Multifocal epithelial tumors and field cancerization from loss of mesenchymal CSL signaling

It is currently unclear whether tissue changes surrounding multifocal epithelial tumors are a cause or consequence of cancer. Here, we provide evidence that loss of mesenchymal Notch/CSL signaling causes tissue alterations, including stromal atrophy and inflammation, which precede and are potent triggers for epithelial tumors. Mice carrying a mesenchymal-specific deletion of CSL/RBP-Jκ, a key Notch effector, exhibit spontaneous multifocal keratinocyte tumors that develop after dermal atrophy and inflammation. CSL-deficient dermal fibroblasts promote increased tumor cell proliferation through upregulation of c-Jun and c-Fos expression and consequently higher levels of diffusible growth factors, inflammatory cytokines, and matrix-remodeling enzymes. In human skin samples, stromal fields adjacent to multifocal premalignant actinic keratosis lesions exhibit decreased Notch/CSL signaling and associated molecular changes. Importantly, these changes in gene expression are also induced by UVA, a known environmental cause of cutaneous field cancerization and skin cancer.     

Modeling historic incidence trends implies early field cancerization in esophageal squamous cell carcinoma

Patterns of cancer incidence, viewed over extended time periods, reveal important aspects of multistage carcinogenesis. Here we show how a multistage clonal expansion (MSCE) model for cancer can be harnessed to identify biological processes that shape the surprisingly dynamic and disparate incidence patterns of esophageal squamous cell carcinoma (ESCC) in the US population. While the dramatic rise in esophageal adenocarcinoma (EAC) in the US has been largely attributed to reflux related increases in the prevalence of Barrett’s esophagus (BE), the premalignant field in which most EAC are thought to arise, only scant evidence exists for field cancerization contributing to ESCC. Our analyses of incidence patterns suggest that ESCC is associated with a premalignant field that may develop very early in life. Although the risk of ESCC, which is substantially higher in Blacks than Whites, is generally assumed to be associated with late-childhood and adult exposures to carcinogens, such as from tobacco smoking, alcohol consumption and various industrial exposures, the temporal trends we identify for ESCC suggest an onset distribution of field-defects before age 10, most strongly among Blacks. These trends differ significantly in shape and strength from field-defect trends that we estimate for US Whites. Moreover, the rates of ESCC-predisposing field-defects predicted by the model for cohorts of black children are decreasing for more recent birth cohorts (for Blacks born after 1940). These results point to a potential etiologic role of factors acting early in life, perhaps related to nutritional deficiencies, in the development of ESCC and its predisposing field-defect. Such factors may explain some of the striking racial differences seen in ESCC incidence patterns over time in the US.     

Magnetic field exposure among utility workers

The Electric and Magnetic Field Measurement Project for Utilities—the Electric Power Research Institute (EPRI) Electric and Magnetic Field Digital Exposure (EMDEX) Project (the EPRI EMDEX Project)—was a multifaceted project that entailed technology transfer, measurement protocol design, data management, and exposure assessment analyses. This paper addresses one specific objective of the project: the collection, analysis, and documentation of power-frequency magnetic field exposures for a diverse population of utility workers. Field exposure data measured by an EMDEX system were collected by volunteer utility employees at 59 sites in four countries between September, 1988, and September, 1989. Specially designed sampling procedures and data collection protocols were used to ensure uniform implementation across sites. Volunteers within 13 job classifications recorded which of eight work or three nonwork environments they occupied while wearing an EMDEX meter. Approximately 50,000 hours of magnetic field exposure records taken at 10 s intervals were obtained, about 70% of which were from work environments. Exposures and time spent in environments were analyzed by primary work environment, by occupied environment, and by job classification. Generally, for utility-specific job classifications related to the generation, transmission, and distribution of electricity, the field and exposure measurements in terms of workday mean field were higher than in more general occupations. The job classifications with the highest (median workday mean) exposure were substation operators (0.7 μT) and electricians (0.5μT). Total variance also tended to be largest for utility-specific job classifications. For these workers, the contributions of between-worker and within-worker variances to total variance were about the same. Measurements in utility-specific environments were higher than in more general environments. Estimates of time-integrated exposure indicated that utility-specific job classifications received about one-half or more of their total exposure on the job. The nonwork field and exposure distributions for workers in all job categories were comparable with median nonworkday means of about 0.09 μT. © 1995 Wiley-Liss, Inc.     

Clinical utility of diagnostic guidelines and putative biomarkers in lymphangioleiomyomatosis

Background

Lymphangioleiomyomatosis is a rare disease occurring almost exclusively in women. Diagnosis often requires surgical biopsy and the clinical course varies between patients with no predictors of progression. We evaluated recent diagnostic guidelines, clinical features and serum biomarkers as diagnostic and prognostic tools.

Methods

Serum vascular endothelial growth factor-D (VEGF-D), angiotensin converting enzyme (ACE), matrix metalloproteinases (MMP) -2 and -9, clinical phenotype, thoracic and abdominal computerised tomography, lung function and quality of life were examined in a cohort of 58 patients. 32 healthy female controls had serum biomarkers measured.

Results

Serum VEGF-D, ACE and total MMP-2 levels were elevated in patients. VEGF-D was the strongest discriminator between patients and controls (median = 1174 vs. 332 pg/ml p < 0.0001 with an area under the receiver operating characteristic curve of 0.967, 95% CI 0.93-1.01). Application of European Respiratory Society criteria allowed a definite diagnosis without biopsy in 69%. Adding VEGF-D measurement to ERS criteria further reduced the need for biopsy by 10%. VEGF-D was associated with lymphatic involvement (p = 0.017) but not the presence of angiomyolipomas.

Conclusions

Combining ERS criteria and serum VEGF-D reduces the need for lung biopsy in LAM. VEGF-D was associated with lymphatic disease but not lung function.     

Clinical utility of telomere length measurements in cancer

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Clinical utility of prostate carcinoma molecular diagnostic tests

Instead of relying on serum prostate-specific antigen (PSA) to identify patients for prostate biopsy, new laboratory tests are needed that have improved specificity for prostate carcinoma (CaP), allow accurate classification of clinically insignificant CaPs, allow for detection of clinically significant CaP in patients without elevated serum PSA, and allow for identification of aggressive forms of CaP, which may warrant adjunctive or even molecularly targeted therapy in the future. Over the last several years, high-throughput gene expression profiling and proteinomics have led to the identification of genes and proteins that are specifically overexpressed in CaP. Molecular diagnostic techniques readily translated to the clinical laboratory have been incorporated into the development of new tests based on these novel molecular alterations in CaP. Some of these tests already have well-documented clinical utility, such as in facilitating prostate biopsy decisions, and are routinely available. The current review focuses on the biological, clinical, and laboratory aspects of the most promising of these current and near-future molecular CaP tests.     

Alternate indices of electric and magnetic field exposures among Ontario electrical utility workers

Epidemiologic studies examining the risk of cancer among occupational groups exposed to electric fields (EF) and or magnetic fields (MF) have relied on traditional summaries of exposure such as the time weighted arithmetic or geometric mean exposure. Findings from animal and cellular studies support the consideration of alternative measures of exposure capable of capturing threshold and intermittent measures of field strength. The main objective of this study was to identify a series of suitable exposure metrics for an ongoing cancer incidence study in a cohort of Ontario electric utility workers. Principal components analysis (PCA) and correlational analysis were used to explore the relationships within and between series of EF and MF exposure indices. Exposure data were collected using personal monitors worn by a sample of 820 workers which yielded 4247 worker days of measurement data. For both EF and MF, the first axis of the PCA identified a series of intercorrelated indices that included the geometric mean, median and arithmetic mean. A considerable portion of the variability in EF and MF exposures were accounted for by two other principal component axes. The second axes for EF and MF exposures were representative of the standard deviation (standard deviation) and thresholds of field measures. To a lesser extent, the variability in the exposure variable was explained by time dependent indices which consisted of autocorrelations at 5 min lags and average transitions in field strength. Our results suggest that the variability in exposure data can only be accounted for by using several exposure indices, and consequently, a series of metrics should be used when exploring the risk of cancer owing to MF and EF exposure in this cohort. Furthermore, the poor correlations observed between indices of MF and EF reinforce the need to be take both fields into account when assessing the risk of cancer in this occupational group. Bioelectromagnetics 19:140–151, 1998. © 1998 Wiley-Liss, Inc.     

Correlations among indices of electric and magnetic field exposure in electric utility workers

Power-frequency electric and magnetic fields are known to exhibit marked temporal variation, yet in the absence of clear biological indications, the most appropriate summary indices for use in epidemiologic studies are unknown. In order to assess the statistical patterns among candidate indices, data on 4383 worker-days for magnetic fields and 2082 worker-days for electric fields collected for the Electric and Magnetic Field Project for Electric Utilities using the EMDEX meter [Bracken (1990): Palo Alto, CA: Electric Power Research Institute] were analyzed. We examined correlations at the individual and job title group levels among indices of exposure to both electric and magnetic fields, including the arithmetic mean, geometric mean, median, 20th and 90th percentiles, time above lower cutoffs of 20 V/m and 0.2 μT, and time above higher cutoffs of 100 V/m and 2.0 μT. For both electric and magnetic fields, the arithmetic mean was highly correlated with the 90th percentile; moderately correlated with the geometric mean, median, and lower and higher cutoff scores; and weakly correlated with the 20th percentile. Electric and magnetic field indices were generally weakly correlated with one another. Rank-order correlation coefficients were consistently greater than product-moment correlation coefficients. Job title group summary scores showed higher correlations among electric field indices and magnetic field indices and between electric and magnetic field indices than was found for individual worker-days, with only the 20th percentile clearly independent of the others. These results suggest that individuals' exposures are adequately characterized by a measure of central tendency for electric and magnetic fields, such as the arithmetic or geometric mean, and an indicator of a lower threshold or cutoff for each field type, such as the 20th percentile or proportion of time above 20 V/m or 0.2 μT. A single measure of central tendency for each type of field appears to be adequate when exposures are assessed at the job title level. © 1994 Wiley-Liss, Inc.     

Clinical implications of matrix metalloproteinases

Matrix metalloproteinases (MMPs) are a family of neutral proteinases that are important for normal development, wound healing, and a wide variety of pathological processes, including the spread of metastatic cancer cells, arthritic destruction of joints, atherosclerosis, pulmonary fibrosis, emphysema and neuroinflammation. In the central nervous system (CNS), MMPs have been shown to degrade components of the basal lamina, leading to disruption of the blood brain barrier and to contribute to the neuroinflammatory responses in many neurological diseases. Inhibition of MMPs have been shown to prevent progression of these diseases. Currently, certain MMP inhibitors have entered into clinical trials. A goal to the future should be to design selective synthetic inhibitors of MMPs that have minimum side effects. MMP inhibitors are designed in such a way that these can not only bind at the active site of the proteinases but also to have the characteristics to bind to other sites of MMPs which might be a promising route for therapy. To name a few: catechins, a component isolated from green tea; and Novastal, derived from extracts of shark cartilage are currently in clinical trials for the treatment of MMP-mediated diseases.     

Clinical status and implications of antimalarial drug resistance

Africa carries the greatest burden of disease caused by Plasmodium falciparum, and we can expect this burden to rise in the near future, mainly because of drug resistance. Although effective drugs are available (such as artemether-lumefantrine, mefloquine, atovaquone-proguanil and halofantrine) they are uniformly too expensive for routine use. Affordable options include chloroquine plus sulfadoxine-pyrimethamine (SP), amodiaquine (alone or in combination with SP) and chlorproguanil-dapsone. Artemisinin combination therapy may offer considerable advantages over alternative therapies, but its introduction faces considerable logistic difficulty.