tbuckley/cabot-search huggingface dataset:
PB2384 EFFECTS OF IMMUNOSUPPRESSIVE DRUGS FREQUENTLY USED IN THE PREVENTION AND TREATMENT OF GRAFT-VERSUS-HOST DISEASE ON INNATE LYMPHOID CELL FUNCTION AND SURVIVAL
Authors: S. Omar, N. Haverkate, V. van Hoeven, B. Blom, M. Hazenberg
Journal: HemaSphere (2019)

Background: Graft-versus-host disease (GvHD) is an inflammatory disease that frequently occurs after allogeneic hematopoietic stem cell transplantation (allo-HSCT). In GvHD, donor T cells are harmful and cause damage to recipients’ healthy tissue. Other immune cells such as innate lymphoid cells (ILCs) are beneficial, as they are important for the maintenance and repair of epithelial barriers. ILC3s for example, produce interleukin (IL)-22, a cytokine important for intestinal epithelial cell homeostasis, and regulatory ILCs can suppress T-cell activation. We have previously shown that higher ILC counts before and after allo-HSCT were associated with a reduced risk to develop GvHD. Following allogeneic HSCT, immunosuppressive drugs are used to prevent and treat GvHD. However, such immunosuppressive medications could potentially suppress the beneficial effects of ILCs. Aims: We investigate the effect of immunosuppressive drugs frequently used in the prevention and treatment of GvHD on the survival, proliferation, activation and function of ILCs in vitro. Methods: Tonsil-derived T cells and ILC3s were FACS sorted and labeled with the CellTraceTM Violet dye. After 24-h rest, T cells were stimulated with anti-CD3/CD28 beads and ILC3s were stimulated with IL-2, IL-1β and IL-23. After stimulation (1 hour), immune suppressants or vehicle control were added to both cell types. After 4 days of incubation, cytokine production was analyzed by ELISA and cell survival, proliferation and activation was analyzed by flow cytometry. Results: Prednisolone had similar effects on T cells and ILC3s. It inhibited cytokine production by both cell types, but did not affect T cell and ILC3 proliferation or activation. However, non-cytotoxic concentrations of methotrexate (MTX), mycophenolic acid (MMF) and imatinib (Gleevec) differentially affected T cells and ILCs. MTX suppressed T cell proliferation and activation but had no effect on ILC3s. MMF inhibited T cell proliferation, but did not affect activation or cytokine production of either cell type. Finally, imatinib suppressed T cell proliferation, activation and function, but had no effect on ILC3 proliferation and function. Other immunosuppressive compounds are currently under investigation. Summary/Conclusion: Our data demonstrate that commonly used immunosuppressive drugs directed at suppressing T-cell function and applied to prevent and treat GvHD can have different effects on ILC activation, proliferation and function. These findings will help to develop strategies to maximize the use of the protective function of ILCs in addition to suppressing T cell alloreactivity, in the prevention and treatment of GvHD.
The concept of molecular structure in structure–activity relationship studies and drug design
Authors: Bernard Testa, Lemont B. Kier
Journal: Medicinal Research Reviews (1991)

We can justify the use of any model, method, or algorithm if we clearly state our goals, understand the basis of our procedures, and fully appreciate the true nature and limitations of the results. As we have illustrated here, the creation of new wisdom may appear to be a consequence of our labors. There are cases, however, where this creation may be only an illusion. In any analysis of structure-activity, property-activity, or structure-property relationships, the degree of understanding of the nature of the starting data therefore determines the level of confidence ascribable to any result and prediction. This is, in essence, the message of our inquisitive meditations on the deep nature of structure-activity relationships.
Evolutionary Routes in Metastatic Uveal Melanomas Depend on <i>MBD4</i> Alterations
Authors: Manuel Rodrigues, Lenha Mobuchon, Alexandre Houy, Samar Alsafadi, Sylvain Baulande, Odette Mariani, Benjamin Marande, Khadija Ait Rais, Monique K. Van der Kooij, Ellen Kapiteijn, Sieta Gassama, Sophie Gardrat, Raymond L. Barnhill, Vincent Servois, Rémi Dendale, Marc Putterman, Sarah Tick, Sophie Piperno-Neumann, Nathalie Cassoux, Gaëlle Pierron, Joshua J. Waterfall, Sergio Roman-Roman, Pascale Mariani, Marc-Henri Stern
Journal: Clinical Cancer Research (2019)

Abstract Purpose: Uveal melanomas (UM) are genetically simple tumors carrying few copy number alterations (CNA) and a low mutation burden, except in rare MBD4-deficient, hypermutated cases. The genomics of uveal melanoma metastatic progression has not been described. We assessed the genetic heterogeneity of primary and metastatic MBD4-proficient and -deficient uveal melanomas. Experimental Design: We prospectively collected 75 metastatic and 16 primary samples from 25 consecutive uveal melanoma patients, and performed whole-exome sequencing. Results: MBD4-proficient uveal melanomas contained stable genomes at the nucleotide level, acquiring few new single nucleotide variants (SNVs; 16 vs. 13 in metastases and primary tumors, respectively), and no new driver mutation. Five CNAs were recurrently acquired in metastases (losses of 1p, 6q, gains of 1q, 8q, and isodisomy 3). In contrast, MBD4-deficient uveal melanomas carried more than 266 SNVs per sample, with high genetic heterogeneity and TP53, SMARCA4, and GNAS new driver mutations. SNVs in MBD4-deficient contexts were exploited to unveil the timeline of oncogenic events, revealing that metastatic clones arose early after tumor onset. Surprisingly, metastases were not enriched in monosomy 3, a previously defined metastatic risk genomic feature. Monosomy 3 was associated with shorter metastatic-free interval compared with disomy 3 rather than higher rate of relapse. Conclusions: MBD4-proficient uveal melanomas are stable at the nucleotide level, without new actionable alterations when metastatic. In contrast, MBD4 deficiency is associated with high genetic heterogeneity and acquisition of new driver mutations. Monosomy 3 is associated with time to relapse rather than rate of relapse, thus opening avenues for a new genetic prognostic classification of uveal melanomas.
Government policy interventions to reduce human antimicrobial use: A systematic review and evidence map
Authors: Susan Rogers Van Katwyk, Jeremy M. Grimshaw, Miriam Nkangu, Ranjana Nagi, Marc Mendelson, Monica Taljaard, Steven J. Hoffman
Journal: PLoS Medicine (2019)

Growing political attention to antimicrobial resistance (AMR) offers a rare opportunity for achieving meaningful action. Many governments have developed national AMR action plans, but most have not yet implemented policy interventions to reduce antimicrobial overuse. A systematic evidence map can support governments in making evidence-informed decisions about implementing programs to reduce AMR, by identifying, describing, and assessing the full range of evaluated government policy options to reduce antimicrobial use in humans.Seven databases were searched from inception to January 28, 2019, (MEDLINE, CINAHL, EMBASE, PAIS Index, Cochrane Central Register of Controlled Trials, Web of Science, and PubMed). We identified studies that (1) clearly described a government policy intervention aimed at reducing human antimicrobial use, and (2) applied a quantitative design to measure the impact. We found 69 unique evaluations of government policy interventions carried out across 4 of the 6 WHO regions. These evaluations included randomized controlled trials (n = 4), non-randomized controlled trials (n = 3), controlled before-and-after designs (n = 7), interrupted time series designs (n = 25), uncontrolled before-and-after designs (n = 18), descriptive designs (n = 10), and cohort designs (n = 2). From these we identified 17 unique policy options for governments to reduce the human use of antimicrobials. Many studies evaluated public awareness campaigns (n = 17) and antimicrobial guidelines (n = 13); however, others offered different policy options such as professional regulation, restricted reimbursement, pay for performance, and prescription requirements. Identifying these policies can inform the development of future policies and evaluations in different contexts and health systems. Limitations of our study include the possible omission of unpublished initiatives, and that policies not evaluated with respect to antimicrobial use have not been captured in this review.To our knowledge this is the first study to provide policy makers with synthesized evidence on specific government policy interventions addressing AMR. In the future, governments should ensure that AMR policy interventions are evaluated using rigorous study designs and that study results are published.PROSPERO CRD42017067514.
The hepatic-targeted, resveratrol loaded nanoparticles for relief of high fat diet-induced nonalcoholic fatty liver disease
Authors: Wendi Teng, Liyun Zhao, Songtao Yang, Chengying Zhang, Meiyu Liu, Jie Luo, Junhua Jin, Ming Zhang, Chen Bao, Dan Li, Wei Xiong, Yuan Li, Fazheng Ren
Journal: Journal of Controlled Release (2019)
Providence in Medicine
Authors: Colleen R. Kelly
Journal: Annals of Internal Medicine (2019)

On Being a Doctor18 June 2019Providence in MedicineColleen R. Kelly, MDColleen R. Kelly, MDWarren Alpert Medical School of Brown University and Lifespan Physician Group Gastroenterology, Providence, Rhode Island (C.R.K.)Search for more papers by this authorAuthor, Article, and Disclosure Informationhttps://doi.org/10.7326/M19-0236 Audio Reading - “Providence in Medicine” Audio. Michael A. Lacombe, MD, Annals Associate Editor, reads “Providence in Medicine” by Colleen R. Kelly, MD Your browser does not support the audio element. Audio player progress bar Step backward in current audio track Play current audio trackPause current audio track Step forward in current audio track Mute current audio trackUnmute current audio track 00:00/ SectionsAboutFull TextPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail Men occasionally stumble over the truth, but most of them pick themselves up and hurry off as if nothing had happened.—Winston ChurchillAtheist friends and family members have nearly convinced me that the God I believed in fervently as a Catholic schoolchild does not exist. The Supreme Being, so they tell me, is a human creation to help our brains find order in experiences or, more cynically, a means of controlling the masses as humans formed organized societies. I stopped dragging my kids to church on Sunday mornings a couple of years ago, preferring to make pancakes, drink coffee, and ... Author, Article, and Disclosure InformationAffiliations: Warren Alpert Medical School of Brown University and Lifespan Physician Group Gastroenterology, Providence, Rhode Island (C.R.K.)Corresponding Author: Colleen R. Kelly, MD, 146 West River Street, Suite 1H, Providence, RI 02904; e-mail, [email protected]edu. PreviousarticleNextarticle Advertisement Audio Reading - “Providence in Medicine” Audio. Michael A. Lacombe, MD, Annals Associate Editor, reads “Providence in Medicine” by Colleen R. Kelly, MD Your browser does not support the audio element. Audio player progress bar Step backward in current audio track Play current audio trackPause current audio track Step forward in current audio track Mute current audio trackUnmute current audio track 00:00/ FiguresReferencesRelatedDetails Metrics 18 June 2019Volume 170, Issue 12Page: 897-898KeywordsBrainEmotionsFerritinHeartIntensive care unitsMemoryNursesSepsisVisionVital signs ePublished: 18 June 2019 Issue Published: 18 June 2019 Copyright & PermissionsCopyright © 2019 by American College of Physicians. All Rights Reserved.PDF downloadLoading ...
PF417 PONATINIB IN CHILDHOOD PHILADELPHIA POSITIVE LEUKEMIAS: THE EXPERIENCE OF THE INTERNATIONAL REGISTRY OF CHILDHOOD CHRONIC MYLELOID LEUKEMIA (I‐CML‐PED‐STUDY)
Authors: F. Millot, M. Suttorp, E. de Bont, K. Kalwak, B. Nelken, S. Ducassou, Y. Bertrand, A. Baruchel
Journal: HemaSphere (2019)

Background: Ponatinib is effective in adults with Philadelphia positive (Ph+) leukemias but only few case reports are available regarding the use of this so far not‐licensed drug in children and adolescents. Aims: To describe the profile of tolerance and efficacy of compassionate use of ponatinib in children and adolescents with Ph+ leukemias. Methods: Data from 11 children with chronic myeloid leukemia (CML) registered to the I‐CML‐Ped‐Study and from 3 children with Ph+ acute lymphoblastic leukemia (Ph+ ALL) treated with ponatinib were retrospectively collected. Results: In 11 girls and 3 boys (median age 14 years, range: 4.5–17) ponatinib was used as a second (n = 2), third (n = 5), fourth (n = 2), fifth (n = 3), sixth (n = 1) or eighth (n = 1) treatment line. Ponatinib was administered as single therapy in 7 patients while the 7 remaining patients (advanced phases CML n = 5, Ph+ ALL n = 2) received additional chemotherapy. The status of the disease when ponatinib was started was: CML advanced phases (accelerated phase, n = 2; blast crisis, n = 6), CML without achievement of major molecular response (MMR, n = 2), T315I mutation (n = 1) and in Ph+ ALL patients molecular relapse (n = 2) or marrow relapse (n = 1). Six patients were previously transplanted. Ponatinib was used as a bridge to transplant in 5 cases. Dose administered ranged between 15–41 mg/m 2 (median: 27 mg/m 2 ) and median duration of ponatinib treatment was 2.5 months (range: 0.5–14 months). Treatment responses in the 8 patients in CML‐advanced phases were: no response (n = 2), complete hematologic response (n = 1), MMR (n = 3), MR4.5 (n = 1) or unknown (n = 1). In patients in CML chronic phase, achievement of MMR was obtained in 2 of the patients without prior achievement of MMR while no response was observed in the patient with mutation T315I. Two of the 3 patients with Ph+ ALL achieved MR4.5 and MR5 while the remaining patient did not respond. Grade 1 to 4 side effects were recorded in 5 of 7 patients treated with ponatinib alone; toxicity grade 3–4 was reported in 2 patients (hematologic toxicity). No vascular event related to ponatinib was observed. Summary/Conclusion: With the limitation of the retrospective nature of this study, ponatinib may be a reasonable additional treatment option for children with Ph+ leukemias who failed to several lines of therapy.
Loss of KDM6A confers drug resistance in acute myeloid leukemia
Authors: Sophie M. Stief, Anna-Li Hanneforth, Sabrina Weser, Raphael Mattes, Michela Carlet, Wen-Hsin Liu, Michael D. Bartoschek, Helena Domínguez Moreno, Matthias Oettle, Julia Kempf, Binje Vick, Bianka Ksienzyk, Belay Tizazu, Maja Rothenberg-Thurley, Hilmar Quentmeier, Wolfgang Hiddemann, Sebastian Vosberg, Philipp A. Greif, Klaus H. Metzeler, Gunnar Schotta, Sebastian Bultmann, Irmela Jeremias, Heinrich Leonhardt, Karsten Spiekermann
Journal: Leukemia (2019)

Acute myeloid leukemia (AML) is an aggressive hematologic neoplasm resulting from the malignant transformation of myeloid progenitors. Despite intensive chemotherapy leading to initial treatment responses, relapse caused by intrinsic or acquired drug resistance represents a major challenge. Here, we report that histone 3 lysine 27 demethylase KDM6A (UTX) is targeted by inactivating mutations and mutation-independent regulation in relapsed AML. Analyses of matched diagnosis and relapse specimens from individuals with KDM6A mutations showed an outgrowth of the KDM6A mutated tumor population at relapse. KDM6A expression is heterogeneously regulated and relapse-specific loss of KDM6A was observed in 45.7% of CN-AML patients. KDM6A-null myeloid leukemia cells were more resistant to treatment with the chemotherapeutic agents cytarabine (AraC) and daunorubicin. Inducible re-expression of KDM6A in KDM6A-null cell lines suppressed proliferation and sensitized cells again to AraC treatment. RNA expression analysis and functional studies revealed that resistance to AraC was conferred by downregulation of the nucleoside membrane transporter ENT1 (SLC29A1) by reduced H3K27 acetylation at the ENT1 locus. Our results show that loss of KDM6A provides cells with a selective advantage during chemotherapy, which ultimately leads to the observed outgrowth of clones with KDM6A mutations or reduced KDM6A expression at relapse.
PB1848 CAN VON WILLEBRAND ANTIGEN LEVEL AT THE INITIAL PRESENTATION BE ABLE TO PREDICT THE INHIBITOR DEVELOPMENT IN PATIENTS WITH SEVERE HEMOPHILIA A?
Authors: S. Aytac, F. Gumruk, M. çetin
Journal: HemaSphere (2019)

Background: There is a large heterogeneity in bleeding events and arthropaty among patients with severe Hemophilia A which is multifactorial. Mostly FVIII gene mutations seems to influence phenotype however underlying prothrombotic risk factors and FVIII half life may both have an affect on the heterogeneity.VWF is the specific carrier of factor VIII in plasma and protecs it from proteolytic degradation,prolonging its half life in circulation and efficiently localizing it at the site of vasculary injuiry. Aims: Here, we want to evaluate von Willebrand antigen levels of the children with severe Hemophilia A at the initial diagnose and want to figure out whether low initial von Willebrand antigen (VWF:Ag) levels may asssociated with a frequent bleeding phenotype or not, retrospectively. Methods: We retrospectively evaluate charts of 40 children with severe hemophilia A who was diagnosed in between 1997 and 2017 at the Hacettepe University, Department of Pediatric Hematology. All of these patients were receiving prophylaxis and among those 40 patients only 6 had a history of inhibitor in which 2 of them still persist. Results: Mean VWF:Ag levels were found to be 114 ± 40 (32‐200)IU/dL. Ten out of 40 children VWF:Ag levels was found to be under 100IU/dL and from those 5 out of ten were found to be under 80IU/dL. Interestingly none of them were have the blood group ’O’. Initial bleeding age were found to be lower (median 6 months)in patients with low VWF:Ag (&lt;100IU/dL) than that of the patients with high VWF:Ag (≥100IU/dL)(median 18 months)(p = 0.05).2/10 had a history of inhibitor (1 low titer 1 high titer) development and 7/10 had a target joint which requires radiosyneviectomy during the follow up period.On the other hand 4 out of 30 patients with VWF:Ag&gt;100IU/dL had a history of inhibitor development (4 high titre inhibitor: 2 was still found to be positive) and 5/30 had a target joint. Summary/Conclusion: Despite we do not have the half lifes of FVIII, a significant shorter half life in patients with a low VWF:Ag level was previosly reported. Although there is no follow up of VWF:Ag levels in this small group of patients with a frequent bleeders initial VWF:Ag levels may give some clues about the clinical outcome.
Response by Bansal et al to Letter Regarding Article, “Dysfunctional and Proinflammatory Regulatory T-Lymphocytes Are Essential for Adverse Cardiac Remodeling in Ischemic Cardiomyopathy”
Authors: Shyam S. Bansal, M. Ameen Ismahil, Mehak Goel, Guihua Zhou, Gregg Rokosh, Tariq Hamid, Sumanth D. Prabhu
Journal: Circulation (2019)
Plasma adiponectin to predict incident cancer in a large multiethnic population-based cohort study.
Authors: Muhammad Shaalan Beg, Sadia Saleem, Aslan Turer, Colby Ayers, Song Zhang, Philipp Scherer, Susan Lakoski
Journal: Journal of Clinical Oncology (2013)

1560 Background: Previous retrospective studies have suggested an inverse relationship between cancer and markers of insulin resistance, including adiponectin. Whether circulating levels of adiponectin are associated with future cancer incidence has not been well demonstrated. As such, we examined the association of adiponectin on the risk of future cancer development in a large population based cohort study. Methods: The Dallas Heart Study (DHS) is a multiethnic population based study of 3,531 Dallas County residents with an intentional oversampling of minorities which are underrepresented in other population studies. Incident and prevalent cancer cases were identified in the DHS by the Texas Cancer Registry. Cases were defined as ‘incident’ if they were diagnosed 24 months after enrollment into DHS. Fasting blood samples were obtained from DHS participants between 2000 and 2002, and used for biomarker analysis. Univariate and multivariate analysis was performed to test the association of incident cancer and adiponectin after adjusting for age, diabetes status, gender, ethnicity and body mass index (BMI). Results: Of 3,531 individuals, 150 incident cancer cases were diagnosed. The study population comprised 55.8% females, 51.5% were black and 39.6% had a BMI above 30 kg/m2. Mean adiponectin was 8.12 μg/ml in incident cancer group and 7.46 μg/ml in non-cancer group (p=0.129). In multivariable analysis, adiponectin was not an independent predictor of cancer incidence after adjusting for age, diabetes status, gender, ethnicity and BMI (p=0.167) Conclusions: Previous population based studies have demonstrated conflicting results on the association of markers insulin resistance, including adiponectin, and cancer incidence. In this study of a predominant ethnic minority population, an association between adiponectin and cancer incidence was not seen. Further prospective studies are needed to understand the association between markers of insulin resistance and risk of future cancer risk.
Abstract 17576: Right Atrial and Right Ventricular Deformation Are Reflections of Right Ventricular Afterload in Predicting Outcomes in Pediatric Pulmonary Hypertension
Authors: Pei-Ni Jone, Ling Li, Matthew J Mulvahill, Mary Craft, D. Dunbar Ivy, Shelby Kutty
Journal: Circulation (2016)

Background: Pulmonary hypertension (PH) results in right ventricular (RV) dysfunction. Elevated right atrial (RA) pressure is prognostic of adverse outcomes in PH. Strain imaging provides quantitat...
PS1086 THE INCIDENCE AND CLINICAL IMPACT OF RHOA G17 V MUTATION IN ANGIOIMMUNOBLASTIC T-CELL LYMPHOMA PATIENTS
Authors: Y.-T. Hsu, S.-S. Li, L.-Y. Hung, C.-C. Yeh, T.-Y. Chen, K.-C. Chang
Journal: HemaSphere (2019)

Background: The Doxorubicin based R-CHOP regimen remains the standard of care for the upfront treatment of DLBCL. The advent of oral idarubicin permitted to develop an all-oral ambulatory oro-CIEP regimen. Aims: We hypothesized this regimen would improve the treatment of elderly DLBCL. Methods: We have performed a phase 1/2 study to determine the MTD[CA1] of idarubicin in the oro-CIEP regimen. Idarubicin was orally administrated on day 1 with starting dose at 20 mg/m2 and escalated per 10 mg/m2 increment. Results: Twenty-six newly diagnosed patients were enrolled, median age of 71 years (range, 62–80). All first 3 patients developed a DLT at level 3 (40 mg/m2), and 14 patients were then enrolled at RP2D 30 mg/m2 in the phase 2. The most significant hematological toxicities were thrombocytopenia grade 3 or 4 (3.3%) and neutropenia grade 3 or 4 (26%); and extra-hematological toxicities were infectious disease (5% grade 3 or 4). Second primary malignancies were reported in three patients. No toxic related death was observed. ORR and CR rates were 85% and 77%, respectively. The 5-year overall survival and event free survival were 65% (95%CI 41;81) and 65% (95%CI 42;81), respectively. Summary/Conclusion: This analysis shows that oral idarubicin at the MTD of 30 mg/m2 is safe and active in elderly DLBCL. The results we have observed, particularly overall survival seemed to be superimposable to previous publications with the regular CHOP-like regimens for this population. Further improvements in the protocol will be introduced with the subcutaneous anti-CD20 immunotherapy approach. This data needs to be confirmed in the context of a larger study.