tbuckley/cabot-search huggingface dataset:
“Yes, but will it work for my patients?” Driving clinically relevant research with benchmark datasets
Authors: Trishan Panch, Tom J. Pollard, Heather Mattie, Emily Lindemer, Pearse A. Keane, Leo Anthony Celi
Journal: npj Digital Medicine (2020)

Abstract Benchmark datasets have a powerful normative influence: by determining how the real world is represented in data, they define which problems will first be solved by algorithms built using the datasets and, by extension, who these algorithms will work for . It is desirable for these datasets to serve four functions: (1) enabling the creation of clinically relevant algorithms; (2) facilitating like-for-like comparison of algorithmic performance; (3) ensuring reproducibility of algorithms; (4) asserting a normative influence on the clinical domains and diversity of patients that will potentially benefit from technological advances. Without benchmark datasets that satisfy these functions, it is impossible to address two perennial concerns of clinicians experienced in computational research: “the data scientists just go where the data is rather than where the needs are,” and, “yes, but will this work for my patients?” If algorithms are to be developed and applied for the care of patients, then it is prudent for the research community to create benchmark datasets proactively, across specialties. As yet, best practice in this area has not been defined. Broadly speaking, efforts will include design of the dataset; compliance and contracting issues relating to the sharing of sensitive data; enabling access and reuse; and planning for translation of algorithms to the clinical environment. If a deliberate and systematic approach is not followed, not only will the considerable benefits of clinical algorithms fail to be realized, but the potential harms may be regressively incurred across existing gradients of social inequity.
Diagnostic accuracy of novel ultrasonographic halo score for giant cell arteritis: methodological issues
Authors: Hadis Ghajari, Siamak Sabour
Journal: Annals of the Rheumatic Diseases (2020)

Diagnostic accuracy of novel ultrasonographic halo score for giant cell arteritis: methodological issuesWe were interested to read the paper authored by Dasgupta et al published in Annals of the Rheumatic Diseases. 1 In a prospective study design, 89 patients suspected of giant cell arteritis (GCA) were included.The authors used receiver operating characteristic, sensitivity, specificity and likelihood ratio (LR) for assessing the diagnostic accuracy of halo counts and halo scores and their relationship with disease severity in detecting GCA.Final clinical diagnosis after 6 months was considered as gold standard.In conclusion, they reported that both halo count and halo score can quantify the extent of vascular inflammation in GCA, and halo score has a better detecting of GCA rather than Halo count.Although we admire this excellent study, we would like to explain some methodological issues that can cause misinterpretation.First of all, there is a difference between test research and diagnostic research.Diagnostic accuracy is focused on a test's added contribution to estimate the diagnostic probability of disease presence or absence. 2 In this way, the authors need to apply several tests and measure the performance of the new test in comparison with others.However, in the current study, the authors tended to evaluate test accuracy since they did not consider other tests and hence cannot provide information about the diagnostic added value of the test. 3In fact, without the diagnostic added value, there is no evidence about the beneficial diagnostic yields of the new test. 4Another limitation relates to the interpretation of the amount of LRs.Dasgupta et al interpreted that a positive LR greater than 6.41 and 2.0 can effectively predict the GCA and temporal artery (TA) biopsy, respectively.It should be noted that the range of LR+ is one to infinity and the higher the LR+, the more accurate the test is.Actually, an LR+ equal to 2 or 6 is a clear evidence for inaccuracy of the tests. 5Also, assessing the diagnostic OR for GCA (halo count: 4.1, halo score: 5.40) and temporal artery biopsy (TAB) (halo count: 12.77, halo score: 9.4) confirms the inaccuracy of both tests.Finally, for assessing diagnostic accuracy, it is important to evaluate both the discrimination and calibration of the new test.Without assessing calibration, it is not possible to compare the probability of the observed and predicted GCA and how these probabilities agree with the observed proportions of later developing disease. 6e thus argue that there are some methodological limitations and approaches to overcome them for assessing diagnostic accuracy; otherwise, misinterpretation cannot be avoided.
Untangling the Gordian Knot of Vitamin D Supplementation and Type 2 Diabetes Prevention
Authors: Anastassios G. Pittas, Ethan M. Balk
Journal: Diabetes Care (2020)

Approximately one-third of the adult U.S. population has prediabetes, ∼5–10% of whom will progress to diabetes per year (1,2). Intensive lifestyle changes delay progression to diabetes; however, sustaining lifestyle changes long term is challenging and often insufficient to prevent development of diabetes (3). Simple, inexpensive, and sustainable approaches to complement lifestyle changes are therefore needed to lower diabetes risk in people with prediabetes.

Over the last decade, vitamin D has emerged as a potential modifier of the pathophysiology of type 2 diabetes and vitamin D supplementation has been hypothesized as a promising intervention to lower diabetes risk (4). Observational studies report consistent associations between higher blood 25-hydroxy vitamin D [25(OH)D] concentration and lower risk of developing type 2 diabetes in diverse cohorts (5). Mechanistic studies provide a strong biological basis for an important role of vitamin D in improving pancreatic β-cell function, but there is less evidence on its effects on insulin resistance (6). Until recently, evidence from trials examining the effect of vitamin D supplementation for diabetes prevention was lacking.

In 2019, the U.S.-based Vitamin D and Type 2 Diabetes (D2d) study reported that participants with prediabetes assigned to vitamin D supplementation had a 12% decrease in risk of developing diabetes compared with placebo, but the change was not statistically significant (hazard ratio [HR] 0.88 [95% CI 0.75–1.04) (7). The effect size in D2d was nearly identical to those reported by two similar but smaller trials (Tromso \[Norway], HR 0.90 [95% CI 0.69–1.18], and Diabetes Prevention with active Vitamin D [DPVD\] \[Japan\], HR 0.87 [95% CI 0.68–1.09]) (8,9). Prior meta-analyses did not include these recent trials; thus, the field is ripe for updated meta-analyses.

In the current issue of Diabetes Care , two meta-analyses on this topic are published (10,11) . Pramono …
Prospective Comparison Between Saline and Radiocontrast for Intracoronary Imaging With Optical Coherence Tomography
Authors: Ankita K. Gore, Evan Shlofmitz, Keyvan Karimi Galougahi, Gregory Petrossian, Allen Jeremias, Fernando A. Sosa, Hussein M. Rahim, Gregg W. Stone, Gary S. Mintz, Akiko Maehara, Richard A. Shlofmitz, Ziad A. Ali
Journal: JACC. Cardiovascular imaging (2020)
SARS–CoV-2 infection of the placenta
Authors: Hillary Hosier, Shelli F. Farhadian, Raffaella A. Morotti, Uma Deshmukh, Alice Lu-Culligan, Katherine H. Campbell, Yuki Yasumoto, Chantal B.F. Vogels, Arnau Casanovas-Massana, Pavithra Vijayakumar, Bertie Geng, Camila D. Odio, John Fournier, Anderson F. Brito, Joseph R. Fauver, Feimei Liu, Tara Alpert, Reshef Tal, Klara Szigeti-Buck, Sudhir Perincheri, Christopher Larsen, Aileen M. Gariepy, Gabriela Aguilar, Kristen L. Fardelmann, Malini Harigopal, Hugh S. Taylor, Christian M. Pettker, Anne L. Wyllie, Charles Dela Cruz, Aaron M. Ring, Nathan D. Grubaugh, Albert I. Ko, Tamas L. Horvath, Akiko Iwasaki, Uma M. Reddy, Heather S. Lipkind
Journal: Journal of Clinical Investigation (2020)

BACKGROUND. The effects of the novel coronavirus disease 2019 (COVID-19) in pregnancy remain relatively unknown. We present a case of second trimester pregnancy with symptomatic COVID-19 complicated by severe preeclampsia and placental abruption.
Economic Vulnerability of Households With Essential Workers
Authors: Grace McCormack, Christopher Avery, Ariella Kahn-Lang Spitzer, Amitabh Chandra
Journal: JAMA (2020)

This study uses 2018 national survey data to characterize the proportion of essential workers in the US overall and living in economically vulnerable households, defined as income <$40 000 or at least 1 member uninsured or older than age 65.
The clinical impact of time to response in de novo accelerated‐phase chronic myeloid leukemia
Authors: Maro Ohanian, Hagop M. Kantarjian, Mahran Shoukier, Sara Dellasala, Arine Musaelyan, Graciela M. Nogueras Gonzalez, Elias Jabbour, Lynne Abruzzo, Srdan Verstovsek, Gautam Borthakur, Farhad Ravandi, Guillermo Garcia‐Manero, Gevorg Tamamyan, Richard Champlin, Sherry Pierce, Alessandra Ferrajoli, Tapan Kadia, Jorge E. Cortes
Journal: American Journal of Hematology (2020)

We aimed to describe the impact of time to response on the outcomes of 75 patients with accelerated-phase chronic myeloid leukemia (CML-AP) at diagnosis. Patients had at least 1 feature of AP: blasts ≥15% (n = 2), basophils ≥20% (n = 19), platelets <100 × 109 /L (n = 7), cytogenetic clonal evolution (n = 34), or more than one factor (n = 13). Thirty-three patients received imatinib; 42 received a second-generation tyrosine kinase inhibitor (2GTKI) (19 dasatinib and 23 nilotinib). We used chi-square and Kaplan-Meier analyses to determine the impact of various degrees of molecular and cytogenetic response at early time points (3 and 6 months) on rates of overall cytogenetic and molecular response, overall survival (OS), event-free survival (EFS), transformation-free survival (TFS), and failure-free survival (FFS). After a median follow-up of 96 months (range: 18-224 months), the overall rate of complete cytogenetic response was 79%, of major molecular response, 71%, and of molecular reponse (MR)4.5, 59%. Patients who achieved a major cytogenetic response (MCyR) (n = 49) at 3 months had significantly better 3-year OS (94% vs 75%; P = .002), TFS (98% vs 73%; P < .001), EFS (93% vs 42%; P < .001), and FFS (83% vs 25%; P < .001) rates than patients who did not have MCyR at 3 months. Most (67%) who eventually achieved sustained MR4.5 had achieved MCyR at 3 months. In de novo CML-AP, early response at 3 and 6 months is a strong determinant of long-term outcome.
Synteny-Guided Resolution of Gene Trees Clarifies the Functional Impact of Whole-Genome Duplications
Authors: Elise Parey, Alexandra Louis, Cédric Cabau, Yann Guiguen, Hugues Roest Crollius, Camille Berthelot
Journal: Molecular Biology and Evolution (2020)

Abstract Whole-genome duplications (WGDs) have major impacts on the evolution of species, as they produce new gene copies contributing substantially to adaptation, isolation, phenotypic robustness, and evolvability. They result in large, complex gene families with recurrent gene losses in descendant species that sequence-based phylogenetic methods fail to reconstruct accurately. As a result, orthologs and paralogs are difficult to identify reliably in WGD-descended species, which hinders the exploration of functional consequences of WGDs. Here, we present Synteny-guided CORrection of Paralogies and Orthologies (SCORPiOs), a novel method to reconstruct gene phylogenies in the context of a known WGD event. WGDs generate large duplicated syntenic regions, which SCORPiOs systematically leverages as a complement to sequence evolution to infer the evolutionary history of genes. We applied SCORPiOs to the 320-My-old WGD at the origin of teleost fish. We find that almost one in four teleost gene phylogenies in the Ensembl database (3,394) are inconsistent with their syntenic contexts. For 70% of these gene families (2,387), we were able to propose an improved phylogenetic tree consistent with both the molecular substitution distances and the local syntenic information. We show that these synteny-guided phylogenies are more congruent with the species tree, with sequence evolution and with expected expression conservation patterns than those produced by state-of-the-art methods. Finally, we show that synteny-guided gene trees emphasize contributions of WGD paralogs to evolutionary innovations in the teleost clade.
Activity of Multiple Targetable Therapies in FLT3-Mutated (mu) Acute Myeloid Leukemia (AML) Patients (pts) with Concurrent Isocitrate Dehydrogenase Mutation (IDHm)
Authors: Jorge Cortes, Mansour Alfayez, Tapan M. Kadia, Marina Y Konopleva, Farhad Ravandi, Jorge E. Cortes, Elias Jabbour, Guillermo Garcia-Manero, Sherry A. Pierce, Musa E. Yilmaz, Nicholas J. Short, Koji Sasaki, Lucia Masarova, Naveen Pemmaraju, Gautam M. Borthakur, Hagop M. Kantarjian, Courtney D. DiNardo, Naval G. Daver
Journal: Blood (2019)
Heroism in the Face of the COVID-19 Pandemic
Authors: Ajay J. Kirtane, Roxana Mehran, Ann Marie Navar, Robert O. Bonow
Journal: JAMA Cardiology (2020)

Pamela H. Lai, MD, PhD, MSc; Elizabeth A. Lancet, DrPH, MPH; Michael D. Weiden, MS, MD; Mayris P. Webber, DrPH, MPH; Rachel Zeig-Owens, DrPH, MPH; Charles B. Hall, PhD; David J. Prezant, MD
The plasma and intracellular pharmacokinetics of clofarabine in pediatric leukemia patients
Authors: Simon Joel, Essam Ghazaly, Hazel Smith, Pamela Kearns, Vaskar Saha
Journal: Cancer Research (2007)

1566  Background. Clofarabine is a novel nucleoside analog halogenated on both the purine and arabinosyl parts of the molecule, resulting in multiple mechanisms of action. As with other nucleoside analogs the drug must be phosphorylated intracellularly to clofarabine triphosphate to exert its effects. Activity of the drug in leukaemia has been shown to be related to intracellular clofarabine TP concentration (Blood.2003;102:2379-2386), although in paediatric patients (pts) such data is limited. We have therefore investigated the plasma, intracellular and urinary pharmacokinetics of clofarabine in paediatric ALL pts entered into a European phase II clinical trial.  Methods. Pts received clofarabine (52 mg/m2) as a single agent by IV infusion over 2 hrs daily for 5 days. Blood samples were collected before and at the end of infusion on each day. 24-hr urine collections were performed on selected pts on days 1 and 5 of treatment and then for 2 days post treatment. Plasma was separated and stored (-70°C) and PBMC’s then isolated by Ficoll density gradient centrifugation. After washing, cells were lysed and the lysate stored at -70°C until analysis. Plasma clofarabine was determined by LC-MS-MS and urinary clofarabine and intracellular clofarabine TP by different LC assays with gradient elution and UV detection.  Results. Median plasma clofarabine (n=25) at the end of infusion (EOI) on day 1 was 1.58 µM (0.45 - 3.17 µM) and was not different between pts who did or did not respond to treatment. Plasma clofarabine fell to 0.06 µM (0.04 - 0.27 µM) prior to the day 2 infusion. EOI plasma clofarabine on day 2 was 2.06 µM (0.72-5.09 µM), significantly increased from day 1 (p=0.01). Median EOI plasma clofarabine for days 3-5 remained between 2.17-2.49 µM. Intracellular clofarabine TP (n=13) also showed marked variability between pts, ranging from 3 to 85 µM at the EOI on day 1 (median 9 µM). Median day 2:day1 EOI clofarabine TP ratio was higher in pts who responded to treatment (2.1 (0.3 - 3.9) µM vs 0.7 (0.2 - 0.8) µM, p=0.048). Urinary clofarabine dose recovery in 5 pts studied to date on days 1, 5, 6 and 7 (days 6 and 7 post-treatment) were 48±18 %, 46±12 %, 5±3 % and 2 ± 2 %. A ketoclofarabine metabolite, reported in animal studies, was not detected in any sample.  Conclusions. Plasma clofarabine and intracellular clofarabine TP concentration showed marked variability between pts, even with BSA based dosing. Intracellular clofarabine TP concentration was predictive of outcome in this patient group and may be useful as an early indicator of drug activity. Renal excretion accounts for around 50% of the administered clofarabine dose and does not show accumulation with daily dosing. These studies are continuing.
ctDNA monitoring using patient-specific sequencing and integration of variant reads
Authors: Jonathan C. M. Wan, Katrin Heider, Davina Gale, Suzanne Murphy, Eyal Fisher, Florent Mouliere, Andrea Ruiz-Valdepenas, Angela Santonja, James Morris, Dineika Chandrananda, Andrea Marshall, Andrew B. Gill, Pui Ying Chan, Emily Barker, Gemma Young, Wendy N. Cooper, Irena Hudecova, Francesco Marass, Richard Mair, Kevin M. Brindle, Grant D. Stewart, Jean E. Abraham, Carlos Caldas, Doris M. Rassl, Robert C. Rintoul, Constantine Alifrangis, Mark R. Middleton, Ferdia A. Gallagher, Christine Parkinson, Amer Durrani, Ultan McDermott, Christopher G. Smith, Charles Massie, Pippa G. Corrie, Nitzan Rosenfeld
Journal: Science Translational Medicine (2020)

Integration of variant reads across patient-specific mutation loci enables sensitive ctDNA quantification in plasma cell-free DNA sequencing data.
Abstract IA20: Circulating tumor cells: Biology and clinical applications as liquid biopsy
Authors: Klaus Pantel
Journal: Clinical Cancer Research (2020)

Abstract The analysis of circulating tumor cells (CTCs) in blood may provide clinically relevant information as “liquid biopsy” and provide new insights into tumor biology (Alix-Panabieres, Pantel, Nature Rev Cancer 2014; Keller, Pantel, Nature Rev Cancer 2019). Various technologies have been developed over the past 10 years, which include label-dependent assays based on the expression of tumor-associated cell surface antigens and label-independent assays based on physical properties of tumors cells distinct from the surrounding leukocytes (Pantel, Alix-Panabieres, Nature Rev Cancer 2019). After detection, CTCs can be further analyzed at the DNA, RNA, and protein level to obtain global information on tumor biology and targets relevant to cancer therapy (Pantel, Alix-Panabieres, Nature Rev Clin Oncol 2019). Liquid biopsy analyses with validated platforms provide reliable information on prognosis and may serve to identify therapeutic targets or mechanisms of resistance on metastatic cells. Metastatic cells might have unique characteristics that can differ from the bulk of cancer cells in the primary tumor currently used for stratification of patients to systemic therapy. Moreover, monitoring of blood samples before, during, and after systemic therapy (e.g., chemotherapy or targeted therapy) provides unique information for the future clinical management of the individual cancer patient and serves as surrogate marker for response to therapy (Alix-Panabieres, Pantel, Cancer Discovery 2016; Bardelli, Pantel, Cancer Cell 2017). Citation Format: Klaus Pantel. Circulating tumor cells: Biology and clinical applications as liquid biopsy [abstract]. In: Proceedings of the AACR Special Conference on Advances in Liquid Biopsies; Jan 13-16, 2020; Miami, FL. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(11_Suppl):Abstract nr IA20.
Molecular Basis of Atrial Fibrillation Pathophysiology and Therapy
Authors: Stanley Nattel, Jordi Heijman, Liping Zhou, Dobromir Dobrev
Journal: Circulation Research (2020)

Atrial fibrillation (AF) is a highly prevalent arrhythmia, with substantial associated morbidity and mortality. There have been significant management advances over the past 2 decades, but the burden of the disease continues to increase and there is certainly plenty of room for improvement in treatment options. A potential key to therapeutic innovation is a better understanding of underlying fundamental mechanisms. This article reviews recent advances in understanding the molecular basis for AF, with a particular emphasis on relating these new insights to opportunities for clinical translation. We first review the evidence relating basic electrophysiological mechanisms to the characteristics of clinical AF. We then discuss the molecular control of factors leading to some of the principal determinants, including abnormalities in impulse conduction (such as tissue fibrosis and other extra-cardiomyocyte alterations, connexin dysregulation and Na
Injectable thermo-responsive nano-hydrogel loading triptolide for the anti-breast cancer enhancement via localized treatment based on “two strikes” effects
Authors: Yaoyao Luo, Jingjing Li, Yichen Hu, Fei Gao, George Pak-Heng Leung, Funeng Geng, Chaomei Fu, Jinming Zhang
Journal: Acta Pharmaceutica Sinica B (2020)

The clinical application of triptolide (TPL) in tumor therapy has been greatly limited by its toxicity and inefficient delivery. Herein, a localized and sustained-release thermo-sensitive hydrogel was developed for the intra-tumor administration of TPL. Based on the amphiphilic structure of poly (N-isopropylacrylamide-co-acrylic acid)-g-F68 copolymer, it was able to form nano-micelles to efficiently encapsulate TPL, and then turn into a hydrogel at 37 °C. [email protected] exhibited a sustained drug release profile in vitro and a stronger anticancer effect caused by "two strikes". The "first strike" was its enhanced cytotoxicity compared to free TPL, due to the enhanced pro-apoptosis effect observed in both MDA-MB-231 and MCF-7 cells caused by the regulation of endogenous mitochondrial pathways. Furthermore, [email protected] exhibited a "second-strike" through its anti-angiogenesis capabilities mediated through VEGFR-2 signaling inhibition. As expected, after intra-tumoral injection at a 0.45 mg/kg TPL-equivalent dose three times over 14 days in 4T1 tumor-bearing mice, [email protected] led to lower systemic toxicity and higher antitumor efficacy compared to multiple injections of TPL. In this regard, these findings indicate that this injectable thermo-responsive hydrogel carries great potential for TPL as a safe and effective cancer therapy.
Cardiac Magnetic Resonance Feature Tracking Global Longitudinal Strain and Prognosis After Heart Transplantation
Authors: Chetan Shenoy, Simone Romano, Andrew Hughes, Osama Okasha, Prabhjot S. Nijjar, Pratik Velangi, Cindy M. Martin, Mehmet Akçakaya, Afshin Farzaneh-Far
Journal: JACC. Cardiovascular imaging (2020)
Abstract B53: Extracellular vesicle-based liquid biopsy via lipid-based nanoprobes
Authors: Siyang Zheng, Hongzhang He, Faming Wang, Yuan Wan
Journal: Clinical Cancer Research (2020)

Abstract Extracellular vesicles (EVs) can mediate intercellular communication by transferring cargo proteins and nucleic acids between cells. The pathophysiologic roles and clinical value of EVs are under intense investigation, yet most studies are limited by technical challenges in the isolation of nanoscale EVs (nEVs). Here, we report a lipid-nanoprobe system that enables spontaneous labeling of nEVs for subsequent magnetic enrichment in 15 minutes, with isolation efficiency and cargo composition similar to what can be achieved by the much slower and bulkier method of ultracentrifugation. We also show that this approach allows for downstream analyses of nucleic acids and proteins, enabling the identification of EGFR and KRAS mutations following nEV isolation from the blood plasma of non-small cell lung cancer patients. The efficiency and versatility of the lipid-nanoprobe approach open up opportunities in point-of-care cancer diagnostics. Citation Format: Siyang Zheng, Hongzhang He, Faming Wang, Yuan Wan. Extracellular vesicle-based liquid biopsy via lipid-based nanoprobes [abstract]. In: Proceedings of the AACR Special Conference on Advances in Liquid Biopsies; Jan 13-16, 2020; Miami, FL. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(11_Suppl):Abstract nr B53.