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1.
Anat Rec (Hoboken) ; 2021 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-34469051

RESUMO

Alzheimer's disease (AD) is a fatal neurodegenerative disease for which currently no cure is available. Electroacupuncture (EA) has been widely used in China as an alternative therapeutic approach for neurological diseases. The cognitive decline in patients with AD has been reported to be closely related to the deposition of amyloid-ß (Aß) in the hippocampus of the brain, and the Morris water maze (MWM) test is a widely used method for assessing the behavior of animal models. In this study, the MWM test was performed to evaluate the effects of EA treatment on cognitive function and memory, and the micro-positron emission tomography scan was used to assess the hippocampal Aß deposition. The results showed that the cognitive function of APP/PS1 mice was significantly improved and the rate of [18F]AV-45 uptake was reduced in the EA group, compared with the AD group. Our study suggested that EA can exert a therapeutic effect in AD by improving spatial learning and memory and inhibiting the hippocampal Aß deposition.

2.
Aging (Albany NY) ; 13(13): 17568-17591, 2021 07 04.
Artigo em Inglês | MEDLINE | ID: mdl-34226295

RESUMO

The homeostasis of the ocular lens is maintained by a microcirculation system propagated through gap junction channels. It is well established that the intercellular communications of the lens become deteriorative during aging. However, the molecular basis for this change in human lenses has not been well defined. Here, we present evidence to show that over 90% of Cx46 and Cx50 are lost in the fiber cells of normal human lenses aged 50 and above. From transparent to cataractous lenses, while Cx43 was upregulated, both Cx46 and Cx50 were significantly down-regulated in the lens epithelia. During aging of mouse lenses, Cx43 remained unchanged, but both Cx46 and Cx50 were significantly downregulated. Under oxidative stress treatment, mouse lenses develop in vitro cataractogenesis. Associated with this process, Cx43 was significantly upregulated, in contrast, Cx46 and Cx50 were sharply downregulated. Together, our results for the first time reveal that downregulation in Cx46 and Cx50 levels appears to be the major reason for the diminished coupling conductance, and the aging-dependent loss of Cx46 and Cx50 promotes senile cataractogenesis.


Assuntos
Envelhecimento/fisiologia , Catarata/genética , Catarata/patologia , Conexinas/biossíntese , Conexinas/genética , Cristalino/patologia , Idoso , Idoso de 80 Anos ou mais , Envelhecimento/metabolismo , Envelhecimento/patologia , Animais , Epitélio Corneano/patologia , Feminino , Regulação da Expressão Gênica , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Pessoa de Meia-Idade
3.
Nat Commun ; 12(1): 60, 2021 01 04.
Artigo em Inglês | MEDLINE | ID: mdl-33397900

RESUMO

Long nanopore reads are advantageous in de novo genome assembly. However, nanopore reads usually have broad error distribution and high-error-rate subsequences. Existing error correction tools cannot correct nanopore reads efficiently and effectively. Most methods trim high-error-rate subsequences during error correction, which reduces both the length of the reads and contiguity of the final assembly. Here, we develop an error correction, and de novo assembly tool designed to overcome complex errors in nanopore reads. We propose an adaptive read selection and two-step progressive method to quickly correct nanopore reads to high accuracy. We introduce a two-stage assembler to utilize the full length of nanopore reads. Our tool achieves superior performance in both error correction and de novo assembling nanopore reads. It requires only 8122 hours to assemble a 35X coverage human genome and achieves a 2.47-fold improvement in NG50. Furthermore, our assembly of the human WERI cell line shows an NG50 of 22 Mbp. The high-quality assembly of nanopore reads can significantly reduce false positives in structure variation detection.


Assuntos
Nanoporos , Análise de Sequência de DNA , Linhagem Celular , Cromossomos Humanos/genética , Genoma Humano , Humanos , Retinoblastoma/genética , Software
4.
Lancet Digit Health ; 3(2): e88-e97, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33509389

RESUMO

BACKGROUND: Ocular changes are traditionally associated with only a few hepatobiliary diseases. These changes are non-specific and have a low detection rate, limiting their potential use as clinically independent diagnostic features. Therefore, we aimed to engineer deep learning models to establish associations between ocular features and major hepatobiliary diseases and to advance automated screening and identification of hepatobiliary diseases from ocular images. METHODS: We did a multicentre, prospective study to develop models using slit-lamp or retinal fundus images from participants in three hepatobiliary departments and two medical examination centres. Included participants were older than 18 years and had complete clinical information; participants diagnosed with acute hepatobiliary diseases were excluded. We trained seven slit-lamp models and seven fundus models (with or without hepatobiliary disease [screening model] or one specific disease type within six categories [identifying model]) using a development dataset, and we tested the models with an external test dataset. Additionally, we did a visual explanation and occlusion test. Model performances were evaluated using the area under the receiver operating characteristic curve (AUROC), sensitivity, specificity, and F1* score. FINDINGS: Between Dec 16, 2018, and July 31, 2019, we collected data from 1252 participants (from the Department of Hepatobiliary Surgery of the Third Affiliated Hospital of Sun Yat-sen University, the Department of Infectious Diseases of the Affiliated Huadu Hospital of Southern Medical University, and the Nantian Medical Centre of Aikang Health Care [Guangzhou, China]) for the development dataset; between Aug 14, 2019, and Jan 31, 2020, we collected data from 537 participants (from the Department of Infectious Diseases of the Third Affiliated Hospital of Sun Yat-sen University and the Huanshidong Medical Centre of Aikang Health Care [Guangzhou, China]) for the test dataset. The AUROC for screening for hepatobiliary diseases of the slit-lamp model was 0·74 (95% CI 0·71-0·76), whereas that of the fundus model was 0·68 (0·65-0·71). For the identification of hepatobiliary diseases, the AUROCs were 0·93 (0·91-0·94; slit-lamp) and 0·84 (0·81-0·86; fundus) for liver cancer, 0·90 (0·88-0·91; slit-lamp) and 0·83 (0·81-0·86; fundus) for liver cirrhosis, and ranged 0·58-0·69 (0·55-0·71; slit-lamp) and 0·62-0·70 (0·58-0·73; fundus) for other hepatobiliary diseases, including chronic viral hepatitis, non-alcoholic fatty liver disease, cholelithiasis, and hepatic cyst. In addition to the conjunctiva and sclera, our deep learning model revealed that the structures of the iris and fundus also contributed to the classification. INTERPRETATION: Our study established qualitative associations between ocular features and major hepatobiliary diseases, providing a non-invasive, convenient, and complementary method for hepatobiliary disease screening and identification, which could be applied as an opportunistic screening tool. FUNDING: Science and Technology Planning Projects of Guangdong Province; National Key R&D Program of China; Guangzhou Key Laboratory Project; National Natural Science Foundation of China.


Assuntos
Algoritmos , Simulação por Computador , Aprendizado Profundo , Doenças do Sistema Digestório/diagnóstico , Olho , Programas de Rastreamento/métodos , Modelos Biológicos , Adulto , Área Sob a Curva , China , Túnica Conjuntiva/diagnóstico por imagem , Doenças do Sistema Digestório/complicações , Olho/diagnóstico por imagem , Fundo de Olho , Humanos , Iris/diagnóstico por imagem , Fígado , Pessoa de Meia-Idade , Fotografação/métodos , Estudos Prospectivos , Curva ROC , Esclera/diagnóstico por imagem , Microscopia com Lâmpada de Fenda/métodos
5.
CNS Neurosci Ther ; 27(4): 449-463, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33314758

RESUMO

AIMS: Acyl-CoA synthetase long chain family member 4 (ACSL4) is closely related to tumor genesis and development in certain tissues. However, the function of ACSL4 in early brain injury (EBI) caused by subarachnoid hemorrhage (SAH) is unclear. In this study, we investigated the expression patterns and role of ACSL4 in SAH and post-SAH EBI using a rat model of SAH. METHODS: The rat model of SAH was induced by autologous blood injection into the prechiasmatic cistern of rats. We also used two specific inhibitors of ferroptosis (Ferrostatin-1 and Liproxstatin-1) to investigate the role of ferroptosis in EBI. RESULTS: We found that ACSL4 levels in brain tissue increased significantly in post-SAH EBI. Inhibiting the expression of ACSL4 using small interfering RNAs alleviated inflammation, blood-brain barrier (BBB) impairment, oxidative stress, brain edema, and behavioral and cognitive deficits, and increased the number of surviving neurons, after SAH. Similar effects were obtained by suppressing ferroptosis. CONCLUSIONS: ACSL4 exacerbated SAH-induced EBI by mediating ferroptosis. These findings may provide a theoretical basis for potential therapy aimed at alleviating post-SAH EBI.

6.
World J Gastrointest Oncol ; 12(11): 1216-1236, 2020 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-33250957

RESUMO

BACKGROUND: Programmed death ligand 1 (PD-L1) immunotherapy remains poorly efficacious in colorectal cancer (CRC). The recepteur d'origine nantais (RON) receptor tyrosine kinase plays an important role in regulating tumor immunity. AIM: To identify the patterns of RON and PD-L1 expression and explore their clinical significance in CRC. METHODS: Gene expression data from the Gene Expression Omnibus database (GEO; n = 290) and patients at the First Affiliated Hospital, Zhejiang University School of Medicine (FAHZUSM; n = 381) were analyzed to determine the prognostic value of RON and PD-L1 expression within the tumor microenvironment of CRC. HT29 cell line was treated with BMS-777607 to explore the relationship between RON activity and PD-L1 expression. Signaling pathways and protein expression perturbed by RON inhibition were evaluated by cellular immunofluorescence and Western blot. RESULTS: In the GEO patient cohort, cut-off values for RON and PD-L1 expression were determined to be 7.70 and 4.3, respectively. Stratification of patients based on these cutoffs demonstrated that high expression of RON and PD-L1 was associated with a poor prognosis. In the FAHZUSM cohort, rates of high expression of RON in tumor cells, high PD-L1 expression in tumor cells and tumor infiltrating monocytes, and both high RON and high PD-L1 expression in the tumor microenvironment were 121 (32%), 43 (11%), 91 (24%), and 51 (13.4%), respectively. High expression of RON was significantly correlated with high expression of PD-L1 in the tumor cell compartment (P < 0.001). High expression of RON and that of PD-L1 were independent prognostic factors for poorer overall survival. Concurrent high expression of both RON and PD-L1 in the tumor microenvironment was significantly associated with a poor prognosis. In vitro, BMS-777607 inhibited the phosphorylation of RON, inhibited PD-L1 expression, and attenuated activation of the ERK1/2 and AKT signaling pathways in CRC cells. CONCLUSION: RON, PD-L1, and their crosstalk are significant in predicting the prognostic value of CRC. Moreover, phosphorylation of RON upregulates PD-L1 expression, which provides a novel approach to immunotherapy in CRC.

7.
Trials ; 21(1): 813, 2020 Sep 29.
Artigo em Inglês | MEDLINE | ID: mdl-32993769

RESUMO

BACKGROUND: Currently, whether and when intraocular pressure (IOP)-lowering medication should be used in glaucoma suspects with high myopia (GSHM) remains unknown. Glaucoma suspects are visual field (VF) defects that cannot be explained by myopic macular changes or other retinal and neurologic conditions. Glaucoma progression is defined by VF deterioration. Here we describe the rationale, design, and methodology of a randomized controlled trial (RCT) designed to evaluate the effects of medically lowering IOP in GSHM (GSHM study). METHODS: The GSHM study is an open-label, single-center, RCT for GSHM. Overall, 264 newly diagnosed participants, aged 35 to 65 years, will be recruited at the Zhongshan Ophthalmic Center, Sun Yat-sen University, between 2020 and 2021. Participants will be randomly divided into two arms at a 1:1 ratio. Participants in the intervention arm will receive IOP-lowering medication, while participants in the control arm will be followed up without treatment for 36 months or until they reach the end point. Only one eye per participant will be eligible for the study. If both eyes are eligible, the eye with the worse VF will be recruited. The primary outcome is the incidence of glaucoma suspect progression by VF testing over 36 months. The secondary outcomes include the incidence of changes in the optic nerve head morphology including the retinal nerve fiber layer, and retinal ganglion cell-inner plexiform layer loss, progression of myopic maculopathy, visual function loss, and change in the quality of life. Statistical analyses will include baseline characteristics comparison between the intervention and control groups using a two-sample t-test and Wilcoxon rank sum test; generalized linear models with Poisson regression for the primary outcome; Kaplan-Meier curve and log-rank test for the incidence of the secondary outcome; and longitudinal analyses to assess trends in outcomes across time. DISCUSSION: To the best of our knowledge, the GSHM study is the first RCT to investigate the impact of medically lowering IOP in GSHM. The results will have implications for the clinical management of GSHM. TRIAL REGISTRATION: ClinicalTrials.gov NCT04296916 . Registered on 4 March 2020.


Assuntos
Glaucoma , Miopia , Progressão da Doença , Glaucoma/diagnóstico , Glaucoma/tratamento farmacológico , Humanos , Pressão Intraocular , Miopia/diagnóstico , Miopia/tratamento farmacológico , Ensaios Clínicos Controlados Aleatórios como Assunto , Transtornos da Visão
8.
Cancer Res Treat ; 52(3): 973-986, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32324988

RESUMO

PURPOSE: Triple-negative breast cancer (TNBC) is highly malignant and has poor prognosis and a high mortality rate. The lack of effective therapy has spurred our investigation of new targets for treating this malignant cancer. Here, we identified RON (macrophage-stimulating 1 receptor) and MET (MET proto-oncogene, receptor tyrosine kinase) as a prognostic biomarker and therapeutic targets for potential TNBC treatment. Materials and Methods: We analyzed RON and MET expression in 187 primary TNBC clinical samples with immunohistochemistry. We validated the targeted therapeutic effects of RON and MET in TNBC using three tyrosine kinase inhibitors (TKIs): BMS-777607, INCB28060, and tivantinib. The preclinical therapeutic efficacy of the TKIs was mainly estimated using a TNBC xenograft model. RESULTS: Patients with TNBC had widespread, abnormal expression of RON and MET. There was RON overexpression, MET overexpression, and RON and MET co-overexpression in 63 (33.7%), 63 (33.7%), and 43 cases (23.0%), respectively, which had poor prognosis and short survival. In vivo, the TKI targeting RON ant MET inhibited the activation of the downstream signaling molecules, inhibited TNBC cell migration and proliferation, and increased TNBC cell apoptosis; in the xenograft model, they significantly inhibited tumor growth and shrank tumor volumes. The TKI targeting RON and Met, such as BMS-777607 and tivantinib, yielded stronger anti-tumor effects than INCB28060. CONCLUSION: RON and MET co-overexpression can be significant pathological characteristics in TNBC for poor prognosis. TKIs targeting RON and MET have stronger drug development potential for treating TNBC.


Assuntos
Biomarcadores Tumorais/metabolismo , Inibidores de Proteínas Quinases/farmacologia , Proteínas Proto-Oncogênicas c-met/metabolismo , Receptores Proteína Tirosina Quinases/metabolismo , Neoplasias de Mama Triplo Negativas/mortalidade , Adulto , Idoso , Idoso de 80 Anos ou mais , Animais , Apoptose , Biomarcadores Tumorais/genética , Movimento Celular , Proliferação de Células , Feminino , Seguimentos , Regulação Neoplásica da Expressão Gênica , Humanos , Camundongos , Camundongos Nus , Pessoa de Meia-Idade , Prognóstico , Proteínas Proto-Oncogênicas c-met/genética , Receptores Proteína Tirosina Quinases/genética , Taxa de Sobrevida , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Neoplasias de Mama Triplo Negativas/metabolismo , Neoplasias de Mama Triplo Negativas/patologia , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de Xenoenxerto
9.
Int J Ophthalmol ; 13(2): 284-291, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32090039

RESUMO

AIM: To develop a novel approach called the Autoacuity Tester, and to evaluate its validity, especially the sensitivity and specificity for detecting amblyopia. METHODS: Children aged from 3 to 12y (n=552) were enrolled in the study. The validity of the Autoacuity Tester was evaluated by comparing it to the Tumbling E Early Treatment Diabetic Retinopathy Study (ETDRS) acuity chart for school age children, and Lea Symbols and Teller acuity card (TAC) for preschool children. The repeatability was assessed by coefficient of repeatability (COR). The sensitivity and specificity for detecting amblyopia were calculated. RESULTS: The mean difference (95% limits of agreement) between the Autoacuity Tester and the ETDRS tests were -0.03 (-0.24, 0.19) logMAR for the school age group. In preschool children, the mean difference was 0.04 (-0.14, 0.21) logMAR between the Autoacuity Tester and the TAC and 0.00 (-0.17, 0.18) logMAR between the Autoacuity Tester and the Lea Symbols. For the school age group, the COR was 0.20 logMAR for the Autoacuity Tester and 0.18 logMAR for the ETDRS. For the preschool group, the COR was 0.13 logMAR for the Autoacuity Tester and 0.21 logMAR for TAC. The Autoacuity Tester (88%) is more sensitive than TAC (72%) in detecting amblyopia (P=0.04), while had similar specificity (92% vs 90%, P=0.20). CONCLUSION: The Autoacuity Tester provides a reliable alternative for assessing visual acuity, and offers advantage of higher testability and repeatability for preschool children.

10.
Int J Ophthalmol ; 12(12): 1839-1847, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31850165

RESUMO

AIM: To study the change in ocular refraction in patients with pediatric cataracts (PCs) after lens extraction. METHODS: A total of 1258 patients who were undergoing cataract extraction with/without intraocular lens (IOL) implantation were recruited during preoperative examinations between Jan 2010 and Oct 2013. Patient ages ranged from 1.5mo to 14y. Follow-ups were conducted at 1wk, 1, and 3mo postoperatively and every 3mo in the first year, then 6mo thereafter. Ocular refraction [evaluated as spherical equivalent (SE)] and yearly myopic shift (YMS) were recorded and statistically analyzed among patients with age at surgery, baseline ocular refraction, gender, postoperative time and laterality (bilateral vs unilateral). RESULTS: By Dec 31st 2015, 1172 participants had been followed for more than 2y. The median follow-up period was 3y. The critical factors affecting the ocular refraction of PC patients were baseline ocular refraction, postoperative time for both aphakic and pseudophakic eyes. YMS grew most rapidly in young childhood and early adolescence. CONCLUSION: After lens surgeries, ocular refraction in PC patients shows an individual difference of change. Further concerns should be raising to monitor the rapid myopic shift at early adolescence of these patients.

11.
Front Oncol ; 9: 1377, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31867280

RESUMO

RON (recepteur d'origine nantais) and MET (hepatocyte growth factor receptor) are tyrosine kinase receptors. Various cancers have aberrant RON and MET expression and activation, which contribute to cancer cell proliferation, invasiveness, and metastasis. Here, we explored RON and MET expression in pancreatic cancer and their relationship with overall survival (OS) time, and evaluated their significance as therapeutic targets of tyrosine kinase inhibitors in pancreatic cancer. We enrolled 227 patients with pancreatic cancer in the study. RON and MET expression was analyzed by immunohistochemical staining. Four human pancreatic cancer cell lines expressing variable levels of RON or MET and four MET superfamily inhibitors (BMS777607, PHA665752, INCB28060, Tivantinib) were used. The effect of the four tyrosine kinase inhibitors on cell viability, migration, and apoptosis were determined using cell viability, scratch wound healing, and Caspase-Glo 3/7 assays. Cellular signaling was analyzed by immunoprecipitation and western blotting. The therapeutic efficacy of the tyrosine kinase inhibitors was determined with mouse xenograft pancreatic cancer models in vivo. There was wide aberrant RON and MET expression in the cancer tissues. In 227 pancreatic cancer samples, 33% had RON overexpression, 41% had MET overexpression, and 15.4% had RON and MET co-overexpression. RON and MET expression were highly correlated. RON and MET expression levels were significantly related to OS. Patients with RON and MET co-overexpression had poorer OS. BMS777607 and PHA665752 inhibited pancreatic cancer cell viability and migration, and promoted apoptosis by inhibiting RON and MET phosphorylation and further inhibiting the downstream signaling pathways in vitro. They also inhibited tumor growth and further inhibited phosphorylated (phosphor)-RON and phospho-MET expression in the mouse xenograft models in vivo effectively. INCB28060, which inhibits the MET signaling pathway alone, was not effective. RON and MET can be important indicators of prognosis in pancreatic cancer. Tyrosine kinase inhibitors targeting RON and MET in pancreatic cancer are a novel and potential approach for pancreatic cancer therapy.

12.
Int J Ophthalmol ; 12(10): 1517-1523, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31637185

RESUMO

AIM: To investigate the mechanism of celastrol in inhibiting lens epithelial cells (LECs) fibrosis, which is the pathological basis of cataract. METHODS: Human LEC line SRA01/04 was treated with celastrol and transforming growth factor-ß2 (TGF-ß2). Wound-healing assay, proliferation assay, flow cytometry, real-time polymerase chain reaction (PCR), Western blot and immunocytochemical staining were used to detect the pathological changes of celastrol on LECs. Then, we cultured Sprague-Dawley rat lens in medium as a semi-in vivo model to find the function of celastrol further. RESULTS: We found that celastrol inhibited the migration of LECs, as well as proliferation (P<0.05). In addition, it induced the G2/M phase arrest by cell cycle-related proteins (P<0.01). Moreover, celastrol inhibited epithelial-mesenchymal transition (EMT) by the blockade of TGF-ß/Smad and Jagged/Notch signaling pathways. CONCLUSION: Our study demonstrates that celastrol could inhibit TGF-ß2-induced lens fibrosis and raises the possibility that celastrol could be a potential novel drug in prevention and treatment of fibrotic cataract.

13.
J Immunother Cancer ; 7(1): 250, 2019 09 13.
Artigo em Inglês | MEDLINE | ID: mdl-31519211

RESUMO

BACKGROUND: Antibody-drug conjugates (ADCs) targeting the RON receptor, a tumorigenic factor contributing to cancer malignancy, has been considered as a novel strategy for cancer therapy. Here we describe a humanized antibody recognizing the RON plexin-semaphorin-integrin (PSI) domain with increased drug delivery capability for potential clinical application. METHOD: Monoclonal antibody PCM5B14 specific to the human and monkey RON PSI domain was generated and characterized by various immunological methods. Humanized antibody H5B14 was created by grafting PCM5B14 complementarity-determining regions into human IgG1/κ acceptor frameworks and conjugated with monomethyl auristatin E and duocarmycin to form two H5B14-based ADCs. Stability of H5B14-based ADCs in human plasma was measured using hydrophobic interaction chromatography. Various biochemical and biological assays were used to determine ADC- regulated RON internalization, cell viability, spheroid formation, and death of cancer stem-like cells. Efficacies of H5B14-based ADCs in vivo were validated using tumor xenograft models. Maximal tolerated doses of H5B14-based ADCs were established in mice. RESULTS: H5B14 was highly specific to the human RON PSI domain and superior over other anti-RON ADCs in induction of RON internalization in various cancer cell lines tested. H5B14-based ADCS had a drug to antibody ratio of ~ 3.70:1 and were stable in human plasma with a minimal dissociation within a 10-day period. Functionally, H5B14-mediated drug delivery decreased cell viability at early stages with an average IC50 at ~ 20 nM in multiple cancer cell lines examined. H5B14-based ADCs also inhibited spheroid formation and caused death of cancer stem-like cells with RON+/CD44+/ESA+ phenotypes. In vivo, H5B14-based ADCs in a single injection inhibited tumor xenograft growth mediated by multiple cancer cell lines. Tumoristatic concentrations calculated from xenograft tumor models were in the range of 0.63 to 2.0 mg/kg bodyweight. Significantly, H5B14-based ADCs were capable of eradicating tumors at variable levels across multiple xenograft models regardless their malignant statuses. Toxicologically, H5B14-based ADCs were well tolerated in mice up to 60 mg/kg. CONCLUSION: H5B14-based ADCs targeting the RON PSI domain are superior in inducing RON internalization, leading to robust drug delivery and overall inhibition and eradication of tumors in multiple xenograft models. These findings warrant H5B14-based ADCs for clinical trials in the future.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Imunoconjugados/administração & dosagem , Neoplasias/tratamento farmacológico , Receptores Proteína Tirosina Quinases/antagonistas & inibidores , Animais , Anticorpos Monoclonais Humanizados/administração & dosagem , Anticorpos Monoclonais Humanizados/imunologia , Protocolos de Quimioterapia Combinada Antineoplásica/imunologia , Linhagem Celular Tumoral , Duocarmicinas/administração & dosagem , Duocarmicinas/imunologia , Feminino , Humanos , Imunoconjugados/imunologia , Dose Máxima Tolerável , Camundongos , Neoplasias/imunologia , Oligopeptídeos/administração & dosagem , Oligopeptídeos/imunologia , Domínios Proteicos/imunologia , Receptores Proteína Tirosina Quinases/imunologia , Ensaios Antitumorais Modelo de Xenoenxerto
14.
Int J Ophthalmol ; 12(8): 1323-1329, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31456924

RESUMO

AIM: To investigate the behavioral and psychological disorders and the prevalence of parent ratings of attention deficit hyperactivity disorder (ADHD) symptoms among children with bilateral congenital cataracts (CCs). METHODS: This cross-sectional study investigated children with bilateral CC aged 3-8y (CC group) using Conners' Parent Rating Scale-48 (CPRS-48) from July to December 2016. The abnormal rates of psychological symptoms in CC children and normal vision (NV) children were compared using the Chi-square test. The scores of CC children were compared with those of NV children and the Chinese urban norm using the independent samples t-test and one-sample t-test, respectively. RESULTS: A total of 262 valid questionnaires were collected. The ratio of CC children to NV children was 119:143. The overall rate of psychological symptoms in CC children was 2.28 times higher than that in NV children (46.22% vs 20.28%, Pearson's χ 2=20.062; P<0.001). CC children showed higher scores for conduct problems, learning problems, impulsiveness/hyperactivity, anxiety, and hyperactivity index than NV children and the Chinese urban norm, particularly between the ages of 3 and 5y. Furthermore, male children aged between 6 and 8y showed a higher impulsive/hyperactive score than females of the same age (t=6.083, P<0.001). CONCLUSION: Children with bilateral CCs have a higher rate of ADHD symptoms than children with NV. This study provides clinical evidence that screening for psychological symptoms and particularly for ADHD symptoms in children with bilateral CC are recommended for an early diagnosis and timely treatment.

15.
Int J Ophthalmol ; 10(12): 1835-1843, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-29259901

RESUMO

AIM: To compare visual prognoses and postoperative adverse events of congenital cataract surgery performed at different times and using different surgical approaches. METHODS: In this prospective, randomized controlled trial, we recruited congenital cataract patients aged 3mo or younger before cataract surgery. Sixty-one eligible patients were randomly assigned to two groups according to surgical timing: a 3-month-old group and a 6-month-old group. Each eye underwent one of three randomly assigned surgical procedures, as follows: surgery A, lens aspiration (I/A); surgery B, lens aspiration with posterior continuous curvilinear capsulorhexis (I/A+PCCC); and surgery C, lens aspiration with posterior continuous curvilinear capsulorhexis and anterior vitrectomy (I/A+PCCC+A-Vit). The long-term best-corrected visual acuity (BCVA) and the incidence of complications in the different groups were compared and analyzed. RESULTS: A total of 57 participants (114 eyes) with a mean follow-up period of 48.7mo were included in the final analysis. The overall logMAR BCVA in the 6-month-old group was better than that in the 3-month-old group (0.81±0.28 vs 0.96±0.30; P=0.02). The overall logMAR BCVA scores in the surgery B group were lower than the scores in the A and C groups (A: 0.80±0.29, B: 1.02±0.28, and C: 0.84±0.28; P=0.007). A multivariate linear regression revealed no significant relationships between the incidence of complications and long-term BCVA. CONCLUSION: It might be safer and more beneficial for bilateral total congenital cataract patients to undergo surgery at 6mo of age than 3mo. Moreover, with rigorous follow-up and timely intervention, the postoperative complications in these patients are treatable and do not compromise visual outcomes.

16.
Am J Cancer Res ; 6(12): 2816-2830, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-28042502

RESUMO

Uveal melanoma (UM) is the most common primary ocular malignancy in adults. Currently, no beneficial systemic therapy is available; therefore, there is an urgent need for effective targeted therapeutic drugs. As verteporfin has shown anti-neoplastic activity in several types of cancers, here we hypothesized and investigated the efficacy of verteporfin against UM cells without light activation. MTS assay, flow cytometry analysis of apoptosis, Western blotting of relevant proteins, transwell migration and invasion assay, melanosphere culture, and measurement of ALDH+ populations, were used to evaluate the effects of verteporfin on UM cells. We found that verteporfin disrupted the interaction between YAP and TEAD4 in UM cells and decreased the expression of YAP targeted downstream genes. Verteporfin treatment decreased the cytoplasmic and nuclear levels of YAP and induced lysosome-dependent degradation of YAP protein. Verteporfin exhibited distinct inhibitory effect on the proliferation of four lines of UM cells (e.g., 92.1, Mel 270, Omm 1 and Omm 2.3), and induced apoptosis through the intrinsic pathway. Additionally, verteporfin suppressed migration and invasion of UM cells, impaired the traits of cancer stem-like cells (e.g., melanosphere formation capacity, and ALDH+ cell population). This study demonstrated the anti-neoplastic activity of verteporfin against UM cells in vitro, providing a rationale for evaluating this agent in clinical investigation.

17.
Proc Natl Acad Sci U S A ; 111(15): 5574-9, 2014 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-24706897

RESUMO

The mammalian small ubiquitin-like modifiers (SUMOs) are actively involved in regulating differentiation of different cell types. However, the functional differences between SUMO isoforms and their mechanisms of action remain largely unknown. Using the ocular lens as a model system, we demonstrate that different SUMOs display distinct functions in regulating differentiation of epithelial cells into fiber cells. During lens differentiation, SUMO1 and SUMO2/3 displayed different expression, localization, and targets, suggesting differential functions. Indeed, overexpression of SUMO2/3, but not SUMO1, inhibited basic (b) FGF-induced cell differentiation. In contrast, knockdown of SUMO1, but not SUMO2/3, also inhibited bFGF action. Mechanistically, specificity protein 1 (Sp1), a major transcription factor that controls expression of lens-specific genes such as ß-crystallins, was positively regulated by SUMO1 but negatively regulated by SUMO2. SUMO2 was found to inhibit Sp1 functions through several mechanisms: sumoylating it at K683 to attenuate DNA binding, and at K16 to increase its turnover. SUMO2 also interfered with the interaction between Sp1 and the coactivator, p300, and recruited a repressor, Sp3 to ß-crystallin gene promoters, to negatively regulate their expression. Thus, stable SUMO1, but diminishing SUMO2/3, during lens development is necessary for normal lens differentiation. In support of this conclusion, SUMO1 and Sp1 formed complexes during early and later stages of lens development. In contrast, an interaction between SUMO2/3 and Sp1 was detected only during the initial lens vesicle stage. Together, our results establish distinct roles of different SUMO isoforms and demonstrate for the first time, to our knowledge, that Sp1 acts as a major transcription factor target for SUMO control of cell differentiation.


Assuntos
Diferenciação Celular/fisiologia , Células Epiteliais/fisiologia , Regulação da Expressão Gênica/fisiologia , Cristalino/crescimento & desenvolvimento , Proteínas Modificadoras Pequenas Relacionadas à Ubiquitina/metabolismo , Fator de Transcrição Sp1/metabolismo , Sumoilação/fisiologia , Animais , Western Blotting , Imunoprecipitação da Cromatina , Primers do DNA/genética , Ensaio de Desvio de Mobilidade Eletroforética , Fatores de Crescimento de Fibroblastos/metabolismo , Imuno-Histoquímica , Imunoprecipitação , Cristalino/citologia , Camundongos , Reação em Cadeia da Polimerase Via Transcriptase Reversa
18.
J Fluoresc ; 24(3): 657-63, 2014 May.
Artigo em Inglês | MEDLINE | ID: mdl-24337815

RESUMO

This paper presents the preparation of a pyrazoline compound and the properties of its UV-Vis absorption and fluorescence emission. Moreover, this compound can be used to determine Hg(2+) ion with selectivity and sensitivity in the EtOH:H2O =9:1 (v/v) solution. This sensor forms a 1:1 complex with Hg(2+) and shows a fluorescent enhancement with good tolerance of other metal ions. This sensor is very sensitive with fluorometric detection limit of 3.85 × 10(-10) M. In addition, the fluorescent probe has practical application in cells imaging.


Assuntos
Técnicas Biossensoriais , Corantes Fluorescentes/química , Mercúrio/análise , Pirazóis/química , Estrutura Molecular , Espectrometria de Fluorescência
19.
Zhonghua Yan Ke Za Zhi ; 49(5): 389-91, 2013 May.
Artigo em Chinês | MEDLINE | ID: mdl-24021176

RESUMO

Phacoemulsification and intraocular lens implantation is the most effective treatment of cataract.Traditional intraocular lens were mainly monofocal. Postoperative patients can return to a certain distance vision or near vision, but because of the loss of accommodative power, patients must rely on glasses to complete the work of the different distances, the postoperative life there is still a lot of inconvenience. In recent years, the design of multifocal intraocular lens has been the focus of basic and applied research in cataract, but so far the researchers still could not have agreement with the strengths and weaknesses of the multifocal and monofocal intraocular lens. There are three major controversies: First of all, whether it is worth the expense of contrast sensitivity and increased visual disturbance in return for compensatory adjustment? Second, whether it is possible to really get the full range of vision and to get rid of dependence on glasses to use multifocal intraocular lens? Third, how to grasp the indications of multifocal intraocular lens to play to their strengths.


Assuntos
Lentes Intraoculares , Desenho de Prótese , Sensibilidades de Contraste , Humanos , Acuidade Visual
20.
Cornea ; 32(4): e25-30, 2013 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-23073488

RESUMO

PURPOSE: The purpose was to determine the interchangeability of ultrasound biomicroscopy (UBM) and anterior segment optical coherence tomography (AS-OCT) for corneal opacity depth measurement. METHODS: Twenty-six eyes of 26 consecutive patients with corneal opacities were examined by both AS-OCT and UBM. The corneal thickness and the corneal opacity depth were measured and compared. The interchangeability was determined by Bland-Altman plotting. RESULTS: The difference in the full corneal thickness and in the corneal opacity depth between OCT and UBM was 5 ± 7 µm and -1 ± 8 µm, respectively. There were strong correlations and no significant differences between the paired parameters (all r > 0.99, P < 0.01). The limits of agreement were 5 ± 14 µm for the corneal thickness and -1 ± 14.8 µm for the corneal opacity depth. CONCLUSIONS: AS-OCT and UBM may be used interchangeably for measuring both full corneal thickness and corneal opacity depth in patients with corneal opacity.


Assuntos
Opacidade da Córnea/diagnóstico , Microscopia Acústica , Tomografia de Coerência Óptica , Adolescente , Adulto , Idoso , Substância Própria/patologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Reprodutibilidade dos Testes , Adulto Jovem
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