tbuckley/cabot-search huggingface dataset:
Activating mutations in BRAF characterize a spectrum of pediatric low-grade gliomas
Authors: Margaret J. Dougherty, Mariarita Santi, Marcia S. Brose, Changqing Ma, Adam C. Resnick, Angela J. Sievert, Phillip B. Storm, Jaclyn A. Biegel
Journal: Neuro-Oncology (2010)

In the present study, DNA from 27 grade I and grade II pediatric gliomas, including ganglioglioma, desmoplastic infantile ganglioglioma, dysembryoplastic neuroepithelial tumor, and pleomorphic xanthoastrocytoma was analyzed using the Illumina 610K Beadchip SNP-based oligonucleotide array. Several consistent abnormalities, including gain of chromosome 7 and loss of 9p21 were observed. Based on our previous studies, in which we demonstrated BRAF mutations in 3 gangliogliomas, 31 tumors were screened for activating mutations in exons 11 and 15 of the BRAF oncogene or a KIAA1549-BRAF fusion product. There were no cases with a KIAA1549-BRAF fusion. A BRAF V600E mutation was detected in 14 of 31 tumors, which was not correlated with any consistent pattern of aberrations detected by the SNP array analysis. Tumors were also screened for mutations in codon 132 in exon 4 of IDH1, exons 2 and 3 of KRAS, and exons 2-9 of TP53. No mutations in KRAS or TP53 were identified in any of the samples, and there was only 1 IDH1 R132H mutation detected among the sample set. BRAF mutations constitute a major genetic alteration in this histologic group of pediatric brain tumors and may serve as a molecular target for biologically based inhibitors.
Myocardial Fibroma in Gorlin Syndrome by Cardiac Magnetic Resonance Imaging
Authors: Andrew T. Yan, Donna M. Coffey, Yi Li, Wing-Sze Chan, Adolphe J. Shayne, Tuan M. Luu, Ronald B. Skorstad, Maung M. Khin, Kenneth A. Brown, Martin J. Lipton, Raymond Y. Kwong
Journal: Circulation (2006)
Death Following Creatine Kinase-MB Elevation After Coronary Intervention
Authors: Stephen G. Ellis, Derek Chew, Albert Chan, Patrick L. Whitlow, Jakob P. Schneider, Eric J. Topol
Journal: Circulation (2002)

Background— Creatine kinase (CK)-MB elevation after percutaneous coronary intervention (PCI) has been associated with subsequent cardiac death. The patients at risk, the timing of risk, and potential treatment implications are uncertain. Methods and Results— Eight thousand, four hundred nine consecutive non– acute myocardial infarction patients with successful PCI and no emergency surgery or Q-wave myocardial infarction were followed for 38±25 months; 1446 (17.2%) had post-PCI CK-MB above normal on routine ascertainment. Patients were prospectively stratified into those with CK-MB 1 to 5× or CK-MB &gt;5× normal. No patient with CK-MB 1 to 5× normal died during the first week after PCI, and excess risk of early death for patients with CK-MB elevation occurred primarily in the first 3 to 4 months. The actuarial 4-month risk of death was 8.9%, 1.9%, and 1.2% for patients with CK-MB &gt;5×, CK-MB 1 to 5×, and CK-MB ≤1× normal ( P &lt;0.001). Death within 4 months was independently correlated with the degree of CK-MB elevation, creatinine ≥2 mg%, post-PCI C-reactive protein, low ejection fraction, age, and congestive heart failure class ( P &lt;0.01 for all). In a matched subset analysis, incomplete revascularization ( P &lt;0.001), congestive heart failure class ( P =0.005), and no statin treatment at hospital discharge ( P =0.009) were associated with death. Conclusions— Patients with CK-MB elevation after PCI are at excess risk of death for 3 to 4 months, although prolonging hospitalization for CK-MB 1 to 5× is unlikely to modify risk. CK-MB &gt;5× normal, incomplete revascularization, elevated C-reactive protein, heart failure, the elderly, and hospital discharge without on statin therapy increases risk. Several of these factors suggest that inflammation may play a part in the excess risk of death.
Human immunodeficiency virus (HIV) Tat-reactive antibodies present in normal HIV-negative sera and depleted in HIV-positive sera. Identification of the epitope.
Authors: T C Rodman, F H Pruslin, S E To, R Winston
Journal: The Journal of Experimental Medicine (1992)

We have detected, in sera of normal human immunodeficiency virus (HIV)-free subjects, IgM antibodies reactive with the Tat protein of HIV in significant titers and at very high frequency, and, in HIV-positive sera, progressively lower titers as HIV pathogenesis ensues. Epitope analysis indicates that the Tat-reactive antibodies of both HIV-negative and HIV-positive sera are homologous, suggesting, therefore, that their decline in HIV-positive sera may represent attrition of a host defense factor. The identified epitope displays minimal homology with that previously defined for another set of IgM antibodies shown to be present in normal sera, deficient in HIV-positive sera, and postulated to be natural antibodies. We propose that the Tat-reactive antibodies, as well, are a set of natural antibodies and that the normal humoral immune system includes a repertoire of antibodies, nonimmunogenic in origin, that contribute to immune homeostasis and, consequently, to host resistance to HIV pathogenesis.
Outbreak of hepatitis C virus infection during sclerotherapy of varicose veins: Long-term follow-up of 196 patients (4535 patient-years)
Authors: Victor de Lédinghen, Pascale Trimoulet, Paul-Régis Mannant, Francis Dumas, Patrick Champbenoît, Christian Baldit, Juliette Foucher, Muriel Faure, Julien Vergniol, Laurent Castéra, Julien Bertet, Hervé Fleury, Patrice Couzigou, Pierre-Henri Bernard
Journal: Journal of Hepatology (2006)
Risk factors for pulmonary tuberculosis in community-acquired pneumonia
Authors: D. Aggarwal, P. R. Mohapatra, P. Chikkahonnaiah
Journal: European Respiratory Journal (2014)

Risk factors for pulmonary tuberculosis in community-acquired pneumoniaTo the Editor:We read with interest the study by CAVALLAZZI et al. [1] in which authors have devised a subset of risk factors that can efficiently predict pulmonary tuberculosis (TB) in patients of community-acquired pneumonia (CAP).Although they have improvised upon existing Centers for Disease Control and Prevention (CDC) list of risk factors, the study requires discussion regarding its practical value.TB is a chronic disease with symptoms ranging from a few weeks to several months, while CAP is generally an acute process.Duration of presenting symptoms seems to be a strong factor differentiating TB from CAP, which has not been evaluated in the study.The results of the study should be interpreted with caution as they may not be universally applicable.Only 85 (1.2%) out of 6976 patients were from Asia, Africa and Australia [1], the regions that harbour an estimated 80% of incident cases of TB [2].Mantoux positivity and recent exposure to TB were found to be significant risk factors for predicting TB in their study [1].However, with 40% of the Indian population infected with Mycobacterium tuberculosis [3], its relevance seems questionable.Pulmonary TB presents with a wide spectrum of clinical and radiological features that may affect the sensitivity and specificity of its risk factors.Asymptomatic presentation, normal chest radiographs [4], lower zone disease [5], Mantoux negativity (as in immunocompromised), co-infection with bacteria and fungus, associated comorbidities like COPD are important features that can falsely shift the diagnosis away from TB.Hence, absence of TB risk factors in pneumonia should not mean ''exclusion of tuberculosis'' but should be followed by a screening sputum microscopy for acid fast bacilli, especially in areas of high disease burden.Further research is required, incorporating prospective cases from TB endemic countries, which may add new risk factors or change their hierarchy leading to better TB prediction.
Phase I and Pharmacokinetic Trial of Intraperitoneal Etoposide in Combination With the Multidrug-Resistance-Modulating Agent Dipyridamole
Authors: S. Isonishi, S. Kirmani, S. Kim, S. C. Plaxe, P. S. Braly, E. F. McClay, S. B. Howell
Journal: JNCI Journal of the National Cancer Institute (1991)

Journal Article Phase I and Pharmacokinetic Trial of Intraperitoneal Etoposide in Combination With the Multidrug-Resistance-Modulating Agent Dipyridamole Get access Seiji Isonishi, Seiji Isonishi Department of Medicine, The Cancer Center, University of CaliforniaSan Diego, La Jolla, Calif Search for other works by this author on: Oxford Academic PubMed Google Scholar Saeeda Kirmani, Saeeda Kirmani Department of Medicine, The Cancer Center, University of CaliforniaSan Diego, La Jolla, Calif Search for other works by this author on: Oxford Academic PubMed Google Scholar Sinil Kim, Sinil Kim Department of Medicine, The Cancer Center, University of CaliforniaSan Diego, La Jolla, Calif Search for other works by this author on: Oxford Academic PubMed Google Scholar Steven C. Plaxe, Steven C. Plaxe Department of Reproductive Medicine, The Cancer Center, University of CaliforniaSan Diego, La Jolla, Calif Search for other works by this author on: Oxford Academic PubMed Google Scholar Patricia S. Braly, Patricia S. Braly Department of Reproductive Medicine, The Cancer Center, University of CaliforniaSan Diego, La Jolla, Calif Search for other works by this author on: Oxford Academic PubMed Google Scholar Edward F. McClay, Edward F. McClay Department of Medicine, The Cancer Center, University of CaliforniaSan Diego, La Jolla, Calif Search for other works by this author on: Oxford Academic PubMed Google Scholar Stephen B. Howell Stephen B. Howell * Department of Medicine, The Cancer Center, University of CaliforniaSan Diego, La Jolla, Calif *Correspondenee to: Stephen B. Howell, MD, Department of Medicine 0812, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093 Search for other works by this author on: Oxford Academic PubMed Google Scholar JNCI: Journal of the National Cancer Institute, Volume 83, Issue 9, 1 May 1991, Pages 621–626, https://doi.org/10.1093/jnci/83.9.621 Published: 01 May 1991 Article history Received: 25 October 1990 Accepted: 21 February 1991 Published: 01 May 1991
Heteroclitic Immunization Induces Tumor Immunity
Authors: Ruben Dyall, Wilbur B. Bowne, Lawrence W. Weber, Joel LeMaoult, Paul Szabo, Yoichi Moroi, Gregory Piskun, Jonathan J. Lewis, Alan N. Houghton, Janko Nikolić-Žugić
Journal: The Journal of Experimental Medicine (1998)

In tumor transplantation models in mice, cytotoxic T lymphocytes (CTLs) are typically the primary effector cells. CTLs recognize major histocompatibility complex (MHC) class I–associated peptides expressed by tumors, leading to tumor rejection. Peptides presented by cancer cells can originate from viral proteins, normal self-proteins regulated during differentiation, or altered proteins derived from genetic alterations. However, many tumor peptides recognized by CTLs are poor immunogens, unable to induce activation and differentiation of effector CTLs. We used MHC binding motifs and the knowledge of class I:peptide:TCR structure to design heteroclitic CTL vaccines that exploit the expression of poorly immunogenic tumor peptides. The in vivo potency of this approach was demonstrated using viral and self-(differentiation) antigens as models. First, a synthetic variant of a viral antigen was expressed as a tumor antigen, and heteroclitic immunization with peptides and DNA was used to protect against tumor challenge and elicit regression of 3-d tumors. Second, a peptide from a relevant self-antigen of the tyrosinase family expressed by melanoma cells was used to design a heteroclitic peptide vaccine that successfully induced tumor protection. These results establish the in vivo applicability of heteroclitic immunization against tumors, including immunity to poorly immunogenic self-proteins.
Such stuff as dreams are made on? Elaborative encoding, the ancient art of memory, and the hippocampus
Authors: Sue Llewellyn
Journal: Behavioral and Brain Sciences (2013)

This article argues that rapid eye movement (REM) dreaming is elaborative encoding for episodic memories. Elaborative encoding in REM can, at least partially, be understood through ancient art of memory (AAOM) principles: visualization, bizarre association, organization, narration, embodiment, and location. These principles render recent memories more distinctive through novel and meaningful association with emotionally salient, remote memories. The AAOM optimizes memory performance, suggesting that its principles may predict aspects of how episodic memory is configured in the brain. Integration and segregation are fundamental organizing principles in the cerebral cortex. Episodic memory networks interconnect profusely within the cortex, creating omnidirectional "landmark" junctions. Memories may be integrated at junctions but segregated along connecting network paths that meet at junctions. Episodic junctions may be instantiated during non-rapid eye movement (NREM) sleep after hippocampal associational function during REM dreams. Hippocampal association involves relating, binding, and integrating episodic memories into a mnemonic compositional whole. This often bizarre, composite image has not been present to the senses; it is not "real" because it hyperassociates several memories. During REM sleep, on the phenomenological level, this composite image is experienced as a dream scene. A dream scene may be instantiated as omnidirectional neocortical junction and retained by the hippocampus as an index. On episodic memory retrieval, an external stimulus (or an internal representation) is matched by the hippocampus against its indices. One or more indices then reference the relevant neocortical junctions from which episodic memories can be retrieved. Episodic junctions reach a processing (rather than conscious) level during normal wake to enable retrieval. If this hypothesis is correct, the stuff of dreams is the stuff of memory.
Molecular Pathway for the Localized Formation of the Sinoatrial Node
Authors: Mathilda T.M. Mommersteeg, Willem M.H. Hoogaars, Owen W.J. Prall, Corrie de Gier-de Vries, Cornelia Wiese, Danielle E.W. Clout, Virginia E. Papaioannou, Nigel A. Brown, Richard P. Harvey, Antoon F.M. Moorman, Vincent M. Christoffels
Journal: Circulation Research (2007)

The sinoatrial node, which resides at the junction of the right atrium and the superior caval vein, contains specialized myocardial cells that initiate the heart beat. Despite this fundamental role in heart function, the embryonic origin and mechanisms of localized formation of the sinoatrial node have not been defined. Here we show that subsequent to the formation of the Nkx2-5 –positive heart tube, cells bordering the inflow tract of the heart tube give rise to the Nkx2-5 –negative myocardial cells of the sinoatrial node and the sinus horns. Using genetic models, we show that as the myocardium of the heart tube matures, Nkx2-5 suppresses pacemaker channel gene Hcn4 and T-box transcription factor gene Tbx3 , thereby enforcing a progressive confinement of their expression to the forming Nkx2-5 –negative sinoatrial node and sinus horns. Thus, Nkx2-5 is essential for establishing a gene expression border between the atrium and sinoatrial node. Tbx3 was found to suppress chamber differentiation, providing an additional mechanism by which the Tbx3 -positive sinoatrial node is shielded from differentiating into atrial myocardium. Pitx2c -deficient fetuses form sinoatrial nodes with indistinguishable molecular signatures at both the right and left sinuatrial junction, indicating that Pitx2c functions within the left/right pathway to suppress a default program for sinuatrial node formation on the left. Our molecular pathway provides a mechanism for how pacemaker activity becomes progressively relegated to the most recently added components of the venous pole of the heart and, ultimately, to the junction of the right atrium and superior caval vein.
Metronomic topotecan for colorectal cancer: a promising new option
Authors: Dingzhi Wang, Ofer Margalit, Raymond N DuBois
Journal: Gut (2012)

Colorectal cancer (CRC) is the second leading cause of cancer-related mortality and the fourth most common malignant neoplasm in the USA. Depending on the stage at diagnosis, liver and lung metastases occur in about 20–70% and 10–20% of patients, respectively. Unfortunately, distant metastases are the major cause of death for patients with advanced CRC. Despite use of standard therapies for metastatic CRC, treatment has only minimally improved survival, resulting in a medium survival of ∼2 years. As current chemotherapeutic drugs are used at maximum tolerated doses or high dose in standard therapies, toxicity remains a major issue for patients. Therefore, if the standard therapies could have prolonged breaks between successive cycles of drug administration, this could allow for recovery from toxic side effects. To solve this problem, Dr. Timothy Browder at Harvard Medical School first proposed metronomic chemotherapy to minimise toxicity by targeting the tumour-associated endothelium via frequent use of chemotherapeutic drugs at low doses over a longer period of time. Although the definition of metronomic chemotherapy varies, it now generally refers to the continuous administration of traditional chemotherapy, sometimes on a daily basis, at relatively low, minimally toxic doses, for longer periods. This emerging approach has been extensively evaluated in clinical trials and animal models.1 Hackl et al 2 report for the first time that metronomic oral topotecan therapy in adjuvant and metastatic settings prolongs survival and reduces liver metastasis in mouse models of metastatic CRC. Their findings provide a rational for clinical trials of metronomic oral topotecan …
Mast Cells Contribute to Peripheral Tolerance and Attenuate Autoimmune Vasculitis
Authors: Poh-Yi Gan, Shaun A. Summers, Joshua D. Ooi, Kim M. O’Sullivan, Diana S.Y. Tan, Ruth C.M. Muljadi, Dragana Odobasic, A. Richard Kitching, Stephen R. Holdsworth
Journal: Journal of the American Society of Nephrology (2012)

Mast cells contribute to the modulation of the immune response, but their role in autoimmune renal disease is not well understood. Here, we induced autoimmunity resulting in focal necrotizing GN by immunizing wild-type or mast cell-deficient (Kit(W-sh/W-sh)) mice with myeloperoxidase. Mast cell-deficient mice exhibited more antimyeloperoxidase CD4+ T cells, enhanced dermal delayed-type hypersensitivity responses to myeloperoxidase, and more severe focal necrotizing GN. Furthermore, the lymph nodes draining the sites of immunization had fewer Tregs and reduced production of IL-10 in mice lacking mast cells. Reconstituting these mice with mast cells significantly increased the numbers of Tregs in the lymph nodes and attenuated both autoimmunity and severity of disease. After immunization with myeloperoxidase, mast cells migrated from the skin to the lymph nodes to contact Tregs. In an ex vivo assay, mast cells enhanced Treg suppression through IL-10. Reconstitution of mast cell-deficient mice with IL-10-deficient mast cells led to enhanced autoimmunity to myeloperoxidase and greater disease severity compared with reconstitution with IL-10-intact mast cells. Taken together, these studies establish a role for mast cells in mediating peripheral tolerance to myeloperoxidase, protecting them from the development of focal necrotizing GN in ANCA-associated vasculitis.
An inducible mouse model for skin cancer reveals distinct roles for gain- and loss-of-function p53 mutations
Authors: Carlos Caulin, Thao Nguyen, Gene A. Lang, Thea M. Goepfert, Bill R. Brinkley, Wei-Wen Cai, Guillermina Lozano, Dennis R. Roop
Journal: Journal of Clinical Investigation (2007)

Mutations in ras and p53 are the most prevalent mutations found in human nonmelanoma skin cancers. Although some p53 mutations cause a loss of function, most result in expression of altered forms of p53, which may exhibit gain-of-function properties. Therefore, understanding the consequences of acquiring p53 gain-of-function versus loss-of-function mutations is critical for the generation of effective therapies for tumors harboring p53 mutations. Here we describe an inducible mouse model in which skin tumor formation is initiated by activation of an endogenous K-rasG12D allele. Using this model we compared the consequences of activating the p53 gain-of-function mutation p53R172H and of deleting the p53 gene. Activation of the p53R172H allele resulted in increased skin tumor formation, accelerated tumor progression, and induction of metastasis compared with deletion of p53. Consistent with these observations, the p53R172H tumors exhibited aneuploidy associated with centrosome amplification, which may underlie the mechanism by which p53R172H exerts its oncogenic properties. These results clearly demonstrate that p53 gain-of-function mutations confer poorer prognosis than loss of p53 during skin carcinogenesis and have important implications for the future design of therapies for tumors that exhibit p53 gain-of-function mutations.
Human C3 glomerulopathy provides unique insights into complement factor H–related protein function
Authors: V. Michael Holers
Journal: Journal of Clinical Investigation (2013)

The study in this issue of the JCI by Tortajada et al. demonstrates that a duplication within the gene complement factor H–related 1 (CFHR1; encoding FHR1) leads to the production of an aberrant larger form of the protein. Elegant in vitro studies of the mutant and normal variants demonstrate an unexpected mechanism of action of FHR1, wherein homodimeration and hetero-oligomerization with FHR2 and FHR5 generates more avid molecules that very effectively compete with FH binding to surfaces and impair its ability to regulate local complement activation. As variants of FHRs are linked to many human inflammatory and autoimmune diseases, these and other recently published structure/function studies of these proteins provide key insights into their complement regulatory activities and likely roles in disease.
Establishment and characterization of a megakaryoblast cell line with amplification of MLL
Authors: RJ Allen, SD Smith, RL Moldwin, M-M Lu, L Giordano, C Vignon, Y Suto, A Harden, R Tomek, T Veldman, T Ried, RA Larson, MM Le Beau, JD Rowley, N Zeleznik-Le
Journal: Leukemia (1998)
Radiographic Progression-Free Survival As a Response Biomarker in Metastatic Castration-Resistant Prostate Cancer: COU-AA-302 Results
Authors: Michael J. Morris, Arturo Molina, Eric J. Small, Johann S. de Bono, Christopher J. Logothetis, Karim Fizazi, Paul de Souza, Philip W. Kantoff, Celestia S. Higano, Jinhui Li, Thian Kheoh, Steven M. Larson, Shannon L. Matheny, Vahid Naini, Tomasz Burzykowski, Thomas W. Griffin, Howard I. Scher, Charles J. Ryan
Journal: Journal of Clinical Oncology (2015)

Progression-free survival (PFS) in metastatic castration-resistant prostate cancer (mCRPC) trials has been inconsistently defined and poorly associated with overall survival (OS). A reproducible quantitative definition of radiographic PFS (rPFS) was tested for association with a coprimary end point of OS in a randomized trial of abiraterone in patients with mCRPC.rPFS was defined as ≥ two new lesions on an 8-week bone scan plus two additional lesions on a confirmatory scan, ≥ two new confirmed lesions on any scan ≥ 12 weeks after random assignment, and/or progression in nodes or viscera on cross-sectional imaging, or death. rPFS was assessed by independent review at 15% of deaths and by investigator review at 15% and 40% of deaths. rPFS and OS association was evaluated by Spearman's correlation.A total of 1,088 patients were randomly assigned to abiraterone plus prednisone or prednisone alone. At first interim analysis, the hazard ratio (HR) by independent review was 0.43 (95% CI, 0.35 to 0.52; P < .001; abiraterone plus prednisone: median rPFS, not estimable; prednisone: median rPFS, 8.3 months). Similar HRs were obtained by investigator review at the first two interim analyses (HR, 0.49; 95% CI, 0.41 to 0.60; P < .001 and HR, 0.53; 95% CI, 0.45 to 0.62; P < .001, respectively), validating the imaging data assay used. Spearman's correlation coefficient between rPFS and OS was 0.72.rPFS was highly consistent and highly associated with OS, providing initial prospective evidence on further developing rPFS as an intermediate end point in mCRPC trials.