Recurrent and persistent fever after SARS-CoV-2 infection in patients with follicular lymphoma: A case series.

Although persistent or recurrent COVID-19 infection is well described in some immunosuppressed patient cohort, to date, there have been no reports of this phenomenon in the context of repeatedly negative SARS-CoV-2 testing in the upper respiratory tract. We reported six patients with follicular lymphoma who developed recurrent symptomatic COVID-19 infection. They tested persistently negative for SARS-CoV-2 on pharyngeal swabs and ultimately confirmed by bronchoalveolar lavage fluid metagenomics next-generation sequencing. All six patients presented with lymphopenia and B-cell depletion, and five of them received the anti-cluster of differentiation 20 treatment in the last year. Persistent fever was the most common symptom and bilateral ground-glass opacities were the primary pattern on chest computed tomography. A relatively long course of unnecessary and ineffective antibacterial and/or antifungal treatments was administered until the definitive diagnosis. Persistent fever subsided rapidly with nirmatrelvir/ritonavir treatment. Our case highlighted that recurrent COVID-19 infection should be suspected in immunocompromised patients with persistent fever despite negative pharyngeal swabs, and urgent bronchoalveolar lavage fluid testing is necessary. Treatment with nirmatrelvir/ritonavir appeared to be very effective in these patients.

Clinical characteristics and prognostic factors of non-tuberculous mycobacterial disease in patients with rheumatoid arthritis.

BACKGROUND/AIMS: This study aimed to identify the clinical characteristics of patients with concurrent rheumatoid arthritis (RA) and suspected non-tuberculous mycobacterial (NTM) infections as well as determine their prognostic factors. METHODS: We retrospectively reviewed the medical records of 91 patients with RA whose computed tomography (CT) findings suggested NTM infection. Subsequently, we compared the clinical characteristics between patients with and without clinical or radiological exacerbation of NTM-pulmonary disease (PD) and investigated the risk factors for the exacerbation and associated mortality. RESULTS: The mean age of patients with RA and suspected NTM-PD was 65.0 ± 10.2 years. The nodular/bronchiectatic (NB) form of NTM-PD was the predominant radiographic feature (78.0%). During follow-up, 36 patients (41.9%) experienced a radiological or clinical exacerbation of NTM-PD, whereas 12 patients (13.2%) died. Combined interstitial lung disease (ILD), microbiologically confirmed NTM-PD, and NB with the fibrocavitary (FC) form on chest CT were identified as risk factors for the clinical or radiological exacerbation of NTM-PD. Hydroxychloroquine use was identified as a good prognostic factor. Conversely, history of tuberculosis, ILD, smoking, microbiologically confirmed NTM-PD, and NB with the FC form on chest CT were identified as poor prognostic factors for mortality in suspected NTM-PD. CONCLUSION: ILD and NB with the FC form on chest CT were associated with NTM-PD exacerbation and mortality. Hydroxychloroquine use may lower the risk of NTM-PD exacerbation. Therefore, radiographic features and presence of ILD should be considered when predicting the prognosis of patients with RA and suspected NTM-PD.

Targeting the mechano-microenvironment and liver cancer stem cells: a promising therapeutic strategy for liver cancer.

Over the past 2 decades, cancer stem cells (CSCs) have been identified as the root cause of cancer occurrence, progression, chemoradioresistance, recurrence, and metastasis. Targeting CSCs is a novel therapeutic strategy for cancer management and treatment. Liver cancer (LC) is a malignant disease that can endanger human health. Studies are increasingly suggesting that changes in the liver mechanical microenvironment are a primary driver triggering the occurrence and development of liver cancer. In this review, we summarize current understanding of the roles of the liver mechano-microenvironment and liver cancer stem cells (LCSCs) in liver cancer progression. We also discuss the relationship between the mechanical heterogeneity of liver cancer tissues and LCSC recruitment and metastasis. Finally, we highlight potential mechanosensitive molecules in LCSCs and mechanotherapy in liver cancer. Understanding the roles and regulatory mechanisms of the mechano-microenvironment and LCSCs may provide fundamental insights into liver cancer progression and aid in further development of novel therapeutic strategies.

Metabolic dependency of non-small cell lung cancer cells affected by three-dimensional scaffold and its stiffness.

Three-dimensional (3D) extracellular matrix (ECM) microenvironment is an important regulator of the stiffness of the tumors. Cancer cells require heterogeneous metabolic phenotypes to cope with resistance in the malignant process. However, how the stiffness of the matrix affects the metabolic phenotypes of cancer cells, is lacking. In this study, the young's modulus of the synthesized collagen-chitosan scaffolds was adjusted according to the percentage ratio of collagen to chitosan. We cultured non-small cell lung cancer (NSCLC) cells in four different microenvironments (two-dimensional (2D) plates, stiffest 0.5-0.5 porous collagen-chitosan scaffolds, middle stiff 0.5-1 porous collagen-chitosan scaffolds, and softest 0.5-2 porous collagen-chitosan scaffolds) to investigate the influence of the difference of 2D and 3D cultures as well as the 3D scaffolds with different stiffnesses on the metabolic dependency of NSCLC cells. The results revealed that NSCLC cells cultured in 3D collagen-chitosan scaffolds displayed higher capacity of mitochondrial metabolism and fatty acid metabolism than that cultured in 2D culture. The metabolic response of NSCLC cells is differential for 3D scaffolds with different stiffnesses. The cells cultured in middle stiff 0.5-1 scaffolds displayed a higher potential of mitochondrial metabolism than that of stiffer 0.5-0.5 scaffolds and softer 0.5-2 scaffolds. Furthermore, NSCLC cells culture in 3D scaffolds displayed drug resistance compared with that in 2D culture which maybe via the hyperactivation of the mTOR pathway. Moreover, the cells cultured in 0.5-1 scaffolds showed higher ROS levels, which were counterbalanced by an equally high expression of antioxidant enzymes when compared to the cells grown in 2D culture, which may be regulated by the increased expression of PGC-1α. Together, these results demonstrate that differences in the microenvironments of cancer cells profoundly impact their metabolic dependencies.

Siraitia grosvenorii (Swingle) C. Jeffrey: Research Progress of Its Active Components, Pharmacological Effects, and Extraction Methods.

Siraitia grosvenorii (Swingle) C. Jeffrey, a perennial vine of the Cucurbitaceae family, is a unique medicine food homology species from China. S. grosvenorii can be used as a natural sweetener in the food industry and as a traditional medicine for moistening the lungs, quenching a cough, smoothing the intestines, and relieving constipation. Additionally, the fruits, roots, stems, and leaves of S. grosvenorii are rich in active ingredients, and have pharmacological effects such as immune regulation, hypoglycemia, and antioxidant, hepatoprotective, and antitumor effects, etc. Therefore, S. grosvenorii has broad application prospects in the pharmaceutical industry. This paper reviews the bioactive components, pharmacological effects, and extraction methods of S. grosvenorii, summarizes them, and proposes their future development directions. This current overview highlights the value of S. grosvenorii. By documenting the comprehensive information of S. grosvenorii, the review aims to provide the appropriate guidelines for its future in-depth development and the utilization of S. grosvenorii resources for their roles as active ingredient (triterpenoids, flavonoids, and polysaccharides, etc.) sources in the food industry and in the development of functional foods.

Association between SYVN1 and SEL1 genetic polymorphisms and remission in rheumatoid arthritis patients treated with TNF-α inhibitors: a machine learning approach.

Rheumatoid arthritis (RA) is a severe chronic inflammatory condition that affects joint synovium. Suppressor/enhancer of lin-12-like (SEL1L)-Synoviolin 1 (SYVN1)-mediated endoplasmic reticulum-associated degradation (ERAD) is highly associated with RA development. Although targeting SEL1L-SYVN1-mediated ERAD can be beneficial, studies that evaluate the association between polymorphisms in their genes and remission from the disease in RA patients taking tumor necrosis factor (TNF)-α inhibitors have yet to be carried out. Hence, the purpose of this study was to investigate the association between SYVN1 and SEL1L polymorphisms and TNF-α inhibitor response using various machine learning models. A total of 12 single-nucleotide polymorphisms (SNPs), including 5 SNPs in SYVN1 and 7 SNPs of SEL1L were investigated. Logistic regression analysis was used to examine the relationship between genetic polymorphisms and response to treatment. Various machine learning methods were employed to evaluate factors associated with remission in patients receiving TNF-α inhibitors. After adjusting for covariates, we found that sulfasalazine and rs2025214 in SEL1L increase the remission rates by approximately 3.3 and 2.8 times, respectively (95% confidence intervals 1.126-9.695 and 1.074-7.358, respectively). Machine learning approaches showed acceptable prediction estimates for remission in RA patients receiving TNF-α inhibitors, with the area under the receiver-operating curve (AUROC) values ranging from 0.60 to 0.65. A polymorphism of the SEL1L gene (rs2025214) and sulfasalazine were found to be associated with treatment response in RA patients receiving TNF-α inhibitors. These preliminary data could be used to tailor treatment for RA patients using TNF-α inhibitors.

Retention Rate and Safety of Biologic and Targeted Synthetic DMARDs in Patients with RA-Associated Interstitial Lung Disease: A KOBIO Registry Study.

OBJECTIVES: This study aimed to evaluate the long-term retention and safety of biologic disease-modifying antirheumatic drugs (bDMARDs) and targeted synthetic DMARDs (tsDMARDs) and identify the factors associated with drug withdrawal in patients with rheumatoid arthritis (RA) with interstitial lung disease (ILD) enrolled in the Korean College of Rheumatology Biologics and Targeted Therapy registry. METHODS: We investigated adults with RA (n = 2266) administered with bDMARDs or tsDMARDs between 2012 and 2021. Propensity score matching (1:3) was performed between patients with RA with ILD (RA-ILD) and without ILD (RA-no ILD). The Kaplan-Meier method was used to analyse drug survival and a logistic regression model to identify withdrawal-related factors in RA-ILD. RESULTS: One hundred and fifty-nine patients with RA-ILD were matched with 477 patients with RA-no ILD. The 5-year drug retention rate was lower in RA-ILD than in RA-no ILD (log-rank p = 0.020), and both the ILD and no-ILD groups had statistical differences of drug retention rate among agents (log-rank p = 0.019 and 0.020, respectively). In the RA-ILD group, Janus kinase inhibitors had the highest drug retention rate (64.3%), and tumour necrosis factor-α inhibitors showed the lowest retention rate (30.6%). Approximately 58.5% and 48.4% of the patients with RA-ILD and RA-no ILD, respectively, withdrew from their regimen, and the main cause of withdrawal in RA-ILD was adverse events, followed by inefficacy. In the logistic regression analysis, current smoking had a negative effect on drug retention (odds ratio [OR]: 9.938, 95% confidence interval [CI]: 2.550-38.733; p < 0.001), while concomitant corticosteroid use had a protective effect against withdrawal (OR: 0.284, 95% CI: 0.008-0.917; p = 0.035) in RA-ILD. CONCLUSION: The patients with RA-ILD had lower bDMARD and tsDMARD retention rates than those with RA-no ILD. In the RA-ILD group, current smoking and concomitant corticosteroid use were associated factors affecting drug withdrawal.

Stiffer-Matrix-Induced PGC-1α Upregulation Enhanced Mitochondrial Biogenesis and Oxidative Stress Resistance in Non-small Cell Lung Cancer.

Introduction: Metabolic strategies in different microenvironments can affect cancer metabolic adaptation, ultimately influencing the therapeutic response. Understanding the metabolic alterations of cancer cells in different microenvironments is critical for therapeutic success. Methods: In this study, we cultured non-small cell lung cancer cells in three different microenvironments (two-dimensional (2D) plates, soft elastic three-dimensional (3D) porous 2 wt% scaffolds, and stiff elastic 3D porous 4 wt% scaffolds) to investigate the effects of different matrix elasticity as well as 2D and 3D culture settings on the metabolic adaptation of cancer cells. Results: The results revealed that PGC-1α expression is sensitive to the elasticity of the 3D scaffold. PGC-1α expression was markedly increased in cancer cells cultured in stiff elastic 3D porous 4 wt% scaffolds compared with cells cultured in soft elastic 3D porous 2 wt% scaffolds or 2D plates, enhancing mitochondrial biogenesis and oxidative stress resistance of non-small cell lung cancer through increased reactive oxygen species (ROS) detoxification capacity. However, phosphofructokinase-1 (PFK-1) expression, a key rate-limiting enzyme in glycolysis, did not change significantly in the three microenvironments, indicating that microenvironments may not affect the early stage of glycolysis. Conversely, monocarboxylate transporter 1 (MCT1) expression in 3D culture was significantly reduced compared to 2D culture but without significant difference between soft and stiff scaffolds, indicating that MCT1 expression is more sensitive to the shape of the different cultures of 2D and 3D microenvironment surrounding cells but is unaffected by the scaffold elasticity. Conclusions: Together, these results demonstrate that differences in the microenvironment of cancer cells profoundly impact their metabolic response.

Scavenging dicarbonyls with 5'-O-pentyl-pyridoxamine increases HDL net cholesterol efflux capacity and attenuates atherosclerosis and insulin resistance.

OBJECTIVE: Oxidative stress contributes to the development of insulin resistance (IR) and atherosclerosis. Peroxidation of lipids produces reactive dicarbonyls such as Isolevuglandins (IsoLG) and malondialdehyde (MDA) that covalently bind plasma/cellular proteins, phospholipids, and DNA leading to altered function and toxicity. We examined whether scavenging reactive dicarbonyls with 5'-O-pentyl-pyridoxamine (PPM) protects against the development of IR and atherosclerosis in Ldlr-/- mice. METHODS: Male or female Ldlr-/- mice were fed a western diet (WD) for 16 weeks and treated with PPM versus vehicle alone. Plaque extent, dicarbonyl-lysyl adducts, efferocytosis, apoptosis, macrophage inflammation, and necrotic area were measured. Plasma MDA-LDL adducts and the in vivo and in vitro effects of PPM on the ability of HDL to reduce macrophage cholesterol were measured. Blood Ly6Chi monocytes and ex vivo 5-ethynyl-2'-deoxyuridine (EdU) incorporation into bone marrow CD11b+ monocytes and CD34+ hematopoietic stem and progenitor cells (HSPC) were also examined. IR was examined by measuring fasting glucose/insulin levels and tolerance to insulin/glucose challenge. RESULTS: PPM reduced the proximal aortic atherosclerosis by 48% and by 46% in female and male Ldlr-/- mice, respectively. PPM also decreased IR and hepatic fat and inflammation in male Ldlr-/- mice. Importantly, PPM decreased plasma MDA-LDL adducts and prevented the accumulation of plaque MDA- and IsoLG-lysyl adducts in Ldlr-/- mice. In addition, PPM increased the net cholesterol efflux capacity of HDL from Ldlr-/- mice and prevented both the in vitro impairment of HDL net cholesterol efflux capacity and apoAI crosslinking by MPO generated hypochlorous acid. Moreover, PPM decreased features of plaque instability including decreased proinflammatory M1-like macrophages, IL-1ß expression, myeloperoxidase, apoptosis, and necrotic core. In contrast, PPM increased M2-like macrophages, Tregs, fibrous cap thickness, and efferocytosis. Furthermore, PPM reduced inflammatory monocytosis as evidenced by decreased blood Ly6Chi monocytes and proliferation of bone marrow monocytes and HSPC from Ldlr-/- mice. CONCLUSIONS: PPM has pleotropic atheroprotective effects in a murine model of familial hypercholesterolemia, supporting the therapeutic potential of reactive dicarbonyl scavenging in the treatment of IR and atherosclerotic cardiovascular disease.

A link between CD8+CD27-CD28- T cells expressing chemerin chemokine-like receptor 1 and rheumatoid arthritis.

OBJECTIVES: Transcription of the chemerin chemokine-like receptor 1 (CMKLR1) has been observed in T cell subsets, but its role in T cells has not been well studied. As previously reported, the levels of its ligand, chemerin, are increased in the plasma and synovial fluid of patients with rheumatoid arthritis (RA); hence, we aimed to explore the expression and role of CMKLR1 in the T cells of these patients. METHODS: Peripheral blood and synovial fluid from patients with RA or osteoarthritis and healthy individuals were collected to analyse the frequency of CD27-CD28- T cells and the expression of CMKLR1 and TNF-α by flow cytometry. Chemotaxis of T cells was assessed using a Transwell migration assay. Chemerin levels were measured using an enzyme-linked immunosorbent assay. RESULTS: CMKLR1 was preferentially expressed in CD27-CD28- T cell subsets. Its surface levels were reduced by stimulation with anti-CD3 antibody or chemerin. We found a correlation between CMKLR1+CD8+CD27-CD28- T cell frequency and disease activity score 28 of RA. Chemerin treatment up-regulated but CMKLR1 inhibitor treatment down-regulated TNF-α expression in CD8+CD27-CD28- T cells, half of which express CMKLR1 on average. Moreover, chemerin induced migration of these cells. Analysis of blood and synovial fluid samples of RA showed a reduction of CMKLR1+CD27-CD28- T cell levels in the synovial fluid, with a few exceptions. CONCLUSIONS: Our results suggest that CMKLR1 expression in T cells may be involved in RA pathogenesis through modulation of TNF-α expression and cell migration.

The Beneficial Effect of a Healthy Dietary Pattern on Androgen Deprivation Therapy-Related Metabolic Abnormalities in Patients with Prostate Cancer: A Meta-Analysis Based on Randomized Controlled Trials and Systematic Review.

Metabolic abnormalities as side effects of androgen-deprivation therapy (ADT) can accelerate progression of prostate cancer (PCa) and increase risks of cardiovascular diseases. A healthy dietary pattern (DP) plays an important role in regulating glycolipid metabolism, while evidence about DP on ADT-related metabolic abnormalities is still controversial. To explore the effect of DP on metabolic outcomes in PCa patients with ADT, PubMed, Embase, Cochrane, and CINAHL were searched from inception to 10 September 2022. Risk of biases was evaluated through Cochrane Collaboration's Tool. If heterogeneity was low, the fixed-effects model was carried out; otherwise, the random-effects model was used. Data were determined by calculating mean difference (MD) or standardized MD (SMD) with 95% confidence intervals (CIs). Nine studies involving 421 patients were included. The results showed that healthy DP significantly improved glycated hemoglobin (MD: −0.13; 95% CI: −0.24, −0.02; p = 0.020), body mass index (MD: −1.02; 95% CI: −1.29, −0.75; p < 0.001), body fat mass (MD: −1.78; 95% CI: −2.58, −0.97; p < 0.001), triglyceride (MD: −0.28; 95% CI: −0.51, −0.04; p = 0.020), systolic blood pressure (MD: −6.30; 95% CI: −11.15, −1.44; p = 0.010), and diastolic blood pressure (MD: −2.94; 95% CI: −5.63, −0.25; p = 0.030), although its beneficial effects on other glycolipid metabolic indicators were not found. Additionally, a healthy DP also lowered the level of PSA (MD: −1.79; 95% CI: −2.25, −1.33; p < 0.001). The meta-analysis demonstrated that a healthy DP could improve ADT-related metabolic abnormalities and be worthy of being recommended for PCa patients with ADT.

Effects of RETN polymorphisms on treatment response in rheumatoid arthritis patients receiving TNF-α inhibitors and utilization of machine-learning algorithms.

This study was designed to investigate the effects of polymorphisms in RETN on remission in RA patients receiving TNF-α inhibitors. In addition, machine learning algorithms were trained to predict remission. Ten single-nucleotide polymorphisms were investigated. Univariate and multivariable analyses were performed to evaluate associations between genetic polymorphisms and the efficacy of TNF-α inhibitors. A random forest-based classification approach was used to assess the importance of different variables associated with the efficacy of TNF-α inhibitors. Various machine learning methods were used for finding vital factors and prediction of remission. The eight most significant features included in the multivariable analysis were sex, age, hypertension, sulfasalazine, rs1862513, rs3219178, rs3219177, and rs3745369. T-allele carriers of rs3219177 and males showed approximately 6.0- and 3.6-fold higher remission rates compared to those with the CC genotype and females, respectively. The elastic net algorithm was the best machine-learning method for predicting remission of patients with RA treated with TNF-α inhibitors. On the basis of the results of this study, it may be possible to design individually tailored treatment regimens to predict the efficacy of TNF-α inhibitors.

Sex hormones affect the pathogenesis and clinical characteristics of systemic lupus erythematosus.

Systemic lupus erythematosus (SLE) affects women more frequently than men, similar to the female predilection for other autoimmune diseases. Moreover, male patients with SLE exhibit different clinical features than female patients. Sex-associated differences in SLE required special considerations for disease management such as during pregnancy or hormone replacement therapy (HRT). Sex hormones, namely, estrogen and testosterone, are known to affect immune responses and autoimmunity. While estrogen and progesterone promote type I immune response, and testosterone enhances T-helper 1 response. Sex hormones also influence Toll-like receptor pathways, and estrogen receptor signaling is involved in the activation and tolerance of immune cells. Further, the clinical features of SLE vary according to hormonal changes in female patients. Alterations in sex hormones during pregnancy can alter the disease activity of SLE, which is associated with pregnancy outcomes. Additionally, HRT may change SLE status. Sex hormones affect the pathogenesis, clinical features, and management of SLE; thus, understanding the occurrence and exacerbation of disease caused by sex hormones is necessary to improve its management.

Nanocarriers for drug-delivery systems using a ureido-derivatized polymer gatekeeper for temperature-controlled spatiotemporal on-off drug release.

Accidental chemotherapy extravasation exacerbates the side effects of anticancer drugs. Therefore, drug-delivery nanocarriers should be designed to avoid persistent drug release at off-target sites and promote burst drug release at on-target. Considering these requirements, poly(allylamine)-co-poly(allylurea) (PAU), a ureido-derivatized temperature responsive polymer with upper critical solution temperature (UCSTs), is an ideal material. This report describes the fabrication, characterization, and in vitro cellular toxicity of PAU polymer-grafted magnetic mesoporous silica nanoparticles as drug-delivery nanocarriers. A UCST of 43 °C and an ultranarrow transition temperature range of 39-43 °C was realized, ensuring that the nanocarriers suppressed undesirable leakage to below 10 % of the drug loading for 8 h in the absence of a thermal stimulus. A drug release burst of up to 75 % of the drug loading was achieved within 30 min after the stimulus, reducing the viability of the in vitro cancer cells to 12 %. Therefore, the ureido-derivatized polymer is one of the most suitable gatekeepers for drug-delivery nanocarriers.

Correlations between salivary gland scintigraphy and histopathologic data of salivary glands in patients with primary Sjogren's syndrome.

OBJECTIVES: Our aim was to evaluate the association between salivary gland scintigraphy and the clinical parameters, including histological characteristics of salivary glands, in patients with primary Sjogren's syndrome (pSS). METHODS: Forty-one pSS patients were included in the study. The patients who had received salivary gland scintigraphy and minor salivary gland biopsy were retrospectively analyzed. Salivary gland scintigraphy was interpreted via semi-quantitative methods obtained by calculating the peak uptake and washout of each gland using regions of interest. All specimens were examined by pathologists for focus scores and leukocyte common antigen (LCA) to determine the degree of inflammatory infiltration. RESULTS: The mean age of pSS patients was 46.4 years, 82.9% were female, and the mean duration of symptoms was 2.5 years. The focus score was negatively correlated to the mean peak uptake (r = ‒0.396; p = 0.019), mean uptake (r = ‒0.388; p = 0.021), and mean percentage washout (r = ‒0.391; p = 0.02). In addition, the focus score and number of LCA positive cells per mm2 were correlated with the clinical parameters including erythrocyte sedimentation rate, globulin, rheumatoid factor, unstimulated whole saliva, and stimulated whole saliva flow. The number of LCA positive cells per mm2 was negatively correlated to leukocytes and hemoglobin. CONCLUSION: Although the diagnostic role of salivary gland biopsy is widely accepted and features in the classification criteria of Sjogren's syndrome, salivary gland scintigraphy may be an acceptable alternative method especially if a non-invasive test is required.

Elevated expression of TLR2 and its correlation with disease activity and clinical manifestations in adult-onset Still's disease.

This study investigated the role of Toll-like receptor 1 (TLR1), TLR2, TLR4, TLR7, and TLR9 in patients with adult-onset Still's disease (AOSD). This study included 20 patients with AOSD and 15 healthy controls (HCs). TLR expression in the peripheral blood was quantified using flow cytometry; TLR expression pattern, in the skin lesions and lymph nodes (LNs) of patients with AOSD, was evaluated immunohistochemically. Significantly higher mean intensities of cells presenting TLR2 and TLR7 from whole blood were observed in patients with AOSD than in HCs. TLR2 expression in whole cells correlated with systemic scores, levels of lactate dehydrogenase and ferritin and serum levels of interleukin-1ß (IL-1ß), IL-6, and IL-18. The percentage of TLR2-positive inflammatory cells was higher in skin biopsy samples from patients with AOSD than those in HCs. TLR9-expressing positive inflammatory cell counts were higher in skin lesions from patients with AOSD than those in the HC, eczema, and psoriasis groups. The expression levels of TLR1, TLR4, TLR7, and TLR9 were higher in LNs of patients with AOSD than in those with T cell lymphoma and reactive lymphadenopathy. Circulating TLR2- and TLR7-positive cells may contribute to the pathogenesis of AOSD. Furthermore, immunohistochemical staining for TLRs in skin lesions and LNs may aid in differentiating AOSD from similar conditions.

S100A8 in Serum, Urine, and Saliva as a Potential Biomarker for Systemic Lupus Erythematosus.

Objectives: This study aimed to elucidate the potential of serum, urine, and saliva S100 calcium-binding protein A8 protein (S100A8) levels as biomarkers for systemic lupus erythematosus (SLE). Methods: Serum, urine, and saliva samples were obtained from 249 patients with SLE from the Ajou lupus cohort and 52 age- and sex-matched healthy controls (HCs). The concentrations of S100A8 were quantified using an ELISA, and a receiver operating characteristic curve was used to analyze whether they may be used as biomarkers for diagnosing SLE. Results: Among 249 SLE patients included in our study, the mean SLE disease activity index (SLEDAI)-2K was 7.16 ± 5.61, and the number of patients with lupus flare was 11. Patients with SLE showed a 2.7-fold increase in serum S100A8 levels compared with that in HCs (1,890.6 vs. 709 pg/ml, p < 0.001). In urine and saliva, the average S100A8 levels were significantly higher in patients with SLE compared with those in HCs (urine, 2,029.4 vs. 1,096.7 pg/ml, p = 0.001; saliva, 290,496.3 vs. 47,742 pg/ml, p < 0.001). For SLE diagnosis, the area under the receiver operating characteristic curve was 0.831 for serum S100A8 (95% CI, 0.765-0.897), 0.751 for urine S100A8 (95% CI, 0.648-0.854), and 0.729 for salivary S100A8 (95% CI, 0.646-0.812). Pearson's correlation analysis showed that S100A8 in serum, urine, and saliva was significantly associated with the SLEDAI (r = 0.267, p < 0.001; r = 0.274, p < 0.001; and r = 0.629, p < 0.001, respectively). Among the clinical manifestations, nephritis was the most influential factor related to SLE in the concentration of S100A8 in serum, urine, and saliva. Conclusion: This is the first study to show that the expression of S100A8 in serum, urine, and saliva is significantly higher in patients with SLE than in HCs and is associated with disease activity markers. Therefore, we suggest that S100A8 protein could be a potential biomarker for SLE.

Multifunctional liposomal nanostructure-mediated siRNA/bortezomib co-delivery for SHARP1 knockdown in MLL-AF6 acute myeloid leukemia.

Acute myeloid leukemia (AML) has an extremely poor prognosis and high relapse and fatality rates. New therapeutic mechanisms for molecular targeted delivery are urgently needed to improve patient survival. In this study, we targeted the oncogenic transcription factor SHARP1 using multifunctional small interfering RNA (siRNA) and bortezomib (BTZ)-loaded cRGD-guided PEGylated cationic liposomal nanostructures to monitor their antileukemic activity in MLL-AF6 AML cells. Efficient siRNA/BTZ co-delivery by the nanostructures inhibited cell viability and the clonogenic growth as well as stimulated apoptosis of AML cells. We hypothesized that SHARP1 downregulation induced the accumulation of non-functional MLL-AF6, DOT1L, MEN1, and LEDGF fusion proteins, preventing MLL-AF complex formation and downregulating RAS-GTP and Bcl-2 expression, consequently triggering autophagy and apoptosis. The BTZ combination substantially augmented therapeutic synergy and enhanced autophagic and apoptotic events. Our findings demonstrate a state-of-the-art biodegradable nanoplatform for siRNA/BTZ co-delivery with targeted SHARP1 knockdown, demonstrating a potential therapeutic option for MLL-AF6 AML.

Clinical Features and Drug Retention of TNF Inhibitors in Older Patients with Ankylosing Spondylitis: Results from the KOBIO Registry.

OBJECTIVES: This study aimed to analyse the clinical features and outcomes of and reasons for discontinuing tumour necrosis factor (TNF) inhibitor therapy in older patients with ankylosing spondylitis (AS). METHODS: Data were extracted from the nationwide Korean College of Rheumatology Biologics registry. Clinical variables and outcomes were compared, and drug retention rate was evaluated. RESULTS: Among 1524 patients with AS treated with TNF inhibitors, 306 were aged ≥ 50 years ('older patients'). Fewer patients were male, the incidence of hypertension and diabetes was higher (all p < 0.001), and the proportion of peripheral arthritis (35.6 vs. 27.1%), Ankylosing Spondylitis Disease Activity Score‒erythrocyte sedimentation rate (4.0 ± 1.1 vs. 3.6 ± 1.0), and Bath Ankylosing Spondylitis Functional Index (4.2 ± 2.6 vs. 3.3 ± 2.5) were all higher in older patients. Although the drug retention rate was lower (log-rank p = 0.018) and lack of efficacy and adverse events were more frequent in older patients (both p < 0.001), drug retention rates were not different after propensity score matching (log-rank p = 0.23). Improvements in disease activity and manifestations were comparable between groups, except for the incidence of peripheral arthritis, which decreased significantly less in older patients over 3 and 5 years. CONCLUSION: Improvements in disease-related clinical factors and drug retention rates were not different between older and younger patients with AS receiving TNF inhibitors. However, the incidence of adverse events was higher in older patients.

Atomically Precise Water-Soluble Graphene Quantum Dot for Cancer Sonodynamic Therapy.

Although water-soluble graphene quantum dots (GQDs) have shown various promising bio-applications due to their intriguing optical and chemical properties, the large heterogeneity in compositions, sizes, and shapes of these GQDs hampers the better understanding of their structure-properties correlation and further uses in terms of large-scale manufacturing practices and safety concerns. It is shown here that a water-soluble atomically-precise GQD (WAGQD-C96 ) is synthesized and exhibits a deep-red emission and excellent sonodynamic sensitization. By decorating sterically hindered water-soluble functional groups, WAGQD-C96 can be monodispersed in water without further aggregation. The deep-red emission of WAGQD-C96 facilitates the tracking of its bio-process, showing a good cell-uptake and long-time retention in tumor tissue. Compared to traditional molecular sonosensitizers, WAGQD-C96 generates superior reactive oxygen species and demonstrates excellent tumor inhibition potency as an anti-cancer sonosensitizer in in vivo studies. A good biosafety of WAGQD-C96 is validated in both in vitro and in vivo assays.