tbuckley/cabot-search huggingface dataset:
First-in-human trial of ONC201 in patients with refractory solid tumors.
Authors: Mark N. Stein, Nancy Chan, Ann W. Silk, Bruno Fang, Howard Kaufman, Bruce George Haffty, Tracie Saunders, Saltanat Najmi, Ling Zheng, Martin Stogniew, Joshua E. Allen, Wolfgang Oster, Joseph R. Bertino, Janice M. Mehnert
Journal: Journal of Clinical Oncology (2016)

2514 Background: ONC201 is an orally active, first-in-class small molecule activator of the integrated stress response that selectively upregulates ATF4 to trigger tumor cell death. Preclinical studies have established the compelling antitumor efficacy of the small molecule in a range of advanced solid tumors as well as its excellent safety profile in animals. A first-in-human phase I study of ONC201 was conducted to determine its recommended phase II dose (RP2D) in patients with advanced solid tumors. Methods: This open-label study treated 10 patients during the single-patient cohort dose escalation portion of the trial. The human starting dose was 125mg, which represents 1/10th of the no-adverse-adverse-effect-level in animal toxicology studies using standard allometric conversion. Results: The RP2D was defined as 625 mg and no Grade > 1 drug-related adverse events occurred on this trial, which enrolled patients at increasing dose levels of 125mg, 250mg, 375mg, 500mg, and finally 625mg. Pharmacokinetic analysis revealed saturation of absorption at 375mg, suggesting dose escalation above 625mg was not warranted. The terminal half-life was 9.6 hours, Cmax values ranged from 1.5 - 7.5 ug/mL (~3.9-19.4 uM), and the AUC was 25 hr ug/L. Prolonged induction of caspase-cleaved keratin 18 and induction of TRAIL was observed in serum samples. Eight of 10 patients had stable disease and one patient with endometrial cancer underwent a mixed response. 17 of 25 additional patients have been accrued in an ongoing expansion phase. The available results from the expansion cohort confirm the excellent safety, and the pharmacokinetic and pharmacodynamic profiles of ONC201 at the recommended phase II dose of 625mg every three weeks. Conclusions: This study demonstrates that ONC201 is well tolerated and active at an oral dose of 625mg, warranting further evaluation in lead indications. Clinical trial information: NCT02250781.
BASCULE syndrome: old wine in new bottles?
Authors: D.H. McGibbon
Journal: British Journal of Dermatology (2016)

Bessis et al1 describe what they believe to be a new syndrome, Bier's Anemic Spots associated with Cyanosis and Urticaria-Like Eruption. In doing so they have provided a nice description and beautiful pictures of orthostatic acrocyanosis (OA).2 They describe four cases, three of whom triggered the eruption after standing and one by mechanical pressure. There was a uniform background cyanosis in which pink macules were scattered. In the centre of some of these pink macules pinpoint to 1-2mm papules are seen.

This article is protected by copyright. All rights reserved.
A phase 2 study of the histone deacetylase (HDAC) inhibitor mocetinostat in patients with urothelial carcinoma (UC) and inactivating alterations of acetyltransferase genes.
Authors: Noah M. Hahn, Joel Picus, Richard Martin Bambury, Sumanta Kumar Pal, Lowell L. Hart, Petros Grivas, Matthew I. Milowsky, Ajjai Shivaram Alva, Guru Sonpavde, Amir Mortazavi, Joaquim Bellmunt, Elizabeth A. Guancial, Sumati Gupta, Richard C. Chao, Mary A. Collier, James Christensen, Isan Chen, Jonathan E. Rosenberg
Journal: Journal of Clinical Oncology (2015)

TPS4575 Background: Platinum-based chemotherapy is standard treatment for advanced UC, but no standard exists after first-line therapy. Mocetinostat (MGCD0103) is a spectrum selective inhibitor of HDAC 1, 2, 3 and 11. Site specific histone acetylation is regulated by the interaction of CREBBP and EP300 acetyltransferases with HDACs 1 and 2. Inactivating alterations of the genes CREBBP and/or EP300 are associated with responsiveness to mocetinostat in preclinical cancer models and are reported in the tumors of ~28% of patients (pts) with UC (TCGA, Nature2014; 507:315), providing a clinical proof of principle opportunity for mocetinostat. Methods: This single-arm Phase 2 trial evaluates the efficacy of mocetinostat in pts with unresectable or metastatic UC and inactivating alterations of CREBBP and/or EP300 as determined by next generation gene sequencing performed by qualified local labs or the FoundationOne platform. Eligible pts have received at least one prior platinum-based chemotherapy regimen and have measurable disease. The primary endpoint is Objective Response Rate (ORR) by RECIST 1.1. Secondary objectives evaluate safety, progression-free and overall survival, and pharmacokinetics. Exploratory objectives assess predictive biomarkers of response and mechanisms of acquired resistance through analysis of gene alterations in tumor and circulating tumor DNA. The study will enroll in 3 stages; among 15 pts, if at least 3 experience objective response or 6 are progression-free at 4-months, 18 pts will be added; if at least 9 objective responses are observed among these 33 pts, 67 pts will be added, for a total of 100 pts. Mocetinostat capsules are administered orally three times weekly, beginning with 70 mg per dose during the first cycle in pts in the first stage and then increasing to 90 mg per dose for the remainder of the study, as tolerability permits. The final sample size of 100 pts will provide 99% power to reject the null hypothesis that ORR rate is ≤ 15% (assuming a true ORR of 35%), using an exact test for single proportion (two-sided α = 5%). Status: Enrollment into the study opened in December 2014. Clinical trial information: NCT02236195.
Abstract 406: Enhancer templated RNAs as predictors of therapeutic response to epigenetic therapy
Authors: Ron Firestein, Mark McCleland, Kathryn Mesh, Florian Gnad
Journal: Cancer Research (2016)

Abstract Colon tumors arise in a stepwise fashion from either discrete genetic perturbations or epigenetic dysregulation. To uncover the key epigenetic regulators that drive colon cancer growth, we utilized a CRISPR loss of function screen and identified a number of essential genes, including the Bromodomain and Extraterminal (BET) protein, BRD4. We find BRD4 is critical for colon cancer proliferation and its loss leads to differentiation effects in vivo. JQ1, a BET inhibitor, preferentially reduced growth in a subset of epigenetically dysregulated colon cancers, characterized by the CpG island methylator phenotype (CIMP). Integrated transcriptomic and genomic analyses defined a distinct super-enhancer in CIMP(+) colon cancers that regulates cMYC transcription. We find that the CCAT1 long non-coding RNA (lncRNA) is transcribed from this super-enhancer and is exquisitely sensitive to BET inhibition. Concordantly, cMYC transcription and cell growth were tightly correlated with the presence of CCAT1 RNA in a variety of tumor types. Taken together, we propose CCAT1 as a clinically tractable biomarker for identifying patients likely to benefit from BET inhibitors. Citation Format: Ron Firestein, Mark McCleland, Kathryn Mesh, Florian Gnad. Enhancer templated RNAs as predictors of therapeutic response to epigenetic therapy. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 406.
Abstract 3654: In vivo CRISPR screen identidied Nf1 as a new tumor suppressor recurrently inactivated in liver cancer
Authors: Chunqing Song
Journal: Cancer Research (2016)

Abstract Our CRISPR screen identified NF1, encoding a RasGAP, as a new tumor-suppressor gene. CRISPR mediated loss-of-function mutations in NF1 led to increase RAS activation and increased tumor formation in liver cells. NF1 expression was reduced in 60% (225/373) of human HCC and was associated with reduced patient survival. Point mutations of NF1 was found in 3% of HCC. These findings identify NF1 inactivation as a new tumor suppressor in the liver and highlight the importance of RasGAPs in liver cancer. Citation Format: Chunqing Song. In vivo CRISPR screen identidied Nf1 as a new tumor suppressor recurrently inactivated in liver cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3654.
MicroRNA quantitative profiling for micrometastasis detection in gastrointestinal cancer
Authors: M. Valladares Ayerbes, S. M. Díaz Prado, V. Medina Villaamil, I. Santamarina Caínzos, M. Haz Conde, M. J. Lorenzo Patiño, G. Aparicio Gallego, G. Alonso Curbera, M. Reboredo López, L. alvo CMartínez, C. H. U. Juan Canalejo
Journal: Journal of Clinical Oncology (2008)

15058 Background: Quantitative Real Time PCR (qPCR) is a highly sensitive method for detecting nucleic acids of circulating tumor cells. MicroRNAs, small non-coding and single-stranded RNAs, are proposed as new molecular markers for cancer diagnosis. Recently studies demonstrated miRNA expression profiles specific of each tissue and even of each tumor type. We hypothesized tumor specific miRNA detection and quantification in peripheral blood samples could reflect the presence of circulating tumor cells.Objective: Identify miRNAs with diagnostic value for circulating tumor cells detection in blood samples from patients with gastrointestinal (GI) cancer. Use bioinformatic tools to select miRNA highly expressed in GI cancer but absent in healthy blood and bone marrow. Methods: miRGator, miRBase, smiRNAdb and GeneHub-GEPIS SEARCH databases were used for bioinformatic profiling. RNA enriched in miRNAs was isolated from cell lines (n=13), normal colonic mucosa (n=3) and healthy blood samples (n=19). mirVana miRNA and RiboPure Blood isolation kits respectively were used. qPCR experiments were performed on a LightCycler 480 Instrument (Roche) using qRT-PCR miRNA Detection Kit (Ambion). U6 and 5S miRNAs were used as internal controls. Results: Potential up-regulated miRNAs of note from this bioinformatic analysis include tissue-specific and oncogenic miRNAs. Among this miR-21, miR-20, miR-194, miR-17–5p, miR-29b, miR-27a, miR-155 were selected. In order to validate the usefulness of this miRNAs as molecular markers for blood micrometastasis detection, qPCR experiments were performed. Among all of them, miR-21, miR-29b and miR-194 showed the most remarkable results. They were overexpressed in all GI tumor cell lines. Conclusions: These results suggest that this bioinformatic approach is a useful high-throughout method to identified GI tumor-associated miRNAs. These selected miRNAs should be further evaluated for their potential as GI tumor markers. Supported by: Grants PI06/1541 and PI07/0477 from Fondo de Investigaciones Sanitarias (FIS), Instituto de Salud Carlos III S. Díaz Prado is beneficiary of an Isidro Parga Pondal contract from Xunta de Galicia (Spain). No significant financial relationships to disclose.
Planned Parenthood v Casey [letter]
Authors: Duraski Rm
Journal: JAMA (1993)

J. Benshoof opposes the requirement that parents provide their consent in order for their minor children to have an abortion.  This author claims that her article Planned Parenthood vs. Casey: The Impact of the New Undue Burden Standard on Reproductive Health Care is full of misleading statements.  He considers Benshoof to be a proabortion apologist who in emphasizing the right to privacy as the central issue obscures the issue of the existence of human life in the fetus.  The author further claims that Benshoof misstates Roe vs. Wade on the issue of fetus viability.  Benshoof has problems with the Pennsylvania informed consent statute.  This author instead believes that the requirements help ensure good medical practice.  A patient should always know all the options before making a decision.  Accordingly counseling which fails to present alternatives to abortion is biased in favor of abortion.
P65 Why has emergency oxygen administration failed to improve despite ‘best practice’ interventions?: Abstract P65 Table 1.
Authors: SG Paranahewa, S Sithamparanathan, R Taylor, T Pepper, T O'Shaughnessy, WM Ricketts
Journal: Thorax (2013)

<h3>Introduction and Objectives</h3> Despite instigating all operational and educational recommendations in the BTS Emergency Oxygen Guideline (local policy, standardised prescription and bedside documentation and training) our performance in the BTS annual Emergency Oxygen Audit has failed to improve, in line with national findings, with only 56% of oxygen prescribed, none signed for and 66.7% outside the target range at the most recent audit. Our aim was to investigate the reasons underlying this. <h3>Methods</h3> A link to an online survey was emailed to all junior doctors and nursing staff on hospital mailing lists. The survey was designed to utilise Pathman’s four stages of guideline compliance (awareness, agreement, adoption and adherence) (1). <h3>Results</h3> Results are summarised in Table 1. Free text comments focussed on a desire by both doctors and nurses for the prescription chart to be clearer and to be located in a more prominent area of the drug chart, whilst doctors were concerned their prescriptions were not followed, nurses commented that doctors frequently failed to prescribe oxygen correctly, if at all. <h3>Discussion</h3> Responders reported good levels of awareness, agreement and adoption, yet adherence, as measured by audit, performance in prescribing and administration scenarios and an inability to locate guidelines on the Trust intranet would suggest that further intervention is required. The high level of belief that their own application of the guidelines, by both medical and nursing staff, is good would suggest that either this self-selected cohort perform better than their less interested peers or that lack of awareness, so called “unconscious incompetence”(2), is a concern. Generally the desire is for yet more training, however, our concern remains that this has limited effect and systems need to be strengthened to improve oxygen prescribing and administration. <h3>References</h3> 1. Pathman <i>et al</i>. The awareness-to-adherence model of the steps to clinical guideline compliance. The case of paediatric vaccine recommendations. <i>Medical Care</i> 1996;34:873–89. 2. Conscious Competency - The Mark of a Competent Instructor. <i>The Personnel Journal.</i> 1974;53:538–9.
Brief Report: Arthritis in KRN T Cell Receptor–Transgenic Mice Does Not Require Interleukin‐17 or Th17 Cells
Authors: Jennifer L. Auger, Hannah M. Cowan, Brianna J. Engelson, Sakeen W. Kashem, Immo Prinz, Bryce A. Binstadt
Journal: Arthritis & Rheumatology (2016)

Objective Th17 cells and interleukin‐17 (IL‐17) cytokine family members are implicated in the pathogenesis of many rheumatic diseases. Most studies in mouse models of inflammatory arthritis have demonstrated a key role for the proinflammatory cytokine IL‐17A and its receptor, the IL‐17 receptor (IL‐17R) A/C heterodimer. The aim of this study was to use a rigorous genetic approach to evaluate the contribution of Th17 cells and IL‐17 in the autoantibody‐dependent KRN T cell receptor–transgenic mouse model of arthritis. Methods We bred KRN mice expressing the major histocompatibility complex class II molecule A g7 (referred to as K/B/g7 mice) and genetically lacking the related cytokines IL‐17A and IL‐17F or their critical receptor subunit, IL‐17RA. Using bone marrow transplantation, we generated mice in which hematopoietic cells from K/B/g7 donor mice lacked the key Th17‐differentiating transcription factor, retinoic acid receptor–related orphan nuclear receptor γt (Rorγt). Results K/B/g7 mice lacking both IL‐17A and IL‐17F produced normal titers of pathogenic autoantibodies, and arthritis developed in a typical manner. Similarly, neither IL‐17RA nor Rorγt expression by hematopoietic cells was required for disease development in this model. Conclusion Despite prior reports suggesting that Th17 cells and IL‐17A are crucially involved in the pathogenesis of arthritis in K/BxN mice, the results presented here provide genetic evidence that IL‐17A and IL‐17F, IL‐17RA, and Rorγt expression by hematopoietic cells are dispensable for normal arthritis progression in the K/B/g7 mouse model system. We discuss potential explanations for the discrepancies between these 2 highly similar model systems. These findings plus those in other mouse models of arthritis provide insight regarding why therapeutic biologic agents targeting the Th17/IL‐17 axis are beneficial in some human rheumatic diseases but not others.
Abstract 14731: Association of Longitudinal Changes in CRP, IL-6, and Fibrinogen Level With Cardiovascular Disease Events: The Multi-Ethnic Study of Atherosclerosis (MESA)
Authors: Hooman Bakhshi, Mohammad R Ostovaneh, Bharath Ambale Venkatesh, Matthew Allison, David Herrington, Mary Cushman, Moyses Szklo, Colin O Wu, Michael Blaha, Matthew Budoff, Russell Tracy, David A Bluemke, João A Lima
Journal: Circulation (2015)

Background: Inflammatory biomarkers have been used for cardiovascular disease (CVD) risk stratification. However, the relevance of longitudinal changes in levels of these biomarkers in relation to CVD is unclear. Methods: MESA is a population-based cohort consisting of 6814 participants free of symptomatic cardiovascular disease at baseline. We included all participants who had blood assayed for measurement of inflammatory biomarkers - C-reactive protein (CRP), Interleukin-6 (IL-6), and fibrinogen measured at baseline and follow-up 2-4 years later (n=1,362). Coronary heart disease (CHD) was assessed as any of myocardial infarction, resuscitated cardiac arrest, definite angina, probable angina (if followed by revascularization) and CHD death. CVD was considered a composite of CHD, stroke, stroke death, atherosclerotic death and CVD death. Cox proportional hazard regression analysis was used to assess the association of annual longitudinal changes in inflammatory biomarker level and time to first CHD and CVD event after adjustment for traditional risk factors and demographics. Results: The mean (SD) age was 61.6 (9.8) years and 55% were male. Over 8.6 median (IQR, 8.4-9.3) years of follow-up, there were 87 CHD and 121 CVD events. The median (IQR) CRP (mg/L), IL-6 (pg/ml) and fibrinogen (mg/dl) levels at baseline were 1.74(0.82-3.95) 1.11(0.71-1.72) and 332(292-382); and at follow-up were 1.4(0.69-3.03), 1.76(1.16-2.72) and 421(371-476). An increase in IL6 of 1 pg/mL/year was associated with a 26% increased risk of total CVD events independent of risk factors, while an increase of 1 mg/L/year of CRP was independently associated with a 7% and 6% increased risk of both CHD and CVD events respectively. There were no significant associations with changes in fibrinogen. Conclusion: Longitudinal increases in the inflammatory biomarkers CRP and IL6 are associated with higher risk of future cardiovascular events in a multi-ethnic population.
Long-term overall survival (OS) with nivolumab in previously treated patients with advanced renal cell carcinoma (aRCC) from phase I and II studies.
Authors: David F. McDermott, Robert J. Motzer, Michael B. Atkins, Elizabeth R. Plimack, Mario Sznol, Saby George, Charles G. Drake, Brian I. Rini, Toni K. Choueiri, Timothy Kuzel, Jeffrey Alan Sosman, David C. Smith, Ulka N. Vaishampayan, John D. Powderly, Suzanne Louise Topalian, Huanyu Zhao, Ian M. Waxman, Hans J. Hammers
Journal: Journal of Clinical Oncology (2016)

4507 Background: Nivolumab, a programmed death-1 (PD-1) immune checkpoint inhibitor, was recently approved by the FDA for patients with clear-cell aRCC previously treated with anti-angiogenic therapy based on results from the phase III CheckMate 025 study, which showed significantly longer median OS for nivolumab vs everolimus (25.0 vs 19.6 months; P = 0.002) with a minimum follow-up of 14 months (Motzer et al, N Engl J Med 2015;373:1803–13). Because of the early survival benefit seen in the phase III study, there is increased interest in the potential for nivolumab to provide long-term OS. Here, we report long-term OS results from phase I and II nivolumab studies. Methods: Patients with Eastern Cooperative Oncology Group performance status ≤2 and prior systemic treatment with 1–5 regimens received nivolumab (1 or 10 mg/kg) every 2 weeks in a phase I open-label study (NCT00730639; McDermott et al, J Clin Oncol 2015;33:2013–20). Patients with Karnofsky performance status ≥70% and prior treatment with 1–3 regimens in the metastatic setting received nivolumab (0.3, 2, or 10 mg/kg) every 3 weeks in a phase II randomized study (NCT01354431; Motzer et al, J Clin Oncol 2015;33:1430–37). In both studies, OS was estimated by the Kaplan–Meier method. Results: 34 patients with aRCC were treated in the phase I study. At a minimum follow-up of 50.5 months, objective response rate (ORR) was 29% and the median duration of response was 12.9 months. The 3- and 5-year OS rates were 41% and 34%. 167 patients with aRCC were treated in the phase II study. At a minimum follow-up of 38 months, ORR was 21% and the median duration of response was 22 months. The 3-year OS rate was 35%. Additional data will be presented including 4-year OS rate from the phase II study and long-term OS by subgroups. Conclusions: With about one-third of patients treated with nivolumab alive at 5 years in the phase I study and 3 years in the phase II study, this is the longest follow-up reported to date with any anti-PD-1/PD-L1 agent in aRCC. Potential predictors of long-term survival with nivolumab in this previously treated population are being explored. Clinical trial information: NCT00730639 and NCT01354431.
Primary ciliary dyskinesia: the patients grow up
Authors: Claudia E. Kuehni, Myrofora Goutaki, Mary Carroll, Jane S. Lucas
Journal: European Respiratory Journal (2016)

The study by Shah et al. [1] in this issue of the European Respiratory Journal presents data from the largest study of adults with primary ciliary dyskinesia (PCD) described up to date. It asks important questions relating to the phenotype and prognosis of this rare disease. The article describes the practices of a single UK PCD centre, and since the patterns of referral and follow-up vary between clinics, is not representative of all adults with PCD. However, the data represent a wealth of clinical experiences and give us pointers for further studies. PCD is no longer a childhood disease and standards of care should be established from birth to late adulthood <http://ow.ly/sORE300ZXI3> All authors participate in the network of COST Action BEAT-PCD: Better Evidence to Advance Therapeutic options for PCD (BM 1407). C.E. Kuehni, M. Goutaki and J.S. Lucas are members of the European Respiratory Society Task Force for PCD Diagnostics (ERS TF-2014-04). The views expressed in this manuscript do not reflect official views of these collaborations.