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Neuropathic pain (NP) is a chronic pain condition caused by lesion or disease of the somatosensory nervous system. Repetitive transcranial magnetic stimulation (rTMS) is a neuroregulatory tool that uses pulsed magnetic fields to modulate the cerebral cortex. This review aimed to ascertain the therapeutic effect of rTMS on NP and potential factors regulating the therapeutic effect of rTMS. Database search included Web of Science, Embase, Pubmed, and Cochrane Library from inception to July 2021. Eligible studies included randomized controlled studies of the analgesic effects of rTMS in patients with NP. Thirty-eight studies were included. Random effect analysis showed effect sizes of -0.66 (95 % CI, -0.87 to -0.46), indicating that real rTMS was better than sham condition in reducing pain (P < 0.001). This comprehensive review indicated that stimulation frequency, intervention site, and location of lesion were important factors affecting the therapeutic effect. The findings of this study may guide clinical decisions and future research.

Unfractionated heparin (UFH) is an anionic glycosaminoglycan that is widely used to prevent blood clotting. However, in certain cases, unwanted side effects can require it to be neutralized. Protamine sulfate (PS), a basic peptide rich in arginine, is the only approved antagonist for UFH neutralization. Many adverse reactions occur with the clinical application of PS, including systemic hypotension, pulmonary hypertension, and anaphylaxis. We previously described R15, a linear peptide composed of 15 arginine molecules, as a potential UFH antagonist. In this study, the in‐depth safety of R15 was explored to reveal its merits and associated risks in comparison with PS. In vitro safety studies investigated the interactions of R15 with erythrocytes, fibrin, complement, and rat plasma. In vivo safety studies explored potential toxicity and immunogenicity of R15 and the UFH–R15 complex. Results showed that both PS and R15 can induce erythrocyte aggregation, thicken fibrin fibers, activate complement, and cause anticoagulation in a concentration‐dependent manner. However, those influences weakened in whole blood or in live animals and were avoided when R15 was in a complex with UFH. We found dramatically enhanced complement activation when there was excess UFH in analyses involving UFH–PS complexes, and a slight increase in those involving UFH–R15 complexes. Within 2 h, R15 was degraded in rat plasma in vitro, whereas PS was not. Enhanced creatinine was found after a single intravenous injection of PS or R15 (900 U·kg−1, body weight), suggesting possible abnormal renal function. The UFH–PS complex, but not the UFH–R15 complex, exhibited obvious immunogenicity. In conclusion, R15 is nonimmunogenic and potentially safe at a therapeutic dose to reverse the effects of UFH., Safety studies of R15, a new heparin antagonist, were investigated in comparison with PS (protamine sulfate). R15 was degradable in plasma of rats within 2 h, whereas PS was not. Dramatically enhanced complement activation was observed for UFH–PS complex with excess UFH (unfractionated heparin). UFH–PS complex possessed immunogenicity that was completely absent for the UFH–R15 complex.

This study aimed to investigate the correlation of Jun N-terminal kinase pathway associated phosphatase (JKAP) with inflammation, disease activity, and clinical efficacy to triple conventional disease-modifying anti-rheumatic drugs (cDMARDs) in rheumatoid arthritis (RA) patients. A total of 119 active RA patients about to receive triple cDMARDs treatment were enrolled. Serum JKAP was detected by enzyme-linked immunosorbent assay at week0, week6, week12, and week24 (W24). According to clinical response status or remission status at W24, RA patients were classified as response patients and non-response patients, or remission patients and non-remission patients, respectively. JKAP was negatively correlated with erythrocyte sedimentation rate (ESR), C-reactive protein, and 28-joints disease activity score based on ESR (DAS28 score (ESR)), while JKAP was not correlated with disease duration, tender joint count, swollen joint count, health assessment questionnaire for rheumatoid arthritis or treatment history. Furthermore, during 24-week triple cDMARDs treatment, JKAP was increased overtime. Subgroup analyses showed that JKAP displayed a rising trend in response patients, remission patients, non-remission patients but not non-response patients, meanwhile its increment was more obvious in remission patients versus non-remission patients. Additionally, JKAP at W24 was higher in response patients compared with non-response patients, and JKAP at W12 and W24 was higher in remission patients compared with non-remission patients. Longitudinal monitor of JKAP might reflect clinical efficacy to the treatment of triple cDMARDs, which could improve outcomes in RA patients.

ObjectivesThe study of sex differences in hyperuricemia can provide not only a theoretical basis for this clinical phenomenon but also new therapeutic targets for urate-lowering therapy. In the current study, we aimed to confirm that estradiol can promote intestinal ATP binding cassette subfamily G member 2 (ABCG2) expression to increase urate excretion through the PI3K/Akt pathway.MethodsThe estradiol levels of hyperuricemia/gout patients and healthy controls were compared, and a hyperuricemia mouse model was used to observe the urate-lowering effect of estradiol and the changes in ABCG2 expression in the kidney and intestine. In vivo and in vitro intestinal urate transport models were established to verify the urate transport function regulated by estradiol. The molecular pathway by which estradiol regulates ABCG2 expression in intestinal cells was explored.ResultsThe estradiol level of hyperuricemia/gout patients was significantly lower than that of healthy controls. Administering estradiol benzoate (EB) to both male hyperuricemic mice and female mice after removing the ovaries confirmed the urate-lowering effect of estradiol, and hyperuricemia and estradiol upregulated the expression of intestinal ABCG2. Estradiol has been confirmed to promote urate transport by upregulating ABCG2 expression in intestinal urate excretion models in vivo and in vitro. Estradiol regulates the expression of intestinal ABCG2 through the PI3K/Akt pathway.ConclusionOur study revealed that estradiol regulates intestinal ABCG2 through the PI3K/Akt pathway to promote urate excretion, thereby reducing serum urate levels.

Dasatinib is a multi-target protein tyrosine kinase inhibitor. Due to its potent inhibition of Src, Abl, the platelet-derived growth factor receptor (PDGFR) family kinases, and other oncogenic kinases, it has been investigated as a targeted therapy for a broad spectrum of cancer types. However, its efficacy has not been significantly extended beyond leukemia. The mechanism of resistance to dasatinib in a wide array of cancers is not clear. In the present study, we investigated the effect of dasatinib on hepatocellular carcinoma cell growth and explored the underlying mechanisms. Our results showed that dasatinib potently inhibited the proliferation of SNU-449 cells, but not that of other cell lines, such as SK-Hep-1, even though it inhibited the phosphorylation of Src on both negative and positive regulation sites in all these cells. Dasatinib activated the phosphoinositide-dependent protein kinase1 (PDK1)/protein kinase B (Akt)/mammalian target of rapamycin (mTOR) signaling pathway in SK-Hep-1 cells, but not in SNU-449 cells. Blocking the Akt/mTOR signaling pathway strongly promoted the efficacy of dasatinib in SK-Hep-1 cells. In SNU-449 cells, dasatinib promoted apoptosis and the cleavage of caspase-3 and caspase-7, induced cell cycle arrest in the G1 phase, and inhibited the expression of Cyclin-dependent kinase (CDK4)/6/CyclinD1 complex. These findings demonstrate that dasatinib exerts its anti-proliferative effect on hepatocellular cell proliferation by blocking the Src family kinases; however, it causes Akt activation, which compromises dasatinib as an anti-cancer drug.

The pandemic of COVID-19 has caused global social impact and high health risk. Clinical observations have suggested that elevated levels of inflammatory mediators are associated with disease severities in COVID-19 patients, in which the immunological profiles indicate the hyperactivation of innate immune cells and dysregulated adaptive immune responses. The increasing prevalence and disease progression of COVID-19 has emerged as a pressing challenge for the management of rheumatic patients with immune dysregulations. Here we review the immune dysregulations in COVID-19 and discuss the management of COVID-19 patients with rheumatic diseases.

OBJECTIVE To investigate the role of the inflammatory lipid mediator leukotriene B4 (LTB4 ) and its receptor, BLT1, in the development and progression of systemic sclerosis (SSc). METHODS Serum levels of LTB4 were compared in 64 patients with SSc and 80 healthy controls. Skin and lung tissue sections from patients with SSc and healthy donors were immunostained for leukotriene A4 hydrolase (LTA4 H), the critical enzyme for LTB4 synthesis, and BLT1, in combination with different cell markers. In mouse models of SSc using bleomycin or angiotensin II challenge or immunization with the DNA topoisomerase I, genetic or pharmacologic interruption of the LTB4 -BLT1 axis in mice was carried out to assess its effects on systemic disease features and myofibroblast markers. Immunoblotting was performed to examine the signaling pathway in fibroblasts and endothelial cells following stimulation with LTB4 or with serum from SSc patients. RESULTS Serum LTB4 levels were 44.93% higher in patients with SSc than in matched healthy controls (mean ± SD 220.3 ± 74.75 pg/ml versus 152.0 ± 68.05 pg/ml; P < 0.0001), and this was associated with the patient subsets of SSc-associated interstitial lung disease and diffuse cutaneous SSc. Levels of LTA4 H and BLT1 were increased in lesional areas of the skin and lungs of SSc patients, and both were abundant in myofibroblasts and endothelial cells. Interruption of the LTB4 -BLT1 axis in mouse models of SSc significantly mitigated dermal and pulmonary fibrosis, with 54.00% and 52.65% fewer α-smooth muscle actin-positive myofibroblasts accumulating in the skin and lungs of mice, respectively, after bleomycin challenge. Immunoblotting of cultures with recombinant LTB4 -stimulated fibroblasts and endothelial cells or with serum from SSc patients showed that fibroblast-myofibroblast and endothelial-mesenchymal transitions were promoted via BLT1, and that this was dependent on activation of the phosphatidylinositol 3-kinase (PI3K)/Akt/mechanistic target of rapamycin (mTOR) pathway but independent of the release of transforming growth factor β (TGFβ) by fibroblasts or endothelial cells. CONCLUSION The LTB4 -BLT1 axis may contribute to fibrosis in SSc by directly promoting myofibroblast differentiation via the PI3K/Akt/mTOR pathway, and this appears to operate independently of autocrine secretion of TGFβ.

The slow accumulation of inflammatory biomarker levels in the body—also known as inflammaging—has been linked to a myriad of age-related diseases. Some of these include neurodegenerative conditions such as Parkinson’s disease, obesity, type II diabetes, cardiovascular disease, and many others. Though a direct correlation has not been established, research connecting age-related hearing loss (ARHL)—the number one communication disorder and one of the most prevalent neurodegenerative diseases of our aged population—and inflammaging has gained interest. Research, thus far, has found that inflammatory markers, such as IL-6 and white blood cells, are associated with ARHL in humans and animals. Moreover, studies investigating ion channels and mitochondrial involvement have shown promising relationships between their functions and inflammaging in the cochlea. In this review, we summarize key findings in inflammaging within the auditory system, the involvement of ion channels and mitochondrial functions, and lastly discuss potential treatment options focusing on controlling inflammation as we age.

Metastasis is the leading cause of death in non-small cell lung cancer (NSCLC) patients. Previously, we reported that miR-744 exerted proto-oncogenic function in nasopharyngeal carcinoma, but the role of miR-744 during NSCLC development has not been established. We focused on the function and molecular mechanism of miR-744 in NSCLC. The clinical cohort data from TCGA were analyzed for the correlation of miR-744 and outcomes in NSCLC patients. Gain- and loss-of-function experiment was performed by transfection with miR-744 agomir or antagomir in NSCLC cell lines. The expression of mRNA and protein were analyzed by qPCR assays and Western blotting respectively. Cellular proliferation, migration, and invasion were analyzed by CCK8 assays, wound healing, and transwell assays, respectively. Promoter activities and gene transcription were analyzed by luciferase reporter assays. Xenograft model was applied for in vivo study. High miR-744 expression correlated with lymph node metastasis and poor prognosis in NSCLC patient. MiR-744 aggravated the growth, invasion, and metastasis of NSCLC cells eventually induced the malignant phenotype and promotes radio/chemoresistance in vitro. The -1195 to -1227 and -298 to -323 bp upstream of c-FOS gene was observed to bind with miR-744. Lastly, miR-744 acted as a tumor promoter in lung cancer growth and metastasis in vivo. Taken together, our results indicated that miR-744 up-regulated c-Fos by binding with its promoter contributed to development of NSCLC cells malignant phenotype. Our findings highlight the potential value of miR-744, which may serve as a possible therapeutic target for NSCLC.

PurposeRadiation therapy (RT) induces an immune response, but the relationship of this response with tumor type is not fully understood. This meta-analysis further elucidated this relationship by analyzing the changes in T lymphocyte subsets in different tumors before and after radiotherapy.MethodsWe searched English-language electronic databases including PubMed, EMBASE, and the Cochrane Library to collect studies on the changes in peripheral blood CD3+ T lymphocytes, CD4+ T lymphocytes, and CD8+ T lymphocytes before and after radiotherapy in tumor patients from January 2015 to April 2021. The quality of the included literature was evaluated using the NOS scale provided by the Cochrane Collaboration, and statistical software RevMan 5.4 was used to analyze the included literature. PResultsA total of 19 studies in 16 articles involving 877 tumor patients were included. All data were collected within 1 month before or after radiotherapy. Meta-analysis showed that numbers of CD3+ T lymphocytes (SMD: -0.40; 95% CI [-0.75, -0.04]; p = 0.03) and CD4+ T lymphocytes (SMD: -0.43; 95% CI: [-0.85, -0.02]; p = 0.04) were significantly reduced after radiotherapy compared with before treatment, but there was no statistically significant difference for CD8+ T lymphocytes (SMD: 0.33; 95% CI: [-0.88, 0.74]; p = 0.12). Subgroup analysis showed that peripheral blood T lymphocytes decreased in head and neck cancer. However, in prostate cancer and breast cancer, there was no significant change in peripheral blood. 1 month after radiotherapy, it has a potential proliferation and activation effect on lymphocytes in esophageal cancer and lung cancer. The results showed that CD8+T lymphocytes increased in peripheral blood after SBRT. Radiotherapy alone reduced CD3+ T lymphocyte numbers.ConclusionsWithin 1 month of radiotherapy, patients have obvious immunological changes, which can cause apoptosis and reduction of T lymphocytes, and affect the balance of peripheral blood immune cells. The degree of immune response induced by radiotherapy differed between tumor types.

To produce specific antibodies for the detection and quantification of copper ions, bifunctional chelators (BFCs) are commonly applied in the preparation of copper conjugates. However, some copper-chelator complexes exhibit limited stability under in vivo conditions. In this study, Cu2+ was coupled with carrier proteins via three different macrocyclic BFCs: p-SCN-Bn-DOTA, p-SCN-Bn-NOTA, and p-SCN-Bn-TETA. The stability in plasma and the immunogenicity of three copper immunoconjugates were compared. The chelators other than p-SCN-Bn-DOTA were very stable in plasma, with

Inner ear disorders such as sensorineural deafness and genetic diseases may one day be treated with local drug delivery to the inner ear. Current pharmacokinetic models have been based on invasive methods to measure drug concentrations, limiting them in spatial resolution, and restricting the research to larger rodents. We developed an intracochlear pharmacokinetic model based on an imaging, learning-prediction (LP) paradigm for learning transport parameters in the murine cochlea. This was achieved using noninvasive micro-computed tomography imaging of the cochlea during in vivo infusion of a contrast agent at the basal end of scala tympani through a cochleostomy. Each scan was registered in 3-D to a cochlear atlas to segment the cochlear regions with high accuracy, enabling concentrations to be extracted along the length of each scala. These spatio-temporal concentration profiles were used to learn a concentration dependent diffusion coefficient, and transport parameters between the major scalae and to clearance. The LP model results are comparable to the current state of the art model, and can simulate concentrations for cases involving different infusion molecules and different drug delivery protocols. Forward simulation results with pulsatile delivery suggest the pharmacokinetic model can be used to optimize drug delivery protocols to reduce total drug delivered and the potential for toxic side effects. While developed in the challenging murine cochlea, the processes are scalable to larger animals and different drug infusion paradigms.

Objectives Acute gout is an inflammatory response to MSU crystals. In our previous research, Sirt1 was shown to have an effect in preventing acute gouty inflammation. In the current study, we aimed to investigate the underlying mechanism involving Sirt1 in acute gout. Methods The cytological changes and Sirt1 expression in the synovium were observed in patients with acute or intermittent gout. The effect of Sirt1 and its mechanism in gout were studied in macrophages, C57BL/6 mice and Sirt1+/− mice. Results Sirt1 expression was increased in the peripheral blood mononuclear cells (PBMCs) of patients with acute gout but not in the chronic tophus tissue. The arthritis score and numbers of inflammatory cells in injured paw tissue from murine gout models were upregulated in Sirt1+/− mice compared with wild-type mice. A PCR array of the paw tissue from murine gout models indicated that Sirt1 activation might attenuate MSU-induced inflammation by altering the polarization state of macrophages. Furthermore, in patients with acute gout, the phagocytosis of MSU crystals by a macrophage was found in a smear of the joint fluid and large amounts of macrophages were also found in the synovium. The activation of Sirt1 in gouty mice actually decreased the tendency toward M1 polarization. The inhibition of PI3K/Akt partially blocked the anti-inflammatory effect of Sirt1 and the translocation of STAT6, and phosphorylated STAT6 expression was decreased in RAW 264.7 cells treated with MSU crystals. Conclusion Our studies revealed that Sirt1 ameliorates MSU-induced inflammation by altering macrophage polarization via the PI3K/Akt/STAT6 pathway.

Recent evidence suggests that modulation of the large-conductance, calcium-activated potassium (BK) channel regulates auditory processing in the brain. Because ion channel expression often changes during aging, this could be a factor in age-related hearing loss. The current study explored how the novel BK channel modulator LS3 shapes central auditory processing in young and old adult mice. In vivo extracellular recordings in the auditory midbrain demonstrated that LS3 differentially modulates neural processing along the tonotopic axis. Though sound-evoked activity was reduced in the mid and ventral tonotopic regions, LS3 enhanced excitatory drive and sound-evoked responses for some neurons in the dorsal, low-frequency region. Behavioral assessment using acoustic reflex modification audiometry indicated improved tone salience following systemic LS3 administration. Moderation of these responses with aging correlated with an age-related decline in BK channel expression. These findings suggest that targeting the BK channel enhances responsivity to tonal sounds, providing the potential to improve hearing acuity and treat hearing loss.

BackgroundEvaluation of monosodium urate (MSU) crystal deposition and related lesion in joints using ultrasound in gout and hyperuricemia patients. MethodsTotal 202 gout patients and 43 asymptomatic hyperuricemia patients were included, the clinical data and ultrasunic assessment results were collected and statistically analyzed. ResultsDeposition of MSU crystals were found in 25.58% (11/43) of the patients with asymptomatic hyperuricemia and 76.24% (154/202) of the patients with gout. In the all examined 1082 joints from gout patients, 33.09% (358/1082) of them were detected MSU crystals. In MSU crystal positive joints, 77.37% (277/358) of them had history of attacks. Among the joints of gouty arthritis, 56.88% (277/487) of them were found MSU crystals. Double contour sign (DCS), hyperechoic aggregate (HAG) and Tophi were found in 32.65% (159/487), 7.80% (38/487) and 24.64% (120/487) of the joints, respectively. DCS and Tophi, but not HAG, appeared increasingly in gout duration extension. In the patients with more than 15 years of gout history, DCS, Tophi and HAG were found in 48.18%, 40.00%, 6.36% of US assessed joints, respectively. In the gout patients, synovial lesion and bone erosion were found in 17.74% (192/1082) and 7.58% (82/1082) of joints, respectively. Synovial lesion was related with HAG, while bone erosion was related to tophi and DCS. Nephrolithiasis was detected in 20.30% (41/202) of gout patients and 4.65% (2/43) of hyperuricemia patients, indicating nephrolithiasis occurred in more gout patients than in hyperuricemia patients.ConclusionHAG is the early sign of MSU crystal deposition in joints. Early urate lowering therapy (ULT) may reduce HAG and ameliorate synovitis and synovial hypertrophy. DCS and tophi are the risk factors of bone erosion. Early ULT should be considered in the gout patients with DCS or tophi. And nephrolithiasis was remarkably relevant to MSU crystal deposition in joints in gout patients.

BackgroundNon-small cell lung cancer (NSCLC) accounts for about 85% of lung cancers. This study aimed to discover the potential miRNA biomarkers for early detection of NSCLC.MethodsTotal circulating miRNAs were extracted from six patients and six volunteers and run on the miRNA chip. The differentially expressed miRNAs acquired by data mining were intersected with chip results, and qRT-PCR were carried out. Then the differentially miRNAs were validated by using a validation cohort (120 participants). ROC curves were established to evaluate the diagnostic efficacy of the differentially circulating miRNAs. The target genes of the differential miRNAs were identified using the miRTarBase database, and follow-up GO and KEGG enrichment analysis were conducted.ResultsWe identified 577 miRNA which screened according to the criteria (fold change > 2 and p value < 0.05). Among them, seven circulating miRNAs passed additional filtering based on data mining. These miRNAs were further validated in the training and validation cohort. miR-492, miR-590-3p, and miR-631 were differentially expressed in the patients’ serum, and the area under the ROC curve (AUC) values of these miRNAs were 0.789, 0.792, and 0.711, respectively. When using them as a combination to discriminate healthy volunteers from patients, the AUC reached 0.828 (95% CI, 0.750–0.905, p = 0.000) with a sensitivity of 86.7% and specificity of 71.7%. The follow-up enrichment analysis showed that target genes of three miRNA were associated with tumorigenesis and progression, such as cell cycle and P53 signaling pathway.ConclusionsThe combination of miR-492, miR-590-3p, and miR-631 can be utilized to distinguish healthy individuals and early-stage NSCLC patients.ImpactThe combination of miR-492, miR-590-3p, and miR-631 might be a promising serum biomarker in patients for the early diagnosis of NSCLC.

Background: With the aging of the population, the number of total hip replacement surgeries is increasing globally. Hip replacement has undergone revolutionary advancements in surgical methods and materials. Due to the short length of hospitalization, rehabilitation care is mainly home-based. The needs and concerns about such home-based rehabilitation are constantly changing, requiring continuous attention. Objective: To explore effective methods for comprehensively identifying older patients’ self-reported outcomes after home-based rehabilitation for hip replacement, in order to develop appropriate intervention strategies for patient rehabilitation care in the future. Methods: This study constructed a corpus of patients’ self-reported rehabilitation care problems after hip replacement, based on the Omaha classification system. This study used the Python development language and implemented artificial intelligence to match the corpus data on the cooperation platform, to identify the main health-related problems reported by the patients, and to perform statistical analyses. Results: Most patients had physical health-related problems. More than 80% of these problems were related to neuromusculoskeletal function, interpersonal relationships, pain, health care supervision, physical activity, vision, nutrition, and residential environment. The most common period in which patients' self-reported problems arose was 6 months post-surgery. The relevant labels that were moderately related to these problems were: Physiology—Speech and Language and Physiology—Mind (r = 0.45), Health-Related Behaviors—Nutrition and Health-Related Behaviors—Compliance with Doctors' Prescription (r = 0.40). Conclusion: Physiological issues remain the main health-related issues for home-based rehabilitation after hip replacement in older patients. Precision care has become an important principle of rehabilitation care. This study used big data law to obtain the largest quantitative network data possible. The artificial intelligence capture was fully automated, which greatly improved efficiency, as compared to manual data entering.

Objectives This study aims to determine a role of interleukin‐17A (IL‐17) in salivary gland (SG) dysfunction and therapeutic effects of targeting IL‐17 in SG for treating autoimmune sialadenitis in primary Sjögren’s syndrome (pSS). Methods Salivary IL‐17 levels and IL‐17‐secreting cells in labial glands of pSS patients were examined. Kinetic changes of IL‐17‐producing cells in SG from mice with experimental Sjögren’s syndrome (ESS) were analysed. To determine a role of IL‐17 in salivary secretion, IL‐17‐deficient mice and constructed chimeric mice with IL‐17 receptor C (IL‐17RC) deficiency in non‐hematopoietic and hematopoietic cells were examined for saliva flow rates during ESS development. Both human and murine primary SG epithelial cells were treated with IL‐17 for measuring cholinergic activation‐induced calcium movement. Moreover, SG functions were assessed in ESS mice with salivary retrograde cannulation of IL‐17 neutralisation antibodies. Results Increased salivary IL‐17 levels were negatively correlated with saliva flow rates in pSS patients. Both IL‐17‐deficient mice and chimeric mice with non‐hematopoietic cell‐restricted IL‐17RC deficiency exhibited no obvious salivary reduction while chimeric mice with hematopoietic cell‐restricted IL‐17RC deficiency showed significantly decreased saliva secretion during ESS development. In SG epithelial cells, IL‐17 inhibited acetylcholine‐induced calcium movement and downregulated the expression of transient receptor potential canonical 1 via promoting Nfkbiz mRNA stabilisation. Moreover, local IL‐17 neutralisation in SG markedly attenuated hyposalivation and ameliorated tissue inflammation in ESS mice. Conclusion These findings identify a novel function of IL‐17 in driving salivary dysfunction during pSS development and may provide a new therapeutic strategy for targeting SG dysfunction in pSS patients., In this study, we found that increased salivary IL‐17 levels were negatively correlated with saliva flow rates in patients with primary Sjögren’s syndrome (pSS). We further identified a novel function of IL‐17 in driving salivary dysfunction by impairing transient receptor potential canonical 1‐mediated calcium movement during pSS pathogenesis. This pre‐clinical study demonstrated that neutralization of IL‐17 in salivary glands attenuated hyposalivation and ameliorated tissue inflammation in mice with experimental SS, suggesting a therapeutic potential of local targeting IL‐17 for treating xerostomia and autoimmune sialadenitis in pSS patients.

Background Carpal tunnel syndrome (CTS) is a common cause of pain, numbness and tingling in the wrist and hand region and is associated with repetitive wrist and hand use in office workers. However, scarce knowledge exists about the epidemiology of clinically confirmed CTS among Chinese office workers. This study aimed to investigate the prevalence of wrist/hand symptoms and CTS in office workers in China and to identify associated risk factors. Methods A cross-sectional survey was carried out in a metropolitan city in China involving 969 respondents (aged 17–49 years) from 30 workplaces. A questionnaire was distributed to each participant to collect their demographic, work-related physical and psychosocial factors, and wrist and hand symptoms. The wrist and hand pain/numbness symptoms were marked on a body chart and the nature and intensity of symptoms, nocturnal symptoms, as well as aggravating activities were also recorded. Clinically confirmed CTS cases were screened based on the history, Phalen’s test, Tinel Sign and skin sensation testing among symptomatic respondents. Logistic regression was employed to estimate the odds ratio (OR) and 95% confidence interval (95% CI) for the occurrence of self-reported wrist and hand symptoms and clinically confirmed CTS. Results The clinically confirmed CTS prevalence was 9.6%. The prevalence of wrist and hand symptoms were 22 and 15%, respectively. Frequently working in pain was associated with higher odds of CTS. Multivariate modelling adjusted for age and gender showed that prolonged computer use time and working without breaks were associated with presence of wrist/hand symptoms (adjusted ORs: 1.11 (95% CI 1.02–1.22) and 1.88 (95% CI 1.12–3.14)). Educational level was inversely associated with CTS and smoking was associated with wrist/hand complaints (adjusted OR: 2.20 (95% CI 1.19–4.07)). Conclusions The prevalence of work-related clinically confirmed CTS symptoms among young office workers in China is high. Frequently working in pain is closely associated with clinically confirmed CTS. Intense computer use and no breaks at work are associated with wrist and hand symptoms.

Background: Recent studies have shown an increase in the prevalence of hyperuricemia (HUA) worldwide. However, representative national data suggesting national trends of HUA in China are lacking. Methods: Using a multi-stage, stratified, cluster-randomized sampling design, two cross-sectional surveys (representative of national and provincial information) were conducted in 31 provinces (autonomous regions and municipalities) in mainland China, with 166,861 Chinese adults in 2015–16 and 168,351 in 2018–19. Serum uric acid (SUA) levels of all participants were measured after a >10-hour overnight fast. HUA was defined when SUA was >420 μmol/L. Prevalence estimates were weighted to represent the total population considering the complex sampling design. Multivariable logistic regression models estimated factors associated with HUA. Findings: The overall HUA prevalence in the Chinese adult population was 11.1% (95% CI, 10.3–11.8%) in 2015–16 and 14.0% (95% CI, 13.1-14.8%) in 2018–19; an alarming rise was observed in the three years. HUA was more common in men with 19.3% (95% CI, 17.9–20.7%) in 2015–16 and 24.4% (95% CI, 23.0–25.8%) in 2018–19. The HUA prevalence also escalated from 2.8% (95% CI, 2.5-3.0%) in 2015–16 to 3.6% (95% CI, 3.2–4.0%) in 2018–19 in women. Various risk factors, including urban culture, settlement in the East, Zhuang descent, high education, heavy or frequent beer drinking, high red meat intake, physical inactivity, high BMI, central obesity, hypertension, hyperlipidemia, and low eGFR, were significantly associated with HUA. Interpretation: The estimated HUA prevalence among Chinese adults was 14.0% in 2018–19; significant escalating trends were observed between 2015 and 2019. Therefore, HUA is a public health problem in China. Funding: Chinese Central Government and National Key R&D Program of China. Declaration of Interest: We declare no competing interests. Ethical Approval: The ethical review committee of the Chinese Center for Disease Control and Prevention (China CDC) approved the 2015 CCDRFS (approval number 201519- A) and that of the National Center for Chronic and Noncommunicable Disease Control and Prevention, China CDC approved the 2018 CCDRFS (approval number 201819).

BackgroundPregnant women in Shanghai have long been at risk for mild iodine deficiency. Because thyroid autoimmunity in pregnant women can lead to premature birth and miscarriage as well as neurodevelopmental deficits in the fetus, the aim of this study was to explore the association of iodine nutrition status with thyroid antibodies during pregnancy.MethodsA pregnancy-birth cohort was conducted including 4635 pregnant women in Shanghai, China. The eligible participants underwent a face-to-face interview and completed questionnaire surveys to collected baseline information and diet intake. Spot urine samples were collected to test urine iodine. Thyroid antibodies including thyroid peroxidase antibodies (TPOAb), thyroglobulin antibodies (TgAb) and thyrotrophic antibodies (TRAb) were tested. Single-factor analysis and logistic regression were used to evaluate the association between iodine status and thyroid autoimmunity during pregnancy.FindingsThe median urinary iodine excretion level in the sample was 138·14 µg/L (interquartile range [IQR] 80·90-219·00 µg/L). The proportion of patients with iodine deficiency was significantly higher among those who consumed non-iodized salt (36·9% vs. 33·1%; p = 0·04). After adjusting for age, educational status, former smoker status, former drinker status, first pregnancy, and previous thyroid disease, non-iodized salt (odds ratio [OR] = 1·394 [confidence interval, CI, 1·165-1·562]; p = 0·003), iodine-rich food (OR = 0·681 [CI 0·585-0·793]; p = 0·003), iodized nutritional supplements (OR = 0·427 [CI 0·347-0·526]; p = 0·003), were found to be individually associated with thyroid autoimmunity in all participants. The results of the multivariable restricted cubic spline regression analysis showed a non-linear relationship between the continuous change in iodine intake and thyroid autoimmunity (p = 0·019). Participants with iodine deficiency (urinary iodine concentration

Radiotherapy plays an increasingly crucial role in the treatment of non-small cell lung cancer (NSCLC). Local tumor recurrence and tumor progression caused by intratumoral heterogeneity induced radiotherapy resistance remain the primary causes of radiotherapy failure. However, the lack of a suitable cell line model has hampered the exploration of the dynamic mechanisms of radiation resistance. We established 3 groups of equidifferent gradient dose irradiation surviving/resistant human lung cancer cell lines based on A549, H520, and H460 cells with clinical conventional fractionated radiotherapy (CFRT) (2 Gy × 20 F, 2 Gy × 30 F, and 2 Gy × 40 F). The radiosensitivity of the cells was detected by clone formation assay, EDU cell proliferation assay, neutral comet assay, and γ-H2AX immunofluorescence staining. The radiosensitivity and proliferation viability were increased in a received dose-dependent manner. Compared with parental cells, DNA double-strand breaks (DSBs) in cell lines that received higher-dose irradiation were significantly reduced. We successfully constructed equidifferent gradient dose irradiation surviving/resistant NSCLC cell lines whose radiation surviving and resistant abilities were increased in a received dose-dependent manner. This preclinical cell model could be used to dynamically observe and detect the radiation surviving/resistant biomarkers during radiotherapy stress, elucidate the mechanism of radiation resistance.

The aim of this study was to identify the effects of melatonin on acute gouty inflammation and to investigate the underlying mechanisms. We found significantly lower serum melatonin levels in gout patients in the acute phase than in those in the remission phase or in normal individuals. The mRNA expression of melatonin receptor 2 (MT2) was also lower in gout patients than in normal individuals. To verify the in-vivo role of melatonin, a gouty arthritis model was established by intraarticular injection of monosodium urate (MSU, 1 mg) crystals into the paws of C57BL/6 mice. Joint inflammation in the mouse model was evaluated by measuring the thickness of the right paw/left paw, and the inflammation index was determined by examining infiltrating neutrophils with haematoxylin and eosin (H&E) staining. Melatonin was found to reduce both paw thickness and the inflammation index in the mouse model, and melatonin also reduced the mRNA levels of interleukin-1 beta (IL-1β), IL-6 and NLR family pyrin domain containing 3 (NLRP3) inflammasome. To mimic gouty inflammation in vitro, mouse peritoneal macrophages were stimulated with lipopolysaccharides (LPS) plus MSU. Melatonin was revealed to reduce IL-1β secretion by stimulated macrophages. The mRNA expression levels of IL-1β and IL-6 were also inhibited by melatonin. Western blot analysis showed that the expression of NLRP3, caspase-1 and pro-IL-1β was also inhibited by melatonin. In conclusion, our study demonstrated that melatonin alleviated gouty inflammation in vivo and in vitro, and the underlying mechanism may involve inhibiting the assembly of the NLRP3 inflammasome.

Gout is a common metabolic disease with growing burden, caused by monosodium urate (MSU) microcrystal deposition. In situ and chemical-specific histological identification of MSU is crucial in the diagnosis and management of gout, yet it remains inaccessible for current histological methods. Methods: Stimulated Raman scattering (SRS) microscopy was utilized to image MSU based on its fingerprint Raman spectra. We first tested SRS for the diagnosis capability of gout and the differentiation power from pseudogout with rat models of acute gout arthritis, calcium pyrophosphate deposition disease (CPDD) and comorbidity. Then, human synovial fluid and surgical specimens (n=120) were were imaged with SRS to obtain the histopathology of MSU and collagen fibers. Finally, quantitative SRS analysis was performed in gout tissue of different physiological phases (n=120) to correlate with traditional histopathology including H&E and immunohistochemistry staining. Results: We demonstrated that SRS is capable of early diagnosis of gout, rapid detection of MSU in synovial fluid and fresh unprocessed surgical tissues, and accurate differentiation of gout from pseudogout in various pathophysiological conditions. Furthermore, quantitative SRS analysis revealed the optical characteristics of MSU deposition at different pathophysiological stages, which were found to matched well with corresponding immunofluorescence histochemistry features. Conclusion: Our work demonstrated the potential of SRS microscopy for rapid intraoperative diagnosis of gout and may facilitate future fundamental researches of MSU-based diseases.

Na+–K+–2Cl− Cotransporter (NKCC1) is a protein that aids in the active transport of sodium, potassium, and chloride ions across cell membranes. It has been shown that long-term systemic treatment with aldosterone (ALD) can enhance NKCC1 protein expression and activity in the aging cochlea resulting in improved hearing. In the present work, we used a cell line with confirmed NKCC1 expression to demonstrate that in vitro application of ALD increased outward voltage-gated potassium currents significantly, and simultaneously upregulated whole lysate and membrane portion NKCC1 protein expression. These ALD-induced changes were blocked by applying the mineralocorticoid receptor antagonist eplerenone. However, application of the NKCC1 inhibitor bumetanide or the potassium channel antagonist Tetraethyl ammonium had no effect. In addition, NKKC1 mRNA levels remained stable, indicating that ALD modulates NKCC1 protein expression via the activation of mineralocorticoid receptors and post-transcriptional modifications. Further, in vitro electrophysiology experiments, with ALD in the presence of NKCC1, K+ channel and mineralocorticoid receptor inhibitors, revealed interactions between NKCC1 and outward K+ channels, mediated by a mineralocorticoid receptor-ALD complex. These results provide evidence of the therapeutic potential of ALD for the prevention/treatment of inner ear disorders such as age-related hearing loss.

Background: Metastasis is the leading cause of lung cancer associated death. Here, we focused on the function and molecular mechanism of miR-744 and its potential clinical application in lung carcinoma. Methods: The clinical cohort and data from TCGA were analyzed for the correlation of miR-744 and outcomes. Multiple NSCLC cell lines and a xenograft model were applied for the functional studies. Reporter assays were explored for transcriptional regulatory mechanism.Results: It was confirmed that the overexpression of miR-744 was significantly correlated with lymph node metastasis and poor prognosis in NSCLC. Both in vitro and in vivo studies revealed that miR-744 overexpression aggravated the growth, invasion and metastasis of NSCLC cells. MiR-744 enhanced the resistance of lung cancer cells to radiotherapy and paclitaxel. MiR-744 positively regulated C-FOS by directly binding to the promoter of C-FOS and -1195 to -1227 and -298 to -323 bp upstream of C-FOS gene were the direct and efficient miR-744 binding sites. MiR-744 could also indirectly upregulate c-FOS protein by activating MAPK pathway.Conclusion: Our findings uncover the function and a novel mechanism of miR-744 in mediating growth and metastasis of NSCLC cells. Our data suggests that miR-744 may serve as a possible therapeutic target for NSCLC.

Objective CXCL4, a chemokine with antiangiogenic property, is reported to be involved in systemic sclerosis (SSc) related pulmonary arterial hypertension (PAH). We investigated the contribution of CXCL4 to SSc development by focusing on the correlation of circulatory CXCL4 levels with their peripheral vasculopathy, as well as the effect of CXCL4 on endothelial cell dysfunction and angiogenesis disturbance in SSc and the potential signaling.MethodsWe measured the serum CXCL4 levels in 58 patients with SSc, 10 patients with the very early diagnosis of SSc (VEDOSS), and 80 healthy controls. Then, CXCL4 levels were correlated with their clinical features, especially the peripheral vasculopathy. These observations were further validated in an additional cohort including 50 SSc patients, 12 VEDOSS patients, and 80 healthy controls. Moreover, we studied the anti-angiogenesis effects and the underlying signaling of CXCL4 in human umbilical vein endothelial cells (HUVECs) in vitro. ResultsCirculating levels of the CXCL4 were 103.62% higher in patients with SSc and 201.51 % higher in patients with VEDOSS than matched HCs, and these observations were confirmed in two independent cohorts. CXCL4 levels were closely associated with digital ulcers (DU) and nailfold video capillaroscopy (NVC) abnormalities in SSc. The proliferation, migration, and tube formation of HUVECs were significantly inhibited by recombinant human CXCL4 or SSc derived serum, which reversed by CXCL4 neutralizing antibody, but not CXCR3 inhibitor. CXCL4 downregulated the transcription factor Friend leukaemia integration factor‐1 (Fli-1) via c-Abl signaling. Furthermore, CXCL4 blocked the transforming growth factor (TGF) -β or platelet-derived growth factor (PDGF) induced cell proliferation of HUVECs. Conclusions CXCL4 may contribute to peripheral vasculopathy in SSc by downregulating Fli-1 via c-Abl signaling in endothelial cells and interfering angiogenesis.

Background Endocrown restoration is widely used to restore endodontically treated teeth. However, the clinical effects of different computer-aided design/computer-aided manufacturing (CAD/CAM) materials for endocrown restoration are not clear. The primary objective of this trial is to compare the clinical efficacy of resin-based bloc and ceramic endocrowns for restoring endodontically treated teeth. Methods The proposed resin-based bloc and ceramic endocrown assessment trial is a parallel group-designed randomized controlled trial. We will recruit 156 adults between 18 and 75 years old with a minimum of one such molar. The inclusion criteria were good oral hygiene habits, root apex of molar without evident damage, receipt of standard endodontic treatment, need for endocrown restoration, and only one endocrown restoration performed per patient. Patients participating in another study or those with systemic diseases, disabilities, or known allergies to used materials will be excluded. All patients will be randomized and restored with resin-based bloc and ceramic endocrown according to a random number table. Clinical evaluations will be performed at baseline and after treatment at 6, 12, and 24 months, in accordance with the modified Federation Dentaire Internationale (FDI) criteria, by two independent evaluators. The primary outcome is marginal adaptation; secondary outcomes include wear, tooth integrity, fracture of material and retention, marginal staining, and patient view. All data will be analyzed by an independent statistician. Signed rank-sum tests will be used for intragroup comparisons. Wilcoxon rank-sum tests will be used for intergroup comparisons. Hierarchical logistic regression will be used to adjust the baseline and other important indicators. Discussion This study will investigate endocrowns of two CAD/CAM materials for endodontically treated molars. The results may help clinicians choose the better CAD/CAM material option and explain to patients the advantages and disadvantages of these two materials with evidence-based support. For patients, the results may lead to improvement in long-term restoration. Trial registration ClinicalTrials.gov NCT04033380. Registered on 24 July 2019

s Background Ultrasound is a useful tool to evaluate and quantify skin lesions. Few studies have assessed the criterion validity of skin ultrasound in systemic sclerosis (SSc). The aims of the study were to investigate skin thickness and stiffness using ultrasound and shear wave elastography (SWE) in SSc and to validate skin ultrasound measurements against histological skin thickness. Methods A total of 22 patients with diffuse cutaneous SSc (dcSSc), 22 with limited cutaneous SSc (lcSSc), and 22 age- and gender-matched healthy controls were enrolled. Skin thickness and stiffness were measured by B-mode ultrasound with SWE imaging on the bilateral fingers and hands. Additional ultrasound evaluation was carried out in 13 patients (9 dcSSc and 4 lcSSc) on their dorsal forearms, followed by skin biopsy conducted in the same skin areas. Correlations between ultrasound measurements and histological skin thickness and modified Rodnan skin score (mRSS) were investigated using Spearman’s correlation. Results Compared with controls, ultrasound-measured skin thickness and skin stiffness were significantly higher in patients with SSc (p r = 0.6926, p = 0.009). A weaker association was also observed between histological skin thickness and local mRSS (r = 0.5867, p = 0.050). Conclusions Ultrasound is a reliable tool for quantifying skin involvement in SSc. Ultrasound-measured skin thickness showed good agreement with histological skin thickness.

Recent advances in audiological research, biomedical and chemical engineering, and hearing sciences suggest that effective biomedical treatments, technological interventions, and acoustic-based therapies will soon bring some exciting opportunities to delay or treat key aspects of age-related hearing loss (ARHL), or presbycusis. In the present chapter, some of the provocative research that is paving the way for these upcoming successful interventions, including the groundwork for a first FDA-approved drug or system to treat acquired hearing loss, including age-related, is presented. Impactful work on drug and medicinal discoveries and developments; localized drug delivery possibilities, including micropumps and hydrogels; and acoustic/technological approaches for effective interventions are highlighted in the present chapter. In the same way that cochlear implant development has been remarkable in the past decades, starting with the initial one-channel cochlear implants developed and tested early on at the House Ear Institute, we will soon experience remarkable breakthroughs for interventions to prevent or treat presbycusis.

Synopsis Age-related hearing loss (ARHL) – presbycusis—is a highly prevalent neurodegenerative and communication disorder. Progress has been made for understanding perceptual declines and biological bases of ARHL in human and animal model research. Loss of sound sensitivity, and deficits in complex processing including speech, are perceptual hallmarks of ARHL. Loss or damage to cochlear cells, including hair cells, stria vascularis cells and auditory nerve fibers are important structural changes. Disruptions of antioxidant and neurotransmitter systems occur, along with upregulation of apoptotic pathways. Clinically, presbycusis is not treatable; but as our understanding of the biological bases progresses, successful biomedical interventions will emerge.

Background: The satisfactory prognostic indicator of gastric cancer patients after surgery is still lacking. Peri-operative plasma extracellular vesicular (EV) PD-L1 has been demonstrated as a potential prognosis biomarker in many types of cancers. The prognostic value of post-operative plasma EV PD-L1 has not been characterized. Methods: We evaluated the prognostic value of pre-operative, post-operative and change in plasma EV PD-L1, as well as plasma soluble PD-L1, in short-term survival of gastric cancer patients after surgery. The Kaplan-Meier survival model and Cox proportional hazards models for both univariate and multivariate analyses were used. Findings: The prognostic value of post-operative EV PD-L1 is superior to that of pre-operative EV PD-L1 on gastric cancer patients after resection. The levels of post-operative EV PD-L1 and EV PD-L1 change are independent prognostic factors for overall survival and recurrence free survival of gastric cancer patients. High plasma level of post-operative ePD-L1 correlates significantly with poor survival, while high change in ePD-L1 level brings the significant survival benefit. Interpretation: The level of plasma post-operative EV PD-L1 could be considered as a prognostic biomarker of GC patients after resection. Funding Statement: This work was supported by following foundations: (a). National Natural Science Foundation of China (No. 30901821, 81172136, 82072737, 81201810). (b). Natural Science Foundation of Shanxi (No. 201701D121165, 201901D111190). (c). Research Project Supported by Shanxi Scholarship Council of China(No. 2020-194). (d). International Science and Technology Cooperation Project of Shanxi Provincial Key R&D Program (No. 201703D421023). (e). Shanxi Youth Science and Technology Research Fund (No. 201801D221069). (f). Open Fund from Key Laboratory of Cellular Physiology (Shanxi Medical University), Ministry of Education, China (No. KLMEC/SXMU202011). (g). Shanxi “1331 Project” Key Subjects Construction (No. 1331KSC). (h). Shanxi Province Science Foundation for Distinguished Young Scholar (No. 201901D211547). (i). Science and Research Fund of Shanxi Health Commission(No. 2019059). (j). the Doctor Project of Shanxi Cancer Hospital, China (No. 2017A06). (k). the Key Research Project of Shanxi Province, China (No. 201703D321010-1). (l). Natural Science Foundation of Guangdong Province, China (No. 2015A030313057). Declaration of Interests: The authors declare no conflict of interest. Ethics Approval Statement: All subjects had provided written informed consent. This study was approved by Shanxi Cancer Hospital Ethics Committee.

The field of hearing and deafness research is about to enter an era where new cochlear drug delivery methodologies will become more innovative and plentiful. The present report provides a representative review of previous studies where efficacious results have been obtained with animal models, primarily rodents, for protection against acute hearing loss such as acoustic trauma due to noise overexposure, antibiotic use and cancer chemotherapies. These approaches were initiated using systemic injections or oral administrations of otoprotectants. Now, exciting new options for local drug delivery, which opens up the possibilities for utilization of novel otoprotective drugs or compounds that might not be suitable for systemic use, or might interfere with the efficacious actions of chemotherapeutic agents or antibiotics, are being developed. These include interesting use of nanoparticles (with or without magnetic field supplementation), hydrogels, cochlear micropumps, and new transtympanic injectable compounds, sometimes in combination with cochlear implants.

AIMS To evaluate the fluctuation of serum uric acid (SUA) during acute gout (AG) and explore its potential mechanisms. METHODS Data such as SUA, urinary uric acid and 24-hour uric acid urinary excretion were collected from 126 patients diagnosed with gout and were analyzed. RESULTS Serum uric acid was negatively correlated with age in gout patients, and significantly elevated in patients aged ≤50 years. Twenty-four-hour uric acid urinary excretion was affected by SUA, creatinine clearance, age, body mass index and urine volume. In contrast, clearance of uric acid and fractional excretion of uric acid (FEur) were more stable. SUA was significantly downregulated during acute attacks. Of the AG patients, 34.92% had detected SUA

Introduction Recombinant neorudin (EPR-hirudin, EH) is an inactive prodrug that is converted to its active metabolite, hirudin variant 2-Lys47 (HV2), at the thrombus site. We aimed to investigate the mechanism underlying site-selective bioconversion of EH to HV2 at the thrombus target site and metabolic transformation of EH in patients with deep vein thrombosis (DVT). Materials and methods Metabolites in healthy volunteer plasma and urine after intravenous administration of EH were determined to elucidate how EH was metabolised after releasing HV2 at the target site in patients with DVT. After intravenous administration of EH in rats with venous thrombosis, the concentrations of EH in the blood and thrombus and the antithrombotic activity of EH were measured to predict whether EH could release HV2 at the thrombus site to exert anticoagulant effect in patients with DVT. Results In healthy volunteers, EH and HV2 were predominantly excreted in the urine. Nine EH metabolites and ten HV2 metabolites truncated at the C-terminal were identified as N-terminal fragments, and these had the same cleavage sites. In rats with venous thrombosis, the area under the curve ratio of HV2 between the thrombus and blood was 29.5. The weight of wet thrombus was decreased with the production of HV2 by the cleavage of EH. The prothrombin time (PT) and prothrombin time (TT) changed proportionally to the concentration of EH and HV2 in the blood. Conclusion EH selectively accumulates and releases HV2 in the thrombus to exert antithrombotic effects, thus lowering the bleeding risk. Moreover, after conversion, EH may follow the same metabolic profile as that of HV2 in patients with DVT.