tbuckley/cabot-search huggingface dataset:
Abstract 645: The effect of rhBMP-2 on in vitro osteosarcoma tumorigenesis and on pulmonary growth and development
Authors: David S. Geller, So Hak Chung, Wendong Zhang, Sajida Piperdi, Carrie Freeman, Bang Hoang, Rui Yang, Michael Roth, Jonathan Gill, Richard Gorlick
Journal: Cancer Research (2016)

Abstract Introduction: Complete surgical resection is a critical component of care for patients with osteosarcoma (OS). Limb-salvage surgery is performed in over 90% of cases. Non-union is a well-recognized complication of allograft reconstructions, frequently performed following tumor extirpation. Bone Morphogenetic Protein-2 (BMP-2) has been shown to be osteoinductive and could theoretically improve allograft-host bone union. The purpose of this investigation is to evaluate the effect of exogenous recombinant human BMP-2 (rhBMP-2) on osteosarcoma. Methods: Functional assays were performed using five standard osteosarcoma cell lines and three patient derived xenograft cell lines. Random migration motility was measured via wound healing scratch assay. Migration (haptotaxis) was quantitatively measured using Boyden Chamber assay. Invasion was assessed using the Biocoat Matrigel Invasion Kit. Cell proliferation rate was measured by using MTT reagent. Metastatic disease was assessed using a xenograft murine model. Results: Findings suggest that exogenous rhBMP-2 does not meaningfully affect osteosarcoma migration, invasion or proliferation across all tested lines. Average corrected lung weight in the single-dose rhBMP-2 experiment was 1.56 g in the experimental group versus 1.67 g in the control group (p = 0.69). Average corrected lung weight in the triple-dose rhBMP-2 experiment was 1.23 g in the experimental group versus 1.06 g in the control group (p = 0.07). Conclusions and Future Directions: Results support the contention that exposure of osteosarcoma to exogenous rhBMP-2 does not increase either in vitro tumorigenesis or pulmonary disease growth and development within this experimental model. While results are compelling, additional characterization and confirmation of these findings are necessary safety prerequisites prior to proposing clinical application. Citation Format: David S. Geller, So Hak Chung, Wendong Zhang, Sajida Piperdi, Carrie Freeman, Bang Hoang, Rui Yang, Michael Roth, Jonathan Gill, Richard Gorlick. The effect of rhBMP-2 on in vitro osteosarcoma tumorigenesis and on pulmonary growth and development. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 645.
Contactin-Associated Protein-like 2 Antibodies
Authors: Christian G. Bien
Journal: JAMA Neurology (2016)

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Childhood Paroxysmal Nocturnal Hemoglobinuria (PNH), a Report of 11 Cases in the Netherlands.
Authors: M.M. Van Den Heuvel-Eib, R.G.M. Bredius, M.L. te Winkel, R. Tamminga, J. de Kraker, N. Schouten-van Meeteren, M. Bruin, E.T. Korthof
Journal: Blood (2004)
Abstract 2550: Identification of novel BRCA founder mutations in middle eastern breast cancer patients using capture and sanger sequencing analysis
Authors: Rong Bu, Abdul K. Siraj, Khadija A. S. Al-Obaisi, Shaham Beg, Mohsen Al Hazmi, Yan Kong, Dahish Ajarim, Fouad Al-Dayel, Khawla S. Al-Kuraya
Journal: Cancer Research (2016)

Abstract Ethnic differences of breast cancer genomics have prompted us to investigate the spectra of BRCA1 and BRCA2 mutations in different populations. The prevalence and effect of BRCA 1 and BRCA 2 mutations in Saudi population is not fully explored. We conducted this study to characterize the prevalence of BRCA mutations in Middle Eastern breast cancer patients from Saudi Arabia. A total of 486 clinically high risk breast cancer patients were recruited from the King Faisal Specialist Hospital &amp; Research Centre from 1990 and 2011. Comprehensive BRCA1 and BRCA2 mutation screening was performed using capture sequencing and/or Sanger Sequencing of all coding exons of BRCA1 and BRCA2 in 190 cases. Thereafter, the validation was done using a panel of detected mutations in an additional 296 high risk breast cancer cases. Among the total 486 cases analyzed, 9 deleterious BRCA mutations were identified in 28 (5.8%) cases, comprising 25 cases in BRCA 1 and three cases in BRCA 2. The six BRCA 1 recurrent mutations (c. 1140dupG, c.4065_4068delTCAA, c.4136_4137delCT, c.4524G&amp;gt;A, c.5251C&amp;gt;T and c.5530delC) accounted for 96% (24/25) of all BRCA 1 mutant cases in this cohort. The one recurrent BRCA 2 mutation (c.7007G&amp;gt;A) accounted for 66.6% (2/3) of all BRCA2 mutant cases. Haplotype analysis was performed to confirm two BRCA1 recurrent mutations are novel putative founder mutation. In this study our findings suggest that BRCA mutations account for substantial proportion of high risk breast cancer cases in Middle Eastern population. Knowing the spectrum and frequency of founder mutation in this population will help in developing cost-effective rapid screening assay which can facilitate genetic testing and counseling for breast cancer risk assessment. Citation Format: Rong Bu, Abdul K. Siraj, Khadija A. S. Al-Obaisi, Shaham Beg, Mohsen Al Hazmi, Yan Kong, Dahish Ajarim, Fouad Al-Dayel, Khawla S. Al-Kuraya. Identification of novel BRCA founder mutations in middle eastern breast cancer patients using capture and sanger sequencing analysis. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2550.
Abstract 5097: Tissue stiffness regulates multinucleation in mammary epithelial cells
Authors: Allison K. Simi, Derek C. Radisky, Celeste M. Nelson
Journal: Cancer Research (2016)

Abstract This study investigates how increased stiffness of the tumor microenvironment (TME) can facilitate cellular multinucleation. Multinucleation is an easily observable marker for polyploidy, facilitating the quantification of this phenotype. Polyploidy is commonly an intermediate to aneuploidy, defined as an abnormal number of chromosomes, a phenotype found in 85% of solid cancers that can drive tumorigenesis. Up to 37% percent of tumors exhibit whole-genome doubling, which typically precedes other somatic copy number alterations. Additionally, induction of tetraploidy in human cells promoted increased tolerance for mutation, resistance to chemotherapeutic drugs, and transformation in culture. Tumors are inherently stiffer than normal tissue, and this property has been shown to affect cell growth and proliferation. Similarly, cell cycle errors have long been linked to chromosomal abnormalities. Here, we used engineered two-dimensional substrata that mimic tumor and normal microenvironments to investigate how matrix stiffness regulates multinucleation in mammary epithelial cells. Cells cultured on “stiff” substrata, representing tumor tissue, showed a nearly 14-fold increase in multinucleation compared to cells cultured on “soft” substrata, representing normal tissue. We found that multinucleation was regulated in part by signaling downstream of MMP3, a protease commonly upregulated in cancer. This signaling depended on expression of the Rac1 splice variant, Rac1b, production of reactive oxygen species (ROS), and expression of Snail. Under all conditions, cells cultured on soft substrata maintained a low frequency of multinucleation. We also investigated biochemical effectors downstream of Snail. Aurora A kinase (Aurora A) is a mitotic regulator commonly elevated in cancer that has been shown to induce multinucleation in mammary epithelial cells and increase tumor incidence in mice. We found using microarray analysis that MMP3 increases the levels of Aurora A in mammary epithelial cells. We further discovered that upregulation of Aurora A in response to MMP3 signaling was limited to one transcript variant. These data suggest that an increase in multinucleation is driven by the stiffening of the tissue during tumorigenesis, in part by MMP3-induced signaling and regulation of Aurora A splicing. More broadly, these data suggest a key role for the mechanical properties of the tumor microenvironment in cancer progression. Citation Format: Allison K. Simi, Derek C. Radisky, Celeste M. Nelson. Tissue stiffness regulates multinucleation in mammary epithelial cells. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 5097.
Inhibition of epoxyeicosatrienoic acid production in rats with cirrhosis has beneficial effects on portal hypertension by reducing splanchnic vasodilation
Authors: Marco Di Pascoli, Francesca Zampieri, Alberto Verardo, Paola Pesce, Cristian Turato, Paolo Angeli, David Sacerdoti, Massimo Bolognesi
Journal: Hepatology (2016)

In cirrhosis, 11,12-epoxyeicosatrienoic acid (EET) induces mesenteric arterial vasodilation, which contributes to the onset of portal hypertension. We evaluated the hemodynamic effects of in vivo inhibition of EET production in experimental cirrhosis. Sixteen control rats and 16 rats with carbon tetrachloride-induced cirrhosis were studied. Eight controls and eight rats with cirrhosis were treated with the specific epoxygenase inhibitor N-(methylsulfonyl)-2-(2-propynyloxy)-benzenehexanamide (MS-PPOH; 20 mg/kg/day) for 3 consecutive days. Portal blood flow and renal and splenic resistive indexes were calculated through echographic measurements, while portal and systemic pressures were measured through polyethylene-50 catheters. Small resistance mesenteric arteries were connected to a pressure servo controller in a video-monitored perfusion system, and concentration-response curves to phenylephrine and acetylcholine were evaluated. EET levels were measured in tissue homogenates of rat liver, kidney, and aorta, using an enzyme-linked immunosorbent assay. Urinary Na(+) excretion function was also evaluated. In rats with cirrhosis, treatment with MS-PPOH significantly reduced portal blood flow and portal pressure compared to vehicle (13.6 ± 5.7 versus 25.3 ± 7.1 mL/min/100 g body weight, P < 0.05; 9.6 ± 1.1 versus 12.2 ± 2.3 mm Hg, P < 0.05; respectively) without effects on systemic pressure. An increased response to acetylcholine of mesenteric arteries from rats with cirrhosis (50% effect concentration -7.083 ± 0.197 versus -6.517 ± 0.73 in control rats, P < 0.05) was reversed after inhibition of EET production (-6.388 ± 0.263, P < 0.05). In liver, kidney, and aorta from animals with cirrhosis, treatment with MS-PPOH reversed the increase in EET levels. In both controls and rats with cirrhosis, MS-PPOH increased urinary Na(+) excretion.In rats with cirrhosis, in vivo inhibition of EET production normalizes the response of mesenteric arteries to vasodilators, with beneficial effects on portal hypertension. (Hepatology 2016;64:923-930).
Abstract 4856: Selective human estrogen receptor partial agonist (ShERPAs) for treatment of tamoxifen-resistant ER+ breast cancer
Authors: Loruhama M. Delgado-Rivera
Journal: Cancer Research (2016)

Abstract Estrogen receptor positive (ER+) breast cancer represents a significant cause of death among women in the US, which is exacerbated by resistance to 1st line endocrine therapies, notably tamoxifen, which occurs in 50% of patients. Estrogen fuels growth of endocrine-dependent cancers and yet estradiol (E2) and ERá agonist, diethylstilbestrol, were used successfully in the clinic in greats cancer therapy in the 20th century. The side effects associated with these treatments are considered unacceptable, spurring the pursuit of safer, alternative therapeutic agents and the model systems to develop and optimize these agents. Three breast cancer cell lines that demonstrate resistance to tamoxifen and endocrine independence in 2D (MCF-7:5C), or 3D (T-47D:PKCá and T-47D:TAM1) cell cultures; and comparison to the parent endocrine-dependent cell lines provides a set of model systems able to test the hypothesis that a selective estrogen mimic (SEM) will provide a safe, therapeutic approach to ER+ endocrine-independent breast cancer overexpressing the PKCá biomarker. A partial agonist at ERá was selected as such a therapeutic approach: The use of partial agonists will allow us to retain the beneficial properties of E2, while attenuating the unwanted side effects. Selective human Estrogen Receptor Partial Agonists (ShERPAs) were designed, synthesized, and validated, using a combination of time-resolved FRET (TR-FRET) on ERá/SRC3 recruitment, isolated ERá affinity, and cell-based assays. ShERPAs were identified containing novel structures derived from the selective estrogen receptor modulators (SERMs) bazedoxifene and raloxifene, and their scaffolds, 3-methylindole and benzothiophene, respectively. Examples with favorable pharmacokinetic properties were validated in xenograft models of tamoxifen-resistant breast cancer. Citation Format: Loruhama M. Delgado-Rivera. Selective human estrogen receptor partial agonist (ShERPAs) for treatment of tamoxifen-resistant ER+ breast cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4856.
Abstract 362: A homogeneous bioluminescent succinate assay for detection of jumonjiC domain-containing histone demethylase activities
Authors: Juliano Alves, Said Goueli, Hicham Zegzouti
Journal: Cancer Research (2016)

Abstract JumonjiC domain-containing histone lysine demethylases (JMJCs) play a pivotal role in determining the epigenetic status of the genome, leading to either transcriptional repression or activation of target genes by counteracting the activities of histone lysine methyltransferases. Because of their implication in cancer, they have become validated drug targets. Therefore, assays for this enzyme subfamily are desirable in order to facilitate the identification of selective and potent inhibitors for drug discovery and as basic research tools. Since succinate is one of the products of the demethylation reaction catalyzed by these enzymes, an assay that detects succinate would be suitable for monitoring all JMJC activities as well as other succinate-forming enzymes (i.e.: dioxygenases). Thus, a bioluminescent and homogenous succinate detection assay for measuring JMJC activity was developed, and it is performed in a two-step format that relies on converting the succinate product to ATP, and then to light in a robust luciferase reaction. The light output is proportional to succinate concentration from low nM to 15μM, and the assay is highly sensitive and robust, two features that are highly desirable and essential for measuring the activity of the majority of JMJC demethylase subfamilies. Therefore, the succinate detection assay is a simple-to-use method that does not require antibodies or modified substrates. Examples of various applications of this succinate detection assay will be presented, including studies on specificity of different substrates by diverse JMJCs, as well as mode of action studies using specific inhibitors. The development of this succinate detection assay will make it possible to investigate a large number of JMJC demethylases and could have significant impact on diverse areas of Epigenetics research. Citation Format: Juliano Alves, Said Goueli, Hicham Zegzouti. A homogeneous bioluminescent succinate assay for detection of jumonjiC domain-containing histone demethylase activities. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 362.
Adenosine-Induced Atrial Fibrillation
Authors: Ning Li, Thomas A. Csepe, Brian J. Hansen, Lidiya V. Sul, Anuradha Kalyanasundaram, Stanislav O. Zakharkin, Jichao Zhao, Avirup Guha, David R. Van Wagoner, Ahmet Kilic, Peter J. Mohler, Paul M. L. Janssen, Brandon J. Biesiadecki, John D. Hummel, Raul Weiss, Vadim V. Fedorov
Journal: Circulation (2016)

Background: Adenosine provokes atrial fibrillation (AF) with a higher activation frequency in right atria (RA) versus left atria (LA) in patients, but the underlying molecular and functional substrates are unclear. We tested the hypothesis that adenosine-induced AF is driven by localized reentry in RA areas with highest expression of adenosine A1 receptor and its downstream GIRK (G protein-coupled inwardly rectifying potassium channels) channels ( I K,Ado ). Methods: We applied biatrial optical mapping and immunoblot mapping of various atrial regions to reveal the mechanism of adenosine-induced AF in explanted failing and nonfailing human hearts (n=37). Results: Optical mapping of coronary-perfused atria (n=24) revealed that adenosine perfusion (10–100 µmol/L) produced more significant shortening of action potential durations in RA (from 290±45 to 239±41 ms, 17.3±10.4%; P &lt;0.01) than LA (from 307±24 to 286±23 ms, 6.7±6.6%; P &lt;0.01). In 10 hearts, adenosine induced AF (317±116 s) that, when sustained (≥2 minutes), was primarily maintained by 1 to 2 localized reentrant drivers in lateral RA. Tertiapin (10–100 nmol/L), a selective GIRK channel blocker, counteracted adenosine-induced action potential duration shortening and prevented AF induction. Immunoblotting showed that the superior/middle lateral RA had significantly higher adenosine A1 receptor (2.7±1.7-fold; P &lt;0.01) and GIRK4 (1.7±0.8-fold; P &lt;0.05) protein expression than lateral/posterior LA. Conclusions: This study revealed a 3-fold RA-to-LA adenosine A1 receptor protein expression gradient in the human heart, leading to significantly greater RA versus LA repolarization sensitivity in response to adenosine. Sustained adenosine-induced AF is maintained by reentrant drivers localized in lateral RA regions with the highest adenosine A1 receptor/GIRK4 expression. Selective atrial GIRK channel blockade may effectively treat AF during conditions with increased endogenous adenosine.
MicroRNAs Specific for Immune-Privileged Diffuse Large B-Cell Lymphoma.
Authors: JanLukas Robertus, Geert Harms, Tjasso Blokzijl, Daphne de Jong, Marije Booman, Stefano Rosati, Ed Schuuring, Philip M. Kluin, Anke van den Berg
Journal: Blood (2007)
Safety of same-day pegfilgrastim administration and incidence of cystitis and ureteritis in mCRPC treated with cabazitaxel ± carboplatin.
Authors: Mehmet Asim Bilen, Diana H. Cauley, Bradley J. Atkinson, Hsiang-Chun Chen, Diana Kaya, Xuemei Wang, Raghu Vikram, Shi-Ming Tu, Paul Gettys Corn, Jeri Kim
Journal: Journal of Clinical Oncology (2016)

e16513 Background: Cabazitaxel (CBZ) is a novel taxane approved after docetaxel in patients (pts) with metastatic castration resistant prostate cancer (mCRPC). Though myeloid growth factors are commonly employed, optimal timing of administration has not been well studied. In a retrospective study, we assessed the effects of same-day pegfilgrastim (P) administration after CBZ ± carboplatin (C) in heavily treated mCRPC pts. Also, we evaluated by CT scans the frequency of cystitis and ureteritis (urinary tract inflammation [UI]) during and/or after therapy. Methods: From January 2010 to January 2014, 151 consecutive mCRPC pts were treated with CBZ±C at a single institution. We assessed absolute neutrophil count recovery, incidence of neutropenia, neutropenic fever, antibiotic usage, treatment delays or discontinuation, dose reduction, and hospitalization with P administration. Radiologists blinded to therapy reviewed CT scans to detect UI. Fisher's exact test was used to evaluate the relationships between timing of P (same day vs. after 24 hours) and UI. Kaplan-Meier method was used to estimate event-free probabilities. Results: Median age of pts was 69 (41-88 yrs), disproportionately white (78%), and likely to have a Gleason score > 9 (9-10, 54%). Most had adenocarcinoma (96%), bone metastasis (89%), and prior docetaxel therapy (83%). Median number of cycles of CBZ±C treatment was 3 (range, 1-12). Median overall survival was 9 months (95% CI, 8-11). One patient ( < 1%) had neutropenia; 38 pts (25%) had infection. During cycle 1, a significantly higher proportion of pts receiving P after 24 hours developed infection than did those receiving P the same day (26% vs. 6%, p= .01). Differences in subsequent cycles between timing of P and the infection rate were not significant. In cases with baseline and follow-up CT scans, 18/84 (21%) were positive for UI. No correlation was observed between UI detected on scans and timing of P. Conclusions: Same-day P administration after CBZ±C treatment in pts with mCRPC is feasible. UI rate (21%) was higher than that reported anecdotally. Results need to be prospectively validated.
Therapeutic Strategies and Pharmacological Tools Influencing S1P Signaling and Metabolism
Authors: Dominik Vogt, Holger Stark
Journal: Medicinal Research Reviews (2016)

During the last two decades the study of the sphingolipid anabolic, catabolic, and signaling pathways has attracted enormous interest. Especially the introduction of fingolimod into market as first p.o. therapeutic for the treatment of multiple sclerosis has boosted this effect. Although the complex regulation of sphingosine-1-phosphate (S1P) and other catabolic and anabolic sphingosine-related compounds is not fully understood, the influence on different (patho)physiological states from inflammation to cytotoxicity as well as the availability of versatile pharmacological tools that represent new approaches to study these states are described. Here, we have summarized various aspects concerning the many faces of sphingolipid function modulation by different pharmacological tools up to clinical candidates. Due to the immense heterogeneity of physiological or pharmacological actions and complex cross regulations, it is difficult to predict their role in upcoming therapeutic approaches. Currently, inflammatory, immunological, and/or antitumor aspects are discussed.