tbuckley/cabot-search huggingface dataset:
Undescended Testicle
Authors: D. J. Tibbs
Journal: BMJ (1965)

Hospital Infectious Diseases Unit.There were 191 cases in the 0-5 age group, 796 in the 6-15 age group, and 469 over 15 years of age.During the years 1960, 1961, and 1962 only, all cases notified were questioned for further epidemiological information, including occupation, history of known contact with other cases, and any prophylactic inoculations, other injections, and blood-transfusions dur- ing the six months prior to onset of symptoms.Unfortunately, as a result of an exten- sive outbreak of paratyphoid in the Edin- burgh area in the early months of 1963 and a shortage of sanitary inspector staff, this epidemiological inquiry had to be suspended and has not yet been restarted, although the notifications have continued to be recorded.During these three years, out of a total of 850 cases, there were 83 (mainly school- children) who had had prophylactic inocula- tions within six months of falling ill, seven who had other injections-for example, penicillin-and six only (all but one over 15 years) who gave a history of recent blood- transfusion.While it is intended to make further use of the wealth of epidemiological material already available in this department, we whole- heartedly endorse Dr. Zuckerman's plea for acute hepatitis to be made notifiable on a national scale so that further knowledge and understanding of the epidemiology can be achieved.-Weare, etc.,
Targeting DNA Damage and Repair in Acute Myeloid Leukemia Carrying Internal Tandem Duplication of Fms-like Tyrosine Kinase 3 (FLT3-ITD) - a Mechanistic Study
Authors: Ka Lam Nelson Ng, Claire Lynn, Thomas Wing Yan Leung, Eric Chi Wai So, Anskar Yu Hung Leung
Journal: Blood (2019)
Combining the Antidepressant Drugs
Authors: J. Randell
Journal: BMJ (1965)

MEDBRITSH JUNsignificantly absorbed from the large areas of inflamed skin which may have to be treated.In his brief account of haemangiomata Dr. Beare mentions the ulceration which may occur in the larger cavernous lesions, particularly in areas which are readily traumatized.I have been impressed by the curious degree of pain from such ulcerated areas, and, for example, when they are present in the napkin area a child will often start crying as soon as it knows the napkin is going to be changed.-I am, etc., Bristol 8.
Metabolic Remodeling Promotes Cardiac Hypertrophy by Directing Glucose to Aspartate Biosynthesis
Authors: Julia Ritterhoff, Sara Young, Outi Villet, Dan Shao, F. Carnevale Neto, Lisa F. Bettcher, Yun-Wei A. Hsu, Stephen C. Kolwicz, Daniel Raftery, Rong Tian
Journal: Circulation Research (2019)

Hypertrophied hearts switch from mainly using fatty acids (FAs) to an increased reliance on glucose for energy production. It has been shown that preserving FA oxidation (FAO) prevents the pathological shift of substrate preference, preserves cardiac function and energetics, and reduces cardiomyocyte hypertrophy during cardiac stresses. However, it remains elusive whether substrate metabolism regulates cardiomyocyte hypertrophy directly or via a secondary effect of improving cardiac energetics.The goal of this study was to determine the mechanisms of how preservation of FAO prevents the hypertrophic growth of cardiomyocytes.We cultured adult rat cardiomyocytes in a medium containing glucose and mixed-chain FAs and induced pathological hypertrophy by phenylephrine. Phenylephrine-induced hypertrophy was associated with increased glucose consumption and higher intracellular aspartate levels, resulting in increased synthesis of nucleotides, RNA, and proteins. These changes could be prevented by increasing FAO via deletion of ACC2 (acetyl-CoA-carboxylase 2) in phenylephrine-stimulated cardiomyocytes and in pressure overload-induced cardiac hypertrophy in vivo. Furthermore, aspartate supplementation was sufficient to reverse the antihypertrophic effect of ACC2 deletion demonstrating a causal role of elevated aspartate level in cardiomyocyte hypertrophy. 15N and 13C stable isotope tracing revealed that glucose but not glutamine contributed to increased biosynthesis of aspartate, which supplied nitrogen for nucleotide synthesis during cardiomyocyte hypertrophy.Our data show that increased glucose consumption is required to support aspartate synthesis that drives the increase of biomass during cardiac hypertrophy. Preservation of FAO prevents the shift of metabolic flux into the anabolic pathway and maintains catabolic metabolism for energy production, thus preventing cardiac hypertrophy and improving myocardial energetics.
CSIG-13. PROTEIN KINASE CI DRIVES BOTH TUMOR INVASION AND PROLIFERATION AND IS A COMPELLING TARGET FOR THE TREATMENT OF GLIOBLASTOMA
Authors: Rajappa Kenchappa, Amanda Luu, Rita West, Ann Mladek, Jann Sarkaria, Yi Liu, Nicole Murray, Alan Fields, Steven Rosenfeld
Journal: Neuro-Oncology (2019)

Abstract In glioblastoma (GBM), invasion and proliferation are reciprocally related—e.g., targeting one stimulates the other. Thus, effective therapy for GBM requires finding targets that drive both invasion and proliferation and which are druggable, ideally with FDA approved therapeutics. We find that the atypical protein kinase C isoform, PKCi meets these criteria. Using a human GBM tissue microarray, we find that PKCi protein expression fits a bimodal distribution, with &gt;35% of GBMs showing high levels of PKCi expression. Genetic deletion of Prkci, the gene encoding mouse PKCi, impairs tumor invasion and proliferation both in vitro and in vivo, and significantly prolongs survival in an immunocompetent PDGF-driven orthotopic mouse model of GBM. PKCi can be selectively targeted with Auranofin, a small molecule PKCi inhibitor that has been FDA approved for treatment of inflammatory diseases. Like genetic deletion of Prkci Auranofin treatment significantly prolongs survival in our murine GBM model, and does so to a similar degree. Interestingly, analysis of a panel of human and murine GBM cells reveals that sensitivity to Auranofin inhibition of transformed growth directly correlates with expression of PKCi, indicating that PKCi expression profiling could serve as a predictive biomarker for responsiveness to Auranofin. However, genetically deleting or pharmacologically inactivating PKCi does not permanently arrest tumor growth, implying that GBM cells acquire mechanisms that allow them to compensate for the loss of this important signaling molecule. We are currently examining potential “escape” mechanisms through ‘omics-based approaches, which may enable us to enhance the therapeutic potential of Auranofin. Taken together, our results demonstrate that PKCi is a compelling therapeutic target for treatment of GBM that deserves further investigation.
COMP-01. MODELING THE EVOLUTION OF PLOIDY IN A RESOURCE RESTRICTED ENVIRONMENT
Authors: Noemi Andor, Jill Barnholtz-Sloan, Hanlee Ji
Journal: Neuro-Oncology (2019)

Abstract Progression of lower-grade gliomas (LGG) to glioblastoma (GBM) is accompanied by a phenotypic switch to an invasive cell phenotype. Converging evidence from colorectal-, breast-, and lung-cancers, suggests a strong enrichment of high ploidy cells among metastatic lesions as compared to the primary. Even in normal development: trophoblast giant cells are responsible for invading the placenta during embryogenesis and these cells often have tens of copies of the genome. We formulate a mechanistic Grow-or-go model that postulates higher energy demands of high-ploidy cells as driver of invasive behavior. The unit we are modeling is a cell, that comes with a certain ploidy, proliferation-, and death-rate. Variations in ploidy emerge as a result of chromosome missegregations. For each cell we calculate the probability of cell-division as a function of energy availability in the neighborhood vs. ploidy-dependent energy demand of the cell. Underlying this comparison is the dual role of integrin signaling: integrin-mediated signals allow cells to progress from G1 to S-phase. At the same time integrins mediate cell migration. The model was implemented as a cellular automaton and 2,500 simulations were ran at variable energies and missegregation rates. In low-energy environments high-ploidy clones were enriched at the leading edge of the tumor. This was not the case in high-energy environments. We applied the model to analyze previously published exome sequencing data from 14 multi-spatial and longitudinal LGG biopsies. Using the size and ploidy of co-existing clones as summary statistics for Approximate Bayesian Computation, we infer relative chromosome missegregation rates in primary LGG. A higher missegregation rate was predictive of faster progression of LGG to GBM (multivariate Cox: HR = 7.96, P = 0.041). Future validation experiments will evaluate the potential of the model to explain differences in the prognostic power of integrin signaling and cell cycle progression between males and females.
Lenalidomide Maintenance Prolongs Progression-Free Survival and Does Not Impact the Aggressiveness of Clinical Relapse: Data from Long-Term Follow up of the Myeloma XI Trial
Authors: Charlotte Pawlyn, Faith E. Davies, Kara-Louise Royle, David Cairns, Gordon Cook, Mark T Drayson, Walter M Gregory, Matthew Jenner, John R Jones, Martin F. Kaiser, Roger G. Owen, Nigel H. Russell, Gareth Morgan, Graham Jackson
Journal: Blood (2019)
Outcomes after Plerixafor Plus FLAG-IDA (PLERIFLAG) Versus FLAG-IDA +/- Gentuzumab for Adult Patients with First Relapsed/Refractory AML: A Propensity Score Analysis from the Pethema Registry
Authors: Juan Miguel M. Bergua Burgues, Isabel Cano-Ferri, David Martínez-Cuadron, Blanca Boluda, Pilar Martínez-Sánchez, Rebeca Rodríguez-Veiga, Jordi Esteve, Susana Vives, Josefina Serrano, Maria-Belen Vidriales, Olga Salamero, Carlos Carretero, Ana Jimenez-Ubieto, Ignacio Casas, Rocio Cardesa, Marina Diaz-Beyá, Salut Brunet, Celina Benavente, Jose Antonio Pérez-Simón, Federico Moscardo, Eliana Aguiar, Manuel Perez Encinas, Aurelio López Martínez, Carlos Rguez, A. Cabello, Jorge Labrador, Lissette Del Pilar Costilla, Claudia Sossa, Teresa Bernal Del Castillo, Miguel A. Sanz, Pau Montesinos
Journal: Blood (2019)
Allogeneic Stem Cell Transplantation (alloHSCT) for Chronic Lymphocytic Leukemia (CLL) in the Era of Novel Agents
Authors: Lindsey E. Roeker, Jennifer R. Brown, Peter Dreger, Oscar B Lahoud, Toby A. Eyre, Danielle M. Brander, Alan Skarbnik, Catherine C. Coombs, Haesook T. Kim, Steven T Manchini, Timothy J Voorhees, Kim H. Orchard, Harriet S Walter, Arvind K. Arumainathan, Andrea Sitlinger, Craig S. Sauter, Sergio A Giralt, Miguel-Angel Perales, Anthony R. Mato
Journal: Blood (2019)
RASP 4: Ancestral State Reconstruction Tool for Multiple Genes and Characters
Authors: Yan Yu, Christopher Blair, Xingjin He
Journal: Molecular Biology and Evolution (2019)

With the continual progress of sequencing techniques, genome-scale data are increasingly used in phylogenetic studies. With more data from throughout the genome, the relationship between genes and different kinds of characters is receiving more attention. Here, we present version 4 of RASP, a software to reconstruct ancestral states through phylogenetic trees. RASP can apply generalized statistical ancestral reconstruction methods to phylogenies, explore the phylogenetic signal of characters to particular trees, calculate distances between trees, and cluster trees into groups. RASP 4 has an improved graphic user interface and is freely available from http://mnh.scu.edu.cn/soft/blog/RASP (program) and https://github.com/sculab/RASP (source code).
PATH-17. HYPERPROGRESSIVE DISEASE IN PATIENTS WITH RECURRENT HIGH GRADE GLIOMAS TREATED WITH IMMUNE CHECKPOINT INHIBITORS OR CYTOTOXIC THERAPIES
Authors: Laura Donovan, Samuel Gedailovich, Adela Joanta-Gomez, Andrew Lassman, Fabio Iwamoto
Journal: Neuro-Oncology (2019)

Abstract BACKGROUND Hyperprogressive disease (HPD), defined as a ≥ 2-fold increase in tumor growth rate (TGR) compared to baseline following initiation of immune checkpoint inhibitors (ICI), has been described in solid tumors but is not well explored high grade gliomas (HGG). We investigated the rate of HPD in HGG patients receiving ICIs for first or second recurrence compared to those treated with non-immunotherapy agents. METHODS Patients with HGG receiving ICIs for 1st or 2nd recurrence compared to a controls receiving other therapies at first progression. Prior or concurrent bevacizumab or anti-VEGFR were exclusionary due to pseudoresponse and decreased enhancement with these drugs. HPD was calculated by comparing TGR immediately before and after treatment. RESULTS 49 patients met inclusion criteria (27 ICI, 25 control). 25/27 patients receiving ICIs and 20/22 patients in the control group were evaluable in the analysis. The ICI group included 60% men (15/25) and 80% (20/25) had a diagnosis of primary GBM. 68% were treated at first progression (17/25). Controls were 80% male (16/20) and all had a diagnosis of primary GBM. 28% (7/25) of patients met criteria for HPD in the ICI group compared to 4/20 controls (20%). Median OS in patients with primary GBM was 26mo in the ICI group vs. 15.9mo in controls. Median survival past progression in patients with primary GBM receiving ICI for 1st recurrence (13/25) was 12mo vs. 10.6mo in controls. 40% of patients in both groups had next generation sequencing (5/7 with HPD in ICI and 2/4 in control). EGFR alterations and MDM2/4 amplifications were not associated with HPD whereas PTEN mutations were more common in HPD (71% vs. 33.3%). CONCLUSION HPD is observed in patients with HGG treated with ICI at comparable rates to those with other cancers, but was also observed in 20% of patients receiving other therapies.
TMOD-02. A MODEL OF THE INITIATION AND GENOMIC LANDSCAPE OF GLIOBLASTOMA (GBM)
Authors: Alexandra Bohm, Jessica DePetro, Carmen Binding, Cameron Grisdale, Matthaeus Ware, Sam Lawn, Nick Chahley, Shazreh Bukhari, Cindy Chen, Amanda Gerber, Kaitlin Thomas, Haley Pedersen, Hiba Omairi, Michael Blough, J Gregory Cairncross
Journal: Neuro-Oncology (2019)

Abstract IDH-wildtype GBM is the most common variant of this cancer and occurs in older adults. Unfortunately patients’ tumors are either inherently resistant to standard treatment, which includes radio- and chemo-therapy, or acquire resistance during the therapeutic process. Additionally, although effective in other cancers, targeted therapies have yielded disappointing results in GBM, perhaps because the fully developed disease has significant cellular and molecular heterogeneity, allowing the tumour to adapt to treatments. Better insight into managing GBM might result from a detailed knowledge of its initiating events, which have not yet been elucidated. With this in mind, we developed a mouse model of GBM in which the earliest stages can be studied. This ex vivo model recreates GBM by culturing subventricular zone (SVZ) cells, the putative ‘cell of origin’ of GBM in platelet-derived growth factor A (PDGFA). Under this condition SVZ cells from p53 null mice transform, becoming exogenous growth factor independent and tumorigenic in immune-competent mice. In contrast, wildtype SVZ cells do not proliferate in PDGFA and null cells in EGF/FGF do not transform. To discover why p53 null SVZ cells uniquely transform in PDGFA, we performed array comparative genomic hybridization (aCGH) on cells before and after transformation in PDGFA and whole genome sequencing (WGS) on transformed cells and tumours generated from PDGFA-transformed cells. aCGH and WGS revealed that the genomic landscape of transformed cells displayed a striking similarity to that observed in primary human GBM. Specifically, these studies showed that chromosomal alterations are a hallmark of culturing SVZ cells in PDGFA, an intriguing finding considering GBM is also characterized by a specific landscape of copy number alterations. This model may resemble the pathogenesis of human GBM and be leveraged to investigate the early stages of tumorigenesis, further leading to the development of preventative strategies and novel therapeutics.
Quantitative Investigation of Pharmacologically Modulated Signaling and Efficacy in ABC DLBCL Using a Systems Pharmacology Model
Authors: Kosinsky Yuri, Lulu Chu, Millie Shah, Karthick Vishwanathan, Connie Larsson, Andrew Bloecher, Brandon Willis, Hannah Dry, Kirill Peskov, Joseph Ware, Andrew Mortlock, Gabriel Helmlinger
Journal: Blood (2019)
Abstract 11242: Enhanced Cardiac and Vascular Responses of L-Carnitine in Heart Failure: Assessment by Left Ventricular Pressure-Volume Analysis
Authors: Xiaowei Zhang, Heng-Jie Cheng, Tomohiko Ukai, Hideo Tachibana, Zhi Zhang, Tiankai Li, Che-Ping Cheng
Journal: Circulation (2018)

Background: L-Carnitine (L-C), a vitamin-like and a naturally-occurring amino acid that is essential for normal metabolism of long-chain fatty acids in the myocardium. There is growing evidence tha...
Molecular Characterization of Ph-Negative Myeloproliferative Neoplasms in Tumor Circulating Nucleic Acids
Authors: Nieves Garcia-Gisbert, Lierni Fernández-Ibarrondo, Concepción Fernández-Rodríguez, Laura Camacho, Anna Angona, Joan Gibert, Xavier Calvo, Leonor Arenillas, Raquel Longarón, Marcio Andrade, Antonio Salar, Carles Besses, Beatriz Bellosillo
Journal: Blood (2019)
Diagnosis of Hysteria
Authors: L. J. F. Warnants, D. H. Marjot
Journal: BMJ (1965)

BRIT reaction to oral phenoxymethylpenicillin in 1957.1Regarding treatment of any anaphylactoid reaction, I am sure prompt recognition is vital, and I am equally sure that prompt administration of adrenaline is the correct initial course because it is effective, acts quickly, and every doctor carries it in his bag.-Iam, etc., Leeds 17.
A Specific Mesenchymal Stem and Progenitor Cell (MSPC) Subpopulation with a Multi-Potent Gene Signature Is Transcriptionally Altered in the Setting of Myelodysplastic Syndrome (MDS) in Primary Human Bone Marrow Aspirates
Authors: Thomas J Fountaine, Mark W LaMere, Daniel K Byun, Jason R Myers, John M Ashton, Jane L. Liesveld, Youmna Kfoury, David T. Scadden, Michael W. Becker, Laura M. Calvi
Journal: Blood (2019)
Genetic regulation of gene expression and splicing during a 10-year period of human aging
Authors: Brunilda Balliu, Matthew Durrant, Olivia de Goede, Nathan Abell, Xin Li, Boxiang Liu, Michael J. Gloudemans, Naomi L. Cook, Kevin S. Smith, David A. Knowles, Mauro Pala, Francesco Cucca, David Schlessinger, Siddhartha Jaiswal, Chiara Sabatti, Lars Lind, Erik Ingelsson, Stephen B. Montgomery
Journal: Genome biology (2019)

Molecular and cellular changes are intrinsic to aging and age-related diseases. Prior cross-sectional studies have investigated the combined effects of age and genetics on gene expression and alternative splicing; however, there has been no long-term, longitudinal characterization of these molecular changes, especially in older age.We perform RNA sequencing in whole blood from the same individuals at ages 70 and 80 to quantify how gene expression, alternative splicing, and their genetic regulation are altered during this 10-year period of advanced aging at a population and individual level. We observe that individuals are more similar to their own expression profiles later in life than profiles of other individuals their own age. We identify 1291 and 294 genes differentially expressed and alternatively spliced with age, as well as 529 genes with outlying individual trajectories. Further, we observe a strong correlation of genetic effects on expression and splicing between the two ages, with a small subset of tested genes showing a reduction in genetic associations with expression and splicing in older age.These findings demonstrate that, although the transcriptome and its genetic regulation is mostly stable late in life, a small subset of genes is dynamic and is characterized by a reduction in genetic regulation, most likely due to increasing environmental variance with age.
FLT3-ITD Activates Cytoplasmic Drosha-Dependent Non-Canonical Mechanisms of Mir-155 Biogenesis in Acute Myeloid Leukemia
Authors: Le Xuan Truong Nguyen, Bin Zhang, Dinh Hoa Hoang, Dandan Zhao, Sergio Branciamore, Davide Maestrini, Yu-Lin SU, Sonia Rodriguez, Flavia Pichiorri, Steven Rosen, Michael A. Caligiuri, Stephen J. Forman, Ling Li, Marcin Kortylewski, Russell Rockne, Ya-Huei Kuo, Nadia Carlesso, Guido Marcucci
Journal: Blood (2019)
Renal impairment in multiple myeloma patients following zoledronic acid or ibandronate treatment
Authors: L. Antràs, M. Smith, M. Neary, J. Green, N. Wintfeld, M. Duh
Journal: Journal of Clinical Oncology (2006)

17501 Background: Although bisphosphonates prevent skeletal complications, agents differ with respect to renal safety. Ibandronate (IB) is a single-nitrogen, noncyclic bisphosphonate that has shown a renal safety profile comparable to placebo in phase III trials. This retrospective study aimed to compare renal impairment rates in multiple myeloma (MM) patients treated with IB or zoledronic acid (ZO). Methods: Medical records in a German oncology clinic (Praxisklinik für Hämatologie und Onkologie Koblenz, Koblenz, Germany) from May 2001 to December 2005 were retrospectively reviewed. Creatinine measurements were analyzed from baseline (before ZO or IB treatment) to last evaluation for each patient. Renal impairment was defined as (1) a serum creatinine (SCr) increase of ≥0.5 mg/dL or ≥1.0 mg/dL from baseline values of &lt;1.4 mg/dL or ≥1.4 mg/dL, respectively, or (2) a ≥25% decrease in glomerular filtration rate (GFR; abbreviated MDRD formula) from baseline. Patients treated sequentially with both ZO and IB were included as separate observations. Andersen-Gill extension of the Cox model was used for multiple-event analysis. Results: In 84 MM patients, 69 received ZO and 40 received IB, with 25 patients receiving both drugs. Compared with IB, the ZO group had a significantly better baseline renal function (mean SCr 1.01 vs 1.34, p = 0.007; mean GFR 75.9 vs 57.3, p = 0.0002). Data analysis showed that ZO treatment increased the relative risk (RR) of renal impairment by ∼3-fold compared with IB (renal impairment rates: ZO 39.1% vs IB 10.8%, RR = 3.6, p = 0.002 [SCr]; 62.3% vs 24.3%, RR = 2.6, p = 0.0002 [GFR]). The incidence rate of renal impairment was higher for ZO than IB (SCr: 1.14 vs 0.48 events per person-year, p = 0.169; GFR: 2.65 vs 0.87 events per person-year, p = 0.007). Multiple-event analysis found significantly higher hazards ratios for ZO over IB (SCr = 5.3; GFR = 2.7; both p &lt; 0.0001). Conclusions: In this retrospective review, MM patients were significantly more likely to experience renal impairment with ZO than with IB. A prospective randomized study is warranted for further validation. [Table: see text]