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The reinvigoration of anti-tumor T cells in response to immune checkpoint blockade (ICB) therapy is well established. Whether and how ICB therapy manipulates antibody-mediated immune response in cancer environments, however, remains elusive. Using tandem mass spectrometric analysis of modification of immunoglobulin G (IgG) from hepatoma tissues, we identified a role of ICB therapy in catalyzing IgG sialylation in the Fc region. Effector T cells triggered sialylation of IgG via an interferon (IFN)-γ-ST6Gal-I-dependent pathway. DC-SIGN+ macrophages represented the main target cells of sialylated IgG. Upon interacting with sialylated IgG, DC-SIGN stimulated Raf-1-elicited elevation of ATF3, which inactivated cGAS-STING pathway and eliminated subsequent type-I-IFN-triggered antitumorigenic immunity. Although enhanced IgG sialylation in tumors predicted improved therapeutic outcomes for patients receiving ICB therapy, impeding IgG sialylation augmented antitumorigenic T cell immunity after ICB therapy. Thus, targeting antibody-based negative feedback action of ICB therapy has potential for improving efficacy of cancer immunotherapies.
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Carcinoma Hepatocelular , Interferon Tipo I , Neoplasias Hepáticas , Humanos , Imunoglobulina G , Carcinoma Hepatocelular/tratamento farmacológico , Neoplasias Hepáticas/tratamento farmacológico , Imunoterapia/métodosRESUMO
Antibody responses develop following SARS-CoV-2 infection, but little is known about their epitope specificities, clonality, binding affinities, epitopes, and neutralizing activity. We isolated B cells specific for the SARS-CoV-2 envelope glycoprotein spike (S) from a COVID-19-infected subject 21 days after the onset of clinical disease. 45 S-specific monoclonal antibodies were generated. They had undergone minimal somatic mutation with limited clonal expansion, and three bound the receptor-binding domain (RBD). Two antibodies neutralized SARS-CoV-2. The most potent antibody bound the RBD and prevented binding to the ACE2 receptor, while the other bound outside the RBD. Thus, most anti-S antibodies that were generated in this patient during the first weeks of COVID-19 infection were non-neutralizing and target epitopes outside the RBD. Antibodies that disrupt the SARS-CoV-2 S-ACE2 interaction can potently neutralize the virus without undergoing extensive maturation. Such antibodies have potential preventive and/or therapeutic potential and can serve as templates for vaccine design.
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Anticorpos Neutralizantes/imunologia , Anticorpos Antivirais/imunologia , Betacoronavirus/imunologia , Hipermutação Somática de Imunoglobulina/genética , Glicoproteína da Espícula de Coronavírus/imunologia , Enzima de Conversão de Angiotensina 2 , Anticorpos Monoclonais/imunologia , Linfócitos B/imunologia , Sítios de Ligação , COVID-19 , Infecções por Coronavirus/imunologia , Infecções por Coronavirus/prevenção & controle , Epitopos de Linfócito B/imunologia , Humanos , Pandemias/prevenção & controle , Peptidil Dipeptidase A/metabolismo , Pneumonia Viral/imunologia , Pneumonia Viral/prevenção & controle , Ligação Proteica , Receptores Virais/metabolismo , SARS-CoV-2 , Glicoproteína da Espícula de Coronavírus/metabolismo , Vacinas Virais/imunologiaRESUMO
MOTIVATION: Genetic variants present differential effects on humans according to various environmental exposures, the so-called "gene-environment interactions" (GxE). Many diseases can be diagnosed with multiple traits, such as obesity, diabetes, and dyslipidemia. I developed a multivariate scale test (MST) for detecting the GxE of a disease with several continuous traits. Given a significant MST result, I continued to search for which trait and which E enriched the GxE signals. Simulation studies were performed to compare MST with the univariate scale test (UST). RESULTS: MST can gain more power than UST because of (1) integrating more traits with GxE information and (2) the less harsh penalty on multiple testing. However, if only few traits account for GxE, MST may lose power due to aggregating non-informative traits into the test statistic. As an example, MST was applied to a discovery set of 93 708 Taiwan Biobank (TWB) individuals and a replication set of 25 200 TWB individuals. From among 2 570 487 SNPs with minor allele frequencies ≥5%, MST identified 18 independent variance quantitative trait loci (P < 2.4E-9 in the discovery cohort and P < 2.8E-5 in the replication cohort) and 41 GxE signals (P < .00027) based on eight trait domains (including 29 traits). AVAILABILITY AND IMPLEMENTATION: https://github.com/WanYuLin/Multivariate-scale-test-MST.
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Interação Gene-Ambiente , Polimorfismo de Nucleotídeo Único , Locos de Características Quantitativas , Humanos , Frequência do Gene , Estudo de Associação Genômica AmplaRESUMO
Microglia regulate synaptic function in various ways, including the microglial displacement of the surrounding GABAergic synapses, which provides important neuroprotection from certain diseases. However, the physiological role and underlying mechanisms of microglial synaptic displacement remain unclear. In this study, we observed that microglia exhibited heterogeneity during the displacement of GABAergic synapses surrounding neuronal soma in different cortical regions under physiological conditions. Through three-dimensional reconstruction, in vitro co-culture, two-photon calcium imaging, and local field potentials recording, we found that IL-1ß negatively modulated microglial synaptic displacement to coordinate regional heterogeneity in the motor cortex, which impacted the homeostasis of the neural network and improved motor learning ability. We used the Cre-Loxp system and found that IL-1R1 on glutamatergic neurons, rather than that on microglia or GABAergic neurons, mediated the negative effect of IL-1ß on synaptic displacement. This study demonstrates that IL-1ß is critical for the regional heterogeneity of synaptic displacement by coordinating different actions of neurons and microglia via IL-1R1, which impacts both neural network homeostasis and motor learning ability. It provides a theoretical basis for elucidating the physiological role and mechanism of microglial displacement of GABAergic synapses.
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Aprendizagem , Microglia , Cálcio , Neurônios GABAérgicos , Interleucina-1beta , SinapsesRESUMO
BACKGROUND: Metabolic associated fatty liver disease (MAFLD), a prevalent liver disorder affecting one-third of the global population, encompasses a spectrum ranging from fatty liver to severe hepatic steatosis. Both genetic and lifestyle factors, particularly diet and nutrition, contribute to its etiology. Folate deficiency, a frequently encountered type of malnutrition, has been associated with the pathogenesis of MAFLD and shown to impact lipid deposition. However, the underlying mechanisms of this relationship remain incompletely understood. We investigated the impact of disturbed folate-mediated one-carbon metabolism (OCM) on hepatic lipid metabolism both in vitro using human hepatoma cells and in vivo using transgenic fluorescent zebrafish displaying extent-, stage-, and duration-controllable folate deficiency upon induction. RESULTS: Disturbed folate-mediated one-carbon metabolism, either by inducing folate deficiency or adding anti-folate drug, compromises autophagy and causes lipid accumulation in liver cells. Disturbed folate status down-regulates cathepsin L, a key enzyme involved in autophagy, through inhibiting mTOR signaling. Interfered mitochondrial biology, including mitochondria relocation and increased fusion-fission dynamics, also occurs in folate-deficient hepatocytes. Folate supplementation effectively mitigated the impaired autophagy and lipid accumulation caused by the inhibition of cathepsin L activity, even when the inhibition was not directly related to folate deficiency. CONCLUSIONS: Disruption of folate-mediated OCM diminishes cathepsin L expression and impedes autophagy via mTOR signaling, leading to lipid accumulation within hepatocytes. These findings underscore the crucial role of folate in modulating autophagic processes and regulating lipid metabolism in the liver.
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Autofagia , Ácido Fólico , Hepatócitos , Homeostase , Metabolismo dos Lipídeos , Peixe-Zebra , Autofagia/fisiologia , Ácido Fólico/metabolismo , Humanos , Hepatócitos/metabolismo , Animais , Deficiência de Ácido Fólico/metabolismoRESUMO
BACKGROUND: Carbapenemase-producing Enterobacterales (CPE) are challenging in healthcare, with resistance to multiple classes of antibiotics. This study describes the emergence of imipenemase (IMP)-encoding CPE among diverse Enterobacterales species between 2016 and 2019 across a London regional network. METHODS: We performed a network analysis of patient pathways, using electronic health records, to identify contacts between IMP-encoding CPE-positive patients. Genomes of IMP-encoding CPE isolates were overlaid with patient contacts to imply potential transmission events. RESULTS: Genomic analysis of 84 Enterobacterales isolates revealed diverse species (predominantly Klebsiella spp, Enterobacter spp, and Escherichia coli); 86% (72 of 84) harbored an IncHI2 plasmid carrying blaIMP and colistin resistance gene mcr-9 (68 of 72). Phylogenetic analysis of IncHI2 plasmids identified 3 lineages showing significant association with patient contacts and movements between 4 hospital sites and across medical specialties, which was missed in initial investigations. CONCLUSIONS: Combined, our patient network and plasmid analyses demonstrate an interspecies, plasmid-mediated outbreak of blaIMPCPE, which remained unidentified during standard investigations. With DNA sequencing and multimodal data incorporation, the outbreak investigation approach proposed here provides a framework for real-time identification of key factors causing pathogen spread. Plasmid-level outbreak analysis reveals that resistance spread may be wider than suspected, allowing more interventions to stop transmission within hospital networks.SummaryThis was an investigation, using integrated pathway networks and genomics methods, of the emergence of imipenemase-encoding carbapenemase-producing Enterobacterales among diverse Enterobacterales species between 2016 and 2019 in patients across a London regional hospital network, which was missed on routine investigations.
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Proteínas de Bactérias , Surtos de Doenças , Infecções por Enterobacteriaceae , Plasmídeos , beta-Lactamases , Humanos , Plasmídeos/genética , beta-Lactamases/genética , Infecções por Enterobacteriaceae/epidemiologia , Infecções por Enterobacteriaceae/microbiologia , Infecções por Enterobacteriaceae/transmissão , Proteínas de Bactérias/genética , Londres/epidemiologia , Antibacterianos/farmacologia , Filogenia , Genoma Bacteriano , Masculino , Feminino , Pessoa de Meia-Idade , Testes de Sensibilidade Microbiana , Adulto , Enterobacteriaceae/genética , Enterobacteriaceae/efeitos dos fármacos , Idoso , Enterobacteriáceas Resistentes a Carbapenêmicos/genética , Enterobacteriáceas Resistentes a Carbapenêmicos/isolamento & purificação , Colistina/farmacologiaRESUMO
In patients with nasopharyngeal carcinoma (NPC), the alteration of immune responses in peripheral blood remains unclear. In this study, we established an immune cell profile for patients with NPC and used flow cytometry and machine learning (ML) to identify the characteristics of this profile. After isolation of circulating leukocytes, the proportions of 104 immune cell subsets were compared between NPC group and the healthy control group (HC). Data obtained from the immune cell profile were subjected to ML training to differentiate between the immune cell profiles of the NPC and HC groups. We observed that subjects in the NPC group presented higher proportions of T cells, memory B cells, short-lived plasma cells, IgG-positive B cells, regulatory T cells, MHC II+ T cells, CTLA4+ T cells and PD-1+ T cells than subjects in the HC group, indicating weaker and compromised cellular and humoral immune responses. ML revealed that monocytes, PD-1+ CD4 T cells, memory B cells, CTLA4+ CD4 Treg cells and PD-1+ CD8 T cells were strongly contributed to the difference in immune cell profiles between the NPC and HC groups. This alteration can be fundamental in developing novel immunotherapies for NPC.
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Citometria de Fluxo , Aprendizado de Máquina , Carcinoma Nasofaríngeo , Neoplasias Nasofaríngeas , Humanos , Carcinoma Nasofaríngeo/imunologia , Carcinoma Nasofaríngeo/patologia , Citometria de Fluxo/métodos , Masculino , Feminino , Pessoa de Meia-Idade , Neoplasias Nasofaríngeas/imunologia , Neoplasias Nasofaríngeas/patologia , Adulto , Receptor de Morte Celular Programada 1/metabolismo , Linfócitos T CD8-Positivos/imunologia , Estudos de Casos e Controles , IdosoRESUMO
To highlight the genetic architecture for epigenetic aging, McCartney et al. recently identified 137 significant single-nucleotide polymorphisms based on genome-wide association study (GWAS) meta-analyses of four epigenetic clocks and two epigenetic surrogate markers. However, none Asian ancestry studies have been included in this or previous meta-analyses. I performed a GWAS on blood DNA methylation (DNAm) levels of 2309 Taiwan Biobank (TWB) participants. Owing to the fact that the sample size of an individual GWAS of DNAm data is still not large, I adopted the 'prioritized subset analysis' (PSA) method to boost the power of a GWAS. The four epigenetic clocks and the two epigenetic surrogate markers were investigated, respectively. I replicated 21 out of the 137 aging-associated genetic loci by applying the PSA method to the TWB DNAm data. Moreover, I identified five novel loci, including rs117530284 that was associated with the 'epigenetic age acceleration' (EAA) according to Lu et al.'s GrimAge (called 'GrimEAA'). Considering 16 covariates (sex, BMI, smoking status, drinking status, regular exercise, educational attainment and the first 10 ancestry principal components), each 'A' allele of rs117530284 in the IBA57 gene was found to be associated with a 1.5943-year GrimEAA (95% confidence interval = [1.0748, 2.1138]). IBA57 is a protein coding gene and is associated with multiple mitochondrial dysfunctions syndromes. A decline in mitochondrial activity and quality is associated with aging and many age-related diseases. This is one of the first DNAm GWAS for individuals of Asian ancestry.
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Metilação de DNA , Estudo de Associação Genômica Ampla , Envelhecimento/genética , Bancos de Espécimes Biológicos , Biomarcadores/metabolismo , Metilação de DNA/genética , Epigênese Genética , Estudo de Associação Genômica Ampla/métodos , Humanos , TaiwanRESUMO
BACKGROUND & AIMS: Previous studies confirm vonoprazan-amoxicillin effectiveness for Helicobacter pylori. This study aims to investigate vonoprazan with varying amoxicillin dose and duration. METHODS: This multicenter, prospective, randomized controlled, noninferiority trial enrolled patients with treatment naive H pylori infection from 5 clinical centers. Eligible participants were randomly assigned to H-VA-10 (vonoprazan 20 mg twice a day (b.i.d.) + amoxicillin 750 mg 4 times a day, 10 days), L-VA-10 (vonoprazan 20 mg b.i.d. + amoxicillin 1000 mg b.i.d, 10 days), and H-VA-14 (vonoprazan 20 mg b.i.d + amoxicillin 750 mg 4 times a day, 14 days) in a 1:1:1 ratio. The eradication rate was assessed using the 13C-urea breath test at least 28 days after treatment. RESULTS: Of the 623 eligible patients, 516 patients were randomized. In both the intention-to-treat and per-protocol analyses, eradication rates were comparable between H-VA-10 and H-VA-14 groups (86.6% vs 89.5% and 90.9% vs 94.5%, P = .021 and .013 for noninferiority, respectively). However, eradication rates were significantly lower in the L-VA-10 group than the H-VA-14 group (79.7% vs 89.5% and 82.0% vs 94.5%, P = .488 and .759, respectively). Rates of study withdrawal, loss to follow-up, and adverse events were similar across study groups. CONCLUSIONS: H-VA-10 and H-VA-14 regimens provide satisfactory efficacy for H pylori infection, and the L-VA-10 regimen was inferior. CLINICALTRIALS: gov number: NCT05719831.
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Amoxicilina , Antibacterianos , Quimioterapia Combinada , Infecções por Helicobacter , Helicobacter pylori , Pirróis , Sulfonamidas , Humanos , Sulfonamidas/administração & dosagem , Sulfonamidas/efeitos adversos , Infecções por Helicobacter/tratamento farmacológico , Masculino , Feminino , Pessoa de Meia-Idade , Pirróis/administração & dosagem , Pirróis/efeitos adversos , Estudos Prospectivos , Amoxicilina/administração & dosagem , Amoxicilina/efeitos adversos , Helicobacter pylori/efeitos dos fármacos , Antibacterianos/administração & dosagem , Antibacterianos/efeitos adversos , Antibacterianos/uso terapêutico , Resultado do Tratamento , Idoso , Adulto , Inibidores da Bomba de Prótons/administração & dosagem , Inibidores da Bomba de Prótons/efeitos adversos , Inibidores da Bomba de Prótons/uso terapêutico , Esquema de MedicaçãoRESUMO
Rapid separation and enrichment of targets in biological matrixes are of significant interest in multiple life sciences disciplines. Molecularly imprinted polymers (MIPs) have vital applications in extraction and sample cleanup owing to their excellent specificity and selectivity. However, the low mass transfer rate, caused by the heterogeneity of imprinted cavities in polymer networks and strong driving forces, significantly limits its application in high-throughput analysis. Herein, one novel metal affinity-oriented surface imprinting method was proposed to fabricate an MIP with an ultrathin imprinting layer. MIPs were prepared by immobilized template molecules on magnetic nanoparticles (NPs) with metal ions as bridges via coordination, and then polymerization was done. Under the optimized conditions, the thickness of the imprinting layer was merely 1 nm, and the adsorption toward VAL well matched the Langmuir model. Moreover, it took just 5 min to achieve adsorption equilibrium significantly faster than other reported MIPs toward VAL. Adsorption capacity still can reach 25.3 mg/g ascribed to the high imprinting efficiency of the method (the imprinting factor was as high as 5). All evidence proved that recognition sites were all external cavities and were evenly distributed on the surface of the NPs. The obtained MIP NPs exhibited excellent selectivity and specificity toward VAL, with good dispersibility and stability. Coupled with high-performance liquid chromatography, it was successfully used as a dispersed solid phase extraction material to determine VAL in serum. Average recoveries are over 90.0% with relative standard deviations less than 2.14% at three spiked levels (n = 3). All evidence testified that the MIPs fabricated with the proposed method showed a fast trans mass rate and a large rebinding capacity. The method can potentially use high-throughput separation and enrichment of target molecules in batch samples to meet practical applications.
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Impressão Molecular , Polímeros Molecularmente Impressos , Valsartana , Adsorção , Polímeros Molecularmente Impressos/química , Valsartana/química , Propriedades de Superfície , Nanopartículas de Magnetita/química , Cromatografia Líquida de Alta PressãoRESUMO
The poor healing characteristics of diabetic foot ulcers are partially attributed to diabetes-induced pro-inflammatory wounds. Our previous study reported that both miR-146a-5p and miR-200b-3p decrease endothelial inflammation in human aortic endothelial cells and db/db diabetic mice. Although miR-146a-5p has been reported to improve diabetic wound healing, the role of miR-200b-3p is not clear. This study compared the roles of these miRNAs in diabetic wound healing. Two 8-mm full-thickness wounds were created in 12-week-old male db/db mice on the left and right back. After surgery, 100 ng miR-146a-5p, miR-200b-3p, or miR-negative control (NC) was injected in each wound. Full-thickness skin samples were harvested from mice at the 14th day for real-time polymerase chain reaction and immunohistochemistry analyses. At the 14th day, the miR-200b-3p group showed better wound healing and greater granulation tissue thickness than the miR-146a-5p group. The miR-200b-3p group showed a significant decrease of IL-6 and IL-1ß gene expression and a significant increase of Col3α1 gene expression compared to those in the miR-NC group. The miR-200b-3p group had the lowest gene expression of TGF-ß1, followed by the miR-146a-5p and miR-NC groups. Our findings suggest that the miR-200b-3p group had better healing characteristics than the other two groups. Immunohistochemical staining revealed that CD68 immunoreactivity was significantly decreased in both the miR-146a-5p and miR-200b-3p groups compared with that in the miR-NC group. In addition, CD31 immunoreactivity was significantly higher in the miR-200b-3p group than in the miR-146a-5p group. In conclusion, these results suggest that miR-200b-3p is more effective than miR-146a-5p in promoting diabetic wound healing through its anti-inflammatory and pro-angiogenic effects.
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Due to the higher value of deeply-reduced products, electrocatalytic CO2 reduction reaction (CO2 RR) to multi-electron-transfer products has received more attention. One attractive strategy is to decouple individual steps within the complicated pathway via multi-component catalysts design in the concept of tandem catalysts. Here, a composite of Cu@BIF-144(Zn) (BIF = boron imidazolate framework) is synthesized by using an anion framework BIF-144(Zn) as host to impregnate Cu2+ ions that are further reduced to Cu nanoparticles (NPs) via in situ electrochemical transformation. Due to the microenvironment modulation by functional BH(im)3 - on the pore surfaces, the Cu@BIF-144(Zn) catalyst exhibits a perfect synergetic effect between the BIF-144(Zn) host and the Cu NP guest during CO2 RR. Electrochemistry results show that Cu@BIF-144(Zn) catalysts can effectively enhance the selectivity and activity for the CO2 reduction to multi-electron-transfer products, with the maximum FECH4 value of 41.8% at -1.6 V and FEC2H4 value of 12.9% at -1.5 V versus RHE. The Cu@BIF-144(Zn) tandem catalyst with CO-rich microenvironment generated by the Zn catalytic center in the BIF-144(Zn) skeleton enhanced deep reduction on the incorporated Cu NPs for the CO2 RR to multi-electron-transfer products.
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In-sensor computing has attracted considerable interest as a solution for overcoming the energy efficiency and response time limitations of the traditional von Neumann architecture. Recently, emerging memristors based on transition-metal oxides (TMOs) have attracted attention as promising candidates for in-memory computing owing to their tunable conductance, high speed, and low operational energy. However, the poor photoresponse of TMOs presents challenges for integrating sensing and processing units into a single device. This integration is crucial for eliminating the need for a sensor/processor interface and achieving energy-efficient in-sensor computing systems. In this study, a Si/CuO heterojunction-based photomemristor is proposed that combines the reversible resistive switching behavior of CuO with the appropriate optical absorption bandgap of the Si substrate. The proposed photomemristor demonstrates a simultaneous reconfigurable, non-volatile, and self-powered photoresponse, producing a microampere-level photocurrent at zero bias. The controlled migration of oxygen vacancies in CuO result in distinct energy-band bending at the interface, enabling multiple levels of photoresponsivity. Additionally, the device exhibits high stability and ultrafast response speed to the built-in electric field. Furthermore, the prototype photomemristor can be trained to emulate the attention-driven nature of the human visual system, indicating the tremendous potential of TMO-based photomemristors as hardware foundations for in-sensor computing.
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Solid-state sodium metal batteries have been extensively investigated because of their potential to improve safety, cost-effectiveness, and energy density. The development of such batteries urgently required a solid-state electrolyte with fast Na-ion conduction and favorable interfacial compatibility. Herein, the progress on developing the NaB3H8 solid-state electrolytes is reported, which show a liquid-like ionic conductivity of 0.05 S cm-1 at 56 °C with an activation energy of 0.35 eV after an order-disorder phase transformation, matching or surpassing the best single-anion hydridoborate conductors investigated up to now. The steady polarization voltage and significantly decreased resistance are achieved in the symmetric Na/NaB3H8/Na cell, indicating the great electrochemical stability and favorable interfacial contact with the Na metal of NaB3H8. Furthermore, a Na/NaB3H8/TiS2 battery, the first high-rate (up to 1 C) solid-state sodium metal battery using the single-anion hydridoborate electrolyte, is demonstrated, which exhibits superior rate capability (168.2 mAh g-1 at 0.1 C and 141.2 mAh g-1 at 1 C) and long-term cycling stability (70.9% capacity retention at 1 C after 300 cycles) at 30 °C. This work may present a new possibility to solve the interfacial limitations and find a new group of solid-state electrolytes for high-performance sodium metal batteries.
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INTRODUCTION: Post-kala-azar dermal leishmaniasis (PKDL) arises as a dermal complication following a visceral leishmaniasis (VL) infection. Current treatment options for PKDL are unsatisfactory, and there is a knowledge gap regarding the distribution of antileishmanial compounds within human skin. The present study investigated the skin distribution of miltefosine in PKDL patients, with the aim to improve the understanding of the pharmacokinetics at the skin target site in PKDL. METHODS: Fifty-two PKDL patients underwent treatment with liposomal amphotericin B (20â mg/kg) plus miltefosine (allometric dosing) for 21 days. Plasma concentrations of miltefosine were measured on study days 8, 15, 22 and 30, while a punch skin biopsy was taken on day 22. A physiologically based pharmacokinetic (PBPK) model was developed to evaluate the distribution of miltefosine into the skin. RESULTS: Following the allometric weight-based dosing regimen, median miltefosine concentrations on day 22 were 43.73â µg/g (IQR: 21.94-60.65â µg/g) in skin and 33.29â µg/mL (IQR: 25.9-42.58â µg/mL) in plasma. The median individual concentration ratio of skin to plasma was 1.19 (IQR: 0.79-1.9). In 87% (45/52) of patients, skin exposure was above the suggested EC90 PK target of 10.6â mg/L associated with in vitro susceptibility. Simulations indicated that the residence time of miltefosine in the skin would be more than 2-fold longer than in plasma, estimated by a mean residence time of 604 versus 266 hours, respectively. CONCLUSION: This study provides the first accurate measurements of miltefosine penetration into the skin, demonstrating substantial exposure and prolonged retention of miltefosine within the skin. These findings support the use of miltefosine in cutaneous manifestations of leishmaniasis. In combination with parasitological and clinical data, these results are critical for the future optimization of combination therapies with miltefosine in the treatment of PKDL.
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Anfotericina B , Antiprotozoários , Leishmaniose Cutânea , Leishmaniose Visceral , Fosforilcolina , Pele , Humanos , Fosforilcolina/análogos & derivados , Fosforilcolina/farmacocinética , Fosforilcolina/administração & dosagem , Fosforilcolina/uso terapêutico , Antiprotozoários/farmacocinética , Antiprotozoários/administração & dosagem , Antiprotozoários/uso terapêutico , Masculino , Adulto , Leishmaniose Cutânea/tratamento farmacológico , Leishmaniose Cutânea/parasitologia , Feminino , Pele/parasitologia , Leishmaniose Visceral/tratamento farmacológico , Pessoa de Meia-Idade , Adulto Jovem , Anfotericina B/farmacocinética , Anfotericina B/uso terapêutico , Anfotericina B/administração & dosagem , Adolescente , Ásia MeridionalRESUMO
OBJECTIVE: To evaluate the causal relationship between sleep fragmentation (SF) parameters with general and abdominal obesity in free-living conditions. METHODS: SF parameters were assessed by ActiGraph accelerometers for 7 consecutive days. Obesity was measured at baseline and 1-year follow-up with InBody S10 body composition analyzer. RESULTS: At baseline, the mean age of the study population was 18.7 years old (SD = 0.9) and 139 (35.7%) were male. Each 1-unit increase of baseline sleep fragmentation index (SFI) was associated with 0.08 kg/m2-increase of body mass index (BMI) (95% CI: 0.03, 0.14), 0.20%-increase of percentage of body fat (PBF) (95% CI: 0.07, 0.32), 0.15 kg-increase of fat mass (FM) (95% CI: 0.03, 0.27), 0.15 cm-increase of waist circumference (WC) (95% CI: 0.03, 0.26) and 0.91 cm2-increase of visceral fat area (VFA) (95% CI: 0.36, 1.46) at the 1-year follow-up. In addition, each 1-unit increase of baseline SFI was associated with 15% increased risk of general obesity (OR = 1.15, 95% CI = 1.04-1.28; p = 0.006) and 7% increased risk of abdominal obesity (OR = 1.07, 95% CI = 1.01-1.13; p = 0.021) in the following year. CONCLUSIONS: Fragmented sleep is independently associated with an increased risk of both general and abdominal obesity. The result highlights SF as a modifiable risk factor for the prevention and treatment of obesity.
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Compared to the integer-order vector field, the fractional-order vector field has an additional degree of control freedom, which will bring rich photophysical properties and what we believe to be novel nonlinear optical phenomena. In this work, we theoretically and experimentally investigate the focusing, propagation, and spatial self-phase modulation (SSPM) of fractional-order linearly polarized vector fields (FLPVFs). It is shown that the weak focusing field of FLPVF exhibits an asymmetric intensity distribution. Intriguingly, its state of polarization (SoP) has a hybrid polarization distribution. When this focused FLPVF propagates to the far field in free space, its SoP degenerates into a localized linearly polarization distribution. However, after the focused FLPVF passes through an isotropic nonlinear Kerr medium, its SoP exhibits a hybrid polarization distribution. Additionally, unlike the self-diffraction intensity pattern of integer-order linearly polarized vector field (ILPVF) with a concentric multi-ring structure, the SSPM pattern of FLPVF is a symmetry broken self-diffraction intensity pattern. The presented work provides a nonlinear optics approach for manipulating both the SoP and intensity distributions of the light field.
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BACKGROUND: Lytic Epstein-Barr virus (EBV) infection plays a major role in the pathogenesis of nasopharyngeal carcinoma (NPC). For patients with recurrent or metastatic NPC and resistant to conventional therapies, adoptive cell therapy using EBV-specific cytotoxic T cells (EBV-CTLs) is a promising option. However, the long production period (around 3 to 4 weeks) and low EBV-CTL purity (approximately 40% of total CD8 T cells) in the cell product limits the application of EBV-CTLs in clinics. Thus, this study aimed to establish a protocol for the rapid production of EBV-CTLs. METHODS: By culturing peripheral blood mononuclear cells (PBMCs) from EBV-seropositive donors with EBV-specific peptides and interleukin (IL)-2, IL-15, and interferon α (IFN-α) for 9 days, we identified that IL-15 can enhance IL-2-mediated CTL activation and significantly increase the yield of CTLs. RESULTS: When IFN-α was used in IL-2/IL-15-mediated CTL production from days 0 to 6, the productivity of EBV-CTLs and EBV-specific cytotoxicity significantly were reinforced relative to EBV-CTLs from IL-2/IL-15 treatment. Additionally, IFN-α-induced production improvement of virus-specific CTLs was not only the case for EBV-CTLs but also for cytomegalovirus-specific CTLs. CONCLUSION: We established a novel protocol to rapidly expand highly pure EBV-CTLs from PBMCs, which can produce EBV-CTLs in 9 days and does not require feeder cells during cultivation.
Assuntos
Herpesvirus Humano 4 , Linfócitos T Citotóxicos , Humanos , Linfócitos T Citotóxicos/imunologia , Herpesvirus Humano 4/imunologia , Infecções por Vírus Epstein-Barr/imunologia , Infecções por Vírus Epstein-Barr/virologia , Interleucina-2/metabolismo , Interleucina-2/farmacologia , Leucócitos Mononucleares/imunologia , Leucócitos Mononucleares/virologia , Interleucina-15/metabolismo , Interferon-alfa/metabolismo , Citotoxicidade Imunológica , Carcinoma Nasofaríngeo/virologia , Carcinoma Nasofaríngeo/imunologia , Carcinoma Nasofaríngeo/patologia , Neoplasias Nasofaríngeas/imunologia , Neoplasias Nasofaríngeas/virologia , Neoplasias Nasofaríngeas/patologia , Ativação Linfocitária/imunologia , Imunoterapia Adotiva/métodosRESUMO
OBJECTIVE: To evaluate the effects of DEAR weight management in overweight patients undergoing fertility-sparing treatment for endometrial cancer or atypical hyperplasia. METHODS: Women with endometrial cancer or atypical hyperplasia who received fertility-sparing treatment and had a body mass index of >25 kg/m2 were randomly allocated to the DEAR (DEAR weight management) and control (self weight management) groups. Body morphology and composition, glycolipid metabolism, and tumor outcomes were assessed in both groups before and at 3 and 6 months after intervention. RESULTS: Overall, 72 subjects were included (36 in each group). Following intervention, the DEAR group showed significantly lower median body weight (69.45 vs. 78.05), body mass index (26.19 vs. 29.15), lipid accumulation index (29.21 vs. 57.86), body fat mass (24.00 vs. 29.30), visceral fat area (112.5 vs. 133.3), and glycolipid metabolic indices (except high density lipoprotein) than the control group (P < 0.05) and showed a decreasing trend. The test group achieved significantly higher complete remission (88.46% vs. 57.14%; P < 0.05); the time to complete remission did not differ significantly (P > 0.05). CONCLUSIONS: DEAR weight management can improve the studied parameters and complete remission rates in this population. REGISTRATION: NCT06169449.
Assuntos
Neoplasias do Endométrio , Preservação da Fertilidade , Sobrepeso , Humanos , Feminino , Sobrepeso/complicações , Sobrepeso/metabolismo , Adulto , Neoplasias do Endométrio/patologia , Preservação da Fertilidade/métodos , Índice de Massa Corporal , Hiperplasia EndometrialRESUMO
OBJECTIVES: The objective of this study was to describe healthcare resource use (HCRU) in addition to treatment patterns and discontinuations, in patients with ovarian cancer (OC) initiating PARP inhibitor (PARPi) maintenance treatment in a US community oncology setting. METHODS: This was a retrospective study of patients with OC initiating PARPi monotherapy maintenance during 01/01/2017 to 06/30/2019 (followed until 12/31/2019). Patients aged ≥18 years at first diagnosis of OC with ≥2 visits within The US Oncology Network were included. Structured and chart review data as well as claims data were used to describe treatment patterns and HCRU. RESULTS: Of the 162 charts reviewed, the median age of patients was 66 years and 80% had stage III or IV disease at diagnosis. In the niraparib, rucaparib and olaparib groups, proportions of patients experiencing dose interruptions were 51%, 50%, and 28%, and discontinuations due to toxicity were 37%, 17% and 15%, respectively. Within the first 6 months, mean numbers of total claims were 43.5, 56.4, and 36.0 in the niraparib, rucaparib, and olaparib groups, and laboratory claims were 13.9, 19.4, and 15.6, respectively. Proportions of patients with hospitalizations (niraparib 40%, rucaparib 32%, olaparib 19%; p = 0.03), also differed as did emergency department visits (niraparib 37%, rucaparib 23%, olaparib 16%; p = 0.02). CONCLUSION: Despite patients initiating niraparib having higher rates of dose management events and toxicity-related discontinuations, outpatient and laboratory utilization were similar across all three PARPi. Adequate monitoring of these medications, with differing toxicities, should be emphasized to potentially decrease dose reductions and toxicities.