tbuckley/cabot-search huggingface dataset:
Identification of novel mutations in hemochromatosis genes by targeted next generation sequencing in Italian patients with unexplained iron overload
Authors: Sadaf Badar, Fabiana Busti, Alberto Ferrarini, Luciano Xumerle, Paolo Bozzini, Paola Capelli, Roberto Pozzi‐Mucelli, Natascia Campostrini, Giovanna De Matteis, Sergio Marin Vargas, Alejandro Giorgetti, Massimo Delledonne, Oliviero Olivieri, Domenico Girelli
Journal: American Journal of Hematology (2016)

Hereditary hemochromatosis, one of the commonest genetic disorder in Caucasians, is mainly associated to homozygosity for the C282Y mutation in the HFE gene, which is highly prevalent (allele frequency up to near 10% in Northern Europe) and easily detectable through a widely available “first level” molecular test. However, in certain geographical regions like the Mediterranean area, up to 30% of patients with a HH phenotype has a negative or non‐diagnostic ( i.e . simple heterozygosity) test, because of a known heterogeneity involving at least four other genes ( HAMP , HJV , TFR2 , and SLC40A1 ). Mutations in such genes are generally rare/private, making the diagnosis of atypical HH essentially a matter of exclusion in clinical practice (from here the term of “non‐HFE” HH), unless cumbersome traditional sequencing is applied. We developed a Next Generation Sequencing (NGS)‐based test targeting the five HH genes, and applied it to patients with clinically relevant iron overload (IO) and a non‐diagnostic first level genetic test. We identified several mutations, some of which were novel ( i.e. HFE W163X, HAMP R59X, and TFR2 D555N) and allowed molecular reclassification of “non‐HFE” HH clinical diagnosis, particularly in some highly selected IO patients without concurring acquired risk factors. This NGS‐based “second level” genetic test may represent a useful tool for molecular diagnosis of HH in patients in whom HH phenotype remains unexplained after the search of common HFE mutations. Am. J. Hematol. 91:420–425, 2016. © 2016 Wiley Periodicals, Inc.
Abstract 1101: Reexpression of hSNF5 regulates the transcriptional activity of the <i>p21</i> promoter through p53 dependent or independent mechanisms in malignant rhabdoid tumors
Authors: Yasumichi Kuwahara, Aubri Charboneau, Erik S. Knudsen, Bernard E. Wissman
Journal: Cancer Research (2010)

Abstract Malignant rhabdoid tumor (MRT), a highly aggressive cancer of young children, displays inactivation of the hSNF5 gene in primary tumors and cell lines. We have previously reported that reexpression of hSNF5 in MRT cell lines causes a G1 arrest via p21WAF1/CIP1 (p21) mRNA induction. However, the mechanisms of p21 promoter activation by hSNF5 remain unclear. Because p21 is a transcriptional target of the p53 tumor suppressor gene, we determined the role of p53 in hSNF5-induced p21 activation. We reexpressed hSNF5 in the A204 and TTC642 MRT cell lines, with or without stable knockdown of p53 expression, using adenoviral vectors expressing either hSNF5 and GFP or GFP. While loss of p53 expression significantly inhibited p21 transcriptional activity induced by hSNF5 in A204 cells at 24 hours, it did not alter its activity by hSNF5 after 24 hours in the TTC642 cells. These results suggested that the up-regulation p21 transcription by hSNF5 operated through p53-dependent and -independent mechanisms in the A204 and TTC642 cell lines, respectively. Next, we used chromatin immunoprecipitation (ChIP) analysis of the p21 promoter to determine where hSNF5 appeared at the p21 promoter and whether its recruitment altered binding of other transcription factors or the chromatin landscape. Our results indicated that reexpressed hSNF5 binds within 1 kb of transcript start site (TSS), with maximal enrichment at the TSS in both cell lines. Furthermore, histone acetyltransferases (HATs), RNA polymerase II (RNAPII), and BRG-1 are assembled with p53 and CDK8 (co-activator of p53 transcriptional program) by reexpression of hSNF5 in A204 cells. In contrast, while p53 and CDK8 occupancy did not change after hSNF5 reexpression in the TTC642 cells, HATs, RNAPII, and BRG-1 levels increased at the p21 promoter. These findings correlated with the results of p53 knock-down experiments. Furthermore, histone H3K36 tri-methylation increased downstream of the TSS in both cell lines. These results suggested hSNF5 regulates the initiation activity of the p21 promoter by either itself or p53 recruitment, resulting in the mRNA elongation. Our findings demonstrate that while induction of p21 transcription by hSNF5 in A204 cells depends on p53, it occurs independently of p53 in TTC642 cells. The lack of dependence upon p53 appears to extend to other MRT cell lines tested in our laboratory. Furthermore, our results suggest that hSNF5 may alter p21 transcriptional initiation by itself or through the recruitment of other uncharacterized transcription factors. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1101.
Occupational Respiratory Diseases
Authors: William S. Beckett
Journal: New England Journal of Medicine (2000)

Materials inhaled in the workplace can lead to all the major chronic lung diseases except those due to vascular disease. The physician should consider the possibility of occupational exposure when a working or retired adult presents with unexplained respiratory illness. Even exposure in office buildings1 and hospitals2 occasionally causes illness. Identifying a workplace-related cause of disease is important because it can lead to cure and to prevention for others. Because of differences in the metabolism and susceptibility of hosts, one occupational agent may cause many diseases, just as cigarette smoke causes several distinct disorders. Conversely, one respiratory disease may have . . .
Schmorl’s Node Mimicking Metastasis in a Patient With Breast Cancer
Authors: Harmandeep Singh, Punit Sharma, Niraj Naswa, Aftab Hasan Nazar, Bangkim Chandra Khangembam, Manas Kumar Sahoo, Rakesh Kumar
Journal: Clinical Nuclear Medicine (2012)

Schmorl's node (SN) is a common entity characterized by protrusion of intervertebral disc material through a break in the subchondral end plate of a vertebral body. They can show increased 99mTC methylene diphosphonate uptake on bone scintigraphy mimicking metastasis and can be symptomatic. Differentiation of SN from metastasis is essential for appropriate patient management. Here, we present a case where increased 99mTC methylene diphosphonate uptake in a dorsal vertebra was found to be because of SN by using single-photon emission computed tomography-computed tomography.
Abstract P1-05-05: Podocalyxin is a key regulator of breast cancer progression and metastasis.
Authors: KA Snyder, MR Hughes, M Graves, C Roskelly, KM McNagny
Journal: Cancer Research (2012)

Abstract Podocalyxin (gene name Podxl) is a CD34-related sialomucin that has been shown to be important in regulating cell adhesion, migration, and polarity of hematopoietic progenitors and vascular endothelia. In breast cancer, we have shown that podocalyxin is overexpressed on a subset of node-negative tumors and its expression is strongly associated with poor overall survival. To determine whether podocalyxin directly regulates breast cancer cell behavior, we ectopically expressed podocalyxin in the human breast cancer cell line, MCF7, which expresses low levels of endogenous podocalyxin, is minimally invasive, and non-metastatic. Upon ectopic expression of podocalyxin, MCF7 “bulge apically”, produce apical and lateral microvilli, are less adhesive in vitro, and are delayed in targeting integrins to the basolateral surface. In contrast to MCF7, MDA-MB-231 is a basal-like breast cancer cell-line, which expresses high levels of endogenous podocalyxin, exhibits poorly polarized monolayer and mammosphere architecture in vitro and forms “metastatic” lung tumors in vivo. Using Podxl-targeted shRNA vectors we show that expression of podocalyxin is required for MDA-MB-231 cells to form distant metastases in a competitive in vivo assay utilizing humanized NOD/SCIDIL-2rγ−/− (NSG) mice. Previously, we observed that Podxl-deficient hematopoietic cells have impaired CXCR4-mediated chemotaxis to CXCL12, a known axis for tumor metastasis. Our current hypothesis is that podocalyxin regulates chemotaxis of tumor-initiating cells (TICs) to the CXCL12-rich tissues of the lungs, liver, and bone marrow. Up-regulation of podocalyxin on breast cancer cells may be a key event in tumor progression and likely enables these cells to sense chemokines and metastasize to peripheral sites. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P1-05-05.
Government Agencies Assess Expenses
Authors: N. Volkers
Journal: JNCI Journal of the National Cancer Institute (1992)

Journal Article Government Agencies Assess Expenses Get access Nancy Volkers Nancy Volkers Search for other works by this author on: Oxford Academic PubMed Google Scholar JNCI: Journal of the National Cancer Institute, Volume 84, Issue 5, 4 March 1992, Pages 296–297, https://doi.org/10.1093/jnci/84.5.296 Published: 04 March 1992
Abstract 2224: Next-generation sequencing and bioinformatics analysis identified up-regulation of TGFBI and SOX4 in human glioblastoma
Authors: Biaoyang Lin, Anup Madan, Xuefeng Fang, Jae-Geun Yoon, Gregory Foltz
Journal: Cancer Research (2010)

Abstract A comprehensive network-based understanding of molecular pathways abnormally altered in glioblastoma multiforme (GBM) is essential for developing effective therapeutic approaches for this deadly disease. Applying a next generation sequencing technology, massively parallel signature sequencing (MPSS), we identified a total of 4535 genes that are differentially expressed between normal brain and GBM tissue. The expression changes of three up-regulated genes, CHI3L1, CHI3L2, and FOXM1, and two down-regulated genes, neurogranin and L1CAM, were confirmed by quantitative PCR. Of note, pathway analysis revealed that TGF- β was significantly up-regulated in GBM tumor samples. An integrative pathway analysis of the TGF β signaling network identified two novel TGF—β signaling pathways mediated by SOX4 (sex determining region Y-box 4) and TGFBI (transforming growth factor beta 1 induced). Quantitative RT-PCR and immunohistochemistry staining showed that their expressions are elevated in GBM tissues compared with normal brain tissues at RNA and protein levels. In vitro functional studies confirmed that TGFBI and SOX4 expression is increased by TGF- β stimulation and decreased by a specific inhibitor of TGF- β receptor 1 kinase. The comprehensive identification of genes involved in TGF- β signaling provides further insight into GBM biology and novel therapeutic targets for further investigation. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2224.
More HOPE for Prevention with Statins
Authors: William C. Cushman, David C. Goff
Journal: New England Journal of Medicine (2016)

In view of the worldwide burden of cardiovascular disease and the high cost of and poor adherence to medication regimens for the prevention of cardiovascular disease, the concept of a "polypill" — a single pill that combines several medications — is an attractive public health approach. However, evidence that each component of a polypill would independently reduce the risk of cardiovascular events and that the combination of agents would be safe is lacking. The primary results of the Heart Outcomes Prevention Evaluation (HOPE)–3 trial are now reported in three articles in the Journal.13 HOPE-3 was a double-blind, randomized, . . .
OUTCOMES IN OUTPATIENTS WITH HEART FAILURE AND PRESERVED EJECTION FRACTION
Authors: Vasiliki Georgiopoulou, Gregory Burkman, Taylor A. Lebeis, Kanwal Farooq, Akash Patel, Song Li, Mariyah Yazdani, Nikolaos Spilias, Javed Butler, Andreas Kalogeropoulos
Journal: Journal of the American College of Cardiology (2015)
The Treatment of Kawasaki Syndrome with Intravenous Gamma Globulin
Authors: Jane W. Newburger, Masato Takahashi, Jane C. Burns, Alexa S. Beiser, Kyung Ja Chung, C. Elise Duffy, Mary P. Glode, Wilbert H. Mason, Venudhar Reddy, Stephen P. Sanders, Stanford T. Shulman, James W. Wiggins, Raquel V. Hicks, David R. Fulton, Alan B. Lewis, Donald Y.M. Leung, Theodore Colton, Fred S. Rosen, Marian E. Melish
Journal: New England Journal of Medicine (1986)

We compared the efficacy of intravenous gamma globulin plus aspirin with that of aspirin alone in reducing the frequency of coronary-artery abnormalities in children with acute Kawasaki syndrome in a multicenter, randomized trial. Children randomly assigned to the gamma globulin group received intravenous gamma globulin, 400 mg per kilogram of body weight per day, for four consecutive days; both treatment groups received aspirin, 100 mg per kilogram per day, through the 14th day of illness, then 3 to 5 mg per kilogram per day. Two-dimensional echocardiograms were interpreted blindly and independently by two or more readers. Two weeks after enrollment, coronary-artery abnormalities were present in 18 of 78 children (23 percent) in the aspirin group, as compared with 6 of 75 (8 percent) in the gamma globulin group (P = 0.01). Seven weeks after enrollment, abnormalities were present in 14 of 79 children (18 percent) in the aspirin group and in 3 of 79 (4 percent) in the gamma globulin group (P = 0.005). No child had serious adverse effects from receiving gamma globulin. We conclude that high-dose intravenous gamma globulin is safe and effective in reducing the prevalence of coronary-artery abnormalities when administered early in the course of Kawasaki syndrome.
AB0219 The relationship between the pinch strength and functional status in the patients with rheumatoid arthritis: a controlled study
Authors: E. Durmus, N. Paker, D. Bugdayci
Journal: Annals of the Rheumatic Diseases (2013)

<h3>Background</h3> Grip strength decrases and functional status impairs because of the arthritis and pain in the wrist and hand joints, decrased muscle strength in RA. <h3>Objectives</h3> The aim of this study was to investigate the relationship between the pinch strength and functional status in patients with rheumatoid arthritis (RA) and to compare the results with that of controls’. <h3>Methods</h3> Forty patients with RA were included in this study. Control group consisted age and sex matched 40 healty individuals. Grip strength and pinch strength were evaluated by Jamar dynamometer in all patients. Disease activity (DAS 28) was used for the assessment of disease activity. Hand functions were evaluated by using Duruöz Hand Index (DHI). Health Assessment Questionnaire (HAQ) was used for the evaluation activities of dailiy living. <h3>Results</h3> Mean grip strength in RA and control group was 16.9 ± 6.98 kg and 23.16 ± 9.32 kg, respectively. Mean pinch strengthin RA and control group was 4.87 ± 1.78 kg and 6.35 ± 2.16 kg, respectively. Both grip strength and pinch strengthwas lower in the RA group than that of the controls’ (p&lt;0.05). There was a statistically significant weak negative correlation between the grip strength and disease activity in RA (p=0.045). A moderate negative relationship between the pinch strength and disease activity was found in the patient group (p=0.002). Pinch strength was correlated positively with the HAQ and DHI scores in RA (p=0.002, r=0.478, p=0.006, r=0.429). <h3>Conclusions</h3> As a result, pinch strength was lower in patients with RA. In this study pinch strength were found to be correlated with the functional status in RA. Moreover, pinch strength corelated positively with disease activity. Decreased pinch strength indicates the impairment in the daily living activities and functional status. <h3>Disclosure of Interest</h3> None Declared
Abstract 643: Targeting cancer with a selective ATP-mimetic inhibitor of polo like kinase-2
Authors: Shashidhar S. Jatiani, Stephen C. Cosenza, Vinay K. Billa, M.V. Ramana Reddy, E Premkumar Reddy
Journal: Cancer Research (2011)

Abstract The Polo like kinases play key roles in mitosis. While the upregulation of PLK1 in cancer is well documented and PLK3 has been demonstrated to be a tumor suppressor, little is known about the oncogenic significance of PLK2. PLK2 kinase activity is essential for centriolar duplication and is also believed to play a regulatory role in the survival pathway by physically stabilizing the TSC1/2 complex in tumor cells under hypoxic conditions. Protein tyrosine hyper-phosphorylation and the upregulation of serine/threonine kinases associated with cell cycle progression have been linked to the etiology of cancer. In our attempt to develop ATP-mimetic compounds that are cytotoxic against a panel of cancer cell lines, we identified several sulfonyl pyridopyrimidines that possess nanomolar activity. The most potent of these compounds, ON1231320, was found to be a specific PLK2 inhibitor when profiled against a panel of 288 wild-type, 55 mutant and 12 special kinases. Further in vitro testing revealed that ON1231320 is a selective inhibitor of PLK2 with no inhibitory activity against PLK1, PLK3 and PLK4. Confirmation of this interaction and its selectivity was obtained from pull down studies using lysates of tumor cells and a biotinylated analog of ON1231320. The cytotoxic effect of the drug is mediated by apoptosis as evidenced by the induction of Caspase 3/7 activity and by the cleavage of PARP in a dose dependent manner. ON1231320 affects cell cycle progression by blocking tumor cells in the G2/M phase however it does not affect normal human fibroblasts. ON123120 exhibits an excellent safety profile with no overt signs of toxicity, no loss of body weight and 100% survival in mice given a single peritoneal dose of 200 mg/kg. Our ongoing efforts include efficacy studies in nude mouse models, identification of the structural determinants of the interaction between ON1231320 and PLK2 by computational and crystallographic methods and the identification of novel PLK2 substrates to elucidate its role in cancer biology. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 643. doi:10.1158/1538-7445.AM2011-643
Abstract LB-188: Chk1 suppresses bypass of mitosis and tetraploidization in p53-deficient cells
Authors: Deborah F. Wilsker, Jon H. Chung, Fred Bunz
Journal: Cancer Research (2011)

Abstract Many checkpoint-deficient cancer cells are unable to maintain a numerically stable chromosome complement. The Chk1 kinase has a well-established role in the DNA damage checkpoint responses and is also essential for viability; however little is known about its role throughout the unperturbed cell cycle. Here, we rigorously examine the role of Chk1 in the maintenance of cell ploidy and mitotic progression. Using recombinant adeno-associated virus-based gene targeting techniques, we disrupted one allele of CHK1 in human cancer cell lines that are proficient or deficient for the tumor suppressor p53. We assessed ploidy by fluorescence in situ hybridization and metaphase chromosome analysis, and examined cell cycle progression by live cell time-lapse fluorescent microscopy, DNA labeling, flow cytometry and biochemical analysis. Loss of one CHK1 allele caused an elevated frequency of mitotic bypass in p53-deficient cells. CHK1-haploinsufficient, p53-deficient cells frequently underwent sequential rounds of DNA synthesis without an intervening mitosis, which caused whole genome endoreduplication and tetraploidization. CHK1 haploinsufficient cells exhibited reduced Cdk1 activity, which has been shown to lead to the bypass of mitosis. This mitotic bypass phenotype could be suppressed by targeted reversion of a p53 mutation or by exogenous Cdk1 expression. Interestingly, the rate of mitotic bypass was independent of upstream signaling by ATR to Chk1 and was not associated with DNA damage. These findings demonstrate a previously unrecognized role for Chk1 in promoting the initiation of mitosis during the cancer cell cycle and thereby maintaining ploidy. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr LB-188. doi:10.1158/1538-7445.AM2011-LB-188
Presacral Hematopoietic Tissue: Correlation of Radionuclide and MRI Findings
Authors: PRASANTA KARAK, KAMAL C. SHOUKRI, RICHARD P. SPENCER, HARRY H. CHEN, JOHN A. VENTO
Journal: Clinical Nuclear Medicine (1998)

A 68-year-old woman with evidence of vertebral compression underwent MRI that revealed a presacral mass; the area enhanced on gadolinium administration. Biopsy of the mass and the vertebra revealed blood and hematopoietic cells. Tc-99m-sulfur colloid image confirmed extramedullary hematopoiesis. The patient did not have a hemoglobinopathy, and could have an occult malignancy.
Radiation Damage to Normal Tissues in the Diagnosis and Treatment of Nonmalignant Conditions and Its Surgical Repair
Authors: Ernest M. Daland
Journal: New England Journal of Medicine (1951)

IRRADIATION in the form of either radium, x-ray or isotopes, is a valuable procedure in the treatment of disease. It is not, however, without its dangers and should always be administered by an expert. In its early days the dangers to the operator and to the patient were not recognized. Today the expert does recognize them, and the men receiving training under him are warned of them. In a search to discover all the possible benefits of irradiation countless conditions were subjected to treatment, and in many it was found of no value. The present generation should have learned of . . .