF-kappa B-dependent up-regulation of miR-425. And it represents a new pathway for the repression of phosphatase and tensin homolog activation and the promotion of cell survival upon IL-1ß induction.


Assuntos
Proliferação de Células , Neoplasias Gástricas , Apoptose , Linhagem Celular Tumoral , Sobrevivência Celular , Regulação da Expressão Gênica , Humanos , Interleucina-1beta , MicroRNAs , NF-kappa B , PTEN Fosfo-Hidrolase , Regulação para Cima
15.
Mol Cancer ; 13: 40, 2014 Feb 26.
Artigo em Inglês | MEDLINE | ID: mdl-24571667

RESUMO

Overexpression of the proinflammatory cytokine IL-1ß is associated with diverse diseases, including cancer. Alteration of microRNAs has been observed in cancer cells exposed to proinflammatory cytokines, yet their function in inflammation stress remains elusive. Here, we show that IL-1ß induces the upregulation of miR-425, which negatively regulates phosphatase and tensin homolog expression by targeting its 3' UTR. An increase in miR-425 depends on IL-1ß-induced NF-kappaB activation, which enhances miR-425 gene transcription upon IL-1ß induction. Consequently, repression of phosphatase and tensin homolog by miR-425 promotes gastric cancer cell proliferation, which is required to protect cells from cisplatin-induced apoptosis. Taken together, our data support a critical role for NF-kappaB-dependent upregulation of miR-425, which represents a new pathway for the repression of phosphatase and tensin homolog activation and the promotion of cell survival upon IL-1ß induction.


Assuntos
Adenocarcinoma/metabolismo , Regulação Neoplásica da Expressão Gênica/fisiologia , MicroRNAs/metabolismo , NF-kappa B/metabolismo , PTEN Fosfo-Hidrolase/metabolismo , Neoplasias Gástricas/metabolismo , Adenocarcinoma/genética , Animais , Proliferação de Células , Imunoprecipitação da Cromatina , Xenoenxertos , Humanos , Immunoblotting , Interleucina-1beta/genética , Interleucina-1beta/metabolismo , Camundongos , Camundongos Nus , MicroRNAs/genética , NF-kappa B/genética , PTEN Fosfo-Hidrolase/genética , Reação em Cadeia da Polimerase em Tempo Real , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Neoplasias Gástricas/genética , Regulação para Cima
16.
Tumour Biol ; 35(3): 2167-74, 2014 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-24146278

RESUMO

Prostate stem cell antigen (PSCA) is a glycosylphosphatidylinositol-anchored 123-amino acid protein related to the cell proliferation inhibition and/or cell death induction activity which has attracted considerable attention as a candidate gene for gastric cancer (GC) since it was first identified through genome-wide association approach. Since then, the relationship between PSCA polymorphisms (rs2294008, rs2976392) and GC has been reported in various ethnic groups; however, these studies have yielded inconsistent results. To investigate this inconsistency, we performed a meta-analysis of 16 studies involving a total of 18,820 cases and 35,756 controls for the two widely studied polymorphisms of PSCA on genetic susceptibility for GC. Overall, the summary odds ratio for GC was 1.46 (95% CI 1.30-1.69, P < 10(-5)) and 1.49 (95% CI 1.22-1.82, P < 10(-4)) for PSCA rs2294008 and rs2976392 polymorphisms, respectively. Meanwhile, haplotype analyses of the two polymorphisms revealed a significant association between the combination of these alleles and GC risk. When stratifying for ethnicity, significantly increased risks were found for rs2294008 and rs2976392 polymorphism among East Asians in all genetic models, while no significant associations were observed for the rs2294008 polymorphism in Caucasians. In the stratified analyses according to histological type, and source of controls, evidence of gene-disease association was still obtained. In addition, our data indicate that rs2294008 of PSCA is involved in GC susceptibility and confer its effect primarily in noncardia tumors (OR = 1.30, 95% CI 1.12-1.53, P < 10(-4)). Our findings demonstrated that rs2294008 and rs2976392 polymorphism of PSCA is a risk-conferring factor associated with increased GC susceptibility, especially in East Asians.


Assuntos
Antígenos de Neoplasias/genética , Predisposição Genética para Doença/genética , Proteínas de Neoplasias/genética , Polimorfismo de Nucleotídeo Único/genética , Neoplasias Gástricas/genética , Povo Asiático/genética , Estudos de Casos e Controles , Proteínas Ligadas por GPI/genética , Haplótipos , Humanos , Fatores de Risco , População Branca/genética
17.
Cochrane Database Syst Rev ; (5): CD008836, 2012 May 16.
Artigo em Inglês | MEDLINE | ID: mdl-22592734

RESUMO

BACKGROUND: Small bowel obstruction (SBO) is one of the most common emergent complications of general surgery. Intra-abdominal adhesions are the leading cause of SBO. Because surgery can induce new adhesions, non-operative management is preferred in the absence of signs of peritonitis or strangulation. Oral traditional Chinese herbal medicine has long been used as a non-operative therapy to treat adhesive SBO in China. Many controlled trials have been conducted to investigate its therapeutic value in resolving adhesive SBO. OBJECTIVES: The aim of this review was to assess the efficacy and safety of oral traditional Chinese medicine (TCM) for adhesive small bowel obstruction. SEARCH METHODS: We searched the following databases, without regard to language or publishing restrictions: the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, Chinese Biomedical Database (CBM), China National Knowledge Infrastructure/Chinese Academic Journals full-text Database (CNKI), and VIP (a full-text database of Chinese journals). The searches were conducted in November 2011. SELECTION CRITERIA: Randomised controlled trials and quasi-randomised controlled trials comparing Chinese medicines administered orally, via the gastric canal, or both with a placebo or conventional therapy in participants diagnosed with adhesive SBO were considered. We also considered trials of TCM (oral administration, gastric tube perfusion, or both) plus conventional therapy compared with conventional therapy alone for patients with adhesive SBO. Studies addressing the safety and efficacy of oral traditional Chinese medicinal agents in the treatment of adhesive SBO were also considered. DATA COLLECTION AND ANALYSIS: Two authors collected the data independently. We assessed the risk of bias according to the following methodological criteria: random sequence generation, allocation concealment, blinding, incomplete outcome data, selective outcome reporting and other sources of bias. Dichotomous data are presented as risk ratios (OR) and 95% confidence intervals (CI); continuous outcomes are presented as mean differences (MD) and 95% CIs. The data analyses were carried out using Review Manager 5.1. For cases in which necessary information was not reported in the paper, we contacted the primary authors for additional information. MAIN RESULTS: Five randomised trials involving 664 participants were analysed. Five different herbal medicines were tested in these trials, including Huo-Xue-Tong-Fu decoction, Xiao-Cheng-Qi-Tang decoction, a combination of Xiao-Cheng-Qi-Tang and Si-Jun-Zi-Tang decoctions, Chang-Nian-Lian-Song-Jie-Tang decoction, and Fufang-Da-Cheng-Qi-Tang decoction. There were variations in the tested herbal compositions and methods of medicine administration. The main outcomes reported in the trials were effects on abdominal pain, abdominal distension, constipation defection, time of first defecation after treatment, and reoperation rate during the course of the disease. Secondary outcomes selected for this review were not available, including complications such as small bowel perfusion (bowel resection, system complications, and other possible complications), length of hospital stay, cost of hospitalisation, and time from admission to surgical intervention. The results of five trials showed that patients receiving TCM combined with conventional therapy seemed to have improved outcomes compared with patients receiving conventional treatment alone (OR 4.24, 95% CI 2.83 to 6.36).However, we cannot conclusively determine the efficacy of TCM in this review due to inadequate reporting, low methodological quality, and the prevalence of various biases in the reviewed studies. Furthermore, because none of the reviewed trials discussed adverse events, we could not evaluate the safety of TCM for adhesive SBO patients. All trials were conducted and published in China. AUTHORS' CONCLUSIONS: Although many studies have assessed the use of TCM products for adhesive SBO, most were excluded from this review due to their methodological limitations. This systematic review did not find sufficient evidence to support the objective efficacy and safety of TCM for patients with adhesive SBO. The positive evidence should be interpreted with caution given the insufficient number of studies with large sample sizes, the absence of well-designed, high-quality trials, and the lack of safety information. Therefore, further studies with larger sample sizes and high-quality, randomised, and controlled trials are necessary to produce more accurate and meaningful data on the efficacy of Chinese herbal medicines for adhesive SBO.


Assuntos
Medicamentos de Ervas Chinesas/administração & dosagem , Obstrução Intestinal/tratamento farmacológico , Intestino Delgado , Fitoterapia/métodos , Complicações Pós-Operatórias/tratamento farmacológico , Combinação de Medicamentos , Humanos , Obstrução Intestinal/etiologia , Medicina Tradicional Chinesa/métodos , Extratos Vegetais , Ensaios Clínicos Controlados Aleatórios como Assunto , Aderências Teciduais/tratamento farmacológico
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