tbuckley/cabot-search huggingface dataset:
Toxicity of Antibacterial Agents: Mechanism of Action on Mammalian Cells
Authors: W E Sanders, C C Sanders
Journal: The Annual Review of Pharmacology and Toxicology (1979)

Antibacterial agents may adversely affect the host either directly or indi­ rectly. Direct injury, or toxicity, is the focal point of this review. Indirect injury may result from (a) induction of an allergic or hypersensitivity reaction in which components of the immune system (antibody, activated cells, complement) mediate damage to host tissues or (b) alteration of the ecological balance of the normal microbial flora which facilitates superin­ fection or impairs epithelial physiology or nutrition. These indirect effects have been reviewed elsewhere (1, 2) and will not be considered further. An extraordinary number and a wide variety of toxic reactions have been reported following administration of antibacterial agents. Limitations of space have dictated that only a few of these be considered in this review. Priority was given those reactions for which the mechanism of drug action is either relatively well understood or currently the subject of intense inter­ est or controversy. In certain instances, the mechanism of toxicity for mammalian (eucaryotic) cells is very similar to or identical with that for sensitive bacterial (procaryotic) cells. In order to simplify discussion, we refer to these very similar mechanisms as pharmacological effects and in­ clude a list of the mechanisms of antibacterial action as they are presently perceived for each group of drugs considered (Table 1). We attempt to differentiate those mechanisms that are unique to mammalian cells from those that appear to be pharmacological.
Properties of the Novel Proinflammatory Supergene "Intercrine" Cytokine Family
Authors: J J Oppenheim, C O Zachariae, N Mukaida, K Matsushima
Journal: Annual Review of Immunology (1991)

A family consisting of at least ten distinct novel 8-10 kd cytokines has been identified over the past 12 years. These cytokines exhibit from 20 to 45% homology in amino acid sequence, are probably all basic heparin-binding polypeptides, and have proinflammatory and reparative activities. The cDNA for these cytokines are characterized by conserved single open reading frames, typical signal sequences in the 5' region, and AT rich sequences in the 3' untranslated regions. Those human cytokines known as interleukin 8, platelet factor 4, beta thromboglobulin, IP-10 and melanoma growth stimulating factor or GRO can be assigned to a subfamily based on their location on chromosome 4 and unique structural features, whereas the second subset consisting of LD78, ACT-2, I-309, RANTES, and macrophage chemotactic and activating factor (MCAF) are all closely linked on human chromosome 17. In this review we have summarized and discussed the available information concerning the regulation and structure of the genes, the structure and biochemical properties of the polypeptide products, their receptors, signal transduction, cell sources, and in vitro as well as in vivo activities of these cytokines.
Modification of Kiel and working formulation classifications for improved survival prediction in non-Hodgkin's lymphoma.
Authors: J M Nabholtz, S Friedman, F Collin, J Guerrin
Journal: Journal of Clinical Oncology (1987)

The total survival of 203 patients with non-Hodgkin's lymphoma (NHL) was analyzed according to the working formulation (WF) and "expanded" Kiel classifications. The original Kiel classification consisting of low grade (LG) and high grade (HG) forms corresponded well to the LG and HG forms of the WF. When an expanded Kiel containing an intermediate grade (IG) composed of the original LG diffuse group was devised, this gave a much better separation of survival of the three grades as compared with the WF where the survival of IG and HG forms were nonsignificantly different. The main reason for this difference was the inclusion of the so-called centroblastic diffuse form in the HG Kiel, but in the IG according to the WF. In a "modified" WF analysis where this histologic entity was placed in the HG subgroup, the three survival curves then gave excellent separation like the expanded Kiel classification. Since the centroblastic diffuse form (and its analogous forms according to other classifications) has a poor prognosis, it is important that it be so recognized and treated accordingly with aggressive therapy. We propose either our expanded Kiel or modified WF classification of the three grade forms as an excellent predictor of survival.
A First-in-Human Phase I Study of the Oral p38 MAPK Inhibitor, Ralimetinib (LY2228820 Dimesylate), in Patients with Advanced Cancer
Authors: Amita Patnaik, Paul Haluska, Anthony W. Tolcher, Charles Erlichman, Kyriakos P. Papadopoulos, Janet L. Lensing, Muralidhar Beeram, Julian R. Molina, Drew W. Rasco, Rebecca R. Arcos, Claudia S. Kelly, Sameera R. Wijayawardana, Xuekui Zhang, Louis F. Stancato, Robert Bell, Peipei Shi, Palaniappan Kulanthaivel, Celine Pitou, Lynette B. Mulle, Daphne L. Farrington, Edward M. Chan, Matthew P. Goetz
Journal: Clinical Cancer Research (2015)

p38 MAPK regulates the production of cytokines in the tumor microenvironment and enables cancer cells to survive despite oncogenic stress, radiotherapy, chemotherapy, and targeted therapies. Ralimetinib (LY2228820 dimesylate) is a selective small-molecule inhibitor of p38 MAPK. This phase I study aimed to evaluate the safety and tolerability of ralimetinib, as a single agent and in combination with tamoxifen, when administered orally to patients with advanced cancer.The study design consisted of a dose-escalation phase performed in a 3+3 design (Part A; n = 54), two dose-confirmation phases [Part B at 420 mg (n = 18) and Part C at 300 mg (n = 8)], and a tumor-specific expansion phase in combination with tamoxifen for women with hormone receptor-positive metastatic breast cancer refractory to aromatase inhibitors (Part D; n = 9). Ralimetinib was administered orally every 12 hours on days 1 to 14 of a 28-day cycle.Eighty-nine patients received ralimetinib at 11 dose levels (10, 20, 40, 65, 90, 120, 160, 200, 300, 420, and 560 mg). Plasma exposure of ralimetinib (Cmax and AUC) increased in a dose-dependent manner. After a single dose, ralimetinib inhibited p38 MAPK-induced phosphorylation of MAPKAP-K2 in peripheral blood mononuclear cells. The most common adverse events, possibly drug-related, included rash, fatigue, nausea, constipation, pruritus, and vomiting. The recommended phase II dose was 300 mg every 12 hours as monotherapy or in combination with tamoxifen. Although no patients achieved a complete response or partial response,19 patients (21.3%) achieved stable disease with a median duration of 3.7 months, with 9 of these patients on study for ≥ 6 cycles.Ralimetinib demonstrated acceptable safety, tolerability, and pharmacokinetics for patients with advanced cancer.
Trans effects of chromosome aneuploidies on DNA methylation patterns in human Down syndrome and mouse models
Authors: Maite Mendioroz, Catherine Do, Xiaoling Jiang, Chunhong Liu, Huferesh K. Darbary, Charles F. Lang, John Lin, Anna Thomas, Sayeda Abu-Amero, Philip Stanier, Alexis Temkin, Alexander Yale, Meng-Min Liu, Yang Li, Martha Salas, Kristi Kerkel, George Capone, Wayne Silverman, Y. Eugene Yu, Gudrun Moore, Jerzy Wegiel, Benjamin Tycko
Journal: Genome biology (2015)

Trisomy 21 causes Down syndrome (DS), but the mechanisms by which the extra chromosome leads to deficient intellectual and immune function are not well understood.Here, we profile CpG methylation in DS and control cerebral and cerebellar cortex of adults and cerebrum of fetuses. We purify neuronal and non-neuronal nuclei and T lymphocytes and find biologically relevant genes with DS-specific methylation (DS-DM) in each of these cell types. Some genes show brain-specific DS-DM, while others show stronger DS-DM in T cells. Both 5-methyl-cytosine and 5-hydroxy-methyl-cytosine contribute to the DS-DM. Thirty percent of genes with DS-DM in adult brain cells also show DS-DM in fetal brains, indicating early onset of these epigenetic changes, and we find early maturation of methylation patterns in DS brain and lymphocytes. Some, but not all, of the DS-DM genes show differential expression. DS-DM preferentially affected CpGs in or near specific transcription factor binding sites (TFBSs), implicating a mechanism involving altered TFBS occupancy. Methyl-seq of brain DNA from mouse models with sub-chromosomal duplications mimicking DS reveals partial but significant overlaps with human DS-DM and shows that multiple chromosome 21 genes contribute to the downstream epigenetic effects.These data point to novel biological mechanisms in DS and have general implications for trans effects of chromosomal duplications and aneuploidies on epigenetic patterning.
Control of Human Appetite: Implications for The Intake of Dietary Fat
Authors: J. E. Bludell, C. L. Lawton, J. R. Cotton, J. I. Macdiarmid
Journal: Annual Review of Nutrition (1996)

The human appetite system contains central and peripheral mechanisms that interact with environmental features, especially with the physical and nutrient composition of the food supply. Foods varying in nutrient composition exert different physiologic effects, some of which function as satiety signals. High-fat diets (low food quotient) lead to high levels of energy intake. This effect is termed passive overconsumption and overcomes fat-induced physiological satiety signals. High-fat foods exert a weak effect on satiation (intra-meal satiety), and fat has a weaker effect, joule for joule, on postingestive satiety than do other macronutrients. The frequency of obesity is greater among high-fat than low-fat consumers. However, the development of obesity on a high-fat diet is not a biological inevitability. The investigation of people who resist the weight-inducing properties of high-fat diets is a key research strategy. Understanding the appetite control system suggests behavioral, nutritional, and pharmacologic strategies for modifying dietary fat intake.
Intraperitoneal injection of microencapsulated Sertoli cells restores muscle morphology and performance in dystrophic mice
Authors: Sara Chiappalupi, Giovanni Luca, Francesca Mancuso, Luca Madaro, Francesca Fallarino, Carmine Nicoletti, Mario Calvitti, Iva Arato, Giulia Falabella, Laura Salvadori, Antonio Di Meo, Antonello Bufalari, Stefano Giovagnoli, Riccardo Calafiore, Rosario Donato, Guglielmo Sorci
Journal: Biomaterials (2015)
Cyclin E1 Inhibition can Overcome Sorafenib Resistance in Hepatocellular Carcinoma Cells Through Mcl-1 Suppression
Authors: Chiun Hsu, Liang-In Lin, Yu-Che Cheng, Zi-Rui Feng, Yu-Yun Shao, Ann-Lii Cheng, Da-Liang Ou
Journal: Clinical Cancer Research (2015)

To clarify the effects of cyclin E1 suppression on antitumor efficacy of sorafenib in hepatocellular carcinoma cells and to explore the potential of combining sorafenib with cyclin-dependent kinase (CDK) inhibition in therapy.The effects of cyclin E1 suppression on sorafenib-induced apoptosis were tested in both sorafenib-sensitive (Huh-7 and HepG2, IC50 5-6 μmol/L) and sorafenib-resistant (Huh-7R and HepG2R, IC50 14-15 μmol/L) hepatocellular carcinoma cells. The activity of pertinent signaling pathways and the expression of cell cycle and apoptosis-related proteins were measured using Western blotting. Efficacy of sorafenib combined with the pan-CDK inhibitor flavopiridol was tested both in vitro and in xenograft experiments. The pertinent downstream mediators of antitumor efficacy were tested in transient transfection and RNA interference experiments.Cyclin E1 mRNA and protein expressions were suppressed after sorafenib treatment in sorafenib-sensitive but not in sorafenib-resistant hepatocellular carcinoma cells. Changes in cyclin E2 or D1 were not correlated with sorafenib sensitivity. The knockdown of cyclin E1 expression reversed the resistance of hepatocellular carcinoma cells to sorafenib in terms of cell growth and apoptosis induction, whereas the overexpression of cyclin E1 increased the resistance to sorafenib. The growth-inhibitory and apoptosis-inducing effects of sorafenib were enhanced by flavopiridol, and Mcl-1 suppression was determined to play a critical role in mediating this enhancing effect.The cyclin E1 suppression in hepatocellular carcinoma cells may serve as a pharmacodynamic biomarker for predicting sorafenib efficacy. The combination of sorafenib and CDK inhibitors may improve the efficacy of sorafenib in hepatocellular carcinoma. Clin Cancer Res; 22(10); 2555-64. ©2015 AACR.
Affective disorder in the families of women with normal weight bulimia
Authors: S L Stern, K N Dixon, E Nemzer, M D Lake, R A Sansone, D J Smeltzer, S Lantz, S S Schrier
Journal: American Journal of Psychiatry (1984)

The authors determined the lifetime prevalence of affective disorder in the first- and second-degree relatives, excluding children, of 27 bulimic women who had never had anorexia nervosa and 27 women with no history of an eating disorder. Family diagnoses were made blind to the proband's diagnosis. The prevalence of affective disorder was 9% in the relatives of the bulimic probands and 10% in the relatives of the control probands, a nonsignificant difference. These findings are in contrast to reports of an increased prevalence of affective disorder in the relatives of patients with anorexia nervosa.
P1102 : No histological features of alcohol induced steatohepatitis can identify patients at risk of cirrhosis and premature death
Authors: S. Semb, S. Neermark, S. Dam-Larsen, M.B. Franzmann, J. Albrectsen, T. Kallemose, U. Becker, F. Bendtsen
Journal: Journal of Hepatology (2015)
The Impact of Missing Data on Species Tree Estimation
Authors: Zhenxiang Xi, Liang Liu, Charles C. Davis
Journal: Molecular Biology and Evolution (2015)

Phylogeneticists are increasingly assembling genome-scale data sets that include hundreds of genes to resolve their focal clades. Although these data sets commonly include a moderate to high amount of missing data, there remains no consensus on their impact to species tree estimation. Here, using several simulated and empirical data sets, we assess the effects of missing data on species tree estimation under varying degrees of incomplete lineage sorting (ILS) and gene rate heterogeneity. We demonstrate that concatenation (RAxML), gene-tree-based coalescent (ASTRAL, MP-EST, and STAR), and supertree (matrix representation with parsimony [MRP]) methods perform reliably, so long as missing data are randomly distributed (by gene and/or by species) and that a sufficiently large number of genes are sampled. When data sets are indecisive sensu Sanderson et al. (2010. Phylogenomics with incomplete taxon coverage: the limits to inference. BMC Evol Biol. 10:155) and/or ILS is high, however, high amounts of missing data that are randomly distributed require exhaustive levels of gene sampling, likely exceeding most empirical studies to date. Moreover, missing data become especially problematic when they are nonrandomly distributed. We demonstrate that STAR produces inconsistent results when the amount of nonrandom missing data is high, regardless of the degree of ILS and gene rate heterogeneity. Similarly, concatenation methods using maximum likelihood can be misled by nonrandom missing data in the presence of gene rate heterogeneity, which becomes further exacerbated when combined with high ILS. In contrast, ASTRAL, MP-EST, and MRP are more robust under all of these scenarios. These results underscore the importance of understanding the influence of missing data in the phylogenomics era.
What went wrong at Addenbrooke’s?
Authors: Richard Vize
Journal: BMJ (2015)

The world renowned hospital is now in special measures. <b>Richard Vize</b> speaks to its newly departed leader, Keith McNeil, and other insiders about the “unforgiving” inspection regime, the NHS’s obsession with “grip,” and how the roots of Addenbrooke’s problems can be found in many other hospitals
Fine Particle Pollution, Alanine Transaminase, and Liver Cancer: A Taiwanese Prospective Cohort Study (REVEAL-HBV)
Authors: Wen-Chi Pan, Chih-Da Wu, Mu-Jean Chen, Yen-Tsung Huang, Chien-Jen Chen, Huey-Jen Su, Hwai-I Yang
Journal: JNCI Journal of the National Cancer Institute (2015)

Exposure to fine particulate matter (PM2.5) may promote hepatic tumorgenesis through low-grade inflammation. Therefore, we assessed the association of long-term exposure levels of PM2.5 and subsequent risk of hepatocellular carcinoma (HCC) and investigated the mediation effect of inflammation as represented by alanine aminotransferase (ALT) on this association. Between 1991 and 1992, we recruited 23 820 participants in Taiwan with no history of HCC. Case patients of HCC were ascertained through computerized data linkage with the National Cancer Registry and death certification systems. Participants' exposures to PM2.5 were based on a four-year average retrieved from stationary monitoring sites. Cox proportional hazards models were used to assess the association between PM2.5 exposure and HCC incidence. Mediation effects of ALT on PM2.5-associated HCC incidence were estimated. A total of 464 HCC cases were newly diagnosed with a median follow-up of 16.9 years. Statistically significantly increasing trends between PM2.5 exposures and ALT were observed on the Main Island and Penghu Islets. The adjusted hazard ratio (HR) for HCC on the Penghu Islets was 1.22 (95% confidence interval [CI] = 1.02 to 1.47) per PM2.5 interquartile range (IQR) increment (0.73 µg/m(3)) exposure. We also found a positive association between PM2.5 exposure (per IQR increment, 13.1 µg/m(3)) and HCC incidence on the Main Island. Furthermore, ALT had a statistically significant mediation effect on PM2.5-associated HCC incidence (HR = 1.17, 95% CI = 1.02 to1.52 on the Main Island; HR = 1.04, 95% CI = 1.03 to 1.07 on the Penghu Islets) per PM2.5 IQR increment. Long-term PM2.5 exposure increased the risk for liver cancer, and chronic inflammation of the liver may underlie the pathogenesis.
There Are No Words
Authors: Carol Snyder Halberstadt
Journal: JAMA (2015)

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Indian objection to export of human tissue for research
Authors: P. Forster
Journal: BMJ (2003)

Editor—With reference to our recent paper in the Proceedings of the National Academy of Sciences on the mutation rate of mtDNA, Murdur says that Indian scientists are accusing the foreign researchers of violating the national guidelines.1,2 He omitted, however, to make any mention of the first author of our paper, Lucy Forster, who is herself Indian, from Kerala, where the thorium rich sand is located. The research formed the basis for her PhD dissertation.

None of the coauthors was aware of the guidelines to which your correspondent refers, neither have we now been able to find any mention of them on the website of the Indian Council of Medical Research. It is in any case not likely that the research in question as such would lead to a patent or other commercial applications. It does, however, lead to the interesting conclusion, relevant to human population history, that some high estimates for the mtDNA mutation rate are not well founded.
Follicular lymphoma: 2015 update on diagnosis and management
Authors: Arnold Freedman
Journal: American Journal of Hematology (2015)

Follicular lymphoma is generally an indolent B cell lymphoproliferative disorder of transformed follicular center B cells. Follicular lymphoma (FL) is characterized by diffuse lymphoadenopathy, bone marrow involvement, splenomegaly, and less commonly other extranodal sites of involvement. In general, cytopenias can occur but constitutional symptoms of fever, night sweats, and weight loss are uncommon.Diagnosis is based on histology of preferably a biopsy of a lymph node. Immunohistochemical staining is positive in virtually all cases for cell surface CD19, CD20, CD10, and monoclonal immunoglobulin, as well as cytoplasmic expression of bcl-2 protein. The overwhelming majority of cases have the characteristic t(14;18) translocation involving the IgH/bcl-2 genes.The Follicular Lymphoma International Prognostic Index prognostic model for FL uses five independent predictors of inferior survival: age >60 years, hemoglobin <12 g/dL, serum LDH > normal, Ann Arbor stage III/IV, number of involved nodal areas > 4. The presence of 0, 1, 2, and ≥ 3 adverse factors defines low, intermediate, and high-risk disease. With the use of more modern therapies, outcomes have improved.Observation continues to be adequate for asymptomatic patients with low bulk disease and no cytopenias, with no survival advantage for early treatment with either chemotherapy or rituximab alone. For patients needing therapy, most patients are treated with chemotherapy plus rituximab, which has improved response rates, duration of response and overall survival. Randomized studies have shown additional benefit for maintenance rituximab both following chemotherapy-rituximab and single agent rituximab. Experimental therapies as well as stem cell transplantation (SCT) are considered for recurrent disease.