Platelet-to-lymphocyte ratios as a haematological marker of synovitis in rheumatoid arthritis with normal acute phase reactant level.

BACKGROUND: Although normal acute phase reactants (APRs) play an important role in assessing disease activity of rheumatoid arthritis (RA), some studies pointed out the discordance between disease activity and APR level. Neutrophil-to-lymphocyte ratios (NLRs), platelet-to-lymphocyte ratios (PLRs) and lymphocyte-to-monocyte ratios (LMRs) have been reported to be sensitive measures of inflammatory reaction. This study aims to explore the value of these haematological makers in assessment of APR-negative RA patients. METHODS: Out of a cohort of 418 consecutive patients with RA, we enrolled 135 patients with normal APR for this study. We performed ultrasound assessments to evaluate synovitis and bone erosion in the affected joints. Synovitis was evaluated by ultrasound grey scale (GS) and power Doppler (PD) with semi-quantitative scoring (0-3). Demographic, clinical and laboratory data were collected from the patients. Disease Activity Score-28 joints (DAS28), NLR, MLR and PLR were calculated. RESULTS: In RA patients with normal APR, PLR exhibited a positive correlation with ultrasound-detected synovitis and bone erosion, whereas NLR, MLR showed no significant correlation with ultrasonography parameters. The area under the ROC curve (AUC) for identifying synovitis with a GS grade ≥2 based on a PLR cutoff value of ≥159.6 was 0.7868 (sensitivity: 80.95%, specificity: 74.24%). For synovitis with a PD grade ≥2, the AUC was 0.7690, using a PLR cutoff value of ≥166.1 (sensitivity: 68.0%, specificity: 83.87%). CONCLUSIONS: Our findings suggested that PLR might be a reliable and cost-effective marker for identifying moderate-to-severe synovitis in RA patients with normal APR.

A Rare Case of Neurosarcoidosis Overlapped with Sjogren's Syndrome.

The coexisting of sarcoidosis and Sjögren's syndrome (SS) has long been neglected since sarcoidosis is considered as an exclusion criterion for SS. We described a 55-year-old woman, who was diagnosed with coexisting neurosarcoidosis and Sjögren's syndrome for 16 years. She presented with erythema nodosum, progressive sensory and motor impairment of the extremities, dry mouth, and dry eyes. High-resolution computed tomography (HRCT) of the chest showed symmetrical pulmonary micronodules, interstitial changes, and enlarged mediastinal lymph nodes. Spine magnetic resonance imaging (MRI) showed syringomyelia and thickening of the T3-9 spinal cord. She was with positive ANA and anti-SSA antibodies, impaired function of the lacrimal, salivary gland and renal tubules. Biopsy of skin and lung nodules revealed non-caseous granuloma. Salivary gland biopsy showed focal lymphocyte infiltration. Classification criteria for sarcoidosis and Sjogren's syndrome were fulfilled in this patient based on clinical and laboratory features. This case extends our understanding of overlapped Sjogren's syndrome with sarcoidosis and provides a referential value for clinical diagnosis.

The COVID-19 vaccine: Attitudes and vaccination in patients with autoimmune inflammatory rheumatic diseases.

Background: We examined attitudes toward the COVID-19 vaccine, potential factors underlying these attitudes, and ways to increase vaccination willingness in autoimmune inflammatory rheumatic diseases (AIIRD) patients. Methods: A multicenter, web-based, observational survey using an online questionnaire was conducted among AIIRD patients aged ≥18 years from May 24, 2021, to June 3, 2021. Participants were 3104 AIIRD patients (2921 unvaccinated and 183 vaccinated). Results: Of the unvaccinated patients, 32.9% were willing to receive the COVID-19 vaccine, 45.0% were uncertain, and 14.8% were unwilling. When vaccination was recommended by physicians, patients' willingness increased to 93.8%. Participants' main concerns were that the vaccine may aggravate AIIRD disease (63.0%) and may cause vaccine-related adverse events (19.9%). Female patients were less likely to be vaccinated. However, patients who had children aged ≤18 years were more willing to be vaccinated. In addition, vaccination willingness was higher in patients with trust in the safety and efficacy of the COVID-19 vaccine. Notably, 183 (5.9%) patients were vaccinated. The major vaccination side effects were injection reaction, myalgia, and fatigue. At a median follow-up of 88 (38, 131) days, patients' disease activities were stable. Conclusions: The findings show that AIIRD patients were unwilling to receive the COVID-19 vaccine because of fears of potential disease exacerbation and additional adverse events. Sociodemographic characteristics and concerns about COVID-19 disease and vaccines had a significant effect on vaccination willingness.

Antioxidant and Hepatoprotective Effects of Acidic-Hydrolysis Residue Polysaccharides from Shiitake Culinary-Medicinal Mushroom Lentinus edodes (Agaricomycetes) in Mice.

The present work was designed to investigate the antioxidant and hepatoprotective effects of acidic-hydrolysis Lentinus edodes residue polysaccharides (Ac-LRP) on lipopolysaccharide-induced liver injury in mice. Hepatoprotective effects were observed in liver treated with Ac-LRP at doses of 200, 400, and 600 mg/kg body weight, respectively. Activities of superoxide dismutase, glutathione peroxide, catalase, total antioxidant capacity, alanine aminotransferase, aspartate aminotransferase, and alkaline phosphatase and levels of total cholesterol, triglyceride, malondialdehyde, and lipid peroxidation in liver or serum samples were analyzed. Ac-LRP reduced the incidence of liver necrosis detected via histological observations. In addition, Ac-LRP chemical bonds and ultrastructure were measured. These results provided valuable evidence supporting the utilization of Ac-LRP as a functional food and natural medicine for the treatment of liver injury.

Characterization and anti-diabetic nephropathic ability of mycelium polysaccharides from Coprinus comatus.

It seems quite necessary for obtaining effective substances from natural products against the diabetic nephropathic (DN) with the presently clinical problems of accompanying side-effects and lowing life qualities. This work aimed to characterize the primary structure of Coprinus comatus mycelium polysaccharides (CMP) and investigate the abilities against DN in streptozotocin induced mice models. The results indicated that CMP could improve insulin resistance and energy metabolism, and significantly suppress dysfunction on kidney and relieve the renal oxidative stress and inflammation in DN mice. Besides, the western blot results suggested that CMP reversed renal injury by modulating the PTEN/PI3K/Akt and Wnt-1/ß-catenin pathways. The structure analysis indicated the typical characterizations with the major monosaccharide-compositions of galactose, α-pyranose configuration and proper molecular weights of 495.8 kDa possibly contributed to the anti-diabetic nephropathic effects of CMP. The results suggested that polysaccharides form C. comatus could be used as functional foods/drugs on preventing diabetic nephropathy.

Predictors of Poor Outcome of Anti-MDA5-Associated Rapidly Progressive Interstitial Lung Disease in a Chinese Cohort with Dermatomyositis.

OBJECTIVE: Antimelanoma differentiation-associated protein 5 (anti-MDA5) autoantibody has been reported in dermatomyositis (DM) to be associated with rapidly progressive interstitial lung disease (RP-ILD). Our study is aimed at determining the clinical characteristics and prognostic factors underpinning anti-MDA5-associated RP-ILD. METHODS: Patients with anti-MDA5-associated DM (aMDA5-DM) were identified at the Peking University People's Hospital. The presence of anti-MDA5 antibody was determined by immunoblotting. Kaplan-Meier, chi-square test, univariate, and multivariate data analyses were used. RESULTS: Out of 213 patients with DM and clinically amyopathic dermatomyositis (CADM), 20.7% (44/213) of patients were identified as aMDA5-DM. Amongst the aMDA5-DM patients, 63.6% (28/44) were identified as having anti-MDA5-associated RP-ILD. During the follow-up, 32.1% (9/28) of patients with anti-MDA5-associated RP-ILD died of respiratory failure. We identified older age and periungual erythema as two independent risk factors for RP-ILD mortality. Age ≥ 57 years at disease onset was significantly associated with poor survival (P = 0.02) in patients with anti-MDA5-associated RP-ILD, while patients with periungual erythema had a better survival rate than those without periungual erythema (P < 0.05). CONCLUSIONS: Anti-MDA5-associated RP-ILD is significantly associated with poor survival rates in DM/CADM patients. More effective intervention should be administered to anti-MDA5-associated RP-ILD patients, especially to senior patients and those without periungual erythema.

Dendrimer-Inspired Nanomaterials for the in Vivo Delivery of siRNA to Lung Vasculature.

Targeted RNA delivery to lung endothelial cells has the potential to treat conditions that involve inflammation, such as chronic asthma and obstructive pulmonary disease. To this end, chemically modified dendrimer nanomaterials were synthesized and optimized for targeted small interfering RNA (siRNA) delivery to lung vasculature. Using a combinatorial approach, the free amines on multigenerational poly(amido amine) and poly(propylenimine) dendrimers were substituted with alkyl chains of increasing length. The top performing materials from in vivo screens were found to primarily target Tie2-expressing lung endothelial cells. At high doses, the dendrimer-lipid derivatives did not cause chronic increases in proinflammatory cytokines, and animals did not suffer weight loss due to toxicity. We believe these materials have potential as agents for the pulmonary delivery of RNA therapeutics.

Small RNA combination therapy for lung cancer.

MicroRNAs (miRNAs) and siRNAs have enormous potential as cancer therapeutics, but their effective delivery to most solid tumors has been difficult. Here, we show that a new lung-targeting nanoparticle is capable of delivering miRNA mimics and siRNAs to lung adenocarcinoma cells in vitro and to tumors in a genetically engineered mouse model of lung cancer based on activation of oncogenic Kirsten rat sarcoma viral oncogene homolog (Kras) and loss of p53 function. Therapeutic delivery of miR-34a, a p53-regulated tumor suppressor miRNA, restored miR-34a levels in lung tumors, specifically down-regulated miR-34a target genes, and slowed tumor growth. The delivery of siRNAs targeting Kras reduced Kras gene expression and MAPK signaling, increased apoptosis, and inhibited tumor growth. The combination of miR-34a and siRNA targeting Kras improved therapeutic responses over those observed with either small RNA alone, leading to tumor regression. Furthermore, nanoparticle-mediated small RNA delivery plus conventional, cisplatin-based chemotherapy prolonged survival in this model compared with chemotherapy alone. These findings demonstrate that RNA combination therapy is possible in an autochthonous model of lung cancer and provide preclinical support for the use of small RNA therapies in patients who have cancer.

CRISPR-mediated direct mutation of cancer genes in the mouse liver.

The study of cancer genes in mouse models has traditionally relied on genetically-engineered strains made via transgenesis or gene targeting in embryonic stem cells. Here we describe a new method of cancer model generation using the CRISPR/Cas (clustered regularly interspaced short palindromic repeats/CRISPR-associated proteins) system in vivo in wild-type mice. We used hydrodynamic injection to deliver a CRISPR plasmid DNA expressing Cas9 and single guide RNAs (sgRNAs) to the liver that directly target the tumour suppressor genes Pten (ref. 5) and p53 (also known as TP53 and Trp53) (ref. 6), alone and in combination. CRISPR-mediated Pten mutation led to elevated Akt phosphorylation and lipid accumulation in hepatocytes, phenocopying the effects of deletion of the gene using Cre-LoxP technology. Simultaneous targeting of Pten and p53 induced liver tumours that mimicked those caused by Cre-loxP-mediated deletion of Pten and p53. DNA sequencing of liver and tumour tissue revealed insertion or deletion mutations of the tumour suppressor genes, including bi-allelic mutations of both Pten and p53 in tumours. Furthermore, co-injection of Cas9 plasmids harbouring sgRNAs targeting the ß-catenin gene and a single-stranded DNA oligonucleotide donor carrying activating point mutations led to the generation of hepatocytes with nuclear localization of ß-catenin. This study demonstrates the feasibility of direct mutation of tumour suppressor genes and oncogenes in the liver using the CRISPR/Cas system, which presents a new avenue for rapid development of liver cancer models and functional genomics.