tbuckley/cabot-search huggingface dataset:
p53 in malignant glioma: 20 years later and still much to learn
Authors: C David James
Journal: Neuro-Oncology (2010)

p53, as a key and common mutagenic target in the development of malignant glioma, was initially brought to the attention of the neuro-oncology community more than 20 years ago (Nature 1989;342:705–708). As of March 3, 2010, a PubMed search for articles containing glioma and p53 in the title or abstract yielded 1647 hits. Clearly, p53 has and continues to hold our interest as we persevere to understand its many roles in glioma development and biology.

Due to the numerous cellular processes that are directly or indirectly influenced by p53 function, it often seems that the more we learn about p53, the more we appreciate how much remains to be learned. The incompleteness of our understanding is suggested in the titles of two articles published in the current (Geng et al1) and April (Kim et al2) issues of Neuro-Oncology. It is noteworthy that these two studies, conducted independently by teams of investigators in different countries and continents, each address GBM's response to the quinoline derivative chloroquine, and each approaches GBM's chloroquine response from a p53 perspective. However, the conclusions of these studies are surprisingly distinct, as indicated by their titles.

In the former (Kim et al2), established GBM cell lines were tested, in the presence and absence of endogenous p53 knockdown, for their apoptotic response to chloroquine. GBM cells expressing wild-type p53 underwent decreased chloroquine-induced apoptosis when treated in a p53-depleted state. In the latter investigation, for which some of the same cell lines were used as in the former study and in which cell lines were treated with chloroquine at similar concentrations, the opposite was concluded: that cellular p53 status was not a key determinant of chloroquine-induced cell death. These distinct conclusions may be associated with the time frames of the experiments: the former involving an analysis of effects over periods as long as 7 days and showing a time-dependent increase in the extent of chloriquine anti-tumor activity in GBM with wild-type vs. mutant p53 and the latter involving an analysis of chloroquine's effects at a single time point: 1 day. Potentially, the combined results of these reports indicate that short-term, p53-independent chloroquine anti-tumor effects exist through influence on autophagic response (Geng et al1), whereas long-term cellular response to treatment with chloroquine is p53 dependent through influence on caspase-mediated apoptosis.

Regardless of whether this or alternative hypotheses help explain the basis for the different interpretations of GBM p53 status and response to chloroquine, these studies share a common theme of being p53 centric with respect to interpretation and serve to highlight our continuing fascination with this tumor suppressor gene and its protein product.
Concordant Release of Glycolysis Proteins into the Plasma Preceding a Diagnosis of ER+ Breast Cancer
Authors: Lynn M. Amon, Sharon J. Pitteri, Christopher I. Li, Martin McIntosh, Jon J. Ladd, Mary Disis, Peggy Porter, Chee Hong Wong, Qing Zhang, Paul Lampe, Ross L. Prentice, Samir M. Hanash
Journal: Cancer Research (2012)

Although the identification of peripheral blood biomarkers would enhance early detection strategies for breast cancer, the discovery of protein markers has been challenging. In this study, we sought to identify coordinated changes in plasma proteins associated with breast cancer based on large-scale quantitative mass spectrometry. We analyzed plasma samples collected up to 74 weeks before diagnosis from 420 estrogen receptor (ER)(+) cases and matched controls enrolled in the Women's Health Initiative cohort. A gene set enrichment analysis was applied to 467 quantified proteins, linking their corresponding genes to particular biologic pathways. On the basis of differences in the concentration of individual proteins, glycolysis pathway proteins exhibited a statistically significant difference between cases and controls. In particular, the enrichment was observed among cases in which blood was drawn closer to diagnosis (effect size for the 0-38 weeks prediagnostic group, 1.91; P, 8.3E-05). Analysis of plasmas collected at the time of diagnosis from an independent set of cases and controls confirmed upregulated levels of glycolysis proteins among cases relative to controls. Together, our findings indicate that the concomitant release of glycolysis proteins into the plasma is a pathophysiologic event that precedes a diagnosis of ER(+) breast cancer.
Severe extravasation injury: an avoidable iatrogenic disaster?
Authors: D A Burd, G Santis, T M Milward
Journal: BMJ (1985)

A propos d'une observation: extravasation d'un produit de contraste radiologique (Conray 420) ayant amene la mort de la malade. Des precautions particulieres devraient etre prises lors de l'administration par voie veineuse de produits hyperosmolaires, toxiques pour les tissus ou capables de provoquer une ischemie. Certains malades courent des risques plus grands: tres jeunes, tres âges, diabetiques, inconscients, etc.
Hereditary Hypophosphatemic Rickets with Hypercalciuria Is Not Caused by Mutations in the Na/Pi Cotransporter NPT2 Gene
Authors: ANDREW O. JONES, JORDANA TZENOVA, DANIELLE FRAPPIER, M. JOYCE CRUMLEY, NICOLE M. ROSLIN, CLAUDINE H. KOS, MARTIN TIEDER, CRAIG B. LANGMAN, WILLEM PROESMANS, THOMAS O. CARPENTER, ALLAN RICE, DONALD ANDERSON, KENNETH MORGAN, T. MARY FUJIWARA, HARRIET S. TENENHOUSE
Journal: Journal of the American Society of Nephrology (2001)

Abstract. Hereditary hypophosphatemic rickets with hypercalciuria (HHRH), a renal phosphate (Pi) wasting disease first described in an extended Bedouin kindred, is characterized by hypophosphatemia, elevated serum 1,25-dihydroxyvitamin D levels, hypercalciuria, rickets, and osteomalacia. Correction of all abnormalities, except for renal Pi wasting, can be achieved by oral Pi supplementation. These findings and the demonstration that mice that are homozygous for the disrupted Na/Pi cotransporter gene Npt2 exhibit many of the biochemical features of HHRH suggested that mutations in the human orthologue NPT2 might be responsible for HHRH. The NPT2 gene in affected individuals from the Bedouin kindred and four small families was screened for mutations to test this hypothesis. No putative disease-causing mutation was found. Two single nucleotide polymorphisms (SNP), a silent substitution in exon 7 and a nucleotide substitution in intron 4, were identified, and neither consistently segregated with HHRH in the Bedouin kindred. Linkage analysis indicated that the two NPT2 intragenic SNP as well as five microsatellite markers in the NPT2 gene region were not linked to HHRH in the Bedouin kindred. Therefore, this is evidence to exclude NPT2 as a candidate gene for HHRH in the families that were studied.
Natural Antibody Repertoires: Development and Functional Role in Inhibiting Allergic Airway Disease
Authors: John F. Kearney, Preeyam Patel, Emily K. Stefanov, R. Glenn King
Journal: Annual Review of Immunology (2015)

In this review we discuss the effects of microbial exposure on the B cell repertoire. Neonatal exposure to conserved bacterial carbohydrates and phospholipids permanently reprograms the natural antibody repertoire directed toward these antigens by clonal expansion, alterations in clonal dominance, and increased serum antibody levels. These epitopes are present not only in bacterial cell walls, but also in common environmental allergens. Neonatal immunization with bacterial polysaccharide vaccines results in attenuated allergic airway responses to fungi-, house dust mite-, and cockroach-associated allergens in mouse models. The similarities between mouse and human natural antibody repertoires suggest that reduced microbial exposure in children may have the opposite effect, providing a potential mechanistic explanation for the hygiene hypothesis. We propose that understanding the effects of childhood infections on the natural antibody repertoire and the mechanisms of antibody-mediated immunoregulation observed in allergy models will lead to the development of prevention/interventional strategies for treatment of allergic asthma.
Type I interferon rapidly restricts infectious hepatitis C virus particle genesis
Authors: Luke W. Meredith, Michelle J. Farquhar, Alexander W. Tarr, Jane A. McKeating
Journal: Hepatology (2014)

Interferon-alpha (IFNα) has been used to treat chronic hepatitis C virus (HCV) infection for over 20 years with varying efficacy, depending on the infecting viral genotype. The mechanism of action of IFNα is not fully understood, but is thought to target multiple stages of the HCV lifecycle, inhibiting viral transcription and translation leading to a degradation of viral RNA and protein expression in the infected cell. IFNα induces the expression of an array of interferon-stimulated genes within minutes of receptor engagement; however, the impact of these early responses on the viral lifecycle are unknown. We demonstrate that IFNα inhibits the genesis of infectious extracellular HCV particles within 2 hours of treating infected cells, with minimal effect on the intracellular viral burden. Importantly, this short duration of IFNα treatment of infected cells significantly reduced cell-free and cell-to-cell dissemination. The secreted viral particles showed no apparent change in protein content or density, demonstrating that IFNα inhibits particle infectivity but not secretion rates. To investigate whether particles released from IFNα-treated cells have a reduced capacity to establish infection we used HCV lentiviral pseudotypes (HCVpp) and demonstrated a defect in cell entry. Using a panel of monoclonal antibodies targeting the E2 glycoprotein, we demonstrate that IFNα alters glycoprotein conformation and receptor utilization.These observations show a previously unreported and rapid effect of IFNα on HCV particle infectivity that inhibits de novo infection events. Evasion of this response may be a contributing factor in whether a patient achieves early or rapid virological response, a key indicator of progression to sustained virological response or clearance of viral infection.
A Transcriptional Profiling Study of CCAAT/Enhancer Binding Protein Targets Identifies Hepatocyte Nuclear Factor 3β as a Novel Tumor Suppressor in Lung Cancer
Authors: Balazs Halmos, Daniela S. Bassères, Stefano Monti, Francesco D‘Aló, Tajhal Dayaram, Katalin Ferenczi, Bas J. Wouters, Claudia S. Huettner, Todd R. Golub, Daniel G. Tenen
Journal: Cancer Research (2004)

Abstract We showed previously that CCAAT/enhancer binding protein α (C/EBPα), a tissue-specific transcription factor, is a candidate tumor suppressor in lung cancer. In the present study, we have performed a transcriptional profiling study of C/EBPα target genes using an inducible cell line system. This study led to the identification of hepatocyte nuclear factor 3β (HNF3β), a transcription factor known to play a role in airway differentiation, as a downstream target of C/EBPα. We found down-regulation of HNF3β expression in a large proportion of lung cancer cell lines examined and identified two novel mutants of HNF3β, as well as hypermethylation of the HNF3β promoter. We also developed a tetracycline-inducible cell line model to study the cellular consequences of HNF3β expression. Conditional expression of HNF3β led to significant growth reduction, proliferation arrest, apoptosis, and loss of clonogenic ability, suggesting additionally that HNF3β is a novel tumor suppressor in lung cancer. This is the first study to show genetic abnormalities of lung-specific differentiation pathways in the development of lung cancer.
Effectiveness of early switch from intravenous to oral antibiotics in severe community acquired pneumonia: multicentre randomised trial
Authors: Jan Jelrik Oosterheert, Marc J M Bonten, Margriet M E Schneider, Erik Buskens, Jan-Willem J Lammers, Willem M N Hustinx, Mark H H Kramer, Jan M Prins, Peter H Th J Slee, Karin Kaasjager, Andy I M Hoepelman
Journal: BMJ (2006)

Objectives To compare the effectiveness of an early switch to oral antibiotics with the standard 7 day course of intravenous antibiotics in severe community acquired pneumonia. Design Multicentre randomised controlled trial. Setting Five teaching hospitals and 2 university medical centres in the Netherlands. Participants 302 patients in non-intensive care wards with severe community acquired pneumonia. 265 patients fulfilled the study requirements. Intervention Three days of treatment with intravenous antibiotics followed, when clinically stable, by oral antibiotics or by 7 days of intravenous antibiotics. Main outcome measures Clinical cure and length of hospital stay. Results 302 patients were randomised (mean age 69.5 (standard deviation 14.0), mean pneumonia severity score 112.7 (26.0)). 37 patients were excluded from analysis because of early dropout before day 3, leaving 265 patients for intention to treat analysis. Mortality at day 28 was 4% in the intervention group and 6% in the control group (mean difference 2%, 95% confidence interval −3% to 8%). Clinical cure was 83% in the intervention group and 85% in the control group (2%, −7% to 10%). Duration of intravenous treatment and length of hospital stay were reduced in the intervention group, with mean differences of 3.4 days (3.6 (1.5) v 7.0 (2.0) days; 2.8 to 3.9) and 1.9 days (9.6 (5.0) v 11.5 (4.9) days; 0.6 to 3.2), respectively. Conclusions Early switch from intravenous to oral antibiotics in patients with severe community acquired pneumonia is safe and decreases length of hospital stay by 2 days. Trial registration Clinical Trials [NCT00273676][1]. [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT00273676&atom=%2Fbmj%2F333%2F7580%2F1193.atom
A theoretical framework for quantifying blood volume flow rate from dynamic angiographic data and application to vessel-encoded arterial spin labeling MRI
Authors: Thomas W. Okell, Michael A. Chappell, Peter Jezzard
Journal: Medical Image Analysis (2013)

Angiographic methods can provide valuable information on vessel morphology and hemodynamics, but are often qualitative in nature, somewhat limiting their ability for comparison across arteries and subjects. In this work we present a method for quantifying absolute blood volume flow rates within large vessels using dynamic angiographic data. First, a kinetic model incorporating relative blood volume, bolus dispersion and signal attenuation is fitted to the data. A self-calibration method is also described for both 2D and 3D data sets to convert the relative blood volume parameter into absolute units. The parameter values are then used to simulate the signal arising from a very short bolus, in the absence of signal attenuation, which can be readily encompassed within a vessel mask of interest. The volume flow rate can then be determined by calculating the resultant blood volume within the vessel mask divided by the simulated bolus duration. This method is applied to non-contrast magnetic resonance imaging data from a flow phantom and also to the cerebral arteries of healthy volunteers acquired using a 2D vessel-encoded pseudocontinuous arterial spin labeling pulse sequence. This allows the quantitative flow contribution in downstream vessels to be determined from each major brain-feeding artery. Excellent agreement was found between the actual and estimated flow rates in the phantom, particularly below 4.5 ml/s, typical of the cerebral vasculature. Flow rates measured in healthy volunteers were generally consistent with values found in the literature. This method is likely to be of use in patients with a variety of cerebrovascular diseases, such as the assessment of collateral flow in patients with steno-occlusive disease or the evaluation of arteriovenous malformations.
Combined Therapy With 5-Azacytidine and Hydrocortisone in Glucocorticoid-Sensitive and -Resistant Mouse P1798 Lymphosarcoma1
Authors: C.-W. Chi, M. M. Ip
Journal: JNCI Journal of the National Cancer Institute (1988)

Journal Article Combined Therapy With 5-Azacytidine and Hydrocortisone in Glucocorticoid-Sensitive and -Resistant Mouse P1798 Lymphosarcoma1 Get access Chin-Wen Chi, Chin-Wen Chi 4 3Grace Cancer Drug Center, Roswell Park Memorial InstituteBuffalo, NY 4Present address: Biochemical Oncology Laboratory, Medical Research Center Veterans General Hospital, Taipei, 112, Taiwan, Republic of China. Search for other works by this author on: Oxford Academic PubMed Google Scholar Margot M. Ip Margot M. Ip 3Grace Cancer Drug Center, Roswell Park Memorial InstituteBuffalo, NY Search for other works by this author on: Oxford Academic PubMed Google Scholar JNCI: Journal of the National Cancer Institute, Volume 80, Issue 12, 17 August 1988, Pages 912–918, https://doi.org/10.1093/jnci/80.12.912 Published: 17 August 1988 Article history Received: 11 December 1987 Accepted: 01 January 1988 Revision received: 02 March 1988 Published: 17 August 1988
DIFFERENCES IN IMMUNIZATION AND SENSITIZATION IN RABBITS INJECTED WITH RELATIVELY AVIRULENT OR HIGHLY VIRULENT CULTURES OF THE SAME STRAIN (H) OF HEMOLYTIC STREPTOCOCCUS
Authors: D. Murray Angevine
Journal: The Journal of Experimental Medicine (1939)

1. When a relatively avirulent strain of hemolytic streptococcus was injected into the skin of rabbits a considerable amount of skin sensitivity to streptococcus filtrate developed, and there was scant demonstrable immunity. 2. When the same strain of streptococcus was made highly virulent by repeated passages through rabbits, little sensitization and considerable immunity was produced. 3. Rabbits injected with a virulent culture of hemolytic streptococcus developed agglutinins and precipitins earlier and in larger amounts than animals injected with the avirulent form of the same organism. 4. Increase in virulence of hemolytic streptococci enhances the ability to protect against local infection and increases antibody formation but diminishes the production of sensitization. Avirulent and virulent strains of this microorganism have similar relations.
DNA-PKcs and Artemis function in the end-joining phase of immunoglobulin heavy chain class switch recombination
Authors: Sonia Franco, Michael M. Murphy, Gang Li, Tiffany Borjeson, Cristian Boboila, Frederick W. Alt
Journal: The Journal of Experimental Medicine (2008)

The DNA-dependent protein kinase catalytic subunit (DNA-PKcs) and Artemis are classical nonhomologous DNA end-joining (C-NHEJ) factors required for joining a subset of DNA double-strand breaks (DSB), particularly those requiring end processing. In mature B cells, activation-induced cytidine deaminase (AID) initiates class switch recombination (CSR) by introducing lesions into S regions upstream of two recombining C(H) exons, which are processed into DSBs and rejoined by C-NHEJ to complete CSR. The function of DNA-PKcs in CSR has been controversial with some reports but not others showing that DNA-PKcs-deficient mice are significantly impaired for CSR. Artemis-deficient B cells reportedly undergo CSR at normal levels. Overall, it is still not known whether there are any CSR-associated DSBs that require DNA-PKcs and/or Artemis to be joined. Here, we have used an immunoglobulin (Ig)H locus-specific fluorescent in situ hybridization assay to unequivocally demonstrate that both DNA-PKcs and, unexpectedly, Artemis are necessary for joining a subset of AID-dependent DSBs. In the absence of either factor, B cells activated for CSR frequently generate AID-dependent IgH locus chromosomal breaks and translocations. We also find that under specific activation conditions, DNA-PKcs(-/-) B cells with chromosomal breaks are eliminated or at least prevented from progressing to metaphase via a p53-dependent response.
Circulating Tumor Cells and Sample Size: The More, the Better
Authors: Zarina S. Lalmahomed, Jaco Kraan, Jan W. Gratama, Bianca Mostert, Stefan Sleijfer, Cornelis Verhoef
Journal: Journal of Clinical Oncology (2010)

TO THEEDITOR: With interest we read the article by Jiao et al, 1 who studied the presence of circulating tumor cells (CTCs) in blood of patients with colorectal liver metastases (CRLM) by automated immunomagnetic enrichment and image cytometry using the CellSearch system (Veridex, Raritan, NJ). They showed CTCs to be present in the hepatic macrocirculation in significantly higher numbersthanintheperipheralcirculation(median,187[range,0to500]v median 1 [range 0 to 6]). Despite the number of evaluated patients in this study being small, the low number of detected CTCs in the peripheral circulation may suggest that CTC enumeration and characterization plays no role in this specific patient population. Enumeration and in particular characterization of CTC holds great promise for patient management and research purposes. 2 Of severalassaysenablingCTCdetection(reviewedbyMostertetal 3 ),the CellSearch system has been approved by the US Food and Drug Administration for use in metastatic breast, prostate, and colorectal cancer.Accordingtothemanufacturer’sinstructions,CTCenumeration should be performed in 7.5 mL blood. In the first study of 196 patientswithmetastaticcolorectalcancerwhoseCTCsweremeasured with the CellSearch system. At least 2 CTCs per 7.5 mL blood were detected in 30% of patients, whereas only 17% had 5 CTCs per 7.5 mL blood. 4 In a subsequent publication by Cohen et al 5 investigating the prognostic role of CTCs in advanced colorectal cancer, patients with a CTC count above a threshold of 3 CTCs per 7.5 mL blood had a worse outcome after systemic therapy compared with patients with lower CTC counts. The 430 patients in this study received first-, second-, or third-line chemotherapy, of whom 26% had a CTC count3 CTC threshold, whereas 48% of the patients had1 CTC per 7.5 mL blood. In a third study of 451 patients with metastatic colorectal cancer, at least 3 CTCs per 7.5 mL blood were detected in 29% of the patients. 6 From these studies we can conclude that the number of detectable CTCs in patients with advanced colorectal cancer using the CellSearch System is low to even below detection limit, which is in contrast to other tumor types. In metastatic breast and prostate cancer, the percentage of patients with a CTC count of 5 CTCs per 7.5 mL was 66% and 49%, respectively. 7,8 Not surprisingly and in line with thefindings of Jiao et al, 1 in nonmetastastic colorectal cancer, the number of patients with detectable CTCs is even lower thaninadvanceddisease.Onestudyrevealed2CTCs/7.5mLintwo
Primary cell-mediated lympholysis response to a maternally transmitted antigen.
Authors: R Smith, D P Huston, R R Rich
Journal: The Journal of Experimental Medicine (1982)

Mta-specific cytotoxic T lymphocyte (CTL) can be generated in primary cultures of (NZB X B10.D2)F1 spleen cells with H-2-compatible BALB/c stimulator cells. The CTL lyse reciprocal Mta+ (B10.D2 X NZB)F1 as well as H-2-disparate targets, such as B10, B6, and B6-Tlaa; they do not lyse targets from NZB or any F1 hybrid of an NZB mother. The lysis of 51Cr-labeled B10 targets is completely inhibited by unlabeled targets from Mta+ (B10.D2 X NZB)F1, but not from the reciprocal Mta- F1, thus demonstrating H-2-unrestricted lysis of Mta.