tbuckley/cabot-search huggingface dataset:
Use of microorganisms for the study of drug metabolism: An update
Authors: Alice M. Clark, Charles D. Hufford
Journal: Medicinal Research Reviews (1991)

The use of microorganisms as tools in the study of drug metabolism appears to be gaining popularity. The selected examples cited here provide additional evidence of the utility of these systems as alternative in vitro models for studying drug metabolism in humans. However, as was noted earlier, this model, nor any other in vitro model system could ever replace animals in biomedical research. However, it is apparent from the numerous examples cited here and in the previous review of this area that microorganisms are a reliable, reproducible alternative to small animals as predictive models in drug metabolism studies. The continuing development of techniques that reduce the use of animals in research is encouraged and this procedure appears to be gaining more widespread acceptance for such use.
A Novel Class of SINE Elements Derived from 5S rRNA
Authors: V. V. Kapitonov
Journal: Molecular Biology and Evolution (2003)

Eukaryotic genomes are colonized by different retroposons, including short interspersed repetitive elements (SINEs). All currently known SINEs are derived from tRNA and 7SL RNA genes and exploit their type 2 internal pol III promoters. We report here a novel class of SINE elements, called SINE3, derived from 5S rRNA. SINE3s are transcribed from the type 1 internal pol III promoter. Approximately 10,000 copies of SINE3 elements are present in the zebrafish genome, they constitute approximately 0.4% of the genomic DNA. Some elements are as little as 1% diverged from each other, indicating that the retrotransposition of SINE3 in zebrafish is an ongoing process. The 3′-tail of SINE3 is significantly similar to that of CR1-like non-LTR retrotransposons, represented by numerous subfamilies in the zebrafish genome. Analogously to CR1-like elements, SINE3 copies are not flanked by target site duplications, and their 3′ termini are composed of (ACATT)n and (ATT)n microsatellites, specific for different subfamilies of SINE3. Given the common structural features, it is highly likely that the enzymatic machinery encoded by CR1-like elements powers proliferation of SINE3.
MicroRNAs as Prognostic Indicators and Therapeutic Targets: Potential Effect on Breast Cancer Management
Authors: Aoife J. Lowery, Nicola Miller, Roisin E. McNeill, Michael J. Kerin
Journal: Clinical Cancer Research (2008)

Abstract The discovery of microRNAs (miRNA) as novel modulators of gene expression has resulted in a rapidly expanding repertoire of molecules in this family, as reflected in the concomitant expansion of scientific literature. MiRNAs are a category of naturally occurring RNA molecules that play important regulatory roles in plants and animals by targeting mRNAs for cleavage or translational repression. Characteristically, miRNAs are noncoding, single-stranded short (18-22 nucleotides) RNAs, features which possibly explain why they had not been intensively investigated until recently. Accumulating experimental evidence indicates that miRNAs play a pivotal role in many cellular functions via the regulation of gene expression. Furthermore, their dysregulation and/or mutation has been shown in carcinogenesis. We provide a brief review of miRNA biogenesis and discuss the technical challenges of modifying experimental techniques to facilitate the identification and characterization of these small RNAs. MiRNA function and their involvement in malignancy, particularly their putative role as oncogenes or tumor suppressors is also discussed, with a specific emphasis on breast cancer. Finally, we comment on the potential role of miRNAs in breast cancer management, particularly in improving current prognostic tools and achieving the goal of individualized cancer treatment.
Infant With a Papular Eruption Localized to the Back
Authors: Karin Eshagh, Cynthia M. C. DeKlotz, Sheila Fallon Friedlander
Journal: JAMA Pediatrics (2014)

A 9-week-old girl had a rash on her back that had been present for 7 weeks. The rashwasasymptomatic andstartedas redbumps that then evolved into pustules and blisters. On further questioning, it was discovered that thepatient’s fatherworked in a nursing home that had experienced a recent outbreak of scabies. Shortly after the onsetof theoutbreak, thepatient andall familymemberswere treated with 2 once-weekly doses of permethrin, 5%, cream. All other family members had significant improvement with the treatment; however, our patient’s lesions continued to worsen during the subsequent 2 weeks. On physical examination, the patient had numerous erythematousmacules, papules, andpustules onher back.Manyof the lesions had superimposed hemorrhagic crust and surrounding scale. In addition, several grouped papules were noted, including some in a linear array (Figure 1A andB). The rest of her cutaneous examination results were unremarkable except for a few fading pink papules noted on her left abdomen (Figure 1C). A B C
THE HIDDEN DANGER OF ENDURANCE RACES: ANALGESIC USE AMONG ULTRAMARATHON RUNNERS
Authors: Bernd Volker Scheer, Encarna Valero Burgos
Journal: British Journal of Sports Medicine (2013)

Background Ultramarathon races have gained popularity in recent years and test the limits of human endurance. Runners often take analgesic medication during endurance foot races which may lead to gastrointestinal complications, altered renal function, and is associated with the development of hyponatremia and rhabdomyolysis. Methods We conducted a prospective survey study to gather data on prevalence, awareness, and reasons for consumption of analgesic medication used among ultramarathon runners during the Al Andalus Ultimate Trail 2012. Data were obtained post race using a direct-interview technique on standardized questionnaires. Results Thirty-two ultramarathon runners (26 male, 6 female, mean age 39.5±7.9, previous ultramarathon experience 7.7±9) participated in the study. The majority of runners (53%) did not take any form of analgesic; 44% said they had used them sometime during the race and training; and 3% had used them regularly. Nonsteroidal anti-inflammatory drugs (NSAID) were most commonly used (60%) followed by Paracetamol (40%). The reasons for use were to reduce musculoskeletal pain (65%) or to combat fatigue (24%). All runners felt that taking an analgesic provided effective relief. Only 6 % of athletes obtained them through a prescription from their doctor. The main sources of recommendation were fellow runners and friends (56%), self initiative (22%) or coaches (6%). They were mainly obtained in shops (47%) and chemists (47%) and rarely on the Internet (6%). Two thirds of runners said they were aware of adverse effects, naming mainly renal failure (27%), gastrointestinal problems (18%) and liver failure (9%). Conclusion We found a high prevalence of analgesic medication use among ultramarathon runners. A third of runners were not aware of any adverse effects or dangers associated with analgesic consumption. Analgesic medication may have deleterious effects on the body and its performance. Pre-race education programmes may help increase awareness of effects, risks and appropriate use, and consumption.
Stressful life events and the onset of asthma
Authors: R. Lietzén, P. Virtanen, M. Kivimäki, L. Sillanmäki, J. Vahtera, M. Koskenvuo
Journal: European Respiratory Journal (2010)

The status of stressful life events as a risk factor for asthma is unclear and may be dependent on pre-existing allergic rhinitis. This study examined whether exposure to stressful life events predicted the onset of asthma in adults. This is a prospective, population-based cohort study of 16,881 males and females, aged 20–54 yrs and free of diagnosed asthma at the beginning of the follow-up (January 1, 2004). Data about stressful life events were gathered with a postal survey. The onset of asthma was ascertained through national registers until December 31, 2005. During the follow-up period, 192 incident cases of asthma were identified. High total exposure to stressful life events, as indicated by a cumulative severity score, predicted the onset of asthma (hazard ratio 1.96, 95% CI 1.22–3.13). This association was robust to adjustment for demographics, smoking and having a cat/dog at home and it was observed both among those with and without allergic rhinitis at baseline. Of the 10 most stressful life events, the illness of a family member, marital problems, divorce or separation and conflicts with a supervisor were associated with the onset of asthma. Our study suggests that stressful life events may increase the onset of asthma.
Expression of smooth muscle cell phenotype by rat mesangial cells in immune complex nephritis. Alpha-smooth muscle actin is a marker of mesangial cell proliferation.
Authors: R J Johnson, H Iida, C E Alpers, M W Majesky, S M Schwartz, P Pritzi, K Gordon, A M Gown
Journal: Journal of Clinical Investigation (1991)

Mesangial cell proliferation is common in glomerulonephritis but it is unclear if proliferation is associated with any in vivo alteration in phenotype. We investigated whether mesangial of mesangial proliferative nephritis induced with antibody to the Thy-1 antigen present on mesangial cells. At day 3 glomeruli displayed de novo immunostaining for alpha-smooth muscle actin in a mesangial pattern, correlating with the onset of proliferation, and persisting until day 14. An increase in desmin and vimentin in mesangial regions was also noted. Immunoelectron microscopy confirmed that the actin-positive cells were mesangial cells, and double immunolabeling demonstrated that the smooth muscle actin-positive cells were actively proliferating. Northern analysis of isolated glomerular RNA confirmed an increase in alpha and beta/gamma actin mRNA at days 3 and 5. Complement depletion or platelet depletion prevented or reduced proliferation, respectively; these maneuvers also prevented smooth muscle actin and actin gene expression. Studies of five other experimental models of nephritis confirmed that smooth muscle actin expression is a marker for mesangial cell injury. Thus, mesangial cell proliferation in glomerulonephritis in the rat is associated with a distinct phenotypic change in which mesangial cell assume smooth muscle cell characteristics.
Cellular and molecular mechanisms of asbestos carcinogenicity: implications for biopersistence.
Authors: J C Barrett
Journal: Environmental Health Perspectives (1994)

Carcinogenic agents can influence the carcinogenic process either by mutating critical target genes or by increasing the number of cells at risk for mutations. Cytogenetic and molecular studies of asbestos-related cancers indicate that inactivation or loss of multiple tumor suppressor genes occurs during lung cancer development. Aneuploidy and other chromosomal changes induced by asbestos fibers may be involved in genetic alterations in asbestos-related cancers. Furthermore, asbestos fibers may influence the carcinogenic process by inducing cell proliferation, free radicals, or other promotional mechanisms. Therefore, asbestos fibers may act at multiple stages of the carcinogenic process by both genetic and epigenetic mechanisms. Biopersistence is undoubtedly important in fiber carcinogenicity. However, the time required for a fiber to remain in the lung to exert a cancer-related effect is difficult to specify.
Cholesterol precursors and facial clefting
Authors: Forbes D. Porter
Journal: Journal of Clinical Investigation (2006)

Inborn errors of cholesterol synthesis cause human malformation syndromes, including Smith-Lemli-Opitz syndrome, lathosterolosis, desmosterolosis, X-linked dominant chondrodysplasia punctata type 2, and congenital hemidysplasia with ichthyosiform erythroderma and limb defects. Because adequate cholesterol is not transported across the placenta, low cholesterol and elevated sterol precursor levels are present during embryogenesis. It has been debated whether the malformations result from low cholesterol or the buildup of sterol precursors. In this issue of the JCI, Engelking et al. provide evidence that sterol precursor accumulation plays a pivotal role in the genesis of facial malformations (see the related article beginning on page 2356).
Hysteria and Antisocial Behavior: Further Evidence of an Association
Authors: SAMUEL B. GUZE, ROBERT A. WOODRUFF, PAULA J. CLAYTON
Journal: American Journal of Psychiatry (1971)

The authors report on a controlled comparison of women with hysteria and women with anxiety neurosis that confirms other work, suggesting again that there is a significant clinical and familial association between hysteria and antisocial behavior or sociopathy.
PTEN inhibits IL-2 receptor-mediated expansion of CD4+CD25+ Tregs
Authors: P. T. Walsh
Journal: Journal of Clinical Investigation (2006)

One of the greatest barriers against harnessing the potential of CD4+CD25+ Tregs as a cellular immunotherapy is their hypoproliferative phenotype. We have previously shown that the hypoproliferative response of Tregs to IL-2 is associated with defective downstream PI3K signaling. Here, we demonstrate that targeted deletion of the lipid phosphatase PTEN (phosphatase and tensin homolog deleted on chromosome 10) regulates the peripheral homeostasis of Tregs in vivo and allows their expansion ex vivo in response to IL-2 alone. PTEN deficiency does not adversely affect either the thymic development or the function of Tregs, which retain their ability to suppress responder T cells in vitro and prevent colitis in vivo. Conversely, reexpression of PTEN in PTEN-deficient Tregs as well as in activated CD4+ T cells inhibits IL-2–dependent proliferation, confirming PTEN as a negative regulator of IL-2 receptor signaling. These data demonstrate that PTEN regulates the "anergic" response of Tregs to IL-2 in vitro and Treg homeostasis in vivo and indicate that inhibition of PTEN activity may facilitate the expansion of these cells for potential use in cellular immunotherapy.
Antiretroviral Regimens in Pregnancy and Breast-Feeding in Botswana
Authors: R.L. Shapiro, M.D. Hughes, A. Ogwu, D. Kitch, S. Lockman, C. Moffat, J. Makhema, S. Moyo, I. Thior, K. McIntosh, E. van Widenfelt, J. Leidner, K. Powis, A. Asmelash, E. Tumbare, S. Zwerski, U. Sharma, E. Handelsman, K. Mburu, O. Jayeoba, E. Moko, S. Souda, E. Lubega, M. Akhtar, C. Wester, R. Tuomola, W. Snowden, M. Martinez-Tristani, L. Mazhani, M. Essex
Journal: New England Journal of Medicine (2010)

The most effective highly active antiretroviral therapy (HAART) to prevent mother-to-child transmission of human immunodeficiency virus type 1 (HIV-1) in pregnancy and its efficacy during breast-feeding are unknown.
Association Between Brain-Derived Neurotrophic Factor Val66Met Gene Polymorphism and Progressive Brain Volume Changes in Schizophrenia
Authors: Beng-Choon Ho, Nancy C. Andreasen, Jeffrey D. Dawson, Thomas H. Wassink
Journal: American Journal of Psychiatry (2007)

Objective: Factors underlying progressive brain volume changes in schizophrenia remain poorly understood. The authors investigated whether a gene polymorphism influencing neuroplasticity may contribute to longitudinal brain volume alterations. Method: High-resolution magnetic resonance (MR) images of the whole brain were obtained for 119 patients with recent-onset schizophrenia spectrum disorders. Changes in brain volumes over an average of 3 years were compared between brain-derived neurotrophic factor (BDNF) val66met genotype groupings. Exploratory analyses were conducted to examine relationships between antipsychotic treatment and brain volume changes as well as the effects of BDNF genotype on changes in cognition and symptoms. Results: Significant genotype effects were observed on within-subject changes in volumes of frontal lobe gray matter, lateral ventricles, and sulcal CSF. Met allele carriers had significantly greater reductions in frontal gray matter volume, with reciprocal volume increases in the lateral ventricles and sulcal (especially frontal and temporal) CSF than Val homozygous patients. Independent of BDNF genotype, more antipsychotic exposure between MRI scans correlated with greater volume reductions in frontal gray matter, particularly among patients who were initially treatment naive. There were no statistically significant genotype effects on within-subject changes in cognition or symptoms. Conclusions: BDNF Met variant may be one of several factors affecting progressive brain volume changes in schizophrenia.
Molecular Pathways: Preclinical Models and Clinical Trials with Metformin in Breast Cancer
Authors: Alastair M. Thompson
Journal: Clinical Cancer Research (2014)

Abstract Metformin, an oral biguanide widely used to treat diabetes, has considerable potential and is in clinical trials as an experimental preventive or therapeutic agent for a range of cancers. Direct actions targeting cellular pathways, particularly via AMP-activated protein kinase and through inhibiting mitochondrial ATP synthesis, or systemic mechanisms involving insulin and insulin-like growth factors have been much studied in vitro and in preclinical models. Epidemiologic and retrospective studies also provide clinical evidence in support of metformin as an antitumor agent. Preoperative window-of-opportunity trials confirm the safety of metformin in women with primary breast cancer, and demonstrate reduction in tumor cell proliferation and complex pathways of gene suppression or overexpression attributable to metformin. Confirmation of insulin-mediated effects, independent of body mass index, also supports the potential benefit of adjuvant metformin therapy. Neoadjuvant, adjuvant, and advanced disease trials combining metformin with established anticancer agents are under way or proposed. Companion biomarker studies will utilize in vitro and preclinical understanding of the relevant molecular pathways to, in future, refine patient and tumor selection for metformin therapy. Clin Cancer Res; 20(10); 2508–15. ©2014 AACR.
A-Z of nutritional supplements: dietary supplements, sports nutrition foods and ergogenic aids for health and performance--Part 27
Authors: Andrew M Jones, Satoshi Haramizu, Mayur Ranchordas, Louise Burke, Samantha Stear, Linda M Castell
Journal: British Journal of Sports Medicine (2011)

Welcome to Part 27, where we finish ‘N’ with nitrates and nootkatone and move onto ‘O’ starting with octacosanol. The first review focuses on what has become quite a hot topic in sport nutrition in the recent years with the BBC leading with a headline in August 2009 that ‘Beetroot Juice boosts Stamina’. The BBC was describing a study from Professor Andy Jones' group: in his brief review for Part 27, he describes the link between supplementing the diet with nitrate-rich beetroot juice to enhance NO availability and the consequential proposed mechanisms that could lead to an improvement in exercise performance. The other two reviews deal with substances that are generally found as plant extracts: nootkatone, a chemical found in the essential oil of grapefruit and other plants including cedars, which is used predominantly as a flavouring compound but also as a natural insecticide; and policosanol, a wheat-germ extract whose main component is octacosanol.

### AM Jones

Nitric oxide (NO) is an important physiological signalling molecule that can modulate skeletal muscle function through its role in the regulation of blood flow, muscle contractility, glucose and calcium homeostasis and mitochondrial biogenesis and respiration.1 Until quite recently, it was considered that NO was generated solely through the oxidation of the amino acid l-arginine in a reaction catalysed by nitric oxide synthase (NOS).2 It is now appreciated, however, that NO may also be produced by the reduction of nitrate to nitrite and subsequently of nitrite to NO.3 This pathway may be particularly important in hypoxia. Nitrate and nitrite are present in the body as products of NO production through NOS and are also modulated through the diet. Nitrate in foods (particularly green leafy vegetables) can be reduced to nitrite by oral bacteria, leading to an increased plasma nitrite concentration that serves as a …
Heat shock protein 72 expression allows permissive replication of oncolytic adenovirus dl1520 (ONYX-015) in rat glioblastoma cells.
Authors: Jonathan Madara, James A Krewet, Maulik Shah
Journal: Molecular Cancer (2005)

In this study we have made novel observations with regards to potentiation of the tumoricidal activity of the oncolytic adenovirus, dl1520 (ONYX-015) in rat glioblastoma cell lines expressing heat shock protein 72 (HSP72) due to permissive virus replication. ONYX-015 is a conditionally replicating adenovirus that is deleted for the E1B 55 kDA gene product whose normal function is to interact with cell-cycle regulatory proteins to permit virus replication. However, many murine and rodent cell lines are not permissive for adenovirus replication. Previously, it has been reported that the heat shock response is necessary for adenovirus replication and that induction of heat shock proteins is mediated by E1 region gene products. Therefore, we hypothesized that HSP72 expression may allow for permissive replication of ONYX-015 in previously non-permissive cells. Rat glioma cell lines 9L and RT2 were transfected with a plasmids expressing HSP72 or GFP. After infection with ONYX-015, no tumoricidal activity is observed in GFP expressing cell lines despite adequate transduction. In contrast, HSP72 transfected cells show cytopathic effects by 72 hours and greater than 75% loss of viability by 96 hours. Burst assays show active virus replication in the HSP72 expressing cell lines. Therefore, 9L-HSP72 and RT2-HSP72 are ideal models to evaluate the efficacy of ONYX-015 in an immunocompetent rat model. Our study has implications for creating rodent tumor models for pre-clinical studies with E1 region deleted conditionally replicating adenovirus.
The Structural Basis of PI3K Cancer Mutations: From Mechanism to Therapy
Authors: Shujuan Liu, Stefan Knapp, Ahmed Ashour Ahmed
Journal: Cancer Research (2014)

Abstract While genetic alteration in the p85α-p110α (PI3K) complex represents one of the most frequent driver mutations in cancer, the wild-type complex is also required for driving cancer progression through mutations in related pathways. Understanding the mechanistic basis of the function of the phosphoinositide 3-kinase (PI3K) is essential for designing optimal therapeutic targeting strategies. Recent structural data of the p85α/p110α complex unraveled key insights into the molecular mechanisms of the activation of the complex and provided plausible explanations for the well-established biochemical data on p85/p110 dimer regulation. A wealth of biochemical and biologic information supported by recent genetic findings provides a strong basis for additional p110-independent function of p85α in the regulation of cell survival. In this article, we review the structural, biochemical, and biologic mechanisms through which p85α regulates the cancer cell life cycle with an emphasis on the recently discovered genetic alterations in cancer. As cancer progression is dependent on multiple biologic processes, targeting key drivers such as the PI3K may be required for efficacious therapy of heterogeneous tumors typically present in patients with late-stage disease. Cancer Res; 74(3); 641–6. ©2014 AACR.