tbuckley/cabot-search huggingface dataset:
Suppression of bone turnover following treatment with zoledronic acid in patients wtih metastatic breast cancer: Duration of effect—The SuBDuE study.
Authors: C. E. Simmons, E. Amir, E. Lee, S. Hogeveen, R. A. Dent, P. J. Goodwin, M. Clemons
Journal: Journal of Clinical Oncology (2010)

TPS121 Background: Bone is the most common site of spread of breast cancer and bone complications cause substantial morbidity to this patient population. A major goal of treatment is to prevent or delay the onset of bone complications. Bisphosphonates (BPs) inhibit osteoclast-mediated bone resorption, and upon diagnosis of bone metastases, current guidelines suggest initiation of therapy with BPs to decrease the likelihood of experiencing one of these complications. BPs are generally well tolerated but side effects such as hypocalcemia, renal impairment and osteonecrosis of the jaw can occur. Recently, attention has focused on biomarkers of bone turnover and their association with the development of bone complications, specifically, breakdown products of type I collagen named serum C-telopeptide (CTX) and bone alkaline phosphatase (BAP). High levels of CTX and BAP have been shown to be associated with increased risk of bone complications. The optimal treatment interval for BP therapy women with bone metastases is unknown, but is empirically administered every 3-4 weeks. The cost of such treatment is high, and the risk of exposing patients to potential serious side effects with uncertain benefit warrants investigation. Here, we propose to determine the duration of suppression of bone turnover in response to zoledronic acid (ZA) in patients with breast cancer metastatic to bone. Methods: Patients with a new diagnosis of bone metastases from breast cancer who have not yet started BP therapy will be enrolled. CTX and BAP measurement will be taken at baseline, and patients will then receive one 4mg IV dose of ZA. CTX and BAP will be measured again at week 4 after infusion, and then once every 2 weeks for a total of 12 weeks, or until the CTX or BAP value rises above the lesser of 50% of the baseline value, or 600 nmol/mmol creatinine, at which point patients will come off study and be treated with standard BP therapy. Pain and quality of life questionnaires will also be completed to ensure that symptoms are not worsened by withholding monthly bisphosphonate therapy. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Novartis
A phase I trial of BKM120 combined with vemurafenib in BRAFV600<sup>E/k</sup> mutant advanced melanoma.
Authors: Alain Patrick Algazi, Christian Posch, Susana Ortiz-Urda, Alyson Cockerill, Pamela N. Munster, Adil Daud
Journal: Journal of Clinical Oncology (2014)

9101 Background: Vemurafenib induces transient objective responses in half of BRAFV600Emutant melanoma patients and a median PFS of 5.3 months. PTEN loss and PI3K activation are common in BRAF mutant metastatic melanoma, and PI3K activation has been implicated as a cause acquired resistance to BRAF inhibitors. This phase I study tested the safety of combining the BRAF inhibitor, vemurafenib, with the PI3K inhibitor, BKM120, in patients with metastatic BRAF mutant melanoma. Methods: Vemurafenib-naïve patients receive a single dose of oral BKM120 (d -7) then vemurafenib twice daily with BKM120 daily (starting on c1d1). Patients with prior progression on vemurafenib received both vemurafenib and BKM120 starting on c1d1 after a vemurafenib washout of at least 14 days. Serial biopsies prior to treatment, on cycle 1 day 15, and at progression were obtained for pharmacodynamics analysis in patients with visible or palpable tumors. 3 + 3 dose escalation was planned starting at vemurafenib 720 mg PO twice daily with BKM120 60 mg daily. Results: Four BRAF inhibitor naïve patients andfour BRAF inhibitor refractory patients were treated on study with vemurafenib 720 mg PO bid and BKM120 60 mg PO daily. Two BRAF inhibitor naïve patient experienced DLTs (myalgias, DRESS syndrome). One vemurafenib naïve patient was inevaluable due to non-compliance and had minimal exposure to study drug. Two of four BRAF inhibitor refractory patients experienced DLTs (myalgias, febrile neutropenia). One BRAF inhibitor-resistant patient had a mixed response to treatment with a 35.9% reduction in target lesions and two new small subcutaneous lesions. Conclusions: Combination therapy with vemurafenib and BKM120 in BRAF-V600E/K mutant melanoma was not tolerated in either BRAF inhibitor naïve or BRAF inhibitor resistant patients. Clinical trial information: NCT01512251.
Health-related quality of life in unresectable hepatocellular carcinoma (HCC) in patients treated with TACE or 90-Yttrium
Authors: J. L. Steel, M. Olek, B. I. Carr
Journal: Journal of Clinical Oncology (2005)

8149 Background: Nonsurgical treatment options for unresectable HCC are limited and have modest survival benefits. As a result, health related quality of life (HRQL) has become essential when testing new therapies. The aims of the present study were to test differences in HRQL in HCC patients (pts) treated with 90-Yttrium or transarterial chemoembolization (TACE). Methods: In this prospective, nonrandomized study, 127 pts with biopsy-proven, unresectable HCC, and a prognosis greater than 3 months (mos), were recruited for participation. 79 pts were treated with TACE and 48 pts with 90-Yttrium. HRQL was assessed using the Functional Assessment of Cancer Therapy-Hepatobiliary at diagnosis, 3-, 6-, and 12 mos or until death. Survival was measured in months from diagnosis till death. Results: Using Analyses of Variance (ANOVA), pts referred for treatment with TACE had significantly larger mean tumor size, vascular invasion, and higher bilirubin, WBC, GGTP, and PT at baseline. Using repeated measures Analysis of Covariance (ANCOVA), covarying for significant differences in disease-specific variables at diagnosis, pts treated with 90-Yttrium reported a better functional well-being [F(1,40)=5.7, p=0.02] and overall quality of life [F(1,38)=4.6, p=0.04] at 3-mos follow-up. Pts in both treatment groups reported significant improvement in emotional well-being at 3-mos follow-up [F(1,20)=5.4, p=0.03]. No significant differences in HRQL were observed at 6- or 12-mos follow-up. Conclusions: Treatment of unresectable HCC with Yttrium-90 resulted in better functional well-being and overall HRQL at 3-mos follow-up compared to pts treated with TACE, while covarying for disease-specific differences at diagnosis. It is likely that no differences in HRQL were observed at 6- and 12-months follow-up secondary the high rates of death in pts treated with TACE, compared to 90-Yttrium, at 6-mos (60% vs 40%) and 12-mos (85% vs 65%) and as a result, high levels of attrition in assessment of HRQL were observed due to severe illness and death at 6-mos (N=10 vs 16) and 12-mos follow-up (N=2 vs 7). A randomized control trial assessing HRQL and survival benefits of 90-Yttrium is warranted. No significant financial relationships to disclose.
WNK1 kinase balances T cell adhesion versus migration in vivo
Authors: Robert Köchl, Flavian Thelen, Lesley Vanes, Tiago F Brazão, Kathryn Fountain, Jian Xie, Chou-Long Huang, Ruth Lyck, Jens V Stein, Victor L J Tybulewicz
Journal: Nature Immunology (2016)
Ethyl cellulose nanocarriers and nanocrystals differentially deliver dexamethasone into intact, tape-stripped or sodium lauryl sulfate-exposed ex vivo human skin - assessment by intradermal microdialysis and extraction from the different skin layers
Authors: Nadine Döge, Stefan Hönzke, Fabian Schumacher, Benjamin Balzus, Miriam Colombo, Sabrina Hadam, Fiorenza Rancan, Ulrike Blume-Peytavi, Monika Schäfer-Korting, Anke Schindler, Eckart Rühl, Per Stahl Skov, Martin K. Church, Sarah Hedtrich, Burkhard Kleuser, Roland Bodmeier, Annika Vogt
Journal: Journal of Controlled Release (2016)
Search for familial clustering of cancer in monoclonal gammopathy of unknown significance
Authors: K Hemminki, A Försti, J Sundquist, X Li
Journal: Blood Cancer Journal (2016)

Monoclonal gammopathy of undetermined significance (MGUS) is an asymptomatic pre-malignant clonal condition which is diagnosed, often coincidentally, through high levels of immunoglobulin derived serum M-protein produced by a plasma cell clone.1, 2 The prevalence of MGUS increases with age and it is some 3% at age 60 years and reaching close to 10% at age over 80 years.3 MGUS is a precursor condition for multiple myeloma (MM) and lymphoplasmacytic lymphoma/Waldenstrom macroglobulinema (LPL/WM). Both MGUS and MM show familial clustering among and between these diseases, suggesting that they share genetic susceptibility.4, 5 In addition, relatives of MGUS patients have an increased risk of other malignancies of the B-cell lineages, LPL/WM and chronic lymphocytic leukemia (CLL).5 No increases were observed in other B-cell or other hematological neoplasms. However, borderline increases of bladder cancers (relative risk 1.4) and spinal cord tumors (3.0) were reported.6 Many of these studies originated from Sweden where 4458 persons with MGUS were identified from 1966 to 2005.5
Reductions in γ-GIobin mRNA Levels Restricted to the Cytoplasm of 5-Fluorouridine Treated K-562 Human Erythroleukemia Cells
Authors: R Heimer, A C Sartorelli
Journal: Cancer Communications (1990)

RNA synthesis in K-562 human erythroleukemia cells was markedly curtailed by exposure to the uridine analogue 5-fluorouridine (FUrd). The inhibition of ribosomal RNA synthesis was accompanied by rapid declines in the steady-state levels of several, but not all, mRNAs, including gamma-globin mRNA. In this report, we demonstrate that gamma-globin mRNA species were decreased by as much as 40% within 2 hr of exposure to micromolar concentrations of FUrd. The decline in gamma-globin mRNA occurred at a rate that outstripped the normal rate of degradation of this mRNA by a factor of 25. The decline in cytoplasmic mRNA was not mirrored in the nucleus; northern blotting revealed that pre-mRNA levels were not reduced. Nuclease protection analyses of precursors from FUrd treated and untreated control cells did not reveal any qualitative differences. Thus, the decrease was not accounted for by drug-induced inhibition of new gamma-globin mRNA synthesis or misincorporation but must have been due to an FUrd-induced increase in gamma-globin mRNA degradation. Drug-induced instability of RNA was not a generalized feature of FUrd exposure, since neither beta-actin mRNA nor cytoplasmic rRNA, whose stabilities in untreated cells are similar to that of gamma-globin mRNA, were affected. Furthermore, the instability of gamma-globin mRNA did not decrease globin protein levels, presumably because the stability of the protein was not altered. The mechanism by which specific increased degradation of gamma-globin mRNA occurred is unknown, but it may have been due to the activation of cytoplasmic endonuclease.
Quadruple-Negative GIST Is a Sentinel for Unrecognized Neurofibromatosis Type 1 Syndrome
Authors: Daniela Gasparotto, Sabrina Rossi, Maurizio Polano, Elena Tamborini, Erica Lorenzetto, Marta Sbaraglia, Alessia Mondello, Marco Massani, Stefano Lamon, Raffaella Bracci, Alessandra Mandolesi, Elisabetta Frate, Franco Stanzial, Jerin Agaj, Guido Mazzoleni, Silvana Pilotti, Alessandro Gronchi, Angelo Paolo Dei Tos, Roberta Maestro
Journal: Clinical Cancer Research (2016)

The majority of gastrointestinal stromal tumors (GIST) are driven by KIT, PDGFRA, or, less commonly, BRAF mutations, and SDH gene inactivation is involved in a limited fraction of gastric lesions. However, about 10% of GISTs are devoid of any of such alterations and are poorly responsive to standard treatments. This study aims to shed light on the molecular drivers of quadruple-negative GISTs.Twenty-two sporadic quadruple-negative GISTs with no prior association with Neurofibromatosis Type 1 syndrome were molecularly profiled for a panel of genes belonging to tyrosine kinase pathways or previously implicated in GISTs. For comparison purposes, 24 GISTs carrying KIT, PDGFRA, or SDH gene mutations were also analyzed. Molecular findings were correlated to clinicopathologic features.Most quadruple-negative GISTs featured intestinal localization, with a female predilection. About 60% (13/22) of quadruple-negative tumors carried NF1 pathogenic mutations, often associated with biallelic inactivation. The analysis of normal tissues, available in 11 cases, indicated the constitutional nature of the NF1 mutation in 7 of 11 cases, unveiling an unrecognized Neurofibromatosis Type 1 syndromic condition. Multifocality and a multinodular pattern of growth were common findings in NF1-mutated quadruple-negative GISTs.NF1 gene mutations are frequent in quadruple-negative GISTs and are often constitutional, indicating that a significant fraction of patients with apparently sporadic quadruple-negative GISTs are affected by unrecognized Neurofibromatosis Type 1 syndrome. Hence, a diagnosis of quadruple-negative GIST, especially if multifocal or with a multinodular growth pattern and a nongastric location, should alert the clinician to a possible Neurofibromatosis Type 1 syndromic condition. Clin Cancer Res; 23(1); 273-82. ©2016 AACR.
10 year survival after breast-conserving surgery plus radiotherapy compared with mastectomy in early breast cancer in the Netherlands: a population-based study
Authors: Marissa C van Maaren, Linda de Munck, Geertruida H de Bock, Jan J Jobsen, Thijs van Dalen, Sabine C Linn, Philip Poortmans, Luc J A Strobbe, Sabine Siesling
Journal: The Lancet Oncology (2016)
Idiopathic pulmonary fibrosis: another step in understanding the burden of this disease
Authors: John Hutchinson
Journal: European Respiratory Journal (2016)

The past 25 years have seen a steady increase in the number of studies examining the incidence of idiopathic pulmonary fibrosis (IPF) worldwide [1, 2]. In general, early studies tended to involve clinicians collating cases from their local area [3, 4] or asking interested colleagues to contribute to registries [5, 6], whereas later studies have made use of large databases collected for clinical care or administrative reasons [7–10]. These later studies boasted far greater numbers, though with some concern about the validity of the cases, the reliability of clinical coding and generalisability to the wider population. A recent systematic review estimated the incidence of IPF to be 3–9 cases per 100 000 in Europe and North America, although this included a heterogenous mix of studies with different case definitions and populations, and several less reliable estimates had to be excluded [2]. Therefore, identifying the true incidence of IPF remains a challenge [11]. Idiopathic pulmonary fibrosis: good-quality Canadian study with high incidence adds to the epidemiological jigsaw <http://ow.ly/gArO300hdSx> With thanks to Richard Hubbard (University of Nottingham, Nottingham, UK) for his comments on this work.
First Line Treatment with the R-VAD+C Regimen Followed by ASCT for Patients under 65 with a Mantle Cell Lymphoma (MCL). From the GOELAMS Group.
Authors: Remy Gressin, Sylvie Caulet Maugendre, Ghandi Damaj, Noel-Jean Milpied, Delphine Senecal, Mathilde Hunault Berger, Abdrrazak El Yamani, Herve Maisonneuve, Olivier Tournilhac, Philippe Solal Celigny, Philippe Quitet, Pierre Feugier, Cachera Choufy, Jean Fontan, Martine Escoffre Barbe, Jerome Cornillon, Annie Lemevel, Claude Martin, Philippe Moreau, Philippe Colombat
Journal: Blood (2006)
Tissue Engineering and Repair of the Damaged Heart490Transplantation of adipose mesenchymal cells overexpressing telomerase and myocardin preserved cardiac function and promoted tissue repair in murine myocardial infarction491Targeting the hippo signalling pathway to enhance the therapeutic potential of iPS-derived cardiomyocytes492Porous silicon nanoneedles for localised in situ gene transfer for cardiac therapy
Authors: R Madonna, A Robertson, P Campagnolo, D Taylor, P Lyubomir, AS Gobin, YJ Geng, P Ferdinandy, R De Caterina, M Cabriera, E Perin, JT Willerson, T Mohammed, E Cartwright, D Oceandy, C Chiappini, V Leonardo, M Becce, F Perbellini, C Terracciano, N Smart, SA Harding, MM Stevens
Journal: Cardiovascular Research (2016)

Rationale:The success of stem cell therapies for acute myocardial infarction (AMI) has been hampered by poor cellular engraftment and survival, which may be partly due to the harmful microenvironment within ischemic myocardium.However, it may be possible to promote survival and cardiomyogenesis of transplanted adult mesenchymal cells by inducing the overexpression of myocardin (MYOCD), a promyogenic transcription factor with anti-apoptotic activity, and telomerase reverse transcriptase (TERT), an antisenescence protein.Objectives: We used a murine model of AMI to assess the efficacy of transplanted adipose tissuederived mesenchymal stromal cells (AT-MSCs) engineered to overexpress MYOCD and TERT.Methods: Twelve-month-old C57BL/6 mice underwent coronary artery ligation to induce AMI and were randomized into 3 treatment groups: phosphate-buffered saline (PBS) (20mL; n=7), mocktransduced AT-MSCs (2.5x105 cells in 20mL; n=5), or AT-MSCs overexpressing TERT and MYOCD (2.5x105 cells in 20mL; n=7).Sham-operated mice (n=7) were used as controls.The AT-MSCs were obtained from 12-month-old male green fluorescent protein-transgenic C57BL/6 mice and transduced with lentiviral vectors encoding TERT and MYOCD.Results: When transplanted into the infarcted hearts of C57BL/6 mice, AT-MSCs overexpressing TERT and MYOCD preserved myocardial fractional shortening (Figure A), increased arteriogenesis and cell engraftment and decreased fibrosis formation (Figure B), compared with PBS alone or mocktransduced AT-MSCs.These effects were accompanied by increased numbers of Ki-67+ cells and c-kit+ cells (Figure B) and enhanced expression of cardiac actin, GATA4, Nkx2.5, and myocardin A (Figure C).Conclusions: Delivering TERT and MYOCD genes into AT-MSCs before transplantation promotes activation of the cardiomyogenic pathway, vasculogenesis, and stem cell survival in a murine model of AMI.
Early Intervention in Lung Cancers With Rapid Plasma Genotyping for<i>EGFR</i>and<i>KRAS</i>Mutations—Reply
Authors: Adrian G. Sacher, Ryan S. Alden, Geoffrey R. Oxnard
Journal: JAMA Oncology (2016)

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Mesenchymal Stem Cells, Fibroblasts and Pericytes: Different Functional States of the Same Cell?.
Authors: Dimas T. Covas, Rodrigo A. Penepucci, Aparecida M. Fontes, Maristela Orellana, Karen L. Prata, Luciano Neder, Luiz C. Perez, Rita C. Carrara, Amelia G. Araujo, Marco A. Zago
Journal: Blood (2005)
Case 47-1974
Authors: Richard C. Cabot, Robert E. Scully, Betty U. McNeely, Lloyd Axelrod, Austin L. Vickery
Journal: New England Journal of Medicine (1974)

Presentation of CaseA 60-year-old woman was admitted to the hospital because of chronic diarrhea and peptic ulcers.She was well until 20 years previously, when ureteral colic developed, and medical evaluation revealed hypercalcemia. Parathyroid exploration disclosed enlargement of all four glands that was originally interpreted as due to adenomas but was reinterpreted as primary chief-cell hyperplasia; three parathyroid glands and half of a fourth gland were resected (Fig. 1). Two years later, on return from a trip to Peru and Mexico, diarrhea developed. Physical and laboratory examination disclosed no abnormality, and treatment for amebiasis gave no relief. She continued . . .
Mechanistic Insights Into Ventricular Arrhythmias Associated With Sickle Cell Disease: Role Of Abnormal Repolarization
Authors: I D Greener, C A Rutledge, T Abassi, K Yadav, A B Desai, M Oberoi, P Chunduru, D P Parikh, J GN Garcia, Victor R. Gordeuk, Cheryl A. Hillery, S c Dudley, Roberto F Machado, A A Desai
Journal: Blood (2013)
PD2-2-2: Identification of differentially expressed genes in the course of lung adenocarcinoma development.
Authors: Yoichi Anami, Tadashi Ishiyama, Chigusa Okubo, Junko Kano, Tatsuo Iijima, Yukio Morishita, Masayuki Noguchi
Journal: Journal of Thoracic Oncology (2007)
Combination of Imatinib Mesylate and AKT Inhibitor Provides Synergistic Effects in Preclinical Study of Gastrointestinal Stromal Tumor
Authors: Phillip Zook, Harsh B. Pathak, Martin G. Belinsky, Lawrence Gersz, Karthik Devarajan, Yan Zhou, Andrew K. Godwin, Margaret von Mehren, Lori Rink
Journal: Clinical Cancer Research (2016)

Gastrointestinal stromal tumors (GIST) generally harbor activating mutations in the receptor tyrosine kinase KIT or in the related platelet-derived growth factor receptor alpha (PDGFRA). GIST treated with imatinib mesylate or second-line therapies that target mutant forms of these receptors generally escape disease control and progress over time. Inhibiting additional molecular targets may provide more substantial disease control. Recent studies have implicated the PI3K/AKT pathway in the survival of imatinib mesylate-resistant GIST cell lines and tumors.Here, we performed in vitro and in vivo studies evaluating the novel combination of imatinib mesylate with the AKT inhibitor MK-2206 in GIST. Whole-transcriptome sequencing (WTS) of xenografts was performed to explore the molecular aspects of tumor response to this novel combination and to potentially identify additional therapeutic targets in GIST.This drug combination demonstrated significant synergistic effects in a panel of imatinib mesylate-sensitive and -resistant GIST cell lines. Furthermore, combination therapy provided significantly greater efficacy, as measured by tumor response and animal survival, in imatinib mesylate-sensitive GIST xenografts as compared with treatment with imatinib mesylate or MK-2206 alone. WTS implicated two neural genes, brain expressed X-linked 1 and neuronal pentraxin I, whose expression was significantly upregulated in combination-treated tumors compared with tumors treated with the two monotherapies.These studies provide strong preclinical justification for combining imatinib mesylate with an AKT inhibitor as a front-line therapy in GIST. In addition, the WTS implicated the BCL-2/BAX/BAD apoptotic pathway as a potential mechanism for this enhanced combination effect. Clin Cancer Res; 23(1); 171-80. ©2016 AACR.