tbuckley/cabot-search huggingface dataset:
Treatment response in the PIVENS trial is associated with decreased hedgehog pathway activity
Authors: Cynthia D. Guy, Ayako Suzuki, Manal F. Abdelmalek, James L. Burchette, Anna Mae Diehl
Journal: Hepatology (2014)

Hedgehog (Hh) ligand production by ballooned hepatocytes drives nonalcoholic steatohepatitis (NASH) progression in mice. The NIDDK‐sponsored PIVENS trial (NCT00063622) showed that vitamin E (VitE) improved NASH. We investigated whether VitE treatment and improvement in NASH were associated with changes in Hh pathway activity. Immunohistochemistry (IHC) was performed on both pre‐ and posttreatment liver biopsies of 59 PIVENS patients randomized to VitE (n = 30) or placebo (n = 29). Sonic Hh (Shh) ligand‐producing cells and Shh‐responsive cells were quantified. The latter was accomplished by triple IHC for gli2+ (marker of Hh signaling), sox‐9 (progenitor marker), and α‐smooth muscle actin (α‐SMA; myofibroblast marker). Ballooned hepatocytes were quantified by keratin 8/18 and ubiquitin (K8/18/Ub) staining. IHC results were correlated with primary clinical and histologic PIVENS data. Pretreatment clinical, histologic, and IHC parameters did not differ significantly in the two treatment groups. Regardless of treatment arm, the number of Shh+ hepatocytes correlated with K8/18/Ub foci (r 2 = 0.47, P &lt; 0.001) and aspartate aminotransferase (AST) (r 2 = 0.15, P = 0.002). Treatment‐related changes in the numbers of Shh+ hepatocytes correlated with changes in serum AST (partial r 2 = 0.75, P &lt; 0.0001), hepatocyte ballooning ( P = 0.004), the ductular reaction (i.e., numbers of gli2+/sox9+ cells; P = 0.03 and α‐SMA+ cells; P = 0.10), and fibrosis stage ( P = 0.02). Treatment response was associated with a greater decrease in Shh+ hepatocytes than nonresponse ( P = 0.007). The VitE group demonstrated a greater reduction in K8/18/Ub+ foci ( P &lt; 0.08) and Shh+ hepatocytes ( P &lt; 0.05) than the placebo group, effects that became more significant after correction for baseline differences and multiple linear regression analysis. Conclusion : During PIVENS, treatment response correlated with loss of Shh+ hepatocytes and improvement in Hh‐regulated processes that promote NASH progression. (H epatology 2015;61:98–107)
The Use of Anencephalic Infants as Organ Sources
Authors: D A Shewmon, A M Capron, W J Peacock, B L Schulman
Journal: JAMA (1989)

The recent abandonment of the only active US protocol for harvesting organs from anencephalic "donors" indicates both the practical and the ethical problems inherent in such an effort. Various data suggest that surprisingly few such organs would actually end up benefiting other children. Attempts to revise either the Uniform Anatomical Gift Act or the Uniform Determination of Death Act to allow organ removal from spontaneously breathing anencephalic infants face major ethical objections. Even if this posed no ethical problem in theory, the ultimate harm to society would not be offset by the good of the few surviving recipients of these organs. Furthermore, providing anencephalic infants with intensive care would tend to preserve the brain stem as effectively as the other organs, predictably rendering the occurrence of brain death unlikely. Thus, despite the great need for newborn organs, anencephalic infants are not as attractive a source as some had hoped. (<i>JAMA</i>. 1989;261:1773-1781)
Reduction of Intimal Hyperplasia by Naroparcil, a 4-Methylumbelliferyl β- <scp>d</scp> -Xyloside Analogue, After Arterial Injury in the Hypercholesterolemic Rabbit
Authors: Philippe Gabriel Steg, Marianne Ziol, Ouafae Tahlil, Claude Robert, Philippe Masson, Didier Pruneau, Patrick Bruneval, Pierre Bélichard
Journal: Circulation Research (1995)

Abstract 4-Methylumbelliferyl β-D-xylosides (β- d -xylosides) inhibit proteoglycan synthesis, and this is associated with reduced proliferation and extracellular matrix production by vascular smooth muscle cells. This study evaluated whether treatment with naroparcil, a β- d -xyloside analogue, reduced intimal hyperplasia after arterial injury in the hypercholesterolemic rabbit. Forty-two rabbits were assigned to three groups that received either a 1% cholesterol-enriched diet (group 1, n=15) or the same diet with added 100 mg · kg −1 naroparcil (group 2, n=15) or 300 mg · kg −1 naroparcil (group 3, n=12). All animals underwent iliac artery endothelial abrasion at day 14 and were killed at day 56. At the time of death, the angiographic minimal luminal diameter was significantly larger in both treated groups. Morphometric analysis showed a larger luminal area in treated rabbits (groups 2 and 3) compared with control rabbits (group 1) (0.75±0.54 and 0.85±0.61 mm 2 versus 0.32±0.25 mm 2 , respectively; P &lt;.05), with a decreased intimal thickness in groups 2 and 3 (average reduction of 37% and 39%, respectively, compared with group 1; P &lt;.05) but without changes in medial area. Total vessel area was comparable among all groups. In the media, immunohistochemistry suggested reduced infiltration by macrophages and a larger fractional area of smooth muscle cells. There were no differences in plasma or arterial wall cholesterol content between groups. Plasma levels of glycosaminoglycans and dermatan sulfate content were increased only in group 3. In this model, oral treatment with naroparcil appears to preserve the arterial lumen and reduce intimal thickness after arterial injury.
Peroxisome Proliferator-Activated Receptor Family and Its Relationship to Renal Complications of the Metabolic Syndrome
Authors: Youfei Guan
Journal: Journal of the American Society of Nephrology (2004)

Peroxisome proliferator-activated receptors (PPAR) are members of the nuclear hormone receptor superfamily of ligand-activated transcription factors. Three PPAR isoforms, designated PPARα, -β/δ, and -γ, have been identified and attracted enormous attention as a result of the key role that these receptors play in regulating adipogenesis, lipid metabolism, insulin sensitivity, inflammation, and BP. Growing evidence points to a causative relationship between PPAR activity and the metabolic syndrome, including insulin resistance, glucose intolerance or type 2 diabetes, obesity, dyslipidemia, hypertension, atherosclerosis, and albuminuria. Importantly, both PPAR-α activators, such as the fibric acid class of hypolipidemic drugs, and PPAR-γ agonists, including antidiabetic thiazolidinediones, have been proved to be effective for improving diverse aspects of the metabolic syndrome. All three PPAR isoforms seem to play important roles in the development of diabetic nephropathy in type 2 diabetes. Accumulating data suggesting that PPAR may serve as potential therapeutic targets for treating the metabolic syndrome and its related renal complications have begun to emerge. This article reviews the literature pertaining to the action, ligand selectivity, and physiologic role of PPAR. Particular emphasis is placed on their pathogenic roles in the metabolic syndrome and the therapeutic utility of PPAR modulators in the treatment of diabetic nephropathy.
Expression of Valosin-Containing Protein in Colorectal Carcinomas as a Predictor for Disease Recurrence and Prognosis
Authors: Shinji Yamamoto, Yasuhiko Tomita, Yoshihiko Hoshida, Masato Sakon, Masao Kameyama, Shingi Imaoka, Mitsugu Sekimoto, Shoji Nakamori, Morito Monden, Katsuyuki Aozasa
Journal: Clinical Cancer Research (2004)

Abstract Purpose: Valosin-containing protein (VCP or p97) is associated with antiapoptotic function and metastasis via activation of the nuclear factor-κB signaling pathway. The present study was designed to investigate the prognostic significance of VCP expression in colorectal adenocarcinoma. Experimental Design: We analyzed VCP expression immunohistochemically in 129 patients with colorectal carcinoma ages 35–84 years. The staining intensity of tumor cells was categorized as either weaker-to-equal (low VCP expression) or stronger (high expression) than that in noncancerous colonic mucosa. We also analyzed 8 colorectal adenomas and 10 metastatic foci. Results: Low VCP expression was noted in 41 (31.8%) cases and high expression in 88 (68.2%) cases. A low level of VCP expression was noted in all adenomas, whereas a high level was seen in all metastatic tumors. A significant difference was observed in depth of invasion (T1–2 versus T3–4, P &amp;lt; 0.05), presence or absence of venous invasion (P &amp;lt; 0.05), and tumor stage (I and II versus III and IV; P &amp;lt; 0.05) between adenocarcinomas with low and high VCP expression. Patients with high VCP-expressing tumors had a higher recurrence rate (P &amp;lt; 0.001) and poorer disease-free and overall survival (P &amp;lt; 0.01 and P &amp;lt; 0.05, respectively) compared with the low expression group. Multivariate analysis revealed VCP expression level to be an independent prognosticator for both disease-free and overall survival. VCP level was an indicator of disease-free survival in both stage II and III (pathological Tumor-Node-Metastasis classification, P &amp;lt; 0.05 and &amp;lt;0.01, respectively). Conclusions: A high expression level of VCP in tumors is a poor prognostic marker in patients with colorectal carcinomas.
Binding of myelin basic protein peptides to human histocompatibility leukocyte antigen class II molecules and their recognition by T cells from multiple sclerosis patients.
Authors: A Valli, A Sette, L Kappos, C Oseroff, J Sidney, G Miescher, M Hochberger, E D Albert, L Adorini
Journal: Journal of Clinical Investigation (1993)

Multiple sclerosis (MS) is an autoimmune disease in which myelin proteins have been implicated as autoantigens recognized by pathogenic autoreactive T cells. To study the relationship between human myelin basic protein (hMBP) and HLA alleles associated to MS susceptibility, such as DRB1*1501, the binding of synthetic peptides spanning the entire hMBP sequence to 10 purified HLA-DR molecules was determined. All the hMBP peptides tested showed binding affinity for at least one of the DR molecules analyzed, but three hMBP peptides, included in sequences 13-32, 84-103, and 144-163 were found capable of binding to three or more DR molecules. The hMBP peptide 84-103 was the most degenerate in binding, in that it bound to 9 out of 10 DR molecules tested. Interestingly, it bound with highest affinity to DRB1*1501 molecules. To correlate the binding pattern of hMBP peptides to HLA class II molecules with their recognition by T cells, 61 hMBP-specific T cell lines (TCL) were established from the peripheral blood of 20 MS patients, who were homozygous, heterozygous, or negative for DRB1*1501. Analysis of hMBP epitopes recognized by these TCL and their HLA restriction demonstrated a very good correlation between binding data and T cell proliferation to hMBP peptides. Although virtually all hMBP peptides tested could be recognized by at least one TCL from MS patients, three immunodominant T cell epitopes were apparent among the TCL examined, corresponding exactly to the hMBP peptides capable of binding to several DR molecules. No major difference could be detected in the recognition of immunodominant hMBP peptides by TCL from DRB1*1501 positive or negative MS patients. These results have implications for the role of hMBP as relevant autoantigen, and of DRB1*1501 as susceptibility allele in MS.
ZD6474 Suppresses Oncogenic RET Isoforms in a <i>Drosophila</i> Model for Type 2 Multiple Endocrine Neoplasia Syndromes and Papillary Thyroid Carcinoma
Authors: Marcos Vidal, Samuel Wells, Anderson Ryan, Ross Cagan
Journal: Cancer Research (2005)

Abstract Patients with hereditary medullary thyroid carcinoma (MTC) associated with multiple endocrine neoplasia (MEN) types 2A and 2B and familial MTC (FMTC) have mutations in the RET proto-oncogene. Approximately 40 percent of patients with papillary thyroid carcinoma (PTC) typically have either intrachromosomal or extrachromosomal rearrangements that join the promoter and NH2-terminal domains of unrelated genes to the COOH-terminal fragment of RET. The RET point mutations associated with MEN2A, MEN2B, or FMTC, or the chromosomal breakpoints and translocations associated with PTC, typically activate the RET receptor tyrosine kinase (RTK). RET kinase inhibitors are likely to be beneficial for patients with hereditary MTC, where currently there is no effective chemotherapy or radiation therapy. Recently, the low molecular weight tyrosine kinase inhibitor ZD6474 was found to block the enzymatic activity of RET-derived oncoproteins in cultured cell lines. We have developed a Drosophila model for MEN2A and MEN2B diseases by targeting oncogenic forms of RET to the developing Drosophila eye. Here we show that, when fed orally, ZD6474 suppressed RET-mediated phenotypes within the context of this in vivo model. Importantly, ZD6474 showed high efficacy and very low toxicity. This compound failed to significantly suppress an activated form of another RTK, the Drosophila epidermal growth factor receptor, nor did it suppress the activity of downstream components of the RET/Ras pathway. Our results support the view that targeting chemical kinase inhibitors such as ZD6474 to tissues with oncogenic forms of RET is a useful treatment strategy for RET-dependent carcinomas.
Towards a theory of intelligence beyond <i>g</i>
Authors: James R. Flynn
Journal: Behavioral and Brain Sciences (2006)

Brain physiology and IQ gains over time both show that various cognitive skills, such as on-the-spot problem solving and arithmetic reasoning, are functionally independent, despite being bundled up in the correlational matrix called g . We need a theory of intelligence that treats the physiology and sociology of intelligence as having integrity equal to the psychology of individual differences.
Workshop IV. Aetiopathogenetic factors in Reiter's syndrome. Adjuvant disease: pathology and immune reactivity.
Authors: C M Pearson, Y H Chang
Journal: Annals of the Rheumatic Diseases (1979)

<h3>Objectives:</h3> To examine the changes in nitric oxide (NO), asymmetric dimethylarginine (ADMA), symmetric dimethylarginine (SDMA), and L-arginine levels in schizophrenia during acute psychotic exacerbation and in bipolar disorder during mania and to compare those changes to healthy controls. <h3>Methods:</h3> Thirty schizophrenia patients with acute psychotic exacerbation and 30 bipolar disorder patients with mania, who attended the Psychiatry Department, Erenköy Hospital for Mental and Nervous Diseases, Istanbul, Turkey, in 2010. Thirty healthy controls were included. The diagnosis was made using the Structured Clinical Interview for Axis I Disorders (SCID-I) interviews. Patients’ demographic data were recorded, and NO, SDMA, L-arginine, and ADMA levels were studied. <h3>Results:</h3> Nitric oxide levels in schizophrenia patients were significantly lower than the control group. Nitric oxide levels in the bipolar group were lower than the control group but the difference was not statistically significant. The levels of SDMA, ADMA, and L-arginine were found to be significantly higher in schizophrenia and bipolar disorder patients than the control group. The disease duration was slightly negatively correlated with NO levels in bipolar patients. In schizophrenia patients, the disease severity was slightly positively correlated with NO levels. <h3>Conclusion:</h3> Significant changes in NO, SDMA, ADMA, and L-arginine levels in schizophrenia and bipolar disorder patients suggest that NO and inhibitors of NO might be implicated in the neurobiology of schizophrenia and bipolar disorder.
Pulsed‐dye laser treatment for recalcitrant viral warts: a retrospective case series of 227 patients
Authors: E.E. Sparreboom, H.G. Luijks, H.A.L. Luiting‐Welkenhuyzen, P.W.J.M. Willems, C.P.M. Groeneveld, H.J. Bovenschen
Journal: British Journal of Dermatology (2014)

Journal Article Pulsed‐dye laser treatment for recalcitrant viral warts: a retrospective case series of 227 patients Get access E.E. Sparreboom, E.E. Sparreboom Department of Dermatology Máxima Medical Centre Veldhoven De Run 4600 P.O. Box 7777 5500 MB Veldhoven the Netherlands Search for other works by this author on: Oxford Academic Google Scholar H.G. Luijks, H.G. Luijks Department of Dermatology Máxima Medical Centre Veldhoven De Run 4600 P.O. Box 7777 5500 MB Veldhoven the Netherlands Search for other works by this author on: Oxford Academic Google Scholar H.A.L. Luiting‐Welkenhuyzen, H.A.L. Luiting‐Welkenhuyzen Department of Dermatology Máxima Medical Centre Veldhoven De Run 4600 P.O. Box 7777 5500 MB Veldhoven the Netherlands Search for other works by this author on: Oxford Academic Google Scholar P.W.J.M. Willems, P.W.J.M. Willems Department of Dermatology Máxima Medical Centre Veldhoven De Run 4600 P.O. Box 7777 5500 MB Veldhoven the Netherlands Search for other works by this author on: Oxford Academic Google Scholar C.P.M. Groeneveld, C.P.M. Groeneveld Department of Dermatology Máxima Medical Centre Veldhoven De Run 4600 P.O. Box 7777 5500 MB Veldhoven the Netherlands Search for other works by this author on: Oxford Academic Google Scholar H.J. Bovenschen H.J. Bovenschen Department of Dermatology Máxima Medical Centre Veldhoven De Run 4600 P.O. Box 7777 5500 MB Veldhoven the Netherlands Correspondence: H.J. Bovenschen. E‐mail: J.Bovenschen@mmc.nl Search for other works by this author on: Oxford Academic Google Scholar British Journal of Dermatology, Volume 171, Issue 5, 1 November 2014, Pages 1270–1273, https://doi.org/10.1111/bjd.13099 Published: 01 November 2014
Isolation and characterization of a cDNA clone encoding the 60-kD component of the human SS-A/Ro ribonucleoprotein autoantigen.
Authors: E Ben-Chetrit, B J Gandy, E M Tan, K F Sullivan
Journal: Journal of Clinical Investigation (1989)

SS-A/Ro is a nucleocytoplasmic ribonucleoprotein (RNP) particle that is a common target of autoimmune response in Sjögren's syndrome (SS) and systemic lupus erythematosus (SLE). Previously, SS-A/Ro has been shown to be composed of at least two polypeptide antigens of 60 and 52 kD noncovalently associated with a set of small RNAs, designated Y1-Y5. A serum from an SS patient was selected to screen a lambda gt11 cDNA library constructed from human T cell lymphoblastic leukemia (MOLT-4) mRNA. An immunoreactive clone was isolated that possessed a 1.8-kb cDNA insert. In vitro transcription and translation of the cDNA resulted in the synthesis of a 57.5-kD polypeptide which was specifically immunoprecipitated by SS-A/Ro antisera. The identity of the cDNA encoded protein as the 60-kD SS-A/Ro antigen was established by proteolytic peptide mapping of the cDNA-encoded protein and the 60-kD HeLa cell antigen. The sequence of the cDNA shows that the 60-kD SS-A/Ro protein possesses both RNA binding protein consensus sequences and a single zinc-finger motif. Recombinant SS-A/Ro antigen produced in bacteria proved to be a sensitive and specific reagent for detection of anti-SS-A/Ro antibodies in patient sera. The availability of the 60-kD SS-A/Ro cDNA will enable detailed analysis of the molecular structure and function of the SS-A/Ro RNP particle and its role in autoimmune pathology.
Inactivation of the Invasion Inhibitory Gene <i>IIp45</i> by Alternative Splicing in Gliomas
Authors: Sonya W. Song, Gregory N. Fuller, Hong Zheng, Wei Zhang
Journal: Cancer Research (2005)

Abstract The invasion inhibitory protein 45 (IIp45) we recently identified was underexpressed in glioblastoma multiforme, the most malignant form of glioma. The IIp45 gene is located at chromosome 1p36 where frequent deletions have been reported in various types of tumors, including gliomas, raising the possibility that IIp45 may be a classic tumor suppressor gene that can be inactivated by frequent point mutations. To test this hypothesis, we sequenced the IIp45 gene in 59 diffuse glioma samples of different grades and histologic subtypes and identified a possible point mutation or a rare polymorphism in only one sample (1.7%), suggesting that IIp45 is not a classic tumor suppressor gene such as p53. Instead, reverse transcription-PCR and subsequent sequencing results revealed a tumor-specific IIp45 spliced isoform (IIp45S) in 20 of 59 (34%) gliomas examined, particularly in glioblastoma multiformes, including native tissue samples (15 of 25; 60%) and cell lines (5 of 5; 100%). The alternative splicing event is independent of 1p36 deletion, which is not common in glioblastoma multiforme. The IIp45S transcript was not detected in any of 18 normal organs, including fetal and adult brain. We determined that the IIp45S isoform results from exclusion of IIp45 exon 7 and encodes a variant protein that carries a COOH terminus different from that of IIp45 due to a frame-shift mutation. IIp45S protein was undetectable in glioma tissues, although IIp45S mRNA was prevalent. We found that IIp45S, once translated, is rapidly degraded by an ubiquitin-proteasome mechanism. Thus, the IIp45 gene is inactivated by a tumor-specific alternative splicing that generates an aberrant and unstable IIp45 isoform in infiltrative gliomas.
Regulation of prohepcidin processing and activity by the subtilisin-like proprotein convertases Furin, PC5, PACE4 and PC7
Authors: N Scamuffa, A Basak, C Lalou, A Wargnier, J Marcinkiewicz, G Siegfried, M Chretien, F Calvo, N G Seidah, A-M Khatib
Journal: Gut (2008)

<h3>Background and aims:</h3> Hepcidin is an iron homoeostasis regulator peptide. Loss-of-function mutations cause juvenile haemochromatosis while its over-expression results in anaemia. However, the mechanism and function of preprohepcidin conversion to mature hepcidins (25, 22 and 20 amino acid C-terminal peptides) are not well known. After removal of the signal peptide, the first proteolytic cleavage occurs within the basic motif RRRRR<sup>59</sup>DT, suggesting the involvement of proprotein convertase (PC) family members in this process. <h3>Methods and results:</h3> Using cell transfection experiments, the processing of preprohepcidin in the human hepatocyte line Huh-7 was found to be inhibited by the Furin inhibitors serpin α1-antitrypsin (α1-PDX) and prosegment preproFurin (ppFurin). Site-directed mutagenesis analysis confirmed the RRRRR<sup>59</sup>DT preprohepcidin cleavage site. In parallel, the lack of preprohepcidin processing found in the PC activity-deficient cell line LoVo was restored by the expression of Furin, paired basic amino acid cleaving enzyme 4 (PACE4), PC5 or PC7. This finding is consistent with the in vitro digestions of a synthetic peptide mimicking the cleavage site of preprohepcidin. In addition, during mouse embryonic development the major expression of hepcidin found in the liver coincided with that of Furin. While hepcidin induces the degradation of the iron transporter ferroportin, its RRRRR<sup>59</sup> to SSSSS<sup>59</sup> mutant is not active. <h3>Conclusions:</h3> These results demonstrate the key role of the convertases Furin, PACE4, PC5 and/or PC7 in the generation and secretion of active hepcidin and suggest that the control of hepcidin processing as a potential therapeutic/diagnostic strategy in hepcidin-related disorders such as haemochromatosis, inflammatory diseases, anaemia and cancer.