Smoking history and epidermal growth factor receptor expression as predictors of survival benefit from erlotinib for patients with non-small-cell lung cancer in the National Cancer Institute of Canada Clinical Trials Group study BR.21

BACKGROUND: Erlotinib is an oral, reversible inhibitor of the HER1/epidermal growth factor receptor (EGFR) tyrosine kinase. A survival advantage for erlotinib compared with placebo was demonstrated in the National Cancer Institute of Canada Clinical Trials Group study BR.21, a randomized double-blind study of 731 patients with advanced-stage non-small-cell lung cancer. PATIENTS AND METHODS: In this retrospective, exploratory investigation, univariate and multivariate analyses of survival of the 311 patients with available EGFR status by immunohistochemistry and known smoking history were performed to determine which factor might be more important for predicting clinical outcome. RESULTS: A marginally significant interaction was observed between smoking history and treatment (P = 0.054). The hazard ratios (HRs) were 0.42 among never-smokers and 0.87 for smokers, indicating that erlotinib was beneficial in both subsets but more effective in patients who had never smoked. The HRs for patients with EGFR-positive and EGFR-negative tumors were 0.65 and 0.83, respectively; however, the interaction between EGFR status and treatment was not significant in univariate or multivariate analyses. Patients with EGFR-positive tumors who never smoked had the greatest survival benefit from erlotinib relative to placebo (HR, 0.28; P = 0.0007). CONCLUSION: These data suggest that never-smokers and patients with EGFR-positive tumors might experience an enhanced benefit from erlotinib compared with placebo but that smoking history might be more predictive of survival benefit than EGFR expression. Subset analyses of ever-smokers revealed significant survival advantages for men and patients with squamous cell histology. Male ever-smokers with squamous cell non-small-cell lung cancer derived a significant survival benefit from erlotinib (HR, 0.66; P = 0.015) despite a very low tumor response rate.     

Complication-free labor in operated-on Cushing's syndrome

By the casuistical report on a successfully carried out gravidity of a 21 years old female patient without suprarenal glands which have been removed totally because of a hyperplasia of the suprarenal cortex on both sides, the problems of gravidities and their successful carrying to the term of operated femal patients with Cushing's disease are dealt with. Under experienced substitution therapy and an intensive care a gravidity without complications is to be expected. The apprehension is unfounded that overdosage of corticoid during gravidity could induce malformations of new-born children. The substitution dosis during gravidity is discussed by literature.     

Pharmacologic differentiation of inflammation and fibrosis in the rat bleomycin model

RATIONALE: The model most often used to study the pathogenesis of pulmonary fibroses is the bleomycin (BLM)-induced lung fibrosis model. Several treatments have been efficacious in this model, but not in the clinic. OBJECTIVES: To describe the time course of inflammation and fibrosis in the BLM model and to study the effect of timing of antiinflammatory and antifibrotic treatments on efficacy. METHODS AND MEASUREMENTS: Rats were given single intratracheal injections of BLM on Day 0. At specified time points, 10 rats were killed and their lungs studied for proinflammatory cytokines and for profibrotic growth factor mRNA. After a single intratracheal injection of BLM on Day 0, rats were treated from Day 1 or 10 daily with oral prednisolone (10 mg/kg) or oral imatinib mesylate (50 mg/kg) for 21 d. RESULTS: After BLM administration, the expression of inflammatory cytokines was elevated and returned to background levels at later time points. Profibrotic gene expression peaked between Days 9 and 14 and remained elevated till the end of the experiment, suggesting a "switch" between inflammation and fibrosis in this interval. Antiinflammatory treatment (oral prednisolone) was beneficial when commenced at Day 1, but had no effect if administered from Day 10 onward. However, imatinib mesylate was effective independently of the dosing regime. CONCLUSIONS: The response of the BLM model to antifibrotic or antiinflammatory interventions is critically dependent on timing after the initial injury.     

Strategies for Mentor Matching: Lessons Learned

Mentoring serves to guide early stage researchers toward opportunities which can further their careers. The most beneficial mentoring experience occurs when both the mentor and mentee share a common background and have appropriate expectations. Our CTSA serves individuals in a five state region with widely disparate needs and we have often struggled to provide appropriate guidance for those requesting mentoring services. Here we present an overview of our past mentor identification strategy along with a proposed new direction to increase flexibility, sustainability and better serve researchers in our region.     

Attachment of primary neonatal rat astrocytes to vitronectin is mediated by integrins alphavbeta5 and alpha8beta1: modulation by the type 1 plasminogen activator inhibitor

Vitronectin is expressed in a cell-specific manner in the developing brain and concentrated in the brain during disease processes, such as germinal matrix hemorrhage and infarction, in which there is breakdown of the blood-brain barrier. In this study, we identified the integrin receptors that mediate attachment of primary neonatal rat astrocytes to vitronectin. Using fluorescent activated cell sorter and immunoprecipitation analyses, we established that the vitronectin receptor integrins alphavbeta5 and alpha8beta1, but not alphavbeta3, are expressed on neonatal rat astrocytes. Attachment of the neonatal astrocytes to vitronectin was inhibited (85%) in an additive manner by neutralizing anti-alphavbeta5 and anti-beta1 antibodies. Attachment to vitronectin was also inhibited in a dose-dependent manner by the type I plasminogen activator inhibitor (PAI-1), a serine protease inhibitor. Our data demonstrate that unstimulated primary neonatal rat astrocytes attach to vitronectin, utilizing integrins alphavbeta5 and alpha8beta1, and that this attachment is regulated by PAI-1.     

Functional and biochemical rationales for the 24-hour-long duration of action of olodaterol

β(2)-Adrenoceptor (β(2)-AR) agonists are powerful bronchodilators and play a pivotal role in the management of pulmonary obstructive diseases, such as asthma and chronic obstructive pulmonary disease. Although these agents first were used many years ago, progress in drug development has resulted in better tolerated, long-acting β(2)-AR agonists (LABAs), such as formoterol and salmeterol. Although LABAs have been on the market for several years, relatively little is known on the rationale(s) behind their long duration of action. In this study, we focused on olodaterol (previously known as BI1744CL), a novel inhaled LABA, which provides a bronchodilating effect lasting 24 h and is currently in Phase III clinical trials. To understand the rationale behind its long duration of action, different aspects of olodaterol were analyzed (i.e., its lipophilicity and propensity to accumulate in the lipid bilayer as well as its tight binding to the β(2)-AR). In line with its physicochemical properties, olodaterol associated moderately with lipid bilayers. Instead, kinetic as well as equilibrium binding studies indicated the presence of a stable [(3)H]olodaterol/β(2)-AR complex with a dissociation half-life of 17.8 h due to ternary complex formation. The tight binding of olodaterol to the human β(2)-AR and stabilization of the ternary complex were confirmed in functional experiments monitoring adenylyl cyclase activity after extensive washout. Taken together, binding, kinetic, and functional data support the existence of a stable complex with the β(2)-AR that, with a dissociation half-life >17 h, might indeed be a rationale for the 24-h duration of action of olodaterol.     

The Mental Health Needs Council of Harris County: A Case Report on Community Collaboration and Adult Mental Illness Prevalence Assessment and Service Need Analysis

Accurate mental illness prevalence and service needs assessment are critical to the development and delivery of effective mental health programs. Assessment precision and efficient service development and delivery are best facilitated by a close collaboration of all relevant major stakeholders. This report examines the history, mission, and composition of the Mental Health Needs Council of Harris County, Texas. This Council, located in Houston, has for the past 25 years investigated mental health service problems and recommended strategies for their solution. This Council consists of all of Harris County’s major public service providers, professional groups and advocacy organizations. This report traces the evolution of the Council’s prevalence and needs assessment methodologies. Its current methodologies are examined. These assessment strategies are applicable to other metropolitan areas. The Mental Health Needs Council is a model for effective community collaboration on the needs and problems of persons with mental illness.