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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 , Corona de Proteínas , Macrófagos/metabolismo , Corona de Proteínas/metabolismo , Corona de Proteínas/química , Animales , Ratones , Nanopartículas/química , HumanosRESUMEN
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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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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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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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 , Inmunoconjugados , Receptores de Glucocorticoides , Ensayos Antitumor por Modelo de Xenoinjerto , Humanos , Animales , Antígenos CD19/inmunología , Ratones , Inmunoconjugados/farmacología , Inmunoconjugados/uso terapéutico , Receptores de Glucocorticoides/antagonistas & inhibidores , Anticuerpos Monoclonales Humanizados/farmacología , Anticuerpos Monoclonales Humanizados/uso terapéutico , Anticuerpos Monoclonales Humanizados/administración & dosificación , Linfoma de Células B/tratamiento farmacológico , Linfoma de Células B/patología , Línea Celular Tumoral , Ratones SCID , Femenino , Maitansina/análogos & derivadosRESUMEN
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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Anticuerpos , Artritis Experimental , Inmunoconjugados , Esteroides , Humanos , Animales , Ratones , Preparaciones Farmacéuticas , Receptores de Glucocorticoides/uso terapéutico , Inhibidores del Factor de Necrosis Tumoral/uso terapéutico , Glucocorticoides/farmacología , Glucocorticoides/uso terapéutico , Factor de Necrosis Tumoral alfa/metabolismo , Modelos Animales de Enfermedad , Inmunoconjugados/farmacología , Inmunoconjugados/uso terapéuticoRESUMEN
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: 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 , Absceso Pulmonar , Embolia Pulmonar , Venas Pulmonares , Accidente Cerebrovascular , Trombosis de la Vena , Humanos , Masculino , Adulto Joven , Adulto , Absceso Pulmonar/complicaciones , Absceso Pulmonar/diagnóstico por imagen , Absceso Pulmonar/terapia , Venas Pulmonares/diagnóstico por imagen , Trombosis de la Vena/complicaciones , Trombosis de la Vena/diagnóstico por imagen , Trombosis de la Vena/tratamiento farmacológico , Accidente Cerebrovascular/diagnóstico , Accidente Cerebrovascular/diagnóstico por imagen , Embolia Pulmonar/diagnósticoRESUMEN
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 , Sepsis , Humanos , Ratones , Animales , Receptor PAR-1/metabolismo , Actinas/metabolismo , Fosforilación , Lipopolisacáridos/farmacología , Transducción de Señal , Células Endoteliales de la Vena Umbilical Humana/metabolismo , Proteína de Unión al GTP rhoA/metabolismo , Sepsis/metabolismo , Quinasas Asociadas a rho/metabolismo , Permeabilidad CapilarRESUMEN
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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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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Espondiloartritis , Inhibidores del Factor de Necrosis Tumoral , Humanos , Estudios de Casos y Controles , Inhibidores del Factor de Necrosis Tumoral/uso terapéutico , Espondiloartritis/complicaciones , Espondiloartritis/tratamiento farmacológico , Recuento de Plaquetas , FibrinógenoRESUMEN
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.
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Sordera , Bocio Nodular , Pérdida Auditiva Sensorineural , Hipopotasemia , Bicarbonatos , Cloruros , Femenino , Bocio Nodular/complicaciones , Bocio Nodular/diagnóstico , Bocio Nodular/genética , Pérdida Auditiva Sensorineural/diagnóstico , Pérdida Auditiva Sensorineural/genética , Humanos , Hipopotasemia/genética , Yoduros/metabolismo , Persona de Mediana Edad , Mutación , Potasio , Transportadores de Sulfato/genéticaRESUMEN
Costimulatory receptors such as glucocorticoid-induced tumor necrosis factor receptor-related protein (GITR) play key roles in regulating the effector functions of T cells. In human clinical trials, however, GITR agonist antibodies have shown limited therapeutic effect, which may be due to suboptimal receptor clustering-mediated signaling. To overcome this potential limitation, a rational protein engineering approach is needed to optimize GITR agonist-based immunotherapies. Here we show a bispecific molecule consisting of an anti-PD-1 antibody fused with a multimeric GITR ligand (GITR-L) that induces PD-1-dependent and FcγR-independent GITR clustering, resulting in enhanced activation, proliferation and memory differentiation of primed antigen-specific GITR+PD-1+ T cells. The anti-PD-1-GITR-L bispecific is a PD-1-directed GITR-L construct that demonstrated dose-dependent, immunologically driven tumor growth inhibition in syngeneic, genetically engineered and xenograft humanized mouse tumor models, with a dose-dependent correlation between target saturation and Ki67 and TIGIT upregulation on memory T cells. Anti-PD-1-GITR-L thus represents a bispecific approach to directing GITR agonism for cancer immunotherapy.
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Neoplasias , Receptor de Muerte Celular Programada 1 , Animales , Análisis por Conglomerados , Modelos Animales de Enfermedad , Proteína Relacionada con TNFR Inducida por Glucocorticoide/agonistas , Humanos , Inmunoterapia/métodos , Ratones , Neoplasias/tratamiento farmacológico , Receptores del Factor de Necrosis Tumoral/agonistas , Linfocitos TRESUMEN
BACKGROUND: Long non-coding RNAs (lncRNAs) are widely involved in gene transcription regulation and which act as epigenetic modifiers in many diseases. OBJECTIVE: To determine whether lncRNAs are involved in ischemic stroke (IS), we analyzed the expression profile of lncRNAs and mRNAs in IS. METHODS: RNA sequencing was performed on the blood of three pairs of IS patients and healthy controls. Differential expression analysis was used to identify differentially expressed lncRNAs (DElncRNAs) and mRNAs (DEmRNAs). Based on the co-expression relationships between lncRNA and mRNA, a series of bioinformatics analysis including GO and KEGG enrichment analysis and PPI analysis, were conducted to predict the function of lncRNA. RESULTS: RNA sequencing produced a total of 5 DElncRNAs and 144 DEmRNAs. Influenza A pathway and Herpes simplex infection pathway were the most significant pathways. EP300 and NFKB1 were the most important target proteins, and Human leucocyte antigen (HLA) family were the key genes in IS. CONCLUSIONS: Analysis of this study revealed that dysregulated lncRNAs in IS may lead to IS by affecting the immune and inflammation system.
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Biología Computacional/métodos , Regulación de la Expresión Génica , Accidente Cerebrovascular Isquémico/genética , ARN Largo no Codificante/genética , ARN Mensajero/genética , Análisis de Secuencia de ARN/métodos , Transducción de Señal/genética , Progresión de la Enfermedad , Perfilación de la Expresión Génica/métodos , Ontología de Genes , Redes Reguladoras de Genes/genética , Antígenos HLA/genética , Antígenos HLA/metabolismo , Humanos , Inflamación/genética , Accidente Cerebrovascular Isquémico/inmunología , Accidente Cerebrovascular Isquémico/metabolismo , Accidente Cerebrovascular Isquémico/patología , Masculino , Persona de Mediana Edad , Subunidad p50 de NF-kappa B/genética , Subunidad p50 de NF-kappa B/metabolismo , Mapas de Interacción de Proteínas/genética , Transducción de Señal/inmunologíaRESUMEN
BACKGROUND: Increasing epidemic of ischemic stroke (IS) makes it urgent to understand the pathogenesis and regulatory mechanism, previous studies have described microRNAs (miRNAs) is part of the brain's response to ischemia. OBJECTIVE: The aim of this study was to screen potential biomarkers for the prediction and novel treatment of IS. METHODS: Differentially expressed miRNAs were screened from three newly diagnosed IS patients and three controls by RNA sequencing technology. Furthermore, target prediction databases were then used to analysis the target genes of different expressed miRNAs, and the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway database were used to identify the functions and the main biochemical and signal pathways of differentially expressed target genes. RESULTS: Our results revealed that 27 miRNAs were differentially expressed in IS, among which, hsa-miR-659-5p was the most highly increased and was first found to be associated with IS. In addition, KEGG pathway analyses showed that differentially expressed miRNAs were mainly significantly enriched in lysosome pathway, cytokine-cytokine receptor interaction pathway, spliceosome pathway, base excision repair pathway. CONCLUSIONS: miRNAs were involved in IS pathogenesis, and hsa-miR-659-5p, hsa-miR-151a-3p and hsa-miR-29c-5p as the three highest |log2FoldChange| regulation in this study, which may be the biomarkers of IS and need further study.
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Biomarcadores/metabolismo , Perfilación de la Expresión Génica , Accidente Cerebrovascular Isquémico/genética , MicroARNs/genética , Transducción de Señal/genética , Análisis por Conglomerados , Redes Reguladoras de Genes , Humanos , Accidente Cerebrovascular Isquémico/diagnóstico , Masculino , Persona de Mediana Edad , Análisis de Secuencia de ARNRESUMEN
Classical dendritic cells (cDCs) in mice have been divided into 2 major subsets based on the expression of nuclear transcription factors: a CD8+Irf8+Batf3 dependent (DC1) subset, and a CD8-Irf4+ (DC2) subset. We found that the CD8+DC1 subset can be further divided into CD8+DC1a and CD8+DC1b subsets by differences in surface receptors, gene expression, and function. Whereas all 3 DC subsets can act alone to induce potent Th1 cytokine responses to class I and II MHC restricted peptides derived from ovalbumin (OVA) by OT-I and OT-II transgenic T cells, only the DC1b subset could effectively present glycolipid antigens to natural killer T (NKT) cells. Vaccination with OVA protein pulsed DC1b and DC2 cells were more effective in reducing the growth of the B16-OVA melanoma as compared to pulsed DC1a cells in wild type mice. In conclusion, the Batf3-/- dependent DC1 cells can be further divided into two subsets with different immune functional profiles in vitro and in vivo.
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Antígenos CD8/inmunología , Células Dendríticas/inmunología , Activación de Linfocitos/inmunología , Transcriptoma/inmunología , Animales , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , FenotipoRESUMEN
OBJECTIVE: To investigate the diagnosis and treatment of Multiple Endocrine Neoplasia Type 1 (MEN1), improve our understanding of the disease and highlight the importance of life-long follow-up of affected individuals. METHODS: A retrospective analysis was performed on 1 MEN1 patient with long-term follow-up at the First Affiliated Hospital of Anhui Medical University. RESULTS: A 51-year-old woman was diagnosed with MEN1 14 years ago, but exhibited a suspected disease course of at least 20 years. Prior to admission, the patient reported a cough lasting for two months. The patient's thyroid hormone, sex hormone, insulin, cortisol, parathyroid hormone, and ACTH circadian rhythm findings were within normal ranges. The patient exhibited elevated blood calcium levels. Examination led to the detection of thymoma and pancreatic neoplasms, whereas no obvious abnormalities were detected in her parathyroid gland or adrenal gland as determined via computed tomography (CT). Genetic analyses revealed a mutation in the MEN1 gene in this patient. As the patient had no relevant clinical symptoms, she refused surgical treatment, and follow-up was continued. It was learned through follow-up that the patient underwent anterior mediastinal lesion resection and partial rib resection in June 2020 because she re-examined the chest CT showed that the anterior mediastinal mass was significantly larger than that in 2019. Pathology suggested neuroendocrine tumors. The patient is currently recovering well. CONCLUSION: MEN1 is an uncommon condition in clinical settings, and it is important that clinicians be made aware of this disorder so that they can provide patients with appropriate and timely treatments.
Asunto(s)
Neoplasia Endocrina Múltiple Tipo 1 , Neoplasias Pancreáticas , Glándulas Suprarrenales , Femenino , Estudios de Seguimiento , Humanos , Persona de Mediana Edad , Neoplasia Endocrina Múltiple Tipo 1/diagnóstico , Neoplasia Endocrina Múltiple Tipo 1/genética , Neoplasia Endocrina Múltiple Tipo 1/cirugía , Neoplasias Pancreáticas/diagnóstico , Estudios RetrospectivosRESUMEN
Replacement of failed organs followed by safe withdrawal of immunosuppressive drugs has long been the goal of organ transplantation. We studied changes in the balance of T cells and myeloid cells in the blood of HLA-matched and -mismatched patients given living donor kidney transplants followed by total lymphoid irradiation, anti-thymocyte globulin conditioning, and donor hematopoietic cell transplant to induce mixed chimerism and immune tolerance. The clinical trials were based on a conditioning regimen used to establish mixed chimerism and tolerance in mice. In preclinical murine studies, there was a profound depletion of T cells and an increase in immunosuppressive polymorphonuclear (pmn) myeloid-derived suppressor cells (MDSCs) in the spleen and blood following transplant. Selective depletion of pmn MDSCs in mice abrogated mixed chimerism and tolerance. In our clinical trials, patients given an analogous tolerance conditioning regimen developed similar changes, including profound depletion of T cells and a marked increase in MDSCs in blood posttransplant. Posttransplant pmn MDSCs transiently increased expression of lectin-type oxidized LDL receptor-1, a marker of immunosuppression, and production of the T-cell inhibitor arginase-1. These posttransplant pmn MDSCs suppressed the activation, proliferation, and inflammatory cytokine secretion of autologous T-cell receptor microbead-stimulated pretransplant T cells when cocultured in vitro. In conclusion, we elucidated changes in receptors and function of immunosuppressive myeloid cells in patients enrolled in the tolerance protocol that were nearly identical to those of MDSCs required for tolerance in mice. These trials were registered at www.clinicaltrials.gov as #NCT00319657 and #NCT01165762.