tbuckley/cabot-search huggingface dataset:
Pulmonary and cerebral microvasculopathy in a patient with sickle cell disease: A role for dense red blood cells?
Authors: Amandine Ségot, Jean‐François Deux, Titien Thuillier, Bernard Maitre, Frédéric Galactéros, Pablo Bartolucci
Journal: American Journal of Hematology (2016)

A 26-years old patient with homozygous sickle cell disease (SCD) exhibited a progressive deterioration in respiratory function resulting in permanent oxygen-dependent dyspnea and cognitive deterioration in a 3-year time frame. Laboratory studies showed Hb 9 g/dl, HbF 7%, lactate dehydrogenase 1.5 times the upper limit of the normal range and 50% of dehydrated dense red blood cells (DRBCs, with a density >1.11, measured with phthalate density profiles) 1. Echocardiography showed a Tricuspid Regurgitation Velocity (TRV) of 2.9 m/s and right heart catheterization a mean pulmonary arterial pressure (PAPm) of 23 mmHg which increased to 40 mmHg after exertion. Lung scintigraphy showed pulmonary peripheral perfusion defects of 52% and 42%, right and left, respectively. Computed Tomography Angiography showed a “death-tree” image due to peripheral vessel rarefaction with a false parenchymal ground-glass aspect in central normal perfused areas (Image 1A,B). Hb saturation dropped to 70% during the 6 minute-walk test (6MWT). Cerebral angio-magnetic resonance imaging showed silent infarcts in junction zones, probably due to microvascular damages without vasculopathy at angio-MRI (Image 1C,D). With 2 years of combined therapy including blood-exchange transfusions (BET) to maintain HbS below 30%, hydroxyurea (HU), bosentan and anticoagulation by coumadin, the patient improved dramatically: dyspnea improved from grade III to grade II NYHA, accompanied by a major cognitive improvement. DRBC decreased from 50% at baseline (HbS = 82%), to 23% after 6 months of BET alone (HbS = 38%) and 5.2% after one year of combined therapy (HbS = 39%). TRV decreased from 2.9 to 2.7m/s, and exertion systolic pulmonary artery pressure at echocardiography also decreased from 110 to 96 mmHg. The O2 saturation's nadir during 6MWT increased to 87%, as compared with 70% before treatment. A remarkable finding in this case was the extremely elevated DRBC count (50%): while it is impossible to establish if this played a primary role in the progressive respiratory and mental deterioration of this patient, or was just an expression of the severe hypoxia, it is worth noting that BET alone could not normalize the DRBC and only the combination of BET and hydroxyurea resulted in a dramatic reduction of the number of dense cells. DRBC count is an important parameter for SCD, both at baseline and in response to therapy2-4. Lung Computed Tomography Angiography: peripheral vessel rarefaction with a false parenchymal groundglass aspect in central normal perfused areas and peripheral perfusion defects (A and B). Brain Magnetic Resonance Imaging (MRI) and angio-MRI: hypersignals on junction zones and microvasculopathy (C and D).
Caring for the Patient — A Thrice-Told Tale
Authors: Alex. M. Burgess, Alex. M. Burgess
Journal: New England Journal of Medicine (1966)

For some patients, though conscious that their condition is perilous, recover their health simply through their contentment with the goodness of the physician. (Hippocrates, Precepts, Chapter 6.)FROM the earliest times the importance of the physician himself as a force in the treatment of the patient has been recognized by thoughtful people. Indeed, until recent times one could say that this was his greatest, and at times his only, contribution to the recovery of his patient. The more new and effective tools he is given to work with, the greater his possibilities of positive accomplishment, and the greater his . . .
The Value of HBME-1 and Claudin-1 Expression Profile in the Distinction of BRAF-Like and RAS-Like Phenotypes in Papillary Thyroid Carcinoma
Authors: Hasan Gucer, Pelin Bagci, Recep Bedir, Ibrahim Sehitoglu, Ozgur Mete
Journal: Endocrine Pathology (2016)
DSM-III diagnoses associated with dyspepsia of unknown cause
Authors: G Magni, F di Mario, G Bernasconi, G Mastropaolo
Journal: American Journal of Psychiatry (1987)

The frequencies of DSM-III diagnoses in 30 patients with dyspepsia of unknown origin and 20 patients with organic dyspepsia were compared. Dyspepsia of unknown origin was associated with a higher prevalence of psychiatric diagnoses (86.7% versus 25.0%), particularly anxiety disturbances (66.7%).
ICU physicians’ and nurses’ perceptions of terminal extubation and terminal weaning: a self-questionnaire study
Authors: Alice Cottereau, René Robert, Amélie le Gouge, Mélanie Adda, Juliette Audibert, François Barbier, Patrick Bardou, Simon Bourcier, Alexandre Boyer, François Brenas, Emmanuel Canet, Daniel Da Silva, Vincent Das, Arnaud Desachy, Jérôme Devaquet, Nathalie Embriaco, Beatrice Eon, Marc Feissel, Diane Friedman, Frédérique Ganster, Maïté Garrouste-Orgeas, Guillaume Grillet, Olivier Guisset, Christophe Guitton, Rebecca Hamidfar-Roy, Anne-Claire Hyacinthe, Sebastien Jochmans, Fabien Lion, Mercé Jourdain, Alexandre Lautrette, Nicolas Lerolle, Olivier Lesieur, Philippe Mateu, Bruno Megarbane, Emmanuelle Mercier, Jonathan Messika, Paul Morin-Longuet, Bénédicte Philippon-Jouve, Jean-Pierre Quenot, Anne Renault, Xavier Repesse, Jean-Philippe Rigaud, Ségolène Robin, Antoine Roquilly, Amélie Seguin, Didier Thevenin, Patrice Tirot, Laetitia Contentin, Nancy Kentish-Barnes, Jean Reignier
Journal: Intensive Care Medicine (2016)
A novel approach to administration of peptides in women: Systemic absorption of a GnRH agonist via transvaginal ring delivery system
Authors: A.B. Kimball, E. Javorsky, E.S. Ron, W. Crowley,, R. Langer
Journal: Journal of Controlled Release (2016)

trans-Epithelial delivery of medication across the vagina has proven successful for administration of small, lipophilic molecules such as sex steroids. However, little information is available regarding the vaginal delivery of larger and more polar molecules that currently require parenteral administration because the vaginal epithelium is perceived as a barrier to absorption of larger molecular weight (MW) molecules. Six healthy women underwent administration of 18 or 36 mg of leuprolide, a GnRH agonist and a larger MW peptide, via a novel ethylene vinyl acetate (EVA) ring transvaginal drug delivery system (TVDS). Serum levels rose within 8 h following insertion: low dose at 310 pg/ml and high dose at 1220 pg/ml, i.e. levels typically following parenteral injections of leuprolide. GnRHa biological activity was validated by secretion of gonadotropins and sex steroids. These results demonstrate that the non-keratinized vaginal epithelium permits a rapid absorption of a biologically active peptide and that there is significant potential for a novel TVDS to deliver peptides and possibly other macromolecules therapeutically. Current routes of administration of medications can include oral, subcutaneous, intravenous, intramuscular, transcutaneous, etc. Many of these approaches have limitations, including pain, poor tolerability, lack of adherence, and inadequate delivery. Peptides, in particular, cannot typically be given orally because they are broken down in the intestinal tract before they are absorbed. While the skin is an attractive way to deliver medications, its superb intrinsic barrier function often makes this route untenable at times. The vaginal epithelium, in contrast, is not keratinized and can allow absorption of other molecules. In this study, we demonstrate that a novel transvaginal drug delivery system (TVDS) is capable of delivering peptide therapeutics to women in a non-parenteral fashion as demonstrated by both blood levels and biologic effects of its delivery.
BMET-31DEVELOPMENT AND APPLICATION OF A NOVEL MODEL OF HUMAN LUNG-TO-BRAIN METASTASIS TO IDENTIFY UNIQUE METASTATIC GENE SIGNATURES
Authors: Mohini Singh, Chitra Venugopal, Nicole McFarlane, David Bakhshinyan, Sujeivan Mahendram, Kevin Brown, Amy Tong, Kathrin Durrer, Robin Hallett, John Hassell, Jason Moffat, Sheila Singh
Journal: Neuro-Oncology (2015)

Brain Metastases (BM) are the most common type of cerebral tumor in adult, occurring at a rate 10 times greater than that of primary brain cancers. The inherent abilities of a primary tumor cell capable of initiating a BM resembles that of a cancer stem cell (CSCs). Previous work conducted in our lab identified a population of CSCs within lung-derived brain metastases. We hypothesize that a subgroup of CSCs, termed brain metastasis-initiating cells (BMICs), are responsible for the initiation of BM and are identifiable by an exclusive subset of genes that regulate self-renewal and metastasis. Despite the prevalence and lethality of BM, there is no clinically relevant model that fully reflects metastasis in patients. We recently generated a novel human-mouse xenotransplantation model of BM that allows for interrogation of each phase of the metastatic process from lung to brain, through injection of human patient-derived GFP-expressing BMICs into immunocompromised mice via three routes: 1) intracranial (IC), 2) intrathoracic (IT) and 3) intravascular/intracardiac (IV). GFP+ cells were harvested from the lungs and/or brains from each injection route, and RNA was submitted for microarray analysis to identify a unique metastatic and tissue-specific gene signature. In order to identify genes involved in self-renewal and tumor initiation, we also performed RNA interference screens in vitro and in vivo on BMIC lines against 150 genes implicated in BM formation. Further in vitro validation of select hit genes identified SPOCK1 and TWIST2 as essential regulators of cell proliferation, sphere formation, and migration. Future work will validate the role of these genes in our established in vivo metastasis models. We also aim to examine their expression in primary lung FFPE samples to determine if they are predictive biomarkers of lung-to-brain metastasis in prospective cohorts of newly diagnosed lung cancer patients, and to determine their potential as therapeutic targets.
Characteristics of Primary Tumors Induced by Carcinogenic Polycyclic Hydrocarbons in Syrian Hamsters
Authors: J. A. DiPaolo, R. L. Nelson, P. J. Donovan
Journal: JNCI Journal of the National Cancer Institute (1971)

Six primary subcutaneous tumors induced with a single injection of benzo[a]pyrene or 7,12-dimethylbenz[a]anthracene were analyzed for histopathology, growth in vitro, transplantability, and karyology. All tumors were fibrosarcomas with varying degrees of differentiation. Tumor cultures were characterized by rapid growth and increase in acidity of medium followed by quick degeneration and survival of a few cells which produced a population that grew indefinitely in vitro. The initial populations were diploid, near diploid, or tetraploid and had some acentric pieces, chromatid rearrangements, and marker chromosomes but without any common karyotypic change. Subsequently, heteroploidy increased. Cells lacked orientation and occasionally piled up. Cloning without a feeder resulted in diverse colonies, some of which were randomly oriented with crisscrossing of filaments. Tumors derived from these cultures were transplantable into hamsters. These tumors were more anaplastic than primary tumors. Comparison of these studies with in vitro studies in which quantitative transformation was obtained with Syrian hamster embryo cells and polycyclic hydrocarbon carcinogens leads to the conclusion that in vitro investigations of transformation provide information relevant to in vivo transformation.
GENO-12CLONAL EVOLUTION AND GENOMIC DIVERSITY IN A PANEL GLIOBLASTOMA TUMORS, NEUROSPHERE CULTURES AND ORTHOTOPIC XENOGRAFTS
Authors: Ana deCarvalho, Hoon Kim, Laila Poisson, Claudius Mueller, David Cherba, Mary Winn, Emanuel Petricoin, Roel Verhaak, Tom Mikkelsen
Journal: Neuro-Oncology (2015)

Molecular heterogeneity in glioblastoma (GBM) tumors presents major challenges to effective treatments. Well characterized patient-derived xenograft models are critical to support the development of better therapies and biomarkers. We established neurosphere cultures (NS) from twelve freshly resected primary and one recurrent GBM tumor and derived orthotopic xenografts in triplicate. All samples were analyzed using exome, low pass whole genome, RNA sequencing and reverse phase protein array (RPPA). We observed that 85% of mutations present in the tumor samples were transmitted to the NS. A majority of mutations shared by both tumor and NS were captured by xenografts with high cellular frequencies suggesting clonal mutations. Few mutations not present in the tumor samples were detected at low frequency in the NPs and approximately 66% of these were transmitted to the xenografts. A median number of 14 mutations were acquired in xenografts relative to NS, suggesting that the brain environment promotes novel somatic events. Genomic profiling of four matching late passage NS revealed that 15 % of the mutations detected in their early passage progenitors were lost, but as many as 59 novel mutations were acquired in extended culture. Consensus hierarchical gene expression profile clustering revealed that 70% of the tumors formed one cluster, while the NP and matching xenografts clustered together in several groups, including one characterized by EGFR amplification and mutations, another encompassing all the proneural subtype. Consistent with these observations, GBM transcriptional subtypes were conserved between tumor and matched NS in 42% of cases, and between NS and xenografts in 92% of cases. Importantly, signaling pathways significantly altered among sample modalities were identified by RPPA and RNAseq analysis, with implications for drug studies. In a panel of GBMs representative of all subclasses, remarkable conservation of original clonal mutations and evidence for clonal evolution were observed in the matched tumor-NP-xenografts.
cAMP/CREB-regulated LINC00473 marks LKB1-inactivated lung cancer and mediates tumor growth
Authors: Zirong Chen, Jian-Liang Li, Shuibin Lin, Chunxia Cao, Nicholas T. Gimbrone, Rongqiang Yang, Dongtao A. Fu, Miranda B. Carper, Eric B. Haura, Matthew B. Schabath, Jianrong Lu, Antonio L. Amelio, W. Douglas Cress, Frederic J. Kaye, Lizi Wu
Journal: Journal of Clinical Investigation (2016)

The LKB1 tumor suppressor gene is frequently mutated and inactivated in non-small cell lung cancer (NSCLC). Loss of LKB1 promotes cancer progression and influences therapeutic responses in preclinical studies; however, specific targeted therapies for lung cancer with LKB1 inactivation are currently unavailable. Here, we have identified a long noncoding RNA (lncRNA) signature that is associated with the loss of LKB1 function. We discovered that LINC00473 is consistently the most highly induced gene in LKB1-inactivated human primary NSCLC samples and derived cell lines. Elevated LINC00473 expression correlated with poor prognosis, and sustained LINC00473 expression was required for the growth and survival of LKB1-inactivated NSCLC cells. Mechanistically, LINC00473 was induced by LKB1 inactivation and subsequent cyclic AMP-responsive element-binding protein (CREB)/CREB-regulated transcription coactivator (CRTC) activation. We determined that LINC00473 is a nuclear lncRNA and interacts with NONO, a component of the cAMP signaling pathway, thereby facilitating CRTC/CREB-mediated transcription. Collectively, our study demonstrates that LINC00473 expression potentially serves as a robust biomarker for tumor LKB1 functional status that can be integrated into clinical trials for patient selection and treatment evaluation, and implicates LINC00473 as a therapeutic target for LKB1-inactivated NSCLC.
Multiple Myeloma Mortality in Relation to Obesity Among African Americans
Authors: Jennifer S. Sonderman, Traci N. Bethea, Cari M. Kitahara, Alpa V. Patel, Chinonye Harvey, Synnøve F. Knutsen, Yikyung Park, Song-Yi Park, Gary E. Fraser, Lauren R. Teras, Mark P. Purdue, Rachael Z. Stolzenberg-Solomon, Elizabeth M. Gillanders, Julie R. Palmer, Laurence N. Kolonel, William J. Blot
Journal: JNCI Journal of the National Cancer Institute (2016)

Multiple myeloma (MM) incidence and mortality are higher among African Americans (AAs) than among other population groups. The prevalence of obesity is also elevated among AAs, but few studies have examined risk of this cancer in relation to body size among AAs. We combined data from seven prospective cohorts tracking mortality among 239 597 AA adults and used Cox proportional hazards regression to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for death because of MM according to body mass index (BMI) at cohort entry, adjusted for age (as time-scale) and sex. Relative to those with normal BMIs (18.5-25 kg/m 2 ), mortality increased monotonically as BMI increased, with hazard ratios reaching 1.43 (95% CI = 1.03 to 1.97) for BMIs of 35 kg/m 2 or greater. The findings suggest that obesity is a risk factor for MM and a contributor to the elevated rates and rising incidence trends of MM among AAs in the United States.
Natriuretic Peptide Receptor Guanylyl Cyclase-A in Podocytes is Renoprotective but Dispensable for Physiologic Renal Function
Authors: Janina Staffel, Daniela Valletta, Anna Federlein, Katharina Ehm, Regine Volkmann, Andrea M. Füchsl, Ralph Witzgall, Michaela Kuhn, Frank Schweda
Journal: Journal of the American Society of Nephrology (2016)

The cardiac natriuretic peptides (NPs), atrial NP and B-type NP, regulate fluid homeostasis and arterial BP through renal actions involving increased GFR and vascular and tubular effects. Guanylyl cyclase-A (GC-A), the transmembrane cGMP-producing receptor shared by these peptides, is expressed in different renal cell types, including podocytes, where its function is unclear. To study the effects of NPs on podocytes, we generated mice with a podocyte-specific knockout of GC-A (Podo-GC-A KO). Despite the marked reduction of GC-A mRNA in GC-A KO podocytes to 1% of the control level, Podo-GC-A KO mice and control littermates did not differ in BP, GFR, or natriuresis under baseline conditions. Moreover, infusion of synthetic NPs similarly increased the GFR and renal perfusion in both genotypes. Administration of the mineralocorticoid deoxycorticosterone-acetate (DOCA) in combination with high salt intake induced arterial hypertension of similar magnitude in Podo-GC-A KO mice and controls. However, only Podo-GC-A KO mice developed massive albuminuria (controls: 35-fold; KO: 5400-fold versus baseline), hypoalbuminemia, reduced GFR, and marked glomerular damage. Furthermore, DOCA treatment led to decreased expression of the slit diaphragm-associated proteins podocin, nephrin, and synaptopodin and to enhanced transient receptor potential canonical 6 (TRPC6) channel expression and ATP-induced calcium influx in podocytes of Podo-GC-A KO mice. Concomitant treatment of Podo-GC-A KO mice with the TRPC channel blocker SKF96365 markedly ameliorated albuminuria and glomerular damage in response to DOCA. In conclusion, the physiologic effects of NPs on GFR and natriuresis do not involve podocytes. However, NP/GC-A/cGMP signaling protects podocyte integrity under pathologic conditions, most likely by suppression of TRPC channels.
Consensus on precision medicine for metastatic cancers: a report from the MAP conference
Authors: C. Swanton, J.-C. Soria, A. Bardelli, A. Biankin, C. Caldas, S. Chandarlapaty, L. de Koning, C. Dive, J. Feunteun, S.-Y. Leung, R. Marais, E.R. Mardis, N. McGranahan, G. Middleton, S.A. Quezada, J. Rodón, N. Rosenfeld, C. Sotiriou, F. André
Journal: Annals of Oncology (2016)
Pre-Clinical Analysis Of The Novel Antifolate Pralatrexate In Multiple Myeloma Reveals Functional Biomarkers Correlated With Response
Authors: Michael Mangone, Anna H Mei, Luigi Scotto, Michele Visentin, Enrica Marchi, I. David Goldman, Constantine S. Mitsiades, Owen A. O'Connor, Hearn J. Cho
Journal: Blood (2013)
Comparative Cistromics Reveals Genomic Cross-talk between FOXA1 and ERα in Tamoxifen-Associated Endometrial Carcinomas
Authors: Marjolein Droog, Ekaterina Nevedomskaya, Yongsoo Kim, Tesa Severson, Koen D. Flach, Mark Opdam, Karianne Schuurman, Patrycja Gradowska, Michael Hauptmann, Gwen Dackus, Harry Hollema, Marian J. Mourits, Petra Nederlof, Hester van Boven, Sabine C. Linn, Lodewyk Wessels, Flora E. van Leeuwen, Wilbert Zwart
Journal: Cancer Research (2016)

Tamoxifen, a small-molecule antagonist of the transcription factor estrogen receptor alpha (ERα) used to treat breast cancer, increases risks of endometrial cancer. However, no parallels of ERα transcriptional action in breast and endometrial tumors have been found that might explain this effect. In this study, we addressed this issue with a genome-wide assessment of ERα-chromatin interactions in surgical specimens obtained from patients with tamoxifen-associated endometrial cancer. ERα was found at active enhancers in endometrial cancer cells as marked by the presence of RNA polymerase II and the histone marker H3K27Ac. These ERα binding sites were highly conserved between breast and endometrial cancer and enriched in binding motifs for the transcription factor FOXA1, which displayed substantial overlap with ERα binding sites proximal to genes involved in classical ERα target genes. Multifactorial ChIP-seq data integration from the endometrial cancer cell line Ishikawa illustrated a functional genomic network involving ERα and FOXA1 together with the enhancer-enriched transcriptional regulators p300, FOXM1, TEAD4, FNFIC, CEBP8, and TCF12. Immunohistochemical analysis of 230 primary endometrial tumor specimens showed that lack of FOXA1 and ERα expression was associated with a longer interval between breast cancer and the emergence of endometrial cancer, exclusively in tamoxifen-treated patients. Our results define conserved sites for a genomic interplay between FOXA1 and ERα in breast cancer and tamoxifen-associated endometrial cancer. In addition, FOXA1 and ERα are associated with the interval time between breast cancer and endometrial cancer only in tamoxifen-treated breast cancer patients. Cancer Res; 76(13); 3773-84. ©2016 AACR.
Fitness and Coronary Artery Calcification—Reply
Authors: Ravi V. Shah, Venkatesh L. Murthy, Joao A. C. Lima
Journal: JAMA Internal Medicine (2016)

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Case 12-2001
Authors: Mark H. Libenson, Jane M. Yang
Journal: New England Journal of Medicine (2001)

Presentation of CaseA 16-year-old boy was admitted to the hospital because of an altered mental and emotional status.At an uncertain interval before admission, the patient began to have diarrhea. One week before admission, a sore throat and productive cough developed, with a vague sensation of fever, and he took an antihistamine. Although usually quiet, he became confused on noon of the day before admission and began to “talk nonsense.” He was seen at another hospital, where he mentioned something that suggested an injection of illicit drugs. He spat at the nursing staff and used profane language. After haloperidol . . .