Paclitaxel and vinorelbine cause synergistic increases in apoptosis but not in microtubular disruption in human lung adenocarcinoma cells (A-549)

Concurrent administration of paclitaxel and vinorelbine results in cytotoxicity in vivo and in vitro in a number of tumor cell lines, yet the mechanisms of enhanced cell killing are undefined. In studies here, we show that low concentrations (1 nM) of paclitaxel and vinorelbine in combination result in enhanced cell killing by apoptosis (P<0.05) in the human lung adenocarcinoma cell line, A-549. In contrast, necrotic cell death and formation of multinucleated cells, which were significantly increased by paclitaxel (P<0.05) alone, but not vinorelbine, were not increased synergistically by both drugs. Paclitaxel also caused microtubular disruption which was not observed with vinorelbine. These data provide further rationale for the combined use of paclitaxel and vinorelbine in clinical trials, and suggest that the cooperative effects of drugs on apoptosis are not mediated through similar disruptional effects on microtubules.     

Projections of lung cancer mortality in West Germany: a case study in Bayesian prediction

We apply a generalized Bayesian age-period-cohort (APC) model to a data-set on lung cancer mortality in West Germany, in the period 1952-1996. Our goal is to predict future death rates until the year 2010, separately for males and females. Since age and period are not measured on the same grid, we propose a generalized APC model where consecutive cohort parameters represent strongly overlapping birth cohorts. This approach results in a rather large number of parameters, where standard algorithms for statistical inference by Markov chain Monte Carlo methods turn out to be computationally intensive. We propose a more efficient implementation based on ideas of block sampling from the time series literature. We entertain two different formulations, penalizing either first or second differences of age, period and cohort parameters. To assess the predictive quality of both formulations, we first forecast the rates for the period 1987-1996 based on data until 1986. A comparison with the actual observed rates is made based on a predictive deviance criterion. Predictions of lung cancer mortality until 2010 are then reported and a modification of the formulation in order to include information on cigarette consumption is finally described.To whom correspondence should be addressed. Currently at Imperial College School of Medicine, Department of Epidemiology and Public Health, Norfolk Place, London W2 1PG, UK.     

Targeting apoptotic signalling pathway and pro-inflammatory cytokine expression as therapeutic intervention in TPE induced lung damage

Tropical pulmonary eosinophilia (TPE) is an occult manifestation of filariasis, brought about by helminth parasites Wuchereria bancrofti and Brugia malayi. Treatment of patients suffering from TPE involves the administration of diethyl carbamazine and Ivermectin. Although the drugs are able to block acute inflammation, they are not able to alleviate chronic basal inflammation. We have attempted to examine the disease by targeting two important components; namely filarial parasitic sheath proteins (FPP) induced apoptosis and pro-inflammatory cytokine response in human laryngeal carcinoma cells of epithelial origin (HEp-2) cells an epithelial cell line. Earlier studies by us have shown that FPP exposure induced apoptosis in these cells. In this study with hydrocortisone, calpain inhibitor (ALLN) and phorbol myristate acetate (PMA) treatments we demonstrate that apoptosis is inhibited as shown by [3H] thymidine incorporation studies, propidium iodide staining and Annexin V staining. Hydrocortisone at a dose, which inhibits cell death also down regulated, the expression of pro-inflammatory cytokines IL-6 and IL-8. These findings give us insights into the multifaceted approach one may adopt to target critical signalling molecules using appropriate inhibitors, which could eventually be used to reduce lung damage in TPE.     

Life-prolonging effect of immunocell BAK (BRM-activated killer) therapy for advanced solid cancer patients: prognostic significance of serum immunosuppressive acidic protein levels

We devised an innovative type of immunocell therapy called BRM (biological response modifier)-activated killer (BAK) therapy, which utilizes most of non-MHC (major histocompatibility complex) restricted lymphocytes, CD56⁺ cells including T cells and NK cells. Peripheral blood lymphocytes were selected by immobilizing them with anti-CD3 monoclonal antibody, cultured for 2 weeks with serum-free medium containing IL-2, and then were reactivated by 1,000 U/ml of IFN- for 15 min. The patients were infused with about 6×10⁹ BAK cells by intravenous drip infusion at 1-month intervals. All advanced solid cancer patients who had received chemotherapy but for whom it was not effective or have refused chemotherapy were included in the present study. A good marker of impairment of host immune response by chemotherapy is an immunosuppressive acidic protein (IAP) level in serum above 580 g/ml; survival rates were compared with the high (>580 g/ml) and the low (580 g/ml) serum IAP groups. We enrolled in this study 23 immunosuppressed patients whose IAP levels in serum were over 580 g/ml, and 42 immunoreactive solid cancer outpatients whose IAP level in serum were under 580 g/ml and whose performance statuses were over 80% on the Karnofsky scale. After giving informed consent, patients were treated with BAK therapy on an outpatient basis at our hospital. The ethical review board of the Miyagi Cancer Center approved this pilot study. Treated with BAK therapy, the mean survival of immunosuppressed patients was 4.6 months. On the other hand, survival for one of immunoreactive advanced postoperative patients (stage IV) and inoperable lung cancer patients (stage IIIb) was 24.7 months. The difference in survival between the 2 groups was significant (P<0.01). This shows that BAK therapy is not indicated for an advanced cancer patient whose serum IAP is over 580 g/ml, perhaps due to extensive chemotherapy. Overall response to BAK therapy was complete response (CR) in 5 cases, partial response (PR) in 1 case, and prolonged no change (NC) in 26 cases, with an effectiveness rate at 76.2% in 42 advanced stage IIIb and IV cancer patients. BAK therapy has a life-prolonging effect without any adverse effects and maintains satisfactory quality of life (QOL) for advanced cancer patients.     

The effects of Escherichia coli capsule, O-antigen, host neutrophils, and complement in a rat model of Gram-negative pneumonia

Gram-negative enteric bacilli are agents of life-threatening pneumonia. The role of the bacterial capsule and O-antigen moiety of lipopolysaccharide in the pathogenesis of Gram-negative pneumonia was assessed. In a rat model of pneumonia the LD(50) of a wild-type extraintestinal pathogenic Escherichia coli strain (CP9) was significantly less than its isogenic derivatives deficient in capsule (CP9.137), O-antigen (CP921) or both capsule and O-antigen (CP923) (P< or =0.003). Studies using complement depleted or neutropenic animals established that both neutrophils and complement are important for the pulmonary clearance of E. coli. Data from these studies also support that capsule and O-antigen serve, at least in part, to counter the complement and neutrophil components of the pulmonary host defense response. Lastly, the contribution of E. coli versus neutrophils in causing lung injury was examined. Findings suggest that E. coli virulence factors and/or non-neutrophil host factors are more important mediators of lung injury than neutrophils. These findings extend our understanding of Gram-negative pneumonia and have treatment implications.     

Association between lung cancer screening and smoking cessation

IntroductionAdults with high-risk smoking histories benefit from annual lung cancer screening. It is unclear if there is an association between lung cancer screening and smoking cessation among U.S. adults who receive screening.MethodsWe performed this population-based cross-sectional study using data from the Behavioral Risk Factor Surveillance System (2017–2020). We defined individuals eligible for lung cancer screening as adults 55–80 years old with ≥ 30 pack-year smoking history who were currently smoking or quit within the last 15 years. We assessed the association between lung cancer screening and current smoking status.ResultsBetween 2017 and 2020, 12,382 participants met screening criteria. Current smoking was reported by 5685 (45.9 %) participants, of whom 40.4 % (2298) reported a cessation attempt in the prior year. Lung cancer screening was reported by only 2022 (16.3 %) eligible participants. Lung cancer screening was associated with lower likelihood of currently smoking (odds ratio [OR] 0.705, 95 % CI 0.626–0.793) compared to individuals who did not receive screening. Screening was also associated with higher likelihood of reporting a cessation attempt in the prior year (OR 1.562, 95 % CI 1.345–1.815) compared to individuals who did not receive screening.ConclusionsReceipt of lung cancer screening was associated with lower smoking rates and more frequent cessation attempts among U.S. adults. Better implementation of lung cancer screening programs is critical and may profoundly increase smoking cessation in this population at risk of developing lung cancer.     

NLRP3炎症小体对克雷伯杆菌肺炎小鼠肺脏病理损伤的调节作用

摘要 目的：探讨含NLR家族PYRIN域蛋白3（NLR family pyrin domain containing 3,NLRP3）炎症小体对克雷伯杆菌肺炎小鼠肺脏病理损伤的调节作用。方法：56只C57BL/6小鼠随机平分为两组-模型组与对照组,模型组小鼠通过气管注射肺炎克雷伯杆菌建立克雷伯杆菌肺炎模型,对照组小鼠注射等体积的生理盐水,记录与观察肺脏病理损伤情况。结果：模型组建模第7 d与第14 d的肺泡灌洗液髓过氧化酶（Myeloperoxidase,MPO）活性都高于对照组（P<0.05）。模型组建模第7 d与第14 d的肺脏、脾脏、肝脏系数与肺脏病理评分、NLRP3蛋白相对表达水平都高于对照组（P<0.05）。在模型组中,建模第14 d的NLRP3蛋白相对表达水平与肺脏病理评分、肺脏系数、脾脏系数、肝脏系数、肺泡灌洗液MPO活性都存在正相关性（P<0.05）。结论：克雷伯杆菌肺炎小鼠NLRP3炎症小体呈现高表达状况,可介导小鼠肺脏病理损伤,促进MPO活性增加,加重多脏器损伤。