tbuckley/cabot-search huggingface dataset:
Slow fractional removal of nonextractable iodine from rat tissue after injection of labeled l-thyroxine and 3,5,3′-triiodo-l-thyronine
Authors: Jack H. Oppenheimer, Martin I. Surks, Harold L. Schwartz
Journal: Journal of Clinical Investigation (1972)

Previous studies have shown that a small but significant proportion of radioiodine from labeled L-thyroxine (T(4)) and 3,5,3'-triiodo-L-thyronine (T(3)) is incorporated into plasma and tissue proteins and is not, therefore, extractable with ethanol or other organic solvents. Other studies have shown that the complex consists, at least in part, of the iodothyronine in apparent covalent linkage with protein. In the present series of experiments the disappearance rate of nonextractable iodine (NEI) was determined in plasma, liver, and kidney after the injection of rats with a single dose of T(4) and T(3) labeled with radioiodine in the phenolic ring. The t(1/2) of NEI decay was substantially longer than the t(1/2) of the initial metabolic removal of T(4) (16 hr) and T(3) (4-6 hr). Thus, between days 3 and 11 the average t(1/2) of plasma NEI derived from T(4) was 2.2 days, from T(3), 1.9 days; kidney NEI from T(4), 7.4 days, from T(3), 6.1 days; hepatic NEI from T(4), 4.3 days, from T(3), 5.2 days. The slow disappearance of liver NEI was of special interest in connection with an analysis of previously published data by Tata and associates dealing with the sequential tissue effects after the injection of a single dose of T(3) into thyroidectomized rats. The t(1/2) of decay of the various biological effects measured, primarily in the liver, appeared similar to each other, averaging between 4 and 6 days. These findings are compatible with the existence of a single long-lived intermediate governing the tissue expression of thyroid hormone. The t(1/2) of hepatic NEI in similarly prepared animals (thyroidectomized and injected with 25 mug of T(3)) was found to be 4.5 days. The coincidence in the slow fractional disappearance rates of hepatic NEI and the dissipation of hormonal tissue effects raises the distinct possibility that T(3) interacts with specific cellular receptor sites to form covalent complexes which are slowly removed and serve both to initiate and to perpetuate hormonal action. A mathematical analysis of hormonal reaction mechanisms, based on the assumption of a linearly responsive system, a t(1/2) of T(3) of 4 hr, and a t(1/2) of 4.5 days for the postulated long-lived "messenger" suggests that maximal expression of hormonal activity cannot be attained before 20 hr after the injection of a hormone pulse. This value is broadly consonant with the observed data accumulated by Tata and associates. The existence of a long-lived messenger, possibly a species of NEI, would therefore explain not only the slow dissipation of hormonal effects but also the well-recognized "lag-time" in the expression of hormonal action.
TGF-β–dependent pathogenesis of mitral valve prolapse in a mouse model of Marfan syndrome
Authors: Connie M. Ng, Alan Cheng, Loretha A. Myers, Francisco Martinez-Murillo, Chunfa Jie, Djahida Bedja, Kathleen L. Gabrielson, Jennifer M.W. Hausladen, Robert P. Mecham, Daniel P. Judge, Harry C. Dietz
Journal: Journal of Clinical Investigation (2004)

Mitral valve prolapse (MVP) is a common human phenotype, yet little is known about the pathogenesis of this condition. MVP can occur in the context of genetic syndromes, including Marfan syndrome (MFS), an autosomal-dominant connective tissue disorder caused by mutations in fibrillin-1. Fibrillin-1 contributes to the regulated activation of the cytokine TGF-beta, and enhanced signaling is a consequence of fibrillin-1 deficiency. We thus hypothesized that increased TGF-beta signaling may contribute to the multisystem pathogenesis of MFS, including the development of myxomatous changes of the atrioventricular valves. Mitral valves from fibrillin-1-deficient mice exhibited postnatally acquired alterations in architecture that correlated both temporally and spatially with increased cell proliferation, decreased apoptosis, and excess TGF-beta activation and signaling. In addition, TGF-beta antagonism in vivo rescued the valve phenotype, suggesting a cause and effect relationship. Expression analyses identified increased expression of numerous TGF-beta-related genes that regulate cell proliferation and survival and plausibly contribute to myxomatous valve disease. These studies validate a novel, genetically engineered murine model of myxomatous changes of the mitral valve and provide critical insight into the pathogenetic mechanism of such changes in MFS and perhaps more common nonsyndromic variants of mitral valve disease.
AMPA receptor ligands: Synthetic and pharmacological studies of polyamines and polyamine toxins
Authors: Kristian Strømgaard, Ian Mellor
Journal: Medicinal Research Reviews (2004)

Alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptors (AMPAR), subtype of the ionotropic glutamate receptors (IGRs), mediate fast synaptic transmission in the central nervous system (CNS), and are involved in many neurological disorders, as well as being a key player in the formation of memory. Hence, ligands affecting AMPARs are highly important for the study of the structure and function of this receptor, and in this regard polyamine-based ligands, particularly polyamine toxins, are unique as they selectively block Ca2+ -permeable AMPARs. Indeed, endogenous intracellular polyamines are known to modulate the function of these receptors in vivo. In this study, recent developments in the medicinal chemistry of polyamine-based ligands are given, particularly focusing on the use of solid-phase synthesis (SPS) as a tool for the facile generation of libraries of polyamine toxin analogues. Moreover, the recent development of highly potent and very selective AMPAR ligands is described. Additionally, we provide a detailed account on the mechanism and site of action of AMPAR blockade by polyamine-based ligands, including examples of how these ligands are used as tools to study AMPAR, and a comparison with their action on other ionotropic receptors.
Rare Variants in <i>RTEL1</i> Are Associated with Familial Interstitial Pneumonia
Authors: Joy D. Cogan, Jonathan A. Kropski, Min Zhao, Daphne B. Mitchell, Lynette Rives, Cheryl Markin, Errine T. Garnett, Keri H. Montgomery, Wendi R. Mason, David F. McKean, Julia Powers, Elissa Murphy, Lana M. Olson, Leena Choi, Dong-Sheng Cheng, Elizabeth Marchani Blue, Lisa R. Young, Lisa H. Lancaster, Mark P. Steele, Kevin K. Brown, Marvin I. Schwarz, Tasha E. Fingerlin, David A. Schwartz, William E. Lawson, James E. Loyd, Zhongming Zhao, John A. Phillips, Timothy S. Blackwell
Journal: American Journal of Respiratory and Critical Care Medicine (2015)

Rationale: Up to 20% of cases of idiopathic interstitial pneumonia cluster in families, comprising the syndrome of familial interstitial pneumonia (FIP); however, the genetic basis of FIP remains uncertain in most families.Objectives: To determine if new disease-causing rare genetic variants could be identified using whole-exome sequencing of affected members from FIP families, providing additional insights into disease pathogenesis.Methods: Affected subjects from 25 kindreds were selected from an ongoing FIP registry for whole-exome sequencing from genomic DNA. Candidate rare variants were confirmed by Sanger sequencing, and cosegregation analysis was performed in families, followed by additional sequencing of affected individuals from another 163 kindreds.Measurements and Main Results: We identified a potentially damaging rare variant in the gene encoding for regulator of telomere elongation helicase 1 (RTEL1) that segregated with disease and was associated with very short telomeres in peripheral blood mononuclear cells in 1 of 25 families in our original whole-exome sequencing cohort. Evaluation of affected individuals in 163 additional kindreds revealed another eight families (4.7%) with heterozygous rare variants in RTEL1 that segregated with clinical FIP. Probands and unaffected carriers of these rare variants had short telomeres (<10% for age) in peripheral blood mononuclear cells and increased T-circle formation, suggesting impaired RTEL1 function.Conclusions: Rare loss-of-function variants in RTEL1 represent a newly defined genetic predisposition for FIP, supporting the importance of telomere-related pathways in pulmonary fibrosis.
mRNA Translation
Authors: Balakuntalam S Kasinath, Meenalakshmi M Mariappan, Kavithalakshmi Sataranatarajan, Myung Ja Lee, Denis Feliers
Journal: Journal of the American Society of Nephrology (2006)

<h3>Abstract</h3> The Kihansi spray toad, <i>Nectophrynoides asperginis</i>, became extinct in the wild despite population monitoring and conservation management of its habitat in the Kihansi gorge, Tanzania. Anecdotal evidence has indicated human induced habitat modification, predators, pesticides and disease as possible causes of a rapid population decline and the species extirpation. Here, we systematically investigate the role of disease in the extinction event of the wild toad population. The amphibian chytrid fungus, <i>Batrachochytrium dendrobatidis</i>, was detected in spray toads that died during the extinction event and subsequently in other amphibian species in Kihansi Gorge and the adjacent Udagaji Gorge, but not in any toads collected prior to this. Following the population decline, the remnant spray toad population gradually disappeared over a nine-month period. We demonstrate how demographic and behavioral attributes predisposed the spray toads to chytridiomycosis, due to <i>B. dendrobatidis</i> infection, and how epidemic disease could have been exacerbated by altered environmental conditions in the spray wetlands. Our results show that chytridiomycosis was the proximate cause of extinction in the wild of <i>N. asperginis</i>. This represents the first known case of extinction by disease of an amphibian species in Africa. A captive breeding program in the US and Tanzania ensures the survival of the species and a reintroduction program is underway. However, we caution that chytridiomycosis remains an existing threat that requires a comprehensive mitigation strategy before the desired conservation outcome of an established population of repatriated toads can be achieved.
ANTIBODIES INVOLVED IN ANTIGEN-INDUCED RELEASE OF SLOW REACTING SUBSTANCE OF ANAPHYLAXIS (SRS-A) IN THE GUINEA PIG AND RAT
Authors: Daniel J. Stechschulte, K. Frank Austen, Kurt J. Bloch
Journal: The Journal of Experimental Medicine (1967)

The antigen-induced release of SRS-A and histamine was studied in the guinea pig and rat using whole and fractionated antiserum preparations. Guinea pig 7Sgamma(1)-antibody sensitized sliced guinea pig lung tissue for antigen-induced release of both SRS-A and histamine; neither substance was released from lung tissue prepared with 7Sgamma(1)-antibody. Rats injected intraperitoneally with hyperimmune rabbit or rat antiserum released only SRS-A in significant amounts when challenged with antigen by the same route. A definite time interval between the injection of antiserum and challenge with antigen was required for optimal release of SRS-A. Fractionation of rat antiserum demonstrated that the immunoglobulin responsible for most of the SRS-A release from rat peritoneal tissue was a gammaG-antibody or fraction thereof. Acting in this capacity, the gammaG-antibody or its subfraction may be considered a second type of homocytotropic antibody. Fractions of rat antisera containing the first type of homocytotropic antibody, i.e. antibody mediating release of histamine and serotonin, prepared peritoneal tissues for the release of large amounts of these pharmacological agents and only small amounts of SRS-A. Two different mechanisms for the production of PCA lesions in the rat were considered. One of these involves the antigen-induced release of histamine and serotonin from mast cells sensitized by homocytotropic antibody. This reaction has an optimal latent period of 24-72 hr. The second mechanism involves the local combination of antigen with "hyperimmune" heterologous or homologous antisera. This reaction can be elicited after a latent period of 4 but not 24 hr; host complement and leukocyte lysosomal enzymes, as well as SRS-A, may be involved.
Hyperthermia-Induced Proteasome Inhibition and Loss of Androgen Receptor Expression in Human Prostate Cancer Cells
Authors: Frank Pajonk, Arndt van Ophoven, William H. McBride
Journal: Cancer Research (2005)

Abstract Prostate cancer is the second leading cause of death in men in western countries and is usually treated by surgery and/or radiotherapy. More recently, hyperthermia has been introduced into clinical trials investigating a possible effect in the first-line treatment of prostate cancer. However, the molecular mechanisms of hyperthermia are not completely understood. In this study, we investigated the effects of hyperthermia on proteasome function and its significance for signal transduction, cell death and androgen receptor (AR) expression in PC-3, LnCaP, and DU-145 human and TRAMP-C2 murine prostate cancer cells. Hyperthermia caused apoptosis and radiosensitization and decreased 26S proteasome activity in all three human cell lines to about 40% of untreated control cells. 20S proteasome activity was not affected by heat. Heat treatment inhibited constitutive and radiation-induced activation of nuclear factor κB caused by stabilization of IκB. Although stabilization of AR by proteasome inhibitors has been reported previously, AR protein levels in LnCaP cells decreased dramatically after heat. Our data suggest that inhibition of proteasome function and dependent signal transduction pathways might be a major molecular mechanisms of heat-induced apoptosis and radiosensitization. Hyperthermia abrogates AR expression in androgen-dependent cells and might thus promote malignant progression of prostate cancer.
Human Polynucleotide Phosphorylase (<b> <i>hPNPase</i> </b> <b> <i>old-35</i> </b>)
Authors: Devanand Sarkar, Irina V. Lebedeva, Luni Emdad, Dong-chul Kang, Albert S. Baldwin, Paul B. Fisher
Journal: Cancer Research (2004)

Abstract Chronic inflammation is a characteristic feature of aging, and the relationship between cellular senescence and inflammation, although extensively studied, is not well understood. An overlapping pathway screen identified human polynucleotide phosphorylase (hPNPaseold-35), an evolutionary conserved 3′,5′-exoribonuclease, as a gene up-regulated during both terminal differentiation and cellular senescence. Enhanced expression of hPNPaseold-35 via a replication-incompetent adenovirus (Ad.hPNPaseold-35) in human melanoma cells and normal human melanocytes results in a characteristic senescence-like phenotype. Reactive oxygen species (ROS) play a key role in the induction of both in vitro and in vivo senescence. We now document that overexpression of hPNPaseold-35 results in increased production of ROS, leading to activation of the nuclear factor (NF)-κB pathway. Ad.hPNPaseold-35 infection promotes degradation of IκBα and nuclear translocation of NF-κB and markedly increases binding of the transcriptional activator p50/p65. The generation of ROS and activation of NF-κB by hPNPaseold-35 are prevented by treatment with a cell-permeable antioxidant, N-acetyl-l-cysteine. Infection with Ad.hPNPaseold-35 enhances the production of interleukin (IL)-6 and IL-8, two classical NF-κB-responsive cytokines, and this induction is inhibited by N-acetyl-l-cysteine. A cytokine array reveals that Ad.hPNPaseold-35 infection specifically induces the expression of proinflammatory cytokines, such as IL-6, IL-8, RANTES, and matrix metalloproteinase (MMP)-3. We hypothesize that hPNPaseold-35 might play a significant role in producing pathological changes associated with aging by generating proinflammatory cytokines via ROS and NF-κB. Understanding the relationship between hPNPaseold-35 and inflammation and aging provides a unique opportunity to mechanistically comprehend and potentially intervene in these physiologically important processes.
Tumour necrosis factor-alpha expression by activated monocytes and altered T-cell homeostasis in ascitic alcoholic cirrhosis: amelioration with norfloxacin
Authors: Agustı́n Albillos, Antonio de la Hera, Eduardo Reyes, Jorge Monserrat, Leticia Muñoz, Mónica Nieto, Alfredo Prieto, Eva Sanz, Melchor Alvarez-Mon
Journal: Journal of Hepatology (2004)
Splice acceptor site mutation of the transporter associated with antigen processing-1 gene in human bare lymphocyte syndrome
Authors: Hiroshi Furukawa, Shigeo Murata, Toshio Yabe, Naoki Shimbara, Naoto Keicho, Kouichi Kashiwase, Kaoru Watanabe, Yoshihide Ishikawa, Tatsuya Akaza, Kenji Tadokoro, Shigeto Tohma, Tetsufumi Inoue, Katsushi Tokunaga, Kazuhiko Yamamoto, Keiji Tanaka, Takeo Juji
Journal: Journal of Clinical Investigation (1999)

Expression of histocompatibility leukocyte antigen (HLA) class I molecules on the cell surface depends on the heterodimer of the transporter associated with antigen processing 1 and 2 (TAP1 and TAP2), which transport peptides cleaved by proteasome to the class I molecules. Defects in the TAP2 protein have been reported in two families with HLA class I deficiency, the so-called bare lymphocyte syndrome (BLS) type I. We have, to our knowledge, identified for the first time a splice site mutation in the TAP1 gene of another BLS patient. In addition, class I heavy chains (HCs) did not form the normal complex with tapasin in the endoplasmic reticulum (ER) of the cells of our patient.
Incidence and Predictors of Early and Late Mortality After Transcatheter Aortic Valve Implantation in 663 Patients With Severe Aortic Stenosis
Authors: Corrado Tamburino, Davide Capodanno, Angelo Ramondo, Anna Sonia Petronio, Federica Ettori, Gennaro Santoro, Silvio Klugmann, Francesco Bedogni, Francesco Maisano, Antonio Marzocchi, Arnaldo Poli, David Antoniucci, Massimo Napodano, Marco De Carlo, Claudia Fiorina, Gian Paolo Ussia
Journal: Circulation (2011)

Background— There is a lack of information on the incidence and predictors of early mortality at 30 days and late mortality between 30 days and 1 year after transcatheter aortic valve implantation (TAVI) with the self-expanding CoreValve Revalving prosthesis. Methods and Results— A total of 663 consecutive patients (mean age 81.0±7.3 years) underwent TAVI with the third generation 18-Fr CoreValve device in 14 centers. Procedural success and intraprocedural mortality were 98% and 0.9%, respectively. The cumulative incidences of mortality were 5.4% at 30 days, 12.2% at 6 months, and 15.0% at 1 year. The incidence density of mortality was 12.3 per 100 person-year of observation. Clinical and hemodynamic benefits observed acutely after TAVI were sustained at 1 year. Paravalvular leakages were trace to mild in the majority of cases. Conversion to open heart surgery (odds ratio [OR] 38.68), cardiac tamponade (OR 10.97), major access site complications (OR 8.47), left ventricular ejection fraction &lt;40% (OR 3.51), prior balloon valvuloplasty (OR 2.87), and diabetes mellitus (OR 2.66) were independent predictors of mortality at 30 days, whereas prior stroke (hazard ratio [HR] 5.47), postprocedural paravalvular leak ≥2+ (HR 3.79), prior acute pulmonary edema (HR 2.70), and chronic kidney disease (HR 2.53) were independent predictors of mortality between 30 days and 1 year. Conclusions— Benefit of TAVI with the CoreValve Revalving System is maintained over time up to 1 year, with acceptable mortality rates at various time points. Although procedural complications are strongly associated with early mortality at 30 days, comorbidities and postprocedural paravalvular aortic regurgitation ≥2+ mainly impact late outcomes between 30 days and 1 year.
Characterisation of oestrogen receptor, progesterone receptor, trefoil factor 1, and epidermal growth factor and its receptor in pancreatic cystic neoplasms and pancreatic ductal adenocarcinoma
Authors: T-S Yeh
Journal: Gut (2002)

<b>Background and aims:</b> The pancreatic cystic neoplasms, including solid pseudopapillary tumour (SPT), mucinous cystic neoplasm (MCN), and intraductal papillary mucin producing tumour (IPMT), have their characteristic clinicopathological features. A systematic investigation of oestrogen receptor (OR), progesterone receptor (PR), trefoil factor 1(TFF1), and epidermal growth factor and its receptor (EGF and EGFR) expressed in pancreatic cystic neoplasms and pancreatic ductal adenocarcinoma was determined to elucidate their corresponding sex and age predilection, cell origin, and pathway of malignant transformation. <b>Methods:</b> Surgical specimens of SPT (n=10), MCN (n=12), IPMT (n=10), and ductal adenocarcinoma (n=20) were studied. The expression of OR, PR, TFF1, EGF, and EGFR were each determined in each disease entity using monoclonal antibodies by immunohistochemical method. The results were correlated with the clinicopathological data. <b>Results:</b> PR was expressed in all 10 SPT, whereas OR was expressed in none of 10 SPT. TFF1 was not or weakly expressed in SPT. Although EGF was strongly expressed in seven of 10 SPT, synchronous expression of EGF and its receptor was expressed in none of 10 SPT. Of the 12 MCN, six had PR expression in the stroma cells but not in the neoplastic epithelium, seven had a moderate or strong expression of TFF1, and 10 had no or weak EGFR expression, irrespective of their benigneity or malignancy. Synchronous expression of EGF and EGFR was observed in only one of 12 MCN. Among 10 IPMT, TFF1 and EGFR were moderately or strongly expressed in all six malignancies, whereas TFF1 and EGFR were not or weakly expressed in three of four benigneity. Of 20 ductal adenocarcinomas, TFF1 and EGFR were moderately or strongly expressed in 16 and 12, respectively. Synchronous expression of EGF and EGFR was observed in six of 10 IPMT and nine of 20 ductal adenocarcinoma, respectively. <b>Conclusion:</b> PR was uniquely expressed in SPT, and OR and PR were expressed in stroma of MCN, reflecting their sex and age predilection. TFF1 expression was related to EGFR such as in IPMT and ductal adenocarcinoma, not related to EGFR such as in MCN, and not related to hormonal receptors such as in SPT. EGF and its receptor might play a part in the malignant transformation of IPMT and ductal adenocarcinoma, but not of SPT and MCN.
HLA-DR antigens in primary biliary cirrhosis: lack of association.
Authors: M F Bassendine, P J Dewar, O F James
Journal: Gut (1985)

A study of HLA-DR antigen in 75 patients with primary biliary cirrhosis has been carried out in order to test the hypothesis that genetic factors related to genes controlling immune responses might be important in the pathogenesis of primary biliary cirrhosis. The frequencies of HLA-DR locus antigens was not significantly different from those in 200 normal controls, nor were those of tissue antigens on the A and B loci. No HLA-DR antigen was significantly associated with the appearance of granulomata on liver biopsy (possibly good prognosis) or with raised serum bilirubin (possibly bad prognosis); nor was there any association between any HLA-DR antigen and adverse reactions to D-penicillamine treatment in 17 patients with such adverse reactions. It is concluded that genetic traits related to HLA antigens studied are probably not important in the aetiology of the disease.