CHRNA5 polymorphism and susceptibility to lung cancer in a Chinese population

Polymorphisms in the nicotinic acetylcholine receptor subunit CHRNA5 gene have been associated with lung cancer positive susceptibility in European and American populations. In the present hospital-based, case-control study, we determined whether polymorphism in rs503464 of CHRNA5 is associated with lung cancer risk in Chinese individuals. A single nucleotide polymorphism in CHRNA5 rs503464, c.-166T>A (hereafter T>A), was identified using TaqMan-MGB probes with sequencing via PCR in 600 lung cancer cases and 600 healthy individuals. Genotype frequencies for rs503464 (T>A) were in Hardy-Weinberg equilibrium for the control population. However, genotype frequencies were significantly different between cases and controls (P < 0.05), while allele frequencies were not significantly different between groups. Compared to homozygous genotypes (TT or AA), the risk of lung cancer in those with the heterozygous genotype (TA) was significantly lower (OR = 0.611, 95%CI = 0.486-0.768, P = 0.001). Using genotype AA as a reference, the risk of lung cancer for those with genotype TA was increased 1.5 times (OR = 1.496, 95%CI = 1.120-1.997, P = 0.006). However, no difference in risk was observed between T allele carriers and A allele carriers (OR = 0.914, 95%CI = 0.779-1.073, P = 0.270). Stratification analysis showed that the protective effect of TA was more pronounced in those younger than 60 years, nonsmokers, or those without a family history of cancer, as well as in patients with adenocarcinoma or squamous cell carcinoma in clinical stages III or IV (P < 0.05). Therefore, the heterozygous genotype c.-166T>A at rs503464 of CHRNA5 may be associated with reduced risk of lung cancer, thus representing a susceptibility allele in Chinese individuals.

Predicting the Risk of Lung Cancer in Never-smokers

Despite being considered a disease of smokers, approximately 10-15% of lung cancer cases occur in never-smokers. Lung cancer risk prediction models have demonstrated excellent ability to discriminate cases from non-cases, and have been shown to be more efficient at selecting individuals for future screening than current criteria. Existing models have primarily been developed in populations of smokers, thus there was a need to develop an accurate model in never-smokers. This study focused on developing and validating a model using never-smokers from the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial. Cox regression analysis, with six-year follow-up, was used for model building. Predictors included: age, body mass index, education level, personal history of cancer, family history of lung cancer, previous chest X-ray, and secondhand smoke exposure. This model achieved fair discrimination (optimism corrected c-statistic = 0.6645) and good calibration. This represents an improvement on existing neversmoker models, but is not suitable for individual-level risk prediction.

Consumption of black tea and coffee and the risk of lung cancer

Objectif: Étudier l’association entre la consommation de café, la consommation de thé noir et le risque de cancer du poumon. Méthodologie: Cette recherche utilise les données obtenues lors d’une étude cas-témoin effectuée à Montréal avec des résidents canadiens âgés entre 35 et 75 ans recrutés entre 1996 et 2001. Les cas étaient des individus atteints du cancer et diagnostiqués entre 1996 et 1997 dans l’un des 18 hôpitaux de la région du Grand-Montréal. Les contrôles on été sélectionnés à partir de la liste électorale et appariés selon la fréquence de distribution des cas par groupe d’âge de 5 ans, par sexe et par district électoral. Au total, 1130 cas et 1484 contrôles ont été inclus dans cette étude. Les rapports de cote (RC) et les intervalles de confiance de 95% (CI) des associations entre la consommation de thé noir, de café et le cancer du poumon ont été estimés à l’aide de la régression logistique non conditionnelle. Quatre aspects de la consommation ont été analysés dans des modèles multivariés distincts: la fréquence de consommation, la consommation journalière moyenne, la durée de consommation et la consommation cumulative. Les covariables potentielles considérées incluaient : l’âge, le sexe, l’historique de tabagisme, le statut du répondant, l’ethnicité, la consommation d’alcool, la consommation de fruit et de légume, l’apport énergétique journalier, l’exposition a des agents professionnelle et les variables socio-économiques . Des analyses secondaires par le sexe, le tabagisme et le type histologique de cancer on été effectuées. Résultats : Aucune association statistiquement significative n’a été observée entre la consommation de thé noir et le cancer du poumon. Nos résultats suggèrent qu’une consommation de ≥ 50 ans était associée avec une augmentation du risque d’adénocarcinome comparée à aucune consommation. Nous avons observé une association inverse statistiquement significative entre la consommation occasionnelle de café et le cancer du poumon (RC : 0.32, 95%CI : 0.17-0.59). La durée de consommation de café n’était pas associée avec le cancer du poumon. Conclusion : Nos résultats suggèrent que la consommation à long terme de thé noir pourrait augmenter le risque d’adénocarcinome. D’un autre côté, la consommation occasionnelle de café pourrait réduire le risque de cancer du poumon.

Functional studies of the deubiquitinating enzymes USP19, USP4 and UCH-L1

El marcaje de proteínas con ubiquitina, conocido como ubiquitinación, cumple diferentes funciones que incluyen la regulación de varios procesos celulares, tales como: la degradación de proteínas por medio del proteosoma, la reparación del ADN, la señalización mediada por receptores de membrana, y la endocitosis, entre otras (1). Las moléculas de ubiquitina pueden ser removidas de sus sustratos gracias a la acción de un gran grupo de proteasas, llamadas enzimas deubiquitinizantes (DUBs) (2). Las DUBs son esenciales para la manutención de la homeostasis de la ubiquitina y para la regulación del estado de ubiquitinación de diferentes sustratos. El gran número y la diversidad de DUBs descritas refleja tanto su especificidad como su utilización para regular un amplio espectro de sustratos y vías celulares. Aunque muchas DUBs han sido estudiadas a profundidad, actualmente se desconocen los sustratos y las funciones biológicas de la mayoría de ellas. En este trabajo se investigaron las funciones de las DUBs: USP19, USP4 y UCH-L1. Utilizando varias técnicas de biología molecular y celular se encontró que: i) USP19 es regulada por las ubiquitin ligasas SIAH1 y SIAH2 ii) USP19 es importante para regular HIF-1α, un factor de transcripción clave en la respuesta celular a hipoxia, iii) USP4 interactúa con el proteosoma, iv) La quimera mCherry-UCH-L1 reproduce parcialmente los fenotipos que nuestro grupo ha descrito previamente al usar otros constructos de la misma enzima, y v) UCH-L1 promueve la internalización de la bacteria Yersinia pseudotuberculosis.

Radon in homes and risk of lung cancer: collaborative analysis of individual data from 13 European case-control studies

Objective: To determine the risk of lung cancer associated with exposure at home to the radioactive disintegration products of naturally Occurring radon gas. Design: Collaborative analysis of individual data from 13 case-control studies of residential radon and lung cancer. Setting Nine European countries. Subjects 7148 cases Of lung cancer and 14 208 controls. Main outcome measures: Relative risks of lung cancer and radon gas concentrations in homes inhabited during the previous 5-34 years measured in becquerels (radon disintegrations per second) per cubic incite (Bq/m(3)) Of household air. Results: The mean measured radon concentration in homes of people in tire control group was 97 Bq/m(3), with 11% measuring > 200 and 4% measuring > 400 Bq/m(3). For cases of lung cancer the mean concentration was 104 Bq/m(3). The risk of lung cancer increased by 8.4% (95% confidence interval 3.0% to 15.8%) per 100 Bq/m(3) increase in measured radon (P = 0.0007). This corresponds to an increase of 16% (5% to 31%) per 100 Bq/m(3) increase in usual radon-that is, after correction for the dilution caused by random uncertainties in measuring radon concentrations. The dose-response relation seemed to be linear with no threshold and remained significant (P=0.04) in analyses limited to individuals from homes with measured radon < 200 Bq/m(3). The proportionate excess risk did not differ significantly with study, age, sex, or smoking. In the absence of other causes of death, the absolute risks of lung cancer by age 75 years at usual radon concentrations of 0, 100, and 400 Bq/m(3) would be about 0.4%, 0.5%, and 0.7%, respectively, for lifelong non-smokers, and about 25 times greater (10%, 12%, and 16%) for cigarette smokers. Conclusions: Collectively, though not separately, these studies show appreciable hazards from residential radon, particularly for smokers and recent ex-smokers, and indicate that it is responsible for about 2% of all deaths from cancer in Europe.

Push or pull? : The relationship between quality of care and use of complementary and alternative medicine among patients with lung cancer in Sweden

Little is known about relationships between quality of care (QoC) and use of complementary and alternative medicine (CAM) among patients with lung cancer (LC). Purpose: This study examines CAM-use among patients with LC in Sweden, associations between QoC and CAM-use among these patients, and reported aspects of LC-care perceived as particularly positive and negative by patients, as well as suggestions for improving QoC. Methods: Survey data from 94 patient members of the Swedish LC patient organization about CAM-use and QoC as measured by the instrument “Quality from the patient’s perspective” were analyzed. Results: Fifty (53%) LC-patients used CAM, with 40 of the CAM-users reporting that CAM helped them. The most common CAMs used were dietary supplements and natural remedies, followed by prayer. Significantly more patients reported using prayer and meditation for cure than was the case for other types of CAM used. Less than half the CAM-users reported having spoken with staff from the biomedical health care system about their CAM-use. Patients provided numerous suggestions for improving LC-care in a variety of areas, aiming at a more effective and cohesive care trajectory. No differences in QoC were found between CAM-users and non-CAM-users, but differences in CAM-use i.e. type of CAM, reasons for using CAM, and CAM-provider consulted could be associated with different experiences of care. Conclusions: It is important to recognize that CAM-users are not a homogeneous group but might seek different types of CAMs and CAM-providers in different situations depending on experiences of care.

Squamous cell lung carcinoma in a cat

Primary lung neoplasms are rare in small animals and present variable clinical signs. Here we report a case of a 4-year-old male cat which presented with apathy, dyspnea and pleural effusion. The cytological analysis of the pleural effusion revealed massive presence of atypical cells and the histopathological examination of the lung demonstrated tissue infiltration by atypical cells arranged in solid nests. The cytological and histopathological findings were compatible with squamous cell lung carcinoma.

Immunomodulatory effects of low dose chemotherapy and perspectives of its combination with immunotherapy

Given that cancer is one of the main causes of death worldwide, many efforts have been directed toward discovering new treatments and approaches to cure or control this group of diseases. Chemotherapy is the main treatment for cancer; however, a conventional schedule based on maximum tolerated dose (MTD) shows several side effects and frequently allows the development of drug resistance. On the other side, low dose chemotherapy involves antiangiogenic and immunomodulatory processes that help host to fight against tumor cells, with lower grade of side effects. In this review, we present evidence that metronomic chemotherapy, based on the frequent administration of low or intermediate doses of chemotherapeutics, can be better than or as efficient as MTD. Finally, we present some data indicating that noncytotoxic concentrations of antineoplastic agents are able to both up-regulate the immune system and increase the susceptibility of tumor cells to cytotoxic T lymphocytes. Taken together, data from the literature provides us with sufficient evidence that low concentrations of selected chemotherapeutic agents, rather than conventional high doses, should be evaluated in combination with immunotherapy. Copyright © 2012 UICC.

Therapeutic Delivery of miR-200c Enhances Radiosensitivity in Lung Cancer

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

Brazilian green propolis induced apoptosis in human lung cancer A549 cells through mitochondrial-mediated pathway

Propolis effect on the growth and apoptosis of human lung adenocarcinoma (A549 cells) was investigated as well as its mechanisms. Cells were incubated with propolis for 72 h, and 3-(4,5- dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide and lactate dehydrogenase assays were employed to assess cell viability and the inhibitory concentration (IC). Apoptosis was detected by Acridine Orange/Ethidium Bromide and 4',6-diamidino-2-phenylindole staining after 24 and 48 h of incubation with ¼ IC50 of propolis by testing the mitochondrial membrane potential (ΔΨm) and the expression of apoptosis-related genes (p53, Caspase-3, Bax, Bcl-2, Bcl-XL , Noxa, Puma and p21) by reverse transcription polymerase chain reaction. Propolis displayed antiproliferative and cytotoxic effects on A549 cells in a dose- and time-dependent manner, but it did not suppress the growth of normal Vero cells. An enhanced apoptosis was seen in A549 propolis-treated cells after 48 h compared with the control cells. Propolis decreased mitochondrial membrane potential by overexpression of pro-apoptotic genes (Bax and Noxa) and reduction of the antiapoptotic gene Bcl-XL . The expression level of other genes remained unchanged (p53, Caspse-3 and Bax), whereas p21 expression was increased. Propolis induced caspase-independent apoptosis through a p53-independent mitochondrial pathway, and cell cycle arrest by upregulation of p21. Although propolis induces apoptosis mainly by p53-independent manner, it may be induced by another pathway, and new insights may arise for preventing or treating lung cancer.

Perdite aeree prolungate dopo resezione polmonare

Il tumore del polmone e una delle neoplasie più diagnosticate dal 1985 e rimane ancora oggi la causa più frequente di morte cancro-correlata nel mondo. Una resezione polmonare anatomica completa continua ad essere il cardine della terapia per il tumore non a piccole cellule. Perdite aeree prolungate (PAL) sono la più comune complicanza dopo una chirurgia polmonare e sono state riportate con un’incidenza compresa tra il 3-26%, simile sia nelle resezioni polmonari per via toracotomica sia in quelle per via toracoscopica. Fattori di rischio descritti sono scissure interlobari incomplete, patologie polmonari sottostanti (come enfisema, fibrosi, tubercolosi o neoplasie), aderenze pleuriche, pazienti anziani (>75 anni) e bassa capacita di diffusione. Lo sviluppo di strumentazione all’avanguardia e di nuove tecniche chirurgiche ha contribuito a ridurre l’incidenza di queste complicanze. Considerando l’alto impatto clinico e socio-economico di queste problematiche, e stata inoltre sviluppata una varietà di complementari naturali e materiali sintetici molti utili nella gestione delle perdite aeree.

Inhibition of tissue transglutaminase sensitizes TRAIL-resistant lung cancer cells through upregulation of death receptor 5

Tissue transglutaminase (TG2) is implicated in cellular processes such as apoptosis and cell migration. Its acyl transferase activity cross-links certain proteins, among them transcription factors were described. We show here that the TG2 inhibitor KCC009 reversed resistance to tumor necrosis factor-related apoptosis-inducing factor (TRAIL) in lung cancer cells. Sensitization required upregulation of death receptor 5 (DR5) but not of death receptor 4. Upregulation of DR5 involved the first intron of the DR5 gene albeit it was independent from p53 and nuclear factor kappa B. In conclusion, inhibition of tissue transglutaminase provides an interesting strategy for sensitization to TRAIL-induced apoptosis in p53-deficient lung cancer cells.

Targeting phosphoinositide 3-kinase signalling in lung cancer

Lung cancer is the leading cause of cancer-related mortality worldwide and more than 1 million people annually die in consequence of lung cancer. Although an improvement in lung cancer treatment could be achieved, especially in the last decade, the development of additional therapeutic strategies is urgently required in order to provide improved survival benefit for patients. Lung cancer formation is caused by genetic modifications commonly caused by tobacco smoking. Numerous studies have demonstrated the role of extracellular growth factors in lung cancer cell proliferation, metastasis, and chemoresistance. Mutations and amplifications in molecules related to receptor tyrosine signalling, such as EGFR, ErbB2, c-Met, c-Kit, VEGFR, PI3K, and PTEN are only some of the alterations known to contribute to the development of lung cancer. The phosphoinositide 3-kinase (PI3K) pathway, fundamental for cell development, growth, and survival, is known to be frequently altered in neoplasia, including carcinomas of the lung. Based on the high frequency of alterations, which include mutations and amplifications, leading to over-activation of certain upstream/downstream mediators, targeting components of the PI3K signalling pathway is considered to be a promising therapeutic approach in cancer treatment. In this article we will summarize the current knowledge about the involvement of PI3K signalling in lung cancer and discuss the development of targeted therapies involving PI3K pathway inhibitors.

The Src inhibitor AZD0530 blocks invasion and may act as a radiosensitizer in lung cancer cells

BACKGROUND: With the emergence of Src inhibitors in clinical trials, improved knowledge of the molecular responses of cancer cells to these agents is warranted. This will facilitate the development of tests to identify patients who may benefit from these agents, allow drug activity to be monitored and rationalize the combination of these agents with other treatment modalities. METHODS: This study evaluated the molecular and functional effects of Src inhibitor AZD0530 in human lung cancer cells, by Western blotting and reverse transcription-polymerase chain reaction, and by assays for cell viability, migration, and invasion. RESULTS: Src was activated in four of five cell lines tested and the level corresponded with the invasive potential and the histologic subtype. Clinically relevant, submicromolar concentrations of AZD0530 blocked Src and focal adhesion kinase, resulting in significant inhibition of cell migration and Matrigel invasion. Reactivation of STAT3 and up-regulation of JAK indicated a potential mechanism of resistance. AZD0530 gave a potent and sustained blockage of AKT and enhanced the sensitivity to irradiation. CONCLUSIONS: The results indicated that AZD0530, aside from being a potent inhibitor of tumor cell invasion which could translate to inhibition of disease progression in the clinic, may also lower resistance of lung cancer cells to pro-apoptotic signals.

Crizotinib inhibits migration and expression of ID1 in MET-positive lung cancer cells: implications for MET targeting in oncology

ABSTRACT Aims: ID1 is an important component of the MET-SRC signaling pathway, which is a regulator of cell migration and invasion. We hypothesized that the ALK/MET inhibitor crizotinib inhibits migration via MET-SRC-ID1, rather than ALK. Materials & methods: We used ALK fusion-positive and -negative lung cancer cell lines; crizotinib, PHA-665752, and saracatinib, and stable transfection with shMET. We performed western blotting for p-ALK, ALK, p-MET, MET, p-SRC, SRC and ID1, and quantitative real-time PCR for ID1. Results: Crizotinib decreased p-MET, p-SRC and ID1 levels in ALK- and or MET-positive cell lines and inhibited cell migration. Knockdown of MET was comparable with the effect of crizotinib. Conclusion: The effects of crizotinib on ID1 expression and cancer cell migration were associated with the presence of activated MET, rather than ALK fusion.