tbuckley/cabot-search huggingface dataset:
APOBEC signature mutation generates an oncogenic enhancer that drives LMO1 expression in T-ALL
Authors: Z Li, B J Abraham, A Berezovskaya, N Farah, Y Liu, T Leon, A Fielding, S H Tan, T Sanda, A S Weintraub, B Li, S Shen, J Zhang, M R Mansour, R A Young, A T Look
Journal: Leukemia (2017)

Oncogenic driver mutations are those that provide a proliferative or survival advantage to neoplastic cells, resulting in clonal selection. Although most cancer-causing mutations have been detected in the protein-coding regions of the cancer genome; driver mutations have recently also been discovered within noncoding genomic sequences. Thus, a current challenge is to gain precise understanding of how these unique genomic elements function in cancer pathogenesis, while clarifying mechanisms of gene regulation and identifying new targets for therapeutic intervention. Here we report a C-to-T single nucleotide transition that occurs as a somatic mutation in noncoding sequences 4 kb upstream of the transcriptional start site of the LMO1 oncogene in primary samples from patients with T-cell acute lymphoblastic leukaemia. This single nucleotide alteration conforms to an APOBEC-like cytidine deaminase mutational signature, and generates a new binding site for the MYB transcription factor, leading to the formation of an aberrant transcriptional enhancer complex that drives high levels of expression of the LMO1 oncogene. Since APOBEC-signature mutations are common in a broad spectrum of human cancers, we suggest that noncoding nucleotide transitions such as the one described here may activate potent oncogenic enhancers not only in T-lymphoid cells but in other cell lineages as well.
White Paper AGA: POWER — Practice Guide on Obesity and Weight Management, Education, and Resources
Authors: Andres Acosta, Sarah Streett, Mathew D. Kroh, Lawrence J. Cheskin, Katherine H. Saunders, Marina Kurian, Marsha Schofield, Sarah E. Barlow, Louis Aronne
Journal: Clinical Gastroenterology and Hepatology (2017)
The outcome of 267 Philadelphia positive adults in the international UKALL12/ECOG E 2993 study. Final analysis and the role of allogeneic transplant in those under 50 years.
Authors: A H Goldstone, R Chopra, G Buck, M Richards, J M Franklin, H M Lazarus, P H Wiemik, M S Tallman, H G Prentice, J Durrant, J M Rowe
Journal: Blood (2003)
Platelets Mediate Clearance of Lymphocytic Choriomeningitis Virus Infection Preventing Lethal Hemorrhage.
Authors: Matteo Iannacone, Giovanni Sitia, Masanori Isogawa, Jason K. Whitmire, Patrizia Marchese, Francis V. Chisari, Zaverio M. Ruggeri, Luca G. Guidotti
Journal: Blood (2006)
Kinome-Wide RNA Interference Screen Reveals a Role for PDK1 in Acquired Resistance to CDK4/6 Inhibition in ER-Positive Breast Cancer
Authors: Valerie M. Jansen, Neil E. Bhola, Joshua A. Bauer, Luigi Formisano, Kyung-Min Lee, Katherine E. Hutchinson, Agnieszka K. Witkiewicz, Preston D. Moore, Mónica Valéria Estrada, Violeta Sánchez, Paula G. Ericsson, Melinda E. Sanders, Paula R. Pohlmann, Michael J. Pishvaian, David A. Riddle, Teresa C. Dugger, Wenyi Wei, Erik S. Knudsen, Carlos L. Arteaga
Journal: Cancer Research (2017)

Acquired resistance to cyclin-dependent kinases 4 and 6 (CDK4/6) small-molecule inhibitors in breast cancer arises through mechanisms that are yet uncharacterized. In this study, we used a kinome-wide siRNA screen to identify kinases that, when downregulated, yield sensitivity to the CDK4/6 inhibitor ribociclib. In this manner, we identified 3-phosphoinositide-dependent protein kinase 1 (PDK1) as a key modifier of ribociclib sensitivity in estrogen receptor-positive MCF-7 breast cancer cells. Pharmacologic inhibition of PDK1 with GSK2334470 in combination with ribociclib or palbociclib, another CDK4/6 inhibitor, synergistically inhibited proliferation and increased apoptosis in a panel of ER-positive breast cancer cell lines. Ribociclib-resistant breast cancer cells selected by chronic drug exposure displayed a relative increase in the levels of PDK1 and activation of the AKT pathway. Analysis of these cells revealed that CDK4/6 inhibition failed to induce cell-cycle arrest or senescence. Mechanistic investigations showed that resistant cells coordinately upregulated expression of cyclins A, E, and D1, activated phospho-CDK2, and phospho-S477/T479 AKT. Treatment with GSK2334470 or the CDK2 inhibitor dinaciclib was sufficient to reverse these events and to restore the sensitivity of ribociclib-resistant cells to CDK4/6 inhibitors. Ribociclib, in combination with GSK2334470 or the PI3Kα inhibitor alpelisib, decreased xenograft tumor growth more potently than each drug alone. Taken together, our results highlight a role for the PI3K-PDK1 signaling pathway in mediating acquired resistance to CDK4/6 inhibitors.
Abstract OT1-04-03: Randomized phase II study of induction bevacizumab, etoposide and cisplatin followed by whole brain radiotherapy (WBRT) versus WBRT alone in breast cancer with untreated brain metastases (A-PLUS)
Authors: Y-S Lu, L-M Tseng, J-C Yu, K-M Rau, T-Y Chao, S-C Chen, C-F Chiu, Y-C Chang, TW-W Chen, C-H Lin, D-Y Chang, T-C Chao, S-M Huang, C-S Huang, A-L Cheng
Journal: Cancer Research (2017)

Abstract Background For breast cancer (BC) patients with brain metastases (BM) who are not suitable for surgery/radiosurgery, whole brain radiotherapy (WBRT) remained the only standard treatment. Recently, we have demonstrated that bevacizumab preconditioning followed by etoposide and cisplatin (BEEP) is a highly effective treatment for BM of BC progressing from WBRT (Clin Cancer Res. 2015;21(8):1851). The CNS objective response rate is 77.1% according to volumetric criteria, and 60% according to RECIST 1.1. It has been demonstrated that enlarged brain tumor size is a predictor of WBRT failure. We hypothesized that, for BC with BM, induction BEEP treatment could decrease the size of brain metastases and thereby enhance effectiveness of WBRT. Methods This is a Phase II, randomized, open-labelled study (NCT02185352). Key inclusion criteria: BC with measurable brain metastatic tumor who had not received WBRT and not suitable for surgery or radiosurgery; KPS ≥30%. Key exclusion criteria: patients who had leptomeningeal metastases; history of disease progression during prior cisplatin treatment. In the experimental arm, patients will be treated by induction BEEP for three cycles followed by WBRT. In the control arm, patients will receive upfront WBRT for brain metastases. The BEEP regimen consist of bevacizumab (15 mg/kg) on Day 1 and, with a 1 day window period, followed by etoposide (70 mg/m2/day, Day 2 to Day 4) and cisplatin (70 mg/m2, Day 2), in a 21-day cycle. Stratification is based on the Graded Prognostic Assessment (GPA) score. Primary endpoint: brain-specific progression free survival (PFS) according to RECIST 1.1; key secondary endpoint: the 2-month brain-specific objective response rate (BS-ORR) of BEEP alone and WBRT alone. Other secondary endpoints include overall survival, extra-CNS tumor PFS, safety, time-to-improvement of neurological function,brain-specific PFS according to volumetric criteria, and BS-ORR. Approximately 126 patients will be 2:1 randomized. Multi-center recruitment is ongoing. To our knowledge this is the first randomized trial investigating a targeted therapy plus chemotherapy as induction regimen followed by WBRT as first line treatment for BC with BM. Citation Format: Lu Y-S, Tseng L-M, Yu J-C, Rau K-M, Chao T-Y, Chen S-C, Chiu C-F, Chang Y-C, Chen TW-W, Lin C-H, Chang D-Y, Chao T-C, Huang S-M, Huang C-S, Cheng A-L. Randomized phase II study of induction bevacizumab, etoposide and cisplatin followed by whole brain radiotherapy (WBRT) versus WBRT alone in breast cancer with untreated brain metastases (A-PLUS) [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 OT1-04-03.
<i>Cyp24a1</i> Attenuation Limits Progression of <i>BrafV600E</i>-Induced Papillary Thyroid Cancer Cells and Sensitizes Them to BRAFV600E Inhibitor PLX4720
Authors: Minjing Zou, Essa Y. Baitei, Huda A. BinEssa, Futwan A. Al-Mohanna, Ranjit S. Parhar, René St-Arnaud, Shioko Kimura, Catrin Pritchard, Ali S. Alzahrani, Abdullah M. Assiri, Brian F. Meyer, Yufei Shi
Journal: Cancer Research (2017)

Abstract CYP24A1, the primary inactivating enzyme for vitamin D, is often overexpressed in human cancers, potentially neutralizing the antitumor effects of calcitriol, the active form of vitamin D. However, it is unclear whether CYP24A1 expression serves as a functional contributor versus only a biomarker for tumor progression. In this study, we investigated the role of CYP24A1 on malignant progression of a murine model of BrafV600E-induced papillary thyroid cancer (PTC). Mice harboring wild-type Cyp24a1 (BVECyp24a1-wt) developed PTC at 5 weeks of age. Mice harboring a homozygous deletion of Cyp24a1 (BVECyp24a1-null) exhibited a 4-fold reduction in tumor growth. Notably, we found the tumorigenic potential of BVECyp24a1-null-derived tumor cells to be nearly abolished in immunocompromised nude mice. This phenotype was associated with downregulation of the MAPK, PI3K/Akt, and TGFβ signaling pathways and a loss of epithelial–mesenchymal transition (EMT) in BVECyp24a1-null cells, associated with downregulation of genes involved in EMT, tumor invasion, and metastasis. While calcitriol treatment did not decrease cell proliferation in BVECyp24a1-null cells, it strengthened antitumor responses to the BRAFV600E inhibitor PLX4720 in both BVECyp24a1-null and BVECyp24a1-wt cells. Our findings offer direct evidence that Cyp24a1 functions as an oncogene in PTC, where its overexpression activates multiple signaling cascades to promote malignant progression and resistance to PLX4720 treatment. Cancer Res; 77(8); 2161–72. ©2017 AACR.
SENP1 promotes hypoxia-induced cancer stemness by HIF-1α deSUMOylation and SENP1/HIF-1α positive feedback loop
Authors: Chun-Ping Cui, Carmen Chak-Lui Wong, Alan Ka-Lun Kai, Daniel Wai-Hung Ho, Eunice Yuen-Ting Lau, Yu-Man Tsui, Lo-Kong Chan, Tan-To Cheung, Kenneth Siu-Ho Chok, Albert C Y Chan, Regina Cheuk-Lam Lo, Joyce Man-Fong Lee, Terence Kin-Wah Lee, Irene Oi Lin Ng
Journal: Gut (2017)

Objective We investigated the effect and mechanism of hypoxic microenvironment and hypoxia-inducible factors (HIFs) on hepatocellular carcinoma (HCC) cancer stemness. Design HCC cancer stemness was analysed by self-renewal ability, chemoresistance, expression of stemness-related genes and cancer stem cell (CSC) marker-positive cell population. Specific small ubiquitin-like modifier (SUMO) proteases 1 (SENP1) mRNA level was examined with quantitative PCR in human paired HCCs. Immunoprecipitation was used to examine the binding of proteins and chromatin immunoprecipitation assay to detect the binding of HIFs with hypoxia response element sequence. In vivo characterisation was performed in immunocompromised mice and stem cell frequency was analysed. Results We showed that hypoxia enhanced the stemness of HCC cells and hepatocarcinogenesis through enhancing HIF-1α deSUMOylation by SENP1 and increasing stabilisation and transcriptional activity of HIF-1α. Furthermore, we demonstrated that SENP1 is a direct target of HIF-1/2α and a previously unrecognised positive feedback loop exists between SENP1 and HIF-1α. Conclusions Taken together, our findings suggest the significance of this positive feedback loop between HIF-1α and SENP1 in contributing to the increased cancer stemness in HCC and hepatocarcinogenesis under hypoxia. Drugs that specifically target SENP1 may offer a potential novel therapeutic approach for HCC.
Liver-related morbidity and mortality in patients with Chronic Hepatitis C and cirrhosis with and without sustained virologic response
Authors: S. Hallager, S. Ladelund, P. B. Christensen, M. Clausen, A. L. Laursen, A. Moller, P. Schlicthting, L. G. Madsen, J. Gerstoft, S. Lunding, K. E. Gronbaek, H. Krarup, N. Weis
Journal: Hepatology (2016)
HIV and predictors of advanced cancer at presentation: Uganda.
Authors: Manoj Menon, Anna Coghill, Innocent Oswald Mutyaba, Warren Phipps, Fred Machyo Okuku, John M. Harlan, Jackson Orem, Corey Casper
Journal: Journal of Clinical Oncology (2014)

6620 Background: The HIV epidemic has contributed to the increasing incidence of cancer in sub-Saharan Africa (SSA), where most patients with cancer present at an advanced stage. However, improved access to HIV care and treatment centers in SSA may facilitate earlier diagnosis of cancer among HIV+ patients. To test this hypothesis, we characterized the stage of cancer and evaluated predictors of advanced stage at presentation among patients in Uganda. Methods: We conducted a retrospective analysis of adult patients who presented for care at 1 of 2 tertiary care sites in Kampala, Uganda with any of 5 specific cancers between 2003 and 2010. Demographic, clinical and laboratory data were abstracted from the medical record along with the outcome measure of advanced stage of disease (clinical stage 3 or 4). We utilized bivariate analyses to identify measures with p<0.20 for inclusion in a multivariate logistic regression model. Results: We analyzed 802 patients with the following cancers: cervical (39%), breast (27%), NHL (17%), esophageal (9%) and HL (8%). Nearly 80% presented at an advanced stage and 34% had HIV infection. The median age was 44 years. Over 90% of patients were symptomatic and the median duration of symptoms prior to presentation was 5 months. The median hemoglobin (hgb) level at presentation was 11.1g/dl (IQR 4.4 g/dl). In bivariate analyses of all cancer types, higher hgb, fewer symptoms, shorter symptom duration, younger age and HIV infection were associated with less advanced cancer. The association between HIV infection and less advanced stage of cancer was significant at p<0.01 for only the AIDS-defining cancers (i.e. cervical cancer and NHL). In the multivariate model, HIV+ patients were less likely (p=0.01) to present at an advanced stage, as were patients with higher hgb (p=0.03) and fewer symptoms (p<0.01). Conclusions: Patients with limited access to primary care may present with advanced cancer due to a delay in diagnosis. However, patients with HIV now have better access to clinical care. Utilization of this growing infrastructure to increase cancer screening and referral is promising and deserves continued support, as the prognosis of HIV+ patients with advanced cancer is characterized by poor survival, even in resource-abundant regions.
Abstract P4-10-03: Pterostilbene enhances TRAIL-induced apoptosis in TRAIL-resistant triple negative breast cancer cells
Authors: Y-C Wu, H-C Wang, C-J Chen, L-C Liu, T-D Way
Journal: Cancer Research (2017)

Abstract Triple-negative breast cancer (TNBC) is refractory to commonly used chemotherapeutic agents, as a result it leads to relatively poor prognosis. TNF-related apoptosis-inducing ligand (TRAIL) is currently in clinical trials as a treatment for cancer. Unfortunately, patients develop resistance to the TRAIL, therefore, agents that can sensitize cells to TRAIL are urgently needed. Pterostilbene (PTER), a natural dimethylated analog of resveratrol, is known to have diverse pharmacologic activities. In the present study, we investigated whether PTER affect TRAIL-induced apoptosis and its mechanism in TRAIL-resistant TNBC cells. First, our results indicated that PTER induced apoptosis in TNBC BT-20 cells. Next, we found that PTER enhanced TRAIL-induced apoptosis in TRAIL-resistant TNBC BT20 and MDA-MB-468 cells. We demonstrated that PTER induced both death receptor (DR)-5, DR4 and decreased decoy receptor (DcR)-2 expression. PTER also decreased the expression of anti-apoptotic proteins survivin, Bcl-xL and c-FLIPS/L, but had minimal effect on the expression of Bcl-2. PTER caused the cleavage of bid protein and enhanced the expression of pro-apoptotic Bax. Moreover, we found that PTER induced DR4 and DR5 expression through the reactive oxygen species (ROS) –mediated activation of extracellular signal-regulated kinase 1/2 (ERK 1/2) and p38 mitogen activated protein kinase (p38 MAPK). Overall, our results show that PTER can potentiate TRAIL-induced apoptosis through the ROS–mediated activation of ERK 1/2 and p38 MAPK leading to DR4 and DR5 induction and down-regulation of anti-apoptotic proteins. Citation Format: Wu Y-C, Wang H-C, Chen C-J, Liu L-C, Way T-D. Pterostilbene enhances TRAIL-induced apoptosis in TRAIL-resistant triple negative breast cancer cells [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 P4-10-03.
Edo- S101, a New Alkylating Histone-Deacetylase Inhibitor (HDACi) Fusion Molecule, Has Superior Activity Against Myeloma and B Cell Lymphoma and Strong Synergy with Proteasome Inhibitors in Vitro
Authors: Marianne Kraus, Jürgen Bader, Thomas Mehrling, Christoph Driessen
Journal: Blood (2014)
A Quantitative Analysis of Subclonal and Clonal Gene Mutations Occurring Pre- and Post-Therapy in 53 Cases of Chronic Lymphocytic Leukemia
Authors: Nisar A. Amin, Erlene Kuizon Seymour, Peter Ulintz, Kamlai Saiya-Cork, Brian Parkin, Kerby Shedden, Sami N. Malek
Journal: Blood (2015)
Clinical Significance of Complete Cytogenetic Response (CCyR) and Major Molecular Response (MMR) Achieved with Different Treatment Modalities Used As Frontline Therapy In Chronic Myeloid Leukemia (CML) Chronic Phase (CP)
Authors: Mona Lisa Alattar, Hagop M. Kantarjian, Elias Jabbour, Alfonso Quintas-Cardama, Elizabeth M Burton, Gautam Borthakur, Srdan Verstovsek, William G. Wierda, Marina Konopleva, Jan A. Burger, Susan O'Brien, Jorge E. Cortes
Journal: Blood (2011)
Abstract OT1-02-10: A phase 2 study of poziotinib in patients with HER2-positive metastatic breast cancer (MBC) who have received prior HER2 regimens for MBC
Authors: K Lathrop, J Lucas, JL Vacirca, G Bhat, MR Choi, M Naughton
Journal: Cancer Research (2017)

Abstract Background: Poziotinib is a novel, oral, quinazoline-based pan-HER inhibitor that irreversibly blocks signaling through the epidermal growth factor receptor (EGFR) family of tyrosine-kinase receptors, including EGFR (HER1/ErbB1/EGFR), HER2 (ErbB2), and HER4 (ErbB4), as well as HER receptor mutations. This, in turn, leads to inhibition of the proliferation of tumor cells that overexpress these receptors. It is well established that breast cancers are associated with a mutation in, or overexpression of, members of the EGFR receptor family. The primary objective of this Phase 2 study is to evaluate the Objective Response Rate (ORR) of poziotinib in patients with human epidermal growth factor receptor 2 (HER2)-positive MBC. The secondary efficacy variables are Progression-Free Survival (PFS), Disease Control Rate (DCR), Overall Survival (OS), and Time to Progression (TTP). Trial Design: This is a Phase 2, open-label, multicenter study to evaluate the efficacy, safety and tolerability of poziotinib in patients with HER2-positive MBC who have received at least 2 prior HER2- directed treatment regimens. Each treatment cycle is 21 days in duration. During each cycle, eligible patients receive 24 mg of poziotinib orally (as three 8-mg tablets) once daily for 14 days, followed by a 7 day treatment-free period. Eligibility Criteria: Eligible patients are at least 18 years of age, have confirmed HER2 overexpression, adequate hematologic, renal and hepatic function, and have received at least 2 prior HER2-directed therapy regimens, including trastuzumab and trastuzumab emtansine (TDM-1). Patients are excluded if they have prior exposure to poziotinib, a history of congestive heart failure, left ventricular ejection fraction &amp;lt;50%, unable to take oral medications, or have conditions that cause malabsorption. A 30 day wash out period from previous chemotherapeutic or radiation therapies is required. Statistical Methods: The purpose of this study is to evaluate the efficacy of poziotinib compared to the efficacy of other standard HER2-positive breast cancer treatments as reported in the literature. The ORR will be analyzed descriptively along with the 95% CI. The secondary efficacy variables will be analyzed descriptively. Target Accrual: Approximately 70 patients. Enrollment began February 2016. Contact Information: For more information or to refer a patient, email: spi-poz-201@sppirx.com or fax: 1-949-398-9711. Citation Format: Lathrop K, Lucas J, Vacirca JL, Bhat G, Choi MR, Naughton M. A phase 2 study of poziotinib in patients with HER2-positive metastatic breast cancer (MBC) who have received prior HER2 regimens for MBC [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 OT1-02-10.
Dose-Intensive (R-HCVAD) and High Dose Therapy (ASCT) Frontline Strategies More Than Double PFS Over Standard Therapy in MCL Patients
Authors: Anthony R Mato, Ewelina A Protomastro, Tania Zielonka, Tatyana Feldman, Scott D Rowley, Michele L Donato, Andrew L Pecora, Pritish K. Bhattacharyya, Mary Timberg, Susan Stives, Gabriella Gadaleta, Coleen Bejot, Andre Goy
Journal: Blood (2012)
Opioid Agonist Treatment for Patients With Dependence on Prescription Opioids
Authors: Suzanne Nielsen, Briony Larance, Nicholas Lintzeris
Journal: JAMA (2017)

Are different opioid agonist treatments (eg, methadone vs buprenorphine) associated with differences in efficacy for treating prescription opioid dependence, and is long-term maintenance of opioid agonist treatment associated with differences in efficacy compared with opioid taper or psychological treatments alone?For patients who are dependent on prescription opioids, long-term maintenance of opioid agonists is associated with less prescription opioid use and better adherence to medication and psychological therapies for opioid dependence compared with opioid taper or psychological treatments alone. Methadone maintenance was not associated with differences in therapeutic efficacy compared with buprenorphine maintenance treatment. Evidence quality was low to moderate.
Triple negative breast cancer: Adjuvant treatment and outcome of 62 patients
Authors: H. Koussis, A. Scola, M. Maruzzo, C. Ghiotto, E. Orvieto, F. Bozza, G. Zavagno, A. Jirillo
Journal: Journal of Clinical Oncology (2009)

e11636 Background: Triple negative breast cancer (TNBC) represents around 12–20%. They are high risk in view of poorly differentiated tumor shortened survival, younger age, increased mortality rate in the first 5 years, increased risk of brain metastasis, rapid progression from distant recurrence to death of patients. To provide further insight we have undertaken a comprehensive multi year review of demographics tumor features adjuvant treatment and outcomes in this patients group. Methods: A retrospective analysis of all patients with TNBC treated by adjuvant chemotherapy between January 2000 and June 2008 was done though chart review. Results: Sixty-two patients were seen in our institution. The median age at diagnosis was 57 years (range 27–86 yrs). Forty-three patients underwent conservative breast cancer surgery, mastectomy 19 patients. All patients underwent axillary lymph nodes dissection or sentinel lymph node biopsy. The stage of the disease at diagnosis was: I in 22, IIA in 22, IIB in 8, IIIA in 4, IIIB in 2 and stage 0 in 4 patients. After multidisciplinary evaluation 58 patients received adjuvant treatment with: anthracycline based regimen in 30, anthracycline plus taxane in 4 and 24 patients were treated with Cyclophosphamide, methotrexate and 5-Fluorouracil (CMF) regimen. After median 13 months (4–71), 8 (13.7%) relapses were observed: 6 out 8 were anthracycline based regimen treated. The pattern of disease spread was: local recurrence 5, lymph node 1, liver 2 patients. The median follow-up was 25 months (range 95–1). Conclusions: Treatment options for TNBC are limited because of lack of targeted treatment. Current, old and new drugs alone or in combination (anthracycline, taxanes, platinum salts, bevacizumab, erlotinib, dasatinib, cetuximab) are used in an experimental setting. No significant financial relationships to disclose.