This paper presents a generic and patient-specific classification system designed for robust and accurate detection of ECG heartbeat patterns. The proposed feature extraction process utilizes ...morphological wavelet transform features, which are projected onto a lower dimensional feature space using principal component analysis, and temporal features from the ECG data. For the pattern recognition unit, feedforward and fully connected artificial neural networks, which are optimally designed for each patient by the proposed multidimensional particle swarm optimization technique, are employed. By using relatively small common and patient-specific training data, the proposed classification system can adapt to significant interpatient variations in ECG patterns by training the optimal network structure, and thus, achieves higher accuracy over larger datasets. The classification experiments over a benchmark database demonstrate that the proposed system achieves such average accuracies and sensitivities better than most of the current state-of-the-art algorithms for detection of ventricular ectopic beats (VEBs) and supra-VEBs (SVEBs). Over the entire database, the average accuracy-sensitivity performances of the proposed system for VEB and SVEB detections are 98.3%-84.6% and 97.4%-63.5%, respectively. Finally, due to its parameter-invariant nature, the proposed system is highly generic, and thus, applicable to any ECG dataset.
Tumours are comprised of a highly heterogeneous population of cells, of which only a small subset of stem-like cells possess the ability to regenerate tumours in vivo. These cancer stem cells (CSCs) ...represent a significant clinical challenge as they are resistant to conventional cancer therapies and play essential roles in metastasis and tumour relapse. Despite this realization and great interest in CSCs, it has been difficult to develop CSC-targeted treatments due to our limited understanding of CSC biology. Here, we present evidence that specific histone deacetylases (HDACs) play essential roles in the CSC phenotype. Utilizing a novel CSC model, we discovered that the HDACs, HDAC1 and HDAC7, are specifically over-expressed in CSCs when compared to non-stem-tumour-cells (nsTCs). Furthermore, we determine that HDAC1 and HDAC7 are necessary to maintain CSCs, and that over-expression of HDAC7 is sufficient to augment the CSC phenotype. We also demonstrate that clinically available HDAC inhibitors (HDACi) targeting HDAC1 and HDAC7 can be used to preferentially target CSCs. These results provide actionable insights that can be rapidly translated into CSC-specific therapies.
p27 restrains normal cell growth, but PI3K-dependent C-terminal phosphorylation of p27 at threonine 157 (T157) and T198 promotes cancer cell invasion. Here, we describe an oncogenic feedforward loop ...in which p27pT157pT198 binds Janus kinase 2 (JAK2) promoting STAT3 (signal transducer and activator of transcription 3) recruitment and activation. STAT3 induces TWIST1 to drive a p27-dependent epithelial-mesenchymal transition (EMT) and further activates AKT contributing to acquisition and maintenance of metastatic potential. p27 knockdown in highly metastatic PI3K-activated cells reduces STAT3 binding to the TWIST1 promoter, TWIST1 promoter activity and TWIST1 expression, reverts EMT and impairs metastasis, whereas activated STAT3 rescues p27 knockdown. Cell cycle-defective phosphomimetic p27T157DT198D (p27CK-DD) activates STAT3 to induce a TWIST1-dependent EMT in human mammary epithelial cells and increases breast and bladder cancer invasion and metastasis. Data support a mechanism in which PI3K-deregulated p27 binds JAK2, to drive STAT3 activation and EMT through STAT3-mediated TWIST1 induction. Furthermore, STAT3, once activated, feeds forward to further activate AKT.
Prolongation of ovarian epithelial cancer survival depends on early detection or improved responses to chemotherapy. Gains in either have been modest at best. Understanding the diverse pathogenesis ...of this disease is critical to early intervention or prevention. This review addresses six important variables, including (i) cell of origin, (ii) site of origin, (iii) initial genotoxic events, (iv) risks imposed by hereditary and other promoting conditions, (v) subsequent factors that promote different patterns of metastatic spread, and (vi) prospects for intervention. This review proposes two distinct pathways to pelvic epithelial cancer. The first initiates in ovarian surface epithelium (OSE), Mullerian inclusions or endometriosis in the ovary. The second arises from the endosalpinx and encompasses a subset of serous carcinomas. The serous carcinogenic sequence in the distal fallopian tube is described and contrasted with lower grade serous tumors based on tumour location, earliest genetic change and ability (or lack of) to undergo terminal (ciliated) differentiation. Ultimately, a clear understanding of tumour origin and the mechanism(s) leading to the earliest phases of the serous and endometrioid carcinogenic sequences may hold the greatest promise for designing prevention strategies and/or developing new therapies.
Tumor-associated angiogenesis is postulated to be regulated by the balance between pro- and anti-angiogenic factors. We demonstrate here that the critical step in establishing the angiogenic ...capability of human tumor cells is the repression of a key secreted anti-angiogenic factor, thrombospondin-1 (Tsp-1). This repression is essential for tumor formation by mammary epithelial cells and kidney cells engineered to express SV40 early region proteins, hTERT, and H-RasV12. In transformed epithelial cells, a signaling pathway leading from Ras to Tsp-1 repression induces the sequential activation of PI3 kinase, Rho and ROCK, leading to activation of Myc through phosphorylation, thereby enabling Myc to repress Tsp-1 transcription. In transformed fibroblasts, however, the repression of Tsp-1 can be achieved by an alternative mechanism involving inactivation of both p53 and pRb. We thus describe novel mechanisms by which the activation of oncogenes in epithelial cells and the inactivation of tumor suppressors in fibroblasts permits angiogenesis and, in turn, tumor formation.
Epithelial ovarian tumors present a complex clinical, diagnostic and therapeutic challenge because of the difficulty of early detection, lack of known precursor lesions and high mortality rates. ...Endometrioid ovarian carcinomas are frequently associated with endometriosis, but the mechanism for this association remains unknown. Here we present the first genetic models of peritoneal endometriosis and endometrioid ovarian adenocarcinoma in mice, both based on the activation of an oncogenic K-ras allele. In addition, we find that expression of oncogenic K-ras or conditional Pten deletion within the ovarian surface epithelium gives rise to preneoplastic ovarian lesions with an endometrioid glandular morphology. Furthermore, the combination of the two mutations in the ovary leads to the induction of invasive and widely metastatic endometrioid ovarian adenocarcinomas with complete penetrance and a disease latency of only 7 weeks. The ovarian cancer model described in this study recapitulates the specific tumor histomorphology and metastatic potential of the human disease.
MycER after various treatment times with 4-HT. (b) Immunoblot analysis of Tsp-1, -Actin and Ras proteins expressed by kidney-derived cells expressing low levels of oncogenic Ras plus MycER after ...various treatment times with 4-HT. (c) Immunoblot analysis of Myc and Ras proteins in low Ras cells expressing MycER (wt) and high Ras cells expressing DNMycER (DN). (d) Immunoblot analysis of Tsp-1, phospho Myc, -Actin and Ras proteins expressed by kidney-derived cells expressing high levels of oncogenic Ras transfected with S62AMyc(62) or S71AMyc (71) genes. (e) Immunoblot analysis of Tsp-1, -Actin and Ras proteins expressed by kidney-derived cells expressing low levels of oncogenic Ras, or high levels of oncogenic Ras that were mock transfected or transfected with S62AMyc (62) andS71AMyc (71) genes. (f) Ribonuclease protection assay of ODC and cyclophilin expressed in kidney-derived cells expressing no oncogenic Ras ( ), low levels of oncogenic Ras, or high levels of oncogenic Ras that were mock transfected or transfected with wtMyc (58), S62AMyc (62) or S71AMyc (71) genes
Tumor angiogenesis is postulated to be regulated by the balance between pro- and anti-angiogenic factors. We demonstrate that the critical step in establishing the angiogenic capability of human ...cells is the repression of the critical anti-angiogenic factor, thrombospondin-1 (Tsp-1). This repression is essential for tumor formation by mammary epithelial cells and kidney cells engineered to express SV40 early region proteins, hTERT, and H-RasV12. We have uncovered the signaling pathway leading from Ras to Tsp-1 repression. Ras induces the sequential activation of PI3 kinase, Rho, and ROCK, leading to activation of Myc through phosphorylation; phosphorylation of Myc via this mechanism enables it to repress Tsp-1 expression. We thus describe a novel mechanism by which the cooperative activity of the oncogenes, ras and myc, leads directly to angiogenesis and tumor formation.
Using the unprecedented observational capabilities deployed duringthe Cooperative Atmosphere-Surface Exchange Study-99 (CASES-99),we found three distinct turbulence events on the night of 18October ...1999, each of which was associated with differentphenomena: a density current, solitary waves, and downwardpropagating waves from a low-level jet. In this study, we focus onthe first event, the density current and its associatedintermittent turbulence. As the cold density current propagatedthrough the CASES-99 site, eddy motions in the upper part of thedensity current led to periodic overturning of the stratifiedflow, local thermal instability and a downward diffusion ofturbulent mixing. Propagation of the density current induced asecondary circulation. The descending motion following the head ofthe density current resulted in strong stratification, a sharpreduction in the turbulence, and a sudden increase in the windspeed. As the wind surge propagated toward the surface, shearinstability generated upward diffusion of turbulent mixing. Wedemonstrate in detail that the height and sequence of the localthermal and shear instabilities associated with the dynamics ofthe density current are responsible for the apparent intermittentturbulence.PUBLICATION ABSTRACT
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