[Advances in the use of bevacizumab for the treatment of respiratory papilloma].

Respiratory papilloma is a relatively common benign tumor of the respiratory tract, and a few patients may develop malignant changes. The disease has an insidious onset and lacks specific clinical manifestations, and its manifestations are closely related to the growth mode, location and size of the tumor. It can involve multiple parts, such as the larynx, trachea, bronchus, and lung parenchyma, which cause coughing, hoarseness, dysphonia, and, in severe cases, may lead to obstruction of the respiratory tract. At present, the treatment of respiratory papilloma lacks standardization, and there is no effective method to cure the disease. Surgery remains the main treatment for alleviating patients' symptoms and preventing airway obstruction. However, due to the high recurrence rate of respiratory papilloma, multiple surgeries are often needed, which reduces the quality of life of patients and increases their disease burden and economic burden. Bevacizumab, a vascular endothelial growth factor-binding antibody inhibitor, is a promising adjuvant treatment modality that shows good potential for reducing symptoms and the frequency of surgery. This article aimed to review the efficacy and safety of bevacizumab for the treatment of respiratory papilloma and discuss the differences and efficacy of the systemic application and intralesional injection of bevacizumab for the treatment of respiratory papilloma.

[Effect of SHP-1 knockout in airway epithelial cells on emphysema phenotype in chronic obstructive pulmonary disease in mice].

Objective: To construct and characterize conditional Src homology region 2 protein tyrosine phosphatase 1 (SHP-1) knockout mice in airway epithelial cells and to observe the effect of defective SHP-1 expression in airway epithelial cells on the emphysema phenotype in chronic obstructive pulmonary disease (COPD). Methods: To detect the expression of SHP-1 in the airway epithelium of COPD patients. CRISPR/Cas9 technology was used to construct SHP-1flox/flox transgenic mice, which were mated with airway epithelial Clara protein 10-cyclase recombinase and estrogen receptor fusion transgenic mice (CC10-CreER+/+), and after intraperitoneal injection of tamoxifen, airway epithelial SHP-1 knockout mice were obtained (SHP-1flox/floxCC10-CreER+/-, SHP-1Δ/Δ). Mouse tail and lung tissue DNA was extracted and PCR amplified to discriminate the genotype of the mice; the knockout effect of SHP-1 gene in airway epithelial cells was verified by qRT-PCR, Western blotting, and immunofluorescence. In addition, an emphysema mouse model was constructed using elastase to assess the severity of emphysema in each group of mice. Results: Airway epithelial SHP-1 was significantly downregulated in COPD patients. Genotyping confirmed that SHP-1Δ/Δ mice expressed CC10-CreER and SHP-1-flox. After tamoxifen induction, we demonstrated the absence of SHP-1 protein expression in airway epithelial cells of SHP-1Δ/Δ mice at the DNA, RNA, and protein levels, indicating that airway epithelial cell-specific SHP-1 knockout mice had been successfully constructed. In the emphysema animal model, SHP-1Δ/Δ mice had a more severe emphysema phenotype compared with the control group, which was manifested by disorganization of alveolar structure in lung tissue and rupture and fusion of alveolar walls to form pulmonary alveoli. Conclusions: The present study successfully established and characterized the SHP-1 knockout mouse model of airway epithelial cells, which provides a new experimental tool for the in-depth elucidation of the role of SHP-1 in the emphysema process of COPD and its mechanism.

[Incidence and risk factors for cardiovascular events in patients hospitalized with community-acquired pneumonia].

Objective: To explore the incidence, risk factors of cardiovascular events (CVE) and their impact on 30-day mortality in patients hospitalized with community-acquired pneumonia (CAP). Methods: This is a multicenter, retrospective study. Patients hospitalized with CAP from 5 teaching hospitals in Beijing, Shandong and Yunnan provinces during 1 January 2013 to 31 December 2015 were included and clinical data were retrieved from the Hospital Information System (HIS), and patients were divided into CVE group and non-CVE group. Age, sex, comorbidities, pneumonia severity index(PSI)/CURB-65 score, routine blood test, biochemical examinations, radiological findings on admission and mortality on 30-day after admission were analyzed. The primary endpoint was acute CVE during hospitalization, the secondary endpoint was 30-day death after admission. Multivariate Cox regression analysis was used to explore the risk factors for CVE. Kaplan-Meier survival curve was used to compare the difference on 30-day mortality between CVE patients and non-CVE patients by Log-rank test. Multivariate Cox regression model was used to assess the impact of CVE on the 30-day mortality among CAP patients after adjustment with age, sex, comorbidities, PSI/CURB-65 score. Results: A total of 3 561 CAP patients were included into the final analysis, including 210 (5.9%) patients in CVE group and 3 351 (94.1%) patients in non-CVE group. Compared with patients in non-CVE group, patients in CVE group were older (P<0.001), prevalence of hypertension, coronary heart disease, chronic heart failure, cerebrovascular disease, chronic obstructive pulmonary disease, chronic kidney disease, aspiration risk and bedrid were significantly higher (all P<0.001); prevalence of CURB-65 score 3-5 and PSI risk class Ⅳ/Ⅴ were also significantly higher (both P<0.001). The proportion of axillary temperature<36 ℃, respiratory rate≥30 beats/minutes, confusion, leukocytes>10×10(9)/L, hemoglobin<100 g/L, platelets>300×10(9)/L, albumin<35 g/L, blood urea nitrogen>7 mmol/L, fasting blood glucose>11 mmol/L, serum C-reaction protein>100 mg/L, serum procalcitonin≥2 µg/L, arterial pH<7.35, arterial PO(2)/FiO(2)≤300 mmHg (1 mmHg=0.133 kPa), and multilobar infiltrates and pleural effusion on chest X-ray or CT scan were significantly higher in CVE group than in non-CVE group(all P<0.05); the 30-day mortality was significantly higher in CVE group than in non-CVE group(P<0.001). The incidence of CVE was significantly higher in patients with cardiovascular and cerebrovascular disease(CVD) than in patients without CVD (13.9%(150/1 079) vs. 2.4%(60/2 482), χ(2)=178.737, P<0.001). Meanwhile, the incidence of CVE increased with PSI in patients with Ⅰ/Ⅱ, Ⅲ and Ⅳ/Ⅴ class, respectively(χ(2)=228.350, P<0.001); and CURB-65 score 0-1, 2 and 3-5, respectively (χ(2)=387.154, P<0.001). Cox regression analysis revealed that age (HR=1.05, 95%CI 1.02-1.09, P=0.002), coronary heart disease (HR=1.88, 95%CI 1.01-3.51, P=0.048), chronic heart failure (HR=4.25, 95%CI 1.89-9.52, P<0.001), PSI risk class (HR=1.66, 95%CI 1.50-2.62, P=0.029) and serum procalcitonin≥ 2 µg/L (HR=3.72, 95%CI 1.60-8.66, P=0.002) were independent risk factors for CVE in CAP patients. Kaplan-Meier curve showed that the survival probability of patients with CVE was significantly lower than patients without CVE (P<0.001). After adjustment for age, sex, comorbidities and PSI/CURB-65 score, Cox regression model showed that CVE was associated with increased 30-day mortality in CAP patients (HR=6.05, 95%CI 3.11-11.76, P<0.001). Conclusions: Although the incidence of CVE is not high in Chinese patients hospitalized with CAP, CVE is common in patients with severe pneumonia and in patients with CVD. Age, cardiovascular disease, PSI risk class and serum procalcitonin are the risk factors for CVE in this patient cohort. CVE is related to increased 30-day mortality in CAP patients.

[Clinical characteristics and prognosis of long-term glucocorticoid users with community-acquired pneumonia].

Objective: To explore the clinical features, etiological features and prognostic risk factors of long-term glucocorticoid users with community-acquired pneumonia (CAP). Methods: A retrospective study included 100 long-term glucocorticoid users with CAP (G-CAP group) from 11 hospitals of China between January 2014 and December 2014, while 100 non-immunocompromised patients with community-acquired pneumonia were enrolled as controls (nICH-CAP group). Characteristics including age, gender, underlying diseases, corticosteroids, symptoms, disease severity, imaging manifestations, etiology, respiratory failure, mechanical ventilation, whether the application of vasoactive drugs, antibiotics application, hospital mortality rate between the two groups were compared, and the prognostic factors of G-CAP were investigated using Logistic regression. Results: The peripheral blood lymphocytes[1.06(0.70, 1.68) vs 1.44 (0.87, 1.98)]in G-CAP group was less than nICH-CAP group (P<0.05). CT with pulmonary interstitial change (28.6% vs 9.9%), the proportion of patients with respiratory failure (25.0% vs 7.0%), mechanical ventilation (9.0% vs 2.0%), noninvasive mechanical ventilation (12.0% vs 2.0%), septic shock (9.0% vs 2.0%), and the hospital mortality rate (13.0% vs 3.0%) in G-CAP group were significantly higher than in nICH-CAP group (all P<0.05). Bacterial infection accounted for the highest proportion of infection (61.3%) in G-CAP group, but also virus infection (19.4%) and mixed infection (16.1%). Pseudomonas accounted for the highest proportion (47.4%) in bacterial infection of G-CAP. Logistic regression analysis showed that peripheral blood lymphocytes (OR=0.004, 95% CI: 0.000-0.234; P<0.05) and respiratory failure (OR=17.766, 95% CI: 4.933-131.0; P<0.05) were independent predictors of death in G-CAP group. Conclusions: The proportion of severe pneumonia and the mortality rate of patients with G-CAP are higher than the patients with nICH-CAP. Lymphopenia and respiratory failure are associated with poor outcome of patients with G-CAP.

Lipogenesis stimulatory and inhibitory activities of the insulin mediators.

Incubating plasma membranes prepared from pig liver with varying concentrations of insulin (50-1000 microU/ml) resulted in the release of at least two insulin chemical mediators. One of them was fraction 1 of insulin mediator (M. W. 3700-4000 daltons) which had a significant lipogenesis-stimulating activity. The other was fraction 2 of insulin mediator (M. W. about 1000 daltons) which exhibited a lipogenesis-inhibitory activity. The ratio of yield between the two mediators produced from the membranes was not only dependent on the concentration but also on the potency of insulin and its analogs added. The result showed that there was more production of fraction 2 than fraction 1 with the inducer at low concentration (100 microU/ml), while the production of fraction 1 from the plasma membranes incubated with high concentration of insulin (300 microU/ml) was higher than fraction 2. On the other hand, insulin and its analogs which have different biological activities and receptor binding activities have been used to induce the insulin mediators. The results obtained were similar to those mentioned above. This suggested that the generation of the mediators was dependent on the biological potences but not the binding activities.

Adenylate cyclase-modulating mediators of insulin.

Plasma membranes prepared from pig liver incubated with insulin (50-300 microU/ml) resulted in the release of at least two insulin chemical mediators. They appeared to modulate the activity of adenylate cyclase in liver plasma membranes of pig. One of them was fraction 1 of insulin mediator (M. W. about 3700-4000 dalton) which markedly stimulated the activity of the enzyme, the other was fraction 2 of insulin mediator (M. W. about 1000 dalton) which inhibited the enzyme activity. The results showed that the inhibitor of fraction 2 generated was significantly higher than that of fraction 1 when the membranes were incubated with insulin of low concentration (50-100 microU/ml). On the other hand, the generation of stimulator of fraction 1 from plasma membranes incubated with insulin of high concentration (200 microU/ml) was higher than that of fraction 2. So the ratio of yield between two mediators produced from the membranes was dependent on the concentration of insulin added. The results also showed that the effect of fraction 1 of insulin mediator on adenylate cyclase activity in liver cell plasma membranes was biphasic while fraction 2 of insulin mediator showed an inhibitory effect only even though it was at very high concentration. The results that both mediators combined with Gpp(NH)p and forskolin to affect the enzyme activity show that the action of insulin mediators likely resides in the GTP regulatory component of adenylate cyclase.

The role of insulin mediators in regulation of cAMP and lipogenesis as well as in diabetes.

Plasma membranes prepared from pig, mouse and rat liver incubated with insulin resulted in the release of at least two insulin chemical mediators. These mediators, identified as fractions 1 and 3, were found to inhibit cAMP level in response to lipolytic hormone and forskolin and to enhance lipogenesis in adipocytes of rat. Fractions 1 and 3 have been estimated to have molecular weights of 3700-4000 and 1000-1500 dalton, respectively. This initial report will focus on fraction 1. Interestingly, liver membranes from diabetic animals were found not to release mediators in the presence of insulin. However, following in vivo treatment of diabetic animals with insulin, the liver membranes appeared to restore its ability in generating chemical mediators in response to insulin.