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1.
Sci Adv ; 6(20): eaaz8411, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32426500

RESUMO

Transcriptional status determines the HIV replicative state in infected patients. However, the transcriptional mechanisms for proviral replication control remain unclear. In this study, we show that, apart from its function in HIV integration, LEDGF/p75 differentially regulates HIV transcription in latency and proviral reactivation. During latency, LEDGF/p75 suppresses proviral transcription via promoter-proximal pausing of RNA polymerase II (Pol II) by recruiting PAF1 complex to the provirus. Following latency reversal, MLL1 complex competitively displaces PAF1 from the provirus through casein kinase II (CKII)-dependent association with LEDGF/p75. Depleting or pharmacologically inhibiting CKII prevents PAF1 dissociation and abrogates the recruitment of both MLL1 and Super Elongation Complex (SEC) to the provirus, thereby impairing transcriptional reactivation for latency reversal. These findings, therefore, provide a mechanistic understanding of how LEDGF/p75 coordinates its distinct regulatory functions at different stages of the post-integrated HIV life cycles. Targeting these mechanisms may have a therapeutic potential to eradicate HIV infection.

2.
J Biomed Mater Res A ; 108(4): 984-991, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31904174

RESUMO

Mesenchymal stem cells (MSCs) have been widely applied in biomedicine due to their ability to differentiate into many different cell types and their ability to synthesize a broad spectrum of growth factors and cytokines that directly and indirectly influence other cells in their vicinity. To guide MSC infiltration to a bone fracture site, we developed a novel self-assembled Nano-Matrix which can be used as an injectable scaffold to repair bone fractures. The Nano-Matrix is formed by Janus base nanotubes (JBNTs) and fibronectin (FN). JBNTs are nucleobase-derived nanotubes mimicking collagen fibers, and FN is one of the cell adhesive glycoproteins which is responsible for cell-extracellular matrix interactions and guides stem cell migration and differentiation to desired cells types. Here, we demonstrated the successful fabrication and characterization of the JBNT/FN Nano-Matrix as well as its excellent bioactivity that encouraged human MSC migration and adhesion. This work lays a solid foundation for using the Nano-Matrix as an injectable approach to improve MSC retention and function during bone fracture healing.

3.
Artigo em Inglês | MEDLINE | ID: mdl-31765713

RESUMO

OBJECTIVES: Abnormal retina structures, such as thinner retinal nerve fiber layer (RNFL), have been frequently reported in patients with Alzheimer's disease (AD). However, the association between RNFL and brain structures in cognitively normal adults remains unknown. We therefore set out to conduct a cross-sectional investigation to determine whether RNFL thickness is associated with brain structure volumes in nondemented older adults. METHODS: We measured RNFL thickness by optical coherence tomography and brain structure volumes by 3 T magnetic resonance imaging. Cognitive function was assessed using the Chinese version of Repeatable Battery for the Assessment of Neurological Status. Pearson correlation was initially employed to screen for the potential associations among RNFL thickness, brain structure volumes and cognitive function. And then, multivariable linear regression models were conducted to further examine such associations adjusting for possible confounding factors, including age, sex, years of education and the estimated total intracranial volume (eTIV). RESULTS: 113 participants (≥ 65 years old) were screened and 80 of them (mean age: 68 ± 5.3 years; 48% male) were included in the final analysis. RNFL thickness in temporal quadrant was associated with medial temporal lobes volumes [unadjusted: r = 0.155, P = 0.175; adjusted: ß = 0.205 (0.014, 0.383), P = 0.035], and especially associated with the hippocampus volume [unadjusted: r = 0.213, P = 0.062; adjusted: ß = 0.251 (0.060, 0.435), P = 0.011] after adjusted for age, sex, years of education and eTIV. Moreover, it showed that RNFL thickness in inferior quadrant [unadjusted: r = 0.221, P = 0.052; adjusted: ß = 0.226 (0.010. 0.446), P = 0.041] was significantly associated with occipital lobes volumes after the adjustment of age, sex, years of education and eTIV, and selectively associated with the substructure of lingual gyrus volume [unadjusted: r = 0.223, P = 0.050; adjusted: ß = 0.278 (0.058, 0.487), P = 0.014]. In addition, average RNFL thickness was associated with the cognitive domain of visuospatial/constructional [unadjusted: r = 0.114, P = 0.322; adjusted: ß = 0.216 (0.006, 0.426), P = 0.044] after the adjustment in these nondemented older adults. CONCLUSIONS: Quadrant-specific associations exist between RNFL thickness and brain regions vulnerable to aging or neurodegeneration in older adults with normal cognition. These findings would promote further investigations into using RNFL as a noninvasive and less expensive biomarker of neurocognitive aging and AD-related neurodegeneration.

4.
Neurophotonics ; 6(3): 035014, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31572743

RESUMO

Accurate histopathological diagnosis is essential for facilitating the optimal surgical management of intracranial germinoma. Current intraoperative histological methods are time- and labor-intensive and often produce artifacts. Multiphoton microscopy (MPM) is a label-free imaging technique that can produce intraoperative histological images of fresh, unprocessed surgical specimens. We employ an MPM based on second-harmonic generation and two-photon excited fluorescence microscopy to image fresh, unfixed, and unstained human germinoma specimens. We show that label-free MPM is not only capable of identifying various cells in human germinoma tissue but also capable of revealing the characteristics of germinoma such as granuloma, stromal fibrosis, calcification, as well as the abnormal and uneven structures of blood vessels. In conjunction with custom-developed image-processing algorithms, MPM can further quantify and characterize the extent of stromal fibrosis and calcification. Our results provide insight into how MPM can deliver rapid diagnostic histological data that could inform the surgical management of intracranial germinoma.

5.
Anesthesiology ; 131(3): 492-500, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31335550

RESUMO

BACKGROUND: Postoperative delirium is one of the most common complications in the elderly surgical population. However, its long-term outcomes remain largely to be determined. Therefore a prospective cohort study was conducted to determine the association between postoperative delirium and long-term decline in activities of daily living and postoperative mortality. The hypothesis in the present study was that postoperative delirium was associated with a greater decline in activities of daily living and higher mortality within 24 to 36 months after anesthesia and surgery. METHODS: The participants (at least 65 yr old) having the surgeries of (1) proximal femoral nail, (2) hip replacement, or (3) open reduction and internal fixation under general anesthesia were enrolled. The Confusion Assessment Method algorithm was administered to diagnose delirium before and on the first, second, and fourth days after the surgery. Activities of daily living were evaluated by using the Chinese version of the activities of daily living scale (range, 14 to 56 points), and preoperative cognitive function was assessed by using the Chinese Mini-Mental State Examination (range, 0 to 30 points). The follow-up assessments, including activities of daily living and mortality, were conducted between 24 and 36 months after anesthesia and surgery. RESULTS: Of 130 participants (80 ± 6 yr, 24% male), 34 (26%) developed postoperative delirium during the hospitalization. There were 32% of the participants who were lost to follow-up, resulting in 88 participants who were finally included in the data analysis. The participants with postoperative delirium had a greater decline in activities of daily living (16 ± 15 vs. 9 ± 15, P = 0.037) and higher 36-month mortality (8 of 28, 29% vs. 7 of 75, 9%; P = 0.009) as compared with the participants without postoperative delirium. CONCLUSIONS: Postoperative delirium was associated with long-term detrimental outcomes, including greater decline in activities of daily living and a higher rate of postoperative mortality.


Assuntos
Atividades Cotidianas/psicologia , Delírio/epidemiologia , Delírio/psicologia , Complicações Pós-Operatórias/epidemiologia , Complicações Pós-Operatórias/psicologia , Idoso , Idoso de 80 Anos ou mais , China/epidemiologia , Estudos de Coortes , Feminino , Humanos , Estudos Longitudinais , Masculino , Estudos Prospectivos , Fatores de Risco
6.
Mol Cancer Ther ; 18(11): 2021-2029, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31341031

RESUMO

Chondrosarcoma is a highly aggressive primary malignant bone tumor mostly occurring in adults. There are no effective systemic treatments, and patients with this disease have poor survival. miR-181a is an oncomiR that is overexpressed in high-grade chondrosarcoma and promotes tumor progression. Regulator of G-protein signaling 16 (RGS16) is a target of miR-181a. Inhibition of RGS16 expression by miR-181a enhances CXC chemokine receptor 4 signaling, which in turn increases MMP1 and VEGF expression, angiogenesis, and metastasis. Here, we report the results of systemic treatment with anti-miRNA oligonucleotides (AMO) directed against miR-181a utilizing a nanopiece delivery platform (NPs). NPs were combined with a molecular beacon or anti-miR-181a oligonucleotides and are shown to transfect chondrosarcoma cells in vitro and in vivo Intratumoral injection and systemic delivery had similar effects on miR-181a expression in nude mice bearing chondrosarcoma xenografts. Systemic delivery of NPs carrying anti-miR-181a also restored RGS16 expression, decreased expression of VEGF and MMP1, MMP activity, and tumor volume by 32% at day 38, and prolonged survival from 23% to 45%. In conclusion, these data support that systemic delivery of AMO shows promise for chondrosarcoma treatment.

7.
J Biophotonics ; 12(10): e201900136, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31251837

RESUMO

Tumor microenvironment and metabolic activity in gliomas are the important biomarkers to evaluate the progression of gliomas. Many evidences have suggested that the targeting of metabolic activity and tumor microenvironment simultaneously can be more effective to take the tumor therapy. Therefore, the noninvasive, accurate assessment of tumor microenvironment and metabolic activity is quite important in clinical practice. Multiphoton microscopy (MPM), based on two-photon-excited fluorescence and second harmonic generation was performed on unstained glioma tissues. With our combined image analysis approaches, our research findings indicate that MPM is able to qualitatively and quantitatively describe the microenvironment characteristics in gliomas, such as collage deposition in extracellular matrix, lymphocyte infiltration and tumor angiogenesis, etc. Meanwhile, the metabolic activity can also be quantitatively evaluated by optical redox ratio, NADH and FAD intensity. With the microendoscope and fiberscope are portable, MPM technique can be used to perform in-vivo studies and clinical examinations in gliomas.

8.
Sci Adv ; 5(6): eaaw3593, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-31183407

RESUMO

Positive transcription elongation factor b (P-TEFb) functions as a central regulator of transcription elongation. Activation of P-TEFb occurs through its dissociation from the transcriptionally inactive P-TEFb/HEXIM1/7SK snRNP complex. However, the mechanisms of signal-regulated P-TEFb activation and its roles in human diseases remain largely unknown. Here, we demonstrate that cAMP-PKA signaling disrupts the inactive P-TEFb/HEXIM1/7SK snRNP complex by PKA-mediated phosphorylation of HEXIM1 at serine-158. The cAMP pathway plays central roles in the development of autosomal dominant polycystic kidney disease (ADPKD), and we show that P-TEFb is hyperactivated in mouse and human ADPKD kidneys. Genetic activation of P-TEFb promotes cyst formation in a zebrafish ADPKD model, while pharmacological inhibition of P-TEFb attenuates cyst development by suppressing the pathological gene expression program in ADPKD mice. Our study therefore elucidates a mechanism by which P-TEFb activation by cAMP-PKA signaling promotes cystogenesis in ADPKD.

9.
J Alzheimers Dis ; 69(3): 709-716, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31127777

RESUMO

 Previous studies showed that the Confusion Assessment Method based delirium severity evaluation tool (CAM-S) had good reliability and validity. However, there is no Chinese version of the CAM-S. Therefore, we set out to perform a prospective investigation in older Chinese patients who had total joint replacement surgery under general anesthesia in Tenth People's Hospital in Shanghai, P.R. China. A total of 576 participants, aged 60 years or older, were screened, 179 participants were enrolled, and 125 of them were included for the final analysis. Pre-operative evaluations were conducted one day before the surgery. Postoperative evaluations were conducted twice daily from postoperative day 1 to day 3. The incidence of postoperative delirium was 24.8%. The Chinese version of CAM-S [including a Short Form (CAM-S Short Form) and a Long Form (CAM-S Long Form)] had an optimal reliability reflected by internal consistency (Cronbach's α= 0.748 and 0.839 for CAM-S Short Form and CAM-S Long Form respectively), split-halves reliability (Pearson correlation coefficient = 0.372 and 0.384 for CAM-S Short Form and CAM-S Long Form respectively), and inter-rater reliability (intra-class correlation coefficients = 0.629 and 0.945 for CAM-S Short Form and CAM-S Long Form respectively). Additionally, the Chinese version of CAM-S also showed a good discriminate validity. The domain scores of CAM-S were inversely correlated with corresponding domain scores of the MMSE. Finally, a receiver operating characteristic (ROC) analysis obtained an optimal cutoff point of 2.5 for CAM-S Short Form and 3.5 for CAM-S Long Form in recognizing delirium diagnosed by CAM. The areas under the ROC were 0.989 (95% CI 0.972 - 1.000, p < 0.001) and 0.964 (95% CI 0.946 - 0.982, p < 0.001), respectively. These data suggest that the Chinese version of CAM-S has good reliability and validity in evaluating postoperative delirium in geriatric Chinese patients and may be a useful tool to assess the severity of delirium.

10.
J Gastric Cancer ; 19(1): 121-131, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30944765

RESUMO

Purpose: The significance of neuroendocrine differentiation (NED) in gastric carcinoma (GC) is controversial, leading to ambiguous concepts in traditional classifications. This study aimed to determine the prognostic threshold of meaningful NED in GC and clarify its unclear features in existing classifications. Materials and Methods: Immunohistochemical staining for synaptophysin, chromogranin A, and neural cell adhesion molecule was performed for 945 GC specimens. Survival analysis was performed using the log-rank test and univariate/multivariate models with percentages of NED (PNED) and demographic and clinicopathological parameters. Results: In total, 275 (29.1%) cases were immunoreactive to at least 1 neuroendocrine (NE) marker. GC-NED was more common in the upper third of the stomach. PNED, and Borrmann's classification and tumor, lymph node, metastasis stages were independent prognostic factors. The cutoff PNED was 10%, beyond which patients had significantly worse outcomes, although the risk did not increase with higher PNED. Tumors with ≥10% NED tended to manifest as Borrmann type III lesion with mixed/diffuse morphology and poorer histological differentiation; the NE components in this population mainly grew in insulae/nests, which differed from the predominant growth pattern (glandular/acinar) in GC with <10% NED. Conclusions: GC with ≥10% NED should be classified as a distinct subtype because of its worse prognosis, and more attention should be paid to the necessity of additional therapeutics for NE components.

11.
Front Aging Neurosci ; 11: 69, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31031615

RESUMO

Backgrounds: Abnormal retinal nerve fiber layer (RNFL) thickness has been observed in patients with Alzheimer's disease (AD) and therefore suggested to be a potential biomarker of AD. However, whether the changes in RNFL thickness are associated with the atrophy of brain structure volumes remains unknown. We, therefore, set out a prospective investigation to determine the association between longitudinal changes of RNFL thickness and brain atrophy in nondemented older participants over a period of 12 months. Materials and Methods: We measured the RNFL thickness using optical coherence tomography (OCT) and brain structure volumes by 3T magnetic resonance imaging (MRI) before and after 12 months. Cognitive function was assessed using the Chinese version of Mini-Mental State Examination (CMMSE) and Repeatable Battery for the Assessment of Neurological Status. Associations among the changes of RNFL, brain structures and cognitive function were analyzed with Spearman correlation and multiple linear regression models adjusting for the confounding factors. Results: Fifty old participants were screened and 40 participants (mean age 71.8 ± 3.9 years, 60% were male) were enrolled at baseline. Among them, 28 participants completed the follow-up assessments. The average reduction of RNFL thickness was inversely associated with the decrease of central cingulate cortex volume after the adjustment of age and total intracranial volume (ß = -0.41, P = 0.039). Specifically, the reduction of RNFL thickness in the inferior, not other quadrants, was independently associated with the decline of central cingulate cortex volume after the adjustment (ß = -0.52, P = 0.006). Moreover, RNFL thinning, central cingulate cortex atrophy and the aggregation of white matter hyperintensities (WMH) were found associated with episodic memory in these older adults with normal cognition. Conclusions: RNFL thinning was associated with cingulate cortex atrophy and episodic memory decline in old participants. The longitudinal changes of RNFL thickness are suggested to be a useful complementary index of neurocognitive aging or neurodegeneration.

12.
J Biophotonics ; 12(9): e201900006, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-30868750

RESUMO

Currently, the targeted treatment of tumor based on the tumor microenvironment is newly developed. Blood vessels are the key parts in the tumor microenvironment, which is taken as a new visible target for tumor therapy. Multiphoton microscopy (MPM), based on the second harmonic generation and two-photon excited fluorescence, is available to make the label-free analysis on the blood vessels in human gliomas. MPM can reveal the vascular morphological characteristics in gliomas, including vascular malformation, intense vascular proliferation, perivascular collagen deposition, perivascular lymphocytes aggregation and microvascular proliferation. In addition, the image analysis algorithms were developed to automatically calculate the perivascular collagen content, vascular cavity area, lumen area, wall area and vessel number. Thus, the vascular morphology, the perivascular collagen deposition and intense vascular proliferation degree can be further quantitatively characterized. Compared with the pathological analysis, the combination of MPM and image analysis has potential advantages in making a quantitative and qualitative analyzing on vascular morphology in glioma microenvironment. As micro-endoscope and two-photon fiberscope are technologically improved, this combined method will be a useful imaging way to make the real-time research on the targeting tumor microenvironment in gliomas.

13.
Thyroid ; 29(6): 809-823, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30924726

RESUMO

Background: Anaplastic thyroid carcinoma (ATC) is one of the most aggressive malignancies, with no effective treatment currently available. The molecular mechanisms of ATC carcinogenesis remain poorly understood. The objective of this study was to investigate the mechanisms and functions of super-enhancer (SE)-driven oncogenic transcriptional addiction in the progression of ATC and identify new drug targets for ATC treatments. Methods: High-throughput chemical screening was performed to identify new drugs inhibiting ATC cell growth. Cell viability assay, colony formation analysis, cell-cycle analysis, and animal study were used to examine the effects of drug treatments on ATC progression. Chromatin immunoprecipitation sequencing was conducted to establish a SE landscape of ATC. Integrative analysis of RNA sequencing, chromatin immunoprecipitation sequencing, and CRISPR/Cas9-mediated gene editing was used to identify THZ1 target genes. Drug combination analysis was performed to assess drug synergy. Patient samples were analyzed to evaluate candidate biomarkers of prognosis in ATC. Results: THZ1, a covalent inhibitor of cyclin-dependent kinase 7 (CDK7), was identified as a potent anti-ATC compound by high-throughput chemical screening. ATC cells, but not papillary thyroid carcinoma cells, are exceptionally sensitive to CDK7 inhibition. An integrative analysis of both gene expression profiles and SE features revealed that the SE-mediated oncogenic transcriptional amplification mediates the vulnerability of ATC cells to THZ1 treatment. Combining this integrative analysis with functional assays led to the discovery of a number of novel cancer genes of ATC, including PPP1R15A, SMG9, and KLF2. Inhibition of PPP1R15A with Guanabenz or Sephin1 greatly suppresses ATC growth. Significantly, the expression level of PPP1R15A is correlated with CDK7 expression in ATC tissue samples. Elevated expression of PPP1R15A and CDK7 are both associated with poor clinical prognosis in ATC patients. Importantly, CDK7 or PPP1R15A inhibition sensitizes ATC cells to conventional chemotherapy. Conclusions: Taken together, these findings demonstrate transcriptional addiction in ATC pathobiology and identify CDK7 and PPP1R15A as potential biomarkers and therapeutic targets for ATC.

14.
Eur J Nutr ; 58(2): 905, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30666402

RESUMO

In the original publication of the article error has occurred in Fig. 1b.

15.
Langmuir ; 34(37): 11126-11138, 2018 09 18.
Artigo em Inglês | MEDLINE | ID: mdl-30138560

RESUMO

In biomineralization and bioinspired mineralization, substrates and additives function synergistically in providing structural control of the mineralized layers including their orientation, polymorph, morphology, hierarchical architecture, etc. Herein, a novel type of granular aragonitic CaCO3-poly(acrylic acid) substrate guides the mineralization of prismatic CaCO3 thin films of distinct morphology and polymorph in the presence of different additives including organic compounds and polymers. For instance, weakly charged amino acids lead to columnar aragonite overlayers, while their charged counterparts and organic acids/bases inhibit the overgrowth. Employment of several specific soluble polymer additives in overgrowth instead results in calcitic overlayers with distinct hierarchical architecture, good hardness/Young's modulus, and under-water superoleophobicity. Interestingly, self-organized patterns in the CaCO3-poly(l-glutamic acid) overlayer are obtained under proper mineralization conditions. We demonstrate that the granular seed comprised of mineralized and polymeric constituents is a versatile platform for obtaining prismatic CaCO3 thin films, where structural control can be realized by the employment of different types of additives in overgrowth. We expect the methodology to be applied to a broad spectrum of bioinspired, prismatic-type crystalline products, aiming for the development of high-performance hybrids.

16.
BMC Infect Dis ; 18(1): 398, 2018 08 13.
Artigo em Inglês | MEDLINE | ID: mdl-30103690

RESUMO

BACKGROUND: Hand, foot, and mouth disease (HFMD) has been recognized as one of the leading infectious diseases among children in China, which causes hundreds of annual deaths since 2008. In China, the reports of monthly HFMD cases usually have a delay of 1-2 months due to the time needed for collecting and processing clinical information. This time lag is far from optimal for policymakers making decisions. To alleviate this information gap, this study uses a meta learning framework and combines publicly Internet-based information (Baidu search queries) for real-time estimation of HFMD cases. METHODS: We incorporate Baidu index into modeling to nowcast the monthly HFMD incidences in Guangxi, Zhejiang, Henan provinces and the whole China. We develop a meta learning framework to select appropriate predictive model based on the statistical and time series meta features. Our proposed approach is assessed for the HFMD cases within the time period from July 2015 to June 2016 using multiple evaluation metrics including root mean squared error (RMSE) and correlation coefficient (Corr). RESULTS: For the four areas: whole China, Guangxi, Zhejiang, and Henan, our approach is superior to the best competing models, reducing the RMSE by 37, 20, 20, and 30% respectively. Compared with all the alternative predictive methods, our estimates show the strongest correlation with the observations. CONCLUSIONS: In this study, the proposed meta learning method significantly improves the HFMD prediction accuracy, demonstrating that: (1) the Internet-based information offers the possibility for effective HFMD nowcasts; (2) the meta learning approach is capable of adapting to a wide variety of data, and enables selecting appropriate method for improving the nowcasting accuracy.


Assuntos
Doença de Mão, Pé e Boca/epidemiologia , Armazenamento e Recuperação da Informação , Internet , China/epidemiologia , Humanos , Incidência , Modelos Biológicos
17.
Acta Biomater ; 76: 29-38, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-29940371

RESUMO

Articular cartilage has a very limited ability to self-heal after injury or degeneration due to its low cellularity, poor proliferative activity, and avascular nature. Current clinical options are able to alleviate patient suffering, but cannot sufficiently regenerate the lost tissue. Biomimetic scaffolds that recapitulate the important features of the extracellular matrix (ECM) of cartilage are hypothesized to be advantageous in supporting cell growth, chondrogenic differentiation, and integration of regenerated cartilage with native cartilage, ultimately restoring the injured tissue to its normal function. It remains a challenge to support and maintain articular cartilage regenerated by bone marrow-derived mesenchymal stem cells (BMSCs), which are prone to hypertrophy and endochondral ossification after implantation in vivo. In the present work, a nanofibrous poly(l-lactic acid) (NF PLLA) scaffold developed by our group was utilized because of the desired highly porous structure, high interconnectivity, and collagen-like NF architecture to support rabbit BMSCs for articular cartilage regeneration. We further hypothesized that matrilin-3 (MATN3), a non-collagenous, cartilage-specific ECM protein, would enhance the microenvironment of the NF PLLA scaffold for cartilage regeneration and maintain the cartilage property. To test this hypothesis, we seeded BMSCs on the NF PLLA scaffold with or without MATN3. We found that MATN3 suppresses hypertrophy in this 3D culture system in vitro. Subcutaneous implantation of the chondrogenic cell/scaffold constructs in a nude mouse model showed that pretreatment with MATN3 was able to maintain chondrogenesis and prevent hypertrophy and endochondral ossification in vivo. These results demonstrate that the porous NF PLLA scaffold treated with MATN3 represents an advantageous 3D microenvironment for cartilage regeneration and phenotype maintenance, and is a promising strategy for articular cartilage repair. STATEMENT OF SIGNIFICANCE: Articular cartilage defects, caused by trauma, inflammation, or joint instability, may ultimately lead to debilitating pain and disability. Bone marrow-derived mesenchymal stem cells (BMSCs) are an attractive cell source for articular cartilage tissue engineering. However, chondrogenic induction of BMSCs is often accompanied by undesired hypertrophy, which can lead to calcification and ultimately damage the cartilage. Therefore, a therapy to prevent hypertrophy and endochondral ossification is of paramount importance to adequately regenerate articular cartilage. We hypothesized that MATN3 (a non-collagenous ECM protein expressed exclusively in cartilage) may improve regeneration of articular cartilage with BMSCs by maintaining chondrogenesis and preventing hypertrophic transition in an ECM mimicking nanofibrous scaffold. Our results showed that the administration of MATN3 to the cell/nanofibrous scaffold constructs favorably maintained chondrogenesis and prevented hypertrophy/endochondral ossification in the chondrogenic constructs in vitro and in vivo. The combination of nanofibrous PLLA scaffolds and MATN3 treatment provides a very promising strategy to generate chondrogenic grafts with phenotypic stability for articular cartilage repair.


Assuntos
Materiais Biomiméticos/química , Cartilagem , Células Imobilizadas , Proteínas Matrilinas/química , Transplante de Células-Tronco Mesenquimais/métodos , Células-Tronco Mesenquimais , Nanofibras/química , Osteogênese , Poliésteres/química , Regeneração , Tecidos Suporte/química , Animais , Cartilagem/lesões , Cartilagem/fisiologia , Células Imobilizadas/metabolismo , Células Imobilizadas/patologia , Células Imobilizadas/transplante , Hipertrofia , Células-Tronco Mesenquimais/metabolismo , Células-Tronco Mesenquimais/patologia , Coelhos
18.
Oncol Rep ; 40(1): 49-60, 2018 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-29749528

RESUMO

Claudin­3 expression is associated with gastric cancer progression, but the role of epigenetic modifications remains unclear. We investigated methylation of the claudin­3 promoter and expression profiles in gastric adenocarcinoma and their associations with clinicopathological characteristics and prognosis of the patients. A total of 122 patients with advanced gastric cancer [stage IIB­IV, with lymph node (LN) metastasis] were enrolled. Each patient provided 4 tissue samples: normal gastric epithelium, intestinal metaplasia, primary tumor and metastatic LN. Claudin­3 protein expression was examined by immunohistochemistry. Claudin­3 promoter methylation was determined by methylation­specific PCR and verified by bisulfite sequencing PCR. Claudin­3 mRNA expression was measured by real­time PCR in a subset of cases, and its correlation with protein expression was analyzed using Spearman correlation. Kaplan­Meier survival analysis was performed (log­rank test). Factors associated with survival were identified by Cox regression. The strong expression rate of claudin­3 in intestinal metaplasia, primary tumor, metastatic LN and normal gastric epithelium was 91.8, 58.2, 30.3 and 13.9%, respectively. The promoter hypermethylation rate in intestinal metaplasia, primary tumor, normal gastric epithelium and metastatic LN was 5.7, 27.9, 36.9 and 49.2%, respectively. Claudin­3 mRNA and protein expression were positively correlated (P<0.001) with normal gastric epithelium (rs=0.745), intestinal metaplasia (rs=0.876), primary gastric adenocarcinoma (rs=0.915) and metastatic LN (rs=0.819). Claudin­3 mRNA expression was negatively correlated with claudin­3 promoter methylation. Median patient survival was 38, 22 and 11 months in the hypomethylated, partially methylated and hypermethylated groups, respectively (P<0.001). Claudin­3 promoter methylation status (HR: 5.67; 95% CI: 2.27­14.17) but not claudin­3 expression was an independent predictor of survival. Claudin­3 promoter hypermethylation reduces claudin­3 expression and independently predicts poor prognosis.


Assuntos
Adenocarcinoma/genética , Claudina-3/genética , Metilação de DNA/genética , Metaplasia/genética , Neoplasias Gástricas/genética , Adenocarcinoma/patologia , Idoso , Biomarcadores Tumorais/genética , Intervalo Livre de Doença , Epigênese Genética , Feminino , Mucosa Gástrica/patologia , Regulação Neoplásica da Expressão Gênica , Humanos , Imuno-Histoquímica , Metástase Linfática , Masculino , Metaplasia/patologia , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Prognóstico , Regiões Promotoras Genéticas , Neoplasias Gástricas/patologia
19.
Langmuir ; 34(21): 6063-6069, 2018 05 29.
Artigo em Inglês | MEDLINE | ID: mdl-29737857

RESUMO

Underwater superoleophobic surfaces have attracted great attention due to their broad applications such as anti-oil adhesion, oil capture and transportation, and oil/water separation. However, it is often fairly complex and time-consuming, involved in the construction of micro/nanostructures and the regulation of chemical compositions; there is an urgent need to develop new strategies to conquer these problems. Inspired by the strong anchoring capability and easy accessibility of plant polyphenols, we can readily and rapidly fabricate tannic acid (TA) coated copper surfaces with the excellent underwater super oil-repellent property. To achieve the optimal condition for TA modification, the influence of immersion time, TA concentration, and pH value on underwater-oil wettability and adhesion has been systematically explored. Furthermore, the underwater super oil-repellent feature can be widely achieved for different oils and on various metal sheets, suggesting the potential applications for plenty of fields such as anti-oil pollution.

20.
Oncol Lett ; 15(6): 8261-8268, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29805560

RESUMO

Death associated protein kinase 1 (DAPK1) is a notable serine/threonine kinase involved in the regulation of multiple cellular pathways, including apoptosis and autophagy. Although DAPK1 is usually considered to be a tumor suppressor, it was previously reported to promote the viability of p53 mutant cancer cell lines and possess physiological oncogenic functions in breast cancer. However, the ability of endogenous DAPK1 to suppress breast cancer cell mobility has not been assessed. In the present study, the prognostic function of DAPK1 in a Chinese patient cohort was evaluated, and no significant association was observed between DAPK1 expression and patient survival or lymph node metastasis. In order to investigate the physiological function of endogenous DAPK1, stable inducible DAPK1 knockdown MCF7 and MDA-MB-231 cell lines were established. Consistent with previous studies, endogenous DAPK1 only regulated cell viability in p53 mutant MDA-MB-231 cells. However, knockdown of DAPK1 did not significantly affect cell motility of either MCF7 or MDA-MB-231 cells. Altogether, these results further explored the function of endogenous DAPK1 in breast cancer and may shed light in understanding the molecular signaling pathways regulating the physiological function of DAPK1.

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