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Introduction: Interleukin-17A (IL-17A) plays a crucial role in the pathogenesis of ankylosing spondylitis (AS), although not all patients respond to traditional IL-17A antibody treatments. QX002N injection, as a new monoclonal antibody targeting IL-17A, has shown potential in treating AS, offering a new treatment option for patients who do not respond well to existing therapies., Methods: A randomized, open, parallel, single-center, phase I study was conducted to assess the pharmacokinetics, safety, and immunogenicity of single doses of QX002N injection administered intravenously (IV) or subcutaneously (SC) to healthy Chinese volunteers. Blood samples were collected at specified time intervals, and then serum concentrations of QX002N were analyzed by enzyme-linked immunosorbent assay., Results: Pharmacokinetic analysis of the drug concentration-time data showed that the mean maximum observed serum QX002N concentration (C max ) was 110 and 33.9 µg/ml, respectively. The average area under the drug concentration-time curves from 0 to the time of the last quantifiable concentration (AUC last ) were 52,656 and 36,269 µg·h/ml, respectively and the average area under the drug concentration-time curves from 0 to infinity (AUC inf ) were 54,867 and 38,194 µg·h/ml, respectively. The absolute bioavailability of QX002N after SC injection was 69.6%., Conclusions: Immunogenicity was assessed and all the subjects in this study were Anti-drug antibody (ADA)-negative, which means no subjects appeared to develop immunogenicity to QX002N. All the results testify to the safety of QX002N injection, which is satisfactory after IV or SC dosing in healthy subjects., Trial Registration: www.chinadrugtirals.org.cn , CTR20220430., (© 2024. The Author(s).)

Vaccination plays a key role in preventing morbidity and mortality caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). We aimed to evaluate the safety and immunogenicity of a SARS-CoV-2 messenger ribonucleic acid (mRNA) vaccine SYS6006. In the two randomized, observer-blinded, placebo-controlled phase 1 trials, 40 adult participants aged 18-59 years and 40 elderly participants aged 60 years or more were randomized to receive two doses of SYS6006 or placebo (saline). Adverse events (AEs) were collected through 30 days post the second vaccination. Immunogenicity was assessed by live-virus neutralizing antibody (Nab), spike protein (S1) binding antibody (S1-IgG), and cellular immunity. The result showed that 7/15, 9/15 and 4/10 adult participants, and 9/15, 8/15 and 4/10 elderly participants reported at least one AE in the 20-µg, 30-µg and placebo groups, respectively. Most AEs were grade 1. Injection-site pain was the most common AE. Two adults and one elder reported fever. No vaccination-related serious AE was reported. SYS6006 elicited wild-type Nab response with a peak geometric mean titer of 232.1 and 130.6 (adults), and 48.7 and 66.7 (elders), in the 20-µg and 30-µg groups, respectively. SYS6006 induced moderate-to-robust Nab response against Delta, and slight Nab response against Omicron BA.2 and BA.5. Robust IgG response against wild type and BA.2 was observed. Cellular immune response was induced. In conclusion, two-dose primary vaccination with SYS6006 demonstrated good safety and immunogenicity during a follow-up period of 51 days in immunologically naive population aged 18 years or more. (Trial registry: Chictr.org.cn ChiCTR2200059103 and ChiCTR2200059104).

The production of textiles has undergone a considerable transformation, progressing from its primitive origins in hand-weaving to the implementation of contemporary automated systems. Weaving yarn into fabric is a crucial process in the textile industry that requires meticulous attention to output quality products, particularly in the tension control section. The efficiency of the tension controller in relation to the yarn tension significantly affects the quality of the resulting fabric, as proper tension control leads to strong, uniform, and aesthetically pleasing fabric, while poor tension control can cause defects and yarn breakage, leading to production downtime and increased costs. Maintaining the desired yarn tension during textile production is crucial, although it poses several problems, such as the continuous diameter change of the unwinder and rewinder sections leading to system change. Another problem faced by the industrial operation is maintaining proper tension on the yarn while changing the roll-to-roll operation velocity. In this paper, an optimized method for controlling yarn tension through the cascade control of tension and position, incorporating feedback controllers, feedforward, and disturbance observers, has been proposed to make the system more robust and suitable for industrial use. In addition, an optimum signal processor has been designed to obtain sensor data with reduced noise and minimal phase difference.

Background: Many smokers have undiagnosed chronic obstructive pulmonary disease (COPD), and yet screening for COPD is not recommended. Smokers who know that they have airflow limitation are more likely to quit smoking. This study aims to identify the prevalence and predictors of airflow limitation among smokers in primary care., Methods: Current smokers ≥ 40 years old who were asymptomatic clinic attendees in a primary care setting were recruited consecutively for two months. We used a two-step strategy. Step 1: participants filled in a questionnaire. Step 2: Assessment of airflow limitation using a pocket spirometer. Multiple logistic regression was utilised to determine the best risk predictors for airflow limitation., Results: Three hundred participants were recruited. Mean age was 58.35 (SD 10.30) years old and mean smoking history was 34.56 pack-years (SD 25.23). One in two smokers were found to have airflow limitation; the predictors were Indian ethnicity, prolonged smoking pack-year history and Lung Function Questionnaire score ≤ 18. Readiness to quit smoking and the awareness of COPD were low., Conclusions: The high prevalence of airflow limitation and low readiness to quit smoking imply urgency with helping smokers to quit smoking. Identifying airflow limitation as an additional motivator for smoking cessation intervention may be considered. A two-step case-finding method is potentially feasible.

TRPV4 belongs to the 'Transient Receptor Potential' (TRP) superfamily. It has been identified to profoundly affect a variety of physiological processes, including nociception, heat sensation and inflammation. Unlike other TRP superfamily channels, its role in cancers are unknown until recently when we reported TRPV4 to be required for cancer cell softness that may promote breast cancer cell extravasation and metastasis. Here, we elucidated the molecular mechanisms mediated by TRPV4 in the metastatic breast cancer cells. TRPV4-mediated signaling was demonstrated to involve Ca 2+ -dependent activation of AKT and downregulation of E-cadherin expression, which was abolished upon TRPV4 silencing. Functionally, TRPV4-enhanced breast caner cell transendothelial migration requires AKT activity while a combination of transcriptional and post-translational regulation contributed to the TRPV4-mediated E-cadherin downregulation. Finally, mass spectrometry analysis revealed that TRPV4 is required for the expression of a network of secreted proteins involved in extracellular matrix remodeling. In conclusion, TRPV4 may regulate breast cancer metastasis by regulating cell softness through the Ca 2+ -dependent AKT-E-cadherin signaling axis and regulation of the expression of extracellular proteins.

Cigarette smoking enhances oxidative stress and airway inflammation in asthma, the mechanisms of which are largely unknown. Myeloid-derived regulatory cells (MDRC) are free radical producing immature myeloid cells with immunoregulatory properties that have recently been demonstrated as critical regulators of allergic airway inflammation. NO (nitric oxide)-producing immunosuppressive MDRC suppress T-cell proliferation and airway-hyper responsiveness (AHR), while the O2(•-) (superoxide)-producing MDRC are proinflammatory. We hypothesized that cigarette smoke (CS) exposure may impact MDRC function and contribute to exacerbations in asthma. Exposure of bone marrow (BM)-derived NO-producing MDRC to CS reduced the production of NO and its metabolites and inhibited their potential to suppress T-cell proliferation. Production of immunoregulatory cytokine IL-10 was significantly inhibited, while proinflammatory cytokines IL-6, IL-1β, TNF-α and IL-33 were enhanced in CS-exposed BM-MDRC. Additionally, CS exposure increased NF-κB activation and induced BM-MDRC-mediated production of O2(•-), via NF-κB-dependent pathway. Intratracheal transfer of smoke-exposed MDRC-producing proinflammatory cytokines increased NF-κB activation, reactive oxygen species and mucin production in vivo and exacerbated AHR in C57BL/6 mice, mice deficient in Type I IFNR and MyD88, both with reduced numbers of endogenous MDRC. Thus CS exposure modulates MDRC function and contributes to asthma exacerbation and identifies MDRC as potential targets for asthma therapy.

The urokinase-type plasminogen activator receptor (uPAR) is a glycosylphosphatidylinositol-linked membrane protein with no cytosolic domain that localizes to lipid raft microdomains. Our laboratory and others have documented that lung fibroblasts from patients with idiopathic pulmonary fibrosis (IPF) exhibit a hypermotile phenotype. This study was undertaken to elucidate the molecular mechanism whereby uPAR ligation with its cognate ligand, urokinase, induces a motile phenotype in human lung fibroblasts. We found that uPAR ligation with the urokinase receptor binding domain (amino-terminal fragment) leads to enhanced migration of fibroblasts on fibronectin in a protease-independent, lipid raft-dependent manner. Ligation of uPAR with the amino-terminal fragment recruited α5β1 integrin and the acylated form of the Src family kinase, Fyn, to lipid rafts. The biological consequences of this translocation were an increase in fibroblast motility and a switch of the integrin-initiated signal pathway for migration away from the lipid raft-independent focal adhesion kinase pathway and toward a lipid raft-dependent caveolin-Fyn-Shc pathway. Furthermore, an integrin homologous peptide as well as an antibody that competes with β1 for uPAR binding have the ability to block this effect. In addition, its relative insensitivity to cholesterol depletion suggests that the interactions of α5β1 integrin and uPAR drive the translocation of α5β1 integrin-acylated Fyn signaling complexes into lipid rafts upon uPAR ligation through protein-protein interactions. This signal switch is a novel pathway leading to the hypermotile phenotype of IPF patient-derived fibroblasts, seen with uPAR ligation. This uPAR dependent, fibrotic matrix-selective, and profibrotic fibroblast phenotype may be amenable to targeted therapeutics designed to ameliorate IPF.

Chemoresistance due to heterogeneity of the tumor microenvironment (TME) hampers the long-term efficacy of first-line therapies for lung cancer. Current combination therapies for lung cancer provide only modest improvement in survival, implicating necessity for novel approaches that suppress malignant growth and stimulate long-term antitumor immunity. Oxidative stress in the TME promotes immunosuppression by tumor-infiltrating myeloid-derived suppressor cells (MDSC), which inhibit host protective antitumor immunity. Using a murine model of lung cancer, we demonstrate that a combination treatment with gemcitabine and a superoxide dismutase mimetic targets immunosuppressive MDSC in the TME and enhances the quantity and quality of both effector and memory CD8(+) T-cell responses. At the effector cell function level, the unique combination therapy targeting MDSC and redox signaling greatly enhanced cytolytic CD8(+) T-cell response and further decreased regulatory T cell infiltration. For long-term antitumor effects, this therapy altered the metabolism of memory cells with self-renewing phenotype and provided a preferential advantage for survival of memory subsets with long-term efficacy and persistence. Adoptive transfer of memory cells from this combination therapy prolonged survival of tumor-bearing recipients. Furthermore, the adoptively transferred memory cells responded to tumor rechallenge exerting long-term persistence. This approach offers a new paradigm to inhibit immunosuppression by direct targeting of MDSC function, to generate effector and persistent memory cells for tumor eradication, and to prevent lung cancer relapse., (©2013 AACR)

Matrix stiffening and myofibroblast resistance to apoptosis are cardinal features of chronic fibrotic diseases involving diverse organ systems. The interactions between altered tissue biomechanics and cellular signaling that sustain progressive fibrosis are not well defined. In this study, we used ex vivo and in vivo approaches to define a mechanotransduction pathway involving Rho/Rho kinase (Rho/ROCK), actin cytoskeletal remodeling, and a mechanosensitive transcription factor, megakaryoblastic leukemia 1 (MKL1), that coordinately regulate myofibroblast differentiation and survival. Both in an experimental mouse model of lung fibrosis and in human subjects with idiopathic pulmonary fibrosis (IPF), we observed activation of the Rho/ROCK pathway, enhanced actin cytoskeletal polymerization, and MKL1 cytoplasmic-nuclear shuttling. Pharmacologic disruption of this mechanotransduction pathway with the ROCK inhibitor fasudil induced myofibroblast apoptosis through a mechanism involving downregulation of BCL-2 and activation of the intrinsic mitochondrial apoptotic pathway. Treatment with fasudil during the postinflammatory fibrotic phase of lung injury or genetic ablation of Mkl1 protected mice from experimental lung fibrosis. These studies indicate that targeting mechanosensitive signaling in myofibroblasts to trigger the intrinsic apoptosis pathway may be an effective approach for treatment of fibrotic disorders.

Fibroblasts from patients with pulmonary fibrosis express higher levels of the receptor for urokinase, and the extent of fibrosis in some animal models exhibits a dependence on the urokinase receptor. Recent observations have identified the urokinase receptor as a trans-interacting receptor with consequences on signaling and cell responses that vary depending on its interacting partner, the relative levels of expression, and the state of cellular transformation. We undertook this study to define the urokinase-type plasminogen activator cellular receptor (u-PAR)-integrin interactions and to determine the functional consequences of such interactions on normal human lung fibroblast attachment and migration. u-PAR colocalizes in lammelipodia/filopodia with relevant integrins that mediate fibroblast attachment and spreading on the provisional matrix proteins vitronectin, fibronectin, and collagens. Inhibitory antibody studies have revealed that human lung fibroblasts utilize alpha(v)beta(5) to attach to vitronectin, predominantly alpha(5)beta(1) (and alpha(v)beta(3)) to attach to fibronectin, and alpha(1)beta(1), alpha(2)beta(1), and alpha(3)beta(1) to attach to collagen. Blocking studies with alpha-integrin subunit decoy peptides and u-PAR neutralizing antibodies indicate that u-PAR modulates the integrin-mediated attachment to purified provisional matrix proteins, to anti-integrin antibodies, or to fibroproliferative lesions from fibrotic lungs. Furthermore, these decoy peptides blunt fibroblast spreading and migration. We show that u-PAR can interact with multiple alpha-integrins but with a preference for alpha(3). Taken together, these data demonstrate that u-PAR may interact with multiple integrins in normal human lung fibroblasts thereby promoting attachment, spreading, and migration. Modulation of fibroblast invasion would be expected to lead to amelioration of fibroproliferative diseases of the lung.

The effect of drinking Chinese green tea on the risk of stomach cancer was evaluated in a population-based case-control study conducted in Shanghai, China, from October 1991 to December 1993. Eligible cases were incident cases of primary stomach cancer diagnosed during the study period among residents of Hongkou district and Nanhui county aged under 80 years. Controls were selected from the same street or commune where the case resided and were matched to the cases on age (within three years) and gender. A total of 711 cases and 711 matched controls, more than 90 percent of the eligible subjects, completed the interview. Information was obtained on the types of tea used, age when habitual tea drinking started, frequency of new batches of tea leaves used per day, number of cups brewed from each batch, total duration of drinking for each batch, strength and temperature of the tea consumed. Statistical analysis was based on modelling through conditional logistic regression. After adjusting for age, gender, place of residence, education, birthplace, alcohol consumption, and cigarette smoking, the odds ratio (OR) comparing drinkers of green tea with nondrinkers was 0.71 (95 percent confidence interval = 0.54-0.93). The adjusted OR decreased with increasing number of new batches of the green tea consumed each day (P value trend = 0.006). With the largest series of stomach cancer cases to date, this study found green-tea consumption associated with lower risk of stomach cancer. Among drinkers of green tea, the risk of stomach cancer did not depend on the age when habitual green-tea drinking started. Green tea may disrupt gastric carcinogenesis at both the intermediate and the late stages.