tbuckley/cabot-search huggingface dataset:
Inducible Gene Targeting in Postnatal Myocardium by Cardiac-Specific Expression of a Hormone-Activated Cre Fusion Protein
Authors: Tetsuo Minamino, Vinciane Gaussin, Francesco J. DeMayo, Michael D. Schneider
Journal: Circulation Research (2001)

Cardiac-restricted expression of Cre recombinase can provoke lineage-specific gene excision in the myocardium. However, confounding early lethality may still preclude using loss-of-function models to study the postnatal heart. Here, we have tested whether inducible, heart-specific recombination can be triggered after birth by transgenic expression of a Cre fusion protein that incorporates a mutated progesterone receptor ligand binding domain (PR1) that is activated by the synthetic antiprogestin, RU486, but not by endogenous steroid hormones. CrePR1 driven by the alpha-myosin heavy chain (alphaMHC) promoter was expressed specifically in heart. Translocation of CrePR1 from cytoplasm to nuclei in ventricular myocytes was induced by RU486. To establish whether this approach can mediate cardiac-specific, drug-dependent excision between loxP sites in vivo, we mated alphaMHC-CrePR1 mice with a ubiquitously expressed (ROSA26) Cre reporter line. Offspring harboring alphaMHC-CrePR1 and/or the floxed allele were injected with RU486 versus vehicle, and the prevalence of beta-galactosidase (beta-gal)-positive cells was determined, indicative of Cre-mediated excision. Little or no baseline recombination was seen 1 week after birth. Cardiac-restricted, RU486-inducible recombination was demonstrated in bigenic mice at age 3 and 6 weeks, using each of 3 independent CrePR1 lines. Recombination in the absence of ligand paralleled the levels of CrePR1 protein expression and was more evident at 6 weeks. Thus, conditional, posttranslational activation of a Cre fusion protein can bypass potential embryonic and perinatal effects on the heart and permits inducible recombination in cardiac muscle. High levels of the chimeric Cre protein, in particular, were associated with progressive recombination in the absence of drug.
Characteristics of hepatocellular carcinoma in Italy
Authors: Tommaso Stroffolini, Pietro Andreone, Angelo Andriulli, Antonio Ascione, Antonio Craxì, Maria Chiaramonte, Domenico Galante, Onofrio Giuseppe Manghisi, Roberto Mazzanti, Cinzia Medaglia, Giampaolo Pilleri, Gian Ludovico Rapaccini, Rosa Giovanna Simonetti, Gloria Taliani, Maria Elena Tosti, Erica Villa, Giovanni Gasbarrini
Journal: Journal of Hepatology (1998)
Polychlorinated Biphenyls and Organochlorine Pesticides in Plasma Predict Development of Type 2 Diabetes in the Elderly
Authors: Duk-Hee Lee, P. Monica Lind, David R. Jacobs, Samira Salihovic, Bert van Bavel, Lars Lind
Journal: Diabetes Care (2011)

Persistent organic pollutants (POPs), lipophilic chemicals that accumulate mainly in adipose tissue, have recently been linked to type 2 diabetes. However, evidence from prospective studies is sparse. This study was performed to evaluate prospective associations of type 2 diabetes with selected POPs among the elderly.Nineteen POPs (14 polychlorinated biphenyl [PCB] congeners, 3 organochlorine pesticides, 1 brominated diphenyl ether, and 1 dioxin) were measured in plasma collected at baseline in 725 participants, aged 70 years, of the Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS).After adjusting for known type 2 diabetes risk factors, including obesity, odds ratios (ORs) (95% CIs) for type 2 diabetes at age 75 years (n = 36) according to the quintiles of a summary measure of concentrations of PCBs (vs. the lowest quintile) were 4.5, 5.1, 8.8 (1.8-42.7), and 7.5 (1.4-38.8) (P(trend) <0.01). Among organochlorine pesticides, adjusted ORs across concentrations of trans-nonachlor showed that P(trend) = 0.03. Adjusted ORs (95% CIs) across quintiles of the sum of three organochlorine pesticides were 1.1, 1.6, 1.5, and 3.4 (1.0-11.7) (P(trend) = 0.03). Neither brominated diphenyl ether 47 nor dioxin was significantly associated with incident diabetes. The sum of PCBs improved reclassification significantly when added to traditional risk factors for diabetes.Despite the small number of incident cases, this study found that environmental exposure to some POPs substantially increased risk of future type 2 diabetes in an elderly population.
Characterization of Renal Toxicity in Mice Administered the Marine Biotoxin Domoic Acid
Authors: Jason A Funk, Michael G Janech, Joshua C Dillon, John J Bissler, Brian J Siroky, P Darwin Bell
Journal: Journal of the American Society of Nephrology (2014)

Domoic acid (DA), an excitatory amino acid produced by diatoms belonging to the genus Pseudo-nitzschia, is a glutamate analog responsible for the neurologic condition referred to as amnesic shellfish poisoning. To date, the renal effects of DA have been underappreciated, although renal filtration is the primary route of systemic elimination and the kidney expresses ionotropic glutamate receptors. To characterize the renal effects of DA, we administered either a neurotoxic dose of DA or doses below the recognized limit of toxicity to adult Sv128/Black Swiss mice. DA preferentially accumulated in the kidney and elicited marked renal vascular and tubular damage consistent with acute tubular necrosis, apoptosis, and renal tubular cell desquamation, with toxic vacuolization and mitochondrial swelling as hallmarks of the cellular damage. Doses≥0.1 mg/kg DA elevated the renal injury biomarkers kidney injury molecule-1 and neutrophil gelatinase-associated lipocalin, and doses≥0.005 mg/kg induced the early response genes c-fos and junb. Coadministration of DA with the broad spectrum excitatory amino acid antagonist kynurenic acid inhibited induction of c-fos, junb, and neutrophil gelatinase-associated lipocalin. These findings suggest that the kidney may be susceptible to excitotoxic agonists, and renal effects should be considered when examining glutamate receptor activation. Additionally, these results indicate that DA is a potent nephrotoxicant, and potential renal toxicity may require consideration when determining safe levels for human exposure.
Analysis of a human V beta gene subfamily.
Authors: G Siu, E C Strauss, E Lai, L E Hood
Journal: The Journal of Experimental Medicine (1986)

We have isolated and sequenced five germline V beta gene segments that are homologous to the V region of the YT35 cDNA encoding the beta chain of the T cell antigen receptor from the tumor MOLT-3. One of these gene segments is identical to the YT35 V segment, and therefore is the corresponding germline V beta gene segment encoding the YT35 cDNA. The other four V beta members exhibit 77-98% homology to the YT35 V gene segment. Two of these V beta gene segments are pseudogenes. Analyses of the coding region sequences reveal that, although the V beta segments are very diverse, they are mutating at a rate comparable to that observed in most eukaryotic genes. Analyses of the genomic clones show that the spacing distance between germline V beta gene segments ranges from 3 kb to greater than 30 kb, and the entire V beta 8 subfamily appears to be linked by a total of no more than 110 kb of DNA.
Exhaled Breath Condensate pH
Authors: Richard M. Effros
Journal: American Journal of Respiratory and Critical Care Medicine (2006)

To the Editor: 

Vaughan et al. 1 are to be congratulated for the most extensive study of the pH of exhaled breath condensates (EBC) yet reported. However, there is reason to doubt that the pH of the condensate provides a reliable measure of the pH of fluid lining the airways. As noted in our recent study 2, the average concentration of NH4+ is 20 times greater than that of any …
Regions of Interest–Based Discriminant Analysis of DaTSCAN SPECT and FDG-PET for the Classification of Dementia
Authors: Valentina Garibotto, Marie Louise Montandon, Claire Tabouret Viaud, Mohamed Allaoua, Frédéric Assal, Pierre R. Burkhard, Osman Ratib, Habib Zaidi
Journal: Clinical Nuclear Medicine (2013)

Purpose Neuroimaging is increasingly used to support the clinical diagnosis of patients with cognitive impairment. Dopamine transporter (DAT) imaging, such as DaTSCAN SPECT, tests the integrity of the nigrostriatal pathway, whereas FDG-PET identifies typical patterns of cortical and subcortical hypometabolism. The aim of this study was to assess the relative contribution of DAT and regional glucose metabolism imaging to the differential diagnosis. Patients and Methods Twenty-seven subjects were investigated for neurodegenerative dementia associated with parkinsonism of variable severity by FDG-PET and DaTSCAN SPECT. They were grouped according to the clinically established diagnosis, including probable Alzheimer disease (5 subjects), corticobasal degeneration (6 subjects), Lewy body dementia (8 subjects), frontotemporal dementia (4 subjects), and Parkinson disease with dementia (4 subjects). Normalized FDG uptake and DAT uptake ratios were obtained by the BRASS software. We used a discriminant analysis with a stepwise method and a leave-one-out cross-validation. Results With the use of regional values of normalized FDG uptake, 85.2% and 55.6% of the patients were correctly classified by the discriminant analysis and the cross-validation, respectively. When DAT alone was considered, the results were 59.3% and 51.9%, whereas the combination of both DAT and normalized FDG uptake yielded 100% and 88.9% of accurate classifications. Conclusions This automated analysis approach shows that the information provided by normalized FDG uptake and DAT is not redundant for the differential diagnosis of dementia and that taking into account both normalized FDG uptake and DAT uptake allows a better classification of individual patients. These results further support the usefulness of both modalities in the clinical workup of dementia.
Abstract SY18-01: Hypoxia, metabolism, and tumor progression
Authors: M. Celeste Simon
Journal: Cancer Research (2012)

Abstract Solid tumors exhibit heterogeneous microenvironments, often characterized by limiting concentrations of oxygen (O2), glucose, and other nutrients. How oncogenic mutations alter stress response pathways, metabolism, and cell survival in the face of these challenges is incompletely understood. Here we report that constitutive mTORC1 activity renders hypoxic cells dependent on exogenous desaturated lipids, as levels of de novo synthesized unsaturated fatty acids are reduced under low O2. Specifically, we demonstrate that hypoxic Tsc2-/- cells deprived of serum lipids undergo mTORC1-dependent apoptosis associated with elevated reactive oxygen species (ROS), a persistent unfolded protein response (UPR), and a failure to fully activate autophagy. Of note, UPR activation and cell death can be reversed by the addition of unsaturated fatty acids or ROS inhibitors. Our data suggest that cancer cells committed to unregulated growth within ischemic tumor microenvironments are unable to balance protein and lipid synthesis due to a critical limitation in desaturated fatty acids. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr SY18-01. doi:1538-7445.AM2012-SY18-01
Metabolic syndrome and rare gynecological cancers in the Metabolic syndrome and Cancer project (Me-Can)
Authors: G. Nagel, H. Concin, T. Bjørge, K. Rapp, J. Manjer, G. Hallmans, G. Diem, C. Häggström, A. Engeland, M. Almquist, H. Jonsson, R. Selmer, T. Stocks, S. Tretli, H. Ulmer, P. Stattin, A. Lukanova
Journal: Annals of Oncology (2010)
Prognosis and Treatment of Patients With Breast Tumors of One Centimeter or Less and Negative Axillary Lymph Nodes
Authors: B Fisher, J Dignam, E Tan-Chiu, S Anderson, E R Fisher, J L Wittliff, N Wolmark
Journal: JNCI Journal of the National Cancer Institute (2001)

Background: Uncertainty about prognosis and treatment of axillary lymph node-negative patients with estrogen receptor (ER)-negative or ER-positive invasive breast tumors of 1 cm or less prompted the analysis of data from five National Surgical Adjuvant Breast and Bowel Project randomized clinical trials. Methods: Two hundred thirty-five patients with ER-negative tumors and 1024 patients with ER-positive tumors were identified in these trials. Patients with ER-negative tumors received surgery alone or surgery and chemotherapy. Patients with ER-positive tumors received surgery alone; surgery and tamoxifen; or surgery, tamoxifen, and chemotherapy. End points were relapse-free survival (RFS), event-free survival, and overall survival. A result was considered to be statistically significant with a P value of .05 or less; all statistical tests were two-sided. Results: The 8-year RFS of women with ER-negative tumors who received surgery alone or with chemotherapy was 81% and 90%, respectively (P = .06). Survival was similar in both groups (93% and 91%; P = .65). The 8-year RFS of women with ER-positive tumors was 86% after surgery alone, 93% when tamoxifen was added (P = .01), and 95% after the addition of tamoxifen and chemotherapy (P = .07 compared with tamoxifen). Survival in the three groups was 90%, 92% (P = .41), and 97%, respectively. The difference between the latter two groups was significant (P = .01). Regardless of ER status or treatment, overall mortality was 8%; one half of the deaths were related to breast cancer. Several covariates affected the risk of recurrence in ER-negative and ER-positive patients. Risk was greater in women with tumors of 1 cm than in those with tumors of less than 1 cm, in women aged 49 years or younger than in those aged 50 years or older, and in women with infiltrating ductal or lobular carcinoma than in those with other histologic tumor types. Conclusions: Chemotherapy and/or tamoxifen should be considered for the treatment of women with ER-negative or ER-positive tumors of 1 cm or less and negative axillary lymph nodes.
Percutaneous absorption of the sunscreen benzophenone-3 after repeated whole-body applications, with and without ultraviolet irradiation
Authors: H. Gonzalez, A. Farbrot, O. Larkö, A-M. Wennberg
Journal: British Journal of Dermatology (2005)

Benzophenone-3 (BZ-3; 2-hydroxy-4-methoxybenzophenone, oxybenzone) is commonly used to absorb ultraviolet (UV) radiation. BZ-3 penetrates the skin and can be found in the urine. The amount varies between 0.4% and 2%. This seems to be the main metabolic pathway in rats.To investigate the total amount of BZ-3 excreted in the urine after repeated topical whole-body applications of a sunscreen and to see if UV radiation has any effect on the amount excreted.Twenty-five volunteers applied a commercially available sunscreen containing 4% BZ-3 morning and night for 5 days. Their urine was measured during those 5 days and during a further 5 days after the last application. They were divided into groups A (unirradiated) and B. Group B received UV radiation according to skin type: UVA between 400 and 707 J cm(-2), and UVB between 0.46 and 2.0 J cm(-2). BZ-3 in urine was analysed with a high-performance liquid chromatography method.The volunteers excreted 1.2-8.7% (mean 3.7%) of the total amount of BZ-3 applied. There was no significant difference between the two groups (P < 0.99, t-test).We show that a large amount of BZ-3 is absorbed. BZ-3 is accumulated in the body as the volunteers excreted BZ-3 5 days after the last application.
Low frequency of CD94/NKG2A+ T lymphocytes in patients with HTLV-1-associated myelopathy/tropical spastic paraparesis, but not in asymptomatic carriers
Authors: Mineki Saito, Veronique M Braud, Peter Goon, Emmanuel Hanon, Graham P Taylor, Akiko Saito, Nobutaka Eiraku, Yuetsu Tanaka, Koichiro Usuku, Jonathan N Weber, Mitsuhiro Osame, Charles R M Bangham
Journal: Blood (2003)
Biologically Targeted Cancer Therapy and Marginal Benefits: Are We Making Too Much of Too Little or Are We Achieving Too Little by Giving Too Much?
Authors: Tito Fojo, David R. Parkinson
Journal: Clinical Cancer Research (2010)

Abstract We describe the development and approval of biologically targeted agents in the clinic through examples chosen from the experience with inhibitors of the epidermal growth factor (EGF) and VEGF pathways. Despite extensive biological rationale for the use of these classes of molecules, marginal clinical benefits have been observed in broad patient populations, and the agents have entered into general clinical practice. We discuss why this situation is unsatisfactory because marginal general benefit may often be at the expense of toxicity to nonbenefiting or even harmed patients. Finally, we point out that emerging technologies bring the promise of allowing the identification of patients who might potentially benefit from a therapy. However, development of this technology will not move forward without broader recognition of its need by the range of stakeholders, including patients, advocates, academic and private oncologists, drug sponsors, and those who develop drugs and diagnostic tests. Clin Cancer Res; 16(24); 5972–80. ©2010 AACR.
Identification of interferon-gamma as the lymphokine that activates human macrophage oxidative metabolism and antimicrobial activity.
Authors: C F Nathan, H W Murray, M E Wiebe, B Y Rubin
Journal: The Journal of Experimental Medicine (1983)

Human blood mononuclear leukocytes stimulated with toxoplasma antigen, concanavalin A, mezerein plus lentil lectin, or staphylococcal enterotoxin A secreted a factor (macrophage-activating factor, or MAF) that enhanced the capacity of human macrophages to release H2O2 and to kill toxoplasmas. The same lymphoid supernatants contained IFN gamma but not IFN alpha or IFN beta. The MAF activity of six of seven unfractionated supernatants was completely eliminated by a monoclonal antibody that neutralizes IFN gamma, and MAF in the remaining supernatant was almost completely neutralized. Native IFN gamma partially purified by two independent protocols to specific activities of 1 X 10(6) and 10(7) U/mg protein was enriched in MAF activity at least as much as in antiviral activity. The capacity of macrophages to secrete H2O2 after incubation in partially purified native IFN gamma (mean peak stimulation, 8.8-fold) was greater than with unpurified lymphokines (3.8-fold) and sometimes equaled or exceeded the capacity of freshly harvested monocytes. The MAF activity of the partially purified native IFN gamma preparations was abolished by monoclonal anti-IFN gamma. Finally, IFN gamma of greater than 99% estimated purity was isolated (at Genentech, Inc.) from bacteria transformed with the cloned human gene for this lymphokine. Recombinant IFN gamma had potent MAF activity, stimulating the peroxide-releasing capacity of macrophages an average of 19.8-fold at peak response and enhancing their ability to kill toxoplasmas from 2.6 +/- 1.3% for untreated cells to 54 +/- 0.4% for treated cells. Attainment of 50% of the maximal elevation in peroxide-releasing capacity required a geometric mean concentration of 0.1 antiviral U/ml of recombinant IFN gamma, which is estimated to be approximately 6 picomolar for this preparation. Peroxide secretory capacity and toxoplasmacidal activity of macrophages peaked 2-4 d after exposure to IFN gamma. Peroxide-secretory capacity remained elevated during at least 6 d of continuous exposure, but the effect of IFN gamma was reversed within about 3 d of its removal. Activation was usually but not invariably accompanied by characteristic changes in cell morphology. Thus, IFN gamma activates human macrophage oxidative metabolism and antimicrobial activity, and appeared to be the only factor consistently capable of doing so in the diverse LK preparations tested.
CENTRAL NERVOUS SYSTEM NEURONAL MIGRATION
Authors: Mary E. Hatten
Journal: Annual Review of Neuroscience (1999)

▪ Abstract Widespread cell migrations are the hallmark of vertebrate brain development. In the early embryo, morphogenetic movements of precursor cells establish the rhombomeres of the hindbrain, the external germinal layer of the cerebellum, and the regional boundaries of the forebrain. In midgestation, after primary neurogenesis in compact ventricular zones has commenced, individual postmitotic cells undergo directed migrations along the glial fiber system. Radial migrations establish the neuronal layers. Three molecules have been shown to function in glial guided migration—astrotactin, glial growth factor, and erbB. In the postnatal period, a wave of secondary neurogenesis produces huge numbers of interneurons destined for the cerebellar cortex, the hippocampal formation, and the olfactory bulb. Molecular analysis of the genes that mark stages of secondary neurogenesis show similar expression patterns of a number of genes. Thus these three regions may have genetic pathways in common. Finally, we consider emerging studies on neurological mutant mice, such as reeler, and human brain malformations. Positional cloning and identification of mutated genes has led to new insights on laminar patterning in brain.
Genetic Heterogeneity of the Epidermal Growth Factor Receptor in Non–Small Cell Lung Cancer Cell Lines Revealed by a Rapid and Sensitive Detection System, the Peptide Nucleic Acid-Locked Nucleic Acid PCR Clamp
Authors: Yoshiaki Nagai, Hitoshi Miyazawa, None Huqun, Tomoaki Tanaka, Kiyoshi Udagawa, Motoyasu Kato, Shunichiro Fukuyama, Akemi Yokote, Kunihiko Kobayashi, Minoru Kanazawa, Koichi Hagiwara
Journal: Cancer Research (2005)

Lung cancer is one of the leading causes of the cancer death worldwide. Gefitinib is an inhibitor of the tyrosine kinase activity of the epidermal growth factor receptor (EGFR) and has been introduced in the treatment of advanced lung cancers. The responsiveness to gefitinib has been linked to the presence of EGFR mutations. Clinical samples contain many normal cells in addition to cancer cells. A method capable of detecting EGFR mutations in a large background of wild-type EGFR genes could provide a superior clinical test. We developed a rapid and sensitive detection system for EGFR mutations named the peptide nucleic acid-locked nucleic acid (PNA-LNA) PCR clamp that can detect EGFR mutations in the presence of 100-to 1,000-fold background of wild-type EGFR. We used this method to screen 30 non-small cell lung cancer cell lines established from Japanese patients. In addition to 11 cell lines that have mutations, we found 12 cell lines in which specific mutations are observed only in the subpopulation(s) of the cells. Genetic heterogeneity of EGFR suggests that the EGFR gene is unstable in established cancers and the heterogeneity may explain variable clinical responses of lung cancers to gefitinib.