The diagnostic value of a 12-lead electrocardiogram in patients with cardiac tamponade due to a malignant pericardial effusion

Background. Cardiac tamponade can occur when a large amount of fluid, gas, singly or in combination, accumulating within the pericardium, compresses the heart causing circulatory compromise. Although previous investigators have found the 12-lead ECG to have a poor predictive value in diagnosing cardiac tamponade, very few studies have evaluated it as a follow up tool for ruling in or ruling out tamponade in patients with previously diagnosed malignant pericardial effusions. ^ Methods. 127 patients with malignant pericardial effusions at the MD Anderson Cancer Center were included in this retrospective study. While 83 of these patients had a cardiac tamponade diagnosed by echocardiographic criteria (Gold standard), 44 did not. We computed the sensitivity (Se), specificity (Sp), positive (PPV) and negative predictive values (NPV) for individual and combinations of ECG abnormalities. Individual ECG abnormalities were also entered singly into a univariate logistic regression model to predict tamponade. ^ Results. For patients with effusions of all sizes, electrical alternans had a Se, Sp, PPV and NPV of 22.61%, 97.61%, 95% and 39.25% respectively. These parameters for low voltage complexes were 55.95%, 74.44%, 81.03%, 46.37% respectively. The presence of all three ECG abnormalities had a Se = 8.33%, Sp = 100%, PPV = 100% and NPV = 35.83% while the presence of at least one of the three ECG abnormalities had a Se = 89.28%, Sp = 46.51%, PPV = 76.53%, NPV = 68.96%. For patients with effusions of all sizes electrical alternans had an OR of 12.28 (1.58–95.17, p = 0.016), while the presence of at least one ECG abnormality had an OR of 7.25 (2.9–18.1, p = 0.000) in predicting tamponade. ^ Conclusions. Although individual ECG abnormalities had low sensitivities, specificities, NPVs and PPVs with the exception of electrical alternans, the presence of at least one of the three ECG abnormalities had a high sensitivity in diagnosing cardiac tamponade. This could point to its potential use as a screening test with a correspondingly high NPV to rule out a diagnosis of tamponade in patients with malignant pericardial effusions. This could save expensive echocardiographic assessments in patients with previously diagnosed pericardial effusions. ^

Immune and genetic risk factors in glioma

Despite extensive research, the etiology of adult glioma remains largely unknown. We sought to further explore the role of immune and genetic factors in glioma etiology using data from the Harris County Brain Tumor Study and the first U.S. genome-wide association study of glioma. First, using a case-control study design, we examined the association between adult glioma risk and surrogates of the timing and frequency of common early childhood infections, birth order and sibship size, respectively. We found that each one-unit increase in birth order was associated with a 12% decreased risk of glioma development in adulthood (OR=0.88, 95% CI=0.81-0.96); however, sibship size was not associated with adult glioma risk (OR=0.96, 95% CI=0.91-1.02). Second, we used a multi-strategic approach to explore the relationships between glioma risk, history of asthma/allergies, and 23 functional SNPs in 11 inflammation genes. We found three inflammation gene SNPs to be significantly associated with glioma risk (COX2/PTGS2 rs20417 [OR=1.41]; IL10 rs1800896 [OR=1.57]; and IL13 rs20541 [OR=0.39]). Joint effects analysis of the risk-conferring alleles of these three SNPs revealed a trend of increasing risk with increasing number of adverse alleles among those without asthma/allergies (p<0.0001). Finally, we conducted a case-only study to explore pairwise SNP-SNP interactions in immune-related pathways among a population of 1304 non-Hispanic white glioma cases. After correction for multiple comparisons, we found 279 significant SNP-SNP interactions among polymorphisms of immune-related genes, many of which have not been previously examined. Our results, cumulatively, suggest an important role for immune and genetic factors in glioma etiology and provide several new hypotheses for future studies.^

Ethnic differences in tumor characteristics, treatment and survival in glioma patients

Purpose. A descriptive analysis of glioma patients by race was carried out in order to better elucidate potential differences between races in demographics, treatment, characteristics, prognosis and survival. ^ Patients and Methods. Among 1,967 patients ≥ 18 years diagnosed with glioma seen between July 2000 and September 2006 at The University of Texas M.D. Anderson Cancer Center (UTMDACC). Data were collated from the UTMDACC Patient History Database (PHDB) and the UTMDACC Tumor Registry Database (TRDB). Chi-square analysis, uni- /multivariate Cox proportional hazards modeling and survival analysis were used to analyze differences by race. ^ Results. Demographic, treatment and histologic differences exist between races. Though risk differences were seen between races, race was not found to be a significant predictor in multivariate regression analysis after accounting for age, surgery, chemotherapy, radiation, tumor type as stratified by WHO tumor grade. Age was the most consistent predictor in risk for death. Overall survival by race was significantly different (p=0.0049) only in low-grade gliomas after adjustment for age although survival differences were very slight. ^ Conclusion. Among this cohort of glioma patients, age was the strongest predictor for survival. It is likely that survival is more influenced by age, time to treatment, tumor grade and surgical expertise rather than racial differences. However, age at diagnosis, gender ratios, histology and history of cancer differed significantly between race and genetic differences to this effect cannot be excluded. ^

Transcriptional regulation of lung tumor suppressor GPRC5A in malignant and normal cells

Chronic exposure of the airways to cigarette smoke induces inflammatory response and genomic instability that play important roles in lung cancer development. Nuclear factor kappa B (NF-κB), the major intracellular mediator of inflammatory signals, is frequently activated in preneoplastic and malignant lung lesions. ^ Previously, we had shown that a lung tumor suppressor GPRC5A is frequently repressed in human non-small cell lung cancers (NSCLC) cells and lung tumor specimens. Recently, other groups have shown that human GPRC5A transcript levels are higher in bronchial samples of former than of current smokers. These results suggested that smoking represses GPRC5A expression and thus promotes the occurrence of lung cancer. We hypothesized that cigarette smoking or associated inflammatory response repressed GPRC5A expression through NF-κB signaling. ^ To determine the effect of inflammation, we examined GPRC5A protein expression in several lung cell lines following by TNF-α treatment. TNF-α significantly suppressed GPRC5A expression in normal small airway epithelial cells (SAEC) as well as in Calu-1 cells. Real-time PCR analysis indicated that TNF-α inhibits GPRC5A expression at the transcriptional level. NF-κB, the major downstream effectors of TNF-α signaling, mediates TNF-α-induced repression of GPRC5A because over-expression of NF-κB suppressed GPRC5A. To determine the region in the GPRC5A promoter through which NF-κB acts, we examined the ability of TNF-α to inhibit a series of reporter constructs with different deletions of GPRC5A promoter. The luciferase assay showed that the potential NF-κB binding sites containing region are irresponsible for TNF-α-induced suppression. Further analysis using constructs with different deletions in p65 revealed that NF-κB-mediated repression of GPRC5A is transcription-independent. Co-immunoprecipitation assays revealed that NF-κB could form a complex with RAR/RXR heterodimer. Moreover, the inhibitory effect of NF-κB has been found to be proportional to NF-κB/RAR ratio in luciferase assay. Finally, Chromatin IP demonstrated that NF-κB/p65 bound to GPRC5A promoter as well as RAR/RXR and suppressed transcription. Taken together, we propose that inflammation-induced NF-κB activation disrupts the RA signaling and suppresses GPRC5A expression and thus contributes to the oncogenesis of lung cancer. Our studies shed new light on the pathogenesis of lung cancer and potentially provide novel interventions for preventing and treating this disease. ^

Occupation and glioma: The Harris County Brain Tumor Study, 2001--2010

The relationship between occupational exposures and glioma has not been adequately assessed due to the lack of studies in current scientific literature. To address this disparity, the Harris County Brain Tumor Study, an ongoing population-based case-control study, began in January 2001. Longest-held occupation for 382 cases and 629 controls were frequency matched on age (within 5 years), sex, and race and placed into 14 predetermined occupational categories. Adjusted odds ratios and 95% confidence intervals were calculated for each category using multiple logistic regression. Potential confounders assessed included sex, age, smoking status, education and income. For all subjects, significantly elevated adjusted odds ratios were found in health-related (aOR=1.66; 95%CI=1.03, 2.68), teaching (aOR=1.84; 95%CI=1.17, 2.88), and protective service (aOR=3.6; 95%CI=1.05, 12.31) occupational categories after controlling for sex and education. A significantly lowered odds ratio was seen in the writers, artists, and entertainers category (aOR=0.14; 95%CI=0.03, 0.58). In the stratified analyses, which controlled for education, males had a significantly elevated odds ratio for protective service workers (aOR=4.83; 95%CI=1.24, 18.83) while a significantly lower odds ratio was found in mechanics and machine operators (aOR=0.33; 95%CI=0.12,0.87). In females, we observed a significantly elevated odds ratio in teachers (aOR=1.99; 95%CI=1.20,3.31) and a significantly lower odds ratio in clerical workers (aOR=0.63; 95%CI=0.45,0.90). These analyses revealed several significant associations and allowed for separate analyses by gender, distinguishing this study from many glioma studies. Further analyses should provide a large enough sample size to stratify by gender as well as histological subtype.^

Elucidating the IGFBP2 signaling pathway in glioma development and progression

Diffuse gliomas are highly lethal central nervous system malignancies which, unfortunately, are the most common primary brain tumor and also the least responsive to the very few therapeutic modalities currently available to treat them. IGFBP2 is a newly recognized oncogene that is operative in multiple cancer types, including glioma, and shows promise for a targeted therapeutic approach. Elevated IGFBP2 expression is present in high-grade glioma and correlates with poor survival. We have previously demonstrated that IGFBP2 induces glioma development and progression in a spontaneous glioma mouse model, which highlighted its significance and potential for future therapy. However, we did not yet know the key physiological pathways associated with this newly characterized oncogene. We first evaluated human glioma genomics data harnessed from the publicly available Rembrandt source to identify major pathways associated with IGFBP2 expression. Integrin and ILK, among other cell migration and invasion-related pathways, were the most prominently associated. We confirmed that these pathways are regulated by IGFBP2 in glioma cells lines, and demonstrated that 1) IGFBP2 activates integrin α5β1, leading to the activation of key pathways important in glioma; 2) IGFBP2 mediates cell migration pathways through ILK; and 3) IGFBP2 activates NF-kB via an integrin α5 interaction. We then sought to determine whether this was a physiologically active signaling pathway in vivo by assessing its ability to induce glioma progression in the RCAS/tv-a spontaneous glioma mouse model. We found that ILK is a key downstream mediator of IGFBP2 that is required for the induction of glioma progression. Most significantly, a genetic therapeutic approach revealed that perturbation of any point in the pathway thwarted tumor progression, providing strong evidence that targeting the key players could potentially produce a significant benefit for human glioma patients. The elucidation of this signaling pathway is a critical step, since efforts to create a small molecule drug targeting IGFBP2 have so far not been successful, but a number of inhibitors of the other pathway constituents, including ILK, integrin and NF-kB, have been developed.

Fibulin-2 stabilizes tumor extracellular matrix and drives malignant progression of lung adenocarcinoma

The ECM of epithelial carcinomas undergoes structural remodeling during periods of uncontrolled growth, creating regional heterogeneity and torsional stress. How tumors maintain ECM integrity in the face of dynamic biophysical forces is still largely unclear. This study addresses these deficiencies using mouse models of human lung adenocarcinoma. Spontaneous lung tumors were marked by disorganized basement membranes, dense collagen networks, and increased tissue stiffness. Metastasis-prone lung adenocarcinoma cells secreted fibulin-2 (Fbln2), a matrix glycoprotein involved in ECM supra-molecular assembly. Fibulin-2 depletion in tumor cells decreased the intra-tumoral abundance of matrix metalloproteinases and reduced collagen cross-linking and tumor compressive properties resulting in inhibited tumor growth and metastasis. Fbln2 deposition within intra-tumoral fibrotic bands was a predictor of poor clinical outcome in patients. Collectively, these findings support a feed-forward model in which tumor cells secrete matrix-stabilizing factors required for the assembly of ECM that preferentially favors malignant progression. To our knowledge, this is the first evidence that tumor cells directly regulate the integrity of their surrounding matrix through the secretion of matrix-stabilizing factors such as fibulin-2. These findings open a new avenue of research into matrix assembly molecules as potential therapeutic targets in cancer patients.

αvβ8 Integrin Interacts with RhoGDI1 to Regulate Rac1 and Cdc42 Activation and Drive Glioblastoma Cell Invasion

As an interface between the circulatory and central nervous systems, the neurovascular unit is vital to the development and survival of tumors. The malignant brain cancer glioblastoma multiforme (GBM) displays invasive growth behaviors that are major impediments to surgical resection and targeted therapies. Adhesion and signaling pathways that drive GBM cell invasion remain largely uncharacterized. Here we have utilized human GBM cell lines, primary patient samples, and pre-clinical mouse models to demonstrate that integrin αvβ8 is a major driver of GBM cell invasion. β8 integrin is overexpressed in many human GBM cells, with higher integrin expression correlating with increased invasion and diminished patient survival. Silencing β8 integrin in human GBM cells leads to impaired tumor cell invasion due to hyperactivation of the Rho GTPases Rac1 and Cdc42. β8 integrin associates with Rho GDP Dissociation Inhibitor 1 (RhoGDI1), an intracellular signaling effector that sequesters Rho GTPases in their inactive GDP-bound states. Silencing RhoGDI1 expression or uncoupling αvβ8 integrin-RhoGDI1 protein interactions blocks GBM cell invasion due to Rho GTPase hyperactivation. These data reveal for the first time that αvβ8 integrin, via interactions with RhoGDI1, suppresses activation of Rho proteins to promote GBM cell invasiveness. Hence, targeting the αvβ8 integrin-RhoGDI1 signaling axis may be an effective strategy for blocking GBM cell invasion.

Galectin-3 Enhances the Malignant Melanoma Phenotype by Regulating Autotaxin

In melanoma patient specimens and cell lines, the over expression of galectin-3 is associated with disease progression and metastatic potential. Herein, we have sought out to determine whether galectin-3 affects the malignant melanoma phenotype by regulating downstream target genes. To that end, galectin-3 was stably silenced by utilizing the lentivirus-incorporated small hairpin RNA in two metastatic melanoma cell lines, WM2664 and A375SM, and subjected to gene expression microarray analysis. We identified and validated the lysophospholipase D enzyme, autotaxin, a promoter of migration, invasion, and tumorigenesis, to be down regulated after silencing galectin-3. Silencing galectin-3 significantly reduced the promoter activity of autotaxin. Interestingly, we also found the transcription factor NFAT1 to have reduced protein expression after silencing galectin-3. Electrophoretic mobility shift assays from previous reports have shown that NFAT1 binds to the autotaxin promoter in two locations. ChIP analysis was performed, and we observed a complete loss of bound NFAT1 to the autotaxin promoter after silencing galectin-3 in melanoma cells. Mutation of the NFAT1 binding sites at either location reduces autotaxin promoter activity. Silencing NFAT1 reduces autotaxin expression while over expressing NFAT1 in NFAT1 negative SB-2 melanoma cells induces autotaxin expression. These data suggest that galectin-3 silencing reduces autotaxin transcription by reducing the amount of NFAT1 protein expression. Rescue of galectin-3 rescues both NFAT1 and autotaxin. We also show that the re-expression of autotaxin in galectin-3 shRNA melanoma cells rescues the angiogenic phenotype in vivo. Furthermore, we identify NFAT1 as a potent inducer of tumor growth and experimental lung metastasis. Our data elucidate a previously unidentified mechanism by which galectin-3 regulates autotaxin and assign a novel role for NFAT1 during melanoma progression.

Expression of p53, {\it * ras\/} and PCNA in human colonic neoplasms: Possible biomarkers of malignant potential

Colorectal cancer is a leading cause of cancer mortality and early detection can significantly improve the clinical outcome. Most colorectal cancers arise from benign neoplastic lesions recognized as adenomas. Only a small percentage of all adenomas will become malignant. Thus, there is a need to identify specific markers of malignant potential. Studies at the molecular level have demonstrated an accumulation of genetic alterations, some hereditary but for the most occurring in somatic cells. The most common are the activation of ras, an oncogene involved in signal transduction, and the inactivation of p53, a tumor suppressor gene implicated in cell cycle regulation. In this study, 38 carcinomas, 95 adenomas and 20 benign polyps were analyzed by immunohistochemistry for the abnormal expression of p53 and ras proteins. An index of cellular proliferation was also measured by labeling with PCNA. A general overexpression of p53 was immunodetected in 66% of the carcinomas, while 26% of adenomas displayed scattered individual positive cells or a focal high concentration of positive cells. This later was more associated with severe dysplasia. Ras protein was detected in 37% of carcinomas and 32% of adenomas mostly throughout the tissue. p53 immunodetection was more frequent in adenomas originating in colons with synchronous carcinomas, particularly in patients with familial adenomatous polyposis and it may be a useful marker in these cases. Difference in the frequency of p53 and ras alterationbs was related to the location of the neoplasm. Immunodetection of p53 protein was correlated to the presence of a mutation in p53 gene at exon 7 and 5 in 4/6 carcinomas studied and 2 villous adenomas. Thus, we characterized in adenomas the abnormal expression of two proteins encoded by the most commonly altered genes in colorectal cancer. p53 alteration appears to be more specifically associated with transition to malignancy than ras. By using immunohistochemistry, a technique that keeps the architecture of the tissue intact, it was possible to correlate these alterations to histopathological characteristics that were associated with higher risks for transformation: villous content, dysplasia and size of adenoma. ^

YKL -40, a vascular -associated serum marker for glioblastoma, correlates with chronic activation of AKT

YKL-40 is a secreted glycoprotein that has been reported to be expressed in pathologic conditions of extracellular matrix degradation and angiogenesis, such as rheumatoid arthritis, severe osteoarthritis, primary colorectal cancer, metastatic breast cancer, and recurrent ovarian cancer (Dehn, Hogdall et al. 2003). ^ We have identified YKL-40 as a serum marker for glioblastoma multiforme (GBM) using microarray analysis from samples of GBM. We compared the gene expression profile of 19 gliomas to pooled normal brain tissue using the Incyte 10,000 gene expression array. The most differentially expressed gene in this analysis was YKL-40; it was detected in GBM samples with a range of 3 to 62-fold elevation over normal brain. Western blot analysis of glioma samples for YKL-40 protein levels revealed substantial elevation in approximately 65% of GBMs, and undetectable levels in lower-grade gliomas and normal brain tissue. ELISA analysis on serum samples of glioma patients showed that YKL-40 levels were substantially elevated in many of the GBM patients. Statistical analysis indicated that in patients with glioma, serum YKL-40 levels correlate with tumor grade and potentially tumor burden in GBM. ^ Furthermore, we found that YKL-40 expression by in-situ hybridization on a brain tumor tissue array was limited to GBM's and gliosarcomas (GSA), and that YKL-40 expression was specific to the GBM component of GSA. Additional in-situ hybridization analysis, found it to be regionally associated with tumor vasculature as well as activated AKT expression in both human and mouse GBM's. Correlation of elevated YKL-40 with phospho-AKT was confirmed by Western blot analysis on a series of glioblastoma tumors, and inhibition of PI3 Kinase signaling by addition of LY294002 also decreased secretion of YKL-40 over a 7-day period in U87 glioblastoma cell tine. Lastly, YKL-40 expression was induced in response to serum starvation and altered by interaction with specific extracellular matrix (ECM) modules. In summary, we have identified the first accurate serum marker for high-grade gliomas. Furthermore, our findings indicate that YKL-40 is a highly expressed vascular-related glycoprotein in human GBM tissue and that it is affected by the AKT signaling pathway and interaction with components of brain ECM proteins. ^

Tracking recurrent concepts using context

The problem of recurring concepts in data stream classification is a special case of concept drift where concepts may reappear. Although several existing methods are able to learn in the presence of concept drift, few consider contextual information when tracking recurring concepts. Nevertheless, in many real-world scenarios context information is available and can be exploited to improve existing approaches in the detection or even anticipation of recurring concepts. In this work, we propose the extension of existing approaches to deal with the problem of recurring concepts by reusing previously learned decision models in situations where concepts reappear. The different underlying concepts are identified using an existing drift detection method, based on the error-rate of the learning process. A method to associate context information and learned decision models is proposed to improve the adaptation to recurring concepts. The method also addresses the challenge of retrieving the most appropriate concept for a particular context. Finally, to deal with situations of memory scarcity, an intelligent strategy to discard models is proposed. The experiments conducted so far, using synthetic and real datasets, show promising results and make it possible to analyze the trade-off between the accuracy gains and the learned models storage cost.