tbuckley/cabot-search huggingface dataset:
Asynchronous Ca <sup>2+</sup> Waves in Intact Venous Smooth Muscle
Authors: Dietrich O. Ruehlmann, Cheng-Han Lee, Damon Poburko, Cornelis van Breemen
Journal: Circulation Research (2000)

Abstract —The rabbit inferior vena cava (IVC) is a large-capacitance vessel that displays typical contractile dose-response curves for caffeine and phenylephrine (PE). Using confocal microscopy on the endothelium-denuded IVC, we undertook experiments to correlate these whole-tissue contractile dose-response curves with changes in subcellular [Ca 2+ ] i signals in the in situ vascular smooth muscle cells (VSMCs). We observed that both caffeine and PE initially elicited Ca 2+ waves in individual VSMCs. The [Ca 2+ ] i in cells challenged with caffeine subsequently returned to baseline whereas the [Ca 2+ ] i in cells challenged with PE exhibited repetitive asynchronous Ca 2+ waves. These [Ca 2+ ] i oscillations were related to Ca 2+ release from the sarcoplasmic reticulum as they were inhibited by ryanodine and caffeine. The lack of synchronicity of the [Ca 2+ ] i oscillations between VSMCs can explain the observed tonic contraction at the whole-tissue level. The nature of these Ca 2+ waves was further characterized. For caffeine, the amplitude was all-or-none in nature, with individual cells differing in sensitivity, leading to their recruitment at different concentrations of the agonist. This concentration dependency of recruitment appears to form the basis for the concentration dependency of caffeine-induced contraction. Furthermore, the speed of the Ca 2+ waves correlated positively with the concentration of caffeine. In the case of PE, we observed the same characteristics with respect to wave speed, amplitude, and recruitment. Increasing concentrations of PE also enhance the frequency of the [Ca 2+ ] i oscillations. We therefore conclude that PE stimulates whole-tissue contractility through differential recruitment of VSMCs and enhancement of the frequency of asynchronous [Ca 2+ ] i oscillations once the cells are recruited. The full text of this article is available at http://www.circresaha.org.
The Tumor Suppressive MicroRNA<i>miR-218</i>Targets the mTOR Component<i>Rictor</i>and Inhibits AKT Phosphorylation in Oral Cancer
Authors: Atsushi Uesugi, Ken-ichi Kozaki, Tomohiko Tsuruta, Mayuko Furuta, Kei-ichi Morita, Issei Imoto, Ken Omura, Johji Inazawa
Journal: Cancer Research (2011)

The incidence of oral squamous cell carcinoma (OSCC) is rising rapidly in developed countries, posing a growing challenge due to the poor management of this type of malignancy at present. In this study, we profiled tumor suppressive microRNAs (miRNAs) that are silenced by DNA hypermethylation in OSCC using a function-based screening approach. This approach employed a cell proliferation assay for 327 synthetic miRNAs in two OSCC cell lines. Among the 110 miRNAs identified in this set that exhibited inhibitory properties, we compared DNA methylation and expression status in a wider panel of OSCC cell lines and primary tumor tissues, resulting in the identification of miR-218 and miR-585 as functionally significant miRNA genes that are frequently silenced in OSCC by DNA hypermethylation. Ectopic expression of miR-218 and miR-585 in OSCC cells lacking endogenous expression reduced cell growth in part through caspase-mediated apoptosis. Notably, miR-218 reduced levels of the rapamycin-insensitive component of mTOR, Rictor, in a manner associated with a suppression of Akt S473 phosphorylation. Together our findings define miR-585 as a tumor suppressive function that is often epigenetically silenced in OSCC, and they identify Rictor as a novel target of miR-218, suggesting that activation of the mTOR-Akt signaling pathway induced by Rictor contributes centrally to oral carcinogenesis.
Plasma Levels of Tumor Necrosis Factor-α, Angiotensin II, Growth Hormone, and IGF-I Are Not Elevated in Insulin-Resistant Obese Individuals With Impaired Glucose Tolerance
Authors: Matthias Blüher, Juergen Kratzsch, Ralf Paschke
Journal: Diabetes Care (2001)

OBJECTIVE— To investigate the relationship between insulin resistance and plasma concentrations of free fatty acids (FFAs), leptin, and potential agonists of the insulin receptor substrate (IRS) system, including tumor necrosis factor-α (TNF-α), IGF-I, growth hormone (GH), and angiotensin II in individuals with impaired glucose tolerance (IGT). RESEARCH DESIGN AND METHODS— Because glucose toxicity per se leads to insulin resistance, the determination of the primary metabolic alterations leading to insulin resistance is best accomplished in individuals who are at an increased risk to develop type 2 diabetes. Therefore, 48 subjects with IGT and insulin resistance (IR), characterized by hyperinsulinemic-euglycemic clamps, were compared with 52 healthy insulin-sensitive (IS) control subjects with respect to the relationship between the plasma levels of TNF-α, IGF-I, GH, angiotensin II, FFA,leptin, and insulin resistance. RESULTS— Between the IR and the IS groups, there were no significant differences in the plasma concentrations of TNF-α, GH,angiotensin II, IGF-I, and leptin. However, plasma FFA levels were significantly elevated in the IR group compared with the IS group after matching for BMI. CONCLUSIONS— The plasma concentrations of FFA, but not TNF-α, IGF-I, GH, and angiotensin II, are elevated in patients at an early stage of insulin resistance, suggesting that FFAs, but not the other modulators of the IRS system, may be a primary metabolic abnormality leading to insulin resistance.
Dose-dense paclitaxel once a week in combination with carboplatin every 3 weeks for advanced ovarian cancer: a phase 3, open-label, randomised controlled trial
Authors: Noriyuki Katsumata, Makoto Yasuda, Fumiaki Takahashi, Seiji Isonishi, Toshiko Jobo, Daisuke Aoki, Hiroshi Tsuda, Toru Sugiyama, Shoji Kodama, Eizo Kimura, Kazunori Ochiai, Kiichiro Noda
Journal: The Lancet (2009)
THE RELATION OF THE RETICULO-ENDOTHELIAL SYSTEM TO THE FORMATION OF AMYLOID
Authors: H. Smetana
Journal: The Journal of Experimental Medicine (1927)

The facts presented suggest strongly that reticulo-endothelial cells are actively concerned in the formation of amyloid. Points in favor of this theory are as follows: 1. The appearance of amyloid in places where reticulo-endothelial cells are normally present, sometimes in very large number. 2. The formation of early amyloid in the small solitary patches, which suggests its local formation. 3. The occurrence of solitary patches of amyloid apparently located within the capillaries of the liver. 4. The manifold relations between reticulo-endothelial cells marked out by phagocytized ink granules, loose ink particles and amyloid, described in the text. 5. The impossibility of demonstrating reticulo-endothelial cells in areas of forming amyloid by intravenous injections of India ink. 6. The delayed appearance of amyloid in animals after blockage of the reticulo-endothelial cells by repeated intravenous injections of India ink.
Massive growth of yeasts in resected stomach
Authors: I. Borg, F. Heijkenskjold, B. Nilehn, L. Wehlin
Journal: Gut (1966)

EDITORIAL SYNOPSIS Three cases are reported in which gastric resection according to the Billroth I technique was later followed by symptoms of fullness after meals and vomiting.X-ray examination showed a bezoar-like mass with the radiopacity of soft tissue in the remnant of the stomach in each case.Gastric aspiration produced mucous material which on microscopic examination and culture was found to be swarming with yeasts.The authors discuss the frequency and clinical significance of the condition.
Successful treatment of cerebral vasculitis in an HIV-positive patient with anti-CD25 treatment
Authors: C M G Nieuwhof, J Damoiseaux, J W Cohen Tervaert
Journal: Annals of the Rheumatic Diseases (2006)

A 33-year-old HIV-seropositive man presented with recurrent oral candidiasis, weight loss, and lymphadenopathy.1 CD4 count was 73 cells/ml, and viral load was 296 000 copies/ml. Zidovudine, lamivudine and efavirenz were started, after which the patient showed an increase in CD4 count to 444 cells/ml. In the following weeks he developed progressive paresis of his left arm, left-sided facial weakness, bulbar dysarthia and dysphagia, which remitted when highly active antiretroviral therapy (HAART) was discontinued. However, his condition worsened again on resumption of HAART. Laboratory results showed a CD4 count of 441 cells/ml, a viral load of 105 copies/ml, a C reactive protein concentration of 18 mg/l and a sedimentation rate of 107 mm in the first hour. Serological tests for hepatitis B, hepatitis C and syphilis were negative, as were those for ANA, ANCA, rheumatoid factor and cryoglobulins. Complement (CH50) was …
Noninvasive diagnosis of ruptured peripheral atherosclerotic lesions and myocardial infarction by antibody profiling
Authors: Kitty B.J.M. Cleutjens, Birgit C.G. Faber, Mat Rousch, Ruben van Doorn, Tilman M. Hackeng, Cornelis Vink, Piet Geusens, Hugo ten Cate, Johannes Waltenberger, Vadim Tchaikovski, Marc Lobbes, Veerle Somers, Anneke Sijbers, Darcey Black, Peter J.E.H.M. Kitslaar, Mat J.A.P. Daemen
Journal: Journal of Clinical Investigation (2008)

Novel biomarkers, such as circulating (auto)antibody signatures, may improve early detection and treatment of ruptured atherosclerotic lesions and accompanying cardiovascular events, such as myocardial infarction. Using a phage-display library derived from cDNAs preferentially expressed in ruptured peripheral human atherosclerotic plaques, we performed serological antigen selection to isolate displayed cDNA products specifically interacting with antibodies in sera from patients with proven ruptured peripheral atherosclerotic lesions. Two cDNA products were subsequently evaluated on a validation series of patients with peripheral atherosclerotic lesions, healthy controls, and patients with coronary artery disease at different stages. Our biomarker set was able to discriminate between patients with peripheral ruptured lesions and patients with peripheral stable plaques with 100% specificity and 76% sensitivity. Furthermore, 93% of patients with an acute myocardial infarction (AMI) tested positive for our biomarkers, whereas all patients with stable angina pectoris tested negative. Moreover, 90% of AMI patients who initially tested negative for troponin T, for which a positive result is known to indicate myocardial infarction, tested positive for our biomarkers upon hospital admission. In conclusion, antibody profiling constitutes a promising approach for noninvasive diagnosis of atherosclerotic lesions, because a positive serum response against a set of 2 cDNA products showed a strong association with the presence of ruptured peripheral atherosclerotic lesions and myocardial infarction.
Apocynin-induced vasodilation involves Rho kinase inhibition but not NADPH oxidase inhibition
Authors: T. Schluter, A. C. Steinbach, A. Steffen, R. Rettig, O. Grisk
Journal: Cardiovascular Research (2008)

The present study was designed to test the hypothesis that NADPH oxidase inhibition with apocynin would lower blood pressure and improve endothelial function in spontaneously hypertensive rats (SHRs). Although apocyin effectively dilated arterial segments in vitro, it failed to lower blood pressure or improve endothelial function. Further experiments were performed in normotensive rats and in NADPH oxidase subunit knock-out mice to test if apocynin-induced vasodilation depends on NADPH oxidase inhibition at all.SHRs were treated with apocynin orally or i.v. Arterial pressure was recorded directly. Rat and mouse arterial function was investigated in vitro by small vessel wire myography. NADPH oxidase activity was measured in human granulocytes and in rat vascular preparations. Rho kinase activity was determined by Western blot analysis. Apocynin did not reduce arterial pressure acutely in SHR when given at 50, 100, or 150 mg kg(-1) day(-1) orally over 1-week intervals or when given i.v. Apocynin potently inhibited granulocyte NADPH oxidase but not vascular NADPH-oxidase-dependent oxygen radical formation unless exogenous peroxidase was added to vascular preparations. Apocynin dilated rat intrarenal and coronary arteries independently of pharmacological interventions that reduce vascular superoxide radical abundance and actions. Aortic rings from p47phox(-/-) mice were more sensitive to apocynin-induced dilation than wild-type aortic rings. Rho kinase inhibition reduced or prevented the inhibitory effect of apocynin on agonist-induced vasoconstriction and apocynin inhibited the phosphorylation of Rho kinase substrates.Apocynin per se does not inhibit vascular NADPH-oxidase-dependent superoxide formation. Its in vitro vasodilator actions are not due to NADPH oxidase inhibition but may be explained at least in part by inhibition of Rho kinase activity. The discrepancy between apocynin-induced vasodilation in vitro and the failure of apocynin to lower arterial pressure in SHR suggests opposing effects on arterial pressure-regulating systems in vivo. Its use as a pharmacological tool to investigate vascular NADPH oxidase should be discontinued.
Reply: Arousal Threshold in Obstructive Sleep Apnea
Authors: Danny J. Eckert, David P. White, Amy S. Jordan, Atul Malhotra, Andrew Wellman
Journal: American Journal of Respiratory and Critical Care Medicine (2014)

children with OSA have higher arousal thresholds to a number of respiratory stimuli (such as hypercapnia [2] and inspiratory resistance loading [3]), but not to nonrespiratory stimuli (4), compared with age-matched control subjects.The arousal threshold changes over the course of normal development, with children having a higher arousal threshold compared with adults (5).However, the study by Eckert and coworkers showing blunted respiratory arousal thresholds in adults with OSA suggests that deficits in arousal are a common pathogenic mechanism for OSA across the age spectrum.
Fragile X syndrome: causes, diagnosis, mechanisms, and therapeutics
Authors: Claudia Bagni, Flora Tassone, Giovanni Neri, Randi Hagerman
Journal: Journal of Clinical Investigation (2012)

Fragile X syndrome (FXS) is the most frequent form of inherited intellectual disability and is also linked to other neurologic and psychiatric disorders. FXS is caused by a triplet expansion that inhibits expression of the FMR1 gene; the gene product, FMRP, regulates mRNA metabolism in the brain and thus controls the expression of key molecules involved in receptor signaling and spine morphology. While there is no definitive cure for FXS, the understanding of FMRP function has paved the way for rational treatment designs that could potentially reverse many of the neurobiological changes observed in FXS. Additionally, behavioral, pharmacological, and cognitive interventions can raise the quality of life for both patients and their families.
Visual Image Reconstruction from Human Brain Activity using a Combination of Multiscale Local Image Decoders
Authors: Yoichi Miyawaki, Hajime Uchida, Okito Yamashita, Masa-aki Sato, Yusuke Morito, Hiroki C. Tanabe, Norihiro Sadato, Yukiyasu Kamitani
Journal: Neuron (2008)
Randomized Phase III Trial of Single-Agent Pemetrexed Versus Carboplatin and Pemetrexed in Patients With Advanced Non–Small-Cell Lung Cancer and Eastern Cooperative Oncology Group Performance Status of 2
Authors: Mauro Zukin, Carlos H. Barrios, Jose Rodrigues Pereira, Ronaldo De Albuquerque Ribeiro, Carlos Augusto de Mendonça Beato, Yeni Neron do Nascimento, Andre Murad, Fabio A. Franke, Maristela Precivale, Luiz Henrique de Lima Araujo, Clarissa Serodio Da Rocha Baldotto, Fernando Meton Vieira, Isabele A. Small, Carlos G. Ferreira, Rogerio C. Lilenbaum
Journal: Journal of Clinical Oncology (2013)

To compare single-agent pemetrexed (P) versus the combination of carboplatin and pemetrexed (CP) in first-line therapy for patients with advanced non-small-cell lung cancer (NSCLC) with an Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 2.In a multicenter phase III randomized trial, patients with advanced NSCLC, ECOG PS of 2, any histology at first and later amended to nonsquamous only, no prior chemotherapy, and adequate organ function were randomly assigned to P alone (500 mg/m(2)) or CP (area under the curve of 5 and 500 mg/m(2), respectively) administered every 3 weeks for a total of four cycles. The primary end point was overall survival (OS).A total of 205 eligible patients were enrolled from eight centers in Brazil and one in the United States from April 2008 to July 2011. The response rates were 10.3% for P and 23.8% for CP (P = .032). In the intent-to-treat population, the median PFS was 2.8 months for P and 5.8 months for CP (hazard ratio [HR], 0.46; 95% CI, 0.35 to 0.63; P < .001), and the median OS was 5.3 months for P and 9.3 months for CP (HR, 0.62; 95% CI, 0.46 to 0.83; P = .001). One-year survival rates were 21.9% and 40.1%, respectively. Similar results were seen when patients with squamous disease were excluded from the analysis. Anemia (grade 3, 3.9%; grade 4, 11.7%) and neutropenia (grade 3, 1%; grade 4, 6.8%) were more frequent with CP. There were four treatment-related deaths in the CP arm.Combination chemotherapy with CP significantly improves survival in patients with advanced NSCLC and ECOG PS of 2.
The Role of Protein Binding in Induction of Apoptosis by Phenethyl Isothiocyanate and Sulforaphane in Human Non–Small Lung Cancer Cells
Authors: Lixin Mi, Xiantao Wang, Sudha Govind, Brian L. Hood, Timothy D. Veenstra, Thomas P. Conrads, Daniel T. Saha, Radoslav Goldman, Fung-Lung Chung
Journal: Cancer Research (2007)

Abstract Induction of apoptosis underlies a mechanism for inhibiting tumorigenesis by phenethyl isothiocyanate (PEITC) and sulforaphane (SFN). However, the upstream events by which isothiocyanates (ITC) induce apoptosis have not been fully investigated. As electrophiles, ITCs could trigger apoptosis by binding to DNA or proteins or by inducing oxidative stress. To better understand the molecular mechanisms of apoptosis by ITCs, we examined, as a first step, the role of these events in human non–small lung cancer A549 cells. PEITC was a more potent inducer than SFN; it induced apoptosis at 20 μmol/L, whereas SFN induced at 40 μmol/L but not at 20 μmol/L. To study binding with cellular proteins and DNA, cells were treated with 14C-ITCs; the initial protein binding by PEITC was almost 3-fold than that of SFN. The binding by PEITC increased with time, whereas binding by SFN remained low. Therefore, 4 h after incubation proteins became the predominant targets for PEITC with a 6-fold binding than that of SFN. To characterize the chemical nature of binding by the ITCs, we used bovine serum albumin (BSA) as a surrogate protein. PEITC also modified BSA covalently to a greater extent than SFN occurring exclusively at cysteine residues. Surprisingly, neither PEITC nor SFN bound to DNA or RNA at detectable levels or caused significant DNA strand breakage. The levels of oxidative damage in cells, measured as reactive oxygen species, 8-oxo-deoxyguanosine, and protein carbonyls formation, were greater in cells treated with SFN than PEITC. Because PEITC is a stronger inducer of apoptosis than SFN, these results indicate that direct covalent binding to cellular proteins is an important early event in the induction of apoptosis by the ITCs. [Cancer Res 2007;67(13):6409–16]
Randomized Clinical Trial of Dialysate Cooling and Effects on Brain White Matter
Authors: Mohamed T. Eldehni, Aghogho Odudu, Christopher W. McIntyre
Journal: Journal of the American Society of Nephrology (2014)

Hemodialysis is associated with significant circulatory stress that could produce recurrent and cumulative ischemic insults to multiple organs, such as the brain. We aimed to characterize hemodialysis-induced brain injury by longitudinally studying the effects of hemodialysis on brain white matter microstructure and further examine if the use of cooled dialysate could provide protection against hemodialysis-associated brain injury. In total, 73 patients on incident hemodialysis starting within 6 months were randomized to dialyze with a dialysate temperature of either 37°C or 0.5°C below the core body temperature and followed up for 1 year. Brain white matter microstructure was studied by diffusion tensor magnetic resonance imaging at baseline and follow-up (38 patients available for paired analysis). Intradialytic hemodynamic stress was quantified using the extrema points analysis model. Patients on hemodialysis exhibited a pattern of ischemic brain injury (increased fractional anisotropy and reduced radial diffusivity). Cooled dialysate improved hemodynamic tolerability, and changes in brain white matter were associated with hemodynamic instability (higher mean arterial pressure extrema points frequencies were associated with higher fractional anisotropy [peak r=0.443, P<0.03] and lower radial diffusivity [peak r=−0.439, P<0.02]). Patients who dialyzed at 0.5°C below core body temperature exhibited complete protection against white matter changes at 1 year. Our data suggest that hemodialysis results in significant brain injury and that improvement in hemodynamic tolerability achieved by using cooled dialysate is effective at abrogating these effects. This intervention can be delivered without additional cost and is universally applicable.
Another brick in the wall: adrenomedullin and prognosis in community-acquired pneumonia
Authors: Stefan Krüger, Dirk Frechen
Journal: European Respiratory Journal (2012)

Community-acquired pneumonia (CAP) continues to be a major healthcare problem. The associated mortality of 14% in hospitalised patients is still high [1]. Established clinical scores, such as the Pneumonia Severity Index (PSI) and CRB-65 score (confusion, respiratory frequency ≥30 breaths·min−1, systolic blood pressure <90 mmHg or diastolic blood pressure ≤60 mmHg, and age ≥65 yrs) are used for the determination of mortality risk. Since CAP is an infectious disease, we traditionally use biomarkers of infection for diagnostic and prognostic purposes. Inflammatory markers such as white blood cell (WBC) count and C-reactive protein (CRP) are still widely used in the management of CAP, although it is well known that their value for the diagnosis of clinically relevant bacterial infection and prediction of death and complications in CAP is limited. With respect to better diagnosis and guidance of antibiotic therapy, procalcitonin (PCT) is much better, with a broad spectrum of interventional studies in the field of lower respiratory tract infections [2]. However, PCT is not the ideal biomarker for prognosis in CAP, where cardiovascular biomarkers show better predictive value [3–5].

In the current issue of the European Respiratory Journal , Bello et al. [6] adds another brick to the multifaceted wall of prognostic assessment in CAP. The authors performed a prospective study in immunocompetent CAP patients and evaluated whether the prognostic role of pro-adrenomedullin (proADM) depends on different aetiologies of CAP. They compared …