Somatic mutations affect key pathways in lung adenocarcinoma

Determining the genetic basis of cancer requires comprehensive analyses of large collections of histopathologically well- classified primary tumours. Here we report the results of a collaborative study to discover somatic mutations in 188 human lung adenocarcinomas. DNA sequencing of 623 genes with known or potential relationships to cancer revealed more than 1,000 somatic mutations across the samples. Our analysis identified 26 genes that are mutated at significantly high frequencies and thus are probably involved in carcinogenesis. The frequently mutated genes include tyrosine kinases, among them the EGFR homologue ERBB4; multiple ephrin receptor genes, notably EPHA3; vascular endothelial growth factor receptor KDR; and NTRK genes. These data provide evidence of somatic mutations in primary lung adenocarcinoma for several tumour suppressor genes involved in other cancers - including NF1, APC, RB1 and ATM - and for sequence changes in PTPRD as well as the frequently deleted gene LRP1B. The observed mutational profiles correlate with clinical features, smoking status and DNA repair defects. These results are reinforced by data integration including single nucleotide polymorphism array and gene expression array. Our findings shed further light on several important signalling pathways involved in lung adenocarcinoma, and suggest new molecular targets for treatment.National Human Genome Research InstituteWe thank A. Lash, M.F. Zakowski, M.G. Kris and V. Rusch for intellectual contributions, and many members of the Baylor Human Genome Sequencing Center, the Broad Institute of Harvard and MIT, and the Genome Center at Washington University for support. This work was funded by grants from the National Human Genome Research Institute to E.S.L., R.A.G. and R.K.W.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/62885/1/nature07423.pd

Mortality at 5 years among very elderly patients undergoing high sensitivity troponin T testing for suspected acute coronary syndromes

Patients aged ≥80 years old often present to Emergency Departments (ED) with symptoms potentially due to an acute coronary syndrome (ACS). This study aimed to evaluate associations between baseline level(s) of high sensitivity troponin T (HsTnT), adjudicated diagnoses and outcomes. Consecutive patients aged ≥80 years were studied, who presented to the ED at Liverpool Hospital, NSW, Australia during the 4 months period March to June 2014 (inclusive) with symptoms suggestive of an ACS, and who had at least one HsTnT assay performed. Diagnoses were based on the fourth universal definition of MI (myocardial infarction) including type-1 MI, type-2 MI, acute myocardial injury, chronic myocardial injury; the rest were termed “other diagnoses”. Patients were categorised by baseline HsTnT levels 1) ≤14 ng/L, 2) 15–29 ng/L, 3) 30–49 ng/L and 4) ≥50 ng/L. Of 2,773 patients screened, 545 were aged ≥80 years (median age 85 [IQR 82–88]); median follow-up was 32 months (IQR 5–56). The respective rates of adjudicated diagnoses were type-I MI 3.1%, type-2 MI 13%, acute myocardial injury 9.5%, chronic myocardial injury 56% and 18.6% had other diagnoses. Mortality rates increased, irrespective of adjudicated diagnoses with increasing HsTnT levels (ng/L): 17% (16/96) for ≤14; 35% (67/194) for 15–29; 51% (65/127) for 30–49; and 64% (82/128) for ≥50 ng/L; log rank p0.001. On multi-variable analyses, after adjusting for potential confounding factors including age, hypertension, chronic kidney disease (CKD) and chronic obstructive pulmonary disease (COPD), MI type was not associated with late mortality. Among patients aged ≥80 years higher HsTnT levels, irrespective of adjudicated diagnoses, were associated with increased mortality. Most very elderly patients presenting with symptoms suggestive of an ACS undergoing HsTnT testing in EDs had elevated levels most commonly due to chronic myocardial injury. Whether any interventions can modify outcomes require prospective evaluation

Type-II myocardial infarction and chronic myocardial injury rates, invasive management and 4-year mortality among consecutive patients undergoing high-sensitivity troponin T testing in the emergency department

Aims: As assessment of patients with suspected acute coronary syndromes (ACS) in emergency departments (EDs) represents a major workload because high-sensitivity troponin (HsTn) T and I levels are frequently measured, and a minority of patients have final diagnosis of myocardial infarction (MI). We determined the relative frequencies of three patients groups: Type-I MI, Type-II MI (including acute myocardial injury). Methods and results: Among 2738 consecutive patients with suspected ACS presenting to ED at Liverpool Hospital, Australia, between March and June 2014. We studied the use of invasive and pharmacological therapies, and 4-year outcomes. Adjudication of MI was according to the 4th universal definition as follows: (i) Type-I MI; (ii) Type-II MI (including acute myocardial injury), and (iii) chronic myocardial injury. Of 995 patients (36%) [median age 76 years (interquartile range 65–83)] with ≥2 HsTnT measurements and one >14 ng/L, 727 (73%) had chronic myocardial injury, 171 (17%) had Type-II MI, and 97 (9.7%) had Type-I MI; respective late mortality rates to 48 months were 33%, 43%, and 14% (P < 0.001). In-hospital angiography rates were 95% for patients with Type-I MI, [62% had percutaneous coronary intervention (PCI)] 24% (7% PCI) for those with Type-II MI, and 3.4% for chronic myocardial injury. On Cox modelling for mortality relative to Type 1 MI, adjusted hazard ratios were 1.94 [95% confidence intervals (CIs) 1.06–3.57]; P = 0.032 for Type 2 MI, and for chronic myocardial injury 1.14 (95% CIs 0.64–2.02); P = 0.66. Conclusion: Among unselected patients undergoing HsTnT testing in EDs, Type-II MI including acute myocardial injury was more common than Type-I MI. Chronic myocardial injury, which occurred in three of four patients. Whereas patients with Type-II MI had higher late mortality than those with Type-I MI, after multivariable analyses mortality rates were marginally different

Prognostic implications of high-sensitivity troponin T levels among patients attending emergency departments and evaluated for an acute coronary syndrome

Background: With increasing age, patients with suspected acute coronary syndromes (ACS) and elevated high-sensitivity troponin T (HsTnT) levels, type-1 myocardial infarction (MI) is diagnosed less often, though associations among these factors, gender, and prognosis is unclear. Methods: Patients presenting to the emergency department (ED) with potential ACS who underwent HsTnT testing were prospectively identified and followed. Diagnoses were adjudicated according to the Fourth Universal Definition of MI as follows: type-1 MI, type-2 MI, acute myocardial injury, chronic myocardial injury, and other diagnoses. Age in years was categorized: younger (<65); elderly (65-79), and very elderly (≥80). Results: Among 2738 patients with HsTnT measurements, 1611 were suitable for adjudication (42% ages 65 years and younger). Type-2 MI and chronic myocardial injury diagnoses were more common in those ages 65 years and older, whereas younger patients had more type-1 MI diagnoses. Late mortality rates at median 41 months (interquartile range [IQR] 10-57) were 44% (223 out of 506) in those ages 80 years and older, 22% (92 out of 423) in patients 65-79 years, and 7% (46 out of 682) in those 65 years and younger, irrespective of adjudicated diagnoses, log rank P ≤ .001. On multivariable analyses, the adjusted mortality hazard ratios for increasing HsTnT levels irrespective of diagnoses were attenuated in those age 80 years and older compared to younger patients. Conclusions: Patients ages 65 years and older constituted ~60% of ED attendances of patients with suspected ACS, and more had type 2 MI and chronic myocardial injury diagnoses compared to younger patients. The relative mortality impact of HsTnT levels was lower among elderly patients irrespective of adjudicated diagnoses

Annual program review chemical recovery.

"March 26, 1997."Fundamentals of dregs removal : Project number: F017-07 / Jeff Empie , Maribeth Amundsen ; Electro-membrane processing, chloride purge from esp catch / P.Pfromm , H.-J. Rapp , C. Brown ; Selective chloride removal from the kraft process: new results: project F017 / Peter H. Pfromm , Hans-Jurgen Rapp ; Behaviors of VOC and sulfur compounds in kraft mill: project F01708 / J.Y. Zhu ... [et al.] ; Volatile organic compounds (VOC) in kraft mills streams - Part I: Method development for quantification of VOC contents in liquids and vapor-liquid phase equilibrium partitioning: project F017 / J.Y. Zhu ; X.S. Chai , and B. Dhasmana ; Kraft recovery furnace modeling capability / W.J. Frederick ... [et al.] -- Slide Material

Research priorities in spasmodic dysphonia

Objective: To identify research priorities to increase understanding of the pathogenesis, diagnosis, and improved treatment of spasmodic dysphonia. Study Design and Setting: A multidisciplinary working group was formed that included both scientists and clinicians from multiple disciplines (otolaryngology, neurology, speech pathology, genetics, and neuroscience) to review currently available information on spasmodic dysphonia and to identify research priorities. Results: Operational definitions for spasmodic dysphonia at different levels of certainty were recommended for diagnosis and recommendations made for a multicenter multidisciplinary validation study. Conclusions: The highest priority is to characterize the disorder and identify risk factors that may contribute to its onset. Future research should compare and contrast spasmodic dysphonia with other forms of focal dystonia. Development of animal models is recommended to explore hypotheses related to pathogenesis. Improved understanding of the pathophysiology of spasmodic dysphonia should provide the basis for developing new treatment options and exploratory clinical trials. Significance: This document should foster future research to improve the care of patients with this chronic debilitating voice and speech disorder by otolaryngology, neurology, and speech pathology. © 2008 American Academy of Otolaryngology-Head and Neck Surgery Foundation