tbuckley/cabot-search huggingface dataset:
Hemochromatosis Terminating in Polycythemia and Hepatoma, with Observations on the Natural History of Hemochromatosis
Authors: James H. Jandl, Charles S. Davidson, Walter H. Abelmann, Richard A. MacDonald
Journal: New England Journal of Medicine (1963)

LIVER tumors, usually hepatomas, are relatively frequent in cases of hepatic cirrhosis, occurring in approximately 3 or 4 per cent of patients with alcoholic cirrhosis and in a somewhat higher percentage (approximately 6 to 14 per cent) of those with postnecrotic cirrhosis or hemochromatosis.1 , 2 Polycythemia is encountered in association with tumors of a number of tissues, including the liver.3 4 5 6 7 The present report concerns a patient with hemochromatosis who was followed for several years, and in whom, during the last few months of life, a fulminant polycythemia and cancer of the liver developed simultaneously.Case ReportThe patient was 58 years . . .
Reply
Authors: Satoru Hagiwara, Naoshi Nishida, Masatoshi Kudo
Journal: Hepatology (2015)

Potential conflict of interest: Nothing to report. We read with great interest the Bloks et al. correspondence and appreciate the important point raised by them regarding ABCG2. In the current analysis, we studied ABCG2 expression, and not that of ABCC2/MRP2, by using immunohistochemistry and quantitative polymerase chain reaction (PCR), as cited in the reference 3 of the article.1 However, we accidentally mixed up the names of these two molecules because they belong to the same ABC transporters and erroneously referred to ABCG2 as ABCC2 during the preparation of the manuscript. Whole‐exome sequencing did not show any specific mutation in the ABCG2 (and in the ABCC2) genes in both patients. The anti‐ABCG2 antibody for IHC was purchased from ALEXIS Co. (Lausen, Switzerland); the quantitative PCR primers used for measuring ABCG2 expression were TTCGGCTTGCAACAACTATGA (forward) and CACCACGGATAAACTGAGTTCCA (reverse). We are ready to open the detail of the methods so that these can be reproduced. Regarding the differences in the expression of ABCG2 on hepatocellular protoporphyrin deposition, we understand the concern being pointed out. Probably, it should be ideal to examine expression of ABCG2 in the liver of the older brother in the recovery phase; however, this was difficult owing to the ethical considerations and risk of complications. Therefore, we measured the levels of other membrane transporters, ABCG6 and PEPT1,1 together with ABCG2, by using quantitative PCR. We did not find any differences in ABCG6 and PEPT1 expression between the two brothers; the differences in ABCG2 expression were unique among the genes of transporter proteins examined. This result, at least partially, indicates that the reduction in ABCG2 levels in the older brother was a cause of the liver damage, and not its consequence. We also understand that the potential contribution of other candidate transporters in the development of erythropoietic protoporphyria‐associated liver disease deserves further investigation.
Abstract IA04: Using genome editing to model MLL rearranged leukemias
Authors: Erin Breese, Corina Buechele, Michael Cleary, Matthew Porteus
Journal: Cancer Research (2016)

Abstract MLL rearranged leukemias, particularly those associated with infant acute lymphoblastic leukemias, continue to have a generally poorer prognosis than other childhood leukemias. Improved understanding of these leukemias has been gained by using transgenic mouse models and retroviral transduction of human cells but each of these approaches has well recognized limitations. With the recent development of an expanded genome editing toolbox, it is now possible to use genome editing in primary human hematopoietic stem and progenitor cells (HSPCs) to directly re-create genomic rearrangements, including those involving the MLL gene. Using these tools we have generated MLL-AF4 and MLL-AF9 translocations in HSPCs and studied the biologic properties of these cells. Moreover, we have further used genome editing of HSPCs to knock-in the AF9 fusion partner into the MLL locus to create the MLL-AF9 fusion. When the modified HSPCs were transplanted into immunodeficient mice (NSG), these modified cells gave rise to ALL, mixed phenotype leukemias, and AML. These results now give a powerful new way to study the developmental biology and pathogenesis of MLL rearranged leukemias and provide a proof-of-concept of how genome editing of human HSPCs can be used to study a wide variety of hematologic disorders. Citation Format: Erin Breese, Corina Buechele, Michael Cleary, Matthew Porteus. Using genome editing to model MLL rearranged leukemias. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Pediatric Cancer Research: From Mechanisms and Models to Treatment and Survivorship; 2015 Nov 9-12; Fort Lauderdale, FL. Philadelphia (PA): AACR; Cancer Res 2016;76(5 Suppl):Abstract nr IA04.
Leptospirosis in the United States
Authors: Clark W. Heath, Aaron D. Alexander, Mildred M. Galton
Journal: New England Journal of Medicine (1965)

THE most recent comprehensive review of leptospirosis in the United States was presented by Molner, Meyer and Raskin1 in 1948. Since that time, knowledge concerning the epidemiologic and clinical characteristics of leptospirosis in this country has greatly expanded. Numerous pathogenic leptospiral serotypes have now been demonstrated in a broad range of animal hosts, both domestic and wild.2 3 4 5 6 Improved procedures in laboratory diagnosis have become more widely available and have greatly facilitated the detection of leptospiral infection. In addition, the medical profession has grown increasingly aware that the clinical manifestations of human leptospirosis are by no means limited to the relatively . . .
M30 Respiratory Skills Course for Post-graduate Medical Trainees; Inspiring Future Respiratory Trainees
Authors: R Young, T McLellan, C Walters
Journal: Thorax (2015)

<h3>Introduction/objectives</h3> Respiratory medicine curriculum requires medical registrars to be competent in procedural skills such as intercostal chest drain (ICD) insertion, non-invasive ventilation (NIV) and thoracic ultrasound.<sup>1</sup> Previous research<sup>2</sup> has shown that medical registrars do not feel confident in performing respiratory related procedural skills and required further training in these skills. The aim of this research was to assess medical trainees’ experience and confidence in performing respiratory procedural skills and the influence a respiratory skills course had on trainees’ career aspirations and their confidence to perform these skills. <h3>Methods</h3> A respiratory skills course consisting of three evening sessions was designed and delivered to medical trainees’. Teaching was delivered through small group tutorial, simulation and practice on real patients. A pre- and post-course survey was designed, consisting of closed, Likert style and free-text response questions. This was distributed to eleven attendees at the course. <h3>Results</h3> 50% of course attendees had received previous teaching on NIV and thoracic ultrasound whilst 70% had previous teaching on ICD insertion. The majority of candidates did not feel confident in performing the procedural skills prior to the course. Following the course, all attendees felt that the course had improved their confidence and knowledge in performing all three procedural skills (Figure 1). One candidate stated that the course had ‘made me more enthusiastic about my career choice in respiratory medicine.’ <h3>Conclusion</h3> Although this study was small, the results are positive. There are however, implications to running further courses due to the willingness of faculty to facilitate sessions in their own time. This research does show that medical trainees do not feel confident in performing procedural skills, highlighting the need for more sustainable teaching in these areas to improve confidence and thus inspire trainees in medical careers. <h3>References</h3> 1 Joint Royal Colleges of Physicians Training Board. Specialty training curriculum for respiratory medicine 2010. Available at: http://www.jrcptb.org.uk. [Accessed 13 July 2015] 2 Scott A, Byrne D, Garvey JF, O’Regan A. How confident are medical registrars in performing respiratory orientated procedural skills? <i>Irish J Med Sci. </i>2014;<b>183</b>(11):508
441P Bevacizumab (BEV) combination chemotherapies (CCTs) for patients (Pts) with high-risk factors of pulmonary hemorrhage (PH) in advanced non-small cell lung cancer (NSCLC)
Authors: A. Hata, C. Okuda, R. Kaji, K. Masago, S. Fujita, N. Katakami, K. Takayama, K. Miura
Journal: Annals of Oncology (2015)
Chronic Pyelonephritis Simulating Adrenocortical Insufficiency
Authors: Harvey E. Nussbaum, William G. Bernhard, Virginius D. Mattia
Journal: New England Journal of Medicine (1952)

THE clinical picture of a shock-like state presenting signs and symptoms indistinguishable from those of adrenal insufficiency may occur in patients with chronic renal disease with normal adrenal glands. This was first noted by Thorn, Koepf and Clinton in 19441 and by Sawyer and Solez in 1949.2 The former group had observed 2 cases, the latter 1. This report is the third to appear in the literature and represents the fourth such case.This particular entity, named "salt-losing nephritis" by Thorn, is not to be confused with nephritis coexisting with adrenal cortical insufficiency.3 It must also be appreciated that Addison's . . .
P72 T2 biomarkers relate to exacerbations and control in refractory asthma
Authors: S Srivastava, A Sahal, A Mansur
Journal: Thorax (2015)

<h3>Background</h3> T2 biomarkers have been shown to predict responsiveness to corticosteroids and possibly relate to asthma exacerbations and control. T2 biomarkers in the form of fraction exhaled nitric oxide (FeNO), peripheral blood eosinophils (PBE), and serum periostin are easier to measure and probable surrogate markers for induced sputum eosinophilia (ISE). The relationships between PBE, FeNO and periostin particularly in refractory asthma have been conflicting. A composite score of T2 biomarkers has also been postulated to predict exacerbations and may be more sensitive.<sup>1</sup> <h3>Aim</h3> To explore the relationship between the T2 biomarkers individually, and in the form of composite score to asthma exacerbations and control. <h3>Methods</h3> Unselected consecutive patients with confirmed diagnosis of refractory asthma (ATS) attending a tertiary severe asthma centre were recruited following an informed consent. Participants were evaluated for the followings: demographics, exacerbations requiring corticosteroids in the preceding 12 months, asthma control questionnaire (Juniper ACQ7), lung function, FeNO, PBE, and periostin measurement. The composite T2 score of all the 3 biomarkers was calculated as previously reported (reference). Statistical analyses were conducted using MedCalc software. <h3>Results</h3> One-hundred and fifteen patients were recruited with mean age 45 yrs, 88 (69.8%) females, mean inhaled corticosteroids (BDP equivalent) = 1,647 µg/day, on maintenance OCS = 63 (55%), mean FEV1 = 2.0 L (SD1.8–2.1), FEV1% pred = 68%, and mean FEV1/FVC ratio = 71% (SD = 68–74). A significant positive correlation between FeNO and PBE was observed (r = 0.39, p = 0.004), but not with periostin. Only FeNO significantly correlated to exacerbations (r = 0.42, p = 0.0008) and only periostin correlated significantly to ACQ7 score (r = 0.33, p = 0.0053). In addition, the biomarkers composite score significantly correlated with exacerbations (r = 0.4, p = 0.0031) (Figure 1), but not ACQ7. <h3>Conclusion</h3> In real life settings, FeNO correlated with historical exacerbations and the T2 composite score displayed a dose response correlation with exacerbations frequency. Periostin correlated with ACQ7 but not exacerbations. Further research is required to confirm these findings. <h3>Reference</h3> 1 Heaney LG, <i>et al</i>. <i>Thorax</i> 2015;<b>0</b>:1–3. doi:10.1136/thoraxjnl-2015-207326
Seamless Oncology-Drug Development
Authors: Tatiana M. Prowell, Marc R. Theoret, Richard Pazdur
Journal: New England Journal of Medicine (2016)

Interview with Dr. Alice Shaw on a new model for accelerating the development of promising oncology drugs. (10:06)Download Increasingly, firms developing cancer drugs are forgoing standard phased development for a seamless approach of adding cohorts to a first-in-human trial to study doses and activity in various cancers. Key regulatory interactions and protections may therefore be missing.
Stellate Block as an Adjunct to the Treatment of Pulmonary Embolism
Authors: Henry H. Faxon, John H. Flynn, Ruth M. Anderson
Journal: New England Journal of Medicine (1951)

MUCH interest has been evinced in recent years in the manifestations of thromboembolic disease. A voluminous literature has appeared concerning the use of anticoagulants and femoral-vein ligation. These measures, however, have been directed primarily toward preventing pulmonary embolism rather than at influencing the immediate effects of the emboli themselves, and little progress has been made in augmenting the meager list of measures that are of use in the treatment of the acute phase of the condition.The methods of immediate treatment can be divided into operative technics and all others, including the use of drugs, general supportive measures and minor . . .
ATCT-14CHEMOSENSITIVITY OF PRIMARY AND METASTATIC CNS TUMORS TO 4-DEMETHYL-4-CHOLESTERYLOXYCARBONYLPENCLOMEDINE (DM-CHOC-PEN) AND TEMOZOLOMIDE
Authors: Juan Carlos Vera, Michael Strong, Mansour Mathkour, Juanita Garces, Lee Roy Morgan, Ed Benes, Marcus Ware
Journal: Neuro-Oncology (2015)

BACKGROUND: The efficacy of TMZ in the treatment of high-grade astrocytomas is limited by drug-resistance mediated by O6-methylguanine-DNA methyltransferase (MGMT). Brain metastases are difficult to treat and currently no standard chemotherapeutic therapies exist. 4-Demethyl-4-cholesteryloxycarbonylpenclomedine (DM-CHOC-PEN) is a polychlorinated pyridine cholesteryl carbonate whose mechanism of action is via alkylation of DNA at N7-guanine. This agent has had early therapeutic success in treating both primary and metastatic CNS malignancies in Phase I and Phase II clinical trials. METHODS: To better understand the sensitivity and mechanisms of resistance in primary and metastatic CNS tumors, we collected tissue from subjects (n = 38) enrolled between March 2014 - January 2015 for chemosensitivity studies. These included high-grade astrocytomas (9), metastatic brain tumors (6) meningiomas (6), and other more benign tumors such as pituitary adenomas (4), hemangioblastoma (1), and chondrosarcoma (1). Using viable tumor cell explants from surgery, cells were grown under standard conditions (RPMI/FBS, 5%CO2, 37°C), in vitro chemosensitivity profiles were obtained comparing DM-CHOC-PEN vs. TMZ and other commonly used anti-cancer agents. RESULTS: Tumor cells exhibited higher susceptibility to DM-CHOC-PEN than to TMZ (RR = 3.19, p = 0.0029, 95% confidence interval [CI], 1.3-7.8 vs. TMZ). In a subgroup analysis of high-grade astrocytomas, atypical meningiomas, and secondary metastases in this cohort, an association was noted between TMZ-resistance (µIC50 = 3.3, S.D. = 0.46) and DM-CHOC-PEN-sensitivity (µIC50 = 1.0, S.D = 0.26) using two-sample independent, Student's t-test with Fisher's exact P-value (p = 0.0001, t(23.72) = 4.5, df = 27.17). CONCLUSIONS: These preliminary results suggest that DM-CHOC-PEN may promote cell death in tumors possessing acquired MGMT-mediated drug-resistance. Furthermore, it supports roles for this promising new agent in the treatment of primary and metastatic brain tumors and in treatment of high-grade astrocytomas, either in combination with TMZ or alone in cases of TMZ-resistance.
Mutation in the Gene Coding for Coagulation Factor V and the Risk of Myocardial Infarction, Stroke, and Venous Thrombosis in Apparently Healthy Men
Authors: Paul M. Ridker, Charles H. Hennekens, Klaus Lindpaintner, Meir J. Stampfer, Paul R. Eisenberg, Joseph P. Miletich
Journal: New England Journal of Medicine (1995)

A specific point mutation in the gene coding for coagulation factor V is associated with resistance to degradation by activated protein C, a recently described abnormality of coagulation that may be associated with an increased risk of venous thrombosis. Whether this mutation also predisposes patients to arterial thrombosis is unknown, as is the value of screening for the mutation in order to define the risk of venous thrombosis among unselected healthy people.
Pharmacologic-based dosing of carboplatin: a better method.
Authors: K R Hande
Journal: Journal of Clinical Oncology (1993)

AbstractDecember 01, 1993 Share on Pharmacologic-based dosing of carboplatin: a better method.Author: K R HandeAuthors Info & AffiliationsPublication: Journal of Clinical OncologyVolume 11, Number 12https://doi.org/10.1200/JCO.1993.11.12.2295 Get Access
Scanning Electron Microscopy of Human T-Cell and B-Cell Rosettes
Authors: Peck Sun Lin, Amiel G. Cooper, Henry H. Wortis
Journal: New England Journal of Medicine (1973)

Abstract The surface of human lymphocytes was studied by scanning electron microscopy. Lymphocytes from peripheral blood or tonsils were identified as thymus-derived (T) cells or thymus-independent (B) cells by virtue of the ability of T cells to form rosettes with sheep red cells and for some B cells to form rosettes with complement-coated human red blood cells. The rosettes were gluteraldehyde fixed and subsequently examined by scanning electron microscopy. Lymphocytes, both rosetting and non-rosetting, had multiple surface microvilli. As compared to rosetting B cells, rosetting T cells were generally smaller and smoother, with fewer and shorter microvilli. Microvilli appeared to be the sole cell-cell contact point between T cells and sheep red blood cells; B cells made contact through both villous and non-villous areas. Microvilli are an important mode of primary contact between lymphocytes and the outside world. (N Engl J Med 289:548–551, 1973)
NCO-02DONEPEZIL THERAPY FOR PATIENTS WITH BRAIN TUMORS: A PILOT STUDY
Authors: Denise Correa, Maria Kryza-Lacombe, Raymond Baser, Howard Thaler, Lisa DeAngelis
Journal: Neuro-Oncology (2015)

BACKGROUND: Cognitive dysfunction is prevalent among brain tumor patients treated with radiotherapy (RT) and chemotherapy. However, there are no approved pharmacological interventions for improving cognitive functions in cancer patients. Donepezil, an acetylcholinesterase inhibitor, has been shown to provide cognitive and functional benefits in patients with Alzheimer's disease and other neurological diseases without known cholinergic deficiency. The goal of this pilot study was to examine the efficacy of donepezil in improving cognitive functions in brain tumor patients treated with RT + chemotherapy or chemotherapy alone. METHODS: Fifteen patients (mean age = 59 years, range = 43-85) received a single daily dose of donepezil (5mg for 4 weeks, 10 mg for 20 weeks), and completed cognitive evaluations prior to initiating therapy (baseline), and about 12 weeks (mid-study) and 24 weeks (end-of-study) subsequent to initiation of donepezil therapy. Twelve patients (80%) had primary brain tumors; 12 (80%) had been treated with RT + chemotherapy and 3 (20%) had chemotherapy alone. Mean time since treatment completion was 70 months (range = 7-161). Patients had no disease progression during the study period. RESULTS: The results of linear mixed models analysis, controlling for each patient's baseline cognitive test score, showed a significant post-baseline improvement in attention (WAIS-III Digit Span Forward; p = 0.037) and graphomotor speed (WAIS-III Digit Symbol; p = 0.035). There was also a significant improvement in visual memory (BVMT-R-delay; p = 0.025), but this was primarily due to improvement from baseline to 12 weeks, as scores at 24 weeks returned to near baseline levels. Four patients (27%) required dose reduction to 5 mg during the study due to adverse effects. CONCLUSIONS: The findings of this pilot study suggest that treatment with donepezil may improve some aspects of cognitive functions in brain tumor patients. Similar findings were reported in two prior trials of donepezil in brain tumor survivors (Shaw et al., 2006; Rapp et al., 2015).
Abstract 2867: Adrenergic Receptor Polymorphisms and Prevention of Atrial Fibrillation with Bucindolol in Patients with Heart Failure
Authors: William Sauer, Christopher M Lowery, Chakra Budhathoki, Brian D Lowes, Michael R Bristow
Journal: Circulation (2007)

Background: β-blockers have been shown to prevent atrial fibrillation (AF) in patients with low left ventricular ejection fraction (LVEF) and chronic heart failure (CHF). We hypothesized that there may be genotype specific responses to β-blocker therapy for prevention of AF. Methods: The β-blocker Evaluation of Survival Trial (BEST) was a randomized trial of bucindolol in patients with NYHA Class III–IV CHF and LVEF ≤0.35. From a substudy of genotyped subjects, we identified those with the high functioning Arg389 β1 adrenergic receptor polymorphism and the loss of function 322–325 α2c adrenergic receptor deletion polymorphism. The incidence of AF was prospectively recorded as an adverse event during the trial. Results: Of the 1040 subjects in the genotyped cohort, there were a total of 493 Arg389 β1 receptor homozygotes vs. 547 Gly389 carriers and 207 α2c deletion carriers vs. 833 wild-types. The diplotypes included 418 subjects with both Arg/Arg389 β1 receptors and wild type α2c, 484 with one of these, and 134 carrying both the α2c deletion and the β1 Gly389 polymorphisms. For the genetic substudy, bucindolol was associated with a lower incidence of AF (7.0% vs. 10.7%; p = 0.03). There was a significant drug-gene interaction for prevention of AF with both polymorphisms (β-1 overall p = 0.04; α2c overall p = 0.04). Arg389 homozygotes randomized to bucindolol had a lower incidence of new onset AF during the trial than those randomized to placebo (5.1% vs. 11.9%; p &lt; 0.01) as for wild type α2c homozygotes (7.1% vs. 11.2%; p = 0.04). This reduction in AF incidence was not seen in β-1 Gly389 carriers (8.9% vs. 9.7%; p = 0.77) and α2c deletion carriers (6.8% vs. 8.7%; p = 0.79). Subjects with the Arg/Arg389 β-1/wild-type α2c receptor diplotype randomized to bucindolol had a lower rate of AF occurrence than those with only one or neither of these genotypes (both: 5.2% vs. 11.7%; p = 0.02; one: 8.2% vs. 11.2%; p = 0.28; neither: 8.5% vs. 6.7%; p = 0.75). Conclusion: Subjects with CHF and Arg/Arg389 β1 or wild type α2c adrenergic receptors treated with bucindolol had a lower rate of new onset AF than those randomized to placebo. This treatment effect was not observed in the population of β-1 Gly389 or the α2c deletion carriers, indicating a pharmacogenetic interaction.