tbuckley/cabot-search huggingface dataset:
Genome-Wide DNA Methylation Analysis Reveals Epigenetic Dysregulation of MicroRNA-34A in <i>TP53</i>-Associated Cancer Susceptibility
Authors: Nardin Samuel, Gavin Wilson, Mathieu Lemire, Badr Id Said, Youliang Lou, Weili Li, Diana Merino, Ana Novokmet, James Tran, Kim E. Nichols, Jonathan L. Finlay, Sanaa Choufani, Marc Remke, Vijay Ramaswamy, Florence M.G. Cavalli, Christine Elser, Lynn Meister, Michael D. Taylor, Uri Tabori, Meredith Irwin, Rosanna Weksberg, Jonathan D. Wasserman, Andrew D. Paterson, Jordan R. Hansford, Maria Isabel W. Achatz, Thomas J. Hudson, David Malkin
Journal: Journal of Clinical Oncology (2016)

Although the link between mutant TP53 and human cancer is unequivocal, a significant knowledge gap exists in clinically actionable molecular targets in Li-Fraumeni syndrome (LFS), a highly penetrant cancer predisposition syndrome associated with germline mutations in TP53. This study surveyed the epigenome to identify functionally and clinically relevant novel genes implicated in LFS.We performed genome-wide methylation analyses of peripheral blood leukocyte DNA in germline TP53 mutation carriers (n = 72) and individuals with TP53 wild type in whom histologically comparable malignancies developed (n = 111). Targeted bisulfite pyrosequencing was performed on a validation cohort of 30 TP53 mutation carriers and 46 patients with TP53 wild type, and candidate sites were evaluated in primary tumors from patients with LFS across multiple histologic tumor types.In 183 patients, distinct DNA methylation signatures were associated with deleterious TP53 mutations in peripheral blood leukocytes. TP53-associated DNA methylation marks occurred in genomic regions that harbored p53 binding sites and in genes encoding p53 pathway proteins. Moreover, loss-of-function TP53 mutations were significantly associated with differential methylation at the locus encoding microRNA miR-34A, a key component of the p53 regulatory network (adjusted P < .001), and validated in an independent patient cohort (n = 76, P < .001). Targeted bisulfite pyrosequencing demonstrated that miR-34A was inactivated by hypermethylation across many histologic types of primary tumors from patients with LFS. Moreover, miR-34A tumor hypermethylation was associated with decreased overall survival in a cohort of 29 patients with choroid plexus carcinomas, a characteristic LFS tumor (P < .05).Epigenetic dysregulation of miR-34A may comprise an important path in TP53-associated cancer predisposition and represents a therapeutically actionable target with potential clinical relevance.
Presence of cerebral microbleeds is associated with worse executive function in pediatric brain tumor survivors
Authors: Erika Roddy, Katherine Sear, Erin Felton, Benita Tamrazi, Karen Gauvain, Joseph Torkildson, Benedict Del Buono, David Samuel, Daphne A. Haas-Kogan, Josephine Chen, Robert E. Goldsby, Anuradha Banerjee, Janine M. Lupo, Annette M. Molinaro, Heather J. Fullerton, Sabine Mueller
Journal: Neuro-Oncology (2016)

A specific form of small-vessel vasculopathy—cerebral microbleeds (CMBs)—has been linked to various types of dementia in adults. We assessed the incidence of CMBs and their association with neurocognitive function in pediatric brain tumor survivors. In a multi-institutional cohort of 149 pediatric brain tumor patients who received cranial radiation therapy (CRT) between 1987 and 2014 at age <21 years and 16 patients who did not receive CRT, we determined the presence of CMBs on brain MRIs. Neurocognitive function was assessed using a computerized testing program (CogState). We used survival analysis to determine cumulative incidence of CMBs and Poisson regression to examine risk factors for CMBs. Linear regression models were used to assess effect of CMBs on neurocognitive function. The cumulative incidence of CMBs was 48.8% (95% CI: 38.3–60.5) at 5 years. Children who had whole brain irradiation developed CMBs at a rate 4 times greater than those treated with focal irradiation ( P < .001). In multivariable analysis, children with CMBs performed worse on the Groton Maze Learning test (GML) compared with those without CMBs ( Z -score –1.9; 95% CI: –2.7, –1.1; P < .001), indicating worse executive function when CMBs are present. CMBs in the frontal lobe were associated with worse performance on the GML ( Z -score –2.4; 95% CI: –2.9, –1.8; P < .001). Presence of CMBs in the temporal lobes affected verbal memory ( Z -score –2.0; 95% CI: –3.3, –0.7; P = .005). CMBs are common and associated with neurocognitive dysfunction in pediatric brain tumor survivors treated with radiation.
Bosutinib As Therapy for Chronic Phase Chronic Myeloid Leukemia Following Resistance or Intolerance to Imatinib: 36-Month Minimum Follow-up Update
Authors: Jorge E. Cortes, Hagop M. Kantarjian, Dong-Wook Kim, Anna G Turkina, Zhi-Xiang Shen, H. Jean Khoury, Tim H Brümmendorf, Philippe Schafhausen, Edo Vellenga, Ricardo Pasquini, Vikram Mathews, Tamas Masszi, Simon Durrant, Kimmo Porkka, Eric Leip, Virginia Kelly, Nadine Besson, Carlo Gambacorti-Passerini
Journal: Blood (2012)
Factor XIa–specific IgG and a reversal agent to probe factor XI function in thrombosis and hemostasis
Authors: Tovo David, Yun Cheol Kim, Lauren K. Ely, Isaac Rondon, Huilan Gao, Peter O’Brien, Michael W. Bolt, Anthony J. Coyle, Jorge L. Garcia, Eric A. Flounders, Thomas Mikita, Shaun R. Coughlin
Journal: Science Translational Medicine (2016)

A noneffector, active site–dependent human IgG1 specific to factor XIa inhibits thrombus formation in two animal models at clinically relevant doses without a detectable effect on hemostasis.
A phase 3 open-label, randomized, multicenter study of Imprime PGG in combination with cetuximab in patients with KRAS wild type metastatic colorectal cancer.
Authors: Richard Dale Huhn, Jamie Lowe, Michele Grady, Corina Candiani Taitt, Michele Anne Gargano, Ada H. Braun
Journal: Journal of Clinical Oncology (2015)

TPS787 Background: Imprime PGG (Imprime) is a novel immune modulator (complex carbohydrate biologic), which harnesses innate immune cells to enhance killing of antibody-targeted tumor cells. In a phase 2 single-arm clinical trial in mCRC, the combination of Imprime with cetuximab resulted in 24% ORR, 62% disease control rate (DCR), and median time to progression (TTP) of 12 wks (Tamayo ME, Ann Onc 2010), representing approximate 100% increases vs historical control (Cunningham, NEJM 2004). ORR was 45%, DCR, 82% and TTP, 24 wks in pts with KRAS WT tumors (post hoc analysis). Single-agent cetuximab has been shown to improve objective response rate (ORR), progression-free survival (PFS) and overall survival (OS) in patients (pts) with epidermal growth factor receptor (EGFR) expressing, KRAS wild-type (WT) metastatic colorectal cancer (mCRC) who failed oxaliplatin- and irinotecan-based therapy or are intolerant to irinotecan. The mechanism of action of cetuximab is thought to rely on competitive blockade of endogenous ligand binding and downstream signaling, internalization and down regulation of EGFR, as well as antibody-dependent cellular cytotoxicity (ADCC) (Erbitux SmPC). The current trial, sponsored by Biothera (registered with ClinicalTrials.gov NCT01309126) is to confirm these findings in phase 3. Methods: Eligible pts will have had prior oxaliplatin- and irinotecan-based therapy or be intolerant to irinotecan, and will meet key inclusion criteria including measurable disease and ECOG performance status of 0 or 1. In a 2:1 randomization, stratified by geographic region, prior chemotherapy and site, approximately 795 pts will receive weekly open-label Imprime plus cetuximab or cetuximab alone. The primary endpoint of the study is OS and primary analysis will occur when ~709 deaths have occurred. Secondary endpoints include PFS, ORR (based on RECIST 1.1), quality of life, safety and pharmacokinetics. Exploratory endpoints include biomarker analyses. Pt screening and enrollment is underway in the United States and Europe. Clinical trial information: NCT01309126.
Leukocytes and the Risk of Ischemic Diseases
Authors: Stefania Lamon-Fava
Journal: JAMA (1987)

<h3>To the Editor.—</h3> We are writing in reference to the article concerning the role of the white blood cell (WBC) count as an independent predictor for the risk of ischemic diseases.<sup>1</sup>The authors mention the possibility that the WBC count could merely be a marker for stress. To support their statement that stress is a cardiovascular risk factor associated with increased blood catecholamine levels and with an elevated WBC count, they quote an article by Friedman et al<sup>2</sup>that not only does not mention leukocytes at all, but does not even mention the word<i>stress</i>. This article reports instead the results of a study on catecholamine secretion in the type A behavior pattern, an action/emotion complex characterized by aggressive and competitive drive and an enhanced sense of urgency. We are surprised that the authors did not consider the possibility that the type A behavior pattern, rather than stress,
S60 Efficacy and safety of aclidinium/formoterol fixed-dose combination in patients with COPD, stratified by ICS use: Abstract S60 Table 1
Authors: D Singh, A D’Urzo, E Garcia Gil
Journal: Thorax (2015)

<h3>Introduction and objectives</h3> This was a secondary analysis, stratified by concomitant inhaled corticosteroid (ICS) use, based on pooled data from ACLIFORM (NCT01462942) and AUGMENT (NCT01437397), two Phase III, 24-week, randomised, double-blind studies of twice-daily aclidinium/formoterol (AB/FF) fixed-dose combination in patients with moderate to severe airflow obstruction. <h3>Methods</h3> Patients received twice-daily AB/FF 400/12 μg, AB/FF 400/6 μg, AB 400 μg, FF 12 μg or placebo (PBO). Any baseline ICS use was continued throughout. Assessments: change from baseline in 1-hour morning post-dose and morning pre-dose (trough) forced expiratory volume in 1 s (FEV<sub>1</sub>) at Week 24 and Transition Dyspnoea Index (TDI) score (pre-planned), rate of exacerbations and adverse events (AEs). <h3>Results</h3> Analyses included 3398 patients (mean age 63.5 years; 60.5% male; baseline ICS use range 38.7–40.0%). In patients using ICS, AB/FF 400/12 µg improved post-dose FEV<sub>1</sub>, trough FEV<sub>1 </sub>(Table 1), and TDI vs PBO by 297 mL, 145 mL and 1.59 units, respectively (all p &lt; 0.001). In addition, in patients receiving concomitant ICS, AB/FF 400/12 µg improved post-dose FEV<sub>1 </sub>and trough FEV<sub>1</sub> (Table 1) by 109 mL and 71 mL, respectively, vs FF alone (both p &lt; 0.001) and by 151 mL and 54 mL, respectively, vs AB alone (p &lt; 0.001 and p &lt; 0.05, respectively). In patients not using ICS, there were improvements with AB/FF 400/12 µg in post-dose FEV<sub>1</sub>, trough FEV<sub>1</sub> (Table 1) and TDI of 290 mL, 135 mL and 1.36 units vs PBO, respectively (all p &lt; 0.001). The exacerbation rate was higher in patients using ICS (0.67) vs those who did not (0.36) and AB/FF 400/12 µg significantly reduced the rate of exacerbations vs PBO (p &lt; 0.05; Table 1). The overall AE frequency was similar throughout (range with ICS, 54.8–60.7%; without, 56.0–60.3%). The most common AEs across patient groups were COPD exacerbation, nasopharyngitis and headache, irrespective of ICS use. <h3>Conclusion</h3> In this analysis, aclidinium/formoterol 400/12 µg twice daily improved bronchodilation and dyspnoea in patients independent of ICS use and reduced exacerbations in patients using ICS. Combining AB and FF along with an ICS increased bronchodilation vs either monotherapy. AE frequencies were similar between the patient groups, regardless of ICS use.
NOTCH1 Mutations Are Associated with High CD49d Expression in Chronic Lymphocytic Leukemia
Authors: Antonella Zucchetto, Chiara Caldana, Federico Pozzo, Silvia Rasi, Carmela Ciardullo, Dania Benedetti, Erika Tissino, Francesca Maria Rossi, Riccardo Bomben, Francesco Zaja, Gabriele Pozzato, Francesco Di Raimondo, Giovanni Del Poeta, Michele Dal Bo, Davide Rossi, Gianluca Gaidano, Valter Gattei
Journal: Blood (2014)
Current Status of Distress Screening in Designated Cancer Hospitals: A Cross-Sectional Nationwide Survey in Japan
Authors: Toru Okuyama, Yoshiyuki Kizawa, Tatsuya Morita, Hiroya Kinoshita, Megumi Uchida, Asami Shimada, Akemi Shirado Naito, Tatsuo Akechi
Journal: Journal of the National Comprehensive Cancer Network (2016)

Background: The purpose of this study was to investigate the current status of distress screening implementation in Japanese designated cancer hospitals. Subjects and Methods: This was a cross-sectional observational study. Palliative care team representatives in all designated cancer hospitals in Japan completed an ad hoc questionnaire. Demographic data in 2014 were obtained from the Ministry of Health, Labour and Welfare in Japan. Results: Of 422 institutions, 389 responded (92%) and data were obtained from 379 (90%). Approximately 90% of institutions had implemented a distress screening program at some level, and approximately 60% had just started screening. Among those institutions that screened, 77% provided individualized triage to specialized services within the institutions, whereas 60% did not routinely follow-up with patients who had positive screening results. The estimated median percentage of screened patients referred to palliative care teams was 0.4% in outpatient settings and 6.3% in inpatient settings. Although 68% of respondents perceived that screening was useful overall, they also reported difficulties when conducting screening with patients, reporting “no established effective treatment for problems screened” (66%), “patients complain it is difficult to express their distress using scales” (58%), and that it was “difficult to manage screened problems because of lack of time” (49%). Eight perceived barriers to implementing distress screening programs in hospitals were identified; a lack of human resources ranked highest. Conclusions: Implementation of distress screening in designated cancer hospitals in Japan has just begun. Policymakers should acknowledge that screening can be beneficial for patients when it is implemented with appropriate resources and established methods.
Hepatitis E in blood donors: investigation of the natural course of asymptomatic infection, Germany, 2011
Authors: Tanja Vollmer, Juergen Diekmann, Matthias Eberhardt, Cornelius Knabbe, Jens Dreier
Journal: Eurosurveillance (2016)

Asymptomatic hepatitis E virus (HEV) infections have been found in blood donors from various European countries, but the natural course is rarely specified. Here, we compared the progression of HEV viraemia, serostatus and liver-specific enzymes in 10 blood donors with clinically asymptomatic genotype 3 HEV infection, measuring HEV RNA concentrations, plasma concentrations of alanine/aspartate aminotransferase, glutamate dehydrogenase and bilirubin and anti-HEV IgA, IgM and IgG antibodies. RNA concentrations ranged from 77.2 to 2.19×10(5) IU/mL, with viraemia lasting from less than 10 to 52 days. Donors showed a typical progression of a recent HEV infection but differed in the first detection of anti-HEV IgA, IgM and IgG and seropositivity of the antibody classes. The diagnostic window between HEV RNA detection and first occurrence of anti-HEV antibodies ranged from eight to 48 days, depending on the serological assay used. The progression of laboratory parameters of asymptomatic HEV infection was largely comparable to the progression of symptomatic HEV infection, but only four of 10 donors showed elevated liver-specific parameters. Our results help elucidate the risk of transfusion-associated HEV infection and provide a basis for development of screening strategies. The diagnostic window illustrates that infectious blood donors can be efficiently identified only by RNA screening.
Genetic analyses in a cohort of children with pulmonary hypertension
Authors: Marilyne Levy, Mélanie Eyries, Isabelle Szezepanski, Magalie Ladouceur, Sophie Nadaud, Damien Bonnet, Florent Soubrier
Journal: European Respiratory Journal (2016)

The prevalence of germline mutations in paediatric pulmonary hypertension (PH) is poorly documented. The objective of this study was to determine the mutation frequency in PH genes in a paediatric cohort and describe the clinical characteristics of mutation carriers.The study involved 66 index cases with PH: 35 children with idiopathic pulmonary arterial hypertension (IPAH); five children with familial PAH (FPAH); three children with pulmonary veno-occlusive disease (PVOD); and 23 children with PAH associated with congenital heart disease (APAH-CHD).No mutations were found in the 23 children with APAH-CHD. In the 40 children with IPAH or FPAH, 12 mutations were found: five on BMPR2; four on ACVRL1; and three on TBX4. In the three PVOD cases, two carried the EIF2AK4 mutation. Mutation carriers had a more severe disease at diagnosis and more aggressive first-line therapy was required. The three patients with PVOD had a very severe disease at diagnosis and required a lung transplantation.The genetic architecture of paediatric PAH is enriched in ACVRL1 and TBX4 mutations compared to adult PAH, but further studies are required to confirm these results. Childhood-onset PAH in children carrying a mutation in one of the genes tested has a more severe presentation at diagnosis but a similar outcome to that observed in non-carriers.
Surveillance of varicella and herpes zoster in Slovenia, 1996 – 2005
Authors: M Socan, M Blaško
Journal: Eurosurveillance (2007)

In Slovenia, varicella and herpes zoster infections are case-based mandatorily notifiable diseases. We present surveillance data for a period of ten years (1996 - 2005). Incidences of varicella ranged from 456 to 777 per 100 000 population in all age groups. As many as 75% of varicella cases reported were in pre-school children, with children aged three and four years being most affected. The incidence of varicella increased between October and January and was lowest in August and September; the seasonal pattern matches patterns in the school calendar. Herpes zoster was declared a reportable disease in 1995. In 2005, 1627 cases were notified (81.3/100 000). Female cases outnumbered male. The highest incidence of herpes zoster was noted in elderly individuals over 70 years of age. Complications, such as zoster meningitis and meningoencephalitis, were rarely reported (3.05/1 000 000).
Does physical function impact the acceptability of routine patient-reported outcome surveys in cancer patients?
Authors: Lauren Wong, Catherine Brown, Andrea Perez-Cosio, Yvonne Leung, Mindy Liang, Gursharan Gill, Samantha Sarabia, Sabrina Yeung, Aixin Liu, Doris Howell, Geoffrey Liu
Journal: Journal of Clinical Oncology (2016)

67 Background: Patient-reported outcome measures (PROMs) are used to collect cancer-related symptom and symptomatic toxicity data. Understanding factors that affect the acceptability of PROMs is useful for improving the participation of such routine screening practices. We investigated the association between patient’s functional status on their acceptance and perception of usefulness of tablet technology to routine collection of PROM data in the clinical setting. Methods: 279 adult cancer outpatients at Toronto’s Princess Margaret Cancer Centre completed two physical function surveys, the HAQ-DI and WHODAS, using touchscreen tablet technology. Patient socio-demographics and their willingness of completing PROMs on a routine basis were also collected. Results: The median age was 62 (range: 20–94); 50% male, and 68% Caucasian. Patients were recruited from breast (10.4%), gastrointestinal (10.4%), genitourinary (14%), gynecology (14.3%), head &amp; neck (17.9%), hematology (17.6%), and thoracic (15.4%) cancer clinics. 87% were willing to complete the survey on a touchscreen tablet, 74% did not find it time-consuming, and 4% found completion of the survey made their clinic visit more difficult. Only 1% found the questions upsetting or distressful; however, less than 60% were willing to complete similar surveys at every visit. Being Caucasian (p = 0.015) and Canadian-born (p = 0.021) were significantly associated with acceptability of the survey on a regular basis. However, HAQ-DI and WHODAS are not significantly associated with willingness to complete PROMs regularly (p = 0.30 &amp; p = 0.16 respectively). Conclusions: Physical function status is not associated with acceptability; however, ethnicity does play a role where Canadian-born and Caucasian patients are more likely to complete PROMs regularly. Despite this, over 40% of patients were not willing to fill in the PROMs at each visit. Socio-cultural factors may impact on patients’ perceptions of the value of routine screening; however, assessment burden may also limit willingness to complete surveys on an ongoing basis. Further research is underway to gain more insight into the limiting factors of patients to complete the survey routinely.
Aspergillus Specific PCR and Galactomannan of Bronchoalveolar Lavage Are Superior to Concomitant Same-Day Testing of Concurrent Blood Samples in Immunocompromised Hematological Patients with Suspected Invasive Aspergillosis
Authors: Tobias Boch, Birgit Spiess, Oliver Cornely, Werner J. Heinz, Joachim Hahn, Stefan W. Krause, Hartmut Bertz, Wolf-Karsten Hofmann, Dieter Buchheidt, Mark Reinwald
Journal: Blood (2015)
Carbohydrate Antigen-125–Guided Therapy in Acute Heart Failure
Authors: Julio Núñez, Pau Llàcer, Vicente Bertomeu-González, Maria José Bosch, Pilar Merlos, Sergio García-Blas, Vicente Montagud, Vicent Bodí, Vicente Bertomeu-Martínez, Valle Pedrosa, Andrea Mendizábal, Alberto Cordero, Jorge Gallego, Patricia Palau, Gema Miñana, Enrique Santas, Salvador Morell, Angel Llàcer, Francisco J. Chorro, Juan Sanchis, Lorenzo Fácila, Julio Núñez, Sergio Garcia-Blas, Juan Sanchis, Vicent Bodí, Enrique Santas, Miryam Olivares, Clara Bonanad, Lourdes Bondanza, Angel Llàcer, Francisco J. Chorro, Maria José Bosch, Pilar Merlos, Jorge Gallego, Patricia Palau, Pau Llàcer, Andrea Mendizabal, Gema Miñana, Valle Pedrosa, Montserrat Salvador, Antonio Camps, Gonzalo Salvador, Vicente Bertomeu-González, Vicente Bertomeu-Martínez, Alberto Cordero, José Moreno, Juan Quiles, Adriana López Pineda, Lorenzo Fácila, Vicente Montagud, Rosa Fonfria, Maria Teresa Jareño, Joaquina Belchi, Eva Rumiz, Salvador Morell
Journal: JACC Heart Failure (2016)
Adverse Outcomes of Underuse of β-Blockers in Elderly Patients
Authors: Zvonko Rumboldt
Journal: JAMA (1997)

To the Editor.  —The timely and most instructive article by Soumerai et al 1 about the underuse of β-blockers in secondary prevention of MI in the New Jersey area (only 21% of the eligibile elderly patients were receiving such a therapy) prompted us to report a related comparison from Europe. Analyzing the discharge letters issued to patients successfully treated for AMI in Barcelona, Spain, Agusti et al 2 have shown that in 1983 only 20% of the patients were advised to take β-blockers; this figure increased to 34% in 1988. At the time of discharge, all patients discharged from Barcelona hospitals receive enough medicine to last them for a few days and a discharge letter recommending that their family physicians should prescribe the same treatment for them. Assessing discharge letters sent to all patients with a diagnosis of AMI in Split, Croatia (another Mediterranean town with similar climate and approach), we 3 found
Mendelian randomization analysis demonstrates that low vitamin D is unlikely causative for pediatric asthma
Authors: Erik B. Hysinger, Jeffrey D. Roizen, Frank D. Mentch, Lyam Vazquez, John J. Connolly, Jonathan P. Bradfield, Berta Almoguera, Patrick M. Sleiman, Julian L. Allen, Michael A. Levine, Hakon Hakonarson
Journal: Journal of Allergy and Clinical Immunology (2016)