tbuckley/cabot-search huggingface dataset:
Serum Glomerular Permeability Activity in Patients with Podocin Mutations (NPHS2) and Steroid-ResistantNephrotic Syndrome
Authors: Michele Carraro, Gianluca Caridi, Maurizio Bruschi, Mary Artero, Roberta Bertelli, Cristina Zennaro, Luca Musante, Giovanni Candiano, Francesco Perfumo, Gian Marco Ghiggeri
Journal: Journal of the American Society of Nephrology (2002)

ABSTRACT. A plasma factor displaying permeability activity in vitro and possibly determining proteinuria has been hypothesized in idiopathic focal segmental glomerulosclerosis (FSGS). In vitro permeability activity (Palb) was determined in sera of five patients with autosomal recessive steroid-resistant nephrotic syndrome (NPHS2), an inherited condition indistinguishable from idiopathic FSGS on clinical grounds, but in which proteinuria is determined by homozygous mutations of podocin, a key component of the glomerular podocyte. All patients had presented intractable proteinuria with nephrotic syndrome; four developed renal failure and received a renal allograft. For comparison, sera from 31 children with nephrotic syndrome were tested. Pretransplant Palb was high in all cases (mean 0.81 ± 0.06), equivalent to levels observed in idiopathic FSGS. Overall, Palb did not correlate with proteinuria. The posttransplant outcome was complicated in two patients by recurrence of proteinuria after 10 and 300 d, respectively, that responded to plasmapheresis plus cyclophosphamide. Palb levels were high at the time of the recurrence episodes and steadily decreased after plasmapheresis, to reach normal levels in the absence of proteinuria after the seventh cycle. In an attempt to explain high Palb in these patients, putative inhibitors of the permeability activity were studied. Coincubation of serum with homologous nephrotic urine reduced Palb to 0, whereas normal urine did not determine any change, which suggests loss of inhibitory substances in nephrotic urine. The urinary levels of the serum Palb inhibitors apo J and apo E were negligible in all cases, thus suggesting that other urinary inhibitors were responsible for the neutralizing effect. These data indicate that Palb is high in NPHS2, probably resulting from loss of inhibitors in urine. Lack of correlation of Palb with proteinuria suggests a selective loss of inhibitors. As in idiopathic FSGS, proteinuria may also recur after renal transplantation in NPHS2 patients, and post-transplant proteinuria is associated with high Palb. The relationship between elevated Palb and proteinuria in NPHS2 remains to be determined.
Stem and Progenitor-Like Cells Contribute to the Aggressive Behavior of Human Epithelial Ovarian Cancer
Authors: Sharmila A. Bapat, Avinash M. Mali, Chaitanyananda B. Koppikar, Nawneet K. Kurrey
Journal: Cancer Research (2005)

Abstract The cellular mechanisms underlying the increasing aggressiveness associated with ovarian cancer progression are poorly understood. Coupled with a lack of identification of specific markers that could aid early diagnoses, the disease becomes a major cause of cancer-related mortality in women. Here we present direct evidence that the aggressiveness of human ovarian cancer may be a result of transformation and dysfunction of stem cells in the ovary. A single tumorigenic clone was isolated among a mixed population of cells derived from the ascites of a patient with advanced ovarian cancer. During the course of the study, yet another clone underwent spontaneous transformation in culture, providing a model of disease progression. Both the transformed clones possess stem cell–like characteristics and differentiate to grow in an anchorage-independent manner in vitro as spheroids, although further maturation and tissue-specific differentiation was arrested. Significantly, tumors established from these clones in animal models are similar to those in the human disease in their histopathology and cell architecture. Furthermore, the tumorigenic clones, even on serial transplantation continue to establish tumors, thereby confirming their identity as tumor stem cells. These findings suggest that: (a) stem cell transformation can be the underlying cause of ovarian cancer and (b) continuing stochastic events of stem and progenitor cell transformation define the increasing aggression that is characteristically associated with the disease.
Norepinephrine ignites local hotspots of neuronal excitation: How arousal amplifies selectivity in perception and memory
Authors: Mara Mather, David Clewett, Michiko Sakaki, Carolyn W. Harley
Journal: Behavioral and Brain Sciences (2015)

Abstract Emotional arousal enhances perception and memory of high-priority information but impairs processing of other information. Here, we propose that, under arousal, local glutamate levels signal the current strength of a representation and interact with norepinephrine (NE) to enhance high priority representations and out-compete or suppress lower priority representations. In our "glutamate amplifies noradrenergic effects" (GANE) model, high glutamate at the site of prioritized representations increases local NE release from the locus coeruleus (LC) to generate “NE hotspots.” At these NE hotspots, local glutamate and NE release are mutually enhancing and amplify activation of prioritized representations. In contrast, arousal-induced LC activity inhibits less active representations via two mechanisms: 1) Where there are hotspots, lateral inhibition is amplified; 2) Where no hotspots emerge, NE levels are only high enough to activate low-threshold inhibitory adrenoreceptors. Thus, LC activation promotes a few hotspots of excitation in the context of widespread suppression, enhancing high priority representations while suppressing the rest. Hotspots also help synchronize oscillations across neural ensembles transmitting high-priority information. Furthermore, brain structures that detect stimulus priority interact with phasic NE release to preferentially route such information through large-scale functional brain networks. A surge of NE before, during, or after encoding enhances synaptic plasticity at NE hotspots, triggering local protein synthesis processes that enhance selective memory consolidation. Together, these noradrenergic mechanisms promote selective attention and memory under arousal. GANE not only reconciles apparently contradictory findings in the emotion-cognition literature but also extends previous influential theories of LC neuromodulation by proposing specific mechanisms for how LC-NE activity increases neural gain.
A role for MARCKS, the alpha isozyme of protein kinase C and myosin I in zymosan phagocytosis by macrophages.
Authors: L H Allen, A Aderem
Journal: The Journal of Experimental Medicine (1995)

Myristoylated, alanine-rich C-kinase substrate (MARCKS) is a lipopolysaccharide-induced protein kinase C (PKC) substrate that has been proposed to regulate actin-membrane interactions, as well as actin structure at the membrane. We studied the distribution of MARCKS, the alpha isozyme of PKC (PKC alpha), and myosin I in lipopolysaccharide-treated peritoneal macrophages ingesting zymosan particles. MARCKS, PKC alpha, and myosin I colocalized with F-actin and talin in the cortical cytoplasm adjacent to forming phagocytic cups. After particle ingestion was completed, myosin I, F-actin, and talin were no longer enriched in the vicinity of the phagosome. By contrast, MARCKS and PKC alpha remained associated with the phagosome membrane until after acquisition of the lysosomal marker Lamp-1. Vinculin was not detected on phagosomes at any time point examined. Phagocytosis of zymosan was accompanied by rapid and sustained phosphorylation of MARCKS. Inhibitors of PKC reduced zymosan binding to the macrophage surface and blocked the focal accumulation of F-actin, talin, phosphotyrosine-containing proteins, MARCKS, and PKC alpha beneath attached particles. We propose that PKC-dependent phosphorylation is an early signal required for zymosan phagocytosis and that MARCKS and PKC alpha have a role in phagosome maturation. The colocalization of F-actin and MARCKS at the cytoplasmic face of the nascent phagosome reinforces the hypothesis that MARCKS regulates actin structure at the membrane. Our data also suggest that myosin I functions as a mechanical motor during particle uptake.
Risk factors for chronic thromboembolic pulmonary hypertension
Authors: D. Bonderman, H. Wilkens, S. Wakounig, H-J. Schäfers, P. Jansa, J. Lindner, I. Simkova, A. M. Martischnig, J. Dudczak, R. Sadushi, N. Skoro-Sajer, W. Klepetko, I. M. Lang
Journal: European Respiratory Journal (2008)

Chronic thromboembolic pulmonary hypertension (CTEPH) is characterised by nonresolving pulmonary thromboemboli that can be treated by surgical pulmonary endarterectomy (PEA). The authors of the present study sought to confirm known and to identify novel CTEPH risk factors in a controlled retrospective cohort study of prevalent CTEPH cases collected in three European centres offering PEA. Data from CTEPH patients were compared with nonthromboembolic pre-capillary pulmonary arterial hypertension cohorts at the participating institutions. The study population comprised 687 patients assessed at the time of diagnosis between 1996 and 2007. Ventriculo-atrial shunts and infected pacemakers (odds ratio (OR) 76.40, 95% confidence interval (CI) 7.67–10,351), splenectomy (OR 17.87, 95% CI 1.56–2,438), previous venous thromboembolism (VTE; OR 4.52, 95% CI 2.35–9.12), recurrent VTE (OR 14.49, 95% CI 5.40–43.08), blood groups other than 0 (2.09, 95% CI 1.12–3.94), and lupus anticoagulant/antiphospholipid antibodies (OR 4.20, 95% CI 1.56–12.21) were more often associated with CTEPH. Thyroid replacement therapy (OR 6.10, 95% CI 2.73–15.05) and a history of malignancy (OR 3.76, 95% CI 1.47–10.43) emerged as novel CTEPH risk factors. In conclusion, the European database study confirmed previous knowledge of chronic thromboembolic pulmonary hypertension risk factors, and identified thyroid replacement therapy and a history of malignancy as new medical conditions associated with chronic thromboembolic pulmonary hypertension.
Prognostic Implications of Molecular and Immunohistochemical Profiles of the Rb and p53 Cell Cycle Regulatory Pathways in Primary Non–Small Cell Lung Carcinoma
Authors: Louise Burke, Douglas B. Flieder, Donald G. Guinee, Elizabeth Brambilla, Andrew N. Freedman, William P. Bennett, Raymond T. Jones, Andrew Borkowski, Neil A. Caporaso, Marian Fleming, Victor Trastek, Peter Pairolero, Henry Tazelaar, David Midthun, James R. Jett, Lance A. Liotta, William D. Travis, Curtis C. Harris
Journal: Clinical Cancer Research (2005)

Many studies have highlighted the aberrant expression and prognostic significance of individual proteins in either the Rb (particularly cyclin D1, p16INK4A, and pRb) or the p53 (p53 and p21Waf1) pathways in non-small cell lung cancer. We hypothesize that cumulative abnormalities within each and between these pathways would have significant prognostic potential regarding survival.Our study population consisted of 106 consecutive surgically resected cases of predominantly early-stage non-small cell lung cancer from the National Cancer Institute-Mayo Clinic series, and assessment of proteins involved both immunohistochemical (cyclin D1, p21Waf1, pRb, p16INK4A, and p53) and mutational analysis (p53) in relationship to staging and survival.Cyclin D1 overexpression was noted in 48% of the tumors, p16INK4A negative in 53%, pRb negative in 17%, p53 immunopositive in 50%, p53 mutation frequency in 48%, and p21(Waf1) overexpression in 47%, none with prognostic significance. Cyclin D1 overexpression in pRb-negative tumors revealed a significantly worse prognosis with a mean survival of 2.3 years (P = 0.004). A simultaneous p53 mutation dramatically reduced the mean survival time to 0.9 years (P = 0.007). Cyclin D1 overexpression with either a p53 mutation or a p53 overexpression was also associated with a significantly poorer prognosis (P = 0.0033 and 0.0063, respectively).Some cumulative abnormalities in the Rb and p53 pathways (e.g., cyclin D1 overexpression and p53 mutations) significantly cooperate to predict a poor prognosis; however, the complexity of the cell cycle protein interaction in any given tumor warrants caution in interpreting survival results when specific protein abnormalities are taken in isolation.
Response to: ‘Which B-cell subset should we target in lupus?’ by Ferraccioli and Houssiau
Authors: Gururaj Arumugakani, Edward M Vital, Md Yuzaiful Md Yusof, Dennis G McGonagle, Paul Emery
Journal: Annals of the Rheumatic Diseases (2014)

We read with interest the editorial by Ferraccioli and Houssiau proposing the specific targeting of long-lived plasma cells (PCs) in human lupus nephritis (LN).1 The authors present a cogent summary of experiments showing that long-lived PCs alone are sufficient to induce murine LN, and that targeting of PCs in these models is successful. However, we believe that clinical experience with the treatment of human SLE indicates that plasmablasts and short-lived PCs, recently derived from autoreactive B cells, are more important in the …
Extreme conservation of non-repetitive non-coding regions near HoxDcomplex of vertebrates
Authors: Chilaka Sabarinadh, Subbaya Subramanian, Rakesh K Mishra
Journal: Genome biology (2003)

Homeotic gene complexes determine the anterior-posterior body axis in animals. The expression pattern and function of hox genes along this axis is colinear with the order in which they are organized in the complex. This 'chromosomal organization and functional correspondence' is conserved in all bilaterians investigated. Although the molecular basis of this 'colinearity' in not yet understood, it is possible that there are control elements within or in the proximity of these complexes that establish and maintain the expression patterns of hox genes in a coordinated fashion. We report here an unprecedented conservation of non-coding DNA sequences adjacent to the HoxD complex of vertebrates. Stretches of hundreds of base pairs in a 7 kb region, upstream of HoxD complex, show 100% conservation from fish to human. Using primers designed from these sequences of human HoxD complex, we amplified the corresponding regions from different vertebrates, including mammals, aves, reptiles, amphibians and pisces. Such a high degree of conservation, where no variation was allowed during ~500 million years of evolution, suggests critical function for these sequences in the regulation of the HoxD complex. Furthermore, these sequences provide a molecular handle to gain insight into the mechanism of regulation of this complex.
Comment on: Bernstein. Reducing Foot Wounds in Diabetes. Diabetes Care 2013;36:e48
Authors: Stephan Morbach, Andrea Icks, Gerhard Rümenapf, David G. Armstrong
Journal: Diabetes Care (2013)

We very much appreciate the article by Dr. Bernstein regarding callus debridement and, in fact, agree with him in that calluses and their treatment are not trivial affairs in the patient with diabetes, neuropathy, and peripheral artery disease (1). Just as we have all seen devastating consequences with coumadin therapy or colitis caused by antibiotic dosing, callus debridement in the wrong hands can lead to significant morbidity too. This is increasingly true as our formerly mainly neuropathic patients are now increasingly often neuroischemic (2). We would argue, though, that—just as with coumadin or colitis—the lack of treatment can lead to even more devastation. In terms of calluses, …
Role of Nitric Oxide in the Control of Renal Oxygen Consumption and the Regulation of Chemical Work in the Kidney
Authors: Sarra K. Laycock, Traci Vogel, Paul R. Forfia, Joshua Tuzman, Xiaobin Xu, Manuel Ochoa, Carl I. Thompson, Alberto Nasjletti, Thomas H. Hintze
Journal: Circulation Research (1998)

Abstract —Inhibition of NO synthesis has recently been shown to increase oxygen extraction in vivo, and NO has been proposed to play a significant role in the regulation of oxygen consumption by both skeletal and cardiac muscle in vivo and in vitro. It was our aim to determine whether NO also has such a role in the kidney, a tissue with a relatively low basal oxygen extraction. In chronically instrumented conscious dogs, administration of an inhibitor of NO synthase, nitro- l -arginine (NLA, 30 mg/kg IV), caused a maintained increase in mean arterial pressure and renal vascular resistance and a decrease in heart rate (all P &lt;0.05). At 60 minutes, urine flow rate and glomerular flow rate decreased by 44±12% and 45±7%, respectively; moreover, the amount of sodium reabsorbed fell from 16±1.7 to 8.5±1.1 mmol/min (all P &lt;0.05). At this time, oxygen uptake and extraction increased markedly by 115±37% and 102±34%, respectively ( P &lt;0.05). Oxygen consumption also significantly increased from 4.5±0.6 to 7.1±0.9 mL O 2 /min. Most important, the ratio of oxygen consumption to sodium reabsorbed increased dramatically from 0.33±0.07 to 0.75±0.11 mL O 2 /mmol Na + ( P &lt;0.05), suggesting a reduction in renal efficiency for transporting sodium. In vitro, both a NO-donating agent and the NO synthase–stimulating agonist bradykinin significantly decreased both cortical and medullary renal oxygen consumption. In conclusion, NO plays a role in maintaining a balance between oxygen consumption and sodium reabsorption, the major ATP-consuming process in the kidney, in conscious dogs, and NO can inhibit mitochondrial oxygen consumption in canine renal slices in vitro.
Microparticles in stable and exacerbated COPD patients
Authors: Istvan Ruzsics, Szandra Singoszki, M Balázs Illés, Veronika Sárosi, Zoltán Balikó, Margit Tokés-Füzsi, Tamás Koszegi, Gábor Woth, István Vermes, Gábor L. Kovács
Journal: European Respiratory Journal (2013)

Introduction: the influence of COPD on the endothelium and on the circulating microparticulum numbers is not completely understood. Microparticles (MP) are cell membrane-derived vesicles in the circulation originating from apoptotic or activated cells with 0,1-1,0µm size. Their outer membrane layer are rich in phosphatidylserine (PS) and phosphatidylethanolamine (PE). The origin of MPs is detectable, as these vesicles inherit the surface protein characteristics of their host cells (eg. white blood cells, platelets, red blood cells and endothelial cells). Objective: we aimed to compare MP numbers with different cellular origine in stable COPD patients and during exacerbation, associated with and without cardiovascular disease. Methods: we measured the MP numbers in 40 stable COPD patients, (20 with and 20 without cardiovascular disease) and in 20 patients with exacerbation compared to 20 healthy volunteers. MPs were defined as Annexin V-positive events in a size gate between 0,5-1,0 um and measured by Beckman-Coulter FC 500 flow cytomter. The cellular origine of MPs was detected by fluorochrome labelled antibodies: platelet (CD41, CD61, CD42a, PAC1), endothelial (CD31, CD62E) white blood cell (CD45,CD13) monocyte (CD14) and red blood cell (GlyA). Results: the total MP number in COPD patients were significantly higher then in healthy volunteers. CD42a+ (platelet origin), CD62E+ (endothelial origin) and CD14+ (monocyte origin) MP numbers were significantly higher in patients with exacerbated COPD than in the stable COPD patients. Conclusions: endothelial damage, mainly in pulmonary capillaries occurs during exacerbation. The role of platelet and monocyte origin MPs in COPD patients is not clear yet.
Discovery of estrogen receptor α target genes and response elements in breast tumor cells
Authors: Chin-Yo Lin, Anders Ström, Vinsensius Berlian Vega, Say Li Kong, Ai Li Yeo, Jane S Thomsen, Wan Ching Chan, Balraj Doray, Dhinoth K Bangarusamy, Adaikalavan Ramasamy, Liza A Vergara, Suisheng Tang, Allen Chong, Vladimir B Bajic, Lance D Miller, Jan-Åke Gustafsson, Edison T Liu
Journal: Genome biology (2004)

Abstract Background Estrogens and their receptors are important in human development, physiology and disease. In this study, we utilized an integrated genome-wide molecular and computational approach to characterize the interaction between the activated estrogen receptor (ER) and the regulatory elements of candidate target genes. Results Of around 19,000 genes surveyed in this study, we observed 137 ER-regulated genes in T-47D cells, of which only 89 were direct target genes. Meta-analysis of heterogeneous in vitro and in vivo datasets showed that the expression profiles in T-47D and MCF-7 cells are remarkably similar and overlap with genes differentially expressed between ER-positive and ER-negative tumors. Computational analysis revealed a significant enrichment of putative estrogen response elements (EREs) in the cis -regulatory regions of direct target genes. Chromatin immunoprecipitation confirmed ligand-dependent ER binding at the computationally predicted EREs in our highest ranked ER direct target genes, NRIP1 , GREB1 and ABCA3 . Wider examination of the cis -regulatory regions flanking the transcriptional start sites showed species conservation in mouse-human comparisons in only 6% of predicted EREs. Conclusions Only a small core set of human genes, validated across experimental systems and closely associated with ER status in breast tumors, appear to be sufficient to induce ER effects in breast cancer cells. That cis -regulatory regions of these core ER target genes are poorly conserved suggests that different evolutionary mechanisms are operative at transcriptional control elements than at coding regions. These results predict that certain biological effects of estrogen signaling will differ between mouse and human to a larger extent than previously thought.
A new mutation, gld, that produces lymphoproliferation and autoimmunity in C3H/HeJ mice.
Authors: J B Roths, E D Murphy, E M Eicher
Journal: The Journal of Experimental Medicine (1984)

A newly discovered autosomal recessive mutation, generalized lymphoproliferative disease (gld), in the C3H/HeJ strain of mice, determines the development of early onset massive lymphoid hyperplasia with autoimmunity. Significant lymph node enlargement is apparent as early as 12 wk of age. By 20 wk, lymph nodes are 50-fold heavier than those of coisogenic C3H/HeJ-+/+ mice. There is a concomitant increase in the numbers of peripheral blood lymphocytes. Analysis of C3H-gld lymph node lymphocyte subsets by immunofluorescence indicates an increase in numbers of B cells, T cells, and null (Thy-1-, sIg-) lymphocytes by 6-, 15-, and 33-fold compared with congeneic control mice. Serologically, gld/gld mice develop antinuclear antibodies (including anti-dsDNA), thymocyte-binding autoantibody, and hypergammaglobulinemia with major increases in several immunoglobulin isotypes. Mutant gld mice live only one-half as long as normal controls (12 and 23 mo, respectively). Interstitial pneumonitis was found in virtually all C3H-gld mice autopsied when moribund. Although immune complexes were detected in the glomerulus by immunofluorescence techniques, only 14% of the autopsied mice had significant lupus-like nephritis. Vascular disease was not found. The pattern of early onset massive lymph node enlargement, hypergammaglobulinemia, and production of antinuclear autoantibodies resembles the basic abnormal phenotype induced by the lpr (lymphoproliferation) mutation. The mutations gld and lpr are not allelic. Linkage studies indicate that gld is located between Pep-3 and Lp on chromosome 1. This new mutation adds another genetically well-defined model to the list of murine lymphoproliferative/autoimmune disorders that may be exploited to gain a clearer understanding of immunoregulatory defects and for identifying common pathogenetic factors involved in systemic autoimmune diseases.