tbuckley/cabot-search huggingface dataset:
Hereditary tyrosinemia. Formation of succinylacetone-amino acid adducts.
Authors: S Manabe, S Sassa, A Kappas
Journal: The Journal of Experimental Medicine (1985)

Succinylacetone (SA) (4,6-dioxoheptanoic acid) is an abnormal metabolite produced in patients with hereditary tyrosinemia as a consequence of an inherited deficiency of fumaryl acetoacetate hydrolase activity. Patients with this disease are associated with a number of abnormalities, including aminoaciduria, proteinuria, liver failure, commonly hepatoma, and decreased GSH concentration in the liver. In the course of our studies of tyrosinemia, we found that the urine of patients with this disorder contains material(s) that absorbs light at 315 nm. We investigated the nature of the 315 nm material in detail. SA was found to react with amino acids and protein nonenzymatically, to form stable adducts at physiological temperature and pH. All SA adducts with amino acids and/or proteins exhibited an absorption peak at 315 nm. Although all amino acids reacted with SA, the most reactive amino acid was lysine (Lys), followed, in order, by glycine, methionine, phenylalanine, serine, alanine, and glutamine. SA-adducts were unstable at pH below 6, while they were made considerably more stable after reduction with NaBH4, suggesting that SA forms an adduct via Schiff base formation. High-performance liquid chromatography (HPLC) analysis of urines from patients with tyrosinemia revealed the existence of SA-glycine, SA-methionine, SA-tyrosine, and SA-phenylalanine. After digestion of urines with proteinase K, three more HPLC peaks appeared, which all corresponded to SA-Lys adducts. TLC analysis of SA-Lys showed that SA-Lys could form as many as seven different adducts. No SA-adduct peaks were observed in HPLC in urines from normal subjects, patients with other forms of aminoaciduria, or patients with the nephrotic syndrome. In addition to amino acids and proteins, SA reacted with reduced glutathione (GSH) and formed a stable adduct. These findings suggest that SA adduct formation with amino acids, GSH, and proteins is a significant process occurring in tyrosinemia, and may account for certain of the pathologic findings in this hereditary disorder.
Questions of the Month: Answers?
Authors: MICHAEL L. LEVIN
Journal: Annals of Internal Medicine (1970)

Letters and Comments1 September 1970Questions of the Month: Answers?MICHAEL L. LEVIN, M.D.MICHAEL L. LEVIN, M.D.Search for more papers by this authorAuthor, Article, and Disclosure Informationhttps://doi.org/10.7326/0003-4819-73-3-490_2 SectionsAboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail ExcerptTo the editor: In reference to the answer for Question 250 (May ANNALS, p. 654), I wonder if an alternative answer might be more appropriate. Since eitherStreptococcusorStaphylococcuscould be the causal agent for the pneumonia and empyema described, I feel drainage of the right pleural space with chest tubes and either a combination of penicillin and a semisynthetic penicillin or cephalothin would provide more appropriate coverage. While awaiting bacteriologic confirmation I think one must consider the possibility of streptococcal disease. Although it is less common than staphylococcal disease, it also would be predisposed to by the answers... This content is PDF only. To continue reading please click on the PDF icon. Author, Article, and Disclosure InformationAffiliations: Division of Infectious Diseases Department of Medicine Sinai Hospital of Baltimore, Inc. Belvedere Ave. at Greenspring Baltimore, Md. 21215 PreviousarticleNextarticle Advertisement FiguresReferencesRelatedDetails Metrics 1 September 1970Volume 73, Issue 3Page: 490-491KeywordsPenicillinPneumoniaStaphylococcusStreptococcusThorax ePublished: 1 December 2008 Issue Published: 1 September 1970 PDF downloadLoading ...
P252 THE CHEMICAL CHAPERON 4-PHENYLBUTYRATE PREVENTS EPIGENETIC ALTERATIONS AND CARCINOGENESIS IN NASH–HCC MODEL MICE
Authors: K. Kon, K. Ikejima, A. Uchiyama, T. Aoyama, K. Arai, M. Morinaga, S. Yamashina, S. Watanabe
Journal: Journal of Hepatology (2014)
Calpains in the cardiovascular system
Authors: J. Inserte
Journal: Cardiovascular Research (2012)

Although proteolytic systems have received much less attention than the processes controlling protein synthesis, their importance for maintaining cellular function is becoming increasingly recognized.Among them are the calpains, a large family of non-lysosomal calciumdependent cysteine proteases.In contrast with other major proteolytic systems such as the proteasome and the lysosomal proteases that are degradative, calpains produce a limited proteolysis of specific substrates.Owing to their dependence on Ca 2+ , calpains have attracted much attention as modulators implicated in a wide variety of biological phenomena including proliferation, cell migration, differentiation, protein homoeostasis, and cell signalling. 1 -5 The genetic alterations in tissue-specific calpains are responsible for various diseases, providing solid evidence of the physiological importance of these enzymes. 5,6owever, many reports have demonstrated that exaggerated calpain activation exacerbates those pathologies that are associated with the loss of Ca 2+ control. 5 -7 In these situations, calpain inhibition constitutes a potential therapeutic strategy.In this Review Focus of Cardiovascular Research, five review articles highlight the current understanding we have gained about the physiological and pathophysiological roles of calpains in the cardiovascular system.First, Sorimachi and Ono 8 introduce us to the calpain system, and, accurately using the recently proposed calpain nomenclature, they describe the main characteristics of the different members of this large family of proteases, traditionally divided into classical and non-classical calpains according to their domain structure.Cells have need of an intricate strategy for the tight regulation of calpain activity.This includes the binding of calpain to its specific endogenous inhibitor calpastatin in a substrate-competitive manner, a differential intracellular localization, and the cellular control of Ca 2+ homoeostasis.The authors describe these molecular mechanisms of calpain activation and address classical questions still unanswered, such as how calpains are activated in the cytosol where the Ca 2+ concentration is far below the concentration needed for their activation in vitro. 9Finally,
Abstract 1285: Genetic variations predicting cisplatin cytotoxicity associated with the overall survival in lung cancer patients receiving platinum-based chemotherapy
Authors: Xiang-Lin Tan, Ann M. Moyer, Daniel J. Schaid, Nifang Niu, Anthony Batzler, Liang Li, Zhifu Sun, Ping Yang, Liewei Wang
Journal: Cancer Research (2011)

Abstract Background: Candidate gene and candidate pathway-based pharmacogenomic studies have been used to investigate the inherited variability of prognosis of lung cancer treated with platinum-based chemoptherapy. In order to make it possible to conduct an ‘unbiased’ query across the entire genome, a genome-wide association study (GWAS) in 283 lymphoblastoid cell lines (LCLs) was carried out to help identify candidate SNPs associated with variation in cisplatin cytotoxicity. Furthermore, we set out to test the hypothesis that genetic variation resulting in differences in cisplatin cytotoxicity might influence the overall survival of patients with lung cancer treated with platinum-based antineoplastic agents. Material and Methods: We applied ethnically diverse Coriell “Human Variation Panel” LCLs for GWAS. Then, we picked 168 top significant SNPs selected from GWAS in 283 LCLs and genotyped these SNPs in 1183 lung cancer patients (222 SCLC and 961 NSCLC) who received platinum-based chemotherapy. Genotyping was performed using the Illumina Golden Gate platform. The association of SNPs with lung cancer overall survival was analyzed by Cox regression model after adjusting for disease stage. Functional validation of candidate genes was performed by siRNA screening in NSCLC cell lines CRL5872, H1299 and SCLC cell line CRL5823. Results: A total of 157 SNPs were successfully genotyped for 1183 lung cancer patient samples. The Cox regression analysis indicated that 9 and 10 different SNPs were associated with overall survival for NSCLC and SCLC patients, respectively (p value &amp;lt;0.05). Fifteen genes including 7 genes located in the region of 200kb up or downstream of 4 SNPs (rs11169748, rs2440915, rs5952066 and rs7620841) and 8 genes for which the expression was correlated with three SNPs (rs11169748, rs2440915 and rs5952066) were selected for siRNA screening. Knockdown of DAPK3 and METTL6, for which the expression levels were correlated with the SNPs rs11169748 and rs2440915, significantly decreased cisplatin sensitivity in lung cancer cell lines CRL5872, H1299 and CRL5823. Conclusions: This series of clinical and complementary laboratory-based functional studies identified several candidate genes and SNPs that might help predict treatment outcomes of platinum-based therapy in lung cancer. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1285. doi:10.1158/1538-7445.AM2011-1285
Abstract 4178: Tcl1 enhances keratinocytes’ survival/proliferation by promoting erk and jnk/sap phosphorylation at the expense of p38 and by controlling c-fos expression through miR-29b and miR-181a-1
Authors: Antonella Bresin, Maria Grazia Narducci, Cristina Picchio, Cristina Cristofoletti, Mauro Helmer Citterich, Elisabetta Caprini, Valeria Tocco, Cristina Lazzeri, Giandomenico Russo, Gianluca Ragone
Journal: Cancer Research (2012)

Abstract The Tcl1 oncogene has been initially isolated for its involvement in chromosomal translocations of T-prolymphocytic leukemias and overexpression in B chronic lymphocytic leukemia by enhancing AKT nuclear translocation and allowing the Ser-473 transphosphorylation. Tcl1, also, acts as AP-1 transcriptional inhibitor, by interacting with c-fos and c-jun. More recent works have associated Tcl1 to proliferation and self-renewal ability of ES cells under the direct activation of OCT3/4, Zfx, KLF5 transcription factors, being Tcl1 expressed in preimplantation embryos where it allows the progression beyond the 4-cells stage. We have recently shown that the Tcl1 oncogene is expressed in epidermis and defines secondary hair germ (transient-amplifying, TA) cells differentiation at catagen-telogen (the degenerative-resting phase of the hair follicle (HF)) transition, allowing the proliferation of TA cells in anagen (regenerative phase of the HF), giving the slow-cycling stem cells, the ability to incorporate BrdU. In fact, Tcl1 mutant (Tcl1-/-) affects stem-cell marker CD34 expression and BrdU incorporation in the bulge and TA cells, resulting in skin defects in adults with the onset of alopecia followed by skin wounding. Phenomena that are almost completely rescued by K14-TCL1 transgenic expression, in vivo. Since Tcl1 has a role in maintenance of a normal skin homeostasis in mice, involving both hair growth and epidermis, we used the approach of the expression chip analysis to unravel the pathways that are affected by loss of function and overexpression of Tcl1 in epidermal keratinocytes, by using Tcl1-/- and K14-TCL1;Tcl1-/- mice models. Our findings show that Tcl1 function involves the MAPK pathway, since Tcl1-/- shows increasing in p38MAPK phosphorylation linked to terminal differentiation/senescence/apoptosis of keratinocytes, while K14-driven overexpression shows increasing of p-Erk and p-Sapk/p-Jnk phosphorylations, linked to proliferation/commitment of keratinocytes. These signals flow through the MAPK cascade lead to altered AP1 factor function. In particular, the phosphorylation of AP-1 subunit c-Jun and c-fos transcriptional regulation and cellular localization result also affected. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4178. doi:1538-7445.AM2012-4178
A treatise on the medical jurisprudence of insanity.
Authors: Marjorie C. Meehan
Journal: JAMA (1963)

First published in 1838, Ray's classic work was the first systematic treatise in English which discussed the relations of law and mental illness. It is well worth a reissue. During Ray's lifetime (1807-1881), five editions appeared in the United States and one in England. Now, a new edition has been published as part of the John Harvard Library, a collection of scholarly editions of early American writings. This volume is edited by Dr. Winfred Overholser, former superintendent of St. Elizabeth's Hospital in Washington, and himself an author of important works on the relations of law and psychiatry. Although Ray's classification of mental illness may seem oversimplified and his terms may imply concepts not generally accepted now, many of his comments are pertinent and his case descriptions vivid and thought provoking. He shows little concern with etiology and, by present standards, little knowledge in this regard; however, he does insist on
Most African-American Patients with Rheumatoid Arthritis Do Not Have the Rheumatoid Antigenic Determinant (Epitope)
Authors: D. Olga McDaniel
Journal: Annals of Internal Medicine (1995)

Objective: To evaluate the relation between the presence of the "rheumatoid epitope," defined by a sequence motif in the HLA-DRB1 alleles, and disease severity in African-American patients with rheumatoid arthritis. Design: Cross-sectional study. Setting: Rheumatology outpatient clinics at two university medical centers. Patients: 86 African-American patients with rheumatoid arthritis (66 seropositive and 20 seronegative for the rheumatoid factor) attending the clinics and 88 healthy African-American persons. Measurements: HLA-DRB1 alleles were determined by restriction fragment length polymorphism and by allele-specific oligonucleotide typing of polymerase chain reaction-amplified HLA-DRB1 second exons. Results: With the exception of an increased frequency of HLA-DRB1*04 alleles in seropositive patients with rheumatoid arthritis (27.3%) compared with controls (13.1%) (P = 0.02), the frequencies of HLA-DRB1 alleles were similar in patients and controls. Most seropositive (48 of 66) and seronegative (15 of 20) patients were HLA-DR4 negative, but some (7 of 48 seropositive patients and 3 of 15 seronegative persons) inherited the rheumatoid epitope on a non-DR4 allele. Disease features, including severity, were similar for patients without the epitope and for those with either a single or a double dose of an epitope-positive allele. Positivity for rheumatoid factor, but not for the rheumatoid epitope, was weakly associated with severity in these patients. Conclusion: Most African-American patients with rheumatoid arthritis did not express the rheumatoid epitope. The predisposition to and severity of rheumatoid arthritis in African-Americans appears to be independent of the presence and dose of the shared rheumatoid epitope.
P3-108: Correlative genomics in a phase II clinical trial of first-line therapy of erlotinib for clinically selected patients with advanced non-small cell lung cancer
Authors: Janessa J. Laskin, Trevor Pugh, Lorena Barclay, Margaret Sutcliffe, Diana Ionescu, Stephen Lam, Barbara Melosky, Cheryl Ho, Nevin Murray, Christopher W. Lee, Marco Marra
Journal: Journal of Thoracic Oncology (2007)
Flow Cytometric Screening of Monoclonal Antibodies for Drug or Toxin Targeting to Human Cancer
Authors: L. G. Durrant, R. A. Robins, R. W. Baldwin
Journal: JNCI Journal of the National Cancer Institute (1989)

Monoclonal antibodies (MAbs) that are candidates for antibody-directed therapy were evaluated by a flow cytometric method. This method accurately quantitates the intensity of staining and the percentage of cells from freshly derived primary tumors expressing the relevant cell surface antigens. This method was applied to human colorectal, gastric, and ovarian carcinomas. It allowed calculations of the number of drug molecules that potentially could be delivered by each MAb as well as selection of the optimal combinations of antibodies for treatment of each type of cancer. The binding of all the MAbs varied among the tumors, although combinations of antibodies reduced this problem. A combination of MAbs C14 and NCRC-23 recognized 97% of colorectal tumors. A combination of C14, NCRC-23, and 791T/36 recognized 95% of gastric tumors. Combinations of either 791T/36 and C14 or 791T/36 and NCRC-11 recognized 80% of ovarian tumors. The number of cells binding with a single MAb varied within the tumor. The optimal anti-colorectal tumor antibody was NCRC-23 (anti-carcinoembryonic antigen), which recognized a mean of 65% of the large cells within a tumor at a mean antigen density of 4.9 X 10(5) sites/cell. The optimal anti-gastric tumor antibody was C14 (anti-Y hapten), which recognized a mean of 66% of the large cells within a tumor at a mean antigen density of 4.4 X 10(5) sites/cell. The optimal anti-ovarian antibody was 115/D8, which recognized 54% of the large cells at a mean antigen density of 4.2 X 10(5) sites/cell. These antigen densities were similar to those calculated for HLA/ABC antigens in colorectal and ovarian cancers. However, the gastric tumors expressed elevated levels of major histocompatibility complex class I antigens, with a mean density of 7.3 X 10(5) sites/cell. Combinations of antibodies that recognize a high proportion of tumor cells are likely to be necessary for MAb-drug targeting to prevent tumor recurrence and/or metastases.
Small intestinal adenocarcinoma, duodenal carcinoid tumour, and von Recklinghausen's neurofibromatosis.
Authors: G T Williams, D F Griffiths, E D Williams
Journal: Gut (1988)

<h3></h3> To explore the change in the expression of pentraxin 3 (PTX3)-mRNA and its clinical significance in fetal lung tissues with intrauterine infection related to premature rupture of membranes (PROM). From Oct.2010 to Oct.2011, a total of 12 cases of fetal death, stillbirth, abortion or miscarriage of fetal lung specimens were assigned to this study. Fetal lung samples were devided into two groups according to with or without intrauterine infection related to PROM. Fetal lung tissue specimens were fixed with 4g/L of paraformaldehyde and paraffin embedded within 2h, 4mm serial section, and then HE staining. Light microscope was used to identify whether infection/inflammatory response existed in fetal lung tissues or not. Total RNA samples from fresh lung tissure were reverse transcribed into Cdna. Gly ceraldehyde-3-phosphate (GAPDH) was used as reference gene. qRT-PCR and relative quantitative analysis method were performed to detect the expression of mRNA in lung tissue in two groups. Relative expression of Mrna in two groups were compared by ΔCt method of relative quantification. The results showed that: There was a larger number of neutrophil infiltration, red blood cells leakage, viscous liquid and inflammatory cell exudation in fetal lung tissues of study group. Study group displayed higher expression of PTX3-mRNA than in control group (5.77±0.68 vs. 4.71±0.40, p=0.002). <h3>Conclusions</h3> The expression of PTX3-mRNA was significantly increased in fetal lung tissues with intrauterine infection related with PROM, which can be regarded as a sensitive index for the early diagnosis of fetal intrauterine infection when PROM exists.
Acoustic properties of the normal chest
Authors: F Dalmay, MT Antonini, P Marquet, R Menier
Journal: European Respiratory Journal (1995)

Laennec invented the stethoscope in 1816 and published a treatise on auscultation in 1819. We then had to wait until the 1950s to observe development of modern devices and methods of recording and signal-processing, which allowed objective studies of lung sounds in time and frequency fields. Tracheobronchial sounds generated by ventilation originate in the upper airways, the frequency content of these sounds has led to extensive research. Consolidated lungs act as more efficient sound conductors to the chest wall (bronchial breathing murmur). Tracheobronchial sounds contain higher frequency components compared to vesicular lung sounds. The origin of vesicular lung sounds has been becoming progressively clear for about 10 yrs. It is at least partly produced locally, deep, and probably intralobular. Clearly, further studies need to be performed in order to elucidate the true mechanisms involved in generating vesicular lung sounds, the redistribution of intrapulmonary gas or vibrations caused by the stretching of lung tissue. The devices developed are already useful for monitoring the state of patients in intensive care. Sooner or later, real time analysis and automated diagnosis will become available.
Endoscopy of the Upper Gastrointestinal Tract
Authors: Jacques Van Dam, William R. Brugge
Journal: New England Journal of Medicine (1999)

The rapid development of high-technology procedures has come at a time when the ability of the U.S. health care system to provide expensive services to all patients is increasingly constrained. The inverse relation between expanding medical achievement and contracting resources for health care delivery has stimulated an evaluation of the appropriate use of endoscopic procedures. Serious concern about the effects of a reduction in health care costs on the quality of patient care has led to critical analysis of endoscopic practice.13 There appears, however, to be little consensus on the appropriate uses of endoscopic procedures. In prospective trials involving . . .
The Thucydides syndrome
Authors: A. D. Langmuir
Journal: JAMA (1987)

To the Editor.—  Two articles and an editorial in the Feb 27 issue ofThe Journal 1-3 establish the existence of toxic shock syndrome as a complication of influenza. They also, at least partially, verify the hypothesis that epidemic influenza accompanied by superinfection with noninvasive, toxigenic strains of staphylococci was the explanation for the plague of Athens of 430 to 427 BC. We have proposed the term Thucydides syndrome for this disease. 4   Certain clinical differences exist between the modern cases thus far described and those that occurred in ancient Attica. We believe that these differences can be readily explained in a manner wholly consonant with the known clinical manifestations produced by various staphylococcal exotoxins.  The recent cases follow closely the rather rigid diagnostic criteria first described by Todd et al 5 and codified by the Centers for Disease Control. These include the rapid onset of hypotension, scarlatiniform rash followed
Research priorities in complementary medicine
Authors: E Ernst, N C Abbot
Journal: BMJ (1996)

EDITOR,—Prioritising research in a climate of limited resources has become an important issue; complementary medicine is no exception in this respect.1 Yet it is sometimes claimed that complementary medicine is so fundamentally different, in its operation if not in its goals, from mainstream medicine that its investigation requires a different research agenda.2

In an attempt to determine which priorities are …