An Active Learning Approach for Rapid Characterization of Endothelial Cells in Human Tumors

Currently, no available pathological or molecular measures of tumor angiogenesis predict response to antiangiogenic therapies used in clinical practice. Recognizing that tumor endothelial cells (EC) and EC activation and survival signaling are the direct targets of these therapies, we sought to develop an automated platform for quantifying activity of critical signaling pathways and other biological events in EC of patient tumors by histopathology. Computer image analysis of EC in highly heterogeneous human tumors by a statistical classifier trained using examples selected by human experts performed poorly due to subjectivity and selection bias. We hypothesized that the analysis can be optimized by a more active process to aid experts in identifying informative training examples. To test this hypothesis, we incorporated a novel active learning (AL) algorithm into FARSIGHT image analysis software that aids the expert by seeking out informative examples for the operator to label. The resulting FARSIGHT-AL system identified EC with specificity and sensitivity consistently greater than 0.9 and outperformed traditional supervised classification algorithms. The system modeled individual operator preferences and generated reproducible results. Using the results of EC classification, we also quantified proliferation (Ki67) and activity in important signal transduction pathways (MAP kinase, STAT3) in immunostained human clear cell renal cell carcinoma and other tumors. FARSIGHT-AL enables characterization of EC in conventionally preserved human tumors in a more automated process suitable for testing and validating in clinical trials. The results of our study support a unique opportunity for quantifying angiogenesis in a manner that can now be tested for its ability to identify novel predictive and response biomarkers

Leptin and Adiponectin: new players in the field of tumor cell and leukocyte migration

Adipose tissue is no longer considered to be solely an energy storage, but exerts important endocrine functions, which are primarily mediated by a network of various soluble factors derived from fat cells, called adipocytokines. In addition to their responsibility to influence energy homeostasis, new studies have identified important pathways linking metabolism with the immune system, and demonstrating a modulatory role of adipocytokines in immune function. Additionally, epidemiological studies underline that obesity represents a significant risk factor for the development of cancer, although the exact mechanism of this relationship remains to be determined. Whereas a possible influence of adipocytokines on the proliferation of tumor cells is already known, new evidence has come to light elucidating a modulatory role of this signaling substances in the regulation of migration of leukocytes and tumor cells. The migration of leukocytes is a key feature to fight cancer cells, whereas the locomotion of tumor cells is a prerequisite for tumor formation and metastasis. We herein review the latest tumor biological findings on the role of the most prominent adipocytokines leptin and adiponectin, which are secreted by fat cells, and which are involved in leukocyte migration, tumor growth, invasion and metastasis. This review thus accentuates the complex, interactive involvement of adipocytokines in the regulation of migration of both leukocytes and tumor cells, and gives an insight in the underlying molecular mechanisms

Plasma levels of leptin and mammographic density among postmenopausal women: a cross-sectional study

INTRODUCTION: Obesity has been linked to increased risk of breast cancer in postmenopausal women. Increased peripheral production of estrogens has been regarded as the main cause for this association, but other features of increased body fat mass may also play a part. Leptin is a protein produced mainly by adipose tissue and may represent a growth factor in cancer. We examined the association between leptin plasma levels and mammographic density, a biomarker for breast cancer risk. METHODS: We included data from postmenopausal women aged 55 and older, who participated in a cross-sectional mammography study in Tromsø, Norway. Mammograms, plasma leptin measurements as well as information on anthropometric and hormonal/reproductive factors were available from 967 women. We assessed mammographic density using a previously validated computer-assisted method. Multiple linear regression analysis was applied to investigate the association between mammographic density and quartiles of plasma leptin concentration. Because we hypothesized that the effect of leptin on mammographic density could vary depending on the amount of nondense or fat tissue in the breast, we also performed analyses on plasma leptin levels and mammographic density within tertiles of mammographic nondense area. RESULTS: After adjusting for age, postmenopausal hormone use, number of full-term pregnancies and age of first birth, there was an inverse association between leptin and absolute mammographic density (P(trend )= 0.001). When we additionally adjusted for body mass index and mammographic nondense area, no statistically significant association between plasma leptin and mammographic density was found (P(trend )= 0.16). Stratified analyses suggested that the association between plasma leptin and mammographic density could differ with the amount of nondense area of the mammogram, with the strongest association between leptin and mammographic absolute density in the stratum with the medium breast fat content (P(trend )= 0.003, P for interaction = 0.05). CONCLUSION: We found no overall consistent association between the plasma concentration of leptin and absolute mammographic density. Although weak, there was some suggestion that the association between leptin and mammographic density could differ with the amount of fat tissue in the breast

Exercise and the Prevention of Oesophageal Cancer (EPOC) study protocol: a randomized controlled trial of exercise versus stretching in males with Barrett's oesophagus

<p>Abstract</p> <p>Background</p> <p>Chronic gastro-oesophageal reflux disease and excessive body fat are considered principal causes of Barrett's oesophagus (a metaplastic change in the cells lining the oesophagus) and its neoplastic progression, oesophageal adenocarcinoma. Metabolic disturbances including altered levels of obesity-related cytokines, chronic inflammation and insulin resistance have also been associated with oesophageal cancer development, especially in males. Physical activity may have the potential to abrogate metabolic disturbances in males with Barrett's oesophagus and elicit beneficial reductions in body fat and gastro-oesophageal reflux symptoms. Thus, exercise may be an effective intervention in reducing oesophageal adenocarcinoma risk. However, to date this hypothesis remains untested.</p> <p>The 'Exercise and the Prevention of Oesophageal Cancer Study' will determine whether 24 weeks of exercise training will lead to alterations in risk factors or biomarkers for oesophageal adenocarcinoma in males with Barrett's oesophagus. Our primary outcomes are serum concentrations of leptin, adiponectin, tumour necrosis factor-alpha, C-reactive protein and interleukin-6 as well as insulin resistance. Body composition, gastro-oesophageal reflux disease symptoms, cardiovascular fitness and muscular strength will also be assessed as secondary outcomes.</p> <p>Methods/Design</p> <p>A randomized controlled trial of 80 overweight or obese, inactive males with Barrett's oesophagus will be conducted in Brisbane, Australia. Participants will be randomized to an intervention arm (60 minutes of moderate-intensity aerobic and resistance training, five days per week) or a control arm (45 minutes of stretching, five days per week) for 24 weeks. Primary and secondary endpoints will be measured at baseline (week 0), midpoint (week 12) and at the end of the intervention (week 24).</p> <p>Discussion</p> <p>Due to the increasing incidence and very high mortality associated with oesophageal adenocarcinoma, interventions effective in preventing the progression of Barrett's oesophagus are urgently needed. We propose that exercise may be successful in reducing oesophageal adenocarcinoma risk. This primary prevention trial will also provide information on whether the protective association between physical activity and cancer is causal.</p> <p>Trial Registration</p> <p>ACTRN12609000401257</p

Stability of Phosphorus Species in Seawater

20-23Relative stabilities of various oxidation states, oxyacids and dissolved inorganic complexes of phosphorus in anoxic and oxic marine environments are elucidated. H sub(3) PO sub(2)/P super(0) and H sub(2) PO sub(2)/p super(0) are the strong reducing couples in acidic and basic solutions, respectively, in anoxic conditions. H sub(3) PO sub(4)/H sub(4) P sub(2) O sub(6) and H sub(3) PO sub(2)/P super(0) are the important reducing couples in seawater. HPO and H PO are the stable ones in oxic and anoxic seawaters, respectively. UO (HPO) are the most stable complexes in oxic seawater. Among the PO complexes CaPO is more stable

Property-property relations: 22° and 9° discontinuities in the Arabian Sea

This study uses the relationship between conservative chemical parameters and the relationship between potential temperature and salinity to determine the layers of discontinuity in the Sea of Oman and describe phenomena in situ. The values of salinity, PO, NO, oxygen and the stability of water (E) depending on the potential temperature reveal two layers of discontinuity, one following the isotherm 22.2°C (22 DD) and the each other along the isotherm 9.1° C (9 DD). Layer 22 DD appears to result from mixing of waters of the Gulf (PGW) with shallow salinity maximum (SSMW). This discontinuity is mid-depth of the mixed layer. The mass of water of the Red Sea (RSW) contributes to the discontinuity DD 9. We also determine various physicochemical characteristics of these two layers of discontinuity, as well as those of other water masses and isopycnal surfaces

Carbon and nitrogen budgets of the Arabian Sea

From the available data, carbon and nitrogen budgets have been estimated for the Arabian Sea (0-25&#176;N, 50-80&#176;E), taking into consideration the possible sources of fluxes. By our model calculations the annual fluxes into and out of the Arabian Sea were estimated to be 446 and 530 trillion grams (Tg) for carbon, and 8.06 and 3.60 Tg for nitrogen, respectively. The carbon budget was found to be negatively balanced by 84 Tg year<SUP>-1</SUP>. A possible source to compensate for this deficit could be from the northward movement of Antarctic Bottom Water in the bottom layers, which are probably enriched with anthropogenic carbon dioxide. Annually, ~74 Tg of carbon in the form of carbon dioxide escaped into the atmosphere from the Arabian Sea; this is higher than the global average fluxes from the tropical oceans. The percentage loss of carbon (14.0%) to the atmosphere was much lower than that of nitrogen (56.9%). Out of the total amount of denitrified nitrogen (29.5 Tg) only ~7% was lost to the atmosphere. This model suggests that ~6 Tg N year<SUP>-1</SUP> of denitrified nitrogen of the world's oceans could be liberated to the atmosphere through the surface layer of denitrified areas. A quantitative assessment has been made to account for the excess of nitrogen that could result from N<SUB>2</SUB> fixation by extensive blooms of Trichodesmium in the Arabian Sea. Fluxes from rivers did not seem to contribute significantly to the carbon influx. The burial of carbon through the sedimentation process was not very significant to the total flux. The Arabian Sea was found to be a carbon source for the Persian Gulf and the Red Sea, whereas both of these adjacent seas added nitrogen to the Arabian Sea. Based on the standing crop and net outfluxes, estimated residence times were ~944 and 4.04 &#215; 10<SUP>4</SUP> years for carbon and nitrogen, respectively, in the Arabian Sea