A loop of cancer-stroma-cancer interaction promotes peritoneal metastasis of ovarian cancer via TNFα-TGFα-EGFR.

Peritoneum is the most common site for ovarian cancer metastasis. Here we investigate how cancer epigenetics regulates reciprocal tumor-stromal interactions in peritoneal metastasis of ovarian cancer. Firstly, we find that omental stromal fibroblasts enhance colony formation of metastatic ovarian cancer cells, and de novo expression of transforming growth factor-alpha (TGF-α) is induced in stromal fibroblasts co-cultured with ovarian cancer cells. We also observed an over-expression of tumor necrosis factor-alpha (TNF-α) in ovarian cancer cells, which is regulated by promoter DNA hypomethylation as well as chromatin remodeling. Interestingly, this ovarian cancer-derived TNF-α induces TGF-α transcription in stromal fibroblasts through nuclear factor-κB (NF-κB). We further show that TGF-α secreted by stromal fibroblasts in turn promotes peritoneal metastasis of ovarian cancer through epidermal growth factor receptor (EGFR) signaling. Finally, we identify a TNFα-TGFα-EGFR interacting loop between tumor and stromal compartments of human omental metastases. Our results therefore demonstrate cancer epigenetics induces a loop of cancer-stroma-cancer interaction in omental microenvironment that promotes peritoneal metastasis of ovarian cancer cells via TNFα-TGFα-EGFR.

Dysregulation of microRNA-204 mediates migration and invasion of endometrial cancer by regulating FOXC1.

MicroRNAs (miRNAs) regulate mRNA stability and protein expression, and certain miRNAs have been demonstrated to act either as oncogenes or tumor suppressors. Differential miRNA expression signatures have been documented in many human cancers but the role of miRNAs in endometrioid endometrial cancer (EEC) remains poorly understood. This study identifies significantly dysregulated miRNAs of EEC cells, and characterizes their impact on the malignant phenotype. We studied the expression of 365 human miRNAs using Taqman low density arrays in EECs and normal endometriums. Candidate differentially expressed miRNAs were validated by quantitative real-time PCR. Expression of highly dysregulated miRNAs was examined in vitro through the effect of anti-/pre-miRNA transfection on the malignant phenotype. We identified 16 significantly dysregulated miRNAs in EEC and 7 of these are novel findings with respect to EEC. Antagonizing the function of miR-7, miR-194 and miR-449b, or overexpressing miR-204, repressed migration, invasion and extracellular matrix-adhesion in HEC1A endometrial cancer cells. FOXC1 was determined as a target gene of miR-204, and two binding sites in the 3'-untranslated region were validated by dual luciferase reporter assay. FOXC1 expression was inversely related to miR-204 expression in EEC. Functional analysis revealed the involvement of FOXC1 in migration and invasion of HEC1A cells. Our results present dysfunctional miRNAs in endometrial cancer and identify a crucial role for miR-204-FOXC1 interaction in endometrial cancer progression. This miRNA signature offers a potential biomarker for predicting EEC outcomes, and targeting of these cancer progression- and metastasis-related miRNAs offers a novel potential therapeutic strategy for the disease.

Temporal relationship between air pollution and hospital admissions for asthmatic children in Hong Kong.

BACKGROUND: Many epidemiological studies have shown positive association between respiratory health and current levels of outdoor air pollution in Europe and America. OBJECTIVE: The aim of this study was to investigate the association between air pollution and the number of childhood admissions for asthma in Hong Kong. METHODS: Daily counts of childhood admission for asthma to a large teaching Hospital were obtained from the computerized database for the period 1993-1994. A Poisson regression allowing for seasonal patterns and meteorological conditions was used to assess the associations between the number of Hospital admissions and the three pollutants: nitrogen dioxide, sulphur dioxide and inhalable particles (measured as PM10, particles < 10 microm in aerodynamic diameter). RESULTS: A total of 1217 children under 15 years of age were admitted for asthma during the study period. The calculated annual hospitalization rates were 283 and 178 per 100 000 for boys and girls, respectively. The mean PM10, NO2 and SO2 levels were 44.1 microg/m3, 43.3 microg/m3, and 12.2 microg/m3, respectively. Daily admission for asthma increased significantly with increasing ambient level of nitrogen dioxide (relative risk (RR) = 1.08 per 10 microg/m3 increase), sulphur dioxide (RR = 1.06) and inhalable particles (RR = 1.03). No association was found between hospital admission and humidity, temperature or atmospheric pressure. CONCLUSION: This is the first daily time series study of childhood admissions for asthma and air pollution in Hong Kong. The results support that current levels of air pollution contribute to the respiratory morbidity in asthmatic children in Hong Kong.

Air pollution and hospital admissions for respiratory and cardiovascular diseases in Hong Kong.

OBJECTIVE: To investigate short term effects of concentrations of pollutants in ambient air on hospital admissions for cardiovascular and respiratory diseases in Hong Kong. METHODS: Retrospective ecological study. A Poisson regression was performed of concentrations of daily air pollutant on daily counts of emergency hospital admissions in 12 major hospitals. The effects of time trend, season, and other cyclical factors, temperature, and humidity were accounted for. Autocorrelation and overdispersion were corrected. Daily concentrations of nitrogen dioxide (NO2), sulphur dioxide (SO2), ozone (O3), and particulate matter < 10 microns in aerodynamic diameter (PM10) were obtained from seven air monitoring stations in Hong Kong in 1994 and 1995. Relative risks (RR) of respiratory and cardiovascular disease admissions (for an increase of 10 micrograms/m3 in concentration of air pollutant) were calculated. RESULTS: Significant associations were found between hospital admissions for all respiratory diseases, all cardiovascular diseases, chronic obstructive pulmonary diseases, and heart failure and the concentrations of all four pollutants. Admissions for asthma, pneumonia, and influenza were significantly associated with NO2, O3, and PM10. Relative risk (RR) for admissions for respiratory disease for the four pollutants ranged from 1.013 (for SO2) to 1.022 (for O3), and for admissions for cardiovascular disease, from 1.006 (for PM10) to 1.016 (for SO2). Those aged > or = 65 years were at higher risk. Significant positive interactions were detected between NO2, O3, and PM10, and between O3 and winter months. CONCLUSIONS: Adverse health effects are evident at current ambient concentrations of air pollutants. Further reduction in air pollution is necessary to protect the health of the community, especially that of the high risk group.

The latent class model for multiple binary screening tests.

Given multiple binary tests, such as repeated application of a blind screening test to each individual in a sample, we attempt to estimate the prevalence, sensitivity and specificity of the test without knowing the true disease status of those tested (gold standard). This problem is equivalent to finding the mixing distribution of a mixture of binomial distributions. We suggest a new method to determine the number of latent classes. Our simulations show that the coverage probabilities of the bootstrap confidence intervals of our estimates are correct. Our methods are illustrated by examples from published medical research.

On the heterogeneity of fecundability.

We propose to use a general mixing distribution in modeling the heterogeneity of the fecundability of couples. We introduce a sequence of parameters called canonical moments, which is in one to one correspondence with the moments, to characterize the mixing distribution. By using the bootstrap method, we can estimate the standard errors of our estimates. Our method modifies the usual moment estimates so that the resulting mixing distribution is always supported on [0, 1]. Moreover, the downward bias of the moment estimate of the number of support points would be reduced. Our approach can be used for censored data. The application of our technique in finding the sterile subpopulation is also discussed. The theory is illustrated with several data examples and simulations.

Forced midexpiratory time: reference values and the effect of cigarette smoking.

BACKGROUND: Forced midexpiratory time (FET25-75%), the time required to exhale from 25 to 75% of forced vital capacity (FVC), has been advocated as a relatively volume-independent measure of obstruction. Previous estimates of normal FET25-75% have not systematically studied the effect of age, height, sex, and smoking history. METHODS: We analyzed flow-volume loops from 369 normal lifetime nonsmokers and smokers, a random sample of the population of Michigan. Linear models including age and/or height were considered, with and without logarithmic transformation. RESULTS: The best models used age, or age and height, and no transformation. Age and height contributed much less to the variability of FET25-75% than to spirometric flows previously investigated. The largest r2 was found in the male smokers, with the largest contribution from age, suggesting a smoking effect. CONCLUSIONS: As age was the major contributor to the value of FET25-75% and that contribution was small, we suggest the use of simplified age-stratified reference values derived from our data.

Drug treatment of hypertension in the elderly: a meta-analysis.

PURPOSE: A meta-analysis of the effect of antihypertensive drug treatment on mortality and morbidity in elderly patients. DATA SOURCES: A literature search of published articles from January 1980 to February 1992. STUDY SELECTION: Randomized controlled trials of drug treatment of hypertension with end points for elderly patients reported separately. DATA EXTRACTION: Mortality or morbidity end points or both in patients older than 59 years were pooled by determination of typical odds ratio. A meta-regression was used to study heterogeneity. RESULTS: Nine major trials with 15,559 patients older than 59 years were identified. Death rates in the control group varied between 2.7% and 77.2%; stroke and coronary mortality increased with the severity-of-illness rank (P < 0.001). Overall, treated patients had an approximately 12% reduction in all-cause mortality (odds ratio, 0.88; 95% CI, 0.80 to 0.97; 953 events compared with 1069 events, P = 0.009). There was a 36% reduction in stroke mortality (odds ratio, 0.64; CI, 0.49 to 0.82; 94 events compared with 149 events, P < 0.001) and a 25% reduction in coronary heart disease mortality (odds ratio, 0.75; CI, 0.64 to 0.88; 263 events compared with 350 events, P < 0.001). Coronary morbidity was reduced 15% (odds ratio, 0.85; CI, 0.73 to 0.99; 325 events compared with 379 events, P = 0.036), and stroke morbidity was reduced 35% (odds ratio, 0.65; CI, 0.55 to 0.76; 247 events compared with 382 events, P < 0.001). CONCLUSION: Overall, treatment of hypertension in elderly patients produces a significant benefit in total mortality and cardiovascular morbidity and mortality. However, this benefit may be reduced in the oldest age groups.

Three-year randomised study of high-purity or intermediate-purity factor VIII concentrates in symptom-free HIV-seropositive haemophiliacs: effects on immune status.

The availability of monoclonal-antibody-purified factor VIII (FVIII) concentrates allows us to test the hypothesis, based on in vitro observations, that their use in HIV seropositive haemophiliacs would result in a difference in the rate of deterioration of immune function. We designed a multicentre, prospective, randomised, controlled study of symptom-free HIV-infected patients with haemophilia A who were assigned to receive either an intermediate-purity or monoclonal-antibody-purified product. All had CD4 lymphocyte counts of 100-600/microL, were negative for hepatitis B surface antigen, had not received any antiretroviral or immunomodulating drugs before study entry, and had previously received replacement therapy with intermediate purity FVIII concentrates. Use of antiretroviral therapy was permitted. 60 patients were recruited and 30 were assigned to each group. 35 completed the 3 year study, 20 in the monoclonal arm and 15 in the intermediate-purity arm. Among those completing the study, there were no differences between the two groups in the occurrence of AIDS-defining diagnoses (1 in each group). There were, however, striking and significant differences in terms of changes in absolute CD4 counts. The group receiving monoclonal-antibody-purified concentrates had essentially stable counts while a significant drop was observed in the group receiving intermediate-purity FVIII. These differences were independent of the use of antiretroviral therapy. These observations support the use of high-purity concentrates in the treatment of symptom-free HIV-positive patients with haemophilia A, and they should be taken into account along with cost, by doctors making therapeutic decisions.

Mucin associated Tn and sialosyl-Tn antigen expression in colorectal polyps.

Sialosyl-Tn antigen and its immediate precursor, Tn antigen, are carbohydrate structures associated with the earliest steps of mucin O-linked glycosylation. Both antigens have been shown previously to be highly sensitive and specific markers of colorectal cancer. One hundred and three colorectal polyps (79 adenomatous; 24 hyperplastic) were examined for expression of Tn antigen using vicia villosa isolectin B4, and for sialosyl-Tn antigen by monoclonal antibody TKH2. Tn antigen was expressed by all of the polyps studied. Sialosyl-Tn, on the other hand was expressed weakly by a few cells in 7 of 24 (29%) hyperplastic polyps. Among the adenomatous polyps, 56% expressed sialosyl-Tn and expression correlated with larger adenoma size, greater villous component, and more severe grades of dysplasia. In individuals with two or more synchronous adenomas, the level of sialosyl-Tn expression within an adenoma was associated with the severity of cytological atypia. All the adenomas that contained a focus of invasive carcinoma expressed sialosyl-Tn. These results indicate that colorectal polyps manifest incomplete glycosylation, exposing antigens in the innermost region of mucin oligosaccharides. In addition, the correlation of sialosyl-Tn antigen expression with the adenoma-carcinoma sequence may make this a useful marker for studying malignant progression in the colon.

Radiation-induced meningiomas: experience at the Mount Sinai Hospital and review of the literature.

From the records of The Mount Sinai Hospital, seven cases which met established criteria for radiation-induced meningiomas were identified. This represents the largest series of radiogenic meningiomas documented in North America and includes both intracranial and intraspinal tumors. The records and pathological specimens were reviewed and these data analyzed with other cases retrieved from the world literature. This study reveals that radiation-induced meningiomas can be categorized into three groups based on the amount of radiation administered: 1) low dose; 2) moderate dose and miscellaneous; and 3) high dose. The overwhelming majority of cases had received low-dose irradiation (800 rad) to the scalp for tinea capitis and the second largest group resulted from high-dose irradiation for primary brain tumors (greater than 2000 rad). The unique features distinguishing radiation-induced meningiomas from other meningiomas are reviewed. Although histologically atypical tumors were common in this series, overt malignancy was not encountered. The preoperative management of these lesions should include angiography to evaluate for large-vessel occlusive vasculopathy, a known association of meningiomas induced by high-dose irradiation. Given the propensity these tumors possess for recurrence, a wide bony and dural margin is recommended at surgical resection.

On dependent repeated screening tests.

A screening test is applied n times to a person with known true status. If more than k tests have positive outcomes, then the person is assigned to be screen-positive; otherwise, the person is assigned to be screen-negative. Assuming that the tests are exchangeable, we can characterize the possible dependence among tests by at most n parameters called canonical moments, which can be estimated from the data. The performance characteristics of the composite test (such as likelihood ratios, sensitivity, and specificity) can be computed based on these estimates. Thus, we can choose n and k so that the desired levels of likelihood ratios, sensitivity, and specificity can be achieved. We study the cases n = 2 and n = 3 in detail.

Metastatic patterns in histologic variants of ovarian cancer. An autopsy study.

The autopsy findings of 428 patients with various histologic types of ovarian cancer were studied to determine if metastatic patterns were different. Epithelial tumors were the most frequent (89%), followed by sarcomas (7.2%). Germ cell and stromal tumors each occurred in 1.9% of cases. Sites of metastasis were nearly identical, with no statistical difference among histologic types. The peritoneum was most frequently involved (83% to 100% of cases), but lymph node metastasis was common (50% to 60% of cases). Metastasis was more common to the paraaortic lymph nodes than to the pelvic lymph nodes. In seven of eight stromal tumors, hepatic metastasis was present but did not cause the patient's death. For epithelial tumors, metastasis to distant sites was dependent on nodal and intraperitoneal disease. However, this was not true in the 31 ovarian sarcomas or the series of germ cell or stromal tumors. This finding supports a hematogenous route of metastasis for ovarian sarcomas. Understanding the metastatic potential of ovarian cancer is important in designing effective treatment regimens.

Patient-controlled analgesia in gynecologic oncology. A comparative analysis.

Patient-controlled analgesia (PCA) allows postoperative gynecologic oncology patients to self-administer intravenous analgesia but has not been well compared to standard intramuscular analgesia. Seventy patients undergoing laparotomy were treated with meperidine via PCA or intramuscular administration and evaluated 24 and 48 hours postoperatively. The 35 patients receiving PCA used statistically significantly less meperidine than did the controls at 24 and 48 hours postoperatively. The pharmacy's cost of the drug was statistically significantly less for PCA patients. PCA meperidine was well tolerated, with minimal alterations in consciousness and infrequent nausea.

On repeated screening tests.

We point out the connection between quality control and repeated screening tests, and suggest a practical way to design the repeated screening tests so that the composite test achieves the desired level of sensitivity and specificity. We further point out the benefits of using likelihood ratios to measure the performance of a screening test. Then we investigate repeated tests when we have polytomous disease levels and polytomous diagnostic levels.

Insulin metabolism in depancreatized dogs during hemorrhagic shock.

This study was done to determine why the plasma insulin remained elevated during shock. Mongrel Female dogs (12-15 kg) were depancreatized and maintained on a constant intraportal infusion of porcine insulin while they were bled to reduce and maintain the mean arterial blood pressure at 50 mm Hg for 165 min. Blood samples were taken for glucose and plasma insulin at 15 min intervals. The data show that there was a progressive rise of plasma insulin during the course of hemorrhagic shock. This occurred despite a constant infusion of insulin, the sole source of insulin available to these depancreatized dogs. Since removal of plasma insulin is largely due to insulin utilization, our findings imply that the rise of plasma insulin in hemorrhagic shock is caused by decreased utilization.