tbuckley/cabot-search huggingface dataset:
Triptolide Reduces Cystogenesis in a Model of ADPKD
Authors: Stephanie J. Leuenroth, Natasha Bencivenga, Peter Igarashi, Stefan Somlo, Craig M. Crews
Journal: Journal of the American Society of Nephrology (2008)

Mutations in PKD1 result in autosomal dominant polycystic kidney disease, which is characterized by increased proliferation of tubule cells leading to cyst initiation and subsequent expansion. Given the cell proliferation associated with cyst growth, an attractive therapeutic strategy has been to target the hyperproliferative nature of the disease. We previously demonstrated that the small molecule triptolide induces cellular calcium release through a polycystin-2-dependent pathway, arrests Pkd1(-/-) cell growth, and reduces cystic burden in Pkd1(-/-) embryonic mice. To assess cyst progression in neonates, we used the kidney-specific Pkd1(flox/-);Ksp-Cre mouse model of autosomal dominant polycystic kidney disease, in which the burden of cysts is negligible at birth but then progresses rapidly over days. The number, size, and proliferation rate of cysts were examined. Treatment with triptolide significantly improved renal function at postnatal day 8 by inhibition of the early phases of cyst growth. Because the proliferative index of kidney epithelium in neonates versus adults is significantly different, future studies will need to address whether triptolide delays or reduces cyst progression in the Pkd1 adult model.
The Dutch Bipolar Offspring Study: 12-Year Follow-Up
Authors: Esther Mesman, Willem A. Nolen, Catrien G. Reichart, Marjolein Wals, Manon H.J. Hillegers
Journal: American Journal of Psychiatry (2013)

Offspring of bipolar parents have a genetically increased risk of developing mood disorders. In a longitudinal study, the authors followed a bipolar offspring cohort from adolescence into adulthood to determine the onset, prevalence, and early course of mood disorders and other psychopathology.The Dutch bipolar offspring cohort is a fixed cohort initiated in 1997 (N=140; age range at baseline, 12-21 years). Bipolar offspring were psychiatrically evaluated at baseline and at 1-, 5-, and 12-year follow-ups. Of the original sample, 77% (N=108) were followed for the full 12 years.Overall, 72% of the bipolar offspring developed a lifetime DSM-IV axis I disorder, 54% a mood disorder, and 13% bipolar spectrum disorders. Only 3% met DSM-IV criteria for bipolar I disorder. In 88% of the offspring with a bipolar spectrum disorder, the illness started with a depressive episode. In total, 24% of offspring with a unipolar mood disorder developed a bipolar spectrum disorder over time. Mood disorders were often recurrent (31%), were complex (comorbidity rate, 67%), and started before age 25.Even after 12 years of follow-up, from adolescence into adulthood, bipolar I disorder was rare among bipolar offspring. Nevertheless, the risk of developing severe and recurrent mood disorders and other psychopathology was high. Future follow-up of this and other adult bipolar offspring cohorts is essential to determine whether recurrent mood disorders in bipolar offspring reflect the early stages of bipolar disorder.
Deletion of p66 <sup>shc</sup> Gene Protects Against Age-Related Endothelial Dysfunction
Authors: Pietro Francia, Chiara delli Gatti, Markus Bachschmid, Ines Martin-Padura, Carmine Savoia, Enrica Migliaccio, Pier Giuseppe Pelicci, Marzia Schiavoni, Thomas Felix Lüscher, Massimo Volpe, Francesco Cosentino
Journal: Circulation (2004)

Enhanced production of reactive oxygen species (ROS) has been recognized as the major determinant of age-related endothelial dysfunction. The p66shc protein controls cellular responses to oxidative stress. Mice lacking p66shc (p66shc-/-) have increased resistance to ROS and a 30% prolonged life span. The present study investigates age-dependent changes of endothelial function in this model.Aortic rings from young and old p66shc-/- or wild-type (WT) mice were suspended for isometric tension recording. Nitric oxide (NO) release was measured by a porphyrinic microsensor. Expression of endothelial NO synthase (eNOS), inducible NOS (iNOS), superoxide dismutase, and nitrotyrosine-containing proteins was assessed by Western blotting. Nitrotyrosine residues were also identified by immunohistochemistry. Superoxide (O2-) production was determined by coelenterazine-enhanced chemiluminescence. Endothelium-dependent relaxation in response to acetylcholine was age-dependently impaired in WT mice but not in p66shc-/- mice. Accordingly, an age-related decline of NO release was found in WT but not in p66shc-/- mice. The expression of eNOS and manganese superoxide dismutase was not affected by aging either in WT or in p66shc-/- mice, whereas iNOS was upregulated only in old WT mice. It is interesting that old WT mice displayed a significant increase of O2- production as well as of nitrotyrosine expression compared with young animals. Such age-dependent changes were not found in p66shc-/- mice.We report that inactivation of the p66shc gene protects against age-dependent, ROS-mediated endothelial dysfunction. These findings suggest that the p66shc is part of a signal transduction pathway also relevant to endothelial integrity and may represent a novel target to prevent vascular aging.
Pseudomonas aeruginosa diaminopimelate decarboxylase: evolutionary relationship with other amino acid decarboxylases.
Authors: C Martin, B Cami, P Yeh, P Stragier, C Parsot, J C Patte
Journal: Molecular Biology and Evolution (1988)

The lysA gene encodes meso-diaminopimelate (DAP) decarboxylase (E.C.4.1.1.20), the last enzyme of the lysine biosynthetic pathway in bacteria. We have determined the nucleotide sequence of the lysA gene from Pseudomonas aeruginosa. Comparison of the deduced amino acid sequence of the lysA gene product revealed extensive similarity with the sequences of the functionally equivalent enzymes from Escherichia coli and Corynebacterium glutamicum. Even though both P. aeruginosa and E. coli are Gram-negative bacteria, sequence comparisons indicate a greater similarity between enzymes of P. aeruginosa and the Gram-positive bacterium C. glutamicum than between those of P. aeruginosa and E. coli enzymes. Comparison of DAP decarboxylase with protein sequences present in data bases revealed that bacterial DAP decarboxylases are homologous to mouse (Mus musculus) ornithine decarboxylase (E.C.4.1.1.17), the key enzyme in polyamine biosynthesis in mammals. On the other hand, no similarity was detected between DAP decarboxylases and other bacterial amino acid decarboxylases.
Detection of Ductal Carcinoma In Situ in Women Undergoing Screening Mammography
Authors: Virginia L. Ernster, Rachel Ballard-Barbash, William E. Barlow, Yingye Zheng, Donald L. Weaver, Gary Cutter, Bonnie C. Yankaskas, Robert Rosenberg, Patricia A. Carney, Karla Kerlikowske, Stephen H. Taplin, Nicole Urban, Berta M. Geller
Journal: JNCI Journal of the National Cancer Institute (2002)

With the large number of women having mammography-an estimated 28.4 million U.S. women aged 40 years and older in 1998-the percentage of cancers detected as ductal carcinoma in situ (DCIS), which has an uncertain prognosis, has increased. We pooled data from seven regional mammography registries to determine the percentage of mammographically detected cancers that are DCIS and the rate of DCIS per 1000 mammograms.We analyzed data on 653 833 mammograms from 540 738 women between 40 and 84 years of age who underwent screening mammography at facilities participating in the National Cancer Institute's Breast Cancer Surveillance Consortium (BCSC) throughout 1996 and 1997. Mammography results were linked to population-based cancer and pathology registries. We calculated the percentage of screen-detected breast cancers that were DCIS, the rate of screen-detected DCIS per 1000 mammograms by age and by previous mammography status, and the sensitivity of screening mammography. Statistical tests were two-sided.A total of 3266 cases of breast cancer were identified, 591 DCIS and 2675 invasive breast cancer. The percentage of screen-detected breast cancers that were DCIS decreased with age (from 28.2% [95% confidence interval (CI) = 23.9% to 32.5%] for women aged 40-49 years to 16.0% [95% CI = 13.3% to 18.7%] for women aged 70-84 years). However, the rate of screen-detected DCIS cases per 1000 mammograms increased with age (from 0.56 [95% CI = 0.41 to 0.70] for women aged 40-49 years to 1.07 [95% CI = 0.87 to 1.27] for women aged 70-84 years). Sensitivity of screening mammography in all age groups combined was higher for detecting DCIS (86.0% [95% CI = 83.2% to 88.8%]) than it was for detecting invasive breast cancer (75.1% [95% CI = 73.5% to 76.8%]).Overall, approximately 1 in every 1300 screening mammography examinations leads to a diagnosis of DCIS. Given uncertainty about the natural history of DCIS, the clinical significance of screen-detected DCIS needs further investigation.
Effect of differing doses of inhaled budesonide on markers of airway inflammation in patients with mild asthma
Authors: A. Jatakanon, S. Kharitonov, S. Lim, P. J Barnes
Journal: Thorax (1999)

<h3>BACKGROUND</h3> It is desirable to prescribe the minimal effective dose of inhaled steroids to control asthma. To ensure that inflammation is suppressed whilst using the lowest possible dose, a sensitive and specific method for assessing airway inflammation is needed. <h3>METHODS</h3> The usefulness of exhaled nitric oxide (NO), sputum eosinophils, and methacholine airway responsiveness (PC<sub>20</sub>) for monitoring airway inflammatory changes following four weeks of treatment with an inhaled corticosteroid (budesonide via Turbohaler) were compared. Mild stable steroid naive asthmatic subjects were randomised into two double blind, placebo controlled studies. The first was a parallel group study involving three groups receiving either 100 μg/day budesonide (n = 8), 400 μg/day budesonide (n = 7), or a matched placebo (n = 6). The second was a crossover study involving 10 subjects randomised to receive 1600 μg budesonide or placebo. The groups were matched with respect to age, PC<sub>20</sub>, baseline FEV<sub>1</sub> (% predicted), exhaled NO, and sputum eosinophilia. <h3>RESULTS</h3> There were significant improvements in FEV<sub>1</sub> following 400 μg and 1600 μg budesonide (11.3% and 6.5%, respectively, p&lt;0.05). This was accompanied by significant reductions in eosinophil numbers in induced sputum (0.7 and 0.9 fold, p&lt;0.05). However, levels of exhaled NO were reduced following each budesonide dose while PC<sub>20</sub>was improved only with 1600 μg budesonide. These results suggest that exhaled NO and PC<sub>20</sub> may not reflect the control of airway inflammation as accurately as the number of eosinophils in sputum. There were dose dependent changes in exhaled NO, sputum eosinophils, and PC<sub>20</sub> to inhaled budesonide but a plateau response of exhaled NO was found at a dose of 400 μg daily. <h3>CONCLUSION</h3> Monitoring the number of eosinophils in induced sputum may be the most accurate guide to establish the minimum dose of inhaled steroids needed to control inflammation. This, however, requires further studies involving a larger number of patients.
Bronchial compliance and wall structure during development of the immature human and pig lung
Authors: PK McFawn, HW Mitchell
Journal: European Respiratory Journal (1997)

Maturational changes in the specific compliance could potentially contribute to the development or clinical presentation of respiratory diseases in infants and children. Changes in the specific compliance during development and its structural basis have been well characterized, but changes in bronchial compliance and the mechanisms involved have received little attention. Semistatic pressure-volume curves were generated for isolated bronchial segments from late-term foetal, immature and adult pigs. A small number of bronchi from human infants were also studied. The amount of cartilage in the bronchial wall of pigs of different ages was measured histologically, and morphometric changes in the wall of inflated bronchi were investigated. The specific compliance of bronchi approximately halved from 1 to 4 weeks of age. No change in specific compliance was observed either between 4 week old and adult pigs, or between late-term foetal and 1 week old pigs. Changes in the total wall and cartilage areas did not correlate with changes in specific compliance. Inflation to 20 cmH2O transmural pressure reduced the total wall area of bronchi from 1 week old pigs. Significant changes in bronchial distensibility occur during the early postnatal period. These changes in specific compliance are not caused by an increase in the amount of cartilage. The increase in luminal volume during inflation of bronchial segments occurs, partially, by compression of the airway wall against the cartilage layer.
Physicochemical and Pharmacokinetic Characterization of Highly Potent Recombinant <scp>l</scp>-Methionine γ-Lyase Conjugated with Polyethylene Glycol as an Antitumor Agent
Authors: Tomoaki Takakura, Akio Takimoto, Yoshihide Notsu, Hiroshi Yoshida, Takaomi Ito, Hirofumi Nagatome, Masahiro Ohno, Yoshinao Kobayashi, Takayuki Yoshioka, Kenji Inagaki, Shigeo Yagi, Robert M. Hoffman, Nobuyoshi Esaki
Journal: Cancer Research (2006)

A highly potent recombinant L-methionine gamma-lyase (METase) conjugated with polyethylene glycol (PEG) was characterized physicochemically and pharmacokinetically in vivo and in vitro. Pegylated METase (PEG-METase), which contains pyridoxal 5'-phosphate (PLP) as a cofactor in the molecule, is a potent anticancer agent that can deplete L-methionine from plasma. Although pegylation decreased its specific activity, dithiothreitol (DTT) treatment increased it over three times with the detachment of one PEG moiety modified with a cysteine residue. We can produce DTT-treated PEG-METase on a large scale in sufficient quality for therapeutic use. The superiority of DTT-treated PEG-METase was confirmed by the enhancement of L-methionine depletion and amelioration of pharmacokinetics in mice. The holoenzyme of DTT-treated PEG-METase gave a several times larger area under the plasma concentration curve than that of DTT-untreated PEG-METase, not because of an increase of the half-life but because of high specific activity. Conversely, simultaneous PLP infusion led to a greatly increased half-life of the holoenzyme. DTT-treated PEG-METase administration with PLP infusion was the most useful combination for maximizing the potency of the enzyme. We showed that serum albumin interfered with holoenzyme activity in vitro. The decrease of holoenzyme activity was dependent on the type of serum albumin. We concluded that PLP was released from PEG-METase by serum albumin in vivo and in vitro. The deleterious effect of PLP dissociation from PEG-METase could be improved by supplementing PLP and oleic acid. Their synergistic effect in preventing a decrease of the holoenzyme activity was also observed.
Vasodilator Therapy for Primary Pulmonary Hypertension in Children
Authors: Robyn J. Barst, Greg Maislin, Alfred P. Fishman
Journal: Circulation (1999)

Background —This report presents 13 years of experience with vasodilator therapy for primary pulmonary hypertension (PPH) in children. Two eras were involved: between 1982 and 1987, oral calcium channel blockers were the only agents available for long-term therapy; after 1987, prostacyclin (PGI 2 ) has been available for long-term intravenous use. Methods and Results —Seventy-four children underwent short-term vasodilator testing with intravenous PGI 2 . Those who manifested pulmonary vasodilation (“acute responders”) were treated with oral calcium channel blockers. Until 1987, “acute nonresponders” were treated in the same way as long as they had no serious side effects. When PGI 2 became available for long-term administration, all nonresponders, as well as those who failed to improve clinically and hemodynamically on calcium channel blockers, were treated with long-term PGI 2 . In the 31 responders, calcium channel blockers improved survival compared with the 43 nonresponders ( P =0.0002). Survival was also better in 24 PGI 2 -treated nonresponders compared with 22 nonresponders for whom PGI 2 was unavailable ( P =0.0005) as well as in all children who failed conventional therapy (n=31; P =0.002). Conclusions —Long-term vasodilator therapy improves survival in children with PPH. In acute responders, oral calcium channel blockers generally suffice. In both nonresponders to short-term testing and responders who fail to improve on calcium channel blockers, continuous intravenous infusion of PGI 2 improves survival.
A NOTE ON THE TREATMENT OF LEPROSY
Authors: T. B. Heggs
Journal: BMJ (1923)

APPENDIX C.* Patients who cannot take antimony at all may be given emetine.Emetine is more toxic than antimony tartrate in the large doses necessary -in bilharzia disease, and its after-effects are certainly more serious.Cardiac weakness and peripheral neuritis are fairly common after-effects.C :ases infected in 1900, 1901, and 1903 gave in 1921 18 per cent., 16 per cent., 15 per cent., and 12 per cent.eosinophilia; while several war ggmses gave no eosinophilia when counted in 1921, although ova were prestit in the urine.During treatment eosinophiiia appeared in some of the latter cases and increased as the courlse proceeded.One man infected in 1902 had no symptoms or ova in the urine in 1921, but he gave a 14 per cent.ieosinophilia; he had no other helminth infection.
Co‐Delivery of Antiviral and Antifungal Therapeutics for the Treatment of Sexually Transmitted Infections using a Moldable, Supramolecular Hydrogel
Authors: Ashlynn L.Z. Lee, Victor W.L. Ng, Ghim Lee Poon, Xiyu Ke, James L. Hedrick, Yi Yan Yang
Journal: Advanced Healthcare Materials (2014)

In this investigation, a therapeutic co‐delivery hydrogel system is developed to provide effective HIV prophylaxis, alongside the prevention and/or treatment of candidiasis. Two components—a HIV reverse transcriptase inhibitor, tenofovir, and a cationic macromolecular antifungal agent derived from a vitamin D‐functionalized polycarbonate (VD/BnCl (1:30))—are formulated into biodegradable vitamin D‐functionalized polycarbonate/PEG‐based supramolecular hydrogels. The hydrogels exhibit thixotropic properties and can be easily spread across surfaces for efficient drug absorption. Sustained release of tenofovir from the hydrogel is observed, where approximately 85% tenofovir is released within 3 h. VD/BnCl (1:30) does not impede drug diffusion from the hydrogel as the drug release profiles are similar with and without the polycation. Antimicrobial efficacy studies indicate that the hydrogels kill C. albicans efficiently with a minimum bactericidal concentration (MBC) of 0.25–0.5 g L −1 . These hydrogels also eradicate C. albicans biofilm effectively at 4× MBC. When human dermal fibroblasts (as model mammalian cells) are treated with these hydrogels, cell viability remains high at above 80%, demonstrating excellent biocompatibility. When applied topically, this dual‐functional hydrogel can potentially prevent HIV transmission and eliminate microbes that cause infections in the vulvovagina region.
Biology of Gastrointestinal Stromal Tumors
Authors: Christopher L. Corless, Jonathan A. Fletcher, Michael C. Heinrich
Journal: Journal of Clinical Oncology (2004)

Once a poorly defined pathologic oddity, in recent years, gastrointestinal stromal tumor (GIST) has emerged as a distinct oncogenetic entity that is now center stage in clinical trials of kinase-targeted therapies. This review charts the rapid progress that has established GIST as a model for understanding the role of oncogenic kinase mutations in human tumorigenesis. Approximately 80% to 85% of GISTs harbor activating mutations of the KIT tyrosine kinase. In a series of 322 GISTs (including 140 previously published cases) studied by the authors in detail, mutations in the KIT gene occurred with decreasing frequency in exons 11 (66.1%), 9 (13%), 13 (1.2%), and 17 (0.6%). In the same series, a subset of tumors had mutations in the KIT-related kinase gene PDGF receptor alpha (PDGFRA), which occurred in either exon 18 (5.6%) or 12 (1.5%). The remainder of GISTs (12%) were wild type for both KIT and PDGFRA. Comparative studies of KIT-mutant, PDGFRA-mutant, and wild-type GISTs indicate that there are many similarities between these groups of tumors but also important differences. In particular, the responsiveness of GISTs to treatment with the kinase inhibitor imatinib varies substantially depending on the exonic location of the KIT or PDGFRA mutation. Given these differences, which have implications both for the diagnosis and treatment of GISTs, we propose a molecular-based classification of GIST. Recent studies of familial GIST, pediatric GIST, and variant forms of GIST related to Carney's triad and neurofibromatosis type 1 are discussed in relationship to this molecular classification. In addition, the role of mutation screening in KIT and PDGFRA as a diagnostic and prognostic aid is emphasized in this review.
The role of natural killer cells in periodontitis
Authors: Asaf Wilensky, Stella Chaushu, Lior Shapira
Journal: Periodontology 2000 (2015)

Periodontitis is the most common chronic inflammatory disease of humans. The microbial etiology of the disease is well documented, as is the major role of the host response in disease pathogenesis. As natural killer cells are one of the most important components of innate immunity against bacteria and viruses, they can be expected to act as major players in the development of the disease. Through direct interaction with periodontal pathogens, natural killer cells produce pro-inflammatory cytokines that subsequently may lead to tissue destruction. Indeed, using a murine periodontitis model, such mechanisms have been shown to be involved in bacterial-induced alveolar bone loss. In the present review we document the available literature and evidence base regarding the origin, biology and characteristics of natural killer cells, and their interactions with periodontal pathogens. The potential role of natural killer cells in periodontal pathogenesis and the mechanisms involved are discussed.
Elevated Levels of Oxidative DNA Damage and DNA Repair Enzymes in Human Atherosclerotic Plaques
Authors: Wim Martinet, Michiel W.M. Knaapen, Guido R.Y. De Meyer, Arnold G. Herman, Mark M. Kockx
Journal: Circulation (2002)

Background— The formation of reactive oxygen species is a critical event in atherosclerosis because it promotes cell proliferation, hypertrophy, growth arrest, and/or apoptosis and oxidation of LDL. In the present study, we investigated whether reactive oxygen species-induced oxidative damage to DNA occurs in human atherosclerotic plaques and whether this is accompanied by the upregulation of DNA repair mechanisms. Methods and Results— We observed increased immunoreactivity against the oxidative DNA damage marker 7,8-dihydro-8-oxo-2′-deoxyguanosine (8-oxo-dG) in plaques of the carotid artery compared with the adjacent inner media and nonatherosclerotic mammary arteries. Strong 8-oxo-dG immunoreactivity was found in all cell types of the plaque including macrophages, smooth muscle cells, and endothelial cells. As shown by competitive ELISA, carotid plaques contained 160±29 8-oxo-dG residues/10 5 dG versus 3±1 8-oxo-dG residues/10 5 dG in mammary arteries. Single-cell gel electrophoresis showed elevated levels of DNA strand breaks in the plaque. The overall number of apoptotic nuclei was low (1% to 2%) and did not correlate with the amount of 8-oxo-dG immunoreactive cells (&gt;90%). This suggests that initial damage to DNA occurs at a sublethal level. Several DNA repair systems that are involved in base excision repair (redox factor/AP endonuclease [Ref 1] and poly(ADP-ribose) polymerase 1 [PARP-1]) or nonspecific repair pathways (p53, DNA-dependent protein kinase) were upregulated, as shown by Western blotting and immunohistochemistry. Overexpression of DNA repair enzymes was associated with elevated levels of proliferating cell nuclear antigen. Conclusions— Our findings provide evidence that oxidative DNA damage and repair increase significantly in human atherosclerotic plaques.