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1.
Dev Comp Immunol ; 102: 103486, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31473265

RESUMO

The complement system is a crucial component of the innate immune system that links innate and adaptive immunity. CL-11, a protein similar to Mannose-binding lectin (MBL), plays significant role in the innate immune system in mammals and fish, serving as an initiator of the lectin pathway of complement activation. In this study, a CL-11 homolog (TfCol-11) was identified in roughskin sculpin (Trachidermus fasciatus), and its expression and role in immune responses were characterized. The open reading frame of TfCol-11 is 795 bp long, encoding a 264 amino acid polypeptide. The deduced amino acid sequence of this protein is highly homologous to sequences in other teleosts, and is similar to vertebrate CL-11, containing a canonical collagen-like region, a carbohydrate recognition domain, and a neck region. Recombinant TfCol-11 purified from Escherichia coli(E.coli) was able to bind to different microbes in a Ca2+-independent manner. Meanwhile, a 993 bp-long of partial MASP cDNA with a 96 bp 5' untranslated region (UTR) was also cloned from roughskin sculpin, containing 299 amino acids and consisting of three domains (CUB-EGF-CUB). qRT-PCR indicated that TfCol-11 and MASP mRNAs were predominately co-expressed in the liver. The temporal expression of TfCol-11 and MASP were both drastically up-regulated in the liver, skin, and blood by LPS challenge. Recombinant TfCol-11 purified from E.coli BL21(DE3) was able to agglutinate some bacteria in a Ca2+-dependent manner. In addition, an in vitro pull-down experiment demonstrated that TfCol-11 was able to bind to MASP, and in vivo experiments showed that TfCol-11 was associated with increased membrane attack complex (MAC) levels. It is therefore possible that TfCol-11 may plays a role in activating the complement system and in the defense against invading microorganisms in roughskin sculpin.

2.
Acta Haematol ; : 1-7, 2019 Oct 09.
Artigo em Inglês | MEDLINE | ID: mdl-31597154

RESUMO

Central nervous system complications (CNSCs) after allogeneic hematopoietic stem cell transplantation (allo-HSCT) are common and may be a significant source of morbidity and mortality. We performed a retrospective study of 153 pediatric patients who underwent allo-HSCT to determine CNSC type, incidence, and impact on survival. A total of 34 patients (22.2%) developed CNSCs. The cumulative incidence of CNSCs at 100 days and 3 years was 18.30 and 22.73%, respectively. The most common CNSC was calcineurin inhibitor (CNI)-associated neurotoxicity (50.0%). Risk factors for CNSCs were the time from diagnosis to HSCT ≥4.8 months (p = 0.032) and the development of acute graft-versus-host disease (aGVHD) grade III-IV (p = 0.002). CNSCs after allo-HSCT negatively impacted overall survival (hazard ratio [HR] 1.97, p = 0.043) and nonrelapse mortality (HR 4.84, p < 0.001). In conclusion, CNSCs after allo-HSCT are associated with poor outcomes; patients with severe aGVHD and/or late transplantation should be given more attention.

3.
Nucleic Acids Res ; 2019 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-31612207

RESUMO

The binding of p53-binding protein 1 (53BP1) to damaged chromatin is a critical event in non-homologous DNA end joining (NHEJ)-mediated DNA damage repair. Although several molecular pathways explaining how 53BP1 binds damaged chromatin have been described, the precise underlying mechanisms are still unclear. Here we report that a newly identified H4K16 monomethylation (H4K16me1) mark is involved in 53BP1 binding activity in the DNA damage response (DDR). During the DDR, H4K16me1 rapidly increases as a result of catalyzation by the histone methyltransferase G9a-like protein (GLP). H4K16me1 shows an increased interaction level with 53BP1, which is important for the timely recruitment of 53BP1 to DNA double-strand breaks. Differing from H4K16 acetylation, H4K16me1 enhances the 53BP1-H4K20me2 interaction at damaged chromatin. Consistently, GLP knockdown markedly attenuates 53BP1 foci formation, leading to impaired NHEJ-mediated repair and decreased cell survival. Together, these data support a novel axis of the DNA damage repair pathway based on H4K16me1 catalysis by GLP, which promotes 53BP1 recruitment to permit NHEJ-mediated DNA damage repair.

4.
Int J Cancer ; 2019 Oct 21.
Artigo em Inglês | MEDLINE | ID: mdl-31633798

RESUMO

Whether PD-L1-positive patients derive more overall survival benefit from PD-1/PD-L1 inhibitors in the treatment of advanced solid tumours is unclear. We systematically searched the PubMed, Cochrane library, and EMBASE databases from January 1, 1966 to March 1, 2019 to identify randomized controlled trials of PD-1/PD-L1 inhibitors (nivolumab, pembrolizumab, atezolizumab, durvalumab, avelumab) that had available hazard ratios (HRs) for death according to PD-L1 status. A random-effects model was used to calculate the pooled overall survival (OS) HR and 95% CI among PD-L1-positive and PD-L1-negative patients. An interaction test was performed to evaluate the heterogeneity between the two estimates. A total of 24 randomized trials, involving 12,966 participants, fulfilled the inclusion criteria. An OS benefit of PD-1/PD-L1 inhibitors was found in both PD-L1-positive patients (HR, 0.65; 95% CI, 0.60-0.70) and PD-L1-negative patients (HR, 0.82; 95% CI, 0.74-0.91) even at the minimum cut-off value of 1%. Significant differences in the efficacy of PD-1/PD-L1 inhibitors between PD-L1-positive and PD-L1-negative patients were noted at different cut-off values. Moreover, there was a positive dose-response relationship between PD-L1 positivity and OS benefit (HR for 1%, 0.58, [0.50, 0.67]; 5%, 0.52 [0.43, 0.64]; 10%, 0.50 [0.40, 0.63]). Subgroup analyses showed that these results were generally consistent, regardless of study design, line of treatment, treatment type, tumour type, PD-L1 staining cell type and median follow-up time. We demonstrated that PD-1/PD-L1 inhibitors significantly improved OS in both PD-L1 positive and PD-L1 negative patients compared with controls, but the magnitude of benefit was clinically PD-L1-dependent. This article is protected by copyright. All rights reserved.

5.
J Cell Mol Med ; 2019 Oct 27.
Artigo em Inglês | MEDLINE | ID: mdl-31657123

RESUMO

Radiation-induced lung injury (RILI) is the major complication of thoracic radiation therapy, and no effective treatment is available. This study explored the role of high-mobility group box 1 (HMGB1) in acute RILI and the therapeutic effect of glycyrrhizin, an inhibitor of HMGB1, on RILI. C57BL/6 mice received a 20 Gy dose of X-ray radiation to the whole thorax with or without administration of glycyrrhizin. Severe lung inflammation was present 12 weeks after irradiation, although only a mild change was noted at 2 weeks and could be alleviated by administration of glycyrrhizin. Glycyrrhizin decreased the plasma concentrations of HMGB1 and sRAGE as well as TNF-α, IL-1ß and IL-6 levels in the bronchoalveolar lavage fluid (BALF). The expression of RAGE was decreased while that of TLR4 was significantly increased at 12 weeks, but not 2 weeks, after irradiation in mouse lung tissue. In vitro, the expression of TLR4 increased in RAW 264.7 cells after conditioning with the supernatant from the irradiated MLE-12 cells containing HMGB1 but showed no change when conditioned medium without HMGB1 was used. However, conditioned culture had no effect on RAGE expression in RAW 264.7 cells. Glycyrrhizin also inhibited the related downstream transcription factors of HMGB/TLR4, such as NF-κB, JNK and ERK1/2, in lung tissue and RAW 264.7 cells when TLR4 was activated. In conclusion, the HMGB1/TLR4 pathway mediates RILI and can be mitigated by glycyrrhizin.

6.
Zhongguo Dang Dai Er Ke Za Zhi ; 21(10): 992-997, 2019 Oct.
Artigo em Chinês | MEDLINE | ID: mdl-31642433

RESUMO

OBJECTIVE: To study the association of Nod-like receptor protein 3 (NLRP3) inflammasome with inflammatory response in the acute stage and coronary artery lesion (CAL) in children with Kawasaki disease (KD). METHODS: A total of 42 children with KD who were hospitalized from January to October 2017 were enrolled as the KD group, among whom 9 had CAL (CAL group) and 33 had no CAL (NCAL group). Fifteen age- and gender-matched children with pneumonia and pyrexia were enrolled as the pneumonia-pyrexia group. Fifteen healthy children were enrolled as the healthy control group. Real-time PCR was used to measure the mRNA expression of NLRP3 inflammasome (NLRP3, ASC and caspase-1) in peripheral blood mononuclear cells. The Spearman rank correlation test was used to investigate the correlation of NLRP3 mRNA expression with serum levels of C-reactive protein, erythrocyte sedimentation rate, interleukin-6, interleukin-1ß, procalcitonin, albumin and prealbumin. RESULTS: The KD group had significantly higher mRNA expression of NLRP3, ASC and caspase-1 in the acute stage than the pneumonia-pyrexia and healthy control groups (P<0.05). The CAL group had significantly higher mRNA expression of NLRP3 than the NCAL group (P<0.05). NLRP3 mRNA expression was correlated with C-reactive protein, interleukin-6, interleukin-1ß, and prealbumin levels in children with KD in the acute stage (rs=0.449, 0.376, 0.427, and -0.416 respectively; P<0.05). CONCLUSIONS: NLRP3 inflammasome may participate in inflammatory response in the acute stage and the development of CAL in children with KD.

7.
Nanoscale ; 11(38): 17736-17745, 2019 Oct 03.
Artigo em Inglês | MEDLINE | ID: mdl-31549694

RESUMO

The direct oxidation of alcohols to esters through a green and cost-effective strategy is a fascinating chemical synthesis route. In this study, an environmentally friendly N-doped porous carbon encapsulated Co-based nano-catalyst was prepared via a simple carbonization procedure, utilizing renewable chitosan, accessible dicyandiamide and low-cost Co(OAc)2 as co-precursors. The obtained Co@NC-2-T catalysts were successfully used in selective oxidation of aromatic alcohols with methanol to esters under atmospheric reaction conditions. The Co@NC-2-900 catalyst (added with 2 g dicyandiamide and pyrolyzed at 900 °C) shows optimal activity and applicability and can also be reused at least six times in the oxidative esterification of aromatic alcohols with excellent stability. The presence of superoxide anion radicals in the current catalytic system was detected by the EPR method, and a possible mechanism of alcohol oxidation to ester was proposed on this basis. Thus, this study provides a facile, eco-friendly, and highly efficient catalytic system for oxidative esterification of alcohols.

8.
Bioinformatics ; 2019 Sep 16.
Artigo em Inglês | MEDLINE | ID: mdl-31529022

RESUMO

MOTIVATION: Breast cancer consists of multiple distinct tumor subtypes, and results from epigenetic and genetic aberrations that give rise to distinct transcriptional profiles. Despite previous efforts to understand transcriptional deregulation through transcription factor networks, the transcriptional mechanisms leading to subtypes of the disease remain poorly understood. RESULTS: We used a sophisticated computational search of thousands of expression datasets to define extended signatures of distinct breast cancer subtypes. Using ENCODE ChIP-seq data of surrogate cell lines and motif analysis we observed that these subtypes are determined by a distinct repertoire of lineage-specific transcription factors. Furthermore, specific pattern and abundance of copy number and DNA methylation changes at these TFs and targets, compared to other genes and to normal cells were observed. Overall, distinct transcriptional profiles are linked to genetic and epigenetic alterations at lineage-specific transcriptional regulators in breast cancer subtypes. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

9.
BMJ Open ; 9(9): e026027, 2019 Sep 08.
Artigo em Inglês | MEDLINE | ID: mdl-31501096

RESUMO

OBJECTIVES: To explore the intentions of working-age internal migrants concerning their place of residence in old age and the relevant influencing factors. METHOD: A cross-sectional survey was conducted in the 17 districts of Shanghai, China in 2013. Through multi-stage stratified sampling with probability proportional to size, 7968 internal migrants (aged 15-64 years) were selected and interviewed individually face to face. The primary outcome concerned the intended place of residence in old age of internal migrants living in Shanghai. Information was collected on demographic characteristics, health insurance, economic condition and participation in social activities. Multinomial logistic regression was performed to analyse the factors influencing migrants' intentions concerning their place of residence in old age. RESULTS: A total of 7927 working-age migrants with complete data were analysed. Of these, 57.0% intended to live in their hometown in old age, 17.7% planned to remain in Shanghai and 25.3% were undecided. Those respondents who were male, less educated, from rural areas or Western China, living in rental houses or who had left family members behind in their hometowns were more likely to choose their hometown as their intended residence in old age (p<0.05). Engagement in business, longer residence duration, possession of social insurance and participation in social activities in Shanghai were identified as possible motivators for migrants who intended to remain in Shanghai in old age (p<0.05). CONCLUSIONS: Most of the migrants expressed an intention to remigrate to their hometowns in old age. Education, economic capacity and social insurance influenced internal migrants in their decision. Relevant authorities should monitor the remigration pattern of ageing migrants, strengthen the senior care system and prepare health service resources that are more adequate, especially in the provinces or cities whence the migrants came.

10.
Genome Biol ; 20(1): 192, 2019 09 09.
Artigo em Inglês | MEDLINE | ID: mdl-31500663

RESUMO

We introduce CUT&RUNTools as a flexible, general pipeline for facilitating the identification of chromatin-associated protein binding and genomic footprinting analysis from antibody-targeted CUT&RUN primary cleavage data. CUT&RUNTools extracts endonuclease cut site information from sequences of short-read fragments and produces single-locus binding estimates, aggregate motif footprints, and informative visualizations to support the high-resolution mapping capability of CUT&RUN. CUT&RUNTools is available at https://bitbucket.org/qzhudfci/cutruntools/ .

11.
Environ Pollut ; 255(Pt 1): 113193, 2019 Sep 07.
Artigo em Inglês | MEDLINE | ID: mdl-31521998

RESUMO

Phthalate esters (PAEs), as widely used plasticizers, have been concerned for their possible disruption of estrogen functions via binding to and activating the transcription of estrogen receptors (ERs). Nevertheless, the computational interpretation of the mechanism of ERs activities modulated by PAEs at the molecular level is still insufficient, which hinders the reliable screening of the ERs-active PAEs with high speed and high throughput. To bridge the gap, the in silico simulations considering the effects of coactivators were accomplished to explore the molecular mechanism of action for the purpose of predicting the estrogenic potencies of PAEs. The transcriptional activation functions of human ERα (hERα) modulated by PAEs is predicted via the simulations including binding interaction of PAEs and hERα, conformational changes of PAEs-hERα complexes and recruitment of coactivators. Molecular insight into the diverse estrogen mechanism of action among PAEs with regard to hERα agonists and selective estrogen receptor modulators (SERMs) is provided. Agonist-modulated conformational change of hERα leads to the optimal exposure of its Activation Function 2 (AF-2) surface which, in turn, facilitates the recruitment of coactivators, therefore promoting the transcriptional activation functions of hERα. Conversely, binding interaction of hERα with SERMs among PAEs leads to the conformational change with blocked AF-2 surface, thus preventing the recruitment of coactivators and consequently inhibiting the AF-2 activity. The two-hybrid recombinant yeast is experimentally used for verification. The established in silico evaluation methodology exhibits great promise to speed up the prediction of chemicals which work as hERα agonist or SERMs.

13.
Database (Oxford) ; 20192019 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-31560050

RESUMO

Rice (Oryza sativa L.) is one of the most important crops worldwide. Its relatives, including phylogenetically related species of rice and paddy weeds with a similar ecological niche, can provide crucial genetic resources (such as resistance to biotic and abiotic stresses and high photosynthetic efficiency) for rice research. Although many rice genomic databases have been constructed, a database providing large-scale curated genomic data from rice relatives and offering specific gene resources is still lacking. Here, we present RiceRelativesGD, a user-friendly genomic database of rice relatives. RiceRelativesGD integrates large-scale genomic resources from 2 cultivated rice and 11 rice relatives, including 208 321 specific genes and 13 643 genes related to photosynthesis and responsive to external stimuli. Diverse bioinformatics tools are embedded in the database, which allow users to search, visualize and download the information of interest. To our knowledge, this is the first genomic database providing a centralized genetic resource of rice relatives. RiceRelativesGD will serve as a significant and comprehensive knowledgebase for the rice community.

14.
J Sex Med ; 16(10): 1567-1573, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31447383

RESUMO

INTRODUCTION: Most of conclusions on the relationship between age and reproductive health in aging men relied on cross-sectional data. AIM: To better characterize the natural degradation trajectory of reproductive health of aging men based on longitudinal data. METHODS: A community cohort study was performed in randomly selected men 40 to 80 years old, initiated in 2012 and followed up in 2014 and 2016. Participants were investigated by face-to-face structured interview, including demographic information and International Index of Erectile Function (IIEF-5) and Aging Males' Symptoms (AMS) scales. MAIN OUTCOME MEASURES: The differences among the 3 assessments of IIEF-5 and AMS were analyzed, and progression trajectories were traced. RESULTS: The high degree of variability on AMS and IIEF-5 was evident across individual subjects, as was the variability within individuals. The average IIEF-5 score of 248 subjects decreased from 16.9 to 14.1 during the 4 years, and the total AMS score increased from 22.6-27.0 (P < .001). Longitudinal data, both of individuals and of groups, showed the more rapid increase or decrease on AMS or IIEF-5 scores over 4 years in the 61-70 age group than in other age groups. CLINICAL IMPLICATION: The evidence of the greatest changes on AMS and IIEF-5 scores in the 61-70 age group prompts the importance of early intervention to postpone the degradation of reproductive health. STRENGTH & LIMITATIONS: Compared with cross-sectional data, longitudinal data can provide a more natural progression trajectory of reproductive health of aging male individuals. The low follow-up rate might affect the parameter estimation to some extent. CONCLUSION: Cohort data over 4 years' follow-up showed more abrupt changes on AMS and IIEF-5 scores in the 61-70 age group than in other age groups. Zheng J-B, Liang Q-F, Li J-H, et al. Longitudinal Trends of AMS and IIEF-5 Scores in Randomly-Selected Community Men 40 to 80 Years Old: Preliminary Results. J Sex Med 2019;16:1567-1573.

15.
Br J Cancer ; 121(7): 522-528, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31417188

RESUMO

BACKGROUND: This pooled analysis investigated the prognostic value of depth of response in two cohorts of patients with BRAFV600-mutated metastatic melanoma treated with vemurafenib or cobimetinib plus vemurafenib. METHODS: The data were pooled from BRIM-2, BRIM-3, BRIM-7 and coBRIM. Association of depth of response with survival was estimated by Cox proportional hazards regression, adjusted for clinically relevant covariates. Depth of response was analysed in previously identified prognostic subgroups based on disease characteristics and gene signatures. RESULTS: Greater tumour reduction and longer time to maximal response were significantly associated with longer progression-free survival (PFS) and overall survival (OS) when evaluated as continuous variables. Patients with the deepest responses had long-lasting survival outcomes (median PFS: 14 months; OS: 32 months with vemurafenib; not estimable with cobimetinib plus vemurafenib). Cobimetinib plus vemurafenib improved depth of response versus vemurafenib monotherapy regardless of other prognostic factors, including gene signatures. CONCLUSIONS: Greater depth of response was associated with improved survival, supporting its utility as a measure of treatment efficacy in melanoma and further evaluation of its incorporation into existing prognostic models. Cobimetinib plus vemurafenib improved outcomes across quartiles of response regardless of prognostic factors or gene signatures and provided durable survival benefits in patients with deep responses.

16.
Int J Mol Sci ; 20(16)2019 Aug 07.
Artigo em Inglês | MEDLINE | ID: mdl-31394718

RESUMO

Allelopathy is a central process in crop-weed interactions and is mediated by the release of allelochemicals that result in adverse growth effects on one or the other plant in the interaction. The genomic mechanism for the biosynthesis of many critical allelochemicals is unknown but may involve the clustering of non-homologous biosynthetic genes involved in their formation and regulatory gene modules involved in controlling the coordinated expression within these gene clusters. In this study, we used the transcriptomes from mono- or co-cultured rice and barnyardgrass to investigate the nature of the gene clusters and their regulatory gene modules involved in the allelopathic interactions of these two plants. In addition to the already known biosynthetic gene clusters in barnyardgrass we identified three potential new clusters including one for quercetin biosynthesis and potentially involved in allelopathic interaction with rice. Based on the construction of gene networks, we identified one gene regulatory module containing hub transcription factors, significantly positively co-regulated with both the momilactone A and phytocassane clusters in rice. In barnyardgrass, gene modules and hub genes co-expressed with the gene clusters responsible for 2,4-dihydroxy-7-methoxy-1,4-benzoxazin-3-one (DIMBOA) biosynthesis were also identified. In addition, we found three genes in barnyardgrass encoding indole-3-glycerolphosphate synthase that regulate the expression of the DIMBOA cluster. Our findings offer new insights into the regulatory mechanisms of biosynthetic gene clusters involved in allelopathic interactions between rice and barnyardgrass, and have potential implications in controlling weeds for crop protection.

17.
J Immunother Cancer ; 7(1): 228, 2019 Aug 27.
Artigo em Inglês | MEDLINE | ID: mdl-31455411

RESUMO

BACKGROUND: A sequential combination of radiochemotherapy/endocrinotherapy and cytokine-induced killer cell (CIK) infusion has been shown to be an effective therapy for post-mastectomy breast cancer based on statistical analysis of the patient population. However, whether an individual could obtain an improved prognosis from CIK cell-based treatment remains unknown. In the present study, we focused on immune microenvironment regulation and specifically investigated the relationship between PD-L1 expression and survival benefit from CIK immunotherapy in breast cancer. METHODS: A total of 310 postoperative breast cancer patients who received comprehensive treatment were enrolled in this retrospective study, including 160 patients in the control group (received chemotherapy/radiotherapy/endocrinotherapy) and 150 patients in the CIK cell treatment group (received chemotherapy/radiotherapy/ endocrinotherapy and subsequent CIK infusion). RESULTS: We found that overall survival (OS) and recurrence-free survival (RFS) were significantly better in the CIK group than that in the control group. PD-L1 expression in tumor tissue sections was showed to be an independent prognostic factor for patients in the CIK treatment group using multivariate survival analysis. Further survival analysis in the CIK group showed that patients with PD-L1 tumor expression exhibited longer OS and RFS. In addition, among all patients who were enrolled in this study, only the patients with PD-L1 expression experienced survival benefits from CIK treatment. CONCLUSIONS: Our study showed the relationship between PD-L1 expression and CIK therapy and revealed that PD-L1 expression in the tumor is as an indicator of adjuvant CIK therapy for postoperative breast cancer.

18.
Planta ; 250(5): 1687-1702, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31414203

RESUMO

MAIN CONCLUSION: The study performed genome-wide identification, characterization and evolution analysis of gene clusters for phytoalexin terpenoid biosynthesis in tobacco, and specifically illustrated ones for capsidiol, an efficient defensive specialized metabolite. Terpenoid phytoalexins play an important role in plant self-defense against pest and pathogen attack. Terpenoid biosynthesis involves terpene synthase and cytochrome P450, which always locate and function as cluster(s). In this study, we performed genome-wide investigation of metabolic gene clusters involved in terpenoid production in tobacco (Nicotiana tabacum). Due to the complexity of the tobacco genome, we modified a published prediction pipeline to reduce the influence of the large number of repeats and to improve the annotation of tobacco genes with respect to their metabolic functions. We identified 1181 metabolic gene clusters with 34 of them potentially being involved in terpenoid biosynthesis. Through integration with transcriptome and metabolic pathway annotation analyses, 3 of the 34 terpenoid biosynthesis-related gene clusters were determined to be high-confidence ones, with 2 involved in biosynthesis of capsidiol, a terpenoid recognized as 1 of the effective resistance compounds in the Nicotiana species. The capsidiol-related gene cluster was conserved in N. sylvestris, N. tomentosiformis and N. attenuate. Our findings demonstrate that phytoalexins in tobacco can arise from operon-like gene clusters, a genomic pattern characterized as being beneficial for rapid stress response, gene co-regulation, co-function and co-heredity.

19.
Anticancer Drugs ; 30(8): 774-783, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31274516

RESUMO

DN604, containing a functional dicarboxylato ligand as carboplatin analogue, was significantly studied to explore its potency of antitumour activity. In vitro and in vivo experimental evidence indicated that DN604 exhibited superior antitumor activity than present platinum(II)-based agents in cervix squamous carcinoma SiHa cancer cells. Moreover, DN604 showed negligible toxic effects in vivo as confirmed as Pt accumulation and body weights of mice. Mechanistic studies have shown that DN604 suppressed CK2-mediated MRN complex to improve its antitumor efficacy by promoting DNA double-strand breaks repair. Furthermore, DN604 could inhibit Beclin1 and attenuate CK2-mediated several DSBs repair-related pathways, thus leading to cell apoptosis. Taken together, our research demonstrated that DN604 with the functional dicarboxylato ligand as the leaving group could effectively enhance chemo-sensitivity of SiHa cells to platinum-based agents via suppressing Beclin1 and CK2-mediated MRN-DSBs repair.

20.
Chin Med J (Engl) ; 132(15): 1802-1806, 2019 Aug 05.
Artigo em Inglês | MEDLINE | ID: mdl-31335476

RESUMO

BACKGROUND: Acute ankle fractures can lead to high rate of concomitant intra-articular lesions which may compromise clinical results. The purpose of this study was to evaluate the incidence of concomitant intra-articular lesions in acute ankle fractures with arthroscopy. We also sought to analyze the relationship between intra-articular lesions and the fracture type, as well as the severity of the fracture. METHODS: It was a retrospective cohort study. From April 2014 to December 2015, we have chosen arthroscopy-assisted open reduction and internal fixation (AORIF) for the treatment of unstable acute ankle fractures. All concomitant intra-articular lesions were assessed and documented carefully and prospectively, such as ligament injuries, osteochondral lesions, and tibiofibular syndesmosis injuries. All fractures were classified according to the Lauge-Hansen classification system. The American Orthopedic Foot and Ankle Society's (AOFAS) ankle-hindfoot scale was used to assess post-operative function. Statistical comparisons between the intra-articular lesions, the fracture type, and the severity of the presenting fracture were performed using a Chi-squared analysis. RESULTS: Data of 36 patients were analyzed in the study, including 23 supination-type fractures and 13 pronation-type fractures. The incidence of tibiofibular syndesmosis injuries, chondral lesions, and loose bodies were 92%, 72%, and 39%, respectively. Avulsion fractures of the anterior tibiofibular syndesmosis were more commonly found in supination-type fractures than pronation-type fracture (45% vs. 15%, χ = 5.78, P = 0.02), which would cause mechanical blocking in the anterior portion of the ankle. On the contrary, chondral lesions were more commonly found in the more severe fractures than mild fractures (86% vs. 53%, χ = 4.57, P = 0.03). A mean 41.7 months (range, 33.0-51.0 months) of follow-up was achieved. A mean AOFAS's ankle-hindfoot scale was 96.9, and 97.2% of the patients were satisfied with the procedure. CONCLUSIONS: Acute ankle fractures have a high incidence of concomitant intra-articular lesions. Avulsion fractures of the anterior tibiofibular syndesmosis are more commonly found in supination-type fractures. Chondral lesions are related to the severity of the fractures, but not with the classification of the fractures. AORIF can be one reliable solution in dealing with the associated injuries seen with acute ankle fractures.

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