Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 25
Filtrar
Mais filtros










Base de dados
Intervalo de ano de publicação
1.
Rev Sci Instrum ; 92(1): 013704, 2021 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-33514196

RESUMO

Exploring the corresponding relation between structural and physical properties of materials at the atomic scale remains the fundamental problem in science. With the development of the aberration-corrected transmission electron microscopy (AC-TEM) and the ultrafast optical spectroscopy technique, sub-angstrom-scale spatial resolution and femtosecond-scale temporal resolution can be achieved, respectively. However, the attempt to combine both their advantages is still a great challenge. Here, we develop in situ optical spectroscopy with high temporal resolution in AC-TEM by utilizing a self-designed and manufactured TEM specimen holder, which has the capacity of sub-angstrom-scale spatial resolution and femtosecond-scale temporal resolution. The key and unique design of our apparatus is the use of the fiber bundle, which enables the delivery of focused pulse beams into TEM and collection of optical response simultaneously. The generated focused spot has a size less than 2 µm and can be scanned in plane with an area larger than 75 × 75 µm2. Most importantly, the positive group-velocity dispersion caused by glass fiber is compensated by a pair of diffraction gratings, thus resulting in the generation of pulse beams with a pulse width of about 300 fs (@ 3 mW) in TEM. The in situ experiment, observing the atomic structure of CdSe/ZnS quantum dots in AC-TEM and obtaining the photoluminescence lifetime (∼4.3 ns) in the meantime, has been realized. Further ultrafast optical spectroscopy with femtosecond-scale temporal resolution could be performed in TEM by utilizing this apparatus.

2.
Aging (Albany NY) ; 13(2): 2348-2364, 2020 12 11.
Artigo em Inglês | MEDLINE | ID: mdl-33323548

RESUMO

Long noncoding RNAs (lncRNAs) promote invasion and migration by glioblastoma (GBM) cells. In this study, quantitative real-time polymerase chain reaction was used to detect expression levels of the lncRNA HOTAIRM1 in GBM tissue samples and cells. The function of HOTAIRM1 was examined using wound healing assays, transwell assays, and in vivo experiments after GBM cells were transfected with either sh-ctrl or sh-HOTAIRM1. Luciferase reporter assays and RIP assays were performed to determine the interactions between HOTAIRM1 and miR-153-5p and between miR-153-5p and SNAI2. We also used luciferase reporter assays and ChIP assays to assess the transcriptional regulation of HOTAIRM1 by SNAI2 and CDH1. HOTAIRM1 was significantly overexpressed in GBM tissues and cells. HOTAIRM1 knockdown significantly weakened the migration and invasion by GBM cells. HOTAIRM1 was found to sponge miR-153-5p, and SNAI2 is a direct target of miR-153-5p. In addition, SNAI2 was shown to force HOTAIRM1 expression through directly promoting transcription and suppressing the negative regulation of CDH1 on transcription. Our results indicate a positive feedback loop between HOTAIRM1 and SNAI2, and suggest that the lncRNA HOTAIRM1 is a potential biomarker and therapeutic target in GBM.

3.
Brain Imaging Behav ; 2020 Sep 26.
Artigo em Inglês | MEDLINE | ID: mdl-32979169

RESUMO

To investigate resting-state connectivity and further understand directional aspects of implicit alterations in presbycusis patients, we used degree centrality (DC) and Granger causality analysis (GCA) to detect functional hubs of the whole-brain network and then analyze directional connectivity. Resting-state functional magnetic resonance imaging (fMRI) scans were performed on 40 presbycusis patients and 40 healthy controls matched for age, gender, and education. We used DC analysis and GCA to characterize abnormal brain networks in presbycusis patients. The associations of network centrality and directed functional connectivity (FC) with clinical measures of presbycusis were also examined according to the above results. We found that the network centrality of left frontal middle gyrus (MFG) was significantly lower than that of healthy control group. Unidirectionally, the left MFG revealed increased directional connectivity to the left superior frontal gyrus (SFG), while the left MFG exhibited decreased directional connectivity to the left middle temporal gyrus (MTG) and right lingual gyrus (LinG). And the decreased directional connectivity was found from the left precentral gyrus (PrCG) to the left MFG. In addition, the Trail-Making Test B (TMT-B) score was negatively correlated with the decreased DC of the left MFG (r = -0.359, p = 0.032). Resting-state fMRI provides a novel method for identifying aberrant brain network architecture. These results primarily indicate altered functional hubs and abnormal frontal lobe connectivity patterns that may further reflect executive dysfunction in patients with presbycusis.

4.
Mol Cancer ; 19(1): 128, 2020 08 24.
Artigo em Inglês | MEDLINE | ID: mdl-32838810

RESUMO

BACKGROUND: Deregulated circular RNAs (circRNAs) are associated with the development of cancer and therapy resistance. However, functional research of circRNAs mostly focus on potential miRNA or protein binding and more potential regulation of circRNA on host gene DNA in cancers are yet to be inspected. METHOD: We performed total RNA sequencing on clinical breast cancer samples and identified the expression patterns of circRNAs and corresponding host genes in patient blood, tumor and adjacent normal tissues. qPCR, northern blot and in situ hybridization were used to validate the dysregulation of circRNA circSMARCA5. A series of procedures including R-loop dot-blotting, DNA-RNA immunoprecipitation and mass spectrum, etc. were conducted to explore the regulation of circSMARCA5 on the transcription of exon 15 of SMARCA5. Moreover, immunofluorescence and in vivo experiments were executed to investigate the overexpression of circSMARCA5 with drug sensitivities. RESULTS: We found that circRNAs has average higher expression over its host linear genes in peripheral blood. Compared to adjacent normal tissues, circSMARCA5 is decreased in breast cancer tissues, contrary to host gene SMARCA5. The enforced expression of circSMARCA5 induced drug sensitivity of breast cancer cell lines in vitro and in vivo. Furthermore, we demonstrated that circSMARCA5 can bind to its parent gene locus, forming an R-loop, which results in transcriptional pausing at exon 15 of SMARCA5. CircSMARCA5 expression resulted in the downregulation of SMARCA5 and the production of a truncated nonfunctional protein, and the overexpression of circSMARCA5 was sufficient to improve sensitivity to cytotoxic drugs. CONCLUSION: Our results revealed a new regulatory mechanism for circRNA on its host gene and provided evidence that circSMARCA5 may serve as a therapeutic target for drug-resistant breast cancer patients.

5.
Sci Total Environ ; 707: 135903, 2020 Mar 10.
Artigo em Inglês | MEDLINE | ID: mdl-31972907

RESUMO

To resolve the increasingly higher energy and environmental pressures, the evaluation of environmental efficiency in China's iron and steel industry is essential for identifying a precise energy conservation and emission reduction path. However, current studies have only focused on the efficiency evaluation in national, regional, or enterprise level, lacking the analysis of different processes. Therefore, the objective of this research is to conduct a process-level data envelopment analysis (DEA) to evaluate the environmental efficiency of China's iron and steel industry. Totally, 54 enterprises are contained, as the input-output structure of 5 processes: sintering, coking, ironmaking, steelmaking, and steel rolling are set specifically in this study. In addition, to compare the effects to the efficiency results of different DEA methods, Banker, Charnes & Cooper (BCC) model, Slack-based Measure (SBM) model, and Bootstrap-DEA methods are adopted. Finally, a regression model is used to investigate the key environmental protection strategies influencing the environmental efficiency. The results show that: (1) Within different methods, the average efficiency scores from SBM model are lower than the ones from BCC model, and the Bootstrap-DEA method also has a negative modification. (2) Regional efficiency difference exists, as the enterprises in South China perform best in sintering and coking processes but have the lowest overall efficiency scores. (3) Most enterprises have one or more short board processes. 12 enterprises are the enterprises with individual low environmental efficiency process, while other 25 are the enterprises with imbalanced environmental performances. (4) The coefficient factor between environmental protection investment and the efficiency scores are positive, but the factors of proportion of environmental protection staffs, and whether the enterprise has environmental protection research are negative. In sum, this study is hoped to contribute to formulating more precise environmental management measures in China's iron and steel industry.

6.
Brain Imaging Behav ; 14(3): 917-926, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31270776

RESUMO

Presbycusis, associated with a diminished quality of life characterized by bilateral sensorineural hearing loss at high frequencies, has become an increasingly critical public health problem. This study aimed to identify directed functional connectivity (FC) of the hippocampus in patients with presbycusis and to explore the causes if the directed functional connections of the hippocampus were disrupted. Presbycusis patients (n = 32) and age-, sex-, and education-matched healthy controls (n = 40) were included in this study. The seed regions of bilateral hippocampus were selected to identify directed FC in patients with presbycusis using Granger causality analysis (GCA) approach. Correlation analyses were conducted to detect the associations of disrupted directed FC of hippocampus with clinical measures of presbycusis. Compared to healthy controls, decreased directed FC between inferior parietal lobule, insula, right supplementary motor area, middle temporal gyrus and hippocampus were detected in presbycusis patients. Furthermore, a negative correlation between TMB score and the decline of directed FC from left inferior parietal lobule to left hippocampus (r = -0.423, p = 0.025) and from right inferior parietal lobule to right hippocampus (r = -0.516, p = 0.005) were also observed. The decreased directed functional connections of the hippocampus were detected in patients with presbycusis, which was associated with specific cognitive performance. This study mainly emphasizes the crucial role of hippocampus in presbycusis and will enhance our understanding of the neuropathological mechanisms of presbycusis.

7.
Front Neurosci ; 13: 1299, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31866810

RESUMO

Purpose: The phantom sound of tinnitus is considered to be associated with abnormal functional coupling between the nucleus accumbens (NAc) and the prefrontal cortex, which may form a frontostriatal top-down gating system to evaluate and modulate sensory signals. Resting-state functional magnetic resonance imaging (fMRI) was used to recognize the aberrant directional connectivity of the NAc in chronic tinnitus and to ascertain the relationship between this connectivity and tinnitus characteristics. Methods: Participants included chronic tinnitus patients (n = 50) and healthy controls (n = 55), matched for age, sex, education, and hearing thresholds. The hearing status of both groups was comparable. On the basis of the NAc as a seed region, a Granger causality analysis (GCA) study was conducted to investigate the directional connectivity and the relationship with tinnitus duration or distress. Results: Compared with healthy controls, tinnitus patients exhibited abnormal directional connectivity between the NAc and the prefrontal cortex, principally the middle frontal gyrus (MFG), orbitofrontal cortex (OFC), and inferior frontal gyrus (IFG). Additionally, positive correlations between tinnitus handicap questionnaire (THQ) scores and increased directional connectivity from the right NAc to the left MFG (r = 0.357, p = 0.015) and from the right MFG to the left NAc (r = 0.626, p < 0.001) were observed. Furthermore, the enhanced directional connectivity from the right NAc to the right OFC was positively associated with the duration of tinnitus (r = 0.599, p < 0.001). Conclusion: In concurrence with expectations, tinnitus distress was correlated with enhanced directional connectivity between the NAc and the prefrontal cortex. The current study not only helps illuminate the neural basis of the frontostriatal gating control of tinnitus sensation but also contributes to deciphering the neuropathological features of tinnitus.

8.
Oncol Rep ; 40(6): 3714-3724, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30272343

RESUMO

Adoptive chimeric antigen receptor (CAR) T or NK cells offer new options for cancer treatment. Clinical results indicate that CAR­modified T cell (CAR­T) therapy has curative therapeutic efficacy for hematological malignancies. However, the efficacy of the therapy in most solid tumors, including advanced renal cell carcinoma (RCC), remains highly limited. New regimens, including combination of CAR­T cells with chemical drugs, must be studied to enhance the therapeutic efficacy of CAR­T or NK cells for solid tumors. In the present study, a carbonic anhydrase IX (CAIX)­specific third­generation CAR was transduced into NK92 cells by lentiviral vectors. The immune effects, including cytokine release and cytotoxicity, of the CAR­NK92 cells against CAIX­positive RCC cells were evaluated in vitro. Combination therapeutic effects of bortezomib and CAR­NK92 cells were analyzed in a mouse model with human RCC xenografts. The results revealed that CAIX­specific CAR­NK92 cells specifically recognized in vitro cultured CAIX­positive RCC cells and released cytokines, including IFN­Î³, perforin and granzyme B, and exhibited specific cytotoxicity. The cytotoxicity of the CAR­NK92 cells was enhanced after treating RCC cells with bortezomib in vitro. The suppressive efficacy of bortezomib combined with CAR­NK92 cells against established CAIX­positive tumor xenografts was more significant than that of the monotherapy with either CAR­NK92 cells or bortezomib. Therefore, bortezomib can enhance the effects of the CAR­NK92 cells against RCC in vitro and in vivo. This study provided an experimental basis for the novel clinical regimen of CAIX­specific CAR­modified NK or T cells for the treatment of RCC.


Assuntos
Antígenos de Neoplasias/metabolismo , Bortezomib/administração & dosagem , Anidrase Carbônica IX/metabolismo , Carcinoma de Células Renais/terapia , Neoplasias Renais/terapia , Leucócitos Mononucleares/transplante , Receptores de Antígenos Quiméricos/metabolismo , Animais , Bortezomib/farmacologia , Carcinoma de Células Renais/metabolismo , Linhagem Celular Tumoral , Terapia Baseada em Transplante de Células e Tecidos , Terapia Combinada , Citocinas/metabolismo , Regulação Neoplásica da Expressão Gênica , Humanos , Imunoterapia Adotiva , Neoplasias Renais/metabolismo , Leucócitos Mononucleares/efeitos dos fármacos , Leucócitos Mononucleares/metabolismo , Camundongos , Transdução Genética , Ensaios Antitumorais Modelo de Xenoenxerto
9.
Neuropsychiatr Dis Treat ; 14: 1919-1927, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30122924

RESUMO

Purpose: The default mode network (DMN) has been confirmed to be involved in chronic tinnitus perception. Tinnitus distress may be associated with abnormal functional connectivity (FC) within the DMN regions. The goal of this study was to determine whether tinnitus disrupted the FC patterns within the DMN as measured by using resting-state functional magnetic resonance imaging approach. Patients and methods: Resting-state functional magnetic resonance imaging scans were acquired from 40 chronic bilateral tinnitus patients and 41 healthy controls. Both were age, sex, and education well-matched with normal hearing. Two important DMN regions, the anterior cingulate cortex and posterior cingulate cortex, were chosen as seed regions to detect the FC patterns within the DMN and then determine whether these changes were linked to clinical measures of tinnitus such as tinnitus duration and tinnitus severity. Results: Compared with healthy controls, chronic tinnitus patients manifested significantly enhanced FC between the anterior cingulate cortex and left precuneus, which was correlated with the tinnitus duration (r=0.451, p=0.007). Moreover, enhanced FC between the posterior cingulate cortex and right medial prefrontal cortex in tinnitus patients was positively correlated with the tinnitus distress (r=0.411, p=0.014). Conclusion: Chronic tinnitus patients showed disrupted FC patterns within the DMN regions which are correlated with tinnitus distress. Increased resting-state connectivity pattern of the DMN may play a pivotal role in neuropathological features underlying chronic tinnitus.

10.
Oncol Lett ; 16(2): 2063-2070, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30008901

RESUMO

Chimeric antigen receptor (CAR) T-cell therapies have been demonstrated to have durable and potentially curative therapeutic efficacies in patients with hematological malignancies. Currently, multiple clinical trials in CAR-T cell therapy have been evaluated for the treatment of patients with solid malignancies, but have had less marked therapeutic effects when the agents are used as monotherapies. When summarizing relevant studies, the present study found that combination therapy strategies for solid tumors based on CAR-T cell therapies might be more effective. This review will focus on various aspects of treating solid tumors with CAR-T cell therapy: i) The therapeutic efficacy of CAR-T cell monotherapy, ii) the feasibility of the CAR-T cell therapy in conjunction with chemotherapy, iii) the feasibility of CAR-T cell therapy with radiotherapy, iv) the feasibility of CAR-T cell therapy with chemoradiotherapy, and v) the feasibility of the combination of CAR-T cell therapy with other strategies.

11.
Front Aging Neurosci ; 10: 59, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29556191

RESUMO

Purpose: Chronic subjective tinnitus may arise from aberrant functional coupling between the cerebellum and the cerebral cortex. To explore this hypothesis, we used resting-state functional magnetic resonance imaging (fMRI) to illuminate the functional connectivity network of the cerebellar regions in chronic tinnitus patients and controls. Methods: Resting-state fMRI scans were obtained from 28 chronic tinnitus patients and 29 healthy controls (well matched for age, sex and education) in this study. Cerebellar-cerebral functional connectivity was characterized using a seed-based whole-brain correlation method. The resulting cerebellar functional connectivity measures were correlated with each clinical tinnitus characteristic. Results: Chronic tinnitus patients demonstrated increased functional connectivity between the cerebellum and several cerebral regions, including the superior temporal gyrus (STG), parahippocampal gyrus (PHG), inferior occipital gyrus (IOG), and precentral gyrus. The enhanced functional connectivity between the left cerebellar Lobule VIIb and the right STG was positively correlated with the Tinnitus Handicap Questionnaires (THQ) score (r = 0.577, p = 0.004). Furthermore, the increased functional connectivity between the cerebellar vermis and the right STG was also associated with the THQ score (r = 0.432, p = 0.039). Conclusions: Chronic tinnitus patients have greater cerebellar functional connectivity to certain cerebral brain regions which is associated with specific tinnitus characteristics. Resting-state cerebellar-cerebral functional connectivity disturbances may play a pivotal role in neuropathological features of tinnitus.

12.
Front Behav Neurosci ; 12: 44, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29593512

RESUMO

Purpose: Presbycusis, age-related hearing loss, is believed to involve neural changes in the central nervous system, which is associated with an increased risk of cognitive impairment. The goal of this study was to determine if presbycusis disrupted spontaneous neural activity in specific brain areas involved in auditory processing, attention and cognitive function using resting-state functional magnetic resonance imaging (fMRI) approach. Methods: Hearing and resting-state fMRI measurements were obtained from 22 presbycusis patients and 23 age-, sex- and education-matched healthy controls. To identify changes in spontaneous neural activity associated with age-related hearing loss, we compared the amplitude of low-frequency fluctuations (ALFF) and regional homogeneity (ReHo) of fMRI signals in presbycusis patients vs. controls and then determined if these changes were linked to clinical measures of presbycusis. Results: Compared with healthy controls, presbycusis patients manifested decreased spontaneous activity mainly in the superior temporal gyrus (STG), parahippocampal gyrus (PHG), precuneus and inferior parietal lobule (IPL) as well as increased neural activity in the middle frontal gyrus (MFG), cuneus and postcentral gyrus (PoCG). A significant negative correlation was observed between ALFF/ReHo activity in the STG and average hearing thresholds in presbycusis patients. Increased ALFF/ReHo activity in the MFG was positively correlated with impaired Trail-Making Test B (TMT-B) scores, indicative of impaired cognitive function involving the frontal lobe. Conclusions: Presbycusis patients have disrupted spontaneous neural activity reflected by ALFF and ReHo measurements in several brain regions; these changes are associated with specific cognitive performance and speech/language processing. These findings mainly emphasize the crucial role of aberrant resting-state ALFF/ReHo patterns in presbycusis patients and will lead to a better understanding of the neuropathological mechanisms underlying presbycusis.

13.
Front Neurosci ; 12: 9, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29410609

RESUMO

Purpose: The anterior cingulate cortex (ACC) has been suggested to be involved in chronic subjective tinnitus. Tinnitus may arise from aberrant functional coupling between the ACC and cerebral cortex. To explore this hypothesis, we used resting-state functional magnetic resonance imaging (fMRI) to illuminate the functional connectivity (FC) network of the ACC subregions in chronic tinnitus patients. Methods: Resting-state fMRI scans were obtained from 31 chronic right-sided tinnitus patients and 40 healthy controls (age, sex, and education well-matched) in this study. Rostral ACC and dorsal ACC were selected as seed regions to investigate the intrinsic FC with the whole brain. The resulting FC patterns were correlated with clinical tinnitus characteristics including the tinnitus duration and tinnitus distress. Results: Compared with healthy controls, chronic tinnitus patients showed disrupted FC patterns of ACC within several brain networks, including the auditory cortex, prefrontal cortex, visual cortex, and default mode network (DMN). The Tinnitus Handicap Questionnaires (THQ) scores showed positive correlations with increased FC between the rostral ACC and left precuneus (r = 0.507, p = 0.008) as well as the dorsal ACC and right inferior parietal lobe (r = 0.447, p = 0.022). Conclusions: Chronic tinnitus patients have abnormal FC networks originating from ACC to other selected brain regions that are associated with specific tinnitus characteristics. Resting-state ACC-cortical FC disturbances may play an important role in neuropathological features underlying chronic tinnitus.

14.
Mol Med Rep ; 17(2): 2083-2088, 2018 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-29207115

RESUMO

The immune system serves an important role in controlling and eradicating malignant cells. Immunotherapy for treating tumors has received much attention in recent years due to its marked effect. There are two approaches which currently lead this field: Chimeric antigen receptor­modified T­cell immunotherapy (CAR­T) and programmed cell death protein-1 blockade (PD­1 blockade). CAR­T has emerged as a promising regimen for the treatment of a range of types of cancer, including chronic lymphoid leukemia and neuroblastoma, with studies of long term remission in certain patients. PD­1 blockade has been reported to exert marked clinical responses in patients against a range of types of solid cancer, including advanced melanoma, non­small­cell lung cancer and renal cell carcinoma, in addition to hematological malignancies. While increasing the power of the immune system to fight cancer has been a long­standing goal in oncology, a number of studies have demonstrated the synergistic antitumor effects of combination therapies under the umbrella of immunotherapy. The present review focused on a novel combination approach involving CAR­T and PD­1 blockade. The present reviews aimed to discuss the following four aspects of such an approach: i) Current monotherapy status; ii) rationale for the combination of CAR­T and PD­1 blockade; iii) current status of the combination of CAR­T and PD­1 blockade; and iv) conclusions and future perspectives.


Assuntos
Imunoterapia , Terapia de Alvo Molecular , Neoplasias/imunologia , Neoplasias/terapia , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Receptores de Antígenos de Linfócitos T/metabolismo , Linfócitos T/imunologia , Linfócitos T/metabolismo , Animais , Terapia Combinada , Humanos , Receptores de Antígenos de Linfócitos T/genética
15.
Expert Rev Anticancer Ther ; 17(12): 1099-1106, 2017 12.
Artigo em Inglês | MEDLINE | ID: mdl-29048935

RESUMO

INTRODUCTION: Chimeric antigen receptor modified T cell (CAR-T) therapy has achieved encouraging breakthroughs in the treatment of hematological malignancies. Nevertheless, this success has not yet been extrapolated to solid tumors. This review focuses on new clinical regimens that could improve the therapeutic efficacy of CAR-T in solid tumors. Areas covered: Herein, the authors reviewed recent clinical trials using CAR-T therapies for the treatment of solid tumors. Specifically, this review covered the following areas: (1) the current status of CAR-T cells in the treatment of solid tumors; (2) the major factors constraining the efficacy of CAR-T cells in solid tumors; and (3) opinions regarding the future of CAR-T as a treatment for solid tumors. Expert commentary: While some recent studies have shown promising results, the ultimate success of CAR-T therapies in solid tumor patients will require the following improvements to clinical regimens: (1) local delivery of CAR-T cells; (2) combination of CAR-T cells with chemotherapeutic drugs to treat metastatic tumors; (3) combination of CAR-T with immune checkpoint inhibitors; (4) combination therapy using CAR-T cells targeting two different antigens; and (5) the use of CAR-T as a strategy to prevent tumor recurrence and metastasis after radical resection.


Assuntos
Neoplasias/terapia , Receptores de Antígenos de Linfócitos T/imunologia , Linfócitos T/imunologia , Animais , Antineoplásicos/administração & dosagem , Terapia Combinada , Humanos , Imunoterapia/métodos , Recidiva Local de Neoplasia/prevenção & controle , Neoplasias/imunologia
16.
J Biotechnol ; 260: 18-30, 2017 Oct 20.
Artigo em Inglês | MEDLINE | ID: mdl-28867483

RESUMO

Interactions between protein ligands and receptors play crucial roles in cell-cell signalling. Most of the human cell surface receptors have been identified in the post-Human Genome Project era but many of their corresponding ligands remain unknown. To facilitate the pairing of orphan receptors, 2762 sequences encoding all human single-pass transmembrane proteins were selected for inclusion into a mammalian-cell expression library. This expression library, consisting of all the individual extracellular domains (ECDs), was constructed as a Fab fusion for each protein. In this format, individual ECD can be produced as a soluble protein or displayed on cell surface, depending on the applied heavy-chain Fab configuration. The unique design of the Fab fusion concept used in the library led to not only superior success rate of protein production, but also versatile applications in various high-throughput screening paradigms including protein-protein binding assays as well as cell binding assays, which were not possible for any other existing expression libraries. The protein library was screened against human coagulation factor VIIa (FVIIa), an approved therapeutic for the treatment of hemophilia, for binding partners by AlphaScreen and ForteBio assays. Two previously known physiological ligands of FVIIa, tissue factor (TF) and endothelial protein C receptor (EPCR) were identified by both assays. The cell surface displayed library was screened against V-domain Ig suppressor of T-cell activation (VISTA), an important immune-checkpoint regulator. Immunoglobulin superfamily member 11 (IgSF11), a potential target for cancer immunotherapy, was identified as a new and previously undescribed binding partner for VISTA. The specificity of the binding was confirmed and validated by both fluorescence-activated cell sorting (FACS) and surface plasmon resonance (SPR) assays in different experimental setups.


Assuntos
Proteínas de Membrana , Biblioteca de Peptídeos , Receptores de Superfície Celular , Proteínas Recombinantes de Fusão , Clonagem Molecular , Células HEK293 , Ensaios de Triagem em Larga Escala , Humanos , Fragmentos Fab das Imunoglobulinas/química , Fragmentos Fab das Imunoglobulinas/genética , Fragmentos Fab das Imunoglobulinas/metabolismo , Proteínas de Membrana/química , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Receptores de Superfície Celular/química , Receptores de Superfície Celular/metabolismo , Proteínas Recombinantes de Fusão/química , Proteínas Recombinantes de Fusão/genética , Proteínas Recombinantes de Fusão/metabolismo , Transfecção
17.
Prog Neuropsychopharmacol Biol Psychiatry ; 79(Pt B): 249-257, 2017 10 03.
Artigo em Inglês | MEDLINE | ID: mdl-28689008

RESUMO

Chronic tinnitus is often accompanied with depressive symptom, which may arise from aberrant functional coupling between the amygdala and cerebral cortex. To explore this hypothesis, resting-state functional magnetic resonance imaging (fMRI) was used to investigate the disrupted amygdala-cortical functional connectivity (FC) in chronic tinnitus patients with depressive mood. Chronic tinnitus patients with depressive mood (n=20), without depressive mood (n=20), and well-matched healthy controls (n=23) underwent resting-state fMRI scanning. Amygdala-cortical FC was characterized using a seed-based whole-brain correlation method. The bilateral amygdala FC was compared among the three groups. Compared to non-depressed patients, depressive tinnitus patients showed decreased amygdala FC with the prefrontal cortex and anterior cingulate cortex as well as increased amygdala FC with the postcentral gyrus and lingual gyrus. Relative to healthy controls, depressive tinnitus patients revealed decreased amygdala FC with the superior and middle temporal gyrus, anterior and posterior cingulate cortex, and prefrontal cortex, as well as increased amygdala FC with the postcentral gyrus and lingual gyrus. The current study identified for the first time abnormal resting-state amygdala-cortical FC with the prefrontal-cingulate-temporal circuit in chronic tinnitus patients with depressive mood, which will provide novel insight into the underlying neuropathological mechanisms of tinnitus-induced depressive disorder.


Assuntos
Tonsila do Cerebelo/fisiopatologia , Depressão/fisiopatologia , Giro do Cíngulo/fisiopatologia , Córtex Pré-Frontal/fisiopatologia , Lobo Temporal/fisiopatologia , Zumbido/fisiopatologia , Tonsila do Cerebelo/diagnóstico por imagem , Mapeamento Encefálico , Doença Crônica , Depressão/complicações , Depressão/diagnóstico por imagem , Feminino , Substância Cinzenta/diagnóstico por imagem , Substância Cinzenta/fisiopatologia , Giro do Cíngulo/diagnóstico por imagem , Humanos , Imagem por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Vias Neurais/fisiopatologia , Córtex Pré-Frontal/diagnóstico por imagem , Descanso , Lobo Temporal/diagnóstico por imagem , Zumbido/complicações , Zumbido/diagnóstico por imagem , Zumbido/psicologia , Substância Branca/diagnóstico por imagem , Substância Branca/fisiopatologia
18.
Mol Med Rep ; 15(5): 2925-2930, 2017 May.
Artigo em Inglês | MEDLINE | ID: mdl-28358432

RESUMO

As a tumor-targeting and ­penetrating peptide, iRGD binds to αv integrins and neuropilin­1 receptors, which are expressed at high levels on tumor cells and the surfaces of vasculature. Subsequently, iRGD penetrates deep into the tumor parenchyma with antitumor drugs, imaging agents, immune modulators and biological products. These substances are either chemically linked to the peptide or co­injected with the peptide. The iRGD peptide can be readily synthesized, exhibits significantly improved penetration, compared with traditional peptides, and can effectively inhibit tumor metastasis. Therefore, the peptide is now used widely for the diagnosis and treatment of cancer. However, whether the peptide is able to promote the entry of drugs into non­targeted cells remains to be fully elucidated. In this review, an overview of iRGD is presented, focusing on its identification, mechanism of action and previous studies on its roles in various types of cancer. Studies in previous years have demonstrated the potential of the iRGD protein for tumors diagnosis and targeted treatment, which warrants further investigation.


Assuntos
Neoplasias/tratamento farmacológico , Oligopeptídeos/uso terapêutico , Antineoplásicos/química , Antineoplásicos/uso terapêutico , Doxorrubicina/química , Doxorrubicina/uso terapêutico , Portadores de Fármacos/química , Humanos , Integrinas/química , Integrinas/metabolismo , Metástase Neoplásica , Neoplasias/diagnóstico , Oligopeptídeos/química , Oligopeptídeos/metabolismo
19.
Hum Brain Mapp ; 38(5): 2384-2397, 2017 05.
Artigo em Inglês | MEDLINE | ID: mdl-28112466

RESUMO

The phantom sound of tinnitus is believed to be triggered by aberrant neural activity in the central auditory pathway, but since this debilitating condition is often associated with emotional distress and anxiety, these comorbidities likely arise from maladaptive functional connections to limbic structures such as the amygdala and hippocampus. To test this hypothesis, resting-state functional magnetic resonance imaging (fMRI) was used to identify aberrant effective connectivity of the amygdala and hippocampus in tinnitus patients and to determine the relationship with tinnitus characteristics. Chronic tinnitus patients (n = 26) and age-, sex-, and education-matched healthy controls (n = 23) were included. Both groups were comparable for hearing level. Granger causality analysis utilizing the amygdala and hippocampus as seed regions were used to investigate the directional connectivity and the relationship with tinnitus duration or distress. Relative to healthy controls, tinnitus patients demonstrated abnormal directional connectivity of the amygdala and hippocampus, including primary and association auditory cortex, and other non-auditory areas. Importantly, scores on the Tinnitus Handicap Questionnaires were positively correlated with increased connectivity from the left amygdala to left superior temporal gyrus (r = 0.570, P = 0.005), and from the right amygdala to right superior temporal gyrus (r = 0.487, P = 0.018). Moreover, enhanced effective connectivity from the right hippocampus to left transverse temporal gyrus was correlated with tinnitus duration (r = 0.452, P = 0.030). The results showed that tinnitus distress strongly correlates with enhanced effective connectivity that is directed from the amygdala to the auditory cortex. The longer the phantom sensation, the more likely acute tinnitus becomes permanently encoded by memory traces in the hippocampus. Hum Brain Mapp 38:2384-2397, 2017. © 2017 Wiley Periodicals, Inc.


Assuntos
Córtex Auditivo/fisiopatologia , Mapeamento Encefálico , Sistema Límbico/fisiopatologia , Zumbido/patologia , Adulto , Córtex Auditivo/diagnóstico por imagem , Vias Auditivas/fisiopatologia , Feminino , Lateralidade Funcional , Humanos , Imageamento Tridimensional , Sistema Límbico/diagnóstico por imagem , Imagem por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Rede Nervosa , Descanso , Estatística como Assunto , Zumbido/diagnóstico por imagem
20.
Oncotarget ; 8(6): 9488-9499, 2017 Feb 07.
Artigo em Inglês | MEDLINE | ID: mdl-28055955

RESUMO

Chimeric antigen receptor (CAR)-modified T cell (CAR T) is a promising therapeutic option for patients with cancer. Such an approach requires the identification of tumor-specific antigen targets that are expressed in solid tumors. We developed a new third-generation CAR directed against tissue factor (TF), a surface molecule overexpressed in some types of lung cancer, melanoma and other cancers. First, we demonstrated by immunohistochemistry that TF was overexpressed in squamous cell carcinoma and adenocarcinoma of non-small cell lung cancer (NSCLC) and melanoma using a human tissue microarray. In the presence of TF-positive cancer cells, the CAR-modified T cells (TF-CAR T) were highly activated and showed specific cytotoxicity to TF-positive cancer cells in vitro. In established s.c. xenograft and lung metastasis models, TF-CAR T cells could significantly suppress the growth of s.c. xenograft and metastasis of TF-positive cancer cells. Additionally, the safety evaluation of TF-CAR T cells in vivo showed that the treatment did not cause obvious toxicity in mice. Taken together, these findings indicate that TF-CAR T cells might be a novel potential therapeutic agent for the treatment of patients with TF-positive cancers.


Assuntos
Adenocarcinoma/terapia , Carcinoma Pulmonar de Células não Pequenas/terapia , Carcinoma de Células Escamosas/terapia , Movimento Celular , Proliferação de Células , Imunoterapia Adotiva/métodos , Neoplasias Pulmonares/terapia , Receptores de Antígenos de Linfócitos T/imunologia , Linfócitos T/transplante , Tromboplastina/imunologia , Adenocarcinoma/imunologia , Adenocarcinoma/metabolismo , Adenocarcinoma/secundário , Adenocarcinoma de Pulmão , Animais , Carcinoma Pulmonar de Células não Pequenas/imunologia , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Carcinoma Pulmonar de Células não Pequenas/secundário , Carcinoma de Células Escamosas/imunologia , Carcinoma de Células Escamosas/metabolismo , Carcinoma de Células Escamosas/secundário , Citocinas/imunologia , Citocinas/metabolismo , Citotoxicidade Imunológica , Feminino , Humanos , Neoplasias Pulmonares/imunologia , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Células MCF-7 , Melanoma Experimental/imunologia , Melanoma Experimental/secundário , Melanoma Experimental/terapia , Camundongos Endogâmicos NOD , Camundongos SCID , Invasividade Neoplásica , Receptores de Antígenos de Linfócitos T/metabolismo , Neoplasias Cutâneas/imunologia , Neoplasias Cutâneas/metabolismo , Neoplasias Cutâneas/terapia , Linfócitos T/imunologia , Linfócitos T/metabolismo , Tromboplastina/metabolismo , Fatores de Tempo , Transfecção , Carga Tumoral , Ensaios Antitumorais Modelo de Xenoenxerto
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...