tbuckley/cabot-search huggingface dataset:
Genetics and genomics of Parkinson’s disease
Authors: Michelle K Lin, Matthew J Farrer
Journal: Genome Medicine (2014)

Parkinson's disease (PD) is a progressively debilitating neurodegenerative syndrome. Although best described as a movement disorder, the condition has prominent autonomic, cognitive, psychiatric, sensory and sleep components. Striatal dopaminergic innervation and nigral neurons are progressively lost, with associated Lewy pathology readily apparent on autopsy. Nevertheless, knowledge of the molecular events leading to this pathophysiology is limited. Current therapies offer symptomatic benefit but they fail to slow progression and patients continue to deteriorate. Recent discoveries in sporadic, Mendelian and more complex forms of parkinsonism provide novel insight into disease etiology; 28 genes, including those encoding alpha-synuclein (SNCA), leucine-rich repeat kinase 2 (LRRK2) and microtubule-associated protein tau (MAPT), have been linked and/or associated with PD. A consensus regarding the affected biological pathways and molecular processes has also started to emerge. In early-onset and more a typical PD, deficits in mitophagy pathways and lysosomal function appear to be prominent. By contrast, in more typical late-onset PD, chronic, albeit subtle, dysfunction in synaptic transmission, early endosomal trafficking and receptor recycling, as well as chaperone-mediated autophagy, provide a unifying synthesis of the molecular pathways involved. Disease-modification (neuroprotection) is no longer such an elusive goal given the unparalleled opportunity for diagnosis, translational neuroscience and therapeutic development provided by genetic discovery.
Studies With Cyclophosphamide Labeled With Phosphorus-32: Nucleic Acid Alkylation and Its Effect on DNA Synthesis in Rat Tumor and Normal Tissues
Authors: Kenneth D. Tew, David M. Taylor
Journal: JNCI Journal of the National Cancer Institute (1977)

The gross distribution of levels of [32P]cyclophosphamide ([32P]CY) in August female rats was similar in tumor, intestinal mucosa, spleen, bone marrow, and striated muscle tissue, with slightly higher levels in liver and kidney tissue. A triphasic association with nucleic acids was found and actual alkylation of DNA and RNA reached a maximum of 48 hours post treatment. There was no evidence of 32P-label reutilization that could have accounted for prolonged alkylation. We found that 100 mg CY/kg suppressed the incorporation of [3H]thymidine, [3H]deoxyuridine, and [14C]sodium formate into the DNA of the BICR-A15 carcinoma for at least 10 days. This correlated well with the observed regression of tumor volume. Bone marrow and intestinal mucosa, two tissues which limit chemotherapuetic treatment of the tumor, were less affected by 100 mg CY/kg. Bone marrow had regained normal levels of DNA precursor incorporation by 5 days, and intestinal mucosa had regained normal levels by 3 days. Results indicated that this differential in recovery time may assist in the successful scheduling of vital tissue-sparing drug regimens.
Analysis of Clinical Stage T2 Prostate Cancer: Do Current Subclassifications Represent an Improvement?
Authors: Ilias Cagiannos, Markus Graefen, Pierre I. Karakiewicz, Makato Ohori, James A. Eastham, Farhang Rabbani, William Fair, Thomas M. Wheeler, Peter G. Hammerer, Alexander Haese, Andreas Erbersdobler, Hartwig Huland, Peter T. Scardino, Michael W. Kattan
Journal: Journal of Clinical Oncology (2002)

PURPOSE: The purpose of this study was to determine whether the extent of palpable cancer within the prostate predicts outcome after radical prostatectomy. PATIENTS AND METHODS: We combined prospectively collected data on 1,755 consecutive clinical stage T2 patients treated with radical prostatectomy alone at four institutions. According to the 1992 American Joint Committee on Cancer tumor-node-metastasis system, 645 (37%) were T2a, 758 (43%) were T2b, and 352 (20%) were T2c. Kaplan-Meier and proportional hazards regression analyses were performed on the 1992 and 1997 T2 subclassifications. After controlling for the effects of prostate-specific antigen (PSA) and biopsy Gleason sum, the two staging systems were compared for their ability to predict recurrence-free survival (RFS). Adjusted RFS curves were constructed using the corrected group prognosis method. RESULTS: Follow-up ranged from 1 to 166 months (median, 26 months). Cancer recurred in 417 (24%) of the T2 patients. The 1992 (P = .005) but not the 1997 (P = .100) T2 subclassification predicted outcome after controlling for PSA and Gleason sum. After covariate adjustment, RFS was 7% higher at 5 years in the 1992 T2a subcategory relative to the T2b subcategory. CONCLUSION: The 1992 American Joint Committee on Cancer system is superior to the 1997 system, and the former adds prognostic information to a model containing pretreatment PSA and Gleason sum. These results suggest that 1992 T2 subclassification derived from palpable findings improves prognostication over the 1997 subclassification.
Variability of relaxed expiratory volume and forced inspiratory volume
Authors: M. K. Tandon, A. H. Campbell
Journal: Thorax (1970)

Measurements of relaxed expiratory volume in one second (REV<sub>1·0</sub>) and forced inspiratory volume in one second (FIV<sub>1·0</sub>) were made on 50 subjects on two occasions to know the variability of these procedures in the individual subject. The mean coefficients of variation for REV<sub>1·0</sub> and FIV<sub>1·0</sub> were 6·74% and 8·92%, respectively. The 95% confidence limit of difference between highest readings obtained on two occasions for REV<sub>1·0</sub> and FIV<sub>1·0</sub> was 0·38 litre and 0·214 litre, respectively. These results compare favourably with similar data reported for other ventilatory tests. We feel that if a little time is spent teaching subjects to produce REVs, then reproducible results may be obtained.
A Globin Gene of Ancient Evolutionary Origin in Lower Vertebrates: Evidence for Two Distinct Globin Families in Animals
Authors: Anja Roesner, Christine Fuchs, Thomas Hankeln, Thorsten Burmester
Journal: Molecular Biology and Evolution (2004)

Hemoglobin, myoglobin, neuroglobin, and cytoglobin are four types of vertebrate globins with distinct tissue distributions and functions. Here, we report the identification of a fifth and novel globin gene from fish and amphibians, which has apparently been lost in the evolution of higher vertebrates (Amniota). Because its function is presently unknown, we tentatively call it globin X (GbX). Globin X sequences were obtained from three fish species, the zebrafish Danio rerio, the goldfish Carassius auratus, and the pufferfish Tetraodon nigroviridis, and the clawed frog Silurana tropicalis. Globin X sequences are distinct from vertebrate hemoglobins, myoglobins, neuroglobins, and cytoglobins. Globin X displays the highest identity scores with neuroglobin (∼26% to 35%), although it is not a neuronal protein, as revealed by RT-PCR experiments on goldfish RNA from various tissues. The distal ligand-binding and the proximal heme-binding histidines (E7 and F8), as well as the conserved phenylalanine CD1 are present in the globin X sequences, but because of extensions at the N-terminal and C-terminal, the globin X proteins are longer than the typical eight α-helical globins and comprise about 200 amino acids. In addition to the conserved globin introns at helix positions B12.2 and G7.0, the globin X genes contain two introns in E10.2 and H10.0. The intron in E10.2 is shifted by 1 bp in respect to the vertebrate neuroglobin gene (E11.0), providing possible evidence for an intron sliding event. Phylogenetic analyses confirm an ancient evolutionary relationship of globin X with neuroglobin and suggest the existence of two distinct globin types in the last common ancestor of Protostomia and Deuterostomia.
Low dose inhaled LPS challenge - Reproducibility of the inflammatory response
Authors: Olaf Holz, Frank Schaumann, Ole Janssen, Bianca Lavae-Mokhtari, Heike Biller, Norbert Krug, Jens M. Hohlfeld
Journal: European Respiratory Journal (2012)

Introduction: Inhalaled endotoxin (LPS) is used to study pulmonary inflammation. Conventional inhalation methods require substantial amounts of LPS (15–50µg) to induce a detectable inflammatory response. Authorities often permit LPS challenges only with GMP-grade LPS, which is of limited availability. Here we studied the reproducibility of the response to a low dose of LPS (2µg), which was inhaled by a flow/volume controlled procedure to increase lung deposition.  Methods: Twelve healthy non-smoking volunteers were included. Baseline sputum was evaluated 2-4 weeks prior to the first challenge. On two occasions, separated by 4 weeks, subjects inhaled 2µg LPS (Clinical Center Reference Endotoxin CCRE, NIH), which was nebulized using an Aeroneb solo (Inspiration Medical). Sputum was induced 6h after LPS provocation.  Results: The low dose LPS challenge was well tolerated. Both challenges induced a significant (p  Conclusion: Low dose LPS caused a reproducible inflammatory response. However, we found evidence for a more pronounced increase in monocytes in the second challenge. This needs to be considered in proof of concept studies for novel inflammatory compounds.  CCRE was kindly provided by Dr. A. Suffredini, NIH, Bethesda.
The reconstruction of the nasal ala with interpolated flaps from the cheek and forehead: design and execution modifications to improve surgical outcomes
Authors: J.L. Cook
Journal: British Journal of Dermatology (2014)

The nasal ala, critically important in the function and appearance of the central face, has significant reconstructive demands given the lack of suitable adjacent donor tissue that can be used to repair all but the smallest surgical defects in this area. Interpolated flaps from the forehead and cheek have long been ideal reconstructive alternatives for the repair of larger or more difficult alar wounds, and with the design and execution modifications described here, the dermatological surgeon can offer more appropriate restoration of this critically important aesthetic unit.
Pilot Study of Urinary Biomarkers of Phytoestrogens, Phthalates, and Phenols in Girls
Authors: Mary S. Wolff, Susan L. Teitelbaum, Gayle Windham, Susan M. Pinney, Julie A. Britton, Carol Chelimo, James Godbold, Frank Biro, Lawrence H. Kushi, Christine M. Pfeiffer, Antonia M. Calafat
Journal: Environmental Health Perspectives (2006)

BackgroundHormonally active environmental agents have been measured among U.S. children using exposure biomarkers in urine. However, little is known about their variation by race, age, sex, and geography, and no data exist for newly developed biomarkers.ObjectiveOur goal was to characterize relevant, prevalent exposures for a study of female pubertal development.MethodsIn a pilot study among 90 girls from New York City, New York, Cincinnati, Ohio, and northern California, we measured 25 urinary analytes representing 22 separate agents from three chemical families: phytoestrogens, phthalates, and phenols. Exposures occur chiefly from the diet and from household or personal care products.ResultsParticipants represented four racial/ethnic groups (Asian, black, Hispanic, white), with mean age of 7.77 years. Most analytes were detectable in &gt; 94% of samples. The highest median concentrations for individual analytes in each family were for enterolactone (298 μg/L), monoethylphthalate (MEP; 83.2 μg/L), and benzophenone-3 (BP3; 14.7 μg/L). Few or no data have been reported previously for four metabolites: mono(2-ethyl-5-carboxypentyl) phthalate, triclosan, bisphenol A (BPA), and BP3; these were detected in 67–100% of samples with medians of 1.8–53.2 μg/L. After multivariate adjustment, two analytes, enterolactone and BPA, were higher among girls with body mass index &lt; 85th reference percentile than those at or above the 85th percentile. Three phthalate metabolites differed by race/ethnicity [MEP, mono(2-ethylhexyl) phthalate, and mono-3-carboxypropylphthalate].ConclusionsA wide spectrum of hormonally active exposure biomarkers were detectable and variable among young girls, with high maximal concentrations (&gt; 1,000 μg/L) found for several analytes. They varied by characteristics that may be relevant to development.
Molecular Mechanism of MART-1+/A*0201+ Human Melanoma Resistance to Specific CTL-Killing Despite Functional Tumor–CTL Interaction
Authors: Ali R. Jazirehi, Stavroula Baritaki, Richard C. Koya, Benjamin Bonavida, James S. Economou
Journal: Cancer Research (2010)

Abstract Durable responses in metastatic melanoma patients remain generally difficult to achieve. Adoptive cell therapy (ACT) with ex vivo engineered lymphocytes expressing high affinity T-cell receptors (TCRα/β) for the melanoma antigen MART-127–35/HLA-A*0201 [recognized by F5 cytotoxic T lymphocytes (F5 CTL)] has been found to benefit certain patients. However, many other patients are inherently unresponsive and/or relapse for unknown reasons. To analyze the basis for the acquired resistance and strategies to reverse it, we established F5 CTL–resistant (R) human melanoma clones from relatively sensitive parental lines under selective F5 CTL pressure. Surface MART-127–35/HLA-A*0201 in these clones was unaltered and F5 CTLs recognized and interacted with them similar to the parental lines. Nevertheless, the R clones were resistant to F5 CTL killing, exhibited hyperactivation of the NF-κB survival pathway, and overexpression of the antiapoptotic genes B cell lymphoma protein 2 (Bcl-2), Bcl-2 related gene (long alternatively spliced variant of Bcl-x gene; Bcl-xL), and myeloid cell differentiation 1 (Mcl-1). Sensitivity to F5 CTL-killing could be increased by pharmacological inhibition of the NF-κB pathway, Bcl-2 family members, or the proteasome, the latter of which reduced NF-κB activity and diminished antiapoptotic gene expression. Specific gene-silencing (by siRNA) confirmed the protective role of antiapoptotic factors by reversing R clone resistance. Together, our findings suggest that long-term immunotherapy may impose a selection for the development of resistant cells that are unresponsive to highly avid and specific melanoma-reactive CTLs, despite maintaining expression of functional peptide:MHC complexes, due to activation of antiapoptotic signaling pathways. Though unresponsive to CTL, our results argue that resistant cells can be resensitized to immunotherapy with coadministration of targeted inhibitors to antiapoptotic survival pathways. Cancer Res; 71(4); 1406–17. ©2010 AACR.
Sex and the nose: human pheromonal responses
Authors: M. F Bhutta
Journal: Journal of the Royal Society of Medicine (2007)

The chemosensory functions of the human nose are underappreciated. Traditional teaching is that the sense of smell detects volatile compounds, which may then allow the identification of substances that may be beneficial or harmful—such as good versus putrefied food. However, increasing evidence from research in other animals suggests that olfaction may serve another and more important purpose, that of mate selection in sexual reproduction; indeed, olfaction may be an essential impetus for evolution.
Nitrosative stress in the bronchial mucosa of severe chronic obstructive pulmonary disease
Authors: Fabio L.M. Ricciardolo, Gaetano Caramori, Kazuhiro Ito, Armando Capelli, Paola Brun, Giovanni Abatangelo, Alberto Papi, Kian Fan Chung, Ian Adcock, Peter J. Barnes, Claudio F. Donner, Andrea Rossi, Antonino Di Stefano
Journal: Journal of Allergy and Clinical Immunology (2005)
Helmet Use and Risk of Head Injuries in Alpine Skiers and Snowboarders
Authors: Steinar Sulheim
Journal: JAMA (2006)

Although using a helmet is assumed to reduce the risk of head injuries in alpine sports, this effect is questioned. In contrast to bicycling or inline skating, there is no policy of mandatory helmet use for recreational alpine skiers and snowboarders.To determine the effect of wearing a helmet on the risk of head injury among skiers and snowboarders while correcting for other potential risk factors.Case-control study at 8 major Norwegian alpine resorts during the 2002 winter season, involving 3277 injured skiers and snowboarders reported by the ski patrol and 2992 noninjured controls who were interviewed on Wednesdays and Saturdays. The controls comprised every 10th person entering the bottom main ski lift at each resort during peak hours. The number of participants interviewed corresponded with each resort's anticipated injury count based on earlier years.Injury type, helmet use, and other risk factors (age, sex, nationality, skill level, equipment used, ski school attendance, rented or own equipment) were recorded. A multivariate logistic regression analysis was used to assess the relationship between individual risk factors (including helmet wear) and risk of head injury by comparing skiers with head injuries with uninjured controls, as well as to skiers with injuries other than head injuries.Head injuries accounted for 578 injuries (17.6%). Using a helmet was associated with a 60% reduction in the risk for head injury (odds ratio [OR], 0.40; 95% confidence interval [CI], 0.30-0.55; adjusted for other risk factors) when comparing skiers with head injuries with uninjured controls. The effect was slightly reduced (OR, 0.45; 95% CI, 0.34-0.59) when skiers with other injuries were used as controls. For the 147 potentially severe head injuries, those who were referred to an emergency physician or for hospital treatment, the adjusted OR was 0.43 (95% CI, 0.25-0.77). The risk for head injury was higher among snowboarders than for alpine skiers (adjusted OR, 1.53; 95% CI, 1.22-1.91).Wearing a helmet is associated with reduced risk of head injury among snowboarders and alpine skiers.
Characterization and Clinical Relevance of ALDHbright Populations in Prostate Cancer
Authors: Clémentine Le Magnen, Lukas Bubendorf, Cyrill A. Rentsch, Chantal Mengus, Joel Gsponer, Tobias Zellweger, Malte Rieken, George N. Thalmann, Marco G. Cecchini, Markus Germann, Alexander Bachmann, Stephen Wyler, Michael Heberer, Giulio C. Spagnoli
Journal: Clinical Cancer Research (2013)

High aldehyde dehydrogenase (ALDH) has been suggested to selectively mark cells with high tumorigenic potential in established prostate cancer cell lines. However, the existence of cells with high ALDH activity (ALDH(bright)) in primary prostate cancer specimens has not been shown so far. We investigated the presence, phenotype, and clinical significance of ALDH(bright) populations in clinical prostate cancer specimens.We used ALDEFLUOR technology and fluorescence-activated cell-sorting (FACS) staining to identify and characterize ALDH(bright) populations in cells freshly isolated from clinical prostate cancer specimens. Expression of genes encoding ALDH-specific isoforms was evaluated by quantitative real-time PCR in normal prostate, benign prostatic hyperplasia (BPH), and prostate cancer tissues. ALDH1A1-specific expression and prognostic significance were assessed by staining two tissue microarrays that included more than 500 samples of BPH, prostatic intraepithelial neoplasia (PIN), and multistage prostate cancer.ALDH(bright) cells were detectable in freshly excised prostate cancer specimens (n = 39) and were mainly included within the EpCAM((+)) and Trop2((+)) cell populations. Although several ALDH isoforms were expressed to high extents in prostate cancer, only ALDH1A1 gene expression significantly correlated with ALDH activity (P < 0.01) and was increased in cancers with high Gleason scores (P = 0.03). Most importantly, ALDH1A1 protein was expressed significantly more frequently and at higher levels in advanced-stage than in low-stage prostate cancer and BPH. Notably, ALDH1A1 positivity was associated with poor survival (P = 0.02) in hormone-naïve patients.Our data indicate that ALDH contributes to the identification of subsets of prostate cancer cells of potentially high clinical relevance.
Didanosine Compared with Continuation of Zidovudine in HIV-infected Patients with Signs of Clinical Deterioration While Receiving Zidovudine
Authors: Spotswood L. Spruance
Journal: Annals of Internal Medicine (1994)

Objective: To determine the benefits of switching to didanosine compared with continuing zidovudine among patients infected with human immunodeficiency virus (HIV) who have previously used zidovudine and have signs of clinical deterioration. Design: Randomized, double-blind, two-armed, parallel, comparative clinical trial with a blinded, compassionate crossover provision at 12 weeks. Setting: Outpatient clinics at 19 tertiary care medical centers. Patients: 312 patients infected with HIV who had received zidovudine for 6 months or more, had CD4 cell counts of 300/mm3 or less, and had signs of clinical deterioration within 12 weeks before study entry. Intervention: Peroral didanosine tablets (600 mg/d adjusted for weight, "high dose") or zidovudine capsules (600 mg/d). Measurements: Primary study end points were death, a new acquired immunodeficiency syndrome (AIDS)-defining event, or the combination of two new or recurrent HIV-related diagnoses with a 50% decrease in CD4 cells. Results: Switching to didanosine was associated with fewer end points than continuing zidovudine (relative risk [RR] for zidovudine:didanosine = 1.5; 95% CI, 1.1 to 2.0). This benefit was consistent across subgroups of patients with either AIDS-related complex or AIDS and was most apparent among those with a CD4 count at entry of 100/mm3 or more (RR = 2.2; CI, 1.1 to 4.4). Conclusions: This study shows a positive treatment effect for switching from zidovudine to didanosine among patients with either AIDS-related complex or AIDS and validates the common practice of using clinical signs or a decrease in the CD4 count as an indication for changing therapy. *For members of the Study Group, see the appendix.
Thrombolysis-induced coronary reperfusion causes acute and massive interstitial release of cardiac muscle cell proteins
Authors: Christa Cobbaert, Wim Th. Hermens, Peter P. Kint, Peter J. Klootwijk, Frans Van de Werf, Maarten L. Simoons
Journal: Cardiovascular Research (1997)

Objective: Reperfusion of the infarct-related artery in patients with acute myocardial infarction limits infarct size, but also causes accelerated release into plasma of cardiac tissue proteins. The latter effect could reflect either enhanced protein washout from the heart or abrupt disruption of myocyte membranes. The present study indicates that the latter mechanism prevails. Methods: In 26 patients, patency of the infarct-related artery was determined by coronary angiography 90 min and 5–7 days after thrombolytic treatment. Continuous electrocardiography was performed during the first 24 h after admission. Cumulative release of myoglobin (Mb) and creatine kinase (CK) into plasma was calculated from frequently sampled plasma concentrations. Results: In patients with a patent infarct-related artery after 90 min, the onset of a rapid (> 50%) decrease in ST-vector magnitude coincided with an equally rapid increase in QRS-vector magnitude, and with a sudden onset of release into plasma of Mb as well as CK. In these patients, a maximal initial release rate was observed and cumulative release conformed closely to a simple model for sudden interstitial liberation of proteins. In contrast, protein release started more gradually and could not be fitted to this model, in patients with persistent occlusion of the infarct-related artery at 90 min and absence of ST-vector normalisation. Conclusions: Previous studies have demonstrated significant myocardial salvage by timely reperfusion therapy. Nevertheless, this study indicates that the moment of recanalisation of the infarct-related artery coincides with sudden and massive disruption of myocyte membranes. Attenuation of this effect, if possible, could further improve the benefits of reperfusion therapy.