tbuckley/cabot-search huggingface dataset:
A phase I study of AT9283, an aurora kinase inhibitor, in patients with refractory solid tumors
Authors: R. Kristeleit, H. Calvert, H. Arkenau, D. Olmos, J. Adam, E. R. Plummer, V. Lock, M. Squires, L. Fazal, I. Judson
Journal: Journal of Clinical Oncology (2009)

2566 Background: AT9283, a multitargeted kinase inhibitor, inhibits several closely related tyrosine and serine/threonine kinases with an IC50 of &lt;10 nM including Aurora A and B, JAK and ABL. Exposure of solid tumour cell lines to AT9283 in vitro induces an “aurora inhibitory” phenotype. Cell survival decreases with increased duration of exposure. Methods: A phase I dose escalation study was performed using a 72 hour continuous intravenous (iv) infusion schedule repeated three weekly according to a stand ard “3+3” design. Results: Thirty-three patients have been treated with a median age of 61 (range 33 to 76 years). The maximum tolerated dose (MTD) was 9 mg/m 2 /day. Treatment was well tolerated with febrile neutropenia the only dose limiting toxicity. Other adverse events considered possibly related to AT9283 were reversible and included gastrointestinal disturbance and fatigue. Biological evidence of aurora B inhibition manifest as a reduction in histone H3 phosphorylation in skin biopsies during the infusion was observed at all dose levels. A plateau steady state plasma concentration of AT9283 was achieved within 24 hours of initiating drug infusion at all dose levels and exposure increased linearly with dose. Seven patients received an initial oral dose of AT9283 as an aqueous solution in a fasting state at a dose of 0.9 mg mg/m 2 one week prior to starting iv treatment. Interim pharmacokinetic analysis indicated that the median oral bioavailability was 27% (range 17 to 45%) The best response to treatment was a partial response in one patient with NSCLC (ongoing). An additional 4 patients received at least six cycles of therapy (squamous cell carcinoma of the lung, adenocarcinoma of the esophagus and colorectal carcinoma [2]) with a best response of stable disease. Conclusions: The MTD of AT9283 when administered as a 72 hour continuous iv infusion was 9mg/m 2 /day. Febrile neutropenia is the dose limiting toxicity and evidence of anticancer activity was seen in heavily pre-treated patients. [Table: see text] [Table: see text]
Projections of incident atherosclerotic cardiovascular disease and incident type 2 diabetes across evolving statin treatment guidelines and recommendations: A modelling study
Authors: Joseph C. Engeda, Stefan K. Lhachimi, Wayne D. Rosamond, Jennifer L. Lund, Thomas C. Keyserling, Monika M. Safford, Lisandro D. Colantonio, Paul Muntner, Christy L. Avery
Journal: PLoS Medicine (2020)

Experimental and observational research has suggested the potential for increased type 2 diabetes (T2D) risk among populations taking statins for the primary prevention of atherosclerotic cardiovascular disease (ASCVD). However, few studies have directly compared statin-associated benefits and harms or examined heterogeneity by population subgroups or assumed treatment effect. Thus, we compared ASCVD risk reduction and T2D incidence increases across 3 statin treatment guidelines or recommendations among adults without a history of ASCVD or T2D who were eligible for statin treatment initiation.Simulations were conducted using Markov models that integrated data from contemporary population-based studies of non-Hispanic African American and white adults aged 40-75 years with published meta-analyses. Statin treatment eligibility was determined by predicted 10-year ASCVD risk (5%, 7.5%, or 10%). We calculated the number needed to treat (NNT) to prevent one ASCVD event and the number needed to harm (NNH) to incur one incident case of T2D. The likelihood to be helped or harmed (LHH) was calculated as ratio of NNH to NNT. Heterogeneity in statin-associated benefit was examined by sex, age, and statin-associated T2D relative risk (RR) (range: 1.11-1.55). A total of 61,125,042 U.S. adults (58.5% female; 89.4% white; mean age = 54.7 years) composed our primary prevention population, among whom 13-28 million adults were eligible for statin initiation. Overall, the number of ASCVD events prevented was at least twice as large as the number of incident cases of T2D incurred (LHH range: 2.26-2.90). However, the number of T2D cases incurred surpassed the number of ASCVD events prevented when higher statin-associated T2D RRs were assumed (LHH range: 0.72-0.94). In addition, females (LHH range: 1.74-2.40) and adults aged 40-50 years (LHH range: 1.00-1.14) received lower absolute benefits of statin treatment compared with males (LHH range: 2.55-3.00) and adults aged 70-75 years (LHH range: 3.95-3.96). Projected differences in LHH by age and sex became more pronounced as statin-associated T2D RR increased, with a majority of scenarios projecting LHHs < 1 for females and adults aged 40-50 years. This study's primary limitation was uncertainty in estimates of statin-associated T2D risk, highlighting areas in which additional clinical and public health research is needed.Our projections suggest that females and younger adult populations shoulder the highest relative burden of statin-associated T2D risk.
A population-based gene expression signature of molecular clock phase from a single epidermal sample
Authors: Gang Wu, Marc D. Ruben, Lauren J. Francey, David F. Smith, Joseph D. Sherrill, John E. Oblong, Kevin J. Mills, John B. Hogenesch
Journal: Genome Medicine (2020)

Abstract Background For circadian medicine to influence health, such as when to take a drug or undergo a procedure, a biomarker of molecular clock phase is required––one that is easily measured and generalizable across a broad population. It is not clear that any circadian biomarker yet satisfies these criteria. Methods We analyzed 24-h molecular rhythms in human dermis and epidermis at three distinct body sites, leveraging both longitudinal ( n = 20) and population ( n = 154) data. We applied cyclic ordering by periodic structure (CYCLOPS) to order the population samples where biopsy time was not recorded. With CYCLOPS-predicted phases, we used ZeitZeiger to discover potential biomarkers of clock phase. Results Circadian clock function was strongest in the epidermis, regardless of body site. We identified a 12-gene expression signature that reported molecular clock phase to within 3 h (mean error = 2.5 h) from a single sample of epidermis––the skin’s most superficial layer. This set performed well across body sites, ages, sexes, and detection platforms. Conclusions This research shows that the clock in epidermis is more robust than dermis regardless of body site. To encourage ongoing validation of this putative biomarker in diverse populations, diseases, and experimental designs, we developed SkinPhaser––a user-friendly app to test biomarker performance in datasets ( https://github.com/gangwug/SkinPhaser ).
A comprehensive view of the structure and expression of the ependymoma genome at presentation and relapse
Authors: K. D. Wright, V. Rand, S. E. Leary, S. Mack, B. Coyle, Y. Gillespie, J. Allen, M. D. Taylor, R. Grundy, R. J. Gilbertson
Journal: Journal of Clinical Oncology (2009)

2073 Background: Although pediatric and adult ependymomas are associated with significant mortality and morbidity, little is known about the biology of these tumors. To identify underlying genetic alterations and cellular pathways that drive this disease, we conducted a genomic study of 200 adult and pediatric ependymomas. Methods: Using 500k single nucleotide polymorphism arrays, U133 Affymetrix gene and microRNA (miRNA) expression microarrays, and appropriate bioinformatics, we characterized 56 supratentorial (ST), 104 posterior fossa (PF), and 40 spinal (SP) ependymomas. Real-Time polymerase chain reaction and fluorescence in situ hybridization validated observed genetic events. Results: Gene expression profiles segregated tumors by site and identified disease subgroups within each anatomical region (4 ST, 4 PF, 1 SP). miRNA expression profiles identified these same subgroups, indicating that they are biologically distinct. Subgroup-specific gene expression profiles were dictated partly by developmental regulatory genes and partly by large chromosomal gains (eg. 1q, 5p, 16p) and losses (eg. 9p, 22q). Integrated genetic and expression mapping revealed key candidate tumor suppressor (TSG) and onco- genes, likely drivers of these large alterations. While large chromosomal changes occurred more frequently in SP tumors (p &lt; 0.0001), ST tumors averaged more focal changes (n = 13.2) than PF (n = 6.2) or SP tumors (n = 3.0) (p &lt; 0.0001). A total of 29 and 33 non-random focal amplifications and deletions, respectively, encompassing 402 known genes and miRNA clusters, were validated, of which 80 displayed copy number driven expression. These genetic alterations targeted specific cellular functions (e.g., cell adhesion, cell-cycle, neuronal development) and pathways (e.g., NOTCH, EPHRIN, TP53). Our cohort also included five sample sets consisting of primary tumor and at least two corresponding relapses. Genomic analysis of these tumors identified large chromosomal alterations as well as focal gains and losses associated with disease relapse. Conclusions: We present a highly comprehensive view of the ependymoma genome, including 80 previously unrecognized candidate TSG and oncogenes that may afford diagnostic and therapeutic targets. No significant financial relationships to disclose.
Dimensions of Animal Consciousness
Authors: Jonathan Birch, Alexandra K. Schnell, Nicola S. Clayton
Journal: Trends in Cognitive Sciences (2020)

How does consciousness vary across the animal kingdom? Are some animals 'more conscious' than others? This article presents a multidimensional framework for understanding interspecies variation in states of consciousness. The framework distinguishes five key dimensions of variation: perceptual richness, evaluative richness, integration at a time, integration across time, and self-consciousness. For each dimension, existing experiments that bear on it are reviewed and future experiments are suggested. By assessing a given species against each dimension, we can construct a consciousness profile for that species. On this framework, there is no single scale along which species can be ranked as more or less conscious. Rather, each species has its own distinctive consciousness profile.
Randomized phase III study of canfosfamide (C, TLK286) plus pegylated liposomal doxorubicin (PLD) versus PLD as second-line therapy in platinum (P) refractory or resistant ovarian cancer (OC)
Authors: I. Vergote, N. J. Finkler, J. B. Hall, O. Melnyk, R. P. Edwards, M. Jones, L. Meng, G. L. Brown, E. M. Rankin, J. J. Burke, P. G. Rose
Journal: Journal of Clinical Oncology (2009)

5552 Background: Canfosfamide (C) is a glutathione analog prodrug activated by glutathione S-transferase P1–1. C is synergistic with PLD and PLD increases the expression of GST P1–1 and sensitivity to C in OC cells. Methods: 244 pts were planned with P refractory or resistant (progression within 6 mos. after P) OC following ≤ 2 P regimens, and measurable disease (RECIST). Pts received C at 1,000 mg/m 2 and PLD at 50 mg/m 2 IV or PLD at 50mg/m 2 q4wks until tumor progression. Randomization was stratified by ECOG PS, best prior P response and bulky disease (≥ 5cm). Results: This multinational study randomized 125 pts until June 4, 2007 when the study was temporarily placed on clinical hold to review another C trial. The 65/60 pts were well-balanced for disease characteristics and received a median 3/3.5 cycles per patient (range 1–11/0–17) of C + PLD/PLD, 35 pts (21/14) discontinued study treatment(s) due to the hold, respectively. Most common adverse events (AEs) for C + PLD were hematologic at 66% vs. 44% for PLD and were manageable with dose reductions. Non-hematologic AEs were similar for both arms, except the incidence of Grade 2–3 Palmar-Plantar Erythrodysesthesia (PPE) (9% vs. 21%) and stomatitis (17% vs. 23%) was lower and less severe with C+PLD vs. PLD. Grade 4 PPE (2%) was only observed on the PLD arm. Overall median PFS, the primary endpoint, was 5.6 mos. for C + PLD and 3.7 mos. for PLD (p = 0.7243, HR = 0.92). Objective response rate (ORR) by RECIST was 12.3% for C + PLD vs. 8.3% for PLD. In a planned analysis, 75 pts (40 /35) who were P refractory or primary P resistant observed a median PFS of 5.6 mos. for C + PLD vs. 2.9 mos. for PLD (p = 0.0425, HR = 0.55). ORR for C + PLD was 15.0% (with 1 CR) vs. 5.7% for PLD. Stable disease was observed 42.5% on C + PLD and 37.1% on PLD; median duration of SD was 7.4 mos. and 4.1 mos., respectively (p = 0.0439, HR = 0.49). The median time to response was 2.8 mos. on C + PLD vs. 4.8 mos. on PLD. Conclusions: The overall PFS showed a positive but not statistically significant trend for C +PLD vs. PLD. In the P refractory or primary P resistant population, the median PFS was significantly longer for C+PLD than PLD alone. C may ameliorate the AEs of stomatitis and PPE known to be associated with PLD. [Table: see text]
A phase II randomized four-regimen selection trial incorporating response for sequential chemotherapy in metastatic, unresectable urothelial cancer: Final results from the M. D. Anderson Cancer Center
Authors: A. O. Siefker-Radtke, A. M. Kamat, D. L. Williams, N. M. Tannir, S. Tu, L. C. Pagliaro, C. P. Dinney, R. E. Millikan
Journal: Journal of Clinical Oncology (2009)

5071 Background: We developed a clinical trial incorporating response into the treatment algorithm. Patients meeting a certain threshold of response continued with the same treatment; those with insufficient response were switched to alternative chemotherapy. We now report on final results from this trial. Methods: Patients were randomly assigned to one of four regimens: ifosfamide, doxorubicin, gemcitabine; ifosfamide, paclitaxel, cisplatin; gemcitabine, cisplatin; or cisplatin, gemcitabine, and ifosfamide. To continue with chemotherapy, patients must have had at least a 40% response after the first 6-week interval, and a &gt;90% response after the second 6 weeks. Otherwise, they were re-randomized to alternate chemotherapy. Overall success (OSX) was defined as patients with a &gt;90% response with either front-line or second-line therapy. Surgical consolidation was offered to patients at the discretion of their treating physician. Results: Median overall survival (OS) for 120 patients was 19.1 mo. (3 and 5-yr survival: 33% and 20%). OSX was achieved in 41 patients (median OS: 51 mo.); the median OS in the other 79 patients was 15 mo. (p = 0.0001), with a 5-yr survival of 42% and 10% respectively. Surgical consolidation was performed in 35 patients: 23 with nodal metastases to pelvic and/or RPLN, 6 with cT4b tumors, and an additional 6 patients with distant metastases. Their median OS from surgery was 23.7 months, (5-yr survival: 31%). Surgical consolidation in the setting of OSX was associated with a 42% 5-yr survival as compared to 11% in those undergoing surgery in the absence of OSX. Visceral metastases and poor performance status were associated with a worse prognosis. Conclusions: With sequential therapy, 34% of patients had a &gt;90% response (OSX). A potential benefit in long-term survival was seen in patients who had surgical consolidation in the setting of OSX. This trial design provides a novel method for assessing the benefits of sequential chemotherapy, and enhancing the population of patients who may be offered surgical consolidation in the setting of initially unresectable, or metastatic urothelial cancer. No significant financial relationships to disclose.
Special Consideration for Patients With Morgellons Disease, Even Among Psychodermatology Patients?—Reply
Authors: Arsh Patel, Mohammad Jafferany
Journal: JAMA Dermatology (2020)

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Elagolix Reduces Fibroid-Related Heavy Menstrual Bleeding Long-term
Authors: Anita Slomski
Journal: JAMA (2020)

Elagolix, a gonadotropin-releasing hormone antagonist, plus hormonal add-back therapy reduced heavy menstrual bleeding from uterine leiomyomas during up to 12 months of continuous treatment, according to a trial in Obstetrics &amp; Gynecology.
ACC/AHA 2007 Guidelines on Perioperative Cardiovascular Evaluation and Care for Noncardiac Surgery: Executive Summary
Authors: Lee A. Fleisher, Joshua A. Beckman, Kenneth A. Brown, Hugh Calkins, Elliott Chaikof, Kirsten E. Fleischmann, William K. Freeman, James B. Froehlich, Edward K. Kasper, Judy R. Kersten, Barbara Riegel, John F. Robb
Journal: Journal of the American College of Cardiology (2007)
Assessment of Interobserver Reliability of Nephrologist Examination of Urine Sediment
Authors: Ragnar Palsson, Mia R. Colona, Melanie P. Hoenig, Andrew L. Lundquist, James E. Novak, Mark A. Perazella, Sushrut S. Waikar
Journal: JAMA Network Open (2020)

<h3>Importance</h3> Urine sediment microscopy is commonly performed during the evaluation of kidney disease. Interobserver reliability of nephrologists' urine sediment examination has not been well studied. <h3>Objective</h3> Assess interobserver reliability of the urine sediment examination. <h3>Design, Setting, and Participants</h3> In this diagnostic test study, urine samples were prospectively collected from a convenience sample of adult patients from an academic hospital in the United States undergoing kidney biopsy from July 11, 2018, to March 20, 2019. Digital images and videos of urine sediment findings were captured using a bright-field microscope. These images and videos along with urine dipstick results were incorporated in online surveys and sent to expert nephrologists at 15 US teaching hospitals. They were asked to identify individual sediment findings and the most likely underlying disease process. <h3>Exposures</h3> Urine dipstick results and urine sediment images from patients undergoing native kidney biopsy. <h3>Main Outcomes and Measures</h3> Interobserver reliability of urine sediment microscopy findings estimated by overall percent agreement and Fleiss κ coefficients. Secondary outcomes included concordance of diagnoses suspected by nephrologists with corresponding kidney biopsy results. <h3>Results</h3> In total, 10 surveys from 10 patients containing 76 study questions on individual features were sent to 21 nephrologists, 14 (67%) of whom completed them all. Their combined 1064 responses were analyzed. Overall percent agreement for casts was an estimated 59% (95% CI, 50%-69%), κ = 0.52 (95% CI, 0.42-0.62). For other sediment findings, overall percent agreement was an estimated 69% (95% CI, 61%-77%), κ = 0.65 (95% CI, 0.56-0.73). The κ estimates ranged from 0.13 (95% CI, 0.10-0.17) for mixed cellular casts to 0.90 (95% CI, 0.87-0.94) for squamous epithelial cells. <h3>Conclusions and Relevance</h3> In this study, substantial variability occurred in the interpretation of urine sediment findings, even among expert nephrologists. Educational or technological innovations may help improve the urine sediment as a diagnostic tool.
Interventions to prevent periodontal disease in tobacco‐, alcohol‐, and drug‐dependent individuals
Authors: Purnima S. Kumar
Journal: Periodontology 2000 (2020)

Substance abuse affects more than one sixth of the world's population. More importantly, the nature of the abuse and the type of addictive substances available to individuals is increasing exponentially. All substances with abusive potential impact both the human immuno-inflammatory system and oral microbial communities, and therefore play a critical role in the etiopathogenesis of periodontal diseases. Evidence strongly supports the efficacy of professionally delivered cessation counseling. Dentists, dental therapists, and hygienists are ideally placed to deliver this therapy, and to spearhead efforts to provide behavioral and pharmacologic support for cessation. The purpose of this review is to examine the biologic mechanisms underlying their role in disease causation, to understand the pharmacologic and behavioral basis for their habituation, and to investigate the efficacy of population-based and personalized interventions in prevention of periodontal disease.
A public health approach for prevention of periodontal disease
Authors: Chandrashekar Janakiram, Bruce A. Dye
Journal: Periodontology 2000 (2020)

Abstract Upwards of 1 in 10 adults worldwide may be affected by severe periodontitis, making the disease more prevalent than cardiovascular disease. Despite its global scope, its impact on pain, oral function, and the wellbeing of individuals, and the disproportionate burden of disease and the socioeconomic impact on communities, the perception that periodontal disease is a public health problem remains low. Although there have been substantial improvements in our understanding of the etiology of periodontal disease and how we can prevent and control it, these advances have been primarily focused on individual, patient‐focused approaches. The prevention of periodontal disease depends on improving currently available individual interventions and on determining what public health interventions can be effective and sustainable under real‐life conditions. Currently, public health approaches for periodontal disease prevention and control are lacking. This review traces the historical strategies for prevention of periodontal disease in an epidemiologic transition context, using a modified model developed for cardiovascular disease, and presents a possible public health approach. Improving periodontal disease prevention and control will need to take into consideration the core activities of a public health approach: assessment, policy development, and assurance.