tbuckley/cabot-search huggingface dataset:
Abstract 1088: Differences in p53 signaling following induction of nucleotide pool deficiencies with hydroxyurea or PALA
Authors: Cortney L. Heyer, Richard G. Moran
Journal: Cancer Research (2010)

Abstract The tumor suppressor p53 is stabilized following the induction of deficiencies in nucleotide pool levels by antimetabolites. N-(phosphonacetyl)-L-aspartate (PALA) reversibly inhibits aspartate transcarbamylase, causing interruption of de novo pyrimidine synthesis; hydroxyurea (HU) reversibly inhibits ribonucleotide reductase, inhibiting the conversion of ribonucleotide triphosphates to deoxynucleotide triphosphates. When HCT116, a human colon carcinoma cell line, is treated with either HU or PALA, p53 accumulates and cells arrest in S-phase. Beyond these similarities, the cellular responses to PALA and HU are strikingly different. Chk1 is phosphorylated to a far greater extent in HU-treated HCT116 cells than following PALA treatment. The lack of Chk1 phosphorylation observed during PALA treatment was found to be due to the p53-dependent transcriptional activation of the Wip1 phosphatase, rather than the inactivity of ATR. Chromatin immunoprecipitation studies performed on PALA-treated cells demonstrated the presence of p53 at the Wip1 promoter, and both Wip1 transcript and protein levels were elevated. In contrast, the residency of p53 over the Wip1 promoter was not observed during HU treatment, nor was Wip1 protein or transcript elevated. During PALA treatment of the isogenic p53 null HCT116 cell line, Wip1 transcript levels are not elevated and Chk1 phosphorylation is restored, demonstrating the role of p53 in the elevation of Wip1 following PALA treatment. Although p53 accumulates during both HU and PALA treatment, the responses to the individual drugs differ so greatly that PALA-treated cells undergo a p53-dependent apoptosis while HU-treated cells enter a cytostatic cell cycle arrest. The post-translational modifications of p53 are dissimilar in the two treatments suggesting a variation of signaling to p53 as well as the downstream actions of the modified p53. The accumulated p53 in PALA-treated cells is phosphorylated at serine 46, an event needed to direct p53 to pro-apoptotic promoters; this phenomenon is not observed in HU-treated cells. Hence, during de novo pyrimidine synthesis inhibition, p53 promotes Wip1 transcription causing dephosphorylation of Chk1 leading to apoptosis. When deoxynucleotide triphosphate synthesis is inhibited, Chk1 is phosphorylated promoting cellular arrest in S-phase. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1088.
S100A8 and S100A9 induce a catabolic shift in chondrocytes from human osteoarthritis patients
Authors: R. Schelbergen, A. Blom, A. Sloetjes, T. Vogl, J. Roth, W. B. van den Berg, P. van Lent
Journal: Annals of the Rheumatic Diseases (2011)

<h3>Background and objective</h3> S100A8 and S100A9 are damage associated molecular patterns that are associated with inflammation and cartilage and bone erosion during human rheumatoid arthritis. They are produced in large amounts by monocytes and activated macrophages and can signal via Toll-like receptor 4. Recent studies in our lab show that S100A8 and S100A9 are also associated with cartilage degradation in experimental osteoarthritis (OA). In the present study, the authors investigated whether S100A8, S100A9 and/or S100A8/S100A9 complex could activate human chondrocytes and skew them towards a cartilage breakdown phenotype. Moreover, the authors wondered whether this catabolic shift was specific for chondrocytes from OA patients. <h3>Methods</h3> S100A8 and S100A9 protein detection was performed in human cartilage from OA and non-OA donors using immunohistochemistry. In adjoining slides specific matrix metalloproteinase (MMP) and aggrecanases cartilage breakdown epitopes, VDIPEN and NITEGE, were detected with immunohistochemistry. Human chondrocytes from OA and non-OA donors were isolated and stimulated with recombinant S100A8, S100A9 and S100A8/A9 heterodimer. mRNA levels of MMP, cytokines and cartilage matrix molecules were determined with qPCR and protein levels using Luminex. <h3>Results</h3> S100A8 and S100A9 proteins were abundantly present in and around chondrocytes derived from human cartilage as shown by immunolocalisation, suggesting that these small sized monomeric molecules (12 kD) are able to penetrate the cartilage matrix. Moreover, S100A8 and S100A9 were correlated with VDIPEN and NITEGE cartilage breakdown epitopes. In addition, S100A8 and S100A9, but not the S100A8/A9 heterodimer, upregulated expression of MMP1, −3, −9 and −13 (3- to 6-fold) and cytokines interleukin (IL)-6, IL-8 and MCP-1 (3- to 24-fold) in human OA chondrocytes, on both mRNA and protein level. Furthermore, S100A8 and S100A9 downregulated mRNA expression of matrix molecules aggrecan and collagen type II (2- to 3-fold). Finally, the authors compared the effects of S100A8 and/or S100A9 on OA chondrocytes with those on non-OA chondrocytes. The catabolic effect of S100A8 and S100A9 on MMP1, MMP3 and aggrecan was significantly higher in OA chondrocytes compared to non-OA. <h3>Conclusions</h3> S100A8 and S100A9 are found in and around human chondrocytes. S100A8 and S100A9, but not the heterodimeric S100A8/S100A9 complex, can skew human chondrocytes towards a catabolic phenotype promoting cartilage breakdown. This skewing seems to be specific for chondrocytes from OA patients. S100A8 and/or S100A9 may prove crucial markers for measuring cartilage destruction.
A TYPE SPECIFIC SUBSTANCE DISTINCT FROM THE SPECIFIC CARBOHYDRATE IN PNEUMOCOCCUS TYPE I
Authors: John F. Enders
Journal: The Journal of Experimental Medicine (1930)

1. Evidence has been presented for the existence of a substance distinct from the specific carbohydrate in the autolytic products of Pneumococcus Type I. 2. The substance reacts specifically by precipitating homologous antiserum which either occurs naturally without antibody against the specific carbohydrate or has been deprived of that antibody artificially. 3. In guinea pigs passively sensitized with such antisera the homologous autolysate containing the substance alone produces typical lethal anaphylactic shock. 4. In weakly alkaline solution the substance is destroyed by boiling. In weakly acid solution it resists a temperature of 100°C. for at least ½ hour. Autoclaving for 1 hour at 15 pounds pressure in either acid or alkaline solution destroys its activity as precipitinogen. 5. The substance is resistant to peptic digestion. 6. The chemical nature and the possible identification of the substance as a haptene have been discussed.
Conditional Abatement of Tissue Fibrosis Using Nucleoside Analogs to Selectively Corrupt DNA Replication in Transgenic Fibroblasts
Authors: Masayuki Iwano, Andreas Fischer, Hirokazu Okada, David Plieth, Chengsen Xue, Theodore M. Danoff, Eric G. Neilson
Journal: Molecular Therapy (2001)

Progressive tissue fibrosis can compromise epithelial function resulting in organ failure. Appreciating evidence suggests that fibroblasts provide fibrogenic collagens during such injury. We further tested this notion by attempting to reduce the physiologic consequences of organ fibrosis through the selective killing of fibroblasts at sites of injury. Here, we report the conditional reduction of tissue fibroblasts using the coding sequence for herpesvirus thymidine kinase (ΔTK) put under the control of a cell-specific promoter from the gene encoding fibroblast-specific protein 1 (FSP1). Transgenic fibroblasts from mice carrying FSP1.ΔTK minigenes expressed thymidine kinase concordantly with native FSP1 and, compared to transgenic epithelium, were selectively susceptible to the lethal effects of nucleoside analogs either in culture or during experimental renal fibrosis. The numbers of fibroblasts in fibrogenic kidney tissue were reduced on exposure to nucleoside analogs as was the degree of type I collagen deposition and the extent of fibrosis. Fibroblast reduction following the stress of DNA chain termination highlights the important contribution of cell division during fibrogenesis. Our findings convey a proof of principle regarding the importance of FSP1+ fibroblasts in fibrosis as well as providing a new approach to treating the relentless scarification of tissue.
Hepcidin, iron status, and renal function in chronic renal failure, kidney transplantation, and hemodialysis
Authors: Jolanta Malyszko, Jacek S. Malyszko, Krystyna Pawlak, Michal Mysliwiec
Journal: American Journal of Hematology (2006)

Hepcidin is a small defensin-like peptide whose production by hepatocytes is modulated in response to anemia, hypoxia, or inflammation. Hepcidin could also act as an indicator of functional iron deficiency in these patients. Cross-sectional study was performed to assess hepcidin correlations with renal function, iron status, and hsCRP in patients with chronic renal failure on conservative treatment, on hemodialyses, and in kidney transplant recipients. Iron status, complete blood count, creatinine, albumin, lipids were assessed using standard laboratory methods. GFR was estimated using MDRD formula. Hepcidin and high sensitivity CRP were measured using commercially available kits. Ferritin and hepcidin were higher in hemodialyzed patients, kidney transplant recipients, and patients with chronic renal failure over controls. In patients with chronic renal failure, hepcidin correlated significantly with total protein, albumin, creatinine, and eGRF. In kidney transplant recipients, hepcidin correlated significantly in univariate analysis, with total protein, ferritin, time after transplantation, creatinine, eGRF and tended to correlate with cholesterol. In hemodialyzed patients hepcidin, correlated significantly with triglycerides, albumin, creatinine, urea, residual renal function, and hsCRP. In healthy volunteers, hepcidin was related to triglycerides and ferritin. Multiple regression analysis in hemodialyzed patients showed that hepcidin was independently related to creatinine, triglycerides, and residual renal function. Multiple regression analysis in kidney transplant recipients showed that hepcidin was independently related only to GFR and ferritin. Elevated hepcidin in all groups of patients studied may be due to low grade inflammation, frequently encountered in this population and mainly to impaired renal function. Am. J. Hematol., 2006. © 2006 Wiley-Liss, Inc.
Abstract LB-227: New SRC inhibitors induce p27-mediated apoptosis in mesothelioma cell lines
Authors: Paola Indovina, Francesca Giorgi, Valeria Rizzo, Baharak Khadang, Silvia Schenone, Eliseo Mattioli, Valentina Tomei, Domenico Dimarzo, Iris M. Forte, Vittorio D'Urso, Maurizio Botta, Antonio Giordano, Francesca Pentimalli
Journal: Cancer Research (2011)

Abstract Malignant mesothelioma (MM) is a highly aggressive tumor of the serous membranes for which there is currently no specific curative modality. Recent data suggest that hyperactivation of the tyrosine kinase SRC has a key role in MM development and therefore this kinase represents an important molecular target for MM therapy. We tested new pyrazolo-[3,4-d]-pyrimidine SRC inhibitors on a panel of MM cell lines expressing the active form of SRC. These SRC inhibitors exerted a significant proapoptotic effect on MM cells without affecting the normal mesothelial cell line MET-5A, supporting a possible use of these SRC inhibitors for a safe treatment of MM. We also showed that SRC inhibitor-induced apoptosis occurred concomitantly with an increase in the nuclear stability of the cyclin-dependent kinase inhibitor p27. This finding is remarkable considering that loss of nuclear p27 expression is a well-established adverse prognostic factor in MM and p27 nuclear localization is crucial for its tumor suppressive function. Consistently, SRC inhibition seems to promote the increase in p27 nuclear level also by inactivating the AKT kinase and downregulating cyclin D1, which would otherwise delay p27 nuclear import and provoke its cytoplasmic accumulation. To determine whether p27 stabilization has a direct role in apoptosis induced by SRC inhibition, we stably silenced the CDKN1B gene, encoding p27, in MSTO-211H and REN mesothelioma cells by transduction with lentiviral vectors expressing short hairpin RNAs against the CDKN1B transcript. Strikingly, p27 silencing was able to suppress the apoptosis induced by these SRC inhibitors in both MM cell lines, suggesting that p27 has a crucial proapoptotic role in MM cells treated with SRC inhibitors. Our findings reveal a new mechanism, dependent on p27 nuclear stabilization, by which SRC inhibition can induce apoptosis in MM cells and provide a new rationale for the use of SRC inhibitors in MM therapy. 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 LB-227. doi:10.1158/1538-7445.AM2011-LB-227
A City Dreams: A Survey Approach to Normative Dream Content
Authors: MILTON KRAMER, CAROLYN WINGET, ROY M. WHITMAN
Journal: American Journal of Psychiatry (1971)

The dream reports of an adult population obtained by a survey questionnaire revealed the preoccupations of the population and are different in some aspects from the early memories of the same population. Dream reports contain equal frequencies of aggressive and friendly social interactions, tend to be more negative as to mood and event outcome, have more anxiety than hostility, and refer mainly to the family. Early memories have more familiar settings, oral incorporation, castration anxiety, and overt hostility.
Autophagy and neurodegeneration
Authors: Rebecca A. Frake, Thomas Ricketts, Fiona M. Menzies, David C. Rubinsztein
Journal: Journal of Clinical Investigation (2015)

Most neurodegenerative diseases that afflict humans are associated with the intracytoplasmic deposition of aggregate-prone proteins in neurons. Autophagy is a powerful process for removing such proteins. In this Review, we consider how certain neurodegenerative diseases may be associated with impaired autophagy and how this may affect pathology. We also discuss how autophagy induction may be a plausible therapeutic strategy for some conditions and review studies in various models that support this hypothesis. Finally, we briefly describe some of the signaling pathways that may be amenable to therapeutic targeting for these goals.
Children are another group at risk of hyponatraemia perioperatively
Authors: D. Bohn
Journal: BMJ (1999)

EDITOR—Our poor understanding and practice of giving fluid and electrolytes perioperatively spans all age groups. The editorial by Lane and Allen highlighted elderly postmenopausal women as being particularly at risk of hyponatraemia postoperatively,1 as has been emphasised in several case series, 2 3 and the electronic responses to the editorial also concentrated on this age group (www.bmj.com/cgi/content/full/318/7195/1363#responses).

The use of hypotonic saline is standard practice for the paediatric age group. This practice is based on calculations of normal physiological requirements for salt and …
Accuracy of Fibroscan, Compared With Histology, in Analysis of Liver Fibrosis in Patients With Hepatitis B or C: A United States Multicenter Study
Authors: Nezam H. Afdhal, Bruce R. Bacon, Keyur Patel, Eric J. Lawitz, Stuart C. Gordon, David R. Nelson, Tracy L. Challies, Imad Nasser, Jyotsna Garg, Lee-Jen Wei, John G. McHutchison
Journal: Clinical Gastroenterology and Hepatology (2014)
Morning Peak in Ventricular Tachyarrhythmias Detected by Time of Implantable Cardioverter/Defibrillator Therapy
Authors: Geoffrey H. Tofler, Otavio C. E. Gebara, Murray A. Mittleman, Peter Taylor, William Siegel, Ferdinand J. Venditti, Carl A. Rasmussen, James E. Muller, for the CPI Investigators
Journal: Circulation (1995)

Background A morning peak in occurrence of sudden cardiac death has been identified in epidemiological studies, but the studies are subject to selection bias, with the exclusion of unwitnessed deaths, which are more likely to occur at night. The recent availability of implantable cardioverter/defibrillators that record the time of ventricular tachyarrhythmias requiring either pacing or shock therapy provides an opportunity to clarify the timing of ventricular tachyarrhythmias predisposing to sudden cardiac death. Analysis of the timing of arrhythmias in different patient subgroups, such as patients with poor left ventricular function, may provide further insight into the mechanism of onset of sudden cardiac death. Methods and Results We studied patients in whom a cardioverter/defibrillator (Ventak PRx) was implanted between September 1990 and September 1993 in US centers. Events that could be timed occurred in 483 patients. With an RR cycle length of 240 ms as a cutoff, corresponding to a heart rate of 250 beats per minute, episodes were categorized as rapid (n=1217) or less rapid (n=9266) ventricular tachyarrhythmias. A higher proportion of both rapid and less rapid ventricular tachyarrhythmias began in the late morning compared with other times of the day. The subgroup of patients with ejection fraction &lt;20% at the time of implantation demonstrated a more uniform 24-hour distribution of tachycardias ≤250 beats per minute than patients with higher left ventricular ejection fraction. Conclusions Further investigation of the late morning peak and of precipitants of ventricular tachyarrhythmias by use of data from the implantable cardioverter/defibrillator may provide insight into the pathophysiological mechanisms causing sudden cardiac death.
Congenital syphilis. Why is it still occurring?
Authors: L. Mascola
Journal: JAMA (1984)

A total of 159 cases of early congenital syphilis were reported in the United States during 1982, with Texas reporting 50 cases. We reviewed these Texas cases to identify the most important characteristics on which to focus control efforts. Thirty-eight mothers were 25 years of age or younger; 33 were unmarried. All were from minority groups. No congenital syphilis occurred in whites. Blacks were twice as likely as Hispanics to have an infected infant. Foreign-born Hispanic women were three times more likely to be delivered of an infected child than Hispanics born in the United States. Attendance at prenatal care facilities significantly affected the risk of being delivered of an infected child in both black and Hispanic women; 31 women received no prenatal care. Based on these findings, congenital syphilis in Texas can be reduced primarily through improving prenatal care for high-risk populations and by refining casefinding efforts to control infectious syphilis in the community.
Effects of a nitric oxide synthase inhibitor in humans with septic shock
Authors: A. Petros, G. Lamb, A. Leone, S. Moncada, D. Bennett, P. Vallance
Journal: Cardiovascular Research (1994)

Objective: Studies in animals have indicated that increased production of nitric oxide from an inducible isoform of nitric oxide synthase contributes to the pathophysiology of endotoxic and cytokine induced shock. The aim of this study was to determine the role of nitric oxide in septic shock in humans. Methods: The study was a randomised, double blind, placebo controlled investigation of the effects of the nitric oxide synthase inhibitor NG monomefhyl-L-arginine (L-NMMA) in 12 patients with severe sepsis associated with hypotension. Measurements of haemodynamic, haematologieal, and biochemical variables were made. Results: L-NMMA (0.3 and 1 mg·kg−1) produced a dose dependent increase in mean arterial pressure, systemic vascular resistance, pulmonary vascular resistance, central venous pressure, and pulmonary artery occlusion pressure, and a decrease in cardiac output and heart rate. In response to the highest dose of L-NMMA systemic vascular resistance increased from 547(SEM 92) to 889(143) dyne·s·cm−5, mean arterial blood pressure increased from 80.9(2.9) to 100.5(6.1) mm Hg, and cardiac output decreased from 11.2(2.1) to 8.9(1.9) litres·min−1. Continuous infusion of L-NMMA (1 mg·kg−1·h−1) produced sustained haemodynamic changes. Platelet numbers decreased during the course of the study in both the L-NMMA and the placebo group and did not differ significantly between the groups. Conclusions: Low doses of L-NMMA cause a widespread increase in vascular tone and raise blood pressure in patients with septic shock. Overproduction of nitric oxide appears to be an important mechanism in septic shock in patients, and inhibition of nitric oxide synthesis might provide a novel therapeutic approach to this condition. However, L-NMMA produced a fall in cardiac output and it is possible that this would worsen tissue perfusion. Larger studies examining the effects of L-NMMA on mortality and morbidity are now required. Cardiovascular Research 1994;28:34-39
SELECTING A HOSPITAL FOR AN INTERNSHIP
Authors: HENRY A. CHRISTIAN
Journal: JAMA (1926)

In recent years there has been an increased insistence on an internship in a hospital, subsequent to the completion of the course in the medical school, as a prerequisite to the practice of medicine in any form. Some states have made this a requirement for admission to examination for registration for practice. Medical schools are coming to a very general recognition of the internship as part of the plan of education of the medical student, and whether they award their degree of doctor of medicine before or after the completion of the internship, the medical curriculum is planned on the assumption that the internship will be taken to round out the student's medical course, and that, without it, he will have had an incomplete preparation to begin the practice of medicine. In other words, the internship is recognized as having a definite educational value; to be satisfactory for the student
Active Histoplasma Meningitis of 22 Years' Duration
Authors: Jeffrey A. Gelfand
Journal: JAMA (1975)

HISTOPLASMA meningitis without infection of other organs is an exceedingly rare disease. We have had the opportunity to follow-up a case of<i>Histoplasma</i>meningitis, previously reported 11 years ago,<sup>1</sup>that has now been active for 22 years without major sequelae, a degree of chronicity unique for meningeal infection due to any cause. This case suggests that histoplasmosis that is confined clinically to the meninges may follow a much more chronic course than<i>Histoplasma</i>meningitis with other organ involvement. <h3>Report of a Case</h3> A 58-year-old man was first hospitalized in 1952 for severe headaches. Lumbar puncture and analysis of cerebrospinal fluid (CSF) disclosed an elevated protein level, lymphocytosis, and hypoglycorrhachia. Cultures on this and on subsequent admissions were negative until 1959, when culture of 30 ml of CSF, removed during pneumoencephalography, was positive for<i>Histoplasma capsulatum</i>. Physical examination, roentgenograms, and cultures from multiple sites, including sputum, blood, urine, and bone
ABC of complementary medicine: Herbal medicine
Authors: A. Vickers, C. Zollman
Journal: BMJ (1999)

changes on the basis of nutritional tests provided by commercial companies which advertise laboratory services in the pages of health magazines.Nutritional consultations may be given by a wide range of practitioners with varying levels of training and experience, from complementary practitioners who mainly practise other disciplines through trained nutritional therapists and naturopaths to nurses and doctors who have undertaken further training in nutrition.Nutritional medicine can be a relatively expensive form of complementary medicine.Diagnostic tests can cost from £15 to over £100 per test, nutritional supplements may cost £10-£50 a month, and dietary changes involving organic produce or wholefoods may also have substantial cost implications.