An integrated genomic analysis of lung cancer reveals loss of DUSP4 in EGFR-mutant tumors.

To address the biological heterogeneity of lung cancer, we studied 199 lung adenocarcinomas by integrating genome-wide data on copy number alterations and gene expression with full annotation for major known somatic mutations in this cancer. This showed non-random patterns of copy number alterations significantly linked to EGFR and KRAS mutation status and to distinct clinical outcomes, and led to the discovery of a striking association of EGFR mutations with underexpression of DUSP4, a gene within a broad region of frequent single-copy loss on 8p. DUSP4 is involved in negative feedback control of EGFR signaling, and we provide functional validation for its role as a growth suppressor in EGFR-mutant lung adenocarcinoma. DUSP4 loss also associates with p16/CDKN2A deletion and defines a distinct clinical subset of lung cancer patients. Another novel observation is that of a reciprocal relationship between EGFR and LKB1 mutations. These results highlight the power of integrated genomics to identify candidate driver genes within recurrent broad regions of copy number alteration and to delineate distinct oncogenetic pathways in genetically complex common epithelial cancers

DOK2 inhibits EGFR-mutated lung adenocarcinoma

Somatic mutations in the EGFR proto-oncogene occur in ~15% of human lung adenocarcinomas and the importance of EGFR mutations for the initiation and maintenance of lung cancer is well established from mouse models and cancer therapy trials in human lung cancer patients. Recently, we identified DOK2 as a lung adenocarcinoma tumor suppressor gene. Here we show that genomic loss of DOK2 is associated with EGFR mutations in human lung adenocarcinoma, and we hypothesized that loss of DOK2 might therefore cooperate with EGFR mutations to promote lung tumorigenesis. We tested this hypothesis using genetically engineered mouse models and find that loss of Dok2 in the mouse accelerates lung tumorigenesis initiated by oncogenic EGFR, but not that initiated by mutated Kras. Moreover, we find that DOK2 participates in a negative feedback loop that opposes mutated EGFR; EGFR mutation leads to recruitment of DOK2 to EGFR and DOK2-mediated inhibition of downstream activation of RAS. These data identify DOK2 as a tumor suppressor in EGFR-mutant lung adenocarcinoma

Electrochemical and immunoelectron microscopy evidence of lipid-protein interaction in Langmuir-Blodgett films of the human lung surfactant.

The extracellular lung surfactant surface film (ELSSF) which lines the mammalian lung alveoli at the alveolar air-aqueous cell surface interface is vital in both the breathing and the pulmonary defence processes. The molecular composition of, the structure of and the interaction in the ELSSF was studied, after the ELSSF of human lung lavages could be separated from the subphase and reassembled from its components by using the multicompartment Fromherz-type Langmuir-Blodgett trough. Transmission electron microscopy images of immunogold- labelled and negatively stained isolated film specimens were seen in a continuous layer of mostly phospholipid head groups surfactant-specific protein SpA molecules. Electrical double-layer capacitance and oxygen reduction potential measurements carried out by transferring the surface film from the air-water to a mercury-saline interface of a hanging mercury drop electrode revealed a strong lipid-protein SpA interaction. SpA molecules were partly squeezed out from the film by compression; a proteinless lipid film proved to be a condensed multilayer. Contact with SpA transformed the multilayer into a loose monomolecular film. It is suggested that SpA molecules play a lipid-transporting role, removing lipids in excess from the air-water interface into the aqueous subphase and vice versa. Lipid- protein interaction can be of importance in vivo. An explanation of how the surfactant film works during the two phases of breathing is proposed

Shear behaviour of rock joints with unsaturated infill

Behaviour of soil-infilled rock joints has significant importance with respect to the strength of fractured rock mass. The presence of even a small amount of fine-grained infill material within a joint can reduce its shear strength considerably, depending on the degree of saturation of infill. Therefore, it is crucial to examine how the infill material can adversely affect the joint shear strength. Previous studies of infilled joints have mainly been focused on idealised regular joint patterns owing to the simplicity and reproducibility in laboratory testing. Current literature on infilled rock joints has also neglected the effect of the degree of saturation of infill on the shear behaviour. In most instances, fully saturated infill has been used or assumed, and the contribution of matric suction on the shear strength of joints having unsaturated infill has not been studied. In this study, a series of triaxial tests on natural joint profiles having joint roughness coefficient (JRC) of 10-12 is carried out at constant moisture content. A semi-empirical model is proposed and validated on the basis of laboratory data

Shear strength model for overconsolidated clay-infilled idealised rock joints

Saturated infilled joints can contribute to the instability of rock masses during undrained shearing. This paper reports an experimental investigation into the effect of the overconsolidation of infilled rough joints on undrained shear behaviour. A revised model is presented for predicting the shear strength of rough infilled joints on the basis of experimental tests carried out on idealised sawtoothed joints with natural silty clay as the infill material. Tests were conducted under consolidated undrained conditions in a high-pressure triaxial apparatus on joints having a dip angle of 60°. Pore pressure development in the infill materials was monitored. The results show that the effect of asperities on shear strength is significant up to a critical asperity height to infill thickness ratio (t/a), whereas the shear behaviour is controlled by the infill alone beyond this critical value. The proposed model for predicting the shear strength of rough infilled joints describes how the OCR influences the shear strength, pore water pressure development, and critical t/a ratio

Desmoplastic small round cell tumour in a 74 year old man: an uncommon cause of ascites (case report)

A rare case is provided of a 74 year old man who presented with ascites of unknown etiology. CT scan of the abdomen revealed extensive omental caking, and omental biopsy cytogenetics showed findings in keeping with a diagnosis of desmoplastic small round cell tumour (DSRCT). This case is unique in that it involves a significantly older patient, negative WT1 immunohistochemical staining, and negative cytology. Despite repeated paracenteses and fluid management, the patient died in hospital secondary to renal complications

An Integrated TCGA Pan-Cancer Clinical Data Resource to Drive High-Quality Survival Outcome Analytics

For a decade, The Cancer Genome Atlas (TCGA) program collected clinicopathologic annotation data along with multi-platform molecular profiles of more than 11,000 human tumors across 33 different cancer types. TCGA clinical data contain key features representing the democratized nature of the data collection process. To ensure proper use of this large clinical dataset associated with genomic features, we developed a standardized dataset named the TCGA Pan-Cancer Clinical Data Resource (TCGA-CDR), which includes four major clinical outcome endpoints. In addition to detailing major challenges and statistical limitations encountered during the effort of integrating the acquired clinical data, we present a summary that includes endpoint usage recommendations for each cancer type. These TCGA-CDR findings appear to be consistent with cancer genomics studies independent of the TCGA effort and provide opportunities for investigating cancer biology using clinical correlates at an unprecedented scale. Analysis of clinicopathologic annotations for over 11,000 cancer patients in the TCGA program leads to the generation of TCGA Clinical Data Resource, which provides recommendations of clinical outcome endpoint usage for 33 cancer types

Intraneural synovial sarcoma of the median nerve

Synovial sarcomas are soft-tissue malignancies with a poor prognosis and propensity for distant metastases. Although originally believed to arise from the synovium, these tumors have been found to occur anywhere in the body. We report a rare case of synovial sarcoma arising from the median nerve. To our knowledge, this is the twelfth reported case of intraneural synovial sarcoma, and only the fourth arising from the median nerve. Because the diagnosis may not be apparent until after pathological examination of the surgical specimen, synovial sarcoma should be kept in mind when dealing with what may seem like a benign nerve tumor