AMG487 alleviates influenza A (H1N1) virus-induced pulmonary inflammation through decreasing IFN-γ-producing lymphocytes and IFN-γ concentrations.

BACKGROUND AND PURPOSE: Severe influenza virus-infected patients have high systemic levels of Th1 cytokines (including IFN-γ). Intrapulmonary IFN-γ increases pulmonary IFN-γ-producing T lymphocytes through the CXCR3 pathway. Virus-infected mice lacking IP-10/CXCR3 demonstrate lower pulmonary neutrophilic inflammation. AMG487, an IP-10/CXCR3 antagonist, ameliorates virus-induced lung injury in vivo through decreasing viral loads. This study examined whether AMG487 could treat H1N1 virus-induced mouse illness through reducing viral loads or decreasing the number of lymphocytes or neutrophils. EXPERIMENTAL APPROACH: Here, we studied the above-mentioned effects and underlying mechanisms in vivo. KEY RESULTS: H1N1 virus infection caused bad overall condition and pulmonary inflammation characterized by the infiltration of lymphocytes and neutrophils. From Day-5 to Day-10 post-virus infection, bad overall condition, pulmonary lymphocytes, and IFN-γ concentrations increased, while pulmonary H1N1 viral titres and neutrophils decreased. Both anti-IFN-γ and AMG487 alleviated virus infection-induced bad overall condition and pulmonary lymphocytic inflammation. Pulmonary neutrophilic inflammation was mitigated by AMG487 on Day-5 post-infection, but was not mitigated by AMG487 on Day-10 post-infection. H1N1 virus induced increases of IFN-γ, IP-10, and IFN-γ-producing lymphocytes and activation of the Jak2-Stat1 pathways in mouse lungs, which were inhibited by AMG487. Anti-IFN-γ decreased IFN-γ and IFN-γ-producing lymphocytes on Day-5 post-infection. AMG487 but not anti-IFN-γ decreased viral titres in mouse lung homogenates or BALF. Higher virus load did not increase pulmonary inflammation and IFN-γ concentrations when mice were treated with AMG487. CONCLUSION AND IMPLICATIONS: AMG487 may ameliorate H1N1 virus-induced pulmonary inflammation through decreasing IFN-γ-producing lymphocytes rather than reducing viral loads or neutrophils.

Intrapulmonary IFN-γ instillation causes chronic lymphocytic inflammation in the spleen and lung through the CXCR3 pathway.

Some patients with chronic refractory cough have high levels of pulmonary IFN-γ and IFN-γ-producing T lymphocytes. Pulmonary IFN-γ administration causes acute airway lymphocytic inflammation and cough hypersensitivity by increasing the number of pulmonary IFN-γ-producing T lymphocytes, but these lymphocytes may be recruited from other organs. Intraperitoneal IFN-γ injection can increase the spleen weight of mice. It remains elusive whether pulmonary IFN-γ can induce chronic airway lymphocytic inflammation and cough hypersensitivity by stimulating the proliferation of IFN-γ -producing T lymphocytes in the spleen. Here, we found that pulmonary IFN-γ administration induced chronic airway inflammation and chronic cough hypersensitivity with an increased number of IFN-γ-producing T lymphocytes in the spleen, blood and lung. Pulmonary IFN-γ administration also increased 1) the proliferation of spleen lymphocytes in vivo and 2) the IP-10 level and CXCR3+ T lymphocyte numbers in the spleen and lung of mice. IP-10 could promote the proliferation of spleen lymphocytes in vitro but not blood lymphocytes or lung-resident lymphocytes. AMG487, a potent inhibitor of binding between IP-10 and CXCR3, could block pulmonary IFN-γ instillation-induced chronic airway lymphocytic inflammation and the proliferation of IFN-γ-producing T lymphocytes in mouse spleens. In conclusion, intrapulmonary IFN-γ instillation may induce the proliferation of splenic IFN-γ-producing T lymphocytes through IP-10 and the CXCR3 pathway. The IFN-γ-producing T lymphocytes in blood, partly released from the mouse spleen, may be partly attracted to the lung by pulmonary IP-10 through the CXCR3 pathway. IFN-γ-producing T lymphocytes and IFN-γ in the lung may cause chronic airway lymphocytic inflammation and chronic cough hypersensitivity.

Predictive value of clinical features for anti-reflux therapy response in suspected gastroesophageal reflux-induced chronic cough.

Background: Not all gastroesophageal reflux-induced cough (GERC) patients respond to anti-reflux treatment. It is not certain whether reflux-related symptoms or other clinical characteristics could indicate a successful response to anti-reflux treatment. In this study, we aimed to investigate the relationship between clinical features and anti-reflux response. Methods: We retrospectively analyzed the clinical characteristics of suspected GERC who had reflux-related symptoms or reflux evidence based on abnormal 24-hour esophageal pH value monitoring, or who had no evidence of other common causes of chronic cough in our chronic cough database with a standard case report form. All patients experienced anti-reflux treatment with proton pump inhibitors (PPIs) plus prokinetic agents for at least 2 weeks and were divided into responders and non-responders based on the treatment response. Results: Among 241 patients with suspected GERC, 146 (60.6%) showed a successful response. There was no significant difference in regard to the proportion of reflux-related symptoms, and results of 24-hour esophageal pH value monitoring between responders and non-responders. Compared with non-responders, responders had higher proportions of nasal itching (21.2% vs. 8.4%; P=0.014), tickle in the throat (51.4% vs. 35.8%; P=0.025) and lower proportion of pharyngeal foreign body sensation (32.9% vs. 54.7%; P=0.001). Multivariate analysis showed that nasal itching [hazard ratio (HR): 1.593, 95% confidence interval (CI): 1.025-2.476, P=0.039], tickle in the throat (HR: 1.605, 95% CI: 1.152-2.238, P=0.005), pharyngeal foreign body sensation (HR: 0.499, 95% CI: 0.346-0.720, P<0.001) and sensitivity to at least one cough trigger (HR: 0.480, 95% CI: 0.237-0.973, P=0.042) were associated with the therapeutic response. Conclusions: Over half of suspected GERC patients benefited from anti-reflux therapy. A few clinical features rather than reflux-related symptoms might indicate a response to anti-reflux treatment. Further study is needed for the predictive value.

The risk factors for urinary incontinence in female adults with chronic cough.

BACKGROUND: Female patients with chronic cough are more likely to suffer from urinary incontinence (UI). However, there are few data in regard of risks related with UI in female adults with chronic cough. METHOD: We recruited female adult patients with chronic cough from the cough specialist clinic. Demographic information and clinical characteristics including age, BMI, duration of cough, severity of cough, nature and timing of cough, cough triggers, concomitant symptoms, comorbidities and UI condition were collected. The demographics and clinical features of patients with UI and those without UI were compared. RESULT: A total of 700 female patients with the main symptom of chronic cough were included, of whom 351 (50.1%) presented with UI. As compared with patients without UI, patients with UI showed a longer mean age (years) (49.5 vs. 42.4, p < 0.001), a more severe cough symptom (median of cough Visual Analogue Scale: 65 vs. 50, p < 0.001), a higher prevalence of chronic sinusitis (17.6% vs. 8.6%, p = 0.002), and combined with a higher incidence of abdominal muscle pain due to cough (39.6% vs. 18.7%, p < 0.001).In addition, patients in UI group whose cough were more easily triggered by exercise (28.2% vs. 17.2%, p = 0.048). Multivariate logistic regression analysis indicated the above five variables were risk factors for UI in female adult patients with chronic cough. CONCLUSION: Urinary incontinence is a common complication in female patients with chronic cough. Older age, severe cough, combing with a higher proportion of chronic sinusitis and abdominal muscle pain, a cough easily triggered by exercise are identified as risk factors for urinary incontinence. We should pay more attention to female chronic coughers with these risk factors in clinics.

A New Multi-Sensor Stream Data Augmentation Method for Imbalanced Learning in Complex Manufacturing Process.

Multiple sensors are often mounted in a complex manufacturing process to detect failures. Due to the high reliability of modern manufacturing processes, failures only happen occasionally. Therefore, data collected in practical manufacturing processes are extremely imbalanced, which often brings about bias of supervised learning models. Data collected by the multiple sensors can be regarded as multivariate time series or multi-sensor stream data. The high dimension of multi-sensor stream data makes building models even more challenging. In this study, a new and easy-to-apply data augmentation approach, namely, imbalanced multi-sensor stream data augmentation (IMSDA), is proposed for imbalanced learning. IMSDA can generate high quality of failure data for all dimensions. The generated data can keep the similar temporal property of the original multivariate time series. Both raw data and generated data are used to train the failure detection models, but the models are tested by the same real dataset. The proposed method is applied to a real-world industry case. Results show that IMSDA can not only obtain good quality failure data to reduce the imbalance level but also significantly improve the performance of supervised failure detection models.

The synergistic or adjuvant effect of DINP combined with OVA as a possible mechanism to promote an immune response.

Diisononyl phthalate (DINP) is commonly used as a plasticizer in industrial and consumer product applications. Several studies have suggested a possible link between exposure to DINP and the development of allergic asthma, and the synergistic effect of DINP combined with Ovalbumin (OVA) is a possible way to promote an immune response. These findings are still speculative, since there is insufficient evidence to assess the ability of DINP to influence "allergic asthma pathology". This study was designed to determine any effects of OVA/DINP exposure on airway reactivity, particularly when combined with allergen exposure. Experiments to determine these effects were conducted after 15 days of combined exposure and a subsequent challenge with aerosolized ovalbumin for one week. Airway hyper-responsiveness (lung function), lung tissue pathology, cytokines and oxidative stress biomarkers were investigated. We showed that oral exposure to OVA/DINP could induce airway hyper-responsiveness (AHR), and aggravate airway wall remodeling, and that this deterioration was concomitant with increased immunoglobulin-E and Th2 cytokines secretion. The data also demonstrated that DINP could promote oxidative damage in the lung. In summary, this study showed that DINP has an adjuvant effect on allergic asthma affecting lung function, lung histopathology, immune molecules and causes oxidative damage.

Upregulation of Tyrosine Kinase FYN in Human Thyroid Carcinoma: Role in Modulating Tumor Cell Proliferation, Invasion, and Migration.

Tyrosine kinase FYN-a member of the SRC family of kinases-is associated with mediating mitogenic signals and regulating cell cycle entry, growth, and proliferation. It was hypothesized that FYN is upregulated in thyroid carcinoma, which plays a critical role in tumorigenesis. FYN expression level in thyroid carcinoma tissue and tumor cell lines was determined. Also, the effects of FYN on thyroid cancer (TC) growth, signaling, cell cycle, and apoptosis were evaluated in vitro. FYN was knocked down in thyroid cancer cells (TPC-1) by siRNA to investigate the effects on cell proliferation, invasion, and migration. First, FYN was upregulated both in thyroid carcinoma tissue and in tumor cell lines. Loss of FYN by siRNA weakened proliferation, invasion, and migration of PTC-1 cells. Furthermore, it was demonstrated that knockdown of FYN can inhibit the G0/G1 phase of cell cycle. It was also observed that reduced expression of FYN could increase the level of NF-κB/P65 and IκBα. This study was the first to demonstrate critical positive regulation of thyroid tumorigenesis by FYN, which could be a potential target gene for thyroid carcinoma treatment. In addition, findings from this study highlighted the potential role of FYN inhibitors in TC therapy.