bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract B39: Human FANCA binds to nucleic acids and prefers single-stranded forms
Authors: Yuan Fenghua , Qian Liangyue , Liu Jesse Y. , Zhao Xinliang , Song Limin , D'Urso Gennaro , Jain Chaitanya , Zhang Yanbin
Published: June 2012

Fanconi anemia (FA) is an autosomal recessive or X-linked disorder characterized by bone marrow failure, developmental defects, predisposition to cancer, and hypersensitivity of crosslinking agents. Fanconi anemia complementation group A (FANCA) gene is one of the 15 disease-causing genes and has been found to be mutated in ∼60% of all FA patients. Using the purified human WT-FANCA protein, we report that FANCA possesses intrinsic affinity to nucleic acids. FANCA binds to single-stranded DNA with affinity significantly higher than double-stranded DNA. FANCA also binds to single-stranded RNA with similar affinity to single-stranded DNA. FANCA requires a certain length of nucleic acids for optimal binding. Using DNA and RNA ladders, we determine the minimum numbers of nucleotides required for FANCA recognition are −30 and −40 for DNA and RNA respectively. A patient-derived FANCA truncation mutation, Q772X, has diminished affinity to both DNA and RNA. On the contrary, the complementing C-terminal fragment of Q772X, 772–1455, retains the differentiated DNA binding activity (ssDNA>dsDNA), indicating that the nucleic acids binding domain of FANCA is located at its C-terminus where most disease-causing mutations are found.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the Second AACR International Conference on Frontiers in Basic Cancer Research; 2011 Sep 14-18; San Francisco, CA. Philadelphia (PA): AACR; Cancer Res 2011;71(18 Suppl):Abstract nr B39.
Abstract B68: Chemomodulatory potential of aloe vera gel on DMBA-induced skin papillomagenesis, drug metabolizing and antioxidant enzymes
Authors: Singh M. , Singh S. , Kale R. K.
Published: June 2012

Aloe vera has traditionally been used as a folk medicine around the world. Therefore, we evaluated the chemopreventive potential of A. Vera on cell proliferation and apoptosis in DMBA induced skin papillomagenesis in mice, using three different concentrations as well as its influence on phase-I, phase-II and antioxidant enzymes, glutathione content, lactate dehydrogenase and peroxidative damage in the liver of the mice. DMBA and croton oil was used to induce and promote skin papillomagenesis respectively. Skin papillomagenesis study was done by giving three different doses of A. vera [low dose 1:3 dilution, mid dose 1:1 dilution and high dose 1:0 dilution] to mice till termination of the experiment. Using relatively effective dose [1:1 dilution] of A. vera, its chemopreventive potential was examined at pre-initiational, peri-initiational, post-initiational and promotional stage in terms of tumor incidences and tumor multiplicity. In addition, the expression of cell proliferation, glutathione-S-transferase, and apoptosis were analyzed in the skin tumors by immunohistochemical study. For biochemical studies, mice were given with the same doses of A. Vera gel in drinking water for two weeks. Results showed a significant reduction in the skin tumors (upto 42%) in A. vera gel treated animals, as compared to the control group of animals. A. vera was found to be more effective in inhibiting the tumor multiplicity (upto 72 %) compared to the tumor incidence (30 %). Relative to control (100 %), the tumor incidence were 77 %, 80 %, 92 % and 54% in case of pre-initiational, peri-initiational, post-initiational and promotional treatment of A. Vera gel respectively. Since A. Vera inhibited phase-I enzyme system and enhanced phase-II enzyme system, it could be considered as dual acting chemopreventive agent. Increased antioxidant enzyme system and decreased peroxidation damage suggestive of its potential to enhance the antioxidant status of animals which might contribute to chemopreventive property.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the Second AACR International Conference on Frontiers in Basic Cancer Research; 2011 Sep 14-18; San Francisco, CA. Philadelphia (PA): AACR; Cancer Res 2011;71(18 Suppl):Abstract nr B68.
Abstract C11: Investigation of a novel molecular descriptor for the lead optimization of 4-aminoquinazolines as vascular endothelial growth factor receptor-2 inhibitors
Authors: Kawakami Joel K. , Martinez Yannica , Sasaki Brandi , Harris Melissa , Kurata Wendy E. , Lau Alan F.
Published: June 2012

We investigated the use of infrared vibrational frequency of ligands as a potential novel molecular descriptor in three different molecular target and chemical series. The vibrational energy of a ligand was approximated from the sum of infrared (IR) absorptions of each functional group within a molecule and normalized by its molecular weight (MDIR). Calculations were performed on a set of 4-aminoquinazolines with similar docking scores for the VEGFR2/KDR receptor. 4-Aminoquinazolines with MDIR values ranging 192–196 provided compounds with KDR inhibitory activity. The correlation of KDR inhibitory activity was similarly observed in a separate chemical series, the pyrazolo[1,5-a]pyrimidines. Initial exploration of this molecular descriptor supports a tool for rapid lead optimization in the 4-aminoquinazoline chemical series and a potential method for scaffold hopping in pursuit of new inhibitors.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the Second AACR International Conference on Frontiers in Basic Cancer Research; 2011 Sep 14-18; San Francisco, CA. Philadelphia (PA): AACR; Cancer Res 2011;71(18 Suppl):Abstract nr C11.
Abstract C16: miR-148a regulates the expression of PTEN in hepatitis B associated hepatocellular carcinoma
Authors: Yuan Ke , Lian Zhaorui , Sun Bill , Clayton Marcia M. , Ng Irene O. L. , Feitelson Mark A.
Published: June 2012

Previous work has shown that hepatitis B virus encoded X antigen (HBx) is a trans-regulatory protein that alters the activity of selected transcription factors and cytoplasmic signal transduction pathways. The resulting changes in host gene expression are thought to contribute importantly to the development and progression of hepatocellular carcinoma (HCC). In this context, HBx up-regulates the expression of a unique gene, URG11, which in turn up-regulates β-catenin, thereby contributing importantly to hepatocarcinogenesis. Changes in the expression levels of microRNAs (miRNAs) are also characteristic of many tumors, including HCC. To determine whether altered miRNA expression contributes to the mechanism whereby HBx and URG11 contribute to HCC, recombinant retroviruses encoding HBx, URG11, or the bacterial chloramphenicol acetyltransferase (CAT) gene (the latter used as a negative control) were used to infect separate cultures of HepG2 and Hep3B cells. When these cells were compared by miRNA array analysis, both HBx and URG11 were shown to promote the expression of miR-148a. This was confirmed by quantitative (q)RT/PCR analysis. Elevated levels of miR-148a strongly correlated with HBx positive staining in liver samples from infected patients by qRT/PCR (P< 0.001). To study the function of miR-148a, anti-miR-148a was introduced into HepG2 and Hep3B cells stably expressing HBx or stably over-expressing URG11. Anti-miR-148a suppressed cell proliferation (P < 0.01), cell cycle progression (P < 0.01), cell migration (P < 0.01), anchorage independent growth in soft agar (P < 0.01) and subcutaneous tumor formation in SCID mice (P < 0.05). Introduction of anti-miR-148a also increased PTEN mRNA and protein expression, suggesting that PTEN was targeted by miR-148a. This was verified in experiments where anti-miR-148a failed to suppress PTEN expression when co-transfected with reporter gene mutants of the 3′UTR of PTEN mRNA. When HBx positive HepG2 and Hep3B cells were transiently transfected with URG11 specific siRNA, both URG11 and miR-148a levels were suppressed, suggesting that up-regulated expression of miR-148a in HBx positive cells was URG11 dependent. Finally, anti-miR-148a blocked the stimulation of Akt signaling by HBx and URG11, resulting in decreased expression of β-catenin (P < 0.05). Thus, miR-148a appears to contribute a central role to HBx/URG11 mediated HCC, and may be an early diagnostic marker and/or therapeutic target associated with this tumor type.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the Second AACR International Conference on Frontiers in Basic Cancer Research; 2011 Sep 14-18; San Francisco, CA. Philadelphia (PA): AACR; Cancer Res 2011;71(18 Suppl):Abstract nr C16.
Abstract C30: p53-independent 8-amino-adenosine mediated breast cancer cell death
Authors: Polotskaia Alla , Bargonetti Jill
Published: June 2012

Nucleoside analogues are routinely used as breast cancer chemotherapeutics however which death pathways they trigger in the various subtypes of breast cancer, based on the p53 biomarker status, has not been adequately assessed. Here we compare the effectiveness of the novel compound 8-amino-adenosine to gemcitabine (a commonly used nucleoside analogue for the treatment of breast cancer). Gemcitabine requires functional wild-type p53 to work as a cytotoxic drug and we asked if 8-amino-adenosine could act as a cytotoxic agent independently of p53. We found that regardless of the p53-status, 8-amino-adenosine was highly cytotoxic in a panel of breast cancer cell lines. 8-amino-adenosine was a more effective cytotoxic agent than either gemcitabine or etoposide in the breast cancer cell line MCF-7 (having wild-type p53) or MDA-MB-468 and T47-D, (having oncogenic mutant p53) as well as with the cell line MDA-MB-231 (highly metastatic containing mutant p53). Importantly, in the presence of wild-type p53, in contrast to the outcomes with gemcitabine and etoposide, 8-amino-adenosine did not increase transcription of the p53 target gene p21 or protein levels of either p53 or p21. The death pathway mediated by 8-amino-adenosine in MCF-7 cells was apoptotic as the pan-caspase inhibitor ZVAD blocked cell death and PARP cleavage. Additionally, knockdown of functional p53 by inducible shRNA did not inhibit 8-amino-adenosine mediated cell death, further supporting a p53-independent death pathway. Interestingly, the death pathway mediated by 8-amino-adenosine in the metastatic cell line MDA-MB-231 (containing mutant p53) correlated with an increase in LC3-II and no PARP cleavage, suggesting an increase in autophagy. In conclusion, 8-amino-adenosine is cytotoxic to breast cancer cells with non-functional p53 and may be an effective treatment of breast cancer regardless of the status of the p53 biomarker.

Acknowledgement: We thank Steven T. Rosen, Mala Shanmugam and Nancy Krett for the 8-amino-adenosine compound and valuable discussions. The Breast Cancer Research Foundation supported this work.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the Second AACR International Conference on Frontiers in Basic Cancer Research; 2011 Sep 14-18; San Francisco, CA. Philadelphia (PA): AACR; Cancer Res 2011;71(18 Suppl):Abstract nr C30.
Abstract C57: Role of aneuploidy in cellular adaptation, drug resistance, and cancer
Authors: Rancati Giulia , Pavelka Norman , Zhu Jin , Li Rong
Published: June 2012

Cancer is a multistep Darwinian process whereby mutant cells able to escape internal, environmental, or drug-mediated proliferative roadblocks expand and outcompete less-fit cells. Mutations characterizing this somatic evolution range from single-point mutations to whole-chromosome aneuploidy. Although sequence mutations clearly play a role in cancer evolution, the role of aneuploidy in cancer is far less clear. Previously, we investigated how yeast cells can adapt in response to a proliferative roadblock and the role of aneuploidy during this process. We showed that aneuploidy could provide a source of heritable variation driving the emergence of large phenotypic changes that can be adaptive under strong selective conditions. Recently, we provided evidence that aneuploidy is sufficient to generate global changes at the proteome level and to provide phenotypic variation. Taken together, our data suggest that aneuploidy might thus be beneficial to cancer cells that are trying to escape growth inhibitory signals and chemotherapy treatment.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the Second AACR International Conference on Frontiers in Basic Cancer Research; 2011 Sep 14-18; San Francisco, CA. Philadelphia (PA): AACR; Cancer Res 2011;71(18 Suppl):Abstract nr C57.
Abstract C68: Transforming growth factor-beta and vascular endothelial growth factor are enhanced in plasma of breast cancer patients resistent to hormone therapy
Authors: Zavadova Eva , Konopásek Bohuslav , Vocka Michal , Petruzelka Lubos
Published: June 2012

Even with high therapeutic efficacy of first-line hormonal treatment, most patients with metastatic breast cancer will develop resistance. It appears that a factor contributing to the resistance may be a transforming growth factor-beta (TGF-beta). It is highly immunosuppressive factor that inhibits the natural and specific immunity against tumors and stimulates production of vascular endotelial growth factor (VEGF). Defects in the immune response correlated with poor prognosis and therefore in recent years, research focused on a precise description of the status and function of the immune system and its possible effect in cancer patients.

The purpose of the study was to monitor immune responses in patients with hormone receptor-positive breast cancer resistant to hormone therapy, particularly the examination of cellular (CD4, CD8, HLA-DR) as well as humoral immunity. TGF-beta and VEGF production was monitored and we analyzed the changes during hormonal treatment.

Methods: Patients included in the research project were implemented routine cancer treatment with hormonal therapy. Basic parameters (histological type and grade, the degree of expression of ER and PR, HER2, and the proliferative marker) were established. Patients were evaluated by a cancer clinical immunologist to exclude immune disorders, allergic or autoimmune origin. TGF-beta and VEGF were mesured by ELISA and antitumor cellular immunity (CD4, CD8, antigen presenting cells) will be measured by flow cytometry.

Results: In patients with resistance to hormone therapy mainly depression in cellular immunity was found. Immunglobulin plasma level was decreased as well (mainly IgG4 subtype). Most patients have shown clinical symptoms of immunodeficiency (frequent infections of respiratory or urinary tract, herpetic infections) TGF-beta as well as VEGF plasma level were increased. Significant increase of autoantibodies production was found, particulary in those, involved into blood coagulacion process/antiphospholipide and anticardiolipin autoantibodies.

Conclusion: Correlation of these factors with resistance to hormonal therapy, and the state of anticancer immunity could help in the future with the the prediction of resistance to hormonal therapy and contribute to the selection of targeted immune therapy in cancer patients.

Acknowledgement: This project was supported by grant IGA NT11168-3/2010.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the Second AACR International Conference on Frontiers in Basic Cancer Research; 2011 Sep 14-18; San Francisco, CA. Philadelphia (PA): AACR; Cancer Res 2011;71(18 Suppl):Abstract nr C68.
Abstract IA21: Role of Tet1-catalyzed 5mC hydroxylation in transcriptional regulation and ES cell maintenance
Authors: Zhang Yi , Chase Chevy
Published: June 2012

Epigenetic modifications play important roles in diverse biological processes that range from regulation of gene expression, embryonic development, stem cell reprogramming, and human diseases such as cancers. One of the epigenetic modifications is DNA methylation. Although enzymes responsible for DNA methylation have been well characterized, enzymes responsible for active DNA demethylation in mammalian cells have remained elusive. Recent studies have demonstrated that a novel family of proteins— Tet1–3—have the capacity to convert 5mC to 5hmC, raising the possibility that Tet proteins may catalyze the initial step leading to DNA demethylation. Interestingly, Tet1 plays an important role in stem cell self-renewal and maintenance. To understand how Tet1 contributes to these processes, we profiled the genome-wide location of Tet1 and 5hmC in ES cells. This study revealed that Tet1 has a dual function in activating pluripotency stem cell genes and silencing lineage-specific differentiation genes. Further studies revealed that Tet1 contributes to gene silencing by facilitating recruitment of PRC2. Thus, our studies establish a link between Tet1 and PRC2 and revealed a dual function for Tet1 and 5hmC in transcriptional regulation.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the Second AACR International Conference on Frontiers in Basic Cancer Research; 2011 Sep 14-18; San Francisco, CA. Philadelphia (PA): AACR; Cancer Res 2011;71(18 Suppl):Abstract nr IA21.
Abstract PR7: An oncolytic vaccinia virus encoding the human sodium iodide symporter facilitates long-term deep-tissue image monitoring of virotherapy and targeted radiotherapy of pancreatic cancer
Authors: Haddad Dana , Szalay Aladar A. , Fong Yuman , Zanzonico Pat B. , Carlin Sean , Chen Chun-Hao , Chen Nanhai G. , Zhang Qian , Yu Yong A. , Longo Valerie , Mojica Kelly
Published: June 2012

To assess therapeutic response and potential toxicity of oncolytic virotherapy, a noninvasive, deep-tissue imaging modality is needed. This study aimed to assess the feasibility, parameters, determining factors of serial imaging and long-term monitoring of systemic virotherapy together with radiotherapeutic response of pancreatic cancer xenografts treated with a vaccinia virus encoding the human sodium iodide symporter (hNIS), GLV-1 hi 53.

hNIS, an intrinsic plasma membrane protein, mediates the active transport, and trapping of iodine mainly in the thyroid and some extrathyroidal tissues such as the stomach. Pancreatic cancer xenografts (PANC-1) in nude mice were treated systemically or intratumorally with GLV-1h153 and serially imaged using 124I-PET at 1, 2, 3, and 5 weeks post virus injection and 4 hours post radiotracer injection. At week 1 and 2 post virus injection, mice were also imaged at 1, 8, 24, 48, and 72 hours post radiotracer injection in order to obtain time-activity curves for dosimetry calculations of radioiodine uptake. The PET signal intensity was compared with tumor therapeutic response and optical imaging. Tumors were histologically analyzed for morphology and presence of virus particles. Autoradiography was performed utilizing technecium-pertechtenate and gamma-scintigraphy to assess determining factors for radiouptake in tumors. Combination therapy with GLV-1h153 and systemic radioiodine was also explored. GLV-1h153 successfully facilitated serial long-term imaging of virotherapy with PET signal intensity correlating to antitumor response. Colonization of tumors with GLV-1h153 mediated radioiodine uptake at potentially therapeutic doses. Successful radiouptake required presence of virus, adequate blood flow, and viable tissue, while loss of signal intensity was linked to tumor death and necrosis. Finally, combining systemically administered GLV-1h153 and 131I led to enhanced tumor kill when compared to virus or 131I treatment alone (P<0.001). GLV-1h153 is thus a promising oncolytic agent for the treatment, long-term imaging, and monitoring of the therapeutic response of cancer. GLV-1h153 provided insights into tumor biological activity and facilitated enhanced tumor kill when combined with systemic targeted radiotherapy. Further investigation into parameters and potential synergistic effects of combination therapy is warranted.

This abstract is also presented as Poster C7.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the Second AACR International Conference on Frontiers in Basic Cancer Research; 2011 Sep 14-18; San Francisco, CA. Philadelphia (PA): AACR; Cancer Res 2011;71(18 Suppl):Abstract nr PR7.
Abstract A89: Concentrations of IGF-I and IGFBP3 and pancreatic cancer risk in the European Prospective Investigation into Cancer and Nutrition (EPIC)
Authors: Rohrmann Sabine , Grote Verena A. , Susen Becker , Rinaldi Sabine , Bueno-de-Mesquita Bas , Kaaks Rudolf
Published: June 2012

Background: Insulin-like growth factors (IGFs) and their binding proteins (BPs) regulate cell differentiation and proliferation and have been found to be associated with risk of cancer of various sites. The results of the prospective studies with respect to pancreatic cancer are rather inconsistent, with most studies showing no clear association of circulating IGF-I or IGFBP-3 levels with pancreatic cancer risk (Douglas et al, 2010; Lin et al, 2004; Stolzenberg-Solomon et al, 2004; Wolpin et al, 2007). Because of the inconsistencies of previous studies, we examined the association between IGF-I, IGFBP-3 and pancreatic cancer in the European Prospective Investigation into Cancer and Nutrition (EPIC).

Methods: Following recruitment of the study participants between 1992 and 2000, 638 pancreatic cancer cases were observed until December 2006; 578 of them were primary exocrine pancreatic tumors. Blood specimens were available for 422 of these cases. Serum concentrations of IGF-I and IGFBP-3 were measured using enzyme-linked immunosorbent assays in these 422 cases and 422 controls matched on age, sex, study center, recruitment date, and time since last meal. Conditional logistic regression was used to compute odds ratios (OR) and 95% confidence intervals (CI) adjusted for smoking, history of diabetes, and body mass index.

Results: Neither circulating levels of IGF-I (OR=1.13, 95% CI 0.63–1.81 for top vs. bottom quartile, p-trend 0.57) nor IGFBP-3 (OR=0.94, 95% CI 0.60–1.47, p-trend 0.65) were statistically significantly associated with the risk of pancreatic cancer. There was also no association of the molar IGF-I/IGFBP-3 ratio, an indicator of free IGF-I level, with pancreatic cancer risk (OR=1.35, 95% CI 0.79–2.31, p-trend 0.31). No associations were observed when using only microscopically confirmed cases (n=307) or when we stratified the analyses by sex, follow-up time, waist circumference, history of type-2 diabetes, or circulating C-peptide concentrations.

Conclusion: Based on these results, circulating levels of components of the insulin-like growth factor axis do not appear to be a risk factor for pancreatic cancer, which is consistent with most results of previously published prospective studies.

Citation Information: Cancer Prev Res 2011;4(10 Suppl):A89.
Adipose Stromal Cell Tubule Network Model Provides a Versatile Tool for Vascular Research and Tissue Engineering
Authors: Sarkanen Jertta-Riina , Vuorenpää Hanna , Huttala Outi , Mannerström Bettina , Kuokkanen Hannu , Miettinen Susanna , Heinonen Tuula , Ylikomi Timo
Published: June 2012

The current limitation in designing three-dimensional tissue models is the lack of adequate vascularization with mature and stable vessels. Adipose tissue is known to secrete several angiogenic factors, and human adipose stromal cells (hASC) are known to promote vessel growth, maturation and stabilization. In this study, hASC were induced to angiogenesis with growth factor-enriched medium either in monoculture or in coculture with human umbilical vein endothelial cells (HUVEC) and analyzed for vascular, pericytic and smooth muscle cell markers. hASC and HUVEC cocultures showed an accelerated proliferation rate and the cells self-assembled, independent of the cell passage number, into multilayered three-dimensional tubular networks. The networks of hASC and HUVEC expressed endothelial markers, a complete basement membrane and vessel-supporting cells with contractile properties. A hASC and green fluorescence protein-HUVEC-infection model revealed that cocultures consisted of a mosaic of von Willebrand factor-positive cells derived from both cell populations – hASC and HUVEC. hASC monoculture had passage- and donor-dependent ability to form tubular networks, with half of the cultures presenting tubule structures and basement membrane formation. Pericytic and smooth muscle cell markers were expressed in hASC monoculture even when tubules were absent. By combining the potential properties of hASC and features from the present angiogenesis assays, we generated a natural-like, xeno-free, prevascular-like network in vitro model with excellent reproducibility and minimal limitations in technical performance. This tubular network model is an excellent tool for studying cell interactions during vascular development, for chemical and drug testing and for developing natural-like, multilayered, vascularized, scaffold-free tissue models.
Clinical Correlates of Pain and Anxiety in Prenatal Diagnostic Procedures
Authors: Dadhwal Vatsla , Sharma Aparna K. , Singh Aprajita , Deka Deepika , Mittal Suneeta , Kumar Guresh
Published: June 2012

Objective: To study patient perception of pain and anxiety before and after amniocentesis (AC) and transabdominal chorionic villus sampling (CVS) and the clinical correlates of pain and anxiety. Methods: 92 women underwent AC and 78 CVS. Visual analog scale was used to quantify pain and anxiety, immediately before and after the procedure. Factors which could affect pain and anxiety were noted. Results: The pain and anxiety anticipated before the procedures were significantly less than actually perceived. The pre-procedure anxiety did not correlate with post-procedure pain. There was no correlation between anticipated pain or anxiety and age, parity, education, socioeconomic status, and history of procedure in previous pregnancy in both the AC and CVS groups. Post-procedure pain did not correlate with age, parity, education, socioeconomic status, abdominal scar, placental location, number of needle insertion, repeat procedure or abdominal wall thickness in either group. However, on multiple linear regression the overall post-procedure pain was associated with the number of needle insertions. Conclusion: Though pre-procedure pain and anxiety levels are high, most patient experience less pain and anxiety after the procedure.
Prevalence, Associated Risk Factors and Effects of Hypothyroidism in Pregnancy: A Study from North India
Authors: Goel Poonam , Kaur Jasbinder , Saha Pradip Kumar , Tandon Rimpy , Devi Lajjya
Published: June 2012

Background and Objective: There is a controversy regarding universal versus targeted screening for hypothyroidism during pregnancy. We studied the prevalence and the associated risk factors of hypothyroidism. The secondary objective of the study was to compare the maternal and perinatal outcomes in overt and subclinical hypothyroidism. Methods: We screened 1,005 antenatal patients for hypothyroidism with a thyrotropin assay. Patients diagnosed with hypothyroidism were further tested for anti-thyroid peroxidase antibodies and free thyroxin to determine the cause and type (overt or subclinical) of hypothyroidism. Maternal and perinatal outcomes were compared in the overt, subclinical and euthyroid groups. Results: The overall prevalence of hypothyroidism was 6.3% (overt 2.9% and subclinical 3.4%). Thirty-four (3.4%) new hypothyroid cases could be detected by universal screening. The risk factors for thyroid dysfunction were not significantly different in the screen-positive versus screen-negative patients except for excessive weight gain (p = 0.00). Targeted screening could have missed one third of subclinical hypothyroid cases. Gestational hypertension was significantly greater in the overt hypothyroid group (p = 0.007), and more patients required induction in this group (p = 0.013) but other maternal complications and perinatal outcomes were similar. Conclusion: We recommend universal screening for hypothyroidism in pregnancy in our population, as the prevalence of hypothyroidism is high.
Primitive Retinal Vascular Abnormalities: Tumors and Telangiectasias
Authors: Knutsson Karl Anders , De Benedetto Umberto , Querques Giuseppe , Del Turco Claudia , Bandello Francesco , Lattanzio Rosangela
Published: June 2012

Primitive retinal vascular abnormalities are benign conditions of the retinal circulation that comprise vascular tumors and telangiectasias. The principal vascular tumors of the retina include retinal capillary hemangioma, cavernous hemangioma of the retina, racemose hemangiomatosis of the retina and retinal vasoproliferative tumor, while primary retinal telangiectasias include Coats’ disease, Leber’s miliary aneurysms and idiopathic juxtafoveal telangiectasias. In most cases, these alterations result in significant visual impairment due to exudation determined by the structural abnormalities of the retinal vasculature. The aim of this review is to assess the different clinical and diagnostic features of the single pathological entities and to discuss the available treatment modalities including the onset of intravitreal antivascular endothelial growth factor therapy.
Expression Pattern of Basal Markers in Human Dental Pulp Stem Cells and Tissue
Authors: Martens W. , Wolfs E. , Struys T. , Politis C. , Bronckaers A. , Lambrichts I.
Published: June 2012

Dental pulp stem cells (DPSC) have been characterized as a multipotent stem cell population, with the ability to differentiate into mesodermal and neural cell lineages. Although ‘de novo’ expression of neural markers after differentiation is mostly considered as proof of differentiation, expression of these markers in undifferentiated DPSC is not well described. Therefore, an immunocytochemical analysis was performed to evaluate the neural marker expression of undifferentiated human DPSC (hDPSC) in in vitro cultures. Undifferentiated hDPSC uniformly expressed neural markers β-III-tubulin, S100 protein and synaptophysin. A subset of the population showed a positive immune-reactivity for galactocerebroside, neurofilament and nerve growth factor receptor p75. Furthermore, the location of possible stem cell niches, present in young dental pulp tissue, was determined by means of immunohistochemistry based on mesenchymal and neural marker expression. The results demonstrated the presence of a perivascular niche and a second stem cell niche at the cervical area. In adult dental pulp, only a perivascular niche could be observed. Based on the expression of neural markers in naïve DPSC, it has to be taken into account that not only the marker expression upon neural differentiation must be analyzed, but an ultrastructural analysis of the morphological changes and functional studies must also be performed to confirm a successful differentiation.
Evidence for the Putative Cannabinoid Receptor (GPR55)-Mediated Inhibitory Effects on Intestinal Contractility in Mice
Authors: Ross Gracious R. , Lichtman Aron , Dewey William L. , Akbarali Hamid I.
Published: June 2012

Background: Cannabinoids inhibit intestinal motility via presynaptic cannabinoid receptor type I (CB1) in enteric neurons while cannabinoid receptor type II (CB2) receptors are located mainly in immune cells. The recently de-orphanized G-protein-coupled receptor, GPR55, has been proposed to be the ‘third’ cannabinoid receptor. Although gene expression of GPR55 is evident in the gut, functional evidence for GPR55 in the gut is unknown. In this study, we tested the hypothesis that GPR55 activation inhibits neurogenic contractions in the gut. Methods: We assessed the inhibitory effect of the atypical cannabinoid O-1602, a GPR55 agonist, in mouse colon. Isometric tension recordings in colonic tissue strips were used from either wild-type, GPR55–/– or CB1–/–/CB2–/– knockout mice. Results: O-1602 inhibited the electrical field- induced contractions in the colon strips from wild-type and CB1–/–/CB2–/– in a concentration-dependent manner, suggesting a non-CB1/CB2 receptor-mediated prejunctional effect. The concentration-dependent response of O-1602 was significantly inhibited in GPR55–/– mice. O-1602 did not relax colonic strips precontracted with high K+ (80 mmol/l), indicating no involvement of Ca2+ channel blockade in O-1602-induced relaxation. However, 10 µmol/l O-1602 partially inhibited the exogenous acetylcholine (10 µmol/l)-induced contractions. Moreover, we also assessed the inhibitory effects of JWH015, a CB2/GPR55 agonist on neurogenic contractions of mouse ileum. Surprisingly, the effects of JWH015 were independent of the known cannabinoid receptors. Conclusion: Taken together, these findings suggest that activation of GPR55 leads to inhibition of neurogenic contractions in the gut and are predominantly prejunctional.
Myths About Older People’s Use of Information and Communication Technology
Authors: Wandke Hartmut , Sengpiel Michael , Sönksen Malte
Published: June 2012

This paper discusses six myths common in the field of ‘human-computer interaction (HCI) and older people’. These myths are widespread among computer scientists, engineers and programmers, as well as among the general public and even older individuals themselves. We can define these myths as follows. (1) Just wait and see. Future generations of older people will use computers without problems. This myth differs from those following, as it may lead to a (dangerous) conclusion of avoidance and inactivity by integrating myths 2–6. If the other myths are accepted as being true and one assumes that the problems will eventually solve themselves, it might not seem worthwhile to expend any effort on ‘universal design’ for older people’s use of information and communication technology (ICT). However, we argue that if we do not actively and properly counteract these myths, we will perpetuate them and their grave consequences. (2) Older people are not interested in using computers. They are unaware of computer capabilities. (3) Older people consider computers as useless and unnecessary. (4) Older people lack the physical capabilities to use ICT. (5) Older people simply cannot understand interactive computing technology. (6) You can’t teach an old dog new tricks. The problem of HCI for older people is that they do not learn to use new technologies and interaction techniques. In discussing these myths, we demonstrate that each one contains a grain of truth. However, the myths are improperly overgeneralized and, therefore, often wrong. Such myths are problematic. Designers and engineers often accept them as truths and neglect older users and/or apply information and communication technologies in an age-discriminating manner. Furthermore, the myths are problematic as they lead older people to avoid computer usage (i.e. a self-fulfilling prophecy). We present evidence to support the notion that these myths may often be largely – although not completely – wrong. We then demonstrate how they can be counteracted through user-centered design, training and instruction.
Microbiochemical Analysis of Carious Dentine Using Raman and Fluorescence Spectroscopy
Authors: Almahdy A. , Downey F.C. , Sauro S. , Cook R.J. , Sherriff M. , Richards D. , Watson T.F. , Banerjee A. , Festy F.
Published: June 2012

The aim of this study was to evaluate and correlate objectively the microspectroscopically derived biochemical components of sound, infected and affected carious dentine with their microhardness and autofluorescence (AF) characteristics. Over 3 million high-resolution Raman spectra from 8 extracted human carious teeth were recorded using Raman spectrometer with parallel spectrum acquisition. Green AF signals across each carious lesion from all samples were acquired with a similar spatial resolution using confocal fluorescence microscopy. The Knoop microhardness (KHN) from a total of 233 co-localized areas was recorded from the same samples and allocated subjectively into the three zones. Cluster analysis of the Raman data, performed using in-house software, produced five independent spectral components representing mineral content, protein content, porphyrin fluorescence (PF), putative infected dentine signal (IDS) and affected dentine signal (ADS). The distributions of the 5 Raman components and the AF signal were matched across all samples and their average values were calculated for each corresponding KHN area. The infected dentine was defined significantly by the KHN, AF and by the relative contribution of the mineral, PF and IDS clusters. Protein cluster was not statistically related to the KHN or AF. A delineation between affected and sound dentine was observed using the KHN, AF, PF and ADS parameters. This study concludes that micro-Raman spectroscopy can provide a non-invasive and objective evaluation of different carious dentine zones. Being able to detect and assess clinically the caries-affected dentine during minimally invasive operative caries management is important to control the risk of unnecessary tissue removal.
Fat Mass and Obesity-Associated Gene (FTO) in Eating Disorders: Evidence for Association of the rs9939609 Obesity Risk Allele with Bulimia nervosa and Anorexia nervosa
Authors: Müller Timo D. , Greene Brandon H. , Bellodi Laura , Cavallini Maria C. , Cellini Elena , Di Bella Daniela , Ehrlich Stefan , Erzegovesi Stefano , Estivill Xavier , Fernández-Aranda Fernando , Fichter Manfred , Fleischhaker Christian , Scherag Susann , Gratacòs Monica , Grallert Harald , Herpertz-Dahlmann Beate , Herzog Wolfgang , Illig Thomas , Lehmkuhl Ulrike , Nacmias Benedetta , Ribasés Marta , Ricca Valdo , Schäfer Helmut , Scherag André , Sorbi Sandro , Wichmann Heinz-Erich , Hebebrand Johannes , Hinney Anke
Published: June 2012

Objective: The common single nucleotide polymorphism (SNP) rs9939609 in the fat mass and obesity-associated gene (FTO) is associated with obesity. As genetic variants associated with weight regulation might also be implicated in the etiology of eating disorders, we evaluated whether SNP rs9939609 is associated with bulimia nervosa (BN) and anorexia nervosa (AN). Methods: Association of rs9939609 with BN and AN was assessed in 689 patients with AN, 477 patients with BN, 984 healthy non-population-based controls, and 3,951 population-based controls (KORA-S4). Based on the familial and premorbid occurrence of obesity in patients with BN, we hypothesized an association of the obesity risk A-allele with BN. Results: In accordance with our hypothesis, we observed evidence for association of the rs9939609 A-allele with BN when compared to the non-population-based controls (unadjusted odds ratio (OR) = 1.142, one-sided 95% confidence interval (CI) 1.001–∞; one-sided p = 0.049) and a trend in the population-based controls (OR = 1.124, one-sided 95% CI 0.932–∞; one-sided p = 0.056). Interestingly, compared to both control groups, we further detected a nominal association of the rs9939609 A-allele to AN (OR = 1.181, 95% CI 1.027–1.359, two-sided p = 0.020 or OR = 1.673, 95% CI 1.101–2.541, two-sided p = 0.015,). Conclusion: Our data suggest that the obesity-predisposing FTO allele might be relevant in both AN and BN.
Controlled Exposure of Healthy Young Volunteers to Ozone Causes Cardiovascular Effects
Authors: Devlin Robert B. , Duncan Kelly E. , Jardim Melanie , Schmitt Michael T. , Rappold Ana G. , Diaz-Sanchez David
Published: June 2012

Background—

Recent epidemiology studies have reported associations between short-term ozone exposure and mortality. Such studies have previously reported associations between airborne particulate matter pollution and mortality, and support for a causal relationship has come from controlled-exposure studies that describe pathophysiological mechanisms by which particulate matter could induce acute mortality. In contrast, for ozone, almost no controlled-human-exposure studies have tested whether ozone exposure can modulate the cardiovascular system.

Methods and Results—

Twenty-three young healthy individuals were exposed in a randomized crossover fashion to clean air and to 0.3-ppm ozone for 2 hours while intermittently exercising. Blood was obtained immediately before exposure, immediately afterward, and the next morning. Continuous Holter monitoring began immediately before exposure and continued for 24 hours. Lung function was performed immediately before and immediately after exposure, and bronchoalveolar lavage was performed 24 hours after exposure. Immediately after ozone exposure, we observed a 98.9% increase in interleukin-8, a 21.4% decrease in plasminogen activator inhibitor-1, a 51.3% decrease in the high-frequency component of heart rate variability, and a 1.2% increase in QT duration. Changes in interleukin-1B and plasminogen activator inhibitor-1 were apparent 24 hours after exposure. In agreement with previous studies, we also observed ozone-induced drops in lung function and an increase in pulmonary inflammation.

Conclusions—

This controlled-human-exposure study shows that ozone can cause an increase in vascular markers of inflammation and changes in markers of fibrinolysis and markers that affect autonomic control of heart rate and repolarization. We believe that these findings provide biological plausibility for the epidemiology studies that associate ozone exposure with mortality.

Clinical Trial Registration—

URL:
http://www.clinicaltrials.gov
. Unique identifier: NCT01492517.
The Association Between Medication Adherence and Treatment Intensification With Blood Pressure Control in Resistant Hypertension
Authors: Daugherty Stacie L. , Powers J. David , Magid David J. , Masoudi Frederick A. , Margolis Karen L. , O'Connor Patrick J. , Schmittdiel Julie A. , Ho P. Michael
Published: June 2012

Patients with resistant hypertension are at risk for poor outcomes. Medication adherence and intensification improve blood pressure (BP) control; however, little is known about these processes or their association with outcomes in resistant hypertension. This retrospective study included patients from 2002 to 2006 with incident hypertension from 2 health systems who developed resistant hypertension or uncontrolled BP despite adherence to ≥3 antihypertensive medications. Patterns of hypertension treatment, medication adherence (percentage of days covered), and treatment intensification (increase in medication class or dose) were described in the year after resistant hypertension identification. Then, the association between medication adherence and intensification with 1-year BP control was assessed controlling for patient characteristics. Of the 3550 patients with resistant hypertension, 49% were male, and mean age was 60 years. One year after resistance hypertension determination, fewer patients were taking diuretics (77.7% versus 92.2%;
P
<0.01), β-blockers (71.2% versus 79.4%;
P
<0.01), and angiotensinogen-converting enzyme inhibitor/angiotensin receptor blocker (64.8% versus 70.1%;
P
<0.01) compared with baseline. Rates of BP control improved over 1 year (22% versus 55%;
P
<0.01). During this year, adherence was not associated with 1-year BP control (adjusted odds ratio, 1.18 [95% CI: 0.94–1.47]). Treatment was intensified in 21.6% of visits with elevated BP. Increasing treatment intensity was associated with 1-year BP control (adjusted odds ratio, 1.64 [95% CI, 1.58–1.71]). In this cohort of patients with resistant hypertension, treatment intensification but not medication adherence was significantly associated with 1-year BP control. These findings highlight the need to investigate why patients with uncontrolled BP do not receive treatment intensification.
Maternal Cardiovascular Impairment in Pregnancies Complicated by Severe Fetal Growth Restriction
Authors: Melchiorre Karen , Sutherland George Ross , Liberati Marco , Thilaganathan Basky
Published: June 2012

Fetal growth restriction and preeclampsia are both conditions of placental etiology and associated to increased risk for the long-term development of cardiovascular disease in the mother. At presentation, preeclampsia is associated with maternal global diastolic dysfunction, which is determined, at least in part, by increased afterload and myocardial stiffness. The aim of this study is to test the hypothesis that women with normotensive fetal growth-restricted pregnancies also exhibit global diastolic dysfunction. This was a prospective case-control study conducted over a 3-year period involving 29 preterm fetal growth-restricted pregnancies, 25 preeclamptic with fetal growth restriction pregnancies, and 58 matched control pregnancies. Women were assessed by conventional echocardiography and tissue Doppler imaging at diagnosis of the complication and followed-up at 12 weeks postpartum. Fetal growth-restricted pregnancies are characterized by a lower cardiac index and higher total vascular resistance index than expected for gestation. Compared with controls, fetal growth-restricted pregnancy was associated with significantly increased prevalence (
P
<0.001) of asymptomatic left ventricular diastolic dysfunction (28% versus 4%) and widespread impaired myocardial relaxation (59% versus 21%). Unlike preeclampsia, cardiac geometry and intrinsic myocardial contractility were preserved in fetal growth-restricted pregnancy. Fetal growth-restricted pregnancies are characterized by a low output, high resistance circulatory state, as well as a higher prevalence of asymptomatic global diastolic dysfunction and poor cardiac reserve. These findings may explain the increased long-term cardiovascular risk in these women who have had fetal growth-restricted pregnancies. Further studies are needed to clarify the postnatal natural history of cardiac dysfunction in these women.
Cardiotrophin 1 Is Involved in Cardiac, Vascular, and Renal Fibrosis and Dysfunction
Authors: López-Andrés Natalia , Rousseau Amélie , Akhtar Riaz , Calvier Laurent , Iñigo Carmen , Labat Carlos , Zhao Xuegen , Cruickshank Kennedy , Díez Javier , Zannad Faiez , Lacolley Patrick , Rossignol Patrick
Published: June 2012

Cardiotrophin 1 (CT-1), a cytokine belonging to the interleukin 6 family, is increased in hypertension and in heart failure. We aimed to study the precise role of CT-1 on cardiac, vascular, and renal function; morphology; and remodeling in early stages without hypertension. CT-1 (20 μg/kg per day) or vehicle was administrated to Wistar rats for 6 weeks. Cardiac and vascular functions were analyzed in vivo using M-mode echocardiography, Doppler, and echo tracking device and ex vivo using a scanning acoustic microscopy method. Cardiovascular and renal histomorphology were measured by immunohistochemistry, RT-PCR, and Western blot. Kidney functional properties were assessed by serum creatinine and neutrophile gelatinase-associated lipocalin and microalbuminuria/creatininuria ratio. Without alterations in blood pressure levels, CT-1 treatment increased left ventricular volumes, reduced fractional shortening and ejection fraction, and induced myocardial dilatation and myocardial fibrosis. In the carotid artery of CT-1–treated rats, the circumferential wall stress-incremental elastic modulus curve was shifted leftward, and the acoustic speed of sound in the aorta was augmented, indicating increased arterial stiffness. Vascular media thickness, collagen, and fibronectin content were increased by CT-1 treatment. CT-1–treated rats presented unaltered serum creatinine concentrations but increased urinary and serum neutrophile gelatinase-associated lipocalin and microalbuminuria/creatininuria ratio. This paralleled a glomerular and tubulointerstitial fibrosis accompanied by renal epithelial-mesenchymal transition. CT-1 is a new potent fibrotic agent in heart, vessels, and kidney able to induce cardiovascular-renal dysfunction independent from blood pressure. Thus, CT-1 could be a new target simultaneously integrating alterations of heart, vessels, and kidney in early stages of heart failure.