tbuckley/cabot-search huggingface dataset:
Long‐term follow‐up in peripartum cardiomyopathy patients with contemporary treatment: low mortality, high cardiac recovery, but significant cardiovascular co‐morbidities
Authors: Valeska Moulig, Tobias Jonathan Pfeffer, Melanie Ricke‐Hoch, Stella Schlothauer, Tobias Koenig, Johannes Schwab, Dominik Berliner, Roman Pfister, Guido Michels, Arash Haghikia, Christine S. Falk, David Duncker, Christian Veltmann, Denise Hilfiker‐Kleiner, Johann Bauersachs
Journal: European Journal of Heart Failure (2019)

Aims Peripartum cardiomyopathy (PPCM) establishes late in pregnancy or in the first postpartum months. Many patients recover well within the first year, but long‐term outcome studies on morbidity and mortality are rare. Here, we present 5‐year follow‐up data of a German PPCM cohort. Methods and results Five‐year follow‐up data were available for 66 PPCM patients (mean age 34 ± 5 years) with a mean left ventricular ejection fraction (LVEF) of 26 ± 9% at diagnosis. Ninety‐eight percent initially received standard heart failure therapy (beta‐blockers, angiotensin‐converting enzyme inhibitors/angiotensin receptor blockers, and/or mineralocorticoid receptor antagonists), and 86% were additionally treated with dopamine D2 receptor agonists (mainly bromocriptine) and anticoagulation. After 1 year, mean LVEF had improved to 50 ± 11% ( n = 48) and further increased to 54 ± 7% at 5‐year follow‐up with 72% of patients having achieved full cardiac recovery (LVEF &gt;50%). At 5‐year follow‐up, only three patients (5%) displayed no recovery, of whom one had died. However, 20% had arterial hypertension and 17% arrhythmias, including paroxysmal supraventricular tachycardia, ventricular tachycardia, or ventricular fibrillation. Moreover, 70% were still on at least one heart failure drug. Subsequent pregnancy occurred in 16 patients with two abortions and 14 uneventful pregnancies. Mean LVEF was 55 ± 7% at 5‐year follow‐up in these patients. Conclusion Our PPCM collective treated with standard therapy for heart failure, dopamine D2 receptor agonists, and anticoagulation displays a high and stable long‐term recovery rate with low mortality at 5‐year follow‐up. However, long‐term use of cardiovascular medication, persisting or de novo hypertension and arrhythmias were frequent.
β-Arrestin 1 (ARRB1) serves as a molecular marker of the peripheral circadian rhythm
Authors: Tatsunosuke Tomita, Taisuke Mori, Yoshiaki Onishi
Journal: International Journal of Oral Science (2019)

Abstract The control of the circadian rhythm is important for health because it regulates physiological functions and is associated with health hazards. We aimed to identify a circadian biomarker of health status in human saliva, since collecting saliva is non-invasive, straightforward, and cost-effective. Among 500 genes potentially controlled by the salivary clock identified using chromatin immunoprecipitation (ChIP) assays, 22 of them showed reasonable transcriptional responses according to a DNA array in a salivary model system. Among these 22 genes, ARRB1, which is expressed in human salivary glands, was also expressed in model HSG cells at the transcriptional and translational levels. The profile of ARRB1 expression in human saliva was circadian, suggesting that ARRB1 could serve as a candidate circadian biomarker in saliva. We compared ARRB1 with other biomarkers in salivary samples from jet-lagged individuals. The circadian profile of ARRB1 reflected the time lag more than the profile of melatonin, whereas the profiles of cortisol and α-amylase did not reflect the time lag. Overall, these findings suggest that salivary ARRB1 could serve as a candidate biomarker that could be used to monitor the internal body clock.
Targeting Autophagy Potentiates Imatinib-Induced Cell Death in Philadelphia Positive Cells Including Primary CML Stem Cells.
Authors: Cristian Bellodi, Maria Rosa Lidonnici, Ashley Hamilton, Gudmundur V Helgason, Angela R Soliera, Mattia Ronchetti, Sara Galavotti, Kenneth W Young, Tommaso Selmi, Richard A. Van Etten, Nicholas Donato, Ann Hunter, David Dinsdale, Elena Tirro’, Paolo Vigneri, Pierluigi Nicotera, Martin J.S. Dyer, Tessa Holyoake, Bruno Calabretta, Paolo Salomoni
Journal: Blood (2008)
TMOD-12. THE ROLE OF INTEGRIN α V AND CD44 IN GBM MIGRATION USING HUMAN ORGANOTYPIC SLICES
Authors: Zev Binder, Sarah Hyun Ji Kim, Pei-Hsun Wu, Anjil Giri, Gary Gallia, Carlos Pardo-Villamizar, Denis Wirtz
Journal: Neuro-Oncology (2019)

Abstract Current model systems used for GBM research include traditional in vitro cell line-based assays and in vivo animal studies. In vitro model systems offer the advantages of being easy to use, relatively inexpensive, and fast growing. However, these models lack key elements of the pathology they are attempting to model, including the biochemical and biophysical microenvironment and three-dimensional structure inherent to human brain tissue. In vivo model systems address these limitations, but have restrictions of their own. Species differences may result in non-applicable results and animal experiments are often not designed like clinical trials. Evidence of the limitations of current GBM models is found in the disparity between basic research findings and successful new treatments for GBMs in the clinic. Here we present an alternative model system for the study of human GBM cell motility and invasion, which features advantages of both in vitro and in vivo model systems. Using human organotypic brain slices as scaffolding for tumor growth, we explored the dynamic process of GBM cell invasion within human brain tissue. To demonstrate the utility of the model system, we investigated the effects of depletion of integrin α V (ITGAV) and CD44 on GBM cell motility. These two cell-surface proteins have been identified to have key functions in GBM cell motility. However, knockdown of ITGAV had little effect on tumor cell motility in organotypics while CD44 knockdown significantly reduced cell movement. Finally, we compare motility results from cells in human brain slices to those from cells growing on standard Matrigel and in mouse brain organotypics. We found significant differences in motility depending on the substrate in which the cells were moving. Our findings highlight the physiologic characteristics of human brain organotypics and demonstrate the use of real-time imaging in the ex vivo system.
Elexacaftor–Tezacaftor–Ivacaftor for Cystic Fibrosis with a Single Phe508del Allele
Authors: Peter G. Middleton, Marcus A. Mall, Pavel Dřevínek, Larry C. Lands, Edward F. McKone, Deepika Polineni, Bonnie W. Ramsey, Jennifer L. Taylor-Cousar, Elizabeth Tullis, François Vermeulen, Gautham Marigowda, Charlotte M. McKee, Samuel M. Moskowitz, Nitin Nair, Jessica Savage, Christopher Simard, Simon Tian, David Waltz, Fengjuan Xuan, Steven M. Rowe, Raksha Jain
Journal: New England Journal of Medicine (2019)

Cystic fibrosis is caused by mutations in the gene encoding the cystic fibrosis transmembrane conductance regulator (CFTR) protein, and nearly 90% of patients have at least one copy of the Phe508del CFTR mutation. In a phase 2 trial involving patients who were heterozygous for the Phe508del CFTR mutation and a minimal-function mutation (Phe508del-minimal function genotype), the next-generation CFTR corrector elexacaftor, in combination with tezacaftor and ivacaftor, improved Phe508del CFTR function and clinical outcomes.We conducted a phase 3, randomized, double-blind, placebo-controlled trial to confirm the efficacy and safety of elexacaftor-tezacaftor-ivacaftor in patients 12 years of age or older with cystic fibrosis with Phe508del-minimal function genotypes. Patients were randomly assigned to receive elexacaftor-tezacaftor-ivacaftor or placebo for 24 weeks. The primary end point was absolute change from baseline in percentage of predicted forced expiratory volume in 1 second (FEV1) at week 4.A total of 403 patients underwent randomization and received at least one dose of active treatment or placebo. Elexacaftor-tezacaftor-ivacaftor, relative to placebo, resulted in a percentage of predicted FEV1 that was 13.8 points higher at 4 weeks and 14.3 points higher through 24 weeks, a rate of pulmonary exacerbations that was 63% lower, a respiratory domain score on the Cystic Fibrosis Questionnaire-Revised (range, 0 to 100, with higher scores indicating a higher patient-reported quality of life with regard to respiratory symptoms; minimum clinically important difference, 4 points) that was 20.2 points higher, and a sweat chloride concentration that was 41.8 mmol per liter lower (P<0.001 for all comparisons). Elexacaftor-tezacaftor-ivacaftor was generally safe and had an acceptable side-effect profile. Most patients had adverse events that were mild or moderate. Adverse events leading to discontinuation of the trial regimen occurred in 1% of the patients in the elexacaftor-tezacaftor-ivacaftor group.Elexacaftor-tezacaftor-ivacaftor was efficacious in patients with cystic fibrosis with Phe508del-minimal function genotypes, in whom previous CFTR modulator regimens were ineffective. (Funded by Vertex Pharmaceuticals; VX17-445-102 ClinicalTrials.gov number, NCT03525444.).
Barium Studies in the Aged
Authors: A. N. Exton-Smith, G. Osborne
Journal: BMJ (1961)

MIEDICAL JOURNAL177convenient in patients responding poorly to chlorprop- amide to try the addition of phenformin before recourse to insulin.Diabetes is a progressive disease, though the rate of progression varies greatly.It is not surprising that some patients at first controlled by the sulphonylureas slowly began to relapse, and this was equally true of patients controlled on combined therapy.In some patients the introduction of combined therapy has meant no more than a delay before insulin was introduced.Neverthe- less in other patients treatment by combined therapy has been prolonged, and has been particularly welcomed by elderly patients who would otherwise have required insulin.Whereas it seems clear that oral therapy as at present described is capable of maintaining normoglycaemia, it remains open to question whether this is sufficient to prevent the degenerative complications so commonly seen in diabetics poorly controlled on insulin, since these complications could possibly be due to factors other than hyperglycaemia.However, quite apart from ulti- mate complications, hyperglycaemia leads to troublesome symptoms and predisposes to infection.In the present state of our knowledge, these seem valid reasons to justify the use of oral therapy in responsive patients. SummaryOf 1,450 diabetic patients attending a clinic, 587 (40.4%) were controlled on simple dietary restriction, 608 (42 %) required insulin, and the remaining 255 (17.6%) took oral hypoglycaemic agents.Diabetics deemed suitable for oral therapy who failed to respond to chlorpropamide were given phenformin in small doses as an alternative or as adjuvant therapy.Of 23 such patients, 9 responded to phenformin alone but 14 responded only when the phenformin and chlorpropamide were given together.Phenformin when administered in a single daily 100- mg.slow-disintegration capsule appeared to offer as effective clinical control as when given in divided doses as tablets.Our thanks are due to Dr. K. Boheimer, of Bayer Products, for the supply of phenformin capsules (" dibotin" sustained release capsules).* Also had diverticulitis of sigmoid.
Operation for Varicose Veins
Authors: R. R. Foote
Journal: BMJ (1946)

The whole question of whether it is safer to operate at sea or treat conservatively is often one which weighs heavily enough on the ship surgeon.The introduction of an extra unsafe factor, should he decide to operate, not only adds to the surgeon's responsiblity but is entirely unnecessary for the successful completion, without medical aid, of an operation at sea.-I am, etc., Bristol.
The Interaction of Platelets with Colorectal Cancer Cells Inhibits Tumor Growth but Promotes Metastasis
Authors: Léa Plantureux, Diane Mège, Lydie Crescence, Estelle Carminita, Stéphane Robert, Sylvie Cointe, Nicolas Brouilly, Walid Ezzedine, Françoise Dignat-George, Christophe Dubois, Laurence Panicot-Dubois
Journal: Cancer Research (2019)

Platelets promote metastasis, however, their role in tumor growth remains controversial. Here, we investigated the effect of platelet interactions with colorectal tumor cells. Platelets extravasated into the tumor microenvironment and interacted with tumor cells in a cadherin-6-dependent manner. The interaction induced platelet spreading, release of their granule content, and the generation of three types of microparticles (iMP) that expressed platelet markers, tumor markers, or both. The presence of iMPs was confirmed in colorectal cancer tissue specimens. Platelets significantly reduced tumor growth and increased intratumoral macrophages. This was mediated by iMP recruitment of macrophages via the chemoattractants RANTES, MIF, CCL2, and CXCL12 and activation of their tumor cell killing capacity through IFNγ and IL4, which led to cell-cycle arrest of tumor cells in a p21-dependent manner. In contrast, in the bloodstream, iMPs activated endothelial cells and platelets and induced epithelial-to-mesenchymal transition of tumor cells, promoting metastasis. Altogether, these results indicate that depending on the environment, local or bloodstream, the consequences of the interactions between platelets and a tumor may promote or prevent cancer progression. SIGNIFICANCE: Tumor cell interaction with platelets produces chimeric extracellular vesicles that suppress primary tumor growth by activating tumor-eliminating macrophages, while promoting metastasis through EMT and endothelial activation.
Exposure-Response Analyses and Disease Modeling for Selection and Confirmation of Optimal Dosing Regimen of Isatuximab in Combination Treatment in Patients with Multiple Myeloma
Authors: Fatiha Rachedi, Kimiko Koiwai, Nadia Gaudel-Dedieu, Bernard Sebastien, Hoai-Thu Thai, Raouf El-Cheikh, Claire Brillac, Jean Baptiste Fau, Laurent Nguyen, Li Liu, Frank Campana, Helgi van de Velde, Christine Veyrat-Follet, Dorothee Semiond
Journal: Blood (2019)
RARE-11. SELLAR GERMINOMA MASQUERADING FOR SIX YEARS AS AUTOIMMUNE HYPOPHYSITIS IN A 16-YEAR-OLD GIRL WITHOUT DIABETES INSIPIDUS
Authors: Maya Hrachova, Mari Perez Rosenthal, Kong Xiao-Tang
Journal: Neuro-Oncology (2019)

Abstract INTRODUCTION Germinomas are rare malignant intracranial neoplasms which most commonly occur in young males in the pineal and suprasellar region. Less commonly, germinomas arise in the sellar region, where there is slight female predominance. Diagnostic challenges may arise, as autoimmune hypophysitis has similar clinical, imaging and histopathological features to germinoma. CASE REPORT: A 16-year-old girl (46, XX) presented with primary amenorrhea, failure of sexual development and growth delay. Stimulation tests confirmed panhypopituitarism except diabetes insipidus. Infectious and rheumatological workup was negative. She had normal levels of beta HCG, CEA and alpha-fetoprotein. MRI brain identified an enhancing hypothalamic pituitary stalk and pituitary mass. A biopsy was performed which showed a lymphocyte rich infiltration of the pituitary gland, suggesting autoimmune hypophysitis. She completed 4 cycles of low dose methotrexate weekly and remained on hormone replacement therapy for panhypopituitarism for three years until she developed daily headaches, blurry vision, and secondary amenorrhea. MR imaging showed increased nodularity at the pituitary infundibulum with involvement of the optic chiasm. This lesion progressed on mycophenolic acid, increased doses of hydrocortisone, high doses of prednisone and IV methylprednisolone. She was unable to tolerate azathioprine and rituximab after one year. Subsequently, she underwent partial resection of the suprasellar lesion with the pathology showing germinoma admixed with abundant lymphohistiocytic inflammation. A nongerminomatous component was not present histologically and CSF only showed an elevated beta HCG. Given that the tumor is localized to the central nervous system she is receiving treatment via SIOP CNS GCT 96 protocol. DISCUSSION Autoimmune hypophysitis and germinoma can share similar clinical, radiological and histopathological features. Our case demonstrates the need for careful histologic examination, close clinical and radiological follow up in patients with lymphocyte-rich suprasellar lesions if no response to immunosuppressant therapy is noted.
Identifying miRNA Biomarkers and Predicted Targets Associated with Venous Thromboembolism in Colorectal Cancer Patients
Authors: Ann S. Kim, Matthew F Kalady, Jennifer DeVecchio, Kahraman Tanriverdi, Jane E. Freedman, John Barnard, Tae Hyun Hwang, Alok A Khorana, Keith R McCrae
Journal: Blood (2019)
Second Cancers in Adults with Acute Promyelocytic Leukemia (APL) Treated with or without Arsenic Trioxide (ATO): A SEER-Medicare Analysis
Authors: Kelly J. Norsworthy, Steven T. Bird, Armen Avagyan, Yuchen Li, Sandia Akhtar, Jiemin Liao, Michael Wernecke, Albert B. Deisseroth, Meredith Chuk, Thomas E. MaCurdy, Richard Swain, Jeffrey A. Kelman, Ann T. Farrell, Richard Pazdur, Gideon Blumenthal, David J. Graham
Journal: Blood (2019)
Loss of PTEN in Pediatric T-Cell Acute Lymphoblastic Leukemia Patients: Proteomic and Molecular Characterization
Authors: Paola Bonaccorso, Cristina Bugarin, Chiara Buracchi, Grazia Fazio, Maddalena Paganin, Giuseppe Basso, Andrea Biondi, Giovanni Cazzaniga, Luca Lo Nigro, Giuseppe Gaipa
Journal: Blood (2014)
TMOD-15. IDENTIFYING THE SPATIAL AND TEMPORAL DYNAMICS OF GLIOBLASTOMA SUBPOPULATIONS WITHIN INDIVIDUAL PATIENTS
Authors: Bethan Morris, Lee Curtin, Andrea Hawkins-Daarud, Bernard Bendok, Maciej Mrugala, Jing Li, Nhan Tran, Leland Hu, Ruman Rahman, Stuart Smith, Dorothee Auer, Matthew Hubbard, Markus Owen, Kristin Swanson
Journal: Neuro-Oncology (2019)

Abstract Glioblastomas (GBMs) are known to be complex tumors comprising multiple subpopulations of genetically-distinct cancer cells; it is thought that this genetic variation is a major factor in the lack of observed survival benefit of treatment regimes that target one of these subpopulations. The field of radiogenomics seeks to study correlations between MRI patterns and genetic features of GBM tumors. Spatial radiogenomic maps produced using machine-learning (ML) methods that are trained against information from image-localized patient biopsies identify regions where particular cancer sub-populations are predicted to occur within a GBM, thus non-invasively characterizing the regional genetic variability of these tumors. These tumor subpopulations may also interact with one another, in ways which may be of a competitive or cooperative nature to varying degrees. It is important to ascertain the nature of these interactions, as they may have implications for treatment response to targeted therapies, and characterization of the spatio-temporal dynamics of these co-evolving sub-populations will shed light on why some therapies fail. Here we combine mathematical modeling techniques and spatially-resolved radiogenomic maps to study the nature of these interactions between molecularly-distinct GBM subpopulations. We model the interactions between cell populations using a partial differential equation based formalism. The model is parameterized using radiogenomic ML maps from which we infer the nature of interactions between subpopulations. Furthermore, using maps as inputs, the model turns static maps into dynamic information, thus providing insight into how these subpopulations composing the tumor change over time and the effect this has on observed treatment response for individual patients.
PDTM-38. HISTONE H3.3 SER31 PHOSPHORYLATION REGULATES CHROMOSOME SEGREGATION AND CELL CYCLE CHECKPOINT CONTROL AND IS IMPAIRED IN PEDIATRIC GLIOMAS
Authors: Charles Day, Alyssa Langfald, Sela Fadness, Tatyana Zykova, Leslie Sepaniac, Jason Stumpff, Zigang Dong, Kevin Vaughan, James Robinson, Edward Hinchcliffe
Journal: Neuro-Oncology (2019)

Abstract Diffuse intrinsic pontine glioma (DIPG) carries a signature mutation in histone H3.3 (K27M) that induces epigenetic reprogramming via suppressed Lys27 triple methylation (K27me3). H3.3 has a Ser at position 31, which is adjacent to the K27M DIPG mutation. H3.3 Ser31 is phosphorylated beginning in prophase. This phosphorylation is restricted to pericentromeric heterochromatin and becomes dephosphorylated in anaphase. Surprisingly, chromosome missegregation triggers Ser31 hyperphosphorylation on the lagging chromosome, and masking phosphoS31 prevents p53 accumulation; part of the G1 checkpoint response to aneuploidy. Whether the K27M mutation influences Ser31 phosphorylation, chromosome segregation or G1 checkpoint control is unknown. We show that K27M DIPG cells have reduced pericentromeric phosphoS31 and increased chromosome instability (CIN) compared to normal, diploid human cells. CRISPR-editing of K27M to M27K restored phosphoS31 to WT levels and dramatically decreased the rate of CIN. We also demonstrate that Chk1 is the H3.3 Ser31 kinase. S31A abolishes Ser31 phosphorylation by Chk1, while K27M reduces it by ~60% in vitro. Chk1 knockdown abolishes phosphoS31 in normal, diploid mitotic cells, and induces CIN. In normal, diploid cells, expression of S31A or K27M mutations increased chromosome missegregation, whereas cells expressing a phosphomimetic double mutant (K27M/S31E) divide normally. WT cells arrest following chromosome missegregation. Yet, normal cells expressing H3.3 K27M or S31A do not arrest - despite having wild-type p53. Finally, using RCAS/TVA, we expressed H3F3AS31A in the brains of BRAFV600E mice, and ~50% developed tumors, suggesting that loss of phosphoS31 alone is oncogenic. Importantly, H3.3 S31A-expressing cells are WT for K27me3. Our results demonstrate that expressing H3.3 K27M reduces the population of H3.3 that is phosphorylatable at Ser31, leading to chromosome missegregation and preventing G1 arrest – thus creating proliferating CIN cells. We propose that a single amino acid substitution drives oncogenesis of DIPG, at least impart, by triggering the evolution of complex karyotypes.
The Immunomodulatory Effect of Triptolide on Mesenchymal Stem Cells in Vitro
Authors: Haiping He, Atsuko Takahashi, Yuki Yamamoto, Akiko Hori, Yuta Miharu, Kazuaki Yokoyama, Miwako Narita, Fumitaka Nagamura, Arinobu Tojo, Tonghua Yang, Tokiko Nagamura-Inoue
Journal: Blood (2019)
Oral Contraceptives and Liver Damage
Authors: E. Rice-Wray
Journal: BMJ (1964)

MBDIcRTISH L 1011 injected contrast media, with the risk of dis- placing a fragment towards the thorax, would only seem justified if the fragment could be palpated.'The damaged Braunile was subsequently connected to a disposable giving-set and transfusion under pressure simulated with the aid of a Martin's pump.After 2 minutes the cannula fractured 2 cm.from the tip and the distal portion shot off.The cause of the fracture remains uncertain.It seems un- likely in view of the position (away from a joint) and the short period of use (under 2 hours) that it could be fatigue.A manu- facturing fault, undetected on insertion, can- not be ruled out, but the possibility of the cannula's being nicked by the bevel of the needle on withdrawal seems the most probable cause.Practical safeguards should include great care in the inspection, positioning, and inser- tion of the Braunule, especially in the with- drawal of the needle.On removal of the cannula it should be examined and measured to ensure that it has been entirely recovered.The advisability of pressure-transfusion through such a unit must be open to question.The suggestion in a B.M.7.editorial' that plastic materials for intravascular insertion should contain radio-opaque material should be implemented.
Free Fatty Acid Uptake By Hematopoietic Stem and Progenitor Cells Drives Immune Cell Expansion in Response to Salmonella Typhimurium infection
Authors: Jayna J Mistry, Jamie A Moore, Charlotte Hellmich, Christopher R Marlein, Naiara Beraza, Federica Di Palma, Kristian M Bowles, Stuart A Rushworth
Journal: Blood (2019)