tbuckley/cabot-search huggingface dataset:
The Role of Sodium-Potassium—Activated Adenosine Triphosphatase in the Reabsorption of Sodium by the Kidney*
Authors: Adrian I. Katz, Franklin H. Epstein
Journal: Journal of Clinical Investigation (1967)

In order to evaluate the possible role of sodium- and potassium-activated adenosine triphosphatase in the active transport of sodium by the renal tubules, we examined the effect of large changes in the tubular reabsorptive load of sodium on the Na-K-ATPase activity of rat kidney homogenates. Glomerular filtration and tubular reabsorption of sodium per gram of kidney tissue increased progressively after contralateral uninephrectomy. This was paralleled by an increase in Na-K-ATPase per milligram of protein in a microsomal fraction of kidney cortex. The importance of this change is underlined by the absence of simultaneous increases in other microsomal enzymes such as glucose-6-phosphatase and Mg(++)-dependent ATPase, or in succinic dehydrogenase or glutaminase. Similar increases in Na-K-ATPase were observed when the net tubular reabsorption of sodium was increased by feeding the animals a high-protein diet or after injection of methylprednisolone. On the other hand, Na-K-ATPase was lowered when tubular transport of sodium was reduced by bilateral adrenalectomy. The results of these experiments show that renal Na-K-ATPase changes in an adaptive way when renal reabsorption of sodium is chronically increased or diminished and support the hypothesis that this enzyme system is involved in the process by which sodium is actively transported across the renal tubule.
Airflow Limitation and Airway Dimensions in Chronic Obstructive Pulmonary Disease
Authors: Masaru Hasegawa, Yasuyuki Nasuhara, Yuya Onodera, Hironi Makita, Katsura Nagai, Satoshi Fuke, Yoko Ito, Tomoko Betsuyaku, Masaharu Nishimura
Journal: American Journal of Respiratory and Critical Care Medicine (2006)

Rationale: Chronic obstructive pulmonary disease (COPD) is characterized by airflow limitation caused by emphysema and/or airway narrowing. Computed tomography has been widely used to assess emphysema severity, but less attention has been paid to the assessment of airway disease using computed tomography.Objectives: To obtain longitudinal images and accurately analyze short axis images of airways with an inner diameter ⩾ 2 mm located anywhere in the lung with new software for measuring airway dimensions using curved multiplanar reconstruction.Methods: In 52 patients with clinically stable COPD (stage I, 14; stage II, 22; stage III, 14; stage IV, 2), we used the software to analyze the relationship of the airflow limitation index (FEV1, % predicted) with the airway dimensions from the third to the sixth generations of the apical bronchus (B1) of the right upper lobe and the anterior basal bronchus (B8) of the right lower lobe.Measurements and Main Results: Airway luminal area (Ai) and wall area percent (WA%) were significantly correlated with FEV1 (% predicted). More importantly, the correlation coefficients (r) improved as the airways became smaller in size from the third (segmental) to sixth generations in both bronchi (Ai: r = 0.26, 0.37, 0.58, and 0.64 for B1; r = 0.60, 0.65, 0.63, and 0.73 for B8).Conclusions: We are the first to use three-dimensional computed tomography to demonstrate that airflow limitation in COPD is more closely related to the dimensions of the distal (small) airways than proximal (large) airways.
Lung volume reduction surgery for emphysema: answers are beginning to accumulate
Authors: AB Thompson
Journal: European Respiratory Journal (1996)

End-stage emphysema is a devastating disease, associated with marked morbidity and mortality. The onset of dyspnoea is insidious and unrelenting. By the time medical attention is sought the disease has often progressed to severe, fixed airflow limitation. Medically, the therapeutic options for emphysema have limited efficacy because none can address the anatomical abnormalities which cause the pathophysiological changes seen in emphysema. Lung transplantation is an option for patients with severe emphysema, but advanced age and co-morbid medical conditions often preclude patients with emphysema from being candidates for lung transplantation. Lung volume reductive surgery (LVRS) has emerged as a viable alternative for these patients. Recent publications have begun to address important clinical and mechanistic questions still unanswered about this new procedure. Clearly LVRS improves dyspnoea, oxygenation, and exercise tolerance for the majority of carefully selected patients. Several centres have confirmed the improvements in respiratory function, exercise tolerance and
Recovery of ischaemic injured porcine ileum: evidence for a contributory role of COX-1 and COX-2
Authors: A T Blikslager
Journal: Gut (2002)

Background: We have previously shown that the non-selective cyclooxygenase (COX) inhibitor indomethacin retards recovery of intestinal barrier function in ischaemic injured porcine ileum. However, the relative role of COX-1 and COX-2 elaborated prostaglandins in this process is unclear. Aims: To assess the role of COX-1 and COX-2 elaborated prostaglandins in the recovery of intestinal barrier function by evaluating the effects of selective COX-1 and COX-2 inhibitors on mucosal recovery and eicosanoid production. Methods: Porcine ileal mucosa subjected to 45 minutes of ischaemia was mounted in Ussing chambers, and transepithelial electrical resistance was used as an indicator of mucosal recovery. Prostaglandins E<sub>1</sub> and E<sub>2</sub> (PGE) and 6-keto-PGF<sub>1α</sub> (the stable metabolite of prostaglandin I<sub>2</sub> (PGI<sub>2</sub>)) were measured using ELISA. Thromboxane B<sub>2</sub> (TXB<sub>2</sub>, the stable metabolite of TXA<sub>2</sub>) was measured as a likely indicator of COX-1 activity. Results: Ischaemic injured tissues recovered to control levels of resistance within three hours whereas tissues treated with indomethacin (5×10<sup>−6</sup> M) failed to fully recover, associated with inhibition of eicosanoid production. Injured tissues treated with the selective COX-1 inhibitor SC-560 (5×10<sup>−6</sup> M) or the COX-2 inhibitor NS-398 (5×10<sup>−6</sup> M) recovered to control levels of resistance within three hours, associated with significant elevations of PGE and 6-keto-PGF<sub>1α</sub> compared with untreated tissues. However, SC-560 significantly inhibited TXB<sub>2</sub> production whereas NS-398 had no effect on this eicosanoid, indicating differential actions of these inhibitors related to their COX selectivity. Conclusions: The results suggest that recovery of resistance is triggered by PGE and PGI<sub>2</sub>, which may be elaborated by either COX-1 or COX-2.
Correlation between <b> <i>UDP-Glucuronosyltransferase</i> </b> Genotypes and 4-(Methylnitrosamino)-1-(3-Pyridyl)-1-Butanone Glucuronidation Phenotype in Human Liver Microsomes
Authors: Doris Wiener, Jia-Long Fang, Nicole Dossett, Philip Lazarus
Journal: Cancer Research (2004)

Abstract The nicotine-derived tobacco-specific nitrosamine, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone, is one of the most potent and abundant procarcinogens found in tobacco and tobacco smoke, and glucuronidation of its major metabolite, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL), is an important mechanism for 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone detoxification. Substantial interindividual variability in urinary NNAL glucuronide formation has been observed in smokers and tobacco chewers. To determine whether genetic variations may play a role in this interindividual variability, NNAL-glucuronidating activities were analyzed in 78 human liver microsomal specimens and compared with the prevalence of missense polymorphisms in the two major NNAL-glucuronidating enzymes UGT1A4 and UGT2B7. In vitro assays using liver microsomal specimens from individual subjects demonstrated a 70- and 50-fold variability in NNAL-N-Gluc and NNAL-O-Gluc formation, respectively, and a 20-fold variability in the ratio of NNAL-N-Gluc:NNAL-O-Gluc formation. Microsomes from subjects with a homozygous polymorphic UGT1A424Thr/UGT1A424Thr genotype exhibited a significantly higher (P &amp;lt; 0.05) level of NNAL-N-Gluc activity compared with microsomes from subjects with the wild-type UGT1A424Pro/UGT1A424Pro genotype, and a significantly higher (P &amp;lt; 0.05) number of subjects with liver microsomes having high NNAL-N-Gluc formation activity contained the UGT1A424Thr/UGT1A424Thr genotype. Microsomes from subjects with the homozygous polymorphic UGT2B7268Tyr/UGT2B7268Tyr genotype exhibited a significantly lower level (P &amp;lt; 0.025) of NNAL-O-Gluc activity when compared with microsomes from subjects with the wild-type UGT2B7268His/UGT2B7268His genotype, and a significantly (P &amp;lt; 0.05) higher number of subjects with liver microsomes having low NNAL-O-Gluc formation activity contained the UGT2B7268Tyr/UGT2B7268Tyr genotype. These data suggest that the UGT1A4 codon 24 and UGT2B7 codon 268 polymorphisms may be associated with altered rates glucuronidation and detoxification of NNAL in vivo.
A novel pathway down-modulating T cell activation involves HPK-1–dependent recruitment of 14-3-3 proteins on SLP-76
Authors: Vincenzo Di Bartolo, Benjamin Montagne, Mogjiborahman Salek, Britta Jungwirth, Florent Carrette, Julien Fourtane, Nathalie Sol-Foulon, Frédérique Michel, Olivier Schwartz, Wolf D. Lehmann, Oreste Acuto
Journal: The Journal of Experimental Medicine (2007)

The SH2 domain–containing leukocyte protein of 76 kD (SLP-76) is a pivotal element of the signaling machinery controlling T cell receptor (TCR)-mediated activation. Here, we identify 14-3-3ε and ζ proteins as SLP-76 binding partners. This interaction was induced by TCR ligation and required phosphorylation of SLP-76 at serine 376. Ribonucleic acid interference and in vitro phosphorylation experiments showed that serine 376 is the target of the hematopoietic progenitor kinase 1 (HPK-1). Interestingly, either S376A mutation or HPK-1 knockdown resulted in increased TCR-induced tyrosine phosphorylation of SLP-76 and phospholipase C-γ1. Moreover, an SLP-76–S376A mutant induced higher interleukin 2 gene transcription than wild-type SLP-76. These data reveal a novel negative feedback loop involving HPK-1–dependent serine phosphorylation of SLP-76 and 14-3-3 protein recruitment, which tunes T cell activation.
Identification of ADAMTS7 as a novel locus for coronary atherosclerosis and association of ABO with myocardial infarction in the presence of coronary atherosclerosis: two genome-wide association studies
Authors: Muredach P Reilly, Mingyao Li, Jing He, Jane F Ferguson, Ioannis M Stylianou, Nehal N Mehta, Mary Susan Burnett, Joseph M Devaney, Christopher W Knouff, John R Thompson, Benjamin D Horne, Alexandre FR Stewart, Themistocles L Assimes, Philipp S Wild, Hooman Allayee, Patrick Linsel Nitschke, Riyaz S Patel, Nicola Martinelli, Domenico Girelli, Arshed A Quyyumi, Jeffrey L Anderson, Jeanette Erdmann, Alistair S Hall, Heribert Schunkert, Thomas Quertermous, Stefan Blankenberg, Stanley L Hazen, Robert Roberts, Sekar Kathiresan, Nilesh J Samani, Stephen E Epstein, Daniel J Rader
Journal: The Lancet (2011)
Systems Biology of Tumor Dormancy: Linking Biology and Mathematics on Multiple Scales to Improve Cancer Therapy
Authors: Heiko Enderling, Philip Hahnfeldt, Lynn Hlatky, Nava Almog
Journal: Cancer Research (2012)

For many decades, it has been appreciated that tumor progression is not monotonic, and development of a cancer cell does not equate to inevitable cancer presentation in the clinic. Tumor progression is challenged by numerous intrinsic and extrinsic bottlenecks that can hold the tumor in dormant stages for prolonged periods. Given the complex, multiscale nature of these bottlenecks, the Center of Cancer Systems Biology organized a workshop on critical issues of systems biology of tumor dormancy. The program for the meeting this past July, chaired by N. Almog and H. Enderling, included discussions and interactive breakout sessions on regulation of tumor dormancy by angiogenesis, tumor-immune system interactions, cancer stem cell kinetics, and cell signaling pathways. Three important conclusions emerged from the meeting. The first was the urgent need to differentiate between tumor cell and tumor population dormancy of the primary tumor and metastatic deposits, the second was the continued need for interdisciplinary dialogs, and the third was the need to bring cross-scale mechanistic thinking to the field to achieve a more robust understanding of tumor dormancy and its clinical implications.
Statin-Induced Improvement of Endothelial Progenitor Cell Mobilization, Myocardial Neovascularization, Left Ventricular Function, and Survival After Experimental Myocardial Infarction Requires Endothelial Nitric Oxide Synthase
Authors: Ulf Landmesser, Niels Engberding, Ferdinand H. Bahlmann, Arnd Schaefer, Antje Wiencke, Andre Heineke, Stephan Spiekermann, Denise Hilfiker-Kleiner, Christian Templin, Daniel Kotlarz, Maja Mueller, Martin Fuchs, Burkhard Hornig, Hermann Haller, Helmut Drexler
Journal: Circulation (2004)

Background— Endothelial nitric oxide (eNO) bioavailability is severely reduced after myocardial infarction (MI) and in heart failure. Statins enhance eNO availability by both increasing eNO production and reducing NO inactivation. We therefore studied the effect of statin treatment on eNO availability after MI and tested its role for endothelial progenitor cell mobilization, myocardial neovascularization, left ventricular (LV) dysfunction, remodeling, and survival after MI. Methods and Results— Wild-type (WT) and eNO synthase (eNOS) −/− mice with extensive anterior MI were randomized to treatment with vehicle (V) or atorvastatin (Ator, 50 mg/kg QD by gavage) for 4 weeks starting on day 1 after MI. Ator markedly improved endothelium-dependent, NO-mediated vasorelaxation; mobilization of endothelial progenitor cells; and myocardial neovascularization of the infarct border in WT mice after MI while having no effect in eNOS −/− mice. LV dysfunction and interstitial fibrosis were markedly attenuated by Ator in WT mice, whereas no effect was observed in eNOS −/− mice after MI. Importantly, Ator significantly increased the survival rate during 4 weeks after MI in WT mice (Ator versus V, 80% versus 46%; P &lt;0.01, n=75) but not in eNOS −/− mice (43% versus 48%; NS, n=42). Conclusions— These findings suggest that increased eNO availability is required for statin-induced improvement of endothelial progenitor cell mobilization, myocardial neovascularization, LV dysfunction, interstitial fibrosis, and survival after MI. eNO bioavailability after MI likely represents an important therapeutic target in heart failure after MI and mediates beneficial effects of statin treatment after MI.
CCI-779 Inhibits Cell-Cycle G2–M Progression and Invasion of Castration-Resistant Prostate Cancer via Attenuation of UBE2C Transcription and mRNA Stability
Authors: Hongyan Wang, Chunpeng Zhang, Anna Rorick, Dayong Wu, Ming Chiu, Jennifer Thomas-Ahner, Zhong Chen, Hongyan Chen, Steven K. Clinton, Kenneth K. Chan, Qianben Wang
Journal: Cancer Research (2011)

The cell-cycle G(2)-M phase gene UBE2C is overexpressed in various solid tumors including castration-resistant prostate cancer (CRPC). Our recent studies found UBE2C to be a CRPC-specific androgen receptor (AR) target gene that is necessary for CRPC growth, providing a potential novel target for therapeutic intervention. In this study, we showed that the G(1)-S cell-cycle inhibitor-779 (CCI-779), an mTOR inhibitor, inhibited UBE2C mRNA and protein expression in AR-positive CRPC cell models abl and C4-2B. Treatment with CCI-779 significantly decreased abl cell proliferation in vitro and in vivo through inhibition of cell-cycle progression of both G(2)-M and G(1)-S phases. In addition, exposure of abl and C4-2B cells to CCI-779 also decreased UBE2C-dependent cell invasion. The molecular mechanisms for CCI-779 inhibition of UBE2C gene expression involved a decreased binding of AR coactivators SRC1, SRC3, p300, and MED1 to the UBE2C enhancers, leading to a reduction in RNA polymerase II loading to the UBE2C promoter, and attenuation of UBE2C mRNA stability. Our data suggest that, in addition to its ability to block cell-cycle G(1) to S-phase transition, CCI-779 causes a cell-cycle G(2)-M accumulation and an inhibition of cell invasion through a novel UBE2C-dependent mechanism, which contributes to antitumor activities of CCI-779 in UBE2C overexpressed AR-positive CRPC.
R Jeremy Guyer
Authors: M. G. J. Day
Journal: BMJ (2013)

After house jobs and a stint as a medical registrar and general practitioner in Blackburn, R Jeremy Guyer was appointed to a pathology rotation at St George’s Hospital London SWI. When on call as the RCP, he provided all out of hours emergency service to the labs as was the custom in those times, including cross matching, haematology, biochemistry, and bacteriology. For viral investigation he …
Acute Respiratory Viral Infections Aggravate Arterial Endothelial Dysfunction in Children With Type 1 Diabetes
Authors: Elhadi Aburawi, Petru Liuba, Erkki Pesonen, Seppo Ylä-Herttuala, Sture Sjöblad
Journal: Diabetes Care (2004)

Despite improvements in therapy for children with type 1 diabetes, the prevalence of cardiovascular morbidity in adulthood due to accelerated atherosclerosis remains significant (1). Similar to other cardiovascular risk factors, the diabetic state facilitates arterial endothelial injury, a primary event in the pathogenesis of atherosclerosis (2). Although several pediatric studies have reported an association of diabetes with arterial endothelial dysfunction (3,4), pathogenic animal studies have suggested that even though this disease predisposes to endothelial dysfunction and atherosclerosis, it might not be sufficient to cause them (5).

Notably, type 1 diabetes increases the propensity for both chronic and acute infections in part by weakening the immune mechanisms (6). The risk is particularly increased for respiratory tract infections, but other infections have also been associated with diabetes (7). Furthermore, diabetic patients are at greater risk for infection-related mortality (8), and the excess risk appears to be linked to cardiovascular diseases (9). In the present study, we investigated whether viral respiratory tract infections in children with type 1 diabetes might impose an additional burden on the arterial endothelial function.

A total of 26 children (aged 6–18 years, mean [±SD] age 14 ± 3 years) with type 1 diabetes (duration 6 ± 3 years) were recruited. Of these, 11 children had a clinically manifested upper respiratory tract infection (body temperature >38°C and flu-like symptoms) 6–8 weeks before the …
TAC3/TACR3 Mutations Reveal Preferential Activation of GnRH Release by Neurokinin B in Neonatal Life Followed by Reversal in Adulthood
Authors: Elena Gianetti, Cintia Tusset, Sekoni D. Noel, Margaret G. Au, Andrew A. Dwyer, Virginia A. Hughes, Ana Paula Abreu, Jessica Carroll, Ericka Trarbach, Leticia FG Silveira, Elaine MF Costa, Berenice Bilharinho de Mendonça, Margaret de Castro, Adriana Lofrano, Janet E. Hall, Erol Bolu, Metin Ozata, Richard Quinton, John K. Amory, Susan E. Stewart, Wiebke Arlt, Trevor R. Cole, William F. Crowley, Ursula B. Kaiser, Ana Claudia Latronico, Stephanie B. Seminara
Journal: Endocrine Reviews (2010)

ABSTRACT Context Mutations in TAC3 and TACR3 (encoding neurokinin B and its receptor) have been identified in Turkish patients with hypogonadotropic hypogonadism (IHH), but broader populations have not yet been tested and genotype-phenotype correlations have not been established. Objective A broad cohort of normosmic IHH probands was screened for mutations in TAC3/TACR3 to evaluate the prevalence of such mutations and define the genotype/phenotype relationships. Design Sequencing of TAC3/TACR3; in vitro functional assays, neuroendocrine phenotyping. Setting Tertiary care centers world-wide. Patients or other participants 345 probands, 18 family members, 292 controls. Intervention Examination of reproductive phenotypes throughout reproductive life and pre/post therapy. Main Outcome Measure Rare sequence variants in TAC3/TACR3. Results In TACR3, 19 probands harbored 13 distinct coding sequence rare nucleotide variants (3 nonsense mutations, 6 non-synonymous, 4 synonymous [one predicted to affect splicing]). In TAC3, one homozygous single base pair deletion was identified, resulting in complete loss of the neurokinin B decapeptide. Phenotypic information was available on 16 males and 7 females with coding sequence variants in TACR3/TAC3. Of the 16 males, 15 had microphallus; none of the females had spontaneous thelarche. Seven of the 16 males and 5/7 females were assessed after discontinuation of therapy and 6/7 males and 4/5 females demonstrated evidence for reversibility of their hypogonadotropism. Conclusions Mutations in the neurokinin B pathway are relatively common as causes of hypogonadism. While the neurokinin B pathway appears essential during early sexual development, its importance in sustaining the integrity of the hypothalamic-pituitary-gonadal axis appears attenuated over time.
The Diagnosis and Management of Aortic Dissection
Authors: E. Stanley Crawford
Journal: JAMA (1990)

Aortic dissection is a severe disease. Most untreated patients with types I and II (proximal) dissection and over half of those with type III (distal) dissection die within 1 year. Most of the deaths occur within 2 weeks and are caused by rupture, aortic insufficiency, and branch vessel obstruction. Aortic dissection is suspected in patients with anterior chest and back pain that progresses downward. Diagnosis is confirmed by computed tomography, aortography, or echocardiography. Appropriate medical treatment and corrective surgery, including total aortic replacement, performed in the acute and chronic stages, are now successful in over 90% of the cases; long-term results of treatment are steadily improving and are expected to exceed 50% at 10 years. The keys to a successful outcome are being aware of the symptoms of dissection, early diagnosis, and prompt application of appropriate treatment; diligent follow-up includes controlling blood pressure, decreasing the velocity of left ventricular contraction, monitoring the size of the residual aorta, and taking appropriate action if redissection, aneurysmal formation, or rupture occurs. (<i>JAMA</i>. 1990;264:2537-2541)
Vascular dysfunction in monkeys with diet-induced hyperhomocyst(e)inemia.
Authors: S R Lentz, C G Sobey, D J Piegors, M Y Bhopatkar, F M Faraci, M R Malinow, D D Heistad
Journal: Journal of Clinical Investigation (1996)

Elevated plasma homocyst(e)ine may predispose to complications of vascular disease. Homocysteine alters vasomotor regulatory and anticoagulant properties of cultured vascular endothelial cells, but little is known about effects of hyperhomocyst(e)inemia on vascular function in vivo. We tested the hypothesis that diet-induced moderate hyperhomocyst(e)inemia is associated with vascular dysfunction in cynomolgus monkeys. Plasma homocyst(e)ine increased from 4.O +/- O.2 microM when monkeys were fed normal diet to 10.6 +/- 2.6 microM when they were fed modified diet (mean +/- SE; P = 0.02). Vasomotor responses were assessed in vivo by quantitative angiography and Doppler measurement of blood flow velocity. In response to activation of platelets by intraarterial infusion of collagen, blood flow to the leg decreased by 42 +/- 9% in monkeys fed modified diet, compared with 14 +/- 11% in monkeys fed normal diet (P = 0.008), Responses of resistance vessels to the endothelium-dependent vasodilators acetylcholine and ADP were markedly impaired in hyperhomocyst(e)inemic monkeys, which suggests that increased vasoconstriction in response to collagen may be caused by decreased vasodilator responsiveness to platelet-generated ADP. Relaxation to acetylcholine and, to a lesser extent, nitroprusside, was impaired ex vivo in carotid arteries from monkeys fed modified diet. Thrombomodulin anticoagulant activity in aorta decreased by 34 +/- 15% in hyperhomocyst(e)inemic monkeys (P = 0.03). We conclude that diet-induced moderate hyperhomocyst(e)inemia is associated with altered vascular function.