tbuckley/cabot-search huggingface dataset:
Faster Rise of Exhaled Breath Temperature in Asthma
Authors: PAOLO PAREDI, SERGEI A. KHARITONOV, PETER J. BARNES
Journal: American Journal of Respiratory and Critical Care Medicine (2002)

In asthma there is increased vascularity of the airway mucosa, altering heat loss in the airways. We hypothesized that as a result of these inflammatory changes, asthmatic patients would have elevated rates of the exhaled air temperature increase (Deltae degrees T). We measured Deltae degrees T in 18 asthmatic subjects (mean age +/- SEM, 38 +/- 8 yr; 9 male, FEV(1) 74 +/- 10%) and 16 normal volunteers (mean age +/- SEM, 33 +/- 3 yr) and compared it with exhaled nitric oxide (NO) as a marker of inflammation. Deltae degrees T was measured during a flow- and pressure-controlled single exhalation with a fast response (1 ms) thermometer. The end-expiratory plateau temperature was similar in asthmatic compared with normal subjects (35.75 +/- 0.6 degrees C and 34.45 +/- 0.8 degrees C, p > 0.05). However, Deltae degrees T was greater in asthmatic subjects (8.17 +/- 0.83 degrees C/s and 4.12 +/- 0.41 degrees C/s, p < 0.01) and correlated with NO (r = 0.65, p = 0.034). Deltae degrees T was increased in normal subjects (from 4.28 +/- 0.8 degrees C/s to 7.60 +/- 0.5 degrees C/s, p < 0.01) but not in asthmatic patients (from 8.28 +/- 0.41 degrees C/s to 8.80 +/- 0.41 degrees C/s, p > 0.05) after the inhalation of albuterol, indicating that Deltae degrees T may reflect bronchial blood flow. Asthmatic subjects have elevated Deltae degrees T. This may represent a novel, noninvasive means of measuring airway blood flow and inflammation in asthma.
BACs to the future: new genetic models for cardiovascular discovery
Authors: M. I. Kotlikoff
Journal: Cardiovascular Research (2013)

One of the great challenges of modern biology is to contextualize highly detailed molecular discoveries in order to prioritize the most medically relevant events. The response to heart damage, for example, likely involves tens of thousands of cells of multiple lineages, each undergoing complex signalling cascades that trigger other equally complex molecular interactions including cell migration, lineage induction, secretion, fibrosis, and revascularization. In determining the relevance of discrete molecular events within these broader contexts, we often infer their involvement from experiments in isolated cells under somewhat artificial conditions. How do we know that these exquisitely specific events occur under realistic clinical conditions? If so, to what extent? At what point in the process do they occur (acute damage, repair, etc.)? And perhaps most importantly, are they critical to the process? In short, how do we answer as early as possible the ‘so what’ question with respect to our favourite protein–protein interaction, transcriptional induction, or other molecular event, and thereby avoid spending years studying a potential epiphenomenon?

One approach is to do …
Decreased pulmonary lactoferrin activity facilitates Pseudomonas biofilm formation in CF
Authors: S J Kelly
Journal: Thorax (2004)

▴ Rogan MP, Taggart CC, Greene CM, et al . Loss of microbiological activity and increased formation of biofilm due to decreased lactoferrin activity in patients with cystic fibrosis. J Infect Dis2004;190:1245–53 [OpenUrl][1][Abstract/FREE Full Text][2] Lactoferrin is an important antimicrobial protein in the airways. In this study lactoferrin activity and Pseudomonas biofilm formation were investigated in sputum and bronchoalveolar lavage (BAL) fluid from age and genotype matched cystic fibrosis (CF) patients with and without P aeruginosa colonisation … [1]: {openurl}?query=rft.jtitle%253DJ%2BInfect%2BDis%26rft_id%253Dinfo%253Adoi%252F10.1086%252F423821%26rft_id%253Dinfo%253Apmid%252F15346334%26rft.genre%253Darticle%26rft_val_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Ajournal%26ctx_ver%253DZ39.88-2004%26url_ver%253DZ39.88-2004%26url_ctx_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Actx [2]: /lookup/ijlink?linkType=ABST&journalCode=jinfdis&resid=190/7/1245&atom=%2Fthoraxjnl%2F60%2F1%2F54.atom
Less Efficient G2-M Checkpoint Is Associated with an Increased Risk of Lung Cancer in African Americans
Authors: Yun-Ling Zheng, Christopher A. Loffredo, Anthony J. Alberg, Zhipeng Yu, Raymond T. Jones, Donna Perlmutter, Lindsey Enewold, Mark J. Krasna, Rex Yung, Peter G. Shields, Curtis C. Harris
Journal: Cancer Research (2005)

Abstract Cell cycle checkpoints play critical roles in the maintenance of genomic integrity. The inactivation of checkpoint genes by genetic and epigenetic mechanisms is frequent in all cancer types, as a less-efficient cell cycle control can lead to genetic instability and tumorigenesis. In an on-going case-control study consisting of 216 patients with non–small cell lung cancer, 226 population-based controls, and 114 hospital-based controls, we investigated the relationship of γ-radiation-induced G2-M arrest and lung cancer risk. Peripheral blood lymphocytes were cultured for 90 hours, exposed to 1.0 Gy γ-radiation, and harvested at 3 hours after γ-radiation treatment. γ-Radiation-induced G2-M arrest was measured as the percentage of mitotic cells in untreated cultures minus the percentage of mitotic cells in γ-radiation-treated cultures from the same subject. The mean percentage of γ-radiation-induced G2-M arrest was significantly lower in cases than in population controls (1.18 versus 1.44, P &amp;lt; 0.01) and hospital controls (1.18 versus 1.40, P = 0.01). When dichotomized at the 50th percentile value in combined controls (population and hospital controls), a lower level of γ-radiation-induced G2-M arrest was associated with an increased risk of lung cancer among African Americans after adjusting for baseline mitotic index, age, gender, and pack-years of smoking [adjusted odd ratio (OR), 2.25; 95% confidence interval (95% CI), 0.97-5.20]. A significant trend of an increased risk of lung cancer with a decreased level of G2-M arrest was observed (Ptrend = 0.02) among African Americans, with a lowest-versus-highest quartile adjusted OR of 3.74 (95% CI, 0.98-14.3). This trend was most apparent among African American females (Ptrend &amp;lt; 0.01), with a lowest-versus-highest quartile adjusted OR of 11.75 (95% CI, 1.47-94.04). The results suggest that a less-efficient DNA damage–induced G2-M checkpoint is associated with an increased risk of lung cancer among African Americans. Interestingly, we observed a stronger association of DNA damage–induced G2-M arrest and lung cancer among African Americans when compared with Caucasians. If replicated, these results may provide clues to the exceedingly high lung cancer incidence experienced by African Americans.
Gonadotropin-Releasing Hormone Type II Induces Apoptosis of Human Endometrial Cancer Cells by Activating GADD45α
Authors: Hsien-Ming Wu, Jung-Chien Cheng, Hsin-Shih Wang, Hong-Yuan Huang, Colin D. MacCalman, Peter C.K. Leung
Journal: Cancer Research (2009)

Gonadotropin-releasing hormone type II (GnRH-II) has an antiproliferative effect on human endometrial cancer cells. Apoptosis in cancer cells may play a critical role in regulating cell proliferation. However, more studies are necessary to elucidate the underlying molecular mechanisms and develop potential applications of GnRH-II. Therefore, we explored the mechanisms of GnRH-II-induced apoptosis and the effects of GnRH-II on GADD45alpha activation in human endometrial cancer cell lines. GnRH-II decreased cell viability in a dose- and time-dependent manner. Apoptosis was induced with increased terminal deoxyribonucleotidyl transferase-mediated dUTP nick end labeling apoptotic cells after GnRH-II treatment. Knockdown of the endogenous GnRH-I receptor with small interfering RNA (siRNA) rescued the cells from GnRH-II-mediated cell growth inhibition and abolished the induction of apoptosis. GnRH-II activated extracellular signal-regulated kinase (ERK)-1/2 and p38 mitogen-activated protein kinase (MAPK) in a time-dependent manner, and the activation was abolished by GnRH-I receptor siRNA and MAPK inhibitors. Cells pretreated with MAPK inhibitors were rescued from GnRH-II-mediated cell growth inhibition. Moreover, both inhibitors abolished GnRH-II-induced apoptosis. GnRH-II induced GADD45alpha expression, which was abolished by knockdown of endogenous GnRH-I receptors and MAPK inhibitors. GnRH-II-stimulated cell growth inhibition was rescued by knockdown of endogenous GADD45alpha with siRNA. Cells treated with GADD45alpha siRNA were refractory to GnRH-II-induced apoptosis. Thus, GnRH-II inhibits cell growth by inducing apoptosis through binding of the GnRH-I receptor, activation of the ERK1/2 and p38 MAPK pathways, and induction of GADD45alpha signaling. This finding may provide a new concept relating to the mechanism of GnRH-II-induced antiproliferation and apoptosis in endometrial cancer cells, indicating the possibility of GnRH-II as a promising therapeutic intervention for human endometrial cancer.
Mitochondria in vascular disease
Authors: E. Yu, J. Mercer, M. Bennett
Journal: Cardiovascular Research (2012)

Mitochondria are often regarded as the powerhouse of the cell by generating the ultimate energy transfer molecule, ATP, which is required for a multitude of cellular processes. However, the role of mitochondria goes beyond their capacity to create molecular fuel, to include the generation of reactive oxygen species, the regulation of calcium, and activation of cell death. Mitochondrial dysfunction is part of both normal and premature ageing, but can contribute to inflammation, cell senescence, and apoptosis. Cardiovascular disease, and in particular atherosclerosis, is characterized by DNA damage, inflammation, cell senescence, and apoptosis. Increasing evidence indicates that mitochondrial damage and dysfunction also occur in atherosclerosis and may contribute to the multiple pathological processes underlying the disease. This review summarizes the normal role of mitochondria, the causes and consequences of mitochondrial dysfunction, and the evidence for mitochondrial damage and dysfunction in vascular disease. Finally, we highlight areas of mitochondrial biology that may have therapeutic targets in vascular disease.
Accumulation of albumin-linked and free-form pentosidine in the circulation of uremic patients with end-stage renal failure
Authors: T Miyata, Y Ueda, T Shinzato, Y Iida, S Tanaka, K Kurokawa, C van Ypersele de Strihou, K Maeda
Journal: Journal of the American Society of Nephrology (1996)

Pentosidine is an advanced glycation end product and its formation is shown to be closely related to oxidative processes. Recent studies have shown that pentosidine levels are increased not only in plasma and matrix proteins from diabetic patients, but also markedly in nondiabetic hemodialysis patients. Currently, the mechanism of accumulation and kinetics of pentosidine formation in hemodialysis patients remain unknown. Gel filtration of uremic plasma revealed that plasma pentosidine exists in the albumin fraction (approximately 90%) and, interestingly, in free form (approximately 5%) as well. Plasma free pentosidine was undetectable in subjects with normal renal function. There was a significant correlation between the plasma levels of albumin-linked and free pentosidine in hemodialysis patients. Kinetic studies indicated that dietary pentosidine was absorbed into the circulation and that, after either oral or intravenous administration of pentosidine to intact or nephrectomized rats, the plasma free pentosidine level was closely linked to the level of renal function. These findings demonstrate that: (1) Pentosidine accumulates as albumin-linked and in free form in the circulation of uremic patients; (2) dietary pentosidine can be absorbed into the circulation, thus being one possible origin of circulating free pentosidine; (3) free pentosidine may accumulate as a result of decreased glomerular filtration; and (4) the mechanism of accumulation of albumin-linked pentosidine is not related to high glucose levels. It suggests the simultaneous accumulation, during renal failure, of either unknown pentosidine precursor(s) or catalyst(s) of glycoxidation, independent of glucose.
Mutations in the Na+/K+-ATPase α3 Gene ATP1A3 Are Associated with Rapid-Onset Dystonia Parkinsonism
Authors: Patricia de Carvalho Aguiar, Kathleen J Sweadner, John T Penniston, Jacek Zaremba, Liu Liu, Marsha Caton, Gurutz Linazasoro, Michel Borg, Marina A.J Tijssen, Susan B Bressman, William B Dobyns, Allison Brashear, Laurie J Ozelius
Journal: Neuron (2004)
The Melanocortin-4 Receptor Is Expressed in Enteroendocrine L Cells and Regulates the Release of Peptide YY and Glucagon-like Peptide 1 In Vivo
Authors: Brandon L. Panaro, Iain R. Tough, Maja S. Engelstoft, Robert T. Matthews, Gregory J. Digby, Cathrine L. Møller, Berit Svendsen, Fiona Gribble, Frank Reimann, Jens J. Holst, Birgitte Holst, Thue W. Schwartz, Helen M. Cox, Roger D. Cone
Journal: Cell Metabolism (2014)
Induction of Tumor-specific T Cell Immunity by Anti-DR5 Antibody Therapy
Authors: Kazuyoshi Takeda, Noriko Yamaguchi, Hisaya Akiba, Yuko Kojima, Yoshihiro Hayakawa, Jane E. Tanner, Thomas J. Sayers, Naoko Seki, Ko Okumura, Hideo Yagita, Mark J. Smyth
Journal: The Journal of Experimental Medicine (2004)

Because tumor necrosis factor–related apoptosis-inducing ligand (TRAIL) preferentially induces apoptosis in tumor cells and plays a critical role in tumor surveillance, its receptor is an attractive target for antibody-mediated tumor therapy. Here we report that a monoclonal antibody (mAb) against the mouse TRAIL receptor, DR5, exhibited potent antitumor effects against TRAIL-sensitive tumor cells in vivo by recruiting Fc receptor–expressing innate immune cells, with no apparent systemic toxicity. Administration of the agonistic anti-DR5 mAb also significantly inhibited experimental and spontaneous tumor metastases. Notably, the anti-DR5 mAb-mediated tumor rejection by innate immune cells efficiently evoked tumor-specific T cell immunity that could also eradicate TRAIL-resistant variants. These results suggested that the antibody-based therapy targeting DR5 is an efficient strategy not only to eliminate TRAIL-sensitive tumor cells, but also to induce tumor-specific T cell memory that affords a long-term protection from tumor recurrence.
Regulation of human liver δ-aminolevulinic acid synthase by bile acids
Authors: Anne-Kathrin Peyer, Diana Jung, Markus Beer, Carmela Gnerre, Adrian Keogh, Deborah Stroka, Mihaela Zavolan, Urs-A. Meyer
Journal: Hepatology (2007)

Aminolevulinic acid synthase 1 (ALAS1) is the rate-limiting enzyme of heme synthesis in the liver and is highly regulated to adapt to the metabolic demand of the hepatocyte. In the present study, we describe human hepatic ALAS1 as a new direct target of the bile acid–activated nuclear receptor farnesoid X receptor (FXR). Experiments in primary human hepatocytes and in human liver slices showed that ALAS1 messenger RNA (mRNA) and activity is increased upon exposure to chenodeoxycholic acid (CDCA), the most potent natural FXR ligand, or the synthetic FXR-specific agonist GW4064. Moreover, overexpression of a constitutively active form of FXR further increased ALAS1 mRNA expression. In agreement with these observations, an FXR response element was identified in the 5′ flanking region of human ALAS1 and characterized in reporter gene assays. A highly conserved FXR binding site (IR1) within a 175-bp fragment at −13 kilobases upstream of the transcriptional start site was able to trigger an FXR-specific increase in luciferase activity upon CDCA treatment. Site-directed mutagenesis of IR1 abolished this effect. Binding of FXR/retinoid acid X receptor heterodimers was demonstrated by mobility gel shift experiments. Conclusion: These data strongly support a role of bile acid–activated FXR in the regulation of human ALAS1 and, consequently, hepatic porphyrin and heme synthesis. These data also suggest that elevated endogenous bile acids may precipitate neuropsychiatric attacks in patients with acute hepatic porphyrias. (Hepatology 2007.)
Estradiol and Tamoxifen Regulate Endostatin Generation via Matrix Metalloproteinase Activity in Breast Cancer<i>In vivo</i>
Authors: Ulrika W. Nilsson, Charlotta Dabrosin
Journal: Cancer Research (2006)

Matrix metalloproteinases (MMP) are important regulators of tumor progression and angiogenesis. MMPs generate both proangiogenic and antiangiogenic fragments, such as vascular endothelial growth factor and endostatin. The in vivo activation of MMPs and endostatin generation occur mainly in the extracellular environment by interactions of different cell types. Therefore, these processes are necessary to study in the extracellular space in vivo. Sex steroids play a dominant role in breast carcinogenesis, by largely unknown mechanisms. In the present study, we used in vivo microdialysis to directly quantify MMP-2 and MMP-9 activity and sample endostatin from both stroma (murine) and tumor (human) cells in vivo in solid MCF-7 tumors in nude mice. We found that tamoxifen in combination with estradiol increased tumor MMP-2/MMP-9 in vivo activity, endostatin levels, and decreased tumor vascularization compared with estradiol treatment only. The stroma-derived endostatin was three to five times higher than cancer cell-generated endostatin. After inhibition of MMP-2/MMP-9, endostatin levels decreased, providing evidence that these proteases are highly involved in the generation of endostatin. Our results support the previously reported concept that MMPs may serve as negative regulators of angiogenesis. The regulation of endostatin generation by modulation of MMP-2/MMP-9 activities suggests a previously unrecognized mechanism of estradiol and tamoxifen, which may have implications for the pathogenesis of breast cancer.
Combining Histone Deacetylase Inhibitor Vorinostat with Aurora Kinase Inhibitors Enhances Lymphoma Cell Killing with Repression of c-Myc, hTERT, and microRNA Levels
Authors: Leo Kretzner, Anna Scuto, Pamela M. Dino, Claudia M. Kowolik, Jun Wu, Patrick Ventura, Richard Jove, Stephen J. Forman, Yun Yen, Mark H. Kirschbaum
Journal: Cancer Research (2011)

MK-0457 and MK-5108 are novel aurora kinase inhibitors (AKi) leading to G(2)-M cell-cycle arrest. Growth and survival of multiple lymphoma cell lines were studied with either drug alone or in combination with vorinostat, a histone deacetylase inhibitor (HDACi), using MTS and Annexin V assays, followed by molecular studies. Either of the AKi alone at 100 to 500 nmol/L resulted in approximately 50% reduced cell growth and 10% to 40% apoptosis. Addition of vorinostat reactivated proapoptotic genes and enhanced lymphoma cell death. Quantitative PCR and immunoblotting revealed that epigenetic and protein acetylation mechanisms were responsible for this activity. The prosurvival genes Bcl-X(L) and hTERT were downregulated 5-fold by combination drug treatment, whereas the proapoptotic BAD and BID genes were upregulated 3-fold. The p53 tumor suppressor was stabilized by an increased acetylation in response to vorinostat and a reduced Ser315 phosphorylation in response to aurora kinase A. Vorinostat or trichostatin A decreased MYC mRNA and protein as well as c-Myc-regulated microRNAs. MYC is a critical gene in these responses, as MYC knockdown combined with the expression of the c-Myc antagonist MXD1 raised cell sensitivity to the effects of either AKi. Thus, the HDACi vorinostat leads to both transcriptional and posttranscriptional changes to create a proapoptotic milieu, sensitizing cells to mitosis-specific agents such as AKis.
New cohorts of naive T cells exacerbate ongoing allergy but can be suppressed by regulatory T cells
Authors: F. Hauet‐Broere, W. W. J. Unger, L. A. van Berkel, J. Garssen, M. A. Hoijer, G. Kraal, J. N. Samsom
Journal: Allergy (2005)

Although as pretreatment oral tolerance is a potent means to achieve systemic suppression, its application in ongoing disease is controversial. Here we propose that availability of naive T cells may critically determine whether immunological tolerance is achieved during ongoing antigenic reactivity. Infusion of naive antigen‐specific T cells into mice directly prior to eliciting a secondary T h 2 response induces these naive cells to actively engage in the antigenic response despite presence of established memory. Naive antigen‐specific T‐cells divided faster, produced more interleukin (IL)‐2, IL‐4 and IL‐5 and enhanced immunoglobulin E (IgE) release during a secondary T h 2 response, compared with naive T cells that were infused prior to a primary response. Despite such contribution by new cohorts of naive T cells co‐infusion of mucosal Tr together with naive T cells could suppress enhanced IgE release during a secondary T h 2 response. We conclude that naive T cells contribute to a secondary T h 2 response and although they can still be suppressed in the presence of sufficient numbers of mucosal Tr, they may interfere with potential therapeutic application of mucosal tolerance.
Preparing Health Professionals to Provide Care to Individuals with Disabilities
Authors: Matt Holder, H Barry Waldman, Henry Hood
Journal: International Journal of Oral Science (2009)

To review the perceptions of dental/medical educators and their students in the United States on the adequacy of didactic and clinical preparation to provide service for individuals with disabilities.An e-mailed questionnaire with follow-up was sent to 198 deans of dental/medical schools, 1,628 directors of residency programs in nine medical/dental residency programs, 427 medical students in 12 medical schools, and 368 health related organizations, facilities and programs.More than half (58%) of the responding deans of reported that a curriculum for patients with disabilities was not a high priority at their school. A majority (61%) of deans of medical schools, and 47% of the deans of dental schools, reported that their graduates were competent to treat patients with disabilities. However, majorities of dental/medical school seniors and graduates expressed inadequate competency in the care of these patients. A majority of the directors of medical/dental residencies indicated a need for additional training for their residents.There is need for increased didactic and clinical preparation of dental/medical school graduates in the care of individuals with special health needs. The interest expressed by health profession educators in an effort to develop appropriate curriculum modules provides an opportunity to prepare new graduates for the care of an increasing population of individuals with disabilities.