tbuckley/cabot-search huggingface dataset:
Early cellular rejection after orthotopic liver transplantation correlates with low concentrations of FK506 in hepatic tissue*1
Authors: W SANDBORN
Journal: Hepatology (1995)

We have previously reported that low hepatic tissue cyclosporine levels correlate with early cellular rejection after liver transplantation. The aim of this study is to determine whether there is a similar relationship in patients treated with FK506. Twenty-five liver biopsies were performed in 10 patients immunosuppressed with FK506 without cellular rejection: day 7 = 10; day 14 = 3; day 21 = 9; day 28 = 1; day 35 = 1; and day 42 = 1. These 10 patients without cellular rejection were compared with 7 patients immunosuppressed with FK506 with cellular rejection who underwent a total of 23 liver biopsies, including 9 biopsies that showed rejection: day 7 = 4; day 14 = 2; day 21 = 1; day 28 = 1; and day 49 = 1. There was no significant difference between the nonrejection and current rejection groups in the median plasma concentration of FK506, 0.9 ng/mL versus 0.9 ng/mL (P = .50). In contrast, the median hepatic tissue concentration of FK506 was significantly higher in the nonrejection group than it was in the current rejection group, 144 ng/ g versus 48 ng/g (P = .02). In the current rejection group, 7 of 9 hepatic tissue concentrations of FK506 were <100 ng/g, and in the nonrejection group, 18 of 25 hepatic tissue concentrations were >100 ng/g. Low hepatic tissue concentrations of FK506 correlate with the occurrence of early cellular rejection after liver transplantation, in contrast to plasma concentrations of FK506. A hepatic tissue concentration of FK506 <100 ng/g is 78% sensitive and 72% specific for cellular rejection. These findings support the hypothesis that low hepatic tissue concentrations of immunosuppressives may lead to cellular rejection after liver transplantation.
Apocalypse now?
Authors: Anthony Costello, Mark Maslin
Journal: The Lancet (2008)

This is a good time for catastrophists. Will the credit crunch cause the collapse of the world's financial system? Will climate change from greenhouse gas emissions threaten human survival in the next century? Or, as this book suggests, is the real apocalypse happening now with a massive new extinction phase brought about by industrial damage to the world's ecosystem? Biodiversity is the variety of life on earth, while ecosystems provide materials, conditions, and processes that sustain all life on this planet.
OC-168 Towards individualised risk prediction for crohn's disease
Authors: K M Taylor, N J Prescott, S H Anderson, P M Irving, S L West, D J M Crouch, C G Mathew, J D Sanderson, C M Lewis
Journal: Gut (2012)

<h3>Introduction</h3> Although the RR of developing Crohn9s disease (CD) is increased in first degree relatives (FDR) of probands by 13–27-fold, (1) it is difficult to apply this on an individual basis. Recently, risk models for complex disease using information from genome-wide association and epidemiological studies have been built. Potentially, such models could identify FDR at highest risk of CD, for screening and early intervention. <h3>Aim</h3> To generate a risk model for CD, and ultimately determine if such a model can predict presymptomatic or future development of CD. <h3>Methods</h3> CD patients were contacted to identify asymptomatic FDR aged 18–55 who wished to participate in research into risk prediction and presymptomatic diagnosis of CD. (Recruitment target: 500 FDR) DNA was extracted from saliva. Genetic analysis used the Immunochip (Illumina), and genotypes were determined for disease susceptibility loci established by CD genome-wide meta-analysis. (2) A multiplicative risk model was generated using risk prediction software (REGENT) (3) based on genotype and smoking status, and CD RR determined for each FDR. <h3>Results</h3> The first 100 FDR have been recruited. Demographics: 53% siblings, 36% offspring, 11% parents. Mean age 37, females 66%, smokers 25%, ex-smokers 33%. NOD2 genotype counts were not significantly different to their frequencies in the control population, but were significantly different to cases (13% heterozygous, 0% homozygous, p=0.64 for controls vs FDR, p=0.001 for cases vs FDR). CD RR ranged from 0.04 to 10.07 (median 0.96) and was significantly higher than that in the general population: 19% of FDR had a RR &gt;2, compared to an expected proportion of 11% (p=0.02). Comparison of highest and lowest RR quartiles in FDR showed good separation of RR between the groups. More FDRs in the highest RR quartile had &gt;2 CD-affected relatives compared with FDRs in the lowest RR quartile, but this was not significant (5 vs 1, p=0.19). <h3>Conclusion</h3> Increased RR of CD is confirmed in FDR compared to the general population. Risk stratification is possible, but follow-up is required to determine if such risk scores can be used to predict presymptomatic CD or future development of CD. Additionally, risk awareness may encourage smokers to quit. Once recruitment to the study is completed, FDR in the highest and lowest risk quartiles will proceed to further tests including faecal and serum biomarkers, and capsule endoscopy. All those recruited will undergo follow-up for 10 years. <h3>Competing interests</h3> None declared. <h3>References</h3> 1. <b>Lewis CM</b>, <i>et al. J Med Genet</i> 2007;<b>44</b>:689–94. 2. <b>Franke A</b>, <i>et al. Nat Genet</i> 2010;<b>42</b>:1118–25. 3. http://cran.r-project.org/web/packages/REGENT/index.html
Short-course aminoglycosides as adjunctive empirical therapy in patients with Gram-negative bloodstream infection, a cohort study
Authors: J.W. Timotëus Deelen, W.C. Rottier, A.G.M. Buiting, J.W. Dorigo-Zetsma, J.A.J.W. Kluytmans, P.D. van der Linden, S.F.T. Thijsen, B.J.M. Vlaminckx, A.J.L. Weersink, H.S.M. Ammerlaan, M.J.M. Bonten, C.H. van Werkhoven
Journal: Clinical Microbiology and Infection (2020)

ObjectiveShort-course aminoglycosides as adjunctive empirical therapy to β-lactams in patients with a clinical suspicion of sepsis are used to broaden antibiotic susceptibility coverage and to enhance bacterial killing. We quantified the impact of this approach on 30-day mortality in a subset of sepsis patients with a Gram-negative bloodstream infection.MethodsFrom a prospective cohort study conducted in seven hospitals in the Netherlands between June 2013 and November 2015, we selected all patients with Gram-negative bloodstream infection (GN-BSI). Short-course aminoglycoside therapy was defined as tobramycin, gentamicin or amikacin initiated within a 48-hour time window around blood-culture obtainment, and prescribed for a maximum of 2 days. The outcome of interest was 30-day all-cause mortality. Confounders were selected a priori for adjustment using a propensity score analysis with inverse probability weighting.ResultsA total of 626 individuals with GN-BSI who received β-lactams were included; 156 (24.9%) also received aminoglycosides for a median of 1 day. Patients receiving aminoglycosides more often had septic shock (31/156, 19.9% versus 34/470, 7.2%) and had an eight-fold lower risk of inappropriate treatment (3/156, 1.9% versus 69/470, 14.7%). Thirty-day mortality was 17.3% (27/156) and 13.6% (64/470) for patients receiving and not receiving aminoglycosides, respectively; yielding crude and adjusted odds ratios for 30-day mortality for patients treated with aminoglycosides of 1.33 (95% CI 0.80–2.15) and 1.57 (0.84–2.93), respectively.ConclusionsShort-course adjunctive aminoglycoside treatment as part of empirical therapy with β-lactam antibiotics in patients with GN-BSI did not result in improved outcomes, despite better antibiotic coverage of pathogens.
Focused ultrasound blood brain barrier opening mediated delivery of MRI-visible albumin nanoclusters to the rat brain for localized drug delivery with temporal control
Authors: Megan C. Rich, Jennifer Sherwood, Aundrea F. Bartley, Quentin A. Whitsitt, Magdelene Lee, W.R. Willoughby, Lynn E. Dobrunz, Yuping Bao, Farah D. Lubin, Mark Bolding
Journal: Journal of Controlled Release (2020)
Suberoylanilide Hydroxamic Acid (SAHA), a histone deacetylase (HDAC) inhibitor, induces a unique mitotic effect and potentiates flavopiridol (F) induced apoptosis.
Authors: Haider S. Cheema, Monica V. Motwani, Gary K. Schwartz
Journal: Cancer Research (2004)

2443  SAHA is an HDAC inhibitor that induces prolongation or hyperacetylation of various histones leading to induction of both p21 and p27, resulting in both G1 and G2/M cell cycle arrest. The increase in the G2/M population of cells treated with SAHA has been attributed to an increase in the percentage of G2 cells. However, the effect of SAHA on mitosis is unknown. In view of this we treated MKN-74 gastric cancer cells with increasing concentrations of SAHA. As determined by western blot analysis this resulted in an anticipated time and dose dependent increase in p21. The flow cytometry and MPM-2 labeling of SAHA treated cells showed an unanticipated increase in cells accumulating in the M phase of the cell cycle. The mitotic index (number of cells in mitosis) of asynchronous untreated cells was 3-4%, which was increased to 30% after 12 h treatment of cells with 2.5 μM SAHA. This effect was first evident at 8 hours, peaked at 12-16 hours, and was absent by 30 hours. Similar results were observed with colon cancer Hct116 cells. We examined this process in vivo in Hct116 cells expressing green fluorescence protein-tagged histone 2B (GFP-H2B). The chromatin labeling by GFP-H2B allows real time visualization of chromatin changes by time-lapse videomicroscopy. Treatment of cells with 2.5 μM SAHA showed suppression of mitotic chromosome movement and transient arrest of the cells in prometaphase-like stage. This effect was evident by 6-12 h. There was no evidence of metaphase plate or anaphase spindle formation. Following this cells exit mitosis, as evident by chromatin de-condensation, and majority of cells enter the interphase without undergoing cytokinesis. In view of its effect on mitosis, we tested SAHA in combination with the CDK inhibitor flavopiridol (F). Treatment of MKN-74 cells with 5 μM SAHA and 300 nM F induced apoptosis in less than 3% of the cells. Concurrent treatment of SAHA and F for 24 h did not enhance the induction of apoptosis. The sequential treatment of MKN-74 cells with SAHA for 24 h followed by F for 24 h induced apoptosis in 38 ±2% of the cells which was significantly greater than that observed for SAHA followed by drug free media (4.8±1%). The reverse combination with F for 24 h followed by SAHA for 24 h did not result in enhancement in induction of apoptosis. Similar results were observed with Hct116 cells. The flow cytometry with MPM-2 labeled MKN-74 and Hct116 cells showed that F prevented the SAHA induced transient mitotic arrest when it was either given together with or preceded SAHA. Collectively, our results indicate that SAHA induces a unique mitotic arrest and this effect may be important for potentiation of its cytotoxicity by F. These studies show the promise in utility of this combination in treatment of gastrointestinal malignancies.
Circulating RNA differences between patients with stable and progressive idiopathic pulmonary fibrosis
Authors: Britt Clynick, Helen E. Jo, Tamera J. Corte, Ian N. Glaspole, Christopher Grainge, Peter M.A. Hopkins, Paul N. Reynolds, Sally Chapman, E. Haydn Walters, Christopher Zappala, Gregory J. Keir, Wendy A. Cooper, Annabelle M. Mahar, Samantha Ellis, Nicole S. Goh, Svetlana Baltic, Marisa Ryan, Dino B.A. Tan, Yuben P. Moodley
Journal: European Respiratory Journal (2020)

<b>Gene expression differences were found in the circulation of IPF patients <i>versus</i> healthy controls, of which five were expressed in higher concentrations in progressive <i>versus</i> stable IPF, potentially providing insight into disease pathogenesis</b>https://bit.ly/3bakHCL
Looking back to go forward: adherence to inhaled therapy before biologic therapy in severe asthma
Authors: Richard W. Costello, Breda Cushen
Journal: European Respiratory Journal (2020)

For decades inhaled corticosteroids have been central to the management of asthma and are proven to be effective in maintaining symptom control, reducing exacerbations and preserving quality of life through mediation of airway inflammation. However, a small minority of patients have disease which is refractory to high dose inhaled corticosteroid (ICS) therapy and require additional oral corticosteroids to achieve acceptable control of symptoms and exacerbations. Severe asthma represents less than 10% of the total asthma population [1] but is the most serious, life-affecting and costly form of the condition [2]. Inhaler adherence may inform response to asthma biologic therapy and should continue to be assessed in patients receiving these treatments <https://bit.ly/2RjMBED>
Reply to H.J.A. Adams et al
Authors: Michael Fuchs, Helen Goergen, Carsten Kobe, Peter Borchmann, Andreas Engert
Journal: Journal of Clinical Oncology (2020)

We thank Adams and Kwee 1 for their interest in our HD16 trial 2 and their comments.The study in patients with early-stage favorable Hodgkin lymphoma (HL) was designed to clarify whether additional involved-field radiotherapy of 20 Gy can be omitted in patients with a negative fluorodeoxyglucose (FDG) positron emission tomography (PET) scan after 2 cycles of doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) without relevant loss of progression-free survival (PFS) and whether a positive PET scan after 2 cycles of ABVD is a risk factor in terms of PFS in these patients.
Evolution of Systemic Therapy for Hepatocellular Carcinoma
Authors: Richard S. Finn, Andrew X. Zhu
Journal: Hepatology (2020)

Despite being one of the leading causes of cancer death globally, hepatocellular carcinoma (HCC) has historically not been the focus of novel drug development. That has changed in the past several years, with the results from a number of hallmark phase 3 studies in advanced HCC. In HCC, immune-oncology approaches have garnered much attention; there is still a need to better understand criteria for patient selection and to optimize combination strategies to maximize the potential of these approaches. The next generation of studies will aim at translating our increased understanding of tumor biology into clinical trial design.
The reliability of a deep learning model in clinical out-of-distribution MRI data: A multicohort study
Authors: Gustav Mårtensson, Daniel Ferreira, Tobias Granberg, Lena Cavallin, Ketil Oppedal, Alessandro Padovani, Irena Rektorova, Laura Bonanni, Matteo Pardini, Milica G Kramberger, John-Paul Taylor, Jakub Hort, Jón Snædal, Jaime Kulisevsky, Frederic Blanc, Angelo Antonini, Patrizia Mecocci, Bruno Vellas, Magda Tsolaki, Iwona Kłoszewska, Hilkka Soininen, Simon Lovestone, Andrew Simmons, Dag Aarsland, Eric Westman
Journal: Medical Image Analysis (2020)

Deep learning (DL) methods have in recent years yielded impressive results in medical imaging, with the potential to function as clinical aid to radiologists. However, DL models in medical imaging are often trained on public research cohorts with images acquired with a single scanner or with strict protocol harmonization, which is not representative of a clinical setting. The aim of this study was to investigate how well a DL model performs in unseen clinical datasets-collected with different scanners, protocols and disease populations-and whether more heterogeneous training data improves generalization. In total, 3117 MRI scans of brains from multiple dementia research cohorts and memory clinics, that had been visually rated by a neuroradiologist according to Scheltens' scale of medial temporal atrophy (MTA), were included in this study. By training multiple versions of a convolutional neural network on different subsets of this data to predict MTA ratings, we assessed the impact of including images from a wider distribution during training had on performance in external memory clinic data. Our results showed that our model generalized well to datasets acquired with similar protocols as the training data, but substantially worse in clinical cohorts with visibly different tissue contrasts in the images. This implies that future DL studies investigating performance in out-of-distribution (OOD) MRI data need to assess multiple external cohorts for reliable results. Further, by including data from a wider range of scanners and protocols the performance improved in OOD data, which suggests that more heterogeneous training data makes the model generalize better. To conclude, this is the most comprehensive study to date investigating the domain shift in deep learning on MRI data, and we advocate rigorous evaluation of DL models on clinical data prior to being certified for deployment.
Abstract IA10: Epigenetic remodeling of host metabolic pathways by Epstein-Barr virus (EBV) immortalization
Authors: Jason Lamontagne, Andreas Wiedmer, Paul M. Lieberman
Journal: Cancer Research (2020)

Abstract Epstein-Barr virus (EBV) reprograms host metabolism and gene expression during B-cell immortalization through a highly orchestrated process. The regulatory mechanisms coordinating this reprogramming are not fully elucidated but reflect important events in viral oncogenesis. One clue to this coordinate regulation is provided by the viral-encoded tegument protein BNRF1 that functions in viral chromatin assembly during primary infection and shares extensive structural similarity to a purine biosynthetic enzyme FGARAT (also called PFAS). FGARAT shows strong evolutionary conservation from bacteria to human. Orthologues of BRNF1 are found in all gamma herpesviruses, including KSHV ORF75, and share the common function of disarming components of the PML-nuclear body (PML-NB) and its antiviral functions. We have previously shown that the BNRF1 interacts with the histone H3.3 chaperone DAXX and displaces its interaction with ATRX. ATRX is thought to target Daxx-H3.3 to GC-rich repetitive DNA to repress viral and host telomeric transcription. We found that the BNRF1-DAXX complex changes these functions to facilitate viral gene expression during primary infection, enabling the establishment of EBV latency. However, it is not yet known how the viral FGARAT homology is linked to cellular metabolism and purine biosynthesis. Using metabolomics mass spectrometry, we provide new data indicating that the metabolic pathways are among the most significantly perturbed by EBV during B-cell immortalization. Integrating gene expression (RNA-Seq), chromatin accessibility (ATAC-Seq), and EBV transcription factor binding (ChIP-Seq) we identified several cellular metabolic genes, including adenine deaminase (ADA) and arginosuccinate synthase (ASS1), as a direct target of EBV transcriptional regulation during EBV immortalization. We find that EBV nuclear antigen EBNA1 binds directly to the ADA transcriptional regulatory regions and induces epigenetic changes at this locus. Failure to activate ADA compromises B-cell immortalization. The relationship between BNRF1, EBNA1, and nucleotide metabolism during EBV immortalization will be discussed. These findings suggest that EBV captured a highly conserved purine biosynthetic enzyme to coordinate epigenetic reprogramming with nucleotide metabolism during EBV induced B-cell immortalization. Citation Format: Jason Lamontagne, Andreas Wiedmer, Paul M. Lieberman. Epigenetic remodeling of host metabolic pathways by Epstein-Barr virus (EBV) immortalization [abstract]. In: Proceedings of the AACR Special Conference on the Microbiome, Viruses, and Cancer; 2020 Feb 21-24; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2020;80(8 Suppl):Abstract nr IA10.
Biallelic mutations in SORD cause a common and potentially treatable hereditary neuropathy with implications for diabetes
Authors: Andrea Cortese, Yi Zhu, Adriana P. Rebelo, Sara Negri, Steve Courel, Lisa Abreu, Chelsea J. Bacon, Yunhong Bai, Dana M. Bis-Brewer, Enrico Bugiardini, Elena Buglo, Matt C. Danzi, Shawna M. E. Feely, Alkyoni Athanasiou-Fragkouli, Nourelhoda A. Haridy, Aixa Rodriguez, Alexa Bacha, Ashley Kosikowski, Beth Wood, Brett McCray, Brianna Blume, Carly Siskind, Charlotte Sumner, Daniela Calabrese, David Walk, Dragan Vujovic, Eun Park, Francesco Muntoni, Gabrielle Donlevy, Gyula Acsadi, John Day, Joshua Burns, Jun Li, Karen Krajewski, Kate Eichinger, Kayla Cornett, Krista Mullen, Perez Quiros Laura, Laurie Gutmann, Maria Barrett, Mario Saporta, Mariola Skorupinska, Natalie Grant, Paula Bray, Reza Seyedsadjadi, Riccardo Zuccarino, Richard Finkel, Richard Lewis, Rosemary R. Shy, Sabrina Yum, Sarah Hilbert, Simone Thomas, Steffen Behrens-Spraggins, Tara Jones, Thomas Lloyd, Tiffany Grider, Tim Estilow, Vera Fridman, Rosario Isasi, Alaa Khan, Matilde Laurà, Stefania Magri, Menelaos Pipis, Chiara Pisciotta, Eric Powell, Alexander M. Rossor, Paola Saveri, Janet E. Sowden, Stefano Tozza, Jana Vandrovcova, Julia Dallman, Elena Grignani, Enrico Marchioni, Steven S. Scherer, Beisha Tang, Zhiqiang Lin, Abdullah Al-Ajmi, Rebecca Schüle, Matthis Synofzik, Thierry Maisonobe, Tanya Stojkovic, Michaela Auer-Grumbach, Mohamed A. Abdelhamed, Sherifa A. Hamed, Ruxu Zhang, Fiore Manganelli, Lucio Santoro, Franco Taroni, Davide Pareyson, Henry Houlden, David N. Herrmann, Mary M. Reilly, Michael E. Shy, R. Grace Zhai, Stephan Zuchner
Journal: Nature Genetics (2020)
A Time-Updated, Parsimonious Model to Predict AKI in Hospitalized Children
Authors: Ibrahim Sandokji, Yu Yamamoto, Aditya Biswas, Tanima Arora, Ugochukwu Ugwuowo, Michael Simonov, Ishan Saran, Melissa Martin, Jeffrey M. Testani, Sherry Mansour, Dennis G. Moledina, Jason H. Greenberg, F. Perry Wilson
Journal: Journal of the American Society of Nephrology (2020)

Timely prediction of AKI in children can allow for targeted interventions, but the wealth of data in the electronic health record poses unique modeling challenges.We retrospectively reviewed the electronic medical records of all children younger than 18 years old who had at least two creatinine values measured during a hospital admission from January 2014 through January 2018. We divided the study population into derivation, and internal and external validation cohorts, and used five feature selection techniques to select 10 of 720 potentially predictive variables from the electronic health records. Model performance was assessed by the area under the receiver operating characteristic curve in the validation cohorts. The primary outcome was development of AKI (per the Kidney Disease Improving Global Outcomes creatinine definition) within a moving 48-hour window. Secondary outcomes included severe AKI (stage 2 or 3), inpatient mortality, and length of stay.Among 8473 encounters studied, AKI occurred in 516 (10.2%), 207 (9%), and 27 (2.5%) encounters in the derivation, and internal and external validation cohorts, respectively. The highest-performing model used a machine learning-based genetic algorithm, with an overall receiver operating characteristic curve in the internal validation cohort of 0.76 [95% confidence interval (CI), 0.72 to 0.79] for AKI, 0.79 (95% CI, 0.74 to 0.83) for severe AKI, and 0.81 (95% CI, 0.77 to 0.86) for neonatal AKI. To translate this prediction model into a clinical risk-stratification tool, we identified high- and low-risk threshold points.Using various machine learning algorithms, we identified and validated a time-updated prediction model of ten readily available electronic health record variables to accurately predict imminent AKI in hospitalized children.
Sleep Apnea and Cardiovascular Disease
Authors: Virend K. Somers, David P. White, Raouf Amin, William T. Abraham, Fernando Costa, Antonio Culebras, Stephen Daniels, John S. Floras, Carl E. Hunt, Lyle J. Olson, Thomas G. Pickering, Richard Russell, Mary Woo, Terry Young
Journal: Journal of the American College of Cardiology (2008)