tbuckley/cabot-search huggingface dataset:
Selective splenic artery embolization for the treatment of thrombocytopenia and hypersplenism in paroxysmal nocturnal hemoglobinuria
Authors: David J Araten, Anna Paola Iori, Karen Brown, Giovanni Fernando Torelli, Walter Barberi, Fiammetta Natalino, Maria Stefania De Propris, Corrado Girmenia, Filippo Maria Salvatori, Orly Zelig, Robin Foà, Lucio Luzzatto
Journal: Journal of Hematology & Oncology (2014)

PNH is associated with abdominal vein thrombosis, which can cause splenomegaly and hypersplenism. The combination of thrombosis, splenomegaly, and thrombocytopenia (TST) is challenging because anticoagulants are indicated but thrombocytopenia may increase the bleeding risk. Splenectomy could alleviate thrombocytopenia and reduce portal pressure, but it can cause post-operative thromboses and opportunistic infections. We therefore sought to determine whether selective splenic artery embolization (SSAE) is a safe and effective alternative to splenectomy for TST in patients with PNH. Four patients with PNH and TST received successive rounds of SSAE. By targeting distal vessels for occlusion, we aimed to infarct approximately 1/3 of the spleen with each procedure. Three of 4 patients had an improvement in their platelet count, and 3 of 3 had major improvement in abdominal pain/discomfort. The one patient whose platelet count did not respond had developed marrow failure, and she did well with an allo-SCT. Post-procedure pain and fever were common and manageable; only one patient developed a loculated pleural effusion requiring drainage. One patient, who had had only a partial response to eculizumab, responded to SSAE not only with an improved platelet count, but also with an increase in hemoglobin level and decreased transfusion requirement. These data indicate that SSAE can decrease spleen size and reverse hypersplenism, without exposing the patient to the complications of splenectomy. In addition, SSAE probably reduces the uptake of opsonised red cells in patients who have had a limited response to eculizumab, resulting in an improved quality of life for selected patients.
Mutually exclusive redox forms of HMGB1 promote cell recruitment or proinflammatory cytokine release
Authors: Emilie Venereau, Maura Casalgrandi, Milena Schiraldi, Daniel J. Antoine, Angela Cattaneo, Francesco De Marchis, Jaron Liu, Antonella Antonelli, Alessandro Preti, Lorenzo Raeli, Sara Samadi Shams, Huan Yang, Luca Varani, Ulf Andersson, Kevin J. Tracey, Angela Bachi, Mariagrazia Uguccioni, Marco E. Bianchi
Journal: The Journal of Experimental Medicine (2012)

Tissue damage causes inflammation, by recruiting leukocytes and activating them to release proinflammatory mediators. We show that high-mobility group box 1 protein (HMGB1) orchestrates both processes by switching among mutually exclusive redox states. Reduced cysteines make HMGB1 a chemoattractant, whereas a disulfide bond makes it a proinflammatory cytokine and further cysteine oxidation to sulfonates by reactive oxygen species abrogates both activities. We show that leukocyte recruitment and activation can be separated. A nonoxidizable HMGB1 mutant in which serines replace all cysteines (3S-HMGB1) does not promote cytokine production, but is more effective than wild-type HMGB1 in recruiting leukocytes in vivo. BoxA, a HMGB1 inhibitor, interferes with leukocyte recruitment but not with activation. We detected the different redox forms of HMGB1 ex vivo within injured muscle. HMGB1 is completely reduced at first and disulfide-bonded later. Thus, HMGB1 orchestrates both key events in sterile inflammation, leukocyte recruitment and their induction to secrete inflammatory cytokines, by adopting mutually exclusive redox states.
Turnover and splanchnic metabolism of free fatty acids in hyperthyroid patients.
Authors: L Hagenfeldt, A Wennlung, P Felig, J Wahren
Journal: Journal of Clinical Investigation (1981)

The arterial concentration and turnover rate and the splanchnic exchange of FFA were examined after an overnight fast in a group of 11 female patients with clinical and laboratory evidence of hyperthyroidism. [14C]oleic acid was infused intravenously and the hepatic venous catheter technique was used. As compared with healthy control individuals, the arterial concentrations of FFA and oleic acid were elevated by 30--40% in the hyperthyroid group. Both the turnover rate and the fractional turnover of oleic acid were significantly increased. The turnover rate correlated directly with arterial concentration of oleic acid in both the control and the patient group but the slope was steeper in the patients. The splanchnic uptake of oleic acid was three times higher than in the control group. The augmented uptake was a consequence of elevated arterial concentrations and increased hepatic plasma flow, whereas fractional splanchnic uptake remained unchanged. Ketone body production was four- to fivefold greater in the patients and could be largely accounted for by increased splanchnic FFA uptake. In six patients studied after treatment resulting in a return to normal thyroid function, a significant reduction was observed in arterial FFA, estimated hepatic blood flow, oleic acid turnover, and ketone body production. It is concluded that hyperthyroidism is characterized by increased turnover and splanchnic uptake of FFA and augmented ketogenesis. These findings can be explained on the basis of elevated arterial FFA concentrations and increased blood flow, particularly to the splanchnic bed.
Increased mucosal tumour necrosis factor alpha production in Crohn's disease can be downregulated ex vivo by probiotic bacteria
Authors: N Borruel
Journal: Gut (2002)

Tumour necrosis factor alpha (TNF-alpha) plays a key role in the pathogenesis of intestinal inflammation in Crohn's disease. The effect of bacteria on TNF-alpha release by intestinal mucosa was investigated.Ileal specimens were obtained at surgery from 10 patients with Crohn's disease (ileal stricture) and five disease controls undergoing right hemicolectomy (caecal cancer). Mucosal explants from each specimen were cultured for 24 hours with either non-pathogenic Escherichia coli, Lactobacillus casei DN-114001, L bulgaricus LB10, or L crispatus (each study contained blank wells with no bacteria). Tissue and bacterial viability was confirmed by lactate dehydrogenase (LDH) release and culture. Concentrations of TNF-alpha were measured in supernatants and the phenotype of the intestinal lymphocytes was analysed by flow cytometry.Coculture of mucosa with bacteria did not modify LDH release. Release of TNF-alpha by inflamed Crohn's disease mucosa was significantly reduced by coculture with L casei or L bulgaricus; changes induced by L crispatus or E coli were not significant. The effect of L casei and L bulgaricus was not prevented by protease inhibitors. Coculture with L casei and L bulgaricus reduced the number of CD4 cells as well as TNF-alpha expression among intraepithelial lymphocytes from Crohn's disease mucosa. None of the bacteria induced changes in non-inflamed mucosa.Probiotics interact with immunocompetent cells using the mucosal interface and modulate locally the production of proinflammatory cytokines.
Defective TGF-β Signaling in Bone Marrow–Derived Cells Prevents Hedgehog-Induced Skin Tumors
Authors: Qipeng Fan, Dongsheng Gu, Hailan Liu, Ling Yang, Xiaoli Zhang, Mervin C. Yoder, Mark H. Kaplan, Jingwu Xie
Journal: Cancer Research (2013)

Hedgehog signaling in cancer cells drives changes in the tumor microenvironment that are incompletely understood. Here, we report that hedgehog-driven tumors exhibit an increase in myeloid-derived suppressor cells (MDSC) and a decrease in T cells, indicative of an immunosuppressive tumor microenvironment. This change was associated with activated TGF-β signaling in several cell types in basal cell carcinomas. We determined that TGF-β signaling in bone marrow-derived cells, not keratinocytes, regulates MDSC and promotes tumor development. Tgfbr2 deficiency in the bone marrow-derived cells also reduced the size of previously developed tumors in mice. We identified CCL2 as the major chemokine attracting MDSCs to tumor, whose expression was Tgfbr2-dependent, whereas its receptor CCR2 was highly expressed in MDSC population. CCL2 alone was sufficient to induce migration of MDSCs. Moreover, the CCR2 inhibitors prevented MDSC migration toward skin cells in vitro, and reduced MDSC accumulation and hedgehog signaling-driven tumor development in mice. Our results reveal a signaling network critical for hedgehog signaling in cancer cells to establish an effective immunosuppressive microenvironment during tumor development.
Serum antibodies to distinct epitopes of the tissue‐type plasminogen activator (t‐PA) in patients with systemic lupus erythematosus
Authors: Alejandro Ruiz‐Arguelles, Eduardo Angles‐Cano, Beatriz Perez‐Romano, Guillermo J. Ruiz‐Arguelles, Margarita Deleze, Donato Alarcon‐Segovia, Pascale Gaussem
Journal: American Journal of Hematology (1995)

Abstract Defective fibrinolysis due to decreased tissue‐type plasminogen activator (t‐PA) activity is a well‐established finding in patients with systemic lupus erythematosus (SLE). The possibility that this decrease in t‐PA activity may be related to the presence of autoantibodies directed against t‐PA, and the possible role of these autoantibodies in the patho‐physiology of fibrinolysis in SLE, were investigated. Serum samples from 115 SLE patients and 63 normal volunteers were analyzed for the presence of such antibodies. The search for antibodies to t‐PA was performed by means of several systems, allowing for the identification of epitopes presented in different conformational physical states of t‐PA: free or associated to its inhibitor (PAI‐1) in plasma, specifically bound to fibrin surface, or passively adsorbed to solid supports. Antibodies in variable amounts were detected by all systems used; however, t‐PA activity was not inhibited by the IgG fraction of the positive sera in a fibrin‐agar fibrinolysis system. Moreover, the demonstration of serum anti‐t‐PA antibodies was not associated with clinical or laboratory abnormalities related to vasoocclusive episodes. These results indicate that, as in the case of other autoantibodies, their detection in serum does not imply their direct participation in the pathophysiology of thrombosis in SLE. © 1995 Wiley‐Liss, Inc.
Effectiveness of Gene Expression Profiling for Response Prediction of Rectal Adenocarcinomas to Preoperative Chemoradiotherapy
Authors: B. Michael Ghadimi, Marian Grade, Michael J. Difilippantonio, Sudhir Varma, Richard Simon, Cristina Montagna, Laszlo Füzesi, Claus Langer, Heinz Becker, Torsten Liersch, Thomas Ried
Journal: Journal of Clinical Oncology (2005)

There is a wide spectrum of tumor responsiveness of rectal adenocarcinomas to preoperative chemoradiotherapy ranging from complete response to complete resistance. This study aimed to investigate whether parallel gene expression profiling of the primary tumor can contribute to stratification of patients into groups of responders or nonresponders.Pretherapeutic biopsies from 30 locally advanced rectal carcinomas were analyzed for gene expression signatures using microarrays. All patients were participants of a phase III clinical trial (CAO/ARO/AIO-94, German Rectal Cancer Trial) and were randomized to receive a preoperative combined-modality therapy including fluorouracil and radiation. Class comparison was used to identify a set of genes that were differentially expressed between responders and nonresponders as measured by T level downsizing and histopathologic tumor regression grading.In an initial set of 23 patients, responders and nonresponders showed significantly different expression levels for 54 genes (P < .001). The ability to predict response to therapy using gene expression profiles was rigorously evaluated using leave-one-out cross-validation. Tumor behavior was correctly predicted in 83% of patients (P = .02). Sensitivity (correct prediction of response) was 78%, and specificity (correct prediction of nonresponse) was 86%, with a positive and negative predictive value of 78% and 86%, respectively.Our results suggest that pretherapeutic gene expression profiling may assist in response prediction of rectal adenocarcinomas to preoperative chemoradiotherapy. The implementation of gene expression profiles for treatment stratification and clinical management of cancer patients requires validation in large, independent studies, which are now warranted.
Neurofascin as a novel target for autoantibody-mediated axonal injury
Authors: Emily K. Mathey, Tobias Derfuss, Maria K. Storch, Kieran R. Williams, Kimberly Hales, David R. Woolley, Abdulmonem Al-Hayani, Stephen N. Davies, Matthew N. Rasband, Tomas Olsson, Anja Moldenhauer, Sviataslau Velhin, Reinhard Hohlfeld, Edgar Meinl, Christopher Linington
Journal: The Journal of Experimental Medicine (2007)

Axonal injury is considered the major cause of disability in patients with multiple sclerosis (MS), but the underlying effector mechanisms are poorly understood. Starting with a proteomics-based approach, we identified neurofascin-specific autoantibodies in patients with MS. These autoantibodies recognize the native form of the extracellular domains of both neurofascin 186 (NF186), a neuronal protein concentrated in myelinated fibers at nodes of Ranvier, and NF155, the oligodendrocyte-specific isoform of neurofascin. Our in vitro studies with hippocampal slice cultures indicate that neurofascin antibodies inhibit axonal conduction in a complement-dependent manner. To evaluate whether circulating antineurofascin antibodies mediate a pathogenic effect in vivo, we cotransferred these antibodies with myelin oligodendrocyte glycoprotein–specific encephalitogenic T cells to mimic the inflammatory pathology of MS and breach the blood–brain barrier. In this animal model, antibodies to neurofascin selectively targeted nodes of Ranvier, resulting in deposition of complement, axonal injury, and disease exacerbation. Collectively, these results identify a novel mechanism of immune-mediated axonal injury that can contribute to axonal pathology in MS.
Endocrinology (Surgery of the Endocrines)
Authors: James D. Hardy
Journal: Annual Review of Medicine (1959)

assignment. The endocrine response to surgery has been included. The review is confined to publications in English. Rather than merely to acknowledge briefly  contents of a series of disconnected articles, we have charted a rather deliberate course through  field of surgical endocrinology, taking due note of  publi­ cat ions encountered along  way. The objective has been to provide both a balanced discussion and an effective survey of  pertinent recent litera­ ture. In view of both space and subject limitations, some rather arbitrary re­ strictions have had to be imposed. The following topics will be considered: (a)  endocrine response to major surgery; (b) hypophysectomy for ad­ vanced cancer; (c)  thyroid; (d)  parathyroids; (e )  thymus; (f)  pancreas (limited to diseases of  islets of Langerhans) ; (g)  adrenal cortex; (h)  adrenal medulla; and (z) the ovary and testis.
Expression of the APC gene after transfection into a colonic cancer cell line.
Authors: R Hargest, R Williamson
Journal: Gut (1995)

Mutations in the adenomatous polyposis coli (APC) gene cause the hereditary cancer syndrome familial adenomatous polyposis and are implicated in the early stages of sporadic colorectal carcinogenesis. APC is therefore a promising candidate for use in prophylactic gene therapy of intestinal tissues at high risk of becoming malignant. The aim of the study was to discover if functional full length APC gene can be introduced into somatic gut epithelial cells and to define the optimum conditions for such transfer. Copies of the normal APC gene were introduced into SW480 cells, a colonic epithelial cell line with an APC gene mutation, using plasmid DNA combined with liposomes. Reverse transcriptase polymerase chain reaction and restriction enzyme digestion allowed the endogenous gene to be distinguished from the transgene. It was shown that the normal APC gene is expressed at high levels for 72 hours after transfection and disappears within one week. This study shows that short-term expression of normal APC gene can be achieved after transfection with liposome-DNA complexes at sufficiently high levels to permit assessment of biological effects.
Increased NADH-Oxidase–Mediated Superoxide Production in the Early Stages of Atherosclerosis
Authors: Ascan Warnholtz, Georg Nickenig, Eberhard Schulz, Roland Macharzina, Jan Hinrich Bräsen, Mikhail Skatchkov, Thomas Heitzer, Johannes P. Stasch, Kathy K. Griendling, David G. Harrison, Michael Böhm, Thomas Meinertz, Thomas Münzel
Journal: Circulation (1999)

Background —Angiotensin II activates NAD(P)H-dependent oxidases via AT 1 -receptor stimulation, the most important vascular source of superoxide (O 2 · − ). The AT 1 receptor is upregulated in vitro by low-density lipoprotein. The present study was designed to test whether hypercholesterolemia is associated with increased NAD(P)H-dependent vascular O 2 · − production and whether AT 1 -receptor blockade may inhibit this oxidase and in parallel improve endothelial dysfunction. Methods and Results —Vascular responses were determined by isometric tension studies, and relative rates of vascular O 2 · − production were determined by use of chemiluminescence with lucigenin, a cypridina luciferin analogue, and electron spin resonance studies. AT 1 -receptor mRNA was quantified by Northern analysis, and AT 1 -receptor density was measured by radioligand binding assays. Hypercholesterolemia was associated with impaired endothelium-dependent vasodilation and increased O 2 · − production in intact vessels. In vessel homogenates, we found a significant activation of NADH-driven O 2 · − production in both models of hyperlipidemia. Treatment of cholesterol-fed animals with the AT 1 -receptor antagonist Bay 10-6734 improved endothelial dysfunction, normalized vascular O 2 · − and NADH-oxidase activity, decreased macrophage infiltration, and reduced early plaque formation. In the setting of hypercholesterolemia, the aortic AT 1 receptor mRNA was upregulated to 166±11%, accompanied by a comparable increase in AT 1 -receptor density. Conclusions —Hypercholesterolemia is associated with AT 1 -receptor upregulation, endothelial dysfunction, and increased NADH-dependent vascular O 2 · − production. The improvement of endothelial dysfunction, inhibition of the oxidase, and reduction of early plaque formation by an AT 1 -receptor antagonist suggests a crucial role of angiotensin II–mediated O 2 · − production in the early stage of atherosclerosis.
The Spectrum of Epidemiology Underlying Sudden Cardiac Death
Authors: Meiso Hayashi, Wataru Shimizu, Christine M. Albert
Journal: Circulation Research (2015)

Sudden cardiac death (SCD) from cardiac arrest is a major international public health problem accounting for an estimated 15%-20% of all deaths. Although resuscitation rates are generally improving throughout the world, the majority of individuals who experience a sudden cardiac arrest will not survive. SCD most often develops in older adults with acquired structural heart disease, but it also rarely occurs in the young, where it is more commonly because of inherited disorders. Coronary heart disease is known to be the most common pathology underlying SCD, followed by cardiomyopathies, inherited arrhythmia syndromes, and valvular heart disease. During the past 3 decades, declines in SCD rates have not been as steep as for other causes of coronary heart disease deaths, and there is a growing fraction of SCDs not due to coronary heart disease and ventricular arrhythmias, particularly among certain subsets of the population. The growing heterogeneity of the pathologies and mechanisms underlying SCD present major challenges for SCD prevention, which are magnified further by a frequent lack of recognition of the underlying cardiac condition before death. Multifaceted preventative approaches, which address risk factors in seemingly low-risk and known high-risk populations, will be required to decrease the burden of SCD. In this Compendium, we review the wide-ranging spectrum of epidemiology underlying SCD within both the general population and in high-risk subsets with established cardiac disease placing an emphasis on recent global trends, remaining uncertainties, and potential targeted preventive strategies.
Incidence of cardiovascular disease and cancer in advanced age: prospective cohort study
Authors: J. A Driver, L. Djousse, G. Logroscino, J M. Gaziano, T. Kurth
Journal: BMJ (2008)

<b>Objective</b> To investigate the influence of increasing age on the incidence and remaining lifetime risk of cardiovascular disease and cancer in a cohort of older men. <b>Design</b> Prospective cohort study. <b>Setting</b> United States. <b>Participants</b> 22 048 male doctors aged 40-84 who were free of major disease in 1982. <b>Main outcome measures</b> Incidence and remaining lifetime risk of major cardiovascular disease (myocardial infarction, stroke, and death from cardiovascular disease) and cancer. <b>Results</b> 3252 major cardiovascular events and 5400 incident cancers were confirmed over 23 years of follow-up. The incidence of major cardiovascular disease continued to increase to age 100. Beginning at age 80, however, major cardiovascular disease was more likely to be diagnosed at death. The incidence of cancer peaked in those aged 80-89 and then declined. Cancers detected by screening accounted for most of the decline, whereas most cancers for which there was no screening continued to increase to age 100. Unadjusted cumulative incidence overestimated the risk of cardiovascular disease by 16% and cancer by 8.5%. The remaining lifetime risk of cancer at age 40 was 45.1% (95% confidence interval 43.8% to 46.3%) and at age 90 was 9.6% (7.2% to 11.9%). The remaining lifetime risk of major cardiovascular disease at age 40 was 34.8% (33.1% to 36.5%) and at age 90 was 16.7% (12.9% to 20.6%). <b>Conclusions</b> In this prospective cohort of men, the incidence of new cardiovascular disease continued to increase after age 80 but was most often diagnosed at death. The decrease in incidence of cancer late in life seemed largely due to a decline in cancers usually detected by screening. These findings suggest that people aged 80 and older have a substantial amount of undiagnosed disease. The remaining lifetime risk of both diseases approached a plateau in the 10th decade. This may be due to decreased detection of disease and reporting of symptoms and increased resistance to disease in those who survive to old age. Accurate estimates of disease risk in an aging population require adjustment for competing risks of mortality.