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Myasthenia gravis (MG) is an autoantibody-mediated disease of the neuromuscular junction. Semaphorin 4A (Sema4A) is involved in the activation of T cells in various inflammatory disorders. In this study, we aimed to investigate whether Sema4A is involved in the pathogenesis of MG. We measured serum Sema4A concentrations in 30 treatment-naïve MG patients with acetylcholine receptor (AChR) antibodies, 7 with muscle-specific tyrosine kinase (MuSK) antibodies and 21 normal controls. As a result, serum Sema4A levels were significantly higher in patients with AChR antibody-positive MG and MuSK antibody-positive MG than in controls (p ≤ 0.0001 for both MG groups). Serum Sema4A levels were correlated with AChR antibody levels (Spearman's ρ = 0.39, p = 0.03) and MG Foundation of America clinical classification classes (Spearman's ρ = 0.38, p = 0.04) in patients with AChR antibody-positive MG. In conclusion, high serum Sema4A levels may reflect T-cell activation, and this molecule could be a potential marker of disease activity in MG.
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Miastenia Gravis , Semaforinas , Humanos , Miastenia Gravis/diagnóstico , AutoanticorposRESUMO
BACKGROUND: Anti-aquaporin-4 antibody-positive neuromyelitis optica spectrum disorder (AQP4Ab+NMOSD) is an inflammatory disorder of the central nervous system with relapse-dependent progression. Few studies have reported the effects of prednisolone and biologics on disability progression in AQP4Ab+NMOSD, although it is established that they prevent clinical relapses. This retrospective study investigated long-term disability progression and the effects of therapeutic interventions on disability progression in AQP4Ab+NMOSD. METHODS: This study included a total of 101 patients with AQP4Ab+NMOSD. Disease progression was investigated in the following two cohorts: (1) duration from disease onset to Expanded Disability Status Scale (EDSS) 3.0 in patients who did or did not receive oral prednisolone or biologics before reaching EDSS 3.0 and (2) duration from disease onset to EDSS 6.0 in patients who did or did not receive oral prednisolone or biologics before reaching EDSS 6.0. RESULTS: Approximately half of the untreated patients reached EDSS 3.0 and 6.0 at 10 and 46 months after disease onset, respectively. In addition, 88% and 71% of the untreated patients reached EDSS 3.0 and 6.0 within 10 years after disease onset, respectively. Disability progression, clinical relapses and attack severity were suppressed by prednisolone and biologics. CONCLUSIONS: AQP4Ab+NMOSD is a severely disabling disease. Treatment interventions using prednisolone and biologics are useful in suppressing disability progression in AQP4Ab+NMOSD.
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Aquaporina 4 , Autoanticorpos , Progressão da Doença , Neuromielite Óptica , Prednisolona , Humanos , Neuromielite Óptica/imunologia , Neuromielite Óptica/tratamento farmacológico , Aquaporina 4/imunologia , Feminino , Masculino , Estudos Retrospectivos , Adulto , Pessoa de Meia-Idade , Prednisolona/uso terapêutico , Autoanticorpos/sangue , Avaliação da Deficiência , Adulto Jovem , Idoso , Produtos Biológicos/uso terapêuticoRESUMO
BACKGROUND: Myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) is a rare neuroinflammatory disorder characterized by acute episodes of central nervous system (CNS) demyelination. Previous studies have reported elevated interleukin (IL)-6 in cerebrospinal fluid (CSF) of MOGAD patients. OBJECTIVE: We examined if CSF IL-6 level increase is associated with clinical parameters in MOGAD. METHODS: IL-6 levels were measured using 44 CSF samples during the acute phase and 6 samples during recovery from 34 MOGAD patients, as well as 65 CSF samples from 45 aquaporin-4 antibody-positive neuromyelitis optica spectrum disorder (AQP4Ab + NMOSD), 107 samples from 76 multiple sclerosis patients, and 45 samples from neurodegenerative disease patients. Associations between IL-6 levels and clinical parameters in MOGAD were also evaluated. RESULTS: CSF IL-6 levels were significantly comparably elevated during acute-phase in MOGAD and AQP4Ab + NMOSD, but declined following the acute phase. Among MOGAD patients, CSF IL-6 level was significantly correlated with CSF cell count, greater in patients with brain lesions than spinal cord lesions, and higher in CSF than serum, suggesting that excessive IL-6 is produced predominantly in CNS. Neurological recovery was tended to be poorer in MOGAD patients with higher CSF IL-6 level. CONCLUSION: CSF IL-6 may play important roles in the pathogenesis of MOGAD, especially in CNS inflammation.
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Interleucina-6 , Glicoproteína Mielina-Oligodendrócito , Neuromielite Óptica , Humanos , Glicoproteína Mielina-Oligodendrócito/imunologia , Interleucina-6/líquido cefalorraquidiano , Feminino , Masculino , Adulto , Pessoa de Meia-Idade , Neuromielite Óptica/líquido cefalorraquidiano , Neuromielite Óptica/imunologia , Doenças Autoimunes Desmielinizantes do Sistema Nervoso Central/líquido cefalorraquidiano , Doenças Autoimunes Desmielinizantes do Sistema Nervoso Central/imunologia , Autoanticorpos/líquido cefalorraquidiano , Autoanticorpos/sangue , Adulto Jovem , Aquaporina 4/imunologia , Aquaporina 4/líquido cefalorraquidiano , Adolescente , IdosoRESUMO
BACKGROUND: Cancer immunotherapy aims to unleash the immune system's potential against cancer cells, providing sustained relief for tumors responsive to immune checkpoint inhibitors (ICIs). While promising in gastric cancer (GC) trials, the efficacy of ICIs diminishes in the context of peritoneal dissemination. Our objective is to identify strategies to enhance the impact of ICI treatment specifically for cases involving peritoneal dissemination in GC. METHODS: The therapeutic efficacy of anti-PD1, CTLA4 treatment alone, or in combination was assessed using the YTN16 peritoneal dissemination tumor model. Peritoneum and peritoneal exudate cells were collected for subsequent analysis. Immunohistochemical staining, flow cytometry, and bulk RNA-sequence analyses were conducted to evaluate the tumor microenvironment (TME). A Janus kinase inhibitor (JAKi) was introduced based on the pathway analysis results. RESULTS: Anti-PD1 and anti-CTLA4 combination treatment (dual ICI treatment) demonstrated therapeutic efficacy in certain mice, primarily mediated by CD8 + T cells. However, in mice resistant to dual ICI treatment, even with CD8 + T cell infiltration, most of the T cells exhibited an exhaustion phenotype. Notably, resistant tumors displayed abnormal activation of the Janus Kinase-Signal Transducer and Activator of Transcription (JAK-STAT) pathway compared to the untreated group, with observed infiltration of macrophages, neutrophils, and Tregs in the TME. The concurrent administration of JAKi rescued CD8 + T cells function and reshaped the immunosuppressive TME, resulting in enhanced efficacy of the dual ICI treatment. CONCLUSION: Dual ICI treatment exerts its anti-tumor effects by increasing tumor-specific CD8 + T cell infiltration, and the addition of JAKi further improves ICI resistance by reshaping the immunosuppressive TME.
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Resistencia a Medicamentos Antineoplásicos , Inibidores de Checkpoint Imunológico , Inibidores de Janus Quinases , Camundongos Endogâmicos C57BL , Neoplasias Peritoneais , Neoplasias Gástricas , Microambiente Tumoral , Animais , Neoplasias Gástricas/tratamento farmacológico , Neoplasias Gástricas/patologia , Neoplasias Gástricas/imunologia , Inibidores de Checkpoint Imunológico/farmacologia , Inibidores de Checkpoint Imunológico/uso terapêutico , Camundongos , Neoplasias Peritoneais/secundário , Neoplasias Peritoneais/tratamento farmacológico , Neoplasias Peritoneais/imunologia , Inibidores de Janus Quinases/farmacologia , Inibidores de Janus Quinases/uso terapêutico , Microambiente Tumoral/efeitos dos fármacos , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/efeitos dos fármacos , Antígeno CTLA-4/antagonistas & inibidores , Humanos , Feminino , Receptor de Morte Celular Programada 1/antagonistas & inibidoresRESUMO
Helicobacter suis, a bacterial species naturally hosted by pigs, can colonize the human stomach in the context of gastric diseases such as gastric mucosa-associated lymphoid tissue (MALT) lymphoma. Because H. suis has been successfully isolated from pigs, but not from humans, evidence linking human H. suis infection to gastric diseases has remained incomplete. In this study, we successfully in vitro cultured H. suis directly from human stomachs. Unlike Helicobacter pylori, the viability of H. suis decreases significantly on neutral pH; therefore, we achieved this using a low-pH medium for transport of gastric biopsies. Ultimately, we isolated H. suis from three patients with gastric diseases, including gastric MALT lymphoma. Successful eradication of H. suis yielded significant improvements in endoscopic and histopathological findings. Oral infection of mice with H. suis clinical isolates elicited gastric and systemic inflammatory responses; in addition, progression of gastric mucosal metaplasia was observed 4 mo postinfection. Because H. suis could be isolated from the stomachs of infected mice, our findings satisfied Koch's postulates. Although further prospective clinical studies are needed, H. suis, like H. pylori, is likely a gastric pathogen in humans. Furthermore, comparative genomic analysis of H. suis using complete genomes of clinical isolates revealed that the genome of each H. suis isolate contained highly plastic genomic regions encoding putative strain-specific virulence factors, including type IV secretion system-associated genes, and that H. suis isolates from humans and pigs were genetically very similar, suggesting possible pig-to-human transmission.
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Infecções por Helicobacter/genética , Helicobacter heilmannii/genética , Helicobacter heilmannii/patogenicidade , Gastropatias/microbiologia , Estômago/microbiologia , Fatores de Virulência/genética , Adulto , Animais , Modelos Animais de Doenças , Feminino , Genoma Bacteriano , Helicobacter heilmannii/isolamento & purificação , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Pessoa de Meia-Idade , Suínos , Sistemas de Secreção Tipo IV/genética , Virulência/genéticaRESUMO
OBJECTIVE: To investigate longitudinal brain atrophy in patients with neuromyelitis optica spectrum disorder (NMOSD). METHODS: We investigated the longitudinal brain atrophy rate in patients with aquaporin-4 antibody-positive NMOSD (AQP4+NMOSD) and those with multiple sclerosis (MS) in a retrospective cohort study. Brain volume was calculated with statistical parametric mapping-12. RESULTS: We enrolled 36 patients with AQP4+NMOSD and 60 with MS. Patients with NMOSD were older and had a higher Kurtzke's expanded disability status scale score at baseline MRI compared with those with MS. Disease duration, annual relapse rate and intervals from the last attack and from disease-modifying drugs initiation were not significantly different between the two groups. Lower normalised lesion volume and higher normalised white matter volume were found in patients with NMOSD compared with those with MS at baseline MRI. However, the annualised atrophy rate of normalised brain volume was similar between the NMOSD (median 0.47; IQR 0.75; p=0.49) and MS (median 0.46; IQR 0.84) groups. After adjustment of age and the presence of clinical relapse, no differences of the annualised atrophy rate of normalised brain volume also were found for NMOSD and MS. Patients with AQP4+NMOSD with long cord lesion showed higher annualised atrophy rate of normalised grey matter volume compared with those without long cord lesion. CONCLUSIONS: Silent progression of brain atrophy was present in patients with AQP4+NMOSD, as shown in patients with MS, even in the clinically inactive age-matched cases. Subclinical dying back degeneration may explain the brain atrophy in patients with AQP4 +NMOSD.
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Encéfalo/patologia , Neuromielite Óptica/patologia , Aquaporina 4 , Atrofia , Autoanticorpos , Estudos de Coortes , Feminino , Substância Cinzenta/patologia , Humanos , Estudos Longitudinais , Imageamento por Ressonância Magnética , Masculino , Esclerose Múltipla/patologia , Estudos RetrospectivosRESUMO
Polyrotaxanes (PRXs) containing acetylated α-cyclodextrins exhibit a temperature-dependent phase transition in aqueous solutions across their lower critical solution temperature (LCST) of approximately 26.6 °C. To gain insights into the interactions of acetylated PRXs (Ac-PRXs) with biological components, thermoresponsive supramolecular surfaces were prepared by coating tissue culture polystyrene (TCPS) surfaces with Ac-PRX triblock copolymers, and their surface properties across the LCST were evaluated. The wettability and protein adsorption of Ac-PRX-coated surfaces changed significantly between 10 and 37 °C, whereas the uncoated TCPS and unmodified PRX-coated surfaces did not alter the wettability and protein adsorption at 10 and 37 °C. The adhesion, proliferation, morphology, and adhesion strength of NIH/3T3 cells on Ac-PRX-coated surfaces were found to be similar to those of the uncoated and unmodified PRX-coated surfaces. However, the adhesion strength of NIH/3T3 cells on Ac-PRX-coated surfaces decreased drastically at 10 °C. Consequently, the cells spontaneously detached from the Ac-PRX-coated surfaces without enzymatic treatment. Additionally, when incubating confluent cells at 10 °C, the cells detached from Ac-PRX-coated surfaces as cell sheets while retaining extracellular matrix proteins. The findings of this study provide new directions for the design of thermoresponsive supramolecular biointerfaces for applications in bioseparation and cell manipulation.
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Rotaxanos , Animais , Camundongos , Adesão Celular , Poloxâmero , Polímeros/farmacologia , Propriedades de SuperfícieRESUMO
OBJECTIVE: To investigate the immunological characteristics and their clinical relevance in anti-myelin oligodendrocyte glycoprotein (MOG)-IgG-associated and anti-aquaporin-4 (AQP4)-IgG-associated disorders (MOGAD and AQPAD) and multiple sclerosis (MS). METHODS: We measured peripheral blood helper T cell subsets (Th1, Th2, Th17 and regulatory T cell (Treg)) in patients with MOGAD (n=26), AQPAD (n=32) and MS (n=28) in the attack and remission phases by flow cytometry with intracellular cytokine staining. We also studied their correlation with clinical parameters. Ten normal subjects served as healthy controls. RESULTS: In all the three disorders, Th17 significantly increased at attack, and downregulated in the remission phases, although still elevated compare with healthy controls. MOGAD and AQPAD patients shared the common T cell profiles, while the extent of Th17 shift was more prominent in AQPAD. Patients with MS showed decreased Th2 than ones with MOGAD and AQPAD at attack. In terms of clinical correlation, MS patients showed that higher Th1 and Th17 proportion was associated with more frequent relapse and more severe clinical disability, whereas in MOGAD, higher Treg was associated with milder clinical severity. In AQPAD, no obvious correlation of Th profiles with clinical manifestation was found. CONCLUSIONS: The present study first investigated intracellular cytokine levels among MOGAD, AQPAD and MS. The different patterns and extent of helper T cell profiles could reflect the pathogenesis of each disorders, and may affect disease severity and activity.
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Aquaporina 4/imunologia , Esclerose Múltipla/imunologia , Glicoproteína Mielina-Oligodendrócito/imunologia , Linfócitos T Auxiliares-Indutores/imunologia , Adulto , Doenças Autoimunes do Sistema Nervoso/imunologia , Feminino , Citometria de Fluxo , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
BACKGROUND: Neurological disorders with IgG antibodies against myelin-oligodendrocyte glycoprotein (MOG-IgG) have been increasingly recognised as a new type of neuroinflammatory disorder. OBJECTIVE: The study aimed to identify regional and ethnic differences in clinical profiles of MOG-IgG-associated disorders between East Asian (Japanese) and Caucasian (German) patients. METHODS: Demographic, clinical and therapeutic data from 68 MOG-IgG-positive adults were collected (Japanese, n=44; German, n=24). RESULTS: Age and sex were similar between cohorts, with optic neuritis occurring most frequently at onset (Japanese: 61%; German: 58%). However, Japanese patients had a lower annualised relapse rate (0.4 vs 0.8, p=0.019; no relapse, 64% vs 25%, p=0.002) and lower Expanded Disability Status Scale score at the last visit (1.0 vs 2.0; p=0.008), despite similar follow-up periods (mean, 73.9 months vs 73.4 months), than those of German patients, respectively. Cerebral syndromes were more common (27% vs 4%; p=0.021) and myelitis less common (21% vs 50%; p=0.012) in Japanese than in German patients, respectively. Japanese patients were more commonly treated with long-term corticosteroids (73%), whereas German patients were more commonly treated with rituximab or other immunosuppressants (63%). CONCLUSIONS: Among patients with MOG-IgG, Japanese tended to have a monophasic milder disease, whereas the majority of German patients had a relapsing course and more frequent myelitis, findings compatible with neuromyelitis optica spectrum disorder. Although the attack-prevention treatment regimens were considerably different, genetic and environmental factors may be important to determine clinical phenotypes and disease activity.
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Relative error estimation has been recently used in regression analysis. A crucial issue of the existing relative error estimation procedures is that they are sensitive to outliers. To address this issue, we employ the γ -likelihood function, which is constructed through γ -cross entropy with keeping the original statistical model in use. The estimating equation has a redescending property, a desirable property in robust statistics, for a broad class of noise distributions. To find a minimizer of the negative γ -likelihood function, a majorize-minimization (MM) algorithm is constructed. The proposed algorithm is guaranteed to decrease the negative γ -likelihood function at each iteration. We also derive asymptotic normality of the corresponding estimator together with a simple consistent estimator of the asymptotic covariance matrix, so that we can readily construct approximate confidence sets. Monte Carlo simulation is conducted to investigate the effectiveness of the proposed procedure. Real data analysis illustrates the usefulness of our proposed procedure.
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BACKGROUND: Inflammation in neuromyelitis optica (NMO) is triggered by a serum antibody against the aquaporin-4 (AQP4). This process requires antibody penetration of the blood-brain barrier (BBB), but the mechanisms for BBB disruption in NMO remain unknown. OBJECTIVE: We examined whether changes in cerebrospinal fluid (CSF) and serum matrix metalloproteinases (MMPs), tissue inhibitors of metalloproteinases (TIMPs), and cytokines are associated with BBB disruption in NMO. METHODS: The concentrations 9 MMPs, 4 TIMPs, and 14 cytokines were measured by multiplex assay in CSF and serum samples from 29 NMO patients, 29 relapsing-remitting multiple sclerosis (MS) patients, and 27 patients with other neurological disorders. We also performed immunohistochemistry for MMP-2 and TIMP-1 expression in post-mortem brain tissues from NMO patients. RESULTS: NMO patients exhibited significantly elevated MMP-2, TIMP-1, interleukin-6, and MMP-2/TIMP-2 ratio in CSF (but not sera) than the other groups. The CSF/serum albumin ratio, an index of BBB permeability, was most strongly correlated with CSF MMP-2 concentration, which in turn correlated with CSF interleukin-6 levels. Immunohistochemistry revealed MMP-2- and TIMP-1-positive cells surrounding vessels in NMO lesions. CONCLUSION: In NMO, increased CSF MMP-2, likely induced by interleukin-6 signaling, may disrupt the BBB and enable serum anti-AQP-4 antibodies migration into the central nervous system (CNS).
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Albuminas/líquido cefalorraquidiano , Barreira Hematoencefálica , Interleucina-6/líquido cefalorraquidiano , Metaloproteinase 2 da Matriz/líquido cefalorraquidiano , Neuromielite Óptica/líquido cefalorraquidiano , Adulto , Aquaporina 4/líquido cefalorraquidiano , Aquaporina 4/imunologia , Autoanticorpos/líquido cefalorraquidiano , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Neuromielite Óptica/patologiaRESUMO
BACKGROUND: Recently, new diagnostic criteria for neuromyelitis optica spectrum disorders (NMOSD) were published. OBJECTIVE: Our primary aim was to evaluate the usefulness of the new diagnostic criteria in anti-aquaporin 4 (AQP4) antibody-negative cases. METHODS: Consecutive 471 patients whose anti-AQP4 antibody was measured at Chiba University were reviewed. RESULTS: Four anti-AQP4 antibody negative-patients, who fulfilled the new diagnostic criteria for NMOSD but not 2006 diagnostic criteria for neuromyelitis optica (NMO), were identified. They showed high cerebrospinal fluid interleukin-6 and glial fibrillary acidic protein levels, an absence of oligoclonal bands and/or cloud-like enhancement on magnetic resonance imaging, which are compatible findings for NMO. CONCLUSION: The new diagnostic criteria are clinically useful in seronegative NMOSD.
Assuntos
Encéfalo/diagnóstico por imagem , Proteína Glial Fibrilar Ácida/líquido cefalorraquidiano , Interleucina-6/líquido cefalorraquidiano , Neuromielite Óptica/diagnóstico , Adulto , Aquaporina 4/imunologia , Autoanticorpos/imunologia , Feminino , Humanos , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Mielite Transversa/diagnóstico por imagem , Neuromielite Óptica/líquido cefalorraquidiano , Neuromielite Óptica/diagnóstico por imagem , Neuromielite Óptica/imunologia , Bandas Oligoclonais/líquido cefalorraquidiano , Estudos Retrospectivos , Medula Espinal/diagnóstico por imagemRESUMO
OBJECTIVE: Epstein-Barr virus (EBV) infection has been thought to be a key environmental factor in the development of multiple sclerosis (MS). The aim of this study is to investigate the association of EBV infection with neuromyelitis optica (NMO). METHODS: We measured levels of serum antibodies against EBV antigens, including anti-viral capsid antigen (VCA) IgM, anti-VCA IgG, anti-early antigen (EA) IgM, anti-EA IgG and anti-EBV nuclear antigen-1 IgG, in 50 patients with NMO (including 12 partial form with antiaquaporin 4 antibodies), 51 patients with MS, and 52 healthy controls, and cerebrospinal fluid (CSF) antibodies in 37 patients with NMO and 33 patients with MS with ELISA. RESULT: Compared with patients with MS and normal participants, patients with NMO more frequently had serum anti-EA IgG antibodies (52%), indicating more active viral replication than patients with MS (26%) and controls (25%). The antibody titres were significantly higher in the NMO group than in the MS (p=0.005) and control (p=0.005) groups. The CSF antibody titres were also higher in patients with NMO than in those with MS (p=0.03). CONCLUSIONS: Our results raise the hypothesis that persistent, active EBV replication is present in NMO, and may contribute to the immunological alterations that play a pathogenetic role in the disorder.
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Infecções por Vírus Epstein-Barr/virologia , Herpesvirus Humano 4/fisiologia , Neuromielite Óptica/virologia , Ativação Viral , Adulto , Anticorpos Antivirais/análise , Antígenos Virais/análise , Antígenos Virais/imunologia , Feminino , Herpesvirus Humano 4/imunologia , Humanos , Imunoglobulina G/líquido cefalorraquidiano , Imunoglobulina G/genética , Estudos Longitudinais , Masculino , Esclerose Múltipla/virologiaRESUMO
Good-outcome neuromyelitis optica (NMO) is defined as an Expanded Disability Status Scale (EDSS) score of ≤3.0 at 10 years after onset. The clinical courses of 80 consecutive patients with NMO were analyzed to identify the frequency and features of Japanese patients with good-outcome NMO. Of the 80 patients, 37 had a disease duration of >10 years; of these, eight (21.6%) presented a good outcome. These cases presented lower EDSS scores during the early phase of disease compared with those with conventional NMO. However, half of these patients developed severe disabilities later on, indicating that truly benign NMO is rare.
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Neuromielite Óptica , Adulto , Idoso , Povo Asiático , Estudos de Coortes , Avaliação da Deficiência , Progressão da Doença , Feminino , Humanos , Pessoa de Meia-Idade , Prognóstico , Estudos RetrospectivosAssuntos
Anticorpos Antivirais/sangue , Vírus JC/imunologia , Neuromielite Óptica/sangue , Neuromielite Óptica/imunologia , Adulto , Humanos , Japão , Leucoencefalopatia Multifocal Progressiva/sangue , Leucoencefalopatia Multifocal Progressiva/imunologia , Fatores de Risco , Estudos SoroepidemiológicosRESUMO
Polyrotaxane is a supramolecular assembly consisting of multiple cyclic molecules threaded by a linear polymer. One of the unique properties of polyrotaxane is molecular mobility, cyclic molecules moving along the linear polymer. Molecular mobility of polyrotaxane surfaces affects cell spreading, differentiation, and other cell-related aspects through changing subcellular localization of yes-associated proteins (YAPs). Subcellular YAP localization is also related to cell senescence derived from oxidative stress, which is known to cause cancer, diabetes, and heart disease. Herein, the effects of polyrotaxane surface molecular mobility on subcellular YAP localization and cell senescence following H2 O2 -induced oxidative stress are evaluated in human mesenchymal stem cells (HMSCs) cultured on polyrotaxane surfaces with different molecular mobilities. Oxidative stress promotes cytoplasmic YAP localization in HMSCs on high-mobility polyrotaxane surfaces; however, low-mobility polyrotaxane surfaces more effectively maintain nuclear YAP localization, exhibiting lower senescence-associated ß-galactosidase activity and senescence-related gene expression and DNA damage than that seen with the high-mobility surfaces. These results suggest that the molecular mobility of polyrotaxane surfaces regulates subcellular YAP localization, thereby protecting HMSCs from oxidative stress-induced cell senescence. Applying the molecular mobility of polyrotaxane surfaces to implantable scaffolds can provide insights into the prevention and treatment of diseases caused by oxidative stress.
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Senescência Celular , Ciclodextrinas , Células-Tronco Mesenquimais , Estresse Oxidativo , Polímeros , Rotaxanos , Humanos , Senescência Celular/efeitos dos fármacos , Senescência Celular/genética , Células-Tronco Mesenquimais/citologia , Células-Tronco Mesenquimais/efeitos dos fármacos , Células-Tronco Mesenquimais/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Estresse Oxidativo/genética , Polímeros/farmacologia , Rotaxanos/farmacologia , Peróxido de Hidrogênio/metabolismo , Peróxido de Hidrogênio/farmacologia , Proteínas de Sinalização YAP/metabolismo , beta-Galactosidase/metabolismo , Dano ao DNA/efeitos dos fármacos , Alicerces Teciduais/química , Proliferação de Células/efeitos dos fármacos , Forma Celular/efeitos dos fármacos , Perfilação da Expressão Gênica , Ciclodextrinas/farmacologiaRESUMO
Cancer cells recognize physical cues transmitted from the surrounding microenvironment, and accordingly alter the migration and chemosensitivity. Cell adhesive biomaterials with tunable physical properties can contribute to the understanding of cancer cell responses, and development of new cancer therapies. Previously, it was reported that polyrotaxane-based surfaces with molecular mobility effectively modulate cellular functions via the yes-associated protein (YAP)-related signaling pathway. In the present study, the impact of molecular mobility of polyrotaxane surfaces on the migration and chemosensitivity of lung (A549), pancreatic (BxPC-3), and breast cancer (MDA-MB-231) cell lines is investigated, and it is found that the cellular spreading of adherent A549 and BxPC-3 cells and nuclear YAP translocation are promoted on low-mobility surfaces, suggesting that cancer cells alter their subcellular YAP localization in response to molecular mobility. Furthermore, low-mobility surfaces suppress cellular migration more than high-mobility surfaces. Additionally, low-mobility surfaces promote the cisplatin chemosensitivity of each cancer cell line to a greater extent than high-mobility surfaces. These results suggest that the molecular mobility of polyrotaxane surfaces suppresses cellular migration and enhances chemosensitivity via the subcellular translocation of YAP in cancer cells. Biointerfaces based on polyrotaxanes can thus be a new platform for elucidating cancer cell migration and chemoresistance mechanisms.
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Cisplatino , Neoplasias , Humanos , Cisplatino/farmacologia , Materiais Biocompatíveis/farmacologia , Poloxâmero , Linhagem Celular , Linhagem Celular Tumoral , Microambiente TumoralRESUMO
In medical image diagnosis, identifying the attention region, i.e., the region of interest for which the diagnosis is made, is an important task. Various methods have been developed to automatically identify target regions from given medical images. However, in actual medical practice, the diagnosis is made based on both the images and various clinical records. Consequently, pathologists examine medical images with prior knowledge of the patients and the attention regions may change depending on the clinical records. In this study, we propose a method, called the Personalized Attention Mechanism (PersAM) method, by which the attention regions in medical images according to the clinical records. The primary idea underlying the PersAM method is the encoding of the relationships between medical images and clinical records using a variant of the Transformer architecture. To demonstrate the effectiveness of the PersAM method, we applied it to a large-scale digital pathology problem involving identifying the subtypes of 842 malignant lymphoma patients based on their gigapixel whole-slide images and clinical records.
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Lymphatic drainage in the central nervous system is regulated by meningeal lymphatic vasculature, and recurrent neuroinflammation alters lymphatic vessel remodeling. Patients with aquaporin-4 antibody-positive neuromyelitis optica spectrum disorder (AQP4 + NMOSD) were reported to demonstrate worse outcomes compared with patients with anti-myelin oligodendrocyte glycoprotein-associated disorders (MOGAD). This study aimed to investigate the serum cytokines relevant to vascular remodeling after attacks and their prognostic role in patients with AQP4 + NMOSD. This study measured the serum levels of 12 cytokines relevant to vascular remodeling, including bone morphogenetic protein-9 (BMP-9) and leptin, in 20 patients with AQP4 + NMOSD and 17 healthy controls (HCs). Disease controls included 18 patients with MOGAD. Serum and cerebrospinal fluid interleukin-6 levels were also measured. Clinical severity was evaluated with Kurtzke's Expanded Disability Status Scale (EDSS). Compared with HCs, patients with AQP4 + NMOSD showed higher BMP-9 (median; 127 vs. 80.7 pg/mL; P = 0.0499) and leptin levels (median; 16,081 vs. 6770 pg/mL; P = 0.0224), but not those with MOGAD. Better improvement in EDSS at 6 months was associated with baseline BMP-9 levels in patients with AQP4 + NMOSD (Spearman's rho = - 0.47; P = 0.037). Serum BMP-9 is upregulated at relapse and may contribute to vascular remodeling in AQP4 + NMOSD. Serum BMP-9 levels could predict clinical recovery 6 months after the attack.