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1.
Artif Intell Med ; 98: 1-9, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31521247

RESUMO

Survival analyses of populations and the establishment of prognoses for individual patients are important activities in the practice of medicine. Standard survival models, such as the Cox proportional hazards model, require extensive feature engineering or prior knowledge to model at an individual level. Some survival analysis models can avoid these problems by using machine learning extended the CPH model, and higher performance has been reported. In this paper, we propose an innovative loss function that is defined as the sum of an extended mean squared error loss and a pairwise ranking loss based on ranking information on survival data. We apply this loss function to optimize a deep feed-forward neural network (RankDeepSurv), which can be used to model survival data. We demonstrate that the performance of our model, RankDeepSurv, is superior to that of other state-of-the-art survival models based on an analysis of 4 public medical clinical datasets. When modelling the prognosis of nasopharyngeal carcinoma (NPC), RankDeepSurv achieved better prognostic accuracy than the CPH established by clinical experts. The difference between high and low risk groups in the RankDeepSurv model is greater than the difference in the CPH. The results show that our method has considerable potential to model survival data in medical settings.

2.
Technol Cancer Res Treat ; 18: 1533033819874807, 2019 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-31522611

RESUMO

Due to the critical role of inflammation in nasopharyngeal carcinoma, we aim to investigate the correlation between nasopharyngeal carcinoma prognosis and the levels of tumor necrosis factor α and macrophages for the development of new prognostic models. The levels of tumor necrosis factor-α and CD68-positive macrophages were measured in 111 primary nasopharyngeal carcinoma specimens by immunohistochemistry. Kaplan-Meier analysis showed that, compared with nonelevated tumor necrosis factor-α levels, elevated tumor necrosis factor α levels were correlated with poorer 10-year distant metastasis-free survival (24.5% vs 5.2%, P = .004) and bone metastasis-free survival (17.0% vs 0.0%, P = .001). Multivariate analysis revealed that tumor necrosis factor α level was an independent prognostic factor for distant metastasis-free survival (hazard ratio = 16.765, P = .001), while the level of CD68-positive macrophages was a favorable independent prognostic factor for cancer-specific survival (hazard ratio = 0.481, P = .023) and disease-free survival (hazard ratio = 0.403, P = .010). Additionally, several prognostic models that considered tumor-node-metastasis stage alone or in combination with tumor necrosis factor α and/or CD68-positive macrophage levels were compared by receiver operating characteristic curve analysis. Interestingly, the T_score model, which considered the tumor necrosis factor α level alone, could better predict the distant metastasis-free survival and bone metastasis-free survival, whereas the MT model, which considered the combination of T stage and CD68-positive macrophage level, could better predict the cancer-specific survival and disease-free survival of patients with nasopharyngeal carcinoma. Elevated tumor necrosis factor-α levels and decreased CD68-positive macrophage levels in primary nasopharyngeal carcinoma tissues are unfavorable prognostic indicators in nasopharyngeal carcinoma. The T_score model or the MT model could be better prognostic models than those currently available for nasopharyngeal carcinoma and could be used to select high-risk patients and aid in the design of individualized immunotherapy.

3.
J Agric Food Chem ; 67(36): 10000-10009, 2019 Sep 11.
Artigo em Inglês | MEDLINE | ID: mdl-31442045

RESUMO

Improving plant resistance against systemic diseases remains a challenging research topic. In this study, we developed a dual-action pesticide-loaded hydrogel with the capacity to significantly induce plant resistance against tobacco mosaic virus (TMV) infection and promote plant growth. We produced an alginate-lentinan-amino-oligosaccharide hydrogel (ALA-hydrogel) by coating the surface of an alginate-lentinan drug-loaded hydrogel (AL-hydrogel) with amino-oligosaccharide using electrostatic action. We determined the formation of the amino-oligosaccharide film using various approaches, including Fourier transform infrared spectrometry, the ζ potential test, scanning electron microscopy, and elemental analysis. It was found that the ALA-hydrogel exhibited stable sustained-release activity, and the release time was significantly longer than that of the AL-hydrogel. In addition, we demonstrated that the ALA-hydrogel was able to continuously and strongly induce plant resistance against TMV and increase the release of calcium ions to promote Nicotiana benthamiana growth. Meanwhile, the ALA-hydrogel maintained an extremely high safety to organisms. Our findings provide an alternative to the traditional approach of applying pesticide for controlling plant viral diseases. In the future, this hydrogel with the simple synthesis method, green synthetic materials, and its efficiency in the induction of plant resistance will attract increasing attention and have good potential to be employed in plant protection and agricultural production.


Assuntos
Antivirais/química , Preparações de Ação Retardada/farmacologia , Portadores de Fármacos/química , Lentinano/química , Lentinano/farmacologia , Doenças das Plantas/virologia , Vírus do Mosaico do Tabaco/fisiologia , Tabaco/virologia , Alginatos/química , Antivirais/farmacologia , Preparações de Ação Retardada/química , Resistência à Doença , Hidrogéis/química , Doenças das Plantas/imunologia , Tabaco/imunologia
4.
Molecules ; 24(13)2019 Jul 04.
Artigo em Inglês | MEDLINE | ID: mdl-31277526

RESUMO

At present, the management of Phytophthora capsici (P. capsici) mainly relies on chemical pesticides. However, along with the resistance generated by P. capsici to these chemical pesticides, the toxicity and non-degradability of this chemical molecule may also cause serious environmental problems. Herein, a new bio-based nano-antifungal material (CNC@CTAB) was made with coating hexadecyl trimethyl ammonium bromide (CTAB) on the surface of a cellulose nanocrystal (CNC). This material was then applied to the prevention of P. capcisi. This particle was facilely fabricated by mixing CTAB and sulfuric group modified CNC in an aqueous solvent. Compared to pure CTAB, the enrichment of CTAB on the CNC surface showed a better anti-oomycete activity both in vitro and in vivo. When CNC@CTAB was applied on P. capsici in vitro, the inhibition rate reached as high as 100%, while on the pepper leaf, the particle could also efficiently prevent the infection of P. capsici, and achieve a disease index as low as zero Thus, considering the high safety of CNC@CTAB in agricultural applications, and its high anti-oomycete activity against P. capsici, we believe that this CNC@CTAB has great application potential as a new green nano-fungicide in P. capsici management during the production of peppers or other vegetables.

5.
Biomed Chromatogr ; 33(10): e4628, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31243781

RESUMO

Wang-Bi tablet (WB) is popularly used for the treatment of rheumatoid arthritis. However, few studies have been carried out on its active ingredients and mechanism. In this study, the effect of WB medicated serum on the changes in differentiation and function in osteoblast was investigated, the results showed that WB induced the production of ALP and mineralized nodules to promote the final maturation of osteoblasts and enhance the function of osteoblasts. The potential mechanism may that WB significantly inhibits gene expressions of RANKL and miR-141, up-regulates the gene expressions of RUNX2 and OPG, decreases expression of DKK-1 and increases levels of ß-catenin protein to promote the activation of Wnt/ß-catenin signaling pathways, which enhances osteogenesis and bone repair function. To investigate which compounds contributed to the activity and mechanisms, a total of 138 compounds were characterized from WB, and 13 parent molecules and eight metabolites in rat serum were rapidly characterized by UPLC-Q-TOF/MS. Total glycosides of paeony, loganin, α-linolenic acid, linoleic acid and naringin from WB may contribute to the actions on osteoblasts according to our study and literature review. Our research provides a method to explore the bioactive ingredients and action mechanisms of WB.

6.
J Biol Chem ; 294(25): 9734-9745, 2019 Jun 21.
Artigo em Inglês | MEDLINE | ID: mdl-31073033

RESUMO

Early diagnosis of nasopharyngeal carcinoma (NPC) is difficult because of a lack of specific symptoms. Many patients have advanced disease at diagnosis, and these patients respond poorly to treatment. New treatments are therefore needed to improve the outcome of NPC. To better understand the molecular pathogenesis of NPC, here we used an NPC cell line in a genome-wide CRISPR-based knockout screen to identify the cellular factors and pathways essential for NPC (i.e. dependence factors). This screen identified the Moz, Ybf2/Sas3, Sas2, Tip60 histone acetyl transferase complex, NF-κB signaling, purine synthesis, and linear ubiquitination pathways; and MDM2 proto-oncogene as NPC dependence factors/pathways. Using gene knock out, complementary DNA rescue, and inhibitor assays, we found that perturbation of these pathways greatly reduces the growth of NPC cell lines but does not affect growth of SV40-immortalized normal nasopharyngeal epithelial cells. These results suggest that targeting these pathways/proteins may hold promise for achieving better treatment of patients with NPC.

7.
Cancer Commun (Lond) ; 38(1): 59, 2018 09 25.
Artigo em Inglês | MEDLINE | ID: mdl-30253801

RESUMO

BACKGROUND: Due to the occult anatomic location of the nasopharynx and frequent presence of adenoid hyperplasia, the positive rate for malignancy identification during biopsy is low, thus leading to delayed or missed diagnosis for nasopharyngeal malignancies upon initial attempt. Here, we aimed to develop an artificial intelligence tool to detect nasopharyngeal malignancies under endoscopic examination based on deep learning. METHODS: An endoscopic images-based nasopharyngeal malignancy detection model (eNPM-DM) consisting of a fully convolutional network based on the inception architecture was developed and fine-tuned using separate training and validation sets for both classification and segmentation. Briefly, a total of 28,966 qualified images were collected. Among these images, 27,536 biopsy-proven images from 7951 individuals obtained from January 1st, 2008, to December 31st, 2016, were split into the training, validation and test sets at a ratio of 7:1:2 using simple randomization. Additionally, 1430 images obtained from January 1st, 2017, to March 31st, 2017, were used as a prospective test set to compare the performance of the established model against oncologist evaluation. The dice similarity coefficient (DSC) was used to evaluate the efficiency of eNPM-DM in automatic segmentation of malignant area from the background of nasopharyngeal endoscopic images, by comparing automatic segmentation with manual segmentation performed by the experts. RESULTS: All images were histopathologically confirmed, and included 5713 (19.7%) normal control, 19,107 (66.0%) nasopharyngeal carcinoma (NPC), 335 (1.2%) NPC and 3811 (13.2%) benign diseases. The eNPM-DM attained an overall accuracy of 88.7% (95% confidence interval (CI) 87.8%-89.5%) in detecting malignancies in the test set. In the prospective comparison phase, eNPM-DM outperformed the experts: the overall accuracy was 88.0% (95% CI 86.1%-89.6%) vs. 80.5% (95% CI 77.0%-84.0%). The eNPM-DM required less time (40 s vs. 110.0 ± 5.8 min) and exhibited encouraging performance in automatic segmentation of nasopharyngeal malignant area from the background, with an average DSC of 0.78 ± 0.24 and 0.75 ± 0.26 in the test and prospective test sets, respectively. CONCLUSIONS: The eNPM-DM outperformed oncologist evaluation in diagnostic classification of nasopharyngeal mass into benign versus malignant, and realized automatic segmentation of malignant area from the background of nasopharyngeal endoscopic images.

8.
J Cancer ; 9(17): 3023-3031, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30210624

RESUMO

Purpose: To date, no guidelines exist for elderly nasopharyngeal carcinoma (NPC) patients (60 years of age or older) due to a lack of prospective clinical trials. This study evaluated the efficacy of concurrent chemotherapy (CCRT) for NPC in elderly patients treated with intensity-modulated radiotherapy (IMRT). Methods: Patients were identified from a prospectively maintained database. A total of 198 consecutive cases of elderly patients with NPC receiving IMRT, including 103 patients treated with IMRT plus CCRT and 95 patients treated with IMRT alone, were analysed from January 2002 to December 2013. Multivariate analysis (MVA) using the Cox proportional hazards model and propensity score analysis (PSA) were performed for overall survival (OS) and disease-free survival (DFS). Finally, sensitivity analysis was performed. Results: The median follow-up time was 55.3 months (range, 3-135.6 months). In the entire cohort, both MVA and PSA models showed that compared with IMRT alone, IMRT plus CCRT significantly improved survival (hazard ratio [HR] 2.143, 95% confidence interval [95% CI] 1.180-3.890; HR 1.961, 95% CI, 1.117-3.443, for OS and DFS, respectively). Similar results were found in the subgroups with high levels of Epstein-Barr virus (EBV) DNA, except in the low-EBV-DNA cohort. The total rates of severe acute toxicity, including leukopenia, neutropenia, stomatitis, and emesis, were significantly higher in the IMRT+CCRT group than in the IMRT-alone group (P < 0.001) but were similar to the rates of severe late toxicity (P = 0.818). Sensitivity analysis confirmed the robustness of our analysis. Conclusions: In the era of IMRT, CCRT retained survival benefits at high EBV DNA levels but not at low EBV DNA levels for elderly NPC patients. Randomized clinical trials are needed to confirm our findings.

9.
J Cancer Res Clin Oncol ; 144(11): 2231-2243, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30109501

RESUMO

PURPOSE: To retrospectively investigate the optimal regimen of concurrent chemotherapy for nasopharyngeal carcinoma (NPC) by comparing clinical outcomes of patients who received platinum-based and non-platinum-based concurrent chemoradiotherapy (CCRT) regimens. METHODS: Based on a prospectively maintained database from 1998 to 2013 in an endemic area, a total of 4608 newly diagnosed, biopsy-proven, and non-disseminated NPC patients were identified and allocated into three cohorts based on concurrent chemotherapy regimens: cisplatin-based (CP) chemotherapy cohort, other platinum-based (OP) chemotherapy cohort, and non-platinum-based (NP) chemotherapy cohort. Overall survival (OS) and disease-free survival (DFS) were estimated using the Cox proportional hazards model and propensity score analysis of treatment using an inverse probability weighting model (PSA/IPTW). Finally, sensitivity analysis estimated the effects of potential unmeasured confounders. RESULTS: The median follow-up time was 68.5 months (range 2-194 months). The multivariate Cox model showed that NP regimens were significantly related with worse survival compared with CP or OP regimens (OS: HR 1.51, 95% CI 1.16-2.00, P = 0.002; HR 1.68, 95% CI 1.24-2.27, P = 0.001; DFS: HR 1.31, 95% CI 1.03-1.66, P = 0.031; HR 1.50, 95% CI 1.14-1.97, P = 0.004, respectively). Meanwhile, no significant survival difference was found between OP and CP regimens. The PSA/IPTW method, CCRT-specific and III-IVB NPC cohort subgroup analysis showed similar results. Sensitivity analysis confirmed the robustness of our results. CONCLUSIONS: Platinum-based concurrent chemotherapy, including both CP and OP regimens, yields better survival benefits for non-metastatic NPC patients than the NP regimen and remains the optimal regimen for these patients.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Quimiorradioterapia/métodos , Neoplasias Nasofaríngeas/terapia , Adolescente , Adulto , Idoso , Criança , Cisplatino/administração & dosagem , Feminino , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Avaliação de Resultados (Cuidados de Saúde)/métodos , Avaliação de Resultados (Cuidados de Saúde)/estatística & dados numéricos , Platina/administração & dosagem , Modelos de Riscos Proporcionais , Estudos Retrospectivos , Adulto Jovem
10.
Ther Adv Med Oncol ; 10: 1758835918782331, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30046357

RESUMO

Background: In the intensity-modulated radiotherapy (IMRT) era, the survival benefit of concurrent chemotherapy for locoregionally advanced nasopharyngeal carcinoma (LA-NPC) remains undetermined. This study aimed to evaluate the benefits of IMRT with concurrent chemotherapy compared with IMRT alone for LA-NPC patients with different plasma Epstein-Barr virus (EBV) DNA levels. Methods: Patients were identified from a prospectively maintained database in an endemic area between November 2002 and December 2013. Cox proportional hazards models, propensity score matching, and inverse probability weighting models were established for survival analysis. Stratification analysis was performed based on interaction effects analysis. Finally, sensitivity analysis was performed considering unmeasured confounders. Results: A total of 1357 eligible patients were enrolled (median follow up 62.4 months; range 3.5-155.8 months). No significant survival differences were observed between groups in the entire cohort. Notably, a significant interaction effect was observed between treatment regimens and EBV DNA levels. In patients with high EBV DNA levels (>4000 copies/ml), all three models showed that IMRT with concurrent chemotherapy significantly improved overall survival [hazard ratio (HR) 2.521, 95% confidence interval (CI) 1.218-5.216], disease-free survival (HR 2.168, 95% CI 1.349-3.483), and distant metastasis-free survival (HR 2.331, 95% CI 1.194-4.551) compared with IMRT alone. No differences were found in patients with low EBV DNA levels. Sensitivity analysis confirmed the robustness of the results. Conclusion: In the IMRT era, concurrent chemotherapy treatment of LA-NPC patients with high EBV DNA levels is reasonable. However, the optimal regimen for LA-NPC patients with low EBV DNA levels needs further validation in randomized clinical trials.

11.
Cancer Manag Res ; 10: 1935-1946, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30022852

RESUMO

Purpose: Tumor stroma cells play an important role in the carcinogenesis and progression of cancer. The aim of the present investigation was to explore the predictive role of carcinoma-associated fibroblasts (CAFs) and tumor-associated macrophages (TAMs) in nasopharyngeal carcinoma (NPC). Patients and methods: The densities of CAFs and TAMs were measured by immunohistochemistry staining for α-smooth muscle actin (α-SMA), CD68, and CD163 in two sets of tissue microarrays including 260 pretreatment NPC tissues, that is, a training test comprising of 152 patients and a validation set comprising of 108 patients. Chi-square tests were performed for comparisons among the groups. Survival rates were estimated by using the Kaplan-Meier method and compared with log-rank tests. Cox proportional hazards models were used to identify significant independent variables. Results: Patients older than 50 years showed a lower expression of CD68, and there was a positive relationship between the densities of CAFs and CD163+ TAMs (p=0.001). In the multivariate analysis of the training test, both α-SMA and CD163 were independent prognostic factors for overall survival and progression-free survival (all p<0.05). Based on the expression levels of α-SMA and CD163, patients were categorized into three groups: high-risk, intermediate-risk, and low-risk groups according to both high, either high, and both low, respectively. Survival analysis and Cox multivariate analysis showed that the risk groups based on α-SMA and CD163 expression were independent predictors for the survival of patients with NPC in the training test, which was also confirmed by the validation test. Conclusion: A patient's risk group based on the level of CD163+ TAMs and CAFs was an independent predictor of survival, which may facilitate patient counseling and individualized treatment.

12.
Oncol Lett ; 16(2): 1634-1640, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30008847

RESUMO

Inhibitor of DNA-binding 3 (ID3) is a helix-loop-helix transcription factor that is associated with cell proliferation, differentiation and drug resistance in human cancer, and with anticancer effects in certain types of cancer cells. The present study investigated whether and how ID3 was involved in multidrug resistance (MDR) in human cisplatin (DDP)-resistant A549/DDP lung adenocarcinoma cells. The underlying mechanism of action was investigated in vitro. Cell Counting Kit-8 (CCK-8) and flow cytometry assays demonstrated that overexpression of ID3 enhanced chemosensitivity and decreased drug efflux in A549/DDP cells. Reverse transcription-quantitative polymerase chain reaction revealed that the expression of anti-apoptotic gene B-cell lymphoma-2 was significantly downregulated in cells expressing exogenous ID3 (P<0.05). These results indicated that ID3 may synergize with DDP to increase apoptosis in A549/DDP cells. ID3 overexpression modulated the activity of phosphoinositide 3-kinase/RAC serine/threonine-protein kinase signaling and downregulated the expression of multi-drug resistance protein-1, indicating that ID3 expression can reverse multi-drug resistance in A549/DDP cells. Collectively, these results indicate that ID3 is a potential effective chemotherapeutic target for the treatment of human DDP-resistant A549 lung adenocarcinoma therapy.

13.
Carbohydr Polym ; 197: 215-226, 2018 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-30007607

RESUMO

A neutral polysaccharide coded as CERP1 was extracted and purified from the residue of Codonopsis pilosula by ethanol precipitation and column chromatography. The structure of CERP1 was determined by HPAEC-PAD, HPLC, HPSEC-MALLS, FT-IR, NMR, and TEM. The results showed that CERP1 was a heteropolysaccharide composed of Arabinose, Glucose, and Galactose in the ratio of 1.00:19.83:6.94. HPSEC-MALLS showed that CERP1 was homogeneous with an absolute molecular weight of 4.840 × 103 Da. The NMR results and the GC-MS result of methylation indicated that 1-linked ß-d-glucose, 1,3-linked ß-d-glucose, 1,6-linked ß-d-glucose and 1,3,6-linked ß-d-galactose were the main linkages in CERP1. TEM results indicated that CERP1 had a homogeneous particle size and good dispersibility both in purified water and 0.05 M sodium sulfate. Pre-treatment with CERP1 could result in a significant improvement of the insulin secretion of the INS-1 cells. While in vivo assays, CERP1 exhibited a potent hypoglycemic effect on T2DM mice for its ability to relieve oxidative stress, ameliorate lipid metabolism, increase glycolytic enzyme activity as well as decrease liver transaminase activity. This study gives a chance for exploring the residue of Codonopsis pilosula.


Assuntos
Codonopsis/química , Hipoglicemiantes/farmacologia , Polissacarídeos/farmacologia , Animais , Linhagem Celular , Hipoglicemiantes/química , Hipoglicemiantes/isolamento & purificação , Insulina/metabolismo , Fígado/efeitos dos fármacos , Fígado/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Estresse Oxidativo/efeitos dos fármacos , Tamanho da Partícula , Polissacarídeos/química , Polissacarídeos/isolamento & purificação , Transaminases/antagonistas & inibidores , Transaminases/metabolismo
14.
Exp Ther Med ; 15(6): 5023-5028, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29805526

RESUMO

[18F]fluorodeoxyglucose positron emission tomography/computed tomography ([18F]FDG-PET/CT) is useful for diagnosing cancers and inflammatory diseases. A polymyositis/dermatomyositis (PM/DM) lesion is an inflammatory heterogeneous disease of the striated muscle. In the present study, the maximum standardized uptake value (SUVmax) was compared between 22 cases with definite or probable PM/DM (PM/DM group) that underwent [18F]FDG-PET/CT examination and the same number of patients with no myopathy. The average proximal muscle FDG uptake value (SUVaverage) for each patient was represented by calculating the average of the SUVmax for these muscles bilaterally. The correlation between creatine kinase (CK), serum creatine kinase isoenzyme, myodynamia of the proximal limb girdle muscle and SUVmax of each muscle group were analyzed. The results indicated that the SUVmax was markedly different between the PM/DM group and the non-myopathy group. It was demonstrated that [18F]FDG-PET/CT has a diagnostic value for PM/DM. The serum CK levels and the SUVaverage were negatively correlated with myodynamia. [18F]FDG-PET/CT may be used for examination to assess the severity of myositis. Furthermore, it may provide detection sites for muscle biopsy in patients with myositis.

15.
Cancer Commun (Lond) ; 38(1): 21, 2018 05 10.
Artigo em Inglês | MEDLINE | ID: mdl-29764487

RESUMO

BACKGROUND: Available data in the literature comparing different induction chemotherapy (IC) regimens on locoregionally advanced nasopharyngeal carcinoma (NPC) are scarce. The purpose of the present study was to evaluate the outcomes of locoregionally advanced NPC patients who were treated with taxane, cisplatin and 5-fluorouracil (TPF) or cisplatin and 5-fluorouracil (PF) as IC followed by concurrent chemoradiotherapy (CCRT). METHODS: In total, 1879 patients with locoregionally advanced NPC treated with IC and CCRT from a prospectively maintained database were included in the present observational study. We compared overall survival (OS), disease-specific survival (DSS), distant metastasis-free survival (DMFS), and locoregional relapse-free survival, using the propensity score method. RESULTS: In total, 1256 patients received TPF or PF as IC backbone. The TPF group showed significantly better OS (hazard ratio [HR], 0.660; 95% confidence interval [CI] 0.442-0.986; P = 0.042), DSS (HR, 0.624; 95% CI 0.411-0.947; P = 0.027) and DMFS (HR, 0.589; 95% CI 0.406-0.855; P = 0.005) compared with the PF group in multivariable analyses. Propensity score matching identified 294 patients in each cohort and confirmed that TPF was associated with significantly improved 5-year OS (88.1% vs. 80.7%; P = 0.042), DSS (88.5% vs. 80.7%; P = 0.021) and DMFS (87.9% vs. 78.6%; P = 0.012) rates compared with the PF group. There were no significant differences in locoregional relapse-free survival before or after matching. CONCLUSIONS: In our study, IC with the TPF regimen combined with CCRT showed improved long-term survival for the patients with locoregionally advanced NPC compared with the PF regimen. However, a prospective randomized clinical trial to validate these findings is necessary.

16.
Cytogenet Genome Res ; 154(3): 132-136, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29742505

RESUMO

Mutations in the COL4A5 gene result in X-linked Alport syndrome, homozygous or compound heterozygous mutations in COL4A3 or COL4A4 are responsible for autosomal recessive Alport syndrome, and heterozygous mutations in COL4A3 or COL4A4 cause autosomal dominant Alport syndrome or benign familial hematuria. Recently, the existence of a digenic inheritance in Alport syndrome has been demonstrated. We here report heterozygous COL4A3 and COL4A4 digenic mutations in cis responsible for benign familial hematuria. Using bioinformatics analyses and pedigree verification, we showed that COL4A4 c.1471C>T and COL4A3 c.3418 + 1G>T variants in cis are pathogenic and co-segregate with the benign familial hematuria. This result suggests that COL4A3 and COL4A4 digenic mutations in cis mimicking an autosomal dominant inheritance should be considered as a novel inheritance pattern of benign familial hematuria, although the disease-causing mechanism remains unknown.


Assuntos
Autoantígenos/genética , Colágeno Tipo IV/genética , Hematúria/genética , Polimorfismo de Nucleotídeo Único , Adulto , Idoso , Idoso de 80 Anos ou mais , Criança , Feminino , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Masculino , Pessoa de Meia-Idade , Linhagem , Análise de Sequência de DNA , Adulto Jovem
17.
Cytogenet Genome Res ; 154(1): 30-36, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29669314

RESUMO

Thin basement membrane nephropathy (TBMN), autosomal dominant Alport syndrome (ADAS), and focal segmental glomerulosclerosis (FSGS) are kidney diseases that differ in clinical diagnosis, treatment, and prognosis. Nevertheless, they may result from the same causative genes. Here, we report 3 COL4A4 heterozygous mutations (p.Gly208Arg, p.Ser513Glufs*2, and p.Met1617Cysfs*39) that lead to 3 different collagen type IV kidney disease phenotypes, manifesting as TBMN, ADAS, and FSGS. Using bioinformatics analyses and pedigree verification, we show that these novel variants are pathogenetic and cosegregate with TBMN, ADAS, and FSGS. Furthermore, we found that the collagen type IV-associated kidney disease phenotypes are heterogeneous, with overlapping pathology and genetic mutations. We propose that COL4A4-associated TBMN, ADAS, and FSGS should be considered as collagen type IV kidney disease subtypes that represent different phases of disease progression.


Assuntos
Colágeno Tipo IV/genética , Glomerulosclerose Segmentar e Focal/genética , Hematúria/genética , Mutação , Nefrite Hereditária/genética , Adulto , Criança , Colágeno Tipo IV/metabolismo , Análise Mutacional de DNA , Membrana Basal Glomerular/metabolismo , Membrana Basal Glomerular/patologia , Membrana Basal Glomerular/ultraestrutura , Glomerulosclerose Segmentar e Focal/metabolismo , Hematúria/metabolismo , Heterozigoto , Humanos , Masculino , Microscopia Eletrônica , Nefrite Hereditária/metabolismo , Fenótipo
18.
J Exp Clin Cancer Res ; 37(1): 85, 2018 Apr 17.
Artigo em Inglês | MEDLINE | ID: mdl-29665837

RESUMO

BACKGROUND: Distant metastasis is the major cause of treatment failure in patients with nasopharyngeal carcinoma (NPC). Although several biomarkers correlate with metastasis and prognosis, the molecular mechanisms of NPC development and progression remain unclear. METHODS: Quantitative RT-PCR (qRT-PCR), western blotting, cell growth, foci formation, migration and invasion assays, and xenograft mouse models were utilized to examine the expression levels and functions of the CXCL5/CXCR2 axis in NPC. A luciferase reporter assay, western blotting, immunofluorescence, and migration and invasion assays were used to identify and verify the ERK/GSK-3ß/Snail signalling pathway. RESULTS: CXCL5 was significantly increased in the sera of NPC patients, and high expression levels of CXCL5/CXCR2 in NPC primary tissues indicated poor survival. CXCL5 and CXCR2 were upregulated in NPC cell lines. Ectopic expression of the CXCL5/CXCR2 axis promoted NPC cell migration and invasion in vitro and the formation of lung metastases in vivo. Mechanistically, the dual overexpression of CXCL5 and CXCR2 promoted cell spreading by inducing the epithelial-mesenchymal transition (EMT) through the activation of the ERK/GSK-3ß/Snail signalling pathway. CONCLUSION: The CXCL5/CXCR2 axis contributes to the EMT of NPC cells by activating ERK/GSK-3ß/Snail signalling, and this axis may be a potential diagnostic marker and therapeutic target for patients with NPC.

19.
Lancet Oncol ; 19(4): 461-473, 2018 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-29501366

RESUMO

BACKGROUND: Cisplatin-based concurrent chemoradiotherapy is currently considered to be the standard treatment regimen for patients with advanced nasopharyngeal carcinoma, but has well known side-effects such as gastrointestinal reactions, nephrotoxicity, and ototoxicity. Nedaplatin was developed to decrease the toxic effects induced by cisplatin, and in this trial we assessed whether a nedaplatin-based concurrent chemoradiotherapy regimen was non-inferior to a cisplatin-based regimen in patients with locoregional, stage II-IVB nasopharyngeal carcinoma. METHODS: We did an open-label, non-inferiority, phase 3, randomised, controlled trial at two centres in China. Patients aged 18-65 years with non-keratinising stage II-IVB (T1-4N1-3 or T3-4N0) nasopharyngeal carcinoma, a Karnofsky score of at least 70, and adequate haematological, renal, and hepatic function were randomly assigned (1:1) to receive intravenously either nedaplatin 100 mg/m2 or cisplatin 100 mg/m2 on days 1, 22, and 43 for three cycles concurrently with intensity-modulated radiotherapy. Randomisation was done manually using a computer-generated random number code and patients were stratified by treatment centre and clinical stage. Patients and clinicians were not masked to treatment allocation. The primary endpoint was progression-free survival at 2 years; non-inferiority was shown if the upper limit of the 95% CI for the difference in 2-year progression-free survival between the two groups did not exceed 10%. Analyses were by both intention to treat and per protocol, including all patients who received at least one complete cycle of chemotherapy. This trial is registered with ClinicalTrials.gov, number NCT01540136, and is currently in follow-up. FINDINGS: Between Jan 16, 2012, and July 16, 2014, we randomly assigned 402 patients to nedaplatin-based (n=201) or cisplatin-based (n=201) concurrent chemoradiotherapy. In the intention-to-treat population, 2-year progression-free survival was 89·9% (95% CI 85·8-94·0) in the cisplatin group and 88·0% (83·5-94·5) in the nedaplatin group, with a difference of 1·9% (95% CI -4·2 to 8·0; pnon-inferiority=0·0048). In the per-protocol analysis (cisplatin group, n=197; nedaplatin group, n=196), 2-year progression-free survival was 89·7% (95% CI 85·4-94·0) in the cisplatin group and 88·7% (84·2-94·5) in the nedaplatin group, with a difference of 1·0% (95% CI -5·2 to 7·0; pnon-inferiority=0·0020). A significantly higher frequency of grade 3 or 4 vomiting (35 [18%] of 198 in the cisplatin group vs 12 [6%] of 200 in the nedaplatin group, p<0·0001), nausea (18 [9%] vs four [2%], p=0·0021), and anorexia (53 [27%] vs 26 [13%], p=0·00070) was observed in the cisplatin group compared with the nedaplatin group. 11 (6%) patients in the nedaplatin group had grade 3 or 4 thrombocytopenia compared with four (2%) in the cisplatin group (p=0·065). Patients in the cisplatin group had a higher frequency of any grade or grade 3 or 4 late auditory or hearing toxicities than did patients in the nedaplatin group (grade 3 or 4: three [2%] in the nedaplatin group vs 11 [6%] in the cisplatin group, p=0·030). No patients died from treatment-related causes. INTERPRETATION: Our findings show that nedaplatin-based concurrent chemoradiotherapy represents an alternative doublet treatment strategy to cisplatin-based concurrent chemoradiotherapy for patients with locoregional, advanced nasopharyngeal carcinoma. Further investigations are needed to explore the potential use of this treatment as induction or adjuvant chemotherapy or in combination with other agents. FUNDING: National Key R&D Program of China, National Natural Science Foundation of China, Sun Yat-sen University Clinical Research 5010 Program, Sci-Tech Project Foundation of Guangzhou City, National Key Basic Research Program of China, Special Support Plan of Guangdong Province, Sci-Tech Project Foundation of Guangdong Province, Health & Medical Collaborative Innovation Project of Guangzhou City, National Science & Technology Pillar Program during the Twelfth Five-year Plan Period, PhD Start-up Fund of Natural Science Foundation of Guangdong Province, Cultivation Foundation for the Junior Teachers in Sun Yat-sen University, and Fundamental Research Funds for the Central Universities.

20.
Braz. j. med. biol. res ; 51(2): e4547, 2018. tab, graf
Artigo em Inglês | LILACS-Express | ID: biblio-889021

RESUMO

Systemic lupus erythematosus (SLE) is a chronic, autoimmune disorder that affects nearly all organs and tissues. As knowledge about the mechanism of SLE has increased, some immunosuppressive agents have become routinely used in clinical care, and infections have become one of the direct causes of mortality in SLE patients. To identify the risk factors indicative of infection in SLE patients, a case control study of our hospital's medical records between 2011 and 2013 was performed. We reviewed the records of 117 SLE patients with infection and 61 SLE patients without infection. Changes in the levels of T cell subsets, immunoglobulin G (IgG), complement C3, complement C4, globulin, and anti-double-stranded DNA (anti-ds-DNA) were detected. CD4+ and CD4+/CD8+ T cell levels were significantly lower and CD8+ T cell levels were significantly greater in SLE patients with infection than in SLE patients without infection. Additionally, the concentrations of IgG in SLE patients with infection were significantly lower than those in SLE patients without infection. However, complement C3, complement C4, globulin, and anti-ds-DNA levels were not significantly different in SLE patients with and without infection. Therefore, clinical testing for T cell subsets and IgG is potentially useful for identifying the presence of infection in SLE patients and for distinguishing a lupus flare from an acute infection.

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