tbuckley/cabot-search huggingface dataset:
Abstract IA12: Regulation of the RNF168-dependent response to DNA double-strand breaks
Authors: Alexandre Orthwein, Daniel Durocher
Journal: Cancer Research (2014)

Abstract The chromatin-based response to DNA double-strand breaks (DSBs) is characterized by the accumulation of DNA repair factors and DNA damage signaling molecules within a large domain that surrounds the lesion. This response is largely dependent on ATM-dependent phosphorylation but also on chromatin ubiquitylation. Indeed, the RNF8 and RNF168 E3 ubiquitin ligases are necessary for the accumulation of proteins such as 53BP1, BRCA1 and RAD18 at sites of DNA damage. The critical importance of this pathway is manifested by the observation that biallelic mutations in the RNF168 gene results in an ataxia-telangiectasia-like syndrome referred to as RIDDLE. We are interested in understanding how this pathway is regulated and how ubiquitin-dependent protein interactions orchestrate the hierarchy of protein recruitment at sites of DNA lesions. I will present our current understanding on the regulation and organization of this signaling cascade and in particular, I will focus my presentation on addressing how the pathway underpinned by RNF168 is regulated during the course of the cell cycle. Citation Format: Alexandre Orthwein, Daniel Durocher. Regulation of the RNF168-dependent response to DNA double-strand breaks. [abstract]. In: Proceedings of the AACR Special Conference: Cancer Susceptibility and Cancer Susceptibility Syndromes; Jan 29-Feb 1, 2014; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(23 Suppl):Abstract nr IA12. doi:10.1158/1538-7445.CANSUSC14-IA12
Monoclonal Gammopathy in Hereditary Spherocytosis: A Possible Pathogenetic Relation
Authors: A. I. Schafer, J. B. Miller, E. P. Lester, T. K. Bowers, Harry S Jacob
Journal: Annals of Internal Medicine (1978)

Two cases of monoclonal gammopathy in patients with hereditary spherocytosis led us to consider the possbile pathogenetic relation between these two disorders. Twelve adult patients with hereditary spherocytosis had significant hypergammaglobulinemia in comparison to normal subjects. Retrospective analysis of previous illness in 140 patients with multiple myeloma showed a significant association between IgA myeloma and previous gallbladder disease. We propose that the chronic reticuloendothelial stimulation due to extravascular hemolysis, possibly potentiated by the inflammation associated with cholelithiasis and cholecystitis, may foster neoplastic transformation of immunocytes in patients with hereditary spherocytosis, ultimately leading to the development of monoclonal gammopathy.
Influence of Docosahexaenoic Acid on Cisplatin Resistance in a Human Small Cell Lung Carcinoma Cell Line
Authors: H. Timmer-Bosscha, G. A. P. Hospers, C. Meijer, N. H. Mulder, F. A. J. Muskiet, I. A. Martini, D. R. A. Uges, E. G. E de Vries
Journal: JNCI Journal of the National Cancer Institute (1989)

In a sensitive, human, small cell lung carcinoma cell line (GLC4) and a cisplatin (CP)-resistant subline (GLC4-CP), the effect of co-culturing with docosahexaenoic acid (DCHA) on CP cytotoxicity was studied. Cells were cultured for 4 days, with 32 μM of DCHA added on days 1 and 3. Incorporation of DCHA into the cellular phospholipids was demonstrated by fatty acid analysis. Supplementation with DCHA led to almost a threefold decrease of resistance in GLC4-CP and had no influence on CP cytotoxicity in GLC4. After culturing with DCHA, cellular platinum (Pt); total Pt bound to DNA; and Pt-GG, Pt-AG, G-Pt-G, and Pt-GMP adduct contents increased in both lines, whereas interstrand cross-link formation was elevated only in GLC4-CP. These experiments demonstrate that DCHA reduces CP resistance. Although an effect on cellular membranes resulting in an increased CP uptake apparently was present, this mechanism does not seem to be responsible for resistance modulation. Rather, an effect on nuclear, probably DNA-related, structures is likely and leads to an increased formation of interstrand cross-links in GLC4-CP. [J Natl Cancer Inst 81: 1069–1075, 1989]
Reply to Carl J. Rossi, Jr.’s Letter to the Editor re: Sung Kim, Shunhua Shen, Dirk F. Moore, et al. Late Gastrointestinal Toxicities Following Radiation Therapy for Prostate Cancer. Eur Urol 2011;60:908–16
Authors: Sung Kim, Weichung J. Shih, Grace L. Lu-Yao
Journal: European Urology (2012)
Identification and induction of human keratinocyte-derived IL-12.
Authors: G Müller, J Saloga, T Germann, I Bellinghausen, M Mohamadzadeh, J Knop, A H Enk
Journal: Journal of Clinical Investigation (1994)

Interleukin 12 is a heterodimeric molecule that serves as a potent co-stimulator enhancing the development of Th1 cells. As one of the classical Th1 cell-mediated responses is contact sensitivity in skin, we wondered whether IL-12 might be produced by epidermal cells and serve as a mediator of this immune response. Using a sensitive, quantitative PCR technique we demonstrate that p35 chain mRNA of IL-12 is produced constitutively by human epidermal cells, whereas p40 chain mRNA can only be detected in epidermis treated with contact allergen, but not epidermis exposed to irritants or tolerogens. Time course studies showed a dramatic induction of IL-12 p40 mRNA 4 h after in vivo allergen treatment reaching peak strength after 6 h. In cell depletion assays we show that epidermal keratinocytes are the major source of this cytokine in the epidermis. This was further supported by analysis of mRNA derived from the human keratinocyte cell line HaCat expressing IL-12 p35 and p40 mRNA upon stimulation. The presence of bioactive IL-12 in supernatants derived from allergen-stimulated epidermal cells was demonstrated by IL-12-specific bioassay. Additional evidence for the functional importance of IL-12 in primary immune reactions in skin was obtained in allogeneic proliferation assays using human haptenated epidermal cells containing Langerhans cells as APC and allogeneic CD4+ T cells as responders. Anti-IL-12 mAb inhibited the proliferation of T cells by approximately 50%. In aggregate our data demonstrate that nonlymphoid keratinocytes are capable of producing functional IL-12 and provide evidence for the functional significance of IL-12 in primary immune responses in skin.
Hepatic reactions to drugs.
Authors: S Sherlock
Journal: Gut (1979)

Focus in this progress report on heatpic rections to drugs is on mechanisms of drug hepatotoxicity (direct -- metabolite-related -- factors immunological factors) hepatotoxic substrances (carbon tetrachloride paracetamol methotrexate other cytotoxic drugs isoniazid rifampicin methyl dopa halothane chlorpromazine and other drugs) sex hormones (cholestasis) sex hormone tumors and androgenic hormones.  The liver is particularly concerned with drug metabolism and particularly with drugs administered orally.  These must be lipid soluble to have passed the membrane of the intestinal cell and must be converted to water soluble compounds for excretion via the urine or bile.  The primary drug metabolising system resides in the microsomal fraction of the liver cell.  Factors determining whether the metabolised drug will be excreted ultimately in bile or urine are multiple and many are unclear.  Factors determining the effect of drugs include age parenchymal liver disease biliary excretion previous drug administration the enterohepatic circulation and the gut flora.
Personality style, differential vulnerability, and clinical course in immunological and cardiovascular disease
Authors: Sidney J. Blatt, Carol E. Cornell, Eva Eshkol
Journal: Clinical Psychology Review (1993)

Recent formulations of two broad personality styles, a dependent (anaclitic) and a self-critical (introjective) personality style (Blatt, 1974, 1990; Blatt & Shichman, 1983), provide a theoretical model for integrating a diversity of findings linking personality factors to the onset and clinical course of immunological and cardiovascular disease. The model of a dependent (anaclitic) personality style appears to provide a structure for integrating, within an independently established conceptual system, the use of repressive defenses, feelings of helplessness, emotional lability, and preoccupations with interpersonal relationships, which have each been found to be predictive factors in neoplastic disease. The model of a self-critical (introjective) personality style appears to provide a conceptual structure for integrating the diverse findings indicating that personality factors of social isolation and mistrust, along with preoccupations with anger, autonomy, assertion, control, and self-worth (e.g., failure and achievement), are important in cardiovascular disease. The formulation of these two personality styles also contributes to understanding the role of personality factors in vulnerability to these two types of disease by suggesting that dependent individuals are more responsive to interpersonal disruption and generally respond to this type of Stressor with passivity and resignation, while self-critical individuals are primarily responsive to loss of self-control and self-worth, and generally react to these Stressors with heightened behavioral and autonomic arousal. These formulations also suggest that these personality styles are linked to clinical course because they make it difficult for individuals to alter behavior and life-style habits in ways that could facilitate obtaining care from medical staff and assistance from social support systems to cope with the impact of the disease process. Furthermore, these formulations have implications for considering different types of psychological interventions as part of comprehensive treatment programs; they raise questions about the role of depression in neoplastic and cardiovascular disease; and they indicate directions that should be explored in future research on the role of personality factors in physical health and illness.
Barium swallow and ultrasound in diagnosis of gastro-oesophageal reflux in children
Authors: A. Massarano
Journal: BMJ (1985)

<h3>Abstract</h3> Symptom-based SARS-CoV-2 screening and testing decisions in children have important implications on daycare and school exclusion policies. Single symptoms account for a substantial volume of testing and disruption to in-person learning and childcare, yet their predictive value is unclear, given the clinical overlap with other circulating respiratory viruses and non-infectious etiologies. We aimed to determine the relative frequency and predictive value of single symptoms for paediatric SARS-CoV-2 infections from an Ottawa COVID-19 assessment centre from October 2020 through April 2021. Overall, 46.3% (n=10,688) of pediatric encounters were for single symptoms, and 2.7% of these tested positive. The most common presenting single symptoms were rhinorrhea (31.8%), cough (17.4%) and fever (14.0%). Among children with high-risk exposures children in each age group, the following single symptoms had a higher proportion of positive SARS-CoV-2 cases compared to no symptoms; fever and fatigue (0-4 years); fever, cough, headache, and rhinorrhea (5-12 years); fever, loss of taste or smell, headache, rhinorrhea, sore throat, and cough (13-17 years). There was no evidence that the single symptom of either rhinorrhea or cough predicted SARS-CoV-2 infections among 0-4 year olds, despite accounting for a large volume (61.1%) of single symptom presentations in the absence of high-risk exposures. Symptom-based screening needs to be responsive to changes in evidence and local factors, including the expected resurgence of other respiratory viruses following relaxation of social distancing/masking, to reduce infection-related risks in schools and daycare settings.
John George Latham Cole
Authors: A. Cole, T. Cole
Journal: BMJ (2011)

<h3>Abstract</h3> TMEM16F is activated by elevated intracellular Ca<sup>2+</sup>, and functions both as a small-conductance ion channel permeable to Ca<sup>2+</sup> and as a phospholipid scramblase. It is important to hold this positive feedback in check to prevent prolonged Ca<sup>2+</sup>-overloading in cells. We hypothesize that TMEM16F shifts its ion selectivity so that it is more permeable to Cl<sup>−</sup> than cations at high intracellular Ca<sup>2+</sup> concentration. We tested this hypothesis with the Q559K mutant that shows no current rundown in excised patch with prolonged Ca<sup>2+</sup> elevation. Recorded in NaCl<sup>−</sup>based solution, the channel shifted its ion selectivity from Na<sup>+</sup>-selective to Cl<sup>−</sup>-selective when intracellular Ca<sup>2+</sup> was increased. The ion selectivity switch did not correlate with changes of channel open state. Rather, it was indicative of an alteration of electrostatic field in the permeation pathway. Shifting ion-selectivity synergistically by intracellular divalent ions and membrane potential could work as a built-in mechanism that allows TMEM16F to brake the positive feedback.
Age-induced T cell troubles
Authors: Amy Maxmen
Journal: The Journal of Experimental Medicine (2009)

The elderly can't fend off infections as vigorously as they once could. [Agius et al.][1] now show that part of the problem—at least in the skin—stems from memory T cells that can't get to their destination.

![Figure][2] 

Fewer adhesion molecules (green and red) are expressed in skin
Magnifying Endoscopy, Stereoscopic Microscopy, and the Microvascular Architecture of Superficial Esophageal Carcinoma
Authors: Y. Kumagai, H. Inoue, K. Nagai, T. Kawano, T. Iwai
Journal: Endoscopy (2002)

Background and Study Aims: In this study we clarify the microvascular architecture of superficial esophageal carcinoma as observed by ultra-high magnification endoscopy and stereoscopic microscopy with Microfil injection. Patients and Methods: We observed two surgically resected specimens of superficial esophageal cancer under stereoscopic microscopy with Microfil injection. In addition, in the histological investigation, we measured the caliber of the vessels at the surface of the tumor. We carried out ultra-high magnification before treatment in 82 patients with superficial esophageal neoplasms. We classified the depth of tumor penetration of superficial esophageal carcinoma into four categories: m1 to m3 (mucosal cancer) and sm (submucosal cancer). Results: By observing the normal esophageal mucosa under a stereoscopic microscope and an ultra-high magnification endoscope, we were able to visualize the intrapapillary capillary loops (IPCL). In cancer lesions, we observed characteristic changes in the superficial microvascular architecture according to the depth of tumor invasion. In m1 invasion, there was dilatation of the IPCL; in m2 invasion, there was dilatation and elongation of the IPCL; in m3, there was a mixed appearance of the IPCL and tumor vessels; and in sm invasion, complete replacement by tumor vessels. On the basis of the above criteria, ultra-high magnification endoscopic observation before treatment showed a rate of agreement between histological depth of invasion and magnified appearance of 60/72 cases (83.3 %) for which satisfactory pictures were obtained. The histological investigation showed the caliber of the IPCL of the m1 cancer lesions (12.9 ± 3.9 µm) to be significantly greater than that of the normal esophageal mucosa (6.9 ± 1.5 µm) (P < 0.0001). Conclusions: Observation of the microvascular architecture of superficial esophageal carcinoma is useful in the diagnosis of the depth of invasion.
Managing Disclosure of Research Misconduct by a Graduate Student to a University Mental Health Professional During a Clinical Counseling Session
Authors: Holly A. Taylor, Benjamin S. Wilfond
Journal: The American Journal of Bioethics (2013)

This case looks at the question of how to consider obligations of confidentiality by a mental health professional who works for an institution and learns that a student has been using a drug intended for an animal research project. Dr. Paul Appelbaum, MD, a psychiatrist at Columbia University, examines the issue of the limits of confidentiality. Nicholas Steneck, PhD, a scholar in research misconduct at the University of Michigan, explores the obligations to report research misconduct. Walter Limehouse, MD, an ethicist at the Medical University of South Carolina, considers the systems issues raised by this case and offers some suggestions that might change the institutional environment.
SOME LESSONS FROM THE DRAFT EXAMINATION
Authors: EUGENE LYMAN FISK
Journal: JAMA (1918)

The general death rate is a rough index to the health of a nation. This factor, however, is a product of so many influences — age, sex and race distribution, and social, industrial and agricultural distribution— that, standing alone, it is not a final and complete indicator of the inherent vitality of a nation. A complete and accurate morbidity rate would supply information of enormous value; but such rates are, of course, lacking. The ideal method for determining the vitality of a nation or of a body of individuals is to ascertain the morbidity rate and death rate, corrected for age and sex distribution and, so far as possible, for other influential factors, and to make a complete and accurate physical survey of the individuals composing the group. The survey of a group having a death rate favorable according to accepted standards will reveal astonishing conditions. It becomes quickly apparent
Measurement of ploidy and cell proliferation in the rodent liver.
Authors: J A Styles
Journal: Environmental Health Perspectives (1993)

In most investigations of cell proliferation in vivo, the population under study consists of mononuclear diploid cells that undergo replication via normal complete division cycles. Because the phenomena associated with the cell cycle are sequential, only one is normally measured and it is usually adequate to quantify the proliferative activity in one of two ways. The first involves labeling the cells undergoing semi-conservative DNA synthesis with a radioactive DNA precursor, preparing autoradiographs of histological sections, and counting labeled nuclei. The other commonly studied parameter of cell proliferation is mitotic activity. The livers of rats and mice, unlike those of other mammals, consist mainly of hepatocytes that contain two classes of cell with respect to nuclei and several ploidy classes. These classes of hepatocytes arise as the result of modified cell division cycles. The peculiar cytological composition of the rodent liver has, until recently, caused difficulties in the measurement and interpretation of cell ploidy and cell proliferation by the above methods. Flow cytometry and fluorescence-activated cell sorting used in conjunction with quantitative fluorescent stains for DNA and fluorescently labeled antibodies to bromodeoxyuridine have permitted the rapid and precise quantification of cell proliferative activity in the rodent liver. Studies using these techniques have revealed that proliferative activity of hepatocytes may occur in different subpopulations of cells depending on the kind of toxicological injury inflicted on the animal.
Examinations and Medical Competence-Reply
Authors: Barry Stimmel
Journal: JAMA (1979)

<h3>In Reply.—</h3> I am the first to agree with Dr McGovern that pass-fail rates of US citizens who take the ECFMG examination are far from optimal in evaluating the quality of education at a foreign medical school. Unfortunately, at present, this is the only assessment that provides a degree of standardization. At the present time almost all US citizens in foreign medical schools who take this examination for the first time do so before graduation, usually in the last year of the medical curriculum, because a pass rate must be presented to the National Resident Matching Program (NRMP) before the student is allowed to participate in the match. Those students enrolled in Mexican medical schools, who need an extra year of clinical training before entering the NRMP, also take this examination at the same time, since a passing score is usually a preliminary requirement of US medical schools sponsoring these
Efficacy of linezolid-based salvage therapy compared with glycopeptide-based therapy in patients with persistent methicillin-resistant Staphylococcus aureus bacteremia
Authors: Hyun Jung Park, Sung-Han Kim, Min-Ju Kim, Yu-Mi Lee, So-Youn Park, Song Mi Moon, Ki-Ho Park, Yong Pil Chong, Sang-Oh Lee, Sang-Ho Choi, Jun Hee Woo, Yang Soo Kim
Journal: Journal of Infection (2012)
Phylogeny of Zebrafish, a “Model Species,” within Danio, a “Model Genus”
Authors: Braedan M. McCluskey, John H. Postlethwait
Journal: Molecular Biology and Evolution (2014)

Zebrafish (Danio rerio) is an important model for vertebrate development, genomics, physiology, behavior, toxicology, and disease. Additionally, work on numerous Danio species is elucidating evolutionary mechanisms for morphological development. Yet, the relationships of zebrafish and its closest relatives remain unclear possibly due to incomplete lineage sorting, speciation with gene flow, and interspecies hybridization. To clarify these relationships, we first constructed phylogenomic data sets from 30,801 restriction-associated DNA (RAD)-tag loci (483,026 variable positions) with clear orthology to a single location in the sequenced zebrafish genome. We then inferred a well-supported species tree for Danio and tested for gene flow during the diversification of the genus. An approach independent of the sequenced zebrafish genome verified all inferred relationships. Although identification of the sister taxon to zebrafish has been contentious, multiple RAD-tag data sets and several analytical methods provided strong evidence for Danio aesculapii as the most closely related extant zebrafish relative studied to date. Data also displayed patterns consistent with gene flow during speciation and postspeciation introgression in the lineage leading to zebrafish. The incorporation of biogeographic data with phylogenomic analyses put these relationships in a phylogeographic context and supplied additional support for D. aesculapii as the sister species to D. rerio. The clear resolution of this study establishes a framework for investigating the evolutionary biology of Danio and the heterogeneity of genome evolution in the recent history of a model organism within an emerging model genus for genetics, development, and evolution.
"TOTAL COLLAPSE ASSOCIATED WITH PHYSICAL EXERTION"
Authors: Arthur M. Master
Journal: JAMA (1942)

To the Editor:—  In the August 22 issue ofThe Journal, on page 1431, is an editorial comment entitled Total Collapse Associated with Physical Exertion. I must take issue with the authors quoted who conclude that severe physical exertion or trauma can produce coronary occlusion.  Reviewing the recent report of Jokl and Suszman (Mechanisms Involved in Acute Fatal Nontraumatic Collapse Associated with Physical Exertion, Am. Heart J.  22 :761 [June] 1942) you write that these authors, analyzing 66 cases of sudden death in which  data and complete necropsy reports were available, came to the not unexpected conclusion that collapse following exertion is almost invariably due to  disease of long standing. You say that the authors found that acute coronary occlusion was the second in order of frequency of the circulatory disease of long duration found at necropsy. Actually, however, in this particular article no clinical data and complete