Role of polymorphisms in codons 143 and 160 of the O6-alkylguanine DNA alkyltransferase gene in lung cancer risk

O6-Alkylguanine DNA alkyltransferase (AGT) plays an important role in the repair of alkylating agent-induced DNA damage and protection from the carcinogenic effects of environmental agents. To examine the importance of the AGT codon 143 and codon 160 polymorphisms in risk for lung cancer and to assess the prevalence of these polymorphisms in different racial groups, we performed genotype analysis of lung cancer patients and matched controls. The prevalence of the AGT143Val allele in controls was 0.07 in Caucasians and 0.03 in African Americans. The AGT143Val allele was not detected in an unmatched Asian control cohort. The prevalence of the AGT160Arg variant allele was 0.01 in Caucasians, 0.02 in African Americans, and 0.03 in Asians. A marginally significant association was observed between the AGT codon 143 (isoleucine/valine) genotype and risk for lung cancer (odds ratio = 2.1; 95% confidence interval = 1.01– 4.7). The prevalence of the AGT160Arg variant allele was similar in lung cancer cases versus matched controls. These results suggest that the AGT codon 143 polymorphism may play an important role in risk for lung cancer

An unusual case of a microscopic alveolar adenoma coexisting with lung carcinoma: a case report and review of the literature

<p>Abstract</p> <p>Introduction</p> <p>Alveolar adenomas are extremely rare, benign, primary lung tumors of unknown histogenesis that are characterized by proliferative type II alveolar epithelium and septal mesenchyma. Mostly incidental, they are clinically important as they can imitate benign primary and secondary malignant tumors and at times are difficult to differentiate from early-stage lung cancer. We describe the case of a 59-year-old man with an incidental microscopic alveolar adenoma coexisting with poorly differentiated lung carcinoma.</p> <p>Case presentation</p> <p>A 59-year-old Caucasian man with a medical history of smoking and chronic obstructive pulmonary disease was incidentally found to have a right upper lobe mass while undergoing a computed tomographic chest scan as part of a chronic obstructive pulmonary disease clinical trial. Our patient underwent a right upper lobectomy after a bronchoscopic biopsy of the mass revealed the mass to be a carcinoma. A pathological examination revealed an incidental, small, 0.2 cm, well circumscribed lesion on the staple line margin of the lobectomy in addition to the carcinoma. Histopathological and immunohistochemical examinations revealed the lesion to be an alveolar adenoma.</p> <p>Conclusions</p> <p>We report the rare presentation of a microscopic alveolar adenoma coexisting with lung carcinoma. Alveolar adenoma is an entirely benign incidental neoplasm that can be precisely diagnosed using immunohistochemical analysis in addition to its unique histopathological characteristics.</p

Treatment of Persistent Pulmonary Air Leaks Using Endobronchial Valves

Background: Prolonged pulmonary air leaks are a significant source of frustration for patients and physicians. When conventional therapy fails, an alternative to prolonged chest tube drainage or surgery is needed. Bronchoscopic blockage of a bronchus can be performed with the hope of accelerating closure of the air leak by reducing the flow of air through the leak. To on knowledge, this article presents the largest series of patients with prolonged air leaks treated with an endobronchial valve. Methods: With Internal Review Board approval, endobronchial valves were compassionately placed using flexible bronchoscopy in patients, with prolonged air leaks at 17 international sites. Results: Between December 2002 and January, 2007, 40 patients (15 women; mean age +/- SD, 60 +/- 14 Years) were treated with one to nine endobronchial valves per patient. The air leaks had recurrent spontaneous pneumothorax (n = 21), postoperative (n = 7), iatrogenic (n = 6), First-time spontaneous pneumothorax (n = 4), bronchoscopic lung volume reduction (n = 1), and trauma (n = 1) etiologies. Nineteen patients (47.5%) had a complete resolution of the air leak, 1.8 (45%) had a reduction, 2 had no change, and I had no reported outcome. The mean time from valve insertion to chest tube removal was 21 days (median, 7.5 days; interquartile range [IQR], 3 to 29 days) and from valve procedure to hospital discharge was 19 +/- 28 days (median, 11 days; IQR, 4 to 27 days). Conclusions: Use of endobronchial valves is an effective, nonsurgical, minimally invasive intervention for patients with prolonged pulmonary air leaks. (CHEST 2009; 136:355-360

Air Current Applied to the Face Improves Exercise Performance in Patients with COPD

Purpose: Improving dyspnea and exercise performance are goals of COPD therapy. We tested the hypothesis that air current applied to the face would lessen dyspnea and improve exercise performance in moderate-severe COPD patients.Methods: We recruited 10 COPD patients (5 men, age 62 ± 6 years, FEV1 0.93 ± 0.11 L (34 ± 3 % predicted), TLC 107 ± 6 %, RV 172 ± 18 %) naïve to the study hypothesis. Each patient was randomized in a crossover fashion to lower extremity ergometry at constant submaximal workload with a 12-diameter fan directed at the patients face or exposed leg. Each patients\u27 studies were separated by at least 1 week. Inspiratory capacity and Borg dyspnea score were measured every 2 min and at maximal exercise.Results: Total exercise time was longer when the fan was directed to the face (14.3 ± 12 vs. 9.4 ± 7.6 min, face vs. leg, respectively, p = 0.03). Inspiratory capacity tended to be greater with the fan directed to the face (1.4 (0.6-3.25) vs. 1.26 (0.56-2.89) L, p = 0.06). There was a reduction in dynamic hyperinflation, as reflected by higher IRV area in the fan on face group (553 ± 562 a.u. vs. 328 ± 319 a.u., p = 0.047). There was a significant improvement in the Borg dyspnea score at maximal exercise (5.0 (0-10) vs. 6.5 (0-10), p = 0.03), despite exercising for 34 % longer with the fan directed to the face.Conclusions: Air current applied to the face improves exercise performance in COPD. Possible mechanisms include an alteration in breathing pattern that diminishes development of dynamic hyperinflation or to a change in perception of breathlessness

Recognition and reprogramming of E3 ubiquitin ligase surfaces by α-helical peptides

Abstract Molecules that induce novel interactions between proteins hold great promise for the study of biological systems and the development of therapeutics, but their discovery has been limited by the complexities of rationally designing interactions between three components, and because known binders to each protein are typically required to inform initial designs. Here, we report a general and rapid method for discovering α-helically constrained (Helicon) polypeptides that cooperatively induce the interaction between two target proteins without relying on previously known binders or an intrinsic affinity between the proteins. We show that Helicons are capable of binding every major class of E3 ubiquitin ligases, which are of great biological and therapeutic interest but remain largely intractable to targeting by small molecules. We then describe a phage-based screening method for discovering “trimerizer” Helicons, and apply it to reprogram E3s to cooperatively bind an enzyme (PPIA), a transcription factor (TEAD4), and a transcriptional coactivator (β-catenin)

Lung Cancer Risk in White and Black Americans

PURPOSE: To test whether differences in smoking-related lung cancer risks in blacks and whites can explain why lung cancer incidence is greater in black males than in white males but about equal in black and white females, given that a greater proportion of blacks are smokers, but smoke far fewer cigarettes per day than do whites. METHODS: A hospital-based case-control study was conducted between 1984 and 1998 that included interviews with 1,710 white male and 1,321 white female cases of histologically confirmed lung cancer, 254 black male and 163 black female cases, and 8,151 controls. Relative risks were estimated via odds ratios using logistic regression, adjusted for age, education, and body mass index. RESULTS. We confirmed prior reports that smoking prevalence is higher but overall dosage is lower among blacks. Overall ORs were similar for blacks and whites, except among the heaviest smoking males (21+ cigarettes per day or 37.5 pack–years), in whom ORs for blacks were considerably greater than for whites. Long-term benefits of cessation were similar for white and black ex-smokers. Smokers of menthol flavored cigarettes were at no greater risk for lung cancer than were smokers of unflavored brands. CONCLUSIONS. Lung cancer risks were similar for whites and blacks with similar smoking habits, except possibly for blacks who were very heavy smokers; this sub-group is unusual in the general population of African American smokers. Explanations of racial disparities in lung cancer risk may need to account for modifying factors including type of cigarette (yield, mentholation), diet, occupation, and host factors such as ability to metabolize mainstream smoke carcinogens

Mirror-image ligand discovery enabled by single-shot fast-flow synthesis of D-proteins

Abstract Widespread adoption of mirror-image biological systems presents difficulties in accessing the requisite D-protein substrates. In particular, mirror-image phage display has the potential for high-throughput generation of biologically stable macrocyclic D-peptide binders with potentially unique recognition modes but is hindered by the individualized optimization required for D-protein chemical synthesis. We demonstrate a general mirror-image phage display pipeline that utilizes automated flow peptide synthesis to prepare D-proteins in a single run. With this approach, we prepare and characterize 12 D-proteins – almost one third of all reported D-proteins to date. With access to mirror-image protein targets, we describe the successful discovery of six macrocyclic D-peptide binders: three to the oncoprotein MDM2, and three to the E3 ubiquitin ligase CHIP. Reliable production of mirror-image proteins can unlock the full potential of D-peptide drug discovery and streamline the study of mirror-image biology more broadly