tbuckley/cabot-search huggingface dataset:
Opposing Pressures of Speed and Efficiency Guide the Evolution of Molecular Machines
Authors: Jason A Wagoner, Ken A Dill
Journal: Molecular Biology and Evolution (2019)

Many biomolecular machines need to be both fast and efficient. How has evolution optimized these machines along the tradeoff between speed and efficiency? We explore this question using optimizable dynamical models along coordinates that are plausible evolutionary degrees of freedom. Data on 11 motors and ion pumps are consistent with the hypothesis that evolution seeks an optimal balance of speed and efficiency, where any further small increase in one of these quantities would come at great expense to the other. For FoF1-ATPases in different species, we also find apparent optimization of the number of subunits in the c-ring, which determines the number of protons pumped per ATP synthesized. Interestingly, these ATPases appear to more optimized for efficiency than for speed, which can be rationalized through their key role as energy transducers in biology. The present modeling shows how the dynamical performance properties of biomolecular motors and pumps may have evolved to suit their corresponding biological actions.
Contact precautions in single-bed or multiple-bed rooms for patients with extended-spectrum β-lactamase-producing Enterobacteriaceae in Dutch hospitals: a cluster-randomised, crossover, non-inferiority study
Authors: Marjolein F Q Kluytmans-van den Bergh, Patricia C J Bruijning-Verhagen, Christina M J E Vandenbroucke-Grauls, Els I G B de Brauwer, Anton G M Buiting, Bram M Diederen, Erika P M van Elzakker, Alex W Friedrich, Joost Hopman, Nashwan al Naiemi, John W A Rossen, Gijs J H M Ruijs, Paul H M Savelkoul, Carlo Verhulst, Margreet C Vos, Andreas Voss, Marc J M Bonten, Jan A J W Kluytmans, Marc Bonten, Martin Bootsma, Els de Brauwer, Patricia Bruijning-Verhagen, Anton Buiting, Bram Diederen, Erika van Elzakker, Alexander Friedrich, Joost Hopman, Greetje Kampinga, Peter van Keulen, Jan Kluytmans, Marjolein Kluytmans-van den Bergh, Nashwan al Naiemi, Guy Oudhuis, Erwin Raangs, Sigrid Rosema, John Rossen, Gijs Ruijs, Paul Savelkoul, Annet Troelstra, Christina Vandenbroucke-Grauls, Kees Verduin, Carlo Verhulst, Margreet Vos, Andreas Voss, Rob Willems, Ina Willemsen
Journal: The Lancet Infectious Diseases (2019)
A phase II study of ADI-PEG 20 in combination with gemcitabine and docetaxel for the treatment of soft tissue sarcoma.
Authors: Brian Andrew Van Tine, Nam Bui, Bethany Prudner, John S. Bomalaski, Bor-Wen Wu, Sant P. Chawla, Kristen N. Ganjoo, Peter John Oppelt, Angela C. Hirbe
Journal: Journal of Clinical Oncology (2019)

TPS11079 Background: The combination of gemcitabine (G) and docetaxel (D) is a standard second line therapy for soft tissue sarcoma (STS) with a modest response rate. Recent studies have looked to add agents to enhance response. We have shown that argininosuccinate synthase 1 (ASS1) expression is silenced in 88% of all sarcomas (n = 708) (Bean et al., 2016, Cell Death and Disease), and that this loss is associated with a reliance on extracellular sources of the amino acid arginine. The arginine depleting enzyme PEGylated arginine deiminase (ADI-PEG 20) depletes extracellular arginine. Preclinical studies have demonstrated that arginine starvation and D administration induce c-Myc-driven hENT1 surface expression overcoming intrinsic cell surface G transporter related resistance. To test this hypothesis, we opened this multi-institutional randomized phase II trial examining the safety and efficacy of ADI-PEG 20 with G + D in STS (NCT03449901) in July of 2018. Methods: Eligible patients are adults with metastatic or unresectable histologically or cytologically confirmed FNCLCC grade 2 or 3 STS that would be standardly treated with G and/or D. Patients are treated with ADI-PEG 20 at a dose of 36 mg/m2 via intramuscular injection on Day -7 of Cycle 1 and then on Days 1, 8, and 15 of each subsequent cycle. G will be given intravenously at a dose of 750 mg/m2 over 90 minutes on Days 1 and 8 and D will be given intravenously at a dose of 75 mg/m2 over 60 minutes on Day 8 of each cycle. The median PFS of metastatic sarcoma patients receiving the standard G + D treatment was estimated to be 6.2 months in a randomized phase II study (Maki et. al., 2007, JCO). With the addition of ADI-PEG 20, we target to improve the median PFS to 9 months, a 45.2% (2.8 months or 12 weeks) improvement in patients treated on G + D + ADI-PEG 20 against the null hypothesis median PFS of 6.2 months to achieve 80% power to detect the improvement in PFS at a 5% alpha level. Tumor specimens (pre- and post-ADI-PEG 20 during week -1) and blood are collected for correlative studies including metabolomics, pharmacodynamics, immunogenicity and ASS1 biomarkers. Quality of life will be measured using FACT-G7. Clinical trial information: NCT03449901.
Predicting Biopsy Outcomes During Active Surveillance for Prostate Cancer: External Validation of the Canary Prostate Active Surveillance Study Risk Calculators in Five Large Active Surveillance Cohorts
Authors: Frank-Jan H. Drost, Daan Nieboer, Todd M. Morgan, Peter R. Carroll, Monique J. Roobol, Bruce Trock, Behfar Ehdaie, Peter Carroll, Christopher Filson, Jeri Kim, Christopher Logothetis, Todd Morgan, Laurence Klotz, Tom Pickles, Eric Hyndman, Caroline M. Moore, Vincent Gnanapragasam, Mieke Van Hemelrijck, Prokar Dasgupta, Chris Bangma, Monique Roobol, Arnauld Villers, Antti Rannikko, Antoinette Perry, Jonas Hugosson, Jose Rubio-Briones, Anders Bjartell, Lukas Hefermehl, Lee Lui Shiong, Mark Frydenberg, Yoshiyuki Kakehi, Byung Ha Chung, Theo van der Kwast, Wim van der Linden, Tim Hulsen, Cees de Jonge, Mike Kattan, Ji Xinge, Kenneth Muir, Artitaya Lophatananon, Michael Fahey, Ewout Steyerberg, Liying Zhang, Daan Nieboer, Kerri Beckmann, Brian Denton, Andrew Hayen, Paul Boutros, Wei Guo, Nicole Benfante, Janet Cowan, Dattatraya Patil, Emily Tolosa, Tae-Kyung Kim, Alexandre Mamedov, Vincent LaPointe, Trafford Crump, Jenna Kimberly-Duffell, Aida Santaolalla, Jonathan Olivier, Tiziana Rancati, Helén Ahlgren, Juanma Mascarós, Annica Löfgren, Kurt Lehmann, Catherine Han Lin, Hiromi Hirama, Kwang Suk Lee, Guido Jenster, Anssi Auvinen, Anders Bjartell, Masoom Haider, Kees van Bochove, Ballentine Carter, Sam Gledhill, Mark Buzza, Chris Bangma, Monique Roobol, Sophie Bruinsma, Jozien Helleman
Journal: European Urology (2019)
Physician concordance with update to ASCO guidelines for antiemetic use with carboplatin AUC ≥ 4.
Authors: Rudolph M. Navari, Kathryn Jean Ruddy, Thomas William LeBlanc, Rebecca Anne Clark-Snow, Rita S. Wickham, Gary Binder, Tammy Bratton Coberly, Ravi C. Potluri, Luke M. Schmerold, Eric Roeland
Journal: Journal of Clinical Oncology (2019)

11595 Background: In 2017, NCCN (2/2017) and ASCO (8/2017) each amended antiemetic guidelines to classify carboplatin AUC ≥4 as highly emetogenic chemotherapy (HEC), recommending upfront triple prophylaxis with an NK1 receptor antagonist (RA) + 5HT3 RA + dexamethasone. Physician concordance with the new recommendations, and the consequences for avoidable post-chemotherapy acute care, merit study. Methods: In a large electronic health record database (IBM Explorys), we identified carboplatin courses of therapy (≥14-day cycles as a proxy for AUC ≥4) and courses with ≥7-day cycles of other HEC and non-HEC therapy from 4Q 2012 through August 2018. Guideline concordance, defined as triple prophylaxis at HEC initiation, was evaluated. We also assessed 30-day post-chemotherapy acute care (inpatient or emergency department) associated with nausea or vomiting (NV) or eight other toxicities deemed avoidable in the US Centers for Medicare &amp; Medicaid’s new oncology outcome measure OP-35. Results: 11,554 carboplatin courses were identified. Before the guideline change, rates of upfront triple prophylaxis grew from 14% in 2013 to 16% in mid-2017. Rates then rose to 26% by 1Q 2018 before dropping to 21% by 3Q 2018; quarterly rates averaged 20% (range 15%-26%) following the guideline change. In 31% of carboplatin courses we noted 30-day acute care use, of which 75% involved ≥1 of the ten OP-35 toxicities. NV (with or without acute care use) was reported in 24% of courses, and 27% of total OP-35 acute care events involved NV. Rates for NV, and for OP-35-related and NV-related acute care after carboplatin, were similar to rates after other HEC chemotherapy, and higher than rates after other non-HEC IV chemotherapy or oral HEC/MEC agents. Conclusions: Use of upfront triple antiemetic prophylaxis has increased only marginally for carboplatin AUC ≥ 4 since its 2017 re-classification as HEC in national guidelines, perhaps due to low awareness of the change. Patients receiving carboplatin had similar rates of NV and related 30-day acute care events as seen for other HEC, confirming that the new HEC definition fits clinical experience. More triple prophylaxis use is needed to reduce NV and NV-related avoidable acute care seen with carboplatin AUC ≥ 4.
Quantitative Ultrasound Spectroscopy for Differentiation of Hepatocellular Carcinoma from At-Risk and Normal Liver Parenchyma
Authors: Isabelle Durot, Rosa M.S. Sigrist, Nishita Kothary, Jarrett Rosenberg, Jürgen K. Willmann, Ahmed El Kaffas
Journal: Clinical Cancer Research (2019)

Quantitative ultrasound approaches can capture tissue morphologic properties to augment clinical diagnostics. This study aims to clinically assess whether quantitative ultrasound spectroscopy (QUS) parameters measured in hepatocellular carcinoma (HCC) tissues can be differentiated from those measured in at-risk or healthy liver parenchyma.This prospective Health Insurance Portability and Accountability Act (HIPAA)-compliant study was approved by the Institutional Review Board. Fifteen patients with HCC, 15 non-HCC patients with chronic liver disease, and 15 healthy volunteers were included (31.1% women; 68.9% men). Ultrasound radiofrequency data were acquired in each patient in both liver lobes at two focal depths (3/9 cm). Region of interests (ROIs) were drawn on HCC and liver parenchyma. The average normalized power spectrum for each ROI was extracted, and a linear regression was fit within the -6 dB bandwidth, from which the midband fit (MBF), spectral intercept (SI), and spectral slope (SS) were extracted. Differences in QUS parameters between the ROIs were tested by a mixed-effects regression.There was a significant intraindividual difference in MBF, SS, and SI between HCC and adjacent liver parenchyma (P < 0.001), and a significant interindividual difference between HCC and at-risk and healthy non-HCC parenchyma (P < 0.001). In patients with HCC, cirrhosis (n = 13) did not significantly change any of the three parameters (P > 0.8) in differentiating HCC from non-HCC parenchyma. MBF (P = 0.12), SI (P = 0.33), and SS (P = 0.57) were not significantly different in non-HCC tissue among the groups.The QUS parameters are significantly different in HCC versus non-HCC liver parenchyma, independent of underlying cirrhosis. This could be leveraged for improved HCC detection with ultrasound in the future.
Outcomes Associated With Clopidogrel-Aspirin Use in Minor Stroke or Transient Ischemic Attack
Authors: Yuesong Pan, Jordan J. Elm, Hao Li, J. Donald Easton, Yilong Wang, Mary Farrant, Xia Meng, Anthony S. Kim, Xingquan Zhao, William J. Meurer, Liping Liu, Dennis Dietrich, Yongjun Wang, S. Claiborne Johnston
Journal: JAMA Neurology (2019)

Dual antiplatelet therapy with clopidogrel and aspirin is effective for secondary prevention after minor ischemic stroke or transient ischemic attack (TIA). Uncertainties remained about the optimal duration of dual antiplatelet therapy for minor stroke or TIA.
Association of Plasma Amylin Concentration With Alzheimer Disease and Brain Structure in Older Adults
Authors: Haihao Zhu, Qiushan Tao, Ting Fang Alvin Ang, Joseph Massaro, Qini Gan, Saraf Salim, Rui-ying Zhu, Vijaya B. Kolachalama, Xiaoling Zhang, Sheral Devine, Sanford H. Auerbach, Charles DeCarli, Rhoda Au, Wei Qiao Qiu
Journal: JAMA Network Open (2019)

<h3>Importance</h3> Preclinical studies suggest that amylin has a U-shaped dose-response association with risk of Alzheimer disease (AD). The association of plasma amylin with AD in humans is unknown. <h3>Objectives</h3> To measure amylin concentration in plasma by using enzyme-linked immunosorbent assay and to study the association between plasma amylin, incidence of AD, and brain structure in humans. <h3>Design, Setting, and Participants</h3> This cohort study used data from the Framingham Heart Study offspring cohort from 1998 to 2015. Using a Monte Carlo approach, participants were divided into 3 plasma amylin concentration groups: (1) low (&lt;75 pmol/L), (2) high (75-2800 pmol/L), and (3) extremely high (≥2800 pmol/L). Data analyses were conducted October 5, 2017, to December 18, 2018. <h3>Exposures</h3> Baseline plasma amylin concentrations at examination 7. <h3>Main Outcomes and Measures</h3> Incidence of dementia or AD and brain volumetric measures from structural magnetic resonance imaging data. <h3>Results</h3> From the Framingham Heart Study offspring cohort, 3061 participants (mean [SD] age at baseline, 61.0 [9.5] years; 1653 [54.0%] women) who had plasma amylin measurements, dementia incidence, and brain volume measurements on record were included in this study. The distribution of plasma amylin concentrations was highly skewed (median [interquartile range], 7.5 [4.6-18.9] pmol/L; mean [SD], 302.3 [1941.0] pmol/L; range, 0.03-44 623.7 pmol/L). Compared with the low plasma amylin concentration group, the high plasma amylin concentration group had a lower rate of AD incidence (2.3% vs 5.6%;<i>P</i> = .04), but the extremely high plasma amylin concentration group had a higher rate of AD incidence (14.3%;<i>P</i> &lt; .001). After adjusting for age, sex, education, body mass index, diabetes, cardiovascular disease, high-density lipoprotein level, and<i>APOE4</i>, high plasma amylin was not associated with decreased AD risk (hazard ratio, 0.42 [95% CI, 0.16-1.14];<i>P</i> = .09) but was positively associated with volume of gray matter in the temporal lobe (β = 0.17 [SE, 0.05];<i>P</i> &lt; .001). In contrast, extremely high plasma amylin concentration was associated with a higher AD risk (hazard ratio, 2.51 [95% CI, 1.38-4.57];<i>P</i> = .003) but not associated with temporal lobe volume (β = 0.02 [SE, 0.07];<i>P</i> = .82). <h3>Conclusions and Relevance</h3> This study found that plasma amylin concentration was associated with AD incidence and brain structure with a U-shaped pattern. These findings are consistent with preclinical findings that suggest amylin is a neuropeptide that is physiological; however, at extremely high concentrations, it may lead to amylin aggregation and therefore may be a risk factor for AD.
Abstract 267: Photoplethysmography-Based Algorithm Uninterruptedly Supports Pulse Detection in Porcine Automatic 30:2 Cardiopulmonary Resuscitation Data by Handling Transitions Between Compressions and Pauses
Authors: Ralph Wijshoff, Jakob Van de Laar, Jens Muehlsteff, Gerrit Jan Noordergraaf
Journal: Circulation (2018)

Introduction: Pulse checks by manual palpation during CPR are challenging, time-consuming and interrupt chest compressions. To support pulse checks during 30:2 CPR, we developed an algorithm to uninterruptedly detect pulse in a photoplethysmography (PPG) signal by handling transitions between compressions and ventilation pauses. We retrospectively evaluated the algorithm on porcine automated-CPR (ACPR) data. Methods: In 10 anesthetised pigs, VF was induced, followed by 20 min of 30:2 ACPR with 2.5 s ventilation pauses (Phase 1). Next, up to four defibrillation attempts were made, each shock followed by 2 min of 30:2 ACPR (Phase 2). Infrared nasal PPG and thoracic impedance (TI) signals were measured, with aortic blood pressure (ABP) as reference. The developed algorithm detected pulse rate (PR) in the PPG signal, by estimating the main frequencies present in the signal and ignoring compression frequencies, where the compression rate (CR) was determined from the TI waveform. The PPG signal was analysed by sliding a 5 s window by 1 s shifts. When analysing a signal with an abrupt change due to the start/end of a compression series, frequency estimates will be compromised. Therefore, the algorithm identified the start/end of compressions in the TI signal and analysed in the 5 s window (1) a compression-free interval of at least 2 s or (2) a compression interval of at least 2.8 s. The window was ignored if no such interval was found. Pulse detection performance was quantified by comparison to pulse presence annotations determined from the protocol and visual inspection of ABP and PPG signals. Results: Table I gives sensitivity for pulse presence (SNV), specificity for arrest (SPC) and positive and negative predictive values (PPV/NPV). Conclusions: Overall, SPC, PPV and NPV are high. In Phase 2, SNV is reasonable in pauses, but compromised during compressions when PR and CR are close. In 30:2 CPR the algorithm can provide frequent detections from 2 s pauses. Table I: detection results.
SKY59: A Long-Lasting Engineered Anti-C5 Antibody for Subcutaneously Injectable Anti-Complement Therapy
Authors: Kenta Haraya, Zenjiro Sampei, Tatsuhiko Tachibana, Taku Fukuzawa, Siok Wan Gan, Meiri Shida-Kawazoe, Yuichiro Shimizu, Masaru Muraoka, Tomoyuki Igawa, Takehisa Kitazawa, Junichi Nezu
Journal: Blood (2018)
AB0033 AGE AND GENDER EFFECTS ON PROGRAMMED CELL DEATH-1 EXPRESSION IN HEALTHY DONORS
Authors: Rosanne Reitsema, Rebeca Hid Cadena, Sander Nijhof, Wayel Abdulahad, Minke G. Huitema, Annemieke Boots, Elisabeth Brouwer, Peter Heeringa
Journal: Annals of the Rheumatic Diseases (2019)

<h3>Background:</h3> Giant cell arteritis (GCA) is the most frequent form of vasculitis affecting the large sized vessels. GCA occurs more frequently in females and exclusively in individuals &gt; 50 years of age but it is unclear how gender and age relate to GCA pathogenesis. In balancing the immune response and preventing immune dysfunction, immune checkpoints are crucial. Recently, the co-inhibitory checkpoint molecule programmed cell death-1 (PD-1) and its ligand PD-L1 were found to be aberrantly expressed in GCA (1). However, data on age and gender related effects on immune checkpoint expression is limited. <h3>Objectives:</h3> To further investigate the contribution of immune checkpoints in GCA pathogenesis and how this relates to ageing and gender differences, we first studied PD-1 expression as a function of age and gender in healthy males and females. <h3>Methods:</h3> Whole blood cells of 13 young healthy donors (mean age 25.5 years, female/male ratio 7:6) and 20 elderly healthy donors (mean age 72.7 years, female/male ratio 11:9) were stained for CD3, CD4, CD45RA, CD25 and PD-1 with monoclonal antibodies and expression was measured with flow cytometry. <h3>Results:</h3> Percentages of PD-1+ cells within CD4+ T cells, memory CD4+ T cells and the subset of non-suppressive regulatory T cells (Tregs, defined as CD4+CD45RA-CD25int) were decreased in elderly post-menopausal females compared to elderly males (Figure 1A-C; p&lt;0.05). Furthermore, the frequency of PD-1+ cells within non-suppressive Tregs was also decreased in post-menopausal females compared to young females (Figure 1C; p&lt;0.05). <h3>Conclusion:</h3> PD-1 expression is decreased in (subsets of) CD4+ T cells of post-menopausal females when compared to younger females and elderly males. These findings suggest that post-menopausal status in females can influence PD-1 expression. Further studies on the relation between hormonal changes and immune checkpoint expression may contribute to understanding why elderly females are predisposed to develop GCA. <h3>Reference</h3> [1] Zhang H, Watanabe R, Berry GJ, Vaglio A, Liao YJ, Warrington KJ, et al. Immunoinhibitory checkpoint deficiency in medium and large vessel vasculitis. Proc Natl Acad Sci.2017Feb7;114(6):E970–9. <h3>Disclosure of Interests:</h3> Rosanne Reitsema: None declared, Rebeca Hid Cadena: None declared, Sander Nijhof: None declared, Wayel Abdulahad: None declared, Minke G. Huitema: None declared, Annemieke Boots Grant/research support from: grant from MSD in 2010-2015, Consultant for: I was a consultant for Grunenthal Germany 2016-2017, Employee of: I was an employee of Organon, Shering-Plough and MSD from 1991-2011, Elisabeth Brouwer Speakers bureau: Dr. Brouwer as an employee of the UMCG received speaker fees and consulting fees from Roche which were paid to the UMCG, Peter Heeringa: None declared
Clinical significance of PRL-3 genomic amplification/expression profiles and preclinical study of PRL-3 inhibitor in human gastrointestinal cancers.
Authors: Keishi Yamashita, Masahiko Watanabe
Journal: Journal of Clinical Oncology (2012)

3071 Background: PRL (phosphatase of regenerating liver) is a tyrosine phosphatase that dephosphorylates molecules involved in cancer invasion and metastasis and subsequently activates either PI3 kinase or Src pathway. PRL-3 was initially identified as a gene that is amplified in metastasis of colorectal cancer. We are thinking much of clinical potential of PRL-3 inhibitor as a molecular targeted therapy in GI cancer. Methods: Immunohistochemistry and genomic status were assessed for PRL-3 in esophageal squamous cell carcinoma (ESCC)(n=88), gastric adenocarcinoma (n=173), and colorectal adenocarcinoma (n=107).RNA interference was used to determine its specific functional roles in GI cancers. Preclinical study using PRL-3 inhibitors (1-4-bromo-2-benzylidene rhodanine) was performed in 4 ESCC and 4 gastric cancer cell lines that were intensely expressed for PRL-3, or TE5 which showed basal level expression. Results: (1) PRL-3 expression is associated with lymph node metastasis in primary ESCC (p=0.0012), gastric adenocarcinoma (p&lt;0.0001), and colorectal carcinoma (p&lt;0.0001). In the primary tumors with lymph node metastasis, its expression was recognized in 96, 80, 86%, respectively. (2) If restricted to patients with PRL-3 expression, genomic amplification was found exclusively in stage IV ESCC (30%), and stage III/IV gastric cancer (40%). In colorectal cancer, PRL-3 genomic amplification is found in 35% of stage III/IV, but only in 10% of stage II (p=0.002). (3) PRL-3 RNA interference robustly suppressed metastatic cancer phenotypes. (4) PRL-3 inhibitor suppressed phenotypes as well in a dose dependent manner (0, 1, 10, and 50 mM). Interestingly, 10 mM of the inhibitor could not suppress muscle cell (C2C12) that endogenously express PRL-3, but 50 mM suppressed it. Conclusions: PRL-3 inhibitor has a great clinical potential to suppress tumors with metastatic ability, that was represented by lymph node metastasis or recurrent disease of GI cancers.
Addressing Limitations in Case-Control Study of Patients Undergoing Resuscitative Endovascular Balloon Occlusion of the Aorta—Reply
Authors: Bellal Joseph, Muhammad Zeeshan, Peter Rhee
Journal: JAMA Surgery (2019)

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