tbuckley/cabot-search huggingface dataset:
Role of CD24 in HER2-positive breast cancer.
Authors: Mari Hosonaga, Yoshimi Arima, Norio Kohno, Hideyuki Saya
Journal: Journal of Clinical Oncology (2014)

e11572 Background: Human epidermal growth factor receptor 2 (HER2) is a transmembrane kinase receptor, which promotes the RAS/RAF/MEK/ERK and the PI3K/AKT/mTOR pathways. The standard treatment for HER2-positive breast cancer is a combination of chemotherapy plus an anti-HER2 agent, such as trastuzumab and lapatinib. HER2-positive breast cancers are predominantly positive for CD24, which is a glycosyl phosphatidylinositol (GPI)-anchored membrane protein. Overexpression of CD24 in breast cancer is associated with a poor prognosis. We hypothesize that the co-expression of HER2 with CD24 is associated with the therapeutic resistance of HER2-positive breast cancer cells. Methods: We established HER2-expressing cell lines by introducing a wild type HER2 gene into MDA-MB-231 triple-negative (ER-/PgR-/HER2-) breast cancer cells. We used the HER2-positive breast cancer cell lines BT-474, HCC202, SKBR3, and HCC1569. To investigate the relevance of CD24 expression in HER2-positive breast cancer, we analyzed HER2 and CD24 expressions by using flow cytometry. We also analyzed the phosphorylation levels of AKT and ERK in those cells by western blot. Results: Flow cytometry analysis revealed that the percentage of CD24-positive cells was markedly higher in the HER2-high fraction than in the HER2-low/negative fraction. The knockdown of CD24 decreased the expression of HER2 and the phosphorylation of AKT, whereas knockdown of HER2 did not affect the expression of CD24. We also found that knockdown of CD24 enhanced the anti-proliferative and death-promoting effects of lapatinib in HER2-positive breast cancer cells. Conclusions: CD24 supports both the expression of HER2 and the consequent activation of the PIK3/AKT signaling pathway so as to promote cell survival. CD24 appears to contribute to the resistance to HER2-targeted therapy and is itself a potential therapeutic target in HER2-positive breast cancer.
Identification of sequence variants influencing immunoglobulin levels
Authors: Stefan Jonsson, Gardar Sveinbjornsson, Aitzkoa Lopez de Lapuente Portilla, Bhairavi Swaminathan, Rosina Plomp, Gillian Dekkers, Ram Ajore, Mina Ali, Arthur E H Bentlage, Evelina Elmér, Gudmundur I Eyjolfsson, Sigurjon A Gudjonsson, Urban Gullberg, Arnaldur Gylfason, Bjarni V Halldorsson, Markus Hansson, Hilma Holm, Åsa Johansson, Ellinor Johnsson, Aslaug Jonasdottir, Bjorn R Ludviksson, Asmundur Oddsson, Isleifur Olafsson, Sigurgeir Olafsson, Olof Sigurdardottir, Asgeir Sigurdsson, Lilja Stefansdottir, Gisli Masson, Patrick Sulem, Manfred Wuhrer, Anna-Karin Wihlborg, Gudmar Thorleifsson, Daniel F Gudbjartsson, Unnur Thorsteinsdottir, Gestur Vidarsson, Ingileif Jonsdottir, Björn Nilsson, Kari Stefansson
Journal: Nature Genetics (2017)
A Phase I/II Open-Label, Dose Escalation Study to Investigate the Safety, Pharmacokinetics, Pharmacodynamics and Clinical Activity of GSK525762 in Subjects with Relapsed, Refractory Hematologic Malignancies
Authors: Gautam Borthakur, Mark A Dawson, Eytan M. Stein, Anastasios Karadimitris, Brian J.P Huntly, Michael J. Dickinson, Aristeidis Chaidos, Thierry Horner, John Brennan, January Baron, Brandon E. Kremer, Arindam Dhar
Journal: Blood (2016)
Propensity score analysis investigating the role of hormonal maintenance (HM) for advanced breast carcinoma with luminal subtype (ABC-Lum): Implication for prognostic modeling, post-progression and conditional survival (PPS/CS).
Authors: Luisa Carbognin, Isabella Sperduti, Mariangela Ciccarese, Alessandra Fabi, Sara Pilotto, Luciana Petrucelli, Sabrina Vari, Rosa Chiara ForcignanÃ Â², Rolando Nortilli, Cecilia Vicentini, Matteo Brunelli, Diana Giannarelli, Giampaolo Tortora, Emilio Bria
Journal: Journal of Clinical Oncology (2016)

545 Background: The aim of this analysis was to investigate the impact of HM for ABC-Lum and to develop and validate a prognostic model on the basis of clinical, pathological and therapeutic predictors. Methods: Clinicopathological data of ABC-lum patients (pts) from 3 institutions were retrospectively correlated to progression-free and overall survival (PFS/OS). A propensity score analysis was performed for non-progressive pts after chemotherapy (CT) to screen for the prognostic role of HM. A continuous score to identify risk classes was derived according to model ratios. The performance of the risk-class model was tested for PPS and CS as well. Results: Data from 335 pts were gathered (median f.u. 58 mo.). HM resulted to be a significant prognostic factor for PFS (HR 2.01, 95% CI 1.43-2.82, p<0.0001) and OS (HR 1.82, 95% CI 1.18-1.29, p=0.006), for the 132 non-progressive pts after CT. Log-rank analysis corrected for propensity score is shown in the table. In the whole pts’ sample, Ki67, Performance Status (PS) and number of metastatic sites were significant predictors at the multivariate analysis for PFS, whereas Ki67, PS, brain metastases, PFS after 1st line therapy, number of chemotherapy lines, hormonal therapy and HM were significant predictors for OS. A 2-class model significantly differentiated low- and high-risk patients for 2yrs PFS (31.5% and 11.0%, p<0.0001), 3yrs OS (57.1% and 4.8%, p<0.0001), and 3yrs PPS (35.8% and 0%, p<0.0001). A 3-class model separated low-, intermediate-, and high-risk patients for 2yrs PFS (40.8%, 24.4%, and 11.0%, p<0.0001), 3yrs OS (68.1%, 24.8%, and 4.8%, p<0.0001) and 3yrs PPS (43.0%, 12.1%, and 0%, p<0.0001). Both models were internally cross-validated and equally discriminate the ABC-Lum prognosis for CS as well. Conclusions: HM after upfront chemotherapy significantly impacts on the overall prognosis of ABC-Lum, and should be considered with other 'easy-to-obtain' clinical, pathological and therapeutic parameters to accurately separate pts’ into different risk classes. HM No HM p-value 2-yrs PFS (%) 33.9 20.3 0.01 3-yrs OS (%) 62.3 43.2 0.03
Uncovering the arrhythmogenic potential of TRPM4 activation in atrial-derived HL-1 cells using novel recording and numerical approaches
Authors: Yaopeng Hu, Yubin Duan, Ayako Takeuchi, Lin Hai-Kurahara, Jun Ichikawa, Keizo Hiraishi, Tomohiro Numata, Hiroki Ohara, Gentaro Iribe, Michio Nakaya, Masayuki X. Mori, Satoshi Matsuoka, Genshan Ma, Ryuji Inoue
Journal: Cardiovascular Research (2017)

Transient receptor potential cation channel subfamily melastatin member 4 (TRPM4), a Ca2+-activated nonselective cation channel abundantly expressed in the heart, has been implicated in conduction block and other arrhythmic propensities associated with cardiac remodelling and injury. The present study aimed to quantitatively evaluate the arrhythmogenic potential of TRPM4.Patch clamp and biochemical analyses were performed using expression system and an immortalized atrial cardiomyocyte cell line (HL-1), and numerical model simulation was employed. After rapid desensitization, robust reactivation of TRPM4 channels required high micromolar concentrations of Ca2+. However, upon evaluation with a newly devised, ionomycin-permeabilized cell-attached (Iono-C/A) recording technique, submicromolar concentrations of Ca2+ (apparent Kd = ∼500 nM) were enough to activate this channel. Similar submicromolar Ca2+ dependency was also observed with sharp electrode whole-cell recording and in experiments coexpressing TRPM4 and L-type voltage-dependent Ca2+ channels. Numerical simulations using a number of action potential (AP) models (HL-1, Nygren, Luo-Rudy) incorporating the Ca2+- and voltage-dependent gating parameters of TRPM4, as assessed by Iono-C/A recording, indicated that a few-fold increase in TRPM4 activity is sufficient to delay late AP repolarization and further increases (≥ six-fold) evoke early afterdepolarization. These model predictions are consistent with electrophysiological data from angiotensin II-treated HL-1 cells in which TRPM4 expression and activity were enhanced.These results collectively indicate that the TRPM4 channel is activated by a physiological range of Ca2+ concentrations and its excessive activity can cause arrhythmic changes. Moreover, these results demonstrate potential utility of the first AP models incorporating TRPM4 gating for in silico assessment of arrhythmogenicity in remodelling cardiac tissue.
VP4- and VP7-specific antibodies mediate heterotypic immunity to rotavirus in humans
Authors: Nitya Nair, Ningguo Feng, Lisa K. Blum, Mrinmoy Sanyal, Siyuan Ding, Baoming Jiang, Adrish Sen, John M. Morton, Xiao-Song He, William H. Robinson, Harry B. Greenberg
Journal: Science Translational Medicine (2017)

Individual human VP4- and VP7-binding monoclonal antibodies mediate serotype cross-reactive neutralizing immunity to rotaviruses.
Genome wide hypermethylated phenotype in VHL, SDHD, and SDHB associated pheochromcytomas (PCC).
Authors: Justin D. Kaner, Carmen Sanchez-Claros, Ziqiang Yuan, Jessica Pastoriza, Asha Adem, Karel Pacak, Steven K. Libutti
Journal: Journal of Clinical Oncology (2016)

e13017 Background: PCCs are rare neuroendocrine tumors and their pathogenesis is not well understood. Epigenetic changes are seen in many human tumors, and these changes may play a role in the development of PCCs. Using a high-throughput global DNA methylation approach, HELP-tagging, we sought to determine the differential methylation pattern of human VHL-PCCs, SDHD-PCCs, SDHB-PCCs and sporadic PCCs compared to normal adrenal tissue. Methods: Normal adrenal glands (n = 4), VHL-PCCs (n = 5), SDHD-PCCs (n = 6), SDHB-PCCs (n = 6), and sporadic-PCCs (n = 4) were analyzed. We generated HELP-tagging libraries with HpaII- or Msp- digested DNA from all samples. Massively-parallel sequencing with an Illumina HiSeq 2000 sequencer was performed. Sequences were analyzed and aligned using Illumina pipeline and customized HELP-tagging software. Differential DNA methylation profiles were compared. Differentially methylated loci were defined as those with a methylation change of > 20% and P value < 0.05. These loci were then associated to chromosomes, to gene promoter (± 1000 base pairs from the transcription starting sites) or gene body regions for further analysis. Results: Over 2 million CG dinucleotides were tested for each sample. VHL-PCCs, SDHD-PCCs, and SDHB-PCCs were more globally hypermethylated compared to normal cells. The promoter region of 627, 1,441, 2,313, and 30 genes differed significantly between VHL, SDHD, SDHB, sporadic PCCs and normal (p < 0.05, > 20% methylation change). Among the hypermethylated genes in the promoter region, 227 genes are common to the 3 PCC groups (VHL, SDHD, and SDHB) and 227 common to the two SDH subunits (SDHB and SDHD). The number of uniquely hypermethylated genes in the promoter regions is higher in SDHB than in SDHD or VHL-PCCs. Furthermore, the pathway analysis for SDHB-PCCs shows that the changes were in genes involved in WNT and MAPK signaling pathways. Conclusions: Global DNA hypermethylation is seen in VHL, SDHD, and SDHB-PCCs. These results may shed light on the pathogenesis of PCCs and demonstrate the utility of high throughput genome wide epigenetic analysis. Our results provide a possible future clinical application in identifying new biomarkers and therapeutic targets for PCCs.
Preclinical development of novel naphthalimide formulations
Authors: Shawnya Michaels, Dennis M. Brown
Journal: Cancer Research (2004)

Proc Amer Assoc Cancer Res, Volume 45, 2004

4576 

Quinamed™ (a substituted naphthalimide) affects a number of important cellular targets including topoisomerase II and various proteins in the EGFR pathway and is currently in phase II clinical studies as an i.v. dosage form for the treatment of solid tumors. Quinamed, while efficacious as a single agent, also provides enhanced antitumor activity when used as a chemopotentiator, for example with cisplatin. To facilitate its use in combinatorial therapies, it may be advantageous to develop additional and improved dosage forms customized for other routes of administration and schedules. Formulation development studies are underway evaluating novel routes and dosage formulations for naphthalimides in preclinical models. A number of novel formulation systems appear to be useful. Using the RIF-1 murine tumor growth delay model, we have demonstrated that several of these formulations have efficacy in controlling the growth of solid tumors. Subcutaneous RIF-1 tumor (∼100mm3) bearing (C3H) mice were treated with Quinamed formulations by oral, intravenous, subcutaneous or intraperitoneal routes of administration. Efficacy was evaluated based on the tumor growth delay (number of days required to achieve 4x original tumor volume) expressed in terms of treated/control ratios (T/C). Administration of Quinamed formulations CGX-571-13, CGX-571-17 and CGX-571-11 at 60 mg/Kg all gave a T/C of 1.2 after oral, intramuscular or intraperitoneal administration, respectively. Repeated oral administration of CGX-571-13 at 60 mg/Kg (4x) increased the T/C to 1.3 and did not cause weight loss or lethal toxicities. Subcutaneous administration of CGX-571-15 at 60 mg/Kg also gave a T/C of 1.3. These results indicate that additional Quinamed formulations for oral or subcutaneous routes of administration are feasible and may warrant future clinical development.
Résection muco-sous-muqueuse oesophagienne étendue et circonférentielle en mono-bloc: expérimentation in vivo chez le porc
Authors: F Prat, L Mangialavori, A Chryssostalis, S Chaussade
Journal: Endoscopy (2006)

Les techniques actuelles de surveillance et de mucosectomie endoscopique sont mal adaptées en particulier à la problématique des EBO longs en dysplasie. Nous cherchons à mettre au point une technique de résection en monobloc applicable à l'EBO long en mettant à profit les progrès récents de l'instrumentation d'endoscopie interventionnelle.
Impact of <i>PIK3CA</i> tumor mutation on the association of aspirin or NSAID use and time to breast cancer recurrence.
Authors: Anne Marie McCarthy, Wei He, Susan Regan, Andrew T. Chan, Beverly Moy, A. John Iafrate, Aditya Bardia, Katrina Armstrong
Journal: Journal of Clinical Oncology (2017)

1521 Background: Aspirin or NSAID (A/N) use post diagnosis is associated with lower risk of breast cancer recurrence and mortality in cohort studies. A potential mechanism is that A/Ns may suppress cell growth and induce apoptosis in tumors driven by phosphatidylinositol 3 kinase ( PIK3CA), the most common oncogene mutation in breast cancer. An interaction of A/Ns and PIK3CA mutation has been observed for colorectal cancer prognosis, but has not been studied in breast cancer. The objective was to assess time to breast cancer recurrence (TTR) with respect to A/N use and PIK3CAmutation. Methods: Patients with HR+/HER2- breast cancer treated at Massachusetts General Hospital in 2009-2014 who received tumor genotyping were included. PIK3CA mutations, including 8 common hotspot mutations, were assessed by a high-throughput tumor genotyping assay using DNA from formalin-fixed, paraffin-embedded tumor tissue. A/N use beginning 6 months post diagnosis through metastasis was extracted from electronic medical records using coded data and natural language processing. Patients with de novo metastatic disease or progressive disease within 6 months of primary diagnosis were excluded. TTR was estimated using Cox proportional hazards models. Results: Among breast cancer patients (N=212), 60 (28%) used A/Ns and 69 (33%) had PIK3CA mutation (see Table). After adjusting for age, stage, adjuvant endocrine therapy, radiation, and chemotherapy, A/N users had significantly longer TTR (HR=0.65 p=0.01). The association was similar for wild type (HR=0.58 p=0.01) and PIK3CA mutated tumors (HR=0.60 p=0.06), with no significant interaction of A/N use and PIK3CA (p=0.34). Conclusions: Among HR+ breast cancer patients, those who used A/Ns following primary diagnosis had longer TTR than non-users, regardless of tumor PIK3CA mutation status. The study provides a model for how tumor genomics could be integrated into secondary chemoprevention studies. [Table: see text]
Abstract 645: Sarcoplasmic Reticulum Ca2+ is Required for Catecholamine Stimulated Rate Increases, but not for 'Intrinsic' Automaticity in Sinoatrial Nodal Pacemaker Cells
Authors: Yuejin Wu, Mark E Anderson
Journal: Circulation (2007)

Sarcoplasmic reticulum (SR) calcium is an important contributor to excitation-contraction coupling in ventricular myocytes, and is the major source of Ca2+ for contraction in myocardium. SR Ca2+ co...
Purinergic P2Y receptors: Molecular diversity and implications for treatment of cardiovascular diseases
Authors: Akiyuki Nishimura, Caroline Sunggip, Sayaka Oda, Takuro Numaga-Tomita, Makoto Tsuda, Motohiro Nishida
Journal: Pharmacology & Therapeutics (2017)

Purinergic signaling, mediated mainly by G protein-coupled P2Y receptors (P2YRs), is now attracting attention as a new therapeutic target for preventing or treating cardiovascular diseases. Observations using mice with genetically modified P2YRs and/or treated with a pharmacological P2YR inhibitor have helped us understand the physiological and pathological significance of P2YRs in the cardiovascular system. P2YR-mediated biological functions are predominantly activated by mononucleotides released from non-adrenergic, non-cholinergic nerve endings or non-secretory tissues in response to physical stress or cell injury, though recent studies have suggested the occurrence of ligand-independent P2YR function through receptor-receptor interactions (oligomerization) in several biological processes. In this review, we introduce the functions of P2YRs and possible dimerization with G protein-coupled receptors (GPCRs) in the cardiovascular system. We focus especially on the crosstalk between uridine nucleotide-responsive P2Y6R and angiotensin (Ang) II type1 receptor (AT1R) signaling, and introduce our recent finding that the P2Y6R antagonist MRS2578 interrupts heterodimerization between P2Y6R and AT1R, thereby reducing the risk of AT1R-stimulated hypertension in mice. These results strongly suggest that targeting P2Y6R oligomerization could be an effective new strategy to reduce the risk of cardiovascular diseases.
Extended follow-up in the COGENT study: A randomized study of in-person versus telephone disclosure of cancer genetic test results.
Authors: Angela R. Bradbury, Linda J. Patrick-Miller, Brian L. Egleston, Susan M. Domchek, Olufunmilayo I. Olopade, Michael J. Hall, Mary Beryl Daly, Linda Fleisher, Generosa Grana, Pamela Ganschow, Dominique Fetzer
Journal: Journal of Clinical Oncology (2017)

1504 Background: Alternative delivery models are needed in the era of Precision Medicine given a shortage of genetic providers and increasing utilization of genetic testing. Telephone disclosure (TD) of genetic test results, including multi-gene panel testing, is non-inferior to usual care in-person disclosure (IPD) for short-term distress but failed non-inferiority for knowledge. Longitudinal data including health behaviors are needed. Methods: 970 patients undergoing clinical genetic testing at 5 centers were randomly assigned to usual care IPD (n = 497) or TD (n = 473) of results in the COGENT Study (NCT01736345). Participants completed surveys after pre-test counseling, post-disclosure and at 6 and 12 months. We used non-inferiority tests for primary analyses and T-tests and logistic regressions for secondary analyses. Results: TD was not worse than IPD for anxiety both post-disclosure and at 6 months, but did not reach the non-inferiority threshold for knowledge at either time point. In secondary analyses there were no significant differences in anxiety, depression, or cancer worry between arms, but there was less knowledge gain at 6 (-0.41 v. +0.11 in IPD, p = 0.05) and 12 months (-0.34 v. +0.31 in IPD, p = 0.05) in the TD arm. In the TD arm, 195 (50%) returned for clinical follow-up with a physician to discuss medical management. Not returning for follow-up varied by site and was associated with a negative result, being male and non-white. Knowledge gain at 6 months was lower for those who did not return for follow-up (-0.77) compared to those who returned (-0.17, p = 0.08). There were no significant differences by arm at 6 and 12 months in performance of mammogram, breast MRI, colonoscopy or prophylactic surgeries. Conclusions: Distress is not unacceptably worse with TD, but knowledge failed the test for non-inferiority. Longitudinal knowledge declined more for those who did not return for medical follow-up, but uptake of screening and risk reducing behaviors did not differ by arm. Telephone disclosure of genetic test results, even MGPT, may be a reasonable alternative to in-person disclosure for patients who agree to return to meet with a provider for medical management recommendations. Clinical trial information: NCT01736345.
Abstract 96: A Unique Jervell Lange-Nielsen Syndrome Mutation Modeled in Induced Pluripotent Stem Cell Derived Cardiomyocytes
Authors: Kevin Bersell, Tao Yang, Dan Roden
Journal: Circulation Research (2015)

Introduction: Current screening for mutations in human disease is turning increasingly to next-generation methods that map short reads to a reference sequence. We report here an unusual variant that was undetected by next generation sequencing in a patient diagnosed with Jervell Lange-Nielsen syndrome (JLNS) and initial results in an induced pluripotent stem cell-derived cardiomyocyte (iPSC-CM) model. Methods and Results: A diagnosis of JLNS was made in a middle-aged woman with congenital deafness and QT intervals as long as 800 msec. However, next-generation sequencing found only a heterozygous KCNQ1 mutation, R518X. Convinced by the clinical phenotype that a second causative variant was highly likely, we used Sanger sequencing of PCR KCNQ1 amplicons to identify a 36-basepair poly-adenine tract, encoding 12 lysines, inserted within the coding sequence at the 5’ end of exon 15. Electrophysiological studies in patient-specific IPSC-CMs revealed marked prolongation of ventricular-like action potentials (Figure). Conclusion: Long inserts of the type we identified here have not been previously reported in the long QT syndromes. We speculate that next generation-based short reads containing this variant could not be mapped to a reference sequence and thus this type of variant will be missed by next-generation analysis unless bioinformatics filters are specifically modified to include this possibility. Validation of this long QT syndrome iPSC-CM model provides a human cell based platform for drug discovery and mechanistic studies to further our understanding of disease pathogenesis.
Relamorelin Relieves Constipation and Accelerates Colonic Transit in a Phase 2, Placebo-Controlled, Randomized Trial
Authors: Andres Acosta, Michael Camilleri, Gururaj Kolar, Johanna Iturrino, Lawrence A Szarka, Amy Boldingh, Duane Burton, Michael Ryks, Deborah Rhoten, Alan R Zinsmeister, Sharon C Spence, Keith Gottesdiener, Ernest P Bouras, Maria I Vazquez-Roque
Journal: Clinical Gastroenterology and Hepatology (2015)