tbuckley/cabot-search huggingface dataset:
Legionnaires’ disease in Italy: results of the epidemiological surveillance from 2000 to 2011
Authors: M C Rota, M G Caporali, A Bella, M L Ricci, C Napoli
Journal: Eurosurveillance (2013)

According to the Italian Surveillance System for Legionnaires' disease (LD), physicians must fill in a form for every case and send it through the Local Health Units to the National Institute of Health (Istituto Superiore di Sanità, ISS). Forms reported in the period from 2000 to 2011 were analysed and discussed. A total of 9,803 cases of LD were reported to ISS during the study period. The median age of cases was 63 years, with a ratio male/female of 2.6 and a case fatality rate of 11.8%. The number of cases has been steadily increasing from 192 cases in 2000 to 1,235 in 2010 and 1,008 cases in 2011. The reported cases showed a geographical gradient, with the highest number notified in the north and the lowest in the south. The majority of cases (73.0%) were community-acquired, followed by travel-associated (13.5%) and healthcare-associated cases (9.3%), cases acquired in long-term care facilities (2.1%), and other types of exposure (2.1%). Even though the increasing trend of LD in Italy indicates an improvement in the ability to detect and report cases, the geographical gradient highlights the existence of low reporting areas where the epidemiological surveillance of LD should be further strengthened.
Abstract 17496: Diagnostic Accuracy of a Smartphone based Six-Minute Walk Test
Authors: Gabriel C Brooks, Eric Vittinghoff, Sivaraman Iyer, Gregory M Marcus, Mark J Pletcher, Jeffrey E Olgin
Journal: Circulation (2014)

Introduction: Timely and accurate diagnosis of heart failure exacerbation after discharge is an unmet medical need with enormous societal costs. Six-minute walk tests (6MWT) powerfully predict heart failure exacerbation, but require a clinic visit and valuable personnel time. We sought to determine the diagnostic accuracy of a 6MWT recorded on a novel smartphone App (6MWTApp), which we aim to integrate into a comprehensive digital heart failure monitoring program within the Health eHeart Study.

Hypothesis: We hypothesized that distance calculated using the smartphone measurements would correlate well with physically measured walk distance, at the time of a clinical 6MWT (defined by an r ≥ 0.80).

Methods: Six-Minute Walk Tests were conducted on a clinical 6MWT course by participants who wore, on a hip holster and in a front pocket, iPhones that ran the 6MWTApp. Distances traveled were calculated based on a linear regression model that incorporated the smartphone-measured steps and the patient height, and were compared to the physically measured distance walked at the time of the test.

Results: The 6MWTApp was tested in 52 participants half of whom had heart failure or pulmonary hypertension. The App demonstrated good correlation with measured distance, r = 0.89 95% CI (0.82-0.95). For those with pHTN or CHF the correlation (r) was 0.75 95% CI (0.54-0.96) and for those with neither pHTN or CHF the correlation (r) was 0.92 95% CI (0.85-0.98). There was no difference between phone placement in the front pocket vs worn in a holster on the hip.

Conclusions: Distance walked during a 6MWT is accurately predicted by a 6MWTApp.

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Allogeneic bone marrow transplantation with co-stimulatory blockade induces macrochimerism and tolerance without cytoreductive host treatment
Authors: Thomas Wekerle, Josef Kurtz, Hiroshi Ito, Joseph V. Ronquillo, Victor Dong, Guiling Zhao, Juanita Shaffer, Mohamed H. Sayegh, Megan Sykes
Journal: Nature Medicine (2000)
Transcription inhibition by Actinomycin D as a mechanism-based approach to treatment of Bcr-Abl-positive chronic myelogenous leukemia
Authors: Rong Chen, Cheng-Yu Tsai, William Plunkett
Journal: Cancer Research (2007)

AACR Annual Meeting-- Apr 14-18, 2007; Los Angeles, CA

3211 

The transcription inhibitor flavopiridol reduces the Bcr-Abl mRNA level and induces cell death in the human Bcr-Abl positive chronic myelogenous leukemia (CML) cell line, K562, and in murine Ba/F3 cells made dependent on its expression. This action of flavopiridol is synergistic with the Bcr-Abl kinase inhibitor imatinib. These results support the sequential blockade hypothesis, which proposes that decreasing the cellular levels of oncogene proteins, that are required for tumor cell survival and proliferation, by inhibitors of transcription and/or translation would augment the action of specific kinase inhibitors (Cancer Res., 66:10959, 2006). This strategy would be most effective in tumor cells that are addicted to the expression of an oncogene, and for oncogenes with short intrinsic half-lives in their mRNAs and proteins. The Bcr-Abl addicted CML is an ideal model system to evaluate this strategy. Here, as an extension of this sequential blockade strategy, we studied another transcription inhibitor, actinomycin D (ActD), a polypeptide antibiotic that is useful for the treatment of sarcomas, Wilms’ tumor, testicular cancer and choriocarcinoma. The action of ActD as a transcription inhibitor was confirmed in the K562 cells. ActD inhibited RNA synthesis as measured by [3H]uridine incorporation with an IC50 of 60 ng/ml after 3 hr of incubation. This was associated with a decrease in the transcript level of Bcr-Abl, measured by real-time quantitative PCR. Consequently, the Bcr-Abl protein level also decreased. As K562 cells are critically dependent on the continuous expression of Bcr-Abl for survival, decreasing the expression of Bcr-Abl induced cell death in the cells. This was demonstrated as induction of PARP cleavage visualized by immunoblots, inhibition of cell growth and clonogenicity. ActD also reduced the transcript and protein levels of c-Myc and Mcl-1, other oncoproteins with short turn over rates. However, siRNA knockdown procedures suggested that c-Myc levels did not affect K562 cell viability. Further, the Ba/F3 cells expressing either the wild-type p210 Bcr-Abl, or the imatinib resistant T315I or E255K mutations of Bcr-Abl were equally sensitive to ActD in clonogenic assays, with IC50 values of 1-2 ng/ml, indicting lack of cross resistance. Thus, these data support the use of ActD for treatment of oncogene-addicted tumors such as CML, both to complement the activities of Bcr-Abl kinase-targeted inhibitors such as imatinib, desatinib, and nilotinib, and to overcome resistance to these kinase inhibitors due to mutations in the Bcr-Abl kinase domain. Other short-lived oncogenic kinases that sustain the tumor phenotype could also be targeted by ActD, including the activated c-Kit in gastrointestinal stromal tumors and platelet-derived growth factor receptor in myeloproliferative disorders.
Improved disease markers suggest dual response in a patient with metastatic castration resistant prostate cancer and chronic lymphocytic leukemia following active cellular immunotherapy
Authors: Heather H. Cheng, Colleen Soleau, Evan Y. Yu
Journal: Journal of Hematology & Oncology (2015)

Prostate cancer and chronic lymphocytic leukemia (CLL) are relatively common malignancies associated with advanced age. Although immunotherapy-based strategies are used to treat both, currently, there is no overlap in specific therapies. Sipuleucel-T is an active cellular immunotherapy that improves overall survival for patients with metastatic castration resistant prostate cancer (mCRPC) but is not typically associated with a decline in prostate-specific antigen (PSA) following administration. We report the case of a 78-year-old man with mCRPC and Rai stage 0 CLL who sustained a 12-month decline in both PSA and white blood cell (WBC) count following treatment with APC8015-2 (an investigational form of sipuleucel-T), as part of the phase II ProACT clinical trial. Two years later, the patient received commercial sipuleucel-T and again was noted to have a decline in PSA. Exploratory analysis did not clearly identify any peripheral immune markers associated with response. This case report suggests that treatment with sipuleucel-T can rarely lead to PSA decline, may have dual activity against both prostate cancer and CLL, and that these findings warrant further investigation.
Increased exercise ejection fraction and reversed remodeling after long‐term treatment with metoprolol in congestive heart failure: a randomized, stratified, double‐blind, placebo‐controlled trial in mild to moderate heart failure due to ischemic or idiopathic dilated cardiomyopathy
Authors: F. Waagstein, O. Strömblad, B. Andersson, M. Böhm, M. Darius, W. Delius, F. Goss, K.J. Osterziel, M. Sigmund, S.‐P. Trenkwalder, I. Wahlqvist
Journal: European Journal of Heart Failure (2003)
Outbreak of E. coli O157 infection in the south west of the UK: risks from streams crossing seaside beaches
Authors: C Ihekweazu, M Barlow, S Roberts, H Christensen, B Guttridge, D A Lewis, S Painter
Journal: Eurosurveillance (2006)

In August 2004 seven cases of Escherichia coli O157 infection were identified in children on holiday in Cornwall, southwest England, all of whom had stayed at different sites in the area. Isolates from all seven cases were confirmed as E. coli serogroup O157 phage type 21/28. We carried out a case-control study among holidaymakers who visited the beach. A standardised questionnaire was administered by telephone to parents. They were asked where on the beach the children had played, whether they had had contact with the stream that flowed across the beach, and about their use of food outlets and sources of food eaten. Cases were more likely to have played in the stream than controls (OR [1.72- undefined]). The time spent in the stream by cases was twice spent there by controls. Cases and controls were equally exposed to other suspected risk factors. PFGE profiles for all the cases were indistinguishable. Increased numbers of coliforms were found in the stream prior to the outbreak. Cattle were found grazing upstream. We suggest that the vehicle of infection for an outbreak of acute gastrointestinal illness caused by E. coli O157 was a contaminated freshwater stream flowing across a seaside beach. The onset dates were consistent with a point source. Heavy rainfall in the days preceding the outbreak might have lead to faeces from the cattle potentially contaminated by E. coli O157 contaminating the stream, thereby leading to the outbreak. Control measures included fencing off the part of the stream in which children played, and putting up warning signs around the beach.
Abstract 11393: Computational Protein Design to Re-Engineer Stromal Cell-Derived Factor-1α (SDF) Generates a Supra-Efficient Angiogenic Polypeptide Analog
Authors: William Hiesinger, Jose Manuel Perez-Aguilar, Pavan Atluri, Nicole A Marotta, John R Frederick, J. R Fitzpatrick, Ryan C McCormick, Jeffrey R Muenzer, Rebecca D Levit, Li-Jun Yuan, John W MacArthur, Jeffery G Saven, Y. J Woo
Journal: Circulation (2010)

Background:  After ischemic injury, cardiac secretion of the potent endothelial progenitor stem cell (EPC) chemokine SDF stimulates endogenous neovascularization and myocardial repair, a process insufficiently robust to repair major infarcts. Experimentally, exogenous administration of recombinant SDF enhances neovasculogenesis and cardiac function after MI. However, SDF has a short half-life, is bulky, and very expensive. Smaller analogs of SDF may provide translational advantages including enhanced stability and function, ease of synthesis, lower cost, and potential modulated delivery via engineered biomaterials. In this study, computational protein design was used to create a mathematically more efficient evolution of the native SDF protein.   Methods and Results:  Protein structure modeling utilizing satisfaction of spatial restraints was used to engineer an SDF polypeptide analog (ESA) that combined the N-terminus (activation and binding) and C-terminus (extracellular stabilization) with a diproline residue to limit the conformational flexibility of the peptide backbone and generate an optimal three dimensional polypeptide configuration. EPCs in ESA gradient, assayed by Boyden chamber, showed significantly increased migration compared to both SDF and saline (ESA 567±74 cells/HPF vs SDF 438±46 p=0.037; vs Control 156±45 p=0.001). EPC receptor activation was evaluated by quantifying phosphorylated AKT. ESA had significantly greater pAKT levels than SDF and control (1.64±0.24 vs 1.26±0.187, p=0.01; vs. 0.95±0.08, p   Conclusion:  A novel re-engineered SDF polypeptide analog more efficiently induces EPC migration and improves post-MI cardiac function compared to native SDF protein, and thus offers a more clinically translatable neovasculogenic therapy.
Common variants at 10p12.31, 10q21.1 and 13q12.13 are associated with sporadic pituitary adenoma
Authors: Zhao Ye, Zhiqiang Li, Yongfei Wang, Ying Mao, Ming Shen, Qilin Zhang, Shiqi Li, Liangfu Zhou, Xuefei Shou, Jianhua Chen, Zhijian Song, Zengyi Ma, Zhaoyun Zhang, Yiming Li, Hongying Ye, Chuanxin Huang, Tao Wang, Wenqiang He, Yichao Zhang, Rong Xie, Nidan Qiao, Huijia Qiu, Shan Huang, Meng Wang, Jiawei Shen, Zujia Wen, Wenjin Li, Ke Liu, Juan Zhou, Lin Wang, Jue Ji, Yin Wang, Hong Chen, Haixia Cheng, Zhifeng Shi, Yuqian Zhu, Daoying Geng, Zhenwei Yao, Weijun Tang, Bin Lu, Li Pan, Yi Zhang, Weimin Bao, Jinsong Wu, Kang Zheng, Yongyong Shi, Yao Zhao
Journal: Nature Genetics (2015)
Survey of active verbs in the titles of clinical trial reports Informative titles in the BMJ
Authors: N. W Goodman
Journal: BMJ (2000)

The title of the report of a clinical trial can be indicative (such as "Newbetalol in the treatment of tachycardias") or informative ("Newbetalol prevents tachycardias"). 1 Rosner believes informative titles are "improper and imprudent" and a symptom of "science as product." 2 Weiss objected to an "overly optimistic" title beginning "Improved survival . .." from a pilot study using historical controls. 3 According to the popperian model, hypotheses cannot be proved but only supported or rejected, and then only to an arbitrary level of statistical significance.This makes an informative title incorrect, but rejected hypotheses live on in such titles.I tested the validity of informative titles in clinical reports and their prevalence.
Novel narrow spectrum kinase inhibitors inhibit rhinovirus replication via enhancement of interferon expression in nasal epithelial cells of atopic and non-atopic patients
Authors: Marco Contoli, Kazuhiro Ito, Donatella Poletti, Antonio Pastore, Alberto Papi
Journal: European Respiratory Journal (2011)

RATIONAL  Rhinovirus infection is one of important causes of asthma exacerbation. Deficient innate immune response was reported in asthma accounting for increased susceptibility of asthmatic patients to respiratory viral infections. The aim of this study is to evaluate the effects of RV568 and RV1088, narrow spectrum kinase inhibitors (NSKIs), on HRV16 replication and interferon expression in nasal brushing epithelial cells (NBEC) from atopic (A) and non-atopic (NA) patients.   Methods:  NBECs were collected from 9 A- and 9 NA-rhinitis patients. Cells were treated with RV568, RV1088, fluticasone propionate (FP) or tiotropium bromide (TB), and infected with HRV16 (5MOI). After 1 hr absorption, cells were washed with PBS and then treated with compounds again. At 8hrs after infection, cells were collected to determine viral RNA and IFN-λ, IFN-β mRNAs by real time RT-PCR.   Results:  HRV16 viral load (copy number) was 9 fold higher in NBECs of A-patients than those of NA-patients (48.6×10 5  and 5.4×10 5 , respectively, p=0.083). In addition, IFN-λ expression was significantly lower in A-patients than NA-patients (copy number, 801±122, 1363±174, p=0.02). IFN-β expression showed similar trends. Both RV568 (100nM) and RV1088 (10, 100nM) inhibited HRV16 replication, and significantly increased IFN-λ, -β expression, particularly in A-patients. FP (100nM) and TB (100nM) did not inhibit viral load or increase IFN expression.   Conclusions:  HRV16 infection is more severer in NBECs from A- compared to NA-patients due to deficient HRV16-induced IFN expression, that is restored by RV568 and RV1088.
490. Long Term Expression and Biodistribution of HIV Vector Pseudotyped with Deletion Mutant of the Ebola Envelope Glycoprotein Following Instillation in Airway of Nonhuman Primates
Authors: Gregory P. Schumer, Gary P. Kobinger, Maria F. Medina, Daniel J. Weiner, James M. Wilson
Journal: Molecular Therapy (2004)

Several studies have demonstrated that pseudotyping lentiviral vectors with other viral envelopes can optimize and even alter the tropism to cell types known to be non-permissive to VSV-G-HIV mediated transduction. We and others have demonstrated that HIV vector pseudotyped with the Ebola Zaire (EboZ-GP) envelope can transduce the airway epithelia of immunocompetent C57BL/6 mice through the apical surface of the cells. A group of EboZ-GP envelope deletion mutants was generated to minimize EboZ-GP associated toxicity and perhaps improve vector-mediated transduction. Both reduced cellular toxicity and significant improvement in transduction efficiency has been shown in vitro and in vivo with these deletion mutants. HIV-based vectors pseudotyped with the Non-Toxic EboZ-GP Deletion 4 or 6 (NTD4 or NTD6) and encoding for the b-galactosidase reporter gene were evaluated following instillation in the lung of nonhuman primates (rhesus macaques) and compared to the wild-type EboZ-GP envelope pseudotyped HIV vector. Transduction efficiency was assessed by b-gal. staining and TaqMan PCR 8 to 10 weeks post-administration. In addition, a biodistribution analysis was performed to determine whether HIV vector could leak into other internal organs following lung instillation. TaqMan PCR was used to analyze different organs such as spleen, liver, gonads and brain for the presence of HIV vector genome copies. Results indicate that HIV-based vector pseudotyped with the Non-Toxic EboZ-GP deletion mutant transduces airway epithelia and submucosal glands more efficiently than the wild type EboZ-GP pseudotyped vector. Areas of the transduced lung with pseudotyped HIV vector showed sections with up to 18% of b-gal. positive cells by histochemical staining. The instilled lung contained up to an average of 21 HIV vector genome copies per 100 total lung cells as determined by TaqMan PCR. Overall, this study shows that deletion mutants of the Ebola envelope are less toxic and that in the context of HIV-based vector, transduction efficiency of nonhuman primate airway is improved.
Letter by Klok et al Regarding Article, “ <sup>18</sup> F-Fluorodeoxyglucose Positron Emission Tomography/Computed Tomography Enables the Detection of Recurrent Same-Site Deep Vein Thrombosis by Illuminating Recently Formed, Neutrophil-Rich Thrombus”
Authors: F. A. Klok, M. Tan, M. V. Huisman
Journal: Circulation (2015)
Abstract 13786: Contribution of Medications and Risk Factors to QT Interval Lengthening in the Atherosclerosis Risk in Communities (ARIC) Study
Authors: Khalid A Alburikan, Samuel T Savitz, Eric A Whitsel, James E Tisdale, Elsayed Z Soliman, Emily M Thudium, Carla A Sueta, Anna M Kucharska-Newton, Sally C Stearns, Jo E Rodgers
Journal: Circulation (2014)

Objective: Prolongation of corrected QT interval (QTc) is associated with increased morbidity and mortality, but the association between the number of QT interval prolonging medications (QTPMs) versus selected non-pharmacologic risk factors on the magnitude of QTc lengthening is unknown. We examined these associations in a longitudinal study of a population-based cohort. Methods: We included 15,792 ARIC participants with a resting, standard 12-lead electrocardiogram and ≥ 1 measure of QTc over up to four triennial examinations between 1987 and 1998 (54,638 person-visits). Participants with QRS &gt; 120 ms were excluded (n=2,333). To optimize clinical applicability, QTc was calculated using Bazett’s equation. At each visit, we identified participants using ≥ 1 AzCERT-classified QTPMs, age &gt; 65 years, females, and those with left ventricular hypertrophy (LVH), or QTc &gt; 500 ms at the prior visit. We used linear regression for 36,513 person-visit observations from visits 2-4 to examine QTc lengthening associations. Visit indicators were controlled for time, and standard errors were corrected for repeat observations per person. Results: Use of any QTPM increased from 9% to 17% between visits 1 and 4 and occurred more frequently among females and participants with LVH. Among person-visit observations from Visit 2-4, 70% (n=25,513) had at least one risk factor including age &gt; 65 years (25%), female sex (56%), LVH (8%) and QTc&gt;500 ms (1%). In patients receiving no QTPM, female sex was associated with the greatest QTc lengthening at 13 ms [95% CI 12-13] followed by LVH at 7 ms [6-9], QTc &gt; 500 ms at 7 [4-10], and age &gt; 65 at 2 ms [1-3]. Mean QTc increased with increasing number of QTPMs and risk factors (Table). The greatest QTc lengthening occurred in participants using ≥ 2 medications with ≥ 1 risk factor. Conclusions: Risk factors, particularly female sex, contribute more to QTc lengthening than QTPMs.
An Electron Microscope Study of Spontaneous Mammary Carcinomas in a Subline of Strain DBA Mice2
Authors: Anna Goldfeder, Dorothy Gelber, Dan H. Moore
Journal: JNCI Journal of the National Cancer Institute (1960)

Spontaneous mammary carcinomas of DBA/212 mice proliferated milk-agent particles more abundantly than any tumors studied so far. Acinar spaces were usually filled with the characteristic 100 mµ particles containing nucleoids, and the cell membranes which border the spaces were lined with the forming particles in all stages of development. Particle formation appeared to be at the cell membrane which thickens on the inside and protrudes to form a hemisphere, then further thickens and forms a horseshoe-shaped spheroid, and finally a very thick-shelled sphere which pinches off from the cell. The dense material of the sphere then rearranged itself to form a nucleoid, 20 to 40 mµ in diameter, surrounded by a membranous sac which appeared to be the same morphologically as the cell membrane. While the particles were still attached to the cell they were remarkably constant in diameter, but in the acinar spaces many of them appeared swollen and some contained two nucleoids. Within the cytoplasm of these tumor cells there was an abundance of dense, thin-shelled 60 to 70 mµ spheres of type A, as described by Bernhard. The spheres were usually associated with cytoplasmic vacuoles, but were rarely found near the cell border. Except for these particles and vacuoles, the cells which were so actively exfoliating the milk agent appeared normal and healthy.
Targeting gene-modified hematopoietic cells to the central nervous system: Use of green fluorescent protein uncovers microglial engraftment
Authors: Josef Priller, Alexander Flügel, Tim Wehner, Matthias Boentert, Carola A. Haas, Marco Prinz, Francisco Fernández-Klett, Konstantin Prass, Ingo Bechmann, Bauke A. de Boer, Michael Frotscher, Georg W. Kreutzberg, Derek A. Persons, Ulrich Dirnagl
Journal: Nature Medicine (2001)