tbuckley/cabot-search huggingface dataset:
Risk of serious infections associated with use of immunosuppressive agents in pregnant women with autoimmune inflammatory conditions: cohort study
Authors: Rishi J Desai, Brian T Bateman, Krista F Huybrechts, Elisabetta Patorno, Sonia Hernandez-Diaz, Yoonyoung Park, Sara Z Dejene, Jacqueline Cohen, Helen Mogun, Seoyoung C Kim
Journal: BMJ (2017)

<b>Objective</b>&nbsp;To compare the risk of serious infections associated with use of systemic steroids, non-biologic agents, or tumor necrosis factor α (TNF) inhibitors in pregnancy. <b>Design</b>&nbsp;Observational cohort study. <b>Setting</b>&nbsp;Public (Medicaid, 2001-10) or private (Optum Clinformatics, 2004-15) health insurance programs in the US. <b>Participants</b>&nbsp;4961 pregnant women treated with immunosuppressive drugs for rheumatoid arthritis, systemic lupus erythematosus, ankylosing spondylitis, psoriatic arthritis, or inflammatory bowel disease. <b>Exposure for observational studies</b>&nbsp;Exposure was classified into steroid, non-biologic, or TNF inhibitors on first filled prescription during pregnancy. Because TNF inhibitors are not used to treat systemic lupus erythematosus, patients with this condition were excluded from comparisons involving TNF inhibitors. <b>Main outcome measure</b>&nbsp;The main outcome was occurrence of serious infections during pregnancy, defined by hospital admission for bacterial or opportunistic infections. Hazard ratios were derived using Cox proportional hazard regression models after adjustment for confounding with propensity score fine stratification. A logistic regression model was used to conduct a dose-response analysis among women filling at least one steroid prescription. <b>Results</b>&nbsp;71 out of 4961 pregnant women (0.2%) treated with immunosuppressive agents experienced serious infections. The crude incidence rates of serious infections per 100 person years among 2598 steroid users, 1587 non-biologic users, and 776 TNF inhibitors users included in this study were 3.4 (95% confidence interval 2.5 to 4.7), 2.3 (1.5 to 3.5), and 1.5 (0.7 to 3.0), respectively. No statistically significant differences in the risk of serious infections during pregnancy were observed among users of the three immunosuppressive drug classes: non-biologics <i>v</i> steroids, hazard ratio 0.81 (95% confidence interval 0.48 to 1.37), TNF inhibitors <i>v</i> steroids 0.91 (0.36 to 2.26), and TNF inhibitors <i>v</i> non-biologics 1.36 (0.47 to 3.93). In the dose-response analysis, higher steroid dose was associated with an increased risk of serious infections during pregnancy (coefficient for each unit increase in average prednisone equivalent mg daily dose=0.019, P=0.02). <b>Conclusions</b>&nbsp;Risk of serious infections is similar among pregnant women with systemic inflammatory conditions using steroids, non-biologics, and TNF inhibitors. However, high dose steroid use is an independent risk factor of serious infections in pregnancy.
Antibody–Drug Conjugates Bearing Pyrrolobenzodiazepine or Tubulysin Payloads Are Immunomodulatory and Synergize with Multiple Immunotherapies
Authors: Jonathan Rios-Doria, Jay Harper, Raymond Rothstein, Leslie Wetzel, Jon Chesebrough, Allison Marrero, Cui Chen, Patrick Strout, Kathy Mulgrew, Kelly McGlinchey, Ryan Fleming, Binyam Bezabeh, John Meekin, David Stewart, Maureen Kennedy, Philip Martin, Andrew Buchanan, Nazzareno Dimasi, Emil Michelotti, Robert Hollingsworth
Journal: Cancer Research (2017)

Immunogenic cell death (ICD) is the process by which certain cytotoxic drugs induce apoptosis of tumor cells in a manner that stimulates the immune system. In this study, we investigated whether antibody-drug conjugates (ADCS) conjugated with pyrrolobenzodiazepine dimer (PBD) or tubulysin payloads induce ICD, modulate the immune microenvironment, and could combine with immuno-oncology drugs to enhance antitumor activity. We show that these payloads on their own induced an immune response that prevented the growth of tumors following subsequent tumor cell challenge. ADCs had greater antitumor activity in immunocompetent versus immunodeficient mice, demonstrating a contribution of the immune system to the antitumor activity of these ADCs. ADCs also induced immunologic memory. In the CT26 model, depletion of CD8+ T cells abrogated the activity of ADCs when used alone or in combination with a PD-L1 antibody, confirming a role for T cells in antitumor activity. Combinations of ADCs with immuno-oncology drugs, including PD-1 or PD-L1 antibodies, OX40 ligand, or GITR ligand fusion proteins, produced synergistic antitumor responses. Importantly, synergy was observed in some cases with suboptimal doses of ADCs, potentially providing an approach to achieve potent antitumor responses while minimizing ADC-induced toxicity. Immunophenotyping studies in different tumor models revealed broad immunomodulation of lymphoid and myeloid cells by ADC and ADC/immuno-oncology combinations. These results suggest that it may be possible to develop novel combinatorial therapies with PBD- and tubulysin-based ADC and immuno-oncology drugs that may increase clinical responses. Cancer Res; 77(10); 2686-98. ©2017 AACR.
Assessment of BCR-ABL1 Transcript Levels By Digital PCR (dPCR) in CML Patients who Achieved a Deep Molecular Response (DMR: MR4.0, MR4.5 And MR5.0) with Tkis May Improve the Detection of Minimal Residual Disease (MRD) and the Selection of Patients for Treatment Free Remission (TFR)
Authors: Bernardi Simona, Andrea Di Palma, Federica Cattina, Simone Perucca, Michele Malagola, Mario Tiribelli, Erika Codarin, Maria Teresa Bochicchio, Giuseppina Ruggeri, Luca Franceschini, Valeria Cancelli, Fausto Castagnetti, Simona Soverini, Miriam Fogli, Claudia Venturi, Serena Lavorgna, Chiara Pagani, Cristina Skert, Camilla Zanaglio, Alessandro Turra, Nicola Polverelli, Luigi Caimi, Giuseppe Rossi, Maria Teresa Voso, Gianantonio Rosti, Giovanni Martinelli, Michele Baccarani, Domenico Russo
Journal: Blood (2016)
Similar Rate of Thrombosis in Essential Thrombocythemia and Polycythemia Vera Patients after Stratification for JAK2 V617F Allele Burden.
Authors: Alessandra Carobbio, Guido Finazzi, Elisabetta Antonioli, Paola Guglielmelli, Alessandro M. Vannucchi, Federica Delaini, Alessandro Rambaldi, Tiziano Barbui
Journal: Blood (2008)
Intensive care medicine research agenda on invasive fungal infection in critically ill patients
Authors: Matteo Bassetti, Jose Garnacho-Montero, Thierry Calandra, Bartjan Kullberg, George Dimopoulos, Elie Azoulay, Arunaloke Chakrabarti, Daniel Kett, Cristobal Leon, Luis Ostrosky-Zeichner, Maurizio Sanguinetti, Jean-Francois Timsit, Malcom D. Richardson, Andrew Shorr, Oliver A. Cornely
Journal: Intensive Care Medicine (2017)
Hepatocyte Growth Factor (HGF) Favors Monocyte Differentiation into Interleukin (IL)-10+IL-12neg Regulatory Dendritic Cells.
Authors: Sergio Rutella, Giuseppina Bonanno, Annabella Procoli, Andrea Mariotti, Nathalie Saulnier, Antonio Curti, Giuseppe Leone, Roberto M. Lemoli
Journal: Blood (2005)
Erratum for the Research Article: “CMV-specific T cells generated from naïve T cells recognize atypical epitopes and may be protective in vivo” by P. J. Hanley, J. J. Melenhorst, S. Nikiforow, P. Scheinberg, J. W. Blaney, G. Demmler-Harrison, C. R. Cruz, S. Lam, R. A. Krance, K. S. Leung, C. A. Martinez, H. Liu, D. C. Douek, H. E. Heslop, C. M. Rooney, E. J. Shpall, A. J. Barrett, J. R. Rodgers, C. M. Bollard
Journal: Science Translational Medicine (2016)
Acute Lymphoblastic Leukemia
Authors: Joseph C. Alvarnas, Patrick A. Brown, Patricia Aoun, Karen Kuhn Ballen, Naresh Bellam, William Blum, Michael W. Boyer, Hetty E. Carraway, Peter F. Coccia, Steven E. Coutre, Jennifer Cultrera, Lloyd E. Damon, Daniel J. DeAngelo, Dan Douer, Haydar Frangoul, Olga Frankfurt, Salil Goorha, Michael M. Millenson, Susan O'Brien, Stephen H. Petersdorf, Arati V. Rao, Stephanie Terezakis, Geoffrey Uy, Meir Wetzler, Andrew D. Zelenetz, Maoko Naganuma, Kristina M. Gregory
Journal: Journal of the National Comprehensive Cancer Network (2012)

The inaugural NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for acute lymphoblastic leukemia (ALL) were developed as a result of meetings convened by a multi-disciplinary panel of experts in 2011. These NCCN Guidelines provide recommendations on the diagnostic evaluation and workup for ALL, risk assessment, risk-stratified treatment approaches based on the Philadelphia chromosome status and age (adults vs. adolescents/young adults), assessment of minimal residual disease, and supportive care considerations. It is recommended that patients be treated at specialized centers with expertise in the management of ALL.
CD4+CD25high Foxp3+ Regulatory T-Cells Are Correlated with Different Risk Factors in Myelodysplastic Syndrome (MDS).
Authors: Shahram Y. Kordasti, Wendy Ingram, Janet Hayden, David Darling, Linda Barber, Farzin Farzaneh, Ghulam Mufti
Journal: Blood (2007)
A Frailty Scale Predicts Outcomes of Patients with Newly Diagnosed Multiple Myeloma Who Are Ineligible for Transplant Treated with Continuous Lenalidomide Plus Low-Dose Dexamethasone on the First Trial
Authors: Thierry Facon, Cyrille Hulin, Meletios A. Dimopoulos, Andrew Belch, Nathalie Meuleman, Mohamad Mohty, Wen-Ming Chen, Kihyun Kim, Elena Zamagni, Paula Rodriguez-Otero, William Renwick, Christian Rose, Adrian Tempescul, Antonio Palumbo, Shien Guo, Michael Sturniolo, Annette Ervin-Haynes, Jean-Paul Fermand
Journal: Blood (2015)
Assays for PD-L1 Expression
Authors: Gabriel L. Sica, Suresh S. Ramalingam
Journal: JAMA Oncology (2017)

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 Oncology HomeNew OnlineCurrent IssueFor Authors Podcast 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) 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 Oncology journal
SNP/CGH Microarray Analysis in MDS: Correlation with Conventional Cytogenetic, FISH and Flow Cytometry Findings
Authors: Barbara Katharina Zehentner, Lisa Eidenschink Brodersen, Christine F Stephenson, Jevon Cutler, Monica E. de Baca, Andrew Menssen, Kelle Hammock, Krystal Johnson, Luise Hartmann, Michael R Loken, Denise A. Wells
Journal: Blood (2014)
Abstract PL2: Cell free plasma tumor DNA in breast oncology
Authors: BH Park
Journal: Cancer Research (2017)

Abstract In the past decade, there has been great interest in the use of circulating cell-free DNA to help guide therapy decisions in clinical oncology. Recent work by our group and others suggests that circulating cell-free plasma tumor DNA offers advantages compared to tissue biopsies for mutation profiling. This concept of “liquid biopsy” may allow for a more global genomic picture of metastatic disease since blood serves as a reservoir for all metastatic sites. In addition, cell-free plasma tumor DNA can be measured serially and quantitatively, presenting the possibility of using circulating plasma tumor DNA as a biomarker to measure disease burden and response to therapies for both early and late stage disease. In this session, I will review historic and recent studies demonstrating the clinical potential of measuring cell-free plasma tumor DNA in breast cancer patients for early stage and metastatic disease. I will also outline future steps needed to translate liquid biopsies from research use to clinical practice, and recent work highlighting the first multi-institutional prospective clinical trial evaluating cell-free plasma tumor DNA in early stage breast cancer patients undergoing neoadjuvant chemotherapy. Citation Format: Park BH. Cell free plasma tumor DNA in breast oncology [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr PL2.
T-Cell Depletion and No Post-Transplant Immune Suppression Provides Better Immune Recovery to Aspergillus Than Conventional T Cell-Replete Hematopoietic Transplants.
Authors: Katia Perruccio, Simone Cesaro, Fabiana Topini, Maria Vittoria Gazzola, Emanuela Burchielli, Alessandra Barzan, Franco Aversa, Chiara Messina, Massimo F. Martelli, Andrea Velardi
Journal: Blood (2004)
Abstract BS1-1: Transcription factor stability and stem cell maintenance
Authors: VM Dixit
Journal: Cancer Research (2017)

Abstract Proto-oncogenes ETV1, ETV4, and ETV5 belong to the PEA3 family of ETS transcription factors and have been identified recently in prostate cancer chromosomal rearrangements that result in their overexpression. Little is known, however, about their post-translational regulation. We previously showed that ETV1, ETV4, and ETV5 interact with the ubiquitin ligase COP1. COP1 together with its binding partner DET1 ubiquitinates ETV1, resulting in its proteasomal degradation. Importantly, truncation of ETV1 by the TMPRSS2:ETV1 translocation found in prostate cancer removes its COP1 binding motif and thereby enhances its stability. Consistent with a critical role for COP1 in regulating PEA3 transcription factors, COP1 deficiency in primary mouse prostate cells produced prostate intraepithelial neoplasia in vivo. The relationship between COP1 and ETV1 was also evident in human prostate cancer samples where loss of COP1 expression correlated with elevated ETV1 protein. I will discuss unpublished work that underscores the importance of COP1 as tumor suppressor. References: 1. Wertz I, O'Rourke K, Zhang Z, Dornan D, Arnott D, Deshaies R, and Dixit VM (2004). Human De-Etiolated-1 Regulates c-Jun by Assembling a CUL4A Ubiquitin Ligase. Science 303: 1371-1374. 2. Vitari AC, Leong KG, Newton K,Yee C, O'Rourke K, Liu J, Phu L, Vij R, Ferrando R, Couto SS, Mohan S, Pandita A, Hongo J-A, Arnott D, Gao W-Q, French DM, and Dixit V (2011) COP1 is a Tumor Suppressor that Causes Deregulation of Proto-oncogenic ETS Transcription Factors. Nature 474: 403-408. 3. Suriben R, Kaihara KA, Reichelt M, Kummerfeld SK, Modrusan Z, Dugger DL, Newton K, Webster JD, Liu J, Hebrok M, Dixit VM (2015). β-cell insulin secretion requires the ubiquitin ligase COP1. Cell 163: 1457-1467. Citation Format: Dixit VM. Transcription factor stability and stem cell maintenance [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr BS1-1.
MicroRNA-Mediated Down-Regulation of the Tumor Suppressor Gene PRDM1/Blimp-1 in Diffuse Large B-Cell Lymphomas.
Authors: Kui Nie, Hatim Allawi, Victor Lyamichev, Mario F. Gomez, Yifang Liu, Amy Chadburn, Daniel M. Knowles, Wayne Tam
Journal: Blood (2007)
Abstract P3-17-03: DCIS and the risk of breast cancer death - A case control study
Authors: C Wadsten, H Garmo, I Fredriksson, M Sund, F Wärnberg
Journal: Cancer Research (2017)

Abstract Introduction The risk of breast cancer death after a primary ductal carcinoma in situ (DCIS) is less than 2 % after 10 years. Whereas in situ recurrences do not influence survival, a 17-fold elevated risk of breast cancer specific mortality has been shown for invasive recurrences. Adjuvant radiotherapy (RT) effectively reduces recurrences after breast conserving surgery (BCS) for DCIS, but no studies have been able to demonstrate a survival benefit from adjuvant RT treatment or from choosing mastectomy instead of BCS. Here patient and tumour related risk factors for breast cancer death in women with a pure primary DCIS were studied. Patients and methods Women registered with a primary DCIS, between 1992-2012 in three of Sweden´s health care regions with a population of approximately 5.2 million, were enrolled in a nested case-control study. Out of 6,964 women with DCIS, 96 patients who later died from breast cancer were identified. Four controls per case (n=318) were randomly selected by incidence density sampling. We retrieved medical records and pathology reports and calculated OR with 95% CIs for various variables using conditional logistic regression. Results Of the 96 cases, 10 patients developed distant metastasis without a known local recurrence. In 56 patients death was preceded by an invasive ipsilateral recurrence and in 3 patients by a recurrent ipsilateral DCIS. Seven patients had invasive breast events in both the ipsilateral and the contralateral breast. Seventeen patients had contralateral invasive breast cancer and 3 patients contralateral DCIS. Multifocality and tumour size over 25mm (OR 2.6 (1.6 to 4.2)), positive or uncertain margin status (OR 2.8 (1.6 to 4.9)) and detection outside screening (OR 2.1 (1.2 to 3.9)) increased the risk of breast cancer death in univariate analysis, when adjusted for age and year of diagnosis. Suspicion of micro-invasion and nuclear grade 3 was associated with a nonsignificant increased risk, OR 1.8 (0.6 to 5.0) and 2.6 (0.9-6.5), respectively. The risk was not affected by age or treatment. Tumour size and margin status remained significant in the multivariable analysis, when adjusted for treatment and for contralateral breast cancer (OR 2.0 (1.2 to 3.7)). Conclusion In the present study, large tumours and positive or uncertain margin status were significant risk factors for later breast cancer death after a primary DCIS. More extensive treatment was not related to a lower risk. The significance of tumour biology and nuclear grade will be further examined and evaluated. Citation Format: Wadsten C, Garmo H, Fredriksson I, Sund M, Wärnberg F. DCIS and the risk of breast cancer death - A case control study [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P3-17-03.
Bevacizumab (Bev) for treatment of recurrent serous borderline (SB) or low-grade serous (LGS) ovarian cancer: A retrospective review of the Memorial Sloan-Kettering Cancer Center (MSKCC) experience.
Authors: Rachel N. Grisham, Evis Sala, Qin Zhou, Alexia Iasonos, Deborah DeLair, Gopa Iyer, David Michael Hyman, David R. Spriggs, Carol Aghajanian
Journal: Journal of Clinical Oncology (2013)

5545 Background: LGS ovarian cancer is a rare subtype of ovarian cancer, accounting for 10% of ovarian cancer cases. Patients typically present at an early age, exhibit a protracted clinical course, and have response rates to chemotherapy of &lt; 4%. Limited clinical data suggests that bev may have activity in this disease. The objective of this study was to determine the response rate to treatment with bev in patients with SB or LGS ovarian cancer treated at MSKCC. Methods: Following IRB approval, all patients with a diagnosis of SB or LGS ovarian or primary peritoneal cancer treated with ≥ 1 dose of bev for persistent or recurrent disease were identified. 17 patients were treated at MSKCC between July 2005 and June 2012. Diagnosis was confirmed by a gynecologic pathologist. All imaging was independently reviewed by the study radiologist and response was determined by RECIST 1.1 criteria. Results: 17 patients, 10 with LGS ovarian cancer, 3 with LGS primary peritoneal cancer, and 4 with SB disease were included in the analysis. The mean number of prior therapies was 3.4 (range: 1-9, median: 2). Two patients were treated with bev alone, the remainder (15) received bev in combination with paclitaxel (Pac, 6), topotecan (1), pemetrexed (1), oral cyclophosphamide (3), gemcitabine (Gem, 2), Gem and carboplatin (Carbo) (1), or Pac and Carbo (1) .Two patients were not evaluable for response due to termination of treatment prior to first radiographic assessment. The median duration of bev treatment was 23 weeks (mean: 32.2; range 6-79.4). Conclusions: This data suggests that the addition of bev to cytotoxic chemotherapy may produce dramatically higher response rates than chemotherapy alone in patients with SB and LGS ovarian cancer. A prospective study of bev for treatment of this chemotherapy resistant disease is warranted. [Table: see text]
Modulation of regulatory T cells and myeloid-derived suppressor cells by sorafenib and sunitinib in renal cell carcinoma patients
Authors: A. Floercken, A. Takvorian, A. Singh, W. Hopfenmüller, A. Pezzutto, B. Dörken, J. Westermann
Journal: Journal of Clinical Oncology (2009)

e16002 Background: Induction of regulatory T (Treg) and myeloid-derived suppressor cells (MDSC) is a major mechanism for the escape of tumors from immunological control. Increased levels of Treg cells have been described in renal cell cancer (RCC) patients and seem to correlate with an adverse outcome. Furthermore, reduction of Treg has been reported for RCC patients under sunitinib therapy. The aim of our study was to analyse the influence of sorafenib and sunitinib on the frequency of Treg and MDSC in patients with metastatic RCC (mRCC). Methods: The number of T reg, MDSC and lymphocyte subpopulations was analysed by flowcytometry in peripheral blood (pb) of patients (n=19) with histologically confirmed mRCC under treatment with either sunitinib (50 mg/d, n=11) or sorafenib (800 mg/d, n=8). After informed consent blood samples were taken before and during the 1st, 2nd, and 3rd month of therapy. Flowcytometric analysis was performed using fluorochrome labeled antibodies against CD3, CD4, CD8, CD25, CD127, FOXp3, CD33, C14, CD11b and HLA-DR. Results: The baseline level of Treg did not differ from healthy controls. However, there was a significant increase of CD3+CD4+CD25+FOXp3+Treg (13,5% vs. 36,3% of gated cells, p= 0.02) and the ratio FOXp3+/FOXp3- CD3+CD4+ T cells (0,16% vs. 0,56% of gated cells, p= 0.02) in the group of sorafenib-treated patients compared to sunitinib-treated patients during the 1st month of therapy and thereafter. This effect was confirmed in an intragroup analysis. There was no influence of Sunitinib on the frequency of Treg. Analysis of CD33+/HLA-DR-/11b+ MDSC did not reveal any change under treatment with sorafenib or sunitinib. Conclusions: Sorafenib, but not sunitinib, leads to an early and sustained increase of Treg in pb of mRCC patients. A negative influence of sorafenib on primary immune responses has been described and has mainly been attributed to functional impairment of dendritic cells (DC). Whether altered DC function under sorafenib is responsible for the induction of Treg in RCC patients will have to be addressed in future studies. In immunoresponsive tumors such as RCC, immunological effects of kinase inhibitors are particularly relevant for the design of combination trials with immunotherapeutic agents. No significant financial relationships to disclose.
Abstract P1-06-08: Improved endocrine therapy response prediction using a whole slide digital ER and PR staining score to assess local ER pathway activity in hormone receptor positive breast cancer patients
Authors: H van Ooijen, F van Hemert, J van der Ven, MA de Inda, R Velter, D Halter, E den Biezen-Timmermans, A van Brussel, P van de Wiel, R Wimberger-Friedl, A van de Stolpe
Journal: Cancer Research (2017)

Abstract This abstract was withdrawn by the authors.