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Background:Cordyceps sinensis is a traditional Chinese medicine that has shown promise for the management of chronic bronchitis (CB). We aim to assess the efficacy and safety of a preparation of C sinensis named Bailing capsule (Hirsutella sinensis, Cs-C-Q80) compared with a placebo in patients with CB.Methods: This randomized, double-blind, placebo-controlled, parallel-group clinical trial (Chinese Clinical Trial Registry; registration number: ChiCTR1900025707) recruited patients with CB from eight hospitals in China between May 2019 and December 2020. Patients were randomized 2:1 to receive Bailing capsule or a placebo orally for 48 weeks (2.0 g, three times a day).Results: Among 240 patients who were randomized, 238 (Bailing capsule: 159, placebo: 79) were included in the primary analysis. Bailing capsule significantly reduced the frequency of acute exacerbation of CB (AECB) compared with the placebo during treatment (0.43 ± 0.82 vs. 1.56 ± 1.34; P < 0.001) and follow-up (0.21 ± 0.64 vs. 0.45 ± 0.93; P = 0.026). Bailing capsule improved the severity of expectoration (P = 0.046) and wheezing (P = 0.010) in AECB during follow-up. The severity of CB after treatment was significantly improved in the Bailing capsule group compared with the placebo group (P = 0.035), particularly in terms of expectoration (P = 0.012) and wheezing (P = 0.003). The risk of adverse events, mainly including infectious and invasive diseases and gastrointestinal symptoms, did not significantly differ between the two groups (29.6% vs. 30.4%).Conclusion: In patients with CB, Bailing capsule significantly reduces the frequency of AECB and ameliorates the severity of AECB and CB symptoms.Clinical Trail Registration:https://www.chictr.org.cn, identifer ChiCTR1900025707.

Objective: The aim of this study was to evaluate the efficacy and safety of the Chinese herbal formula San-Huang Gu-Ben Zhi-Ke (SHGBZK) as a treatment for patients with stable chronic obstructive pulmonary disease (COPD) diagnosed with lung-spleen Qi deficiency.Method: A randomized, double-blind, placebo-controlled trial was designed. 98 adults aged between 40 and 80 years with stable COPD diagnosed with lung-spleen Qi deficiency were included. All participants received basic treatment for COPD. Patients in the experimental group took SHGBZK, while the control group took placebo. The primary outcome was the frequency of acute exacerbation. The secondary outcomes were lung function, symptom score, exercise capacity and quality of life.Results: Of 98 patients who underwent randomization, 50 patients in the SHGBZK group and 48 in the placebo group were included in the full analysis set. After 24-week therapy and 28-week follow-up, patients in treatment group had significant improvements in symptom, exercise capacity and quality of life. After Subgroup analysis, the frequency of acute exacerbation in patients with a COPD Assessment Test (CAT) score of at least 10 or a modified Medical Research Council (mMRC) score of at least 2 was significantly lower in the SHGBZK group than in the placebo group. Lung function in patients with frequent exacerbation was significantly higher in the SHGBZK group than in the placebo group. The incidence of adverse events was generally similar in the two groups.Conclusion: SHGBZK had beneficial effects on symptom, exercise capacity and quality of life in stable COPD patients. SHGBZK also had the potential to reduce the frequency of exacerbation and improve lung function in specific groups of COPD patients.Clinical Trial Registration:https://www.chictr.org.cn/showproj.html?proj=26933, identifier ChiCTR1800016349

Objective: Our aim was to systematically investigate the efficacy of Tanreqing (TRQ) injection on in-hospital outcomes among inpatients with frequent or infrequent AECOPD.Methods: In this ongoing, nationwide multicenter registry designed to investigate clinical characteristics, management, and prognoses of Chinese patients admitted for AECOPD in real-world settings, we collected characteristics, comorbidities, in-hospital prognoses, and information on the COPD assessment test (CAT) questionnaire, PEACE questionnaire, and modified British Medical Research Council (mMRC) questionnaire from each enrolled patient. Frequent AECOPD was determined as being admitted to the hospital ≥1 time or visiting the emergency room (ER) ≥ 2 times due to AECOPD within a year. A propensity match method and univariable and multivariable regression models were performed to analyze the efficacy of TRQ on clinical outcomes for inpatients with frequent AECOPD.Results: A total of 4135 inpatients were involved in the analysis, including 868 administered with TRQ and 3267 not administered with TRQ. After propensity score match, among those administered with TRQ, 493 had frequent AECOPD and 358 had infrequent AECOPD. A significant reduction of CAT score at discharge (TRQ median 12, IQR 8.0–16.0; non-TRQ median 13, IQR 9.0–18.0, p = 0.0297), a lower rate of ICU admission (TRQ 0.8% vs. non-TRQ 2.6%, p = 0.0191), and a shorter length of stay (LOS) (TRQ median 11, IQR 9.0–14.0; non-TRQ median 11, IQR 8.0–14.0, p = 0.004) were observed in the TRQ group, compared with the non-TRQ group among frequent AECOPD patients. In the subgroup analysis, for those with a PEACE score >7 on admission, TRQ contributed to a significantly lower CAT score at discharge (p = 0.0084) and a numerically lower ICU admission rate with a marginal statistical significance. Among those with phlegm-heat symptom complex on admission ≥2, a lower CAT score at discharge and a lower ICU admission were also observed in the TRQ group.Conclusion: TRQ injection had better efficacy in patients with frequent AECOPD in reducing ICU admission and alleviating respiratory symptoms, especially for those with higher severity on admission or more phlegm-heat symptoms.

The interaction of lymphoma cells with their microenvironment has an important role in disease pathogenesis and is being actively pursued therapeutically using immunomodulatory drugs, including immune checkpoint inhibitors. Diffuse large B-cell lymphoma (DLBCL) is an aggressive high-grade disease that remains incurable in ~40% of patients treated with R-CHOP immunochemotherapy. The FOXP1 transcription factor is abundantly expressed in such high-risk DLBCL and we recently identified its regulation of immune response signatures, in particular, its suppression of the cell surface expression of major histocompatibility class II (MHC-II), which has a critical role in antigen presentation to T cells. Using CRISPR/Cas9 genome editing we have depleted Foxp1 expression in the aggressive murine A20 lymphoma cell line. When grown in BALB/c mice, this cell line provides a high-fidelity immunocompetent disseminated lymphoma model that displays many characteristics of human DLBCL. Transient Foxp1-depletion using siRNA, and stable depletion using CRISPR (generated by independently targeting Foxp1 exon six or seven) upregulated cell surface I-Ab (MHC-II) expression without impairing cell viability in vitro. RNA sequencing of Foxp1-depleted A20 clones identified commonly deregulated genes, such as the B-cell marker Cd19, and hallmark DLBCL signatures such as MYC-targets and oxidative phosphorylation. Immunocompetent animals bearing Foxp1-depleted A20 lymphomas showed significantly-improved survival, and 20% did not develop tumors; consistent with modulating immune surveillance, this was not observed in immunodeficient NOD SCIDγ mice. The A20 Foxp1 CRISPR model will help to further characterize the contribution of Foxp1 to lymphoma immune evasion and the potential for Foxp1 targeting to synergize with other immunotherapies.

Monoclonal antibodies are among the most clinically effective drugs used to treat cancer. However, their target repertoire is limited as there are relatively few tumor-specific or tumor-associated cell surface or soluble antigens. Intracellular molecules represent nearly half of the human proteome and provide an untapped reservoir of potential therapeutic targets. Antibodies have been developed to target externalized antigens, have also been engineered to enter into cells or may be expressed intracellularly with the aim of binding intracellular antigens. Furthermore, intracellular proteins can be degraded by the proteasome into short, commonly 8–10 amino acid long, peptides that are presented on the cell surface in the context of major histocompatibility complex class I (MHC-I) molecules. These tumor-associated peptide–MHC-I complexes can then be targeted by antibodies known as T-cell receptor mimic (TCRm) or T-cell receptor (TCR)-like antibodies, which recognize epitopes comprising both the peptide and the MHC-I molecule, similar to the recognition of such complexes by the TCR on T cells. Advances in the production of TCRm antibodies have enabled the generation of multiple TCRm antibodies, which have been tested in vitro and in vivo, expanding our understanding of their mechanisms of action and the importance of target epitope selection and expression. This review will summarize multiple approaches to targeting intracellular antigens with therapeutic antibodies, in particular describing the production and characterization of TCRm antibodies, the factors influencing their target identification, their advantages and disadvantages in the context of TCR therapies, and the potential to advance TCRm-based therapies into the clinic.

Objective: This paper briefly reviews the structure and function of NLRP3 inflammasomes, signaling pathway, relationship with synovitis in KOA, and intervention of traditional Chinese medicine (TCM) in NLRP3 inflammasomes as a means to improve its therapeutic potential and clinical application.Method: Literatures about NLRP3 inflammasomes and synovitis in KOA were reviewed to analyze and discuss.Result: NLRP3 inflammasome can activate NF-κB mediated signal transduction, which in turn causes the expression of proinflammatory cytokines, initiates the innate immune response, and triggers synovitis in KOA. The TCM monomer/active ingredient, decoction, external ointment, and acupuncture regulating NLRP3 inflammasomes are helpful to alleviate synovitis in KOA.Conclusion: The NLRP3 inflammasome plays a significant role in the pathogenesis of synovitis in KOA, TCM intervention targeting the NLRP3 inflammasome can be a novel approach and therapeutic direction for the treatment of synovitis in KOA.

IntroductionPhysical activity interventions improve cognitive performance, especially visuospatial working memory (VSWM). However, evidence on the effects of these interventions in children, adolescents, and older adults remains scant. This meta-analysis aimed to identify the effects of physical activity on VSWM improvement in healthy individuals and the best exercise intervention program to improve VSWM capacity.MethodsWe searched for randomized controlled trials (RCTs) of exercise interventions targeting VSWM in healthy individuals from Web of Science, MEDLINE, BIOSIS Previews, PubMed, China National Knowledge Infrastructure, and Wanfang Data (Chinese) databases, from inception to August 20, 2022.ResultsAmong 21 articles (1,595 healthy participants), the heterogeneity test statistic was I2 = 32.3%, p = 0.053. The mean quality scores of the included articles were 6.9 points (reaction time [RT] studies) and 7.5 points (Score studies). Moreover, 28 RCTs were included (10 RT studies and 18 Score studies), and the subgroup analysis found significant effects for elderly participants, children, interventions involving a higher level of cognitive engagement, low and moderate exercise intensity, chronic exercise, exercise duration ≥60 min, and exercise period ≥90 days. Physical activity had a small but significant positive impact on VSWM in healthy individuals. Current evidence confirms the effects of physical activity on VSWM capacity only in children and seniors but not in young adults. Other age groups, including adolescents and middle-aged adults, have not been studied. Prescription of interventions involving high-level cognitive engagement, low and moderate exercise intensity, chronic exercise, exercise for >30 min per session, and exercise for more than 3 months is recommended for children and seniors.DiscussionFuture RCTs would be to fill the gap in studies on adolescents and middle-aged adults, and report detailed exercise intervention programs about different age groups.Systematic Review Registration: PROSPERO (https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42022354737). INPLASY (https://doi.org/10.37766/inplasy2022.8.0053).

The synergy of cavitation and sediment erosion is the most severe destruction in hydraulic machinery in sediment-laden rivers, and currently the physics and mechanism are still lack of understanding. The synergy effects of cavitation and sediment erosion not only reduce the efficiency and life of hydraulic machinery but also cause costs in operation and maintenance. With the rapid development of renewable clean energy and the transformation of water resources, an increasing number of new hydropower stations and water diversion projects are currently planned or under construction, where most of them are in sediment-laden rivers. In the present paper, the research work, including theory, experiment, and simulation, in this field carried out by various investigators are presented and discussed. Physical mechanisms involved in the synergy of cavitation and sediment erosion which is responsible for material damage as investigated by researchers have also been discussed, and would help to identify gaps for future studies.

The clearance flow patterns and pressure distribution determine the clearance axial hydraulic thrust of a pump turbine, which has a substantial impact on the unit axial imbalance. However, due to the tiny size and complex shape of the clearance flow channel, there is no detailed description of the flow patterns and pressure characteristics. In this study, we conducted a model test with particle image velocimetry (PIV) measurements and CFD simulation of a rotating disk flow that was a simplified model of the pump-turbine clearance flow. It is shown that a typical Batchelor flow is formed in the clearance region, demonstrating a “core region + double-boundary layers” distribution for the circumferential velocity along the clearance height direction; the core region rotates at a speed of only around 41–42% of the rotating disk speed and is independent of the clearance inlet pressure and clearance height. Driven by centrifugal force, the flow is radially outward around the rotating disk, while inward around the stationary disk in the meridian section, showing secondary flow vortices. The pressure in the clearance region has a circumferentially symmetric and radially quadratic distribution. Based on the liquid differential equilibrium equation and core region circumferential velocity, the pressure and clearance axial hydraulic thrust in the clearance region can be expressed as a function of the clearance inlet pressure and the square of the runner rotating speed. These findings can be used to investigate axial force imbalance issues of the pump-turbine unit.

Immune checkpoint inhibitors (ICIs) are the most notable breakthrough in tumor treatment. ICIs has been widely used in tumor patients, but its wide range of immune-related adverse events (irAEs) should not be ignored. irAEs can be involved in any organ system, including immune-related cardiotoxicity. Although the cardiotoxicity induced by immune checkpoint inhibitors is rare, it is extremely lethal and has attracted increasing attention. PD-1 and PD-L1 are expressed in human cardiomyocytes, so the application of PD-1/PDL-1 inhibitors can cause many adverse reactions to the cardiovascular system. This review summarizes the latest epidemiological evidence on the cardiovascular toxicity of programmed cell death protein-1(PD-1)/programmed cell death ligand-1(PD-L1) inhibitors and the clinical manifestations, as well as the potential pathological mechanisms. These updates may provide a novel perspective for monitoring early toxicity and establishing appropriate treatment for patients with ICI-related cardiotoxicity.

Monoclonal antibodies are among the most clinically effective drugs used to treat cancer. However, their target repertoire is limited as there are relatively few tumor-specific or tumor-associated cell surface or soluble antigens. Intracellular molecules represent nearly half of the human proteome and provide an untapped reservoir of potential therapeutic targets. Antibodies have been developed to target externalized antigens, have also been engineered to enter into cells or may be expressed intracellularly with the aim of binding intracellular antigens. Furthermore, intracellular proteins can be degraded by the proteasome into short, commonly 8-10 amino acid long, peptides that are presented on the cell surface in the context of major histocompatibility complex class I (MHC-I) molecules. These tumor-associated peptide-MHC-I complexes can then be targeted by antibodies known as T-cell receptor mimic (TCRm) or T-cell receptor (TCR)-like antibodies, which recognize epitopes comprising both the peptide and the MHC-I molecule, similar to the recognition of such complexes by the TCR on T cells. Advances in the production of TCRm antibodies have enabled the generation of multiple TCRm antibodies, which have been tested in vitro and in vivo, expanding our understanding of their mechanisms of action and the importance of target epitope selection and expression. This review will summarize multiple approaches to targeting intracellular antigens with therapeutic antibodies, in particular describing the production and characterization of TCRm antibodies, the factors influencing their target identification, their advantages and disadvantages in the context of TCR therapies, and the potential to advance TCRm-based therapies into the clinic. [ABSTRACT FROM AUTHOR]

The Lower Permian Shanxi Formation in the Eastern Ordos Basin is a set of transitional facies shale, and it is also a key target for shale gas exploration in China. Based on lithofacies classification by X-ray diffraction and kerogen type identification, nanoscale reservoir space, pore volume, pore size distribution, surface area, and fractal characterization were studied using comprehensive methods including N2 and CO2 adsorption, mercury injection capillary pressure, field emission-scanning electron microscopy (FE-SEM), and nuclear magnetic resonance. The results indicate that Shanxi Formation shale can be subdivided into five types of lithofacies: clayey shale (lithofacies I), siliceous clayey shale (lithofacies II), siliceous shale (lithofacies IV), calcareous siliceous shale (lithofacies V), and siliceous calcareous shale (lithofacies VI). Lithofacies V and lithofacies VI are the best lithofacies in terms of organic pore morphology, connectivity, and development degree, followed by lithofacies II. Inorganic pores and microfractures are well developed in all lithofacies. The majority of pores in lithofacies I comprise organic mesopores, but pore volume is contributed by a few inorganic macropores. The pore types and pore volume contributors of lithofacies II are organic macropores. The pore size distribution of lithofacies IV is very similar to that of lithofacies I. The pore size distribution of lithofacies V shows typical bimodal characteristics. It is suggested that the inorganic pores of lithofacies V are mainly macropores, which have the greatest contribution to pore volume, followed by organic mesopores. Total organic carbon (TOC) and thermal maturity do not present obvious controls on pore structure. Vitrinite is the main kerogen type in lithofacies II and IV, and this is associated with disfavored morphology, low connectivity, and poor development degree of organic pores. In contrast, sapropelinite is observed in other shale lithofacies, and it is suggested to be an effective kerogen type that contributes to better development of organic pores.

ObjectiveTo explore the influence of CYP2C19 gene combined with platelet function test on clinical prognosis of patients with complex coronary artery disease receiving antiplatelet therapy after PCI.MethodsA total of 200 patients undergoing PCI in our hospital due to complex coronary artery disease from February 2019 to February 2021 were selected and divided into the control group and the observation group according to whether CYP2C19 gene detection was performed. The control group was treated with dual antiplatelet therapy of classical aspirin combined with clopidogrel, and the observation group was treated with individual antiplatelet therapy. The patients in the two groups were followed up for 1 year after PCI, and their quality of life was assessed using the Seattle Angina Questionnaire (SAQ score). The occurrence of major adverse cardiovascular events (MACE) during the follow-up period was also recorded.ResultsThe incidence of total MACE events in the observation group was slightly less than that in the control group, and the difference was statistically significant (P = 0.040). In particular, the observation group was superior to the control group in reducing the readmission rate of recurrent unstable angina pectoris, and the difference was statistically significant (P = 0.023). The location of coronary culprit lesions with recurrent ischemic events was commonly seen in non-interventional target lesions (interventional/non-interventional target sites: 12.9%: 77.1%). The SAQ score in the observation group was larger than that in the control group, and the difference was statistically significant (P = 0.012). There was no statistical difference in the incidence of major bleeding between the two groups (P = 0.352).ConclusionUsing CYP2C19 genotype combined with platelet function test to guide individualized antiplatelet therapy after complex coronary artery PCI is beneficial to reducing ischemic events in a short period (1 year), mainly due to reducing the risk of readmission for recurrent unstable angina pectoris, and improving the quality of daily life of patients without increasing the risk of massive hemorrhage, which can improve clinical prognosis.