tbuckley/cabot-search huggingface dataset:
Muscle Cholinergic Dilators in the Sinus Baroreceptor Response in Cats
Authors: Toru Takeuchi, John W. Manning
Journal: Circulation Research (1971)

Experiments were done to evaluate the effect of the cholinergic vasodilator system on the flow-pressure relation in the isolated, perfused gastrocnemius and soleus muscles of the cat. Reflex changes in the muscle vascular resistance were produced by maintaining the isolated, perfused carotid sinus at different pressure levels. Flow-pressure curves were obtained from the isolated muscles at high, medium, and low carotid sinus pressures before and after administration of adrenergic or cholinergic blocking drugs or denervation, or both. Following cholinergic receptor blockade, flow-pressure relations at high sinus pressure showed a loss of a dilator component, hut curves at low and medium sinus pressures were the same as controls. Following adrenergic receptor blockade, flow-pressure curves at low and medium sinus pressures were superimposed; however high sinus pressure still produced a decrease in vascular resistance. The remaining vasodilation could be abated by either denervation or anticholinergic agents. The difference between the untreated and the cholinergically blocked flow-pressure responses represented 15-30% of the range of change in vascular resistance evoked by the sinus baroreceptor reflex. Thus, effective withdrawal of sympathetic vasoconstrictor tone did not account for total vasodilation. The data indicate that the sympathetic cholinergic vasodilator system participated in the vascular responses of skeletal muscle during baroreceptor stimulation.
Lung Cancer in the Era of Precision Medicine
Authors: Katerina Politi, Roy S. Herbst
Journal: Clinical Cancer Research (2015)

Abstract The past decade has been transformative for lung cancer patients, physicians, and scientists. The discovery of EGFR mutations that confer sensitivity to tyrosine kinase inhibitors in lung adenocarcinomas in 2004 heralded the beginning of the era of precision medicine for lung cancer. Indeed, it precipitated concerted efforts by many investigators to define molecular subgroups of lung cancer, characterize the genomic landscape of lung cancer subtypes, identify novel therapeutic targets, and define mechanisms of sensitivity and resistance to targeted therapies. The fruits of these efforts are visible every day now in lung cancer clinics: Patients receive molecular testing to determine whether their tumor harbors an actionable mutation, new and improved targeted therapies that can overcome resistance to first-generation drugs are in clinical trials, and drugs targeting the immune system are showing activity in patients. This extraordinary promise is tempered by the sobering fact that even the newest treatments for metastatic disease are rarely curative and are effective only in a small fraction of all patients. Ongoing and future efforts to find new vulnerabilities of lung cancers, unravel the complexity of drug resistance, increase the efficacy of immunotherapies, and perform biomarker-driven clinical trials are necessary to improve outcomes for patients with lung cancer. Clin Cancer Res; 21(10); 2213–20. ©2015 AACR. See all articles in this CCR Focus section, “Progress in Lung Cancer.”
Studies of a popliteal synovial fistula.
Authors: R M Bennett, G R Hughes, E G Bywaters, P J Holt
Journal: Annals of the Rheumatic Diseases (1972)

Synovial fistulae occur only rarely as a spontaneous complication of rheumatoid arthritis, usually in relation to the small joints of the hands and feet (Bywaters, 1953;Rosin and Toghill, 1963).We are unaware of synovial fistulae in relation to a knee joint having been previously described either as a spon- taneous occurrence or as a complication of surgery.The case recorded here afforded a unique opportunity to study synovial fluid output in terms of diurnal volume and composition, including blood loss. Case reportA 51-year-old woman previously in good health, first presented at another hospital with pain in the left forefoot.Over the next 2 years she developed pain and swelling in the left wrist, the right knee, and the small joints of both hands.Rheumatoid arthritis was diagnosed and she was
Mitochondrial DNA alteration in obstructive sleep apnea
Authors: Donato Lacedonia, Elisabetta Crisetti, Giovanna Elisiana Carpagnano, Grazia Cotugno, Grazia Pia Palladino, Giulia Patricelli, Roberto Sabato, Maria Pia Foschino Barbaro
Journal: European Respiratory Journal (2014)

Rationale: Obstructive Sleep Apnea (OSAS) is a common disease associated with increase of cardiovascular risk and characterized by repeated episodes of Intermitted Hypoxia (IH) which induce oxidative stress and systemic inflammation. Mitochondria are organelles with their own DNA (MtDNA) present into the cells and they are involved in the respiratory chain. Oxidative stress can induce damage to nuclear and mitochondrial DNA.

Objectives: The aim of this study was to investigate if the increase of oxidative stress in OSAS patients can induce also MtDNA alteration.

Methods: Content of MtDNA and nuclear DNA (nDNA) was measured into blood cells of OSAS patients by Real Time PCR. The ratio between MtDNA/nDNA was then calculated. Presence of oxidative stress was evaluated by levels of Reactive Oxygen Metabolites (ROMs), measured by diacron reactive oxygen metabolite test (d-ROM test). Differences between OSAS patients and control group were then calculated by T-test and correlation between MtDNA/nDNA and ROMs level was evaluated by Pearson analysis.

Measurements and Main Results: 81 patients (age 56,32±11,96; BMI 38,25±10,37; AHI 48,93±27,17) were compared with 40 control subjects (age 44,05±12,7; BMI 27,38±5,56, AHI 3,2±1,3). MtDNA/nDNA was higher in patients with OSAS than in control group (155,28±54,84 vs 133,33±48,76; p=0,03), also the levels of ROMs were higher in OSAS subjects (344,72±71,66 vs 226±36,77; p=0,02) and they were positive correlated with MtDNA/nDNA (R=0,53, p<0,01).

Conclusions: In OSAS patients there is a Mitochondrial DNA damage induced by increase of oxidative stress. Intermitted hypoxia seems to be the main mechanism which lead to this process.
Inducible Nitric Oxide Synthase Modulates Cyclooxygenase-2 Activity in the Heart of Conscious Rabbits During the Late Phase of Ischemic Preconditioning
Authors: Ken Shinmura, Yu-Ting Xuan, Xian-Liang Tang, Eitaro Kodani, Hui Han, Yanqing Zhu, Roberto Bolli
Journal: Circulation Research (2002)

Cyclooxygenase-2 (COX-2) is known to mediate the cardioprotective effects of the late phase of ischemic preconditioning (PC); however, the signaling pathways involved in COX-2 induction following ischemic PC are unknown. In addition, although inducible nitric oxide synthase (iNOS) has been identified as a co-mediator of late PC together with COX-2, the interaction between iNOS and COX-2 in the heart is unknown. Using conscious rabbits, we found that the induction of COX-2 expression 24 hours after ischemic PC was blocked by pretreatment with inhibitors of protein kinase C (PKC), Src protein tyrosine kinases (PTKs), and nuclear factor-kappaB (NF-kappaB) but not by inhibitors of NOS or scavengers of reactive oxygen species (ROS). The selective iNOS inhibitors SMT and 1400W, given 24 hours after PC, abrogated the increase in myocardial prostaglandin E2 (PGE2) and 6-keto-PGF1alpha, whereas the selective soluble guanylate cyclase inhibitor ODQ had no effect. COX-2 selective inhibitors (celecoxib and NS-398) did not affect iNOS activity. These results demonstrate that (i) ischemic PC upregulates cardiac COX-2 via PKC-, Src PTK-, and NF-kappaB-dependent signaling pathways, whereas generation of NO and ROS is not necessary, and (ii) the activity of newly synthesized COX-2 following PC requires iNOS-derived NO whereas iNOS activity is independent of COX-2-derived prostanoids, indicating that COX-2 is located downstream of iNOS in the protective pathway of late PC. The data also indicate that iNOS modulates COX-2 activity via cGMP-independent mechanisms. To our knowledge, this is the first demonstration that iNOS-derived NO drives prostanoid synthesis by COX-2 in the heart. NO-mediated activation of COX-2 may be a heretofore unrecognized mechanism by which NO exerts its salubrious effects in the late phase of PC.
Estimating Glomerular Filtration Rate in Kidney Transplantation
Authors: Christine White, Ayub Akbari, Naser Hussain, Laurent Dinh, Guido Filler, Nathalie Lepage, Greg A. Knoll
Journal: Journal of the American Society of Nephrology (2005)

Accurate measurement of GFR is critical for the evaluation of new therapies and the care of renal transplant recipients. Although not accurate in renal transplantation, GFR is often estimated using creatinine-based equations. Cystatin C is a marker of GFR that seems to be more accurate than creatinine. Equations to predict GFR based on the serum cystatin C concentration have been developed, but their accuracy in transplantation is unknown. GFR was estimated using four equations (Filler, Le Bricon, Larsson, and Hoek) that are based on serum cystatin C and seven equations that are based on serum creatinine in 117 adult renal transplant recipients. GFR was measured using radiolabeled diethylenetriaminepentaacetic acid (99mTc-DTPA), and the bias, precision, and accuracy of each equation were determined. The mean (99m)Tc-DTPA GFR was 58 +/- 23 ml/min per 1.73 m(2). The cystatin C-based equations of Filler and Le Bricon had the lowest bias (-1.7 and -3.8 ml/min per 1.73 m2), greatest precision (11.4 and 11.8 ml/min per 1.73 m2), and highest accuracy (87 and 89% within 30% of measured GFR, respectively). The cystatin C equations remained accurate even when the measured GFR was >60 ml/min per 1.73 m2. The creatinine-based equations were not as accurate, with only 53 to 80% of estimates within 30% of measured GFR. Cystatin C-based equations are more accurate at predicting GFR in renal transplant recipients than traditional creatinine-based equations. Further prospective studies with repetitive measurement of cystatin C are needed to determine whether cystatin C-based estimates of GFR will be sufficiently accurate to monitor long-term allograft function.
A novel mutation in DAX1 causes delayed-onset adrenal insufficiency and incomplete hypogonadotropic hypogonadism
Authors: Antoine Tabarin, John C. Achermann, Dominique Recan, Véronique Bex, Xavier Bertagna, Sophie Christin-Maitre, Masafumi Ito, J. Larry Jameson, Philippe Bouchard
Journal: Journal of Clinical Investigation (2000)

Mutations in the DAX1 gene cause X-linked adrenal hypoplasia congenita (AHC) and hypogonadotropic hypogonadism (HHG). In affected boys, primary adrenal insufficiency occurs soon after birth or during early childhood; HHG is recognized at the expected time of puberty. In this report, we describe the novel phenotype of a man who presented with apparently isolated adrenal insufficiency at 28 years of age. Examination revealed partial pubertal development and undiagnosed incomplete HHG. Gonadotropin therapy did not improve his marked oligospermia, suggesting a concomitant primary testicular abnormality. Genomic analysis revealed a novel missense mutation, I439S, in DAX1. The mutant DAX-1 protein was studied for its ability to function as a transcriptional repressor of target genes. Consistent with the patient's mild clinical phenotype, the I439S mutation conferred intermediate levels of repressor activity of DAX-1 when compared with mutations associated with classic AHC. This unique case extends the clinical spectrum of AHC to include delayed-onset primary adrenal insufficiency in adulthood and milder forms of HHG. Furthermore, in accordance with findings in Ahch (Dax1) knockout mice, the clinical features in this patient suggest that DAX-1 function is required for spermatogenesis in humans, independent of its known effects on gonadotropin production.
Impact of competitive flow on wall shear stress in coronary surgery: computational fluid dynamics of a LIMA–LAD model
Authors: Håvard Nordgaard, Abigail Swillens, Dag Nordhaug, Idar Kirkeby-Garstad, Denis Van Loo, Nicola Vitale, Patrick Segers, Rune Haaverstad, Lasse Lovstakken
Journal: Cardiovascular Research (2010)

Competitive flow from native coronary vessels is considered a major factor in the failure of coronary bypass grafts. However, the pathophysiological effects are not fully understood. Low and oscillatory wall shear stress (WSS) is known to induce endothelial dysfunction and vascular disease, like atherosclerosis and intimal hyperplasia. The aim was to investigate the impact of competitive flow on WSS in mammary artery bypass grafts.Using computational fluid dynamics, WSS was calculated in a left internal mammary artery (LIMA) graft to the left anterior descending artery in a three-dimensional in vivo porcine coronary artery bypass graft model. The following conditions were investigated: high competitive flow (non-significant coronary lesion), partial competitive flow (significant coronary lesion), and no competitive flow (totally occluded coronary vessel). Time-averaged WSS of LIMA at high, partial, and no competitive flow were 0.3-0.6, 0.6-3.0, and 0.9-3.0 Pa, respectively. Further, oscillatory WSS quantified as the oscillatory shear index (OSI) ranged from (maximum OSI = 0.5 equals zero net WSS) 0.15 to 0.35, <0.05, and <0.05, respectively. Thus, high competitive flow resulted in substantial oscillatory and low WSS. Moderate competitive flow resulted in WSS and OSI similar to the no competitive flow condition.Graft flow is highly dependent on the degree of competitive flow. High competitive flow was found to produce unfavourable WSS consistent with endothelial dysfunction and subsequent graft narrowing and failure. Partial competitive flow, however, may be better tolerated as it was found to be similar to the ideal condition of no competitive flow.
Minimizing the Risk of Amniocentesis for Prenatal Diagnosis
Authors: Arthur I. Goldstein
Journal: JAMA (1977)

Although the risk of amniocentesis in the second trimester of pregnancy is small, untoward sequelae can be further reduced. One hundred twenty amniocenteses were attempted during a two-year period. In eight instances, the patient had to return for a second tap because of bacterial contamination, inadequate number of fetal cells, or inability to obtain amniotic fluid. These eight patients all underwent repated amniocentesis and successful karyotyping. There were no major complications and one minor complication. Two spontaneous abortions were not apparently related to the procedure. In both these cases, fluid could not be obtained because one patient had a blighted ovum with a small sac and the other had large uterine fibromyomas.
Interferon α-induced apoptosis on rat preneoplastic liver is mediated by hepatocytic transforming growth factor β<sub>1</sub>
Authors: María de Luján Alvarez, María Teresa Ronco, Elena J. Ochoa, Juan A. Monti, Cristina E. Carnovale, Gerardo B. Pisani, María Cristina Lugano, María Cristina Carrillo
Journal: Hepatology (2004)

In previous work we showed that interferon alfa-2b (IFN-α2b) increases apoptosis on rat hepatic preneoplastic foci. The aim of this study was to determine if transforming growth factor β 1 (TGF-β 1 ) was involved in the programmed cell death on the foci. Animals were divided into 6 groups: subjected to a 2-phase model (diethylnitrosamine plus 2-acetylaminofluorene) of preneoplasia development (group 1); treated with IFN-α2b during the 2 phases (group 2); treated with IFN-α2b during initiation with diethylnitrosamine (group 3); treated with IFN-α2b during 2-acetylaminofluorene administration (group 4); subjected only to an initiation stage (group 5); and treated with IFN-α2b during the initiation period (group 6). Serum TGF-β 1 levels were increased in IFN-α2b-treated rats. Immunohistochemical studies showed that IFN-α2b significantly increased the quantity of TGF-β 1 -positive hepatocytes in groups 2 to 4. Phosphorylated-Smads-2/3 (p-Smads-2/3) proteins in liver nuclear extracts were significantly elevated. To determine the source of TGF-β 1 , isolated hepatocytes, Kupffer cells, and peritoneal macrophages from animals in groups 1 and 5 were cultured with or without IFN-α2b. IFN-α2b stimulus induced several-fold increases of TGF-β 1 secretion from hepatocytes. Neither Kupffer cells nor peritoneal macrophages secreted detectable TGF-β 1 levels when they were treated with IFN-α2b. IFN-α2b-stimulated cultured hepatocytes from preneoplastic livers showed enhanced apoptosis, measured by fluorescence microscopy and caspase-3 activity. They presented higher nuclear accumulation of p-Smads-2/3, indicating increased TGF-β 1 signaling. When anti-TGF-β 1 was added to the culture media, TGF-β 1 activation and apoptosis induced by IFN-α2b were blocked. In conclusion , IFN-α2b-induced production of TGF-β 1 by hepatocytes from preneoplastic liver is involved in the apoptotic elimination of altered hepatic foci. (Hepatology 2004;40:394-402.)
Radiosurgery as part of the initial management of patients with malignant gliomas.
Authors: J S Loeffler, E Alexander, W M Shea, P Y Wen, H A Fine, H M Kooy, P M Black
Journal: Journal of Clinical Oncology (1992)

PURPOSE Between May 1988 and May 1991, 41 patients with malignant gliomas were enrolled onto a prospective study designed to evaluate the role of radiosurgery as a component of initial management. PATIENTS AND METHODS Thirty-seven patients underwent radiosurgery according to the protocol and were assessable for survival and complications of treatment. Diagnoses included glioblastoma multiforme (GBM) in 23 (62%) cases and anaplastic astrocytoma in 14 (38%) cases. In 20 (54%) cases, surgical resection was attempted initially, whereas 17 (46%) patients underwent biopsy only. Patients in the study group received external-beam radiotherapy that consisted of 5,940 cGy given in 33 fractions to partial brain fields that encompassed the primary tumor with a 3 to 4 cm margin. Radiosurgery, used as a technique for boosting the dose to any residual contrast-enhancing mass lesion, was given 2 to 4 weeks after the completion of conventional radiotherapy. Minimum radiosurgical doses ranged from 1,000 to 2,000 cGy (median, 1,200 cGy), whereas maximum doses ranged from 1,250 to 2,500 cGy (median, 1,500 cGy). The median tumor volume at the time of radiosurgery was 4.8 cm3 (range, 1.2 to 72 cm3). Adjuvant chemotherapy was not given. RESULTS After a median follow-up of 19 months, only nine of 37 (24%) patients have died. Six patients (all glioblastoma multiforme) died of recurrent tumor, whereas death was attributable to complications of treatment in two cases and intercurrent disease in one case. Four patients with recurrent tumor failed at the margins of the radiosurgical treatment volume, whereas two patients progressed locally. One patient is alive with local and marginal failure. Seven (19%) patients underwent reoperation at a median time of 5 months (range, 1 to 14 months) after radiosurgery. CONCLUSION We conclude that radiosurgery is a useful adjunct to other modalities in the initial management of patients with small, radiographically well-defined malignant gliomas.
Oral Cavity and Esophageal Carcinogenesis Modeled in Carcinogen-Treated Mice
Authors: Xiao-Han Tang, Beatrice Knudsen, Debra Bemis, Satish Tickoo, Lorraine J. Gudas
Journal: Clinical Cancer Research (2004)

Abstract Purpose: Squamous cell carcinoma of the oral cavity is one of the most common human neoplasms, and prevention of these carcinomas requires a better understanding of the carcinogenesis process and a model system in which cancer chemoprevention agents can be tested. We have developed a mouse model using the carcinogen 4-nitroquinoline 1-oxide (4-NQO) in the drinking water to induce tumorigenesis in the mouse oral cavity. Experimental Design: 4-NQO was delivered by tongue painting or drinking water to two mouse strains, CBA and C57Bl/6. The incidences of oral cavity carcinogenesis were then compared. In addition, we examined the expression of some of the molecular markers associated with the process of human oral cavity and esophageal carcinogenesis, such as keratin (K) 1, K14, p16, and epidermal growth factor receptor, by immunohistochemistry. Results: After treatment with 4-NQO in the drinking water, massive tumors were observed on the tongues of both CBA and C57Bl/6 female mice. Pathological analyses indicated that flat squamous dysplasias, exophytic papillary squamous tumors (papillomas), and invasive squamous cell carcinomas were present. Immunohistochemistry analyses showed that 4-NQO changed the expression patterns of the intermediate filament proteins K14 and K1. K14 was expressed in the epithelial suprabasal layers, in addition to the basal layer, in tongues from carcinogen-treated animals. In contrast, control animals expressed K14 only in the basal layer. Moreover, we observed more bromodeoxyuridine staining in the tongue epithelia of 4-NQO-treated mice. Reduced expression of the cell cycle inhibitor, p16, was observed, whereas 4-NQO treatment caused an increase in epidermal growth factor receptor expression in the mouse tongues. Interestingly, similar features of carcinogenesis, including multiple, large (up to 0.5 cm) exophytic papillary squamous tumors and invasive squamous cell carcinomas, increased bromodeoxyuridine staining, and increased K14 expression, were also observed in the esophagi of 4-NQO-treated mice. However, no tumors were observed in the remainder of digestive tract (including the forestomach, intestine, and colon) or in the lungs or livers of 4-NQO-treated mice. These results indicate that this murine 4-NQO-induced oral and esophageal carcinogenesis model simulates many aspects of human oral cavity and esophageal carcinogenesis. Conclusions: The availability of this mouse model should permit analysis of oral cavity and esophageal cancer development in various mutant and transgenic mouse strains. This model will also allow testing of cancer chemopreventive drugs in various transgenic mouse strains.
Expression of Extracellular Matrix Metalloproteases Inducer on Micrometastatic and Primary Mammary Carcinoma Cells
Authors: Natalie Reimers, Kristine Zafrakas, Volker Assmann, Cornelia Egen, Lutz Riethdorf, Sabine Riethdorf, Jürgen Berger, Sebastian Ebel, Fritz Jänicke, Guido Sauter, Klaus Pantel
Journal: Clinical Cancer Research (2004)

Abstract Purpose: EMMPRIN (extracellular matrix metalloprotease inducer) is a glycosylated member of the immunoglobulin superfamily known to stimulate the production of matrix metalloproteases (MMPs) 1, 2, and 3 and MT1-MMP in peritumoral fibroblasts. We here evaluated whether EMMPRIN expression is related to tumor progression in human breast cancer. Experimental Design: An immunohistochemical study using high-density tissue microarrays (n = 2222 breast cancer samples) and EMMPRIN-specific antibodies HIM6 and MEM-M6/1 was performed, and staining results were statistically correlated with various clinicopathological parameters. To analyze the putative association between EMMPRIN expression and bone marrow (BM) micrometastasis, an additional set of 55 breast tumors from patients with or without micrometastatic cells as determined with anti-cytokeratin antibody A45-B/B3 were included in our study. Cytokeratin-positive cells in BM were costained with EMMPRIN-specific antibody 1G6.2. Results: Positive EMMPRIN staining correlated significantly with various histopathological risk factors (higher tumor grade, increased tumor size, negative estrogen receptor status and progesterone receptor status, and higher mitotic index) as well as decreased tumor-specific survival (log-rank, P = 0.0027). In particular, in patients &amp;gt; 50 years (i.e., postmenopausal women), EMMPRIN expression was an independent prognosticator as shown by Cox regression analysis (relative risk = 1.7, 95% confidence interval 1.4–4.3, P = 0.036). An involvement of EMMPRIN in tumor progression was also supported by the fact that it was expressed on ∼90% of micrometastatic cells in BM. Conclusions: EMMPRIN expression in primary tumor predicts an unfavorable prognosis in breast cancer, suggesting a crucial role of EMMPRIN in progression of human mammary carcinomas.