tbuckley/cabot-search huggingface dataset:
Abstract #305: Knock-in of human HGF into the mouse genome maintains endogenous HGF regulation and supports the growth of HGF-dependent human cancer cell lines
Authors: Joelle Brodeur, Anthony Monti, Sriram Kollipara, Kelly Connolly, Andrea Boudrow, Hamid Tissire, Kristan Meetze, William Rideout
Journal: Cancer Research (2009)

Hepatocyte growth factor (HGF) and its tyrosine kinase receptor (MET) are implicated in a large number of human tumor types with activation of the pathway frequently associated with poor prognosis. The mutations and amplification of MET seen in tumors tend to make the cells hypersensitive to HGF, not independent of the ligand for activation. Published data suggests that MET expressed on the surface of tumors cells is primarily activated through paracrine signaling rather than autocrine signaling, with HGF being produced by stromal cells. Modeling this pathway in mice has proven to be difficult due to a unidirectional species incompatibility; namely, mouse HGF does not activate human MET, but human HGF activates MET in both species with equal potency. Thus, all established human xenograft cell lines have been selected to grow in mice independent of exogenous HGF_if the human cell line requires HGF for growth it must produce it in an autocrine fashion (e.g. U87). A transgenic mouse model that overexpresses human HGF driven by the MT1 promoter has been shown to accelerate the growth of several established xenograft lines (Zhang et al., 2005). To avoid side effects caused by ubiquitous, unregulated expression of human HGF, we developed a mouse model in which the cDNA of human HGF was knocked into the mouse Hgf locus by homologous recombination, simultaneously deleting several exons of mouse HGF. The homozygous knock-in mice (hHGFki) expressed only the human form of HGF, appeared normal, and were viable and fertile. Thus, human HGF expression was regulated properly from the knock-in allele and human HGF could substitute for mouse HGF during development (earlier knockouts of HGF proved to be lethal at mid-gestation (Schmidt et al., 1995; Uehara et al., 1995). The hHGFki allele was crossed with C3Hscid mice in order to serve as a host strain for human tumor xenografts and mouse tumor allografts. Compared to the MT1-human HGF transgenic mice, immunocompromised hHGFki mice expressed lower concentrations of hHGF in normal liver and blood plasma, but had higher concentrations in serum. The increase in HGF levels upon clotting was most likely due to release of HGF from platelets and lymphocytes, further suggesting that regulation of human HGF expression follows normal patterns. In addition, an HGF-dependent xenograft line (H596) showed accelerated growth in the knock-in mice compared to the transgenic mice. We are employing these mice as hosts for a broad selection of human primary tumors to develop xenografts which retain HGF/MET signaling and permit better preclinical models for anti-HGF antibodies and MET inhibitors.  Citation Information: In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr 305.
Abstract 303: HDL Mimetic Peptide 4F Rescues Pre-existing Pulmonary Hypertension via MicroRNA 193-3p
Authors: Salil Sharma, Soban Umar, Gabe Wong, Denise Mai, Mohamad Navab, Srinu Reddy, Mansoureh Eghbali
Journal: Circulation Research (2013)

Pulmonary hypertension (PH) is a chronic lung disease associated with severe vascular disorders leading to right ventricular(RV) failure. An HDL mimetic peptide, 4F, has been shown to be effective for the treatment of atherosclerosis and a number of inflammatory disorders. Here, we explored whether 4F can rescue advanced PH by controlling the expression of specific microRNAs (miRs). PH was induced in rats by a single injection of monocrotaline (MCT, 60mg/kg, s.c .) or by placing mice in hypoxia chamber(O2≤10%) for 21 days. MCT-rats or hypoxic mice received 4F therapy (50mg/kg/day, s.c .,days 21-30 in MCT model and days 14-21 in hypoxia model). We performed microRNA microarray analysis (non-affymetrix) in lung tissues of CTRL, PH and 4F-rescued groups. OE of miR193 was achieved by intratracheal instillation of 20nM dose at days 16, 21 and 26 in MCT model or at days 14 and 18 in hypoxia model. 4F therapy starting after the establishment of PH in both MCT and hypoxia models improved significantly RV pressure (RVP) and RV hypertrophy index (RVP=46±3 vs RVP=74±1 mmHg in PH; RV/LV+IVS=0.38±0.02 vs RV/(LV+IVS)=0.68±0.05 in PH, p&lt;0.05 vs PH and in hypoxia model RVP=22±3.8 vs. 36.91±5.74 in PH and 20.93±2.52mmHg in ctrl, p&lt;0.05 vs PH ). Microarray and qPCR showed downregulation of miR-193 by ~3 fold in MCT model. 4F therapy normalized miR-193 to ctrl levels. MiR-193 OE in both MCT-rats and hypoxic-mice rescued PH (RVP=38±5.5mmHg, RV/LV+IVS=0.37±0.034 in MCT-rats and RVP=25.48±0.88mmHg in hypoxic-mice). Lung sections showed increased arteriolar muscularization and ox-LDL deposition in the PH group, prevented by miR-193 therapy. In vivo, OE of miR-193 suppressed transcription of in-silico targets ALOX5, a lipoxygenase; IGF1R, insulin-like growth factor 1 receptor and ARHGEF12, a Rho guanine nucleotide exchange factor and decreased human pulmonary artery smooth muscle cell (HPASMC) proliferation in vitro in the presence of serum or 12-HETE by &gt;2 folds whereas miR-193 KD increased proliferation. In conclusion, 4F rescues pre-existing severe PH by targeting genes associated with HETEs and HODEs production, inflammation and growth via inducing miR-193.
Women with symptoms of a urinary tract infection but a negative urine culture: PCR-based quantification of Escherichia coli suggests infection in most cases
Authors: S. Heytens, A. De Sutter, L. Coorevits, P. Cools, J. Boelens, L. Van Simaey, T. Christiaens, M. Vaneechoutte, G. Claeys
Journal: Clinical Microbiology and Infection (2017)
Extranodal Marginal Zone Lymphoma: No Longer Just a Sidekick
Authors: Manali K. Kamdar, Sonali M. Smith
Journal: Journal of Clinical Oncology (2017)

The Oncology Grand Rounds series is designed to place original reports published in the Journal into clinical context. A case presentation is followed by a description of diagnostic and management challenges, a review of the relevant literature, and a summary of the authors' suggested management approaches. The goal of this series is to help readers better understand how to apply the results of key studies, including those published in Journal of Clinical Oncology, to patients seen in their own clinical practice. A 51-year-old healthy female with good performance status presented for gynecologic surgery for a benign condition. A preprocedure chest x-ray showed a right lower lobe infiltrate. A subsequent computed tomography (CT) scan of the chest with contrast revealed a large consolidative right lower lobe mass with surrounding inflammation ( Fig 1A ). Bronchoscopy with biopsy revealed a low-grade lymphoma with the following immunophenotype: CD45+, CD20+, BCL2+, CD10 negative, CD5 negative, cyclin D1 negative, and Ki-67 index of less than 5%. Morphology and immunohistochemistry were most consistent with pulmonary extranodal marginal zone lymphoma (ENMZL; Fig 2 ). The patient was asymptomatic and denied fevers, sweats, weight loss, shortness of breath or dyspnea on exertion, or cough. Her history was notable for exposure to parrots over several months before presentation. Complete staging with a CT of the chest, abdomen, and pelvis with contrast redemonstrated disease that was localized to the chest with mild compression of the pulmonary vasculature but no other evidence of lymphoma. She was referred to discuss management of stage IAE pulmonary ENMZL lymphoma.
P13.04 K16ApoE increases drug-delivery across the blood brain barrier in an animal model of brain metastases
Authors: S. Aasen, H. Espedal, O. Keunen, C. Holte, H. Baghirov, R. Bjerkvig, T. Karlsen, O. Tenstad, D. Olberg, G. Sarkar, F. Thorsen
Journal: Neuro-Oncology (2017)

Individuals with metastatic disease within the brain usually await a poor prognosis. Regardless of the ongoing development of novel drugs, a significant challenge is the delivery of drugs across the blood brain barrier (BBB) and into the metastatic neoplasms. The BBB excludes almost all therapeutic compounds, as highly charged, hydrophilic or large compounds are unable to penetrate the BBB. Different strategies to temporarily open the BBB have been studied previously. Here, we describe a peptide transporter encompassing 16 lysine residues and 20 amino acid residues corresponding to the low density lipoprotein receptor (LDLR) binding domain of apolipoprotein E (ApoE). We show that this peptide, K16ApoE, is able to transiently open the BBB for drug-delivery into experimental brain metastases. The ability of the peptide to open the BBB was studied in vivo using dynamic contrast enhanced magnetic resonance imaging (DCE MRI) in nonobese diabetic/severe combined (nod/scid) mice. Further, cellular effects after treatment with the peptide was investigated in vitro using confocal microscopy, flow cytometry and impedance experiments. The biodistribution of the peptide was studied in blood plasma and several organs using isotope labeled K16ApoE. Finally, we treated animals with the peptide in combination with the B-RAF inhibitor Dabrafenib, only Dabrafenib or vehicle. After intravenously administering the K16ApoE peptide into the mice, a transient opening of the BBB for up to 4 hours was clearly demonstrated by DCE-MRI. Microscopy showed that the peptide disrupted brain endothelial cell monolayers by reducing the barrier properties of the cells. The impedance experiments displayed that the permeability through endothelial cell barriers was increased after treatment with K16ApoE, and dose-dependent cell death was seen. The peptide did not affect endothelial cell tight junctions. The biodistribution study showed that the peptide was eliminated from blood plasma in less than five minutes through the kidneys. In the treatment study it was observed that the group of animals receiving K16ApoE followed by Dabrafenib had smaller tumor volumes than the other two experimental groups. K16ApoE did in combination with Dabrafenib decrease the number of experimental brain metastases, as a therapeutic window up to 4 hours was seen when using the peptide. The described strategy could thus have the potential to improve the treatment of patients with brain metastatic disease.
Comparative Physiology of the Thyroid and Parathyroid Glands
Journal: JAMA (1952)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA HomeNew OnlineCurrent IssueFor Authors Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) Podcasts Clinical Reviews Editors' Summary Medical News Author Interviews More JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA journal
P08.55 δ-catenin modulates bevacizumab-induced glioma invasion
Authors: T. Shimizu, K. Kurozumi
Journal: Neuro-Oncology (2017)

Introduction: Data showing that bevacizumab in combination with temozolomide and radiotherapy improved progression-free survival in patients with newly diagnosed glioblastoma have highlighted the potential of bevacizumab as a glioma therapy. However, while bevacizumab potently suppresses angiogenesis, it has also been reported to cause invasive proliferation. This study examined gene expression in glioma cells to analyze the mechanisms of bevacizumab-induced invasion. Material and Methods: Human glioma U87ΔEGFR cells were stereotactically injected into the brains of animals. Bevacizumab was administered intraperitoneally three times per week. At 18 days after tumor implantation, the brains were removed for histopathology observations and mRNA was extracted from the orthotopic U87ΔEGFR glioma cells. Gene expression was assessed by qRT- PCR arrays, which included factors such as adhesion molecules. Expression of genes-of-interest was compared between the bevacizumab and control groups. In addition, the cytotoxicity of bevacizumab and its effect on U87ΔEGFR invasiveness was investigated. Expression of key factors was targeted by siRNA knockdown, and cell invasiveness was analyzed. Results:In vivo, bevacizumab treatment increased glioma cell invasion, despite reducing angiogenesis. qRT-PCR array analysis revealed upregulation of δ-catenin(CTNND2) and several other factors. In vitro, δ-catenin was upregulated by bevacizumab treatment. A low concentration of bevacizumab was not cytotoxic, but tumor cell motility was increased in scratch wound assays. δ-catenin knockdown decreased the invasiveness of U87ΔEGFR cells. Conclusion: The increase in invasive capacity induced by bevacizumab therapy was associated with upregulation of δ-catenin in invasive tumor cells. This finding suggests that δ- catenin is related to tumor invasion and migration.
Use of unrelated marrow grafts compensates for reduced graft-versus- leukemia reactivity after T-cell-depleted allogeneic marrow transplantation for chronic myelogenous leukemia
Authors: MJ Hessner, DJ Endean, JT Casper, MM Horowitz, CA Keever-Taylor, M Roth, N Flomenberg, WR Drobyski
Journal: Blood (1995)
A phase 1b study to assess the safety of PLX3397, a CSF-1 receptor inhibitor, and paclitaxel in patients with advanced solid tumors.
Authors: Neelesh Sharma, Robert Wesolowski, Laura Reebel, Mary Beth Rodal, Alexandra Peck, Brian West, David Alan Karlin, Afshin Dowlati, Mai H. Le, Lisa M Coussens, Hope S. Rugo
Journal: Journal of Clinical Oncology (2014)

TPS3127 Background: Tumor-associated macrophages (TAMs) mediate resistance to chemotherapy and radiation therapy. Macrophages are regulated in part by colony stimulating factor -1 (CSF-1), which signals through the CSF-1 receptor (CSF-1R) expressed predominantly on TAMs. CSF-1 is expressed by several types of malignancies (including breast and prostate cancer, leiomyosarcoma and glioblastoma) and correlates with extent of TAM presence in tumor parenchyma. Preclinical studies demonstrated that tumor exposure to cytotoxic therapies such as paclitaxel, cisplatin or ionizing radiation lead to increased expression of CSF-1, IL-34 (the other ligand for CSF1R), and chemokines regulating TAM recruitments, CCL8/MCP2. This is associated with an increased presence of TAMs in residual tumors, resulting in a tumor immune microenvironment favoring malignant cell proliferation and survival. PLX3397 is an orally available small molecule inhibitor of CSF-1R with IC50 of ~17 nM. In vivo studies in transgenic MMTV-PyMT mice with late-stage mammary cancer and lung metastases treated with paclitaxel and PLX3397 showed: reduced macrophage infiltration of primary tumor tissue; increased presence of tumor infiltrating CD8+ and CD4+ T-lymphocytes; and reduced tumor growth as well as pulmonary metastases compared to paclitaxel alone (DeNardo et al., 2011). These studies provide clinical rationale to study the combination of PLX3397 and paclitaxel in solid tumors. Safety, pharmacokinetics and pharmacodynamics data of single-agent PLX3397 have been previously presented (Anthony et al., 2011). Methods: In this phase Ib trial, patients with advanced solid tumors are treated with weekly paclitaxel and escalating doses of continuous dosing of oral PLX3397 to establish a RP2D of PLX3397. This will be followed by a dose expansion to a total of 15 patients, to further determine safety and preliminary efficacy of this combination. Exploratory objectives include correlating changes in serum CSF-1 levels and identifying novel biomarkers of clinical activity. This study will support further development of the PLX3397/paclitaxel combination in the I-SPY-2 neoadjuvant breast cancer trial. Clinical trial information: NCT01525602.
Biological markers in environmental health research. Committee on Biological Markers of the National Research Council
Authors: Bernard Goldstein, James Gibson, Rogene Henderson, John Hobbie, Philip Landrigan, Donald Mattison, Frederica Perera, Emil Pfitzer, Ellen Silbergeld, Devra Davis, Richard Thomas, Diane Wagener, Frances Peter
Journal: Environmental Health Perspectives (1987)

These groups will evaluate the status of bio- logical markers for specific biological systems: markers of reproductive and developmental effects, with an em- phasis on neurodevelopmental effects; pulmonary system markers of exposure, effects, and susceptibilities; markers of immunological changes as they relate to cancer, including childhood cancer; and markers of ecological toxicity, including markers of ecosystem exposure and altered processes.As part of this project, the Subcommittee on Reproductive and Developmental Toxicology convened a sym- posium January 12-13, 1987, in Washington, DC.In- vited speakers described their research and its possible application to the development and use of biological markers.This issue of Environmental Health Perspec- tives contains the proceedings of that symposium.In this introductory article, the parent committee sets forth in general terms the broad concepts and definitions of biological markers and discusses the use of markers in environmental health research.The committee's deliberations are continuing; the following is offered as an introduction to the symposium and as an indication of
P10.27 Intractable seizures and IDH mutation in low grade gliomas
Authors: Y. Umemura, A. S. Reiner
Journal: Neuro-Oncology (2017)

OBJECTIVES: To assess seizure intractability in isocitrate dehydrogenase (IDH) mutated and wild-type low-grade gliomas (LGG). BACKGROUND: Many LGG harbor IDH mutations which correlate with better prognosis. IDH mutation is associated with tumor associated epilepsy as the mutant IDH reduces α-ketoglutarate to 2-hydroxyglutarate, which is structurally similar to glutamate. Tumor directed therapy can improve seizure control in LGG patients. METHODS: Retrospective review of patients ≥ 18 years old, histologic proven LGG with known IDH mutation status, seizures, and ≥ 2 encounters in neurology clinic at Memorial Sloan Kettering from 10/2005 - 6/2015. Seizure history was followed until histological high-grade transformation or death. Seizures requiring ≥ 2 changes in anti-epileptic drugs were considered intractable. Incidence rates of intractable seizures were calculated using competing risk survival. Results: We reviewed 62 patients (48% women), median age 38 years with low-grade oligodendroglioma (n=25), astrocytoma (n=26), oligoastrocytoma (n=9), and indeterminate glioma (n=2). Sixteen patients did not harbor IDH mutations. IDH mutations observed were IDH1 R132H (n=44) and IDH2 R172K (n=2). Fifty-six patients (90%) had surgical resection. Twenty-nine (47%) patients received chemotherapy and 21 (34%) received radiotherapy: 16 (26%) received both. The 4-year cumulative incidences of intractable seizures were 13.9% (95%CI: 13.3-14.5) in IDH mutated and 8.6% (95%CI: 7.0-10.1) in IDH wild-type groups. At the time of analysis, 91% (42/46) IDH mutated and 50% (8/16) wild-type patients were alive. The overall survival significantly differed (p<0.0001) between IDH mutated group (median not reached, range 3-127+ months) and IDH wild-type (median 51.9, range 6-122+ months). Conclusions: Patients with IDH mutated LGGs are more likely to have intractable seizures compared to patients with IDH wild-type LGGs. IDH wild-type tumors are often treated as high-grade gliomas due to known association with poor prognosis. Given the epileptogenicity of IDH mutation, more aggressive tumor directed therapy may be considered if seizures are intractable.
A Phase 1b Study Investigating Carfilzomib Administered Once Weekly in Combination with Lenalidomide and Dexamethasone in Patients with Multiple Myeloma
Authors: Noa Biran, David S. Siegel, Jesus G. Berdeja, Edward Faber, Lasika Seneviratne, Melissa Alsina, William Bensinger, Amy S. Kimball, Kefei Zhou, Ola Landgren
Journal: Blood (2016)
P12.05 Role of Dkk-3 in the neoplastic progression of meningiomas. Could it represent a new therapeutic target?
Authors: M. Caffo, L. Minutoli, V. Barresi, E. Esposito, M. Campolo, M. Rinaldi, M. Pino, S. M. Cardali, G. Caruso, A. Germanò
Journal: Neuro-Oncology (2017)

Introduction: Meningiomas are the most common tumors of the CNS, where the incidence is around 25% of all primary brain tumors. The optimal treatment is total resection with removal of the dura mater and bone when infiltrated. The histological grading is the most important prognostic factor. Meningiomas may recur after total surgical resection. WHO grade I meningiomas show a recurrence rate between 7-25%. Atypical meningiomas (WHO grade II) between 29-52%. Anaplastic meningiomas (WHO grade III) between 50-94%. From recent studies the Wnt pathway is emerging as involving in growth and progression of meningioma. However, molecular mechanism driving meningioma invasion are not completely clarified. The gene Dkk-3 (Dickkopf WNT signaling pathway inhibitor 3) encodes one of Dickkopf-related protein family of proteins. The activity of this gene is a tumor-suppressive type. The Dkk-3 protein (Dickkopf-related protein 3) is involved in embryonic development through its interactions with the WNT. The REIC/Dkk-3 expression has been shown to be down-regulated in various cancer cell lines. Aim of our study was to study the role of Dkk-3 expression and claudin-5 in meningiomas of different histotype and histological grade. Material and METHODS: We evaluated how meningiomas modify DKK-3 expression in 20 tumors biopsies assessing both immunohistochemistry and western blotting. The tissue samples were embedded in paraffin for immunohistochemical analysis. The expression strength was analyzed and graded based on the positive ratio and intensity of immunoreactivity. The molecular analyses were performed on frozen sections of tumor tissue, by Western Blot method. Statistical analysis was also performed. Results: The expression of Dkk-3 protein and claudin-5 were significantly reduced in meningioma samples compared to controls. These results were confirmed by immunohistochemistry that reveals a slight expression of Dkk-3 protein in meningioma samples examined. It was also highlighted an irregular positivity of claudin-5 protein, on vascular localization. Claudin-5 levels were inversely regulated in meningiomas proteic extract with decreased levels compared to controls. Conclusions: Overexpression of Dkk-3 has been shown to mediate potent anti-tumor effects including reduced cell proliferation, independent growth, invasion and metastasis, and induced cancer cell specific apoptosis.Our preliminary results can suggest that in meningiomas Dkk-3 and Claudin-5 are downregulated. There is an alteration of the BBB. There is a decreasing of apoptotic susceptibility. The immunoreactivity of vascular neoplastic endothelium can suggest a role in angiogenesis. We suggest that the re-establishment of Dkk-3 expression can represent a new potential therapeutic approach in meningiomas treatment also by modulation of blood-brain barrier permeability.