tbuckley/cabot-search huggingface dataset:
Bidirectional modulation of urge to cough by nasal TRPA1 and TRPM8 agonists in healthy human subjects
Authors: Jana Plevkova, Mariana Brozmanova, Silvia Gavliakova, Vladimir Calkovsky, Ivan Poliacek
Journal: European Respiratory Journal (2012)

Cough, the most important airways defensive mechanism is modulated by many afferent inputs either from respiratory tussigenic areas, but also by afferent drive from other organs. Modulation of cough by nasal afferent inputs could either facilitate cough response or inhibit it in animal models, depending on the type of trigeminal afferents which are stimulated. In recent study we addressed the question of possible bidirectional modulation of cough response in human healthy volunteers by nasal challenges with TRPA1 and TRPM8 agonists respectively. After nasal challenges with AITC, cinnamaldehe, (-) menthol and (+) menthol (all 10-3 M, nasal symptom score, cough threshold (C2), urge to cough (Cu) and cumulative cough response had been tested).  Nasal challenges of TRPA1 relevant agonists induced considerable nasal symptoms, significantly enhanced urge to cough (p   Except the role of trigeminal afferents expressing TRP channels, also olfactory nerve endings, trigemino – olfactoric relationships, smell perception process and other supramedullar influences have to be taken into consideration as relevant enough to modulate cough response in humans.  supported by VEGA 1/0031/11.
GDNF–RET Signaling in ER-Positive Breast Cancers Is a Key Determinant of Response and Resistance to Aromatase Inhibitors
Authors: Andrea Morandi, Lesley-Ann Martin, Qiong Gao, Sunil Pancholi, Alan Mackay, David Robertson, Marketa Zvelebil, Mitch Dowsett, Ivan Plaza-Menacho, Clare M. Isacke
Journal: Cancer Research (2013)

Abstract Most breast cancers at diagnosis are estrogen receptor-positive (ER+) and depend on estrogen for growth and survival. Blocking estrogen biosynthesis by aromatase inhibitors has therefore become a first-line endocrine therapy for postmenopausal women with ER+ breast cancers. Despite providing substantial improvements in patient outcome, aromatase inhibitor resistance remains a major clinical challenge. The receptor tyrosine kinase, RET, and its coreceptor, GFRα1, are upregulated in a subset of ER+ breast cancers, and the RET ligand, glial-derived neurotrophic factor (GDNF) is upregulated by inflammatory cytokines. Here, we report the findings of a multidisciplinary strategy to address the impact of GDNF–RET signaling in the response to aromatase inhibitor treatment. In breast cancer cells in two-dimensional and three-dimensional culture, GDNF-mediated RET signaling is enhanced in a model of aromatase inhibitor resistance. Furthermore, GDNF–RET signaling promoted the survival of aromatase inhibitor-resistant cells and elicited resistance in aromatase inhibitor-sensitive cells. Both these effects were selectively reverted by the RET kinase inhibitor, NVP-BBT594. Gene expression profiling in ER+ cancers defined a proliferation-independent GDNF response signature that prognosed poor patient outcome and, more importantly, predicted poor response to aromatase inhibitor treatment with the development of resistance. We validated these findings by showing increased RET protein expression levels in an independent cohort of aromatase inhibitor-resistant patient specimens. Together, our results establish GDNF–RET signaling as a rational therapeutic target to combat or delay the onset of aromatase inhibitor resistance in breast cancer. Cancer Res; 73(12); 3783–95. ©2013 AACR.
Genetic Approaches to Assessing Evidence for a T Helper Type 1 Cytokine Defect in Adult Asthma
Authors: Illugi F. Birkisson, Eva Halapi, Unnur S. Bjornsdottir, Dana L. Shkolny, Elva Adalsteinsdottir, Thor Arnason, David Gislason, Thorarinn Gislason, Jeffrey Gulcher, Kari Stefansson, Hakon Hakonarson
Journal: American Journal of Respiratory and Critical Care Medicine (2004)

Recent evidence suggests that deficiency in the Th1 cytokine pathway may underlie the susceptibility to allergic asthma. This study examined whether (1) single-nucleotide polymorphisms exist in the promoter region of the two interleukin (IL)-12 subunit genes in patients with asthma; (2) messenger RNA and protein expressions of signal transducers and activators of transcription, IL-12, IFN-γ, and their receptors are altered in asthma; and (3) linkage to genes in the Th1 pathway is present in families with asthma in Iceland. The promoter regions of the IL-12 subunit genes were sequenced in 94 patients with asthma and 94 control subjects without asthma. Linkage was examined in 169 families that included over 570 patients with asthma and 950 of their unaffected relatives. The results demonstrate no evidence of linkage to microsatellite markers in close association with genes within the Th1 pathway, and no polymorphism was detected in the promoter regions of the two IL-12 subunit genes in the cohort with asthma patients. Moreover, we found no differences in the messenger RNA or protein expression signals of genes in the IL-12 pathway between the patients and control subjects. We conclude that decrease in Th1 type cytokine response is unlikely to present a primary event in asthma.
ET-68 * ALTERNATING ELECTRIC FIELDS PERTURB THE LOCALIZATION OF CYTOKINETIC FURROW PROTEINS AND CAUSE ABERRANT MITOTIC EXIT
Authors: A. Yang, T. Holtzman, S. X. Lee, E. Wong, K. Swanson
Journal: Neuro-Oncology (2014)

The NovoTTF-100A is an FDA approved device for the treatment of recurrent Glioblastoma. However, the precise nature of its effects on cells that support its clinical efficacy is poorly understood. We have found that the alternating electric fields generated by the NovoTTF-100A (TTFields) disrupt cells during the metaphase to anaphase transition. Cells exposed to TTFields during mitosis appear normal within metaphase, but exhibit prolonged anaphase accompanied by random and uncontrolled membrane contractions referred to as mitotic blebbing arising from dysregulation of contractile elements normally localized to the cytokinetic furrow. This phenomenon leads to aberrant mitotic exit, leading to decreased proliferation and increased apoptosis that is influenced by p53 mutational status. Further analysis demonstrates that treated cells exhibited features of so-called immunogenic cell death capable of stimulating immune responses deranged cells. The ability of alternating electric fields to thus affect cellular physiology is dependent on their ability to perturb the function of specific proteins that possess high dipole moments. The Septin heterotrimer is composed of Septins 2, 6 and 7 and has a high dipole moment of 2711 Debyes. This Septin complex is essential for the organization and the regulation of cytokinetic furrow contraction which results in daughter cell formation. Importantly, perturbation of Septins or their binding partners is reported to result in mitotic catastrophe similar to that observed during TTFields exposure. We report that TTFields perturb normal Septin localization during both mitosis and cell spreading demonstrating a direct effect of TTFields on a protein involved in mitosis. Together, these data strongly support a model that explains how TTFields interfere with normal mitotic progression by disrupting mitotic furrow regulation causing mitotic catastrophe and aberrant mitotic exit. This leads to a form of immunogenic cell death that may sufficiently reduce intratumoral immune privilege to allow for tumor elimination in some patients.
Relapse of Major Depression in Women Who Continue or Discontinue Antidepressant Medication During Pregnancy
Authors: Constance Guille, C. Neill Epperson
Journal: American Journal of Psychiatry (2013)

We applaud Dr. Chaudron's excellent review of the treatment of depression during pregnancy (1) in the January issue.She has provided a wealth of important information that assists clinicians and their patients in making difficult decisions regarding the use of antidepressant medication during pregnancy and the risks of untreated illness.As Dr. Chaudron astutely points out, decision making can span many months preceding pregnancy and into infancy.Given the breadth and scope of issues that can arise during this time, a single review cannot address them all or provide data to guide all decisions.While the focus of the review is the treatment of depression during pregnancy, a common clinical challenge is whether to continue or discontinue antidepressant medication during pregnancy.We felt this was an important area to further elaborate on, given the prevalence of antidepressant use (2) and currently available conflicting data (3, 4).
Interval cancers in a FOBT-based colorectal cancer population screening programme: implications for stage, gender and tumour site
Authors: R J C Steele, P McClements, C Watling, G Libby, D Weller, D H Brewster, R Black, F A Carey, C G Fraser
Journal: Gut (2011)

Background Between 2000 and 2007, a demonstration pilot of biennial guaiac faecal occult blood test (GFOBT) screening was carried out in Scotland. Methods Interval cancers were defined as cancers diagnosed within 2 years (ie, a complete screening round) of a negative GFOBT. The stage and outcome of the interval cancers were compared with those arising contemporaneously in the non-screened Scottish population. In addition, the gender and site distributions of the interval cancers were compared with those in the screen-detected group and the non-screened population. Results Of the cancers diagnosed in the screened population, interval cancers comprised 31.2% in the first round, 47.7% in the second, and 58.9% in the third, although this was due to a decline in the numbers of screen-detected cancers rather than an increase in interval cancers. There were no consistent differences in the stage distribution of interval cancers and cancers from the non-screened population, and, in all three rounds, both overall and cancer-specific survival were significantly better for patients diagnosed with interval cancers (p<0.01). The percentage of cancers arising in women was significantly higher in the interval cancer group (50.2%) than in either the screen-detected group (35.3%, p<0.001) or the non-screened group (40.6%, p<0.001). In addition, the proportion of both right-sided and rectal cancers was significantly higher in the interval cancer group than in either the screen-detected (p<0.001) or non-screened (p<0.004) groups. Conclusions Although GFOBT screening is associated with substantial interval cancer rates that increase with screening round, the absolute numbers do not. Interval cancers are associated with a better prognosis than cancers arising in a non-screened population, and GFOBT appears to preferentially detect cancers in men and the left side of the colon at the expense of cancers in women and in the right colon and rectum.
Endothelial Cell Coculture Within Tissue-Engineered Cardiomyocyte Sheets Enhances Neovascularization and Improves Cardiac Function of Ischemic Hearts
Authors: Hidekazu Sekine, Tatsuya Shimizu, Kyoko Hobo, Sachiko Sekiya, Joseph Yang, Masayuki Yamato, Hiromi Kurosawa, Eiji Kobayashi, Teruo Okano
Journal: Circulation (2008)

Background— Regenerative therapies, including myocardial tissue engineering, have been pursued as a new possibility to repair the damaged myocardium, and previously the transplantation of layered cardiomyocyte sheets has been shown to be able to improve cardiac function after myocardial infarction. We examined the effects of promoting neovascularization by controlling the densities of cocultured endothelial cells (ECs) within engineered myocardial tissues created using our cell sheet-based tissue engineering approach. Methods and Results— Neonatal rat cardiomyocytes were cocultured with GFP-positive rat-derived ECs on temperature-responsive culture dishes. Cocultured ECs formed cell networks within the cardiomyocyte sheets, which were preserved during cell harvest from the dishes using simple temperature reduction. We also observed significantly increased in vitro production of vessel-forming cytokines by the EC-positive cardiac cell sheets. After layering of 3 cardiac cell sheets to create 3-dimensional myocardial tissues, these patch-like tissue grafts were transplanted onto infarcted rat hearts. Four weeks after transplantation, recovery of cardiac function could be significantly improved by increasing the EC densities within the engineered myocardial tissues. Additionally, when the EC-positive cardiac tissues were transplanted to myocardial infarction models, we observed significantly greater numbers of capillaries in the grafts as compared with the EC-negative cell sheets. Finally, blood vessels originating from the engineered EC-positive cardiac tissues bridged into the infarcted myocardium to connect with capillaries of the host heart. Conclusions— In vitro engineering of 3-dimensional cardiac tissues with preformed EC networks that can be easily connected to host vessels can contribute to the reconstruction of myocardial tissue grafts with a high potential for cardiac function repair. These results indicate that neovascularization can contribute to improved cardiac function after the transplantation of engineered cardiac tissues.
Torasemide Transport by Organic Anion Transporters Contributes to Hyperuricemia
Authors: Yohannes Hagos, Andrew Bahn, Stefan V Vormfelde, Jürgen Brockmöller, Gerhard Burckhardt
Journal: Journal of the American Society of Nephrology (2007)

The high renal clearance of torasemide, the most potent loop diuretic, suggests active tubular secretion in the proximal tubule. Previous studies implicated the organic anion transporters (OAT) in this process; human OAT1 (hOAT1) and hOAT3 are found on the basolateral surface of proximal tubule
Spontaneous abortion, sex ratio, and paternal occupational exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin.
Authors: T M Schnorr, C C Lawson, E A Whelan, D A Dankovic, J A Deddens, L A Piacitelli, J Reefhuis, M H Sweeney, L B Connally, M A Fingerhut
Journal: Environmental Health Perspectives (2001)

There is conflicting research regarding an association between fetal death and paternal exposure to Agent Orange, a phenoxy herbicide widely used in Vietnam that was contaminated with 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). Men who worked in the U.S. factories that produced Agent Orange were exposed to TCDD at levels hundreds of times higher than TCDD levels in the general population. Wives of TCDD-exposed chemical workers and wives of nonexposed neighborhood referents were interviewed to determine reproductive history. Paternal serum TCDD level at time of conception was estimated for each pregnancy using serum samples taken in 1987. Estimated TCDD levels of workers during or after exposure were high (median, 254 ppt; range, 3-16,340 ppt) compared to referent levels (median, 6 ppt; range, 2-19 ppt). No association between paternal TCDD level at the time of conception and spontaneous abortion was observed among pregnancies fathered by workers with TCDD levels of < 20 ppt [odds ratio (OR) = 0.77; 95% confidence interval (CI), 0.48-1.22], 20 to < 255 ppt (OR = 0.81; 95% CI, 0.40-1.63), 255 to < 1,120, (OR = 0.69; 95% CI, 0.30-1.58), and >or= 1,120 ppt (OR = 0.95; 95% CI, 0.42-2.17) compared to pregnancies fathered by referents. The sex ratio [males/(males + females)] of offspring also did not differ by TCDD exposure (0.53 and 0.54 among workers and referents, respectively). We did not find an association between paternal serum TCDD level and spontaneous abortion or sex ratio of offspring in this population. The estimated TCDD levels in this exposed worker population were much higher than in other studies, providing additional evidence that paternal TCDD exposure does not increase the risk of spontaneous abortion at levels above those observed in the general population. The study could not evaluate the effect of father's childhood or prenatal TCDD exposure on subsequent sex ratio.
A simple method for estimating the parameter of substitution rate variation among sites
Authors: X Gu, J Zhang
Journal: Molecular Biology and Evolution (1997)

When the rate variation among sites is described by a gamma distribution, an important problem is how to estimate the shape parameter alpha, which is an index of the degree of among-site rate variation. The parsimony-based methods for estimating alpha are simple but biased, i.e., alpha tends to be overestimated. On the other hand, the likelihood-based methods are asymptotically unbiased but take a huge amount of computational time. In this paper, we have developed a new method to solve this problem: we first estimate the expected number of substitutions at each site, which is corrected for multiple hits, and then estimate the parameter alpha. Our method is computationally as fast as the parsimony method, and the estimation accuracy is much higher than that of parsimony and similar to that of the likelihood method.
Phase I Trial of Intrathecal Liposomal Cytarabine in Children With Neoplastic Meningitis
Authors: L. Bomgaars, J.R. Geyer, J. Franklin, G. Dahl, J. Park, N.J. Winick, R. Klenke, S.L. Berg, S.M. Blaney
Journal: Journal of Clinical Oncology (2004)

We performed a phase I trial of intrathecal (IT) liposomal cytarabine (DepoCyt; Enzon Pharmaceuticals, Piscataway, NJ and SkyePharma Inc, San Diego, CA) to determine the maximum-tolerated dose, the dose-limiting toxicities, and the plasma and CSF pharmacokinetics of IT lipsomal cytarabine in children >/= 3 years of age with advanced meningeal malignancies.Eighteen assessable patients received IT liposomal cytarabine through either an indwelling ventricular access device or via lumbar puncture. Liposomal cytarabine was given once every 2 weeks during induction, once every 4 weeks during consolidation, and once every 8 weeks during the maintenance phase of treatment. The initial dose was 25 mg, with subsequent escalations to 35 and 50 mg. CSF pharmacokinetic samples were obtained in a subset of patients.Arachnoiditis, characterized by fever, headache, nausea, vomiting, and back pain was noted in the first two patients at the 25 mg dose level. Therefore, subsequent patients were treated with dexamethasone, beginning the day of liposomal cytarabine administration and continuing for 5 days. Headache (grade 3) was dose limiting in two of eight patients enrolled at the 50 mg dose level. Eight of the 14 patients assessable for response demonstrated evidence of benefit manifest as prolonged disease stabilization or response.The maximum-tolerated dose and recommended phase II dose of liposomal cytarabine in patients between the ages of 3 and 21 years is 35 mg, administered with dexamethasone (0.15 mg/kg/dose, twice a day for 5 days). A phase II trial of IT liposomal cytarabine in children with CNS leukemia in second or higher relapse is in development.
SIR MALCOLM MORRIS MEMORIAL FUND
Authors: G. H. Monrad-Krohn
Journal: British Journal of Dermatology (1924)

Journal Article SIR MALCOLM MORRIS MEMORIAL FUND Get access G. H. Monrad‐Krohn G. H. Monrad‐Krohn Search for other works by this author on: Oxford Academic Google Scholar British Journal of Dermatology and Syphilis, Volume 36, Issue 6, 1 June 1924, Pages 283–284, https://doi.org/10.1111/j.1365-2133.1924.tb09197.x Published: 01 June 1924
Clonality and Recombination in the Life History of an Asexual Arbuscular Mycorrhizal Fungus
Authors: H. C. den Bakker, N. W. VanKuren, J. B. Morton, T. E. Pawlowska
Journal: Molecular Biology and Evolution (2010)

Arbuscular mycorrhizal (AM) fungi in the phylum Glomeromycota colonize roots of the majority of land plants and assist them in the uptake of mineral nutrients in exchange for plant-assimilated carbon. In the absence of sexual reproductive structures and with asexual spore morphology conserved since the Ordovician, Glomeromycota may be one of the oldest eukaryotic lineages that rely predominantly on asexual reproduction for gene transmission. Clonal population structure detected in the majority of AM fungi examined to date supports this hypothesis. However, evidence of recombination found in few local populations suggests that genetic exchanges may be more common in these organisms than is currently recognized. To explore the significance of clonal expansion versus genetic recombination in the life history of modern Glomeromycota, we examined the global population of a cosmopolitan fungus Glomus etunicatum and made inferences about the population structure and the occurrence of recombination in the history of this species. We sampled eight loci from 84 isolates. We found that although the global population of G. etunicatum showed a pattern of significant differentiation, several haplotypes had a broad geographic distribution spanning multiple continents. Molecular variation among the sampled isolates indicated an overwhelmingly clonal population structure and suggested that clonal expansion plays an important role in the ecological success of modern Glomeromycota. In contrast, a pattern of homoplasy consistent with a history of recombination suggested that gene exchanges are not completely absent from the life history of these organisms, although they are likely to be very rare.
Ethnic Variation in Adiponectin and Leptin Levels and Their Association With Adiposity and Insulin Resistance
Authors: Andrew Mente, Fahad Razak, Stefan Blankenberg, Vlad Vuksan, A. Darlene Davis, Ruby Miller, Koon Teo, Hertzel Gerstein, Arya M. Sharma, Salim Yusuf, Sonia S. Anand
Journal: Diabetes Care (2010)

OBJECTIVE To investigate ethnic differences in adiponectin and leptin concentration and to determine whether these adipokines and a high–glycemic index diet account for ethnic variation in insulin resistance. RESEARCH DESIGN AND METHODS In 1,176 South Asian, Chinese, Aboriginal, and European Canadians, fasting blood samples were drawn, and clinical history and dietary habits including glycemic index/glycemic load were recorded using standardized questionnaires. Insulin resistance was defined using homeostasis model assessment–insulin resistance (HOMA-IR). RESULTS Adiponectin concentrations were significantly higher in Europeans (adjusted mean 12.94 [95% CI 2.27–13.64]) and Aboriginal people (11.87 [11.19–12.59]) than in South Asians (9.35 [8.82–9.92]) and Chinese (8.52 [8.03–9.03]) (overall P &amp;lt; 0.001). Serum leptin was significantly higher in South Asians (11.82 [10.72–13.04]) and Aboriginal people (11.13 [10.13–12.23]) than in Europeans (9.21 [8.38–10.12]) and Chinese (8.25 [7.48–9.10]). BMI and waist circumference were inversely associated with adiponectin in every group except the South Asians (P &amp;lt; 0.001 for interaction). Adiponectin was inversely and leptin was positively associated with HOMA-IR (P &amp;lt; 0.001). The increase in HOMA-IR for each given decrease in adiponectin was larger among South Asians (P = 0.01) and Aboriginal people (P &amp;lt; 0.001) than among Europeans. A high glycemic index was associated with a larger decrease in adiponectin among South Asians (P = 0.03) and Aboriginal people (P &amp;lt; 0.001) and a larger increase in HOMA-IR among South Asians (P &amp;lt; 0.05) relative to that in other groups. CONCLUSIONS South Asians have the least favorable adipokine profile and, like the Aboriginal people, display a greater increase in insulin resistance with decreasing levels of adiponectin. Differences in adipokines and responses to glycemic foods parallel the ethnic differences in insulin resistance.