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1.
Biosci Rep ; 40(3)2020 Mar 27.
Artigo em Inglês | MEDLINE | ID: mdl-32140709

RESUMO

Cholangiocarcinoma (CCA) is a fatal malignant tumor of biliary epithelial cells involving intra- or extra-hepatic bile ducts. The prognosis of CCA is generally poor due to its diagnosis at the late stages. The currently employed chemotherapeutic agents do not increase the survival rate in patients with unresectable CCA. Accordingly, there is a need to identify new therapeutic agents for the effective management of intra- and extra-hepatic CCA. Clinical as well as preclinical studies have suggested the key role of the activation of Wnt/ß-catenin signaling pathway in the induction and progression of CCA. There is an up-regulation of different Wnt ligands including Wnt2, Wnt3, Wnt5, Wnt7 and Wnt10 along with redistribution of ß-catenin (more expression in the nucleus and lesser on the cell surface due to nuclear translocation of ß-catenin) in different types of malignant biliary tumors. Apart from the role of this pathway in the induction and progression of CCA, this pathway is also involved in inducing multidrug resistance by inducing the expression of P-glycoprotein efflux pump on the cancer cells. These deleterious effects of Wnt/ß-catenin signaling are mediated in association with other signaling pathways involving microRNAs (miRNAs), PI3K/AKT/PTEN/GSK-3ß, retinoic acid receptors (RARs), dickkopf-1 (DKK1), protein kinase A regulatory subunit 1 α (PRKAR1A/PKAI), (SLAP), liver kinase B1 (LKB1) and CXCR4. The selective inhibitors of Wnt/ß-catenin signaling may be potentially employed to overcome multidrug-resistant, fatal CCA. The present review discusses the role of Wnt/ß-catenin along with its relation with other signaling pathways in the induction and progression of CCA.

2.
Artigo em Inglês | MEDLINE | ID: mdl-31635929

RESUMO

BACKGROUND: Pneumocystis pneumonia (PCP) is a disease caused by the opportunistic infection of the fungus Pneumocystis jirovecii. Several PCR methods have been developed to aid in the diagnosis of PCP. In this study, we evaluated the performance of a real-time PCR in the diagnosis of PCP, in patients with various underlying diseases. METHODS: Ninety-seven BAL samples and 94 sputum samples from 191 patients were used in the study. Patients were classified as PCP (121 patients) or non-PCP (70 patients) based on their clinical and radiological presentations. RESULTS: Real time PCR amplified the P. jirovecii mitochondrial large-subunit rRNA gene with a detection limit of 68 copies of DNA per reaction. Non-PCP pathogens including 32 different fungi and bacteria were also evaluated. Overall, 71.9% of the samples from PCP patients and 14.5% of those from non-PCP patients were positive for the PCR test with a CT value of the real-time PCR below 45. The main underlying diseases of the patients were hematological or solid malignancies (47.1%) and HIV infection (8.9%). The CT values of the test were significantly lower in BAL samples from PCP patients than those from non-PCP patients (p = 0.024). No non-PCP patient had a CT value below 30, whereas samples from 24.8% of PCP patients with underlying diseases had a CT value below 30. CONCLUSION: Since false positive PCR results were obtained, perhaps due to colonization, we suggest that the diagnosis of PCP should be based on a combination of clinical symptoms, underlying diseases, and PCR results.

3.
Chemotherapy ; 64(1): 42-47, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31163446

RESUMO

OBJECTIVES: We aimed to identify an optimal regimen for low-risk gestational trophoblastic neoplasia (LR-GTN) providing reduction in dosage and toxicity/side effects, enhancement of therapeutic efficacy, and a shorter treatment duration. METHODS: A total of 149 LR-GTN patients were enrolled in the affiliated Beijing Maternity Hospital of Capital Medical University from January 2014 to January 2017 and randomly divided into 3 groups with 50 cases in the methotrexate (MTX) group, 49 in actinomycin D (ACT-D) group, and 50 in ACT-D+MTX group. Follow-up recorded symptoms, physical and bimanual gynecological examinations, routine blood test, serum ß-HCG level, liver and renal functions, electrolytes, electrocardiogram before each treatment course, and pelvic and abdominal B-mode ultrasound or pelvic/abdominal/chest computed tomography. RESULTS: Serum complete remission (SCR) was 96.0, 87.8, and 83.7% for the ACT-D+MTX, ACT-D, and MTX groups, respectively, with SCR being highest in the ACT-D+MTX group, statistically higher than in the MTX group. Vomiting was the only side effect differing significantly by chemotherapy regimen, with a distinctly higher incidence in the ACT-D+MTX group compared with the MTX group (p = 0.028). The reduction rate of serum ß-HCG in the ACT-D+MTX group was significantly greater than in the other 2 groups. CONCLUSION: Combined ACT-D+MTX chemotherapy achieved overall better efficacy and showed less toxicity than ACT-D or MTX alone, and thus can be prioritized for the treatment of LR-GTN.


Assuntos
Antimetabólitos Antineoplásicos/uso terapêutico , Dactinomicina/uso terapêutico , Doença Trofoblástica Gestacional/tratamento farmacológico , Metotrexato/uso terapêutico , Adulto , Antimetabólitos Antineoplásicos/efeitos adversos , Gonadotropina Coriônica/sangue , Dactinomicina/efeitos adversos , Quimioterapia Combinada , Feminino , Doença Trofoblástica Gestacional/patologia , Doenças Hematológicas/etiologia , Humanos , Modelos Logísticos , Metotrexato/efeitos adversos , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Úlceras Orais/etiologia , Gravidez , Prognóstico , Resultado do Tratamento , Adulto Jovem
4.
J Gen Virol ; 100(5): 752-759, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30994443

RESUMO

Influenza A virus mutates rapidly, allowing it to escape natural and vaccine-induced immunity. Neuraminidase (NA) is a surface protein capable of cleaving the glycosidic linkages of neuraminic acids to release newly formed virions from infected cells. Genetic variants within a viral population can influence the emergence of pandemic viruses as well as drug susceptibility and vaccine effectiveness. In the present study, 55 clinical specimens from patients infected with the 2009 pandemic influenza A/H1N1 virus, abbreviated as A(H1N1)pdm09, during the 2015-2016 outbreak season in Taiwan were collected. Whole genomes were obtained through next-generation sequencing. Based on the published sequences from A(H1N1)pdm09 strains worldwide, a mixed population of two distinct variants at NA position 151 was revealed. We initially reasoned that such a mixed population may have emerged during cell culture. However, additional investigations confirmed that these mixed variants were detectable in the specimens of patients. To further investigate the role of the two NA-151 variants in a dynamic population, a reverse genetics system was employed to generate recombinant A(H1N1)pdm09 viruses. It was observed that the mixture of the two distinct variants was characterized by a higher replication rate compared to the recombinant viruses harbouring a single variant. Moreover, an NA inhibition assay revealed that a high frequency of the minor NA-151 variant in A(H1N1)pdm09 was associated with a reduced susceptibility to NA inhibitors. We conclude that two distinct NA-151 variants can be identified in patient specimens and that such variants may increase viral replication and NA activity.


Assuntos
Vírus da Influenza A Subtipo H1N1/genética , Neuraminidase/genética , Proteínas Virais/genética , Animais , Linhagem Celular , Cães , Variação Genética/genética , Células HEK293 , Humanos , Influenza Humana/virologia , Células Madin Darby de Rim Canino , Infecções por Orthomyxoviridae/virologia , Dinâmica Populacional , Replicação Viral/genética
5.
Onco Targets Ther ; 12: 1881-1891, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30881040

RESUMO

Aim: This systematic review was designed to evaluate the efficacy of neoadjuvant chemotherapy with radical surgery vs radical surgery alone for cervical cancer. Methods: A computerized search was done for trials from PubMed, EMBASE, CENTRAL, and Cochrane Database of Systematic Reviews. The trials included neoadjuvant chemotherapy plus radical surgery vs radical surgery alone. We measured overall survival (OS), disease-free survival (DFS), progression-free survival (PFS), local and distant recurrence, lymph node metastasis, and parametrial infiltration per patient. Results: In all, 13 studies involving 2,158 subjects were included. In regard to OS, DFS, PFS, local and distant recurrence, and parametrial infiltration, neoadjuvant chemotherapy plus radical surgery was similar to radical surgery alone. Among them, subgroup analysis of eight studies involving 1,544 patients with locally advanced cervical cancer (FIGO stage IB2-IIB) showed that neoadjuvant chemotherapy (NACT) plus radical surgery significantly improved OS, and decreased local and distant recurrence rates, lymph node metastasis rate, and the level of parametrial infiltration compared to radical surgery alone. Conclusion: The present study demonstrates that preoperative NACT is now an accepted effective procedure in selected patients with locally advanced cervical cancer (FIGO stage IB2-IIB). However, the relationship between NACT and longer DFS and PFS cannot be demonstrated by this meta-analysis. Thus, the decision to use or not to use NACT before radical surgery depends on the surgeon's experience and clinical judgment. Nevertheless, further research in this field is urgently needed to confirm it.

6.
J Microbiol Immunol Infect ; 52(2): 233-241, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30201131

RESUMO

BACKGROUND: Human rhinovirus (HRV) can cause severe illnesses in hospitalized patients. However, there are no studies regarding the prevalence of HRV infection, particularly the recently identified HRV-C, in hospitalized patients reported from Taiwan. METHODS: Respiratory specimens collected from 487 hospitalized patients in designated wards between 2013 and 2014 in a medical center in northern Taiwan were retrospectively detected for HRV. Positive specimens were further determined for genotyping. Medical charts of the HRV-positive patients were reviewed retrospectively. RESULTS: Totally, 76 patients (15.6%) were HRV positive, of which 60 were pediatric patients. HRV-A was identified in 41 (54%) patients, HRV-B in 6 patients (7.9%) and HRV-C in 29 patients (38%). A total of 47 different genotypes were identified. HRV infections were predominant during fall and winter seasons. 21.1% were affected by HRV alone and 78.9% were found to be co-infected with other microorganisms. The detection rate of HRV in children (18.6%) was significantly higher than in adults (9.6%). Compared with pediatric patients, adult patients were significantly associated with underlying disease, Pneumocystis jirovesii pneumonia co-infection, a diagnosis of pneumonia, fatal outcome, hospital acquisition of HRV, antibiotics administration and requiring intensive care, while pediatric patients were significantly associated with viral co-infection. CONCLUSIONS: HRV was a common cause of respiratory tract infection in Taiwan, particularly in pediatric patients. Eighty percent of HRV-infected inpatients had other microorganisms co-infection. Adult patients were more likely to be associated with a severe respiratory disease entity.


Assuntos
Coinfecção/epidemiologia , Epidemiologia Molecular , Infecções por Picornaviridae/epidemiologia , Infecções Respiratórias/epidemiologia , Rhinovirus/classificação , Rhinovirus/patogenicidade , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Antibacterianos/uso terapêutico , Criança , Pré-Escolar , Coinfecção/tratamento farmacológico , Coinfecção/microbiologia , Enterovirus/genética , Enterovirus/patogenicidade , Feminino , Genótipo , Hospitais , Humanos , Lactente , Masculino , Pessoa de Meia-Idade , Tipagem Molecular , Infecções por Picornaviridae/complicações , Pneumonia por Pneumocystis/complicações , Pneumonia por Pneumocystis/tratamento farmacológico , Prevalência , Infecções Respiratórias/tratamento farmacológico , Infecções Respiratórias/microbiologia , Infecções Respiratórias/virologia , Estudos Retrospectivos , Rhinovirus/genética , Taiwan/epidemiologia , Adulto Jovem
7.
J Gynecol Oncol ; 2019 Nov 07.
Artigo em Inglês | MEDLINE | ID: mdl-31912682

RESUMO

OBJECTIVE: This study aimed to identify proteins related to paclitaxel and carboplatin chemoresistance in cervical cancer. METHODS: Quantitative proteomic analysis was performed on normal SiHa cells and those treated with paclitaxel and carboplatin for 14 days, with isobaric tags for relative and absolute quantitation (iTRAQ) analysis. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were used to identify related processes and differentially expressed proteins. RESULTS: A total of 67 and 96 differentially expressed proteins were identified in the paclitaxel- and carboplatin- treated groups, respectively. GO and KEGG enrichment analyses identified 53 (43 upregulated and 10 downregulated) and 85 differentially expressed proteins (70 upregulated and 15 downregulated) in the paclitaxel- and carboplatin-treated groups, respectively. The cell counting kit-8 results revealed that APOA1 was overexpressed in both the paclitaxel- and carboplatin- resistant SiHa cells compared with the control cells. Immunohistochemistry showed that APOA1 was highly expressed in the paclitaxel- and carboplatin- resistant squamous cell carcinoma of the cervix. CONCLUSION: This study is the first to use iTRAQ to identify paclitaxel- and carboplatin- resistance proteins in cervical cells. We identified several proteins previously unassociated with paclitaxel and carboplatin resistance in cervical cancer, thereby expanding our understanding of paclitaxel and carboplatin resistance mechanisms. Moreover, these findings indicate that the APOA1 protein could serve as a potential marker for monitoring and predicting paclitaxel and carboplatin resistance levels.

8.
Medicine (Baltimore) ; 97(22): e10913, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29851821

RESUMO

The purpose of this study is to investigate short-term efficacy as defined by the Response Evaluation Criteria in Solid Tumors (RECIST) and pathological response of neoadjuvant chemotherapy (NACT) comprised of paclitaxel and cisplatin (TP) followed by radical surgery in patients with locally advanced cervical cancer (LACC).This is a prospective study involving 61 women with histologically confirmed LACC referred for NACT following radical surgery at Beijing Obstetrics and Gynecology Hospital between April 2013 and January 2015.The efficacy of NACT was evaluated by the RECIST. The total short-term efficacy of NACT was 91.8% (complete remission and partial remission). The cervical invasion ≤1/2 was 82.4% in the complete remission (CR) group, 46.2% in the partial remission (PR) group, and 20% in the stable disease (SD) group. The difference between groups was statistically significant (P = .012). The slides of all surgical specimens were reviewed and classified according to the Tumor Regression Grade (TRG). The good response was defined by good short-term efficacy (RECIST) and the difference between groups was statistically significant (P = .042). The route of administration of NACT is a factor predicting response to NACT. A significant higher response rate (P = .011) and lower chemotherapy-related adverse events (P < .05) were observed in the artery intervention (AI) group compared to those received NACT via intravenous (IV) route. All patients were followed-up to the last day of 2015 with the median follow-up time of 21.5 months for NACT. For the 61 patients referred for NACT in LACC, 2 patients had relapsed and 1 patient died from the disease.The study showed that the NACT comprised TP for LACC treatment had a significant local effect. It could reduce tumor myometrial invasion and regress tumor. The route of administrating NACT is a predicting factor to the NACT response; 2 cycles of NACT of AI treatment to LACC patients would obtain a desired response with low chemotherapy adverse events.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Cisplatino/administração & dosagem , Histerectomia/métodos , Terapia Neoadjuvante/métodos , Paclitaxel/administração & dosagem , Neoplasias do Colo do Útero/terapia , Adulto , Quimioterapia Adjuvante/métodos , Feminino , Humanos , Quimioterapia de Indução/métodos , Pessoa de Meia-Idade , Estudos Prospectivos , Critérios de Avaliação de Resposta em Tumores Sólidos , Neoplasias do Colo do Útero/patologia
9.
Microb Pathog ; 118: 357-360, 2018 May.
Artigo em Inglês | MEDLINE | ID: mdl-29578061

RESUMO

The current study was designed and performed to investigate the effect of mefloquine on the proliferation and tumor formation potential of liver cancer stem cells. CD133 + HepG2 cells were identified using MACS and showed markedly higher tumor formation potential compared to the parental cells. The secondary tumors formed by CD133 + cells were markedly large in size and more in number compared to the parental cells. Mefloquine treatment of CD133 + HepG2 cells inhibited the proliferation selectively in concentration based manner. The rate of proliferation was inhibited to 82 and 12% in parental and CD133 + sphere forming cells, respectively on treatment with 10 µM concentration of mefloquine. The number of secondary tumors formed by primary tumors was decreased significantly on treatment with 10 µM mefloquine concentration. Treatment of the liver cancer stem cells with mefloquine markedly decreased the potential to undergo self-renewal at 10 µM concentration after 48 h. The results from western blot analysis showed significantly higher expression of cancer stem cell molecules ß-catenin and cyclin D1 in LCSCs. Treatment of the LCSCs with various concentrations of mefloquine reduced the expression levels of ß-catenin and cyclin D1. Administration of the CD133 + cell tumor xenografts in the mice led to the formation of large sized tumors in the control group. However, the tumor growth was inhibited significantly in the mice on treatment with 10 mg/kg doses of mefloquine after day 21. The tumor weight was significantly lower in the animals of mefloquine treatment group compared to the control group. Thus, mefloquine treatment inhibits self-renewal and proliferation potential of cells through targeting ß-catenin pathway.


Assuntos
Carcinoma Hepatocelular/tratamento farmacológico , Neoplasias Hepáticas/tratamento farmacológico , Mefloquina/farmacologia , beta Catenina/efeitos dos fármacos , beta Catenina/metabolismo , Antígeno AC133 , Animais , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Ciclina D1/efeitos dos fármacos , Ciclina D1/metabolismo , Modelos Animais de Doenças , Combinação de Medicamentos , Células Hep G2/efeitos dos fármacos , Humanos , Cloreto de Lítio , Masculino , Mefloquina/administração & dosagem , Camundongos , Camundongos Endogâmicos BALB C , Células-Tronco Neoplásicas/efeitos dos fármacos , Transplante Heterólogo
10.
Future Oncol ; 13(13): 1173-1180, 2017 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-28498036

RESUMO

This study aimed to detect the effect of combination radiotherapy and cantharidin on lung cancer growth. We found that combination therapy with radiotherapy and cantharidin was more effective in inhibiting the tumor growth than radiotherapy or cantharidin alone. It decreased the percentage of CD4+ Tregs and enhanced the percentage of CD8+ T cells, CD4+ Teff cells when comparing to that of single treatment. Combination therapy promoted a great increase in double producing CD8+ T cells and CD4+ Teff cells in tumor infiltrating lymphocytes. Overexpression of CTLA4 reversed the inhibitory action of combination treatment on cancer growth. Our data suggest that combining radiotherapy and cantharidin may have synergistic effects in driving tumor rejection by increasing T-cell infiltration, proliferation and cytokine production.


Assuntos
Carcinoma Pulmonar de Lewis/tratamento farmacológico , Carcinoma Pulmonar de Lewis/radioterapia , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/radioterapia , Animais , Linfócitos T CD4-Positivos/efeitos dos fármacos , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/efeitos da radiação , Linfócitos T CD8-Positivos/efeitos dos fármacos , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/efeitos da radiação , Antígeno CTLA-4/imunologia , Cantaridina/administração & dosagem , Cantaridina/efeitos adversos , Carcinoma Pulmonar de Lewis/imunologia , Carcinoma Pulmonar de Lewis/patologia , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/efeitos da radiação , Terapia Combinada , Modelos Animais de Doenças , Humanos , Neoplasias Pulmonares/imunologia , Neoplasias Pulmonares/patologia , Linfócitos do Interstício Tumoral/efeitos dos fármacos , Linfócitos do Interstício Tumoral/imunologia , Linfócitos do Interstício Tumoral/efeitos da radiação , Camundongos , Linfócitos T Reguladores/efeitos dos fármacos , Linfócitos T Reguladores/imunologia , Linfócitos T Reguladores/efeitos da radiação
12.
Medicine (Baltimore) ; 96(17): e6700, 2017 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-28445274

RESUMO

The purpose of this prospective cohort study is to evaluate the importance of screening and its diagnostic accuracy compared with the pathological diagnosis of cervical intraepithelial neoplasia (CIN) with vaginal intraepithelial neoplasia (VAIN).The prospective study enrolled 419 patients (pts) and was conducted between February 1, 2015 and January 31, 2016 at Beijing Obstetrics and Gynecology Hospital, Capital Medical University.All enrolled pts underwent multipoint biopsy of cervix and vaginal wall directed by colposcopy. All samples of biopsy underwent pathological examination. Among them, 201 pts (48.0%) were diagnosed with CIN, 218 pts (52.0%) were diagnosed with cervicitis, and 51 pts (12.2%) were diagnosed with VAIN. It was found that the incidence of CIN in pts was 4 times higher than that of VAIN. In all 419 patients enrolled, 218 pts had cervicitis with 13 pts (6.0%) of VAIN. There were 201 pts of CIN with 38 pts (18.9%) of VAIN: including 53 pts of CIN3 with 12 pts (22.6%) of VAIN; 49 pts of CIN2 with 9 pts of VAIN (18.4%), and 99 pts of CIN1 with 17 pts of VAIN (17.2%). The incidence of CIN with VAIN (18.9%) was significantly higher than cervicitis with VAIN (6.0%) (χ = 16.39, P = .00). Our results showed that there was a significant consistency between cervical lesions and vaginal lesions (χ = 135.91, P = .00), which indicated that the increase of CIN grades may be related to an increase of the VAIN grades. Our results also showed the significant (p < .05) increase of CIN and VAIN with age (<40 years Kappa = 0.04; 40-50 years Kappa = 0.11; >50 years Kappa = 0.28).This study showed that cytological test can be used as a routine screening method for cervical lesions and vaginal diseases. If the cytology result shows abnormality, and pathological examination confirms that there is no obvious abnormal cervical disease, colposcopy directed vaginal multipoint biopsy should be conducted to exclude vaginal disease. All patients of CIN should routinely undergo vaginal multipoint biopsy (1/3 upper vagina), especially in patients with high-grade CIN and age older than 50 years.


Assuntos
Neoplasia Intraepitelial Cervical/diagnóstico , Neoplasia Intraepitelial Cervical/patologia , Neoplasias do Colo do Útero/diagnóstico , Neoplasias do Colo do Útero/patologia , Neoplasias Vaginais/diagnóstico , Neoplasias Vaginais/patologia , Adulto , Neoplasia Intraepitelial Cervical/complicações , Colposcopia , Detecção Precoce de Câncer , Estudos de Viabilidade , Feminino , Humanos , Biópsia Guiada por Imagem , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Estudos Prospectivos , Neoplasias do Colo do Útero/complicações , Cervicite Uterina/complicações , Neoplasias Vaginais/complicações
13.
Arch Virol ; 162(7): 2003-2012, 2017 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-28424887

RESUMO

Metagenomic approaches to detect viral genomes and variants in clinical samples have various challenges, including low viral titers and bacterial and human genome contamination. To address these limitations, we examined a next-generation sequencing (NGS) and iterative mapping approach for virus detection in clinical samples. We analyzed 40 clinical specimens from hospitalized children diagnosed with acute bronchiolitis, croup, or respiratory tract infections in which virus identification by viral culture or polymerase chain reaction (PCR) was unsuccessful. For our NGS data analysis pipeline, clinical samples were pooled into two NGS groups to reduce sequencing costs, and the depth and coverage of assembled contigs were effectively increased using an iterative mapping approach. PCR was individually performed for each specimen according to the NGS-predicted viral type. We successfully detected previously unidentified respiratory viruses in 26 of 40 specimens using our proposed NGS pipeline. Two dominant populations within the detected viruses were human rhinoviruses (HRVs; n = 14) and human coronavirus NL63 (n = 8), followed by human parainfluenza virus (HPIV), human parechovirus, influenza A virus, respiratory syncytial virus (RSV), and human metapneumovirus. This is the first study reporting the complete genome sequences of HRV-A101, HRV-C3, HPIV-4a, and RSV, as well as an analysis of their genetic variants, in Taiwan. These results demonstrate that this NGS pipeline allows to detect viruses which were not identified by routine diagnostic assays, directly from clinical samples.


Assuntos
Metagenômica/métodos , RNA Viral/genética , Infecções Respiratórias/virologia , Criança , Variação Genética , Genoma Viral , Humanos , RNA Viral/classificação , RNA Viral/isolamento & purificação
14.
Oncotarget ; 8(21): 34820-34835, 2017 May 23.
Artigo em Inglês | MEDLINE | ID: mdl-28422732

RESUMO

Human papillomavirus (HPV) infections predict mortality in Taiwanese patients with oral cavity squamous cell carcinoma (OCSCC). To address their prognostic significance for local recurrence (LR), in this retrospective cohort study we investigated different serologic and molecular markers of HPV 16 infection in 85 consecutive patients with primary OCSCC who received standard treatment and had their sera stored before treatment. Resected tumor specimens were examined with PCR-based assays for HPV 16 E6/E7 mRNA expression. Sera were tested with suspension arrays for the presence of HPV-specific antibodies using synthetic L1 and E6 peptides as well as a synthetic E7 protein. HPV 16 E6/E7 mRNA, anti-L1, anti-E6, and anti-E7 antibodies tested positive in 12%, 25%, 38%, and 41% of the study patients, respectively. Multivariate analysis identified pathological T3/T4, E6/E7 mRNA, and anti-E7 antibodies as independent risk factors for LR, whereas anti-E6 antibodies were an independent protective factor. In patients with ≥ 3 (high-risk group), 2 (intermediate-risk), and ≤ 1 (low-risk) independent risk factors (predictors), the 5-year LR rates were 75%, 42%, and 4%, respectively. Results were validated in an independent cohort. Together, our preliminary data indicate that HPV 16 infections as well as low and high serum levels of anti-E6 and anti-E7 antibodies, respectively, can serve as biomarkers of LR in patients with OCSCC, whereas the clinical usefulness of anti-HPV 16 antibodies for risk stratification of newly diagnosed cases deserves further scrutiny.


Assuntos
Carcinoma de Células Escamosas/virologia , Papillomavirus Humano 16/imunologia , Neoplasias Bucais/virologia , Recidiva Local de Neoplasia/virologia , Infecções por Papillomavirus/sangue , Idoso , Anticorpos Antivirais/metabolismo , Carcinoma de Células Escamosas/sangue , Carcinoma de Células Escamosas/metabolismo , Feminino , Papillomavirus Humano 16/genética , Humanos , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/sangue , Recidiva Local de Neoplasia/metabolismo , Proteínas Oncogênicas Virais/genética , Proteínas Oncogênicas Virais/imunologia , Proteínas E7 de Papillomavirus/genética , Proteínas E7 de Papillomavirus/imunologia , Infecções por Papillomavirus/imunologia , Proteínas Repressoras/genética , Proteínas Repressoras/imunologia , Estudos Retrospectivos , Taiwan
15.
Medicine (Baltimore) ; 95(31): e4416, 2016 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-27495059

RESUMO

Human enterovirus D68 (EV-D68) was first reported in the United States in 1962; thereafter, a few cases were reported from 1970 to 2005, but 2 outbreaks occurred in the Philippines (2008) and the United States (2014). However, little is known regarding the molecular evolution of this globally reemerging virus due to a lack of whole-genome sequences and analyses. Here, all publically available sequences including 147 full and 1248 partial genomes from GenBank were collected and compared at the clade and subclade level; 11 whole genomes isolated in Taiwan (TW) in 2014 were also added to the database. Phylogenetic trees were constructed to identify a new subclade, B3, and represent clade circulations among strains. Nucleotide sequence identities of the VP1 gene were 94% to 95% based on a comparison of subclade B3 to B1 and B2 and 87% to 91% when comparing A, C, and D. The patterns of clade circulation need to be clarified to improve global monitoring of EV-D68, even though this virus showed lower diversity among clades compared with the common enterovirus EV-71. Notably, severe cases isolated from Taiwan and China in 2014 were found in subclade B3. One severe case from Taiwan occurred in a female patient with underlying angioimmunoblastic T-cell lymphoma, from whom a bronchoalveolar lavage specimen was obtained. Although host factors play a key role in disease severity, we cannot exclude the possibility that EV-D68 may trigger clinical symptoms or death. To further investigate the genetic diversity of EV-D68, we reported 34 amino acid (aa) polymorphisms identified by comparing subclade B3 to B1 and B2. Clade D strains had a 1-aa deletion and a 2-aa insertion in the VP1 gene, and 1 of our TW/2014 strains had a shorter deletion in the 5' untranslated region than a previously reported deletion. In summary, a new subclade, genetic indels, and polymorphisms in global strains were discovered elucidating evolutionary and epidemiological trends of EV-D68, and 11 genomes were added to the database. Virus variants may contribute to disease severity and clinical manifestations, and further studies are needed to investigate the associations between genetic diversity and clinical outcomes.


Assuntos
Surtos de Doenças , Enterovirus Humano D/genética , Infecções por Enterovirus/epidemiologia , Infecções Respiratórias/epidemiologia , Adulto , Criança , Pré-Escolar , Infecções por Enterovirus/diagnóstico , Infecções por Enterovirus/genética , Evolução Molecular , Feminino , Variação Genética , Genoma Viral , Estudo de Associação Genômica Ampla , Saúde Global , Humanos , Masculino , Pessoa de Meia-Idade , Dados de Sequência Molecular , Filogenia , Reação em Cadeia da Polimerase/métodos , RNA Viral/análise , RNA Viral/genética , Infecções Respiratórias/genética , Infecções Respiratórias/virologia , Taiwan/epidemiologia
16.
PLoS One ; 11(3): e0151495, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-26986479

RESUMO

Forty-two cytopathic effect (CPE)-positive isolates were collected from 2008 to 2012. All isolates could not be identified for known viral pathogens by routine diagnostic assays. They were pooled into 8 groups of 5-6 isolates to reduce the sequencing cost. Next-generation sequencing (NGS) was conducted for each group of mixed samples, and the proposed data analysis pipeline was used to identify viral pathogens in these mixed samples. Polymerase chain reaction (PCR) or enzyme-linked immunosorbent assay (ELISA) was individually conducted for each of these 42 isolates depending on the predicted viral types in each group. Two isolates remained unknown after these tests. Moreover, iteration mapping was implemented for each of these 2 isolates, and predicted human parechovirus (HPeV) in both. In summary, our NGS pipeline detected the following viruses among the 42 isolates: 29 human rhinoviruses (HRVs), 10 HPeVs, 1 human adenovirus (HAdV), 1 echovirus and 1 rotavirus. We then focused on the 10 identified Taiwanese HPeVs because of their reported clinical significance over HRVs. Their genomes were assembled and their genetic diversity was explored. One novel 6-bp deletion was found in one HPeV-1 virus. In terms of nucleotide heterogeneity, 64 genetic variants were detected from these HPeVs using the mapped NGS reads. Most importantly, a recombination event was found between our HPeV-3 and a known HPeV-4 strain in the database. Similar event was detected in the other HPeV-3 strains in the same clade of the phylogenetic tree. These findings demonstrated that the proposed NGS data analysis pipeline identified unknown viruses from the mixed clinical samples, revealed their genetic identity and variants, and characterized their genetic features in terms of viral evolution.


Assuntos
Variação Genética , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Viroses/virologia , Vírus/genética , Sequência de Aminoácidos , Animais , Linhagem Celular , Linhagem Celular Tumoral , Cães , Ensaio de Imunoadsorção Enzimática/métodos , Genoma Viral/genética , Humanos , Células Madin Darby de Rim Canino , Filogenia , Reação em Cadeia da Polimerase/métodos , Recombinação Genética , Reprodutibilidade dos Testes , Vírus/classificação , Vírus/isolamento & purificação
17.
PLoS One ; 11(2): e0148432, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-26845764

RESUMO

An avian influenza A H7N9 virus emerged in March 2013 and caused a remarkable number of human fatalities. Genome variability in these viruses may provide insights into host adaptability. We scanned over 140 genomes of the H7N9 viruses isolated from humans and identified 104 positions that exhibited seven or more amino acid substitutions. Approximately half of these substitutions were identified in the influenza ribonucleoprotein (RNP) complex. Although PB2 627K of the avian virus promotes replication in humans, 45 of the 147 investigated PB2 sequences retained the E signature at this position, which is an avian characteristic. We discovered 10 PB2 substitutions that covaried with K627E. An RNP activity assay showed that Q591K, D701N, and M535L restored the polymerase activity in human cells when 627K transformed to an avian-like E. Genomic analysis of the human-isolated avian influenza virus is crucial in assessing genome variability, because relationships between position-specific variations can be observed and explored. In this study, we observed alternative positions that can potentially compensate for PB2 627K, a well-known marker for cross-species infection. An RNP assay suggested Q591K, D701N, and M535L as potential markers for an H7N9 virus capable of infecting humans.


Assuntos
Genoma Viral , Genômica , Subtipo H7N9 do Vírus da Influenza A/genética , Influenza Humana/virologia , Substituição de Aminoácidos , Animais , Linhagem Celular , Variação Genética , Genômica/métodos , Humanos , Subtipo H7N9 do Vírus da Influenza A/classificação , Subtipo H7N9 do Vírus da Influenza A/isolamento & purificação , Modelos Moleculares , Mutação , Matrizes de Pontuação de Posição Específica , Conformação Proteica , RNA Replicase/química , RNA Replicase/genética , Proteínas Virais/química , Proteínas Virais/genética
18.
Medicine (Baltimore) ; 94(47): e2069, 2015 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-26632712

RESUMO

Human papillomavirus (HPV) infections are deemed to play a role in the pathogenesis of oral cavity cancer (OCC). However, their exact prevalence and clinical significance remain unclear. Herein, we investigated the prevalence and prognostic value of HPV infections in a large sample of Taiwanese OCC patients.This study was designed as a retrospective cohort study. Between 2004 and 2011, we identified 1002 consecutive patients with newly diagnosed OCC who were scheduled for standard treatment. HPV genotyping was performed in tumor specimens using polymerase chain reaction-based HPV blots. To investigate the temporal trends of HPV infections and their impact on 5-year overall survival (OS), patients were divided into 2 cohorts according to calendar periods: "2004 cohort" (2004-2007; n = 466) and "2008 cohort" (2008-2011; n = 536). Univariate and multivariate Cox regression models were also used to identify the independent predictors of OS in the 2 cohorts. A weighted risk score was assigned to each factor based on the range of their corresponding hazard ratios and validated in both cohorts using the c-statistic.The overall prevalence of HPV infections was 19%, with a trend toward decreasing rates from 2004 to 2011. In patients without risky oral habits, the 5-year OS rate of HPV-positive patients was significantly lower than that of HPV-negative cases (49% vs 80%; P = 0.021). In the 2004 cohort, multivariate analysis identified HPV16, pathological T3/T4, pathological N1/N2, and extracapsular spread as independent adverse prognostic factors for OS. In the 2008 cohort, pathological N1/N2, pathological stage III/IV, and histological tumor depth >8 mm were identified as independent adverse prognostic factors. Using a weighted grading system incorporating HPV16 infection, we devised a prognostic index that identified 4 distinct risk categories with 5-year OS rates ranging from 25% to 89% (c-statistic = 0.76) in the 2004 cohort. The validity of the index was internally confirmed in the 2008 cohort (c-statistic = 0.71).We conclude that HPV infections are common in Taiwanese OCC patients and predict 5-year OS. If independently validated, our composite prognostic score comprising HPV16 infection may be useful for allocating OCC patients to risk-adapted therapies.


Assuntos
Neoplasias Bucais , Papillomaviridae , Infecções por Papillomavirus , Adulto , Estudos de Coortes , Feminino , Técnicas de Genotipagem , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias Bucais/diagnóstico , Neoplasias Bucais/mortalidade , Neoplasias Bucais/virologia , Invasividade Neoplásica , Estadiamento de Neoplasias , Papillomaviridae/genética , Papillomaviridae/isolamento & purificação , Infecções por Papillomavirus/diagnóstico , Infecções por Papillomavirus/epidemiologia , Prevalência , Prognóstico , Modelos de Riscos Proporcionais , Estudos Retrospectivos , Medição de Risco , Fatores de Risco , Taxa de Sobrevida , Taiwan/epidemiologia
19.
Int J Clin Exp Pathol ; 8(2): 1427-34, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-25973027

RESUMO

The expression of CD133 decreases with differentiation of tumor cell, indicating that CD133 is a specific marker for isolation and identification of CSCs. In the present study the effect of Ursolic acid chalcone (UAC) on CD133(+) hepatocellular carcinoma cell (HCC CSCs) differentiation, their self-renewal, tumorigenic capacity and sensitivity to chemotherapeutic drugs was studied. The results demonstrated that UAC inhibits the expression of CD133(+) in a dose and time-dependent manner in PLC/PRF/5 and Huh7 HCC cells. The inhibition was significant at 50 µM and on day 8. The percentage of CD133(+) cells decreased from an initial 59.3% in PLC/PRF/5 to 37.1% and 78.2% in Huh7 to 59.2% on treatment with UAC. There was inhibition of Oct4, Tert, Bmi1, ß-catenin, ABCG2, and tumor sphere-related gene Ep300. In addition it also decreased number of CK19-positive cells and increased number of CK8/18-positive cells. UAC treatment caused a decrease in self-renewal capability and increase in sensitivity to doxorubicin and vincristine drugs in CD133(+) HCC CSCs. Therefore, UAC can be a potent therapeutic agent to target differentiation of CSC in HCC.


Assuntos
Antineoplásicos/farmacologia , Carcinoma Hepatocelular/patologia , Chalcona/farmacologia , Neoplasias Hepáticas/patologia , Células-Tronco Neoplásicas/efeitos dos fármacos , Triterpenos/farmacologia , Antígeno AC133 , Antígenos CD/metabolismo , Diferenciação Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Separação Celular , Ensaio de Imunoadsorção Enzimática , Citometria de Fluxo , Glicoproteínas/metabolismo , Humanos , Peptídeos/metabolismo
20.
PLoS One ; 10(4): e0123248, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-25874631

RESUMO

The members of the genus Picea form a dominant component in many alpine and boreal forests which are the major sink for atmospheric CO2. However, little is known about the growth response and acclimation of CO2 exchange characteristics to high temperature stress in Picea taxa from different altitudes. Gas exchange parameters and growth characteristics were recorded from four year old seedlings of two alpine (Picea likiangensis vars. rubescens and linzhiensis) and two lowland (P. koraiensis and P. meyeri) taxa. Seedlings were grown at moderate (25°C/15°C) and high (35°C/25°C) day/night temperatures, for four months. The approximated biomass increment (ΔD2H) for all taxa decreased under high temperature stress, associated with decreased photosynthesis and increased respiration. However, the two alpine taxa exhibited lower photosynthetic acclimation and higher respiratory acclimation than either lowland taxon. Moreover, higher leaf dry mass per unit area (LMA) and leaf nitrogen content per unit area (Narea), and a smaller change in the nitrogen use efficiency of photosynthesis (PNUE) for lowland taxa indicated that these maintained higher homeostasis of photosynthesis than alpine taxa. The higher respiration rates produced more energy for repair and maintenance biomass, especially for higher photosynthetic activity for lowland taxa, which causes lower respiratory acclimation. Thus, the changes of ΔD2H for alpine spruces were larger than that for lowland spruces. These results indicate that long term heat stress negatively impact on the growth of Picea seedlings, and alpine taxa are more affected than low altitude ones by high temperature stress. Hence the altitude ranges of Picea taxa should be taken into account when predicting changes to carbon fluxes in warmer conditions.


Assuntos
Fotossíntese/fisiologia , Picea/fisiologia , Altitude , Carbono/química , Dióxido de Carbono/química , Nitrogênio/química , Picea/classificação , Folhas de Planta/metabolismo , Sementes/metabolismo , Temperatura Ambiente
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