tbuckley/cabot-search huggingface dataset:
Gain-of-function mutation in the KCNMB1 potassium channel subunit is associated with low prevalence of diastolic hypertension
Authors: José M. Fernández-Fernández, Marta Tomás, Esther Vázquez, Patricio Orio, Ramón Latorre, Mariano Sentí, Jaume Marrugat, Miguel A. Valverde
Journal: Journal of Clinical Investigation (2004)

Hypertension is the most prevalent risk factor for cardiovascular diseases, present in almost 30% of adults. A key element in the control of vascular tone is the large-conductance, Ca(2+)-dependent K(+) (BK) channel. The BK channel in vascular smooth muscle is formed by an ion-conducting alpha subunit and a regulatory beta(1) subunit, which couples local increases in intracellular Ca(2+) to augmented channel activity and vascular relaxation. Our large population-based genetic epidemiological study has identified a new single-nucleotide substitution (G352A) in the beta(1) gene (KCNMB1), corresponding to an E65K mutation in the protein. This mutation results in a gain of function of the channel and is associated with low prevalence of moderate and severe diastolic hypertension. BK-beta(1E65K) channels showed increased Ca(2+) sensitivity, compared with wild-type channels, without changes in channel kinetics. In conclusion, the BK-beta(1E65K) channel might offer a more efficient negative-feedback effect on vascular smooth muscle contractility, consistent with a protective effect of the K allele against the severity of diastolic hypertension.
DYNAMICS OF MULTINUCLEATE GIANT CELL FORMATION, IN VIVO AND IN VITRO
Authors: Martin M. Black
Journal: British Journal of Dermatology (1974)

Journal Article DYNAMICS OF MULTINUCLEATE GIANT CELL FORMATION, IN VIVO AND IN VITRO Get access Martin M. Black Martin M. Black Department of Histopathology, Institute of Dermatology, London W.C.2 Search for other works by this author on: Oxford Academic Google Scholar British Journal of Dermatology, Volume 91, Issue 6, 1 December 1974, Pages 705–709, https://doi.org/10.1111/j.1365-2133.1974.tb12459.x Published: 01 December 1974
Increase in Brain Tumor Permeability in Glioma-Bearing Rats with Nitric Oxide Donors
Authors: Dali Yin, Xiao Wang, Bindu M. Konda, John M. Ong, Jinwei Hu, Manuel R. Sacapano, MinHee K. Ko, Andres J. Espinoza, Dwain K. Irvin, Yan Shu, Keith L. Black
Journal: Clinical Cancer Research (2008)

Abstract Purpose: The blood-brain tumor barrier (BTB) significantly limits the delivery of chemotherapeutics to brain tumors. Nitric oxide (NO) is involved in the regulation of cerebral vascular permeability. We investigated the effects of NO donors, l-arginine and hydroxyurea, on BTB permeability in 9L gliosarcoma-bearing Fischer rats. Experimental Design: The rats implanted with 9L gliosarcoma were dosed orally with hydroxyurea and l-arginine. BTB permeability, defined by the unidirectional transport constant, Ki, for [14C]sucrose was measured. The expression of neural and endothelial NO synthase (NOS) in tumors and normal brain tissue was examined. Further, the levels of NO, l-citrulline, and cGMP in the tumor and normal brain tissue were measured. Results: Oral administration of l-arginine or hydroxyurea significantly increased BTB permeability when compared with the nontreated control. The selective effects were abolished by iberiotoxin, an antagonist of calcium-dependent potassium (KCa) channel that is a cGMP pathway effector. The expression of endothelial NOS, but not neural NOS, was higher in tumor vessels than in those of normal brain. Moreover, the levels of NO, l-citrulline, a byproduct of NO formation from l-arginine, and cGMP were enhanced in the tumor tissue by oral administration of l-arginine and/or hydroxyurea. Conclusions: Oral administration of l-arginine or hydroxyurea selectively increased tumor permeability, which is likely mediated by alteration in cGMP levels. The findings suggest that use of oral NO donors may be a strategy to enhance the delivery of chemotherapeutics to malignant brain tumors.
Epidermal Growth Factor Receptor Inhibitors in Neuro-oncology: Hopes and Disappointments
Authors: Alba A. Brandes, Enrico Franceschi, Alicia Tosoni, Monika E. Hegi, Roger Stupp
Journal: Clinical Cancer Research (2008)

Despite advances in diagnosis and treatment made over the past two decades, high-grade gliomas are still incurable neoplasms. Moreover, after failing adjuvant therapy, few active treatments are available. In this setting, novel agents, such as new chemotherapy compounds and anticancer agents against specific molecular targets, have therefore been investigated. Epidermal growth factor receptor (EGFR) is an intriguing target in high-grade gliomas because it is frequently overexpressed due to amplification of the EGFR gene. Gefitinib and erlotinib act as ATP mimetic agents, binding to the cytoplasmic ATP pocket domain and blocking receptor phosphorylations and, thereby, EGFR-mediated activation of downstream pathways. These drugs have been evaluated in several clinical trials treating recurrent high-grade gliomas with contrasting results. Retrospective correlative analyses generated a plethora of putative predictive factors of activity of EGFR tyrosine kinase inhibitors. The first generations of studies on EGFR inhibitors have not found significant activity of these agents in high-grade gliomas. Furthermore, no clear molecular or clinical predictors have been identified. As with other targeted agents, prospective trials using specific criteria and standardized methods to evaluate tissue biomarkers are required to find predictors of EGFR inhibitors activity in high-grade glioma patients.
The European Community Study Group on diagnostic criteria for Sjogren's syndrome. Sensitivity and specificity of tests for ocular and oral involvement in Sjogren's syndrome.
Authors: C Vitali, H M Moutsopoulos, S Bombardieri
Journal: Annals of the Rheumatic Diseases (1994)

To establish a definitive set of diagnostic criteria in a multicentre European study a selected number of oral and ocular tests were performed on a large number of patients with Sjögrens Syndrome (SS) and controls. The diagnostic accuracy of each test for patients with primary and secondary SS and for controls at different ages, was studied.Each centre received a clinical chart describing the series of tests to be conducted. The tests included: questionnaires for dry eye and dry mouth symptoms, Schirmer's-I-test (ScT), tear fluid lactoferrin level (TFLL), break-up time (BUT) and rose Bengal score (RBS) for the eye evaluation; unstimulated and stimulated whole saliva collection (UWSC and SWSC), salivary gland scintigraphy (SGS), parotid sialography (PS) and minor salivary gland biopsy (MSGB) for oral involvement.Data from 22 centres and 11 countries was collected on a total of 447 patients with SS (246 with primary SS and 201 with secondary SS) and 246 controls (of whom 113 had a connective tissue disease without SS). Among the ocular symptoms, the feeling of dry eye and 'sand in the eye' were the ones most commonly recorded in patients with SS. Similarly, the feeling of dry mouth, appearing either spontaneously or when the patient was eating or breathing, was the most frequent subjective oral symptom. Among the ocular tests, ScT showed the best balance between sensitivity and specificity (76.9% and 72.4% respectively), while RBS was the most specific test (81.7%). ScT and RBS gave also sufficiently concordant results. TFLL and BUT gave considerably less reliable results, which were not concordant with each other or with the other ocular tests. The quantitative lacrimal tests ScT and TFLL produced significantly different results in elderly controls, while RBS did not. Abnormal results for all of the ocular tests were less marked and less frequent in patients with secondary SS than in those with primary SS. The oral tests (except SWSC) were generally more reliable than the ocular tests in diagnosing SS. In particular, PS was the most specific diagnostic tools (100%), while MSGB (where the presence of at least one inflammatory focus was considered as indicative for the diagnosis) showed a good balance between sensitivity and specificity (82.4% and 86.2%, respectively). The tests showed a good degree of agreement, and, with the exception of UWSC, were not influenced by age. In the oral, as in the ocular tests, abnormal results were less frequent and less marked in patients with secondary SS.The results clearly show that ScT and RBS (for the eye evaluation), and SGS, PS, MSGB and UWSC (for salivary gland involvement) are the most reliable tests for the diagnosis of SS. The clinician should be aware, however, that the test results may vary depending on the age of the patient and the type of SS (primary or secondary).
Hemodynamic Effects of a Pressor Amine (Methoxamine) with Predominant Vasoconstrictor Activity
Authors: WILLIAM R. BREWSTER, PATRICIA F. OSGOOD, JAMES P. ISAACS, LEON I. GOLDBERG, Raymond T. W Chock
Journal: Circulation Research (1960)

A pressor amine (methoxamine) which produces peripheral vasoconstriction, while lacking a significant, direct, positive inotropic effect upon ventricular heart muscle, has been shown to produce hemodynamic effects that are in distinct contrast to those resulting from the injection or infusion of l -epinephrine and l -norepinephrine in "physiologic" concentrations or of mephentermine sulfate. The latter 3 amines, possessing a positive inotropic action in addition to varying vasoconstrictor effects, decrease right and left atrial mean pressures while increasing femoral and pulmonary arterial pulse and mean pressures, right and left ventricular stroke works and the cardiac index. Methoxamine injection or infusion, in contrast, resulted in linear increases in the calculated total peripheral resistance and left and right atrial mean pressures. There was a simultaneous rise in right and left ventricular stroke works which were maintained until a maximum rise in the mean arterial pressure was reached. The average stroke volume indices were maintained at near control values in both blocked and unblocked animals. The cardiac index of the normal unblocked dogs decreased in proportion to the decrease in heart rate. Following the peak pressor response to methoxamine, a progressive fall in mean femoral arterial pressure occurred resulting from ventricular failure rather than "tachyphylaxis" to the vasoconstrictor activity of methoxamine. This decrease in systemic arterial pressure was accompanied by: (1) a further rise in calculated total peripheral resistance and in right and left atrial mean pressures, and (2) a fall in right and left ventricular stroke work and stroke volume indices and in the cardiac indices.
Acquired bullous diseases of childhood: re-evaluation of diagnosis by indirect immunofluorescence examination on 1 M NaCl split skin and immunoblotting
Authors: G. KIRTSCHIG, F. WOJNAROWSKA, R.A. MARSDEN, S. EDWARDS, B. BHOGAL, M.M. BLACK
Journal: British Journal of Dermatology (1994)

Journal Article Acquired bullous diseases of childhood: re‐evaluation of diagnosis by indirect immunofluorescence examination on 1 M NaCl split skin and immunoblotting Get access G. KIRTSCHIG, G. KIRTSCHIG Department of Dermatology, University Hospital Marburg, Germany Dr G. Kirtschig, National Cancer Institute, Dermatology Branch, Building 10, Room 12N238, Bethesda, MD 20892, U.S.A. Search for other works by this author on: Oxford Academic Google Scholar F. WOJNAROWSKA, F. WOJNAROWSKA The Churchill Hospital, Oxford, U.K. Search for other works by this author on: Oxford Academic Google Scholar R.A. MARSDEN, R.A. MARSDEN St George's Hospital, Oxford, UK. Search for other works by this author on: Oxford Academic Google Scholar S. EDWARDS, S. EDWARDS Amersham General Hospital, Amersham, U.K. Search for other works by this author on: Oxford Academic Google Scholar B. BHOGAL, B. BHOGAL St John's Institute of Dermatology, London, U.K. Search for other works by this author on: Oxford Academic Google Scholar M.M. BLACK M.M. BLACK St John's Institute of Dermatology, London, U.K. Search for other works by this author on: Oxford Academic Google Scholar British Journal of Dermatology, Volume 130, Issue 5, 1 May 1994, Pages 610–616, https://doi.org/10.1111/j.1365-2133.1994.tb13108.x Published: 01 May 1994 Article history Accepted: 08 September 1993 Published: 01 May 1994
High rate of sustained virological response after a 48 weeks course of interferon (IFN) plus ribavirin in chronic hepatitis C relapsers. Results of a randomised trial
Authors: D. Ouzan, F. Longo, C. Renou, E. Baldini, E. Marine-Barjoan, C. Gueyffier, P. Delasalle, C. Cadot, X. Moreau, G. Dreyfus, D. Bianchi, P. Amoros, S. Benzaken, A. Mousnier, P. Halfon, P. Rampal, A. Tran
Journal: Journal of Hepatology (2002)
Use of a targeted oncolytic poxvirus, JX-594, in patients with refractory primary or metastatic liver cancer: a phase I trial
Authors: Byeong-Ho Park, Taeho Hwang, Ta-Chiang Liu, Daniel Y Sze, Jae-Seok Kim, Hyuk-Chan Kwon, Sung Yong Oh, Sang-Young Han, Jin-Han Yoon, Sook-Hee Hong, Anne Moon, Kelly Speth, Chohee Park, Young-Joo Ahn, Manijeh Daneshmand, Byung Geon Rhee, Herbert M Pinedo, John C Bell, David H Kirn
Journal: The Lancet Oncology (2008)
BLOOD DESTRUCTION DURING EXERCISE
Authors: G. O. Broun
Journal: The Journal of Experimental Medicine (1923)

A definite increase in the percentage of reticulocytes occurs after exercise in animals previously kept to a sedentary life. Concomitant changes in the hemoglobin percentage, plasma-cell ratio, and red count offer evidence in addition to that already reported by the author of the occurrence of an increase in blood destruction under such circumstances. Replacement by transfusion of blood destroyed during exercise prevents the reticulated cell reaction. Animals rendered plethoric and then exercised show no increase in reticulated cells while the plethora persists. The fact is emphasized that exercise must be an important factor in the maintenance of an efficient hematopoietic tissue.
Biological and immunological aspects of malignant mesothelioma
Authors: MJ Garlepp, CC Leong
Journal: European Respiratory Journal (1995)

Malignant mesothelioma (MM) is an aggressive tumour, which is strongly associated with previous asbestos exposure and is resistant to all conventional anticancer therapies. An understanding of the biological properties of MM may provide insights into useful therapeutic strategies, and MM cell lines and animal models have been major contributors to our current knowledge of this tumour. Although karyotypic abnormalities are frequent, there is no clear evidence of a mesothelioma-specific chromosomal aberration. Similarly, there is no evidence of activation or over-expression of a known oncogene, or of the inactivation of currently identified tumour suppressor genes. A number of growth factors, including platelet derived growth factors A and B (PDGF-A and -B), insulin-like growth factor I and transforming growth factor-beta (TGF-beta), and some of their receptors, have been reported to be expressed by MM cells, and each has the potential to play a role as a growth stimulant for MM or to modify immune responses to the tumour. Some data support an autocrine role for PDGF-A. MM cell lines are susceptible to lysis by a variety of immune effector cells, and their growth can often be inhibited by cytokines. The possibility of stimulating an immune response to MM by genetic manipulation of the tumour cells has been investigated using a murine model. The data so far suggest that transfection of allogeneic class I major histocompatibility complex genes or syngeneic class II genes alone is unlikely to induce protective immunity.(ABSTRACT TRUNCATED AT 250 WORDS)
<i>In vivo</i> reflectance confocal microscopy of shave biopsy wounds: feasibility of intraoperative mapping of cancer margins
Authors: A. Scope, U. Mahmood, D.S. Gareau, M. Kenkre, J.A. Lieb, K.S. Nehal, M. Rajadhyaksha
Journal: British Journal of Dermatology (2010)

Reflectance confocal microscopy (RCM) images skin at cellular resolution and has shown utility for the diagnosis of nonmelanoma skin cancer in vivo. Topical application of aluminium chloride (AlCl(3)) enhances contrast in RCM images by brightening nuclei.To investigate feasibility of RCM imaging of shave biopsy wounds using AlCl(3) as a contrast agent.AlCl(3) staining was optimized, in terms of concentration vs. immersion time, on excised tissue ex vivo. RCM imaging protocol was tested in patients undergoing shave biopsies. The RCM images were retrospectively analysed and compared with the corresponding histopathology.For 35% AlCl(3) , routinely used for haemostasis in clinic, minimum immersion time was determined to be 1 min. We identified three consistent patterns of margins on RCM mosaic images by varying depth: epidermal margins, peripheral dermal margins, and deep dermal margins. Tumour islands of basal cell carcinoma were identified at peripheral or deep dermal margins, correlating on histopathology with aggregates of neoplastic basaloid cells. Atypical cobblestone or honeycomb patterns were identified at the epidermal margins in squamous cell carcinomas, correlating with a proliferation of atypical keratinocytes extending to biopsy margins.RCM imaging of shave biopsy wounds is feasible and demonstrates the future possibility of intraoperative mapping in surgical wounds.
On the Expansion of the Pentatricopeptide Repeat Gene Family in Plants
Authors: N. O'Toole, M. Hattori, C. Andres, K. Iida, C. Lurin, C. Schmitz-Linneweber, M. Sugita, I. Small
Journal: Molecular Biology and Evolution (2008)

Pentatricopeptide repeat (PPR) proteins form a huge family in plants (450 members in Arabidopsis and 477 in rice) defined by tandem repetitions of characteristic sequence motifs. Some of these proteins have been shown to play a role in posttranscriptional processes within organelles, and they are thought to be sequence-specific RNA-binding proteins. The origins of this family are obscure as they are lacking from almost all prokaryotes, and the spectacular expansion of the family in land plants is equally enigmatic. In this study, we investigate the growth of the family in plants by undertaking a genome-wide identification and comparison of the PPR genes of 3 organisms: the flowering plants Arabidopsis thaliana and Oryza sativa and the moss Physcomitrella patens. A large majority of the PPR genes in each of the flowering plants are intron less. In contrast, most of the 103 PPR genes in Physcomitrella are intron rich. A phylogenetic comparison of the PPR genes in all 3 species shows similarities between the intron-rich PPR genes in Physcomitrella and the few intron-rich PPR genes in higher plants. Intron-poor PPR genes in all 3 species also display a bias toward a position of their introns at their 5′ ends. These results provide compelling evidence that one or more waves of retrotransposition were responsible for the expansion of the PPR gene family in flowering plants. The differing numbers of PPR proteins are highly correlated with differences in organellar RNA editing between the 3 species.
Potent Systemic Anticancer Activity of Adenovirally Expressed EGFR-Selective TRAIL Fusion Protein
Authors: Edwin Bremer, Gooitzen M van Dam, Marco de Bruyn, Manon van Riezen, Marike Dijkstra, Gera Kamps, Wijnand Helfrich, Hidde Haisma
Journal: Molecular Therapy (2008)

Previously, we demonstrated potent tumor cell-selective pro-apoptotic activity of scFv425:sTRAIL, a recombinant fusion protein comprised of EGFR-directed antibody fragment (scFv425) genetically fused to human soluble TNF-related apoptosis-inducing ligand (sTRAIL). Here, we report on the promising therapeutic systemic tumoricidal activity of scFv425:sTRAIL when produced by the replication-deficient adenovirus Ad-scFv425:sTRAIL. In vitro treatment of EGFR-positive tumor cells with Ad-scFv425:sTRAIL resulted in the potent induction of apoptosis of not only infected tumor cells, but importantly also of up to 60% of noninfected EGFR-positive tumor cells. A single intraocular injection of Ad-scFv425:sTRAIL in tumor-free nu/nu mice resulted in predominant liver infection and concomitant high blood plasma levels of scFv425:sTRAIL. These mice showed no sign of Ad-scFv425:sTRAIL-related liver toxicity. Identical treatment of mice with established intraperitoneal renal cell carcinoma xenografts resulted in rapid and massive tumor load reduction and subsequent long-term survival. Taken together, adenoviral-mediated in vivo production of scFv425:sTRAIL may be exploitable for systemic treatment of EGFR-positive cancer.
Human keratinocytes are a source for tumor necrosis factor alpha: evidence for synthesis and release upon stimulation with endotoxin or ultraviolet light.
Authors: A Köck, T Schwarz, R Kirnbauer, A Urbanski, P Perry, J C Ansel, T A Luger
Journal: The Journal of Experimental Medicine (1990)

Tumor necrosis factor alpha (TNF-alpha), in addition to being cytotoxic for certain tumor cells, has turned out as a multifunctional cytokine that is involved in the regulation of immunity and inflammation. Since human keratinocytes have been demonstrated to be a potent source of various cytokines, it was investigated whether epidermal cells synthesize and release TNF-alpha. Supernatants derived from normal human keratinocytes (HNK) and human epidermoid carcinoma cell lines (KB, A431) were tested both in a TNF-alpha-specific ELISA and a bioassay. In supernatants of untreated epidermal cells, no or minimal TNF-alpha activity was found, while after stimulation with lipopolysaccharide (LPS) or ultraviolet (UV) light, significant amounts were detected. Western blot analysis using an antibody directed against human TNF-alpha revealed a molecular mass of 17 kD for keratinocyte-derived TNF-alpha. These biological and biochemical data were also confirmed by Northern blot analysis revealing mRNA specific for TNF-alpha in LPS- or ultraviolet B (UVB)-treated HNK and KB cells. In addition, increased TNF-alpha levels were detected in the serum obtained from human volunteers 12 and 24 h after a single total body UVB exposure, which caused a severe sunburn reaction. These findings indicate that keratinocytes upon stimulation are able to synthesize and release TNF-alpha, which may gain access to the circulation. Thus, TNF-alpha in concert with other epidermal cell-derived cytokines may mediate local and systemic inflammatory reactions during host defense against injurious events caused by microbial agents or UV irradiation.
Targeting the Cytoplasmic and Nuclear Functions of Signal Transducers and Activators of Transcription 3 for Cancer Therapy
Authors: Doris Germain, David A. Frank
Journal: Clinical Cancer Research (2007)

Abstract Signal transducers and activators of transcription (STAT) are a highly conserved family of transcription factors that are activated by phosphorylation in the cytoplasm, after which they translocate to the nucleus to regulate gene expression. Among the seven STATs, STAT3 is of particular interest due to its constitutive phosphorylation in a large proportion of human cancers and its ability to induce neoplastic transformation. Inhibition of STAT3 can reverse tumor growth in experimental systems while having few effects in normal cells. These findings have implicated STAT3 as a potentially important target for therapeutic intervention. In addition to its well-described role as a transcription factor, STAT3 has been found recently to have important effects in the cytoplasm. Collectively, these functions of STAT3 directly contribute to tumorigenesis, invasion, and metastasis. Given the potential importance of STAT3 as a target for cancer therapy, molecules have been developed that can block STAT3 function at a variety of steps. These drugs show promise as anticancer agents in model systems of a variety of common human cancers. Thus, elucidating the functions of STAT3 and developing agents to inhibit this protein remain important scientific and clinical challenges.
ADAMTS13 activity in thrombotic thrombocytopenic purpura–hemolytic uremic syndrome: relation to presenting features and clinical outcomes in a prospective cohort of 142 patients
Authors: Sara K. Vesely, James N. George, Bernhard Lämmle, Jan-Dirk Studt, Lorenzo Alberio, Mayez A. El-Harake, Gary E. Raskob
Journal: Blood (2003)