tbuckley/cabot-search huggingface dataset:
Safety and efficacy of lapatinib (L)-based therapy in heavily pretreated HER2+ metastatic breast cancer (MBC) patients (pts): A single institution experience.
Authors: J. M. Sepúlveda, G. De Velasco, L. Manso, I. Ghanem, E. M. Ciruelos Gil, E. Vega, C. Mendiola, H. Cortes-Funes
Journal: Journal of Clinical Oncology (2011)

e11008 Background: Lapatinib (L) plus capecitabine is an FDA-approved regimen for patients with HER2+ MBC who have previously received trastuzumab. The aim of this study was to evaluate the efficacy and safety of L in different combinations for the treatment of advanced breast cancer. Methods: Retrospective analysis was undertaken to assess activity of L therapy for pts treated in our institution from July 2007 to September 2010. Pts with HER2 3+ staining by IHC or gene amplification by FISH who were treated with L Expanded Access or Compassionate Program were admitted. Results: 39 pts were evaluated. Median age: 57 years. Thirty-six pts (92.3%) were ECOG 0-1. Median previous chemotherapy lines for advanced disease were 3 (range: 1-12). 32 pts (82%) had received anthracyclines and 34 (89,5%) pts had received trastuzumab in a metastatic setting. 31 pts (79%) received lapatinib-capecitabine combination (1250 mg/d-2500 mg/m2/d), 5 pts (12%) trastuzumab-lapatinib (2 mg/kg weekly-1000mg/d), and 3 pts (7.6%) letrozole-lapatinib treatment (2.5mg/d +1500mg/d). After 15.2 months of follow-up (min 3- max 48.5), the median number of cycles was 5 (range 1-20). We observed 3 complete responses (CR: 7%), 12 partial responses (PR: 33 %), 16 stable disease (SD: 44%), and 5 patients with progressive disease. Overall clinical benefit rate (CR+PR+ SD) was 86% (31 pts). Time to Progression (TTP) was 5.6 months (95% CI: 4.2-6.9). Median overall survival (OS) was 24 months (95% CI: 14.3-33.7) The most common toxicities were: grade 1-2 diarrhea (55%), grade 2 hand-food syndrome (44%) and grade 1-2 asthenia (67%). No grade 4 diarrhea or grade 3-4 hematological events were recorded. No cardiac toxicity events were reported. After progression, 46% of the patients continued receiving lapatinib in combination with chemotherapy or biological treatment. Conclusions: Lapatinib-based therapy seems to be active in heavily pretreated HER-2+ MBC pts, with an 86% clinical benefit rate. Treatment is generally well tolerated, with acceptable grade 1-2 adverse events. No serious cardiac events have been observed. These data are similar to those published in the EGF100151 trial.
53. A Neuro-Specific Gene Therapy Approach to Treat Cognitive Impairment in Down Syndrome by RNA Interference
Authors: Andrea Contestabile, Martina Parrini, Shovan Naskar, Micol Alberti, Anna Rocchi, Marina Nanni, Giuseppe Ronzitti, Federico Mingozzi, Laura Cancedda
Journal: Molecular Therapy (2016)

Down syndrome (DS) is a genetic disorder caused by the presence of a third copy of chromosome 21. DS affects multiple organs, resulting in characteristic facial features, muscular hypotonia, heart defects, brain development impairment, and varying degrees of intellectual disability. Trisomic mouse models of DS reproduce the main cognitive disabilities of the human syndrome. In particular, DS mice show structural and functional synaptic impairment as well as learning and memory deficits, largely determined by altered GABAergic transmission through chloride-permeable GABAa receptors (GABAaR). In particular, we have recently found that intracellular chloride accumulation shifts GABAAR-mediated signaling from inhibitory to excitatory in the adult brain of the Ts65Dn mouse model of DS. Accordingly, intracellular chloride accumulation was paralleled by increased expression of the chloride importer NKCC1 (Na-K-Cl cotransporter) in the brains of both trisomic mice and DS patients. Our findings on NKCC1 as a pivotal molecular target for the rescue of cognitive deficits in DS opens the possibility of a gene therapy approach to treat the disease. Here, to normalize NKCC1 expression and rescue synaptic dysfunctions as well as cognitive deficits in Ts65Dn mice we have developed and characterized a knock-down approach to normalize NKCC1 activity. Reducing the expression of the chloride importer NKCC1 by RNA interference restored GABAAR-mediated inhibition and also rescued the structural dendritic deficits found in trisomic neurons in vitro. Most importantly, focal administration of an AAV expressing a silencing RNA under the transcriptional control of a neuron-specific promoter in the hippocampus of Ts65Dn animals mediated NKCC1 knockdown in vivo and rescued behavioral performance on different learning and memory tests at levels undistinguishable from those of WT mice. Our findings demonstrate that NKCC1 overexpression drives excitatory GABAAR signaling in trisomic cells, leading to structural neuronal abnormalities and behavioral impairments in DS mice. Moreover, our study identifies a new gene therapy target for treatments aimed at rescuing cognitive disabilities in individuals with DS.
Low-Dose Radiotherapy in Patients with Non Hodgkin Lymphoma
Authors: Dulcineia Pereira, Sergio Pereira Chacim, Andre Soares, Edgar Mesquita, Ana Espirito-Santo, Ilidia Moreira, Nelson Domingues, Isabel Oliveira, Luísa Viterbo, Margarida Marques, Rui Henrique, Carla Castro, Angelo Martins, Angelo Oliveira, Jose Mario Mariz
Journal: Blood (2012)
428. Generation of DNA Plasmid-Encoded Neutralizing Monoclonal Antibodies In Vivo
Authors: Seleeke Flingai, Emily Plummer, Ami Patel, Janess Mendoza, Yang Wang, Keith Riemann, Mark Klempner, Kate Broderick, Niranjan Sardesai, Kar Muthumani, David Weiner
Journal: Molecular Therapy (2016)

The development of vaccines against arthropod-borne infectious diseases has been wrought with difficulties. Recent advances in human antibody isolation have uncovered neutralizing monoclonal antibodies (mAbs) that are capable of providing protection against pathogen challenge in various animal models. Yet generating and delivering biologically-relevant levels of such antibodies using conventional monoclonal antibody methodology is impractical, often requiring huge expenses and repeated administrations for clinical benefit. Creating new methods of delivering monoclonal antibodies could drastically tip the scale in the fight against a number of devastating pathogens. Here, we describe an approach to delivering neutralizing mAbs in vivo using DNA plasmid-mediated antibody gene transfer. This approach, which we term DNA mAb (DMAb) delivery, generates biologically relevant levels of mAbs after a single intramuscular injection of antibody-encoding DNA followed by in vivo electroporation (EP). First, we demonstrate the ability of DMAb technology to deliver cross-reactive neutralizing antibodies against DENV into the host circulation. Since this approach allows for genetic tailoring of the exact features of the desired antibody, we incorporated Fc region modifications to a naturally occurring human anti-DENV neutralizing antibody to enhance antibody function in vivo. We show that intramuscular delivery in mice of pDVSF-3 LALA, which encodes a human anti-DENV1-3 IgG1 neutralizing antibody modified with a mutation that abrogates FcγR binding, produces anti-DENV antisera capable of binding and neutralizing DENV1-3. Importantly, mice receiving pDVSF-3 LALA, but not the unmodified pDVSF-3 WT, were protected from both virus-only disease and antibody-enhanced lethal disease. Using a similar, targeted genetic approach to antibody modifications, we also show that DMAbs encoding antibodies against Borrelia burgdorferi (the causative agent of Lyme disease) can undergo extensive amino acid modifications that substantially increase in vivo mAb production levels compared to wild-type DMAb sequences. These data illustrate a subset of the functional optimizations made possible with the DMAb platform. This work was supported by grants funded to DBW through the National Institutes of Health, the DARPA-PROTECT award, and Inovio Pharmaceuticals Inc.
Long Term Remission in Follicular Lymphoma (FL) and Mantle Cell Lymphoma (MCL) with Rituximab Consolidation after High-Dose Chemotherapy and Autologous Stem Cell Transplantation: Extended Follow-Up of a Multicenter Phase II Study.
Authors: Wolfram Brugger, Judith Hirsch, Roland Repp, Gruenebach Frank, Schlimok Guenther, Vogel Wichard, Manz Markus, Brossart Peter, Martin Kaufmann, Arnold Ganser, Karl Fehnle, Martin Gramatzki, Lothar Kanz
Journal: Blood (2005)
Consolidation with Alemtuzumab in First Remission Induces Pronounced MRD Reduction and Clinical Remissions - Update on a Randomized Phase III Trial of the German CLL Study Group (GCLLSG).
Authors: Matthias Ritgen, C. Schweighofer, Günther Fingerle-Rowson, Barbara Eichhorst, Raimunde Busch, Stephan Stilgenbauer, Hartmut Döhner, Michael Kneba, Michael Hallek, Clemens M. Wendtner
Journal: Blood (2004)
Machine-learning prediction of cancer survival: A prospective study examining the impact of combining clinical and genomic data.
Authors: David M. Ashley, Sunil Gupta, Truyen Tran, Luo Wei, Paula K Lorgelly, David Morgan Thomas, Stephen B. Fox, Svetha Venkatesh
Journal: Journal of Clinical Oncology (2015)

6521 Background: Accurate prediction of survival in patients with cancer remains a challenge due to the ever-increasing heterogeneity and complexity of cancer at the molecular level, in treatment options and patient populations. Data mining using machine learning techniques (MLT) may enhance our ability to deal with such complexity. The current work tests the hypothesis that by combining digital data contained in a rich purpose-built epidemiological and clinical cancer registry with patient specific genomic data, using MLT, we could enhance our previously published methods in predicting clinical outcomes. Methods: Cancer 2015 is a large-scale prospective epidemiological, clinical and molecular cohort study in which tumors underwent mutational analysis from using the Illumina TruSeqAmplicon 48 gene Cancer Panel. Data from 1002 patients were used to model survival at 12 months. Machine-learning prediction using comprehensive data that included demography, tumor stream information, co-morbidities, past history and patient presentation details was then compared using the Area Under the Curve (AUC) with a model combining the same data and the mutational status results for each tumor. Results: Of the 48 genes examined mutations in only 4 genes present in patient samples significantly contributed as independent risk factors in predictions of survival, these included: FGFR2 (odds ratio = 4.1304), RB1 (odds ratio = 2.7295), BRAF (odds ratio = 2.2513), KIT (odds ratio = 2.2464 ). However, when considering this entire population the addition of all genomics data did not significantly improve 12 month prediction of survival. Combined clinical and genomics data model yielded an AUC of 0.8502 (0.8468-0.8536) whilst the clinical data model alone yielded an AUC of 0.8464(0.8429- 0.8498). Conclusions: Whilst the presence of some specific mutations contributed to the prediction of survival, overall genomic information in this group did not enhance survival prediction by MLT beyond that of clinical and epidemiological data alone.
Human Papillomavirus Regulates HER3 Expression in Head and Neck Cancer: Implications for Targeted HER3 Therapy in HPV+ Patients
Authors: Toni M. Brand, Stefan Hartmann, Neil E. Bhola, Noah D. Peyser, Hua Li, Yan Zeng, Erin Isaacson Wechsler, Max V. Ranall, Sourav Bandyopadhyay, Umamaheswar Duvvuri, Theresa M. LaVallee, Richard C.K. Jordan, Daniel E. Johnson, Jennifer R. Grandis
Journal: Clinical Cancer Research (2016)

Purpose: Human papillomavirus (HPV) 16 plays an etiologic role in a growing subset of head and neck squamous cell carcinomas (HNSCC), where viral expression of the E6 and E7 oncoproteins is necessary for tumor growth and maintenance. Although patients with HPV+ tumors have a more favorable prognosis, there are currently no HPV-selective therapies. Recent studies identified differential receptor tyrosine kinase (RTK) profiles in HPV+ versus HPV- tumors. One such RTK, HER3, is overexpressed and interacts with phosphoinositide-3-kinase (PI3K) in HPV+ tumors. Therefore, we investigated the role of HPV oncoproteins in regulating HER3-mediated signaling and determined whether HER3 could be a molecular target in HPV+ HNSCC.Experimental Design: HER3 was investigated as a molecular target in HPV+ HNSCC using established cell lines, patient-derived xenografts (PDX), and human tumor specimens. A mechanistic link between HPV and HER3 was examined by augmenting E6 and E7 expression levels in HNSCC cell lines. The dependency of HPV+ and HPV- HNSCC models on HER3 was evaluated with anti-HER3 siRNAs and the clinical stage anti-HER3 monoclonal antibody KTN3379.Results: HER3 was overexpressed in HPV+ HNSCC, where it was associated with worse overall survival in patients with pharyngeal cancer. Further investigation indicated that E6 and E7 regulated HER3 protein expression and downstream PI3K pathway signaling. Targeting HER3 with siRNAs or KTN3379 significantly inhibited the growth of HPV+ cell lines and PDXs.Conclusions: This study uncovers a direct relationship between HPV infection and HER3 in HNSCC and provides a rationale for the clinical evaluation of targeted HER3 therapy for the treatment of HPV+ patients. Clin Cancer Res; 23(12); 3072-83. ©2016 AACR.
Presence of anticitrullinated protein antibodies in a large population-based cohort from the Netherlands
Authors: A van Zanten, S Arends, C Roozendaal, P C Limburg, F Maas, L A Trouw, R E M Toes, T W J Huizinga, H Bootsma, E Brouwer
Journal: Annals of the Rheumatic Diseases (2017)

To determine the prevalence of anticitrullinated protein antibodies (ACPAs) and their association with known rheumatoid arthritis (RA) risk factors in the general population.Lifelines is a multidisciplinary prospective population-based cohort study in the Netherlands. Cross-sectional data from 40 136 participants were used. The detection of ACPA was performed by measuring anti-CCP2 on the Phadia-250 analyser with levels ≥6.2 U/mL considered positive. An extensive questionnaire was taken on demographic and clinical information, including smoking, periodontal health and early symptoms of musculoskeletal disorders. RA was defined by a combination of self-reported RA, medication use for the indication of rheumatism and visiting a medical specialist within the last year.Of the total 40 136 unselected individuals, 401 (1.0%) had ACPA level ≥6.2 U/mL. ACPA positivity was significantly associated with older age, female gender, smoking, joint complaints, RA and first degree relatives with rheumatism. Of the ACPA-positive participants, 22.4% had RA (15.2% had defined RA according to our criteria and 7.2% self-reported RA only). In participants without RA, 311 (0.8%) were ACPA-positive. In the non-RA group, older age, smoking and joint complaints remained significantly more frequently present in ACPA-positive compared with ACPA-negative participants.In this large population-based study, the prevalence of ACPA levels ≥6.2 U/mL was 1.0% for the total group and 0.8% when excluding patients with RA. Older age, smoking and joint complaints were more frequently present in ACPA-positive Lifelines participants. To our knowledge, this study is the largest study to date on ACPA positivity in the general, mostly Caucasian population.
A French prospective pilot study for identifying dihydropyrimidine dehydrogenase (DPD) deficiency in breast cancer patients (pts) receiving capecitabine (cap).
Authors: Marie-Christine Etienne-Grimaldi, Jean-Marc Ferrero, Fabienne Thomas, Christine Bobin-Dubigeon, Jean Louis Merlin, Frederic Pinguet, Christophe Ferrand, Jean-Christophe Boyer, Gilles Romieu, Thomas Bachelot, Xavier Pivot, Veronique Dieras, Remy Largillier, Mireille Mousseau, Anthony Goncalves, Henri Hubert Roche, Jacques Bonneterre, Beatrice De Clercq, Gerard Milano
Journal: Journal of Clinical Oncology (2013)

e13519 Background: For fluoropyrimidines, and especially cap, Health Authorities point out that DPD deficiency confers a significant risk of major toxicity (tox). Identification of at-risk pts is thus relevant. This multicentric prospective study of the French GPCO group (Groupe de Pharmacologie Clinique Oncologique, Unicancer) evaluated the sensitivity, specificity and predictive values of DPD phenotyping and genotyping for predicting severe cap-related tox in metastatic breast cancer pts. Methods: 303 pts were included (15 institutions), 88% received cap as monotherapy, 28% were treated as first line (mean dose at 1 st cycle 1957 mg/m 2 /d). Pre-treatment dihydrouracil (UH2) and uracil (U) plasma concentrations were measured in 286 pts (HPLC assay). DPD genotyping (IVS14+1G&gt;A, 2846A&gt;T, 1679T&gt;G, 464T&gt;A) was done on 281 pts. Severe tox (G3-4 CTCAE v3 criteria) was measured over cycles 1-2. Results: Grade 3-4 tox (diarrhea, vomiting, hematoxicity, hand-foot syndrome) was observed in 19.6% of pts (one toxic death). A marked trend for higher U (median 12.7 vs 10.2 ng/ml, p=0.014) and UH2 (median 110 vs 93 ng/ml, p=0.011) concentrations was observed in pts developing severe tox vs those who didn’t. However, ROC curves showed that these differences were too small for use as reliable tox predictors. The distribution of UH2/U ratio was similar between pts with or without tox (median 9.1 vs 9.6, respectively, p=0.80). The patient with toxic death had a UH2/U ratio of 6.5 and U concentration of 17 ng/ml. Among the 7 pts with a DPD mutation (3 pts IVS14+1, 3 pts 2846A&gt;T, one 1679T&gt;G, all heterozygous), 5 developed severe tox (including toxic death, 2846A&gt;T), one did not, and the last one was not documented. Relative risk for developing severe tox was 4.60 in mut pts vs wt pts (95%CI 2.95-7.16, p=0.001); positive and negative predictive values were 83.3% and 81.9%, respectively; specificity was 99.5% and sensitivity was 9.8%. Conclusions: These data point out that breast cancer pts harbouring a DPD variant allele are candidate to develop severe, up to lethal, cap-related tox. In contrast, pre-treatment UH2/U ratio and U measurements are not reliable predictors of cap tox. Clinical trial information: Eudract 2008-004136-20.
TNFR2 Is Expressed Preferentially By Late Differentiated CD8 T-Cells and Can be Triggered By TNFR2-Specific Ligand to Induce Cell Death of Recently Activated Antigen-Specific T Cells: A Possible Role of TNFR2 in T-Cell Deflation
Authors: Mohammad Raeiszadeh, Matthew Verney, Charles Craddock, Harald Wajant, Paul Moss, Frederick Chen
Journal: Blood (2014)
Key mechanisms underlying cancer stem cell overpopulation in colon carcinomas: Implications for anticancer therapy.
Authors: B. M. Boman, T. Zhang, J. Palazzo
Journal: Journal of Clinical Oncology (2011)

e13548 Background: Since cancer stem cell (SC) overpopulation appears to drive tumor growth in the colon (Boman and Huang, JCO 26:2828-38, 2008), effective or even curative treatments will likely require targeting mechanisms that underlie SC overpopulation. To identify such mechanisms, the organization and distribution of colonocyte cell subpopulations in human colon tissues were investigated as a way to evaluate crypt cell maturation. We hypothesized that maturation of these subpopulations becomes dysregulated during colon tumorigenesis. Methods: Quantitative immunohistochemical mapping of crypt cell subpopulations was done using markers for SC (ALDH1), proliferating cells (DNA-synthesis-licensing proteins: CDT1/geminin/MCM2), cell-cycle arrest (P21), and apoptosis (M30/TUNEL). Staining indices were used to evaluate changes in maturation during the step-wise progression to colon cancer. The rate of crypt cell maturation was measured using clearance of BrdU from pre-labeled wildtype (C57BL/6) and premalignant (ApcMin/+) mouse intestine. Results: In normal human colon, the proportion of cells expressing licensing proteins was low at crypt bottom (where SC reside), high in the lower crypt where proliferating cells reside, and nil in the upper crypt (where differentiated/apoptotic cells reside). In FAP and adenomatous human crypts, SC and proliferating cell populations expanded towards the crypt top while differentiated/apoptotic subpopulations in the upper crypt contracted. ApcMin/+ mouse crypts had slower BrdU clearance than controls. Conclusions: Colonocytes become licensed for DNA synthesis in the transition from SC to proliferating cells; licensing is delayed in premalignant crypts. Moreover, all transitions between cell phenotypes occur more slowly in premalignant human colonic crypts, indicating that crypt cell maturation becomes progressively delayed during colon tumorigenesis. Our data indicate that cancer stem cell overpopulation arises from impaired colonocyte maturation; therapeutically targeting mechanisms to restore cell maturation may reverse SC overpopulation and tumor growth. Supported by NIH DK062146.
Serodiagnosis of Zika virus (ZIKV) infections by a novel NS1-based ELISA devoid of cross-reactivity with dengue virus antibodies: a multicohort study of assay performance, 2015 to 2016
Authors: Katja Steinhagen, Christian Probst, Christiane Radzimski, Jonas Schmidt-Chanasit, Petra Emmerich, Marjan van Esbroeck, Janke Schinkel, Martin P Grobusch, Abraham Goorhuis, Jens M Warnecke, Erik Lattwein, Lars Komorowski, Andrea Deerberg, Sandra Saschenbrecker, Winfried Stöcker, Wolfgang Schlumberger
Journal: Eurosurveillance (2016)

Serological diagnosis of Zika virus (ZIKV) infections is challenging due to high cross-reactivity between flaviviruses. We evaluated the diagnostic performance of a novel anti-ZIKV ELISA based on recombinant ZIKV non-structural protein 1 (NS1). Assay sensitivity was examined using sera from 27 patients with reverse transcription (RT)-PCR-confirmed and 85 with suspected ZIKV infection. Specificity was analysed using sera from 1,015 healthy individuals. Samples from 252 patients with dengue virus (n = 93), West Nile virus (n = 34), Japanese encephalitis virus (n = 25), chikungunya virus (n = 19) or Plasmodium spp. (n = 69) infections and from 12 yellow fever-vaccinated individuals were also examined. In confirmed ZIKV specimens collected ≥ 6 days after symptom onset, ELISA sensitivity was 58.8% (95% confidence interval (CI): 36.0-78.4) for IgM, 88.2% (95% CI: 64.4-98.0) for IgG, and 100% (95% CI: 78.4-100) for IgM/IgG, at 99.8% (95% CI: 99.2-100) specificity. Cross-reactivity with high-level dengue virus antibodies was not detected. Among patients with potentially cross-reactive antibodies anti-ZIKV positive rates were 0.8% (95% CI: 0-3.0) and 0.4% (95% CI: 0-2.4) for IgM and IgG, respectively. Providing high specificity and low cross-reactivity, the NS1-based ELISA has the potential to aid in counselling patients, pregnant women and travellers after returning from ZIKV-endemic areas.
Metabolic Pathways Control Normal and Beta-Thalassemic Erythroid Cell Maturation
Authors: Geníis Camprecióos, Xin Zhang, Valentina D'Escamard, Pauline Rimmele, Carolina L. Bigarella, Brigitte Izac, Carlo Brugnara, Emery H Bresnick, Stefano Rivella, Saghi Ghaffari
Journal: Blood (2012)