tbuckley/cabot-search huggingface dataset:
Laminin Compensation in Collagen α3(IV) Knockout (Alport) Glomeruli Contributes to Permeability Defects
Authors: Dale R. Abrahamson, Kathryn Isom, Eileen Roach, Larysa Stroganova, Adrian Zelenchuk, Jeffrey H. Miner, Patricia L. St. John
Journal: Journal of the American Society of Nephrology (2007)

Alport disease is caused by mutations in genes encoding the alpha3, alpha4, or alpha5 chains of type IV collagen, which form the collagenous network of mature glomerular basement membrane (GBM). In the absence of alpha3, alpha4, alpha5 (IV) collagen, alpha1, alpha2 (IV) collagen persists, which ordinarily is found only in GBM of developing kidney. In addition to dysregulation of collagen IV, Alport GBM contains aberrant laminins, which may contribute to the progressive GBM thickening and splitting, proteinuria, and renal failure seen in this disorder. This study sought to characterize further the laminin dysregulation in collagen alpha3(IV) knockout mice, a model of Alport disease. With the use of confocal microscopy, laminin alpha1 and alpha5 abundance was quantified, and it was found that they co-distributed in significantly large amounts in areas of GBM thickening. In addition, labeling of entire glomeruli for laminin alpha5 was significantly greater in Alport mice than in wild-type siblings. Reverse transcriptase-PCR from isolated glomeruli demonstrated significantly more laminin alpha5 mRNA in Alport mice than in wild-type controls, indicating upregulated transcription of Lama5. For testing glomerular barrier function, ferritin was injected into 2-wk-old Alport and control mice, and GBM was examined by electron microscopy. Highest ferritin levels were seen in Alport GBM thickenings beneath effaced podocyte foot processes, but morphologically normal GBM was significantly permeable as well. We concluded that (1) ultrastructurally normal Alport GBM residing beneath differentiated podocyte foot processes is inherently and abnormally permeable, and (2) upregulation of Lama5 transcription and concentration of laminin alpha1 and alpha5 within Alport GBM thickenings contribute to abnormal permeabilities.
Evaluation of a Systems Navigator Model for Transition From Pediatric to Adult Care for Young Adults With Type 1 Diabetes
Authors: Norma Van Walleghem, Catherine A. MacDonald, Heather J. Dean
Journal: Diabetes Care (2008)

To determine whether a systems navigator service, The Maestro Project, could increase medical surveillance for young adults with type 1 diabetes who transfer from pediatric to adult care.There were two cohorts of participants: 1) a younger group (aged 18 years, n = 82) who had the assistance of the navigator as they graduated from pediatric care and 2) an older group (aged 19-25 years) who were transferred to adult care without this initial support but later enrolled in the program.Of the older group (who did not have initial access to the navigator), 40% dropped out of adult medical care, compared with a dropout rate of 11% for the younger group, who had access to the navigator at the time of transfer from pediatric care.The systems navigator helped improve medical surveillance for both groups, although there was no evidence of improved short-term medical outcomes.
Newborn humans manifest autoantibodies to defined self molecules detected by antigen microarray informatics
Authors: Yifat Merbl, Merav Zucker-Toledano, Francisco J. Quintana, Irun R. Cohen
Journal: Journal of Clinical Investigation (2007)

Autoimmune diseases are often marked by autoantibodies binding to self antigens. However, many healthy persons also manifest autoantibodies that bind to self antigens, known as natural autoantibodies. In order to characterize natural autoantibodies present at birth, we used an antigen microarray (antigen chip) to analyze informatically (with clustering algorithms and correlation mapping) the natural IgM, IgA, and IgG autoantibody repertoires present in 10 pairs of sera from healthy mothers and the cords of their newborn babies. These autoantibodies were found to bind to 305 different, mostly self, molecules. We report that in utero, humans develop IgM and IgA autoantibodies to relatively uniform sets of self molecules. The global patterns of maternal IgM autoantibodies significantly diverged from those at birth, although certain reactivities remained common to both maternal and cord samples. Because maternal IgG antibodies (unlike IgM and IgA) cross the placenta, maternal and cord IgG autoantibodies showed essentially identical reactivities. We found that some self antigens that bind cord autoantibodies were among the target self antigens associated with autoimmune diseases later in life. Thus, the obviously benign autoimmunity prevalent at birth may provide the basis for the emergence of some autoimmune diseases relatively prevalent later in life.
AMPK is essential for energy homeostasis regulation and glucose sensing by POMC and AgRP neurons
Authors: Marc Claret, Mark A. Smith, Rachel L. Batterham, Colin Selman, Agharul I. Choudhury, Lee G.D. Fryer, Melanie Clements, Hind Al-Qassab, Helen Heffron, Allison W. Xu, John R. Speakman, Gregory S. Barsh, Benoit Viollet, Sophie Vaulont, Michael L.J. Ashford, David Carling, Dominic J. Withers
Journal: Journal of Clinical Investigation (2007)

Hypothalamic AMP-activated protein kinase (AMPK) has been suggested to act as a key sensing mechanism, responding to hormones and nutrients in the regulation of energy homeostasis. However, the precise neuronal populations and cellular mechanisms involved are unclear. The effects of long-term manipulation of hypothalamic AMPK on energy balance are also unknown. To directly address such issues, we generated POMCα2KO and AgRPα2KO mice lacking AMPKα2 in proopiomelanocortin– (POMC-) and agouti-related protein–expressing (AgRP-expressing) neurons, key regulators of energy homeostasis. POMCα2KO mice developed obesity due to reduced energy expenditure and dysregulated food intake but remained sensitive to leptin. In contrast, AgRPα2KO mice developed an age-dependent lean phenotype with increased sensitivity to a melanocortin agonist. Electrophysiological studies in AMPKα2-deficient POMC or AgRP neurons revealed normal leptin or insulin action but absent responses to alterations in extracellular glucose levels, showing that glucose-sensing signaling mechanisms in these neurons are distinct from those pathways utilized by leptin or insulin. Taken together with the divergent phenotypes of POMCα2KO and AgRPα2KO mice, our findings suggest that while AMPK plays a key role in hypothalamic function, it does not act as a general sensor and integrator of energy homeostasis in the mediobasal hypothalamus.
p34SEI-1 Inhibits Apoptosis through the Stabilization of the X-Linked Inhibitor of Apoptosis Protein: p34SEI-1 as a Novel Target for Anti–Breast Cancer Strategies
Authors: Seung-Woo Hong, Chang-Jae Kim, Won-Sang Park, Jae-Sik Shin, Soon-Duck Lee, Seong-Gyu Ko, Sam-Il Jung, In-Chul Park, Sung-Kwan An, Won-Keun Lee, Wang-Jae Lee, Dong-Hoon Jin, Myeong-Sok Lee
Journal: Cancer Research (2009)

The p34(SEI-1) protein exerts oncogenic effects via regulation of the cell cycle, which occurs through a direct interaction with cyclin-dependent kinase 4. Such regulation can increase the survival of various types of tumor cells. Here, we show that the antiapoptotic function of p34(SEI-1) increases tumor cell survival by protecting the X-linked inhibitor of apoptosis protein (XIAP) from degradation. Our findings show that p34(SEI-1) inhibits apoptosis. This antiapoptotic effect was eliminated by the suppression of p34(SEI-1) expression. We also determined that direct binding of p34(SEI-1) to the BIR2 domain prevents ubiquitination of XIAP. Interestingly, p34(SEI-1) expression is absent or weak in normal tissues but is strongly expressed in tissues obtained from patients with breast cancer. Furthermore, the expression levels of p34(SEI-1) and XIAP seem to be coordinated in human breast cancer cell lines and tumor tissues. Thus, our findings reveal that p34(SEI-1) uses a novel apoptosis-inhibiting mechanism to stabilize XIAP.
Functional and antigenic similarities between a 94-kD protein of Schistosoma mansoni (SCIP-1) and human CD59.
Authors: M Parizade, R Arnon, P J Lachmann, Z Fishelson
Journal: The Journal of Experimental Medicine (1994)

Schistosomiasis is a parasitic disease affecting approximately 200 million people, primarily in the third world. Schistosoma mansoni, one of the causative agents of this disease, parasitize the human mesenteric and portal blood systems while successfully evading host immune responses. During parasite penetration into the mammalian host and shortly afterwards, the larvae rapidly convert from being sensitive to being resistant to C-mediated killing. Treatment of the C-resistant parasitic forms with trypsin renders the parasite susceptible to C attack, thus indicating the presence of C inhibitory protein(s) on the parasite surface. We describe here an intrinsic schistosome C inhibitory protein (SCIP-1) that exhibits antigenic and functional similarities with the human C-inhibitor CD59. Like CD59, SCIP-1 is capable of inhibiting formation of the C membrane attack complex (MAC), probably by binding to C8 and C9 of the C terminal pathway. In addition, SCIP-1 is apparently also membrane-anchored via glycosyl phosphatidylinositol as it can be specifically released with phosphatidylinositol-specific phospholipase C. Soluble SCIP-1, partially purified from Nonidet P-40 extracts of schistosome tegument is capable of inhibiting hemolysis of sensitized sheep erythrocytes and of rabbit erythrocytes by human C. Anti-human CD59 antibodies block this activity of SCIP-1 and in addition, upon binding to intact parasites, render them vulnerable to killing by human and guinea pig C. SCIP-1 is located on the surface of C-resistant forms of the parasite, i.e., 24-h cultured mechanical schistosomula and in vivo-derived adult worms as revealed by immunofluorescence and immunogold electron microscopy studies. These results identify one of the mechanisms schistosomes use to escape immune attack.
Age and Association of Kidney Measures With Mortality and End-stage Renal Disease
Authors: Stein I. Hallan, Kunihiro Matsushita, Yingying Sang, Bakhtawar K. Mahmoodi, Corri Black, Areef Ishani, Nanne Kleefstra, David Naimark, Paul Roderick, Marcello Tonelli, Jack F. M. Wetzels, Brad C. Astor, Ron T. Gansevoort, Adeera Levin, Chi-Pang Wen, Josef Coresh, for the Chronic Kidney Disease Prognosis Consortium
Journal: JAMA (2012)

Chronic kidney disease (CKD) is prevalent in older individuals, but the risk implications of low estimated glomerular filtration rate (eGFR) and high albuminuria across the full age range are controversial.
EFFECTS OF MAST CELLS ON THE FUNCTION OF ISOLATED HUMAN TENOCYTES
Authors: H Behzad, A Scott
Journal: British Journal of Sports Medicine (2013)

Introduction Tendinopathy, a pathological condition caused by tendon overuse, adversely affects millions of people in athletic and occupational settings worldwide. The underlying molecular mechanisms in the development of tendinopathy are poorly understood, however, increased mast cell numbers have been detected in human patellar tendinopathy specimens. Mast cells are known to increase fibroblast proliferation and collagen production leading to fibrosis in some tissues. The present study was carried out to determine the effects of mast cells on isolated human tendon fibroblasts (tenocytes) and explore a possible role for mast cells in the development of tendinopathy. Methods Primary human tenocytes were isolated from hamstring tendons of healthy donors. Light and electron microscopy were used to examine a physical association between mast cells (HMC-1) and tenocytes, in vitro. Collagen gel contraction assay was used to examine the effects of mast cells on isolated tenocytes. Cell viability and proliferation was assessed by MTS assay. Gene expression was quantitated by qPCR. Results HMC-1 mast cells were shown by light and electron microscopy to physically bind to primary tenocytes through adherent junctions. Immunostaining for stem cell factor (SCF), a mast cell growth factor, showed homogeneous expression of this protein on the surface of tenocytes. Additionally, qPCR showed an increase in tenocyte SCF mRNA expression in the presence of mast cells. In other experiments, both mast cells and mast cell sonicates were shown to induce tenocyte mediated contraction of collagen gel, which appeared to be driven by TGF-β1. MTS assay showed a mast cell mediated increase in tenocyte survival and proliferation. Discussion These findings suggest that either through physical association with tenocytes and/or release of mediators, mast cells could play a role in the regulation and activation of tenocytes. Further studies are underway to investigate the molecular mechanisms of mast cell-tenocyte interactions and whether these could play a role in the pathogenesis of tendinopathy.
Development and in-vivo characterization of supramolecular hydrogels for intrarenal drug delivery
Authors: Patricia Y.W. Dankers, Marja J.A. van Luyn, Ali Huizinga-van der Vlag, Gaby M.L. van Gemert, Arjen H. Petersen, E.W. Meijer, Henk M. Janssen, Anton W. Bosman, Eliane R. Popa
Journal: Biomaterials (2012)
Care for Imminently Dying Cancer Patients: Family Members' Experiences and Recommendations
Authors: Takuya Shinjo, Tatsuya Morita, Kei Hirai, Mitsunori Miyashita, Kazuki Sato, Satoru Tsuneto, Yasuo Shima
Journal: Journal of Clinical Oncology (2009)

PURPOSE The aim of this study was to clarify the level of emotional distress experienced by bereaved family members and the perceived necessity for improvement in the care for imminently dying patients and to explore possible causes of distress and alleviating measures. METHODS A cross-sectional nationwide survey was performed in 2007 of bereaved families of cancer patients at 95 palliative care units across Japan. Results Questionnaires were sent to 670 families, and 76% responded. Families reported their experiences as very distressing in 45% of cases. Regarding care, 1.2% of respondents believed that a lot of improvement was needed, compared with 58% who believed no improvement was needed. Determinants of high-level distress were a younger patient age, being a spouse, and overhearing conversations between the medical staff outside the room at the time of the patient's death; those reporting high-level necessity of improvement were less likely to have encountered attempts to ensure the patient's comfort, received less family coaching on how to care for the patient, and felt that insufficient time was allowed for the family to grieve after the patient's death. CONCLUSION A considerable number of families experienced severe emotional distress when their family member died. Thus, we propose that a desirable care concept for imminently dying cancer patients should include relief of patient suffering, family advisement on how to care for the patient, allowance of enough time for the family to grieve, and ensuring that family members cannot overhear medical staff conversations at the time of the patient's death.
Effect of calcitonin and calcitonin gene-related peptide on pancreatic functions in man.
Authors: C Beglinger, E Koehler, W Born, J A Fischer, U Keller, L E Hanssen, K Gyr
Journal: Gut (1988)

Calcitonin gene-related peptide (CGRP) has recently been identified in central and peripheral nerve fibres, including those of blood vessels supplying the exocrine pancreas, and in pancreatic islet cells. Moreover, receptors have been characterised in the same tissue. The present study examined the effects of human CGRP and of calcitonin on exocrine pancreatic secretion and on islet cell function in nine healthy volunteers. CGRP (300 ng/kg/h) caused, respectively, a 25% and 31% inhibition of caerulein stimulated trypsin and amylase output which was similar to that seen with calcitonin (300 ng/kg/h). Arginine stimulated insulin and glucagon release was unaffected by either CGRP, or calcitonin. Calcitonin gene-related peptide caused cutaneous flushing, but did not affect the pulse rate or arterial blood pressure in the doses tested. Calcitonin gene-related peptide inhibits exocrine pancreatic secretion in vivo in man, but does not affect islet cell hormone release.
Reduced cardiotoxicity and comparable efficacy in a phase IIItrial of pegylated liposomal doxorubicin HCl(CAELYX™/Doxil®) versus conventional doxorubicin forfirst-line treatment of metastatic breast cancer
Authors: M.E.R. O’Brien, N. Wigler, M. Inbar, R. Rosso, E. Grischke, A. Santoro, R. Catane, D.G. Kieback, P. Tomczak, S.P. Ackland, F. Orlandi, L. Mellars, L. Alland, C. Tendler
Journal: Annals of Oncology (2004)
Daphnia pulex didomain hemoglobin: structure and evolution of polymeric hemoglobins and their coding genes
Authors: S. Dewilde, M. L. Van Hauwaert, K. Peeters, J. Vanfleteren, L. Moens
Journal: Molecular Biology and Evolution (1999)

The high-molecular-weight extracellular hemoglobin of Daphnia pulex is composed of at least three different didomain globin chains. The primary structure of one of these chains was determined at the protein and cDNA levels. Each globin domain of the polypeptide chain displays the standard structural characteristics. The first domain is preceded by a 30-residue extension containing an 18-residue unprecedented threonine-rich segment and a 12-residue preA segment which is homologous to the preA segments of other nonvertebrate globin chains. Both domains are linked together by a preA' segment, which is homologous to other preA segments and lacks the threonine-rich segment. Dimerization of the globin chains by the formation of a disulphide bridge linking the unique cysteines near the amino-termini results in a covalent, vertebrate-like tetradomain structure. The flexible amino-terminal extension most likely facilitates dimerization. The gene coding for this globin chain is interrupted by six small introns. Each domain displays two intradomain introns at the conserved positions B12.2 and G7.0. A precoding intron occurs at position preA(-27.0) and a bridge intron at occurs preA'(-13.2). We propose a crossover event as the most likely mechanism for duplication. Arthropod globin trees reflect the added effects of gene diversification, gene duplication, and species evolution. The position of monodomain intracellular globins in the tree suggests that they resemble the ancestral globin more than the derived didomain extracellular globins do.
HNE-induced 5-LO expression is regulated by NF- B/ERK and Sp1/p38 MAPK pathways via EGF receptor in murine macrophages
Authors: S. J. Lee, C. E. Kim, K. W. Seo, C. D. Kim
Journal: Cardiovascular Research (2010)

5-Lipoxygenase (5-LO) has been suggested to be a modulator of atherosclerotic plaque instability and co-exists with 4-hydroxynonenal (HNE) in macrophages in atherosclerotic lesions. To determine the potential role for HNE in 5-LO expression, the molecular mechanisms of 5-LO expression were evaluated in HNE-stimulated macrophages. A genomic sequence of the promoter 2.0 kb upstream of the transcription initiation site was amplified, and a series of sequentially deleted fragments were then fused to a luciferase reporter gene. The promoter region 213 bp upstream of the transcription start site was responsible for the HNE-enhanced transcriptional activity of 5-LO. Site-directed mutagenesis of this region showed that the transcription factors, including stimulating protein 1 (Sp1) and nuclear factor-κB (NF-κB), were associated with up-regulation of HNE-induced 5-LO transcription. Moreover, the role of Sp1 and NF-κB in HNE-induced 5-LO expression was confirmed by siRNA knockdown of Sp1 and NF-κB. The HNE-enhanced Sp1 and NF-κB activities were attenuated by SB203580, a p38 mitogen-activated protein kinase (MAPK) inhibitor, and PD98059, an extracellular signal-regulated kinase (ERK) inhibitor, respectively. In addition, the HNE-enhanced phosphorylation of p38 MAPK and ERK was inhibited by AG1478, an epidermal growth factor receptor (EGFR) antagonist, but not by AG1295, a platelet-derived growth factor receptor (PDGFR) antagonist. 5-LO expression by HNE was regulated at the transcriptional level by the EGFR-mediated activation of Sp1/p38 MAPK and NF-κB/ERK pathways in macrophages, which may lead to the development of therapeutic interventions for regulating 5-LO expression in atherosclerosis.
Laboratory-Observed Behavioral Disinhibition in the Young Offspring of Parents With Bipolar Disorder: A High-Risk Pilot Study
Authors: Dina R. Hirshfeld-Becker, Joseph Biederman, Aude Henin, Stephen V. Faraone, Gabrielle A. Cayton, Jerrold F. Rosenbaum
Journal: American Journal of Psychiatry (2006)

This study tested whether behavioral disinhibition is more prevalent among offspring of parents with bipolar disorder than among offspring of parents without bipolar disorder.The authors conducted a secondary analysis of data from a preexisting high-risk study of offspring at risk for panic disorder and depression (N=278) that had included some children with parents who had bipolar disorder (N=34). Children (ages 2-6) had been classified as behaviorally inhibited, disinhibited, or neither in laboratory assessments.Offspring of bipolar parents had significantly higher rates of behavioral disinhibition than offspring of parents without bipolar disorder. Behavioral inhibition did not differ between groups. Differences were not accounted for by parental panic disorder or major depression or by parental history of attention deficit hyperactivity disorder, conduct disorder, antisocial personality, or substance use disorders.Results suggest a familial link between bipolar disorder in parents and behavioral disinhibition in their offspring. Behavioral disinhibition may be a familially transmitted predisposing factor for dysregulatory distress later in life.
Mutational profile and prognostic significance of TP53 in diffuse large B-cell lymphoma patients treated with R-CHOP: report from an International DLBCL Rituximab-CHOP Consortium Program Study
Authors: Zijun Y. Xu-Monette, Lin Wu, Carlo Visco, Yu Chuan Tai, Alexander Tzankov, Wei-min Liu, Santiago Montes-Moreno, Karen Dybkær, April Chiu, Attilio Orazi, Youli Zu, Govind Bhagat, Kristy L. Richards, Eric D. Hsi, X. Frank Zhao, William W. L. Choi, Xiaoying Zhao, J. Han van Krieken, Qin Huang, Jooryung Huh, Weiyun Ai, Maurilio Ponzoni, Andrés J. M. Ferreri, Fan Zhou, Brad S. Kahl, Jane N. Winter, Wei Xu, Jianyong Li, Ronald S. Go, Yong Li, Miguel A. Piris, Michael B. Møller, Roberto N. Miranda, Lynne V. Abruzzo, L. Jeffrey Medeiros, Ken H. Young
Journal: Blood (2012)
Correction of metabolic deficiencies in the leukocytes of patients with chronic granulomatous disease
Authors: Robert L. Baehner, David G. Nathan, Manfred L. Karnovsky
Journal: Journal of Clinical Investigation (1970)

Polymorphonuclear leukocytes from patients with chronic granulomatous disease (CGD) exhibit metabolic and bactericidal deficiencies that may be the result of inadequate production of H(2)O(2). A hydrogen peroxide-generating system was, therefore, inserted into CGD leukocytes. This was accomplished by allowing the cells to phagocytize latex spherules coated with glucose oxidase. This produced an amelioration in the known metabolic deficiencies of these cells during phagocytosis: (a) intracellular (catalatic) formate oxidation dependent upon hydrogen peroxide production was enhanced fourfold; and (b) hexose monophosphate shunt activity, which other workers have shown to be at least partially dependent upon the availability of H(2)O(2), was markedly stimulated. These data strengthen the evidence that the fundamental metabolic lesion in CGD cells during phagocytosis is indeed deficient production of hydrogen peroxide, probably, as previously shown, due to diminished oxidase for reduced nicotinamide adenine dinucleotide.