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1.
J Zhejiang Univ Sci B ; 20(8): 670-678, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31273964

RESUMO

OBJECTIVE: To determine the clinical, imaging, and histological features, and surgical resection modalities and outcomes of adult sacrococcygeal teratoma (SCT). METHODS: Adult patients with histopathologically diagnosed SCT were enrolled in our hospital between August 2010 and August 2018. Each patient's characteristics and clinical information were reviewed. RESULTS: There were 8 patients in the study (2 males, 6 females) with a median age of 34 years (range, 18-67 years). The time to clinical symptoms was 14 d to 35 years, with a median time of 4 years. Six patients presented with symptoms of sacrococcygeal pain, and four with signs of sacrococcygeal mass and ulceration in the sacrococcygeal region. Six patients were evaluated using a combination of computed tomography (CT) and magnetic resonance imaging (MRI). All patients showed a presacral tumor with heterogeneous intensity on CT images. All patients underwent surgical treatment, including 6 parasacral, 1 transabdominal, and 1 combined anterior-posterior surgery cases. Seven patients were histopathologically diagnosed with benign mature SCT, and have shown no recurrence. One patient had malignant SCT, with recurrence at 84 months after surgery. After a second surgery, the patient had no recurrence within 6 months follow-up after re-resection. CONCLUSIONS: Our retrospective study demonstrated: (1) adult SCT is difficult to diagnose because of a lack of typical clinical symptoms and signs; (2) a combination of CT and MRI examination is beneficial for preoperative diagnosis; (3) the choice of surgical approach and surgical resection modality depends on the size, location, and components of the tumor, which can be defined from preoperative CT and MRI evaluation; (4) most adult SCTs are benign; the surgical outcome for the malignant SCT patient was good after complete resection. Even for the patient with recurrent malignant SCT, the surgical outcome was good after re-resection.

2.
J Immunother Cancer ; 7(1): 193, 2019 Jul 23.
Artigo em Inglês | MEDLINE | ID: mdl-31337439

RESUMO

BACKGROUND: Checkpoint-blockade immunotherapy targeting programmed cell death protein 1 (PD-1) has recently shown promising efficacy in hepatocellular carcinoma (HCC). However, the factors affecting and predicting the response to anti-PD-1 immunotherapy in HCC are still unclear. Herein, we report the dynamic variation characteristics and specificities of the gut microbiome during anti-PD-1 immunotherapy in HCC using metagenomic sequencing. RESULTS: Fecal samples from patients responding to immunotherapy showed higher taxa richness and more gene counts than those of non-responders. For dynamic analysis during anti-PD-1 immunotherapy, the dissimilarity of beta diversity became prominent across patients as early as Week 6. In non-responders, Proteobacteria increased from Week 3, and became predominant at Week 12. Twenty responder-enriched species, including Akkermansia muciniphila and Ruminococcaceae spp., were further identified. The related functional genes and metabolic pathway analysis, such as carbohydrate metabolism and methanogenesis, verified the potential bioactivities of responder-enriched species. CONCLUSIONS: Gut microbiome may have a critical impact on the responses of HCC patients treated with anti-PD-1 immunotherapy. The dynamic variation characteristics of the gut microbiome may provide early predictions of the outcomes of immunotherapy in HCC, which is critical for disease-monitoring and treatment decision-making.

3.
Oncologist ; 24(8): e730-e739, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31127021

RESUMO

BACKGROUND: The long-term prognosis after liver resection for multinodular (≥3 nodules) hepatocellular carcinoma (HCC) is generally considered to be unfavorable. However, the role of liver resection for binodular HCC is less investigated. SUBJECTS, MATERIALS, AND METHODS: From a multicenter database, consecutive patients who underwent curative-intent liver resection for binodular HCC and without macrovascular invasion between 2003 and 2015 were retrospectively reviewed. Patients' clinical variables as well as perioperative and long-term survival outcomes were analyzed. Univariable and multivariable analyses were performed to identify the risk factors associated with overall survival (OS) and recurrence-free survival (RFS) after curative resection. RESULTS: Of 263 enrolled patients, the perioperative 30-day mortality and morbidity rates were 1.5% and 28.5%. The 1-, 3-, and 5-year OS and RFS rates were 81.5%, 52.4%, and 39.1% and 57.1%, 35.8%, and 26.6%, respectively. Multivariable Cox-regression analyses identified preoperative alpha-fetoprotein level >400 µg/L, tumor size with a sum of two nodules >8 cm, tumor size ratio of large/small nodule >1.5 (asymmetrical proportion), unilateral hemiliver distribution of two nodules, distance of ≤3 cm between two nodules, and microvascular invasion in any nodule as independent risk factors associated with decreased OS and RFS. CONCLUSION: Liver resection was safe and feasible in patients with binodular HCC, with acceptable perioperative and long-term outcomes. Sum of two tumor sizes, size ratio and distribution, and distance between two nodules were independent risk factors associated with long-term survival outcomes after surgery. These results may guide clinicians to make individualized surgical decisions and estimate long-term prognosis for these patients. IMPLICATIONS FOR PRACTICE: Liver resection was safe and feasible in patients with binodular hepatocellular carcinoma, with acceptable perioperative and long-term outcomes. The sum of two tumor sizes, the size ratio and distribution of the two nodules, and the distance between two nodules were independent risk factors associated with long-term overall survival and recurrence-free survival after liver resection. The results of this study may guide clinicians to make individualized surgical decisions, estimate long-term prognosis, and plan recurrence surveillance and adjuvant therapy for these patients.

4.
Oncologist ; 24(4): 449-454, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30679319

RESUMO

With the advent of next-generation sequencing (NGS) and precision medicine, investigators have determined that tumors from different tissue sources that have the same types of genetic mutations will have a positive response to the same targeted therapy. This finding has prompted us to seek potential therapeutic targets for patients with carcinoma of unknown primary (CUP) using NGS technology. Here, we reported a case of a woman with CUP resistance to chemotherapy. We detected 450 cancer-related gene alterations using three metastatic tumor specimens and found the presence of EML4 exon13 and ALK exon20 fusion. The tumor did respond to crizotinib, a first-generation ALK inhibitor. When her tumor progressed, circulating tumor DNA detection revealed ALK L1196 M and G1269A mutation resistance to crizotinib, but she had a response to brigatinib. This case revealed that NGS technology used to detect the genetic alterations in patients with CUP might be a reliable method to find potential therapeutic targets, although the primary lesion could not always be confirmed. KEY POINTS: This case exemplifies responsiveness to ALK inhibitor in carcinoma of unknown primary (CUP) with EML4-ALK fusion.Next-generation sequencing is an important diagnostic tool to find potential therapeutic targets in CUP.Liquid biopsy may be useful to provide critical information about resistance mechanisms in CUP to guide sequential treatment decision with targeted therapy.

5.
Transl Oncol ; 12(3): 426-431, 2018 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-30562681

RESUMO

Epidermal growth factor receptor (EGFR) blockade resistance is common in the treatment of RAS wide type colorectal cancer (CRC). During the treatment of cetuximab, acquired resistant genomic alterations always occurs earlier than disease progression observed by medical images. Identification of genomic alterations dynamically might have certain clinical significance. Because of the limitation of repeated tissue biopsy, liquid biopsy is increasingly recognized. Droplet digital polymerase chain reaction (ddPCR) is the main detection methods for circulating tumor DNA (ctDNA), however, the application of next-generation sequencing (NGS) for ctDNA detection becomes more and more popular. Here we develop a NGS-based ctDNA assay and evaluated its sensitivity and specificity while using ddPCR as control. These two technologies were both used for genomic alteration detection for the peripheral blood samples from cetuximab-treated colorectal cancer patients dynamically. Fifteen patients were enrolled in this study, including eight males and seven females. The sensitivity and specificity of our NGS assay were 87.5% and 100% respectively, and liner regression analysis comparing variant allele frequency (VAF) revealed high concordance between NGS and ddPCR (R2=0.98). NGS actually found more mutation information than ddPCR such as the additional dynamic changes of TP53 which were observed in the disease progression patients. Moreover, the variant allele fraction of TP53 was also found by NGS to be changed along with the clinical efficacy evaluation dynamically during the whole treatment process. In conclusion, our newly developed NGS-based ctDNA assay shows similar performance with ddPCR but have more advantages of its high throughput of multigenetic detection for the dynamic monitoring during the treatment of cetuximab in metastasis CRC patients.

6.
Chem Res Toxicol ; 31(10): 1069-1079, 2018 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-30230321

RESUMO

Hand-foot syndrome (HFS), the most common side effect of capecitabine, is a dose-limiting cutaneous toxicity with only rare therapeutic options. The causative mechanisms of HFS are still unclear. Many studies suggested that capecitabine or its metabolites caused the toxicity. This study is attempting to determine if there are any new metabolites that may be present and be linked to toxicity. For this purpose, 25 patients who ingested capecitabine orally were enrolled and divided into HFS positive and negative groups. Urine and plasma samples were collected before administration and five cycles after administration. Eleven phase I and phase II metabolites of capecitabine were detected and identified by ultraperformance liquid chromatography coupled with quadrupole time-of-flight tandem mass spectrometry with a metabolomic approach and MetaboLynxXS. Nine novel metabolites of capecitabine were identified herein, which were not observed in the HFS negative group. Their structures were confirmed by chemical synthesis and nuclear magnetic resonance spectroscopy. The cytotoxities of capecitabine and its metabolites on HaCaT cells were measured. Among them, M9/10 exhibited significant inhibitory activity, and they were produced via acetylation mainly by N-acetyltransferase 2. Our study comprehensively described the metabolism of capecitabine in patients with HFS and detected the novel pathways of capecitabine, which was a positive significance for the mechanism of HFS.

7.
Br J Cancer ; 119(3): 291-295, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-29955136

RESUMO

BACKGROUND: The majority of advanced biliary tract cancer (ABTC) patients will progress after gemcitabine and cisplatin (GP) doublet therapy, while the standard second-line regimen has not been established. We conducted this study to assess the efficacy and safety of second-line irinotecan and capecitabine (XELIRI) regimen vs. irinotecan monotherapy in ABTC patients progressed on GP. METHODS: Sixty-four GP refractory ABTC patients were randomised to either irinotecan 180 mg/m2 on day 1 plus capecitabine 1000 mg/m2 twice daily on days 1-10 of a 14-day cycle (XELIRI-arm) or single-agent irinotecan 180 mg/m2 on day 1 of a 14-day cycle (IRI-arm). Treatments were repeated until disease progression or unacceptable toxicity occurred. RESULTS: A total of 60 patients were included in the analysis. For XELIRI and IRI-arms, respectively, the median PFS was 3.7 vs. 2.4 months, 9-month survival rate 60.9% vs. 32.0%, median OS 10.1 vs. 7.3 months, and disease control rate 63.3% vs. 50.0%. The most common grade 3 or 4 toxicities were leucopaenia and neutropaenia. CONCLUSIONS: This randomised, phase II study of irinotecan-containing regimens in good PS second-line ABTC patients showed a clear benefit of XELIRI regimen over irinotecan monotherapy in prolonging PFS, with acceptable toxicity.

8.
Front Genet ; 9: 34, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29479369

RESUMO

Circular RNAs (circRNAs) have been reported that can be used as biomarkers for colorectal cancers (CRC) and other types of tumors. However, a limited number of studies have been performed investigating the potential role of circRNAs in tumor metastasis. Here, we examined the circRNAs in two CRC cell lines (a primary tumor cell SW480 and its metastasis cell SW620), and found a large set of circRNA (2,919 ncDECs) with significantly differential expression patterns relative to normal cells (NCM460). In addition, we uncovered a set of 623 pmDECs that differ between the primary CRC cells and its metastasis cells. Both differentially expressed circRNA (DEC) sets contain many previously unknown putative CRC-related circRNAs, thereby providing many new circRNAs as candidate biomarkers for CRC development and metastasis. These studies are the first large-scale identification of metastasis-related circRNAs for CRC and provide valuable candidate biomarkers for diagnostic and a starting point for additional investigations of CRC metastasis.

9.
Transl Oncol ; 11(2): 221-232, 2018 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-29367070

RESUMO

Exosomes are extracellular membrane vesicles of 50- to 130-nm diameter secreted by most tumor cells. Exosomes can mediate the intercellular transfer of proteins and RNAs, including microRNAs (miRNAs), and promote both tumorigenesis and premetastatic niche formation. In this study, we performed exosomal RNA sequencing to identify candidate exosomal miRNAs that could be associated with colorectal cancer (CRC) and its distant metastasis. The expression profiles of exosomal miRNA, as secreted by isogenic human primary CRC cell line SW480 and highly metastatic cell line SW620, were analyzed and the potential targets related to tumorigenesis and metastatic progression were investigated. We found that 25 miRNAs had been up-regulated and 5 miRNAs had been down-regulated in exosomes purified from SW620 culture supernatant. Candidate miRNAs were further evaluated for CRC diagnosis using quantitative real-time polymerase chain reaction in CRC patients. Higher expression levels of circulating exosomal miR-17-5p and miR-92a-3p were significantly associated with pathologic stages and grades of the CRC patients. CONCLUSIONS: Circulating exosomal miR-17-5p and miR-92a-3p may provide a promising noninvasive prognostic biomarker for primary and metastatic CRC.

10.
Int J Cancer ; 142(2): 357-368, 2018 01 15.
Artigo em Inglês | MEDLINE | ID: mdl-28921531

RESUMO

Synchronous multifocal tumors are common in the hepatobiliary and pancreatic system but because of similarities in their histological features, oncologists have difficulty in identifying their precise tissue clonal origin through routine histopathological methods. To address this problem and assist in more precise diagnosis, we developed a computational approach for tissue origin diagnosis based on naive Bayes algorithm (TOD-Bayes) using ubiquitous RNA-Seq data. Massive tissue-specific RNA-Seq data sets were first obtained from The Cancer Genome Atlas (TCGA) and ∼1,000 feature genes were used to train and validate the TOD-Bayes algorithm. The accuracy of the model was >95% based on tenfold cross validation by the data from TCGA. A total of 18 clinical cancer samples (including six negative controls) with definitive tissue origin were subsequently used for external validation and 17 of the 18 samples were classified correctly in our study (94.4%). Furthermore, we included as cases studies seven tumor samples, taken from two individuals who suffered from synchronous multifocal tumors across tissues, where the efforts to make a definitive primary cancer diagnosis by traditional diagnostic methods had failed. Using our TOD-Bayes analysis, the two clinical test cases were successfully diagnosed as pancreatic cancer (PC) and cholangiocarcinoma (CC), respectively, in agreement with their clinical outcomes. Based on our findings, we believe that the TOD-Bayes algorithm is a powerful novel methodology to accurately identify the tissue origin of synchronous multifocal tumors of unknown primary cancers using RNA-Seq data and an important step toward more precision-based medicine in cancer diagnosis and treatment.


Assuntos
Algoritmos , Teorema de Bayes , Neoplasias do Sistema Biliar/diagnóstico , Biomarcadores Tumorais/genética , Linhagem da Célula/genética , Neoplasias Hepáticas/diagnóstico , Neoplasias Primárias Múltiplas/diagnóstico , Neoplasias Pancreáticas/diagnóstico , Neoplasias do Sistema Biliar/genética , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Neoplasias Hepáticas/genética , Neoplasias Primárias Múltiplas/genética , Neoplasias Pancreáticas/genética , Prognóstico
11.
World J Surg Oncol ; 15(1): 108, 2017 May 30.
Artigo em Inglês | MEDLINE | ID: mdl-28558772

RESUMO

BACKGROUND: Neutrophil-to-lymphocyte ratio (NLR) is one of the systemic inflammation markers, which has prognostic values in many types of tumor. However, hardly any research has reported the relationship between NLR and pancreatic neuroendocrine tumors (PanNETs). In this study, we aimed to evaluate the predictive value of the preoperative peripheral blood NLR on the clinical outcomes in patients of resectable PanNETs. METHODS: Ninety-five cases of PanNETs registered in the First Affiliated Hospital of Zhejiang University between March 2009 and May 2016 and underwent pancreatic surgery were included in this study. Univariate and multivariate analyses were applied to identify the prognostic factors for PanNETs. Prognostic nomogram and its calibration curve then used R (version 3.3.2) to predict lymph node (LN) metastasis. RESULTS: Among these 95 patients, 52 (54.7%) patients were diagnosed as grade 1 (G1) NET (mitotic count <2/10 HPF, Ki-67 ≤2%), 32 (33.7%) as G2 NET (mitotic count 2-20/10 HPF, Ki-67 3-20%), and 11 (11.6%) as G3 NEC (mitotic count >20/10 HPF, Ki-67 >20%). Increased NLR was found to relate with advanced T stage, LN metastasis, tumor thrombus formation, and advanced grade (p < 0.05 for all). Multivariate logistic regression was performed and indicated that NLR (HR 6.74; p = 0.02) was an independent prognostic factor for LN metastasis. Furthermore, we developed a nomogram based on the combination of NLR, T stage, and grade for LN metastasis with a good discrimination ability with the AUC (area under the curve) of 0.885. This nomogram showed larger AUC than those using NLR (0.725), T stage (0.808), or grade (0.708) alone as a prognostic factor, which means this system achieved a more optional performance in predicting clinical outcomes. Finally, the Kaplan-Meier curve indicated that the recurrence-free survival (RFS) of patients with high NLR (NLR >1.40, RFS 61.1 ± 4.4 months) decreased significantly as compared with those of low NLR (NLR ≤1.40, RFS 63.8 ± 2.9 month, p < 0.05). CONCLUSIONS: The preoperative NLR is a potential independent predictor for LN metastasis and RFS. Our nomogram highlighted the important role of NLR in prognosis, which might be considered as a convenient indicator for lymph node metastasis, especially during the initial diagnosis for resectable PanNETs.


Assuntos
Linfócitos/patologia , Tumores Neuroendócrinos/patologia , Neutrófilos/patologia , Neoplasias Pancreáticas/patologia , Feminino , Seguimentos , Humanos , Metástase Linfática , Masculino , Pessoa de Meia-Idade , Gradação de Tumores , Invasividade Neoplásica , Estadiamento de Neoplasias , Tumores Neuroendócrinos/cirurgia , Nomogramas , Neoplasias Pancreáticas/cirurgia , Valor Preditivo dos Testes , Cuidados Pré-Operatórios , Prognóstico , Curva ROC , Estudos Retrospectivos , Taxa de Sobrevida
12.
BMC Cancer ; 17(1): 191, 2017 03 14.
Artigo em Inglês | MEDLINE | ID: mdl-28292264

RESUMO

BACKGROUND: Targeted therapies are emerging treatment options for gastric cancer (GC). Patient-derived tumor xenograft(PDX) models of GC closely retain the features of the original clinical cancer, offering a powerful tool for preclinical drug efficacy testing. This study aimed to establish PDX GC models, and explore therapeutics targeting Her2, MET(cMet), and FGFR2, which may assist doctor to select the proper target therapy for selected patients. METHODS: GC tissues from 32 patients were collected and implanted into immuno-deficient mice. Using immunohistochemistry(IHC) and fluorescent in-situ hybridization (FISH), protein levels and/or gene amplification of Her2, cMet and FGFR2 in those tissues were assessed. Finally, anti-tumor efficacy was tested in the PDX models using targeted inhibitors. RESULTS: A total of 9 passable PDX models were successfully established from 32 gastric cancer xenograft donors, consisting of HER2,cMet and FGFR2 alterations with percentages of 4(12.5%), 8(25.0%) and 1(3.1%) respectively. Crizotinib and AZD4547 exerted marked antitumor effects exclusively in PDX models with cMet (G30,G31) and FGFR2(G03) amplification. Interestingly, synergistic antitumor activity was observed in G03 (FGFR2-amplifed and cMet non-amplified but IHC [2+]) with simultaneous treatment with Crizotinib and ADZ4547 at day 30 post-treatment. Further in vitro biochemistry study showed a synergistic inhibition of the MAPK/ERK pathway. HER2,cMet and FGFR2 alterations were found in 17 (10.4%), 32(19.6%) and 6(3.7%) in a group of 163 GC patients, and cMet gene amplification or protein overexpression(IHC 3+) was associated with poor prognosis. CONCLUSIONS: These PDX GC models provide an ideal platform for drug screening and evaluation. GC patients with positive cMet or FGFR2 gene amplification may potentially benefit from cMet or FGFR2 targeted therapies or combined targeted therapy.


Assuntos
Proteínas Proto-Oncogênicas c-met/metabolismo , Receptor ErbB-2/metabolismo , Receptor Tipo 2 de Fator de Crescimento de Fibroblastos/metabolismo , Neoplasias Gástricas/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto/métodos , Animais , Antineoplásicos/farmacologia , Benzamidas/farmacologia , Linhagem Celular Tumoral , Crizotinibe , Sinergismo Farmacológico , Feminino , Humanos , Estimativa de Kaplan-Meier , Camundongos Endogâmicos BALB C , Camundongos Nus , Pessoa de Meia-Idade , Terapia de Alvo Molecular/métodos , Piperazinas/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Proteínas Proto-Oncogênicas c-met/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-met/genética , Pirazóis/farmacologia , Piridinas/farmacologia , Receptor ErbB-2/antagonistas & inibidores , Receptor ErbB-2/genética , Receptor Tipo 2 de Fator de Crescimento de Fibroblastos/antagonistas & inibidores , Receptor Tipo 2 de Fator de Crescimento de Fibroblastos/genética , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genética , Neoplasias Gástricas/tratamento farmacológico , Neoplasias Gástricas/genética , Resultado do Tratamento , Células Tumorais Cultivadas
13.
Oncotarget ; 8(7): 11877-11886, 2017 Feb 14.
Artigo em Inglês | MEDLINE | ID: mdl-28060753

RESUMO

The entire process of Clostridium difficile colonization to infection develops in large intestine. However, the real colonization pattern of C. difficile in preoperative colorectal cancer patients has not been studied. In this study, 33 C. difficile strains (16.1%) were isolated from stool samples of 205 preoperative colorectal cancer patients. C. difficile colonization rates in lymph node metastasis patients (22.3%) were significantly higher than lymph node negative patients (10.8%) (OR=2.314, 95%CI=1.023-5.235, P =0.025). Meanwhile, patients positive for stool occult blood had lower C. difficile colonization rates than negative patients (11.5% vs. 24.0%, OR=0.300, 95%CI=0.131-0.685, P =0.019). A total of 16 sequence types were revealed by multilocus sequence typing. Minimum spanning tree and time-space cluster analysis indicated that all C. difficile isolates were epidemiologically unrelated. Antibiotic susceptibility testing showed all isolates were susceptible to vancomycin and metronidazole. The results suggested that the prevalence of C. difficile colonization is high in preoperative colorectal cancer patients, and the colonization is not acquired in the hospital. Since lymph node metastasis colorectal cancer patients inevitably require adjuvant chemotherapy and C. difficile infection may halt the ongoing treatment, the call for sustained monitoring of C. difficile in those patients is apparently urgent.


Assuntos
Clostridium difficile/isolamento & purificação , Neoplasias Colorretais/microbiologia , Enterocolite Pseudomembranosa/microbiologia , Neoplasias Colorretais/epidemiologia , Neoplasias Colorretais/patologia , Enterocolite Pseudomembranosa/epidemiologia , Enterocolite Pseudomembranosa/patologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Período Pré-Operatório
14.
RNA Biol ; 14(8): 1055-1063, 2017 08 03.
Artigo em Inglês | MEDLINE | ID: mdl-27739910

RESUMO

Circular RNAs (circRNAs) have been identified in diverse eukaryotic species and are characterized by RNA backsplicing events. Current available methods for circRNA identification are able to determine the start and end locations of circRNAs in the genome but not their full-length sequences. In this study, we developed a method to assemble the full-length sequences of circRNAs using the backsplicing RNA-Seq reads and their corresponding paired-end reads. By applying the method to an rRNA-depleted/RNase R-treated RNA-Seq dataset, we for the first time identified full-length sequences of nearly 3,000 circRNAs in rice. We further showed that alternative circularization of circRNA is a common feature in rice and, surprisingly, found that the junction sites of a large number of rice circRNAs are flanked by diverse non-GT/AG splicing signals while most human exonic circRNAs are flanked by canonical GT/AG splicing signals. Our study provides a method for genome-wide identification of full-length circRNAs and expands our understanding of splicing signals of circRNAs.


Assuntos
Processamento Alternativo , Genoma de Planta , Oryza/genética , Sítios de Splice de RNA , RNA de Plantas/genética , RNA/genética , Sequência de Bases , Conjuntos de Dados como Assunto , Exorribonucleases/química , Humanos , Oryza/metabolismo , RNA/química , RNA/metabolismo , Estabilidade de RNA , RNA de Plantas/química , RNA de Plantas/metabolismo , RNA Ribossômico/química , Análise de Sequência de RNA
15.
Oncotarget ; 8(3): 5016-5025, 2017 Jan 17.
Artigo em Inglês | MEDLINE | ID: mdl-28008139

RESUMO

Synchronous multifocal tumors often pose a diagnostic challenge for oncologists. The purpose of this study was to determine the clonal origin and metastatic relationship of synchronous multifocal tumors in the hepatobiliary and pancreatic system using multi-omic platforms. DNA samples were extracted from three masses harvested from a 50-year-old Han Chinese male patient who suffered from synchronous multifocal tumors in the pancreatic tail, upper biliary duct, and omentum at the time of diagnosis. The clonal origin of these samples was tested using two platforms: next-generation sequencing (NGS) of 390 key genes harboring cancer-relevant actionable mutations and whole-genome copy number variation (CNV) chip analysis. The NGS approach revealed high mutational concordance, and the gene CNV profiles were similar between lesions. Whole-genome CNVs for the three samples were further investigated using an Affymetrix chip. Using matched CNV chip data from The Cancer Genome Atlas (TCGA), we developed a computational model that generated tissue-specific CNV signatures for hepatocellular carcinoma, pancreatic carcinoma, and cholangiocarcinoma to accurately identify the origin of the tumor samples. After adding the patient's CNV chip data to the model, all three samples were clustered into the pancreatic cancer branch. Both our NGS and CNV chip analyses suggested that clinically diagnosed synchronous pancreatic cancer and cholangiocarcinoma originated from the same cell population in the pancreas in our patient. This study highlights the use of genomic tools to infer the origin of synchronous multifocal tumors, which could help to improve the accuracy of cancer diagnosis.


Assuntos
Neoplasias dos Ductos Biliares/genética , Neoplasias Hepáticas/genética , Neoplasias Primárias Múltiplas/genética , Neoplasias Pancreáticas/genética , Neoplasias dos Ductos Biliares/diagnóstico por imagem , Carcinoma Hepatocelular/diagnóstico por imagem , Carcinoma Hepatocelular/genética , Colangiocarcinoma/diagnóstico por imagem , Colangiocarcinoma/genética , Biologia Computacional/métodos , Variações do Número de Cópias de DNA , Genômica/métodos , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Neoplasias Hepáticas/diagnóstico por imagem , Masculino , Pessoa de Meia-Idade , Mutação , Neoplasias Primárias Múltiplas/diagnóstico por imagem , Neoplasias Pancreáticas/diagnóstico por imagem , Análise de Sequência de DNA
16.
Oncotarget ; 7(16): 21404-15, 2016 Apr 19.
Artigo em Inglês | MEDLINE | ID: mdl-26870893

RESUMO

Golgi phosphoprotein 2 (GP73) is highly expressed in hepatocellular carcinoma (HCC) cells, where it serves as a biomarker and indicator of disease progression. We used MTS assays, anchorage-independent cell colony formation assays and a xenograft tumor model to show that GP73-specific siRNAs inhibit HCC proliferation in HepG2, SMMC-7721, and Huh7 cell lines and in vivo. Following GP73 silencing, levels of p-Rb, a factor related to metastasis, were reduced, but cell cycle progression was unaffected. Our results suggest that GP73 silencing may not directly suppress proliferation, but may instead inhibit cell motility. Results from proliferation assays suggest GP73 reduces expression of epithelial mesenchymal transition (EMT)-related factors and promotes cell motility, while transwell migration and invasion assays indicated a possible role in metastasis. Immunofluorescence co-localization microscopy and immunoblotting showed that GP73 decreases expression of N-cadherin and E-cadherin, two key factors in EMT, which may in turn decrease intracellular adhesive forces and promote cell motility. This study confirmed that GP73 expression leads to increased expression of EMT-related proteins and that GP73 silencing reduces HCC cell migration in vitro. These findings suggest that GP73 silencing through siRNA delivery may provide a novel low-toxicity therapy for the inhibition of tumor proliferation and metastasis.


Assuntos
Carcinoma Hepatocelular/genética , Neoplasias Hepáticas/genética , Proteínas de Membrana/genética , Interferência de RNA , Animais , Caderinas/metabolismo , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patologia , Linhagem Celular , Linhagem Celular Tumoral , Movimento Celular/genética , Proliferação de Células/genética , Regulação Neoplásica da Expressão Gênica , Células Hep G2 , Humanos , Immunoblotting , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patologia , Masculino , Proteínas de Membrana/metabolismo , Camundongos Endogâmicos BALB C , Camundongos Nus , Microscopia Confocal , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Transplante Heterólogo
17.
Biosci Rep ; 35(3)2015 Apr 22.
Artigo em Inglês | MEDLINE | ID: mdl-26182361

RESUMO

Autophagy refers to a lysosomal degradative pathway or a process of self-cannibalization. This pathway maintains nutrients levels for vital cellular functions during periods of starvation and it provides cells with survival advantages under various stress situations. However, the mechanisms responsible for the induction and regulation of autophagy are poorly understood. The c-Jun NH2-terminal kinase (JNK) signal transduction pathway functions to induce defence mechanisms that protect organisms against acute oxidative and xenobiotic insults. This pathway has also been repeatedly linked to the molecular events involved in autophagy regulation. The present review will focus on recent advances in understanding of the relationship between mitogen-activated protein kinase (MAPK)/JNK signalling and autophagic cell death.


Assuntos
Autofagia/fisiologia , Proteínas Quinases JNK Ativadas por Mitógeno/metabolismo , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Animais , Proteína Beclina-1/genética , Proteína Beclina-1/metabolismo , Humanos , Transdução de Sinais
18.
Clin Chim Acta ; 447: 66-70, 2015 Jul 20.
Artigo em Inglês | MEDLINE | ID: mdl-26032866

RESUMO

BACKGROUND: Serum soluble CD40 ligand (sCD40L) concentrations are increased in patients with nasopharyngeal carcinoma (NPC). This study further evaluated the relationship between plasma sCD40L concentrations and long-term survival of NPC. METHODS: Plasma sCD40L concentrations of 312 patients and 312 healthy controls were determined using an ELISA. The associations of plasma sCD40L concentrations with 5-year overall survival, progression-free survival, distant metastasis-free survival, and locoregional relapse-free survival were investigated by univariate and multivariate analyses. RESULTS: Plasma sCD40L concentrations were substantially higher in patients than in healthy subjects and also correlated highly with tumor classification, lymph node classification and tumor node metastasis stage. sCD40L emerged as an independent predictor for 5-year overall survival, progression-free survival, distant metastasis-free survival, and locoregional relapse-free survival using univariate and multivariate Cox regression analysis. CONCLUSIONS: High plasma sCD40L concentration is correlated with stage progression of NPC as well as associated with poor survival of NPC. It is suggested that sCD40L should have the potential to be a prognostic biomarker for NPC.


Assuntos
Ligante de CD40/sangue , Ligante de CD40/química , Neoplasias Nasofaríngeas/sangue , Neoplasias Nasofaríngeas/diagnóstico , Biomarcadores Tumorais/sangue , Biomarcadores Tumorais/química , Carcinoma , Estudos de Casos e Controles , Intervalo Livre de Doença , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Carcinoma Nasofaríngeo , Solubilidade
19.
Asian Pac J Cancer Prev ; 16(9): 3941-4, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-25987065

RESUMO

BACKGROUND: Aberrant expression of HOX gene expression has been observed in cancer. The purpose of this study was to investigate the alteration of HOXA5 and HOXA9 expression and their clinical significance in acute meloid leukemia (AML). MATERIALS AND METHODS: The expression of HOXA5 and HOXA9 genes of bone marrow samples from 75 newly diagnosed AML patients and 22 healthy controls for comparison were examined by Real- time quantitative PCR (RQ-PCR) assay. Statistical analysis was conducted to evaluate HOXA5 and HOXA9 expression as possible biomarkers for AML. RESULTS: The results showed that the complete remission rate (52.6%) of the patients who highly expressed HOXA5 and HOXA9 was significantly lower than that (88.9%) in patients who lowly express the genes (P=0.015). Spearmann correlation coefficients indicated that the expression levels for HOXA5 and HOXA9 genes were highly interrelated (r=0.657, P<0.001). Meanwhile, we detected significant correlations between HOXA9 expression and age in this limited set of patients (P=0.009). CONCLUSIONS: The results suggest a prognostic impact of increased expression of HOXA5 and HOXA9 in AML patients.


Assuntos
Proteínas de Homeodomínio/genética , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/patologia , Adulto , Idoso , Estudos de Casos e Controles , Análise Citogenética , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Prognóstico , RNA Mensageiro/genética , Reação em Cadeia da Polimerase em Tempo Real , Reação em Cadeia da Polimerase Via Transcriptase Reversa
20.
Cancer Prev Res (Phila) ; 8(6): 518-27, 2015 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-25804611

RESUMO

Metformin is a widely prescribed drug for the treatment of type II diabetes. Although epidemiologic data have provided a strong rationale for investigating the potential of this biguanide for use in cancer prevention and control, uncertainty exists whether metformin should be expected to have an impact in nondiabetic patients. Furthermore, little attention has been given to the possibility that other biguanides may have anticancer activity. In this study, the effects of clinically relevant doses of metformin (9.3 mmol/kg diet), buformin (7.6 mmol/kg diet), and phenformin (5.0 mmol/kg diet) were compared with rats fed control diet (AIN93-G) during the post-initiation stage of 1-methyl-1-nitrosourea-induced (50 mg/kg body weight) mammary carcinogenesis (n = 30/group). Plasma, liver, skeletal muscle, visceral fat, mammary gland, and mammary carcinoma concentrations of the biguanides were determined. In comparison with the control group, buformin decreased cancer incidence, multiplicity, and burden, whereas metformin and phenformin had no statistically significant effect on the carcinogenic process relative to the control group. Buformin did not alter fasting plasma glucose or insulin. Within mammary carcinomas, evidence was obtained that buformin treatment perturbed signaling pathways related to energy sensing. However, further investigation is needed to determine the relative contributions of host systemic and cell autonomous mechanisms to the anticancer activity of biguanides such as buformin.


Assuntos
Buformina/farmacologia , Transformação Celular Neoplásica/efeitos dos fármacos , Hipoglicemiantes/farmacologia , Neoplasias Mamárias Experimentais/tratamento farmacológico , Metformina/farmacologia , Fenformin/farmacologia , Animais , Apoptose/efeitos dos fármacos , Western Blotting , Carcinógenos/toxicidade , Proliferação de Células/efeitos dos fármacos , Transformação Celular Neoplásica/patologia , Feminino , Neoplasias Mamárias Experimentais/induzido quimicamente , Neoplasias Mamárias Experimentais/patologia , Ratos , Ratos Sprague-Dawley
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