tbuckley/cabot-search huggingface dataset:
Aberrant Presentation of HPA-Reactive Carbohydrates Implies Selectin-Independent Metastasis Formation in Human Prostate Cancer
Authors: Tobias Lange, Mareike Kupfernagel, Daniel Wicklein, Florian Gebauer, Hanna Maar, Kathrin Brügge, Imke Müller, Ronald Simon, Thorsten Schlomm, Guido Sauter, Udo Schumacher
Journal: Clinical Cancer Research (2014)

To investigate the impact of prostate cancer cell surface glycosylation as part of the tumor cell-endothelial cell interaction in prostate cancer metastasis.Glycosyltransferase expression was profiled in metastasis-derived prostate cancer cell lines and compared with primary epithelium. Prostate cancer cells were examined for HPA- and selectin-binding and adhesion to endothelium. Spontaneous metastasis xenograft models were established to test the lectin HPA-binding sites as a marker of metastatic competence and to evaluate E-selectin-binding sites in vivo. The importance of selectins for metastasis formation was analyzed using Sele(-/-)/Selp(-/-) mice. The clinical relevance of HPA- and E-selectin-binding sites in prostate cancer was determined.Glycosyltransferases involved in the synthesis of common HPA-binding sites are downregulated in prostate cancer cells. An absence of HPA-reactive carbohydrates specifically indicates spontaneous metastatic spread of prostate cancer xenografts in vivo and a poor prognosis of patients with prostate cancer. HPA-binding sites decrease in lymph node metastases compared with corresponding primary tumors. Common selectin ligands are absent on prostate cancer cells, which do not adhere to recombinant selectins or endothelium under shear stress in vitro. Spontaneous metastasis formation is largely independent of selectins in vivo. E-selectin-binding sites are detectable in only 2% of patients with prostate cancer without prognostic significance.Prostate cancer is characterized by an inverse functional and prognostic importance of HPA-binding sites compared with other adenocarcinomas. Accordingly, this study surprisingly shows that the selectin-selectin ligand axis, which is essential for extravasation and thus metastasis formation in several malignancies, can be circumvented in prostate cancer.
Abstract 5143: KDM3A promotes cell growth and cisplatin-resistance in ovarian cancer cells
Authors: Sivakumar Ramadoss, Suvajit Sen, Gautam Chaudhuri, Robin Farias-Eisner
Journal: Cancer Research (2014)

Abstract Background: Ovarian cancer is the most lethal gynecological cancer affecting the women worldwide. One of the main challenging hurdles in ovarian cancer treatment is the high recurrence rate due to therapeutic resistance. Recent evidences showed that JmjC-domain (JMJD) containing histone demethylases plays a critical role in controlling gene expression during normal development and cancer progression. Aims: To determine whether histone demethylase plays a role in ovarian cancer progression and therapeutic resistance. Methods: We developed cisplatin-resistance ovarian cancer cell lines SKOV-3 and OVCAR-5 and isolated total RNA to screen the expression pattern of JMJD family genes by real-time RT-PCR. We performed stable knock-down of KDM3A by lentiviral mediated ShRNA transfection and studied its effects on cell proliferation and apoptosis by MTT assay and western blot analysis (PARP, caspase-3), respectively. We also determined the effect of KDM3A knock-down on cell cycle and apoptosis regulators by western blot. Results: Our observations indicated the differential expression of various JMJD family proteins between cisplatin-resistance and sensitive cell lines. To further evaluate our results, we also tested the expression of those differentially expressed JMJD proteins in a widely used cisplatin-resistance and sensitive A2780 cell lines. We observed that KDM3A/JMJD1A is consistently overexpressed in all the cisplatin-resistance cell lines studied. Next, we stably knock-down KDM3A in cisplatin-resistance OVCAR-5 and A2780 cell lines. More interestingly, we found that KDM3A depletion inhibited cell proliferation, induced apoptosis and enhanced the sensitivity to cisplatin treatment. Further, we confirmed that the important regulators of cell cycle and apoptosis including p21 and Bcl-2 were modulated by KDM3A knock-down. Conclusions: Our results indicate that KDM3A is a critical epigenetic factor required for the ovarian cancer growth by promoting cell proliferation and cisplatin-resistance. Our findings might have important clinical implications in targeting ovarian cancer cells by using specific histone demethylase inhibitors. Grant support: This work was supported by Carl and Roberta Deutsch, and Kelly Day Foundations. Citation Format: Sivakumar Ramadoss, Suvajit Sen, Gautam Chaudhuri, Robin Farias-Eisner. KDM3A promotes cell growth and cisplatin-resistance in ovarian cancer cells. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 5143. doi:10.1158/1538-7445.AM2014-5143
Changes in the EGFR amplification and EGFRvIII expression between paired primary and recurrent glioblastomas
Authors: Martin J. van den Bent, Ya Gao, Melissa Kerkhof, Johan M. Kros, Thierry Gorlia, Kitty van Zwieten, Jory Prince, Sjoerd van Duinen, Peter A. Sillevis Smitt, Martin Taphoorn, Pim J. French
Journal: Neuro-Oncology (2015)

The efficacy of novel targeted therapies is often tested at the time of tumor recurrence. However, for glioblastoma (GBM) patients, surgical resections at recurrence are performed only in a minority of patients; therefore, molecular data are predominantly derived from the initial tumor. Molecular data of the initial tumor for patient selection into personalized medicine trials can therefore be used only when the specific genetic change is retained in the recurrent tumor. In this study we determined whether EGFR amplification and expression of the most common mutation in GBMs (EGFRvIII) is retained at tumor recurrence. Because retention of genetic changes may be dependent on the initial treatment, we only used a cohort of GBM samples that were uniformly treated according to the current standard of care (ie, chemo-irradiation with temozolomide). Our data show that, in spite of some quantitative differences, the EGFR amplification status remains stable in the majority (84%) of tumors evaluated. EGFRvIII expression remained similar in 79% of GBMs. However, within the tumors expressing EGFRvIII at initial diagnosis, approximately one-half lose their EGFRvIII expression at tumor recurrence. The relative stability of EGFR amplification indicates that molecular data obtained in the primary tumor can be used to predict the EGFR status of the recurrent tumor, but care should be taken in extrapolating EGFRvIII expression from the primary tumor, particularly when expressed at first diagnosis.
Society for Molecular Biology and Evolution, Council and Business Meetings, 2013, Chicago, IL
Authors: J. O. McInerney
Journal: Molecular Biology and Evolution (2014)

President Sudhir Kumar called the council meeting to order at 9:00 am, Sunday, July 7, 2013. In attendance were President Sudhir Kumar, Past-President Charles Aquadro, PresidentElect Brandon Gaut, Councilors Soojin Yi, Laurent Duret, Yoko Satta, Harmit Malik, Marta Wayne, Secretary James McInerney, online via Internet video link Treasurer Aoife McLysaght, and MBE Editor-in-Chief Bill Martin. In addition, Taras Oleksyk (Puerto Rico) and Carolin Kosiol (Vienna) attended part of the meeting and an Oxford University Press delegation led by Jennifer Boyd attended part of the meeting.
Differential regulation of cardiac excitation–contraction coupling by cAMP phosphodiesterase subtypes
Authors: Delphine Mika, Pierre Bobin, Martine Pomérance, Patrick Lechêne, Ruth E. Westenbroek, William A. Catterall, Grégoire Vandecasteele, Jérôme Leroy, Rodolphe Fischmeister
Journal: Cardiovascular Research (2013)

AimsMultiple phosphodiesterases (PDEs) hydrolyze cAMP in cardiomyocytes, but the functional significance of this diversity is not well understood. Our goal here was to characterize the involvement of three different PDEs (PDE2–4) in cardiac excitation–contraction coupling (ECC).
The pituitary adenylate cyclase–activating polypeptide is a physiological inhibitor of platelet activation
Authors: Kathleen Freson, Hitoshi Hashimoto, Chantal Thys, Christine Wittevrongel, Sophie Danloy, Yoshiko Morita, Norihito Shintani, Yoshiaki Tomiyama, Jos Vermylen, Marc F. Hoylaerts, Akemichi Baba, Chris Van Geet
Journal: Journal of Clinical Investigation (2004)

The pituitary adenylate cyclase–activating polypeptide (PACAP) is a neuropeptide of the vasoactive intestinal peptide/secretin/glucagon superfamily. Studies in two related patients with a partial trisomy 18p revealed three copies of the PACAP gene and elevated PACAP concentrations in plasma. The patients suffer from severe mental retardation and have a bleeding tendency with mild thrombocytopenia, and their fibroblasts show increased PACAP mRNA levels. The PACAP receptor (vasoactive intestinal peptide/pituitary adenylate cyclase–activating peptide receptor 1 [VPAC1]) in platelets and fibroblasts is coupled to adenylyl cyclase activation. Accordingly, we found increased basal cAMP levels in patients' platelets and fibroblasts, providing a basis for the reduced platelet aggregation in these patients. Megakaryocyte-specific transgenic overexpression of PACAP in mice correspondingly increased PACAP release from platelets, reduced platelet activation, and prolonged the tail bleeding time. In contrast, the PACAP antagonist PACAP(6-38) or a monoclonal PACAP antibody enhanced the collagen-induced aggregation of normal human platelets, and in PACAP knockout mice, an increased platelet sensitivity toward collagen was found. Thus, we found that PACAP modulates platelet function and demonstrated what we believe to be the first hemostatic defect associated with PACAP overexpression; our study suggests the therapeutic potential to manage arterial thrombosis or bleeding by administration of PACAP mimetics or inhibitors, respectively.
Evaluation of nephrotoxicity due to the use of colistimethate sodium in a intensive care unit
Authors: Muhammed Emin Akkoyunlu, Bahadir Ceylan, Yasemin Akkoyunlu, Didem Özkan, Hatice Özçelik, Turan Aslan, Levent Kart
Journal: European Respiratory Journal (2013)

Background  Colistimethate sodium is an old antibiotic used for infections caused by multi drug resistant (MDR) Gram (-) bacillus such as Acinetobacter baumannii, Pseudomonas aeruginosa, Klebsiella pneumoniae. Nephrotoxicity is one of the most important side effects developing during the treatment which also limits its use. We investigate the occurance of acute renal failure due to colistimethate sodium.  Material and Method  We evaluated the data of 163 patient referred to the Respiratory ICU of Bezmialem Vakif University and stayed more than 24 hours between september 2012 and Jnuary 2013 retrospectively. 20 of them included in the study who recieved IV Colistimethate sodium because of infections caused by MDR Gram (-) bacillus.  Results  13 of 20 patients are male. Mean age of the patients is 65.75 (42-87). Mean duration of Colistimethate sodium is 10.45 (5-19). 15 of these 20 patients also used inhaler colistimethate sodium. Six of them also recieved contrast material during radiological imaging which can also has nephrotoxicity. During the use of colistimethate sodium acute renal failure developed in 12 of the patients. Hemodialisis was applied 7 patients. 15 of the patients died whereas other 5 of them were discharged. Nine of the patients died who develop acute renal failure whereas 3 of them were discharged.  Conclusion  Acute renal failure occurance rate due to the nephrotoxicity of colistimethate sodium is high. The favor and harms of this drug must be evaluated in further studies.
Enhancement of <i>In vitro</i> and <i>In vivo</i> Tumor Cell Radiosensitivity by the DNA Methylation Inhibitor Zebularine
Authors: Hideaki Dote, David Cerna, William E. Burgan, Donna J. Carter, Michael A. Cerra, Melinda G. Hollingshead, Kevin Camphausen, Philip J. Tofilon
Journal: Clinical Cancer Research (2005)

Aberrant DNA hypermethylation is a frequent finding in tumor cells, which has suggested that inhibition of DNA methylation may be an effective cancer treatment strategy. Because DNA methylation affects gene expression and chromatin structure, parameters considered to influence radioresponse, we investigated the effects of the DNA methylation inhibitor zebularine on the radiosensitivity of human tumor cells. Three human tumor cell lines were used in this study (MiaPaCa, DU145, and U251) and the methylation status of three genes frequently hypermethylated in tumor cells (RASSF1A, HIC-1, and 14-3-3sigma) was determined as a function of zebularine exposure. Zebularine resulted in DNA demethylation in a time-dependent manner, with the maximum loss of methylation detected by 48 hours. Treatment of cells with zebularine for 48 hours also resulted in an increase in radiosensitivity with dose enhancement factors of >1.5. As a measure of radiation-induced DNA damage, gammaH2AX expression was determined. Whereas zebularine had no effect on radiation-induced gammaH2AX foci at 1 hour, the number of gammaH2AX foci per cell was significantly greater in the zebularine-treated cells at 24 hours after irradiation, suggesting the presence of unrepaired DNA damage. Zebularine administration to mice reactivated gene expression in U251 xenografts; irradiation of U251 tumors in mice treated with zebularine resulted in an increase in radiation-induced tumor growth delay. These results indicate that zebularine can enhance tumor cell radiosensitivity in vitro and in vivo and suggest that this effect may involve an inhibition of DNA repair.
<i>PIK3CA</i> Mutational Status in Circulating Tumor Cells Can Change During Disease Recurrence or Progression in Patients with Breast Cancer
Authors: Athina Markou, Sofia Farkona, Christina Schiza, Tonia Efstathiou, Sophia Kounelis, Nikos Malamos, Vassilis Georgoulias, Evi Lianidou
Journal: Clinical Cancer Research (2014)

Molecular characterization of circulating tumor cells (CTC) is crucial for the investigation of molecular-targeted therapies while PIK3CA somatic mutations play a crucial role in therapy response. We investigated the presence of PIK3CA mutations in CTC and whether this is associated with clinical outcome.We developed and validated an ultrasensitive methodology for the detection of PIK3CA mutations that is based on a combination of allele-specific, asymmetric rapid PCR and melting analysis. We analyzed PIK3CA hotspot mutations in: (i) a training group consisting of EpCAM-positive CTC fraction from 37 patients with clinically confirmed metastasis, and 26 healthy female volunteers and 15 primary breast tumor tissues and (ii) an independent group consisting of EpCAM-positive CTC fraction from 57 metastatic and 118 operable breast cancer patients and 76 corresponding primary tumors.The assay could detect 0.05% of mutated dsDNA in the presence of 99.95% wtDNA for both exons (9 and 20) and was highly specific (0/26 healthy donors). PIK3CA mutations were identified in EpCAM-positive CTC in 20 of 57(35.1%) and in 23 of 118 (19.5%) patients with metastatic and operable breast cancer, and in 45 of 76(59.2%) corresponding FFPEs. Our data indicate that PIK3CA mutational status in CTCs can change during disease progression and is associated with worse survival (P = 0.047).PIK3CA hotspot mutations are present at a relatively high frequency in CTCs and their presence is associated with worse survival in patients with breast cancer with metastasis. Evaluation of PIK3CA mutational status in CTCs is a strategy with potential clinical application.
Complication Rate of Percutaneous Liver Biopsies Among Persons With Advanced Chronic Liver Disease in the HALT-C Trial
Authors: Leonard B. Seeff, Gregory T. Everson, Timothy R. Morgan, Teresa M. Curto, William M. Lee, Marc G. Ghany, Mitchell L. Shiffman, Robert J. Fontana, Adrian M. Di Bisceglie, Herbert L. Bonkovsky, Jules L. Dienstag
Journal: Clinical Gastroenterology and Hepatology (2010)
Multiple Resistance at No Cost: Rifampicin and Streptomycin a Dangerous Liaison in the Spread of Antibiotic Resistance
Authors: Paulo Durão, Sandra Trindade, Ana Sousa, Isabel Gordo
Journal: Molecular Biology and Evolution (2015)

Evidence is mounting that epistasis is widespread among mutations. The cost of carrying two deleterious mutations, or the advantage of acquiring two beneficial alleles, is typically lower that the sum of their individual effects. Much less is known on epistasis between beneficial and deleterious mutations, even though this is key to the amount of genetic hitchhiking that may occur during evolution. This is particularly important in the context of antibiotic resistance: Most resistances are deleterious, but some can be beneficial and remarkably rifampicin resistance can emerge de novo in populations evolving without antibiotics. Here we show pervasive positive pairwise epistasis on Escherichia coli fitness between beneficial mutations, which confer resistance to rifampicin, and deleterious mutations, which confer resistance to streptomycin. We find that 65% of double resistant strains outcompete sensitive bacteria in an environment devoid of antibiotics. Weak beneficial mutations may therefore overcome strong deleterious mutations and can even render double mutants strong competitors.
Smoothened as a new therapeutic target for human osteosarcoma
Authors: Masataka Hirotsu, Takao Setoguchi, Hiromi Sasaki, Yukihiro Matsunoshita, Hui Gao, Hiroko Nagao, Osamu Kunigou, Setsuro Komiya
Journal: Molecular Cancer (2010)

Abstract Background The Hedgehog signaling pathway functions as an organizer in embryonic development. Recent studies have demonstrated constitutive activation of Hedgehog pathway in various types of malignancies. However, it remains unclear how Hedgehog pathway is involved in the pathogenesis of osteosarcoma. To explore the involvement of aberrant Hedgehog pathway in the pathogenesis of osteosarcoma, we investigated the expression and activation of Hedgehog pathway in osteosarcoma and examined the effect of SMOOTHENED (SMO) inhibition. Results To evaluate the expression of genes of Hedgehog pathway, we performed real-time PCR and immunohistochemistry using osteosarcoma cell lines and osteosarcoma biopsy specimens. To evaluate the effect of SMO inhibition, we did cell viability, colony formation, cell cycle in vitro and xenograft model in vivo . Real-time PCR revealed that osteosarcoma cell lines over-expressed Sonic hedgehog , Indian hedgehog , PTCH1 , SMO , and GLI . Real-time PCR revealed over-expression of SMO, PTCH1 , and GLI2 in osteosarcoma biopsy specimens. These findings showed that Hedgehog pathway is activated in osteosarcomas. Inhibition of SMO by cyclopamine, a specific inhibitor of SMO, slowed the growth of osteosarcoma in vitro. Cell cycle analysis revealed that cyclopamine promoted G1 arrest. Cyclopamine reduced the expression of accelerators of the cell cycle including cyclin D1, cyclin E1, SKP2, and pRb. On the other hand, p21 cip1 wprotein was up-regulated by cyclopamine treatment. In addition, knockdown of SMO by SMO shRNA prevents osteosarcoma growth in vitro and in vivo. Conclusions These findings suggest that inactivation of SMO may be a useful approach to the treatment of patients with osteosarcoma.
Oncolytic Adenovirus Coding for Granulocyte Macrophage Colony-Stimulating Factor Induces Antitumoral Immunity in Cancer Patients
Authors: Vincenzo Cerullo, Sari Pesonen, Iulia Diaconu, Sophie Escutenaire, Petteri T. Arstila, Matteo Ugolini, Petri Nokisalmi, Mari Raki, Leena Laasonen, Merja Särkioja, Maria Rajecki, Lotta Kangasniemi, Kilian Guse, Andreas Helminen, Laura Ahtiainen, Ari Ristimäki, Anne Räisänen-Sokolowski, Elina Haavisto, Minna Oksanen, Eerika Karli, Aila Karioja-Kallio, Sirkka-Liisa Holm, Mauri Kouri, Timo Joensuu, Anna Kanerva, Akseli Hemminki
Journal: Cancer Research (2010)

Granulocyte macrophage colony-stimulating factor (GMCSF) can mediate antitumor effects by recruiting natural killer cells and by induction of tumor-specific cytotoxic T-cells through antigen-presenting cells. Oncolytic tumor cell-killing can produce a potent costimulatory danger signal and release of tumor epitopes for antigen-presenting cell sampling. Therefore, an oncolytic adenovirus coding for GMCSF was engineered and shown to induce tumor-specific immunity in an immunocompetent syngeneic hamster model. Subsequently, 20 patients with advanced solid tumors refractory to standard therapies were treated with Ad5-D24-GMCSF. Of the 16 radiologically evaluable patients, 2 had complete responses, 1 had a minor response, and 5 had disease stabilization. Responses were frequently seen in injected and noninjected tumors. Treatment was well tolerated and resulted in the induction of both tumor-specific and virus-specific immunity as measured by ELISPOT and pentamer analysis. This is the first time that oncolytic virus-mediated antitumor immunity has been shown in humans. Ad5-D24-GMCSF is promising for further clinical testing.
Long-term health consequences of PCOS
Authors: R. A. Wild
Journal: Human Reproduction Update (2002)

The prevalence of cardiovascular risk factors, insulin resistance/diabetes and/or uterine pathology appears to be increased in women with polycystic ovarian syndrome (PCOS), although more outcome studies are necessary to determine incidence. Data pertaining to some of the potential long-term health consequences associated with PCOS are summarized. Medline, Current Contents and PubMed were searched for studies from the time of our original interest in this issue in 1980 to the present. The review is limited to published human data. The current literature indicate that women with this syndrome cluster risk factors for premature morbidity and mortality. Large multi-site co-operative studies are necessary to evaluate the long-term health outcomes.
The effects of sleeping position on ventilatory responses to carbon dioxide in premature infants
Authors: A. P. R. Smith, T. Saiki, S. Hannam, G. F. Rafferty, A. Greenough
Journal: Thorax (2010)

<h3>Background</h3> The prone sleeping position, particularly in prematurely born infants, is associated with an increased risk of sudden infant death syndrome. A possible mechanism is an impaired ability to respond to respiratory compromise. The hypothesis that the ventilatory response to a carbon dioxide (CO<sub>2</sub>) challenge in convalescent, prematurely born infants would be lower in the prone compared with the supine position was therefore tested. <h3>Methods</h3> In each position, ventilatory responses to increasing levels of inspired CO<sub>2</sub> were assessed. The airway pressure change after the first 100 ms of an occluded inspiration (P<sub>0.1</sub>) and the maximum inspiratory pressure with an occluded airway during crying (P<sub>imax</sub>) were measured; the ratio of the P<sub>0.1</sub> to the P<sub>imax</sub> at each inspired CO<sub>2</sub> level and the slope of the P<sub>0.1</sub>/P<sub>imax</sub> response were calculated. Chest and abdominal wall asynchrony was assessed using inductance plethysmography and functional residual capacity (FRC) measured using a helium gas dilution technique. <h3>Results</h3> Eighteen infants with a median postmenstrual age of 35 (range 35–37) weeks were studied. In the prone versus the supine position, the mean P<sub>0.1</sub> (p=0.002), the mean P<sub>imax</sub> (p=0.006), the increase in P<sub>0.1</sub> with increasing CO<sub>2</sub> (p=0.007) and the P<sub>0.1</sub>/P<sub>imax</sub> response slope (p=0.007) were smaller. Thoracoabdominal asynchrony was not significantly influenced by position or inspired CO<sub>2</sub>. FRC was higher in the prone position (p=0.019). <h3>Conclusions</h3> Convalescent, prematurely born infants have a reduced ventilatory response to CO<sub>2</sub> challenge in the prone position, suggesting they may have an impaired ability to respond to respiratory compromise in that position.