Mendelian randomization reveals the impact of diet on infertility in men and women.

Background: Although studies on the effects of diet on fertility has progressed, some cumulative evidence has piled against popular hypotheses. The aim of our study was to investigate the effects of 31 diets including 23 individual dietary intakes and 8 dietary habits on infertility in men and women. Methods: The datas of diets and infertility were collected from genome-wide association studies (GWAS). Mendelian randomization (MR) methods were used to analyze causal relationships. Multivariate MR (MVMR) adjusted for the effects of other exposures on causality. And MR-Egger, Cochran's Q, radial MR, and MR-PRESSO tests were employed to assess heterogeneity and horizontal pleiotropy. Results: Our study found that coffee intake (OR, 3.6967; 95% CI, 1.0348 - 13.2065; P = 0.0442) and cooked vegetable intakes (OR, 54.7865; 95% CI, 2.9011 - 1030.5500; P = 0.0076) increased the risk of male infertility. For women, beer was a risk factor for infertility (OR, 4.0932; 95% CI, 1.8728 - 8.9461; P = 0.0004); but processed meat was negatively associated with infertility (OR, 0.5148; 95% CI, 0.2730 - 0.9705; P = 0.0401). MVMR demonstrated selenium as a protective factor against female infertility (OR, 7.4474e-12; 95% CI, 5.4780e-22 - 1.0125e-01; P = 0.0314). Conclusion: We found the causal relationships between four diets and infertility. We look forward to more high-quality epidemiologic studies to prove our conclusions.

Efficacy and toxicity of immune checkpoint inhibitors combination therapy for advanced renal cell carcinoma: a systematic review and network meta-analysis.

Background: Although immune checkpoint inhibitors (ICIs) show a significant overall survival advantage over standard advanced renal cell carcinoma (aRCC) therapies, tumor response to these agents remains poor. Some studies have shown that combination therapy including an ICI appears to be the best treatment; however, the overall benefit in terms of efficacy and toxicity still needs to be assessed. Thus, we performed a network meta-analysis to evaluate the differences in the efficacy of several combinations that include an ICI to provide a basis for clinical treatment selection. Methods: We conducted a thorough search of PubMed, EMBASE, and the Cochrane Library for articles from January 2010 to June 2023. R 4.4.2 and STATA 16.0 were used to analyze data; hazard ratio (HR) and odds ratio (OR) with 95% confidence intervals (CI) were used to assess the results. Results: An indirect comparison showed that nivolumab plus cabozantinib and pembrolizumab plus lenvatinib were the most effective treatments for progression-free survival (PFS), with no significant differences between the two interventions (HR, 1.31; 95% CI, 0.96-1.78; P=0.08); rank probability showed that pembrolizumab plus lenvatinib had a 57.1% chance of being the preferred treatment. In the absence of indirect comparisons between pembrolizumab plus axitinib, nivolumab plus ipilimumab, avelumab plus axitinib, nivolumab plus cabozantinib, and pembrolizumab plus lenvatinib, pembrolizumab plus axitinib (40.2%) was the best treatment option for overall survival (OS). Compared to pembrolizumab plus lenvatinib, nivolumab plus ipilimumab (OR, 0.07; 95% CI, 0.01-0.65; P=0.02) and pembrolizumab plus axitinib (OR, 0.05; 95% CI, 0.00-0.78; P<0.001) had a lower incidence of overall adverse events (AEs). Conclusion: Pembrolizumab plus lenvatinib and pembrolizumab plus axitinib resulted in the highest PFS and OS rates, respectively. Pembrolizumab plus axitinib may be the best option when AEs are a concern. Systematic review registration: https://inplasy.com/, identifier INPLASY202410078.

Topology-Optimized Splints vs Casts for Distal Radius Fractures: A Randomized Clinical Trial.

Importance: To date, there is currently no evidence-based medical support for the efficacy of topology-optimized splints in treating distal radius fractures. Objective: To assess the clinical efficacy and complication rates of topology-optimized splints in the treatment of distal radius fractures after closed manual reduction. Design, Setting, and Participants: This 12-week, multicenter, open-label, analyst-blinded randomized clinical trial (comprising a 6-week intervention followed by a 6-week observational phase) was carried out from December 3, 2021, to March 10, 2023, among 110 participants with distal radius fractures. Statistical analysis was performed on an intention-to-treat basis between June 3 and 30, 2023. Intervention: Participants were randomly assigned to 2 groups: the intervention group received topology-optimized splint immobilization and the control group received cast immobilization after closed manual reduction for 6weeks. After this period, immobilization was removed, and wrist rehabilitation activities commenced. Main Outcomes and Measures: The primary outcome was the Gartland-Werley (G-W) wrist score at 6 weeks (where higher scores indicate more severe wrist dysfunction). Secondary outcomes encompassed radiographic parameters, visual analog scale scores, swelling degree grade, complication rates, and 3 dimensions of G-W wrist scores. Results: A total of 110 patients (mean [SD] age, 64.1 [12.7] years; 89 women [81%]) enrolled in the clinical trial, and complete outcome measurements were obtained for 101 patients (92%). Median G-W scores at 6 weeks were 15 (IQR, 13-18) for the splint group and 17 (IQR, 13-18) for the cast group (mean difference, -2.0 [95% CI, -3.4 to -0.6]; P = .03), indicating a statistically significant advantage for the splint group. At 12 weeks, no clinically significant differences in G-W scores between the 2 groups were observed. Complication rates, including shoulder-elbow pain and dysfunction and skin irritation, were less common in the splint group (shoulder-elbow pain and dysfunction: risk ratio, 0.28 [95% CI, 0.08-0.93]; P = .03; skin irritation: risk ratio, 0.30 [95% CI, 0.10-0.89]; P = .02). Conclusions and Relevance: Findings of this randomized clinical trial suggest that patients with distal radius fractures that were managed with topology-optimized splints had better wrist functional outcomes and fewer complications at 6 weeks compared with those who received casting, with no difference at week 12. Therefore, topology-optimized splints with improved performance have the potential to be an advisable approach in the management of distal radius fractures. Trial Registration: Chinese Clinical Trial Registry: ChiCTR2000036480.

Selective Laser Melting Additive Manufactured Tantalum: Effect of Microstructure and Impurities on the Strengthening-Toughing Mechanism.

The balance between the strength and the toughness of pure tantalum (Ta) fabricated with selective laser melting (SLM) additive manufacturing is a major challenge due to the defect generation and affinity for oxygen and nitrogen. This study investigated the effects of energy density and post-vacuum annealing on the relative density and microstructure of SLMed tantalum. The influences of microstructure and impurities on strength and toughness were mainly analyzed. The results indicated that the toughness of SLMed tantalum significantly increased due to a reduction in pore defects and oxygen-nitrogen impurities, with energy density decreasing from 342 J/mm3 to 190 J/mm3. The oxygen impurities mainly stemmed from the gas inclusions of tantalum powders, while nitrogen impurities were mainly from the chemical reaction between the molten liquid tantalum and nitrogen in the atmosphere. The proportion of <110> texture decreased after vacuum-annealing at 1200 °C, while that of the <100> texture increased. Concurrently, the density of dislocations and small-angle grain boundaries significantly decreased while the resistance of the deformation dislocation slip was significantly reduced, enhancing the fractured elongation up to 28% at the expense of 14% tensile strength.

Characteristics of different asthma phenotypes associated with cough: a prospective, multicenter survey in China.

BACKGROUND: Asthma is a heterogeneous disease with variable symptoms, which presents with cough either as the sole or predominant symptom with or without wheezing. We compared the clinical and pathophysiological characteristics of cough predominant asthma (CPA), cough variant asthma (CVA) and classic asthma (CA) in order to determine any differential phenotypic traits. METHODS: In 20 clinics across China, a total of 2088 patients were finally recruited, including 327 CVA, 1041 CPA and 720 CA patients. We recorded cough and wheezing visual analogue scale, Leicester cough questionnaire (LCQ) and asthma control test scores. Fractional exhaled nitric oxide (FeNO), induced sputum cell counts, and capsaicin cough challenge were also measured and compared. RESULTS: CPA patients more frequently presented with cough as the initial symptom, and laryngeal symptoms (p < 0.001), had less symptoms related with rhinitis/sinusitis and gastroesophageal reflux (p < 0.05) than CA patients. Comorbidities including rhinitis and gastroesophageal reflux were similar, while the proportion of COPD and bronchiectasis was higher in CA patients. There were no differences in FeNO levels, sputum eosinophil and neutrophil counts, FEV1 (%pred) decreased from CVA to CPA to CA patients (p < 0.001). Cough sensitivity was higher in CVA and CPA compared to CA (p < 0.001), and was positively correlated with LCQ scores. CONCLUSIONS: CVA, CPA and CA can be distinguished by the presence of laryngeal symptoms, cough sensitivity and airflow obstruction. Asthma-associated chronic cough was not associated with airway inflammation or comorbidities in our cohort. Trial registration The Chinese Clinical Trial Registration Center, ChiCTR-POC-17011646, 13 June 2017.

Corrigendum: Metformin Ameliorates Inflammation and Airway Remodeling of Experimental Allergic Asthma in Mice by Restoring AMPKα Activity.

[This corrects the article DOI: 10.3389/fphar.2022.780148.].

Cynarin suppresses gouty arthritis induced by monosodium urate crystals.

The study is aimed to determine the effects of cynarin (Cyn) on mice with gouty arthritis (GA) induced by monosodium urate (MSU). We measured swelling in the hind paws of mice in vivo using Vernier calipers and ultrasound. The liver, kidney, and hind paws were stained with hematoxylin-eosin, and M1 type macrophages were detected in the hind paws using anti-F4/80 and anti-iNOS antibodies. The mRNA expression of inflammatory factors in bone marrow-derived macrophages (BMDMs) and in the hind paws was detected via quantitative reverse transcription-polymerase chain reaction (qRT-PCR). Nucleotide-binding oligomerization domain (NOD)-like receptor (NLR) family pyrin domain containing 3 (NLRP3) inflammasomes and the nuclear factor kappa B (NF-κB) and mitogen-activated protein kinase (MAPK) pathways were analyzed via western blotting. Cyn was detected in vitro using Cell Counting Kit-8 (CCK-8). Cyn treatment reduced hind paw swelling and M1 macrophage infiltration, suppressed the mRNA expression of inflammatory factors, and inhibited NLRP3 inflammasome activation in vivo, in addition to inhibiting the phosphorylation of IKKa/ß, p65, and c-Jun NH 2-terminal kinase (JNK). Furthermore, Cyn exerted anti-inflammatory and anti-swelling effects in mice with GA by regulating the NF-κB and JNK pathways and NLRP3 inflammasomes.

Metformin Ameliorates Inflammation and Airway Remodeling of Experimental Allergic Asthma in Mice by Restoring AMPKα Activity.

Metformin has been involved in modulating inflammatory state and inhibiting cell proliferation and angiogenesis. This study aimed to determine whether metformin alleviates airway inflammation and remodeling of experimental allergic asthma and elucidate the underlying mechanism. We sensitized and challenged mice with ovalbumin (OVA) to induce allergic asthma. During the challenge period, metformin was administered by intraperitoneal injection. By histopathological and immunohistochemical analyses, metformin-treated mice showed a significant alleviation in airway inflammation, and in the parameters of airway remodeling including goblet cell hyperplasia, collagen deposition and airway smooth muscle hypertrophy compared to those in the OVA-challenged mice. We also observed elevated levels of multiple cytokines (IL-4, IL-5, IL-13, TNF-α, TGF-ß1 and MMP-9) in the bronchoalveolar lavage fluid, OVA-specific IgE in the serum and angiogenesis-related factors (VEGF, SDF-1 and CXCR4) in the plasma from asthmatic mice, while metformin reduced all these parameters. Additionally, the activity of 5'-adenosine monophosphate-activated protein kinase a (AMPKα) in the lungs from OVA-challenged mice was remarkably lower than control ones, while after metformin treatment, the ratio of p-AMPKα to AMPKα was upregulated and new blood vessels in the sub-epithelial area as evidenced by CD31 staining were effectively suppressed. These results indicate that metformin ameliorates airway inflammation and remodeling in an OVA-induced chronic asthmatic model and its protective role could be associated with the restoration of AMPKα activity and decreased asthma-related angiogenesis.

Response of patients with chest tightness variant asthma with routine asthma treatment regimen: A 1-year multicenter, prospective, real-world study.

BACKGROUND: Asthmatic patients with chest tightness as their only presenting symptom (chest tightness variant asthma [CTVA]) have clinical characteristics of eosinophilic airway inflammation similar to those of classic asthma (CA); however, whether CTVA has similar response to antiasthma treatment as compared with CA remains unclear. OBJECTIVE: The response of 76 CTVA patients to standard asthma treatments with inhaled corticosteroids with long-acting beta-agonists was explored in a 52-week multicenter, prospective, real-world study. RESULTS: After 52 weeks of treatment with therapy regimens used for CA, the mean 5-point Asthma Control Questionnaire (ACQ-5) score decreased markedly from 1.38(first administration) to 0.71 (52 weeks, mean decrease: 0.674, 95%CI: 0.447-0.900, P<.001).The mean asthma quality-of-life questionnaire (AQLQ) score increased from 5.77 (first administration) to 6.20 (52 weeks, mean increase: 0.441, 95% CI 0.258-0.625, P<.001). Furthermore, at week 52, FVC, FEV1 %, the diurnal variation in PEFand the PD20-FEV1 were significantly improved. Subgroup analysis revealed that the patients at first administration in the responsive group had higher ACQ-5 scores than those in the nonresponsive group (P < .05). CONCLUSION: In conclusion, patients with CTVA had a good therapeutic response to the guideline-recommended routine treatment (containing inhaled corticosteroids). The association between the treatment response and the severity of CTVA suggested that CTVA patients with higher ACQ-5 scores had better therapeutic effects.

Network Pharmacology to Identify the Pharmacological Mechanisms of a Traditional Chinese Medicine Derived from Trachelospermum jasminoides in Patients with Rheumatoid Arthritis.

BACKGROUND This study used a network pharmacology approach to identify the pharmacological mechanisms of a traditional Chinese medicine derived from Trachelospermum jasminoides (Lindl.) Lem. in patients with rheumatoid arthritis (RA). MATERIAL AND METHODS Known compounds of T. jasminoides were obtained from the Traditional Chinese Medicine Systems Pharmacology (TCMSP) database, the Shanghai Institute of Organic Chemistry of Chinese Academy of Science, Chemistry (CASC) database, and a literature search. Putative targets of identified compounds were predicted by SwissTargetPrediction. RA-related targets were achieved from the Therapeutic Target database, Drugbank database, Pharmacogenomics Knowledgebase, and Online Mendelian Inheritance in Man database. The protein-protein interaction (PPI) network was built by STRING. CluGO was utilized for Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Ontology (GO) enrichment analysis. RESULTS A total of 354 potential targets were predicted for the 17 bioactive compounds in T. jasminoides; 69 of these targets overlapped with RA-related targets. A PPI network was composed and 2 clusters of 59 and 42 nodes each were excavated. GO and KEGG enrichment analysis of the overlapping targets and the 2 clusters was mainly grouped into immunity, inflammation, estrogen, anxiety, and depression processes. CONCLUSIONS Our study illustrated that T. jasminoides alleviates RA through the interleukin-17 signaling pathway, the tumor necrosis factor signaling pathway, and other immune and inflammatory-related processes. It also may exert effects in regulating cell differentiation and potentially has anti-anxiety, anti-depression, and estrogen-like effects.

The extract of Trachelospermum jasminoides (Lindl.) Lem. vines inhibits osteoclast differentiation through the NF-κB, MAPK and AKT signaling pathways.

Osteoclasts are the only cells in the body with a bone-resorption function. The identification of anti-osteoclastogenic agents is important in managing bone loss diseases. The dried vines of Trachelospermum jasminoides (Lindl.) Lem. have been used as a herbal medicine to treat musculoskeletal soreness in East Asia for hundreds of years. In the present study, we focused on the effect of Trachelospermum jasminoides (Lindl.) Lem. extract (TJE) on osteoclast differentiation. As indicated by tartrate-resistant acid phosphatase (TRAP) staining, TJE inhibited osteoclastogenesis induced by receptor activator of nuclear factor-κB ligand from bone marrow-derived monocytes/macrophages without showing any cytotoxicity. In addition, TJE effectively suppressed F-actin ring formation and the bone-resorption function of osteoclasts. The subsequent studies such as network pharmacology and molecular investigation, revealed that TJE inhibited osteoclastogenesis-related genes in a dose- and time-dependent manner through NF-κB, MAPK and AKT-mediated mechanism followed by the nuclear factor of activated T cells, cytoplasmic 1 (NFATc1)/c-Fos pathway. Our study could potentially explain the underlying molecular pharmacology of TJE in osteoclast-related diseases. What's more, it suggested that network pharmacology could help the modernization of traditional Chinese medicine.

Disruption of the Notch pathway aggravates airway inflammation by inhibiting regulatory T cell differentiation via regulation of plasmacytoid dendritic cells.

Plasmacytoid dendritic cells (pDCs) regulate immunity and promote tolerance in asthma. Notch signalling is a highly conserved pathway that regulates the immune response; however, its role in pDC-mediated asthmatic airway inflammation is unclear. This study clarified the effects of Notch signalling on pDC-mediated airway inflammation using murine models of ovalbumin-sensitized allergic asthma. RBP-J-deficient pDCs (RBP-J-/- pDCs) were co-cultured with naïve CD4+ T cells and supernatants and T cell subtypes were analysed. RBP-J-/- pDCs were intranasally transferred to the airways of ovalbumin-sensitized recipient mice. Lung samples of all mice were subjected to tests for histopathology, cytokine profile of bronchoalveolar lavage fluid, airway hyperactivity and expression of T helper type 1 (Th1)/Th2 cells, regulatory T cells and type 2 innate lymphoid cells (ILC2s). The results showed that pDCs with and without RBP-J deficiency significantly differed in expression levels of cluster of differentiation 83 (CD83), but not CD80, CD86 and major histocompatibility complex class II. Co-culturing pDCs with naïve T cells revealed a poorer immunosuppressive effect of RBP-J-/- pDCs. This may be attributed to the lower expression levels of inducible co-stimulator ligand and lower production of interleukin 10 in RBP-J-/- pDCs than in control pDCs, which impeded T cell activation and Treg suppression. RBP-J-/- pDCs were associated with high ILC2 expression and severe Th2 immune responses and airway inflammation. Therefore, Notch signalling is critical for pDC-dependent immunoregulation, and RBP-J deficiency reduces pDC-based immunosuppression via T cell activation and Th cell differentiation. Thus, this pathway may be a therapeutic target for pDC-based anti-asthma immunotherapy.

The expression of ß-Defensin-2, IL-22, IL-22R1 and IL-10R2 in rat model of Klebsiella pneumonia and their correlation with histological grades.

Backgrounds and Aims:Klebsiella pneumoniae represents the most common opportunistic pathogen contributing to Klebsiella pneumonia in hospital-acquired infections. Klebsiella pneumonia has a rapidly progressive clinical course and multi-drug resistant (MDR). Identification of the effective biochemical markers is crucial for improving early diagnosis and treatment of Klebsiella pneumonia. The aims of our study are to 1) investigate the expression of ß-Defensin-2(rßD2), IL-22, IL-22R1 and IL-10R2 in Klebsiella pneumonia-infected rats and 2) their association with the histological grades of Klebsiella pneumonia.Methods and Materials: Fifty specific pathogen free (SPF) male SD rats were randomly divided into two groups: control group (treated with normal saline) and pneumonia group (treated with K. pneumoniae). All animals were sacrificed 1 h, 12 h, 1 d, 3 d, 5 d post infection. The severity and property of pneumonia was evaluated by histopathologic observation and pathogen identification. The mRNA expression of rßD2, IL-22, IL-22R1 and IL-10R2 was measured by RT-qPCR assay. The expression of rßD2 in rat lung tissue was determined by Western blot analysis, and the level of IL-22 in rat serum was determined by ELISA.Results: Histopathologic examination and bacterial counting of lung tissues confirmed the successful establishment of rat pneumonia model. The gene expression of rßD2, IL-22, IL-22R1 and IL-10R2 in pneumonia rats were significantly higher than those in healthy control mice (P < 0.05). The expression of rßD2 was correlated with histological grades of Klebsiella pneumonia and the level of IL-22. RT-qPCR results showed that the peak expression of IL-22R1 appeared earlier than IL-10R2 in rat pneumonia model.Conclusions: The expression of rßD2 and IL-22 was increased significantly at early stage in rat Klebsiella pneumonia model, suggesting that IL-22 and rßD2 might serve as potential biomarkers for the early diagnosis of Klebsiella pneumonia.

Prevalence and risk factors of asthma in mainland China: The CARE study.

BACKGROUND: There are limited population based data on the prevalence of asthma in China. The China Asthma and Risk factors Epidemiologic (CARE) survey was designed to understand the prevalence and risk factors for asthma in mainland China. OBJECTIVES: The CARE survey aims to demonstrate the prevalence and risk factors of asthma in mainland China among adolescents (age >14 years) and adults. METHODS: The survey was performed between February 2010 and August 2012 in eight provinces/cities of seven areas in mainland China. The inhabitants (age, >14 years) recruited in this survey were through multi-stage cluster random sampling. Asthma diagnosis was based on medical history and lung function tests. Multivariable logistic regression was used to analyzed the risk factors for asthma. RESULTS: The study included 164 215 subjects (men, 79 692 [48.53%]; women, 84 523 [51.47%]). 2034 (1.24%) were asthmatic patients. Among all asthmatic patients, 521 (25.61%) were newly diagnosed. Univariable regression analysis showed that risk factors for asthma included smoking, first-degree relatives with asthma, allergic rhinitis, chronic bronchitis, COPD, pollinosis, allergic pneumonia, concomitant allergic diseases, BMI and raising pets. Multivariable logistic regression indicated that asthma risk factors included women, age stratification, smoking, first-degree relatives suffering from asthma or pollinosis, combined with allergic rhinitis, eczema or GERD. CONCLUSIONS: We speculated that the prevalence of asthma is increasing in mainland China among individuals aged >14 years in the past 10 years. A number of risk factors were identified. The risk factors of asthma would be further elucidated in our future work. CLINICAL IMPLICATIONS: Our CARE study highlights that asthma epidemic in mainland China should be paid more attention.

EPO modified MSCs can inhibit asthmatic airway remodeling in an animal model.

There was no effective measures can be obtained at present to reverse or prevent airway remodeling. We investigated the therapeutic effect of Erythropoietin (EPO) gene modified mesenchymal stem cells (MSCs) on asthmatic airway remodeling and the possible underlied molecular mechanisms. EPO gene was transfected into MSCs via lentivirus vector. The transfected cells (EPO-MSCs) were identified by flow cytometry and the EPO secreting function was detected by PCR and Western blot. MSCs or EPO-MSCs were administrated to albumin (OVA)-induced chronic asthmatic mouse model via tail veins. The asthmatic phenotype was analyzed. Number of cells in bronchoalveolar lavage fluid (BALF) was counted using a hemocytometer. Histological findings of airways were evaluated by microscopic examination. The concentrations of interleukin 4(IL-4), interleukin 5(IL-5), and interleukin 13(IL-13) in lung homogenate were determined by ELISA. The activation state of transforming growth factor-ß 1 (TGF-ß1), Transforming growth factor beta-activated kinase 1 (TAK1), and p38 Mitogen Activated Protein Kinase (p38MAPK) signaling was detected by Real-Time PCR and Western blotting. EPO-MSCs were successfully constructed. EPO-MSCs showed a more potently suppressive effect on local asthmatic airway inflammation and the level of IL-4, IL-5, and IL-13 in lung tissue than MSCs. Moreover, the numbers of goblet cells, the thicknesses of smooth muscle layer, collagen density, percentage of proliferating cell nuclear antigen positive (PCNA+ ) mesenchymal cells, and von Willebrand factor positive(vWF+ ) vessels were also significantly inhibited by EPO-MSCs. Furthermore, EPO-MSCs could downregulate the expression of TGF-ß1, TAK1, and p38MAPK in lung tissue both in mRNA level and in protein level. EPO gene modified MSCs may more efficiently attenuate asthmatic airway remodeling, which maybe related with the downregulation of TGF-ß1-TAK1-p38MAPK pathway activity.

Notch signaling pathway regulates the growth and the expression of inflammatory cytokines in mouse basophils.

Basophils (BAs) are the least common granulocytes of all leukocytes, but they play an important role in orchestrating of chronic allergic inflammation. The Notch signaling pathway is a highly conserved pathway that influences cell lineage decisions and differentiation during various stages of development. However, the relationship between Notch signaling and BA remains to be elucidate. Here, we report that several Notch signaling molecules were found to be expressed in BAs. γ-secretase inhibitor (GSI) treatment increase BAs apoptosis, and suppress BAs proliferation. Furthermore, GSI reduced BAs in the S phase, with a concomitant accumulation in G1 and G2 phases. In addition, GSI also significantly down-regulated mRNA levels of cytokines IL-4, IL-6 and IL-13 induced by A23187, and this effect was dependent on MAPK pathway. Finally, IL-6 inhibition was specifically associated with ERK and IL-13 with JNK. Therefore, Notch signaling regulates BA biological function, at least partially via the modulation of MAPK.

Transcription factor RBP-J-mediated signalling regulates basophil immunoregulatory function in mouse asthma model.

Basophils (BA) play an important role in the promotion of aberrant T helper type 2 (Th2) immune responses in asthma. It is not only the effective cell, but also modulates the initiation of Th2 immune responses. We earlier demonstrated that Notch signalling regulates the biological function of BAin vitro. However, whether this pathway plays the same role in vivo is not clear. The purpose of the present study was to investigate the effect of Notch signalling on BA function in the regulation of allergic airway inflammation in a murine model of asthma. Bone marrow BA were prepared by bone marrow cell culture in the presence of recombinant interleukin-3 (rIL-3; 300 pg/ml) for 7 days, followed by isolation of the CD49b+ microbeads. The recombination signal binding protein J (RBP-J-/- ) BA were co-cultured with T cells, and the supernatant and the T-cell subtypes were examined. The results indicated disruption of the capacity of BA for antigen presentation alongside an up-regulation of the immunoregulatory function. This was possibly due to the low expression of OX40L in the RBP-J-/- BA. Basophils were adoptively transferred to ovalbumin-sensitized recipient mice, to establish an asthma model. Lung pathology, cytokine profiles of brobchoalveolar fluid, airway hyperactivity and the absolute number of Th1/Th2 cells in lungs were determined. Overall, our results indicate that the RBP-J-mediated Notch signalling is critical for BA-dependent immunoregulation. Deficiency of RBP-J influences the immunoregulatory functions of BA, which include activation of T cells and their differentiation into T helper cell subtypes. The Notch signalling pathway is a potential therapeutic target for BA-based immunotherapy against asthma.

Effects of para-toluenesulfonamide intratumoral injection on non-small cell lung carcinoma with severe central airway obstruction: A multi-center, non-randomized, single-arm, open-label trial.

BACKGROUND: Severe malignant airway obstruction (SMAO) is a life-threatening form of non-small cell lung carcinoma (NSCLC). OBJECTIVES: To determine the efficacy and safety of para-toluenesulfonamide (PTS) intratumoral injection in NSCLC-SMAO. METHODS: Ninety patients with NSCLC-SAO received repeated courses of PTS intratumoral injection until tumor sizes had reduced by 50% or greater. Primary endpoint was objective alleviation rate, assessed by chest computed tomography (CT) and bronchoscopy, at day 7 and 30 following final dosing. Secondary endpoints included airway obstruction, spirometry, quality-of-life and survival time. RESULTS: In full-analysis set (N=88), using RECIST criteria, PTS treatment resulted in a significant objective alleviation rate [chest CT: 59.1% (95%CI: 48.1%-69.5%), bronchoscopy: 48.9% (95%CI: 38.1%-59.8%) at day 7; chest CT: 43.2% (95%CI: 32.7%-54.2%), bronchoscopy: 29.6% (95%CI: 20.3%-40.2%) at day 30]. There was a remarkable increase in FVC (mean difference: 0.35 liters, 95%CI: 0.16-0.53 liters), FEV1 (mean difference: 0.27 liters, 95%CI: 0.07-0.48 liters), Baseline Dyspnea Index (mean difference: 64.8%, 95%CI: 53.9-74.7%) and Functional Assessment of Cancer Therapy-Lung Cancer Subscale (mean difference: 6·9, 95%CI: 3.8-9.9) at day 7 post-treatment. We noted significantly reduced prevalence of atelectasis (by 42.9%) and Eastern Cooperative Oncology Group physical performance scale (mean difference: 7.2, 95%CI: 3.9-10.5). Median survival time was 394 days in full-analysis set and 460 days in per-protocol set. Adverse events were reported in 64.0% of subjects. Seven severe adverse events (7.9%) were reported, of which three led to death (drug-related in one case). CONCLUSION: PTS intratumoral injection is effective and well tolerated for palliative therapy of NSCLC-SMAO.