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BACKGROUND: Tumor microenvironment actually reduces antitumor effect against the immune attack by exclusion of CD8+T cells. Progranulin (PGRN) is a multifunctional growth factor with significant pathological effects in multiple tumors; however, its role in immunity evasion of breast cancer (BCa) is not completely understood. METHODS: We depleted GRN (PGRN gene) genetically in mice or specifically in PY8119 murine BCa cell line, and mouse models of orthotopic or subcutaneous transplantation were used. Chimeric mice-deficient of PGRN (Grn-/-) in bone marrow (BM) compartment was also generated. Association of PGRN expression with chemokine production or BCa development was investigated by histological and immunological assays. RESULTS: We found PGRN was involved in exhaustion of cytotoxic CD8+T cell in BCa with the increasing expressions of M2 markers and intercellular cell adhesion molecule-1 (ICAM-1) on macrophages. Specifically, ablation of PGRN in PY8119 cells reduced tumor burden, accompanied by the infiltrating of cytotoxic CD8+T cells into tumor nests. Moreover, our result revealed that blockade of PD-1 in PGRN-depleted tumors exhibited better antitumor effect in vivo and significantly decreased tumor burden. CONCLUSION: These findings suggest that inhibition of PGRN may act as a potential immune-therapeutic strategy by recovering infiltration of CD8+T cell in BCa tissue and thereby enhancing the response to anti-PD-1 therapy.
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Molécula 1 de Adesão Intercelular , Neoplasias , Animais , Camundongos , Linfócitos T CD8-Positivos , Linhagem Celular Tumoral , Molécula 1 de Adesão Intercelular/metabolismo , Peptídeos e Proteínas de Sinalização Intercelular/genética , Progranulinas/genética , Microambiente TumoralRESUMO
BACKGROUND: Alzheimer's disease (AD) is the most common neurodegenerative disorder without effective therapy and lack diagnosis strategy for preclinical AD patients. There is an urgent need for development of both early diagnosis and therapeutic intervention of AD. RESULTS: Herein, we developed a nanotheranostics platform consisting of Curcumin (Cur), an anti-inflammatory molecule, and superparamagnetic iron oxide (SPIO) nanoparticles encapsulated by diblock 1,2-dio-leoyl-sn-glycero-3-phosphoethanolamine-n-[poly(ethylene glycol)] (DSPE-PEG) that are modified with CRT and QSH peptides on its surface. Furthermore, we demonstrated that this multifunctional nanomaterial efficiently reduced ß-amyloid plaque burden specifically in APP/PS1 transgenic mice, with the process noninvasively detected by magnetic resonance imaging (MRI) and the two-dimensional MRI images were computed into three-dimension (3D) plot. Our data demonstrated highly sensitive in vivo detection of ß-amyloid plaques which more closely revealed real deposition of Aß than previously reported and we quantified the volumes of plaques for the first time based on 3D plot. In addition, memory deficits of the mice were significantly rescued, probably related to inhibition of NLR Family Pyrin Domain Containing 3 (NLRP3) inflammasomes. CONCLUSIONS: Gathered data demonstrated that this theranostic platform may have both early diagnostic and therapeutic potential in AD.
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Doença de Alzheimer , Curcumina , Doença de Alzheimer/diagnóstico por imagem , Doença de Alzheimer/tratamento farmacológico , Peptídeos beta-Amiloides/química , Animais , Cognição , Curcumina/química , Curcumina/farmacologia , Curcumina/uso terapêutico , Modelos Animais de Doenças , Imageamento por Ressonância Magnética , Camundongos , Camundongos Transgênicos , Proteína 3 que Contém Domínio de Pirina da Família NLR , Placa Amiloide/diagnóstico por imagem , Placa Amiloide/tratamento farmacológico , Nanomedicina TeranósticaRESUMO
Neurotropin (NTP) is a widely used drug in China and Japan mainly for the treatment of chronic pain and peripheral inflammation. Nevertheless, the effects of NTP on neuroinflammation have not been explored. In this study, we investigated the anti-inflammatory effects of NTP in lipopolysaccharide (LPS)-stimulated BV-2 microglial cells and its underlying mechanisms. BV-2 cells were pretreated with NTP for 12 h before exposure to LPS. The expression of pro-inflammatory cytokines (TNF-α and IL-6) were detected by RT-PCR and EILSA at mRNA and protein levels, respectively. Western blotting was conducted to measure the protein levels of major genes in MAPKs and NF-κB signaling pathways. Results demonstrated that NTP could attenuate the production of pro-inflammatory cytokines. Furthermore, NTP inhibited the activation of NF-κB signaling by decreasing the translocation of NF-κB p65 to the nucleus and suppressed the MAPKs signaling pathway via inhibition of the phosphorylation of p38, ERK and JNK. Taken together, these findings suggest that neurotropin exerts anti-inflammatory effects by suppressing the production of pro-inflammatory mediators via inhibition of NF-κB and MAPKs signaling pathways in LPS-stimulated BV-2 cells.
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Lipopolissacarídeos/efeitos adversos , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Microglia/patologia , NF-kappa B/metabolismo , Inflamação Neurogênica/induzido quimicamente , Inflamação Neurogênica/prevenção & controle , Polissacarídeos/farmacologia , Polissacarídeos/uso terapêutico , Animais , Anti-Inflamatórios , Células Cultivadas , Citocinas/metabolismo , Mediadores da Inflamação/metabolismo , Interleucina-6/metabolismo , Camundongos , Inflamação Neurogênica/metabolismo , Fator de Necrose Tumoral alfa/metabolismoRESUMO
BACKGROUND: Tooth loss is suggested to be associated with an increased risk of dementia in many studies. But the relationship between tooth loss and dementia is not yet fully understood. This systematic review and meta-analysis aimed to determine the relative effect of tooth loss on dementia risk. METHODS: An electronic search of PubMed, Scopus, Embase, and Web of Knowledge was conducted in March 2018 to identify relevant observational studies with the English language restriction. Studies were included if they assessed the relationship between tooth loss and risk of dementia. Study quality was detected by the modified Downs and Black scale. Odds risks (ORs) were pooled using a random-effects model in the crude model. RESULTS: The literature search initially yielded 1574 articles, and 21 observational studies published between 1994 and 2017 were finally included for the analyses. The crude results with random-effects model showed that patients with multiple tooth loss had higher incidence of dementia (OR 2.62, 95% CI 1.90-3.61, P < 0.001, I2 = 90.40%). The association remained noted when only adjusted results were pooled from 18 studies (OR 1.55, 95% CI 1.41-1.70, P = 0.13, I2 = 28.00%). Meta-regression analysis showed that study design explained about 16.52% of heterogeneity in the crude model. The overall quality rating scores of studies ranged from 11 to 16. CONCLUSIONS: Findings from this review evidenced that tooth loss is positively associated with an increased risk of dementia in adults. Future well-designed longitudinal researches examining the direct and indirect relationship between tooth loss and dementia risk are encouraged.
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Demência/etiologia , Perda de Dente/psicologia , Adulto , Idoso , Demência/epidemiologia , Feminino , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Estudos Observacionais como Assunto , Razão de Chances , Análise de Regressão , Fatores de RiscoRESUMO
BACKGROUND: Cystic brain radionecrosis (CBRN) is a late-onset devastating complication after radiotherapy for head and neck neoplasms, especially for nasopharyngeal carcinoma (NPC). To our knowledge, it has scarcely been reported. METHODS: We retrospectively reviewed all available medical records of NPC patients with CBRN who were treated with surgical intervention. RESULTS: Sixteen patients were identified in this study and the mean latency of CBRN was 9.2 ± 0.9 years. The total irradiation dose of the nasopharynx ranged from 60 to 78 Gy. Cyst-like lesions were observed and there were slightly enhancements on the cyst wall in five patients on patients' brain MRI. All the included patients underwent surgical resection of the cystic necrotic lesion thought temporal approach. Specimens from surgery revealed reactive gliosis and immunopositive cytokines including TNF-α, IL-6 and HIF-2α. Only one patient experienced recurrence and received reoperation after surgery. All the other patients made a good recovery and no operation-related mortality was observed. CONCLUSIONS: CBRN is a delayed but irreversible neurological sequel in irradiated NPC patients. Post-radiotherapy follow-up is quite necessary for those with high risk of CBRN. Proper treatment is needed for early CBRN patients to suppress inflammation in the brain. Timely neurosurgery may benefit patients with late-stage CBRN by alleviating increased intracranial pressure and inflammatory responses.
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Encéfalo/patologia , Carcinoma/radioterapia , Cistos/patologia , Neoplasias Nasofaríngeas/radioterapia , Lesões por Radiação/etiologia , Adulto , Idoso , Carcinoma/patologia , Feminino , Humanos , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Carcinoma Nasofaríngeo , Neoplasias Nasofaríngeas/patologia , Necrose , Recidiva Local de Neoplasia/patologia , Prognóstico , Dosagem Radioterapêutica , Estudos Retrospectivos , Fatores de Risco , Resultado do TratamentoRESUMO
Observational studies suggested an association between hearing impairment and cognitive disorders. However, whether hearing impairment is an independent risk factor or a harbinger of Alzheimer's disease remains controversial. Our goal was to assess the association between hearing impairment (HI) and the risk of Alzheimer's disease (AD) by conducting a meta-analysis of prospective cohort studies. We comprehensively searched the PubMed, Embase, Web of Science and Cochrane Library databases on January 19, 2016 to incorporate all the prospective cohort studies meeting the inclusion criteria to perform a systematic review and meta-analysis. Four prospective cohort studies with comparison between hearing impairment and normal hearing were incorporated, with 7461 participants. The outcomes of three studies were the incidence of Alzheimer's disease and the outcome of the fourth study was the incidence of mild cognitive impairment. The overall combined relative risk of people with hearing impairment to develop Alzheimer's disease was 4.87 (95% CI 0.90-26.35; p = 0.066), compared with the control group. Since both Alzheimer's disease and mild cognitive impairment are cognitive disorders, we incorporated all the four studies and the overall combined relative risk was 2.82 (95% CI 1.47-5.42; p = 0.002), indicating that the difference was significant. This meta-analysis suggests that hearing impairment significantly increases the risk of cognitive disorders and future well-designed prospective cohort studies are awaited to confirm the association between hearing impairment and risk of Alzheimer's disease.
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Doença de Alzheimer/epidemiologia , Transtornos Cognitivos/epidemiologia , Perda Auditiva/epidemiologia , Doença de Alzheimer/etiologia , Transtornos Cognitivos/etiologia , Perda Auditiva/complicações , HumanosRESUMO
BACKGROUND: Cytophagic histiocytic panniculitis (CHP) is a rare form of nodular panniculitis that may progress to panniculitis-like T-cell lymphoma. We report a case of CHP that first manifested as bilateral ptosis, which is the first reported case of this presentation. CASE PRESENTATION: A 25-year-old woman without medical history was referred to the neurology department of our hospital for evaluation of bilateral ptosis. Three months previously, she suddenly complained of bilateral ptosis without apparent cause. Simultaneously, non-painful tender subcutaneous nodules and eschar-like skin lesions were observed on her extremities and trunk. A diagnosis of CHP was made based on skin biopsy from the left thigh showing lobular panniculitis, vasculitis, and adiponecrosis, with infiltration of inflammatory cells, including lymphocytes, histiocytes, and phagocytic histiocytes. Her condition continued to worsen with corticosteroid and immunosuppressive agent (thalidomide) treatment. Significant improvement was noticed after three cycles of chemotherapy of THP-COP (pirarubicin, cyclophosphamide, vincristine, and prednisolone). CONCLUSIONS: CHP is a rare condition whose clinical presentation may include bilateral ptosis and biopsy is required for diagnosis of CHP.
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Blefaroptose/etiologia , Histiócitos/fisiologia , Paniculite/complicações , Adulto , Biópsia , Blefaroptose/diagnóstico , Diagnóstico Diferencial , Feminino , Humanos , Imageamento por Ressonância Magnética , Paniculite/diagnóstico , Pele/patologia , Tomografia Computadorizada por Raios X , Acuidade VisualRESUMO
BACKGROUND: The prevalence and impact of fear of childbirth (FOC) has not been sufficiently understood. We aimed to investigate the prevalence of FOC among Chinese population and its impact on mode of delivery, postpartum mental health and breastfeeding. METHODS: We conducted a prospective cohort study, wherein pregnant women in their third trimester who underwent antenatal assessments at Shanghai Changning Maternity and Infant Health Hospital between September 2020 and March 2021 were recruited. Sociodemographic data of the participants were gathered by self-administered questionnaire, and their FOC was assessed using the Wijma Delivery Expectancy Questionnaire. Participants were followed up to 42 days postpartum. Information regarding their modes of delivery was retrieved from medical records, and data regarding postpartum mental health symptoms and one-month postpartum breastfeeding were obtained through self-administered questionnaires. RESULTS: Among 1287 participants, 461 (35.8 %) had high-level FOC (W-DEQ ≥ 66). Logistic regressions showed that women with high-level of FOC had higher rates of caesarean delivery on maternal request (CDMR) (aOR = 1.55, 95 % CI: 1.00-2.41, p = 0.049), a higher incidence of postpartum mental health symptoms (aOR = 1.68, 95 % CI: 1.09-2.59, p = 0.018), lower rates of one-month postpartum exclusive breastfeeding (aOR = 0.33, 95 % CI: 0.16-0.69, p = 0.003) and mixed feeding (aOR = 0.44, 95 % CI: 0.21-0.91, p = 0.028). LIMITATIONS: The long-term implications of FOC beyond the immediate postpartum period were not explored in the study. CONCLUSIONS: High-level FOC during the third trimester was associated with increased CDMR and postpartum mental health symptoms and reduced breastfeeding establishment. These results underscore the significance of FOC screening and tailored interventions for affected women.
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Aleitamento Materno , Saúde Mental , Feminino , Gravidez , Humanos , Estudos Prospectivos , China/epidemiologia , Parto/psicologia , Período Pós-Parto/psicologia , Medo/psicologia , Inquéritos e Questionários , Parto Obstétrico/psicologiaRESUMO
BACKGROUND: Medial temporal lobe atrophy (MTA) is a diagnostic marker for mild cognitive impairment (MCI) and Alzheimer's disease (AD), but the accuracy of quantitative MTA (QMTA) in diagnosing early AD is unclear. This study aimed to investigate the accuracy of QMTA and its related components (inferior lateral ventricle [ILV] and hippocampus) with MTA in the early diagnosis of MCI and AD. METHODS: This study included four groups: normal (NC), MCI stable (MCIs), MCI converted to AD (MCIs), and mild AD (M-AD) groups. Magnetic resonance image analysis software was used to quantify the hippocampus, ILV, and QMTA. MTA was rated by two experienced neurologists. Receiver operating characteristic area under the curve (AUC) analysis was performed to compare their capability in differentiating AD from NC and MCI, and optimal thresholds were determined using the Youden index. RESULTS: QMTA distinguished M-AD from NC and MCI with higher diagnostic accuracy than MTA, hippocampus, and ILV (AUCNC = 0.976, AUCMCI = 0.836, AUCMCIs = 0.894, AUCMCIc = 0.730). The diagnostic accuracy of QMTA was superior to that of MTA, the hippocampus, and ILV in differentiating MCI from AD. The diagnostic accuracy of QMTA was found to remain the best across age, sex, and pathological subgroups analyzed. The sensitivity (92.45%) and specificity (90.64%) were higher in this study when a cutoff value of 0.635 was chosen for QMTA. CONCLUSIONS: QMTA may be a better choice than the MTA scale or the associated quantitative components alone in identifying AD patients and MCI individuals with higher progression risk.
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Doença de Alzheimer , Disfunção Cognitiva , Humanos , Doença de Alzheimer/diagnóstico por imagem , Doença de Alzheimer/patologia , Diagnóstico Diferencial , Encéfalo/diagnóstico por imagem , Encéfalo/patologia , Hipocampo/patologia , Imageamento por Ressonância Magnética/métodos , Disfunção Cognitiva/diagnóstico por imagem , Disfunção Cognitiva/patologia , Diagnóstico Precoce , Atrofia/diagnóstico por imagem , Atrofia/patologiaRESUMO
An important factor in the development of type 1 diabetes (T1D) is the deficiency of inhibitory immune checkpoint ligands, specifically programmed cell death ligand 1 (PD-L1) and galectin-9 (Gal-9), in ß-cells. Therefore, modulation of pancreas-infiltrated T lymphocytes by exogenous PD-L1 or Gal-9 is an ideal approach for treating new-onset T1D. We genetically engineered macrophage cells to generate artificial extracellular vesicles (aEVs) overexpressing PD-L1 and Gal-9, which could restrict islet autoreactive T lymphocytes and protect ß-cells from destruction. Intriguingly, overexpression of Gal-9 stimulated macrophage polarization to the M2 phenotype with immunosuppressive attributes. Alternatively, both PD-L1- and Gal-9-presenting aEVs (PD-L1-Gal-9 aEVs) favorably adhered to T cells via the interaction of programmed cell death protein 1/PD-L1 or T-cell immunoglobulin mucin 3/Gal-9. Moreover, PD-L1-Gal-9 aEVs prominently promoted effector T-cell apoptosis and splenic regulatory T (Treg) cell formation in vitro. Notably, PD-L1-Gal-9 aEVs efficaciously reversed new-onset hyperglycemia in NOD mice, prevented T1D progression, and decreased the proportion and activation of CD4+ and CD8+ T cells infiltrating the pancreas, which together contributed to the preservation of residual ß-cell survival and mitigation of hyperglycemia.
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Antígeno B7-H1 , Diabetes Mellitus Tipo 1 , Vesículas Extracelulares , Galectinas , Camundongos Endogâmicos NOD , Animais , Diabetes Mellitus Tipo 1/imunologia , Diabetes Mellitus Tipo 1/metabolismo , Vesículas Extracelulares/metabolismo , Antígeno B7-H1/metabolismo , Antígeno B7-H1/genética , Camundongos , Galectinas/metabolismo , Galectinas/genética , Células Secretoras de Insulina/metabolismo , Macrófagos/metabolismo , Linfócitos T Reguladores/imunologia , Bioengenharia/métodos , FemininoRESUMO
Immune-checkpoint blockade (ICB) reinvigorates T cells from exhaustion and potentiates T-cell responses to tumors. However, most patients do not respond to ICB therapy, and only a limited response can be achieved in a "cold" tumor with few infiltrated lymphocytes. Synthetic biology can be used to engineer bacteria as controllable bioreactors to synthesize biotherapeutics in situ. We engineered attenuated Salmonella VNP20009 with synthetic gene circuits to produce PD-1 and Tim-3 scFv to block immunosuppressive receptors on exhausted T cells to reinvigorate their antitumor response. Secreted PD-1 and Tim-3 scFv bound PD-1+ Tim-3+ T cells through their targeting receptors in vitro and potentiated the T-cell secretion of IFN-γ. Engineered bacteria colonized the hypoxic core of the tumor and synthesized PD-1 and Tim-3 scFv in situ, reviving CD4+ T cells and CD8+ T cells to execute an antitumor response. The bacteria also triggered a strong innate immune response, which stimulated the expansion of IFN-γ+ CD4+ T cells within the tumors to induce direct and indirect antitumor immunity.
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Inibidores de Checkpoint Imunológico , Receptor de Morte Celular Programada 1 , Salmonella , Inibidores de Checkpoint Imunológico/farmacologia , Animais , Receptor de Morte Celular Programada 1/metabolismo , Receptor de Morte Celular Programada 1/imunologia , Camundongos , Salmonella/imunologia , Salmonella/genética , Receptor Celular 2 do Vírus da Hepatite A/metabolismo , Receptor Celular 2 do Vírus da Hepatite A/genética , Linhagem Celular Tumoral , Linfócitos T CD8-Positivos/imunologia , Humanos , Interferon gama/metabolismo , Interferon gama/imunologia , Anticorpos de Cadeia Única/imunologia , Anticorpos de Cadeia Única/genética , Anticorpos de Cadeia Única/farmacologia , Camundongos Endogâmicos C57BL , Biologia Sintética/métodos , Linfócitos T CD4-Positivos/imunologia , Imunoterapia/métodosRESUMO
Immune intervention of B cell activation to blockade the production of autoantibodies provokes intense interest in the field of systemic lupus erythematosus (SLE) therapy development. Although the survival rate for SLE is improved, many patients die untimely. Engineered cell membrane vesicles manifest remarkable capacity of targeted drug delivery and immunomodulation of immune cells such as B cells. Herein, this work engineered cellular nanovesicles (NVs) presenting CD40 (CD40 NVs) that can blunt B cells and thus alleviate SLE. CD40 NVs disrupt the CD40/CD40 ligand (CD40L) costimulatory signal axis through the blockade of CD40L on CD4+ T cells. Therefore, the CD40 NVs restrain the generation of the germinal center structure and production of antibodies from B cells. Furthermore, immunosuppressive drug mycophenolate mofetil (MMF) is also encapsulated in the vesicles (MMF-CD40 NVs), which is employed to deplete immunocytes including B cells, T cells, and dendritic cells. Together, CD40 NVs are promising formulations for relieving autoimmunity and lupus nephritis in MRL/lpr mice.
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Lúpus Eritematoso Sistêmico , Nefrite Lúpica , Camundongos , Animais , Nefrite Lúpica/tratamento farmacológico , Ligante de CD40/metabolismo , Camundongos Endogâmicos MRL lpr , Antígenos CD40/metabolismo , Lúpus Eritematoso Sistêmico/tratamento farmacológico , Membrana Celular , Ácido MicofenólicoRESUMO
Background and Objective: Early identification is important for timely Alzheimer's disease (AD) treatment. Apolipoprotein E ε4 allele (APOE-ε4) is an important genetic risk factor for sporadic AD. The AD-Resemblance Atrophy Index (RAI)-a structural magnetic resonance imaging-derived composite index-was found to predict the risk of progression from mild cognitive impairment (MCI) to AD. Therefore, we investigated whether the AD-RAI can predict cognitive decline and progression to AD in patients with MCI carrying APOE ε4. Methods: We included 733 participants with MCI from the Alzheimer's Disease Neuroimaging Initiative Database (ADNI). Their APOE genotypes, cognitive performance, and levels of AD-RAI were assessed at baseline and follow-up. Linear regression models were used to test the correlations between the AD-RAI and baseline cognitive measures, and linear mixed models with random intercepts and slopes were applied to investigate whether AD-RAI and APOE-ε4 can predict the level of cognitive decline. Cox proportional risk regression models were used to test the association of AD-RAI and APOE status with the progression from MCI to AD. Results: The baseline AD-RAI was higher in the MCI converted to AD group than in the MCI stable group (P < 0.001). The AD-RAI was significantly correlated with cognition, and had a synergistic effect with APOE-ε4 to predict the rate of cognitive decline. The AD-RAI predicted the risk and timing of MCI progression to AD. Based on the MCI population carrying APOE-ε4, the median time to progression from MCI to AD was 24 months if the AD-RAI > 0.5, while the median time to progression from MCI to AD was 96 months for patients with an AD-RAI ≤ 0.5. Conclusion: The AD-RAI can predict the risk of progression to AD in people with MCI carrying APOE ε4, is strongly correlated with cognition, and can predict cognitive decline.
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Background: White matter hyperintensities (WMHs) and regional brain lobe atrophy coexist in the brain of patients with Alzheimer's disease (AD), but the association between them in patients with AD still lacks comprehensive investigation and solid imaging data support. Objective: We explored whether WMHs can promote the pathological process of AD by aggravating atrophy in specific brain regions and tried to explain the regional specificity of these relationships. Methods: A sample of 240 adults including 180 normal controls (NCs) and 80 cases with AD were drawn from the ADNI database. T1-weighted magnetic resonance imaging (MRI) and T2-weighted fluid-attenuated MRI of the participants were downloaded and were analyzed using AccuBrain® to generate the quantitative ratio of WMHs (WMHr, WMH volumes corrected by intracranial volume) and regional brain atrophy. We also divided WMHr into periventricular WMHr (PVWMHr) and deep WMHr (DWMHr) for the purpose of this study. The Cholinergic Pathways Hyperintensities Scale (CHIPS) scores were conducted by two evaluators. Independent t-test, Mann-Whitney U test, or χ2 test were used to compare the demographic characteristics, and Spearman correlation coefficient values were used to determine the association between WMHs and different regions of brain atrophy. Results: Positive association between WMHr and quantitative medial temporal lobe atrophy (QMTA) (r s = 0.281, p = 0.011), temporal lobe atrophy (r s = 0.285, p = 0.011), and insular atrophy (r s = 0.406, p < 0.001) was found in the AD group before Bonferroni correction. PVWMHr contributed to these correlations. By separately analyzing the relationship between PVWMHr and brain atrophy, we found that there were still positive correlations after correction in QMTA (r s = 0.325, p = 0.003), temporal lobe atrophy (r s = 0.298, p = 0.007), and insular atrophy (r s = 0.429, p < 0.001) in AD group. Conclusion: WMH severity tends to be associated with regional brain atrophy in patients with AD, especially with medial temporal lobe, temporal lobe, and insular lobe atrophy. PVWMHs were devoted to these correlations.
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There is increasing interest in depleting or repolarizing tumor-associated macrophages (TAMs) to generate a proinflammatory effect. However, TAMs usually display an immunosuppressive M2-like phenotype in the tumor microenvironment. Apparently, developing a macrophage-targeting delivery system with immunomodulatory agents is urgent. In this study, an efficient siRNA and CpG ODNs delivery system (CpG-siRNA-tFNA) was prepared with nucleic acid stepwise self-assembled. The tFNA composed of CpG ODNs and siRNA showed a higher stability and an enhanced cellular uptake efficiency. Moreover, the CpG-siRNA-tFNA effectively reprogrammed TAMs toward M1 phenotype polarization with increased proinflammatory cytokine secretion and NF-κB signal pathway activation, which triggers dramatic antitumor immune responses. Additionally, the CpG-siRNA-tFNA exhibited superior antitumor efficacy in a breast cancer xenograft mouse model without obvious systemic side effects. Taken together, CpG-siRNA-tFNA displayed greatly antitumor effect by facilitating TAM polarization toward M1 phenotypes in favor of immunotherapy. Hence, we have developed an efficient therapeutic strategy with immunomodulatory agents for clinical applications.
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OBJECTIVE: To assess the knowledge of and attitudes towards dementia among Shanghai residents. METHODS: A 10-item optional questionnaire relating to dementia was developed for the project. Questionnaires were randomly distributed to 1806 families, each family had one respondent. RESULTS: A total of 1531 questionnaires were available. Among them, 45% considered 'dementia is a normal part of ageing' and 29-41% correctly identified the symptoms of mild dementia. Of the respondents, 43% indicated that they would not be ashamed of having a demented relative, and 45% did not think that medical care benefited those with dementia. Subgroups analyses showed there was a wider agreement on the concept 'dementia is a normal part of ageing' in the elderly or the females with primary school education background than the counterpart. According to the educational level, the sequence (from the highest to the lowest) of the proportion of respondents who considered a demented relative to be shameful was as follows: middle school group (60.5%) > primary school group (41.3%) > university group (25.2%); according to age group: adult group (59.8%) > elderly group (37.3%) > youth group (30.2%). There was a higher identification rate of the symptoms of mild dementia in women than in men (P < 0.01). According to the educational level, the sequence (from the highest to the lowest) of identification rate was: university group > primary school group > middle school group; according to age group: elderly group > youth group > adult group. There was a significant difference among groups (P < 0.01). Multivariate regression results suggested that the sex, educational level and age had an influence on the concept of 'dementia is part of normal ageing'; the feeling of shame of having demented relatives was influenced by the educational level and age. CONCLUSION: Lack of correct knowledge about dementia and discrimination of dementia are highly prevalent among urban residents in Shanghai.
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Conscientização , Comparação Transcultural , Demência/psicologia , Opinião Pública , População Urbana , Adolescente , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , China , Coleta de Dados , Demência/diagnóstico , Demência/etnologia , Diagnóstico Precoce , Escolaridade , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Vergonha , Inquéritos e Questionários , Adulto JovemRESUMO
Objective To investigate the effect of progranulin (PGRN) on the invasion and migration of mouse breast cancer 4T1 cells and its mechanism. Methods After treated with PGRN (1 µg/mL) for 24 hours, the invasion ability of breast cancer 4T1 cells was detected by TranswellTM invasion assay, the migration ability was detected by scratch test, and the epithelial cadherin (E-cadherin), vimentin mRNA expression was detected by real-time fluorescent quantitative PCR. Western blot assay was used to detect the expression of E-cadherin, vimentin, extracellular signal-regulated kinase 1/2 (ERK1/2) and phosphorylated ERK1/2 (p-ERK1/2). After treated with 1 µg/mL PGRN and ERK1/2 signaling pathway inhibitor U0126 (10 µmol/L) simultaneously, the migration and invasion ability of 4T1 cells and the changes in the expression of E-cadherin, vimentin and p-ERK proteins were detected again. Results After treated with PGRN, the migration and invasion capabilities of breast cancer 4T1 cells were significantly enhanced; E-cadherin expression decreased; vimentin and p-ERK1/2 expression increased. After treated with ERK1/2 signaling pathway inhibitor, the ability of PGRN to promote breast cancer 4T1 cell migration, invasion and epithelial-mesenchymal transition (EMT) was significantly inhibited. Conclusion PGRN can promote the migration and invasion of breast cancer 4T1 cells by promoting EMT and activating the ERK1/2 pathway.
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Neoplasias da Mama , Transição Epitelial-Mesenquimal , Animais , Neoplasias da Mama/genética , Caderinas/genética , Caderinas/metabolismo , Linhagem Celular Tumoral , Movimento Celular , Humanos , Sistema de Sinalização das MAP Quinases , Camundongos , Proteína Quinase 3 Ativada por Mitógeno/genética , Invasividade Neoplásica , ProgranulinasRESUMO
Breast cancer is one of the most malignant diseases world-wide and ranks the first among female cancers. Progranulin (PGRN) plays a carcinogenic role in breast cancer, but its mechanisms are not clear. In addition, there are few reports on the relationship between PGRN and tumor-associated macrophages (TAMs). AIMS: To investigate the effects of exosomes derived from PGRN-/- TAMs on invasion and migration of breast cancer cells. MAIN METHODS: Mouse breast cancer xenograft model was constructed to explore the effect of PGRN-/- tumor environment (TME) on breast cancer. Flow cytometry was used to compare TAMs of wild type (WT) and PGRN-/- tumor tissue. Transwell assay, wound healing assay and western blot were used to explore the effect of WT and PGRN-/- TAMs and their exosomes on invasion, migration and epithelial-mesenchymal transition (EMT) of breast cancer cells. MicroRNA (miRNA) assay was used to find out the differentially expressed miRNA of negative control (NC) and siPGRN-TAMs exosomes. Quantitative PCR and luciferase report assay were used to explore the target gene. KEY FINDINGS: The lung metastasis of breast cancer of PGRN-/- mice was inhibited. PGRN-/- TAMs inhibited invasion, migration and EMT of breast cancer cells through their exosomes. MiR-5100 of PGRN-/- TAMs-derived exosomes was up-regulated, which might regulate expression of CXCL12, thereby inhibiting the CXCL12/CXCR4 axis, and ultimately inhibiting the invasion, migration and EMT of breast cancer cells. SIGNIFICANCE: Our study elucidates a new molecular mechanism of lung metastasis of breast cancer, so it may contribute to efficient prevention and therapeutic strategies.
Assuntos
Neoplasias da Mama/metabolismo , Movimento Celular/fisiologia , Exossomos/metabolismo , Progranulinas/deficiência , Macrófagos Associados a Tumor/metabolismo , Animais , Neoplasias da Mama/genética , Neoplasias da Mama/prevenção & controle , Exossomos/genética , Exossomos/patologia , Feminino , Células HEK293 , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/prevenção & controle , Neoplasias Pulmonares/secundário , Células MCF-7 , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Invasividade Neoplásica/genética , Invasividade Neoplásica/prevenção & controle , Progranulinas/genética , Macrófagos Associados a Tumor/patologia , Ensaios Antitumorais Modelo de Xenoenxerto/métodosRESUMO
BACKGROUND: Progranulin (PGRN), as a multifunctional growth factor, is overexpressed in multiple tumors, but the role of PGRN on tumor immunity is still unclear. Here, we studied the effect of PGRN on breast cancer tumor immunity and its possible molecular mechanism. METHODS: The changes of macrophage phenotypes after PGRN treatment were detected by western blot, quantitative polymerase chain reaction (PCR) and flow cytometry. Western blot was used to study the signal molecular mechanism of PGRN regulating this process. The number and localization of immune cells in Wild-type (WT) and PGRN-/- breast cancer tissues were analyzed by immunohistochemical staining and immunofluorescence techniques. The activation and proliferation of CD8+ T cells were measured by flow cytometry. RESULTS: After being treated with PGRN, the expressions of M2 markers and programmed death ligand 1 (PD-L1) on macrophages increased significantly. Signal transducer and activator of transcription 3 (STAT3) signaling pathway inhibitor Stattic significantly inhibited the expression of PD-L1 and M2 related markers induced by PGRN. In WT group, CD8 were co-localized with macrophages and PD-L1, but not tumor cells. The number of immune cells in PGRN-/- breast cancer tissue increased, and their infiltration into tumor parenchyma was also enhanced. Moreover, in the co-culture system, WT peritoneal macrophages not only reduced the ratio of activated CD8+ T cells but also reduced the proportion of proliferating CD8+ T cells. The addition of programmed death receptor 1 (PD-1) and PD-L1 neutralizing antibodies effectively reversed this effect and restored the immune function of CD8+ T cells. CONCLUSION: These results demonstrate that PGRN promotes M2 polarization and PD-L1 expression by activating the STAT3 signaling pathway. Furthermore, through PD-1/PD-L1 interaction, PGRN can promote the breast tumor immune escape. Our research may provide new ideas and targets for clinical breast cancer immunotherapy.
Assuntos
Antígeno B7-H1/metabolismo , Neoplasias da Mama/tratamento farmacológico , Linfócitos T CD8-Positivos/efeitos dos fármacos , Macrófagos/efeitos dos fármacos , Progranulinas/farmacologia , Macrófagos Associados a Tumor/metabolismo , Animais , Antígeno B7-H1/biossíntese , Antígeno B7-H1/imunologia , Neoplasias da Mama/imunologia , Neoplasias da Mama/patologia , Linfócitos T CD8-Positivos/imunologia , Linhagem Celular Tumoral , Feminino , Humanos , Evasão da Resposta Imune/efeitos dos fármacos , Macrófagos/imunologia , Camundongos , Regulação para Cima/efeitos dos fármacosRESUMO
BACKGROUND: The differential diagnosis of frontotemporal dementia (FTD) and Alzheimer's disease (AD) is difficult due to the overlaps of clinical symptoms. Structural magnetic resonance imaging (sMRI) presents distinct brain atrophy and potentially helps in their differentiation. In this study, we aim at deriving a novel integrated index by leveraging the volumetric measures in brain regions with significant difference between AD and FTD and developing an MRI-based strategy for the differentiation of FTD and AD. METHODS: In this study, the data were acquired from three different databases, including 47 subjects with FTD, 47 subjects with AD, and 47 normal controls in the NACC database; 50 subjects with AD in the ADNI database; and 50 subjects with FTD in the FTLDNI database. The MR images of all subjects were automatically segmented, and the brain atrophy, including the AD resemblance atrophy index (AD-RAI), was quantified using AccuBrain®. A novel MRI index, named the frontotemporal dementia index (FTDI), was derived as the ratio between the weighted sum of the volumetric indexes in "FTD dominant" structures over that obtained from "AD dominant" structures. The weights and the identification of "FTD/AD dominant" structures were acquired from the statistical analysis of NACC data. The differentiation performance of FTDI was validated using independent data from ADNI and FTLDNI databases. RESULTS: AD-RAI is a proven imaging biomarker to identify AD and FTD from NC with significantly higher values (p < 0.001 and AUC = 0.88) as we reported before, while no significant difference was found between AD and FTD (p = 0.647). FTDI showed excellent accuracy in identifying FTD from AD (AUC = 0.90; SEN = 89%, SPE = 75% with threshold value = 1.08). The validation using independent data from ADNI and FTLDNI datasets also confirmed the efficacy of FTDI (AUC = 0.93; SEN = 96%, SPE = 70% with threshold value = 1.08). CONCLUSIONS: Brain atrophy in AD, FTD, and normal elderly shows distinct patterns. In addition to AD-RAI that is designed to detect abnormal brain atrophy in dementia, a novel index specific to FTD is proposed and validated. By combining AD-RAI and FTDI, an MRI-based decision strategy was further proposed as a promising solution for the differential diagnosis of AD and FTD in clinical practice.