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1.
Oncogene ; 2019 Oct 28.
Artigo em Inglês | MEDLINE | ID: mdl-31659258

RESUMO

Gastric cancer (GC) is characterized by extensive local invasion, distant metastasis and poor prognosis. In most cases, GC progression is associated with aberrant expression of cytokines or activation of signaling cascades mediated by tumor-stroma interactions. However, the mechanisms by which these interactions contribute to GC progression are poorly understood. In this study, we find that IL-33 and its receptor ST2L are upregulated in the human GC and served as prognostic markers for poor survival of GC patients. In a co-culture model with GC cells and cancer-associated fibroblasts (CAFs), we further demonstrate that CAFs-derived IL-33 enhances the migration and invasion of GC cells by inducing the epithelial-mesenchymal transition (EMT) through activation of the ERK1/2-SP1-ZEB2 pathway in a ST2L-dependent manner. Furthermore, the secretion of IL-33 by CAFs can be induced by the proinflammatory cytokines TNF-α that is released by GC cells via TNFR2-NF-κB-IRF-1 pathway. Additionally, silencing of IL-33 expression in CAFs or ST2L expression in GC cells inhibits the peritoneal dissemination and metastatic potential of GC cells in nude mice. Taken together, these results characterize a critical role of the interaction between epithelial-stroma mediated by the TNF-α/IL-33/ST2L signaling in GC progression, and provide a rationale for targeting this pathway to treat GC metastasis.

2.
Int J Med Sci ; 16(8): 1142-1148, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31523177

RESUMO

Background: The aims of this study were to investigate the expression pattern of CDK12 protein in gastric cancer, and to analyze the correlations of CDK12 expression between CD8+ cell density and CCL12 expression. Methods: Eighty-six paired tumor and non-tumor samples were collected from patients who underwent radical surgery and had pathological confirmed gastric adenocarcinoma. Immunohistochemistry was used to assess CDK12 expression and CD8+ cell density. Expression of CDK12 and CCL21 mRNA was detected by quantitative reverse transcription-polymerase chain reaction. Results: CDK12 expression in gastric tumor tissues was significantly higher than it in paired non-tumor tissues (P<0.001). High expression of CDK12 was identified in 43 cases (50%), and it was significantly correlated with Lauren's classification (diffuse type) and number of metastatic lymph nodes (≥15). High CDK12 protein level indicated a relative poorer overall survival than patients with CKD12 low expression, while it was not identified as an independent prognostic factor. Median number of CD8+ cells in tumor tissues was 51 (range: 0-292). Number of CD8+ cells was positively correlated with CDK12 expression score in tumor tissues (r=0.243, P=0.024). Positive correlation was also found between CDK12 and CCL21 mRNA expression (r=0.419, P=0.017). Conclusion: High CDK12 expression was detected in gastric cancer which was correlated with malignant phenotypes and worse outcome. Positive correlations of CD8+ cell number and CCL21 mRNA expression with CDK12 level were identified.

3.
BMC Cancer ; 19(1): 932, 2019 Sep 18.
Artigo em Inglês | MEDLINE | ID: mdl-31533660

RESUMO

BACKGROUND: To investigate the implications of prophylactic intraoperative Hyperthermic Intraperitoneal Chemotherapy (HIPEC) with D2 radical gastrectomy for locally advanced Gastric Cancer (AGC) in a randomized case control study. METHOD: Eighty consecutive patients with locally AGC were randomly separated into 2 groups: HIPEC group (Curative Resection + intraoperative HIPEC with cisplatin 50 mg/m2 at 42.0 ± 1.0 °C for 60 min) and Control group (Curative Resection only). Intraoperative and post-operative events, clinical recovery, morbidity and the disease-free survival (DFS) rates were closely monitored. RESULTS: Faster recovery of bowel function (43 ± 5 h vs 68 ± 7, P < 0.05) and shorter postoperative stay (8d vs 14d, P < 0.05) were noted in the HIPEC group. Among the 40 HIPEC group patients, the highest intracranial temperature recorded during the procedure was 38.2 °C but the patient made an eventless recovery. Mild renal dysfunction, hyperbilirubinemia and mild liver dysfunction were recorded in the HIPEC group but their incidences were found to be statistically insignificant when compared with the control group (P > 0.05). The 3 year DFS rate analysis showed that the prophylactic HIPEC group had a higher DFS rate (93% vs 65%, P = 0.0054). The peritoneal recurrence rate was lower in the HIPEC group (3% vs 23%, P < 0.05). CONCLUSION: Prophylactic HIPEC with radical D2 Gastrectomy improves survival and peritoneal recurrence rates for AGC with favorable post-operative recovery at low and acceptable morbidity.

4.
Genome Biol ; 20(1): 149, 2019 07 31.
Artigo em Inglês | MEDLINE | ID: mdl-31366358

RESUMO

The human reference genome is still incomplete, especially for those population-specific or individual-specific regions, which may have important functions. Here, we developed a HUman Pan-genome ANalysis (HUPAN) system to build the human pan-genome. We applied it to 185 deep sequencing and 90 assembled Han Chinese genomes and detected 29.5 Mb novel genomic sequences and at least 188 novel protein-coding genes missing in the human reference genome (GRCh38). It can be an important resource for the human genome-related biomedical studies, such as cancer genome analysis. HUPAN is freely available at http://cgm.sjtu.edu.cn/hupan/ and https://github.com/SJTU-CGM/HUPAN .


Assuntos
Genoma Humano , Software , Grupo com Ancestrais do Continente Africano/genética , Grupo com Ancestrais do Continente Asiático/genética , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Proteínas/genética , Análise de Sequência de DNA
5.
Cancer Biomark ; 26(2): 131-138, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31356198

RESUMO

BACKGROUND: The signaling adapter protein CrkL plays vital roles in multiple cancers. However, the expression pattern of CrkL protein and its clinical significance have not been well characterized in human gastric cancer (GC) so far. OBJECTIVE: To investigate the association of tissue-based CrkL protein expression level with the clinicopathological characteristics and prognosis of GC patients. METHODS: The expression level of CrkL protein in 380 GC patients was analyzed by immunohistochemistry. The associations of CrkL protein expression level with clinicopathologicalal characteristics and clinical outcome were evaluated. RESULTS: Compared with the matched adjacent non-tumor tissues, CrkL protein expression level was significantly up-regulated in tumor tissues. In addition, there was a positive correlation between CrkL and Ki67 expression levels in GC patients. An elevated CrkL level statistically correlated with aggressive clinicopathologicalal characteristics, such as larger tumor size, deeper local invasion, more lymph node metastasis, advanced TNM stage, and poorer prognosis. Notably, multivariate analysis identified tissue-based CrkL level as an independent predictor for the unfavorable prognosis of GC. CONCLUSIONS: These results indicate that CrkL protein may serve as a novel prognostic biomarker in GC.

6.
Gene Ther ; 26(9): 373-385, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31308477

RESUMO

Colorectal cancer (CRC) is the third most common type of cancer. In recent decades, genomic analysis has played an increasingly important role in understanding the molecular mechanisms of CRC. However, its pathogenesis has not been fully uncovered. Identification of genes related to CRC as complete as possible is an important way to investigate its pathogenesis. Therefore, we proposed a new computational method for the identification of novel CRC-associated genes. The proposed method is based on existing proven CRC-associated genes, human protein-protein interaction networks, and random walk with restart algorithm. The utility of the method is indicated by comparing it to the methods based on Guilt-by-association or shortest path algorithm. Using the proposed method, we successfully identified 298 novel CRC-associated genes. Previous studies have validated the involvement of the majority of these 298 novel genes in CRC-associated biological processes, thus suggesting the efficacy and accuracy of our method.

7.
J Exp Clin Cancer Res ; 38(1): 314, 2019 Jul 17.
Artigo em Inglês | MEDLINE | ID: mdl-31315643

RESUMO

BACKGROUND: IDO1 (Indoleamine 2,3-dioxygenase 1) inhibits host anti-tumor immune response by exhausting tryptophan in tumor microenvironment, but the pathogenic mechanisms of IDO1 in gastric cancer (GC) cells need to be further explored. METHODS: The aim of this study was to use CCLE (Cancer Cell Line Encyclopedia) transcriptomic data of GC cell lines for WGCNA (Weighted Gene Co-expression Network Analysis) analysis, and explore the potential functions and mechanisms of IDO1 in GC progression in vitro and in vivo. RESULTS: The higher expression level of IDO1 was identified in 4 out of 7 GC cell lines. Increased IDO1 expression strongly promoted cell migration via its metabolite kynurenine and was associated with pathways of immune activation according to GSEA (Gene Set Enrichment Analysis). The functions of IDO1 were closely associated with extracellular matrix, collagen metabolic and catabolic process by WGCNA analysis. Among five hub genes (AXL, SGCE, COL12A1, ANTXR1, LOXL2), COL12A1 and LOXL2 were upregulated in GC tissues. IDO1 disclosed positive correlation with six collagen genes by coefficient matrix diagram. Knockdown of IDO1 decreased the expression of LOXL2, COL6A1, COL6A2 and COL12A1 in GC cells in both mRNA and protein levels. Of them, knockdown of COL12A1 inhibited cell migration more apparently than knockdown of others. IDO1 and COL12A1 revealed synergistic efficacy on promoting cell migration via a positive feedback sustained by MAPK pathway. This bioprocess was mediated by IDO1 metabolite kynurenine and integrin ß1. A popliteal lymph nodemetastasis model was established for verifying metastatic promotion of IDO1 and COL12A1 in GC. CONCLUSIONS: IDO1 and COL12A1 synergistically promoted GC metastasis. The novel findings suggested that both IDO1 and COL12A1 may be promising targets on anti-cancer treatment in GC.

8.
Nat Commun ; 10(1): 2037, 2019 05 02.
Artigo em Inglês | MEDLINE | ID: mdl-31048690

RESUMO

Genome-wide analysis of genomic signatures might reveal novel mechanisms for gastric cancer (GC) tumorigenesis. Here, we analysis structural variations (SVs) and mutational signatures via whole-genome sequencing of 168 GCs. Our data demonstrates diverse models of complex SVs operative in GC, which lead to high-level amplification of oncogenes. We find varying proportion of tandem-duplications (TDs) among individuals and identify 24 TD hotspots involving well-established cancer genes such as CCND1, ERBB2 and MYC. Specifically, we nominate a novel hotspot involving the super-enhancer of ZFP36L2 presents in approximately 10% GCs from different cohorts, the oncogenic role of which is further confirmed by experimental data. In addition, our data reveal a mutational signature, specifically occurring in noncoding region, significantly enriched in tumors with cadherin 1 mutations, and associated with poor prognoses. Collectively, our data suggest that TDs might serve as an important mechanism for cancer gene activation and provide a novel signature for stratification.


Assuntos
Oncogenes/genética , Neoplasias Gástricas/genética , Fatores de Transcrição/genética , Transcriptoma/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Antígenos CD/genética , Caderinas/genética , Carcinogênese/genética , Linhagem Celular Tumoral , Elementos Facilitadores Genéticos/genética , Éxons/genética , Feminino , Duplicação Gênica/genética , Variação Estrutural do Genoma , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Estômago/patologia , Neoplasias Gástricas/mortalidade , Neoplasias Gástricas/patologia , Análise de Sobrevida , Sequenciamento Completo do Genoma
9.
Hum Vaccin Immunother ; 15(9): 2127-2128, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30932728

RESUMO

Recently Hui Liu commented on a paper titled "Analysis on the risks of severe adverse events in rabies post-exposure prophylaxis and appropriate decision-making procedure" and arose some questions on the paper. In this reply letter, we would like to address the questions to make the previous paper more clear.


Assuntos
Vírus da Raiva , Raiva , Humanos , Profilaxia Pós-Exposição , Vacinação
10.
Cell Physiol Biochem ; 52(3): 606-616, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30907988

RESUMO

BACKGROUND/AIMS: Aberrant expression of miR-106b is a specific symptom of many solid carcinomas. Overexpression of miR-106b has been observed in gastric cancer. The effect of miR-106b on gastric cancer has been investigated in different cell culture models. However, the effect of miR-106b on metastasis of early gastric cancer (EGC) remains unknown. METHODS: In the study, qRT-PCR, FISH, western blot, luciferase reporter assay, migration and invasion assays, flow cytometry and TUNEL staining were used to investigate the effect of miR-106b on metastasis of EGC. RESULTS: To explore the function of miR-106b in EGC, we investigated the downstream signaling of miR-106b and found that ALEX1 was a direct target of miR-106 in gastric cancer cells. Up-regulation of ALEX1 effectively rescued the cell apoptosis induced by miR-106b inhibitor and promoted the expression levels of phosphorylation of JAK1 and STAT3. Moreover, overexpression of JAK1 reduced the cell apoptosis induced by miR-106b inhibitor and decreased the expression levels of the apoptotic proteins in gastric cancer cells. Furthermore, down-regulation of miR-106b promoted apoptosis of gastric cancer cells via inhibiting JAK1/STAT3 signaling pathway in vitro and in vivo. In addition, GLPG0643, a JAK1 inhibitor, enhanced the inhibitory effect of miR-106b inhibitor on gastric cancer growth in vivo. CONCLUSION: These findings provided a potential therapeutic manner for the treatment of metastasis of EGC in clinic.


Assuntos
Proteínas do Domínio Armadillo/metabolismo , MicroRNAs/metabolismo , Proteínas Oncogênicas/metabolismo , Neoplasias Gástricas/patologia , Animais , Antagomirs/metabolismo , Apoptose , Proteínas do Domínio Armadillo/química , Proteínas do Domínio Armadillo/genética , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Regulação para Baixo , Humanos , Janus Quinase 1/antagonistas & inibidores , Janus Quinase 1/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , MicroRNAs/antagonistas & inibidores , MicroRNAs/genética , Metástase Neoplásica , Proteínas Oncogênicas/química , Proteínas Oncogênicas/genética , Inibidores de Proteínas Quinases/farmacologia , Fator de Transcrição STAT3/metabolismo , Transdução de Sinais/efeitos dos fármacos , Neoplasias Gástricas/metabolismo , Regulação para Cima
11.
Gastric Cancer ; 22(5): 955-966, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-30778797

RESUMO

BACKGROUND: Oncostatin M receptor (OSMR) is a member of the interleukin 6 (IL-6) receptor family that transduces signaling events of Oncostatin M (OSM). OSM-OSMR signaling plays a key role in inflammation and cancer progression. However, the role of OSM-OSMR in gastric cancer (GC) is still unknown. METHODS: OSMR expression in GC was determined by real-time PCR (RT-PCR), immunohistochemistry (IHC) and Western blot. The effects of OSM-OSMR on GC cell proliferation, migration, invasion, and epithelial-mesenchymal transition (EMT) in vitro and metastasis in vivo were examined. The pathways underlying OSM-OSMR signaling were explored by Western blot. Regulatory mechanism between SP1 and OSMR was explored in vitro. RESULTS: OSMR was highly expressed in GC tissues and its expression level was closely associated with age, T stage, Lauren classification, lymph node metastasis, TNM stage and worse prognosis of patients with GC. Knockdown of OSMR expression in GC cells significantly inhibited cell proliferation, migration, invasion, and EMT in vitro, as well as tumorigenesis and peritoneal metastasis in vivo induced by OSM. These effects mediated by OSM-OSMR were dependent on the activation of STAT3/FAK/Src signaling. SP1 could bind to the promoter region of human OSMR gene from - 255 to - 246 bp, and transcriptionally regulated OSMR overexpression in GC cells. CONCLUSIONS: OSM-OSMR contributes to GC progression through activating STAT3/FAK/Src signaling, and OSMR is transcriptionally activated by SP1.

12.
J Exp Clin Cancer Res ; 38(1): 52, 2019 Feb 04.
Artigo em Inglês | MEDLINE | ID: mdl-30717785

RESUMO

BACKGROUND: Gastric cancer (GC) has a clear predilection for metastasis toward the omentum which is primarily composed of adipose tissue, indicating that fatty acids may contribute to this phenomenon. However their function remains poorly understood in GC. In this study, we investigated the role of palmitate acid (PA) and its cellular receptor CD36 in the progression of GC. METHODS: Immunohistochemical (IHC) staining was performed to detect CD36 expression in GC tissues and its clinical significance was determined statistically. CD36 over-expression and knock-down expression cell models were developed and tested in vitro. Wound-healing assays, migration assays, and invasion assays were performed and peritoneal implants into nude mice were done to assess the biological effects of PA and CD36. The underlying mechanisms were investigated using western blot, immunofluorescence (IF), quantitative real-time PCR (qRT-PCR) and antibody blocking assays. RESULTS: PA promoted the metastasis of GC by phosphorylation of AKT, which facilitated the nuclear localization of ß-catenin through inactivation of GSK-3ß via phosphorylation. This tumor-promoting effect of PA was mediated by CD36, a cell surface receptor of fatty acids (FAs). The higher the CD36 expression levels in GC tissues correlated with the poorer the prognosis of patients according to the TCGA database, the GEO database and our own clinical data. CONCLUSIONS: Our experiments established CD36 as a key mediator of FA-induced metastasis of GC via the AKT/GSK-3ß/ß-catenin signaling pathway. CD36 might, therefore, constitute a potential therapeutic target for clinical intervention in GC.


Assuntos
Antígenos CD36/metabolismo , Glicogênio Sintase Quinase 3 beta/metabolismo , Ácido Palmítico/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Neoplasias Gástricas/metabolismo , Neoplasias Gástricas/patologia , beta Catenina/metabolismo , Animais , Antígenos CD36/biossíntese , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Feminino , Humanos , Estimativa de Kaplan-Meier , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Pessoa de Meia-Idade , Terapia de Alvo Molecular , Invasividade Neoplásica , Metástase Neoplásica , Estadiamento de Neoplasias , Ácido Palmítico/farmacologia
13.
Biochim Biophys Acta Mol Basis Dis ; 1865(1): 181-192, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30404039

RESUMO

The kinesin family member 14 (KIF14) is a potential oncogene and is involved in the metastasis of various cancers. Nevertheless, its function in gastric cancer (GC) remains poorly defined. The expression of KIF14 was examined in GC cell lines and a clinical cohort of GC specimens by qPCR, western blotting and immunohistochemistry (IHC) staining. The relationship between KIF14 expression and the clinicopathological features was analyzed. The effect of KIF14 on cell proliferation, colony formation, invasion and migration were investigated in vitro and in vivo. The expression of KIF14 was significantly increased in the GC tissues and cell lines. High KIF14 expression was associated with tumor stage, tumor-node-metastasis (TNM) stage and metastasis. KIF14 was an independent prognostic factor for the overall survival of GC, and a higher expression of KIF14 predicted a poorer survival. KIF14 silencing resulted in attenuated proliferation, invasion and migration in human gastric cancer cells, whereas KIF14 ectopic expression facilitated these biological abilities. Notably, the depressed expression of KIF14 inhibited Akt phosphorylation, while overexpressed KIF14 augmented Akt phosphorylation. Additionally, there was a significant correlation between the expression of KIF14 and p­Akt in GC tissues. Importantly, the proliferation, invasion and migration of the GC cells, which was promoted by KIF14 overexpression, was abolished by the Akt inhibitor MK-2206, while Akt overexpression greatly rescued the effects induced by KIF14 knockdown. Our findings are the first to demonstrate that KIF14 is overexpressed in GC, is correlated with poor prognosis and plays a crucial role in the progression and metastasis of GC.


Assuntos
Progressão da Doença , Cinesina/metabolismo , Metástase Neoplásica , Proteínas Oncogênicas/metabolismo , Neoplasias Gástricas/metabolismo , Adulto , Idoso , Carcinogênese , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Células Epiteliais , Feminino , Regulação Neoplásica da Expressão Gênica/genética , Técnicas de Silenciamento de Genes , Células HEK293 , Xenoenxertos , Humanos , Cinesina/genética , Masculino , Pessoa de Meia-Idade , Proteínas Oncogênicas/genética , Prognóstico , Células-Tronco , Neoplasias Gástricas/genética
14.
Zhonghua Wei Chang Wai Ke Za Zhi ; 21(11): 1274-1279, 2018 Nov 25.
Artigo em Chinês | MEDLINE | ID: mdl-30506539

RESUMO

OBJECTIVE: To investigate the clinical characteristics and prognostic factors of reoperation patients with postoperative recurrence or metastasis of gastrointestinal stromal tumor (GIST). METHODS: A retrospective case-control study was performed on the clinical data of 31 patients with GIST who had recurrence or metastasis after the first surgery and underwent one or more operations again from February 2003 to January 2016 at Ruijin Hospital, Shanghai Jiaotong University School of Medicine. The clinical characteristics of these patients were analyzed. Kaplan-Meier survival curve was used to calculate the survival rate, Cox univariate and multivariate regression model was applied to prognosis analysis. RESULTS: Age of these 31 patients at the first operation was 35-78 (median 49) years, including 17 males (54.8%) and 14 females (45.2%). The tumors of 21 cases located in small intestines (67.7%), 2 cases in stomach (6.5%), 4 cases (12.9%) in colorectum and of 4 cases (12.9%) in other sites. According to NIH criteria, risk assessment indicated 26 cases were(83.8%) with high risk, 3 cases (9.7%) with moderate risk, and 2 cases (6.5%) with low risk. After the first operation, 15 cases received the IM (imatinib) therapy regularly based on NCCN guideline,10 cases received the therapy irregularly, and the other 6 cases did not receive the therapy. R0 resection was performed in 29 cases (93.5%) and R1/R2 resection was performed in 2 cases (6.5%). The median interval between the first operation to the recurrence was 32.3 (5.2-117.6) months and the median age of recurrence was 56 years old. Refer to the recurrent location, 28 cases (90.3%) were found in the same location or liver, 1 case in greater omentum, and 2 cases in pelvic cavity. The median diameter of the tumor in reoperation was 6.5 cm. Twenty-three cases(74.2%) received R0 excision and the other 8 cases(25.8%) received R1/R2 excision. At diagnosis of tumor recurrence, 20 cases (64.5%) received the second surgery immediately and the other 11 cases received surgery after imatinib or sunitinib treatment. Twenty-nine (93.5%) patients were followed up for 7.3 to 160.3 (median 49.5) months. After the second surgery, the relapse-free survival (RFS) of the whole group was 3.2 to 148.6(median: 29.7) months. Till the end of follow-up, 9 cases died of recurrence. Among 20 alive cases, 8 cases were living with the tumor, 1 case received the third surgery. The median overall survival (OS) time was 38.4(6.2-160.3) months. The 5-year RFS and the 5-year OS of 15 cases who received regular targeted therapy after the first operation were 73.4% and 81.7% respectively, significantly higher than those of the other 16 cases who received irregular or no targeted therapy(37.6%, P=0.015 and 38.9%,P=0.023,respectively). The 5-year RFS rate and the 5-year OS rate of the 11 patients who were diagnosed or complicated with liver metastasis were 29.8% and 32.2% respectively, which were significantly lower than those of the 20 patients without liver metastasis (79.1% and 88.1% respectively, both P<0.001). Cox model for OS, the results showed that regular targeted therapy after first surgery(HR=0.362, 95%CI:0.210-1.074, P=0.089) and the liver metastasis (HR=5.342, 95%CI: 0.902-12.580, P=0.057) were not the independent risk factors. CONCLUSIONS: Regular targeted therapy according to the guideline after the first operation for GIST patients with recurrence or metastasis may improve the prognosis. Prognosis of GIST patients with postoperative liver metastasis is poor.

15.
Neurosci Bull ; 34(6): 1091-1099, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30413937

RESUMO

Although extensively studied, the exact role of sleep in learning and memory is still not very clear. Sleep deprivation has been most frequently used to explore the effects of sleep on learning and memory, but the results from such studies are inevitably complicated by concurrent stress and distress. Furthermore, it is not clear whether there is a strict time-window between sleep and memory consolidation. In the present study we were able to induce time-locked slow-wave sleep (SWS) in mice by optogenetically stimulating GABAergic neurons in the parafacial zone (PZ), providing a direct approach to analyze the influences of SWS on learning and memory with precise time-windows. We found that SWS induced by light for 30 min immediately or 15 min after the training phase of the object-in-place task significantly prolonged the memory from 30 min to 6 h. However, induction of SWS 30 min after the training phase did not improve memory, suggesting a critical time-window between the induction of a brief episode of SWS and learning for memory consolidation. Application of a gentle touch to the mice during light stimulation to prevent SWS induction also failed to improve memory, indicating the specific role of SWS, but not the activation of PZ GABAergic neurons itself, in memory consolidation. Similar influences of light-induced SWS on memory consolidation also occurred for Y-maze spatial memory and contextual fear memory, but not for cued fear memory. SWS induction immediately before the test phase had no effect on memory performance, indicating that SWS does not affect memory retrieval. Thus, by induction of a brief-episode SWS we have revealed a critical time window for the consolidation of hippocampus-dependent memory.

16.
Zhonghua Wei Chang Wai Ke Za Zhi ; 21(10): 1087-1092, 2018 Oct 25.
Artigo em Chinês | MEDLINE | ID: mdl-30370504

RESUMO

Gastric cancer is the second most common malignancy and the one of the leading causes of cancer-related death in China. In particular, the survival rate of patients with stage IV or unresectable gastric cancer is very poor. Conversion therapy for stage IV gastric cancer has been the main subject with much attention recently. It is defined to achieve an R0 surgical resection after chemotherapy for originally unresectable cancer due to technical and/or oncological reasons. However, the optimal indications for conversion surgery are still controversial, and how to select the most appropriate candidates for conversion therapy remains to be clarified. A new biological category for stage IV gastric cancer proposed by K Yoshida from Gifu University has been tested out in some trials, from which stage IV gastric cancer can be divided into two different classifications based on the absence (category 1: potentially resectable metastasis and category 2: marginally resectable metastasis) or presence (category 3:incurable and unresectable metastasis and category 4: non-curable metastasis) of macroscopic peritoneal dissemination. The optimal indications for conversion therapy mainly include the patients with category 2, and partially for patients with categories 3 and 4. A surgery-oriented classification proposed by Peking University Cancer Hospital tried to classify the stage IV gastric cancer for conversion therapy. It would be classified as resectable and unresectable categories, depending on uhether R0 resection is available by preoperative evaluation. In this classification, unresectable cancer can be further classified as conversed, partly conversed and non-conversed types based on extent of cancer metastasis. The resection of primary and metastatic lesion in unscreened stage IV gastric cancer was not testified to improve survival. REGATTA trial has identified no significant difference in survival rate between the chemotherapy only and palliative gastrectomy with postoperative chemotherapy for stage IV gastric cancer with a single non-curable factor. With development of conversion therapy, a consensus has been reached that the patients with unresectable gastric cancer initially exhibiting one non-curative factor, if having clinical response to chemotherapy, may obtain a survival benefit from subsequent R0 radical gastrectomy. Several novel combined chemotherapy regimens occasionally allow for conversion of an initially unresectable gastric cancer to resectable cancer in clinical practice. Conversion surgery may result in long-term survival in selected patients who respond to chemotherapy. Several previous studies have evaluated the positive prognostic role of surgery after chemotherapy in stage IV gastric cancer patients with one non-curative factor, such as peritoneal metastasis, para-aortic lymph node metastasis or liver metastasis. Gastric cancer is a highly heterogeneous tumor in nature, consisting of varying aggressive biological characteristics. Oncologically stage IV gastric cancer is a systemic disease, and the complete response to any therapy is really very rare, so that conversion therapy is a great clinical challenging problem for gastric cancer patients. Due to the multi-pathway metastasis, perioperative systemic chemotherapy is the most important in conversion therapy for stage IV gastric cancer, and a radical surgical resection is the key to improve prognosis. A good local control does not necessarily lead to prolonged survival in patients with stage IV gastric cancer, in which other sites metastases often emerge even after successful local-regional cancer-oriented treatment. To date, most reports of conversion therapy for gastric cancer were from single-center or retrospective study. If more reliable evidences are to be obtained, more multi-center and prospective RCT studies must be carried out.

17.
Zhonghua Wei Chang Wai Ke Za Zhi ; 21(10): 1093-1098, 2018 Oct 25.
Artigo em Chinês | MEDLINE | ID: mdl-30370505

RESUMO

The incidence of gastric cancer is high in China. Most patients are advanced incurable and by surgery at diagnosis. At present, the treatment of advanced gastric cancer in China has been mainly based on multidisciplinary treatment including surgery, chemotherapy, radiotherapy, molecular targeted therapy, as well as immunotherapy. In the pursuit of the ultimate goal of prolonging survival, from the perspective of management throughout the patient journey, we should further optimize and arrange the strategies, methods, techniques and timing in perioperative treatment. There are still many unsolved problems to promote gastric cancer surgery from simple technical resection to biological resection. Treatment procedure based on evidence-based medicine and efficacy evaluation criteria may result in correct decision. In addition molecular markers based on gene sequencing may help select oppropriate agents and predict efficacy and prognosis. In clinical practice, how to achieve individualized treatment based on precise staging and goal orientation is the aim of continuous efforts to prolong the survival of advanced gastric cancer patients.

18.
Cancer Manag Res ; 10: 3945-3954, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30310315

RESUMO

Objective: The aim of this study was to compare the molecular profiling, including somatic mutation and somatic copy number variation (SCNV), between human epidermal growth factor receptor 2 (HER2)-positive (HER2+) and HER2-negative (HER2-) gastric cancer patients. Patients and methods: Tumor samples were collected from 15 gastric cancer patients, including 10 HER2+ samples and five HER2- samples, which were diagnosed by immunohistochemistry. Whole-genome sequencing was performed by Illumina HiSeq PE150 instrument, along with somatic single nucleotide variant (SNV), somatic structural variation (SV) and SCNV analyses. Results: The average number of somatic SNVs and mutation spectrum were similar between HER2+ and HER2- samples. Transition of C>T was the main type of mutation. For somatic SV, number of intrachromosomal translocation (2,850.3±1,260.4 vs 1,157±586.6, P=0.015) and insertion of large fragment (1,125.6±457.4 vs 500±138.9, P=0.002) in HER2+ samples were higher than those in HER2- samples. For all samples, lysine methyltransferase 2C (KMT2C), ZNF91, TAF1 and MAP4 genes were identified as new significant mutated driver genes. KMT2C gene mutations were mainly detected in HER2+ samples (7/10), which were correlated with the lysine degradation pathway. SERF2 gene mutations were more common in HER2- samples (3/5) than in HER2+ samples (1/10). Copy number gain was the major type of SCNV in both groups, and the average number of SCNVs was similar. In the HER2+ samples, by using the GISTIC algorithm, amplification of known driver genes cyclin-dependent kinase 12 (CDK12, 6/10) and RARA (5/10) was mainly observed, and other amplifications including JUP, GJD3, KRT39, CDC6, RAPGEFL1, WIPF2, FAM65C, KLF5, DACH1 and PIBF1 genes were also observed. Amplifications of solute carrier family 12 member 7 (SLC12A7, 5/5), TTC40 (4/5) and GALNT9 (4/5) genes were mainly detected in HER2- samples. Conclusion: Differences in genomic landscape between HER2+ and HER2- gastric cancer samples were revealed in this study. KMT2C mutation and CDK12 amplification were mainly detected in HER2+ gastric cancer, whereas SERF2 mutation and SLC12A7 amplification were detected in HER2- gastric cancer.

19.
Hum Vaccin Immunother ; : 1-5, 2018 Oct 09.
Artigo em Inglês | MEDLINE | ID: mdl-30299219

RESUMO

Severe adverse events (AEs) following post-exposure rabies vaccination had been occasionally described in previous studies. Once AEs occurred, immediate medical treatment and appropriate change of vaccine and vaccination schedule were of significance. It was also important and challengeable to determine the relationship among adverse reactions, vaccines residues and laboratory tests for patients, to choose a proper vaccine in resumed vaccination, to avoid the reoccurrence of AEs and to ensure adequate immune response. Here, we present steps about how to cope with AEs by giving an example with a two-year-old girl who was identified as category II exposure to rabies, suffered from anaphylaxis after first dose administration with human diploid rabies vaccine (HDCV) so vaccination was temporarily suspended. Dexamethasone was prescribed to her in anti-allergy therapy. Allergy tests indicated that the patient was not sensitive to allergens and heterologous proteins. Vaccine test report showed that residual kanamycin existed in that batch of vaccines. This reminded us to provide her antibiotic skin sensitivity test which found she was allergic to kanamycin. Thus, we could conclude it was the cause of AEs. Then, 0.5 mL lyophilized Purified Vero Cell Rabies Vaccine (PVRV) without any residues was enrolled in the resumed vaccination. To ensure successful immunization, immunogenicity test was also provided which showed adequate immune response (RVNA ≥ 0.5 IU/mL) starting from day14. Besides, no further AEs occurred afterward. This study emphasized the importance of in-depth survey, analysis and implied the necessity to scientifically and properly choose the optimal vaccine for patients and appropriately provide treatments if AEs occurred.

20.
Cancer Biomark ; 2018 Sep 10.
Artigo em Inglês | MEDLINE | ID: mdl-30248047

RESUMO

BACKGROUND: Few biomarkers are available for the prediction of prognosis and recurrence in lymph node (LN)-negative gastric cancer (GC) currently. miR-126 functions as a tumor suppressor in GC, however, its clinical significance in LN-negative GC remains unknown. AIM: To investigate the associations of tissue miR-126 level with the clinicopathological characteristics and clinical outcome of LN-negative GC patients. METHODS: Quantitative real-time polymerase chain reaction was performed to examine the tissue miR-126 level in 315 LN-negative GC patients who underwent curative gastrectomy with D2 lymphadenectomy. The associations of tissue miR-126 level with clinicopathological characteristics and clinical outcome were evaluated. RESULTS: Compared with matched adjacent non-tumor tissues, miR-126 expression was significantly down-regulated in tumor tissues. A reduced tissue miR-126 level statistically correlated with aggressive clinicopathological characteristics, including larger tumor size, deeper local invasion, and poorer prognosis. Notably, multivariate analysis identified advanced T stage and low miR-126 level as independent predictors of the unfavorable prognosis and recurrence of LN-negative GC. CONCLUSIONS: These results indicate for the first time that advanced T stage and low miR-126 level are predictors of unfavorable prognosis and recurrence in LN-negative GC patients. These parameters should be taken into account to stratify patients for adjuvant therapy and close follow-up.

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