Lack of mismatch repair enhances resistance to methylating agents for cells deficient in oxidative demethylation.

The human AlkB homologs, ALKBH2 and ALKBH3, respond to methylation damage to maintain genomic integrity and cellular viability. Both ALKBH2 and ALKBH3 are direct reversal repair (DRR) enzymes that remove 1meA and 3meC lesions commonly generated by alkylating chemotherapeutic agents. Thus, the existence of deficiencies in ALKBH proteins can be exploited in synergy with chemotherapy. In this study, we investigated possible interactions between ALKBH2 and ALKBH3 with other proteins that could alter damage response and discovered an interaction with the mismatch repair (MMR) system. To test whether the lack of active MMR impacts ALKBH2 and/or ALKBH3 response to methylating agents, we generated cells deficient in ALKBH2, ALKBH3, or both in addition to Mlh homolog 1 (MLH1), another MMR protein. We found that MLH1koALKBH3ko cells showed enhanced resistance towards SN1- and SN2-type methylating agents, whereas MLH1koALKBH2ko cells were only resistant to SN1-type methylating agents. Concomitant loss of ALKBH2 and ALKBH3 (ALKBH2ko3ko) rendered cells sensitive to SN1- and SN2-agents, but the additional loss of MLH1 enhanced resistance to both types of damage. We also showed that ALKBH2ko3ko cells have an ATR-dependent arrest at the G2/M checkpoint, increased apoptotic signalling, and replication fork stress in response to methylation. However, these responses were not observed with the loss of functional MLH1 in MLH1koALKBH2ko3ko cells. Finally, in MLH1koALKBH2ko3ko cells, we observed elevated mutant frequency in untreated and temozolomide treated cells. These results suggest that obtaining a more accurate prognosis of chemotherapeutic outcome requires information on the functionality of ALKBH2, ALKBH3, and MLH1.

High-throughput selection of cells based on accumulated growth and division using PicoShell particles.

Production of high-energy lipids by microalgae may provide a sustainable energy source that can help tackle climate change. However, microalgae engineered to produce more lipids usually grow slowly, leading to reduced overall yields. Unfortunately, culture vessels used to select cells based on growth while maintaining high biomass production, such as well plates, water-in-oil droplet emulsions, and nanowell arrays, do not provide production-relevant environments that cells experience in scaled-up cultures (e.g., bioreactors or outdoor cultivation farms). As a result, strains that are developed in the laboratory may not exhibit the same beneficial phenotypic behavior when transferred to industrial production. Here, we introduce PicoShells, picoliter-scale porous hydrogel compartments, that enable >100,000 individual cells to be compartmentalized, cultured in production-relevant environments, and selected based on growth and bioproduct accumulation traits using standard flow cytometers. PicoShells consist of a hollow inner cavity where cells are encapsulated and a porous outer shell that allows for continuous solution exchange with the external environment. PicoShells allow for cell growth directly in culture environments, such as shaking flasks and bioreactors. We experimentally demonstrate that Chlorella sp., Saccharomyces cerevisiae, and Chinese hamster ovary cells, used for bioproduction, grow to significantly larger colony sizes in PicoShells than in water-in-oil droplet emulsions (P < 0.05). We also demonstrate that PicoShells containing faster dividing and growing Chlorella clonal colonies can be selected using a fluorescence-activated cell sorter and regrown. Using the PicoShell process, we select a Chlorella population that accumulates chlorophyll 8% faster than does an unselected population after a single selection cycle.

Trivalent Copper Ion-Mediated Dual Oxidation in the Copper-Catalyzed Fenton-Like System in the Presence of Histidine.

The Cu(II)/H2O2 system is recognized for its potential to degrade recalcitrant organic contaminants and inactivate microorganisms in wastewater. We investigated its unique dual oxidation strategy involving the selective oxidation of copper-complexing ligands and enhanced oxidation of nonchelated organic compounds. L-Histidine (His) and benzoic acid (BA) served as model compounds for basic biomolecular ligands and recalcitrant organic contaminants, respectively. In the presence of both His and BA, the Cu(II)/H2O2 system rapidly degraded His complexed with copper ions within 30 s; however, BA degraded gradually with a 2.3-fold efficiency compared with that in the absence of His. The primary oxidant responsible was the trivalent copper ion [Cu(III)], not hydroxyl radical (•OH), as evidenced by •OH scavenging, hydroxylated BA isomer comparison with UV/H2O2 (a •OH generating system), electron paramagnetic resonance, and colorimetric Cu(III) detection via periodate complexation. Cu(III) selectively oxidized His owing to its strong chelation with copper ions, even in the presence of excess tert-butyl alcohol. This selectivity extended to other copper-complexing ligands, including L-asparagine and L-aspartic acid. The presence of His facilitated H2O2-mediated Cu(II) reduction and increased Cu(III) production, thereby enhancing the degradation of BA and pharmaceuticals. Thus, the Cu(II)/H2O2 system is a promising option for dual-target oxidation in diverse applications.

The association between testosterone deficiency and nocturia: Insights from The National Health and Nutrition Examination Survey data set.

AIMS: To examine the association between testosterone deficiency (TD) and nocturia in males, with specific attention to age and cardiovascular disease (CVD) comorbidity. METHODS: This cross-sectional study utilized the National Health and Nutrition Examination Survey (NHANES) data from 2011 to 2016, assessing 6137 adult male participants. TD was defined by a serum total testosterone (TT) concentration less than 300 ng/dL. Nocturia was determined based on participants' responses to a standard NHANES question regarding the frequency of urination during the night. RESULTS: The study observed a significant association between TD and nocturia (adjusted odds ratio [95% confidence interval] = 1.211 [1.060-1.384], p = 0.005). Moreover, a U-shape pattern was noted in the relationship between serum TT concentration and the relative odds of nocturia. Subgroup analysis revealed a robust correlation between TD and nocturia in those over 60 years old, and those with hypertension, dyslipidemia, and CVDs. CONCLUSION: Our findings suggest a positive correlation between TD and nocturia, particularly among elderly individuals with CVD. This association underscores the potential therapeutic significance of addressing TD in the management of nocturia. Furthermore, longitudinal studies are needed to establish a causal relationship between TD and nocturia.

First report of Perkinsus marinus occurrence associated with wild Pacific oysters Crassostrea gigas from the west coast of Korea.

This study reports the occurrence of Perkinsus marinus associated with wild Pacific oyster (Crassostrea gigas) specimens collected along the west coast of Korea. Confirmation of P. marinus presence was achieved by conventional PCR using World Organization of Animal Health (WOAH)-recommended primers that specifically targeted regions of the rDNA locus (ITS1, 5.8S, and ITS2). Sequencing of 10 samples revealed two distinct sequences differing by a single base pair, indicating potential haplotype variability. One sequence closely resembled the P. marinus strain found in Maryland, USA, whereas the other exhibited divergence, indicative of species diversity in the Korean strain, as was evident from the haplotype network analysis. Further validation involved the Ray's Fluid Thioglycollate Medium (RFTM) assay, which initially yielded inconclusive results, possibly due to low infection intensity. Subsequently, RFTM and 2 M NaOH assays conducted on the isolates in the present study, cultured P. marinus cells in standard DMEM/F12 medium, and a positive P. marinus strain (ATCC 50509), revealed characteristic hypnospores of P. marinus upon Lugol's iodine staining. These comprehensive investigations underscore the conclusive confirmation of P. marinus in Korean waters and mark a significant milestone in our understanding of the distribution and characteristics of this parasite in previously unreported regions.

Quadruple ultrasound, photoacoustic, optical coherence, and fluorescence fusion imaging with a transparent ultrasound transducer.

Ultrasound and optical imagers are used widely in a variety of biological and medical applications. In particular, multimodal implementations combining light and sound have been actively investigated to improve imaging quality. However, the integration of optical sensors with opaque ultrasound transducers suffers from low signal-to-noise ratios, high complexity, and bulky form factors, significantly limiting its applications. Here, we demonstrate a quadruple fusion imaging system using a spherically focused transparent ultrasound transducer that enables seamless integration of ultrasound imaging with photoacoustic imaging, optical coherence tomography, and fluorescence imaging. As a first application, we comprehensively monitored multiparametric responses to chemical and suture injuries in rats' eyes in vivo, such as corneal neovascularization, structural changes, cataracts, and inflammation. As a second application, we successfully performed multimodal imaging of tumors in vivo, visualizing melanomas without using labels and visualizing 4T1 mammary carcinomas using PEGylated gold nanorods. We strongly believe that the seamlessly integrated multimodal system can be used not only in ophthalmology and oncology but also in other healthcare applications with broad impact and interest.

Clinical performance of the STANDARD M10 SARS-CoV-2 rapid RT-PCR assay in patients visiting an emergency department.

In emergency departments, rapid screening of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was important for arranging limited isolation resources and patient care during the coronavirus disease 2019 (COVID-19) pandemic. STANDARD M10 SARS-CoV-2 (SD Biosensor) is a recently developed cartridge-based RT-PCR that provides a turnaround time of 1 h, which is shorter than that for conventional RT-PCR. This study evaluated the clinical performance of STANDARD M10 in patients visiting an emergency department. From March to June 2022, two specimens were collected from patients visiting an emergency department. Each specimen comprised one nasopharyngeal and one oropharyngeal swab. Respective specimens underwent rapid RT-PCR using STANDARD M10 and conventional RT-PCR using Allplex SARS-CoV-2 (Seegene). When discordant results occurred, specimens undergoing the STANDARD M10 were retested with the Allplex to exclude specimen variations. Retest results replaced initial results of the Allplex. Clinical performance of STANDARD M10 was compared with Allplex. The study enrolled 1971 patients. COVID-19 prevalence was 6.2% based on the Allplex. Compared with the Allplex, overall agreement, positive percent agreement, and negative percent agreement of STANDARD M10 were 99.5% (95% CI: 99.1%-99.8%), 95.9% (95% CI: 90.8%-98.3%), and 99.8% (95% CI: 99.4%-99.9%), respectively. Nine discordant results were all positive on droplet digital PCR, except for one specimen that was positive with STANDARD M10. The STANDARD M10 showed reliable diagnostic performance for detecting SARS-CoV-2 from patients visiting in emergency departments and is a useful tool in emergency healthcare systems because of its easy-to-use cartridge-based assay and short resulting time for detecting SARS-CoV-2.

Adjunctive Cilostazol in Patients With High Residual Platelet Reactivity After Drug-Eluting Stent Implantation: A Randomized, Open-Label, Single-Center, Prospective (ADJUST-HPR) Study.

BACKGROUND: Cilostazol as an adjunct to dual antiplatelet therapy (DAPT) postcoronary stenting may further reduce vascular occlusion risks. The aim of this study was to assess the impact of cilostazol on high residual platelet reactivity (HRPR) in patients undergoing drug-eluting coronary stent implantation. METHODS: In a randomized, open-label, single-center, prospective study, the degree of platelet inhibition by cilostazol 100 mg twice daily was assessed on top of conventional DAPT compared with standard clopidogrel and low-dose aspirin combination in poststent patients with HRPR. HRPR was defined as P2Y12 units (PRU) > 240 as measured by the VerifyNow P2Y12 assay. In addition, the platelet activity was assessed by light transmittance aggregometry (LTA) and Multiplate electrode analyzer (MEA). RESULTS: The total of 148 patients were screened, and HRPR was observed in 64 (43.2%). Those were randomized for DAPT versus triple therapy (TAPT). After 30 days, TAPT group exhibited significantly lower rate of HRPR when assessed by all 3 devices (VerifyNow: 40.0 vs. 66.7% P = 0.04, LTA: 6.7 vs. 30.0% P = 0.02, MEA: 10.0 vs. 30.0% P = 0.05 L all vs. DAPT). Also, higher absolute mean difference in TAPT versus DAPT group after 30 days (VerifyNow: 71.3 ± 38.2 vs. 24.6 ± 40.2 P < 0.001, LTA: 23.9 ± 15.1 vs. 9.4 ± 11.8 P < 0.001, MEA: 9.3 ± 12.9 vs. 2.4 ± 17.3 P = 0.08) was observed. CONCLUSIONS: Cilostazol in addition to standard DAPT reduces the incidence of HRPR and diminishes further platelet activity in poststent patients. Whether this favorable laboratory finding will affect clinical outcomes requires an adequately powered randomized trial.

A Case of Marrow Fibrosis with Megakaryocytic Hyperplasia after Short-Term use of Granulocyte Colony-Stimulating Factor.

BACKGROUND: Administration of granulocyte colony-stimulating factors G-SCFs can cause diagnostic challenges because of morphologic alteration of hematopoietic cells. METHODS: We experienced a patient who showed distinctive clinical and morphologic findings after short time use of G-CSF. The clinical information and examination results of the morphology of bone marrow (BM) specimen and karyotype were analyzed by reviewing relevant literature. RESULTS: White blood cell (WBC) counts of the patient were unresponsive to G-CSF and marrow fibrosis and megakaryocytic hyperplasia were accompanied with increase of blasts in BM. Presence of malignant clones was confirmed by cytogenetic aberrations of monosomy 7. CONCLUSIONS: We concluded, BM study including cytogenetic analysis should be performed when such clinical findings are encountered and the possibility of hematologic malignancy should be considered.

Clinical Utility of SARS-CoV-2 Rapid Antigen Test in the Emergency Department.

BACKGROUND: Rapid screening for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was important in the emergency department during the coronavirus disease 2019 (COVID-19) pandemic. Real-time polymerase chain reaction (RT-PCR) is the standard method for detecting SARS-CoV-2, but it requires several hours to provide results. Instead, the rapid antigen test (RAT) has a short turnaround time and can be used at the bedside but shows low sensitivity. To overcome these shortcomings, the clinical utility of stepwise testing of RAT with RT-PCR in the emergency department was analyzed. METHODS: Patients who underwent SARS-CoV-2 RAT (SD Biosensor or Abbott) and RT-PCR (Seegene Allplex or GeneXpert) testing simultaneously at the emergency department in South Korea from January 2021 to March 2022 were enrolled. We compared the performance status of RAT with that of RT-PCR and evaluated the clinical utility of RAT as a screening tool for patients visiting the emergency department. RESULTS: A total of 7,574 patients were included. The overall prevalence of COVID-19 was 1.9% (146/7,574). The sensitivity and specificity of the RAT were 69.2% and 99.9%, respectively, and the positive and negative predictive values were 96.2% and 99.4%, respectively. Based on the cycle threshold (Ct) of the E gene, the sensitivity was 86.0% in patients with Ct < 26, but the sensitivity was 9.3% in patients with Ct ≥ 26. CONCLUSIONS: In the COVID-19 pandemic, RAT can be used as supplement test for the screening strategy using RT-PCR in the emergency department because it is rapid, highly specific, and relatively sensitive in patients with high viral load.

Genomic Mutation Profiles of Patients with Acute Myeloid Leukemia in Korea: a Single-Center Experience.

BACKGROUND: The emergence of next-generation sequencing (NGS) is currently leading the diagnosis of acute myeloid leukemia (AML) and its treatment using a more genetic-level approach. The study aimed to find clinical and prognostic correlations with genomic mutation profiles in Korean patients with AML using NGS. METHODS: This retrospective study enrolled a total of 30 patients who were newly diagnosed with AML from February 2021 to October 2022 in Korea. NGS was used to identify the genetic profiles of 40 genes relevant to AML. The clinical and laboratory data of the patients were analyzed with their genomic mutation profiles. RESULTS: NGS revealed at least one mutation in all patients, with a range of one to seven mutations (median of three mutations). Mutations were commonly associated with TET2, CEBPA, RUNX1, FLT3, IDH2, NPM1, and SRSF2 genes. The TET2 mutation correlated with older (77 vs. 72) patients, and the FLT3 mutation was associated with a higher WBC count (33.4 x 109/L vs. 6.4 x 109/L). The RUNX1 mutation correlated with a lower (44.0 x 109/L vs. 65.5 x 109/L) platelet count, and the NPM1 mutation showed a higher number of blasts in peripheral blood (56.5% vs. 13.0%). Among 16 patients who received induction chemotherapy, mutations in SRSF2, ASXL1, PHF6, SF3B1, and PTPN11 were detected only in patients who failed to achieve complete remission (CR). Meanwhile, mutations in NRAS, TP53, IKZF1, DNMT3A, SH2B3, U2AF1, and WT1 were detected in patients who achieved CR. CONCLUSIONS: Clinical and prognostic correlations were observed according to genomic mutation profiles detected by NGS in Korean patients with AML. An NGS study with a larger cohort of patients would be beneficial to establish the significant prognostic impact on patients with AML.

The Profile of Early Sedation Depth and Clinical Outcomes of Mechanically Ventilated Patients in Korea.

BACKGROUND: Current international guidelines recommend against deep sedation as it is associated with worse outcomes in the intensive care unit (ICU). However, in Korea the prevalence of deep sedation and its impact on patients in the ICU are not well known. METHODS: From April 2020 to July 2021, a multicenter, prospective, longitudinal, noninterventional cohort study was performed in 20 Korean ICUs. Sedation depth extent was divided into light and deep using a mean Richmond Agitation-Sedation Scale value within the first 48 hours. Propensity score matching was used to balance covariables; the outcomes were compared between the two groups. RESULTS: Overall, 631 patients (418 [66.2%] and 213 [33.8%] in the deep and light sedation groups, respectively) were included. Mortality rates were 14.1% and 8.4% in the deep and light sedation groups (P = 0.039), respectively. Kaplan-Meier estimates showed that time to extubation (P < 0.001), ICU length of stay (P = 0.005), and death (P = 0.041) differed between the groups. After adjusting for confounders, early deep sedation was only associated with delayed time to extubation (hazard ratio [HR], 0.66; 95% confidence interval [CI], 0.55-0.80; P < 0.001). In the matched cohort, deep sedation remained significantly associated with delayed time to extubation (HR, 0.68; 95% CI, 0.56-0.83; P < 0.001) but was not associated with ICU length of stay (HR, 0.94; 95% CI, 0.79-1.13; P = 0.500) and in-hospital mortality (HR, 1.19; 95% CI, 0.65-2.17; P = 0.582). CONCLUSION: In many Korean ICUs, early deep sedation was highly prevalent in mechanically ventilated patients and was associated with delayed extubation, but not prolonged ICU stay or in-hospital death.

Sirtuin 6 is a negative regulator of FcεRI signaling and anaphylactic responses.

BACKGROUND: Binding IgE to a cognate allergen causes aggregation of Fcε receptor I (FcεRI) in mast cells, resulting in activation of receptor-associated Src family tyrosine kinases, including Lyn and Syk. Protein tyrosine phosphatase, receptor type C (PTPRC), also known as CD45, has emerged as a positive regulator of FcεRI signaling by dephosphorylation of the inhibitory tyrosine of Lyn. OBJECTIVE: Sirtuin 6 (Sirt6), a NAD+-dependent deacetylase, exhibits an anti-inflammatory property. It remains to be determined, however, whether Sirt6 attenuates mast cell-associated diseases, including anaphylaxis. METHODS: FcεRI signaling and mast cell degranulation were measured after IgE cross-linking in murine bone marrow-derived mast cells (BMMCs) and human cord blood-derived mast cells. To investigate the function of Sirt6 in mast cell activation in vivo, we used mast cell-dependent animal models of passive systemic anaphylaxis (PSA) and passive cutaneous anaphylaxis (PCA). RESULTS: Sirt6-deficient BMMCs augmented IgE-FcεRI-mediated signaling and degranulation compared to wild-type BMMCs. Reconstitution of mast cell-deficient KitW-sh/W-sh mice with BMMCs received from Sirt6 knockout mice developed more severe PSA and PCA compared to mice engrafted with wild-type BMMCs. Similarly, genetic overexpression or pharmacologic activation of Sirt6 suppressed mast cell degranulation and blunted responses to PCA. Mechanistically, Sirt6 deficiency increased PTPRC transcription via acetylating histone H3, leading to enhanced aggregation of FcεRI in BMMCs. Finally, we recapitulated the Sirt6 regulation of PTPRC and FcεRI signaling in human mast cells. CONCLUSIONS: Sirt6 acts as a negative regulator of FcεRI signaling cascade in mast cells by suppressing PTPRC transcription. Activation of Sirt6 may therefore represent a promising and novel therapeutic strategy for anaphylaxis.

Hierarchical Wrinkle-Structured Catalyst Layer/Membrane Interface for Ultralow Pt-Loading Polymer Electrolyte Membrane Fuel Cells (PEMFCs).

The optimal architecture of three-dimensional (3D) interface between a polymer electrolyte membrane (PEM) and catalyst layer (CL) is one of the most important issues to improve PEM fuel cells' (PEMFCs) performance. Here, we report the fabrication of hierarchical wrinkled PEM/CL interface over a large area. We fabricated the hierarchical wrinkles on a multiscale from nanometers to micrometers by bottom-up-based facile, scalable, and simple method. Notably, it allows one to go beyond the limit of the catalyst utilization by extremely enlarged interfacial area. The resulting hierarchical wrinkled PEM/CL displays a dramatically increased electrochemically active surface area (ECSA) and power performance by the enhancement factors of 89% and 67% compared with those of flat interface, which is one of the best enhancements compared to previous PEMFCs. We believe the scalability of hierarchical wrinkled interface can be exploited to design advanced 3D interfaces for high-performance PEMFCs even with ultralow Pt-loading.

Poly(styrene sulfonic acid)-Grafted Carbon Black Synthesized by Surface-Initiated Atom Transfer Radical Polymerization.

Owing to their excellent electrical conductivity and robust mechanical properties, carbon-based nanocomposites are being used in a wide range of applications and devices, such as electromagnetic wave interference shielding, electronic devices, and fuel cells. While several approaches have been developed for synthesizing carbon nanotubes and carbon-black-based polymer nanocomposites, most studies have focused on the simple blending of the carbon material with a polymer matrix. However, this results in uncontrolled interactions between the carbon filler and the polymer chains, leading to the agglomeration of the carbon filler. Herein, we report a new strategy for synthesizing sulfonated polystyrene (PSS)-grafted carbon black nanoparticles (NPs) via surface-initiated atom-transfer radical polymerization. Treatments with O2 plasma and H2O2 result in the effective attachment of the appropriate initiator to the carbon black NPs, thus allowing for the controlled formation of the PSS brushes. The high polymeric processability and desirable mechanical properties of the PSS-grafted carbon black NPs enable them suitable for use in nonfluorinated-hydrocarbon-based polymer electrolyte membranes for fuel cells, which must exhibit high proton conductivity without interrupting the network of channels consisting of ionic clusters (i.e., sulfonic acid moieties).

Calcium ionophore-activated platelets induce eosinophil extracellular trap formation.

BACKGROUND: Platelets play a modulatory role in inflammatory response by secreting a vast array of granules and disintegrating into membrane-bound microparticles upon activation. The interplay between eosinophils and platelets is postulated to be implicated in the pathology of allergic airway inflammation. In this study, we investigated whether activated platelets can induce eosinophil extracellular trap (EET) formation, a cellular process by which activated eosinophils release net-like DNA fibers. METHODS: Platelets were stimulated with the calcium ionophore, A23187, and the platelet agonists, thrombin and adenosine diphosphate (ADP). Platelet cultures were fractionated into conditioned medium (CM) and pellet, which were then overlaid on eosinophils to examine EET formation. RESULTS: The CM and pellet from A23187-activated platelets stimulated eosinophils to generate EET, whereas those from thrombin- or ADP-activated platelets failed to induce such generation. The EET-inducing activity of the A23187-activated platelet culture was linearly proportional to the number of activated platelets. Interestingly, while EET formation induced by the direct stimulation of eosinophils with A23187 was NADPH oxidase (NOX)-dependent, EET formation induced by A23187-activated platelets was NOX-independent and significantly inhibited by necroptosis pathway inhibitors. CONCLUSIONS: Activated platelets and their products may induce EET formation, thereby potentiating their role in eosinophilic airway inflammation.

Impacts of social distancing policy and vaccination during the COVID-19 pandemic in the Republic of Korea.

This paper investigates the dynamic impact of social distancing policy on coronavirus disease (COVID-19) infection control, mobility of people, and consumption expenditures in the Republic of Korea. We employ structural and threshold vector autoregressive (VAR) models using big-data-driven mobility data, credit card expenditure, and a social distancing index. We find that the social distancing policy significantly reduces the spread of COVID-19, but there exists a significant, growing trade-off between infection control and economic activity over time. When the level of stringency in social distancing is already high, its marginal effect on mobility is estimated to be smaller than when social distancing stringency is low. The effect of social distancing also becomes secondary after vaccination. Increased vaccination is found to significantly reduce the critical cases while it increases visitors and consumption expenditures. The results also show that the effect of social distancing policy on mobility reduction is strongest among the population of age under 20 and the weakest among the population of age over 60.

Progression Rates by Age, Sex, Treatment, and Disease Activity by AASLD and EASL Criteria: Data for Precision Medicine.

BACKGROUND & AIMS: Antiviral treatment criteria are based on disease progression risk, and hepatocellular carcinoma (HCC) surveillance recommendations for patients with chronic hepatitis B (CHB) without cirrhosis is based on an annual incidence threshold of 0.2%. However, accurate and precise disease progression estimate data are limited. Thus, we aimed to determine rates of cirrhosis and HCC development stratified by age, sex, treatment status, and disease activity based on the 2018 American Association for the Study of Liver Diseases and 2017 European Association for the Study of the Liver guidelines. METHODS: We analyzed 18,338 patients (8914 treated, 9424 untreated) from 6 centers from the United States and 27 centers from Asia-Pacific countries. The Kaplan-Meier method was used to estimate annual progression rates to cirrhosis or HCC in person-years. RESULTS: The cohort was 63% male, with a mean age of 46.19 years, with baseline cirrhosis of 14.3% and median follow up of 9.60 years. By American Association for the Study of Liver Diseases criteria, depending on age, sex, and disease activity, annual incidence rates ranged from 0.07% to 3.94% for cirrhosis, from 0.04% to 2.19% for HCC in patients without cirrhosis, and from 0.40% to 8.83% for HCC in patients with cirrhosis. Several subgroups of patients without cirrhosis including males younger than 40 years of age and females younger than 50 years of age had annual HCC risk near or exceeding 0.2%. Similar results were found using European Association for the Study of the Liver criteria. CONCLUSION: There is great variability in CHB disease progression rates even among "lower-risk" populations. Future CHB modeling studies, public health planning, and HCC surveillance recommendation should be based on more precise disease progression rates based on sex, age, and disease activity, plus treatment status.

Methotrexate-loaded nanoparticles ameliorate experimental model of autoimmune arthritis by regulating the balance of interleukin-17-producing T cells and regulatory T cells.

BACKGROUND: Rheumatoid arthritis (RA) is a progressive systemic autoimmune disease that is characterized by infiltration of inflammatory cells into the hyperplastic synovial tissue, resulting in subsequent destruction of adjacent articular cartilage and bone. Methotrexate (MTX), the first conventional disease-modifying antirheumatic drug (DMARD), could alleviate articular damage in RA and is implicated in humoral and cellular immune responses. However, MTX has several side effects, so efficient delivery of low-dose MTX is important. METHODS: To investigate the efficacy of MTX-loaded nanoparticles (MTX-NPs) against experimental model of RA, free MTX or MTX-NPs were administered as subcutaneous route to mice with collagen-induced arthritis (CIA) at 3 weeks after CII immunization. The levels of inflammatory factors in tissues were determined by immunohistochemistry, confocal microscopy, real-time PCR, and flow cytometry. RESULTS: MTX-NPs ameliorated arthritic severity and joint destruction in collagen-induced arthritis (CIA) mice compared to free MTX-treated CIA mice. The levels of inflammatory cytokines, including interleukin (IL)-1ß, tumor necrosis factor-α, and vascular endothelial growth factor, were reduced in MTX-NPs-treated mice. Number of CD4 + IL-17 + cells decreased whereas the number of CD4 + CD25 + Foxp3 + cells increased in spleens from MTX- NPs-treated CIA mice compared to MTX-treated CIA mice. The frequency of CD19 + CD25 + Foxp3 + regulatory B cells increased in ex vivo splenocytes from MTX-loaded NPs-treated CIA mice compared to MTX-treated CIA mice. CONCLUSION: The results suggest that MTX-loaded NPs have therapeutic potential for RA.

Contribution of dipeptidyl peptidase 10 to airway dysfunction in patients with NSAID-exacerbated respiratory disease.

BACKGROUND: Genetic variants of dipeptidyl peptidase 10 (DPP10) have been suggested to contribute to the development of NSAID-exacerbated respiratory disease (NERD). However, the mechanisms of how DPP10 contributes to NERD phenotypes remain unclear. OBJECTIVE: To demonstrate the exact role of DPP10 in the pathogenesis of NERD. METHODS: Patients with NERD (n = 110), those with aspirin-tolerant asthma (ATA, n = 130) and healthy control subjects (HCs, n = 80) were enrolled. Clinical characteristics were analysed according to the serum DPP10 levels in both NERD and ATA groups. The function of DPP10 in airway inflammation and remodelling was investigated with in vitro, ex vivo and in vivo experiments. RESULTS: NERD patients had higher levels of serum DPP10 and TGF-ß1 with lower FEV1 than ATA patients or HCs (p < .05 for each). NERD patients with higher DPP10 levels had higher TGF-ß1, but lower FEV1 (p < .05 for all), whilst no differences were noted in ATA patients. Moreover, the seum DPP10 levels had a positive correlation with TGF-ß1 (r = 0.384, p < .001), but a negative correlation with FEV1 (r = -0.230, p = .016) in NERD patients. In in vitro studies, expression of DPP10 in airway epithelial cells was enhanced by TGF-ß1 treatments. Furthermore, DPP10 was found to be produced from immune cells and this molecule induced the ERK phosphorylation in airway epithelial cells, which was suppressed by anti-DPP10 treatment. In asthmatic mouse models, increased levels of DPP10 in the serum and TGF-ß1 in the bronchoalveolar lavage fluid were noted, which were suppressed by anti-DPP10 treatment. Moreover, anti-DPP10 treatment inhibited the ERK phosphorylation and extracellular matrix deposition in the lungs. CONCLUSIONS AND CLINICAL RELEVANCE: These findings suggest that increased production of DPP10 may contribute to TGF-ß1-mediated airway dysfunction in NERD patients, where blockade of DPP10 may have potential benefits.