tbuckley/cabot-search huggingface dataset:
Overexpression of N-Myc Rapidly Causes Acute Myeloid Leukemia in Mice
Authors: Hiroyuki Kawagoe, Ayten Kandilci, Tanya A. Kranenburg, Gerard C. Grosveld
Journal: Cancer Research (2007)

Abstract N-MYC encodes a basic helix-loop-helix/leucine zipper (bHLH/LZ) transcription factor that is frequently overexpressed in human neuroblastoma. N-MYC overexpression has also been reported in human acute myeloid leukemias (AML), which we show here is a frequent event. Myeloid cells in N-Myc–overexpressing mouse bone marrow hyperproliferate but those in c-MYC–overexpressing bone marrow do not. The NH2-terminal transactivation domain, nuclear localization signal, and bHLH/LZ domain of N-Myc are essential for this effect. Microarray analysis revealed 969 differentially expressed genes between N-Myc– and c-MYC–overexpressing myeloid cells. N-Myc–overexpressing cells showed decreased transforming growth factor β signaling and increased c-Jun-NH2-kinase signaling, both of which are associated with proliferation and leukemic transformation of myeloid cells. Mice transplanted with bone marrow expressing wild-type N-Myc developed clonal and transplantable AML after ∼1 month; those transplanted with bone marrow expressing mutant N-Myc did not. Twist, a known suppressor of the p19Arf/p53 pathway, was up-regulated in all tumors. These results show that N-Myc overexpression is highly oncogenic in mouse myeloid cells and suggest that N-MYC up-regulation contributes to human myeloid leukemogenesis. [Cancer Res 2007;67(22):10677–85]
LCAT-Dependent Conversion of Preβ1-HDL into α-Migrating HDL is Severely Delayed in Hemodialysis Patients
Authors: Takashi Miida, Osamu Miyazaki, Osamu Hanyu, Yuichi Nakamura, Satoshi Hirayama, Ichiei Narita, Fumitake Gejyo, Isei Ei, Kazuyuki Tasaki, Yutaka Kohda, Takashi Ohta, Syogo Yata, Isamu Fukamachi, Masahiko Okada
Journal: Journal of the American Society of Nephrology (2003)

ABSTRACT. Preβ1-HDL is a minor HDL subfraction that acts as an efficient initial acceptor of cell-derived free cholesterol. During 37°C incubation, plasma preβ1-HDL decreases over time due to its conversion to α-migrating HDL by lecithin:cholesterol acyltransferase (LCAT). This conversion may be delayed in hemodialysis patients who have decreased LCAT activity. To clarify whether LCAT-dependent conversion of preβ1-HDL to α-migrating HDL is delayed in hemodialysis patients, preβ1-HDL concentrations were determined in 45 hemodialysis patients and 45 gender-matched control subjects before and after 37°C incubation with and without the LCAT inhibitor. It was found that the baseline preβ1-HDL concentration in hemodialysis patients was more than twice that in the controls (44.9 ± 21.4 versus 19.8 ± 6.7 mg/L apoAI; P < 0.001). After 2-h incubation, the LCAT-dependent decrease in preβ1-HDL in hemodialysis patients was about one-third of that in the controls (30 ± 27 versus 97 ± 17% of baseline; P < 0.01). The LCAT-dependent rate of decrease in preβ1-HDL levels (DRpreβ1) was the same for samples from hemodialysis patients exhibiting normal (≥1.03 mmol/L) and low HDL-cholesterol levels (32 ± 32 versus 28 ± 23% of baseline; NS). DRpreβ1 was positively correlated with LCAT activity (r = 0.617; P < 0.001). In conclusion, the LCAT-dependent conversion of preβ1-HDL to α-migrating HDL is severely delayed in hemodialysis patients. The impaired catabolism of preβ1-HDL may accelerate atherosclerosis in hemodialysis patients. E-mail: [email protected]
B cell activation and the establishment of Epstein-Barr virus latency.
Authors: E A Hurley, D A Thorley-Lawson
Journal: The Journal of Experimental Medicine (1988)

Linear EBV genomes undergo a transition to the circular form characteristic of latency by 16-20 h post-infection. This transition requires that the infected cells be activated to the G1 stage of the cell cycle. Cellular proliferation and expression of the activation marker CD23 were not required. Nevertheless, 36 h post-infection, only cells expressing CD23 contained covalently closed, circular episomes (CCC), at an average of one copy per cell. Since the presence of CD23 at this time is predictive that a cell will immortalize, we suggest that the presence of CCC is required for CD23 expression and subsequent immortalization. The one CCC present in each CD23+ cell did not undergo amplification until well after the cells had acquired all of the characteristic phenotypic markers of immortalization. Therefore, while amplification is not necessary for proliferation and immortalization, circularization of a single genome is crucial to the establishment and maintenance of latency by EBV.
Peritransplant absolute lymphocyte count as a predictive factor for advanced recurrence of hepatitis C after liver transplantation
Authors: Shunji Nagai, Atsushi Yoshida, Keisuke Kohno, David Altshuler, Mio Nakamura, Kimberly A. Brown, Marwan S. Abouljoud, Dilip Moonka
Journal: Hepatology (2013)

Lymphocytes play an active role in natural immunity against hepatitis C virus (HCV). We hypothesized that a lower absolute lymphocyte count (ALC) may alter HCV outcome after liver transplantation (LT). The aim of this study was to investigate the impact of peritransplant ALC on HCV recurrence following LT. A total of 289 LT patients between 2005 and 2011 were evaluated. Peritransplant ALC (pre-LT, 2-week, and 1-month post-LT) and immunosuppression were analyzed along with recipient and donor factors in order to determine risk factors for HCV recurrence based on METAVIR fibrosis score. When stratifying patients according to pre- and post-LT ALC (<500/μL versus 500-1,000/μL versus >1,000/μL), lymphopenia was significantly associated with higher rates of HCV recurrence with fibrosis (F2-4). Multivariate Cox regression analysis showed posttransplant ALC at 1 month remained an independent predictive factor for recurrence (P = 0.02, hazard ratio [HR] = 2.47 for <500/μL). When peritransplant ALC was persistently low (<500/μL pre-LT, 2-week, and 1-month post-LT), patients were at significant risk of developing early advanced fibrosis secondary to HCV recurrence (F3-4 within 2 years) (P = 0.02, HR = 3.16). Furthermore, severe pretransplant lymphopenia (<500/μL) was an independent prognostic factor for overall survival (P = 0.01, HR = 3.01). The use of rabbit anti-thymocyte globulin induction (RATG) had a remarkable protective effect on HCV recurrence (P = 0.02, HR = 0.6) despite its potential to induce lymphopenia. Subgroup analysis indicated that negative effects of posttransplant lymphopenia at 1 month (<1,000/μL) were significant regardless of RATG use and the protective effects of RATG were independent of posttransplant lymphopenia.Peritransplant ALC is a novel and useful surrogate marker for prediction of HCV recurrence and patient survival. Immunosuppression protocols and peritransplant management should be scrutinized depending on peritransplant ALC.
Clinical Role of microRNAs in Cytogenetically Normal Acute Myeloid Leukemia: <i>miR-155</i> Upregulation Independently Identifies High-Risk Patients
Authors: Guido Marcucci, Kati S. Maharry, Klaus H. Metzeler, Stefano Volinia, Yue-Zhong Wu, Krzysztof Mrózek, Deedra Nicolet, Jessica Kohlschmidt, Susan P. Whitman, Jason H. Mendler, Sebastian Schwind, Heiko Becker, Ann-Kathrin Eisfeld, Andrew J. Carroll, Bayard L. Powell, Jonathan E. Kolitz, Ramiro Garzon, Michael A. Caligiuri, Richard M. Stone, Clara D. Bloomfield
Journal: Journal of Clinical Oncology (2013)

To evaluate the impact of miR-155 on the outcome of adults with cytogenetically normal (CN) acute myeloid leukemia (AML) in the context of other clinical and molecular prognosticators and to gain insight into the leukemogenic role of this microRNA.We evaluated 363 patients with primary CN-AML. miR-155 levels were measured in pretreatment marrow and blood by NanoString nCounter assays that quantified the expression of the encoding gene MIR155HG. All molecular prognosticators were assessed centrally. miR-155-associated gene and microRNA expression profiles were derived using microarrays.Considering all patients, high miR-155 expression was associated with a lower complete remission (CR) rate (P < .001) and shorter disease-free survival (P = .001) and overall survival (OS; P < .001) after adjusting for age. In multivariable analyses, high miR-155 expression remained an independent predictor for a lower CR rate (P = .007) and shorter OS (P < .001). High miR-155 expressers had approximately 50% reduction in the odds of achieving CR and 60% increase in the risk of death compared with low miR-155 expressers. Although high miR-155 expression was not associated with a distinct microRNA expression profile, it was associated with a gene expression profile enriched for genes involved in cellular mechanisms deregulated in AML (eg, apoptosis, nuclear factor-κB activation, and inflammation), thereby supporting a pivotal and unique role of this microRNA in myeloid leukemogenesis.miR-155 expression levels are associated with clinical outcome independently of other strong clinical and molecular predictors. The availability of emerging compounds with antagonistic activity to microRNAs in the clinic provides the opportunity for future therapeutic targeting of miR-155 in AML.
An Essential Role of Alternative Splicing of <i>c-myc</i> Suppressor FUSE-Binding Protein–Interacting Repressor in Carcinogenesis
Authors: Kazuyuki Matsushita, Takeshi Tomonaga, Hideaki Shimada, Ayumi Shioya, Morihiro Higashi, Hisahiro Matsubara, Kenichi Harigaya, Fumio Nomura, Daniel Libutti, David Levens, Takenori Ochiai
Journal: Cancer Research (2006)

Abstract Elevated expression of c-myc has been detected in a broad range of human cancers, indicating a key role for this oncogene in tumor development. Recently, an interaction between FUSE-binding protein–interacting repressor (FIR) and TFIIH/p89/XPB helicase was found to repress c-myc transcription and might be important for suppressing tumor formation. In this study, we showed that enforced expression of FIR induced apoptosis. Deletion of the NH2-terminal repression domain of FIR rescued the cells from apoptosis as did coexpression of c-Myc with FIR; thus, repression of Myc mediates FIR-driven apoptosis. Surprisingly, a splicing variant of FIR unable to repress c-myc or to drive apoptosis was frequently discovered in human primary colorectal cancers but not in the adjacent normal tissues. Coexpression of this splicing variant with repressor-competent FIR, either in HeLa cells or in the colon cancer cell line SW480, not only abrogated c-Myc suppression but also inhibited apoptosis. These results strongly suggest the expression of this splicing variant promotes tumor development by disabling FIR repression and sustaining high levels of c-Myc and opposing apoptosis in colorectal cancer. (Cancer Res 2006; 66(3): 1409-17)
ENZYMATIC METHYLATION OF ARSENIC SPECIES AND OTHER NEW APPROACHES TO ARSENIC TOXICITY
Authors: H. Vasken Aposhian
Journal: The Annual Review of Pharmacology and Toxicology (1997)

Arsenic metabolism has typically been studied by administering arsenate or arsenite into animals and humans and then studying the metabolites excreted in the urine. Although such studies have yielded information about the beginning and the end of the metabolic pathways for the metabolism of inorganic arsenic compounds, any statements as to the molecular mechanisms of these reactions have had to be highly speculative. Now that the rabbit and the rhesus monkey liver enzymes that transfer methyl groups from S-adenosylmethionine to arsenite and monomethlyarsonic acid have been purified and the reactions characterized, meaningful investigations of species diversity and polymorphism of these enzymes have become possible. New World animals studied thus far appear to be deficient in or totally lacking these enzymes. Old World animals, with the exception of the chimpanzee, have ample amounts of arsenite and monomethylarsonic acid methyltransferases. A hypothesis that the lack of arsenite methyltransferases may have had an evolutionary advantage for certain species is proposed.
<i>BJSM:</i>Serving national sports medicine and sports physiotherapy societies and major international sporting organisations
Authors: Karim M Khan
Journal: British Journal of Sports Medicine (2014)

BJSM's 22 annual issues and terabytes of digital media content have a clear mandate-to serve clinicians who work in the broad field of 'sports and exercise medicine'.The term 'medicine' includes the wide health community including many kinds of practitioners including physiotherapists, doctors, athletic trainers, personal trainers, etc.The journal should serve everyone who aims to improve health through preventing injury and promoting physical activity in an ethical manner.Sports injury and illness prevention, treatment and health promotion through physical activity are core business.Thirteen national clinical organisations that themselves serve sports medicine/ sports physiotherapy currently provide BJSM as a member benefit.Clinicians from South Africa to the Arctic Circle and from Zurich to Los Angeles/Waikiki access the journal online through their member websites (http://bjsm.bmj.com/site/about/).BJSM is accessed over 3.8 million times annually-10 000 hits a day, every day and going up.
Influence of non-inherited maternal HLA-DR antigens on susceptibility to rheumatoid arthritis
Authors: I E van der Horst-Bruinsma, J M W Hazes, G M T. Schreuder, T R D J Radstake, P Barrera, L B A van de Putte, D Mustamu, D van Schaardenburg, F C Breedveld, R R P de Vries
Journal: Annals of the Rheumatic Diseases (1998)

It has recently been observed that non-inherited maternal DR4 antigens (NIMAs) of DR4 negative rheumatoid arthritis (RA) patients were increased compared with non-inherited paternal DR4 antigens (NIPAs). The aim of this study was to determine the prevalence of non-inherited DR4 antigens and DRB1 alleles in parents of RA patients.HLA-DR serology and DRB1 typing was performed in 97 RA patients and their parents. NIMA and NIPA frequencies were compared, stratified according to the presence of DR4 and/or the shared epitope (SE).In DR4 negative patients, NIMA DR4 was increased compared with NIPA DR4 (OR 3.10, 95% CI 0.76, 12.70). When combined with results from a previous study this increase was significant (OR 3.65, 95% CI 1.29, 10.31). The NIMA effect of SE positive DR4 subtypes in this study (OR 4.73, 95% CI 0.94, 23.8) was stronger than the NIMA effect of combined SE positive DRB1 alleles (OR 2.19 95% CI 0.36, 13.22).The association between non-inherited maternal HLA-DR4 alleles and the susceptibility to RA was observed in two independent populations.
High HER2 Expression Correlates with Response to the Combination of Lapatinib and Trastuzumab
Authors: Maurizio Scaltriti, Paolo Nuciforo, Ian Bradbury, Jeff Sperinde, Dominique Agbor-Tarh, Christine Campbell, Ahmed Chenna, John Winslow, Violeta Serra, Josep Lluis Parra, Ludmila Prudkin, José Jimenez, Claudia Aura, Nadia Harbeck, Lajos Pusztai, Catherine Ellis, Holger Eidtmann, Joaquin Arribas, Javier Cortes, Evandro de Azambuja, Martine Piccart, José Baselga
Journal: Clinical Cancer Research (2014)

Abstract Purpose: Expression of p95HER2 has been associated with resistance to trastuzumab-based therapy in patients with metastatic breast cancer. Conversely, high levels of HER2 have been linked with increased clinical benefit from anti-HER2 therapy. In this work, we aimed to investigate whether the levels of p95HER2 and HER2 can predict response to anti-HER2 therapy in patients with breast cancer. Experimental Design: We measured p95HER2 and HER2 by VeraTag and HERmark, respectively, in primary tumors of patients enrolled in the neoadjuvant phase III study NeoALTTO and correlated these variables with pathologic complete response (pCR) and progression-free survival (PFS) following lapatinib (L), trastuzumab (T), or the combination of both agents (L+T). Results: A positive correlation between p95HER2 and HER2 levels was found in the 274 cases (60%) in which quantification of both markers was possible. High levels of these markers were predictive for pCR, especially in the hormone receptor (HR)–positive subset of patients. High HER2 expression was associated with increased pCR rate upon L+T irrespective of the HR status. To examine whether the levels of either p95HER2 or HER2 could predict for PFS in patients treated with lapatinib, trastuzumab or L+T, we fit to the PFS data in Cox models containing log2(p95HER2) or log2(HER2). Both variables correlated with longer PFS. Conclusions: Increasing HER2 protein expression correlated with increased benefit of adding lapatinib to trastuzumab. HER2 expression is a stronger predictor of pCR and PFS than p95HER2 for response to lapatinib, trastuzumab and, more significantly, L+T. Clin Cancer Res; 21(3); 569–76. ©2014 AACR.
Unusual Case of an Intramyocardial Tumor Presenting With a Ventricular Tachycardia
Authors: Laura Domínguez-Pérez, Miguel A. Arias, Justo Juliá-Calvo, Sonia Bartolomé-Mateos, Belén Santos-González, Teresa Colchero, Jesús Jiménez-López, Marta Pachón, Luis Rodríguez-Padial
Journal: Circulation (2012)
Transplantation of transduced chondrocytes protects articular cartilage from interleukin 1-induced extracellular matrix degradation.
Authors: V M Baragi, R R Renkiewicz, H Jordan, J Bonadio, J W Hartman, B J Roessler
Journal: Journal of Clinical Investigation (1995)

Gene therapy used in the context of delivering a therapeutic gene(s) to chondrocytes offers a new approach for treating chondrocyte-mediated cartilage degradation associated with various human arthropathies including osteoarthritis. In this study, gene delivery to human osteoarthritis chondrocytes in monolayer culture was demonstrated using two adenoviral vectors (Ad.CMVlacZ and Ad.RSVntlacZ) carrying the Escherichia coli beta-galactosidase marker gene, and a third vector (Ad.RSV hIL-1ra) containing the cDNA for human interleukin-1 receptor antagonist. At an moi of 10(3) plaque-forming units/chondrocyte, > 90% of the infected cells stained positive for E. coli beta-galactosidase activity, indicating a high efficiency of transduction. Genetically modified chondrocytes were then transplanted onto the articular surface of osteoarthritic cartilage organ cultures with and without the underlying subchondral bone. Both in situ staining of the cartilage organ cultures for E. coli beta-galactosidase activity and examination by scanning electron microscopy indicated that the transplanted chondrocytes adhered and integrated into the articular surface and continued to express transgenic protein. Chondrocytes transduced with Ad.RSV hIL-1ra and seeded onto the surface of osteoarthritic cartilage secreted high levels of biologically active IL-1 receptor antagonist. The Ad.RSV hIL-1ra-treated cartilage samples were resistant to IL1-induced proteoglycan degradation over 10 d of sustained organ culture. These data demonstrate that transplantation of transduced chondrocytes onto the articular surface protects cartilage from IL-1-induced extracellular matrix degradation.
Annotate-it: a Swiss-knife approach to annotation, analysis and interpretation of single nucleotide variation in human disease
Authors: Alejandro Sifrim, Jeroen KJ Van Houdt, Leon-Charles Tranchevent, Beata Nowakowska, Ryo Sakai, Georgios A Pavlopoulos, Koen Devriendt, Joris R Vermeesch, Yves Moreau, Jan Aerts
Journal: Genome Medicine (2012)

The increasing size and complexity of exome/genome sequencing data requires new tools for clinical geneticists to discover disease-causing variants. Bottlenecks in identifying the causative variation include poor cross-sample querying, constantly changing functional annotation and not considering existing knowledge concerning the phenotype. We describe a methodology that facilitates exploration of patient sequencing data towards identification of causal variants under different genetic hypotheses. Annotate-it facilitates handling, analysis and interpretation of high-throughput single nucleotide variant data. We demonstrate our strategy using three case studies. Annotate-it is freely available and test data are accessible to all users at http://www.annotate-it.org .
The consequences of treatment and disease in patients with primary CNS non-Hodgkin's lymphoma: Cognitive function and performance status
Authors: Brian P. O'Neill, Chiao-Hua Wang, Judith R. O'Fallon, Joseph P. Colgan, John D. Earle, Robert L. Krigel, Loren D. Brown, William J. McGinnis
Journal: Neuro-Oncology (1999)

Per protocol, patients with primary CNS non-Hodgkin's lymphoma in an intergroup phase II trial conducted by the North Central Cancer Treatment Group and the Eastern Cooperative Oncology Group had their cognitive functions measured using the Folstein and Folstein Mini-Mental Status Examination (MMSE) and their physical functions measured using the Eastern Cooperative Oncology Group Performance Score (PS) at study entry, at each treatment evaluation, and at quarterly intervals thereafter until disease progression or death. Of the 53 eligible participants who began therapy, 46 (87%) had baseline MMSE scores recorded, 36 (68%) had at least one follow-up MMSE, and 32 (60%) had both, while 52 (98%) had baseline PS, 49 (92%) had at least one follow-up PS, and 48 (91%) had both. Patterns of MMSE and PS values over time were studied in each individual, in the group as a whole, in the 20 patients who completed the study regimen, in the 23 who survived more than a year, and in patients who were classified as nonprogressors at each key evaluation. For each patient, all recorded values were plotted versus time, with dates of disease progression and death included, to look for signs of decline in cognitive or physical function preceding adverse events. Long-term declines in scores of both cognitive and physical function were observed in many treated patients with primary CNS non-Hodgkin's lymphoma. Nearly all patients who were alive more than 52 weeks after study entry had a demonstrable decline in cognitive and physical functionality. Such declines may occur before disease progression is documented; they may also occur in some patients who have long-term follow-up without evidence of disease progression. Declining MMSE and PS was a poor predictor of disease progression. There was no association of PS and toxicity. The data from this study demonstrated the considerable difficulties we encountered conducting an ancillary study such as this within a multicenter clinical trial. Firstly, the test instruments written into the protocol were unable to tell if the declines seen were due to disease, treatment, co-morbidity, or other factors. Secondly, the missing data created difficulties in interpreting outcome.
Identification of Naturally Occurring Fatty Acids of the Myelin Sheath That Resolve Neuroinflammation
Authors: Peggy P. Ho, Jennifer L. Kanter, Amanda M. Johnson, Hrishikesh K. Srinagesh, Eun-Ju Chang, Timothy M. Purdy, Keith van Haren, William R. Wikoff, Tobias Kind, Mohsen Khademi, Laura Y. Matloff, Sirisha Narayana, Eun Mi Hur, Tamsin M. Lindstrom, Zhigang He, Oliver Fiehn, Tomas Olsson, Xianlin Han, May H. Han, Lawrence Steinman, William H. Robinson
Journal: Science Translational Medicine (2012)

Myelin fatty acids resolve neuroinflammation.