tbuckley/cabot-search huggingface dataset:
Randomized Trial of Plasma Exchange or High-Dosage Methylprednisolone as Adjunctive Therapy for Severe Renal Vasculitis
Authors: David R.W. Jayne, Gill Gaskin, Niels Rasmussen, Daniel Abramowicz, Franco Ferrario, Loic Guillevin, Eduardo Mirapeix, Caroline O.S. Savage, Renato A. Sinico, Coen A. Stegeman, Kerstin W. Westman, Fokko J. van der Woude, Robert A.F. de Lind van Wijngaarden, Charles D. Pusey
Journal: Journal of the American Society of Nephrology (2007)

Systemic vasculitis associated with autoantibodies to neutrophil cytoplasmic antigens (ANCA) is the most frequent cause of rapidly progressive glomerulonephritis. Renal failure at presentation carries an increased risk for ESRD and death despite immunosuppressive therapy. This study investigated whether the addition of plasma exchange was more effective than intravenous methylprednisolone in the achievement of renal recovery in those who presented with a serum creatinine >500 micromol/L (5.8 mg/dl). A total of 137 patients with a new diagnosis of ANCA-associated systemic vasculitis confirmed by renal biopsy and serum creatinine >500 micromol/L (5.8 mg/dl) were randomly assigned to receive seven plasma exchanges (n = 70) or 3000 mg of intravenous methylprednisolone (n = 67). Both groups received oral cyclophosphamide and oral prednisolone. The primary end point was dialysis independence at 3 mo. Secondary end points included renal and patient survival at 1 yr and severe adverse event rates. At 3 mo, 33 (49%) of 67 after intravenous methylprednisolone compared with 48 (69%) or 70 after plasma exchange were alive and independent of dialysis (95% confidence interval for the difference 18 to 35%; P = 0.02). As compared with intravenous methylprednisolone, plasma exchange was associated with a reduction in risk for progression to ESRD of 24% (95% confidence interval 6.1 to 41%), from 43 to 19%, at 12 mo. Patient survival and severe adverse event rates at 1 yr were 51 (76%) of 67 and 32 of 67 (48%) in the intravenous methylprednisolone group and 51 (73%) of 70 and 35 of (50%) 70 in the plasma exchange group, respectively. Plasma exchange increased the rate of renal recovery in ANCA-associated systemic vasculitis that presented with renal failure when compared with intravenous methylprednisolone. Patient survival and severe adverse event rates were similar in both groups.
Identification of Gastric Cancer–Related Genes Using a cDNA Microarray Containing Novel Expressed Sequence Tags Expressed in Gastric Cancer Cells
Authors: Jeong-Min Kim, Ho-Yong Sohn, Sun Young Yoon, Jung-Hwa Oh, Jin Ok Yang, Joo Heon Kim, Kyu Sang Song, Seung-Moo Rho, Hyan Sook Yoo, Yong Sung Kim, Jong-Guk Kim, Nam-Soon Kim
Journal: Clinical Cancer Research (2005)

Abstract Purpose: Gastric cancer is one of the most frequently diagnosed malignancies in the world, especially in Korea and Japan. To understand the molecular mechanism associated with gastric carcinogenesis, we attempted to identify novel gastric cancer–related genes using a novel 2K cDNA microarray. Experimental Design: A 2K cDNA microarray was fabricated from 1,995 novel expressed sequence tags (ESTs) showing no hits or a low homology with ESTs in public databases from our 143,452 ESTs collected from gastric cancer cell lines and tissues. An analysis of the gene expression for human gastric cancer cell lines to a normal cell line was done using this cDNA microarray. Data for the different expressed genes were verified using semiquantitative reverse transcription-PCR, Western blotting, and immunohistochemical staining in the gastric cell lines and tissues. Results: Forty genes were identified as either up-regulated or down-regulated genes in human gastric cancer cells. Among these, genes such as SKB1, NT5C3, ZNF9, p30, CDC20, and FEN1, were confirmed to be up-regulated genes in nine gastric cell lines and in 25 pairs of tissue samples from patients by semiquantitative reverse transcription-PCR. On the other hand, genes such as MT2A and CXX1 were identified as down-regulated genes. In particular, the SKB1, CDC20, and FEN1 genes were overexpressed in ≥68% of tissues and the MT2A gene was down-expressed in 72% of the tissues. Western blotting and immunohistochemical analyses for CDC20 and SKB1 showed overexpression and localization changes of the corresponding protein in human gastric cancer tissues. Conclusions: Novel genes that are related to human gastric cancer were identified using cDNA microarray developed in our laboratory. In particular, CDC20 and MT2A represent a potential biomarker of human gastric cancer. These newly identified genes should provide a valuable resource for understanding the molecular mechanism associated with tumorigenesis of gastric carcinogenesis and for the discovery of potential diagnostic markers of gastric cancer.
BRCA1 Phosphorylation Regulates Caspase-3 Activation in UV-Induced Apoptosis
Authors: Sarah A. Martin, Toru Ouchi
Journal: Cancer Research (2005)

Abstract Apoptosis is implemented by death machinery that involves the caspase family of proteins, under the condition of a variety of stresses. Previous studies have shown that mouse embryonic stem cells deficient for caspase-3 are resistant to UV-induced apoptosis and that the active form of caspase-3 translocates to the nucleus. It has also been shown that the breast cancer tumor suppressor, BRCA1, is phosphorylated on Ser1423 and Ser1524 by the ataxia telangiectasia mutated–related kinase (ATR) after UV damage. Here, we show that activation of caspase-3 by UV is abrogated in BRCA1-mutated SNU251 and HCC1937 cells but was restored by reexpressing wild-type (wt) BRCA1, but not phosphorylation-deficient BRCA1Ser1423Ala/Ser1524Ala (BRCA1S1423/1524A). In SNU251 cells expressing BRCA1S1423/1524A, the inhibitory interaction between X-linked inhibitor of apoptosis protein (XIAP) and caspase-9 remains intact after UV, compared with cells expressing wt BRCA1. We determined that XIAP and BRCA1 interact and upon phosphorylation this complex is disrupted. Nuclear translocation of active caspase-3 is detected only when wt BRCA1 is reexpressed. Consistent with this, Rad21, a known substrate of caspase-3, is cleaved only when wt BRCA1 is expressed in vivo. These results propose a model that inhibition of BRCA1 phosphorylation leads to the abrogation of a specific form of apoptosis that is mediated by caspase-3.
Inhibition of the mTORC Pathway in the Antiphospholipid Syndrome
Authors: Guillaume Canaud, Frank Bienaimé, Fanny Tabarin, Guillaume Bataillon, Danielle Seilhean, Laure-Hélène Noël, Marie-Agnès Dragon-Durey, Renaud Snanoudj, Gérard Friedlander, Lise Halbwachs-Mecarelli, Christophe Legendre, Fabiola Terzi
Journal: New England Journal of Medicine (2014)

Although thrombosis is considered the cardinal feature of the antiphospholipid syndrome, chronic vascular lesions are common, particularly in patients with life-threatening complications. In patients who require transplantation, vascular lesions often recur. The molecular pathways involved in the vasculopathy of the antiphospholipid syndrome are unknown, and adequate therapies are lacking.We used double immunostaining to evaluate pathway activation in the mammalian target of rapamycin complex (mTORC) and the nature of cell proliferation in the vessels of patients with primary or secondary antiphospholipid syndrome nephropathy. We also evaluated autopsy specimens from persons who had catastrophic antiphospholipid syndrome. The molecular pathways through which antiphospholipid antibodies modulate the mTORC pathway were evaluated in vitro, and potential pharmacologic inhibitors were also tested in vitro. Finally, we studied the effect of sirolimus in kidney-transplant recipients with the antiphospholipid syndrome.The vascular endothelium of proliferating intrarenal vessels from patients with antiphospholipid syndrome nephropathy showed indications of activation of the mTORC pathway. In cultured vascular endothelial cells, IgG antibodies from patients with the antiphospholipid syndrome stimulated mTORC through the phosphatidylinositol 3-kinase (PI3K)-AKT pathway. Patients with antiphospholipid syndrome nephropathy who required transplantation and were receiving sirolimus had no recurrence of vascular lesions and had decreased vascular proliferation on biopsy as compared with patients with antiphospholipid antibodies who were not receiving sirolimus. Among 10 patients treated with sirolimus, 7 (70%) had a functioning renal allograft 144 months after transplantation versus 3 of 27 untreated patients (11%). Activation of mTORC was also found in the vessels of autopsy specimens from patients with catastrophic antiphospholipid syndrome.Our results suggest that the mTORC pathway is involved in the vascular lesions associated with the antiphospholipid syndrome. (Funded by INSERM and others.).
LASP1 Is a HIF1α Target Gene Critical for Metastasis of Pancreatic Cancer
Authors: Tiansuo Zhao, He Ren, Jing Li, Jing Chen, Huan Zhang, Wen Xin, Yan Sun, Lei Sun, Yongwei Yang, Junwei Sun, Xiuchao Wang, Song Gao, Chongbiao Huang, Huafeng Zhang, Shengyu Yang, Jihui Hao
Journal: Cancer Research (2014)

LASP1 is an actin-binding protein associated with actin assembly dynamics in cancer cells. Here, we report that LASP1 is overexpressed in pancreatic ductal adenocarcinoma (PDAC) where it promotes invasion and metastasis. We found that LASP1 overexpression in PDAC cells was mediated by HIF1α through direct binding to a hypoxia response element in the LASP1 promoter. HIF1α stimulated LASP1 expression in PDAC cells in vitro and mouse tumor xenografts in vivo. Clinically, LASP1 overexpression in PDAC patient specimens was associated significantly with lymph node metastasis and overall survival. Overall, our results defined LASP1 as a direct target gene for HIF1α upregulation that is critical for metastatic progression of PDAC.
INFECTIOUS VIRUS-ANTIBODY COMPLEX IN THE BLOOD OF CHRONICALLY INFECTED MICE
Authors: Abner Louis Notkins, Suellen Mahar, Christina Scheele, Joel Goffman
Journal: The Journal of Experimental Medicine (1966)

If viremic sera from mice chronically infected with lactic dehydrogenase virus (LDV) were first treated with ether or ultraviolet light to inactivate the infectious virus, neutralizing antibody could be demonstrated. Significant amounts of antibody, however, were not detected until the mice had been infected for about 2(1/2) months and its presence did not result in the elimination of the chronic viremia. Virus isolated from sera containing neutralizing antibody was found to be relatively resistant to neutralization by anti-LDV. Further studies revealed that the resistant virus existed in the form of an infectious virus-antibody complex (sensitized virus). The presence of such a complex was demonstrated by the fact that the virus fraction which persisted after in vivo or in vitro exposure to mouse anti-LDV was readily neutralized by goat anti-mouse sera or goat anti-mouse gamma-globulin, whereas virus that had not been previously exposed to mouse anti-LDV was completely resistant to neutralization by goat anti-mouse sera. These findings suggest that (a) sensitization may play an important role in the resistance and susceptibility of a virus to neutralization by antiviral antibody, and (b) an anti-gamma-globulin may prove useful in neutralizing the resistant fraction and in demonstrating otherwise undetectable antiviral antibody.
Structured Writing and Processing Major Stressful Events: A Controlled Trial
Authors: Mirjam J.A. Schoutrop, Alfred Lange, Gerrit Hanewald, Udi Davidovich, Henriëtte Salomon
Journal: Psychotherapy and Psychosomatics (2002)

&lt;i&gt;Background:&lt;/i&gt; Traumatic events may result in a variety of physical and psychological health problems. Self-confrontation with traumatic memories, by putting painful emotions and thoughts into (verbal) words, is associated with psychophysiological benefits. Self-confrontation may be invoked during sessions and enhanced by structural assignments, which the client carries out between the sessions. In this context, writing assignments could be a useful tool in reprocessing traumatic events. The effects of writing assignments have been demonstrated in several case studies and in a number of experimental studies. However, the experimental studies have several limitations, for example the effects of writing on the impact of trauma are not examined. Furthermore, the psychological mechanisms that mediate the effects of trauma on health are less clear. These two issues are the main issues of the current study. &lt;i&gt;Methods:&lt;/i&gt; A group of 26 participants were instructed to write about their negative events during five 45-min sessions over a period of 2 weeks. They were compared at pre-treatment, post-treatment and at 6-week follow-up to a waiting-list control group (n = 22). &lt;i&gt;Results:&lt;/i&gt; The trauma-writing groups experienced fewer intrusions and showed less avoidance behavior from pre-treatment to follow-up, whereas the waiting-list control group did not change significantly. Similar results were found on depressive symptoms. No effects on mood measures were found. &lt;i&gt;Conclusions:&lt;/i&gt; Implications for future research and clinical practice are discussed.
A dose-escalation and pharmacokinetic study of gemcitabine and oxaliplatin in patients with advanced solid tumors
Authors: D. Mavroudis, P. Pappas, C. Kouroussis, S. Kakolyris, S. Agelaki, K. Kalbakis, N. Androulakis, J. Souglakos, N. Vardakis, M. Nikolaidou, G. Samonis, M. Marselos, V. Georgoulias
Journal: Annals of Oncology (2003)
Complementary DNA cloning and expression in Escherichia coli of Aln g I, the major allergen in pollen of alder (Alnus glutinosa)
Authors: Heimo Breiteneder, Fatima Ferreira, Arnold Reikerstorfer, Michael Duchene, Rudolf Valenta, Karin Hoffman-Sommergruber, Christof Ebner, Michael Breitenbach, Dietrich Kraft, Otto Scheiner
Journal: Journal of Allergy and Clinical Immunology (1992)
Emergence of New <i>ALK</i> Mutations at Relapse of Neuroblastoma
Authors: Gudrun Schleiermacher, Niloufar Javanmardi, Virginie Bernard, Quentin Leroy, Julie Cappo, Thomas Rio Frio, Gaelle Pierron, Eve Lapouble, Valérie Combaret, Frank Speleman, Bram de Wilde, Anna Djos, Ingrid Øra, Fredrik Hedborg, Catarina Träger, Britt-Marie Holmqvist, Jonas Abrahamsson, Michel Peuchmaur, Jean Michon, Isabelle Janoueix-Lerosey, Per Kogner, Olivier Delattre, Tommy Martinsson
Journal: Journal of Clinical Oncology (2014)

Purpose In neuroblastoma, the ALK receptor tyrosine kinase is activated by point mutations. We investigated the potential role of ALK mutations in neuroblastoma clonal evolution. Methods We analyzed ALK mutations in 54 paired diagnosis–relapse neuroblastoma samples using Sanger sequencing. When an ALK mutation was observed in one paired sample, a minor mutated component in the other sample was searched for by more than 100,000× deep sequencing of the relevant hotspot, with a sensitivity of 0.17%. Results All nine ALK-mutated cases at diagnosis demonstrated the same mutation at relapse, in one case in only one of several relapse nodules. In five additional cases, the mutation seemed to be relapse specific, four of which were investigated by deep sequencing. In two cases, no mutation evidence was observed at diagnosis. In one case, the mutation was present at a subclonal level (0.798%) at diagnosis, whereas in another case, two different mutations resulting in identical amino acid changes were detected, one only at diagnosis and the other only at relapse. Further evidence of clonal evolution of ALK-mutated cells was provided by establishment of a fully ALK-mutated cell line from a primary sample with an ALK-mutated cell population at subclonal level (6.6%). Conclusion In neuroblastoma, subclonal ALK mutations can be present at diagnosis with subsequent clonal expansion at relapse. Given the potential of ALK-targeted therapy, the significant spatiotemporal variation of ALK mutations is of utmost importance, highlighting the potential of deep sequencing for detection of subclonal mutations with a sensitivity 100-fold that of Sanger sequencing and the importance of serial samplings for therapeutic decisions.
Cardiovascular Dynamics of Vasovagal Reactions in Man
Authors: MURRAY A. GREENE, ADOLPH J. BOLTAX, ROBERT J. ULBERG
Journal: Circulation Research (1961)

The dynamics of vasovagal reactions which occurred in 2 patients during right heart catheterization were studied. Both subjects initially had systemic hypertension with corresponding increases in peripheral resistances. Subject B had considerably decreased blood flow, moderately elevated pulmonary artery and right ventricular end-diastolic pressures, and elevated central blood volume. These parameters were normal in subject A. The characteristic features of the reactions were appreciable declines in cardiac outputs coincident with decreased systemic arterial systolic, diastolic, and pulse pressures, decreased heart rates, and slight increases in calculated peripheral resistances. Stroke volumes were moderately reduced. A slight decrease in pulmonary artery systolic pressure occurred in subject A. In subject B, pulmonary artery and right ventricular enddiastolic pressures declined to normal and central blood volume decreased moderately. The return of heart rate to control values had no significant effects on the other physiologic parameters. The data demonstrate that reductions in cardiac output, due primarily to decreased stroke outputs, were predominantly responsible for the arterial hypotensions during the vasovagal reactions in these 2 subjects. The ineffectiveness of atropine in restoring hemodynamics in one subject suggested the importance of inhibition of efferent sympathetic activity in the etiology of this reaction. The failure of peripheral resistance to compensate for decreased blood flow suggested inhibition of arteriolar tone.
Novel TRPM6 Mutations in 21 Families with Primary Hypomagnesemia and Secondary Hypocalcemia
Authors: Karl P. Schlingmann, Martin C. Sassen, Stefanie Weber, Ulla Pechmann, Kerstin Kusch, Lutz Pelken, Daniel Lotan, Maria Syrrou, Jeffrey J. Prebble, David E.C. Cole, Daniel L. Metzger, Shamima Rahman, Toshihiro Tajima, San-Ging Shu, Siegfried Waldegger, Hannsjoerg W. Seyberth, Martin Konrad
Journal: Journal of the American Society of Nephrology (2005)

Primary hypomagnesemia with secondary hypocalcemia is a rare autosomal recessive disorder characterized by profound hypomagnesemia associated with hypocalcemia. Pathophysiology is related to impaired intestinal absorption of magnesium accompanied by renal magnesium wasting as a result of a reabsorption defect in the distal convoluted tubule. Recently, mutations in the TRPM6 gene coding for TRPM6, a member of the transient receptor potential (TRP) family of cation channels, were identified as the underlying genetic defect. Here, the results of a TRPM6 mutational analysis of 21 families with 28 affected individuals are presented. In this large patient cohort, a retrospective clinical evaluation based on a standardized questionnaire was also performed. Genotype analysis revealed TRPM6 mutations in 37 of 42 expected mutant alleles. Sixteen new TRPM6 mutations were identified, including stop mutations, frame-shift mutations, splice-site mutations, and deletions of exons. Electrophysiologic analysis of mutated ion channels after heterologous expression in Xenopus oocytes proved complete loss of function of TRPM6. Clinical evaluation revealed a homogeneous clinical picture at manifestation with onset in early infancy with generalized cerebral convulsions. Initial laboratory evaluation yielded extremely low serum magnesium levels, low serum calcium levels, and inadequately low parathyroid hormone levels. Treatment usually consisted of acute intravenous magnesium supplementation leading to relief of clinical symptoms and normocalcemia, followed by lifelong oral magnesium supplementation. Serum magnesium levels remained in the subnormal range despite adequate therapy. This is best explained by a disturbed magnesium conservation in the distal convoluted tubule, which emerged in all patients upon magnesium supplementation. Delay of diagnosis resulted in permanent neurologic damage in three patients.
Caveolae and caveolin in transmembrane signaling: Implications for human disease
Authors: C SCHWENCKE, R BRAUNDULLAEUS, C WUNDERLICH, R STRASSER
Journal: Cardiovascular Research (2006)

The identification of various signaling molecules found within caveolae and their functional interaction with the integral membrane protein caveolin, a major structural component of caveolae, suggests that these membrane microdomains participate in transmembrane signaling. Several lines of evidence indicate that caveolin may act as a scaffolding protein by direct interaction with and modulation of the activity of multiple signaling molecules. The compartmentation of various signaling molecules in caveolae and their direct and functional interaction with caveolin provides a paradigm by which these membrane microdomains are involved in regulating signal transduction pathways. By dysregulation of these signal transduction pathways caveolins may be involved in the pathogenesis of various diseases. This review focuses on the implications as well as controversies of the contribution of caveolae and caveolins for several human diseases and the potential implications to therapeutic strategies.
Nonsteroidal Anti-inflammatory Drugs as Anticancer Agents: Mechanistic, Pharmacologic, and Clinical Issues
Authors: M. J. Thun, S. J. Henley, C. Patrono
Journal: JNCI Journal of the National Cancer Institute (2002)

Numerous experimental, epidemiologic, and clinical studies suggest that nonsteroidal anti-inflammatory drugs (NSAIDs), particularly the highly selective cyclooxygenase (COX)-2 inhibitors, have promise as anticancer agents. NSAIDs restore normal apoptosis in human adenomatous colorectal polyps and in various cancer cell lines that have lost adenomatous polyposis coli gene function. NSAIDs also inhibit angiogenesis in cell culture and rodent models of angiogenesis. Many epidemiologic studies have found that long-term use of NSAIDs is associated with a lower risk of colorectal cancer, adenomatous polyps, and, to some extent, other cancers. Two NSAIDs, sulindac and celecoxib, have been found to inhibit the growth of adenomatous polyps and cause regression of existing polyps in randomized trials of patients with familial adenomatous polyposis (FAP). However, unresolved questions about the safety, efficacy, optimal treatment regimen, and mechanism of action of NSAIDs currently limit their clinical application to the prevention of polyposis in FAP patients. Moreover, the development of safe and effective drugs for chemoprevention is complicated by the potential of even rare, serious toxicity to offset the benefit of treatment, particularly when the drug is administered to healthy people who have low annual risk of developing the disease for which treatment is intended. This review considers generic approaches to improve the balance between benefits and risks associated with the use of NSAIDs in chemoprevention. We critically examine the published experimental, clinical, and epidemiologic literature on NSAIDs and cancer, especially that regarding colorectal cancer, and identify strategies to overcome the various logistic and scientific barriers that impede clinical trials of NSAIDs for cancer prevention. Finally, we suggest research opportunities that may help to accelerate the future clinical application of NSAIDs for cancer prevention or treatment.
Deaths from peptic ulceration.
Authors: T V Taylor
Journal: BMJ (1985)

Deaths due to peptic ulceration can be prevented only by curing the ulcer and preventing the ulcer diathesis permanently by either medical or surgical means. Recurrence of ulcers after drug treatment is a major problem, so continuous treatment is often necessary, but there is no evidence that this decreases mortality. Surgery is the only means of permanently removing the ulcer diathesis in most patients, and subsequent mortality is low. A reasonable balance has to be achieved between the two kinds of treatment to prevent most deaths from peptic ulcer.