tbuckley/cabot-search huggingface dataset:
Standing genetic variation as a major contributor to adaptation in the Virginia chicken lines selection experiment
Authors: Zheya Sheng, Mats E. Pettersson, Christa F. Honaker, Paul B. Siegel, Örjan Carlborg
Journal: Genome biology (2015)

Artificial selection provides a powerful approach to study the genetics of adaptation. Using selective-sweep mapping, it is possible to identify genomic regions where allele-frequencies have diverged during selection. To avoid false positive signatures of selection, it is necessary to show that a sweep affects a selected trait before it can be considered adaptive. Here, we confirm candidate, genome-wide distributed selective sweeps originating from the standing genetic variation in a long-term selection experiment on high and low body weight of chickens.Using an intercross between the two divergent chicken lines, 16 adaptive selective sweeps were confirmed based on their association with the body weight at 56 days of age. Although individual additive effects were small, the fixation for alternative alleles across the loci contributed at least 40 % of the phenotypic difference for the selected trait between these lines. The sweeps contributed about half of the additive genetic variance present within and between the lines after 40 generations of selection, corresponding to a considerable portion of the additive genetic variance of the base population.Long-term, single-trait, bi-directional selection in the Virginia chicken lines has resulted in a gradual response to selection for extreme phenotypes without a drastic reduction in the genetic variation. We find that fixation of several standing genetic variants across a highly polygenic genetic architecture made a considerable contribution to long-term selection response. This provides new fundamental insights into the dynamics of standing genetic variation during long-term selection and adaptation.
A Stem Cell Model of Human Tumor Growth: Implications for Tumor Cell Clonogenic Assays&lt;xref ref-type="fn" rid="FN2"&gt;2&lt;/xref&gt;
Authors: W J Mackillop, A Ciampi, J E Till, R N Buick
Journal: JNCI Journal of the National Cancer Institute (1983)

A simple stem cell model of human tumor growth is presented. Three tumor cell populations are predicted: stem, transitional, and end cells. The properties of these cells are discussed in terms of their behavior in currently available technologies for investigation of cell kinetics and for their influence on clinical outcome. Stem cell renewal, transitional cell proliferation, and cell loss are analyzed mathematically to define their influence on the relative proportions of cell populations; it is demonstrated that stem cell renewal has a central role in determining the growth properties of tumors. The impact of a stem cell model on the use of tumor clonogenic assays as predictors of clinical outcome is discussed; opinions are expressed as to the definition of reasonable expectations for current experimental procedures.
Mammographic Breast Density: Effect on Imaging and Breast Cancer Risk
Authors: Renee W. Pinsky, Mark A. Helvie
Journal: Journal of the National Comprehensive Cancer Network (2010)

Mammographic breast density has been studied for more than 30 years. Greater breast density not only is related to decreased sensitivity of mammograms because of a masking effect but also is a major independent risk factor for breast cancer. This article defines breast density and reviews literature on quantification of mammographic density that is key to future clinical and research protocols. Important influences on breast density are addressed, including age, menopausal status, exogenous hormones, and genetics of density. Young women with dense breasts benefit from digital mammographic technique. The potential use of supplemental MRI and ultrasound screening techniques in high-risk women and women with dense breasts is explored, as are potential risk reduction strategies.
SurvNet@RKI – a multistate electronic reporting system for communicable diseases
Authors: D Faensen, H Claus, J Benzler, A Ammon, T Pfoch, T Breuer, G Krause
Journal: Eurosurveillance (2006)

In 2001 Germany implemented a new electronic reporting system for surveillance of notifiable infectious diseases (SurvNet@RKI). The system is currently being used in all 431 local health departments (LHD), the 16 state health departments (SHD) and the Robert Koch-Institut (RKI), the national agency for infectious disease epidemiology. The SurvNet@RKI software is written in MS Access 97 and Visual Basic and it supports MS Access as well as MS SQL Server database management systems as a back-end. The database is designed as a distributed, dynamic database for 73 reporting categories with more than 600 fields and about 7000 predefined entry values. An integrated version management system documents deletion, undeletion, completion and correction of cases at any time and entry level and allows reproduction of previously conducted queries. Integrated algorithms and help functions support data quality and the application of case definitions. RKI makes the system available to all LHDs and SHDs free of charge. RKI receives an average of 300 000 case reports and 6240 outbreak reports per year through this system. A public web-based query interface, SurvStat@RKI, assures extensive and timely publication of the data. During the 5 years that SurvNet@RKI has been running in all LHDs and SHDs in Germany it has coped well with a complex federal structure which makes this system particularly attractive to multinational surveillance networks. The system is currently being migrated to Microsoft C#/.NET and transport formats in XML. Based on our experiences, we provide recommendations for the design and implementation of national or international electronic surveillance systems.
ATP-dependent steps in apoptotic signal transduction.
Authors: Yutaka Eguchi, Anu Srinivasan, Kevin J. Tomaselli, Shigeomi Shimizu, Yoshihide Tsujimoto
Journal: Cancer Research (1999)

Apoptotic changes of the nucleus induced by Fas (Apo1/CD95) stimulation are completely blocked by reducing intracellular ATP level. In this study, we examined the ATP-dependent step(s) of Fas-mediated apoptotic signal transduction using two cell lines. In SKW6.4 (type I) cells characterized by rapid formation of the death-inducing signaling complex on Fas treatment, the activation of caspases 8, 9, and 3, cleavage of DFF45 (ICAD), and release of cytochrome c from the mitochondria to the cytoplasm were not affected by reduction of intracellular ATP, although chromatin condensation and nuclear fragmentation were inhibited. On the other hand, in the Fas-mediated apoptosis of Jurkat (type II) cells, which is characterized by involvement of mitochondria and, thus, shares signal transduction mechanisms with apoptosis induced by other stimuli such as genotoxins, activation of the three caspases, cleavage of DFF45 (ICAD), and nuclear changes were blocked by reduction of intracellular ATP, whereas release of cytochrome c was not affected. These results suggested that the ATP-dependent step(s) of Fas-mediated apoptotic signal transduction in type I cells are only located downstream of caspase 3 activation, whereas the activation of caspase 9 by released cytochrome c is the most upstream ATP-dependent step in type II cells. These observations also confirm the existence of two pathways for Fas-mediated apoptotic signal transduction and suggest that the Apaf-1 (Ced-4 homologue) system for caspase 9 activation operates in an ATP-dependent manner in vivo.
Phase I trial of PN401, an oral prodrug of uridine, to prevent toxicity from fluorouracil in patients with advanced cancer.
Authors: D P Kelsen, D Martin, J O'Neil, G Schwartz, L Saltz, M T Sung, R von Borstel, J Bertino
Journal: Journal of Clinical Oncology (1997)

PURPOSE We performed a phase I study to determine the appropriate dose of PN401, a uridine (URD) prodrug, to use as a rescue agent for fluorouracil (FU) and than to determine the maximum-tolerated dose (MTD) of FU when given with PN401. PATIENTS AND METHODS Patients with advanced cancer received oral PN401 as either a suspension or a tablet in escalating doses. A pharmacokinetic analysis was performed to determine which dose best achieved a target value of sustained levels of URD &gt; or = 50 mumol/L. In the first phase of the study, all patients received a fixed dose of FU 600 mg/m2 as a rapid intravenous bolus followed by 10 doses of PN401 given at 6-hour intervals. PN401 therapy commenced 24 hours after FU. After determination of the appropriate dose of PN401, a second group of patients received escalating doses of FU with a fixed dose of PN401. RESULTS Thirty-eight patients with advanced cancer received PN401 and FU. Pharmacokinetic analysis indicated that either 6.6 g of PN401 as an oral suspension or 6 g given in tablet form resulted in high bioavailability of URD, with sustained plasma concentrations greater than 50 mumol/L. In the second phase of the study, FU doses were escalated from 600 to 1,000 mg/m2. FU was given as a rapid intravenous bolus weekly for 6 weeks with a 2-week rest. The MTD of FU given in this fashion with PN401 rescue was 1,000 mg/m2, at which level two of six patients had neutropenic fever. FU at doses of 800 mg/m2 for 6 weeks was well tolerated without significant toxicity when given with PN401 rescue. CONCLUSION Oral PN401 is well tolerated and total doses of 6 g every 6 hours yield sustained levels of URD in the target range of 50 mumol/L. The MTD of FU with PN401 rescue is 1,000 mg/m2 and the recommended dose for phase II trials is 800 mg/m2 given weekly for 6 weeks with dose escalation. Further studies to define better the appropriate interval for PN401 rescue and the appropriate dose of FU when given with biochemical modulation, such as with leucovorin, are indicated.
The novel elastase inhibitor BAY 85-8501: First-in-man study to evaluate safety, tolerability and pharmacokinetics in healthy male subjects
Authors: Johannes Nagelschmitz, Michael Becka, Dorina Kaufel, Stephan Schwers, Franz von Nussbaum, Volkhart Li, Georg Wensing
Journal: European Respiratory Journal (2014)

Human neutrophil elastase (HNE) is a key mediator of tissue remodeling and inflammation. An excess of HNE activity has been implicated in the pathogenesis of inflammatory pulmonary diseases, e.g. bronchiectasis (BE), COPD, and pulmonary hypertension. HNE inhibitors could potentially restore the protease/anti-protease balance in these diseases providing a new therapeutic target.  BAY 85-8501 is a novel, selective and reversible HNE inhibitor with activity in the picomolar concentration range, which reveals target inhibition in the lung and ameliorates pulmonary inflammation in preclinical models.  This First-in-Man study evaluated BAY 85-8501 in a Single-Dose-Escalation (SDE) design with 0.05, 0.1, 0.2, 0.5 or 1.0 mg as oral liquid formulation in 37 healthy male subjects (27 active, 10 placebo).  The single dose treatments were safe and well tolerated without serious or severe adverse events and without any hints for mode of action or drug substance related adverse effects. All clinical safety parameters (BP, HR, ECG) and clinical laboratory parameters were in the normal range for single doses up to 1 mg.  Drug absorption was fast, max. concentration (C) reached after 1 h, mean drug half-life was up to 145 - 175 h, allowing once daily dosing. Max. C and Area under Curve (0-24) increased in a dose-proportional way. Renal elimination of the unchanged drug is a minor pathway of elimination ( 4%).  SDE up to 1 mg BAY 85-8501 was safe and well tolerated with pharmacokinetics that allow once daily dosing. Drug candidate is adequate for further clinical evaluation in studies in chronic anti-inflammatory treatment of lung diseases.
Can we improve the follow up of asthmatic patients with asthma educational program (PAMA)
Authors: Laia Lamarca Fornell, Xavier Flor Escriche, Silvia Álvarez Álvarez, Montse Estruch Francitorra, Eva Ares Fernández, Cristina Alos Manrique, Cristina Santiago Fernández, Montserrat Reverté Simó, Edurne Pérez Mayo, Angels Raventos Castany, Glòria Sanchez Sanchez, Trinitat Tovar Velasco, M. Victòria Feijoo Rodriguez
Journal: European Respiratory Journal (2014)

Asthma prevalence has increased, becoming a health and economic problem, mainly due to poor control of the disease.  OBJECTIVES  To determine if PAMA implementation:  -Improves disease control and patients9 quality of life  -Reduces number of exacerbations and emergency visits due to asthma  Secondary:  -To determine optimal PAMA application frequency  METHODS  A 3 years long RCT, in 10 urban primary care teams, to evaluate PAMA which includes: patient education: inhalation systems, exacerbation symptoms and treatment action plan, asthma control test (ACT), revision of patient9s technique and delivery of behaviours to avoid list.  Data were collected in an interview with his doctor or nurse. Main data: age, gender, smoking status, asthma severity, treatment, exacerbations, hospital admissions, ACT and quality of life test (mini-AQLQ).  BASELINE RESULTS  498 asthmatic patients were included and randomized into 3 intervention groups: I: PAMA application every 6 months:124; II: every 12 months:120; III: every 18 months:115 and control group: (usual management):139.  Average age 49 years old (SD 16.4). 72% women. 36.9% had intermittent asthma, and 40% moderate persistent, 24.1% presented partially controlled and 5.8% uncontrolled asthma.  47% had no follow-up visits and 51.4% presented exacerbations in the last year with 0.7(SD 1.1) average emergency visits for patient, 55.7% were attended in primary care and 30.9% solved with self-management or phone instructions. Average ACT scoring: 20.9(SD 4.2) and mini-AQLQ: 5.7(SD 1.1).  CONCLUSIONS  The implementation of an educational program with scheduled follow-up visits can reduce the exacerbations as well as improve the asthma control and quality of life.
Transformation of Human Osteosarcoma Cells by a Chemical Carcinogen2
Authors: J. S. Rhim, C. M. Kim, P. Arnstein, R. J. Huebner, E. K. Weisburger, W. A. Nelson-Rees
Journal: JNCI Journal of the National Cancer Institute (1975)

A human osteosarcoma clonal cell line (TE-85, clone F-5) was treated in vitro with various levels of 7,12-dimethylbenz[a]anthracene or dimethyl sulfoxide (control). Cells treated only with the carcinogen underwent morphologic alteration in vitro, and one of these altered cell lines produced tumors subcutaneously and intracerebrally when injected into NIH nude mice.
Early signs of oxidative stress in COPD
Authors: Helen Evsyukova, Marina Palay, Anna Vjushina
Journal: European Respiratory Journal (2012)

Oxidative modification of proteins is the early and most reliable sign of oxidative stress which plays an important role in pathogenesis of COPD. We studied the oxidative modification of proteins in 12 patients with COPD at the exacerbation of the disease, 12 patients at the remission of COPD and 24 healthy subjects. It was shown that COPD patients had an increased amount of carbonyl derivatives originating at the initiation of oxidation amino acid rests of protein at the exacerbation (0.05±0.01U/mg) and remission stage (0.03±0.00U/mg) than in control subjects (0.01±0.00U/mg) (p
A randomized trial of chemoradiation using mitomycin or cisplatin, with or without maintenance cisplatin/5FU in squamous cell carcinoma of the anus (ACT II)
Authors: R. James, S. Wan, R. Glynne-Jones, D. Sebag-Montefiore, L. Kadalayil, J. Northover, D. Cunningham, H. Meadows, J. Ledermann
Journal: Journal of Clinical Oncology (2009)

LBA4009 The full, final text of this abstract will be available in Part II of the 2009 ASCO Annual Meeting Proceedings, distributed onsite at the Meeting on May 30, 2009, and as a supplement to the June 20, 2009, issue of the Journal of Clinical Oncology. [Table: see text]
LMCE3 Treatment Strategy: Results in 99 Consecutively Diagnosed Stage 4 Neuroblastomas in Children Older Than 1 Year at Diagnosis
Authors: D. Frappaz, J. Michon, C. Coze, C. Berger, E. Plouvier, C. Lasset, J.L. Bernard, J.L. Stephan, E. Bouffet, M. Buclon, V. Combaret, A. Fourquet, T. Philip, J.M. Zucker
Journal: Journal of Clinical Oncology (2000)

To tailor postinduction therapy for stage 4 neuroblastoma in children who are older than 1 year at diagnosis according to status after induction.From March 1987 to December 1992, 99 patients who were consecutively admitted were included in the Lyon-Marseille-Curie East of France (LMCE)3 strategy. After induction with the French Society of Pediatric Oncology NB87 regimen and surgery, patients who were in complete remission immediately proceeded to consolidation therapy with vincristine, melphalan, and fractionated total-body irradiation (VMT). All other patients underwent a postinduction strategy before VMT, either an additional megatherapy regimen or further chemotherapy with etoposide/carboplatin.The progression-free survival (PFS) is 29% at 7 years from diagnosis, which compares favorably with that of a similar cohort of 72 patients previously reported by our group (LMCE1; PFS of 20% at 5 years and 8% at 14 years, P =.004). In the multivariate analysis, only age younger than 3 years at diagnosis (P =.0085) and achievement of complete or very good partial remission after NB87 and surgery (P =.00024) remained significant. The PFS of the 87 patients who were included in the postinduction strategy was significantly better than that of the comparable 62 patients on the LMCE1 study (32% v 11% at 7 years; P =.005).The progressive improvements in the LMCE results over the last 10 years suggest that improvements in supportive care measures and increases in each component of this strategy (induction, postinduction, consolidation) may all contribute to increased survival rates.
The antimicrobial peptide CRAMP protects against emphysema
Authors: Christian Herr, Sadek AlAlwani, Rebecca Eschmann, Christoph Beißwenger, Robert Bals
Journal: European Respiratory Journal (2012)

Rationale: COPD is one of the most prevalent causes of death worldwide and is associated with an ongoing destruction of pulmonary structures that finally lead to the development of emphysema. Antimicrobial peptides (AMP) are a part of the innate immune system. The AMP CRAMP is the murine homologue to the human cathelicidin antimicrobial peptide (hCAP-18/LL-37). It plays an important role in angiogenesis, cancer and chemotaxis. This work will show that CRAMP is important for tissue regeneration in an elastase induced model of lung destruction.

Methods: Lung destruction was initiated by two times intratracheal administration of elastase. Ten days after the last administration lung function was measured. Cytokines in BAL were measured by ELISA. The lungs were resected and fixed for stereological analysis. Lung tissue was also used for immunohistological staining and RNA-extraction.

Results: Elastase treated CRAMP-ko animals had significantly higher neutrophil influx, more IL1-β and TNF-α in their BAL as the controls. 30 days after the first elastase treatment CRAMP-ko had a higher mean linear intercept and a significantly decreased pulmonary system resistance and elastance. MMP-9 expression and activity was increased and the concentration of VEGF was decreased in the elastase treated CRAMP-ko as compared to the elastase treated wildtype mice.

Conclusion: This work shows that the antimicrobial peptide CRAMP has a protective function in a model of elastase induced lung destruction. CRAMP-ko animals showed more inflammation, a higher degree of lung destruction as well as a higher expression and activity of MMP-9. The concentration of VEGF was significantly lower in the elastase treated ko animals.
Atopic dermatitis and melanocytic naevi
Authors: A. Broberg, A. Augustsson
Journal: British Journal of Dermatology (2000)

A study was performed to test the clinical impression that adults with severe atopic dermatitis (AD) have a low number of common naevi (CN). The number of CN ≥ 2 mm was investigated in 51 Caucasian patients aged 20–63 years with severe AD since early childhood. The control group consisted of 379 randomly selected subjects, aged 30–50 years, investigated in an earlier study. Patients with AD had a significantly (P < 0·0001) lower total body count of CN (mean 9, median 5) compared with the control group (mean 67, median 53). It was also found that in the AD group there was a significant (P < 0·001) negative correlation between serum IgE and number of CN [rs = – 0·50, 95% CI (– 0·69; – 0·24)]. The explanation for the low number of naevi that we have found in this highly selected subgroup of AD patients is not known. The atopic inflammation in the skin, genetics and treatment used for eczema are possible factors that may influence the formation of melanocytic naevi.
Influence of smoking on sleep and disease severity in a population of obstructive sleep apnea patients
Authors: Oana Claudia Deleanu, Diana Pocora, Ana-Maria Nebunoiu, Dan Stefan Mihaicuta, Florin Dumitru Mihaltan
Journal: European Respiratory Journal (2013)

RATIONALE :Despite many studies,the question of whether and how smoking habits and sleep are related is only partially answered.

OBJECTIVE :To analyse the effects of smoking on sleep architecture and on obstructive sleep apnea(OSA) symptoms,comorbidities and severity of disease.

METHOD :We studied retrospectively 104 OSA patients with normal lung function,without diurnal hypercapnia,without other sleep disrupting diseases who underwent polisomnography(PSG) and compared different groups(active smokers-AS, former-smokers-FS and never-smokers-NS) regarding anthropometrical data,OSA symptoms,severity,comorbidities and sleep study parameters using SPSS.

RESULTS : 32.69% AS, 30.76% FS and 36.53% NS.We found no differences regarding demographic data,OSA symptoms,comorbidities and sleep architecture between AS vs FS and AS vs NS.Analyzing FS vs NS we found that FS are sleepier(10.3±5.3 vs 7.4±4.4),with a higher latency of sleep(26.8±27.5 vs 14.1±12.5) but also with a higher percent of REM sleep(11.5±7.7 vs 8±6.5),p<0.05.Comparing ever-smokers(AS and FS) with NS we found that ever-smokers have a higher arousal index(29.2±25.2 vs 17±14.1,p=0.002),higher AHI(39±27.1 vs 24.5±22.1,p=0.004) and AHI with arousal(16.7±20.2 vs 5.4±7.4,p<0.001) and higher AI in non-REM supine(19.4±25.6 vs 9.2±17.9,p=0.021) despite no difference regarding demographics,BMI and ENT alterations.OSA severity (AHI, AHI with arousal, arousal index, nighttime SpO2) correlates well (r=0.5,p<0.001) with smoking severity(pack-year) but not with nicotine addiction(Fagerstrom).

CONCLUSION : Despite literature findings, it seems that smoking has more influence on OSA severity rather than on sleep architecture in our studied population.
Dissimilar dosing with high-potency and low-potency neuroleptics
Authors: R J Baldessarini, B Katz, P Cotton
Journal: American Journal of Psychiatry (1984)

The authors studied high-potency versus low-potency neuroleptic dosing practices for 110 Boston-area psychiatric inpatients and compared the findings with the dosing practices reported in surveys of nearly 16,000 Veterans Administration patients. Mean chlorpromazine equivalent doses for the most common agents correlated strongly in both samples. Although frequencies of lower doses of both types of agents were similar, doses of potent drugs above the daily equivalent of 1 g of chlorpromazine accounted for more than 40% of prescriptions. The mean chlorpromazine-equivalent dose of popular potent agents (haloperidol or fluphenazine) was 3.54 times as high as that of popular low-potency agents (chlorpromazine or thioridazine). Potent agents are commonly used in mania and schizophrenia, often in relatively high doses, which may carry an excess of risk over unproven added benefit.