Grit and Thoracic Surgery Interest Among Medical Students.

OBJECTIVE: This study evaluated the relationship between medical student Grit and thoracic surgery career interest. DESIGN: An online questionnaire was designed to measure self-reported ratings of Grit among medical student using the Short-Grit scale, as well as thoracic surgery career interest. SETTING: Faculty of Medicine, Dalhousie University, Halifax, NS, Canada. PARTICIPANTS: From 2019 to 2021, 192/367 (52.3%) participants in their first or second year of medical school. The cohort was comprised of 109 (56.8%) females while 115 (59.9%) were <24 years of age. RESULTS: Mean Grit was high (M = 4.159 +/- 0.450) among medical students. There were 80 (41.2%) students interested in thoracic surgery. There was a significant difference in Grit between students with a career interest in thoracic surgery (4.256 +/- 0.442) and those uninterested in thoracic surgery (4.089 +/- 0.444); t(190) = 2.572, p = 0.011; Cohen's D = 0.442. Career interest in thoracic surgery was not influenced by career factor interest. CONCLUSIONS: Grittier students have a career interest in thoracic surgery. Recruitment teams in thoracic surgery residency programs with high rates of burnout and poor psychological wellbeing among trainees may take interest in these findings.

Robotic segmentectomy for early-stage lung cancer.

Lobectomies have long been the gold standard for surgical treatment of early-stage non-small cell lung cancer (NSCLC), with segmentectomies limited to instances of benign disease or as an alternative in patients where lung preservation is indicated. However, a recently published randomized control trial has demonstrated the superiority of segmentectomy over lobectomy in terms of overall survival for early-stage lung cancer. Segmentectomy could thus be considered a standard procedure for small-sized peripheral NSCLC. While segmentectomy via video-assisted thoracic surgery (VATS) is the most widespread approach, development in video instrumentation and thoracic robotic surgery is rapidly gaining interest. Indeed, robotic surgery pioneers boast the advantages in three-dimensional view, improved magnification, ergonomics, dexterity, safety, and ease of surgery with this technology. This review aims to outline robotic-assisted segmentectomy indications, preoperative evaluation, and the operative conduct for the different lung segments from a single surgeon console. There are many ways to perform segmentectomies and therefore this review describes generalized approaches that can be tailored based on experience.

Screening Criteria Evaluation for Expansion in Pulmonary Neoplasias (SCREEN).

The SCREEN study investigated screening eligibility and survival outcomes between heavy smokers and light-or-never-smokers with lung cancer to determine whether expanded risk factor analysis is needed to refine screening criteria. SCREEN is a retrospective study of 917 lung cancer patients diagnosed between 2005 and 2018 in Nova Scotia, Canada. Screening eligibility was determined using the National Lung Screening Trial (NSLT) criteria. Mortality risk between heavy smokers and light-or-never-smokers was compared using proportional-hazards models. The median follow-up was 2.9 years. The cohort was comprised of 179 (46.1%) female heavy smokers and 306 (57.8%) female light-or-never-smokers. Light-or-never-smokers were more likely to have a diagnosis of adenocarcinoma [n=378 (71.6%)] compared to heavy smokers [n=234 (60.5%); P< 0.001]. Heavy smokers were more frequently diagnosed with squamous cell carcinoma [n=111 (28.7%)] compared to light-or-never-smokers, [n=100 (18.9%); P< 0.001]. Overall, 36.9% (338) of patients met NLST screening criteria. There was no difference in 5-year survival between light-or-never-smokers and heavy smokers [55.2% (338) vs 58.5% (529); P = 0.408; HR 1.06, 95% CI 0.80-1.40; P = 0.704]. Multivariate analysis showed that males had an increased mortality risk [HR 2.00 (95% CI 1.57-2.54); P< 0.001]. Half of lung cancer patients were missed with the conventional screening criteria. There were more curable, stage 1 tumors among light-or-never-smokers. Smoking status and age alone may be insufficient predictors of lung cancer risk and prognosis. Expanded risk factor analysis is needed to refine lung cancer screening criteria.

Large bilateral pulmonary arterial venous malformations treated with embolization and lingulectomy in a patient with hereditary hemorrhagic telangiectasia.

A 76-year-old woman with hereditary hemorrhagic telangiectasia presented to the emergency department with chest pain. Workup revealed multiple bilateral pulmonary arteriovenous malformations (PAVMs) with large aneurysmal venous outflow. A collaborative approach between interventional radiology and thoracic surgery was used in the treatment of these PAVMs.

Three-stage approach to resection of left pancoast tumour with spinal and major vessel involvement.

Here we describe the successful outcome of a complex and challenging resection of a left-sided pancoast tumour involving the left subclavian artery and vertebral bodies. The resection was performed following neoadjuvant chemoradiotherapy in a multi-staged fashion involving multiple teams including thoracic surgery, plastic surgery, neurosurgery and vascular surgery. Each operation was less than 6 h, without complication, and the patient was discharged within 1 week of each procedure. This case report highlights the importance of multidisciplinary team collaboration and planning in order to achieve a successful oncologic outcome and a good quality of life following treatment of these challenging tumours. The patient had a good functional outcome and no evidence of recurrence 1.5 years later.

Expression of matrix metalloproteinase-1 in alveolar macrophages, type II pneumocytes, and airways in smokers: relationship to lung function and emphysema.

BACKGROUND: An imbalance between proteolytic enzymes and their inhibitors is thought to be involved in the pathogenesis of chronic obstructive pulmonary disease. Matrix metalloproteinase-1, also known as interstitial collagenase, has been implicated as a potentially important proteinase in the genesis of chronic obstructive pulmonary disease and, more specifically, emphysema. METHODS: We performed quantitative immunohistochemical assessment of matrix metalloproteinase-1 expression in the resected lung of 20 smokers/ex-smokers who had varying severity of airflow obstruction and emphysema and compared this with the lungs of 5 nonsmokers. Emphysema was measured using a morphometric measure of the lungs' surface area/volume ratio and with qualitative and quantitative computed tomography (CT) measures of emphysema. RESULTS: There were significantly more matrix metalloproteinase-1-expressing alveolar macrophages and type II pneumocytes as well as a greater percentage of small airways that stained positively for matrix metalloproteinase-1 in the lungs of smokers than in those of nonsmokers (p < 0.0001, p < 0.0001, and p = 0.0003, respectively). The extent of staining of type II pneumocytes and airways for matrix metalloproteinase-1 was significantly related to the extent of smoking (p = 0.012 and p = 0.013, respectively). In addition, the extent of matrix metalloproteinase-1 staining of alveolar macrophages was related to the lung surface area/volume ratio and to qualitative estimates of emphysema on CT. CONCLUSION: These findings suggest that cigarette smoking increases expression of matrix metalloproteinase-1 in alveolar macrophages as well as in alveolar and small airway epithelial cells. Smokers who develop emphysema have increased alveolar macrophage expression of matrix metalloproteinase-1.

Alveolar macrophage proteinase/antiproteinase expression in lung function and emphysema.

Alveolar macrophages play an important role in chronic obstructive pulmonary disease via production of matrix metalloproteinases (MMPs) and cathepsins as well as their inhibitors, tissue inhibitors of metalloproteinases and cystatin C. We hypothesised that expression levels of these molecules by alveolar macrophages at baseline and after stimulation would be influenced by genotype and associated with chronic obstructive pulmonary disease phenotypes. Quantitative PCR and ELISAs/gelatine zymography were used to investigate expression levels of mRNA and protein, respectively. The relationships of expression with genotype, pulmonary function and emphysema were analysed. The results showed that basal expression level of MMP12 mRNA was inversely related to the diffusing capacity of the lung for carbon monoxide/alveolar volume and to forced expiratory volume in 1 s/forced vital capacity after correction for multiple comparisons. The expression level of MMP12 protein stimulated with lipopolysaccharide was also inversely related to the diffusing capacity of the lung for carbon monoxide/alveolar volume and was positively related to the extent of emphysema. The basal expression of MMP1 mRNA was positively correlated with the extent of emphysema. Cathepsin L protein level was positively associated with forced expiratory volume in 1 s % predicted. We conclude that increased MMP12 and MMP1 expression may play a role in the pathogenesis of emphysema. Cathepsin L and MMP9 may be involved in the development of airflow limitation.

The glutathione peroxidase 1-protein tyrosine phosphatase 1B-protein phosphatase 2A axis. A key determinant of airway inflammation and alveolar destruction.

Protein phosphatase-2A (PP2A) is a primary serine-threonine phosphatase that modulates inflammatory responses in asthma and chronic obstructive pulmonary disease (COPD). Despite its importance, the mechanisms that regulate lung PP2A activity remain to be determined. The redox-sensitive enzyme protein tyrosine phosphatase-1B (PTP1B) activates PP2A by dephosphorylating the catalytic subunit of the protein at tyrosine 307. This study aimed to identify how the interaction between the intracellular antioxidant glutathione peroxidase-1 (GPx-1) and PTP1B affected lung PP2A activity and airway inflammation. Experiments using gene silencing techniques in mouse lung or human small airway epithelial cells determined that knocking down PTP1B expression blocked GPx-1's activation of PP2A and negated the anti-inflammatory effects of GPx-1 protein in the lung. Similarly, the expression of human GPx-1 in transgenic mice significantly increased PP2A and PTP1B activities and prevented chronic cigarette smoke-induced airway inflammation and alveolar destruction. GPx-1 knockout mice, however, exhibited an exaggerated emphysema phenotype, correlating with a nonresponsive PP2A pathway. Importantly, GPx-1-PTP1B-PP2A signaling becomes inactivated in advanced lung disease. Indeed, PTP1B protein was oxidized in the lungs of subjects with advanced emphysema, and cigarette smoke did not increase GPx-1 or PTP1B activity within epithelial cells isolated from subjects with COPD, unlike samples of healthy lung epithelial cells. In conclusion, these findings establish that the GPx-1-PTP1B-PP2A axis plays a critical role in countering the inflammatory and proteolytic responses that result in lung-tissue destruction in response to cigarette smoke exposure.

Functional characterization of the matrix metalloproteinase-1 cigarette smoke-responsive region and association with the lung health study.

BACKGROUND: Prior studies have demonstrated that the distal 1.5 kb of the MMP-1 promoter is fundamental in directing the induction of the MMP-1 gene by cigarette smoke. METHODS: To characterize the genetic variants in the MMP-1 cigarette smoke-responsive element, deep re-sequencing of this element was performed on DNA samples from participants in the Lung Health Study. Furthermore, evidence of Sp1 binding to the MMP-1 promoter was assessed using chromatin immunoprecipitation assays and the influence of cigarette smoke exposure on this interaction was evaluated in cultured human small airway epithelial cells. RESULTS: Ten polymorphisms (four novel) were detected in the cigarette smoke-responsive element. Chromatin immunoprecipitation assays to assess the protein-DNA interactions at Sp1 sites in the MMP-1 promoter showed increased binding to the Sp1 sites in the cigarette smoke-responsive element in small airway epithelial cells treated with cigarette smoke extract. In contrast, a Sp1 site outside of the element exhibited the opposite effect. None of the polymorphisms were more prevalent in the fast decliners versus the slow decliners (fast decliners = mean -4.14% decline in FEV1% predicted per year vs. decline in FEV1% predicted per year). CONCLUSIONS: Sequencing analyses identified four novel polymorphisms within the cigarette smoke-responsive element of the MMP-1 promoter. This study identifies functional activity within the cigarette smoke-responsive element that is influenced by cigarette smoke and examines this region of the promoter within a small patient population.

Protein phosphatase 2A regulates innate immune and proteolytic responses to cigarette smoke exposure in the lung.

Protein phosphatase 2A (PP2A) is the primary serine-threonine phosphatase of eukaryotic cells, and changes in its activity have been linked to neoplastic and neurodegenerative diseases. However, the role of PP2A in noncancerous lung diseases such as chronic obstructive pulmonary disease (COPD) has not been previously examined. This study determined that PP2A activity was significantly increased in the lungs of advanced emphysema subjects compared with age-matched controls. Furthermore, we found that cigarette smoke exposure increases PP2A activity in mouse lung in vivo and in primary human small airway epithelial (SAE) cells in vitro. In mice, intratracheal transfection of PP2A protein prior to cigarette smoke exposure prevented acute smoke-induced lung inflammation. Conversely, inhibiting PP2A activity during smoke exposure exacerbated inflammatory responses in the lung. To further determine how PP2A modulates the responses to cigarette smoke in the lung, enzyme levels were manipulated in SAE cells using protein transfection and short hairpin RNA (shRNA) techniques. Increasing PP2A activity in SAE cells via PP2A protein transfection downregulated cytokine expression and prevented the induction of proteases following cigarette smoke extract (CSE) treatment. Conversely, decreasing enzymatic activity by stably transfecting SAE cells with shRNA for the A subunit of PP2A exacerbated these smoke-mediated responses. This study establishes that PP2A induction by cigarette smoke modulates immune and proteolytic responses to cigarette smoke exposure. Together, these findings suggest that manipulation of PP2A activity may be a plausible means to treat COPD and other inflammatory diseases.

Role of genetic susceptibility to latent adenoviral infection and decreased lung function.

BACKGROUND: Latent adenoviral infection may amplify cigarette smoke-induced lung inflammation and therefore play an important role in the development of chronic obstructive pulmonary disease (COPD). Adenoviruses can evade the human immune response via their 19-kDa protein (19K) which delays the expression of class I human leukocyte antigen (HLA) proteins. The 19K protein shows higher affinity to HLA-B7 and A2 compared with HLA-A1 and A3. The receptor for adenovirus (CXADR) and integrin beta(5) (ITGB5) are host factors which might affect adenovirus infection. Therefore, we investigated the contribution of HLA, CXADR, and ITGB5 genetic variants to the presence of the E1A gene and to level of lung function. METHODS: Study subjects were assayed for HLA-B7, A1, A2 and A3 by PCR-based assays using allele-specific primers. Polymorphisms of the CXADR and ITGB5 genes were genotyped by PCR-based restriction fragment length polymorphism assays. Detection of adenoviral E1A gene was performed by a real-time PCR TaqMan assay. RESULTS: E1A positive individuals had a lower FEV(1) compared with E1A negative individuals. However, there was no significant difference in E1A positivity rate between the high (HLA-B7 and A2) and low (HLA-A1 and A3) 19K affinity groups. There was also no significant difference in FEV(1) level between each affinity group. There was no significant difference in E1A positivity rate or lung function among the CXADR and ITGB5 genotypes. CONCLUSIONS: Genetic variants in HLA, CXADR and ITGB5 do not influence latent adenoviral infections and are not associated with COPD.

Identification of a cigarette smoke-responsive region in the distal MMP-1 promoter.

Tobacco-related diseases are leading causes of death worldwide, and many are associated with expression of matrix metalloproteinase-1 (MMP-1). We have reported extracellular signal-regulated kinase (ERK)1/2-dependent induction of MMP-1 by cigarette smoke in lung epithelial cells. Our objectives were to define regions of the human MMP-1 promoter required for activation by smoke, to identify differences in responses of the 1G/2G -1607 polymorphic promoters to smoke, and to identify relevant transcription factors whose activity in airway epithelial cells is increased by smoke. The responses of deletion and mutant promoter constructs were measured in transfected cells during exposure to cigarette smoke extract (CSE). DNA oligonucleotide arrays were used to identify transcription factors activated after smoke exposure. CSE activated the MMP-1 promoter, and this induction was prevented by PD98059 blockade of ERK1/2 phosphorylation. Deletion studies revealed the distal 1kb promoter region (-4438 to -3280 upstream of the transcription start site) is essential for CSE induction of MMP-1, and confers activation of a minimal promoter. Studies of 1G and 2G MMP-1 polymorphic promoter variants revealed higher 2G allele basal and CSE-responsive activities than the 1G allele. Cotransfection, mithramycin, and electrophoretic mobility shift assay studies identified activating and repressive roles for Sp1 and PEA3 transcription factors, respectively. Oligonucleotide DNA arrays confirmed activation of Sp1 and PEA3 by CSE. These data demonstrate that the MMP-1 promoter is a direct target of cigarette smoke in lung epithelial cells. This characterization of a smoke response region in the distal MMP-1 promoter has implications for smoking-related diseases such as cancer, heart disease, and emphysema.

Matrix metalloproteinase expression by human alveolar macrophages in relation to emphysema.

An abnormal increase in proteolytic enzymes is thought to play a key role in pulmonary emphysema. Alveolar macrophage proteolytic enzymes include cathepsin L, cathepsin S, matrix metalloproteinase 1, 9, and 12, and a number of studies have implicated these proteinases in the alveolar destruction that characterizes emphysema. The aim of this study was to investigate cathepsin L, cathepsin S, matrix metalloproteinase 1, 9, and 12 mRNA expression in alveolar macrophages isolated from patients with varying degrees of emphysema and to correlate their level of expression with measures of emphysema. Alveolar macrophages were isolated from fifty-four patients who underwent surgical resection for lung carcinoma. The level of mRNA expression was determined using real-time PCR. Emphysema was quantified using high-resolution CT scans. Alveolar macrophages were also cultured for 24 h and 48 h; the effect of proinflammatory mediators and promoter polymorphisms on expression was analyzed. There was a significant correlation between matrix metalloproteinase 1 mRNA expression and emphysema. A higher level of matrix metalloproteinase 1 mRNA was associated with more severe emphysema. Matrix metalloproteinase 12 mRNA expression was increased in current smokers as compared with former smokers. Furthermore, there was a negative correlation between matrix metalloproteinase 12 gene expression and carbon monoxide diffusing capacity. The matrix metalloproteinase 9 C-1562T polymorphism significantly influenced matrix metalloproteinase 9 mRNA expression in alveolar macrophages. These results suggest that alveolar macrophage matrix metalloproteinase 1 and 12 may have a role in the lung structural changes leading to the development of emphysema. Furthermore, these data provide evidence to support the concept that multiple proteinases, causing both elastin and collagen degradation, are important in the pathogenesis of pulmonary emphysema.

Bioactive depsides and anthocyanins from jaboticaba (Myrciaria cauliflora).

A new depside, jaboticabin (1), together with 17 known compounds were isolated from the fruit of jaboticaba (Myrciaria cauliflora). The structure of 1 was elucidated by spectroscopic data interpretation. Known compounds were identified by comparison of their spectroscopic data with literature values or by comparison to authentic standards. Compound 1 and the related depside 2-O-(3,4-dihydroxybenzoyl)-2,4,6-trihydroxyphenylacetic acid (2) significantly inhibited chemokine interleukin (IL)-8 production before and after cigarette smoke treatment of cells. Compound 1 was cytotoxic in the HT29 colon cancer cell line (IC50 = 65 microM), and 2 was active against HCT116 colon cancer cells (IC50 = 30 microM). Compounds 1 and 2 also exhibited antiradical activity in the 1,1-diphenyl-2-picrylhydrazyl (DPPH) assay (IC50 = 51.4 and 61.8 microM, respectively). Two anthocyanins, cyanidin 3-glucoside (3) and delphinidin 3-glucoside (4), also showed good activity in these assays.

Contribution of alpha- and beta-defensins to lung function decline and infection in smokers: an association study.

BACKGROUND: Alpha-defensins, which are major constituents of neutrophil azurophilic granules, and beta-defensins, which are expressed in airway epithelial cells, could contribute to the pathogenesis of chronic obstructive pulmonary disease by amplifying cigarette smoke-induced and infection-induced inflammatory reactions leading to lung injury. In Japanese and Chinese populations, two different beta-defensin-1 polymorphisms have been associated with chronic obstructive pulmonary disease phenotypes. We conducted population-based association studies to test whether alpha-defensin and beta-defensin polymorphisms influenced smokers' susceptibility to lung function decline and susceptibility to lower respiratory infection in two groups of white participants in the Lung Health Study (275 = fast decline in lung function and 304 = no decline in lung function). METHODS: Subjects were genotyped for the alpha-defensin-1/alpha-defensin-3 copy number polymorphism and four beta-defensin-1 polymorphisms (G-20A, C-44G, G-52A and Val38Ile). RESULTS: There were no associations between individual polymorphisms or imputed haplotypes and rate of decline in lung function or susceptibility to infection. CONCLUSION: These findings suggest that, in a white population, the defensin polymorphisms tested may not be of importance in determining who develops abnormally rapid lung function decline or is susceptible to developing lower respiratory infections.

Therapeutic response to asthma medications: genotype predictors.

Asthma is a major social and economic burden. Studies have shown that genetic polymorphisms can influence drug efficacy and/or toxicity. The understanding of the pharmacogenetics of asthma will allow therapeutic regimens to be tailored on an individual basis. It is hoped that linkage and association studies will define new therapeutic targets for asthma but until then, studies have focused on improving response to beta(2)-adrenoceptor agonist and leukotriene modifier therapy. Genetic polymorphism may account for interindividual differences in toxicity and efficacy of asthma medications. To date, single nucleotide polymorphism and limited haplotype analysis have provided inconclusive evidence as to how genotype predictors can be used to optimize current asthma therapies based on each patient's genetic profile.

Genetic polymorphisms of matrix metalloproteinases: functional importance in the development of chronic obstructive pulmonary disease?

Chronic obstructive pulmonary disease (COPD) is a major cause of global morbidity and mortality. COPD usually arises from an interaction between both host and environmental risk factors. Cigarette smoking is the major known environmental risk factor for the development of COPD, however, only a minority of smokers (approximately 15 to 20%) develop symptoms. COPD is known to cluster in families, which suggests that there is a genetic predisposition to airflow obstruction. Many candidate genes have been assessed, but the data are often unclear. Here we review evidence that genetic polymorphisms in matrix metalloproteinase genes MMP1, MMP9 and MMP12 may be important in the development of COPD. In a Caucasian population, polymorphisms in the MMP1 and MMP12 genes, but not MMP9, have been suggested to be either causative factors in smoking-related lung injury or are in linkage disequilibrium with other causative polymorphisms. Another study found an association between an MMP9 polymorphism and the development of smoking-induced pulmonary emphysema in Japanese smokers. Understanding the role of genetic polymorphisms in MMP1, MMP9 and MMP12 may help in the discovery of new and more effective therapies.