tbuckley/cabot-search huggingface dataset:
Dissecting the genetics of chronic mucus hypersecretion in smokers with and without COPD
Authors: Akkelies E. Dijkstra, H. Marike Boezen, Maarten van den Berge, Judith M. Vonk, Pieter S. Hiemstra, R. Graham Barr, Kirsten M. Burkart, Ani Manichaikul, Tess D. Pottinger, Edward K. Silverman, Michael H. Cho, James D. Crapo, Terri H. Beaty, Per Bakke, Amund Gulsvik, David A. Lomas, Yohan Bossé, David C. Nickle, Peter D. Paré, Harry J. de Koning, Jan-Willem Lammers, Pieter Zanen, Joanna Smolonska, Ciska Wijmenga, Corry-Anke Brandsma, Harry J.M. Groen, Dirkje S. Postma
Journal: European Respiratory Journal (2014)

Smoking is a notorious risk factor for chronic mucus hypersecretion (CMH). CMH frequently occurs in chronic obstructive pulmonary disease (COPD). The question arises whether the same single-nucleotide polymorphisms (SNPs) are related to CMH in smokers with and without COPD. We performed two genome-wide association studies of CMH under an additive genetic model in male heavy smokers (≥20 pack-years) with COPD (n=849, 39.9% CMH) and without COPD (n=1348, 25.4% CMH), followed by replication and meta-analysis in comparable populations, and assessment of the functional relevance of significantly associated SNPs. Genome-wide association analysis of CMH in COPD and non-COPD subjects yielded no genome-wide significance after replication. In COPD, our top SNP (rs10461985, p=5.43×10 −5 ) was located in the GDNF-AS1 gene that is functionally associated with the GDNF gene. Expression of GDNF in bronchial biopsies of COPD patients was significantly associated with CMH (p=0.007). In non-COPD subjects, four SNPs had a p-value &lt;10 −5 in the meta-analysis, including a SNP (rs4863687) in the MAML3 gene, the T-allele showing modest association with CMH (p=7.57×10 −6 , OR 1.48) and with significantly increased MAML3 expression in lung tissue (p=2.59×10 −12 ). Our data suggest the potential for differential genetic backgrounds of CMH in individuals with and without COPD.
Pathology of the rectal wall in solitary rectal ulcer syndrome and complete rectal prolapse.
Authors: Y S Kang, M A Kamm, A F Engel, I C Talbot
Journal: Gut (1996)

The aetiology and pathology of rectal prolapse and solitary rectal ulcer are poorly understood.To examine the full thickness rectal wall in these two conditions.The pathological abnormalities in the surgically resected rectal wall were studied from nine patients with solitary rectal ulcer syndrome, 11 complete rectal prolapse, and nine cancer controls. Routine haematoxylin and eosin and Van Gieson staining for collagen were performed.The rectal wall from solitary rectal ulcer syndrome specimens was thickened compared with complete rectal prolapse and controls. The major difference was in the muscularis propria (2.2 v 1.1 v 1.2 mm, medians, p < 0.005) and particularly the inner circular muscular layer, and to a lesser extent the submucosal and outer longitudinal muscular layers. Some solitary rectal ulcer syndrome specimens showed unique features such as decussation of the two muscular layers (four of nine), nodular induration of inner circular layer (four of nine) and grouping of outer longitudinal layer into bundles (three of nine); these were not seen in complete rectal prolapse or control specimens.These features, which resemble the features of high pressure sphincter tissue, may be of aetiological importance, and suggest a different pathogenesis for these two disorders. Excess collagen was seen in both disorders, was more severe in solitary rectal ulcer syndrome specimens, and probably reflects a response to repeated trauma.
Effects of radiotherapy and of differences in the extent of surgery for early breast cancer on local recurrence and 15-year survival: an overview of the randomised trials
Authors: M Clarke, R Collins, S Darby, C Davies, P Elphinstone, V Evans, J Godwin, R Gray, C Hicks, S James, E MacKinnon, P McGale, T McHugh, R Peto, C Taylor, Y Wang
Journal: The Lancet (2005)
Mitochondrial DNA mutations in human colonic crypt stem cells
Authors: Robert W. Taylor, Martin J. Barron, Gillian M. Borthwick, Amy Gospel, Patrick F. Chinnery, David C. Samuels, Geoffrey A. Taylor, Stefan M. Plusa, Stephanie J. Needham, Laura C. Greaves, Thomas B.L. Kirkwood, Douglass M. Turnbull
Journal: Journal of Clinical Investigation (2003)

The mitochondrial genome encodes 13 essential subunits of the respiratory chain and has remarkable genetics based on uniparental inheritance. Within human populations, the mitochondrial genome has a high rate of sequence divergence with multiple polymorphic variants and thus has played a major role in examining the evolutionary history of our species. In recent years it has also become apparent that pathogenic mitochondrial DNA (mtDNA) mutations play an important role in neurological and other diseases. Patients harbor many different mtDNA mutations, some of which are mtDNA mutations, some of which are inherited, but others that seem to be sporadic. It has also been suggested that mtDNA mutations play a role in aging and cancer, but the evidence for a causative role in these conditions is less clear. The accumulated data would suggest, however, that mtDNA mutations occur on a frequent basis. In this article we describe a new phenomenon: the accumulation of mtDNA mutations in human colonic crypt stem cells that result in a significant biochemical defect in their progeny. These studies have important consequences not only for understanding of the finding of mtDNA mutations in aging tissues and tumors, but also for determining the frequency of mtDNA mutations within a cell.
Imaging or Imagining? A Neuroethics Challenge Informed by Genetics
Authors: Judy Illes, Eric Racine
Journal: The American Journal of Bioethics (2005)

From a twenty-first century partnership between bioethics and neuroscience, the modern field of neuroethics is emerging, and technologies enabling functional neuroimaging with unprecedented sensitivity have brought new ethical, social and legal issues to the forefront. Some issues, akin to those surrounding modern genetics, raise critical questions regarding prediction of disease, privacy and identity. However, with new and still-evolving insights into our neurobiology and previously unquantifiable features of profoundly personal behaviors such as social attitude, value and moral agency, the difficulty of carefully and properly interpreting the relationship between brain findings and our own self-concept is unprecedented. Therefore, while the ethics of genetics provides a legitimate starting point—even a backbone—for tackling ethical issues in neuroimaging, they do not suffice. Drawing on recent neuroimaging findings and their plausible real-world applications, we argue that interpretation of neuroimaging data is a key epistemological and ethical challenge. This challenge is two-fold. First, at the scientific level, the sheer complexity of neuroscience research poses challenges for integration of knowledge and meaningful interpretation of data. Second, at the social and cultural level, we find that interpretations of imaging studies are bound by cultural and anthropological frameworks. In particular, the introduction of concepts of self and personhood in neuroimaging illustrates the interaction of interpretation levels and is a major reason why ethical reflection on genetics will only partially help settle neuroethical issues. Indeed, ethical interpretation of such findings will necessitate not only traditional bioethical input but also a wider perspective on the construction of scientific knowledge.
Crime Prevention by the Indeterminate Sentence Law
Authors: EMORY F. HODGES
Journal: American Journal of Psychiatry (1971)

This paper reports the first 11 and a half years' experience under Maryland's defective delinquent statute, which utilizes a unique approach in the treatment of dangerous offenders. The author estimates that without the law, about 1,500 additional crimes would have been committed by prisoners after their release if they had been sent to regular prisons rather than the Patuxent Institution. He believes the indeterminate sentence, which is an integral part of the statute, protects society from the defective delinquent and handles him both effectively and humanely.
Cancer-Related Epigenome Changes Associated with Reprogramming to Induced Pluripotent Stem Cells
Authors: Joyce E. Ohm, Prashant Mali, Leander Van Neste, David M. Berman, Liang Liang, Kurinji Pandiyan, Kimberly J. Briggs, Wei Zhang, Pedram Argani, Brian Simons, Wayne Yu, William Matsui, Wim Van Criekinge, Feyruz V. Rassool, Elias Zambidis, Kornel E. Schuebel, Leslie Cope, Jonathan Yen, Helai P. Mohammad, Linzhao Cheng, Stephen B. Baylin
Journal: Cancer Research (2010)

The ability to induce pluripotent stem cells from committed, somatic human cells provides tremendous potential for regenerative medicine. However, there is a defined neoplastic potential inherent to such reprogramming that must be understood and may provide a model for understanding key events in tumorigenesis. Using genome-wide assays, we identify cancer-related epigenetic abnormalities that arise early during reprogramming and persist in induced pluripotent stem cell (iPS) clones. These include hundreds of abnormal gene silencing events, patterns of aberrant responses to epigenetic-modifying drugs resembling those for cancer cells, and presence in iPS and partially reprogrammed cells of cancer-specific gene promoter DNA methylation alterations. Our findings suggest that by studying the process of induced reprogramming, we may gain significant insight into the origins of epigenetic gene silencing associated with human tumorigenesis, and add to means of assessing iPS for safety.
The Antibody-Based Delivery of Interleukin-12 to the Tumor Neovasculature Eradicates Murine Models of Cancer in Combination with Paclitaxel
Authors: Nadine Pasche, Sarah Wulhfard, Francesca Pretto, Elisa Carugati, Dario Neri
Journal: Clinical Cancer Research (2012)

Interleukin-12 (IL12) is a potent proinflammatory cytokine with antitumor activity. Its heterodimeric nature makes it compatible with a large variety of different immunocytokine formats. Here we report the design, production, and characterization of a novel immunocytokine, based on the fusion of the F8 antibody (specific to the alternatively spliced EDA domain of fibronectin, a marker of tumor neovasculature) with IL12 (termed IL12-F8-F8).We developed a novel immunocytokine based on the sequential fusion of interleukin-12 as a single polypeptide with two F8 antibodies in single-chain Fv (scFv) format. The fusion protein was characterized in vitro, and its targeting performance was assessed in vivo. The immunocytokine antitumor activity was studied as monotherapy as well as in combination therapies in three different murine tumor models. Moreover, depletion experiments and tumor analysis revealed a dominant role of natural killer cells for the mechanism of action.IL12-F8-F8 can be produced in mammalian cells, yielding a product of good pharmaceutical quality, capable of selective localization on the tumor neovasculature in vivo, as judged by quantitative biodistribution analysis with radioiodinated protein preparations. The protein potently inhibited tumor growth in three different immunocompetent syngeneic models of cancer. The treatment was generally well tolerated. Moreover, the IL12-F8-F8 fusion protein could be produced both with murine IL12 (mIL12) and with human IL12 (hIL12).The potent antitumor activity of mIL12-F8-F8, studied alone or in combination with paclitaxel in different tumor models, paves the way to the clinical development of the fully human immunocytokine.
Changes in glucose tolerance after endoscopic retrograde cholangiopancreatography.
Authors: Z Tulassay, J Papp, M Szathmari, S Kisfaludy, L Koranyi, G Tamas
Journal: Gut (1981)

Changes in oral glucose-tolerance have been studied in patients subjected to endoscopic retrograde pancreatography. Glucose tolerance is impaired 72 hours after ductography, and significant changes can still be seen even after one month; glucose tolerance returns to normal six to 12 months after pancreatography. In an attempt to discover the mechanism underlying impaired tolerance serial measurements were made of plasma insulin and glucagon levels. The observation that the ratio I/G decreased in these patients indicates that enhanced glucagon release, probably due to mechanical and/or osmotic injury, may be responsible for the hyperglycaemia that is observed.
Therapeutic Index by Combination of Adriamycin and Docetaxel Depends on Dosing Time in Mice
Authors: Mayumi Tabuchi, Hideto To, Hiromi Sakaguchi, Naho Goto, Ayako Takeuchi, Shun Higuchi, Shigehiro Ohdo
Journal: Cancer Research (2005)

Abstract Although the combination of adriamycin and docetaxel showed a better cure rate against metastatic breast cancer, severe myelosuppression and cardiotoxicity were dose-limiting factors. The purpose of this study was to establish a suitable dosing schedule, based on a chronopharmacologic approach, to relieve severe adverse effects. In experiment 1, adriamycin or docetaxel was injected i.p. at 2, 6, 10, 14, 18, or 22 hours after light onset (HALO) to estimate toxicities. In experiment 2, the dosing time dependency of toxicity and pharmacokinetics were assessed in the combination of adriamycin and docetaxel. In addition, G2-M phase in myelocyte cells was determined in nontreated mice. Adverse effects caused by adriamycin were shown to be the worst at 2 HALO and the best at 14 HALO. On the other hand, docetaxel-induced adverse effects were more severe at 14 HALO than at 2 HALO. In the combination study, the D(2)-A(14) group, in which docetaxel was administered at 2 HALO followed by adriamycin at 14 HALO, showed the most toxicity relief of all the treated groups. In the pharmacokinetic study, the dosing time dependency of toxicities was not related to the daily variation of pharmacokinetics of adriamycin and docetaxel. A significant 24-hour rhythm of G2-M phase distribution was found in myelocyte cells of nontreated mice. The daily variation of leukopenia caused by docetaxel corresponded to the 24-hour rhythm of G2-M phase distribution. These findings reveal that the therapeutic index of the combined chemotherapy can be improved by administering adriamycin and docetaxel at the time when the most adverse effects are relieved in each drug.
Methotrexate does not exert immunomodulatory effects on regulatory T cells but on effector T cells
Authors: M. Bulatovic, S. Vastert, W. de Jager, F. Verweij, F. van Wijk, N. Wulffraat, B. Prakken
Journal: Annals of the Rheumatic Diseases (2011)

<h3>Background and objectives</h3> Methotrexate (MTX) is the most commonly used antirheumatic drug in juvenile idiopathic arthritis (JIA). MTX induces 'remission on medication' in 70% of patients and continuous 'remission off medication' in up to 50% of patients. MTX is unique in the realm of antirheumatic drugs since it is currently the only drug that appears capable of establishing immune tolerance in JIA. In spite of this, it is unclear which immunomodulatory mechanisms enable MTX to achieve sustained remission. The authors thus examined the immunomodulatory effects that MTX exerts on two major players in immune tolerance – regulatory (Tregs) and effector (Teffs) T cells. <h3>Materials and methods</h3> Peripheral blood mononuclear cells (PBMCs) from 25 extended oligoarticular and polyarticular JIA patients were isolated before MTX start, 3 and 6 months after MTX start. The authors analysed frequency and phenotype of Tregs by flow cytometry. The function of Tregs was evaluated in CFSE-suppression assays. Proliferation of Teffs was examined in proliferation assays in the presence of anti-CD3. Teff cytokine production was measured ex vivo with flow cytometry upon PMA-ionomycin stimulation. <h3>Results</h3> The frequency of FoxP3<sup>+</sup> Tregs and the FoxP3 content per cell did not change upon MTX start. Suppressive capacity of Tregs appeared to be lower 6 months after MTX start compared to 3 months after MTX and prior to MTX start. In cross-over experiments, however, suppressive capacity of Tregs from all time points was equal. Teffs after MTX start proliferated significantly more in comparison to Teffs prior to MTX upon stimulation with anti-CD3. The authors observed an increase in IFN-γ and TNF-α production. <h3>Conclusions</h3> MTX does not exert immunomodulatory actions on Tregs. Instead, the authors observe changes in Teffs upon MTX start; they show that Teffs after MTX start have increased proliferation. The authors will explore the effect of MTX on Teffs further.
Assessment of Myocardial Viability by Intracellular <sup>23</sup> Na Magnetic Resonance Imaging
Authors: Maurits A. Jansen, Jan G. Van Emous, Marcel G.J. Nederhoff, Cees J.A. Van Echteld
Journal: Circulation (2004)

Background— Because of rapid changes in myocardial intracellular Na + (Na + i ) during ischemia and reperfusion (R), 23 Na magnetic resonance imaging (MRI) appears to be an ideal diagnostic modality for early detection of myocardial ischemia and viability. So far, cardiac 23 Na MRI data are limited and mostly concerned with imaging of total Na + . For proper interpretation, imaging of both Na + i and extracellular Na + is essential. In this study, we tested whether Na + i imaging can be used to assess viability after low-flow (LF) ischemia. Methods and Results— Isolated rat hearts were subjected to LF (1%, 2%, or 3% of control coronary flow) and R. A shift reagent was used to separate Na + i and extracellular Na + resonances. Acquisition-weighted 23 Na chemical shift imaging (CSI) was alternated with 23 Na MR spectroscopy. Already during control perfusion, Na + i could be clearly seen on the images. Na + i image intensity increased with increasing severity of ischemia. During R, Na + i image intensity remained highest in 1% LF hearts. Not only did we find very good correlations between Na + i image intensity at end-R and end-diastolic pressure ( R =0.85, P &lt;0.001) and recovery of the rate-pressure product ( R =−0.88, P &lt;0.001) at end-R, but most interestingly, also Na + i image intensity at end-LF was well correlated with end-diastolic pressure ( R =0.78, P &lt;0.01) and with recovery of the rate-pressure product ( R =−0.81, P &lt;0.01) at end-R. Furthermore, Na + i image intensity at end-LF was well correlated with creatine kinase release during R ( R =0.79, P &lt;0.05) as well as with infarct size ( R =0.77, P &lt;0.05). Conclusions— These data indicate that 23 Na CSI is a promising tool for the assessment of myocardial viability.
Comparison of fluticasone, roflumilast and tiotropium in a model of influenza-induced acute COPD exacerbation
Authors: Matthias Duechs, Eva Wex, Lutz Wollin, Michael Pieper, Florian Gantner, Birgit Jung
Journal: European Respiratory Journal (2013)

Background : Exacerbations of COPD are associated with increased risk of mortality. One major trigger of COPD exacerbations are influenza virus-induced respiratory tract infections.   Aim : To compare the efficacy of the corticosteroid fluticasone to treatment with the PDE4 inhibitor roflumilast, and the long acting anticholinergic tiotropium in a COPD mouse model of acute virus-induced exacerbation.   Methods : BALB/c mice were exposed to cigarette smoke (CS) for 2 weeks and infected with Influenza A H1N1 on day 8. In parallel to CS exposure, mice were treated with fluticasone, roflumilast or tiotropium. Mice were sacrificed on day 12 and pulmonary cell infiltration, cytokines in lung homogenate, lung function and viral replication were assessed.   Results : Treatment with fluticasone showed that virus-induced neutrophilia was not only steroid insensitive, but steroid treatment lead to a worsening of health status, a more rapid and severe loss of body weight, an increase in pro-inflammatory cytokine release (IL-6, IFN-γ, IL-10 and KC), a decline in lung function and an increased viral load. Treatment with roflumilast reduced IFN-γ, IL-6, KC, and IL-10, but had only modest effects on cellular influx. Tiotropium was the only compound tested that did not only reduce IFN-γ, IL-6 and IL-10 but also significantly attenuated pulmonary cellular influx of neutrophils and macrophages.   Conclusion : Our data demonstrate that in this in vivo model of Influenza-induced exacerbation fluticasone worsens health status. In contrast, treatment with roflumilast and tiotropium reduces release of pro-inflammatory cytokines. Furthermore, tiotropium efficiently reduces inflammatory cell infiltration.
Promoting effect of neutrophils on lung tumorigenesis is mediated by CXCR2 and neutrophil elastase
Authors: Lei Gong, Amber M Cumpian, Mauricio S Caetano, Cesar E Ochoa, Maria Miguelina De la Garza, Daniel J Lapid, Seyedeh Golsar Mirabolfathinejad, Burton F Dickey, Qinghua Zhou, Seyed Javad Moghaddam
Journal: Molecular Cancer (2013)

Abstract Background Tumor cells produce various cytokines and chemokines that attract leukocytes. Leukocytes can amplify parenchymal innate immune responses, and have been shown to contribute to tumor promotion. Neutrophils are among the first cells to arrive at sites of inflammation, and the increased number of tumor-associated neutrophils is linked to poorer outcome in patients with lung cancer. Results We have previously shown that COPD-like airway inflammation promotes lung cancer in a K-ras mutant mouse model of lung cancer (CC-LR). This was associated with severe lung neutrophilic influx due to the increased level of neutrophil chemoattractant, KC. To further study the role of neutrophils in lung tumorigenesis, we depleted neutrophils in CC-LR mice using an anti-neutrophil antibody. This resulted in a significant reduction in lung tumor number. We further selectively inhibited the main receptor for neutrophil chemo-attractant KC, CXCR2. Similarly, this resulted in suppression of neutrophil recruitment into the lung of CC-LR mice followed by significant tumor reduction. Neutrophil elastase (NE) is a potent elastolytic enzyme produced by neutrophils at the site of inflammation. We crossed the CC-LR mice with NE knock-out mice, and found that lack of NE significantly inhibits lung cancer development. These were associated with significant reduction in tumor cell proliferation and angiogenesis. Conclusion We conclude that lung cancer promotion by inflammation is partly mediated by activation of the IL-8/CXCR2 pathway and subsequent recruitment of neutrophils and release of neutrophil elastase. This provides a baseline for future clinical trials using the IL-8/CXCR2 pathway or NE inhibitors in patients with lung cancer.