tbuckley/cabot-search huggingface dataset:
Efficiency of whole genome amplification of single circulating tumor cells enriched by CellSearch and sorted by FACS
Authors: Joost F Swennenhuis, Joke Reumers, Kim Thys, Jeroen Aerssens, Leon WMM Terstappen
Journal: Genome Medicine (2013)

Tumor cells in the blood of patients with metastatic carcinomas are associated with poor survival. Knowledge of the cells' genetic make-up can help to guide targeted therapy. We evaluated the efficiency and quality of isolation and amplification of DNA from single circulating tumor cells (CTC).The efficiency of the procedure was determined by spiking blood with SKBR-3 cells, enrichment with the CellSearch system, followed by single cell sorting by fluorescence-activated cell sorting (FACS) and whole genome amplification. A selection of single cell DNA from fixed and unfixed SKBR-3 cells was exome sequenced and the DNA quality analyzed. Single CTC from patients with lung cancer were used to demonstrate the potential of single CTC molecular characterization.The overall efficiency of the procedure from spiked cell to amplified DNA was approximately 20%. Losses attributed to the CellSearch system were around 20%, transfer to FACS around 25%, sorting around 5% and DNA amplification around 25%. Exome sequencing revealed that the quality of the DNA was affected by the fixation of the cells, amplification, and the low starting quantity of DNA. A single fixed cell had an average coverage at 20× depth of 30% when sequencing to an average of 40× depth, whereas a single unfixed cell had 45% coverage. GenomiPhi-amplified genomic DNA had a coverage of 72% versus a coverage of 87% of genomic DNA. Twenty-one percent of the CTC from patients with lung cancer identified by the CellSearch system could be isolated individually and amplified.CTC enriched by the CellSearch system were sorted by FACS, and DNA retrieved and amplified with an overall efficiency of 20%. Analysis of the sequencing data showed that this DNA could be used for variant calling, but not for quantitative measurements such as copy number detection. Close to 55% of the exome of single SKBR-3 cells were successfully sequenced to 20× depth making it possible to call 72% of the variants. The overall coverage was reduced to 30% at 20× depth, making it possible to call 56% of the variants in CellSave-fixed cells.
Chronic myelogenous leukemia: in vitro studies of hematopoietic regulation in a patient undergoing intensive chemotherapy.
Authors: J W Singer, J W Adamson, Z A Arlin, S J Kempin, B D Clarkson, P J Fialkow
Journal: Journal of Clinical Investigation (1981)

A patient heterozygous for the X-linked enzyme glucose-6-phosphate dehydrogenase and with Philadelphia chromosome-positive chronic myelogenous leukemia (CML) was treated with combination chemotherapy and had a partial loss of Philadelphia chromosome accompanied by partial restoration of nonclonal hematopoiesis as determined by glucose-6-phosphate dehydrogenase. Studies of in vitro hematopoiesis were performed after chemotherapy to evaluate the influences of neoplastic stem cells on normal cells and to determine whether there were physical and cell kinetic differences between leukemic stem cells and their normal counterparts. The data revealed the following: (a) The frequencies of normal committed granulocytic stem cells (CFU-C) and erythroid stem cells (BFU-E) in blood did not differ from the frequencies in marrow. (b) Normal late erythroid progenitors (CFU-E) were found at a significantly lower frequency that the more primitive BFU-E. Calculations indicated that not only was there a decrease in CFU-E production by normal BFU-E, but there was also abnormal clonal expansion of CML BFU-E (CFU-E:BFU-E ratio for normal progenitors was 1.1, whereas for the CML clone it was 11.5). (c) No increase in frequency of normal CFU-C was found after marrow cells were exposed to high specific activity tritiated thymidine. (d) Normal CFU-C and those from the CML clone were not separable on the basis of density. (e) The frequency of normal BFU-E was consistently greater than that of CFU-C, suggesting that regulatory differences influence the commitment of normal progenitors to the two pathways.
Association between trans fatty acid intake and 10-year risk of coronary heart disease in the Zutphen Elderly Study: a prospective population-based study
Authors: Claudia M Oomen, Marga C Ocké, Edith JM Feskens, Marie-Agnes J van Erp-Baart, Frans J Kok, Daan Kromhout
Journal: The Lancet (2001)
Heterogeneity of the Transition/Transversion Ratio in Drosophila and Hominidae Genomes
Authors: V. B. Seplyarskiy, P. Kharchenko, A. S. Kondrashov, G. A. Bazykin
Journal: Molecular Biology and Evolution (2012)

Mutation rate varies between sites in the genome. Part of this variation can be explained by well-recognized short nucleotide contexts, but a large component of this variation remains cryptic. We used data on interspecies divergence and intraspecies polymorphism in Drosophila and Hominidae to analyze variation of the average rate of the 12 possible kinds of single-nucleotide mutations and in the transition/transversion ratio κ at single-nucleotide resolution. Both the average mutation rate and κ vary by a factor of ∼3 between nucleotide sites. The characteristic scale of variation in κ is up to at least ∼30 nucleotides in Drosophila and ∼5 nucleotides in Hominidae. Genome segments with locally elevated mutation rates possess lower values of κ; however, a substantial fraction of variation in κ cannot be directly explained by the local mutation rates.
Respiratory risks from household air pollution in low and middle income countries
Authors: Stephen B Gordon, Nigel G Bruce, Jonathan Grigg, Patricia L Hibberd, Om P Kurmi, Kin-bong Hubert Lam, Kevin Mortimer, Kwaku Poku Asante, Kalpana Balakrishnan, John Balmes, Naor Bar-Zeev, Michael N Bates, Patrick N Breysse, Sonia Buist, Zhengming Chen, Deborah Havens, Darby Jack, Surinder Jindal, Haidong Kan, Sumi Mehta, Peter Moschovis, Luke Naeher, Archana Patel, Rogelio Perez-Padilla, Daniel Pope, Jamie Rylance, Sean Semple, William J Martin
Journal: The Lancet Respiratory Medicine (2014)
Lin28b promotes fetal B lymphopoiesis through the transcription factor Arid3a
Authors: Yan Zhou, Yue-Sheng Li, Srinivasa Rao Bandi, Lingjuan Tang, Susan A. Shinton, Kyoko Hayakawa, Richard R. Hardy
Journal: The Journal of Experimental Medicine (2015)

Mouse B cell precursors from fetal liver and adult bone marrow (BM) generate distinctive B cell progeny when transplanted into immunodeficient recipients, supporting a two-pathway model for B lymphopoiesis, fetal “B-1” and adult “B-2.” Recently, Lin28b was shown to be important for the switch between fetal and adult pathways; however, neither the mechanism of Lin28b action nor the importance of B cell antigen receptor (BCR) signaling in this process was addressed. Here, we report key advances in our understanding of the regulation of B-1/B-2 development. First, modulation of Let-7 in fetal pro-B cells is sufficient to alter fetal B-1 development to produce B cells resembling the progeny of adult B-2 development. Second, intact BCR signaling is required for the generation of B1a B cells from Lin28b-transduced BM progenitors, supporting a requirement for ligand-dependent selection, as is the case for normal B1a B cells. Third, the VH repertoire of Lin28b-induced BM B1a B cells differs from that of normal B1a, suggesting persisting differences from fetal progenitors. Finally, we identify the Arid3a transcription factor as a key target of Let-7, whose ectopic expression is sufficient to induce B-1 development in adult pro-B cells and whose silencing by knockdown blocks B-1 development in fetal pro-B cells.
Fruit and vegetable intakes and asthma in the E3N study
Authors: I Romieu
Journal: Thorax (2006)

<b>Background:</b> A study was undertaken to investigate whether dietary intake predicted the prevalence of adult asthma among French women participating in the E3N study. <b>Methods:</b> Of 68 535 women who completed a food frequency questionnaire in 1993 which included 238 food items, 2145 (3.1%) reported having asthma. The distribution of food intake was divided into quartiles (Q<sub>1</sub>–Q<sub>4</sub>) and the prevalence of asthma was compared between the different quartiles (lowest as reference) using logistic regression models on cross sectional data. <b>Results:</b> After adjusting for age, body mass index, menopausal status, smoking status, total caloric intake, physical activity, and use of dietary supplements, women who had a greater intake of tomatoes (OR<sub>Q1–Q4</sub> 0.85 95% CI 0.75 to 0.96, test for trend p = 0.02), carrots (OR<sub>Q1–Q4</sub> 0.81 95% CI 0.72 to 0.92, test for trend p = 0.0003), and leafy vegetables (OR<sub>Q1–Q4</sub> 0.82 95% CI 0.73 to 0.93, test for trend p = 0.0009) had a lower prevalence of asthma. Apples were marginally related to the prevalence of asthma. No other fruits or vegetables were significantly associated with asthma prevalence. <b>Conclusions:</b> These results suggest that the intake of some vegetables may decrease the prevalence of adult asthma.
Phospholipase D1 Drives a Positive Feedback Loop to Reinforce the Wnt/β-Catenin/TCF Signaling Axis
Authors: Dong Woo Kang, Soung-Hoon Lee, Jeong Whan Yoon, Won-Sang Park, Kang-Yell Choi, Do Sik Min
Journal: Cancer Research (2010)

Activation of the Wnt signaling pathway occurs frequently in human cancers, but an understanding of the targets and regulation of this important pathway remains incomplete. In this study, we report that phospholipase D (PLD), a cell survival mediator that is upregulated in cancer, is an important target of the Wnt signaling pathway that functions in a positive feedback loop to reinforce pathway output. PLD1 expression and activity was enhanced by treatment with Wnt3a and glycogen synthase kinase-3 inhibitors, and the Wnt pathway-regulated transcription factors beta-catenin and TCF-4 were required for this effect. Three functional TCF-4-binding sites were identified within the PLD1 promoter. Interestingly, suppressing PLD1 blocked the ability of beta-catenin to transcriptionally activate PLD1 and other Wnt target genes by preventing beta-catenin/TCF-4 complex formation. Conversely, tactics to elevate intracellular levels of phosphatidic acid, the product of PLD1 enzyme activity, enhanced beta-catenin/TCF-4 complex formation as well as beta-catenin-dependent TCF transcriptional activity. In cell-based assays, PLD1 was necessary for the anchorage-independent growth driven by Wnt/beta-catenin signaling, whereas beta-catenin/TCF-4 was necessary for the anchorage-independent growth driven by PLD1 activation. Taken together, our findings define a function for PLD1 in a positive feedback loop of Wnt/beta-catenin/TCF-4 signaling that provides new mechanistic insights into cancer, with implications of novel strategies to disrupt Wnt signaling in cancer.
Distinct Cellular and Molecular Mechanisms Underlie Functional Remodeling of Repolarizing K <sup>+</sup> Currents With Left Ventricular Hypertrophy
Authors: Céline Marionneau, Sylvain Brunet, Thomas P. Flagg, Thomas K. Pilgram, Sophie Demolombe, Jeanne M. Nerbonne
Journal: Circulation Research (2008)

Left ventricular hypertrophy (LVH) is associated with electric remodeling and increased arrhythmia risk, although the underlying mechanisms are poorly understood. In the experiments here, functional voltage-gated (Kv) and inwardly rectifying (Kir) K(+) channel remodeling was examined in a mouse model of pressure overload-induced LVH, produced by transverse aortic constriction (TAC). Action potential durations (APDs) at 90% repolarization in TAC LV myocytes and QT(c) intervals in TAC mice were prolonged. Mean whole-cell membrane capacitance (C(m)) was higher, and I(to,f), I(K,slow), I(ss), and I(K1) densities were lower in TAC, than in sham, LV myocytes. Although the primary determinant of the reduced current densities is the increase in C(m), I(K,slow) amplitudes were decreased and I(ss) amplitudes were increased in TAC LV cells. Further experiments revealed regional differences in the effects of LVH. Cellular hypertrophy and increased I(ss) amplitudes were more pronounced in TAC endocardial LV cells, whereas I(K,slow) amplitudes were selectively reduced in TAC epicardial LV cells. Consistent with the similarities in I(to,f) and I(K1) amplitudes, Kv4.2, Kv4.3, and KChIP2 (I(to,f)), as well as Kir2.1 and Kir2.2 (I(K1)), transcript and protein expression levels were similar in TAC and sham LV. Unexpectedly, expression of I(K,slow) channel subunits Kv1.5 and Kv2.1 was increased in TAC LV. Biochemical experiments also demonstrated that, although total protein was unaltered, cell surface expression of TASK1 was increased in TAC LV. Functional changes in repolarizing K(+) currents with LVH, therefore, result from distinct cellular (cardiomyocyte enlargement) and molecular (alterations in the numbers of functional channels) mechanisms.
Exercise-Induced Increase in Baroreflex Sensitivity Predicts Improved Prognosis After Myocardial Infarction
Authors: Maria Teresa La Rovere, Chiara Bersano, Marco Gnemmi, Giuseppe Specchia, Peter J. Schwartz
Journal: Circulation (2002)

Despite the rational expectation for a survival benefit produced by exercise training among post-myocardial infarction (MI) patients, direct evidence remains elusive. Clinically, changes in autonomic balance toward lower vagal activity have consistently been associated with increased mortality risk; conversely, among both control and post-MI dogs, exercise training improved vagal reflexes and prevented sudden death. Accordingly, we tested the hypothesis that exercise training, if accompanied by a shift toward increased vagal activity of an autonomic marker such as baroreflex sensitivity (BRS), could reduce mortality in post-MI patients.Ninety-five consecutive male patients surviving a first uncomplicated MI were randomly assigned to a 4-week endurance training period or to no training. Age (51+/-8 versus 52+/-8 years), site of MI (anterior 41% versus 43%), left ventricular ejection fraction (52+/-13 versus 51+/-14%), and BRS (7.9+/-5.4 versus 7.9+/-3.4 ms/mm Hg) did not differ between the two groups. After 4 weeks, BRS improved by 26% (P=0.04) in trained patients, whereas it did not change in nontrained patients. During a 10-year follow-up, cardiac mortality among the 16 trained patients who had an exercise-induced increase in BRS >or = 3 ms/mm Hg (responders) was strikingly lower compared with that of the trained patients without such a BRS increase (nonresponders) and that of the nontrained patients (0 of 16 versus 18 of 79 [23%], P=0.04). Cardiac mortality was also lower among responders irrespective of training (4% versus 24%, P=0.04).Post-MI exercise training can favorably modify long-term survival, provided that it is associated with a clear shift of the autonomic balance toward an increase in vagal activity.
Prognostic Significance of <sup>99m</sup>Tc Hynic-rh-Annexin V Scintigraphy During Platinum-Based Chemotherapy in Advanced Lung Cancer
Authors: Marina Kartachova, Nico van Zandwijk, Sjaak Burgers, Harm van Tinteren, Marcel Verheij, Renato Alfredo Valdés Olmos
Journal: Journal of Clinical Oncology (2007)

The purpose of this study was to evaluate if sequential 99mTc Hynic-rh- annexin V scintigraphy (TAS) can predict outcome in patients with advanced lung cancer, shortly after the start of platinum-based chemotherapy.In 16 consecutive chemotherapy-naive patients with advanced stage non-small-cell lung cancer scheduled for platinum-based chemotherapy, TAS was performed before and within 48 hours after the start of therapy. Chemotherapy-induced changes in tumor annexin V uptake, calculated as maximum count per pixel and expressed as percentage to baseline value, were compared with treatment response determined according to Response Evaluation Criteria in Solid Tumors.A significant correlation (r2 = 0.86; P = .0001) was found between annexin V metabolic changes and treatment outcome. All patients with notably increased annexin V tumor uptake showed complete or partial response. Less prominently increased or decreased uptake correlated with stable or progressive disease.TAS is a promising test to predict tumor response in patients with advanced lung cancer early in the course of platinum-based chemotherapy.
Cellular Disposal of miR23b by RAB27-Dependent Exosome Release Is Linked to Acquisition of Metastatic Properties
Authors: Marie Stampe Ostenfeld, Dennis K. Jeppesen, Jens R. Laurberg, Anders T. Boysen, Jesper B. Bramsen, Bjarke Primdal-Bengtson, An Hendrix, Philippe Lamy, Frederik Dagnaes-Hansen, Mads H. Rasmussen, Khan H. Bui, Niels Fristrup, Erik I. Christensen, Iver Nordentoft, Jens P. Morth, Jørgen B. Jensen, Jakob S. Pedersen, Martin Beck, Dan Theodorescu, Michael Borre, Kenneth A. Howard, Lars Dyrskjøt, Torben Falck Ørntoft
Journal: Cancer Research (2014)

Abstract Exosomes are small secreted vesicles that can transfer their content to recipient cells. In cancer, exosome secretion has been implicated in tumor growth and metastatic spread. In this study, we explored the possibility that exosomal pathways might discard tumor-suppressor miRNA that restricts metastatic progression. Secreted miRNA characterized from isogenic bladder carcinoma cell lines with differing metastatic potential were uncoupled from binding to target transcripts or the AGO2–miRISC complex. In metastatic cells, we observed a relative increase in secretion of miRNA with tumor-suppressor functions, including miR23b, miR224, and miR921. Ectopic expression of miR23b inhibited invasion, anoikis, angiogenesis, and pulmonary metastasis. Silencing of the exocytotic RAB family members RAB27A or RAB27B halted miR23b and miR921 secretion and reduced cellular invasion. Clinically, elevated levels of RAB27B expression were linked to poor prognosis in two independent cohorts of patients with bladder cancer. Moreover, highly exocytosed miRNA from metastatic cells, such as miR23b, were reduced in lymph node metastases compared with patient-matched primary tumors and were correlated with increments in miRNA-targeted RNA. Taken together, our results suggested that exosome-mediated secretion of tumor-suppressor miRNA is selected during tumor progression as a mechanism to coordinate activation of a metastatic cascade. Cancer Res; 74(20); 5758–71. ©2014 AACR.
Long-term treatment of chronic obstructive lung disease by Nifedipine: an 18-month haemodynamic study
Authors: AY Saadjian, FF Philip-Joet, R Vestri, AG Arnaud
Journal: European Respiratory Journal (1988)

This long-term controlled study was undertaken to assess the haemodynamic effects of chronic administration of Nifedipine (N). Twenty patients suffering from pulmonary hypertension secondary to chronic obstructive lung disease were divided into two groups. One group (treatment group) was instructed to take 30 mg of N daily and the other (control group) did not take N. Haemodynamic measurements were recorded before and after an 18-month observation period. For patients in the treatment group, Nifedipine was stopped 24 h prior to the second investigation. Acute response to a single dose of Nifedipine (10 mg sublingually) was also evaluated in all patients during the first and second investigations in order to estimate a possible tachyphylaxis. No significant modification in heart rate, mean pulmonary pressure, mean arterial pressure or blood gases was observed. Conversely, a 10% decrease in cardiac output (p less than 0.05) occurred in the control group. Pulmonary vascular response to acute administration of Nifedipine was the same in both groups before and after the observation period. These results suggest that while long-term administration of Nifedipine to patients with chronic obstructive lung disease does not improve pulmonary pressure, it may prevent a decrease in cardiac output. No tachyphylaxis was noted.
Na/Li Countertransport Abnormalities in Type 1 Diabetes With and Without Nephropathy Are Familial
Authors: Paul A. Mead, Robert Wilkinson, Trevor H. Thomas
Journal: Diabetes Care (2001)

OBJECTIVE—To determine whether there is a familial abnormality in erythrocyte Na/Li countertransport (CT) kinetics in the approximate one-third of type 1 diabetic patients that succumb to a familial predisposition to nephropathy. RESEARCH DESIGN AND METHODS—Erythrocyte Na/Li CT kinetics were measured in nondiabetic first-degree relatives of type 1 diabetic patients with nephropathy (DNrel) (n = 32) or without nephropathy (DCrel) (n = 22) and normal control subjects ( n = 25). RESULTS—Increases in outside-site Na ion association rate constant and turnover rate of Na/Li countertransport (CT) in DNrels caused increases in Vmax/Km and Vmax, respectively. Thiol alkylation with N-ethylmaleimide (NEM) modifies these kinetic parameters abnormally in nephropathy. With Na ions at the outside site of the transporter, thiol alkylation causes a large decrease in Vmax; but in their absence, Vmax is decreased in normal control subjects, unchanged in DCrels, or increased in DNrels. The relationship between Vmax values after thiol alkylation with or without Na ions was different in DNrels (P &amp;lt; 0.001). Kinetic parameters with and without thiol alkylation identified 60% of DNrels and 20% of DCrels as abnormal. The single-flux rate assay of Na/Li CT did not give this discrimination, and its use may cause discrepancy between studies. CONCLUSIONS—Clinically normal untreated DNrels have the same abnormality in Na/Li CT as the affected patients. DNrels had a metabolic syndrome with increased BMI and plasma triglycerides, but no elevation in blood pressure. Na/Li CT can detect those type 1 diabetic patients at risk of nephropathy who have a familial abnormality in a membrane thiol protein.
Progressive Multifocal Leukoencephalopathy Associated with Human Immunodeficiency Virus Infection
Authors: JOSEPH R. BERGER
Journal: Annals of Internal Medicine (1987)

Progressive multifocal leukoencephalopathy, a common complication of infections with human immunodeficiency virus (HIV), occurs in as many as 3.8% of patients with the acquired immunodeficiency syndrome (AIDS). We report 16 cases and review 12 previously reported cases of progressive multifocal leukoencephalopathy associated with HIV infection. This illness was the presenting manifestation of HIV infection in 8 cases. Limb weakness, gait abnormalities, visual loss, and altered mental status were the commonest initial complaints. Computed tomography of the brain frequently showed hypodense, nonenhancing white matter lesions. Magnetic resonance imaging was more sensitive than computed tomography in detecting lesions. Cerebrospinal fluid analysis and electroencephalography were nondiagnostic. Impaired cell-mediated immunity was typically noted, even in the absence of other immunodeficiency-associated illnesses. Death occurred within 10 days to 18 months of the onset of symptoms in 22 patients. However, 4 patients remain alive at 3 to 23 months; of these 4, 2 have had significant improvement without treatment. Various therapies were unsuccessful.