RESUMO
The formation of an immunological synapse (IS) is essential for natural killer (NK) cells to eliminate target cells. Despite an advanced understanding of the characteristics of the IS and its formation processes, the mechanisms that regulate its stability via the cytoskeleton are unclear. Here, we show that Nogo receptor 1 (NgR1) has an important function in modulating NK cell-mediated killing by destabilization of IS formation. NgR1 deficiency or blockade resulted in improved tumor control of NK cells by enhancing NK-to-target cell contact stability and regulating F-actin dynamics during IS formation. Patients with tumors expressing abundant NgR1 ligand had poor prognosis despite high levels of NK cell infiltration. Thus, our study identifies NgR1 as an immune checkpoint in IS formation and indicates a potential approach to improve the cytolytic function of NK cells in cancer immunotherapy.
Assuntos
Sinapses Imunológicas , Neoplasias , Humanos , Receptores de Células Matadoras Naturais , Receptor Nogo 1 , Células Matadoras Naturais , Actinas , Neoplasias/patologiaRESUMO
Although anti-citrullinated protein autoantibodies (ACPAs) are a hallmark serological feature of rheumatoid arthritis (RA), the mechanisms and cellular sources behind the generation of the RA citrullinome remain incompletely defined. Peptidylarginine deiminase IV (PAD4), one of the key enzymatic drivers of citrullination in the RA joint, is expressed by granulocytes and monocytes; however, the subcellular localization and contribution of monocyte-derived PAD4 to the generation of citrullinated autoantigens remain underexplored. In this study, we demonstrate that PAD4 displays a widespread cellular distribution in monocytes, including expression on the cell surface. Surface PAD4 was enzymatically active and capable of citrullinating extracellular fibrinogen and endogenous surface proteins in a calcium dose-dependent manner. Fibrinogen citrullinated by monocyte-surface PAD4 could be specifically recognized over native fibrinogen by a panel of eight human monoclonal ACPAs. Several unique PAD4 substrates were identified on the monocyte surface via mass spectrometry, with citrullination of the CD11b and CD18 components of the Mac-1 integrin complex being the most abundant. Citrullinated Mac-1 was found to be a target of ACPAs in 25% of RA patients, and Mac-1 ACPAs were significantly associated with HLA-DRB1 shared epitope alleles, higher C-reactive protein and IL-6 levels, and more erosive joint damage. Our findings implicate the monocyte cell surface as a unique and consequential site of extracellular and cell surface autoantigen generation in RA.
Assuntos
Ácidos Aminossalicílicos , Artrite Reumatoide , Monócitos , Humanos , Desiminases de Arginina em Proteínas , Monócitos/metabolismo , Autoantígenos , Autoanticorpos , Fibrinogênio/metabolismo , Citrulina/metabolismoRESUMO
BACKGROUND: Ciltacabtagene autoleucel (cilta-cel), a B-cell maturation antigen (BCMA)-directed CAR T-cell therapy, is effective in heavily pretreated patients with relapsed or refractory multiple myeloma. We investigated cilta-cel in earlier treatment lines in patients with lenalidomide-refractory disease. METHODS: In this phase 3, randomized, open-label trial, we assigned patients with lenalidomide-refractory multiple myeloma to receive cilta-cel or the physician's choice of effective standard care. All the patients had received one to three previous lines of treatment. The primary outcome was progression-free survival. RESULTS: A total of 419 patients underwent randomization (208 to receive cilta-cel and 211 to receive standard care). At a median follow-up of 15.9 months (range, 0.1 to 27.3), the median progression-free survival was not reached in the cilta-cel group and was 11.8 months in the standard-care group (hazard ratio, 0.26; 95% confidence interval [CI], 0.18 to 0.38; P<0.001). Progression-free survival at 12 months was 75.9% (95% CI, 69.4 to 81.1) in the cilta-cel group and 48.6% (95% CI, 41.5 to 55.3) in the standard-care group. More patients in the cilta-cel group than in the standard-care group had an overall response (84.6% vs. 67.3%), a complete response or better (73.1% vs. 21.8%), and an absence of minimal residual disease (60.6% vs. 15.6%). Death from any cause was reported in 39 patients and 46 patients, respectively (hazard ratio, 0.78; 95% CI, 0.5 to 1.2). Most patients reported grade 3 or 4 adverse events during treatment. Among the 176 patients who received cilta-cel in the as-treated population, 134 (76.1%) had cytokine release syndrome (grade 3 or 4, 1.1%; no grade 5), 8 (4.5%) had immune effector cell-associated neurotoxicity syndrome (all grade 1 or 2), 1 had movement and neurocognitive symptoms (grade 1), 16 (9.1%) had cranial nerve palsy (grade 2, 8.0%; grade 3, 1.1%), and 5 (2.8%) had CAR-T-related peripheral neuropathy (grade 1 or 2, 2.3%; grade 3, 0.6%). CONCLUSIONS: A single cilta-cel infusion resulted in a lower risk of disease progression or death than standard care in lenalidomide-refractory patients with multiple myeloma who had received one to three previous therapies. (Funded by Janssen and Legend Biotech; CARTITUDE-4 ClinicalTrials.gov number, NCT04181827.).
Assuntos
Antineoplásicos Imunológicos , Antígeno de Maturação de Linfócitos B , Imunoterapia Adotiva , Mieloma Múltiplo , Humanos , Lenalidomida/efeitos adversos , Mieloma Múltiplo/tratamento farmacológico , Mieloma Múltiplo/mortalidade , Síndromes Neurotóxicas , Intervalo Livre de Progressão , Antígeno de Maturação de Linfócitos B/imunologia , Imunoterapia Adotiva/métodos , Antineoplásicos Imunológicos/uso terapêutico , Resistencia a Medicamentos AntineoplásicosRESUMO
ABSTRACT: This meta-analysis evaluates the efficacy and safety of chimeric antigen receptor (CAR) T-cell therapy and bispecific antibodies for relapsed/refractory diffuse large B-cell lymphoma (R/R DLBCL). We searched MEDLINE, Embase, and Cochrane databases until July 2023 for trials assessing CAR T-cell therapies and CD20×CD3 bispecific antibodies as third or subsequent lines in R/R DLBCL. Random-effects models estimated the complete response (CR) rate and secondary outcomes, with meta-regressions adjusting for relevant covariates. Sixteen studies comprising 1347 patients were included in the pooled analysis. The pooled CR rate for bispecific antibodies was 0.36 (95% confidence interval [CI], 0.29-0.43), compared with 0.51 (95% CI, 0.46-0.56) for CAR T-cell therapy (P < .01). This superiority persisted when comparing the CAR T-cell-naive patients within the bispecific antibody group, with a CR rate of 0.37 (95% CI, 0.32-0.43). Multivariable meta-regression also revealed better efficacy of CAR T cells with adjustment for the proportion of double-hit lymphoma. The pooled 1-year progression-free survival rate mirrored these findings (0.32 [95% CI, 0.26-0.38] vs 0.44 [95% CI, 0.41-0.48]; P < .01). For adverse events of grade ≥3, the bispecific antibody had incidences of 0.02 (95% CI, 0.01-0.04) for cytokine release syndrome, 0.01 (95% CI, 0.00-0.01) for neurotoxicity, and 0.10 (95% CI, 0.03-0.16) for infections. The CAR T cell had rates of 0.08 (95% CI, 0.03-0.12), 0.11 (95% CI, 0.06-0.17), and 0.17 (95% CI, 0.11-0.22), respectively, with significant differences observed in the first 2 categories. In summary, CAR T-cell therapy outperformed bispecific antibody in achieving higher CR rates, although with an increase in severe adverse events.
Assuntos
Anticorpos Biespecíficos , Imunoterapia Adotiva , Linfoma Difuso de Grandes Células B , Humanos , Anticorpos Biespecíficos/uso terapêutico , Anticorpos Biespecíficos/efeitos adversos , Linfoma Difuso de Grandes Células B/terapia , Linfoma Difuso de Grandes Células B/imunologia , Imunoterapia Adotiva/efeitos adversos , Imunoterapia Adotiva/métodos , Receptores de Antígenos Quiméricos/imunologiaRESUMO
Accumulating evidence indicates that gut microorganisms have a pathogenic role in autoimmune diseases, including in multiple sclerosis1. Studies of experimental autoimmune encephalomyelitis (an animal model of multiple sclerosis)2,3, as well as human studies4-6, have implicated gut microorganisms in the development or severity of multiple sclerosis. However, it remains unclear how gut microorganisms act on the inflammation of extra-intestinal tissues such as the spinal cord. Here we show that two distinct signals from gut microorganisms coordinately activate autoreactive T cells in the small intestine that respond specifically to myelin oligodendrocyte glycoprotein (MOG). After induction of experimental autoimmune encephalomyelitis in mice, MOG-specific CD4+ T cells are observed in the small intestine. Experiments using germ-free mice that were monocolonized with microorganisms from the small intestine demonstrated that a newly isolated strain in the family Erysipelotrichaceae acts similarly to an adjuvant to enhance the responses of T helper 17 cells. Shotgun sequencing of the contents of the small intestine revealed a strain of Lactobacillus reuteri that possesses peptides that potentially mimic MOG. Mice that were co-colonized with these two strains showed experimental autoimmune encephalomyelitis symptoms that were more severe than those of germ-free or monocolonized mice. These data suggest that the synergistic effects that result from the presence of these microorganisms should be considered in the pathogenicity of multiple sclerosis, and that further study of these microorganisms may lead to preventive strategies for this disease.
Assuntos
Encefalomielite Autoimune Experimental/microbiologia , Microbioma Gastrointestinal/imunologia , Inflamação/patologia , Medula Espinal/patologia , Linfócitos T/imunologia , Linfócitos T/patologia , Animais , Modelos Animais de Doenças , Encefalomielite Autoimune Experimental/imunologia , Encefalomielite Autoimune Experimental/patologia , Encefalomielite Autoimune Experimental/prevenção & controle , Feminino , Vida Livre de Germes , Inflamação/imunologia , Intestino Delgado/imunologia , Intestino Delgado/microbiologia , Intestino Delgado/patologia , Limosilactobacillus reuteri/química , Limosilactobacillus reuteri/imunologia , Limosilactobacillus reuteri/patogenicidade , Masculino , Camundongos , Esclerose Múltipla/imunologia , Esclerose Múltipla/microbiologia , Esclerose Múltipla/patologia , Glicoproteína Mielina-Oligodendrócito/química , Glicoproteína Mielina-Oligodendrócito/imunologia , Medula Espinal/imunologia , Células Th17/imunologia , Células Th17/patologiaRESUMO
BACKGROUND: Ibrutinib, a Bruton's tyrosine kinase inhibitor, may have clinical benefit when administered in combination with bendamustine and rituximab and followed by rituximab maintenance therapy in older patients with untreated mantle-cell lymphoma. METHODS: We randomly assigned patients 65 years of age or older to receive ibrutinib (560 mg, administered orally once daily until disease progression or unacceptable toxic effects) or placebo, plus six cycles of bendamustine (90 mg per square meter of body-surface area) and rituximab (375 mg per square meter). Patients with an objective response (complete or partial response) received rituximab maintenance therapy, administered every 8 weeks for up to 12 additional doses. The primary end point was progression-free survival as assessed by the investigators. Overall survival and safety were also assessed. RESULTS: Among 523 patients, 261 were randomly assigned to receive ibrutinib and 262 to receive placebo. At a median follow-up of 84.7 months, the median progression-free survival was 80.6 months in the ibrutinib group and 52.9 months in the placebo group (hazard ratio for disease progression or death, 0.75; 95% confidence interval, 0.59 to 0.96; P = 0.01). The percentage of patients with a complete response was 65.5% in the ibrutinib group and 57.6% in the placebo group (P = 0.06). Overall survival was similar in the two groups. The incidence of grade 3 or 4 adverse events during treatment was 81.5% in the ibrutinib group and 77.3% in the placebo group. CONCLUSIONS: Ibrutinib treatment in combination with standard chemoimmunotherapy significantly prolonged progression-free survival. The safety profile of the combined therapy was consistent with the known profiles of the individual drugs. (Funded by Janssen Research and Development and Pharmacyclics; SHINE ClinicalTrials.gov number, NCT01776840.).
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica , Linfoma de Célula do Manto , Adenina/administração & dosagem , Adenina/análogos & derivados , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Cloridrato de Bendamustina/administração & dosagem , Cloridrato de Bendamustina/efeitos adversos , Progressão da Doença , Humanos , Linfoma de Célula do Manto/tratamento farmacológico , Linfoma de Célula do Manto/mortalidade , Quimioterapia de Manutenção , Piperidinas/administração & dosagem , Piperidinas/efeitos adversos , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/efeitos adversos , Pirazóis/administração & dosagem , Pirazóis/efeitos adversos , Pirimidinas/administração & dosagem , Pirimidinas/efeitos adversos , Indução de Remissão , Rituximab/administração & dosagem , Rituximab/efeitos adversos , Análise de SobrevidaRESUMO
BACKGROUND AND AIMS: Hepatic stellate cells (HSCs) contribute to hepatocellular carcinoma (HCC) progression by regulating multiple factors. However, the entire immunoregulatory functions of HSCs are still obscure. Here, we aim to investigate whether HSCs impose CX3CR1+ macrophages to pro-tumorigenic properties in the peritumoral area. APPROACH AND RESULTS: In single cell RNA-sequencing analysis of HCC patients, a subpopulation of macrophages specifically expressed Arg1 and Cx3cr1 in the peritumoral area, and were highly enriched with retinol metabolism-related genes. Flow cytometry analysis showed significantly increased frequencies of CD14+CD11b+HLA-DRâ macrophages with CX3CR1 in the HCC adjacent region where α-SMA-expressing activated HSCs (aHSCs) showed co-localized expression of CX3CL1. Accordingly, in tumor-bearing mice, Cx3cl1 mRNA expression was notably increased in aHSCs within the adjacent HCC, where infiltration of CX3CR1+Ly6C+ macrophages was mostly observed with decreased CD8+ T cells. In adoptive transfer and in vitro co-culture of myeloid cells, we demonstrated that CX3CR1+Ly6C+ macrophages migrated and highly expressed arginase-1 by interacting with retinoid-enriched aHSCs in the adjacent HCC. Direct treatment of retinoids or co-culturing with retinol-storing mouse aHSCs or human LX-2 cells significantly increased arginase-1 expression in CX3CR1+Ly6C+ macrophages and human blood CD14+ cells, leading to the suppression of CD8+ T cell proliferation. Moreover, genetic deficiency of CX3CR1 in myeloid cells or pharmacological inhibition of retinol metabolism remarkably attenuated HCC development. CONCLUSION: We showed that CX3CR1+Ly6C+ macrophages migrate and interact with aHSCs in the peritumoral region where retinoids induce arginase-1 expression in CX3CR1+Ly6C+ macrophages, subsequently depriving CD8+ T cells of arginine and promoting HCC.
RESUMO
The gut microbiome influences cancer development and the efficacy and safety of chemotherapy but little is known about its effects on lymphoma. We obtained stool samples from treatment-naive, newly diagnosed patients with diffuse large B-cell lymphoma (DLBCL) (n = 189). We first performed 16S ribosomal RNA gene sequencing (n = 158) and then conducted whole-genome shotgun sequencing on additional samples (n = 106). We compared the microbiome data from these patients with data from healthy controls and assessed whether microbiome characteristics were associated with treatment outcomes. The alpha diversity was significantly lower in patients with DLBCL than in healthy controls (P < .001), and the microbial composition differed significantly between the groups (P < .001). The abundance of the Enterobacteriaceae family belonging to the Proteobacteria phylum was markedly higher in patients than in healthy controls. Functional analysis of the microbiome revealed an association with opportunistic pathogenesis through type 1 pili, biofilm formation, and antibiotics resistance. Enterobacteriaceae members were significantly enriched in patients who experienced febrile neutropenia and in those who experienced relapse or progression (P < .001). Interestingly, greater abundance of Enterobacteriaceae correlated with shorter progression-free survival (P = .007). The cytokine profiles of patients whose microbiome was enriched with Enterobacteriaceae were significantly associated with interleukin 6 (P = .035) and interferon gamma (P = .045) levels. In summary, patients with DLBCL exhibited gut microbial dysbiosis. The abundance of Enterobacteriaceae correlated with treatment outcomes and febrile neutropenia. Further study is required to elucidate the origin and role of gut dysbiosis in DLBCL.
Assuntos
Neutropenia Febril , Microbioma Gastrointestinal , Linfoma Difuso de Grandes Células B , Humanos , Disbiose/complicações , Recidiva Local de Neoplasia , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Linfoma Difuso de Grandes Células B/complicações , RNA Ribossômico 16S/análise , RNA Ribossômico 16S/genética , Fezes/microbiologiaRESUMO
N6 -Methyladenosine (m6 A) is the most abundant epitranscriptomic mark and plays a fundamental role in almost every aspect of mRNA metabolism. Although m6 A writers and readers have been widely studied, the roles of m6 A erasers are not well-understood. Here, we investigate the role of FTO, one of the m6 A erasers, in natural killer (NK) cell immunity. We observe that FTO-deficient NK cells are hyperactivated. Fto knockout (Fto-/- ) mouse NK cells prevent melanoma metastasis in vivo, and FTO-deficient human NK cells enhance the antitumor response against leukemia in vitro. We find that FTO negatively regulates IL-2/15-driven JAK/STAT signaling by increasing the mRNA stability of suppressor of cytokine signaling protein (SOCS) family genes. Our results suggest that FTO is an essential modulator of NK cell immunity, providing a new immunotherapeutic strategy for allogeneic NK cell therapies.
Assuntos
Antineoplásicos , Células Matadoras Naturais , Animais , Camundongos , Humanos , Transdução de Sinais , Citocinas , Dioxigenase FTO Dependente de alfa-Cetoglutarato/genéticaRESUMO
BACKGROUND: Limited data are available on short-term dual antiplatelet therapy (DAPT) after percutaneous coronary intervention using third-generation drug-eluting stents with ultrathin struts and advanced polymer technology. We investigated whether 3- to 6-month DAPT was noninferior to 12-month DAPT after implantation of drug-eluting stents with ultrathin struts and advanced polymer technology. METHODS: We performed an open-label, randomized trial at 37 centers in South Korea. We enrolled patients undergoing percutaneous coronary intervention using the Orsiro biodegradable-polymer sirolimus-eluting stents or the Coroflex ISAR polymer-free sirolimus-eluting stents. Patients with ST-segment-elevation myocardial infarction were excluded. Patients were randomly assigned to receive either 3- to 6-month or 12-month DAPT after percutaneous coronary intervention. The choice of antiplatelet medications was at the physician's discretion. The primary outcome was a net adverse clinical event, a composite of cardiac death, target vessel myocardial infarction, clinically driven target lesion revascularization, stent thrombosis, or major bleeding, defined as Bleeding Academic Research Consortium type 3 or 5 at 12 months. The major secondary outcomes were target lesion failure, a composite of cardiac death, target vessel myocardial infarction, clinically driven target lesion revascularization, and major bleeding. RESULTS: A total of 2013 patients (mean age, 65.7±10.5 years; 1487 males [73.9%]; 1110 [55.1%] presented with acute coronary syndrome) were randomly assigned to 3- to 6-month DAPT (n=1002) or 12-month DAPT (n=1011). The primary outcome occurred in 37 (3.7%) patients in the 3- to 6-month DAPT group and 41 (4.1%) in the 12-month DAPT group. The noninferiority of the 3- to 6-month DAPT group to the 12-month DAPT group was met (absolute risk difference, -0.4% [1-sided 95% CI, -∞% to 1.1%]; P<0.001 for noninferiority). There were no significant differences in target lesion failure (hazard ratio, 0.98 [95% CI, 0.56-1.71], P=0.94) or major bleeding (hazard ratio, 0.82 [95% CI, 0.41-1.61], P=0.56) between the 2 groups. Across various subgroups, the treatment effect of 3- to 6-month DAPT was consistent for net adverse clinical event. CONCLUSIONS: Among patients undergoing percutaneous coronary intervention using third-generation drug-eluting stents, 3- to 6-month DAPT was noninferior to 12-month DAPT for net adverse clinical event. Further research is needed to generalize this finding to other populations and to determine the ideal regimen for 3- to 6-month DAPT. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT02601157.
Assuntos
Stents Farmacológicos , Infarto do Miocárdio , Intervenção Coronária Percutânea , Masculino , Humanos , Pessoa de Meia-Idade , Idoso , Inibidores da Agregação Plaquetária/uso terapêutico , Infarto do Miocárdio/tratamento farmacológico , Hemorragia/induzido quimicamente , Sirolimo , Morte , Intervenção Coronária Percutânea/efeitos adversos , Resultado do TratamentoRESUMO
Metal-carbon composites are extensively utilized as electrochemical catalysts but face critical challenges in mass production and stability. We report a scalable manufacturing process for ruthenium surface-embedded fabric electrocatalysts (Ru-SFECs) via conventional fiber/fabric manufacturing. Ru-SFECs have excellent catalytic activity and stability toward the hydrogen evolution reaction, exhibiting a low overpotential of 11.9 mV at a current density of 10 mA cm-2 in an alkaline solution (1.0 M aq KOH solution) with only a slight overpotential increment (6.5%) after 10,000 cycles, whereas under identical conditions, that of commercial Pt/C increases 6-fold (from 1.3 to 7.8 mV). Using semipilot-scale equipment, a protocol is optimized for fabricating continuous self-supported electrocatalytic electrodes. Tailoring the fiber processing parameters (tension and temperature) can optimize the structural development, thereby achieving good catalytic performance and mechanical integrity. These findings underscore the significance of self-supporting catalysts, offering a general framework for stable, binder-free electrocatalytic electrode design.
RESUMO
The optimal treatment strategy for newly diagnosed primary central nervous system lymphoma (PCNSL) has yet to be established, especially in the elderly. In the current study, we conducted a phase II study to evaluate the efficacy and safety of rituximab plus high-dose MTX followed by rituximab plus cytarabine in patients aged ≥60 years newly diagnosed with PCNSL. Patients received an induction treatment of high-dose methotrexate plus rituximab followed by two cycles of a consolidation treatment of cytarabine plus rituximab. The primary end-point was a 2-year progression-free survival (PFS) rate. A total of 35 patients were recruited, and their median age was 73 (range: 60-81). After induction treatment, the complete and partial responses (PRs) were 56% and 20% respectively. Twenty-six patients proceeded to the consolidation treatment; the complete and PRs were 59% and 9% respectively. After a median follow-up duration of 36.0 months, the 2-year PFS rate was 58.7%. Treatment was generally well-tolerated as only three patients were withdrawn from the study due to toxicity, and no treatment-related mortality was reported. The 2-year overall survival rate was 77.9%. The current study may suggest the feasibility of administering high-dose MTX plus cytarabine in PCNSL patients aged ≥60 years and the potential role of additive rituximab.
RESUMO
The manipulation of crystal phases in metal-nonmetal interstitial alloy nanostructures has attracted considerable attention due to the formation of unique electronic structures and surface atomic arrangements, resulting in unprecedented catalytic performances. However, achieving simultaneous control over crystal phase and nonmetal elements in metal-nonmetal interstitial alloy nanostructures has remained a formidable challenge. Here, a novel synthesis approach is presented for PdâB interstitial alloy nanocrystals (NCs) that allows investigation of the crystal-phase- and B-content-dependent catalytic performance. Through comparison of the oxygen reduction reaction (ORR) properties of PdâBX interstitial alloy NCs with different crystal phases and B contents, achieved by precise control of reaction temperature and time, the influences of crystal phase and B contents in the PdâBX interstitial alloy NCs on ORR are precisely investigated. The hexagonal closed packed (hcp) PdB0.5 NCs exhibit superior catalytic activity, with mass activities reaching 2.58 A mg-1, surpassing Pd/C by 10.3 times, attributed to synergistic effects by the hcp crystal phase and relatively high B contents. This study not only provides a novel approach to fabricate interstitial alloy nanostructures with unconventional crystal phases and finely controlled nonmetal elements but also elucidates the importance of crystal phase and nonmetal element content in optimizing electrocatalytic efficiency.
RESUMO
Chlorine has been supplied by the chlor-alkali process that deploys dimensionally stable anodes (DSAs) for the electrochemical chlorine evolution reaction (ClER). The paramount bottlenecks have been ascribed to an intensive usage of precious elements and inevitable competition with the oxygen evolution reaction. Herein, a unique case of Ru2+-O4 active motifs anchored on Magnéli Ti4O7 (Ru-Ti4O7) via a straightforward wet impregnation and mild annealing is reported. The Ru-Ti4O7 performs radically active ClER with minimal deployment of Ru (0.13 wt%), both in 5 m NaCl (pH 2.3) and 0.1 m NaCl (pH 6.5) electrolytes. Scanning electrochemical microscopy demonstrates superior ClER selectivity on Ru-Ti4O7 compared to the DSA. Operando X-ray absorption spectroscopy and density functional theory calculations reveal a universally active ClER (over a wide range of pH and [Cl-]), through a direct adsorption of Cl- on Ru2+-O4 sites as the most plausible pathway, together with stabilized ClO* at low [Cl-] and high pH.
RESUMO
Defect engineering of metal-organic frameworks (MOFs) is a promising strategy for tailoring the interfacial characteristics between MOFs and polymers, aiming to create high-performance mixed matrix membranes (MMMs). This study introduces a new approach using dual defective alkylamine (AA)-modulated zeolitic imidazolate framework-8 (DAZIF-8), to develop high-flux MMMs. Tributylamine (TBA) and triethylamine (TEA) monodentate ligands coordinate with zinc ions in varying compositions. A mixture of Zn(CH3COO)2·2H2O:2-methylimidazole (Mim):AA in a 1:1.75:5 molar ratio facilitates high-yield coordination between Zn and multiple organic ligands, including Zn-Mim, Zn-TEA, and Zn-TBA (>80%). Remarkably, DAZIF-8 containing 3 mol% TBA and 2 mol% TEA exhibits exceptional characteristics, such as a Brunauer-Emmett-Teller surface area of 1745 m2 g-1 and enhanced framework rigidity. Furthermore, dual Zn-AA coordination sites on the framework's outer surface enhance compatibility with the polyimide (PI) matrix through electron donor-acceptor interactions, enabling the fabrication of high-loading MMMs with excellent mechanical durability. Importantly, the PI/DAZIF-8 (60/40 w/w) MMM demonstrates an unprecedented 759% enhancement in ethylene (C2H4) permeability (281 Barrer) with a moderate ethylene/ethane (C2H4/C2H6) selectivity of 2.95 compared to the PI, surpassing the polymeric upper limit for C2H4/C2H6 separation.
RESUMO
BACKGROUND: After neoadjuvant chemotherapy (NAC), the SLN identification rate is lower and has a higher false-negative rate than that at upfront surgery. This clinical trial aimed to confirm the effectiveness of sentinel lymph node (SLN) surgery by determining the lymph node identification rate using multimodal SLN marker methods in patients with advanced breast cancer undergoing NAC. PATIENTS AND METHODS: This clinical study is a prospective single-center randomized controlled trial involving patients with breast cancer receiving NAC. Patients are randomized (1:1:1) into arm A that involves the use of radioisotope (RI) plus indocyanine green fluorescence (ICG-F); arm B, RI plus vital dye; and, arm C, ICG-F plus vital dye. A total of 348 patients are needed. An interim analysis was performed on 50% of the patients enrolled. The primary outcome of this trial was the SLN identification rate. RESULTS: Among the 164 total patients (median age 51 years), T2 and N1 were the most common clinical stages. The identification rate of SLN was 95% in arm A, 92% in arm B, and 79% in arm C. To assess superior efficacy, the one-sided endpoint was set at α < 0.0056. Arms A and C showed a difference of 0.1597 in the detection rate (p = 0.0055). CONCLUSIONS: The use of ICG-F plus vital dye for SLNB was the least effective. The results show that the choice of tracer should be radioisotope in combination with one of the other tracers to have the highest SLN identification rate when SLNB cannot be implemented conventionally due to the circumstances of each institution.
Assuntos
Neoplasias da Mama , Verde de Indocianina , Terapia Neoadjuvante , Biópsia de Linfonodo Sentinela , Linfonodo Sentinela , Humanos , Feminino , Neoplasias da Mama/patologia , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/cirurgia , Pessoa de Meia-Idade , Estudos Prospectivos , Biópsia de Linfonodo Sentinela/métodos , Linfonodo Sentinela/patologia , Linfonodo Sentinela/cirurgia , Linfonodo Sentinela/diagnóstico por imagem , Verde de Indocianina/administração & dosagem , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Prognóstico , Seguimentos , Corantes/administração & dosagem , Compostos Radiofarmacêuticos/administração & dosagem , Quimioterapia Adjuvante , Metástase LinfáticaRESUMO
BACKGROUND: The recurrence of thyroid cancer poses challenges compounded by postoperative fibrosis and anatomic changes. By overcoming the limitations of current localizing dye techniques, indocyanine green-macroaggregated albumin-hyaluronic acid (ICG-MAA-HA) mixture dye promises improved localization. This study aimed to evaluate the efficacy and safety of the dye for recurrent thyroid cancer. METHODS: The nine patients in this study underwent surgery and postoperative ultrasonography. The dye was injected into recurrent lesions in all the patients preoperatively. During surgery, the lesions were confirmed with an imaging system before and after excision. If the lesion was unidentifiable with the naked eye, surgical excision was performed under the corresponding fluorescent guide. Side effects related to the dye injection and completeness of the surgery were evaluated. RESULTS: No side effects such as bleeding, skin tattooing, or pain during or after the dye injection were reported, and no discoloration occurred that interfered with the surgical field of view during surgery. In three cases (33.3 %), because it was difficult to localize metastatic lesions with the naked eye, the operation was successfully completed using an imaging system. The completeness of the surgical resection was confirmed by ultrasonography after an average of 5 months postoperatively. CONCLUSION: The study found that ICG-MAA-HA dye effectively located metastatic and recurrent thyroid cancer and had favorable results in terms of minimal procedural side effects and potential for assisting the surgeon. A large-scale multi-institutional study is necessary to prove the clinical significance regarding patient survival and disease control.
Assuntos
Verde de Indocianina , Neoplasias da Glândula Tireoide , Humanos , Ácido Hialurônico , Corantes , Neoplasias da Glândula Tireoide/diagnóstico por imagem , Neoplasias da Glândula Tireoide/cirurgia , Neoplasias da Glândula Tireoide/patologia , Albuminas , Biópsia de Linfonodo Sentinela/métodosRESUMO
Recently, the pathomechanisms of keloids have been extensively researched using transcriptomic analysis, but most studies did not consider the activity of keloids. We aimed to profile the transcriptomics of keloids according to their clinical activity and location within the keloid lesion, compared with normal and mature scars. Tissue samples were collected (keloid based on its activity (active and inactive), mature scar from keloid patients and normal scar (NS) from non-keloid patients). To reduce possible bias, all keloids assessed in this study had no treatment history and their location was limited to the upper chest or back. Multiomics assessment was performed by using single-cell RNA sequencing and multiplex immunofluorescence. Increased mesenchymal fibroblasts (FBs) was the main feature in keloid patients. Noticeably, the proportion of pro-inflammatory FBs was significantly increased in active keloids compared to inactive ones. To explore the nature of proinflammatory FBs, trajectory analysis was conducted and CCN family associated with mechanical stretch exhibited higher expression in active keloids. For vascular endothelial cells (VECs), the proportion of tip and immature cells increased in keloids compared to NS, especially at the periphery of active keloids. Also, keloid VECs highly expressed genes with characteristics of mesenchymal activation compared to NS, especially those from the active keloid center. Multiomics analysis demonstrated the distinct expression profile of active keloids. Clinically, these findings may provide the future appropriate directions for development of treatment modalities of keloids. Prevention of keloids could be possible by the suppression of mesenchymal activation between FBs and VECs and modulation of proinflammatory FBs may be the key to the control of active keloids.
Assuntos
Fibroblastos , Queloide , Queloide/patologia , Queloide/metabolismo , Humanos , Fibroblastos/metabolismo , Transcriptoma , Células Endoteliais/metabolismo , Feminino , Adulto , Masculino , Perfilação da Expressão Gênica , Análise de Célula ÚnicaRESUMO
The optic nerve head (ONH) is a complex structure wherein the axons of the retinal ganglion cells extrude from the eyeball through three openings: 1) the Bruch's membrane opening (BMO) in the retinal layer, 2) the anterior scleral canal opening in the anterior scleral layer, and 3) the lamina cribrosa (LC). Eyeball expansion during growth induces an offset among openings, since the expansion affects the inner retinal and outer scleral layers differently: the posterior polar retinal structure is preserved by the preferential growth in the equatorial region, whereas no such regional difference is observed in the scleral layer. The various modes and extents of eyeball expansion result in diverse directionality and amount of offset among openings, which causes diverse ONH morphology in adults, especially in myopia. In this review, we summarize the ONH changes that occur during myopic axial elongation. These changes were observed prospectively in our previous studies, wherein LC shift and subsequent offset from the BMO center could be predicted by tracing the central retinal vascular trunk position. This offset induces the formation of γ-zone parapapillary atrophy or externally oblique border tissue. As a presumptive site of glaucomatous damage, the LC/BMO offset may render the LC pores in the opposite direction more vulnerable. To support such speculation, we also summarize the relationship between LC/BMO offset and glaucomatous damage. Indeed, LC/BMO offset is not only the cause of diverse ONH morphology in adults, but is also, potentially, an important clinical marker for assessment of glaucoma.
Assuntos
Lâmina Basilar da Corioide , Glaucoma , Disco Óptico , Humanos , Disco Óptico/patologia , Lâmina Basilar da Corioide/patologia , Glaucoma/fisiopatologia , Glaucoma/patologia , Células Ganglionares da Retina/patologia , Pressão Intraocular/fisiologia , Olho/crescimento & desenvolvimento , Olho/patologia , Doenças do Nervo Óptico/fisiopatologia , Doenças do Nervo Óptico/patologia , Esclera/patologia , Miopia/patologia , Miopia/fisiopatologiaRESUMO
Due to the lack of treatment guidelines for the management of advanced-stage marginal zone lymphoma (MZL), only one chemoimmunotherapy-cyclophosphamide, vincristine, and prednisone plus rituximab (R-CVP)-is reimbursed in the first-line setting in South Korea. The aim of this study was to develop a consensus-based recommendation for the treatment of patients with advanced-stage MZL. Twelve hematologist oncologists participated in a two-round Delphi process to identify consensus on the management of patients with advanced-stage MZL in South Korea. Physicians rated their level of agreement with each statement on a four-point Likert scale. Statements were divided into two sections: definitions used in clinical practice and clinical management of patients with advanced-stage MZL. Consensus was reached for 23 of 33 (69.7%) and 5 of 13 statements (38.5%) in rounds 1 and 2, respectively. There was strong consensus (91.7%) that advanced-stage MZL subtypes are defined according to the Lugano staging system. First-line systemic treatment should be prescribed for patients with symptomatic advanced-stage MZL. Although there was unanimous agreement that R-CVP is the standard first-line treatment for advanced-stage MZL, physicians also agreed that bendamustine with rituximab (BR) has greater efficacy than R-CVP as first-line treatment (91.7%). For the treatment of relapsed/refractory advanced-stage MZL, BR and R-CVP can be repeated in patients with short (< 24 months) and long remission periods (≥ 24 months), respectively. This study provides insights on the management of patients with advanced-stage MZL in South Korea. This may enhance clinical decision-making, thus improving patient outcomes.