Investigation of cAMP microdomains as a path to novel cancer diagnostics

AbstractUnderstanding of cAMP signaling has greatly improved over the past decade. The advent of live cell imaging techniques and more specific pharmacologic modulators has led to an improved understanding of the intricacies by which cAMP is able to modulate such a wide variety of cellular pathways. It is now appreciated that cAMP is able to activate multiple effector proteins at distinct areas in the cell leading to the activation of very different downstream targets. The investigation of signaling proteins in cancer is a common route to the development of diagnostic tools, prognostic tools, and/or therapeutic targets, and in this review we highlight how investigation of cAMP signaling microdomains driven by the soluble adenylyl cyclase in different cancers has led to the development of a novel cancer biomarker. Antibodies directed against the soluble adenylyl cyclase (sAC) are highly specific markers for melanoma especially for lentigo maligna melanoma and are being described as “second generation” cancer diagnostics, which are diagnostics that determine the ‘state’ of a cell and not just identify the cell type. Due to the wide presence of cAMP signaling pathways in cancer, we predict that further investigation of both sAC and other cAMP microdomains will lead to additional cancer biomarkers. This article is part of a Special Issue entitled: The role of soluble adenylyl cyclase in health and disease

Aortopulmonary Window with Interrupted Aortic Arch and Pulmonary Artery Sling: Diagnosis by Echocardiography and Magnetic Resonance Imaging: Case Report and Literature Review

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/71570/1/j.1540-8175.1999.tb00796.x.pd

One-loop Vilkovisky-DeWitt Counterterms for 2D Gravity plus Scalar Field Theory

The divergent part of the one-loop off-shell effective action is computed for a single scalar field coupled to the Ricci curvature of 2D gravity ($c \phi R$), and self interacting by an arbitrary potential term $V(\phi)$. The Vilkovisky-DeWitt effective action is used to compute gauge-fixing independent results. In our background field/covariant gauge we find that the Liouville theory is finite on shell. Off-shell, we find a large class of renormalizable potentials which include the Liouville potential. We also find that for backgrounds satisfying $R=0$, the Liouville theory is finite off shell, as well.Comment: 19 pages, OKHEP 92-00

Bridging the Expertise of Advocates and Academics to Identify Reproductive Justice Learning Outcomes

Phenomenon: Reproductive justice (RJ) is defined by women of color advocates as the right to have children, not have children and parent children while maintaining reproductive autonomy. In the United States, physicians have been complicit in multiple historical reproductive injustices, involving coercive sterilization of thousands of people of color, low income, and disabilities. Currently, reproductive injustices continue to occur; however, physicians have no formal RJ medical education to address injustices. The objective of this study was to engage leading advocates within the movement using a Delphi method to identify critical components for such a curriculum. Approach: In 2016, we invited 65 RJ advocates and leaders to participate in an expert panel to design RJ medical education. A 3-round Delphi survey was distributed electronically to identify content for inclusion in an RJ curriculum. In the next 2 survey rounds, experts offered feedback and revisions and rated agreement with including content recommendations in the final curriculum. We calculated descriptive statistics to analyze quantitative data. A team with educational expertise wrote learning outcomes based on expert content recommendations. Findings: Of the 65 RJ advocates and leaders invited, 41 participated on the expert panel of the Delphi survey. In the first survey, the expert panel recommended 58 RJ content areas through open-ended response. Over the next 2 rounds, there was consensus among the panel to include 52 of 58 of these areas in the curriculum. Recommended content fell into 11 broad domains: access, disparities, and structural competency; advocacy; approaches to reproductive healthcare; contemporary law and policy; cultural safety; historical injustices; lesbian, gay, bisexual, transgender, queer/questioning, and intersex health; oppression, power, and bias training; patient care; reproductive health; and RJ definitions. The 97 learning outcomes created from this process represented both unique and existing educational elements. Insights: A collaborative methodology infused with RJ values can bridge experts in advocacy and academics. New learning outcomes identified through this process can enhance medical education; however, it is just as important to consider education in RJ approaches to care as it is knowledge about that care. We must explore the pedagogic process of RJ medical education while considering that expertise in this area may exist outside of the medical community and thus there is a need to partner with RJ advocates. Finally, we expect to use innovative teaching methods to transform medical education and achieve an RJ focus

The Influence of REE β-Diketone Complexes on the Corrosion Behaviour of Mild Steel and 304 SS in 3.5% NaCl Solution

In the present investigation, four REE β-diketone complexes, namely cerium acetylacetone, cerium hexafluoroacetylacetone, lanthanum acetylacetone, and lanthanum hexafluoroacetylacetone, were investigated as potential corrosion inhibitors for mild steel and 304 stainless steel in 3.5% NaCl solution. The corrosion-inhibition effects of the REE β-diketone complexes were investigated using weight-loss measurements and potentiodynamic polarisation scans. Surface analyses using optical microscopy and scanning electron microscopy (SEM) were used to investigate the morphology of the mild steel and 304 stainless steel after the weight-loss and potentiodynamic tests in 3.5% NaCl solution containing 0.5% mass per volume (m/v) concentration of the tested inhibitor. Fourier transform infrared spectroscopy and Raman spectroscopy were further used to probe the type of corrosion product film that forms on the surface of the tested samples. The obtained results revealed that the four REE β-diketone complexes are very effective inhibitors against corrosion of mild steel and 304 stainless steel in a 3.5% NaCl in a temperature range of 20–60 °C

Characterization of human iodothyronine sulfotransferases

Sulfation is an important pathway of thyroid hormone metabolism that facilitates the degradation of the hormone by the type I iodothyronine deiodinase, but little is known about which human sulfotransferase isoenzymes are involved. We have investigated the sulfation of the prohormone T4, the active hormone T3, and the metabolites rT3 and 3,3'-diiodothyronine (3,3'-T2) by human liver and kidney cytosol as well as by recombinant human SULT1A1 and SULT1A3, previously known as phenol-preferring and monoamine-preferring phenol sulfotransferase, respectively. In all cases, the substrate preference was 3,3'-T2 >> rT3 > T3 > T4. The apparent Km values of 3,3'-T2 and T3 [at 50 micromol/L 3'-phosphoadenosine-5'-phosphosulfate (PAPS)] were 1.02 and 54.9 micromol/L for liver cytosol, 0.64 and 27.8 micromol/L for kidney cytosol, 0.14 and 29.1 micromol/L for SULT1A1, and 33 and 112 micromol/L for SULT1A3, respectively. The apparent Km of PAPS (at 0.1 micromol/L 3,3'-T2) was 6.0 micromol/L for liver cytosol, 9.0 micromol/L for kidney cytosol, 0.65 micromol/L for SULT1A1, and 2.7 micromol/L for SULT1A3. The sulfation of 3,3'-T2 was inhibited by the other iodothyronines in a concentration-dependent manner. The inhibition profiles of the 3,3'-T2 sulfotransferase activities of liver and kidney cytosol obtained by addition of 10 micromol/L of the various analogs were better correlated with the inhibition profile of SULT1A1 than with that of SULT1A3. These results indicate similar substrate specificities for iodothyronine sulfation by native human liver and kidney sulfotransferases and recombinant SULT1A1 and SULT1A3. Of the latter, SULT1A1 clearly shows the highest affinity for both iodothyronines and PAPS, but it remains to be established whether it is the prominent isoenzyme for sulfation of thyroid hormone in human liver and kidney

Relationship between serum thyroid hormones and their associated metabolites, and gene expression bioindicators in the back skin of Rana [Lithobates] catesbeiana tadpoles and frogs during metamorphosis

Anuran metamorphosis is characterized by profound morphological changes including remodeling of tissues and organs. This transition is initiated by thyroid hormones (THs). However, the current knowledge of changing levels of THs during metamorphosis relies on pooled samples using methods known for high variability with sparse reporting of measured variation. Moreover, establishing a clear linkage between key gene expression bioindicators and TH levels throughout the metamorphic process is needed. Using state-of-the-art ultra-high performance liquid chromatography isotope-dilution tandem mass spectrometry, we targeted 12 THs and metabolites in the serum of Rana [Lithobates] catesbeiana (n=5-10) across seven distinct postembryonic stages beginning with premetamorphic tadpoles (Gosner stage 31-33) and continuing through metamorphosis to a juvenile frog (Gosner stage 46). TH levels were related to TH-relevant gene transcripts (thra, thrb, and thibz) in back skin of the same individual animals. Significant increases from basal levels were observed for thyroxine (T4) and 3,3’,5-triiodothyronine (T3) at Gosner stage 41, reaching maximal levels at Gosner stage 44 (28 ± 10 and 2.3 ± 0.5 ng/mL, respectively), and decreasing to basal levels in juvenile frogs. In contrast, 3,5-diiodothyronine (T2) increased significantly at Gosner stage 40 and was maintained elevated until stage 44. While thra transcript levels remained constant and then decreased at the end of metamorphic climax, thrb and thibz were induced to maximal levels at Gosner stage 41, followed by a decrease to basal levels in the froglet. This exemplifies the exquisite timing of events during metamorphosis as classic early response genes are transcribed in anticipation of peak TH concentrations. The distinct T2 concentration profile suggests a biological role of this biomolecule in anuran postembryonic development and an additional aspect that may be a target of anthropogenic chemicals that can disrupt anuran metamorphosis and TH signalling. Hence, as a second aim of the study, we set out to find additional bioindicators of metamorphosis, which can aid future investigations of developmental disruption. Using a sensitive nanoLC-Orbitrap system an untargeted analysis workflow was applied. Among 6,062 endogenous metabolites, 421 showed metamorphosis-dependent concentration dynamics. These potential bioindicators included several carnitines, prostaglandins and some steroid hormones

Bisphenol A-associated epigenomic changes in prepubescent girls: a cross-sectional study in Gharbiah, Egypt

Abstract Background There is now compelling evidence that epigenetic modifications link adult disease susceptibility to environmental exposures during specific life stages, including pre-pubertal development. Animal studies indicate that bisphenol A (BPA), the monomer used in epoxy resins and polycarbonate plastics, may impact health through epigenetic mechanisms, and epidemiological data associate BPA levels with metabolic disorders, behavior changes, and reproductive effects. Thus, we conducted an environmental epidemiology study of BPA exposure and CpG methylation in pre-adolescent girls from Gharbiah, Egypt hypothesizing that methylation profiles exhibit exposure-dependent trends. Methods Urinary concentrations of total (free plus conjugated) species of BPA in spot samples were quantified for 60 girls aged 10 to 13. Genome-wide CpG methylation was concurrently measured in bisulfite-converted saliva DNA using the Infinium HumanMethylation27 BeadChip (N = 46). CpG sites from four candidate genes were validated via quantitative bisulfite pyrosequencing. Results CpG methylation varied widely among girls, and higher urinary BPA concentrations were generally associated with less genomic methylation. Based on pathway analyses, genes exhibiting reduced methylation with increasing urinary BPA were involved in immune function, transport activity, metabolism, and caspase activity. In particular, hypomethylation of CpG targets on chromosome X was associated with higher urinary BPA. Using the Comparative Toxicogenomics Database, we identified a number of candidate genes in our sample that previously have been associated with BPA-related expression change. Conclusions These data indicate that BPA may affect human health through specific epigenomic modification of genes in relevant pathways. Thus, epigenetic epidemiology holds promise for the identification of biomarkers from previous exposures and the development of epigenetic-based diagnostic strategies.http://deepblue.lib.umich.edu/bitstream/2027.42/112909/1/12940_2013_Article_648.pd

Estudio Parto: postpartum diabetes prevention program for hispanic women with abnormal glucose tolerance in pregnancy: a randomised controlled trial – study protocol

Background: Diabetes and obesity have reached epidemic proportions in the U.S. with rates consistently higher among Hispanics as compared to non-Hispanic whites. Among Hispanic women diagnosed with gestational diabetes mellitus (GDM), 50% will go on to develop type 2 diabetes within 5 years of the index pregnancy. Although randomised controlled trials among adults with impaired glucose tolerance have shown that diet and physical activity reduce the risk of type 2 diabetes, such programs have not been tested in high-risk postpartum women. The overall goal of this randomised controlled trial is to test the efficacy of a culturally and linguistically modified, individually-tailored lifestyle intervention to reduce risk factors for type 2 diabetes and cardiovascular disease among postpartum Hispanic women with a history of abnormal glucose tolerance during pregnancy. Methods/Design Hispanic pregnant women who screen positive for GDM will be recruited and randomly assigned to a Lifestyle Intervention (n = 150) or a Health & Wellness (control) Intervention (n = 150). Multimodal contacts (i.e., in-person, telephone, and mailed materials) will be used to deliver the intervention from late pregnancy (29 weeks gestation) to 12 months postpartum. Targets of the intervention are to achieve Institute of Medicine Guidelines for postpartum weight loss; American Congress of Obstetrician and Gynecologist guidelines for physical activity; and American Diabetes Association guidelines for diet. The intervention draws from Social Cognitive Theory and the Transtheoretical Model and addresses the specific cultural and environmental challenges faced by low-income Hispanic women. Assessments will be conducted at enrollment, and at 6-weeks, 6-months, and 12-months postpartum by trained bicultural and bilingual personnel blinded to the intervention arm. Efficacy will be assessed via postpartum weight loss and biomarkers of insulin resistance and cardiovascular risk. Changes in physical activity and diet will be measured via 7-day actigraph data and three unannounced 24-hour dietary recalls at each assessment time period. Discussion Hispanic women are the fastest growing minority group in the U.S. and have the highest rates of sedentary behavior and postpartum diabetes after a diagnosis of GDM. This randomised trial uses a high-reach, low-cost strategy that can readily be translated into clinical practice in underserved and minority populations. Trial registration NCT0167921