tbuckley/cabot-search huggingface dataset:
CDK7 Inhibition Suppresses Castration-Resistant Prostate Cancer through MED1 Inactivation
Authors: Reyaz ur Rasool, Ramakrishnan Natesan, Qu Deng, Shweta Aras, Priti Lal, Samuel Sander Effron, Erick Mitchell-Velasquez, Jessica M. Posimo, Shannon Carskadon, Sylvan C. Baca, Mark M. Pomerantz, Javed Siddiqui, Lauren E. Schwartz, Daniel J. Lee, Nallasivam Palanisamy, Goutham Narla, Robert B. Den, Matthew L. Freedman, Donita C. Brady, Irfan A. Asangani
Journal: Cancer Discovery (2019)

Metastatic castration-resistant prostate cancer (CRPC) is a fatal disease, primarily resulting from the transcriptional addiction driven by androgen receptor (AR). First-line CRPC treatments typically target AR signaling, but are rapidly bypassed, resulting in only a modest survival benefit with antiandrogens. Therapeutic approaches that more effectively block the AR-transcriptional axis are urgently needed. Here, we investigated the molecular mechanism underlying the association between the transcriptional coactivator MED1 and AR as a vulnerability in AR-driven CRPC. MED1 undergoes CDK7-dependent phosphorylation at T1457 and physically engages AR at superenhancer sites, and is essential for AR-mediated transcription. In addition, a CDK7-specific inhibitor, THZ1, blunts AR-dependent neoplastic growth by blocking AR/MED1 corecruitment genome-wide, as well as reverses the hyperphosphorylated MED1-associated enzalutamide-resistant phenotype. In vivo, THZ1 induces tumor regression of AR-amplified human CRPC in a xenograft mouse model. Together, we demonstrate that CDK7 inhibition selectively targets MED1-mediated, AR-dependent oncogenic transcriptional amplification, thus representing a potential new approach for the treatment of CRPC. SIGNIFICANCE: Potent inhibition of AR signaling is critical to treat CRPC. This study uncovers a driver role for CDK7 in regulating AR-mediated transcription through phosphorylation of MED1, thus revealing a therapeutically targetable potential vulnerability in AR-addicted CRPC.See related commentary by Russo et al., p. 1490.This article is highlighted in the In This Issue feature, p. 1469.
Improving person-centered communication of goals, proxy, and advance directives in older patients with advanced cancer: Secondary analysis from a University of Rochester NCI Community Oncology Research Program (NCORP) cluster randomized controlled trial (CRCT).
Authors: Marie Anne Flannery, Eva Culakova, Kah Poh Loh, Ronald M. Epstein, Charles Stewart Kamen, Spencer Obrecht, Nataliya Melnyk, Mary I. Whitehead, Jodi Geer, Jeffrey K. Giguere, Karen Michelle Mustian, Paul Duberstein, William Dale, Supriya Gupta Mohile
Journal: Journal of Clinical Oncology (2019)

11523 Background: Quality person-centered care relies on effective communication between the clinical team and the patient/caregiver eliciting goals and discussing wishes. In a PCORI- and NCI-funded CRCT, we found that providing community-based oncologists with geriatric assessment-guided recommendations led to more and higher quality discussions of age-related issues for older patients with advanced cancer. In this secondary analysis, we assessed whether specific recommendations to oncologists to discuss patient goals, proxy and advance directives resulted in increased communication about these topics. Methods: Patients aged 70+ with advanced solid tumors or lymphoma and at least one impaired geriatric domain (e.g., function, cognition) were enrolled (URCC 13070; PI: Mohile). Oncology practices were randomized to the intervention (oncologists received recommendations to elicit goals and discuss wishes) or usual care. The clinic visit after the oncologist received recommendations was recorded and transcribed; two blinded coders evaluated the transcripts for discussion of the specific topic areas recommended in the intervention. Between arm differences were compared using generalized linear models controlling for practice cluster. Results: From 2014-17, 528 patients (284 intervention) provided transcripts from 31 practices (mean age = 77, range 70-96 years; 49% female; mixed cancer diagnoses). Topics related to patient goals, proxy and advance directive wishes were more often discussed in the intervention arm (goals of care preferences: 9 vs 2%, p = .02, treatment goals: 35 vs 20%. p = .04, elicit caregiver input: 28 vs 3%. p &lt; .01, assess values and goals: 25 vs 7%, p = .07, health care proxy: 40 vs 1%, p = .004, advance directive: 25 vs 1%, p = .002). Conclusions: In this community-based study of older adults providing recommendations to oncologists to discuss specific topics resulted in increased person-centered discussions with patients and caregivers about goals, proxy and advance directive wishes. However, the content areas were discussed in less than half of all visits. Clinical trial information: NCT02107443.
Online education about immunotherapy for melanoma: Outcomes over time.
Authors: Kinjal Parikh, Katie S. Lucero, Patti Repetto, Haleh Kadkhoda, Charlotte Warren, Jacqueline Gearhart, Jeffrey S. Weber
Journal: Journal of Clinical Oncology (2019)

10533 Background: The indications and use of immune checkpoint inhibitors (ICIs) for the treatment of melanoma have grown since the first drug approval in 2011. The expanding evidence base and number of indications challenges clinicians to stay up to date with how best to integrate these agents into treatment pathways. The objective of this study was to assess trends over time in oncologists’ knowledge, competence, and confidence using ICIs in the treatment of melanoma. Methods: A series of online continuing medical education (CME) activities about the role of ICIs in the treatment of melanoma was launched in April 2014; 18 included multiple-choice knowledge/competence questions and a confidence question assessed on a 5-point Likert-type scale before and immediately after the activity. Activities that had at least 30 oncologists participate pre/post are included in this analysis. A pre-/post-assessment study design was used, and educational effect was assessed with Chi-square tests. Analyses were conducted to examine trends in knowledge, competence, and confidence over four years on a quarterly basis. Weighted averages in each of the outcomes were calculated by quarter. Results: A total of 92,373 learners participated from April 2014-March 2018, including 57,432 physicians, of whom 11,922 were oncologists. The average increases from pre- to post-test for knowledge- (12 activities), competence- (11 activities), and confidence-based (9 activities) questions were 21%, 15%, and 6%, respectively (P &lt; 0.01 for all comparisons). The absolute increase in knowledge from pre-test in 2014 (48%) to post-test in 2018 (78%) was 30 percentage points; and for competence, 6% (from 62% in 2014 to 68% in 2018). The mean confidence rating pre-test in 2015 was 2.51 versus 3.37 post-test in 2018. Conclusions: Online CME improves oncologists’ knowledge, competence, and confidence using ICIs in the treatment of melanoma. As new data emerge and indications expand, new educational activities are necessary to reinforce existing knowledge, close persistent gaps, and increase oncologists’ confidence using ICIs in this clinical setting.
18Fluorodeoxyglucose Accumulation in Arterial Tissues Determined by PET Signal Analysis
Authors: Rozh H. Al-Mashhadi, Lars P. Tolbod, Lars Ø. Bloch, Martin M. Bjørklund, Zahra P. Nasr, Zheer Al-Mashhadi, Michael Winterdahl, Jørgen Frøkiær, Erling Falk, Jacob F. Bentzon
Journal: Journal of the American College of Cardiology (2019)

Arterial 18fluorodeoxyglucose (FDG) positron emission tomography (PET) is considered a measure of atherosclerotic plaque macrophages and is used for quantification of disease activity in clinical trials, but the distribution profile of FDG across macrophages and other arterial cells has not been fully clarified. The purpose of this study was to analyze FDG uptake in different arterial tissues and their contribution to PET signal in normal and atherosclerotic arteries. Wild-type and D374Y-PCSK9 transgenic Yucatan minipigs were fed a high-fat, high-cholesterol diet to induce atherosclerosis and subjected to a clinical FDG-PET and computed tomography scan protocol. Volumes of arterial media, intima/lesion, macrophage-rich, and hypoxic tissues were measured in serial histological sections. Distributions of FDG in macrophages and other arterial tissues were quantified using modeling of the in vivo PET signal. In separate transgenic minipigs, the intra-arterial localization of FDG was determined directly by autoradiography. Arterial FDG-PET signal appearance and intensity were similar to human imaging. The modeling approach showed high accuracy in describing the FDG-PET signal and revealed comparable FDG accumulation in macrophages and other arterial tissues, including medial smooth muscle cells. These findings were verified directly by autoradiography of normal and atherosclerotic arteries. FDG is taken up comparably in macrophage-rich and -poor arterial tissues in minipigs. This offers a mechanistic explanation to a growing number of observations in clinical imaging studies that have been difficult to reconcile with macrophage-selective FDG uptake.
P032 Sialic acids inhibit neutrophil extracellular trap formation
Authors: AK Molhoek, MM van Gool, RE Li, M van Egmond, SJ van Vliet, Y van Kooyk
Journal: Annals of the Rheumatic Diseases (2019)

<h3>Career situation of first and presenting author</h3> Student for a master or a PhD <h3>Introduction</h3> In rheumatoid arthritis (RA) activated neutrophils produce neutrophil extracellular traps (NETs), which provide a source of autoantigens that drives the autoimmune process.<sup>1</sup> To identify novel immune processes that dampened neutrophil activity, we investigated a family of inhibitory glycan-binding receptors (Siglecs) that bind a specific type of glycan; called sialic acids.<sup>2</sup> We hypothesize that sialic acid-mediated triggering of siglecs on neutrophils, which express siglec-5, –9 and −14, will reduce their activation. In this study we focused on dampening the activity of neutrophils and thereby NET formation. <h3>Methods</h3> Polymorphonuclear cells (PMNs) were isolated from healthy donors. Neutrophil binding of sialic acid-containing glycoconjugates was assessed by flow cytometry. Neutralizing antibodies for siglec-5/14 and −9 were used to block the interaction with the sialic acid glycoconjugates. For functional assays a branched synthetic molecule containing sialic acids (sialic acid dendrimer) was used. PMNs were rested for 1 hour at 37°C followed by stimulation of sialic acids dendrimers for 30 min. Subsequently, IgA coated beads were added for 30 min to activate the neutrophils. NETosis was quantified via Sytoxgreen and visualised via microscopy, and phagocytosis was measured by flow cytometry. <h3>Results</h3> Binding of sialic acid glycoconjugates was observed on neutrophils. Neutralizing siglec-5/14 and −9 receptor almost completely abolished sialic acid glycoconjugate binding to neutrophils. Neutrophils activated with IgA beads released NETs, as confirmed via microscopy. Triggering neutrophils with sialic acid dendrimer reduced this process of NETosis. The capacity to engulf IgA beads was not affected by sialic acid dendrimer stimulation. <h3>Conclusions</h3> Neutrophils stimulated with sialic acid dendrimers show reduced activation. Patients with RA might benefit from treatment with sialic acid to dampen neutrophil-mediated autoimmune response. <h3>References</h3> Wright HL, Moots RJ, Edwards SW. The multifactorial role of neutrophils in rheumatoid arthritis. <i>Nat Rev Rheumatol</i> 2014;10(10):593–601. Macauley MS, Crocker PR, Paulson JC. Siglec-mediated regulation of immune cell function in disease. <i>Nat Rev Immunol</i> 2014;14(10):653–66. <h3>Disclosure of Interest</h3> None declared.
Discovery of an autoantibody signature for the early diagnosis of knee osteoarthritis: data from the Osteoarthritis Initiative
Authors: María Camacho-Encina, Vanesa Balboa-Barreiro, Ignacio Rego-Perez, Florencia Picchi, Jennifer VanDuin, Ji Qiu, Manuel Fuentes, Natividad Oreiro, Joshua LaBaer, Cristina Ruiz-Romero, Francisco J Blanco
Journal: Annals of the Rheumatic Diseases (2019)

Objective To find autoantibodies (AAbs) in serum that could be useful to predict incidence of radiographic knee osteoarthritis (KOA). Design A Nucleic-acid Programmable Protein Arrays (NAPPA) platform was used to screen AAbs against 2125 human proteins in sera at baseline from participants free of radiographic KOA belonging to the incidence and non-exposed subcohorts of the Osteoarthritis Initiative (OAI) who developed or not, radiographic KOA during a follow-up period of 96 months. NAPPA-ELISA were performed to analyse reactivity against methionine adenosyltransferase two beta (MAT2β) and verify the results in 327 participants from the same subcohorts. The association of MAT2β-AAb levels with KOA incidence was assessed by combining several robust biostatistics analysis (logistic regression, Receiver Operating Characteristic and Kaplan-Meier curves). The proposed prognostic model was replicated in samples from the progression subcohort of the OAI. Results In the screening phase, six AAbs were found significantly different at baseline in samples from incident compared with non-incident participants. In the verification phase, high levels of MAT2β-AAb were significantly associated with the future incidence of KOA and with an earlier development of the disease. The incorporation of this AAb in a clinical model for the prognosis of incident radiographic KOA significantly improved the identification/classification of patients who will develop the disorder. The usefulness of the model to predict radiographic KOA was confirmed on a different OAI subcohort. Conclusions The measurement of AAbs against MAT2β in serum might be highly useful to improve the prediction of OA development, and also to estimate the time to incidence.
Abstract 15216: Circadian Autonomic Inflexibility: A Marker of Ischemic Heart Disease
Authors: Anish Shah, Rachel Lampert, Jack Goldberg, J. Douglas Bremner, Viola Vaccarino, Amit Shah
Journal: Circulation (2018)

Introduction: About one-half of sudden cardiac deaths occur in those without known CAD suggesting the need for better risk-stratification tests. Autonomic dysfunction, measured by low heart rate va...
Fulvestrant Plus Vistusertib vs Fulvestrant Plus Everolimus vs Fulvestrant Alone for Women With Hormone Receptor–Positive Metastatic Breast Cancer
Authors: Peter Schmid, Matthias Zaiss, Catherine Harper-Wynne, Marta Ferreira, Sidharth Dubey, Stephen Chan, Andreas Makris, Gia Nemsadze, Adrian M. Brunt, Sherko Kuemmel, Isabel Ruiz, Antonia Perelló, Anne Kendall, Janet Brown, Hartmut Kristeleit, John Conibear, Cristina Saura, Julien Grenier, Károly Máhr, Michael Schenker, Joohyuk Sohn, Keun Seok Lee, Christopher J. Shepherd, Elisabeth Oelmann, Shah-Jalal Sarker, Aaron Prendergast, Patricia Marosics, Atiyyah Moosa, Cheryl Lawrence, Carike Coetzee, Kelly Mousa, Javier Cortés
Journal: JAMA Oncology (2019)

Randomized clinical trials have demonstrated a substantial benefit of adding everolimus to endocrine therapy. Everolimus inhibits the mammalian target of rapamycin complex 1 (mTORC1) complex but not mTORC2, which can set off an activating feedback loop via mTORC2. Vistusertib, a dual inhibitor of mTORC1 and mTORC2, has demonstrated broad activity in preclinical breast cancer models, showing superior activity to everolimus.
Phase I/II trial of the CXCR4 inhibitor plerixafor in combination with bortezomib as a chemosensitization strategy in relapsed/refractory multiple myeloma
Authors: Irene M. Ghobrial, Chia‐Jen Liu, Oksana Zavidij, Abdel K. Azab, Rachid Baz, Jacob P. Laubach, Yuji Mishima, Philippe Armand, Nikhil C. Munshi, Frank Basile, Michael Constantine, James Vredenburgh, Adam Boruchov, Pamela Crilley, Patrick M. Henrick, Kalvis T. V. Hornburg, Houry Leblebjian, Stacey Chuma, Kaitlen Reyes, Kimberly Noonan, Diane Warren, Robert Schlossman, Claudia Paba‐Prada, Kenneth C. Anderson, Edie Weller, Lorenzo Trippa, Kenneth Shain, Paul G. Richardson
Journal: American Journal of Hematology (2019)

Abstract We tested the hypothesis that using CXCR4 inhibition to target the interaction between the tumor cells and the microenvironment leads to sensitization of the tumor cells to apoptosis. Eligibility criteria included multiple myeloma (MM) patients with 1‐5 prior lines of therapy. The purposes of the phase I study were to evaluate the safety and maximal‐tolerated dose (MTD) of the combination. The treatment‐related adverse events and response rate of the combination were assessed in the phase II study. A total of 58 patients were enrolled in the study. The median age of the patients was 63 years (range, 43‐85), and 78% of them received prior bortezomib. In the phase I study, the MTD was plerixafor 0.32 mg/kg, and bortezomib 1.3 mg/m 2 . The overall response rate for the phase II study was 48.5%, and the clinical benefit rate 60.6%. The median disease‐free survival was 12.6 months. The CyTOF analysis demonstrated significant mobilization of plasma cells, CD34+ stem cells, and immune T cells in response to plerixafor. This is an unprecedented study that examines therapeutic targeting of the bone marrow microenvironment and its interaction with the tumor clone to overcome resistance to therapy. Our results indicate that this novel combination is safe and that the objective response rate is high even in patients with relapsed/refractory MM. ClinicalTrials.gov , NCT00903968.
"Suggestion" and Common Sense.
Journal: JAMA (1923)

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 HomeNew OnlineCurrent IssueFor Authors 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) Podcasts Clinical Reviews Editors' Summary Medical News Author Interviews More 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 journal
Preparation of Decellularized Triphasic Hierarchical Bone‐Fibrocartilage‐Tendon Composite Extracellular Matrix for Enthesis Regeneration
Authors: Mingzhen Su, Qi Zhang, Yiwei Zhu, Shengyu Wang, Jiawen Lv, Jiaan Sun, Pengchen Qiu, Shunwu Fan, Keke Jin, Lei Chen, Xianfeng Lin
Journal: Advanced Healthcare Materials (2019)

Abstract Tendon to bone (enthesis) rupture, which may cause disability and persistent pain, shows high rate of re‐rupture after surgical repair. Tendon or enthesis scaffolds have been widely studied, but few of these materials can recapitulate the tissue continuity. Thus, this study is conducted to prepare a triphasic decellularized bone‐fibrocartilage‐tendon (D‐BFT) composite scaffold. The D‐BFT scaffold is developed using a combination of physical, chemical, and enzymatic treatments using liquid nitrogen, Triton‐X 100, sodium‐dodecyl sulfate, and DNase I, which effectively removes the cell components while preserving the biological composite and microstructure. Moreover, the mechanical properties of D‐BFT are highly preserved and similar to those of the human Achilles tendon. Additionally, in vitro, mesenchymal stem cells (MSCs) adhered, proliferated, and infiltrated into the D‐BFT scaffold, and MSC differentiation is confirmed by up‐regulation of osteogenic‐related and tenogenic‐related genes. The repair outcomes are explored by applying the D‐BFT scaffold in the model of femur‐tibia defects in vivo, which shows good repair results. Thus, the D‐BFT scaffold developed in this study is a promising graft for enthesis regeneration.
A phase I-II study of tipifarnib plus weekly paclitaxel (P) followed by dose-dense doxorubicin/cyclophosphamide (AC) in stage IIb-IIIc breast cancer (BC).
Authors: Eleni Andreopoulou, Ivette Sara Vigoda, Vicente Valero, Dawn L. Hershman, George Raptis, Linda T. Vahdat, Hyo S. Han, John Joseph Wright, Christine M. Pellegrino, Ricardo H. Alvarez, Karen Fehn, Susan Fineberg, Joseph A. Sparano
Journal: Journal of Clinical Oncology (2013)

1118 Background: Tipifarnib (T) is an orally bioavailable farnesyl transferase inhibitor (FTI) that has activity in metastatic BC (J Clin Oncol 2003; 21:2492-9). We previously showed that adding T (200 mg PO BID days 2-7) to preoperative AC was associated with a higher pathologic complete response (pCR) than expected compared with historical data (Clin Cancer Res. 2009;15;2942-8), and preclinical data suggest that FTIs enhance the antineoplastic effects of P (Cancer Res 2005; 65:3883-93). Methods: Eligible pts with HER2-negative clinical stage IIB-IIIC BC received 12 weekly doses of P (80 mg/m2) followed by AC (60/600 mg/m2 every 2 weeks and pegfilgrastim), plus T 100 mg or 200 mg on days 1-3 of each P dose in cohorts of 3-6 pts in the phase I (and T 200 mg PO BID on days 2-7 each AC cycle in both the phase I and II). Simon two-stage design used for the phase II in two strata generally resistant to neoadjuvant chemotherapy. The trial was powered to detect an improvement in breast pathologic complete response (pCR) from 15% to 35% in each stratum (alpha 0.10, beta 0.10), which required breast pCR in at least 4/19 eligible pts in stage I to proceed to stage II, and at least 8/33 pts in stage I and II to be considered promising. Results: Sixty patients accrued in both the phase I and II. Two patients were non evaluable. There were no DLTs in the first 6 evaluable patients treated at dose level 1 and 2.The recommended phase II dose of T identified in the phase I trial was 200 mg BID.All protocol therapy was completed in 43/55 pts (78%) in the phase II, and one pt died of pneumonitis during therapy of uncertain cause. The prespecified efficacy endpoint was not met for either stratum. Conclusions: The addition of the FTI tipifarnib to neoadjuvant sequential weekly paclitaxel followed by dose-dense AC did not result in a higher breast pCR rate compared with historical data. Clinical trial information: NCT00049114. [Table: see text]