Lineage survival oncogenes are activated by somatic DNA alterations in cancers arising from the cell lineages in which these genes play a role in normal development.1,2 Here we show that a peak of genomic amplification on chromosome 3q26.33, found in squamous cell carcinomas (SCCs) of the lung and esophagus, contains the transcription factor gene SOX2—which is mutated in hereditary human esophageal malformations3 and necessary for normal esophageal squamous development4, promotes differentiation and proliferation of basal tracheal cells5 and co-operates in induction of pluripotent stem cells.6,7,8 SOX2 expression is required for proliferation and anchorage-independent growth of lung and esophageal cell lines, as shown by RNA interference experiments. Furthermore, ectopic expression of SOX2 cooperated with FOXE1 or FGFR2 to transform immortalized tracheobronchial epithelial cells. SOX2-driven tumors show expression of markers of both squamous differentiation and pluripotency. These observations identify SOX2 as a novel lineage survival oncogene in lung and esophageal SCC.

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Pericyte loss is an early pathologic feature of diabetic retinopathy, consistently present in retinae of diabetic humans and animals. Because pericyte recruitment and endothelial cell survival are controlled, in part, by the angiopoietin/Tie2 ligand/receptor system, we studied the expression of angiopoietin-2 and -1 in relation to the evolution of pericyte loss in diabetic rat retinae, using quantitative retinal morphometry, and in retinae from mice with heterozygous angiopoietin deficiency (Ang-2 LacZ knock-in mice). Finally, recombinant angiopoietin-2 was injected into eyes of nondiabetic rats, and pericyte numbers were quantitated in retinal capillaries. Angiopoietin-1 protein was present in the normal maturing retina and was upregulated 2.5-fold in diabetic retinae over 3 months of diabetes. In contrast, angiopoietin-2 protein was consistently upregulated more than 30-fold in the retinae of diabetic rats, preceding the onset of pericyte loss. Heterozygous angiopoietin-2 deficiency completely prevented diabetes-induced pericyte loss and reduced the number of acellular capillary segments. Injection of angiopoietin-2 into the eyes of normal rats induced a dose-dependent pericyte loss. These data show that upregulation of angiopoietin-2 plays a critical role in the loss of pericytes in the diabetic retina. Diabetes 53

Shiga toxins (Stxs), encoded by the stxA and stxB genes, are important contributors to the virulence of Escherichia coli O157:H7 and other Stx-producing E. coli (STEC) strains. The stxA and stxB genes in STEC strains are located on the genomes of resident prophages of the family immediately downstream of the phage late promoters (p R ). The phage-encoded Q proteins modify RNA polymerase initiating transcription at the cognate p R promoter which creates transcription complexes that transcend a transcription terminator immediately downstream of p R as well as terminator kilobases distal to p R . To test if this Q-directed processive transcription plays a role in stx 2 AB expression, we constructed a mutant prophage in an O157:H7 clinical isolate from which p R and part of Q were deleted but which has an intact pStx, the previously described stx 2 AB-associated promoter. We report that production of significant levels of Stx2 in this O157:H7 isolate depends on the p R promoter. Since transcription initiating at p R ultimately requires activation of the phage lytic cascade, expression of stx 2 AB in STEC depends primarily on prophage induction. By showing this central role for the prophage in stx 2 AB expression, our findings contradict the prevailing assumption that phages serve merely as agents for virulence gene transfer.Escherichia coli O157:H7 and other Shiga toxin (Stx)-producing E. coli (STEC) strains are responsible for outbreaks and sporadic cases of diarrhea. In some patients, exposure to STEC leads to hemorrhagic colitis and hemolytic uremic syndrome that may lead to death (20). Two major classes of Stxs, Stx1 and Stx2, encoded respectively by stx 1 AB and stx 2 AB, have been identified in STEC (2). The severe clinical consequences of STEC infections are thought to be caused by the activities of Stxs, although Stx2 appears to be more closely associated with these sequelae than does Stx1 (7,28,36). Shiga toxins are of the A-B type, with the glycolipid-binding B subunits being involved in the transport of the enzymatic A subunits into the eukaryotic cell where the A subunit, acting as a glycosylase, catalyzes a cleavage at a unique site in the 28S rRNA (2). The resulting inactivation of the ribosome leads to an inhibition of protein synthesis. More than 60 serotypes of STEC have been associated with human disease (1). The stx genes of many, if not all, STEC strains are in the genomes of prophages of the lambdoid family (19,23,27). This fact probably accounts for the wide dissemination of these genes in diverse E. coli serotypes.Comparison of lambdoid phage genomes (9) has revealed a common arrangement of functionally similar genes and a shared strategy governing gene expression (Fig. 1). In the lysogenic state, the repressor silences transcription of most phage genes (30). Removal of repression, which can occur when DNA damage activates the bacterial SOS response causing RecA-mediated cleavage of the repressor (21), leads to a cascade of regulatory events beginning with expression of the N transcription ant...

Tumors systemically initiate metastatic niches in distant target metastatic organs. These niches, composed of bone marrow-derived hematopoietic cells, provide permissive conditions for future metastases. However, the mechanisms by which these cells mediate outgrowth of metastatic tumor cells are not completely known. Using mouse models of spontaneous breast cancer, we show enhanced recruitment of bone marrow-derived CD11b

Electrocardiography (ECG) is a key non-invasive diagnostic tool for cardiovascular diseases which is increasingly supported by algorithms based on machine learning. Major obstacles for the development of automatic ECG interpretation algorithms are both the lack of public datasets and well-defined benchmarking procedures to allow comparison s of different algorithms. To address these issues, we put forward PTB-XL, the to-date largest freely accessible clinical 12-lead ECG-waveform dataset comprising 21837 records from 18885 patients of 10 seconds length. The ECG-waveform data was annotated by up to two cardiologists as a multi-label dataset, where diagnostic labels were further aggregated into super and subclasses. the dataset covers a broad range of diagnostic classes including, in particular, a large fraction of healthy records. the combination with additional metadata on demographics, additional diagnostic statements, diagnosis likelihoods, manually annotated signal properties as well as suggested folds for splitting training and test sets turns the dataset into a rich resource for the development and the evaluation of automatic ECG interpretation algorithms.

SummaryThe stx genes of many Shiga toxin-encoding Escherichia coli (STEC) strains are encoded by prophages of the l bacteriophage family. In the genome of the Stx1-encoding phage H-19B, the stx 1 AB genes are found ª 1 kb downstream of the late phage promoter, p R ¢, but are known to be regulated by the associated iron-regulated promoter, p Stx1 . Growth of H-19B lysogens in low iron concentrations or in conditions that induce the prophage results in increased Stx1 production. Although the mechanism by which low iron concentration induces Stx1 production is well understood, the mechanisms by which phage induction enhances toxin production have not been extensively characterized. The studies reported here identify the factors that contribute to Stx1 production after induction of the H-19B prophage. We found that replication of the phage genome, with the associated increase in stx 1 AB copy number, is the most quantitatively important mechanism by which H-19B induction increases Stx1 production. Three promoters are shown to be involved in stx 1 AB transcription after phage induction, the iron-regulated p Stx1 and the phage-regulated p R and p R ¢ promoters, the relative importance of which varies with environmental conditions. Late phage transcription initiating

The transcription factor SOX2 (3q26.3-q27) is a key regulator of foregut development and an embryonic stem cell factor cooperating during induction of pluripotency in terminally differentiated somatic cells. Recently, we found SOX2 to be amplified in a subset of squamous cell lung and esophageal cancers. The aim of this study was to explore the prognostic role of SOX2 in a large series of squamous cell carcinomas and adenocarcinomas of the lung. A total of 891 samples from two independent population-based cohorts were assessed by fluorescence in situ hybridization and immunohistochemistry. Furthermore, we assessed for associations between SOX2 amplification/upregulation and clinicopathological features. Similar results were found in the two cohorts. Within squamous cell carcinoma cases, 8% high-level as well as 68 and 65% low-level SOX2 amplifications occurred in the two cohorts, respectively. In adenocarcinomas, no high-level amplification was found and low-level amplification occurred in 6% of the two cohorts. Within squamous cell carcinomas of one cohort, SOX2 amplification was associated with lower tumor grade, while higher levels of SOX2 expression were related to younger age, smaller tumor size, and lower probability of angiolymphatic invasion and metastasis. High SOX2 expression levels proved to be a marker for prolonged overall survival among patients with squamous cell carcinomas. In conclusion, SOX2 amplification and upregulation are frequent events in squamous cell carcinomas of the lung and are associated with indicators of favorable prognosis. Modern Pathology (2011) 24, 944-953;