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Influenza virus infection poses a continual menace to public health. Here, we developed soluble trimeric HA ectodomain vaccines by establishing interprotomer disulfide bonds in the stem region, which effectively preserve the native antigenicity of stem epitopes. The stable trimeric H1 ectodomain proteins exhibited higher thermal stabilities in comparison with unmodified HAs and showed strong binding activities towards a panel of anti-stem cross-reactive antibodies that recognize either interprotomer or intraprotomer epitopes. Negative stain transmission electron microscopy (TEM) analysis revealed the stable trimer architecture of the interprotomer disulfide-stapled WA11#5, NC99#2, and FLD#1 proteins as well as the irregular aggregation of unmodified HA molecules. Immunizations of mice with those trimeric HA ectodomain vaccines formulated with incomplete Freund's adjuvant elicited significantly more potent cross-neutralizing antibody responses and offered broader immuno-protection against lethal infections with heterologous influenza strains compared to unmodified HA proteins. Additionally, the findings of our study indicate that elevated levels of HA stem-specific antibody responses correlate with strengthened cross-protections. Our design strategy has proven effective in trimerizing HA ectodomains derived from both influenza A and B viruses, thereby providing a valuable reference for designing future influenza HA immunogens.
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Clinically, chronic pain and depression often coexist in multiple diseases and reciprocally reinforce each other, which greatly escalates the difficulty of treatment. The neural circuit mechanism underlying the chronic pain/depression comorbidity remains unclear. The present study reports that two distinct subregions in the paraventricular thalamus (PVT) play different roles in this pathological process. In the first subregion PVT posterior (PVP), glutamatergic neurons (PVPGlu) send signals to GABAergic neurons (VLPAGGABA) in the ventrolateral periaqueductal gray (VLPAG), which mediates painful behavior in comorbidity. Meanwhile, in another subregion PVT anterior (PVA), glutamatergic neurons (PVAGlu) send signals to the nucleus accumbens D1-positive neurons and D2-positive neurons (NAcD1âD2), which is involved in depression-like behavior in comorbidity. This study demonstrates that the distinct thalamo-subcortical circuits PVPGluâVLPAGGABA and PVAGluâNAcD1âD2 mediated painful behavior and depression-like behavior following spared nerve injury (SNI), respectively, which provides the circuit-based potential targets for preventing and treating comorbidity.
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BACKGROUND: Pancreatic cancer is one of the most lethal malignancies and the lack of treatment options makes it more deadly. Chimeric Antigen Receptor T-cell (CAR-T) immunotherapy has revolutionized cancer treatment and made great breakthroughs in treating hematological malignancies, however its success in treating solid cancers remains limited mainly due to the lack of tumor-specific antigens. On the other hand, the prolonged traditional manufacturing process poses challenges, taking 2 to 6 weeks and impacting patient outcomes. CD276 has recently emerged as a potential therapeutic target for anti-solid cancer therapy. Here, we investigated the efficacy of CD276 CAR-T and rapidly-manufactured CAR-T against pancreatic cancer. METHODS: In the present study, CD276 CAR-T was prepared by CAR structure carrying 376.96 scFv sequence, CD8 hinge and transmembrane domain, 4-1BB and CD3ζ intracellular domains. Additionally, CD276 rapidly-manufactured CAR-T (named CD276 Dash CAR-T) was innovatively developed by shortening the duration of ex vitro culture to reduce CAR-T manufacturing time. We evaluated the anti-tumor efficacy of CD276 CAR-T and further compared the functional assessment of Dash CAR-T and conventional CAR-T in vitro and in vivo by detecting the immunophenotypes, killing ability, expansion capacity and tumor-eradicating effect of CAR-T. RESULTS: We found that CD276 was strongly expressed in multiple solid cancer cell lines and that CD276 CAR-T could efficiently kill these solid cancer cells. Moreover, Dash CAR-T was successfully manufactured within 48-72 h and the functional validation was carried out subsequently. In vitro, CD276 Dash CAR-T possessed a less-differentiated phenotype and robust proliferative ability compared to conventional CAR-T. In vivo xenograft mouse model, CD276 Dash CAR-T showed enhanced anti-pancreatic cancer efficacy and T cell expansion. Besides, except for the high-dose group, the body weight of mice was maintained stable, and the state of mice was normal. CONCLUSIONS: In this study, we proved CD276 CAR-T exhibited powerful activity against pancreatic cancer cells in vitro and in vivo. More importantly, we demonstrated the manufacturing feasibility, acceptable safety and superior anti-tumor efficacy of CD276 Dash CAR-T generated with reduced time. The results of the above studies indicated that CD276 Dash CAR-T immunotherapy might be a novel and promising strategy for pancreatic cancer treatment.
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Antígenos B7 , Imunoterapia Adotiva , Neoplasias Pancreáticas , Receptores de Antígenos Quiméricos , Neoplasias Pancreáticas/terapia , Neoplasias Pancreáticas/imunologia , Neoplasias Pancreáticas/patologia , Humanos , Animais , Linhagem Celular Tumoral , Receptores de Antígenos Quiméricos/metabolismo , Receptores de Antígenos Quiméricos/imunologia , Imunoterapia Adotiva/métodos , Antígenos B7/metabolismo , Antígenos B7/imunologia , Ensaios Antitumorais Modelo de Xenoenxerto , Camundongos , Proliferação de Células , Linfócitos T/imunologiaRESUMO
Myocardial injury and cardiovascular dysfunction are the most common complications of sepsis, and effective therapeutic candidate is still lacking. This study aims to investigate the protective effect of oxycodone in myocardial injury of lipopolysaccharide-induced sepsis and its related signalling pathways. Wild-type and nuclear factor erythroid 2-related factor 2 (Nrf2)-knockout mice, as well as H9c2 cardiomyocytes cultures treated with lipopolysaccharide (LPS) were used as models of septic myocardial injury. H9c2 cardiomyocytes culture showed that oxycodone protected cells from pyroptosis induced by LPS. Mice model confirmed that oxycodone pretreatment significantly attenuated myocardial pathological damage and improved cardiac function demonstrated by increased ejection fraction (EF) and fractional shortening (FS), as well as decreased cardiac troponin I (cTnI) and creatine kinase isoenzymes MB (CK-MB). Oxycodone also reduced the levels of inflammatory factors and oxidative stress damage induced by LPS, which involves pyroptosis-related proteins including: Nod-like receptor protein 3 (NLRP3), Caspase 1, Apoptosis-associated speck-like protein contain a CARD (ASC), and Gasdermin D (GSDMD). These changes were mediated by Nrf2 and heme oxygenase-1 (HO-1) because Nrf2-knockout mice or Nrf2 knockdown in H9c2 cells significantly reversed the beneficial effect of oxycodone on oxidative stress, inflammatory responses and NLRP3-mediated pyroptosis. Our findings yielded that oxycodone therapy reduces LPS-induced myocardial injury by suppressing NLRP3-mediated pyroptosis via the Nrf2/HO-1 signalling pathway in vivo and in vitro.
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Heme Oxigenase-1 , Inflamação , Lipopolissacarídeos , Miócitos Cardíacos , Fator 2 Relacionado a NF-E2 , Oxicodona , Piroptose , Transdução de Sinais , Animais , Fator 2 Relacionado a NF-E2/metabolismo , Piroptose/efeitos dos fármacos , Lipopolissacarídeos/toxicidade , Transdução de Sinais/efeitos dos fármacos , Camundongos , Inflamação/metabolismo , Inflamação/tratamento farmacológico , Inflamação/patologia , Heme Oxigenase-1/metabolismo , Oxicodona/farmacologia , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/patologia , Masculino , Linhagem Celular , Ratos , Oxirredução/efeitos dos fármacos , Camundongos Knockout , Camundongos Endogâmicos C57BL , Estresse Oxidativo/efeitos dos fármacosRESUMO
PURPOSE: Cutaneous metastasis (CM) accounts for 5-30% of patients with breast cancer (BC) and presents unfavorable response to treatment and poor prognosis. A better understanding of the molecular alterations involved in metastasis is essential, which would help identify diagnostic and efficacy biomarkers for CM. MATERIALS: We retrospectively reviewed a total of 13 patients with histological or cytological diagnosis of breast cancer and CM. Clinical information was extracted from the medical records. The mutational landscape of matched primary tumors with their lymph nodes or CM tissues were analyzed using next-generation sequencing (NGS) of 425 cancer-relevant genes. All tissues were also analyzed by immunohistochemistry (IHC). The association of prognosis with various clinical and molecular factors was also evaluated. RESULTS: More than half of the patients were Ki67 low (< 50%, 53.7%). Most patients (12, 92.3%) had other metastasis sites other than skin. The median time from diagnosis to the presentation of CM (T1) was 15 months (range: 0-94 months) and the median time from CM to death (T2) was 13 months (range 1-78). The most frequently altered genes across the three types of tissues were TP53 (69.6%, 16/23), PIK3CA (34.8%, 8/23), and MYC (26.1%). The number of alterations in CM tends to be higher than in primary tumors (median 8 vs. 6, P = 0.077). Copy number loss in STK11, copy number gain in FGFR4, TERT, AR, FLT4 and VEGFA and mutations in ATRX, SRC, AMER1 and RAD51C were significantly enriched in CM (all P < 0.05). Ki67 high group (> 50%) showed significantly shorter T1 than the Ki67 low group (≤ 50%) (median 12.5 vs. 50.0 months, P = 0.036). TP53, PIK3CA mutations, and TERT amplification group were associated with inferior T2 (median 11 vs. 36 months, P = 0.065; 8 vs. 36 months, P = 0.013, 7 vs. 36 months, P = 0.003, respectively). All p values were not adjusted. CONCLUSION: We compared the genomic features of primary breast cancer tissues with their corresponding CM tissues and discussed potential genes and pathways that may contribute to the skin metastasis of advanced breast cancers patients. TP53, PIK3CA mutant, and TERT amplification may serve as biomarkers for poor prognosis for CM patients.
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Biomarcadores Tumorais , Neoplasias da Mama , Mutação , Neoplasias Cutâneas , Humanos , Feminino , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Neoplasias da Mama/mortalidade , Neoplasias Cutâneas/genética , Neoplasias Cutâneas/patologia , Neoplasias Cutâneas/mortalidade , Pessoa de Meia-Idade , Idoso , Estudos Retrospectivos , Prognóstico , Biomarcadores Tumorais/genética , Adulto , Sequenciamento de Nucleotídeos em Larga Escala , Idoso de 80 Anos ou mais , Imuno-HistoquímicaRESUMO
INTRODUCTION: Evidence has emerged that cardiometabolic multimorbidity (CMM) is associated with dementia, but the underlying mechanisms are poorly understood. METHODS: This population-based study included 5704 older adults. Of these, data were available in 1439 persons for plasma amyloid-ß (Aß), total tau, and neurofilament light chain (NfL) and in 1809 persons for serum cytokines. We defined CMM following two common definitions used in previous studies. Data were analyzed using general linear, logistic, and mediation models. RESULTS: The presence of CMM was significantly associated with an increased likelihood of dementia, Alzheimer's disease (AD), and vascular dementia (VaD) (p < 0.05). CMM was significantly associated with increased plasma Aß40, Aß42, and NfL, whereas CMM that included visceral obesity was associated with increased serum cytokines. The mediation analysis suggested that plasma NfL significantly mediated the association of CMM with AD. DISCUSSION: CMM is associated with dementia, AD, and VaD in older adults. The neurodegenerative pathway is involved in the association of CMM with AD. HIGHLIGHTS: The presence of CMM was associated with increased likelihoods of dementia, AD, and VaD in older adults. CMM was associated with increased AD-related plasma biomarkers and serum inflammatory cytokines. Neurodegenerative pathway was partly involved in the association of CMM with AD.
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BACKGROUND AND OBJECTIVE: Our study aimed to evaluate the associations between platelet count (PC) and in-hospital outcomes for patients with stroke after rt-PA intravenous thrombolysis. METHODS: We identified patients who had been hospitalized with a primary diagnosis of stroke and had received rt-PA intravenous thrombolysis from June 2015 to July 2019 at participating hospitals in the Chinese Stroke Center Alliance. PC measured before intravenous thrombolysis was categorized into the following four groups: severe thrombocytopenia (PC < 100 × 109/L), mild thrombocytopenia (100 ≤ PC < 150 × 109/L), normal PC (150 ≤ PC ≤ 450 × 109/L), and thrombocythemia (PC > 450 × 109/L). Outcomes were determined from clinical data collected during hospitalization. The primary clinical outcome was symptomatic intracranial hemorrhage (sICH). Secondary outcomes were mortality, bleeding events, gastrointestinal (GI) hemorrhage, and in-hospital stroke recurrence. We used multivariate logistic regression models to evaluate the associations between PC and outcomes. RESULTS: We included 44,882 individuals with a median age of 66 years, of whom 34.7 % were female, 951 (2.1 %) had severe thrombocytopenia, 7218 (16.1 %) had mild thrombocytopenia, 36,522 (81.4 %) had a normal PC, and 191 (0.4 %) had thrombocythemia. Both severe and mild thrombocytopenia groups had higher risks of bleeding events (adjusted OR 1.30; 95 % CI,1.01-1.67; p = 0.045; adjusted OR 1.32; 95 % CI,1.19-1.46; p < 0.001) and sICH (adjusted OR 1.48;95 % CI,1.13-1.94; p = 0.005; adjusted OR 1.43;95 % CI,1.27-1.60; p < 0.001) than the normal PC group. Patients with 100 ≤ PC < 150 × 109/L also had a higher risk of in-hospital stroke recurrence (adjusted OR 1.12; 95 % CI,1.02-1.22; p = 0.02). CONCLUSIONS: Intravenous thrombolysis brings a high risk of sICH given PC < 150 × 109/L, especially PC < 100 × 109/L. It indicated that PC < 100 × 109/L is a reasonable contraindication to thrombolysis.
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Fibrinolíticos , AVC Isquêmico , Sistema de Registros , Trombocitopenia , Terapia Trombolítica , Humanos , Feminino , Masculino , Idoso , Trombocitopenia/diagnóstico , Trombocitopenia/induzido quimicamente , Pessoa de Meia-Idade , AVC Isquêmico/diagnóstico , AVC Isquêmico/tratamento farmacológico , AVC Isquêmico/mortalidade , Resultado do Tratamento , China/epidemiologia , Contagem de Plaquetas , Terapia Trombolítica/efeitos adversos , Terapia Trombolítica/mortalidade , Fatores de Risco , Fibrinolíticos/administração & dosagem , Fibrinolíticos/efeitos adversos , Fatores de Tempo , Medição de Risco , Recidiva , Ativador de Plasminogênio Tecidual/administração & dosagem , Ativador de Plasminogênio Tecidual/efeitos adversos , Estudos Retrospectivos , Idoso de 80 Anos ou mais , Hemorragias Intracranianas/induzido quimicamente , Hemorragias Intracranianas/etiologia , Hemorragias Intracranianas/mortalidade , Mortalidade Hospitalar , Administração Intravenosa , Hemorragia Gastrointestinal/mortalidade , Hemorragia Gastrointestinal/induzido quimicamente , Hemorragia Gastrointestinal/diagnósticoRESUMO
GPCR-G protein signaling from endosomes plays a crucial role in various physiological and pathological processes. However, the mechanism by which endosomal G protein signaling is terminated remains largely unknown. In this study, we aimed to investigate the regulatory mechanisms involved in terminating the signaling of Gα subunits from endosomes. Through structural analysis and cell-based assays, we have discovered that SNX25, a protein that targets endosomes via its PXA or PXC domain, interacts with regulator of G protein signaling (RGS) proteins (including RGS2, RGS4, RGS8, and RGS17) in a redox-regulated manner. The interaction between SNX25 and these RGS proteins enhances their GTPase-accelerating activity towards Gαi/q and their ability to bind GDP-bound (inactive form) Gαi/q. As a result, SNX25 recruits these RGS proteins to endosomes, leading to the termination of endosomal Gαi/q signaling. Furthermore, we have found that the SNX25/RGS complex also exerts a negative regulatory effect on Gαi/q signaling from the plasma membrane. This is achieved by recruiting Gαi/q to endosomes and preventing its activation on the plasma membrane. Our findings shed light on the previously unknown role of redox-modulated SNX25 in inhibiting Gαi/q signaling, thereby uncovering a novel mechanism for terminating Gαi/q signaling from endosomes. Importantly, this study expands our understanding of the regulation of GPCR-Gαi/q signaling beyond the plasma membrane.
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Breast tumor-initiating cells (BTICs) of triple-negative breast cancer (TNBC) tissues actively repair DNA and are resistant to treatments including chemotherapy, radiotherapy, and targeted therapy. Herein, it is found that a previously reported secreted protein, sclerostin domain containing 1 (SOSTDC1), is abundantly expressed in BTICs of TNBC cells and positively correlated with a poor patient prognosis. SOSTDC1 knockdown impairs homologous recombination (HR) repair, BTIC maintenance, and sensitized bulk cells and BTICs to Olaparib. Mechanistically, following Olaparib treatment, SOSTDC1 translocates to the nucleus in an importin-α dependent manner. Nuclear SOSTDC1 interacts with the N-terminus of the nucleoprotein, chromatin helicase DNA-binding factor (CHD1), to promote HR repair and BTIC maintenance. Furthermore, nuclear SOSTDC1 bound to ß-transducin repeat-containing protein (ß-TrCP) binding motifs of CHD1 is found, thereby blocking the ß-TrCP-CHD1 interaction and inhibiting ß-TrCP-mediated CHD1 ubiquitination and degradation. Collectively, these findings identify a novel nuclear SOSTDC1 pathway in regulating HR repair and BTIC maintenance, providing insight into the TNBC therapeutic strategies.
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Proteínas Adaptadoras de Transdução de Sinal , Proteínas de Ligação a DNA , Ftalazinas , Piperazinas , Neoplasias de Mama Triplo Negativas , Humanos , Neoplasias de Mama Triplo Negativas/genética , Neoplasias de Mama Triplo Negativas/metabolismo , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Feminino , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/genética , Piperazinas/farmacologia , Ftalazinas/farmacologia , Camundongos , Proteínas de Ligação a DNA/metabolismo , Proteínas de Ligação a DNA/genética , Linhagem Celular Tumoral , Animais , Resistencia a Medicamentos Antineoplásicos/genética , Reparo de DNA por Recombinação/genética , Progressão da Doença , Células-Tronco Neoplásicas/metabolismo , Células-Tronco Neoplásicas/efeitos dos fármacos , Modelos Animais de Doenças , Núcleo Celular/metabolismo , DNA HelicasesRESUMO
BACKGROUND We aimed to assess the effect of dexmedetomidine (Dex) combined with remifentanil on emergence agitation (EA) during awakening from sevoflurane anesthesia for pediatric liver surgery. MATERIAL AND METHODS Sixty children who underwent liver surgery in our hospital were prospectively selected and randomly allocated into group A (placebo+remifentanil+sevoflurane) or group B (Dex+remifentanil+sevoflurane). Mean arterial pressure (MAP) and heart rate (HR) at different time points, agitation score during awakening, behavioral status, pain level, and the incidence of postoperative adverse effects were compared in both groups. RESULTS Children in group B had lower HR and MAP levels immediately after tracheal extubation and 5 min after tracheal extubation than those in group A. The Aono's scores, PAED agitation scores, and CHIPP scores at 15 min and 30 min of admission to the PACU were lower in group B than in group A. The incidence of agitation during postoperative anesthesia awakening was lower in group B in contrast to group A. There was no significant difference in postoperative adverse reactions between group A and group B. CONCLUSIONS In pediatric liver surgery, the use of Dex+remifentanil+sevoflurane anesthesia can reduce the incidence of EA during the awakening period, stabilize hemodynamic levels, and relieve postoperative pain, and has fewer postoperative adverse effects, which warrants clinical application.
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Anestésicos Inalatórios , Dexmedetomidina , Delírio do Despertar , Remifentanil , Sevoflurano , Humanos , Dexmedetomidina/administração & dosagem , Dexmedetomidina/uso terapêutico , Remifentanil/administração & dosagem , Remifentanil/uso terapêutico , Sevoflurano/administração & dosagem , Feminino , Masculino , Anestésicos Inalatórios/administração & dosagem , Anestésicos Inalatórios/efeitos adversos , Pré-Escolar , Delírio do Despertar/prevenção & controle , Delírio do Despertar/etiologia , Delírio do Despertar/epidemiologia , Estudos Prospectivos , Hipnóticos e Sedativos/administração & dosagem , Hipnóticos e Sedativos/uso terapêutico , Lactente , Criança , Agitação Psicomotora/prevenção & controle , Agitação Psicomotora/etiologia , Fígado/cirurgia , Período de Recuperação da Anestesia , Piperidinas/administração & dosagem , Piperidinas/uso terapêutico , Piperidinas/efeitos adversos , Método Duplo-Cego , Quimioterapia Combinada , Éteres Metílicos/administração & dosagem , Éteres Metílicos/efeitos adversos , Analgésicos Opioides/administração & dosagem , Analgésicos Opioides/uso terapêuticoRESUMO
BACKGROUND: We sought to examine the associations of the Lifestyle for Brain Health (LIBRA) index with cognitive function among rural Chinese older adults and to explore the potential role of cluster of differentiation 33 gene (CD33) in the associations. METHODS: This population-based cross-sectional study included 4914 dementia-free participants (age ≥60 years; 56.43 % women) in the 2018 baseline examination of MIND-China. The LIBRA index was generated from 11 factors. We used a neuropsychological test battery to assess episodic memory, verbal fluency, attention, executive function, and global cognition. The CD33(rs3865444) polymorphism was detected using multiple-polymerase chain reaction amplification. Data were analyzed using the general linear regression models. RESULTS: A higher LIBRA index was associated with multivariable-adjusted ß-coefficient (95 %CI) of -0.011(-0.020- -0.001) for global cognitive z-score, -0.020(-0.033- -0.006) for episodic memory, and -0.016(-0.029- -0.004) for verbal fluency. The CD33(rs3865444) was associated with a lower global cognitive z-score in the additive (CA vs. CC: ß-coefficient=0.042; 95 %CI=0.008-0.077), the dominant (CA+AA vs. CC: 0.040; 0.007-0.073), and the over-dominant (CA vs. CC+AA: 0.043; 0.009-0.077) models. Similar results were obtained for verbal fluency and attention. The CD33 gene showed statistical interactions with LIBRA index on cognitive function (Pinteraction<0.05) such that a higher LIBRA index was significantly associated with lower z-scores of global cognition and attention only among CD33 CC carriers (P < 0.05). CONCLUSIONS: This population-based study reveals for the first time that a higher LIBRA index is associated with worse cognitive performance in rural Chinese older adults and that CD33 gene could modify the association.
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Cognição , Estilo de Vida , Testes Neuropsicológicos , População Rural , Lectina 3 Semelhante a Ig de Ligação ao Ácido Siálico , Humanos , Feminino , Masculino , Idoso , Estudos Transversais , Cognição/fisiologia , China/epidemiologia , População Rural/estatística & dados numéricos , Testes Neuropsicológicos/estatística & dados numéricos , Lectina 3 Semelhante a Ig de Ligação ao Ácido Siálico/genética , Pessoa de Meia-Idade , População do Leste AsiáticoRESUMO
OBJECTIVES: This study aims to investigate the use of high-frequency sonography as a tool for detecting inflammatory and destructive changes in the hand and foot joints of patients with early and long-term RA. METHODS: This study employs a prospective cohort design involving 162 patients diagnosed with Rheumatoid arthritis (RA) who meet the American College of Rheumatology/European League Against Rheumatism (ACR/EULAR) classification criteria. Patients were divided into two groups based on disease duration: Group 1 (n = 74) included patients with a disease duration of up to 2 years, or early Ð Ð (ERA;), Group 2 (n = 88) consisted of patients with a disease duration exceeding 2 years, or long-term persistent Ð Ð (LtRA). All patients underwent a clinical assessment of their joints, as well as radiography and arthrosonography, at the beginning of the study and again at 6 and 12 months later. RESULTS: In the general group of patients, ultrasound examination revealed signs of synovitis in the joints of the hands more frequently (66%) compared with clinical examination (56% by a number of swollen joints [NSJ] and 55% by a number of painful joints [NPJ], P < .01). After 6 months of treatment, 12% of the patients achieved full US remission and 24% achieved partial US remission. CONCLUSIONS: Within the scope of comprehensive RA diagnostics, arthrosonography of the joints of the hands and feet, utilizing a combination of greyscale and power Doppler, may surpass radiography in detecting early RA. This method allows for a more accurate assessment of disease activity and progression rates.
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Artrite Reumatoide , Progressão da Doença , Ultrassonografia , Humanos , Artrite Reumatoide/diagnóstico por imagem , Feminino , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Ultrassonografia/métodos , Estudos de Coortes , Adulto , Idoso , Reprodutibilidade dos Testes , Articulação da Mão/diagnóstico por imagemRESUMO
The neuropathological mechanisms underlying the association between sleep duration and mild cognitive impairment remain poorly understood. This population-based study included 2032 dementia-free people (age ≥ 60 years; 55.1% women) derived from participants in the Multimodal Interventions to Delay Dementia and Disability in Rural China; of these, data were available in 841 participants for Alzheimer's plasma biomarkers (e.g. amyloid-ß, total tau and neurofilament light chain), 1044 for serum microvascular biomarkers (e.g. soluble adhesion molecules) and 834 for brain MRI biomarkers (e.g. whiter matter, grey matter, hippocampus, lacunes, enlarged perivascular spaces and white matter hyperintensity WMH). We used electrocardiogram-based cardiopulmonary coupling analysis to measure sleep duration, a neuropsychological test battery to assess cognitive function and the Petersen's criteria to define mild cognitive impairment. Data were analysed with multivariable logistic and general linear models. In the total sample (n = 2032), 510 participants were defined with mild cognitive impairment, including 438 with amnestic mild cognitive impairment and 72 with non-amnestic mild cognitive impairment. Long sleep duration (>8 versus 6-8â h) was significantly associated with increased likelihoods of mild cognitive impairment and non-amnestic mild cognitive impairment and lower scores in global cognition, verbal fluency, attention and executive function (Bonferroni-corrected P < 0.05). In the subsamples, long sleep duration was associated with higher plasma amyloid-ß40 and total tau, a lower amyloid-ß42/amyloid-ß40 ratio and smaller grey matter volume (Bonferroni-corrected P < 0.05). Sleep duration was not significantly associated with serum-soluble adhesion molecules, white matter hyperintensity volume, global enlarged perivascular spaces and lacunes (P > 0.05). Alzheimer's and neurodegenerative pathologies may represent common pathways linking long sleep duration with mild cognitive impairment and low cognition in older adults.
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Wilson disease (WD) is an inherited disorder characterized by abnormal copper metabolism with complex pathological features. Currently, this mechanism of copper overload-induced hepatic injury remains unclear. In this study, male toxic milk (TX) mice were selected as experimental subjects. Copper levels and biochemical indices were measured by atomic absorption spectroscopy (AAS) and kits. Liver tissue ultrastructure was observed by hematoxylin-eosin (H&E), sirius red staining and transmission electron microscopy. Plasma and liver metabolic profiles of TX mice were characterized by untargeted metabolomics. In addition, the expression of enzymes related to arachidonic acid metabolism in liver tissue was detected by Western blotting. The results showed the excessive copper content, concomitant oxidative stress, and hepatic tissue structural damage in TX mice. Seventy-eight metabolites were significantly different in WD, mainly involved in the metabolism of arachidonic acid, glycerophospholipids, sphingolipids, niacin and nicotinamide, and phenylalanine. Furthermore, the arachidonic acid metabolic pathway is an important pathway involved in WD metabolism. The level of arachidonic acid in the liver of TX mice was significantly lower (p < 0.01) compared to the control group. The expression of cytoplasmic phospholipase A2 (cPLA2) and arachidonic acid 12-lipoxygenase (ALOX12), related to the arachidonic acid metabolic pathway, was significantly different in the liver of TX mice (p < 0.01). Modulation of the arachidonic acid metabolic pathway could be a potential therapeutic strategy to alleviate WD symptoms.
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Cobre , Modelos Animais de Doenças , Degeneração Hepatolenticular , Fígado , Metabolômica , Animais , Degeneração Hepatolenticular/metabolismo , Camundongos , Fígado/metabolismo , Masculino , Metabolômica/métodos , Cobre/metabolismo , Ácido Araquidônico/metabolismo , Estresse Oxidativo , Leite/metabolismoRESUMO
Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer with limited therapeutic options. IL1 receptor type 2 (IL1R2) promotes breast tumor-initiating cell (BTIC) self-renewal and tumor growth in TNBC, indicating that targeting it could improve patient treatment. In this study, we observed that IL1R2 blockade strongly attenuated macrophage recruitment and the polarization of tumor-associated macrophages (TAM) to inhibit BTIC self-renewal and CD8+ T-cell exhaustion, which resulted in reduced tumor burden and prolonged survival in TNBC mouse models. IL1R2 activation by TAM-derived IL1ß increased PD-L1 expression by interacting with the transcription factor Yin Yang 1 (YY1) and inducing YY1 ubiquitination and proteasomal degradation in both TAMs and TNBC cells. Loss of YY1 alleviated the transcriptional repression of c-Fos, which is a transcriptional activator of PDL-1. Combined treatment with an IL1R2-neutralizing antibodies and anti-PD-1 led to enhanced antitumor efficacy and reduced TAMs, BTICs, and exhausted CD8+ T cells. These results suggest that IL1R2 blockade might be a strategy to potentiate immune checkpoint blockade efficacy in TNBC to improve patient outcomes. Significance: IL1R2 in both macrophages and breast cancer cells orchestrates an immunosuppressive tumor microenvironment by upregulating PD-L1 expression and can be targeted to enhance the efficacy of anti-PD-1 in triple-negative breast cancer.
Assuntos
Neoplasias de Mama Triplo Negativas , Neoplasias de Mama Triplo Negativas/imunologia , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Neoplasias de Mama Triplo Negativas/patologia , Neoplasias de Mama Triplo Negativas/metabolismo , Animais , Camundongos , Humanos , Feminino , Inibidores de Checkpoint Imunológico/farmacologia , Inibidores de Checkpoint Imunológico/uso terapêutico , Linfócitos T CD8-Positivos/imunologia , Microambiente Tumoral/imunologia , Microambiente Tumoral/efeitos dos fármacos , Macrófagos Associados a Tumor/imunologia , Macrófagos Associados a Tumor/metabolismo , Macrófagos Associados a Tumor/efeitos dos fármacos , Linhagem Celular Tumoral , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Antígeno B7-H1/antagonistas & inibidores , Antígeno B7-H1/metabolismo , Fator de Transcrição YY1/metabolismo , Fator de Transcrição YY1/genética , Ensaios Antitumorais Modelo de Xenoenxerto , Células-Tronco Neoplásicas/metabolismo , Células-Tronco Neoplásicas/imunologia , Células-Tronco Neoplásicas/patologia , Células-Tronco Neoplásicas/efeitos dos fármacosRESUMO
Intracerebral hemorrhage (ICH) is a severe stroke subtype. Secondary injury is a key factor leading to neurological deficits after ICH. Electroacupuncture (EA) can improve the neurological function after ICH, however, its internal mechanism is still unclear. The aim of this study is to investigate whether EA could ameliorate secondary injury after ICH through antioxidative stress and its potential regulatory mechanism. A rat model of ICH was established by injecting autologous blood into striatum. After the intervention of EA and EA combined with peroxisome proliferator-activated receptor-γ (PPARγ) blocker, Zea-longa scores, modified neurological severity scores and open field tests were used to evaluate the neurological function of the rats. Flow cytometry detected tissue reactive oxygen species (ROS) levels. Tissue tumor necrosis factor-α (TNF-α) levels were analyzed by enzyme-linked immunosorbent assays. The protein expressions of PPAR γ, nuclear factor erythroid2-related factor 2 (Nrf2) and γ-glutamylcysteine synthetase (γ-GCS) were detected by Western blot. Immunohistochemistry was used to observe the activation of microglia. The demyelination degree of axon myelin was observed by transmission electron microscope. Compared with the model group, EA intervention improved neurological function, decreased ROS and TNF-α levels, increased the protein expression of PPARγ, Nrf2 and γ-GCS, and reduced the activation of microglia, it also alleviated axonal myelin sheath damage. In addition, the neuroprotective effect of EA was partially attenuated by PPARγ blocker. EA ameliorated the neurological function of secondary injury after ICH in rats, possibly by activating the PPARγ/Nrf2/γ-GCS signaling pathway, reducing microglia activation, and inhibiting oxidative stress, thus alleviating the extent of axonal demyelination plays a role.
Assuntos
Hemorragia Cerebral , Eletroacupuntura , Glutamato-Cisteína Ligase , Fator 2 Relacionado a NF-E2 , Estresse Oxidativo , PPAR gama , Ratos Sprague-Dawley , Animais , PPAR gama/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , Eletroacupuntura/métodos , Estresse Oxidativo/fisiologia , Estresse Oxidativo/efeitos dos fármacos , Hemorragia Cerebral/metabolismo , Hemorragia Cerebral/complicações , Ratos , Masculino , Glutamato-Cisteína Ligase/metabolismo , Transdução de Sinais/fisiologia , Transdução de Sinais/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismoRESUMO
Chlorinated hydrocarbons (CHs) pose significant health risks due to their suspected carcinogenicity, necessitating urgent remediation efforts. While the combination of zero-valent iron (Fe0) and microbial action shows promise in mitigating CH contamination, field studies on this approach are scarce. We devised a novel three-layer permeable reactive barrier (PRB) material incorporating Fe0 and coconut shell biochar, effectively implemented at a typical CH-contaminated site. Field monitoring data revealed conducive conditions for reductive dechlorination of CHs, characterized by low oxygen levels and a relatively neutral pH in the groundwater. The engineered PRB material consistently released organic carbon and iron, fostering the proliferation of CH-dechlorinating bacteria. Over a 250-day operational period, the pilot-scale PRB demonstrated remarkable efficacy in CH removal, achieving removal efficiencies ranging from 21.9% to 99.6% for various CH compounds. Initially, CHs were predominantly eliminated through adsorption and iron-mediated reductive dechlorination. However, microbial reductive dechlorination emerged as the predominant mechanism for sustained and long-term CHs removal. These findings underscore the economic viability and effectiveness of our approach in treating CH-contaminated groundwater, offering promising prospects for broader application in environmental remediation efforts.
Assuntos
Água Subterrânea , Hidrocarbonetos Clorados , Poluentes Químicos da Água , Água Subterrânea/química , Hidrocarbonetos Clorados/química , Poluentes Químicos da Água/química , Biodegradação Ambiental , Recuperação e Remediação Ambiental/métodos , Ferro/química , Carvão Vegetal/químicaRESUMO
To explore the association and impact between viral myocarditis and mortality in patients with severe fever with thrombocytopenia syndrome. A dynamic analysis was conducted between fatal group and nonfatal group regarding the daily epidemiology data, clinical symptoms, and electrocardiogram (ECG), echocardiogram, and laboratory findings. Outcomes of patients with and without viral myocarditis were compared. The association between viral myocarditis and mortality was analyzed. Among 183 severe fever with thrombocytopenia syndrome patients, 32 were in the fatal group and 151 in the nonfatal group; there were 26 (81.25%) with viral myocarditis in the fatal group, 66 (43.70%) with viral myocarditis in the nonfatal group (p < 0.001), 79.35% of patients had abnormal ECG results. The abnormal rate of ECG in the fatal group was 100%, and in the nonfatal group was 74.83%. Univariate analysis found that the number of risk factors gradually increased on Day 7 of the disease course and reached the peak on Day 10. Combined with the dynamic analysis of the disease course, alanine aminotransferase, aspartate aminotransferase, creatine kinase, creatine kinase fraction, lactate dehydrogenase, hydroxybutyrate dehydrogenase, neutrophil count, serum creatinine, Na, Ca, carbon dioxide combining power, amylase, lipase, activated partial thromboplastin time and thrombin time had statistically significant impact on prognosis. The incidence of fever with thrombocytopenia syndrome combined with viral myocarditis is high, especially in the fatal group of patients. Viral myocarditis is closely related to prognosis and is an early risk factor. The time point for changes in myocarditis is Day 7 of the course of the disease.
Assuntos
Miocardite , Febre Grave com Síndrome de Trombocitopenia , Viroses , Humanos , Miocardite/complicações , Miocardite/epidemiologia , Prevalência , Viroses/complicações , Viroses/epidemiologia , Febre/epidemiologia , Progressão da DoençaRESUMO
Systemic lupus erythematosus (SLE) is a chronic autoimmune disease involving multi-system and multi-organ dysfunction, and is easily misdiagnosed early in the disease course. We aimed to accurately predict early SLE nomogram to provide a reference basis for the early clinical diagnosis of SLE. Methods: We retrospectively analyzed 167 patients who were first diagnosed with SLE at Fengxian District Central Hospital, Shanghai, between March 2017 and October 2022. Three groups of 129 physically healthy subjects, 67 patients with rheumatoid arthritis, and 40 patients with rashes were selected as controls during the same period. Patients with SLE and control group were randomly divided into training (n = 217) and validation (n = 141) group. Univariate and multivariate analyses were used to identify independent risk factors for early SLE diagnosis. The independent risk factors for diagnosis were used to construct a nomogram to predict early SLE. Results: Based on the training group, three variables were identified as independently influencing early SLE: platelets (odds ratio OR = 0.993, P = 0.047), albumin (OR = 0.833, P = 0.007), and complement component 1q (OR = 0.956, P = 0.000). The precision of the nomogram was assessed using C-index values and calibration plot diagrams. The C-index values were 0.929 for training group and 0.898 for validation group. Both the training group and validation group calibration curves showed good predicted outcomes. Conclusion: The construction of a nomogram can accurately predict the risk of early SLE. The model showed good discriminatory power and calibration for use in the diagnosis of SLE, providing a visual tool and reference basis for the early diagnosis of SLE.
RESUMO
OBJECTIVE: The purpose of the study was to investigate whether risk factors involved in the degree of asthma control were the same for children of both genders. METHODS: This cross-sectional study collected relevant data from 320 children with asthma attending the respiratory asthma clinic at a local children's hospital. All the patients passed the Asthma Control Test (ACT) or the Childhood Asthma Control Test (cACT), lung-function-related tests, the Children's Depression Inventory (CDI), the Screening Scale for Anxiety-Related Mood Disorders (SCARED), and the Family Personal Information Questionnaire. RESULTS: The study found that gender (p=0.034) was a risk factor for poor asthma control and that girls (odds ratio [OR]=1.669, p=0.042) were more likely to have poor asthma control than boys. Univariate logistic regression analysis found that severe wasting (OR=0.075, p=0.021), depression (OR=43. 550, p<0.001), anxiety (OR=4.769, p=0.036), FEV1% (OR=0.970, p=0.043), FEV1/FVC% (OR=0.921, p=0. 008), and PEF% (OR=0.961, p=0.012) were risk factors for poor asthma control in girls. CONCLUSION: The risk factors for the degree of asthma control in children with asthma appeared to vary according to gender.