Lung cancer is the leading cause of cancer deaths worldwide, yet few genetic markers of lung cancer risk useful for screening exist. The let-7 family-of-microRNAs (miRNA) are global genetic regulators important in controlling lung cancer oncogene expression by binding to the 3 ¶ untranslated regions of their target mRNAs. The purpose of this study was to identify single nucleotide polymorphisms (SNP) that could modify let-7 binding and to assess the effect of such SNPs on target gene regulation and risk for non-small cell lung cancer (NSCLC). let-7 complementary sites (LCS) were sequenced in the KRAS 3 ¶ untranslated region from 74 NSCLC cases to identify mutations and SNPs that correlated with NSCLC. The allele frequency of a previously unidentified SNP at LCS6 was characterized in 2,433 people (representing 46 human populations). The frequency of the variant allele is 18.1% to 20.3% in NSCLC patients and 5.8% in world populations. The association between the SNP and the risk for NSCLC was defined in two independent case-control studies. A case-control study of lung cancer from New Mexico showed a 2.3-fold increased risk (confidence interval, 1.1-4.6; P = 0.02) for NSCLC cancer in patients who smoked <40 pack-years. This association was validated in a second independent case-control study. Functionally, the variant allele results in KRAS overexpression in vitro. The LCS6 variant allele in a KRAS miRANA complementary site is significantly associated with increased risk for NSCLC among moderate smokers and represents a new paradigm for let-7 miRNAs in lung cancer susceptibility. [Cancer Res 2008;68(20):8535-40]

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A RDS, the more severe form of acute lung injury (ALI), is a common and lethal disease in ICUs worldwide. Clinically, ARDS is characterized by acute respiratory failure with severe hypoxemia and diffuse pulmonary infi ltrates. Despite recent advances in critical care and signifi cant efforts invested in the basic research and clinical trials of ARDS, its mortality rate (35%-45%) has remained relatively unchanged since 1994. 1 ARDS usually develops in patients with predisposing conditions that induce systemic infl ammatory response, such as sepsis, pneumonia, major trauma, multiple transfusions, aspiration, and acute pancreatitis, among which sepsis is the most common cause of ARDS. [2][3][4][5] In a large prospective cohort study, severe sepsis with a suspected pulmonary source (46%) or a nonpulmonary source (33%) was the most common risk factor for ALI. 6 On the other hand, only Background: ARDS may occur after either septic or nonseptic injuries. Sepsis is the major cause of ARDS, but little is known about the differences between sepsis-related and non-sepsis-related ARDS. Methods: A total of 2,786 patients with ARDS-predisposing conditions were enrolled consecutively into a prospective cohort, of which 736 patients developed ARDS. We defi ned sepsis-related ARDS as ARDS developing in patients with sepsis and non-sepsis-related ARDS as ARDS developing after nonseptic injuries, such as trauma, aspiration, and multiple transfusions. Patients with both septic and nonseptic risks were excluded from analysis. Results: Compared with patients with non-sepsis-related ARDS (n 5 62), patients with sepsisrelated ARDS (n 5 524) were more likely to be women and to have diabetes, less likely to have preceding surgery, and had longer pre-ICU hospital stays and higher APACHE III (Acute Physiology and Chronic Health Evaluation III) scores (median, 78 vs 65, P , .0001). There were no differences in lung injury score, blood pH, Pa O 2 /F IO 2 ratio, and Pa CO 2 on ARDS diagnosis. However, patients with sepsis-related ARDS had signifi cantly lower Pa O 2 /F IO 2 ratios than patients with nonsepsis-related ARDS patients on ARDS day 3 ( P 5 .018), day 7 ( P 5 .004), and day 14 ( P 5 .004) (repeated-measures analysis, P 5 .011). Compared with patients with non-sepsis-related ARDS, those with sepsis-related had a higher 60-day mortality (38.2% vs 22.6%; P 5 .016), a lower successful extubation rate (53.6% vs 72.6%; P 5 .005), and fewer ICU-free days ( P 5 .0001) and ventilatorfree days ( P 5 .003). In multivariate analysis, age, APACHE III score, liver cirrhosis, metastatic cancer, admission serum bilirubin and glucose levels, and treatment with activated protein C were independently associated with 60-day ARDS mortality. After adjustment, sepsis-related ARDS was no longer associated with higher 60-day mortality (hazard ratio, 1.26; 95% CI, 0.71-2.22). Conclusion: Sepsis-related ARDS has a higher overall disease severity, poorer recovery from lung injury, lower successful extubation rate, and higher mortality than non-sepsis-related ...

Background: COPD is a recognized risk factor for lung cancer, but studies of coexisting COPD in relation to lung cancer outcomes are limited. We assessed the impact of COPD on overall survival (OS) and progression-free survival (PFS) in patients with early-stage non-small cell lung cancer (NSCLC). Abbreviations: HR 5 hazard ratio; HRadj 5 adjusted hazard ratio; MGH 5 Massachusetts General Hospital; NSCLC 5 non-small cell lung cancer; OS 5 overall survival; PFS 5 progression-free survival; SCC 5 squamous cell carcinoma

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Polymorphisms in VEGF may affect survival in early-stage lung cancer.

This study examines the atrophy pattern in and between GM and WM-a subject that has not been widely researched previously.

Background: Hyperbilirubinaemia is a common complication of sepsis. Elevated bilirubin may induce inflammation and apoptosis. It was hypothesised that increased serum bilirubin on Intensive Care Unit (ICU) admission contributes to sepsis-related acute respiratory distress syndrome (ARDS). Methods: Serum bilirubin on ICU admission was measured in 1006 patients with sepsis. Serial serum bilirubin was analysed prospectively in patients with sepsis who had ARDS for a period of 28 days. The effects of clinical factors and variants of the UGT1A1 gene on serum bilirubin levels were determined. Outcomes were ARDS risk and mortality. Results: During 60-day follow-up, 326 patients with sepsis developed ARDS, of whom 144 died from ARDS. The hyperbilirubinaemia (>2.0 mg/dl) rate in patients with ARDS (22.4%) was higher than in those without ARDS (14.1%, p = 0.002). For each 1.0 mg/dl increase in admission bilirubin, ARDS risk and 28-and 60-day ARDS mortalities were increased by 7% (OR = 1.07; p = 0.003), 20% (OR = 1.20; p = 0.002) and 18% (OR = 1.18; p = 0.004), respectively. Compared with subjects with bilirubin levels ,2.0 mg/dl, patients with hyperbilirubinaemia had higher risks of ARDS (OR = 2.12; p = 0.0007) and 28-day (OR = 2.24; p = 0.020) and 60-day ARDS mortalities (OR = 2.09; p = 0.020). In sepsisrelated ARDS, serial bilirubin levels in non-survivors were consistently higher than in survivors (p,0.0001). Clinical variables explained 29.5% of the interindividual variation in bilirubin levels, whereas genetic variants of UGT1A1 contributed 7.5%. Conclusion: In sepsis, a higher serum bilirubin level on ICU admission is associated with subsequent ARDS development and mortality.