tbuckley/cabot-search huggingface dataset:
DNMT3A Haploinsufficiency Transforms <i>FLT3</i>ITD Myeloproliferative Disease into a Rapid, Spontaneous, and Fully Penetrant Acute Myeloid Leukemia
Authors: Sara E. Meyer, Tingting Qin, David E. Muench, Kohei Masuda, Meenakshi Venkatasubramanian, Emily Orr, Lauren Suarez, Steven D. Gore, Ruud Delwel, Elisabeth Paietta, Martin S. Tallman, Hugo Fernandez, Ari Melnick, Michelle M. Le Beau, Scott Kogan, Nathan Salomonis, Maria E. Figueroa, H. Leighton Grimes
Journal: Cancer Discovery (2016)

Abstract Cytogenetically normal acute myeloid leukemia (CN-AML) represents nearly 50% of human AML. Co-occurring mutations in the de novo DNA methyltransferase DNMT3A and the FMS related tyrosine kinase 3 (FLT3) are common in CN-AML and confer a poorer prognosis. We demonstrate that mice with Flt3-internal tandem duplication (Flt3ITD) and inducible deletion of Dnmt3a spontaneously develop a rapidly lethal, completely penetrant, and transplantable AML of normal karyotype. AML cells retain a single Dnmt3a floxed allele, revealing the oncogenic potential of Dnmt3a haploinsufficiency. FLT3ITD/DNMT3A-mutant primary human and murine AML exhibit a similar pattern of global DNA methylation associated with changes in the expression of nearby genes. In the murine model, rescuing Dnmt3a expression was accompanied by DNA remethylation and loss of clonogenic potential, suggesting that Dnmt3a-mutant oncogenic effects are reversible. Dissection of the cellular architecture of the AML model using single-cell assays, including single-cell RNA sequencing, identified clonogenic subpopulations that express genes sensitive to the methylation of nearby genomic loci and responsive to DNMT3A levels. Thus, Dnmt3a haploinsufficiency transforms Flt3ITD myeloproliferative disease by modulating methylation-sensitive gene expression within a clonogenic AML subpopulation. Significance: DNMT3A haploinsufficiency results in reversible epigenetic alterations that transform FLT3ITD-mutant myeloproliferative neoplasm into AML. Cancer Discov; 6(5); 501–15. ©2016 AACR. This article is highlighted in the In This Issue feature, p. 461
Does physical activity increase or decrease the risk of sickle cell disease complications?
Authors: Cyril Martin, Vincent Pialoux, Camille Faes, Emmanuelle Charrin, Sarah Skinner, Philippe Connes
Journal: British Journal of Sports Medicine (2015)

Sickle cell disease (SCD) is the most common inherited disease in the world. Red blood cell sickling, blood cell-endothelium adhesion, blood rheology abnormalities, intravascular haemolysis, and increased oxidative stress and inflammation contribute to the pathophysiology of SCD. Because acute intense exercise may alter these pathophysiological mechanisms, physical activity is usually contra-indicated in patients with SCD. However, recent studies in sickle-cell trait carriers and in a SCD mice model show that regular physical activity could decrease oxidative stress and inflammation, limit blood rheology alterations and increase nitric oxide metabolism. Therefore, supervised habitual physical activity may benefit patients with SCD. This article reviews the literature on the effects of acute and chronic exercise on the biological responses and clinical outcomes of patients with SCD.
Experimental Coinduction of Type D Retrovirus-Associated Pulmonary Carcinoma and Lentivirus-Associated Lymphoid Interstitial Pneumonia in Lambs&lt;xref ref-type="fn" rid="FN2"&gt;2&lt;/xref&gt;
Authors: J C DeMartini, R H Rosadio, J M Sharp, H I Russell, M D Lairmore
Journal: JNCI Journal of the National Cancer Institute (1987)

Two retrovirus-associated pulmonary diseases of sheep [ovine pulmonary carcinoma (OPC); sheep pulmonary adenomatosis], a bronchoalveolar carcinoma, and lymphoid interstitial pneumonia (LIP) were induced simultaneously in 9 of 9 neonatal lambs. The lambs were killed 8-28 weeks after intratracheal injection of lung tumor homogenate or lung fluid derived from sheep with naturally occurring OPC and ovine lentivirus (OvLV) infection. The inoculated lambs developed multifocal neoplasms of alveolar type II cells or nonciliated bronchiolar epithelial cells, LIP, and pulmonary lymph node hyperplasia, and all produced antibody to OvLV. OvLV was isolated from 6 to 7 lambs tested, and infectious center assay of pulmonary lavage cells from 3 lambs revealed that approximately 1 in 1,000 pulmonary lavage cells contained infectious lentivirus. Neither contact control lambs nor control lambs that received ultrafiltered lung fluid developed evidence of either disease or of OvLV infection. Lung fluid or tumor tissue of lambs with OPC contained a 26,000-dalton protein that cross-reacted with antiserum to p27 to Mason-Pfizer monkey virus, a type D retrovirus. The fact that no antigenic cross-reaction between OvLV and type D retroviruses has been demonstrated supports the presence of two retroviruses in sheep with OPC. Although the contributions of each agent to oncogenesis in this model are difficult to evaluate, the rapid development of two retrovirus-induced pulmonary diseases in experimentally inoculated lambs suggests an etiologic or pathogenetic synergism between these two members of the family Retroviridae.
Impact of hypothyroidism on the development of non-alcoholic fatty liver disease: A 4-year retrospective cohort study
Authors: Kil Woo Lee, Ki Bae Bang, Eun Jung Rhee, Heon Ju Kwon, Mi Yeon Lee, Yong Kyun Cho
Journal: Clinical and Molecular Hepatology (2015)

Hypothyroidism is reported to contribute to the development of nonalcoholic fatty liver disease (NAFLD). We compared the risk of the development of NAFLD among three groups with different thyroid hormonal statuses (control, subclinical hypothyroidism, and overt hypothyroidism) in a 4-year retrospective cohort of Korean subjects.Apparently healthy Korean subjects without NAFLD and aged 20-65 years were recruited (n=18,544) at health checkups performed in 2008. Annual health checkups were applied to the cohort for 4 consecutive years until December 2012. Based on their initial serum-free thyroxine (fT4) and thyroid-stimulating hormone (TSH) levels, they were classified into control, subclinical hypothyroidism (TSH >4.2 mIU/L, normal fT4), and overt hypothyroidism (TSH >4.2 mIU/L, fT4 <0.97 ng/dL) groups. NAFLD was diagnosed on the basis of ultrasonography findings.NAFLD developed in 2,348 of the 18,544 subjects, representing an overall incidence of 12.7%: 12.8%, 11.0%, 12.7% in the control, subclinical hypothyroidism, and overt hypothyroidism groups, respectively. The incidence of NAFLD did not differ significantly with the baseline thyroid hormonal status, even after multivariate adjustment (subclinical hypothyroidism group: hazard ratio [HR]=0.965, 95% confidence interval [CI]=0.814-1.143, P=0.67; overt hypothyroidism group: HR=1.255, 95% CI=0.830-1.899, P=0.28).Our results suggest that the subclinical and overt types of hypothyroidism are not related to an increased incidence of NAFLD.
Schizophrenic patients and Schneiderian first-rank symptoms
Authors: M Preiser, W Jeffrey
Journal: American Journal of Psychiatry (1979)

Differences between schizophrenic patients with Schneiderian first-rank symptoms (FRS) and those without FRS at the time of hospitalization indicated FRS were associated with behavior consistent with feelings of passivity and helplessness. The two groups responded equally well to treatment in a therapeutic community. Findings support the contention that FRS are not pathognomonic or prognostic in schizophrenia.
Encouraging Physical Activity in Patients With Diabetes Through Automatic Personalized Feedback via Reinforcement Learning Improves Glycemic Control
Authors: Irit Hochberg, Guy Feraru, Mark Kozdoba, Shie Mannor, Moshe Tennenholtz, Elad Yom-Tov
Journal: Diabetes Care (2016)

Most patients with type 2 diabetes are sedentary despite the clear benefit of regular physical activity, including better glucose control and improvement in quality of life (1). Smartphones could potentially improve patient care by continual communication with patients and sensors that quantify patient behavior (2). Nevertheless, the use of personalized messages that take into account the actual behavior of patients and learn to reinforce it has not yet been reported.

We provided a total of 27 patients with type 2 diabetes who did not perform regular physical activity prior to recruitment with a pedometer installed on their personal smartphones and a personal plan for physical activity. Patients were randomized into a control group ( n = 7) and a treatment group ( n = 20), and received text messages (via the Short Message Service [SMS] on the smartphone) one to seven times a week to encourage physical activity. In the treatment group, the messages consisted …
Determining Non-Irritating Concentration for Intradermal Skin Test with Commonly Prescribed Antibiotics in Korean Adults
Authors: Ha Kyeong Won, Min-Suk Yang, Woo-Jung Song, Yoon-Seok Chang, Sang Heon Cho, Heung-Woo Park, Kyung-Up Min
Journal: Journal of Allergy and Clinical Immunology (2016)
NIMG-29RADIOLABELED TEMOZOLOMIDE CAN MEASURE BEVACIZUMAB INDUCED VASCULAR MODULATION IN PATIENTS WITH RECURRENT GBM
Authors: Elizabeth Gerstner, David Izquierdo, Yangming Ou, Kyree Emblem, Xuezhu Cai, Xiao Da, Dan Chonde, Nicholas Martin, Jacob Hooker, Ciprian Catana, Jayashree Kalpathy-Cramer, Bruce Rosen, Tracy Batchelor
Journal: Neuro-Oncology (2015)

BACKGROUND: Anti-angiogenic agents have been hypothesized to work via vascular pruning as well as by vessel normalization. However, these mechanisms are not mutually exclusive and may occur in the same patient but at different time points during treatment. METHODS: After labeling temozolomide with the positron emitter [11C], we performed MR-PET scans in patients receiving bevacizumab 10mg/kg Q2weeks and temozolomide 50mg/m2 daily. Patients were initially scanned pre-bevacizumab and 1 day post first bevazicumab infusion. The first MR-PET was performed after steady state for oral temozolomide had been achieved to minimize nonspecific binding. MRI included routine sequences and perfusion/permeability imaging. Tumor regions of interest were outlined on the post-contrast images and registered to the PET and MRI images to generate tumor values for SUV, cerebral blood volume, cerebral blood flow, and ktrans. RESULTS: At this time, MRI and PET data is available for 2/7 patients who underwent scanning. In patient 1 the volume of tumor enhancement increased 34% from baseline to 1 day post bevacizumab, median ktrans increased 10%; median CBV decreased 14%; median CBF increased 1.6%, and mean SUV increased 54%. The volume of tumor enhancement in patient 2 decreased 59%, median ktrans decreased 38%; median CBV decreased 43%; median CBF decreased 39%; and mean SUV decreased 38%. CONCLUSIONS: These 2 patients demonstrated different early vascular responses to bevacizumab. Labeling drugs so that they are visible with PET is an intriguing and noninvasive way to measure tumor biology and response to treatment in individual patients. When coupled with dynamic MRI sequences, this technique can be used safely, longitudinally, and may allow for patient-specific adjustment of therapy.
Abstract B35: Establishment of patient-derived xenograft models of acute leukemias.
Authors: Antje Siegert, Bernadette Brzezicha, Annika Wulf-Goldenberg, Iduna Fichtner, Jens Hoffmann
Journal: Clinical Cancer Research (2015)

Abstract Acute leukemia, a hematological malignancy, is characterised by a rapid increase of functionally immature blood cells. Acute Myeloid Leukemia (AML) and Acute Lymphoblastic Leukemia (ALL) are distinguished by their cells of origin. If untreated, AML and ALL are life-threatening and patients show different responses to current standards of care (SoC) therapy. The majority of acute leukemias are genetically heterogeneous and therefore a challenge for the development of new targeted therapies. There is a need to develop robust animal models to investigate leukemia in vivo. Patient-derived xenograft (PDX) mouse models recapitulate many clinical features of cancer. They have proven to be useful tools for the evaluation of novel therapeutic strategies and biomarkers, and for the study of cancer biology. The aim of our work was to establish PDX models of AML and ALL and to characterize their sensitivity to different therapeutic agents. Bone marrow aspirates were obtained from primary and relapsed AML/ALL patients and were intravenously (i.v.) and/or subcutaneously (s.c.) inoculated into immunodeficient mice. Mice were sacrificed when signs of disease were obvious and single cell suspensions of spleens (i.v.) or tumor fragments (s.c.) were transferred to new recipient mice. Chemosensitivity to SoC treatments was tested. In our study several AML-PDX and ALL-PDX were established. These models show different sensitivity to SoC treatment. The models will be used for further investigations like gene expression or mutation analysis or biomarker identification. The established PDX models of AML and ALL are suitable tools for preclinical drug development. In order to cover the complex heterogeneity of acute leukemias, the establishment of further PDX models is currently in progress. Citation Format: Antje Siegert, Bernadette Brzezicha, Annika Wulf-Goldenberg, Iduna Fichtner, Jens Hoffmann. Establishment of patient-derived xenograft models of acute leukemias. [abstract]. In: Proceedings of the AACR Special Conference on Hematologic Malignancies: Translating Discoveries to Novel Therapies; Sep 20-23, 2014; Philadelphia, PA. Philadelphia (PA): AACR; Clin Cancer Res 2015;21(17 Suppl):Abstract nr B35.
Sex-Specific Differences at Presentation and Outcomes Among Patients Undergoing Transcatheter Aortic Valve Replacement
Authors: Susheel Kodali, Mathew R. Williams, Darshan Doshi, Rebecca T. Hahn, Karin H. Humphries, Vuyisile T. Nkomo, David J. Cohen, Pamela S. Douglas, Michael Mack, Ke Xu, Lars Svensson, Vinod H. Thourani, E. Murat Tuzcu, Neil J. Weissman, Martin Leon, Ajay J. Kirtane
Journal: Annals of Internal Medicine (2016)

Background: Female sex is associated with poorer outcomes after surgical aortic valve replacement (SAVR). Data on sex-specific differences after transcatheter aortic valve replacement (TAVR) are conflicting. Objective: To examine sex-specific differences in patients undergoing TAVR in the PARTNER (Placement of Aortic Transcatheter Valves) trial. Design: Secondary analysis of the randomized and nonrandomized portions of the PARTNER trial. (ClinicalTrials.gov: NCT00530894) Setting: 25 hospitals in the United States, Canada, and Germany. Patients: High-risk and inoperable patients (1220 women and 1339 men). Intervention: TAVR. Measurements: Demographic characteristics, cardiac and noncardiac comorbidities, mortality, stroke, rehospitalization, vascular complications, bleeding complications, and echocardiographic valve parameters. Results: At baseline, women had lower rates of hyperlipidemia, diabetes, smoking, and renal disease but higher Society of Thoracic Surgeons Predicted Risk of Mortality scores (11.9% vs. 11.1%; P < 0.001). After TAVR, women had more vascular complications (17.3% vs. 10.0%; difference, 7.29 percentage points [95% CI, 4.63 to 9.95 percentage points]; P < 0.001) and major bleeding (10.5% vs. 7.7%; difference, 2.8 percentage points [CI, 0.57 to 5.04 percentage points]; P = 0.012) but less frequent moderate and severe paravalvular regurgitation (6.0% vs. 14.3%; difference, −8.3 percentage points [CI, −11.7 to −5.0 percentage points]; P < 0.001). At 30 days, the unadjusted all-cause mortality rate (6.5% vs. 5.9%; difference, 0.6 percentage point [CI, −1.29 to 2.45 percentage points]; P = 0.52) and stroke incidence (3.8% vs. 3.0%; difference, 0.8 percentage point [CI, −0.62 to 2.19 percentage points]; P = 0.28) were similar. At 1 year, all-cause mortality was significantly lower in women than in men (19.0% vs. 25.9%; hazard ratio, 0.72 [CI, 0.61 to 0.85]; P < 0.001). Limitation: Secondary analysis that included nonrandomized trial data. Conclusion: Despite a higher incidence of vascular and bleeding complications, women having TAVR had lower mortality than men at 1 year. Thus, sex-specific risk in TAVR is the opposite of that in SAVR, for which female sex has been shown to be independently associated with an adverse prognosis. Primary Funding Source: Edwards Lifesciences.
Association of short sleep duration and rapid decline in renal function
Authors: Ciaran J. McMullan, Gary C. Curhan, John P. Forman
Journal: Kidney International (2016)

The kidney is influenced by circadian rhythms and is entrained to the sleep-wake cycle allowing anticipation of the metabolic and physiological demands of the kidney throughout a 24-hour cycle. Although sleep disruption has been studied extensively in cardiovascular and metabolic disease, its association with chronic kidney disease has not been shown. We examined this in a prospective cohort study of 4238 participants from the Nurses' Health Study and analyzed the association of self-reported sleep duration with decline in renal function over an 11-year period (1989 to 2000). Individuals who reported shorter sleep duration were more likely to experience a rapid decline in estimated glomerular filtration rate (30% or more). Compared with sleeping 7 to 8 hours per night, the adjusted odds ratios for a rapid decline in renal function were a significant 1.79 (95% CI, 1.06-3.03) for 5 hours or less sleep per night, a significant 1.31 (95% CI, 1.01-1.71) for 6 hours sleep per night, but an insignificant 0.88 (95% CI, 0.50-1.57) for 9 or more hours sleep per night. Similarly, there was a significant trend in the adjusted annualized decline in estimated glomerular filtration rate of 1.2 ml/min/1.73 m(2)/year, 0.9 ml/min/1.73 m(2)/year, 0.8 ml/min/1.73 m(2)/year, and 0.8 ml/min/1.73 m(2)/year for individuals sleeping 5 hours or less per night, 6 hours per night, 7 to 8 hours per night, and 9 hours or more per night, respectively. Thus, shorter sleep duration is prospectively and independently associated with faster decline in renal function.
Sarcoma-Specific Antigens: Detection by Complement Fixation With Serum From Sarcoma Patients
Authors: Frederick R. Eilber, Donald L. Morton
Journal: JNCI Journal of the National Cancer Institute (1970)

Complement-fixation studies revealed a high incidence of antibodies to a common sarcoma-specific antigen prepared from tissue cultures derived from human liposarcomas, fibrosarcomas, and osteosarcomas in the serum of sarcoma patients and their close family members. The presence of a common antigen in human sarcomas and the distribution of antisarcoma antibodies support the hypothesis of an associated infectious agent in human osteosarcoma and expand these findings to include soft-tissue sarcomas.
Leukocyte Migration Inhibition in Patients With Ewing's Sarcoma by 3- m Potassium Chloride Extracts of Fresh and Tissue-Cultured Ewing's Sarcomas 2
Authors: J. L. McCoy, L. J. Jerome, G. B. Cannon, T. C. Pomeroy, R. J. Connor, R. K. Oldham, J. L. Weese, R. B. Herberman
Journal: JNCI Journal of the National Cancer Institute (1977)

Leukocyte migration inhibition (LMI) assays were performed to detect cell-mediated immune reactions against tumor-associated antigens (TAA) of Ewing's sarcoma. With the use of crude antigen preparations obtained by 3 m KCI extractions of fresh Ewing's sarcoma or of tissue culture cells derived from a pleural effusion of a Ewing's sarcoma patient, assays were performed with leukocytes from these patients, patients with other cancers, and normal donors. The results demonstrated approximately 60% or greater positive LMI reactivity in Ewing's sarcoma patients, as compared to less than 10% reactivity of normal donors, with the use of extracts of either fresh or tissue-cultured Ewing's sarcoma cells. A lower proportion of positive reactivity was observed in patients with breast and lung cancer. Further specificity tests indicated that a smaller proportion of patients with Ewing's sarcoma had LMI reactivity with KCI extracts of tissue-cultured cells derived from breast cancer or fresh lung cancer celts than did patients with the homologous disease. The results indicate that many patients with Ewing's sarcoma have cell-mediated immunity toward TAA on Ewing's sarcomas. Inasmuch as all the LMI assays were performed with allogeneic extracts, the data also suggested that different Ewing's sarcomas possess common antigens and that some breast and lung cancers may share some TAA with Ewing's sarcoma.
AB0232 Remission on the Basis of Self-Assessment Tools in Patients with Rheumatoid Arthritis Treated with Tocilizumab
Authors: A. Starkova, V. Amirdjanova
Journal: Annals of the Rheumatic Diseases (2015)

<h3>Objectives</h3> To analyze the rate of remissions in RA pts treated with tocilizumab (TCZ) on self-assessment index. <h3>Methods</h3> The study included 42 RA pts, predominantly female, 86% were RF-positive and, 84% - ACCP-positive, mean age 50,5±3,1 y, mean disease duration 5,6±4,74 y., high disease activity was established in 93% patients. Prior to TCZ all pts were receiving DMARDs, mostly methotrexate at average dose 15,0±2,7 mg/week; 14,3% pts - leflunomide 20 mg/day; 11,9% - sulfasalazine 2 g/day for at least 3 months without any improvement. TCZ 8 mg/kg was administered every 4 weeks during 24 weeks. Treatment outcomes were assessed by patients using RAPID-3, DAS<sub>28</sub>, CDAI, SDAI. <h3>Results</h3> Before therapy average RAPID-3 was 15,6 [11,5;18,85]. After first infusion remission by RAPID-3 scale was achieved in 14% patients, at week 12 – in 20,3%, after 16 weeks - in 25%, by week 20 – in 30,5%, by week 24 - in 33,3% patients. After 6 month of TCZ therapy remission or low disease activity was achieved in 61,9% patients. Comparable results in were documented on SDAI (33%), CDAI (31%) and RAPID-3 (33,3%) scales. By week 24 of therapy maximum percentage of remissions was registered by DAS<sub>28</sub> (71,4%). <h3>Conclusions</h3> Remissions rates on RAPID-3 are similar to SDAI and CDAI, and 2-fold lower than the rates by DAS<sub>28</sub> score. The difference in remissions rates is most likely explained by subjective factor in patient9s self-assessment using RAPID-3, CDAI and SDAI scales vs physician9s oversized assessment of patient9s health status using DAS<sub>28</sub>. <h3>Disclosure of Interest</h3> None declared
Prognostic Value of Pyrosequencing of Mgmt Promoter Methylation in Patients with Glioblastoma Treated By Temozolomide and Hypofractionated High-Dose Imrt
Authors: T. Iuchi, S. Yokoi, M. Ohira, R. Shimada, Y. Hasegawa, K. Kawasaki, T. Sakaida
Journal: Annals of Oncology (2014)
Apparent phase advance in diurnal MHPG rhythm in depression
Authors: H E Gwirtsman, A E Halaris, A W Wolf, E DeMet, J E Piletz, M Marler
Journal: American Journal of Psychiatry (1989)

Several investigators have proposed that diurnal rhythms, particularly that of the norepinephrine metabolite 3-methoxy-4-hydroxyphenylglycol (MHPG), show abnormalities in affective disorders. The present study compared diurnal MHPG rhythms in the plasma of 18 male depressed patients and 12 healthy male volunteers. A diurnal rhythm of MHPG closely fit to a cosine model was observed in volunteers and, to a lesser extent, in depressed patients. Patients, especially those with endogenous depression (N = 11), demonstrated an earlier acrophase (mean +/- SD = 12.53 +/- 3.38 hours), and treatment with desipramine was associated with a significant (3-hour) phase delay. This study confirms and extends previous reports of apparent phase advances in circadian noradrenergic rhythms in depressed patients.