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ABSTRACT: Glucocorticoids are key components of the standard-of-care treatment regimens for B-cell malignancy. However, systemic glucocorticoid treatment is associated with several adverse events. ABBV-319 is a CD19-targeting antibody-drug conjugate engineered to reduce glucocorticoid-associated toxicities while possessing 3 distinct mechanisms of action (MOA) to increase therapeutic efficacy: (1) antibody-mediated delivery of a glucocorticoid receptor modulator (GRM) payload to activate apoptosis, (2) inhibition of CD19 signaling, and (3) enhanced fragment crystallizable (Fc)-mediated effector function via afucosylation of the antibody backbone. ABBV-319 elicited potent GRM-driven antitumor activity against multiple malignant B-cell lines in vitro, as well as in cell line-derived xenografts and patient-derived xenografts (PDXs) in vivo. Remarkably, a single dose of ABBV-319 induced sustained tumor regression and enhanced antitumor activity compared with repeated dosing of systemic prednisolone at the maximum tolerated dose in mice. The unconjugated CD19 monoclonal antibody (mAb) also displayed antiproliferative activity in a subset of B-cell lymphoma cell lines through the inhibition of phosphoinositide 3-kinase signaling. Moreover, afucosylation of CD19 mAb enhanced Fc-mediated antibody-dependent cellular cytotoxicity. Notably, ABBV-319 displayed superior efficacy compared with afucosylated CD19 mAb in human CD34+ peripheral blood mononuclear cell-engrafted NSG-Tg(Hu-IL15) transgenic mice, demonstrating enhanced antitumor activity when multiple MOAs are enabled. ABBV-319 also showed durable antitumor activity across multiple B-cell lymphoma PDX models, including nongerminal center B-cell diffuse large B-cell lymphoma and relapsed lymphoma after R-CHOP treatment. Collectively, these data support the ongoing evaluation of ABBV-319 in a phase 1 clinical trial.
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Antígenos CD19 , Imunoconjugados , Receptores de Glucocorticoides , Ensaios Antitumorais Modelo de Xenoenxerto , Humanos , Animais , Antígenos CD19/imunologia , Camundongos , Imunoconjugados/farmacologia , Imunoconjugados/uso terapêutico , Receptores de Glucocorticoides/antagonistas & inibidores , Anticorpos Monoclonais Humanizados/farmacologia , Anticorpos Monoclonais Humanizados/uso terapêutico , Anticorpos Monoclonais Humanizados/administração & dosagem , Linfoma de Células B/tratamento farmacológico , Linfoma de Células B/patologia , Linhagem Celular Tumoral , Camundongos SCID , Feminino , Maitansina/análogos & derivadosRESUMO
The widespread use of plastic products in daily life has raised concerns about the health hazards associated with nanoplastics (NPs). When exposed, NPs are likely to infiltrate the bloodstream, interact with plasma proteins, and trigger macrophage recognition and clearance. In this study, we focused on establishing a correlation between the unique protein coronal signatures of high-density (HDPE) and low-density (LDPE) polyethylene (PE) NPs with their ultimate impact on macrophage recognition and cytotoxicity. We observed that low-density and high-density lipoprotein receptors (LDLR and SR-B1), facilitated by apolipoproteins, played an essential role in PE-NP recognition. Consequently, PE-NPs activated the caspase-3/GSDME pathway and ultimately led to pyroptosis. Advanced imaging techniques, including label-free scattered light confocal imaging and cryo-soft X-ray transmission microscopy with 3D-tomographic reconstruction (nano-CT), provided powerful insights into visualizing NPs-cell interactions. These findings underscore the potential risks of NPs to macrophages and introduce analytical methods for studying the behavior of NPs in biological systems.
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Macrófagos , Polietileno , Coroa de Proteína , Macrófagos/metabolismo , Coroa de Proteína/metabolismo , Coroa de Proteína/química , Animais , Camundongos , Nanopartículas/química , HumanosRESUMO
BACKGROUND: Although most stroke patients have underlying vascular risk factors, it is important to consider infectious causes of stroke in young adults without traditional risk factors or patients with cryptogenic stroke. Pulmonary vein thrombosis and air embolism can potentially cause cerebral infarction. However, the association between infection and pulmonary vein thrombosis or air embolism is often overlooked. In this case, we present a rare infectious cause of stroke and air embolism involving a pulmonary abscess and pulmonary vein thrombosis. CASE PRESENTATION: A 37-year-old male patient initially presented with right-sided pneumonia. During treatment at a local hospital, he developed headaches and left limb weakness. Subsequently, he was transferred to our hospital due to septic shock. Neurological evaluations revealed multiple brain foci and thrombosis in the right superior pulmonary vein. Following treatment with broad-spectrum antibiotics and anticoagulants, the patient's clinical symptoms and inflammatory markers showed improvement. However, a computed tomography scan revealed the formation of a pulmonary abscess, and the patient experienced coma and epilepsy after severe coughing with massive hemoptysis. Multiple air embolisms were observed in the brain computed tomography. Eventually, the patient's family chose to discharge him from the hospital. CONCLUSIONS: This case highlights the rare and complex etiologies of stroke associated with infection in a young patient. Early detection, diagnosis, and appropriate treatment of infected systemic embolism in young patients are crucial to prevent serious complications.
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Embolia Aérea , Abscesso Pulmonar , Embolia Pulmonar , Veias Pulmonares , Acidente Vascular Cerebral , Trombose Venosa , Humanos , Masculino , Adulto Jovem , Adulto , Abscesso Pulmonar/complicações , Abscesso Pulmonar/diagnóstico por imagem , Abscesso Pulmonar/terapia , Veias Pulmonares/diagnóstico por imagem , Trombose Venosa/complicações , Trombose Venosa/diagnóstico por imagem , Trombose Venosa/tratamento farmacológico , Acidente Vascular Cerebral/diagnóstico , Acidente Vascular Cerebral/diagnóstico por imagem , Embolia Pulmonar/diagnósticoRESUMO
The transverse magneto-optical Kerr effect (TMOKE) has attracted widespread scientific interest because of its potential applications in biosensor technology, data storage, optical isolation, and telecommunications. More conventional architectures, including prism-based metal/magnetic multilayers and nanoarrays that integrate plasmonic and magnetic materials, are commonly used to amplify TMOKE through the high-quality propagation of the surface plasmon resonance optical mode. However, the main disadvantages of these architectures are their large ohmic losses and radiation damping, resulting in a large optical spectrum linewidth, which hinders the sensing performance. Here, we use a theoretical approach to show that it is possible to employ a low-loss Fabry-Perot optical mode on a magneto-optical platform for TMOKE signal and gaseous sensing enhancement by means of a single CoFeB ferromagnetic film directly overlayed on an already industrial anodic aluminum oxide/aluminum template. The proposed strategy can therefore potentially be exploited for high-precision and low-loss magneto-optical sensors.
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OBJECTIVE: This study aimed to investigate the clinical and laboratory as well as radiological features of spondyloarthritis (SpA) patients with thrombocytosis and to explore risk factor for thrombocytosis in SpA patients and to assess the effect of antitumor necrosis factor-α (anti-TNF-α) therapy on platelet count in SpA patients with thrombocytosis. METHODS: A total of 145 patients with SpA were included in this study, and non-thrombocytosis was identified in 76 patients while thrombocytosis was found in 69 patients, 38 out of the 69 patients received anti-TNF-α therapy. Logistic regression analysis was performed to investigate risk factors that associated with thrombocytosis. The platelet count of patients in the thrombocytosis group treated with anti-TNF-α therapy on week 0, week 6 and week 12 were collected and compared with conventional therapy group. RESULTS: The proportion of hip involvement (60.86% vs 36.84%, p = 0.004), bath ankylosing spondylitis disease activity index score (4.24 ± 0.55 vs 3.69 ± 0.67, p < 0.001), erythrocyte sedimentation rate (62.22 ± 41.97 mm/hour vs 27.00 ± 25.93 mm/hour, p < 0.001), C-reactive protein (53.45 ± 47.45 mg/L vs 18.91 ± 31.09 mg/L, p < 0.001), fibrinogen (5.77 ± 1.48 g/L vs 4.01 ± 1.32 g/L, P < 0.001), white blood cells (8.15 ± 1.90 × 109/L vs 6.85 ± 2.39 × 109/L, p < 0.001) and neutrophils (5.08 ± 1.55 × 109/L vs 4.01 ± 2.04 × 109/L, p = 0.001) are higher in thrombocytosis group, but hemoglobin and albumin are lower compared to non-thrombocytosis group (122.88 ± 17.25 g/L vs 131.51 ± 16.03 g/L, p = 0.002; 37.19 ± 4.73 g/L vs 39.67 ± 3.99 g/L, p = 0.001, respectively). Multivariable logistic regression analysis indicated that higher white blood cells (OR, 1.644; 95% CI, 1.045-2.587; P = 0.032) and fibrinogen (OR, 2.169; 95% CI, 1.237-3.804; P = 0.007) were independently associated with thrombocytosis in SpA patients. The platelet count in the thrombocytosis group treated with anti-TNF-α therapy on week 6 and week 12 were statistically lower than week 0 (225.05 ± 60.58 × 109/L vs 368.26 ± 54.34 × 109/L, p < 0.001; 201.26 ± 51.48 × 109/L vs 368.26 ± 54.34 × 109/L, p < 0.001) and conventional therapy (week 6, 225.05 ± 60.58 × 109/L vs 370.00 ± 74.05 × 109/L, p < 0.001; week 12, 201.26 ± 51.48 × 109/L vs 303.13 ± 71.49 × 109/L, p < 0.001). CONCLUSION: SpA patients with thrombocytosis have a higher proportion of hip involvement and disease activity compared to non-thrombocytosis SpA patients. The potential risk factors for thrombocytosis in SPA patients were higher white blood cells and fibrinogen. Anti-TNF-α therapy can reduce the increased platelets more effectively and rapidly than conventional treatments in SpA patients with thrombocytosis.
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Espondilartrite , Inibidores do Fator de Necrose Tumoral , Humanos , Estudos de Casos e Controles , Inibidores do Fator de Necrose Tumoral/uso terapêutico , Espondilartrite/complicações , Espondilartrite/tratamento farmacológico , Contagem de Plaquetas , FibrinogênioRESUMO
Type II diabetes mellitus (T2DM) is a metabolic disease with high incidence, which has seriously affected human life and health. The associations among waist circumference (WC), waist-to-hip ratio (WHR), and T2DM were discovered in observational studies. However, the causality of these associations still remains unknown. The present study aims to apply two-sample Mendelian randomization (TSMR) using genetic variants as instrumental variables (IVs) to evaluate the causality among WC, WHR, and T2DM. The participants were from three independent studies in genome-wide association studies (GWAS) datasets, which included 127,997 Europeans for WC, 73,137 Europeans for WHR and 659,316 Europeans for T2DM. Furthermore, 16 were associated WC SNPs and eight were associated WHR SNPs as instrument variables were selected for TSMR using P < 5 × 10-8 standard. The pooled odd ratios (ORs) for the assessment of higher WC and WHR on the risk of T2DM for these SNPs were calculated using inverse variance weighted (IVW) method, and validated through extensively complementary analyses. The OR for T2DM per SD (cm) higher WC was 2.623 (95% CI 2.286-3.010, P = 5.000E-43), and the OR for T2DM per SD (cm) higher WHR was 1.751 (95% CI 1.122-2.733, P = 0.014). Consistent results for other methods were obtained. Furthermore, the range of OR fluctuation between WC and T2DM was from 2.623 to 2.986, while that between WHR and T2DM was from 0.990 to 2.931. Overall, these present results provide genetic support that suggests that the use of TSMR, and higher WC and WHR increased the T2DM risk among the European population.
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Diabetes Mellitus Tipo 2/fisiopatologia , Circunferência da Cintura/fisiologia , Índice de Massa Corporal , Feminino , Estudo de Associação Genômica Ampla/métodos , Humanos , Masculino , Análise da Randomização Mendeliana , Polimorfismo de Nucleotídeo Único/fisiologia , Fatores de Risco , Relação Cintura-Quadril/métodosRESUMO
BACKGROUND: Ischemic stroke (IS) was a significant public health concern and long-chain noncoding RNAs (lncRNAs) were gaining particular importance in stroke biology, however, the potential mechanism of lncRNAs in IS was not fully understood. METHODS: In this study, three diagnosed patients with IS and three controls were selected to establish the lncRNA library. Weighted gene co-expression network analysis (WGCNA) was applied to screen key lncRNA modules associated with IS. The key lncRNAs were identified by module membership (MM) and gene significance (GS). The Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis was used to identify the key pathways and protein-protein interaction (PPI) network method was used to identify the key genes. RESULTS: A total of 3627 lncRNAs were investigated, followed by an analysis of 17 modules, and only one module was highly associated with the IS. The top 10 lncRNAs were identified based on GS and MM. KEGG pathways analysis revealed the top two pathways of the Human T cell Lymphotropic Virus-1 (HTLV-1) infection and the mTOR signaling pathway might influence the progress of IS. Further, genes meeting the top two degree (AKT1 and MAPK14) were selected as the hub genes in the PPI network. CONCLUSION: To summarize, this study identified the key pathways and genes, which might serve as biomarkers and targets for precise diagnosis and treatment of IS in the future.
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AVC Isquêmico/metabolismo , RNA Longo não Codificante/metabolismo , Redes Reguladoras de Genes , Vírus Linfotrópico T Tipo 1 Humano , Humanos , AVC Isquêmico/genética , Mapeamento de Interação de Proteínas , Transdução de Sinais , Serina-Treonina Quinases TOR/metabolismoRESUMO
A major cause of morbidity and mortality for patients who undergo hematologic stem cell transplantation (HSCT) is acute graft-versus-host disease (aGVHD), a mostly T cell-mediated disease. Examination of the T cell receptor (TCR) repertoire of HSCT recipients and the use of next-generation nucleotide sequencing have raised the question of whether features of TCR repertoire reconstitution might reproducibly associate with aGVHD. We hypothesized that the peripheral blood TCR repertoire of patients with steroid-nonresponsive aGVHD would be less diverse. We also hypothesized that patients with GVHD who shared HLA might also share common clones at the time of GVHD diagnosis, thereby potentially providing potential clinical indicators for treatment stratification. We further hypothesized that HSCT recipients with the same HLA mismatch might share a more similar TCR repertoire based on a potentially shared focus of alloreactive responses. We studied 2 separate patient cohorts and 2 separate platforms for measuring TCR repertoire. The first cohort of patients was from a multicenter Phase III randomized double-blinded clinical trial of patients who developed aGVHD (NCT01002742). The second cohort comprised samples from biobanks from 2 transplantation centers and the Center for International Blood and Marrow Transplant Research of patients who underwent mismatched HSCT. There were no statistically significant differences in the TCR diversity of steroid responders and nonresponders among patients with aGVHD on the day of diagnosis. Most clones in the repertoire were unique to each patient, but a small number of clones were found to be both exclusive to and shared among aGVHD nonresponders. We were also able to show a strong correlation between the presence of Vß20 and Vß29 and steroid responsiveness. Using the Bhattacharya coefficient, those patients who shared the same HLA mismatch were shown to be no more similar to one another than to those who had a completely different mismatch. Using 2 separate clinical cohorts and 2 separate platforms for analyzing the TCR repertoire, we have shown that the sampled human TCR repertoire is largely unique to each patient but contains glimmers of common clones of subsets of clones based on responsiveness to steroids in aGVHD on the day of diagnosis. These studies are informative for future strategies to assess for reproducible TCR responses in human alloreactivity and possible markers of GVHD responsiveness to therapy.
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Doença Enxerto-Hospedeiro , Transplante de Células-Tronco Hematopoéticas , Células Clonais , Humanos , Receptores de Antígenos de Linfócitos T/genética , Linfócitos TRESUMO
BACKGROUNDS: We performed this systematic review and meta-analysis to compare the efficacy of new-generation tyrosine kinase inhibitors (NG-TKIs; including dasatinib, nilotinib, bosutinib, radotinib, and ponatinib) versus imatinib for patients with newly diagnosed chronic myeloid leukemia (CML). SUMMARY: We identified randomized controlled trials comparing the efficacy of NG-TKIs versus imatinib as the first-line treatment for CML patients by searching the PubMed, Cochrane library, and EMBASE databases. Two reviewers independently extracted data and assessed study quality. A meta-analysis was performed to calculate risk ratios and 95% CIs using a fixed-effects model.Our study included 10 trials. Overall, treatment with NG-TKIs significantly improved the major molecular response and MR4.5 at all time points, and early molecular response at 3 months. Importantly, overall survival (OS) was significantly higher with the NG-TKIs at 12 months. Besides, NG-TKI-treated patients showed a significantly lower CML-related death and progression to the accelerated phase/blast crisis. Key Messages: In first-line treatment, NG-TKIs are superior to imatinib regarding OS at 12 months, and because molecular response rates were higher with the NG-TKIs at all time points, the NG-TKIs favor treatment-free remission.
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Antineoplásicos/uso terapêutico , Mesilato de Imatinib/uso terapêutico , Leucemia Mieloide de Fase Crônica/tratamento farmacológico , Inibidores de Proteínas Quinases/uso terapêutico , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/efeitos adversos , Antineoplásicos/farmacologia , Feminino , Gastroenteropatias/induzido quimicamente , Doenças Hematológicas/induzido quimicamente , Humanos , Mesilato de Imatinib/efeitos adversos , Leucemia Mieloide de Fase Crônica/genética , Masculino , Pessoa de Meia-Idade , Intervalo Livre de Progressão , Inibidores de Proteínas Quinases/efeitos adversos , Ensaios Clínicos Controlados Aleatórios como Assunto/estatística & dados numéricos , Análise de Sobrevida , Adulto JovemRESUMO
Recycling sewage sludge by pyrolysis has attracted increasing attention for pollutant removal from wastewater and soils. This study scrutinized As(III) sorption behavior on sludge-derived biochar (SDBC) under different pyrolysis conditions and solution chemistry. The SDBC pyrolyzed at a higher temperature showed a lower As(III) sorption capacity and increasingly nonlinear isotherm due to loss of surface sites and deoxygenation-dehydrogenation. The Langmuir sorption capacity on SDBC (3.08-6.04 mg g) was comparable to other waste-derived sorbents, with the highest As(III) sorption on SDBC pyrolyzed at 400°C for 2 h. The As(III) sorption kinetics best fit with the pseudo-second-order equation, thus suggesting the significance of the availability of surface sites and initial concentration. Sorption of As(III) was faster than that of Cr(VI) but slower than that of Pb(II), which was attributed to their differences in molar volume (correlated to diffusion coefficients) and sorption mechanisms. The X-ray photoelectron spectra revealed an increase of oxide oxygen (O) with a decrease of sorbed water, indicative of ligand exchange with hydroxyl groups on SDBC surfaces. The As(III) sorption was not pH dependent in acidic-neutral range (pH < 8) due to the buffering capacity and surface characteristics of the SDBC; however, sorption was promoted by increasing pH in the alkaline range (pH > 8) because of As(III) speciation in solution. An increasing ionic strength (0.001-0.1 mol L) facilitated As(III) sorption, indicating the predominance of ligand exchange over electrostatic interactions, while high concentrations (0.1 mol L) of competing anions (fluoride, sulfate, carbonate, and phosphate) inhibited As(III) sorption. These results suggest that SDBC is applicable for As(III) immobilization in most environmentally relevant conditions.
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Aims: Atrial fibrillation/atrial flutter (AF/AFL) is a critical public health issue worldwide, and its epidemiological patterns have changed over the decades. This work aimed to assess the global trends of AF/AFL and attributable risks from 1990 to 2019. Methods and results: The present study utilized data from the Global Burden of Disease Study 2019 to examine the temporal trends, attributable risks, and projections of AF/AFL. The estimated annual percentage change (EAPC) and age-standardized rate (ASR) were employed for this purpose. The findings revealed that in 2019, AF/AFL accounted for 4.72 million incident cases, 59.70 million prevalent cases, 0.32 million deaths, and 8.39 million disability-adjusted life years (DALYs). Furthermore, the results indicated that males under 70 years of age had a higher incidence, prevalence, and DALYs than females, while the rates were similar for both genders between 70 and 74 years. However, this pattern was reversed in individuals over the age of 75, with females exhibiting a higher total incidence, prevalence, and DALYs than males. The age-standardized rates (ASRs) of prevalence, incidence, mortality, and DALYs increased with an increase in the socio-demographic index (SDI). The three primary contributors to AF/AFL were high systolic blood pressure, high body-mass index, and smoking. Majority of risk factors exhibited a unimodal distribution, with a peak between the ages of 50 and 70. Conclusions: The disease burden of AF/AFL is still severe worldwide and getting worse. To encourage prevention and treatment, systematic regional surveillance of AF/AFL should be put in place.
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Background: C-reactive protein-to-albumin ratio (CRP/ALB) has been proven to represent a biomarker for predicting prognosis in many groups of patients with severe diseases. However, few studies have investigated the association between CRP/ALB and mortality in Japan older people with dysphagia patients. Objective: This retrospective cohort study aimed to assess the prognostic value of C-reactive protein/albumin ratio (CAR) in older Japanese patients with dysphagia. Methods: We analyzed data from 253 patients diagnosed with dysphagia at a single center between January 2014 and January 2017. Cox regression analysis was used to compare the mortality rates across the CAR tertiles. Subgroup analyses were conducted, and Kaplan-Meier curves were used to determine the median survival times. Results: The study included 154 female and 99 male patients, with a median age of 83 years. After adjusting for all covariates, the multivariable Cox regression analysis revealed a significant association between increasing CAR (HR = 1.19, 95% CI: 1.03-1.37, P = 0.022) and the risk of mortality. Compared to the reference group T1 (< 0.149), the adjusted hazard ratios for T2 (0.149-0.815) and T3 (> 0.815) were 1.75 (95% CI: 1.07-2.87, P = 0.027) and 2.15 (95% CI: 1.34-3.46, P = 0.002), respectively. Kaplan-Meier curves indicated median survival times of 864, 371, and 223 days for T1, T2, and T3, respectively. Conclusion: The C-reactive protein/albumin ratio was positively related to mortality in Japan older people with dysphagia patients. There was no interaction for the subgroup analysis. The result was stable.
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BACKGROUND: Acute liver injury (ALI) is a serious syndrome with a high mortality rate due to viral infection, toxic exposure, and autoimmunity, and its severity can range from mildly elevated liver enzymes to severe liver failure. Activation of the nod-like receptor pyrin domain-containing 3 (NLRP3) inflammasome is closely associated with the development of ALI, and the search for an inhibitor targeting this pathway may be a novel therapeutic option. Anoectochilus roxburghii polysaccharide (ARP) is a biologically active ingredient extracted from Anoectochilus roxburghii with immunomodulatory, antioxidant, and anti-inflammatory bioactivities and pharmacological effects. In this study, we focused on D-galactosamine (D-GalN)/lipopolysaccharide (LPS)-induced acute liver injury by ARP through inhibition of NLRP3 inflammasome. METHODS: An inflammasome activation model was established in bone marrow-derived macrophages (BMDMs) to investigate the effects of ARP on caspase-1 cleavage, IL-1ß secretion, and ASC oligomerization in inflammasomes under different agonists. We used the D-GalN/LPS-induced acute liver injury model in mice, intraperitoneally injected ARP or MCC950, and collected liver tissues, serum, and intraperitoneal lavage fluid for pathological and biochemical indexes. RESULTS: ARP effectively inhibited the activation of the NLRP3 inflammasome and had an inhibitory effect on non-classical NLRP3, AIM2, and NLRC4 inflammasomes. It also effectively inhibited the oligomerization of apoptosis-associated speck-like protein (ASC) from a variety of inflammatory vesicles. Meanwhile, ARP has good therapeutic effects on acute liver injury induced by D-GaIN/LPS. CONCLUSION: The inhibitory effect of ARP on a wide range of inflammasomes, as well as its excellent protection against acute liver injury, suggests that ARP may be a candidate for acute liver injury.
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Efficient, narrowband multi-resonance thermally activated delayed fluorescence (MR-TADF) emitters have recently sparked significant interest in high-resolution organic light-emitting diode (OLED) displays. However, almost all the progress in MR-TADF materials has been accomplished using a six-membered ring as the π-core to date. Herein, we present the first example of a five-membered ring π-core-based MR-TADF emitter named Th-BN developed by introducing thiophene instead of hexagonal benzene as the π-core. The introduction of thiophene significantly enhances intramolecular charge transfer intensity and the spin-orbit coupling matrix elements but does not change the intrinsic MR properties. As a result, Th-BN exhibits a narrowband green emission at 512 nm, with a high luminous efficiency of 97%, a narrow full-width at half maximum of 41 nm/0.20 eV, and a rapid reverse intersystem crossing rate of 18.7 × 104 s-1, which is 10 times higher than that of its benzenoid counterpart DtBuCzB. The corresponding green OLEDs based on Th-BN achieve excellent electroluminescence performance with an external quantum efficiency (EQE) of 34.6% and a reduced efficiency roll-off with an EQE of 26.8% at a high luminance of 1000 cd m-2.
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Glucocorticoids (GCs) are efficacious drugs used for treating many inflammatory diseases, but the dose and duration of administration are limited because of severe side effects. We therefore sought to identify an approach to selectively target GCs to inflamed tissue. Previous work identified that anti-tumor necrosis factor (TNF) antibodies that bind to transmembrane TNF undergo internalization; therefore, an anti-TNF antibody-drug conjugate (ADC) would be mechanistically similar, where lysosomal catabolism could release a GC receptor modulator (GRM) payload to dampen immune cell activity. Consequently, we have generated an anti-TNF-GRM ADC with the aim of inhibiting pro-inflammatory cytokine production from stimulated human immune cells. In an acute mouse model of contact hypersensitivity, a murine surrogate anti-TNF-GRM ADC inhibited inflammatory responses with minimal effect on systemic GC biomarkers. In addition, in a mouse model of collagen-induced arthritis, single-dose administration of the ADC, delivered at disease onset, was able to completely inhibit arthritis for greater than 30 days, whereas an anti-TNF monoclonal antibody only partially inhibited disease. ADC treatment at the peak of disease was also able to attenuate the arthritic phenotype. Clinical data for a human anti-TNF-GRM ADC (ABBV-3373) from a single ascending dose phase 1 study in healthy volunteers demonstrated antibody-like pharmacokinetic profiles and a lack of impact on serum cortisol concentrations at predicted therapeutic doses. These data suggest that an anti-TNF-GRM ADC may provide improved efficacy beyond anti-TNF alone in immune mediated diseases while minimizing systemic side effects associated with standard GC treatment.
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Anticorpos , Artrite Experimental , Imunoconjugados , Esteroides , Humanos , Animais , Camundongos , Preparações Farmacêuticas , Receptores de Glucocorticoides/uso terapêutico , Inibidores do Fator de Necrose Tumoral/uso terapêutico , Glucocorticoides/farmacologia , Glucocorticoides/uso terapêutico , Fator de Necrose Tumoral alfa/metabolismo , Modelos Animais de Doenças , Imunoconjugados/farmacologia , Imunoconjugados/uso terapêuticoRESUMO
Sepsis begins with vascular endothelial barrier breakdown and causes widespread organ failure. Protease-activated receptor 1 (PAR1) is an important target for modulating vascular endothelial permeability; however, little research has been undertaken in sepsis, and its putative molecular mechanism remains unknown. The vascular endothelial permeability was examined by detecting FITC-dextran flux. F-actin was examined by immunofluorescence (IF). PAR1, ERM phosphorylation, and RhoA/ROCK signaling pathway expression in lipopolysaccharide (LPS)-stimulated human umbilical vein endothelial cells (HUVECs) line were examined by IF and Western blot. To develop the sepsis model, cecal ligation and puncture (CLP) were conducted. The PAR1 inhibitor SCH79797 was utilized to inhibit PAR1 expression in vivo. Vascular permeability in main organs weres measured by Evans blue dye extravasation. The pathological changes in main organs were examined by HE staining. The expression of PAR1, ERM phosphorylation, and the RhoA/ROCK signaling pathway was examined using IF, immunohistochemical and WB in CLP mice. In vitro, in response to LPS stimulation of HUVECs, PAR1 mediated the phosphorylation of ERM, promoted F-actin rearrangement, and increased endothelial hyperpermeability, all of which were prevented by inhibiting PAR1 or RhoA. Additionally, inhibiting PAR1 expression reduced RhoA and ROCK expression. In vivo, we showed that inhibiting PAR1 expression will reduce ezrin/radixin/moesin (ERM) phosphorylation to relieve vascular endothelial barrier dysfunction and thereby ameliorate multiorgan dysfunction syndrome (MODS) in CLP-induced septic mice. This study revealed that PAR1-mediated phosphorylation of ERM induced endothelial barrier dysfunction, which in turn led to MODS in sepsis, and that the RhoA/ROCK signaling pathway underlay these effects.
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Receptor PAR-1 , Sepse , Humanos , Camundongos , Animais , Receptor PAR-1/metabolismo , Actinas/metabolismo , Fosforilação , Lipopolissacarídeos/farmacologia , Transdução de Sinais , Células Endoteliais da Veia Umbilical Humana/metabolismo , Proteína rhoA de Ligação ao GTP/metabolismo , Sepse/metabolismo , Quinases Associadas a rho/metabolismo , Permeabilidade CapilarRESUMO
BACKGROUND: Whether patients over 85 years old with gastrointestinal cancer should undergo surgery remains controversial. We aimed to describe the changing trends of characteristics to provide more information to decision makers, and strive to find appropriate surgical plan. AIM: To describe the changing trends of characteristics to provide more information to decision makers, and strive to find appropriate surgical plan. METHODS: A total of 218 gastric cancer (GC) patients and 563 colorectal cancer (CRC) patients who underwent surgery between 2001 and 2021 were enrolled in this retrospective analysis. Changes in clinicopathological features, surgical treatments, and survival status were analyzed longitudinally at 5-year intervals. RESULTS: Only 14 GC patients underwent laparoscopic surgery where 219 CRC patients had this procedure. Cardia and esophagogastric junction cancer increased in GC patients, and the proportion of sigmoid colon cancer decreased in CRC patients. Pulmonary infection gradually became the most common postoperative complication, its incidence in period 4 reached 48.79%. However, the incidence of anastomotic leakage decreased from 26.79% to 9.38% (P < 0.01). Additionally, 30-d mortality significantly decreased from 32.14% to 9.01%. Increases were observed in 5-year overall survival (OS) in GC patients from period 1 to period 4 (18.18% vs 33.32%, respectively) and CRC patients (0 vs 36.32%, respectively). Disease-free survival (DFS) also increased in GC and CRC patients (7.14% vs 27.74% and 0 to 36.03%, respectively). The average survival time of GC patients following radial lymphadenectomy was higher than in patients that underwent limited lymphadenectomy (26 vs 22 mo, respectively), the same was seen in CRC patients (44 vs 33 mo, respectively). This advantage was particularly evident in patients with TNM I, but not in patients with TNM II/III period cancer. CONCLUSION: The safety as well as effectiveness of surgery in ultra-elderly patients is increasing. Radical lymphadenectomy has advantages in patients with TNM I gastrointestinal cancer, but not TNM II/III.
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Background: To investigate the change in hypothalamic kisspeptin-1 (Kiss1) expression during the development of polycystic ovary syndrome (PCOS) and hypoglycemic drug intervention. Methods: Letrozole lavage was used to construct a polycystic ovary rat model. After successful modeling, we treated PCOS rats with metformin, pioglitazone, and acarbose, and we then observed changes in weight, estrus, glucose tolerance, insulin resistance, sex hormones, and hypothalamic kiss1 expression. Results: PCOS rats exhibited increased body weight, abnormal estrous cycle, impaired glucose tolerance, insulin resistance, increased testosterone level, increased luteinizing hormone level, and increased Kiss1 expression in the hypothalamus. However, intervention with metformin, pioglitazone, and acarbose improved the reproductive and metabolic disorders as well as reduced hypothalamic Kiss1 expression. Conclusion: The expression of hypothalamic Kiss1 may play an important role in the pathogenesis of PCOS. Metformin, pioglitazone, and acarbose may reduce the expression of hypothalamic Kiss1 by improving insulin resistance, thereby improving reproductive and metabolic disorders in PCOS rats.
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RATIONALE: Pendred syndrome is an autosomal recessive disorder characterized by sensorineural hearing loss, inner ear malformations, goiter, and abnormal organification of iodide. It is caused by mutations in SLC26A4 gene, which encodes pendrin (a transporter of chloride, bicarbonate, and iodide). Pendred syndrome is a common cause of syndromic deafness, but the metabolic abnormalities it causes are often overlooked. Here, we report the case of a patient diagnosed with Pendred syndrome with hypokalemia. PATIENT CONCERNS: A 53-year-old deaf-mute woman was hospitalized due to severe limb asthenia. The emergency examination showed that her blood potassium level was 1.8 mmol/L. DIAGNOSES: Through the genetic test, we found a mutation of SLC26A4 gene in NM_000441: c.2027T>A, p.L676Q, as well as the SLC26A4 exon 5-6 deletion. These genetic variations pointed to Pendred syndrome (an autosomal recessive disorder that mainly affects the inner ear, thyroid, and kidney) which is a common cause of syndromic deafness. INTERVENTIONS: The patient was treated with potassium supplements and screened for the cause of hypokalemia. OUTCOMES: The patient was discharged after her potassium levels rose to the normal range. LESSONS: Patients with Pendred syndrome may also have certain metabolic abnormalities; thus, more attention should be paid to them during clinical diagnosis.