tbuckley/cabot-search huggingface dataset:
Phase 1 study of combinatorial sorafenib, <scp>G‐CSF</scp>, and plerixafor treatment in relapsed/refractory, <scp>FLT3‐ITD</scp>‐mutated acute myelogenous leukemia patients
Authors: Gautam Borthakur, Zhihong Zeng, Jorge E. Cortes, Hsiang‐Chun Chen, Xuelin Huang, Marina Konopleva, Farhad Ravandi, Tapan Kadia, Keyur P. Patel, Naval Daver, Mary A. Kelly, Teresa McQueen, Ru‐Yiu Wang, Hagop Kantarjian, Michael Andreeff
Journal: American Journal of Hematology (2020)

Stroma-leukemia interactions mediated by CXCR4, CD44, VLA4, and their respective ligands contribute to therapy resistance in FLT3-ITD-mutated acute myelogenous leukemia (AML). We conducted a phase 1 study with the combination of sorafenib (a FLT3-ITD inhibitor), plerixafor (a SDF-1/CXCR4 inhibitor), and G-CSF (that cleaves SDF-1, CD44, and VLA4). Twenty-eight patients with relapsed/refractory FLT3-ITD-mutated AML were enrolled from December 2010 to December 2013 at three dose levels of sorafenib (400, 600, and 800 mg twice daily) and G-CSF and plerixafor were administered every other day for seven doses starting on day one. Sorafenib 800 mg twice daily was selected for the expansion phase. While no dose-limiting toxicities (DLT) were encountered in the four-week DLT window, hand-foot syndrome and rash were seen beyond the DLT window, which required dose reductions in most patients. The response rate was 36% (complete response (CR) = 4, complete remission with incomplete platelet recovery (CRp) = 4, complete remission with incomplete hematologic recovery (CRi) = 1, and partial response (PR) = 1) for the intention to treat population. Treatment resulted in 58.4 and 47 mean fold mobilization of blasts and CD34 /38- stem/progenitor cells, respectively, to the circulation. Expression of the adhesion molecules CXCR4, CD44, and VLA4 on circulating leukemia cells correlated negatively with the mobilization of CD34+/38-, CD34+/38-/123+ "progenitor" cells (all P ≤ .002). Mass cytometry analysis of sequential samples from two patients demonstrated resistance emerging early on from sub-clones with persistent Akt and/or ERK signaling. In conclusion, the strategy of combined inhibition of FLT3 kinase and stromal adhesive interactions has promising activity in relapsed/refractory, FLT3-ITD-mutated AML, which warrants further evaluation in the front-line setting.
A very peculiar practice: dermatology in the era of COVID‐19
Authors: S. Walsh, D. Creamer
Journal: British Journal of Dermatology (2020)

Aren't you one of the dermatology consultants?'thestaff nurse was looking at me with slightly narrowed eyes, and an expression that wavered between curiosity, confusion and amusement . . .and then settled on fear and blind panic.It was Saturday morning, and I had just stepped on to a 30-bedded acute coronavirus disease (COVID) ward in the hospital for the start of my shift.I was wearing a hopelessly oversized set of theatre scrubs, with a stethoscope draped unconvincingly around my neck.In the middle of March 2020 the UK government declared its strategic response to the crisis posed by COVID-19, an announcement that set in motion a series of profound changes in the provision of services, in both primary and secondary care, and a complete upheaval in the way all doctors practice medicine.It quickly became apparent that the numbers of extremely ill patients with COVID-19 would swamp the existing acute services.Thus, physicians from a variety of nonacute clinical specialties at our South London hospital were asked to redeploy to COVID wards to bolster the staffing.There was little time to process this alarming directivealarming because acute medicine was for many in the dim and distant past, and alarming because in our new clinical roles we would be exposed to high levels of active infection.The days before were spent furiously reading about a host of acute medical problems: how to manage type 1 respiratory failure, how to insert a venous cannula, how to prescribe heparin.These and similar clinical competencies were to be our primary skill set over the next few weeks while clinical dermatology was temporarily put to one side.
Abstract 9698: Cigarette Smoking and Incident Coronary Heart Disease in African Americans: The Jackson Heart Study
Authors: Adebamike A Oshunbade, Karen A Valle, Wondwosen K Yimer, Arsalan Hamid, Donald Clark, Daisuke Kamimura, Wendy B White, Andrew P DeFilippis, Michael J Blaha, Emelia J Benjamin, Emily O’Brien, Robert J Mentz, Carlos J Rodriguez, Ervin R Fox, Javed Butler, Aruni Bhatnagar, Rose M Robertson, Adolfo Correa, Michael E Hall
Journal: Circulation (2019)

Background: Although African Americans (AAs) have worse coronary heart disease (CHD) outcomes compared with whites, few studies have examined the relationship between cigarette smoking and CHD risk...
Deep MRD profiling defines outcome and unveils different modes of treatment resistance in standard- and high-risk myeloma
Authors: Ibai Goicoechea, Noemi Puig, Maria-Teresa Cedena, Leire Burgos, Lourdes Cordón, María-Belén Vidriales, Juan Flores-Montero, Norma C. Gutierrez, Maria-Jose Calasanz, Maria-Luisa Martin Ramos, David Lara-Astiaso, Amaia Vilas-Zornoza, Diego Alignani, Idoia Rodriguez, Sarai Sarvide, Daniel Alameda, Juan José Garcés, Sara Rodriguez, Vicente Fresquet, Jon Celay, Ramón Garcia-Sanz, Joaquin Martinez-Lopez, Albert Oriol, Rafael Rios, Jesus Martin-Sanchez, Rafael Martinez-Martinez, Josep Sarra, Miguel-Teodoro Hernandez, Javier de la Rubia, Isabel Krsnik, Jose-Maria Moraleda, Luis Palomera, Joan Bargay, Jose-Angel Martinez-Climent, Alberto Orfao, Laura Rosiñol, Maria-Victoria Mateos, Juan-José Lahuerta, Joan Blade, Jesús San Miguel, Bruno Paiva
Journal: Blood (2020)
Racial Disparities in Preemies and Pandemics
Authors: Marin Arnolds, Rupali Gandhi, Mobolaji Famuyide, Dalia Feltman
Journal: The American Journal of Bioethics (2020)

As COVID-19 related hospitalizations surged in other countries and began to rise sharply in the United States, hospitals, healthcare systems, and states began to grapple with the terrifying questio...
Stereoselective metabolism of the environmental mammary carcinogen 6-nitrochrysene (6-NC) and comparative mutagenicity of pure [R,R]- and [S,S]-trans- 1,2-dihydroxy-1,2-dihydro-6-nitrochrysene (1,2-DHD-6-NC) metabolite in a mammary cell line
Authors: Yuan-Wan Sun, Joseph Guttenplan, Wieslawa Kosinska, Jacek Krzeminski, Shantu Amin, Karam El-Bayoumy
Journal: Cancer Research (2008)

5574  The cause of most breast cancers remains unknown. Ubiquitous environmental agents that are known to induce mammary cancer in rodents must be regarded as potential risk factors for inducing analogous human cancers. 6-NC is a powerful mammary carcinogen and mutagen in rats; it is known to be metabolized by ring-oxidation, nitro-reduction and a combination of both pathways in the rat and in several in vitro systems including breast cancer cell lines and human breast tissues. We previously showed that 1,2-DHD-6-NC is the proximate carcinogen and mutagen. Since optically active enantiomers of numerous polynuclear aromatic hydrocarbons (PAH) including chrysene have distinctly different biological activities, we hypothesize that the stereochemical course of 6-NC metabolism and other factors (e.g. levels and conformations of DNA adducts, DNA repair enzymes) all play a critical role in the carcinogenic/mutagenic activities of this agent. As an initial investigation, the enantiomeric, synthetic 1,2-DHD-6-NC was resolved either by derivatization with (-) menthoxyacetyl chloride followed by HPLC separation or by a chiral column; using the above mentioned analytical approaches, 1,2-DHD-6-NC metabolite that had been obtained following the incubation of 6-NC with rat liver microsomes produced 88% of [R,R]- and 12% of [S,S]-enantiomers, as determined by circular dichroism. Using the cII gene of lacI mammary epithelial cells in vitro, we showed that at the highest dose (0.5 μM), the mutant fractions were 28.3 ± 4.5 and 9.3 ± 2.8 mutants/10-5 plaque for [R,R]-and [S,S]-enatiomers, respectively. A linear dose response was noted and the [R,R]- is about 6 × more potent than [S,S]-1,2-DHD-6-NC.  A marked stereoselectivity is observed when [R,R]- and [S,S]-dihydrodiols derived from PAH (e.g. chrysene) are further metabolized to the corresponding dihydrodiol epoxides. In the case of 6-NC, nitro-reduction of [R,R]- and [S,S]-1,2-DHD-6-NC to the corresponding 1,2-dihydroxy-1,2-dihydro-6-hydroxylaminochrysene (1,2-DHD-6-NHOH-C) is responsible for the formation of the major DNA adduct observed in vivo in the mammary glands of rats treated with 6-NC, suggesting that 1,2-DHD-6-NHOH-C is the putative ultimate carcinogen. Future studies will synthesize both [R,R]- and [S,S]- 1,2-DHD-6-NHOH-C and compare their carcinogenicity in the rat mammary gland. Collectively, these studies provide better understanding of the mechanism of carcinogenesis following exposure to 6-NC, a typical environmental pollutant. Support: NCI RO1 35519
Virtual Cardiology—Views From a Muted Microphone
Authors: Erin J. Madriago, Christina Ronai
Journal: JAMA Cardiology (2020)

Virtual Cardiology-Views From a Muted Microphone Women pioneered the field of pediatric cardiology.Maude Abbott's intrepid intellectual curiosity led to a novel approach of comparative anatomy, and her incredible diligence helped classify an extraordinarily diverse set of cardiac lesions.Helen Taussig, the mother of pediatric cardiology, fundamentally defined our field and established the first pediatric cardiology fellowship program.Stella Van Praagh, among many contributions to the field, epitomized academic pediatric cardiology and authored more than 100 scientific publications.The list goes on and on.However, even with this long history, a review of the current state reveals that significant disparities remain between men and women in our field.Despite representing half of medical school graduates and one-third of the workforce, women in medicine are promoted at a much slower rate, represent far fewer roles in leadership, have lower starting salaries, and, according to a study from 2019, make an average of 25% less. 1 In cardiology specifically, leadership role inequality is significant, with only 14% of program directors and 5% of division chiefs being women. 2,3In the world of academic literature, the situation is even more profound, with only 1 woman between 1998 and 2018 serving as editor of a US or European cardiology journal. 4he coronavirus disease 2019 (COVID-19) pandemic has intensified the reality of this gender disparity in medicine.The multiplicity of roles that many women now are required to hold (working simultaneously both at home and "at work" virtually) often do not translate well over now-ubiquitous videoconferencing.Challenges related to working from home are not necessarily sex specific.Male colleagues certainly juggle patient care and childcare, and female colleagues may have partners who share household responsibilities.However, it is many of the traits that women specifically use to be effective in the workplace that are undermining our success in the virtual environment.Multitasking, flexibility, and crisis management skills that have traditionally helped women may be drawing us further into two separate but equally demanding domains.Women across disciplines have acknowledged the challenges of rapidly shifting between roles, moving from one moment of separating 2 bickering siblings to the next of conducting a virtual visit with a patient with complex chronic disease.In group patient discussions, many female colleagues are required to simultaneously hold an infant while trying to advocate for their patients.Even simpler, the sheer number of times that the camera is off in a female physician's home during a videoconference is testament to the numerous interruptions and home predicaments that constantly require immediate attention while working.
Instability of circular RNAs in clinical tissue samples impairs their reliable expression analysis using RT-qPCR: from the myth of their advantage as biomarkers to reality
Authors: Hannah Rochow, Antonia Franz, Monika Jung, Sabine Weickmann, Bernhard Ralla, Ergin Kilic, Carsten Stephan, Annika Fendler, Klaus Jung
Journal: Theranostics (2020)

Background: Circular RNAs (circRNAs) are a new class of RNAs with medical significance.Compared to that of linear mRNA transcripts, the stability of circRNAs against degradation owing to their circular structure is considered advantageous for their use as biomarkers.As systematic studies on the stability of circRNAs depending on the RNA integrity, determined as RNA integrity number (RIN), in clinical tissue samples are lacking, we have investigated this aspect in the present study under model and clinical conditions.Methods: Total RNA isolated from kidney cancer tissue and cell lines (A-498 and HEK-293) with different RIN after thermal degradation was used in model experiments.Further, RNA isolated from kidney cancer and prostate cancer tissue collected under routine surgical conditions, representing clinical samples with RIN ranging from 2 to 9, were examined.Quantitative real-time reverse-transcription polymerase chain reaction (RT-qPCR) analysis of several circRNAs (circEGLN3, circRHOBTB3, circCSNK1G3, circRNA4, and circRNA9), their corresponding linear counterparts, tissue-specific reference genes, and three microRNAs (as controls) was performed.The quantification cycles were converted into relative quantities and normalized to the expression of specific reference genes for the corresponding tissue.The effect of RIN on the expression of different RNA entities was determined using linear regression analysis, and clinical samples were classified into two groups based on RIN greater or lesser than 6.Results: The results of model experiments and clinical sample analyses showed that all relative circRNA expression gradually decreased with reduction in RIN values.The adverse effect of RIN was partially compensated after normalizing the data and limiting the samples to only those with RIN values > 6. Conclusions: Our results suggested that circRNAs are not stable in clinical tissue samples, but are subjected to degradative processes similar to mRNAs.This has not been investigated extensively in circRNA expression studies, and hence must be considered in future for obtaining reliable circRNA expression data.This can be achieved by applying the principles commonly used in mRNA expression studies.
Distinct and temporary-restricted epigenetic mechanisms regulate human αβ and γδ T cell development
Authors: Juliette Roels, Anna Kuchmiy, Matthias De Decker, Steven Strubbe, Marieke Lavaert, Kai Ling Liang, Georges Leclercq, Bart Vandekerckhove, Filip Van Nieuwerburgh, Pieter Van Vlierberghe, Tom Taghon
Journal: Nature Immunology (2020)
Successful endoscopic diagnosis and treatment of blue rubber bleb nevus syndrome
Authors: Xin-Ying Tang, Chao-Hui He, Zhuan Liao
Journal: Endoscopy (2020)

A young man presented with a two-year history of recurrent melena. Several dark-blue elevated skin lesions had been on his right hand and head ([Fig. 1]). The nodules were soft and compressible, and some of them seemed to have lacunae divided by white linear structures. Pathologic examination after a surgical resection two years ago confirmed the lesions as “cavernous hemangioma.” No one in his immediate family had a related vascular malformation. His hemoglobin level was 56 g/L (severe anemia), and the other related tests and physical examinations were unremarkable.
AB0872 EFFICACY AND SAFETY OF THE COMBINATION OF APOCYNIN AND PAEONOL (APPA) IN PATIENTS WITH OSTEOARTHRITIS: AN UNCONTROLLED PATIENT CASE SERIES
Authors: N. Larkins
Journal: Annals of the Rheumatic Diseases (2020)

Background: Apocynin and paeonol are secondary metabolites of plants used in traditional Asian medicine for centuries. The combination of synthetic versions of these two molecules (APPA) was developed initially for the treatment of osteoarthritis (OA) in animals where it has been found at least as effective as meloxicam. Human clinical trials are currently ongoing. Objectives: To report the outcomes from a case series of patients treated with APPA. Methods: Subjects with a diagnosis of OA, who had tried unsuccessfully a number of standard therapies, requested treatment with APPA from the author (NL), often following successful treatment of their animals with the combination or via networking. The usual daily dose was 1240 mg paeonol and 352 mg of apocynin taken as two 400mg capsules twice daily. Results: Twenty-three subjects with a diagnosis of OA of whom 7 were scheduled for surgery have been treated with APPA. There were 10 female and 13 males with an age range from 40 to 81 years. Nine patients had OA of the knees, 5 of whom had bilateral involvement, 7 had hip OA, 5 bilaterally and 2 with end stage bone on bone disease. Four patients had hand OA, one of whom also had disease of the hip, lower back and feet. In 3 patients the joints involved was not recorded. In 19 patients treatment was reported as effective. In 4 patients the treatment was ineffective, all of who were scheduled or had been recommended for surgery. In 2 of these cases cases this was bone on bone The duration of treatment for OA at the last recorded follow-up was reported for 16 patients in whom treatment was deemed effective and ranged from 9 to 120 months (median 24 months). In a further 3 patients the treatment the duration was not reported. In the 4 patients where no benefit was reported APPA was discontinued within a few weeks. In no case was there a report of APPA being discontinued due to adverse events. In 13 patients it was specifically stated that there had been no adverse events whereas for the remaining 10 patients it was not documented whether adverse events had occurred or not. Conclusion: Treatment with APPA was reported as effective by 82.6% of patients. In all patients in which the combination was ineffective the disease was severe with joint replacement recommended or scheduled; in two patients this was bone on bone. This would suggest that APPA is not a simple analgesic, a conclusion supported by effects seen in the rat meniscal tear model where possible disease modifying effects have been reported (1). References: [1]Glasson, S., Bendele, A. and Larkins, N. (2012). APPA provides disease modification in preclinical osteoarthritis. Osteoarthritis and Cartilage 20 : S72 -S73 Abstract 132. Disclosure of Interests: Nicholas Larkins Shareholder of: AKL R and D Ltd, Employee of: AKL R and D Ltd
Producing polished prokaryotic pangenomes with the Panaroo pipeline
Authors: Gerry Tonkin-Hill, Neil MacAlasdair, Christopher Ruis, Aaron Weimann, Gal Horesh, John A. Lees, Rebecca A. Gladstone, Stephanie Lo, Christopher Beaudoin, R. Andres Floto, Simon D.W. Frost, Jukka Corander, Stephen D. Bentley, Julian Parkhill
Journal: Genome biology (2020)

Abstract Population-level comparisons of prokaryotic genomes must take into account the substantial differences in gene content resulting from horizontal gene transfer, gene duplication and gene loss. However, the automated annotation of prokaryotic genomes is imperfect, and errors due to fragmented assemblies, contamination, diverse gene families and mis-assemblies accumulate over the population, leading to profound consequences when analysing the set of all genes found in a species. Here, we introduce Panaroo, a graph-based pangenome clustering tool that is able to account for many of the sources of error introduced during the annotation of prokaryotic genome assemblies. Panaroo is available at https://github.com/gtonkinhill/panaroo .
It’s Time to View Severe Medically Unexplained Symptoms as Red-Flag Symptoms of Depression and Anxiety
Authors: Robert C. Smith
Journal: JAMA Network Open (2020)

Natasha Ruth Saunders, MD, MSc; Sima Gandhi, MSc; Simon Chen, MPH; Simone Vigod, MD, MSc; Kinwah Fung, MSc; Claire De Souza, MD; Hana Saab, PhD; Paul Kurdyak, MD, PhD
Abstract 11971: Gender Differences in Industry Payments Among Cardiologists
Authors: Inbar Raber, Cian P McCarthy, Mahmoud S Al Rifai, Muthiah Vaduganathan, Erin D Michos, Malissa J Wood, Yvonne Smyth, Nasrien E Ibrahim, Doreen DeFaria Yeh, Aarti Asnani, Roxana Mehran, John W McEvoy
Journal: Circulation (2019)

Introduction: Industry payments are a potential source of revenue for cardiologists. It is unknown how this resource is distributed among men and women in cardiology. Hypothesis: Gender differences...
THU0639-HPR GOUT DISEASE ACTIVITY SCORE – FURTHER EVALUATION OF CONSTRUCT AND CONVERGENT VALIDITY
Authors: M. Zlatkovic-Svenda, M. Radak-Perovic
Journal: Annals of the Rheumatic Diseases (2020)

Background: A new instrument for measuring of disease activity in gout is a 4-variable gout disease activity score (GAS), announced in 2016 (1). GAS calculates self-reported number of attacks in the last year, patient visual analogue scale (VAS) for gout severity, serum uric acid level (mg/dL) and the number of tophi, and has shown good psychometric properties (1). Objectives: to test GAS in patients with gout and to evaluate its construct and convergent validity Methods: 74 patients with gout were evaluated successively, as they entered the Institute of Rheumatology in Belgrade. Construct validity was assessed by associationos between GAS and SF-36, using Spearman’s rank correlation coefficients. Convergent validity was evaluated by testing the ability of the GAS score to distinguish between patients grouped by perceived disease severity, perceived general health and physicians perceived disease severity by using Kruskal–Wallis one-way analysis of variance. Computer statistic program SPSS 20.0 was used for data evaluation. Results: For the construct validity, significant correlations were found between GAS and SF-36 subscales, specially for Body pain (r=-0.725), Physical functioning (r=-0.684) and Physical limitations (r=-0.563), whereas Social functioning, Mental health, and Vitality were less affected. Correlation between GAS and Physical component scale of the SF-36 was the most prominent (r=-0.780). For the convergent validity, significant differences in GAS scores were found between patients grouped by perceived general health (p&lt;0,01) and perceived disease severity (p&lt;0,01), and by doctors perceived disease severity (p&lt;0,01), demonstrating the ability of the GAS to distinguish between subgroups of patients. Conclusion: GAS has shown good psyshometric properties in Serbian cohort of patients and has proved to be valid and reliable tool for use in clinical practice. References: [1]Scirè CA, Carrara G, Viroli C, Cimmino MA, Taylor WJ, Manara M, Govoni M, Salaffi F, Punzi L, Montecucco C, Matucci-Cerinic M, Minisola G; Study Group for the Kick-Off of the Italian Network for Gout Study. Development and First Validation of a Disease Activity Score for Gout. Arthritis Care Res (Hoboken). 2016 Oct;68(10):1530-7. Table 1. Characteristics of the examined patients Patient characteristics Mean Std deviation 95% Confidence Interval Age (yrs) 59,27 10,22 56,90-61,51 Disease duration (yrs) 8,75 7,72 7,01-10,49 Number of attacks/last year 3,89 3,74 3,08-4,71 Weight (kg) 91,44 (17,14) 86,52-96,37 Height (cm) 176,73 (7,95) 174,45-179-02 Body Mass Index (kg/m2) 29,14 (4,1) 27,96-30,32 Waist circumference (cm) 102,69 9,56 100,35-105,05 Systolic blood pressure 135,44 14,48 130,43-140,50 Diastolic blood pressure 86.74 9.86 82,31-89,22 Serum urate level (µmol/ L) 485,6 102,09 449,94-521,20 No % Male 71 95,9 Monoarthritis 29 39,2 Olygoarthritis 31 42,1 Polyarthritis 14 18,9 Presence of tophi 17 23 Disclosure of Interests: None declared