tbuckley/cabot-search huggingface dataset:
CD74 associates with Fas and inhibits Fas-mediated apoptosis
Authors: Zuzana Berkova, Shu Wang, Suizhao Wang, Hoyoung Maeng, Jillian Wise, David Hawke, Martin Campbell, Larry Kwak, Felipe Samaniego
Journal: Cancer Research (2008)

819   Resistance to Fas-mediated apoptosis manifested by hematopoietic cancers interferes with the efficacy of currently available chemotherapy. Our prior research on human herpesvirus 8 oncoprotein K1 showed that K1 binds to Fas and interferes with activation of Fas-mediated apoptotic signaling (Wang, W, et al , Blood 2007; 109:5455-62). Herpesvirus proteins often mimic host proteins or their functions, we thus searched for endogenous host proteins associated with inactive Fas in order to identify potential regulators of Fas signaling.  Potential inhibitors of Fas were identified by immunodepletion of cell extracts from B-cell lymphoma-derived BJAB cells with activating anti-Fas antibody and by subsequent coimmunoprecipitation of proteins associated with nonactivated Fas. CD74, the invariant light chain of MHC II, was identifed in complex with inactive Fas by liquid chromatography tandem mass spectroscopy. Interestingly, overexpression of CD74 has been previously reported in hematopoietic cancers: in 43 of 66 cases of pediatric non-Hodgkin lymphomas (Miles, R.R., et al., Br J of Haematology. 2007; 138: 64-71), in 8 out of 14 multiple myeloma-derived cell lines and B-cell lymphoma cell lines Raji and Ramos (Burton, J.D., et al., Clin Cancer Res. 2004; 10: 6606-6611), in 11 of 16 cases of leukemia (Kaddu, S., et al., J Am Acad Dermatol. 1999; 40: 966-978), as well as in 9 out of 11 cases of non-small-cell lung carcinoma (Ioachim, H.L., Am J Surg Pathol. 1996; 20: 64-71). CD74 expression in cancers was thus suspicious.  Through overexpression of CD74 in Fas-positive HEK 293 cells and suppression of CD74 expression in BJAB cell using siRNA technology we have determined that cells overexpressing CD74 are more resistant to agonistic antibody CH-11-induced Fas-mediated apoptosis then their relative controls. We have also mapped the domain of CD74 required for association with Fas to a membrane-proximal region of CD74. Transfection of mice with plasmid encoding full length CD74 protected mice from lethal challenge with agonistic anti-Fas antibody Jo2. All 5 of vector transfected mice died within 6 hours from challenge, while 4 out of 5 CD74 transfected mice survived (P
Vigilância da resistência aos antimicrobianos no homem, nos produtos alimentares e no gado na Dinamarca
Authors: H C Wegener, F Bager, F M Aarestrup
Journal: Eurosurveillance (1997)

A resistencia crescente das bacterias patogenicas aos antimicrobianos tem causado preocupacao, em todo o mundo, de que uso generalizado de agentes antimicrobianos na producao animal possa promover o desenvolvimento de bacterias resistentes ou de genes da resistencia que possam ser transferidos para bacterias que causam doenca no homem. No interesse da saude do consumidor e da saude animal e humana os Ministerios da Agricultura e das Pescas, e da Saude da Dinamarca em 1995 pediram ao Laboratorio Veterinario Dinamarques, a Agencia Dinamarquesa para a Alimentacao, e ao “Statens Serum Institut” para colaborarem na vigilância e investigacao da resistencia antimicrobiana.
CSIG-15. PROTEOMIC AND PHOSPHOPROTEOMIC ANALYSIS OF HUMAN MEDULLOBLASTOMA REVEALS DISTINCT ACTIVATED PATHWAYS BETWEEN SUBGROUPS
Authors: Antoine Forget, Martignetti Loredana, Sebastian Brabetz, Daniel Picard, Stephanie Puget, Laurence Calzone, Patrick Poullet, Arnau Montagud, Stephane Liva, Florent Dingli, Guillaume Arras, Hua Yu, Audrey Mercier, Celio Pouponnot, Damarys Loew, Franck Bourdeaut, Christelle Dufour, Pascale Varlet, Michael Taylor, Marcel Kool, Stefan M Pfister, Emmanuel Barillot, Marc Remke, Ayrault Olivier
Journal: Neuro-Oncology (2017)

Deregulations in fundamental signaling pathways are key events in pathogenesis of cancer. One intriguing illustration that still holds blind spots is the pediatric brain tumor arising from the developing cerebellum: medulloblastoma (MB). Extensive high-throughput sequencing led to the characterization of four MB subgroups (WNT, SHH, Group 3 and Group 4) delineated with distinct molecular signatures and clinical outcomes. However, up-to-date these analyses have not attained the global comprehension of their dynamic network complexity. Wishing to get a comprehensive view of all MB subgroups we employed a multi-scale analysis to integrate genomic copy number (CN), DNA methylation, mRNA, protein and phosphorylation levels across 38 flash frozen primary human MBs (5 WNT, 10 SHH, 10 Group 3 and 13 Group 4). Our proteomic analysis allows to distinguish the four MB subgroups. Interestingly, Group 4 MB is particularly distinguishable from the other subgroups based on phosphorylation profile. Moreover, integration of all omic layers by similarity network fusion allowed precise definition of the four subgroups. Correlation studies between CN, RNA and protein levels showed convergent effects of CN alterations toward cell cycle, RNA and nucleotide metabolism. Importantly, protein levels were poorly predicted by levels of corresponding mRNA with consequence on active pathway prediction. This observation was of particular importance in Group 4 MB in which protein and phosphorylation levels allowed the identification of pathways that were unable to be predicted by RNA data. Ultimately, this led us to the characterization of potential biomarkers of Group 4 MB and promising targetable pathways across subgroups. Altogether, combined multi-scale analyses of MB have allowed us to identify and prioritize novel molecular drivers involved in human MB genesis and progression.
Immunoglobulin G Fc glycans are not essential for antibody-mediated immune suppression to murine erythrocytes
Authors: Danielle Marjoram, Yoelys Cruz-Leal, Lidice Bernardo, Ngoc Phuong Lan Le, Max Crispin, Xiaojie Yu, Makoto Uchikawa, Alan H. Lazarus
Journal: Blood (2017)
PATH-16. THE FEASIBILITY OF THE PERFORMING MOLECULAR GENETIC PROFILING IN PRIMARY CNS LYMPHOMAS AND THE RESULTS OF THE MOLECULAR GENETIC PROFILING-BASED TREATMENTS FOR RECURRENT PRIMARY CNS LYMPHOMAS
Authors: Lyndon Kim, Kevin Judy, James Evans, Christopher Farrell, David Andrews
Journal: Neuro-Oncology (2017)

The treatment of recurrent Primary CNS Lymphoma (PCNSL) is very limited. Once recur, the prognosis is very poor. Traditionally, high-dose methotrexate-based chemotherapy has been used as the first line therapy followed by whole brain radiation therapy at the time of recurrence. High-dose Ara-C, topotecan, temozolomide and pemetrexed have been studied with limited success. Molecular genetic profiling has been used in systemic malignancies but rarely in primary or metastatic brain tumors. PCNSL is considered as a hematologic tumor and therefore, unlike solid tumors, molecular genetic profiling on the tissue was not felt to be feasible. We performed molecular genetic profiling to look for any potential actionable markers or molecular targets for possible treatment purpose. A total of 5 patients with recurrent PCNSL were studied and treatments were provided according to the test results. MRI was obtained every 2-3 months. Total patients: 5. Age: 52-80. Mean average: 73.2 yo. M;F: 3:2. Molecular genetic profiling was performed by NGS, pyrosequencing, ISH and IHC. Tx period: 12/15-4/17. Notable markers: TOPO2 5/5, TOPO1 4/5, methylatedMGMT: 4/5, TUBB3:4/5, negativeERCC1 4/5, BRAFmutation 1/5, PDL1 1/5, ER/PR 0/5, ALK 0/5, PIK3 0/5, KRAS/NRAS 0/4. Tx response: 4 patients evaluable: pt#1, SDx2 mo on topotecan, pt#2 SDx4 mo on temozolomide, pt #3 PRx6 mo continue on temozolomide, pt#4 CRx6 mo on topotecan, pt#5: <2 mo. currently on temozolomide. The results of molecular genetic profiling on PCNSL revealed a striking similarity to primary and other metastatic solid tumor profile that were not recognized in the past, thus, opening a variety of new potential molecular-targeted therapeutic options for the treatment of recurrent PCNSL. Although the number of patients treated with molecular profiling therapy was small, the high number of responders is encouraging and therefore, molecular targeted therapy trial to validate this small cohort results should be considered.
Histamine-releasing factor enhances food allergy
Authors: Tomoaki Ando, Jun-ichi Kashiwakura, Naoka Itoh-Nagato, Hirotaka Yamashita, Minato Baba, Yu Kawakami, Shih Han Tsai, Naoki Inagaki, Kiyoshi Takeda, Tsutomu Iwata, Naoki Shimojo, Takao Fujisawa, Mizuho Nagao, Kenji Matsumoto, Yuko Kawakami, Toshiaki Kawakami
Journal: Journal of Clinical Investigation (2017)

Food allergy occurs due to IgE- and mast cell-dependent intestinal inflammation. Previously, we showed that histamine-releasing factor (HRF), a multifunctional protein secreted during allergy, interacts with a subset of IgE molecules and that the HRF dimer activates mast cells in an HRF-reactive IgE-dependent manner. In this study, we investigated whether HRF plays any role in food allergy. Specifically, we determined that prophylactic and therapeutic administration of HRF inhibitors that block HRF-IgE interactions reduces the incidence of diarrhea and mastocytosis in a murine model of food allergy. Food allergy-associated intestinal inflammation was accompanied by increased secretion of the HRF dimer into the intestine in response to proinflammatory, Th2, and epithelial-derived cytokines and HRF-reactive IgE levels at the elicitation phase. Consistent with these data, patients with egg allergy had higher blood levels of HRF-reactive IgE compared with individuals that were not hypersensitive. Successful oral immunotherapy in egg-allergy patients and food-allergic mice reduced HRF-reactive IgE levels, thereby suggesting a pathological role for HRF in food allergy. Together, these results suggest that antigen and HRF dimer amplify intestinal inflammation by synergistically activating mast cells and indicate that HRF has potential as a therapeutic target in food allergy.
METB-08. Identification Of A Clinically-Actionable Sexual Dimorphism In Glioblastoma Glycolysis
Authors: Joseph Ippolito, Rivka Colen, Comron Hassanzadeh, Yuan James Rao, Maria Ponisio, Christina Tsien, Prakash Chinnaiyan, Joshua Rubin
Journal: Neuro-Oncology (2017)

Sex differences are present in tumor incidence and mortality. In many cancers including GBM, males not only have a higher incidence but also exhibit poorer outcomes. The molecular basis of this phenomenon has not yet been elucidated. Because of increased glucose utilization in normal male development and the inverse correlation between glioma glucose uptake and patient survival, we hypothesized that male GBM would have enhanced glycolysis relative to female GBM. First, biochemical measurements of clinical samples disclosed significant enrichment of glycolytic activity in male GBM measured by pyruvate kinase activity and lactate levels. Next, to determine if a specific compartment in the GBM microenvironment was driving these sex differences in glycolysis, we performed metabolic reconstructions using the IVY glioblastoma atlas. We discovered significant overexpression (q<0.01, fold-change >2) of several glycolytic genes unique to the peri-necrotic compartment suggesting that male GBM had higher necrosis than female GBM. An analysis of clinical MRI datasets confirmed that although males had significantly higher necrosis than females, females were uniquely stratified into “high” and “low” necrosis groups where “high necrosis” females did significantly worse. To address the possibility that glycolysis could stratify females similarly to necrosis, we analyzed glycolytic pathway TCGA RNA-Seq data from male and female primary GBM. Similarly, we discovered that expression of the glycolytic transcriptome more robustly stratified females than males. We cross validated these findings with a small cohort of GBM patients with suspected recurrence who were imaged with FDG-PET. In keeping with female-specific stratification, we discovered that FDG uptake at the suspected recurrence also risk-stratified females. In summary, although male GBM is characterized by higher glycolytic activity, glycolysis has the ability to uniquely risk-stratify female GBM. Together, our findings represent a previously uncharacterized phenomenon that pave the way toward a “sex-based workflow” for GBM stratification employing integrated metabolism and imaging.
TMOD-06. CLONAL DYNAMICS OF HUMAN GLIOBLASTOMA IN RESPONSE TO CHEMORADIOTHERAPY
Authors: Maleeha Qazi, Allison Nixon, David Bakhshinyan, Chitra Venugopal, Parvez Vora, Kevin Brown, Minomi Subapanditha, Nicolas Yelle, Chirayu Chokshi, Mathieu Seyfrid, Jason Moffat, Sheila Singh
Journal: Neuro-Oncology (2017)

Despite aggressive multimodal therapy, human glioblastoma (hGBM), a highly malignant grade IV astrocytic tumour, remains incurable and inevitably relapses. Recent data has implicated intratumoral heterogeneity as the driver of therapy resistance and tumour relapse in hGBM. Thus models that capture the evolution of hGBM biology in response to chemoradiotherapy will allow for the identification of cellular mechanisms that govern GBM therapy failure. In this study, we coupled cellular DNA barcoding technology with our novel in vitro and in vivo chemoradiotherapy model to profile the clonal evolution of hGBM brain tumour initiating cells (BTIC) through therapy. We report the successful barcoding of primary treatment-naive hGBM BTICs at single cell resolution that were then expanded into clonal populations with 40-60x representation per barcode. We then subjected our barcoded cells to in vitro chemoradiotherapy as well as intracranially engrafted barcoded cells into immune-deficient mice for subsequent delivery of in vivo therapy to identify differential barcode selection in two therapy models. Through this, we determined if the same cellular subpopulation is therapy-resistant in vitro and in vivo and whether a pre-existing or a therapy-driven subpopulation(s) seeds hGBM tumour relapse. Profiling the dynamic nature of heterogeneous hGBM subpopulations through disease progression and treatment may lead to identification of the mode(s) of therapy resistance utilized by hGBM which may drive relapse.
P3.01-034 Liquid Biopsy for EGFR Genotyping Using Cell-Free DNA and Extracellular Vesicular DNA of Pleural Effusion in Pulmonary Adenocarcinoma Patients
Authors: J.S. Lee, J.Y. Hur, I.A. Kim, H.J. Kim, C. Choi, J.C. Lee, W.S. Kim, K.Y. Lee
Journal: Journal of Thoracic Oncology (2017)
P3.01-017 Clinical Outcomes of Patients with EGFR T790M + NSCLC on Osimertinib
Authors: W.L. Tan, T.P. Hennedige, Q.S. Ng, S.H. Tan, N.T.A. Tran, B.J.G. Chua, C.K. Toh, E.H. Tan, D. Tan, M. Ang, R. Kanesvaran, A. Jain, T.K.H. Lim, A. Gogna, M. Koh, C.S.P. Yip, C.H. Thng, B. Chowbay, M.H. Tan, W. Lim
Journal: Journal of Thoracic Oncology (2017)
Epidemiología das doenças meningocócicas invasivas na França em 2003
Authors: A Perrocheau, M K Taha, D Lévy-Bruhl
Journal: Eurosurveillance (2005)

A vigilância nacional das doencas meningococicas invasivas (DMI) na Franca esta basada num sistema de declaracao obligatoria. Em Julho de 2002 a definicao de caso foi alargada para incluir os casos clinicos sem confirmacao microbiologica. O sistema de deteccao de alertas (DMI) foi reforcado em 2003 com um sistema de declaracao diaria e uma analise semanal por districto, serogrupo e idade. A avaliacao regular da exhaustividade da vigilância, por meio do metodo de captura-recaptura, permite corrigir a incidencia tomando em compta a subdeclaracao. Em 2003, foram notificados 803 casos. Depois de ser corrigida a subdeclaracao a incidencia foi estimada a 1,78/100 000. Sendo excluidos os casos clinicos declarados seguindo os novos criterios, o aumento em 2002-2003 era de 4%. A incidencia baixava com a idade, sendo os valores mais altos nas criancas de menos de um ano (20/100.000), nas criancas entre 1 e 2 anos (11/100.000) e em jovens de 17 anos (7/100.000). A taxa de mortalidade era de 12%. 59% dos casos eram devidos ao serogrupo B, 32% ao serogrupo C e 5% ao serogrupo W135. Os 4% restantes foram produzidos pelo serogrupo Y e por meningococos nao grupaveis. Os pacientes que tinham recibido antibioticos por via venosa antes de ser hospitalizados tiveram taxas de mortalidade mais baixas comparados com os pacientes que nao tinham sido tratados. 
Em 2003, cinco situacoes requereram uma atencao especial : duas grupos de IIM de serogrupo B, um surto de IIM associado a um estirpe de serogrupo B de um complexo clonal conhecido pela sua alta taxa de letalidade, e dois districtos aonde foi alcancado o limite de alerta dos casos de IIM de serogrupo C e aonde campanhas de vacinacao massiva foram recomendadas.
Psychological resources and strengths in adults living with lung cancer. A pilot study
Authors: G. Palazzolo, S. Schivardi, M.T. Simioni, M. Cagnin, R. Cavallo, M. Sorarù, A. Morabito, L. Sartor, M. Mion, M. Beda, F. Gaion, T. Sava, L. Riccardi
Journal: Annals of Oncology (2017)
P1.17-009 Clinical Significance of Preoperative Neutrophil-Lymphocyte Ratio in Patients with Thymic Epithelial Tumor Undergoing Surgery
Authors: S. Okada, S. Ishihara, N. Ishikawa, T. Furuya, C. Nakazono, N. Miyata, H. Tsunezuka, D. Kato, J. Shimada, M. Inoue
Journal: Journal of Thoracic Oncology (2017)
IMMU-44. INVESTIGATING THE EXPRESSION OF ANTIGEN PROCESSING MOLECULES IN BRAIN METASTASES OF TRIPLE NEGATIVE BREAST CANCERS
Authors: Fraser Henderson, David Cachia, Daniel B Aruch, William Alexander Vandergrift, Pierre Giglio, Sunil J Patel, Abhay K Varma, Scott M Lindhorst, Arabinda Das
Journal: Neuro-Oncology (2017)

Triple-negative breast cancers (TNBC) often exhibit an aggressive phenotype and their progression from the primary tumor setting to the metastatic setting is the critical event defining Stage IV disease, no longer considered curable. The microenvironment at brain sites is known to play a key role in influencing the ultimate fate of metastatic cells. Specifically, defects in MHC class I/II antigen processing molecules may negatively impact the clinical course and the response to T cell-based immunotherapy. In the present investigation, we analyzed the expression level of leukocyte antigen class I/II antigen processing molecules on TNBC cells (mouse: EO771, human: MDA MB231) in primary cell-line specific media and organ (brain) conditioned media to better understand their in vivo metastatic potential. TAP1 encodes a protein necessary for transport of cytosolic peptides into membrane bound organelles for MHC 1 presentation. Our western blot data showed lower level expression of MHC class I/II antigen processing molecules including Transporter associated with Antigen Processing protein 1 (TAP1) on human TNBC cells in both cell-line specific normal media and brain conditioned media. Furthermore, TNBC cells stably transfected with silencing hairpin (sh)RNA for TAP1 demonstrated a decreased susceptibility to cytotoxic T lymphocytes in in both cell-line specific media conditioned media and organ (brain) conditioned media. This data supports the functional significance of TAP expression in TNBC cells. Taken together, our data suggest that patients with low or defective TAP in TNBC cells may be at higher risk for developing brain metastases. The examination of expression of MHC class I/II and related antigen processing molecules, as critical components of the antitumor immune system, may be useful for the prediction of tumor progression and metastasis risk of triple negative breast cancer.
P2.02-063 Oncogenic microRNAs Associated with Poor Prognosis Are Up-Regulated on the Amplicon in Squamous Cell Lung Carcinoma
Authors: S. Yokoi, E. Xia, S. Kanematsu, Y. Suenaga, Y. Moriya, I. Yoshino, T. Iizasa
Journal: Journal of Thoracic Oncology (2017)
Influenza-derived peptides cross-react with allergens and provide asthma protection
Authors: Chrysanthi Skevaki, Christoph Hudemann, Mikhail Matrosovich, Christian Möbs, Sinu Paul, Andreas Wachtendorf, Bilal Alashkar Alhamwe, Daniel P. Potaczek, Stefanie Hagner, Diethard Gemsa, Holger Garn, Alessandro Sette, Harald Renz
Journal: Journal of Allergy and Clinical Immunology (2017)
Últimos cambios de la enfermedad meningocócica en Europa
Authors: B Hubert, D A Caugant
Journal: Eurosurveillance (1997)

Pocas infecciones suscitan tanta alarma social como la que se produce cuando la enfermedad meningococica irrumpe en una comunidad. La capacidad que tiene la Neisseria meningitidis de matar a una criatura sana en escasas horas es una de las razones de este miedo. Es tambien cierto que las medidas preventivas contra esta enfermedad son limitadas y se basan, principalmente, en el tratamiento precoz de los pacientes y la prevencion de casos secundarios.
MA 03.10 Prognostic Factors in NSCLC Patients Treated with a Fourth-Line Therapy
Authors: V. Leroy, J. Labreuche, T. Gey, G. Terce, M.C. Willemin, X. Dhalluin, E. Wasielewski, A. Scherpereel, A. Cortot
Journal: Journal of Thoracic Oncology (2017)
Relatório sobre a primeira estirpe de PVL-SARM comunitário na Letónia
Authors: E Miklaševics, S Hæggman, A Balode, B Sanchez, A Martinsons, B Olsson-Liljequist, U Dumpis
Journal: Eurosurveillance (2004)

No mundo inteiro foram detectadas infeccoes por Staphylococcus aureus resistente a meticilina adquiridas em comunidade (CA-SARM). Este artigo presenta a caracterisacao do primeiro CA-SARM isolado na Letonia. Uma estirpe de PVL-SARM IV ST30 foi isolada de uma amostra nasal e do cateter venoso central de um paciente com febre e falha multiorganica. O perfil de electroforese em campo pulsatil de essa estirpe era indistinguivel do perfil de estirpes MRSA SE00-3 isoladas na Suecia em 2002-2003 originarias de 29 pacientes. Esta estirpe esta ligada a area do Pacifico Sul e a sua emergencia na Suecia e na Letonia e uma prova da sua disseminacao ao nivel mundial.
Three-monthly dynamic evaluation of CEA and CA15-3 and 18-FDG PET vs usual practice in the follow-up of early breast cancer patients: a prospective, multicenter, randomized trial (KRONOS – Patient-Oriented New Surveillance-Study Italy)
Authors: E. Barbieri, M. Gion, L. Mariani, P. Stieber, D. Rubino, S. Fanti, R. Baum, R. Wirtz, A. Bernardi, N. Cacciari, S. Quercia, M. Lenzi, M. Cubelli, C. Pizzirani, M. Carapelle, M. Pagliaro, S. Tomasini, S. Toracchio, C. Zamagni
Journal: Annals of Oncology (2017)
SURG-02. EFFECTS OF HIGH DOSE 5-ALA IN THE RESECTION OF GLIOBLASTOMA
Authors: Alex Michael, Daniel Ryan, Kristin Delfino, Simon Bekker, Jeffrey Cozzens
Journal: Neuro-Oncology (2017)

Prior studies have found more extensive resection of high grade glioma with the use of 5-aminolevulinic acid (5-ALA) fluorescence-guided surgery (FGS) compared to conventional resection alone leading to longer progression free and overall survival.1, 2 Currently the standard dose of 5-ALA is 20mg/kg of patient body weight. The objective of the current study is to investigate how higher doses of 5-ALA affect residual tumor volume (RTV) and overall survival in patients with glioblastoma. As part of a previous phase I and II clinical trial (NCT01128218), 5-ALA was administered at doses of 10, 20, 30, 40 and 50 mg/kg to patients with suspected high grade glioma. A total of 22 patients were found to have newly diagnosed glioblastoma on histology. Patients receiving low doses of 5-ALA (10-30 mg/kg) (n = 6) were compared to those receiving high dose (40-50 mg/kg) (n = 16). Pre- and post-operative contrast enhanced T1W MRI were evaluated with volumetric analysis for RTV and for complete resection of the enhancing tumor (CRET) (volume < 0.0175cm3). Less median RTV was found in the high dose 5-ALA group (0.181 cm3) compared to the low dose group (0.884 cm3) though this was not statistically significant (p = 0.149). Eight of the 16 patients (50%) receiving high dose 5-ALA achieved a CRET compared to zero of the low dose patients (p=0.03). There was no significant difference found in survival between the high dose and low dose Group (p = 0.2849). This study found that high doses of 5-ALA FGS are associated with less RTV and greater probability of CRET. Due to the limited number of patients included, we could not adequately draw any conclusions about dose and its relationship to survival. Further studies with a larger patient population are warranted.