Serum exosome tRFs as a promising biomarker for active tuberculosis and latent tuberculosis infection.

OBJECTIVE: To analyse the expression profiles of serum exosome tRFs/tiRNAs and to explore their diagnostic value in tuberculosis (TB) activity. METHODS: The serum exosome tRF/tiRNA profile was analysed using high-throughput sequencing technology in 5 active tuberculosis (ATB) patients, 5 latent tuberculosis infection (LTBI) patients and 5 healthy controls (HCs). Then, serum exosome tRFs/tiRNAs were validated by quantitative real-time polymerase chain reaction (qRT-PCR), and their diagnostic value was evaluated by receiver operating characteristic curve (ROC) and area under the curve (AUC). Finally, bioinformatics analysis was performed to explore and identify the potential biological pathways induced by tRFs/tiRNAs. RESULTS: The sequencing results revealed that serum exosome tRF/tiRNA expression profiles were different among ATB patients, LTBI patients and HCs. Three tRFs (tRF-56:75-Trp-CCA-4, tRF-1:22-chrM.Ser-GCT and tRF-56:76-Val-TAC-1-M2) were selected for qRT-PCR validation. The results demonstrated that the expression level of tRF-1-22-chrM.Ser-GCT was upregulated in ATB patients, while tRF-56-75-Trp-CCA-4 was downregulated, which was consistent with the sequencing data. The AUCs of tRF-56:75-Trp-CCA-4 and tRF-1:22-chrM. Ser-GCT were 0.824 and 1.000, respectively, which have significant values in the diagnosis of ATB patients. Moreover, the expression levels of tRF-56:75-Trp-CCA-4 and tRF-1:22-chrM.Ser-GCT and tRF-56:76-Val-TAC-1-M2 in ATB patients and LTBI were different, which indicated that these three tRFs could effectively distinguish ATB patients and LTBI patients. CONCLUSION: Our findings indicate that serum exosome tRFs can be used as potential markers for the diagnosis of ATB and LTBI.

Phase II study of novel orally PI3Kα/δ inhibitor TQ-B3525 in relapsed and/or refractory follicular lymphoma.

This registration study assessed clinical outcomes of TQ-B3525, the dual phosphatidylinositol-3-kinase (PI3K) α/δ inhibitor, in relapsed and/or refractory follicular lymphoma (R/R FL). This phase II study (ClinicalTrials.gov NCT04324879. Registered March 27, 2020) comprised run-in stage and stage 2. R/R FL patients after ≥2 lines therapies received oral 20 mg TQ-B3525 once daily in a 28-day cycle until intolerable toxicity or disease progression. Primary endpoint was independent review committee (IRC)-assessed objective response rate (ORR). Based on results (ORR, 88.0%; duration of response [DOR], 11.8 months; progression-free survival [PFS], 12.0 months) in 25 patients at run-in stage, second stage study was initiated and included 82 patients for efficacy/safety analysis. Patients received prior-line (median, 3) therapies, with 56.1% refractory to previous last therapies; 73.2% experienced POD24 at baseline. At stage 2, ORR was 86.6% (71/82; 95% CI, 77.3-93.1%), with 28 (34.2%) complete responses. Disease control rate was 95.1% due to 7 (8.5%) stable diseases. Median time to response was 1.8 months. Among 71 responders, median DOR was not reached; 18-month DOR rate was 51.6%. with median follow-up of 13.3 months, median PFS was 18.5 (95% CI, 10.2-not estimable) months. Median overall survival (OS) was not reached by cutoff date; 24-month OS rate was estimated as 86.1%. Response rates and survival data were consistent across all subgroups. Grade 3 or higher treatment-related adverse events were observed in 63 (76.8%) cases, with neutropenia (22.0%), hyperglycemia (19.5%), and diarrhea (13.4%) being common. TQ-B3525 showed favorable efficacy and safety for R/R FL patients after ≥2 lines prior therapies.

The Isothermal Melting Kinetics of Ultra-High Molecular Weight Polyethylene Crystals.

The isothermal melting behaviors of ultra-high molecular weight polyethylene (UHMWPE) with different entangled states (i.e., nascent and melt-crystallized samples) are studied. For two kinds of UHMWPE samples, the result shows that the relative content of survived crystals (Xs) exponentially decreases with time and reaches a constant value. It is suggested that such a melting behavior is related to the observed nonlinear growth of crystals induced by the kinetically rejected entanglements accumulated at the growth front. Additionally, the exponential decay of Xs with time provides a characteristic melting time (τ) for the melting process. Compared to the melt-crystallized UHMWPE, the τ value of nascent UHMWPE is generally longer even in a higher temperature range, which is mainly because the former has a larger entanglement density difference. Furthermore, these observations demonstrate that UHMWPEs with different entangled states have an analogous melting mechanism since they exhibit a similar melting activation energy (≈1300 kJ mol-1).

Effect of dietary and physical activity behavioral interventions on reducing postpartum weight retention among women with recent gestational diabetes: A systematic review and meta-analysis of randomized controlled trials.

Postpartum weight retention (PPWR) increases the risk of long-term obesity and metabolic disease in women with recent gestational diabetes mellitus (GDM). This systematic review aimed to assess the effectiveness of dietary and physical activity behavior interventions in reducing PPWR. We systematically searched 13 electronic databases to retrieve articles published in English or Chinese before October 22, 2022. Randomized controlled trials (RCTs) that assessed dietary and/or physical activity behaviors interventions on the outcomes of PPWR among women with recent GDM were included. Twelve studies researched a total of 5672 participants. The meta-analysis indicated that dietary and physical activity behaviors interventions showed significant effects on the pooled effect size of body weight changes (WMD = -2.19, 95% CIs: -3.39, -0.98 kg), body mass index (WMD = -0.98, 95% CIs: -1.56, -0.39 kg/m2 ), and waist circumference (WMD = -1.20, 95% CIs: -2.49, 0.08 cm). Furthermore, the intervention group was more likely to achieve weight reduction (OR = 0.76, 95% CIs: 0.67, 0.87) than the control group. Postpartum dietary and physical activity behavior interventions for women with a recent GDM can reduce PPWR, and 1 year postpartum may be a window of opportunity.

Efficacy and safety of generic pomalidomide plus low-dose dexamethasone in relapsed or refractory multiple myeloma: a multicenter, open-label, single-arm trial.

This multicenter, open-label, single-arm trial (ClinicalTrials.gov, NCT05236621) was conducted to confirm the efficacy and safety of generic pomalidomide plus dexamethasone in Chinese patients with relapsed or refractory multiple myeloma (RRMM). Total 79 eligible RRMM patients were planned to be included. Patients were treated with generic pomalidomide (4 mg daily on days 1-21, orally) and low-dose dexamethasone (40 mg/day on days 1, 8, 15, and 22, orally; 20 mg for patients aged > 75 years) in 28-day cycles until disease progression with a maximum treatment duration of 2 years. The primary endpoint is the overall response rate (ORR) assessed by the independent review committee per the 2016 International Myeloma Working Group guidelines. A total of 85 eligible patients were included in this study from 32 centers in China, with a median age of 62.0 (range, 39-76) years, a median prior line of therapy of 4 (range, 1-16), and 41.2% patients with high-risk cytogenetics. The ORR was 38.8% (95% confidence interval (CI), 28.44-50.01). The disease control rate was 67.1% (95% CI, 56.02-76.87), meanwhile, the median progression-free survival was 5.55 months (95% CI, 3.68-7.52). Among the treatment-related adverse events (TRAEs), infective pneumonia (17.6%) was the most frequent non-hematologic adverse event, while a decrease in neutrophil count (52.9%) was the most common grade ≥ 3 TRAE. The study results indicated that the generic pomalidomide demonstrated consistent efficacy and a safety profile similar to the branded pomalidomide when combined with low-dose dexamethasone in Chinese RRMM patients.Registration number ClinicalTrials.gov NCT05236621, retrospectively registered on February 11, 2022.

Effects of women with gestational diabetes mellitus related weight gain on pregnancy outcomes and its experiences in weight management programs: a mixed-methods systematic review.

Introduction: Proper controlling gestational diabetes mellitus (GDM)-related gestational weight gain (GWG) during pregnancy can optimize pregnancy outcomes and improve postpartum glucose homeostasis. This study aimed to explore the existing intervention programs, the effects on pregnancy outcomes, and the experiences of weight management for GDM-related GWG in women with GDM. Methods: This mixed-methods systematic review was retrieved from nine databases. The retrieval time was from the database construction to September 20, 2023, and all studies were published in English and Chinese. The included records used quantitative, qualitative, or mixed methods and reported original studies of weight-related intervention regimens, effects on pregnancy outcomes, and women's experiences and perceptions. This review used a convergent segregated approach to synthesize and integrate research findings from Joanna Briggs Institute (JBI) mixed-methods systematic reviews. Results: There were 16 articles that met the inclusion criteria, and the articles came from seven different countries and included 23,997 women with GDM. The meta-analysis pooled outcomes for the incidence of weight gain exceeding the Institute of Medicine (IOM) recommendations after GDM diagnosis to delivery was 0.31% (95% CI 0.21-0.42). The effectiveness of GDM-related weight interventions in reducing weight gain after GDM diagnosis was supported by quantitative evidence. The GDM-related GWG below the IOM recommendations is a protective factor (OR=0.68, 95%CI 0.48-0.97) for large for gestational Age (LGA), and above the IOM recommendations is a risk factor (OR=1.62, 95%CI 1.15-2.27) for LGA. In addition, no significant statistical significance was found in the pooled outcomes of small for gestational age (SGA). Avoiding excessive weight gain helps to optimize neonatal birth weight, pregnancy outcomes, and maternal blood glucose levels. According to qualitative survey results, some women with GDM experienced weight stigma, and a positive relationship between healthcare providers and GDM women helped in weight management. Conclusion: Following a diagnosis of GDM, weight management interventions positively affected GWG and pregnancy outcomes. In order to improve compliance and safety of weight management in women with GDM, criteria and interventions for weight gain associated with GDM need to be further explored and improved. Systematic Review Registration: https://www.crd.york.ac.uk/PROSPERO/display_record.php?RecordID=404492, identifier CRD42023404492.

Efficacy and safety of QL0911 in adult patients with chronic primary immune thrombocytopenia: A multicenter, randomized, double-blind, placebo-controlled, phase III trial.

Objective: QL0911, a recombinant human thrombopoietin mimetic peptide-Fc fusion protein, is a romiplostim (Nplate®) biosimilar used to treat primary immune thrombocytopenia (ITP). This phase III study aimed to assess the efficacy and safety of QL0911 in adult patients with chronic primary ITP over a 24-week treatment period. Methods: We conducted a double-blind, placebo-controlled, phase III study in patients diagnosed with primary ITP for at least 12 months who had received at least one first-line ITP treatment with no response or recurrence after treatment, or who relapsed after splenectomy at 44 sites in China. Patients were randomly allocated (2:1 ratio) to QL0911 or placebo injection subcutaneously once weekly at an initial dose of 1 µg/kg for 24 weeks. The doses were adjusted to maintain the target platelet counts from 50 × 109/L to 200 × 109/L. Patients and investigators were blinded to the assignment. The primary endpoints were the proportion of patients who achieved a durable platelet response at week 24 (platelet count, ≥ 50 × 109/L during 6 of the last 8 weeks of treatment) and safety. The study was registered at ClinicalTrials.gov (NCT05621330). Results: Between October 2019 and December 2021, 216 patients were randomly assigned (QL0911,144; placebo,72). A durable platelet response was achieved by significantly more patients in the QL0911 group (61.8%, 95% CI: 53.3-69.8; P < 0.0001) than in the placebo group (0%). The mean duration of platelet responses was 15.9 (SE: 0.43) weeks with QL0911, and 1.9 (SE:0.26) week with placebo. Consistent results were achieved in subgroup analyses categorized by baseline splenectomy status (yes/no), concomitant ITP treatment (yes/no), and baseline platelet count (≤ 10 × 109/L, > 10 × 109/L, ≤ 20 × 109/L, > 20 × 109/L, and < 30 × 109/L). The incidence of TEAEs was comparable between the QL0911 and the placebo groups (91.7% and 88.9%, respectively). The most common adverse events overall were ecchymosis (28.5% for QL0911 vs. 37.5% for placebo), upper respiratory tract infections respiratory tract infections (31.9% for QL0911 vs. 27.8% for placebo), and gingival bleeding (17.4% for QL0911 vs. 26.4% for placebo). Conclusion: QL0911 was well-tolerated and increased and maintained platelet counts in adults with ITP. QL0911, a biosimilar to romiplostim (Nplate®), may be a novel treatment option for patients with ITP who have failed or relapsed from first-line treatment in China. Ongoing studies will provide further data on long-term efficacy and safety in such patient populations.

Inhaled pulmonary surfactant biomimetic liposomes for reversing idiopathic pulmonary fibrosis through synergistic therapeutic strategy.

Idiopathic pulmonary fibrosis (IPF) stands as a highly heterogeneous and deadly lung disease, yet the available treatment options remain limited. Combining myofibroblast inhibition with ROS modulation in damaged AECs offers a comprehensive strategy to halt IPF progression, but delivering drugs separately to these cell types is challenging. Inspired by the successful application of pulmonary surfactant (PS) replacement therapy in lung disease treatment, we have developed PS nano-biomimetic liposomes (PSBs) to utilize its natural transport pathway for targeting AECs while reducing lung tissue clearance. In this collaborative pulmonary drug delivery system, PSBs composed of DPPC/POPG/DPPG/CHO (20:9:5:4) were formulated for inhalation. These PSBs loaded with ROS-scavenger astaxanthin (AST) and anti-fibrosis drug pirfenidone (PFD) were aerosolized for precise quantification and mimicking patient inhalation. Through aerosol inhalation, the lipid membrane of PSBs gradually fused with natural PS, enabling AST delivery to AECs by hitchhiking with PS circulation. Simultaneously, PFD was released within the PS barrier, effectively penetrating lung tissue to exert therapeutic effects. In vivo results have shown that PSBs offer numerous therapeutic advantages in mice with IPF, particularly in terms of lung function recovery. This approach addresses the challenges of drug delivery to specific lung cells and offers potential benefits for IPF patients.

Dose-Response Relationship between Gestational Weight Gain and Neonatal Birthweight in Chinese Women with Excess Weight/Obesity and Gestational Diabetes Mellitus.

Total gestational weight gain (GWG) is identified as a strong and potentially controllable predictor of long-term health outcomes in women with gestational diabetes mellitus (GDM) and infants. When the total GWG of women with excess weight/obesity and GDM does not exceed the Institute of Medicine (IOM) suggested range, neonatal birthweight outcomes may be favorable, but the evidence is limited. Therefore, the objective of this study was to evaluate the dose-response relationship between increased total GWG and the risk of neonatal birthweight in Chinese women with excess weight/obesity and GDM. This study obtained electronic medical records (EMR) from the hospital information system (HIS) of the Chongqing Health Center for Women and Children between July 2017, and June 2020. A retrospective study analyzed the effect of the total GWG of women with excess weight/obesity and GDM on neonatal birthweight. The dose-response relationship between total GWG and neonatal birthweight was studied using a generalized linear model and embedded restricted cubic splines (RCS). The average age of all women with GDM was 31.99 ± 4.47 years, and 27.61% were advanced maternal age (≥35 years). The total GWG among women with excess weight and obesity and GDM greater than the IOM recommendations were found in 42.96% and 58.62% of cases, respectively. Total GWG in women with excess weight and excessing the IOM recommended range is a risk factor for large gestational age (LGA) [adjusted odds ratio (aOR) 0.1.47, 1.08-2.01] and macrosomia (aOR 1.55, 1.04-2.31). In the obesity above group, excessive weight gain increased the risk of LGA (aOR 2.92, 1.33-6.41) and macrosomia (aOR 2.83, 1.03-7.72). We used an RCS to examine pregnant women with excess weight and GDM and discovered a linear dose-response relationship between total GWG and LGA/macrosomia. In women with excess weight and obesity, increases in total GWG above the lowest end of the IOM recommendations range (7 kg and 5 kg) were associated with an increased risk of LGA and macrosomia. Therefore, research is urgently needed to support maternal and newborn health to provide recommendations for the ideal weight increase in women with excess weight/obesity and GDM.

Net-Neutral Nanoparticles-Extruded Microcapsules for Oral Delivery of Insulin.

Oral delivery of insulin could widely improve the quality of life of diabetic patients but still requires further exploration. Commonly utilized oral delivery vehicles hardly penetrate the intestinal mucus barrier, thus greatly hurdling their therapeutic efficacy. State-of-the-art technology shows that coating particles with neutral surface charge could reduce adsorption of mucins and improved the transport of particles within mucus. However, the synthesis of net-neutral particles (NNs) usually need complex purification and processing procedure. Herein, the NNs were conveniently constructed by simply adjusting the ratio of positive (chitosan) and negative (γ-glutamic acid) materials. To further achieve the optimal bioavailability of NNs, NNs formed materials were package in to wild chrysanthemum pollens, obtaining pH-triggered nanoparticles-extruding microcapsules (PNMs@insulin). At the small intestine pH value (∼6.0), the amino groups of CS deprotonate gradually and trigger the swelling, followed by the rapid extrusion of NNs through nano-orifices on the pollens' surface. After oral administration of the microcapsules, plasma insulin levels were enhanced significantly with a high oral bioavailability of >40%, leading to a remarkable and longer-sustained blood glucose-reducing effect. Moreover, we discovered that the empty pollen shells could act as a potential saccharide-adsorbing agent, which helps to manage sugar intake. This oral strategy of insulin will provide a vast potential for daily and facile diabetes treatment.

Bradykinin B1 receptor antagonist protects against cold stress-induced erectile dysfunction in rats.

Background: Erectile dysfunction (ED) demonstrates seasonal variation with higher rates in winter, and we hypothesize that endothelial damage in erectile tissue caused by bradykinin receptor B1 (B1R) might be detrimental to this change. Aim: To find out direct correlations between cold stress and ED, through which to further investigate the functional roles of B1R in erectile tissue and to elucidate the therapeutic roles of the B1R antagonist in a cold stress-induced ED rat model. Methods: Cold stress rat models are established through long-term intermittent exposure to low temperature. After their erectile function was assessed, ED rats were treated with the B1R antagonist through intraperitoneal injection. Penile tissues were obtained at the end of the experiment after measurement of intracavernosal pressure/mean arterial pressure (ICP/MAP); the location and distribution of cytokine expression were determined by immunohistochemistry; cytokine levels and NOS and CD31 expression were detected by Western blotting; and collagen fibers and smooth muscles were observed through Masson staining. Outcomes: Cold stress impairs erectile function, and the B1R antagonist protects against it. Results: We observed decreased erection frequency, prolonged erection latency time, decreased ICP/MAP, overexpression of B1R, increased expression of cytokines on cavernous sinus endothelium, and increased levels of collagen fibers/smooth muscles on erectile tissue in response to cold stress. Also, NOS and CD31 expression was downregulated. B1R antagonist treatment shows enhanced erectile function through increased erection frequency, shortened erection latency time, and increased ICP/MAP. Also, it reduces collagen fibers/smooth muscles, TNF-α, TGF-ß1, and IL-6 and upregulates the expression of nNOS and CD31. Clinical Translation: Our findings cast new light on the correlations between cold stress and erectile function and potential new applications of existing B1R antagonist drugs in the field of ED. Strengths and Limitations: Our data support that cold stress impairs erectile function. B1R-mediated, cytokine-induced corpus cavernosum fibrosis and endothelial damage might be the main reason behind it, and B1R inhibition protects against fibrosis and endothelial damage. Other ways of B1R antagonist blocking methods in different types of ED still need to be investigated. Conclusion: Long-term intermittent cold stress impairs erectile function, and B1R-mediated, cytokine-induced corpus cavernosum fibrosis and endothelial damage might be the main reason behind it. B1R inhibition also protects against fibrosis and endothelial damage. Our data support the hypothesis that cold stress impairs erectile function and that B1R blockade ameliorates the symptoms of ED, possibly by reversing fibrosis and endothelial damage in erectile tissue.

Puerperium experience and lifestyle in women with gestational diabetes mellitus and overweight/obesity in China: A qualitative study.

Introduction: Women with overweight or obesity and gestational diabetes mellitus (GDM) are at a high risk of developing type 2 diabetes mellitus (T2DM) and other metabolic diseases. Healthy postpartum lifestyles in women with GDM are important for effectively preventing early T2DM occurrence; however, few studies and guidelines focus in China on this issue. Aims: This qualitative study aimed to understand the puerperium experience and lifestyle of women with overweight/obesity and GDM. Methods: A face-to-face, in-depth, and semi-structured interview was conducted using a hermeneutical phenomenology method to collect data that were analyzed through thematic analysis. Results: Out of 61 recruited women with overweight/obesity and history of GDM, 14 women underwent an interview and provided detailed descriptions of their lifestyle experiences during puerperium. The interview data were used to generate four themes-puerperium dietary behavior, weight perception and "confinement" behavior, family support, disease knowledge, and perceived risk-and nine sub-themes. Conclusion: Unhealthy lifestyles, misconceptions about food, the conflict between physical activity and confinement behavior, a lack of social and family support, and low awareness of disease risk are all common among overweight/obese women with a history of GDM. Thus, we emphasized that healthcare providers should provide continuous preventive care from pregnancy to postpartum and promote long-term health in high-risk populations with a history of GDM associated with overweight/obesity.

Contrast-Enhanced Ultrasound and Magnetic Resonance Enhancement Based on Machine Learning in Cancer Diagnosis in the Context of the Internet of Things Medical System.

As an accurate, safe, and effective noninvasive examination method, imaging examination has been widely used in the diagnosis and differential diagnosis of focal liver lesions. Enhanced ultrasonography (CEUS), enhanced CT (CECT), and enhanced magnetic resonance imaging (CEMRI) are the most commonly used enhanced imaging methods in clinical practice, all of which can accurately determine the nature of liver lesions. The purpose of this paper is to study the application of contrast-enhanced ultrasound and magnetic resonance enhancement in cancer diagnosis based on the Internet of Things medical system. The basic clinical data, CEUS, and enhanced CT/MRI findings of 120 CHC patients were retrospectively analyzed. The clinicopathological features of CHC patients were investigated by contrast-enhanced ultrasonography and CT/MRI enhanced mode. The diagnostic value of contrast-enhanced ultrasound and enhanced CT/MRI combined with tumor markers in CHC was analyzed. The experimental results showed that the sensitivities of CEUS, enhanced MRI, and their combination in diagnosing CHC were 72.44%, 81.56%, and 93.78%, respectively. This experiment has an important value in the diagnosis of primary liver cancer.

Analysis of the therapeutic effect of Dimu Ningshen (TCM formula) on attention deficit hyperactivity disorder based on gut microbiota and serum metabolomics.

BACKGROUND: Attention deficit hyperactivity disorder (ADHD) is a neurodevelopmental disorder diagnosed during adolescence and adulthood. Assessment of the long-term risks of the current drugs for ADHD treatment has been insufficient, and little is known concerning the long-term therapeutic effects of psychostimulants. Commercially available traditional Chinese medicine compound oral preparations [e.g., Dimu Ningshen (DMNS)] have been widely used in the clinical treatment of ADHD, but their influence on the interaction between gut microbes and potential metabolomes remains inconclusive. METHODS: We used a series of behavioral experiments to evaluate the behavioral effects of DMNS on adolescent and adult ADHD rats and used 16S rDNA sequencing of gut microbes and nontarget metabolomics to evaluate the potential pathogenesis of ADHD and explore the biological mechanism of DMNS in ADHD treatment. RESULTS: For the first time, DMNS was shown to reduce the excessive activity of adult and adolescent ADHD rats and improve the attention deficit of adult ADHD rats. DMNS improved the structural composition of the ADHD gut microbiota and reduced the abundance of Ruminococcaceae_NK4A214_group, Ruminococcus_2, and Eubacterium_nodatum_group. Simultaneously, DMNS increased the circulating levels of peripheral monoamine neurotransmitter precursors (e.g., phenylalanine) and reduced the circulating levels of peripheral fatty acid amides (e.g., oleamide). Finally, the changes in the ADHD serum metabolites were strongly correlated with the gut microbiota. CONCLUSION: DMNS has a good effect in treating ADHD, and it may exert this effect by regulating the gut microbiota and affecting metabolites in the peripheral circulation.

Epigenetically-regulated RPN2 gene influences lymphocyte activation and is involved in pathogenesis of rheumatoid arthritis.

BACKGROUND: To identify RA-associated genes and to ascertain epigenetic factors and functional mechanisms underlying RA pathogenesis. METHODS: Peripheral blood mononuclear cells (PBMC) transcriptome- and proteome- wide gene expressions were profiled in a case-control study sample. Differentially expressed genes (DEGs) were discovered and validated independently. In-house PBMC genome-wide SNP genotyping data, miRNA expression data and DNA methylation data in the same sample were utilized to identify SNPs [expression quantitative trait locus (eQTLs) and protein quantitative trait locus (pQTLs)], miRNAs, and DNA methylation positions (DMPs) regulating key DEG of interest. Lentivirus transfection was conducted to study the effects of RPN2 on T lymphocyte activation, proliferation, apoptosis, and inflammatory cytokine expression. Rpn2 protein level in plasma was quantitated by ELISA to assess its performance in discriminating RA cases and controls. RESULTS: Twenty-two DEGs were discovered in PBMCs. The most significant DEG, i.e., RPN2, was validated to be up-regulated with RA in PBMCs. A complex regulatory network for RPN2 gene expression in PBMCs was constructed, which consists of 38 eQTL and 53 pQTL SNPs, 3 miRNAs and 2 DMPs. Besides, RPN2 expression was significantly up-regulated with RA in primary T lymphocytes, as well as in PHA-activated T lymphocytes. RPN2 over-expression in T lymphocytes significantly inhibited apoptosis and IL-4 expression and promoted proliferation and activation. PBMCs-expressed RPN2 mRNA and plasma Rpn2 protein demonstrated superior and modest performances in discriminating RA cases and controls, respectively. CONCLUSIONS: RPN2 gene influences T lymphocyte growth and activation and is involved in the pathogenesis of RA. Rpn2 may serve as a novel protein biomarker for RA diagnosis.

ITGA2 protein is associated with rheumatoid arthritis in Chinese and affects cellular function of T cells.

BACKGROUND: We identified proteins significant for rheumatoid arthritis (RA) in peripheral blood mononuclear cells (PBMCs), and to clarify mechanisms mediated by underlying proteins that may involve in the pathogenesis of RA. METHODS: Proteome-wide protein expressions were profiled by employing label-free quantitative proteomics methodology (Easy-nLC1000 and Q-exactive). The t-test was applied to identify differentially expressed proteins (DEP, p ≤ 0.05) between RA case and control samples. Gene Ontology enrichment analyses and Protein-Protein Interaction analyses were performed to annotate functions of DEPs. The selected DEP was validated in independent samples using Simple Western assay. Plasma protein level of α2 component of integrin (ITGA2) was measured by using ELISA. The DEP, ITGA2, was assessed for its effects on T cell proliferation, cell cycle, apoptosis, and inflammatory cytokine expression. RESULTS: Sixty-four DEPs (p < 0.05) were identified in PBMCs. The selected ITGA2 (Fold Change, FC = 2.20, p = 1.49E-02) was validated to be up-regulated (FC = 12.33, p = 4.90E-2) with RA, and plasma ITGA2 protein level significantly elevated in RA patients vs. controls. Over-expression of ITGA2 could promote proliferation and inhibit apoptosis of Jurkat T cell, and induce IL-8, IFN-γ and TNF-α expression in Jurkat T cells. CONCLUSIONS: ITGA2 protein was significantly over-expressed in PBMCs in RA patients, and affects T cell growth and pro-inflammatory cytokine expression in T cells.

Sleep Deprivation Disturbs Immune Surveillance and Promotes the Progression of Hepatocellular Carcinoma.

Sleep disturbance is common in patients with cancer and is associated with poor prognosis. However, the effects of sleep deprivation (SD) on immune surveillance during the development of hepatocellular carcinoma (HC) and the underlying mechanisms are not known. This was investigated in the present study using mouse models of SD and tumorigenesis. We determined that acute and chronic sleep deprivation (CSD) altered the relative proportions of various immune cell types in blood and peripheral organs. CSD increased tumor volume and weight, an effect that was enhanced with increasing CSD time. Expression of the cell proliferation marker Ki-67 was elevated in tumor tissues, and tumor cell infiltration into adjacent muscles was enhanced by CSD. Multicolor flow cytometry analysis revealed that CSD significantly reduced the numbers of antitumor CD3+ T cells and natural killer (NK) cells and increased that of immunosuppressive CD11b+ cells infiltrating into the tumor microenvironment from the spleen via the peripheral blood. These results indicate that CSD impairs immune surveillance mechanisms and promotes immunosuppression in the tumor microenvironment to accelerate tumor growth, underscoring the importance of alleviating sleep disturbance in HC patients in order to prevent HC progression.

Natron glass beads reveal proto-Silk Road between the Mediterranean and China in the 1st millennium BCE.

Natron-based glass was a vital part of material culture in the Mediterranean and Europe for nearly two millennia, but natron glass found elsewhere on the Eurasian Continent has not received adequate discussion, despite its influence on ancient Asian glass. Here we present a new interpretation of natron glass finds from both the West and the East. After establishing the compositional types and technological sequence of Mediterranean natron glass (eighth-second century BCE) using trace elements, we report the analysis of a mid-1st millennium BCE glass bead from Xinjiang, China, which was likely made with Levantine raw glass, and identify common types of stratified eye beads in Eurasia based on a compositional and typological comparison. Combining these findings, we propose that a considerable number of Mediterranean natron glass products had arrived in East Asia at least by the fifth century BCE, which may have been a contributing factor in the development of native Chinese glass-making. The swift diffusion of natron glass across Eurasia in the 1st millennium BCE was likely facilitated by a three-stage process involving maritime and overland networks and multiple forms of trade and exchange, indicating a highly adaptable and increasingly efficient transcontinental connection along the 'Proto-Silk Road'.