Conformal predictors in early diagnostics of ovarian and breast cancers

The paper describes an application of a recently developed machine learning technique called Mondrian predictors to risk assessment of ovarian and breast cancers. The analysis is based on mass spectrometry profiling of human serum samples that were collected in the United Kingdom Collaborative Trial of Ovarian Cancer Screening. The paper describes the technique and presents the results of classification (diagnosis) and the corresponding measures of confidence of the diagnostics. The main advantage of this approach is a proven validity of prediction. The paper also describes an approach to improve early diagnosis of ovarian and breast cancers since the data in the United Kingdom Collaborative Trial of Ovarian Cancer Screening were collected over a period of seven years and do allow to make observations of changes in human serum over that period of time. Significance of improvement is confirmed statistically (for up to 11 months for Ovarian Cancer and 9 months for Breast Cancer). In addition, the methodology allowed us to pinpoint the same mass spectrometry peaks as previously detected as carrying statistically significant information for discrimination between healthy and diseased patients. The results are discussed

Combinatorial Effect of Non-Steroidal Anti-inflammatory Drugs and NF-κB Inhibitors in Ovarian Cancer Therapy

Several epidemiological studies have correlated the use of non-steroidal anti-inflammatory drugs (NSAID) with reduced risk of ovarian cancer, the most lethal gynecological cancer, diagnosed usually in late stages of the disease. We have previously established that the pro-apoptotic cytokine melanoma differentiation associated gene-7/Interleukin-24 (mda-7/IL-24) is a crucial mediator of NSAID-induced apoptosis in prostate, breast, renal and stomach cancer cells. In this report we evaluated various structurally different NSAIDs for their efficacies to induce apoptosis and mda-7/IL-24 expression in ovarian cancer cells. While several NSAIDs induced apoptosis, Sulindac Sulfide and Diclofenac most potently induced apoptosis and reduced tumor growth. A combination of these agents results in a synergistic effect. Furthermore, mda-7/IL-24 induction by NSAIDs is essential for programmed cell death, since inhibition of mda-7/IL-24 by small interfering RNA abrogates apoptosis. mda-7/IL-24 activation leads to upregulation of growth arrest and DNA damage inducible (GADD) 45 α and γ and JNK activation. The NF-κB family of transcription factors has been implicated in ovarian cancer development. We previously established NF-κB/IκB signaling as an essential step for cell survival in cancer cells and hypothesized that targeting NF-κB could potentiate NSAID-mediated apoptosis induction in ovarian cancer cells. Indeed, combining NSAID treatment with NF-κB inhibitors led to enhanced apoptosis induction. Our results indicate that inhibition of NF-κB in combination with activation of mda-7/IL-24 expression may lead to a new combinatorial therapy for ovarian cancer

Infant High-Grade Gliomas Comprise Multiple Subgroups Characterized by Novel Targetable Gene Fusions and Favorable Outcomes.

Infant high-grade gliomas appear clinically distinct from their counterparts in older children, indicating that histopathologic grading may not accurately reflect the biology of these tumors. We have collected 241 cases under 4 years of age, and carried out histologic review, methylation profiling, and custom panel, genome, or exome sequencing. After excluding tumors representing other established entities or subgroups, we identified 130 cases to be part of an "intrinsic" spectrum of disease specific to the infant population. These included those with targetable MAPK alterations, and a large proportion of remaining cases harboring gene fusions targeting ALK (n = 31), NTRK1/2/3 (n = 21), ROS1 (n = 9), and MET (n = 4) as their driving alterations, with evidence of efficacy of targeted agents in the clinic. These data strongly support the concept that infant gliomas require a change in diagnostic practice and management. SIGNIFICANCE: Infant high-grade gliomas in the cerebral hemispheres comprise novel subgroups, with a prevalence of ALK, NTRK1/2/3, ROS1, or MET gene fusions. Kinase fusion-positive tumors have better outcome and respond to targeted therapy clinically. Other subgroups have poor outcome, with fusion-negative cases possibly representing an epigenetically driven pluripotent stem cell phenotype.See related commentary by Szulzewsky and Cimino, p. 904.This article is highlighted in the In This Issue feature, p. 890

Functional diversity and co-operativity between subclonal populations of paediatric glioblastoma and diffuse intrinsic pontine glioma cells

The failure to develop effective therapies for pediatric glioblastoma (pGBM) and diffuse intrinsic pontine glioma (DIPG) is in part due to their intrinsic heterogeneity. We aimed to quantitatively assess the extent to which this was present in these tumors through subclonal genomic analyses and to determine whether distinct tumor subpopulations may interact to promote tumorigenesis by generating subclonal patient-derived models in vitro and in vivo. Analysis of 142 sequenced tumors revealed multiple tumor subclones, spatially and temporally coexisting in a stable manner as observed by multiple sampling strategies. We isolated genotypically and phenotypically distinct subpopulations that we propose cooperate to enhance tumorigenicity and resistance to therapy. Inactivating mutations in the H4K20 histone methyltransferase KMT5B (SUV420H1), present in <1% of cells, abrogate DNA repair and confer increased invasion and migration on neighboring cells, in vitro and in vivo, through chemokine signaling and modulation of integrins. These data indicate that even rare tumor subpopulations may exert profound effects on tumorigenesis as a whole and may represent a new avenue for therapeutic development. Unraveling the mechanisms of subclonal diversity and communication in pGBM and DIPG will be an important step toward overcoming barriers to effective treatments

steel supercritical fluid extraction system

Conventional supercritical fluid extraction (SFE) system are constructed using stainless steel due to its relative inertness, ready availability, tensile strength and low cost. Recently, metal complex solubilities and metal extraction using chelating agents have been investigated using a stainless steel SFE system. Metal complexes are usually soluble in supercritical carbon dioxide (SC-CO2) and so this was the fluid of choice for the experiments. During the chelation step, temperature and pressure have great effect on the extraction efficiency. Using a metal salt as a sample, and hexafluoroacetylacetone (HFAcAc) as a Ligand, the most efficient extraction conditions were found to be 60 degrees C and 400 atm. However, when contaminated soil was used as a sample, extraction efficiency fell. This was thought to be related to the corrosion of the stainless steel SFE system by the ligand HFAcAc, During the 30 min extraction period, 1678 mu g of iron was obtained. The corrosion of the SFE system was much greater during the soil extraction than during both the metal salt extraction and metal complex solubility experiments. (C) 2000 Elsevier Science B.V. All rights reserved

Elevated fractional exhaled nitric oxide and blood eosinophil counts are associated with a 17q21 asthma risk allele in adult subjects

Elizabeth A Schwantes,1 Michael D Evans,2 Alex Cuskey,1 Alex Burford,1 Judith A Smith,3 Robert F Lemanske Jr,3 Nizar N Jarjour,1 Sameer K Mathur1 1Division of Allergy, Pulmonary and Critical Care, Department of Medicine, 2Department of Biostatistics and Medical Informatics, 3Division of Allergy, Immunology and Rheumatology, Department of Pediatrics, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA Background and objectives: Genome-wide association studies identified single-nucleotide polymorphisms (SNPs) at the 17q21 locus conferring increased risk for childhood-onset asthma. Little is known about how these SNPs impact adult asthma patients. We sought to examine an adult population for associations between rs7216389 (17q21-associated SNP) and features of asthma including fractional exhaled nitric oxide (FeNO), eosinophil counts, and age of asthma onset. Methods: Subjects were genotyped at SNP rs7216389. The geometric mean of FeNO measurements and peripheral blood eosinophil counts from 2008 to 2015 were collected. Demographics and medical history were collected including self-reported allergy diagnoses and age of asthma onset. Eosinophils, monocytes, and peripheral blood mononuclear cells (PBMCs) were isolated for the examination of ORMDL3 expression. Results: FeNO levels from 157 genotyped subjects (31CC, 72CT, and 54TT) and peripheral eosinophil counts from 252 genotyped subjects (46CC, 122CT, and 84TT) were analyzed. In a sub-group analysis of asthma subjects, the number of attributable T alleles was associated with significantly lower age of asthma onset (P=0.03) and greater FeNO levels (geometric mean 30.0&nbsp;ppb TT, 20.0&nbsp;ppb CT, 20.0&nbsp;ppb CC, P=0.02). In the total cohort of subjects, the T allele was associated with a higher percentage of individual eosinophil counts &gt;200/mm3 (45% TT, 26% CT, 24% CC, P=0.005). Eosinophils expressed ORMDL3 mRNA and protein. Conclusion: In adult subjects, the number of T alleles at SNP rs7216389 corresponds to significantly greater FeNO levels and peripheral eosinophil counts. The expression of ORMDL3 in eosinophils suggests that they may participate in mediating the asthma risk associated with the 17q21 locus. Keywords: asthma, eosinophils, fractional exhaled nitric oxide, 17q2