tbuckley/cabot-search huggingface dataset:
Serum Ferritin as a Possible Marker of the Hemochromatosis Allele
Authors: Carole Beaumont, Marcel Simon, Renée Fauchet, Jean-Pierre Hespel, Pierre Brissot, Bernard Genetet, Michel Bourel
Journal: New England Journal of Medicine (1979)

To determine whether a correlation exists between the biochemical expression of hemochromatosis and the HLA genotype, we studied 174 family members of 32 persons with the disease. Persons who shared both HLA haplotypes with the proband (and presumably having two hemochromatosis alleles) differed significantly from those who shared only one haplotype (and presumably having one hemochromatosis allele) in terms of serum iron (P less than 0.001 for both sexes), unsaturated iron-binding capacity (P less than 0.01 for female and P less than 0.0001 for male subjects) and serum ferritin (P less than 0.0001 for female and P less than 0.00001 for male subjects). The only significant difference between relatives having one hemochromatosis allele and age and sex-matched controls was related to serum ferritin values in male subjects (P less than 0.05, despite considerable overlap). In our hands, serum ferritin was the best indicator of disordered iron metabolism and was elevated among most homozygous but among few heterozygous family members.
ALDH2 Polymorphism In Japanese Children With Acquired Aplastic Anemia
Authors: Nozomu Kawashima, Atsushi Narita, Xinan Wang, Yinyan Xu, Hirotoshi Sakaguchi, Sayoko Doisaki, Hideki Muramatsu, Asahito Hama, Koji Nakanishi, Yoshiyuki Takahashi, Seiji Kojima
Journal: Blood (2013)
Activity of the CD20-directed monoclonal antibody GA101 relative to rituximab in Waldenstrom's macroglobulinemia (WM), and applicability to patients expressing FcγRIIIA-158 F/F.
Authors: G. Yang, P. Gong, L. Xu, Z. R. Hunter, Y. Zhou, X. Liu, Y. Cao, B. Ciccarelli, C. J. Patterson, S. P. Treon
Journal: Journal of Clinical Oncology (2010)

8112 Background: Rituximab alone and in combination is an important mainstay of therapy in WM. Rituximab interacts with Fcγ receptors whose binding is largely influenced by polymorphisms in FcγRIIIA-158. Polymorphisms in FcγRIIIA-158 predict overall response to rituximab alone, as well as attainment of VGPR or CR with rituximab combination therapy in WM. Patients expressing V/V or V/F at FcγRIIIA-158 show improved outcomes versus F/F. We therefore have sought novel antibodies which can improve outcomes for patients expressing FcγRIIIA-158-F/F. GA101 is a novel humanized anti-CD20 antibody with a glyco-engineered Fc receptor domain that exhibits increased FcγRIIIA binding. Methods: We examined ADCC activity for GA101 versus rituximab using 1) healthy donor derived NK cells which were genotyped for polymorphic expression at FcγRIIIA-158 against BCWM.1 cells; as well as autologous NK cells which were genotyped against WM patient LPCs. Results: These studies showed a 2.88, 1.88, and 1.22 fold increase in ADCC activity by healthy donor NK cells expressing FcγRIIIA-158 F/F, V/F, and V/V, respectively, against BCWM.1 WM cells for GA101 versus rituximab. Moreover, ADCC activity was enhanced by 1.98, 1.37 and 1.38 fold for autologous NK cells expressing FcγRIIIA-158 F/F, V/F, and V/V, respectively against WM LPCs. In addition, we also observed direct cytotoxicity against BCWM.1 and primary WM patient LPCs by GA101; in comparison, little or no direct apoptotic activity was observed by rituximab. Western blot analysis showed no activation of caspases 3, 6, 7, 9 in GA101 treated BCWM.1 cells, though nuclear translocation of apoptosis inducing factor (AIF) was observed by immunofluorescence microscopy. Conclusions: GA101 is associated with enhanced ADCC activity relative to rituximab by NK cells, particularly those expressing FcγRIIIA-158 F/F. In addition, GA101 initiates direct cell death in WM LPCs through a caspase independent manner. These studies provide the framework for the investigation of GA101 in WM, and suggest potential benefit for those patients who express FcγRIIIA-158 F/F. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Biogen Idec, Celgene, Genetic Technologies, Millennium Biogen Idec, Celgene, Millennium Celgene, Millennium
Occurrence of Acute Wernicke's Encephalopathy during Prolonged Starvation for the Treatment of Obesity
Authors: Ernst J. Drenick, Claricia B. Joven, Marion E. Swendseid
Journal: New England Journal of Medicine (1966)

THE more liberal use of prolonged starvation in the treatment of obesity has posed a number of questions regarding the metabolic requirements of body tissues under these conditions. The need for vitamin supplementation has not been studied adequately as yet.It has been held that total fasting does not result in vitamin B1 deficiency because vitamin need and vitamin excretion diminish after a few days.1 2 3 Ziporin et al.4 have postulated that thiamine requirements decrease with a lowering of caloric intake. Similarly, it has been noted that thiamine requirements fall with diminishing physical activity.5 In the starving obese subject endogenous fat . . .
Suppression of the Hypercalcemia of Thyrotoxicosis by Corticosteroids
Authors: Lee R. Sataline, Charles Powell, George J. Hamwi
Journal: New England Journal of Medicine (1962)

WITHIN the last decade the problem of hypercalcemia has received much emphasis for several reasons. It is now realized that hypercalcemic symptoms may mimic disease of the musculoskeletal, gastrointestinal, urinary and neuropsychiatric systems.1 Furthermore, the causes of hypercalcemia other than hyperparathyroidism are many and include thyrotoxicosis, neoplasm without metastasis, acute osteoporosis, the milk-alkali syndrome and adrenal insufficiency.1 , 2 Unfortunately, there is no single test or procedure that will differentiate the multiple causes, and the diagnosis is often one of exclusion.1 2 3 Osteoporosis and increased fecal and urinary calcium excretion in hyperthyroidism have been recognized for more than fifty years. Although hypercalcemia occurring . . .
Type 2 Biomarkers Define a Prevalent Phenotype in Moderate-to-Severe, Uncontrolled Asthma Patients: A Pooled Analysis from Lebrikizumab All-Comers Phase 2 Trials
Authors: Phillip E. Korenblat, Nicola A. Hanania, Jonathan Corren, Julie K. Olssen, Nikhil Kamath, Sarah Gray, Nicolas Martin, Cecile T.J. Holweg, John G. Matthews, Susan L. Limb, Stephan Korom
Journal: Journal of Allergy and Clinical Immunology (2016)
Non-anesthesiologist administration of propofol sedation for colonoscopy is safe in low risk patients: results of a noninferiority randomized controlled trial
Authors: Alexandre Ferreira, Joana Torres, Elidio Barjas, Joana Nunes, Luisa Glória, Rosa Ferreira, Manuel Rocha, Sónia Pereira, Sofia Dias, Antonio Santos, Marília Cravo
Journal: Endoscopy (2016)

<b>Background and study aims:</b> Propofol provides the best sedation in colonoscopy. The safety of non-anesthesiologist administration of propofol (NAAP) is still a matter of debate. The aim of the current study was to evaluate sedation safety, colonoscopy quality, and patient satisfaction with NAAP. <b>Patients and methods:</b> The study was a single-blinded, noninferiority, randomized controlled trial comparing NAAP (Group A) with anesthesiologist-administered sedation (Group B) performed at a single academic institution. Patients (18 – 80 years) who underwent colonoscopy and were at low anesthetic risk (American Society of Anesthesiologists class I – II) were included. The primary end point was the incidence of adverse events. Secondary end points were propofol dose, patient satisfaction and pain, colonoscopy quality indicators, and procedure and recovery times. <b>Results:</b> A total of 277 patients were included in the analysis. The incidence of adverse events was 39.3 % in Group A and 39.0 % in Group B (absolute difference – 0.3 %, 95 % confidence interval [CI] – 12.0 % to 11.4 %; <i>P</i> = 0.959). There were no sentinel adverse events. The following interventions (Group A vs. Group B) were necessary: atropine administration (0 % vs. 5.5 %; <i>P</i> = 0.004); airway repositioning (8.7 % vs. 4.7 %; <i>P</i> = 0.196); increased oxygen administration (6.7 % vs. 3.9 %; <i>P</i> = 0.317), and increased fluid rate (2.7 % vs. 0.8 %; <i>P</i> = 0.379). There were no differences in cecal intubation and adenoma detection rates. Recovery times were longer in Group B (58 ± 33 vs. 67 ± 29 minutes; <i>P</i> = 0.032). There were no differences in mean propofol dose, withdrawal time, painless colonoscopy, satisfaction, and amnesia. All but two patients (Group B) were willing to repeat the colonoscopy. <b>Conclusions:</b> NAAP is equivalent to anesthesiologist-administered sedation in the rate of adverse events in a low risk population. Trial registration: ClinicalTrials.gov (NCT02067065).
Potentiation of the Effect of Orally Administered Anticoagulants by Phenyramidol Hydrochloride
Authors: Stefan A. Carter
Journal: New England Journal of Medicine (1965)

IT is well known that administration of one drug may inhibit or potentiate the effect of another.1 Such an interaction is of particular clinical importance when anticoagulants are given, because its recognition may prevent serious hemorrhagic complications and may result in a smoother control of the prothrombin time. This report deals with the effect of phenyramidol hydrochloride (Analexin) on the response to orally administered anticoagulants. To my knowledge this is the first report on this action of phenyramidol.Phenyramidol is a 2-(beta-hydroxyphenethylamino)-pyridine hydrochloride marketed for use in acute and chronic conditions in which both muscle spasm and pain are involved. . . .
Abstract 4606: Fine mapping of 64 prostate cancer GWAS regions identifies multiple novel association signals
Authors: Zsofia Kote-Jarai, Ali Amin Al Olama, Tokhir Dadaev, Dennis Hazelett, Qiuyan Li, Daniel Leongamornlert, Ed Saunders, Matthew Feedman, David Conti, Douglas Easton, Gerhard Coetzee, Rosalind Eeles
Journal: Cancer Research (2015)

Abstract Genome-wide association studies (GWAS) have identified 100 common prostate cancer (PrCa) susceptibility loci to date. We performed comprehensive fine-mapping of 64 GWAS regions using genotyping and imputation to a 1000 Genomes reference panel for 25,779 PrCa cases and 26,218 controls of European ancestry from the PRACTICAL Consortium and two UK GWAS studies. In order to identify independent variants associated to PrCa, SNPs significant at P ≤10-4 were included in a stepwise logistic regression (SLR). Where the initial SLR identified multiple independent SNPs in a region, we re-analysed the region conditioning on the top hit. The adjusted results were subsequently trimmed using a P-value cut-off of ≤10-5 and a second SLR performed to identify independently significant index SNPs. We observed a single independent signal at 39 regions, with a novel, more significantly associated index SNP at 35 of these. Amongst these, we confirmed association in the European population for 2 loci previously reported in Asian GWAS. At 16 regions there was evidence for multiple independent signals, 14 of these contain newly identified additional significant associations. Functional annotation using data from ENCODE filtered for PrCa cell lines showed enrichment for overlap with bio-features within the fine-mapped SNP set and eQTL analysis identified novel candidate genes regulated by SNPs discovered in this study. Furthermore, we observed a 7% (from 32%-to 39%) improvement in the estimated proportion of familial relative risk explained through these refined and newly identified genetic variants. This study demonstrates the utility of fine-mapping, in silico functional annotation and eQTL approaches to narrow down the number of candidate functional variants. In addition, since a greater proportion of GWAS loci contained multiple independent risk variants than previously appreciated; this may explain a proportion of the missing heritability of complex diseases. Citation Format: Zsofia Kote-Jarai, Ali Amin Al Olama, Tokhir Dadaev, Dennis Hazelett, Qiuyan Li, Daniel Leongamornlert, Ed Saunders, Matthew Feedman, David Conti, Douglas Easton, Gerhard Coetzee, Rosalind Eeles, The PRACTICAL Consortium. Fine mapping of 64 prostate cancer GWAS regions identifies multiple novel association signals. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4606. doi:10.1158/1538-7445.AM2015-4606
Investigation on the mechanism of dichloroacetate (DCA) induced apoptosis in breast cancer
Authors: L. Ko, J. Allalunis-Turner
Journal: Journal of Clinical Oncology (2009)

e14637 Background: DCA is a generic, orally available, small molecule metabolic modulator that has an established history in the treatment of mitochondrial diseases and lactic acidosis. DCA inhibits pyruvate dehydrogenase kinase (PDK), an inhibitor of pyruvate dehydrogenase, a key enzyme in glucose metabolism. DCA preferentially shifts glucose metabolism in cancer cells from glycolysis to glucose oxidation, reversing the unique aerobic glycolysis found in solid tumors. DCA induced apoptosis in cancer cells as evidenced by the efflux of cytochrome c and apoptosis-inducing factor from the mitochondria. Recent studies suggested apoptosis induction by DCA in glioblastoma, endometrial, prostate, and non-small cell lung cancers. In this study we attempt to establish a link between DCA and apoptosis in breast cancer cell lines. Methods: Six breast cancer cell lines were investigated (BT474, MCF-7, MDA-MB231, MDA- MB468, SKBR3, T47D). Quantitative real-time polymerase chain reaction (RT-PCR) was performed using Taqman probes to identify increased DNA templates of PDK isoforms 1–4, using DCA concentrations from 0 to 20mM. Western blots were performed to identify increased expression of PDK isoforms and correlate findings with Taqman. MTS (3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)- 2-(4-sulfophenyl)-2H-tetrazolium) assays were performed to measure decreased mitochondrial activity and cytotoxicity. Flow cytometry using annexin V and propidium iodide was performed to measure apoptosis and cell death. Results: RT-PCR showed increased DNA expression of all PDK isoforms in MDA-MB231 cells after DCA treatment. The effect was most pronounced at 10mM concentration. 10mM of DCA also increased DNA expression of all PDK isoforms in MCF-7 cells, and PDK1 in T47D cells. MTS assays showed increased cell kill and decreased mitochondrial activity in all six cell lines, with IC50 ranging between 20mM and 30 mM. Flow cytometry showed increased apoptosis induced by DCA at IC50 for BT474 and MCF-7 cell lines. Conclusions: Apoptosis appears to play a role in the mechanism of DCA in breast cancer, with increased PDK isoform expressions, cytotoxicity and decreased mitochondrial activity. Data from flow cytometry suggested DCA-induced apoptosis in two cell lines. No significant financial relationships to disclose.
PTPS-01MOLECULAR PROFILING ANALYSIS OF SELECT PEDIATRIC NEUROEPITHELIAL TUMORS OF THE CENTRAL NERVOUS SYSTEM
Authors: David Arguello, Brian Abbott, Sandeep Reddy, Zoran Gatalica, Santosh Kesari, Leonard Sender
Journal: Neuro-Oncology (2015)

BACKGROUND: Pediatric neuroepithelial tumors of the central nervous system (CNS) comprise a vast group of cancers where optimal treatments may be limited or non-existent given the rarity of these tumors in the pediatric population. As molecular oncology continues identifying novel treatments in adult cancers, a need exists to do the same in the pediatric population. The goal of this study is to retrospectively analyze pediatric tumors profiled at our facility to identify novel chemotherapeutic or targeted options in these diseases. METHODS: A retrospective evaluation of 44 neuroepithelial CNS tumors (e.g. astrocytic tumors, ependymal tumors, tumors with neuroblastic/glioblastic elements) tested via a multiplatform profiling service (Caris Life Sciences, Phoenix, AZ) was performed. Testing consisted of gene sequencing (Sanger or next generation sequencing [NGS]), protein expression (immunohistochemistry [IHC]) and gene amplification (CISH/FISH). RESULTS: Patients were between the ages of 1 and 14 (mean = 7.4 years), with medulloblastoma (n = 10), glioblastoma multiforme (n = 7), and ependymoma (n = 6) being the most common histologies. In a comparison of three major subtypes, astrocytic tumors had the most gene aberrations (i.e. gene amplification or mutation) with abnormalities detected in APC, BRCA2, BRAF, EGFR, ERBB4, KDR, MGMT, and TP53. By contrast, few gene aberrations were found in ependymal tumors and neuroblastic/glioblastic tumors. Interestingly, an ALK abnormality was detected in one ependymoma. Protein evaluation by IHC yielded the most potential targets in all groups. CONCLUSION: Multiplatform tumor profiling identified several targets in molecular profiles of neuroepithelial tumors of the CNS. Astrocytic tumors, comprising anaplastic astrocytoma and glioblastoma multiforme, have the greatest number of potential targets. Ependymoma could potentially be targeted with ALK-targeted therapy capable of crossing the blood-brain barrier. Given the lack of mutations detected, a multiplatform approach may be advisable to identify the best targets in this patient population. Further studies are needed for this underserved patient population.
Focal Suppression and Induction of Hyperplasia by the Bladder Carcinogens Butyl(4-hydroxybutyl)nitrosamine and Butyl(3-carboxypropyl)nitrosamine in Organ-Cultured Rat Bladder Epithelium
Authors: David H. Reese, Rosalind D. Friedman, William Gaffield, Larry K. Keefer
Journal: JNCI Journal of the National Cancer Institute (1978)

The effects of the bladder carcinogens butyl(4-hydroxybutyl)nitrosamine (BBN) and butyl(3-carboxypropyl)-nitros-amine (BCPN) on proliferating transitional rat epithelium in organ culture were studied. At low to intermediate concentration ranges (0.5–2.9 mM), both compounds appeared to stimulate hyperplasia in some regions of epithelia. The major effect of both carcinogens, however, was to suppress hyperplasia in other regions of epithelia and, at higher concentrations (5–6 mM), to cause necrosis. For comparable concentrations, BBN was more effective in suppressing proliferation and causing necrosis than was BCPN.
Outbreak of unusual Salmonella enterica serovar Typhimurium monophasic variant 1,4 [5],12:i:-, Italy, June 2013 to September 2014
Authors: Francesca Cito, Francesca Baldinelli, Paolo Calistri, Elisabetta Di Giannatale, Gaia Scavia, Massimiliano Orsini, Simona Iannetti, Lorena Sacchini, Iolanda Mangone, Luca Candeloro, Annamaria Conte, Carla Ippoliti, Daniela Morelli, Giacomo Migliorati, Nadia Beatrice Barile, Cristina Marfoglia, Stefania Salucci, Cesare Cammà, Maurilia Marcacci, Massimo Ancora, Anna Maria Dionisi, Slawomir Owczartek, Ida Luzzi
Journal: Eurosurveillance (2016)

Monophasic variant of Salmonella enterica subspecies enterica serovar Typhimurium (monophasic S. Typhimurium), with antigenic structure 1,4,[5],12:i:-, appears to be of increasing importance in Europe. In Italy, monophasic S. Typhimurium represented the third most frequent Salmonella serovar isolated from human cases between 2004 and 2008. From June 2013 to October 2014, a total of 206 human cases of salmonellosis were identified in Abruzzo region (Central Italy). Obtained clinical isolates characterised showed S. Typhimurium 1,4,[5],12:i:- with sole resistance to nalidixic acid, which had never been observed in Italy in monophasic S. Typhimurium, neither in humans nor in animals or foods. Epidemiological, microbiological and environmental investigations were conducted to try to identify the outbreak source. Cases were interviewed using a standardised questionnaire and microbiological tests were performed on human as well as environmental samples, including samples from fruit and vegetables, pigs, and surface water. Investigation results did not identify the final vehicle of human infection, although a link between the human cases and the contamination of irrigation water channels was suggested.
Age Dependence and Genetics of Expression of Ecotropic Murine Leukemia Virus in SJL/J Mice&lt;xref ref-type="fn" rid="FN2"&gt;2&lt;/xref&gt;
Authors: Alfonso Colombatti
 6, Anita De Rossi, John Hilkens, D. Collavo, Luigi Chieco-Bianchi
Journal: JNCI Journal of the National Cancer Institute (1979)

The presence of ecotropic murine leukemia virus (MuLV) in mice designated SJL/J-(v+) (SJL/J mice with a high level of MuLV) was studied. Isoenzyme analysis of several genetic markers done to exclude any cross contamination showed concordance with SJL/J markers. Most adult mice expressed high titer N-tropic virus in the tail; spleen, thymus gland, and kidney were seldom positive, and liver was negative. The time course of appearance of infectious ecotropic MuLV in tails of Individuals 10–40 days old indicated that mice might be grouped into two classes according to the earlier or later activation of virus. This pattern had a clear-cut litter distribution. Lymphomatous tissue usually contained a lower virus content than did normal tissue from mice of the same age, as indicated by a 10-fold decrease in the number of both infectious centers and XC plaque-forming units per tumor tissue homogenate. Normal thymus glands of tumor-bearing mice exhibited an analogous decrease in virus titers, whereas thymus glands from old mice expressed high MuLV levels. The high virus phenotype was dominantly expressed in F1 hybrids of several strains. Infectious virus was detectable in spleens of 50% of the segregant first backcross (Bc1) population (DBA/2 × SJL) × DBA/2, indicating that one dominant gene was responsible for the expression of high levels of virus. The progeny of 11 MuLV-positive Bc1 males or females mated to DBA/2 was also distributed into two classes, with a 1:1 ratio between virus-positive (51) and virus-negative (53) mice. The number of infectious centers in F1, Bc1, and second backcross populations suggested that no additional major genetic influences regulate virus expression. Recovery of virus from tail tissue of many F1 and Bc1 hybrids, however, was lower in titer as was the percentage of positive mice. No close correlation between high virus phenotype and three coat color markers (d, a, b) was found.
Case 32-1999
Authors: Sidney S. Braman, Hermes C. Grillo, Eugene J. Mark
Journal: New England Journal of Medicine (1999)

Presentation of CaseA 44-year-old man was admitted to the hospital because of tracheal stenosis.The patient had been well until three years earlier, when a cough developed, accompanied by purulent sputum, spikes of fever, exertional dyspnea, difficulty clearing respiratory tract secretions, and stridor. All the symptoms recurred during repeated bouts of respiratory tract infection. Recently, the patient had become dyspneic even on mild exertion. During the year before admission, he received no antibiotics. There was a remote history of ear surgery performed because “something was too narrow.” There was no history of swelling of the ear or nose, tuberculosis . . .
Treatment of Terminal Leukemic Relapse by Total-Body Irradiation and Intravenous Infusion of Stored Autologous Bone Marrow Obtained during Remission
Authors: Joseph J. McGovern, Paul S. Russell, Leonard Atkins, Edward W. Webster, Martha Duane, J. Worth Estes, David Kelleher
Journal: New England Journal of Medicine (1959)

DURING a remission of acute leukemia in children induced by one of the chemotherapeutic agents the bone marrow may return temporarily to a normal morphologic state. Thus, the question arises whether in some cases the marrow may provide an acceptable source of autologous material for subsequent use as a marrow autograft.1 It has been reported that the infusion of autologous marrow in animals2 3 4 and isologous marrow in man,5 after potentially lethal doses of radiation or chemotherapeutic agents,6 can protect against their otherwise lethal effects by restoring the marrow cell population. It has also been shown that marrow may be preserved . . .