tbuckley/cabot-search huggingface dataset:
Loss of Heterozygosity Occurs via Mitotic Recombination in <b> <i>Trp53</i> </b>+/− Mice and Associates with Mammary Tumor Susceptibility of the BALB/c Strain
Authors: Anneke C. Blackburn, S. Christine McLary, Rizwan Naeem, Jason Luszcz, David W. Stockton, Lawrence A. Donehower, Mansoor Mohammed, John B. Mailhes, Tamar Soferr, Stephen P. Naber, Christopher N. Otis, D. Joseph Jerry
Journal: Cancer Research (2004)

Abstract Loss of heterozygosity (LOH) occurs commonly in cancers causing disruption of tumor suppressor genes and promoting tumor progression. BALB/c-Trp53+/− mice are a model of Li-Fraumeni syndrome, exhibiting a high frequency of mammary tumors and other tumor types seen in patients. However, the frequency of mammary tumors and LOH differs among strains of Trp53+/− mice, with mammary tumors occurring only on a BALB/c genetic background and showing a high frequency of LOH, whereas Trp53+/− mice on a 129/Sv or (C57BL/6 × 129/Sv) mixed background have a very low frequency of mammary tumors and show LOH for Trp53 in only ∼50% of tumors. We have performed studies on tumors from Trp53+/− mice of several genetic backgrounds to examine the mechanism of LOH in BALB/c-Trp53+/− mammary tumors. By Southern blotting, 96% (24 of 25) of BALB/c-Trp53+/− mammary tumors displayed LOH for Trp53. Karyotype analysis indicated that cells lacking one copy of chromosome 11 were present in all five mammary tumors analyzed but were not always the dominant population. Comparative genomic hybridization analysis of these five tumors indicated either loss or retention of the entire chromosome 11. Thus chromosome loss or deletions within chromosome 11 do not account for the LOH observed by Southern blotting. Simple sequence length polymorphism analysis of (C57BL/6 × BALB/c) F1-Trp53+/− mammary tumors showed that LOH occurred over multiple loci and that a combination of maternal and paternal alleles were retained, indicating that mitotic recombination is the most likely mechanism of LOH. Nonmammary tumors of BALB/c mice also showed a high frequency of LOH (22 of 26, 85%) indicating it was not a mammary tumor specific phenomenon but rather a feature of the BALB/c strain. In (C57BL/6 × BALB/c) F1-Trp53+/− mice LOH was observed in 93% (13 of 14) of tumors, indicating that the high frequency of LOH was a dominant genetic trait. Thus the high frequency of LOH for Trp53 in BALB/c-Trp53+/− mammary tumors occurs via mitotic recombination and is a dominant genetic trait that associates with the occurrence of mammary tumors in (C57BL/6 × BALB/c) F1-Trp53+/− mice. These results further implicate double-strand DNA break repair machinery as important contributors to mammary tumorigenesis.
Peak‐flow variability in asthmatic children is not related to wall‐to‐wall carpeting on classroom floors
Authors: P. D. Voûte, J. P. Zock, B. Brunekreef, J. C. de Jongste
Journal: Allergy (1994)

The hypothesis was tested that wall‐to‐wall carpets on school classroom floors have a negative effect on the respiratory health of asthmatic children. Asthmatic patients ( n = 98) were selected from the records of the Sophia Children's Hospital in Rotterdam. The patients were between 5 and 11 years old. All children had peak‐flow measurements three times a day for a 1‐month period. The parents of the children completed a diary in which respiratory symptoms and medication use were recorded daily for the same period. Dust samples were taken from classroom floors, living‐room and bedroom floors, and mattresses of the children. The dust samples were analyzed for Der p I content, the major allergen of the house‐dust mite Dermatophagoides pteronyssinus. The results of the study showed that there was no significant difference between children visiting schools with or without carpeted classroom floors in peak‐flow variability, acute respiratory symptoms, or medication use. The Der p I content of dust collected from classroom floors was much lower than of dust collected from homes. There was a significant correlation between peak‐flow variability and mattress dust Der p I content in asthmatic children sensitized to dust mites, but not between peak‐flow variability and classroom floor dust Der p I content. We concluded that carpeted classroom floors do not contribute to asthma symptom severity, possibly because of the low levels of Der p I on them.
Application of cultured human regulatory T cells requires preclinical in vivo evaluation
Authors: Yvonne Vercoulen, Teun Guichelaar, Jenny Meerding, Maarten Emmelot, Marieke Pingen, Gert Storm, Paul Coffer, Birgit Sawitzki, Anton Martens, Tuna Mutis, Berent Prakken
Journal: Journal of Allergy and Clinical Immunology (2011)
The psoriasis xenograft SCID mouse model: a tool in translational research
Authors: W.-H. Boehncke
Journal: British Journal of Dermatology (2012)

ORIGINAL ARTICLE, p 649 Research on the pathogenesis and treatment of diseases is much easier once suitable animal models are available. Psoriasis has proven to be particularly difficult to model. Sometimes, surprisingly ‘psoriasis‐like’ phenotypes result from relatively simple manipulations such as knocking out or overexpressing single genes. Still, given the multifactorial and polygenic nature of psoriasis, clinicians will always challenge the relevance of data generated in such models. Therefore, the approach of transplanting lesional skin from patients with psoriasis onto immunodeficient mice looks very appealing: not only are all components of the clinical lesion preserved,1 but one can also reconstitute parts of the donor’s immune system in these animals as is routinely done in the field of HIV research.2 Meanwhile, this approach has been used quite frequently not only to address ‘basic’ questions regarding the pathogenesis of psoriasis, but also to test the efficacy of newly developed putative antipsoriatic drugs;3, 4 a track record is beginning to be established with regard to its positive and negative predictive value. Although some groups suggested clinical scores of the skin grafts, assessments regarding the efficacy of a therapeutic approach were mostly based on histology and immunohistochemistry. As a consequence, results obtained were mainly descriptive in nature.
Allotype-specific analysis of anti-(TYR,GLU)-ALA-LYS antibodies produced by Ir-1A high and low responder chimeric mice
Authors: JL Press, HO McDevitt
Journal: The Journal of Experimental Medicine (1977)

Katz et al. (1) have demonstrated a restriction in lymphoid cell interaction when the antigen used is under immune response (Ir) gene control. T cells from (low responder x high responder) F(1) mice primed to the terpolymer L-glutamic acid, L-lysine, L-tyrosine (GLT) can collaborate with 2,4-dinitrophenyl (DNP)-primed B cells from the Ir-GLT high responder but not low responder strain in response to DNP-GLT (1). In contrast are the studies of Bechtol et al. and Bechtol and McDevitt (2,3), who examined the antibody responses of tetraparental mice immunized with the synthetic polypeptide poly-L(Tyr,Glu)-poly D,L-Ala- poly-L-Lys ((T,G)-A-L), an antigen under Ir-1A genetic control. Several tetraparental mice produced anti(T-,G)-A-L antibody of low responder strain immunoglobulin (Ig) allotype (2,3). These results indicated that he Ir-1A gene was not expressed in B cells and implied that interactions among genetically dissimilar cell populations could occur when tolerance existed to H-2 antigenic differences. Recent studies with bone marrow cell chimeric mice have shown that chimeric T cells can interact with H-2 histoincompatible B cells in response to antigens not under Ir gene control (4-6). To clarify whether lymphoid cell chimerism, with presumed tolerance to H-2 incompatibility, would permit effective cell interactions in response to antigens under Ir gene control, bone marrow cell chimeric mice were prepared by using strains differing both for Ig allotype and for high versus low responsiveness to (T,G)-A-L. An antigen-specific and allotype- specific antibody assay was used to discriminate the responses produced by high and low responder strain B cells in these chimeras. The results suggest that lymphoid cell chimerism per se is not sufficient to obviate Ir gene-mediated restriction in cell interaction.
A–Z of nutritional supplements: dietary supplements, sports nutrition foods and ergogenic aids for health and performance: part 39: Table 1
Authors: D S Senchina, L M Burke, S J Stear, L M Castell
Journal: British Journal of Sports Medicine (2012)

Micronutrients, including vitamin supplements, are widely used in the general population and by athletes. A variety of claims or areas of interest have promoted the use of vitamin supplements, with antioxidant claims becoming a popular interest over the past two decades. While the antioxidant issue has typically targeted the prevention of ageing or various diseases associated with oxidative damage, it has also been recognised that exercise is a stimulator of the generation of oxygen radical species. Hence, there has been interest in whether athletes might have additional needs for antioxidant vitamins to counteract such damage. Because of the considerable and long-term interest in this topic, we have devoted an entire part of this series on supplements to the antioxidant vitamins, A, C and E.

### D S Senchina

Vitamins A, C and E are being discussed together in this series because all three have antioxidant properties, though they differ in many other respects (see table 1). Recent research has focused on these vitamins’ antioxidant prospects because exercise induces free radical (ROS, reactive oxygen species) release which leads to cellular damage, fatigue and overtraining. Literally hundreds of studies on antioxidant vitamin supplementation (AVS) and exercise have been published. In the representative sample reviewed here, vitamin A (V-A) was given as β-carotene, vitamin C (V-C) as ascorbic acid and vitamin E (V-E) as α-tocopherol.

View this table:

Table 1 
Properties of vitamins A, C and E.



Systematic training causes the body to develop adaptations naturally to the increase in …
Ischemic preconditioning prevents calpain-mediated impairment of Na+/K+-ATPase activity during early reperfusion☆
Authors: J INSERTE, D GARCIADORADO, V HERNANDO, I BARBA, J SOLERSOLER
Journal: Cardiovascular Research (2006)

We previously demonstrated that ischemic preconditioning (IPC) attenuates calpain activation during reperfusion. Herein, we tested the hypothesis that enhancement of Na+/K+-ATPase activity during early reperfusion as a result of calpain inhibition is involved in the protection afforded by myocardial IPC.Intracellular Na+ concentration ([Na+]i) measured using 23Na-magnetic resonance spectroscopy, Na+/K+-ATPase activity, detachment of Na+/K+-ATPase alpha subunits from the membrane cytoskeleton, degradation of fodrin and ankyrin, and calpain activation were analysed in isolated rat hearts reperfused after 60 min of ischemia with or without previous IPC and different treatments aimed to mimic or blunt the effects of IPC.In non-treated hearts subjected to ischemia (control hearts), reperfusion for 5 min severely reduced Na+/K+-ATPase activity and dissociated alpha1 and alpha2 subunits of Na+/K+-ATPase from the membrane-cytoskeleton complex in parallel with proteolysis of alpha-fodrin and ankyrin-B and calpain activation. IPC accelerated the recovery of [Na+]i, increased Na+/K+-ATPase activity, and prevented dissociation of Na+/K+-ATPase from the membrane-cytoskeleton complex. IPC also prevented alpha-fodrin and ankyrin-B loss and calpain activation, effects that were associated with attenuated lactate dehydrogenase (LDH) release and infarct size and improved contractile recovery. These effects of IPC were reproduced by perfusing the hearts with the calpain inhibitor MDL-28170 and by transient stimulation of cAMP-dependent protein kinase (PKA) with CPT-cAMP, and they were reverted by perfusing with the PKA inhibitor H89.The results of the present study are consistent with the hypothesis that enhanced recovery of Na+/K+-ATPase activity during reperfusion as a result of attenuated calpain-mediated detachment of the protein from the membrane-cytoskeleton complex contributes to the protection afforded by IPC.
Aberrant expression and constitutive activation of STAT3 in cervical carcinogenesis: implications in high-risk human papillomavirus infection
Authors: Shirish Shukla, Gauri Shishodia, Sutapa Mahata, Suresh Hedau, Arvind Pandey, Suresh Bhambhani, Swaraj Batra, Seemi F Basir, Bhudev C Das, Alok C Bharti
Journal: Molecular Cancer (2010)

Abstract Background Recent observations indicate potential role of transcription factor STAT3 in cervical cancer development but its role specifically with respect to HPV infection is not known. Present study has been designed to investigate expression and activation of STAT3 in cervical precancer and cancer in relation to HPV infection during cervical carcinogenesis. Established cervical cancer cell lines and prospectively-collected cervical precancer and cancer tissues were analyzed for the HPV positivity and evaluated for STAT3 expression and its phosphorylation by immunoblotting and immunohistochemistry whereas STAT3-specific DNA binding activity was examined by gel-shift assays. Results Analysis of 120 tissues from cervical precancer and cancer lesions or from normal cervix revealed differentially high levels of constitutively active STAT3 in cervical precancer and cancer lesions, whereas it was absent in normal controls. Similarly, a high level of constitutively active STAT3 expression was observed in HPV-positive cervical cancer cell lines when compared to that of HPV-negative cells. Expression and activity of STAT3 were found to change as a function of severity of cervical lesions from precancer to cancer. Expression of active pSTAT3 was specifically high in cervical precancer and cancer lesions found positive for HPV16. Interestingly, site-specific accumulation of STAT3 was observed in basal and suprabasal layers of HPV16-positive early precancer lesions which is indicative of possible involvement of STAT3 in establishment of HPV infection. In HPV16-positive cases, STAT3 expression and activity were distinctively higher in poorly-differentiated lesions with advanced histopathological grades. Conclusion We demonstrate that in the presence of HPV16, STAT3 is aberrantly-expressed and constitutively-activated in cervical cancer which increases as the lesion progresses thus indicating its potential role in progression of HPV16-mediated cervical carcinogenesis.
Prognosis After the Implantation of an Intra-Aortic Balloon Pump in Cardiac Surgery Calculated With a New Score
Authors: Harald Hausmann, Evgenij V. Potapov, Andreas Koster, Thomas Krabatsch, Julia Stein, Ruhi Yeter, Marian Kukucka, Ralf Sodian, Hermann Kuppe, Roland Hetzer
Journal: Circulation (2002)

Over the past decade, the use of a ventricular-assist device (VAD) in patients with postcardiotomy cardiogenic shock has resulted in hospital discharge rates of 25% to 40% and is improving. Nevertheless, indications for and timing of the implantation of a VAD in patients who have received an intra-aortic balloon pump (IABP) remain unclear.From July 1996 to March 2000, 391 patients with cardiac low-output syndrome who underwent open-heart surgery and had an IABP implanted were analyzed in a retrospective pilot study. The perioperative mortality was 34% (133 patients). Clinical parameters were analyzed 1 hour after IABP support began. Statistical multivariate analysis showed that patients with an adrenaline requirement higher than 0.5 microg x kg(-1) x min(-1), a left atrial pressure >15 mm Hg, urine output <100 mL/h, and mixed venous saturation (SVO(2)) <60% had poor outcomes. Using this data, we developed an IABP score (0 to 5 points) to predict survival early after IABP implantation in cardiac surgery. We evaluated our score by monitoring another 101 patients as a control group prospectively. Additionally, 210 patients who received coronary artery bypass grafting (CABG) exclusively were analyzed. All investigations confirmed the validity of the score.The IABP score can predict survival early after IABP implantation. In patients with a high IABP score, implantation of a VAD should be considered.
AIRE Functions As an E3 Ubiquitin Ligase
Authors: Daisuke Uchida, Shigetsugu Hatakeyama, Akemi Matsushima, Hongwei Han, Satoshi Ishido, Hak Hotta, Jun Kudoh, Nobuyoshi Shimizu, Vassilis Doucas, Keiichi I. Nakayama, Noriyuki Kuroda, Mitsuru Matsumoto
Journal: The Journal of Experimental Medicine (2004)

Autoimmune regulator (AIRE) gene mutation is responsible for the development of autoimmune-polyendocrinopathy-candidiasis ectodermal dystrophy, an organ-specific autoimmune disease with monogenic autosomal recessive inheritance. AIRE is predominantly expressed in medullary epithelial cells of the thymus and is considered to play important roles in the establishment of self-tolerance. AIRE contains two plant homeodomain (PHD) domains, and the novel role of PHD as an E3 ubiquitin (Ub) ligase has just emerged. Here we show that the first PHD (PHD1) of AIRE mediates E3 ligase activity. The significance of this finding was underscored by the fact that disease-causing missense mutations in the PHD1 (C311Y and P326Q) abolished its E3 ligase activity. These results add a novel enzymatic function for AIRE and suggest an indispensable role of the Ub proteasome pathway in the establishment of self-tolerance, in which AIRE is involved.
DNA damage as a molecular link in the pathogenesis of COPD in smokers
Authors: Kazutetsu Aoshiba, Fang Zhou, Takao Tsuji, Atsushi Nagai
Journal: European Respiratory Journal (2012)

In this study, we investigated whether DNA double-strand breaks (DSBs) contribute to the pathogenesis of chronic obstructive pulmonary disease (COPD). We immunofluorescence-stained lung tissue samples obtained from COPD patients, asymptomatic smokers and nonsmokers for markers of DSBs. The numbers of DSB foci (phosphorylated histone 2AX (γH2AX), phosphorylated ATM (ataxia telangiectasia mutated) substrate and phosphorylated p53-binding protein-1 foci) per cell in alveolar type I and II cells and endothelial cells were higher in the COPD patients than in the asymptomatic smokers and nonsmokers. The lung tissue in which type II cells contained higher numbers of γH2AX foci per cell had higher percentages of type II cells that expressed p16 INK4a (p16), phosphorylated nuclear factor (NF)-κB and interleukin (IL)-6, and of alveolar wall cells that expressed active caspase-3. The type II cells that contained higher numbers of γH2AX foci per cell had higher rates of expression of p16, phosphorylated NF-κB, and IL-6. Half of the alveolar wall cells that expressed active-caspase-3 contained γH2AX foci. Type II cells that stained positive for 8-hydroxy-2-deoxyguanosine contained a higher number of γH2AX foci per cell than the type II cells that stained negative. In conclusion, DSBs, at least in part caused by oxidative stress, appear to contribute to the pathogenesis of COPD by inducing apoptosis, cell senescence and pro-inflammatory responses.
Do Placental Genes Affect Maternal Breast Cancer? Association between Offspring's <i>CGB5</i> and <i>CSH1</i> Gene Variants and Maternal Breast Cancer Risk
Authors: Yu Chen, Muhammad G. Kibriya, Farzana Jasmine, Regina M. Santella, Ruby T. Senie, Habibul Ahsan
Journal: Cancer Research (2008)

Abstract The protective effect of full-term pregnancy against breast cancer is thought to be induced by two placental hormones: human chorionic gonadotropin and human chorionic somatotropin hormone (CSH) produced by the placental trophoblastic cells. We hypothesized that variants in placental genes encoding these hormones may alter maternal breast cancer risk subsequent to pregnancy. We conducted a case-control study to examine the association between polymorphisms in a woman's placental (i.e., her offspring's) homologous chorionic gonadotrophin β5 (CGB5) and CSH1 genes and her post-pregnancy breast cancer risk. A total of 293 breast cancer cases and 240 controls with at least one offspring with available DNA were selected from the New York site of the Breast Cancer Family Registry. Three single nucleotide polymorphisms (SNP) in CGB5 and CSH1 genes were genotyped for 844 offspring of the cases and controls. Overall, maternal breast cancer risk did not significantly differ by the offspring's carrier status of the three SNPs. Among women with an earlier age at childbirth (younger than the median age of 26 years), those with a child carrying the variant C allele of CGB5 rs726002 SNP had an elevated breast cancer risk [odds ratio (OR), 2.09; 95% confidence interval (95% CI), 1.17–3.73]. Among women with a later age at childbirth, breast cancer risk did not differ by offspring's carrier status of CGB5 rs726002 SNP (OR, 0.90; 95% CI, 0.53–1.51; P for interaction = 0.04). The findings suggest that placental CGB5 genotype may be predictive of maternal post-pregnancy breast cancer risk among women who give birth early in life. [Cancer Res 2008;68(23):9729–34]
VEGF-A Expression Correlates with <i>TP53</i> Mutations in Non–Small Cell Lung Cancer: Implications for Antiangiogenesis Therapy
Authors: Maria Schwaederlé, Vladimir Lazar, Pierre Validire, Johan Hansson, Ludovic Lacroix, Jean-Charles Soria, Yudi Pawitan, Razelle Kurzrock
Journal: Cancer Research (2015)

Bevacizumab is one of the most widely used antiangiogenic drugs in oncology, but the overall beneficial effects of this VEGF-A targeting agent are relatively modest, in part due to the lack of a biomarker to select patients most likely to respond favorably. Several molecular aberrations in cancer influence angiogenesis, including mutations in the tumor suppressor gene TP53, which occur frequently in many human malignancies. In this study, we present a multiple regression analysis of transcriptomic data in 123 patients with non-small cell lung cancer (NSCLC) showing that TP53 mutations are associated with higher VEGF-A expression (P = 0.006). This association was interesting given a recent retrospective study showing longer progression-free survival in patients with diverse tumors who receive bevacizumab, if tumors harbor mutant TP53 instead of wild-type TP53. Thus, our current findings linking TP53 mutation with VEGF-A upregulation offered a mechanistic explanation for why patients exhibit improved outcomes after bevacizumab treatment when their tumors harbor mutant TP53 versus wild-type TP53. Overall, this work warrants further evaluation of TP53 as a ready biomarker to predict bevacizumab response in NSCLC and possibly other tumor types.
A Randomized Trial Evaluating a Predominantly Fetal Growth–Based Strategy to Guide Management of Gestational Diabetes in Caucasian Women
Authors: Ute M. Schaefer-Graf
Journal: Diabetes Care (2004)

We appreciate Amiel and Blott’s (1) interest in our study (2) and thank them for their helpful discussion. They rightly pointed out that the diagnostic criteria used in Germany at the time of our study had been lower than those of the American Diabetes Association. We were also aware that we treated some women who would have been considered healthy in other countries. To demonstrate that the fetal growth-based approach is also safe for women with a more severe glucose intolerance, we repeated the analysis for a subgroup of women who fulfilled the diagnostic criteria of Carpenter and Coustan (3) (80% of our population). Again, …
Inhibitory effect of a new α-glucosidase inhibitor on fatty liver in Zucker fatty rats
Authors: Yoshiaki Inui, Sumio Kawata, Yuji Matsuzawa, Katsuto Tokunaga, Shigenori Fujioka, Shinji Tamura, Takashi Kobatake, Yoshiaki Kenoxa, Hiroyuki Odaka, Takao Matsuo, Seiichiro Tarui
Journal: Journal of Hepatology (1990)