tbuckley/cabot-search huggingface dataset:
Delayed preconditioning in cardiac myocytes with respect to development of a proinflammatory phenotype: role of SOD and NOS
Authors: T Rui
Journal: Cardiovascular Research (2003)

Objective: Both superoxide dismutase (SOD) and nitric oxide synthase (NOS) have been implicated in delayed preconditioning (DP) to ischemia/reperfusion (I/R) in the heart. We used isolated cardiac myocytes to test the hypothesis that SOD and NOS may interact in the development of DP. Methods: Mouse neonatal cardiac myocytes were challenged with anoxia/reoxygenation (A/R; an in vitro counterpart to I/R) and normoxia/normoxia (N/N) served as the control. Two indices of inflammation were measured: oxidant stress (DHR oxidation) and polymorphonuclear leukocyte (PMN) transendothelial migration (cell culture inserts). The role of SOD was assessed using an antisense approach and the role of NOS was assessed using iNOS and eNOS deficient myocytes. Results: Cardiac myocytes exposed to A/R (1) produced more oxidants (intracellular fluorescence emission from 2.0±0.1 for N/N to 3.0±0.3 for A/R; P <0.05) and (2) promoted PMN migration (% migration from 8.4±0.9 for N/N to 14.1±1.1 for A/R; P <0.05). DP occurred if the myocytes were pretreated with an A/R challenge 24 h earlier. That is, these A/R-induced responses were significantly reduced (fluorescence emission 1.9±0.1 and % migration 8.4±0.7; P <0.05 as compared to A/R with no pretreatment). Myocyte Mn-SOD, but not Cu/Zn-SOD, activity increased 24 h after the initial A/R challenge. A Mn-SOD antisense oligonucleotide prevented the development of DP. DP occurred in iNOS, but not eNOS, deficient myocytes. A/R increased mRNA for eNOS, but not iNOS, in wild-type myocytes. A/R increased Mn-SOD protein in both iNOS and eNOS deficient myocytes. However, Mn-SOD activity increased only in iNOS deficient myocytes. Conclusions: Collectively, these findings suggest that Mn-SOD and eNOS may act in concert in the development of DP in cardiac myocytes.
<i>CDK4</i> and <i>MDM2</i> Gene Alterations Mainly Occur in Highly Proliferative and Aggressive Mantle Cell Lymphomas with Wild-type <i>INK4a/ARF</i> Locus
Authors: Luis Hernández, Silvia Beà, Magda Pinyol, German Ott, Tiemo Katzenberger, Andreas Rosenwald, Francesc Bosch, Armando López-Guillermo, Jan Delabie, Dolors Colomer, Emili Montserrat, Elías Campo
Journal: Cancer Research (2005)

Abstract Amplification of 12q13 locus occurs in some mantle cell lymphomas (MCL), potentially involving CDK4 and MDM2 genes. To determine the role of these genes in MCL, we have examined their gene status and expression and their relationship to INK4a/ARF and p53 gene aberrations in 69 tumors. Increased CDK4 gene copy number was detected in 4 of 19 (21%) highly proliferative blastoid variants and was associated with mRNA and protein overexpression. Three additional cases showed mRNA overexpression with no structural alterations of the gene. MDM2 gene overexpression was detected in three blastoid tumors (16%) with no relationship to gene copy gains. INK4a/ARF and p53 aberrations were observed in 13 and 12 tumors, respectively. Four of the seven lymphomas with CDK4 aberrations had concurrent inactivation of p53 gene, whereas only one case had a concomitant homozygous deletion of INK4a/ARF. No other gene alterations were found in the three cases with MDM2 overexpression. Patients with INK4a/ARF deletions or simultaneous aberrations of p53 and CDK4 had a significantly shorter median survival (17 months) than patients with isolated alterations of p53, MDM2, or CDK4 (32 months) and patients with no alterations in any of these genes (77 months). The prognostic impact of the concomitant oncogenic alterations of the p14ARF/p53 and p16INK4a/CDK4 pathways was independent of the proliferation of the tumors. These findings indicate that CDK4 and MDM2 gene alterations mainly occur in MCL with a wild-type INK4a/ARF locus and may contribute to the higher proliferation and more aggressive behavior of the tumors.
Notable postnatal alterations in the myenteric plexus of normal human bowel
Authors: T Wester, D S O’Briain, P Puri
Journal: Gut (1999)

BACKGROUND Nitric oxide is the most important transmitter in non-adrenergic non-cholinergic nerves in the human gastrointestinal tract. Impaired nitrergic innervation has been described in Hirschsprung’s disease, hypertrophic pyloric stenosis, and intestinal neuronal dysplasia (IND). Recent findings indicate that hyperganglionosis, one of the major criteria of IND, is age dependent. However, information is scanty regarding the neurone density in normal human bowel in the paediatric age group. AIMS To determine neurone density, morphology, and nitric oxide synthase distribution of the normal myenteric plexus at different ages during infancy and childhood. METHODS Specimens were obtained from small bowel and colon in 20 children, aged one day to 15 years, at postmortem examination. Whole mount preparations were made of the myenteric plexus, which were subsequently stained using NADPH diaphorase histochemistry (identical to nitric oxide synthase) and cuprolinic blue (a general neuronal marker). The morphology of the myenteric plexus was described and the neurone density estimated. RESULTS The myenteric plexus meshwork becomes less dense during the first years of life. The density of ganglion cells in the myenteric plexus decreases significantly with age during the first three to four years of life. The NADPH diaphorase positive (nitrergic) subpopulation represents about 34% of all neurones in the myenteric plexus. CONCLUSIONS The notable decrease in neurone density in the myenteric plexus during the first years of life indicates that development is still an ongoing process in the postnatal enteric nervous system. Applied to the clinical situation, this implies that interpretation of enteric nervous system pathology is dependent on the age of the patient.
Mental Imagery in Depression: Phenomenology, Potential Mechanisms, and Treatment Implications
Authors: Emily A. Holmes, Simon E. Blackwell, Stephanie Burnett Heyes, Fritz Renner, Filip Raes
Journal: Annual Review of Clinical Psychology (2016)

Mental imagery is an experience like perception in the absence of a percept. It is a ubiquitous feature of human cognition, yet it has been relatively neglected in the etiology, maintenance, and treatment of depression. Imagery abnormalities in depression include an excess of intrusive negative mental imagery; impoverished positive imagery; bias for observer perspective imagery; and overgeneral memory, in which specific imagery is lacking. We consider the contribution of imagery dysfunctions to depressive psychopathology and implications for cognitive behavioral interventions. Treatment advances capitalizing on the representational format of imagery (as opposed to its content) are reviewed, including imagery rescripting, positive imagery generation, and memory specificity training. Consideration of mental imagery can contribute to clinical assessment and imagery-focused psychological therapeutic techniques and promote investigation of underlying mechanisms for treatment innovation. Research into mental imagery in depression is at an early stage. Work that bridges clinical psychology and neuroscience in the investigation of imagery-related mechanisms is recommended.
Effectiveness and efficiency of search methods in systematic reviews of complex evidence: audit of primary sources
Authors: Trisha Greenhalgh, Richard Peacock
Journal: BMJ (2005)

To describe where papers come from in a systematic review of complex evidence. Method Audit of how the 495 primary sources for the review were originally identified.Only 30% of sources were obtained from the protocol defined at the outset of the study (that is, from the database and hand searches). Fifty one per cent were identified by "snowballing" (such as pursuing references of references), and 24% by personal knowledge or personal contacts.Systematic reviews of complex evidence cannot rely solely on protocol-driven search strategies.
Androgen-Stimulated UDP-Glucose Dehydrogenase Expression Limits Prostate Androgen Availability without Impacting Hyaluronan Levels
Authors: Qin Wei, Robert Galbenus, Ashraf Raza, Ronald L. Cerny, Melanie A. Simpson
Journal: Cancer Research (2009)

Abstract UDP-glucose dehydrogenase (UGDH) oxidizes UDP-glucose to UDP-glucuronate, an essential precursor for production of hyaluronan (HA), proteoglycans, and xenobiotic glucuronides. High levels of HA turnover in prostate cancer are correlated with aggressive progression. UGDH expression is high in the normal prostate, although HA accumulation is virtually undetectable. Thus, its normal role in the prostate may be to provide precursors for glucuronosyltransferase enzymes, which inactivate and solubilize androgens by glucuronidation. In this report, we quantified androgen dependence of UGDH, glucuronosyltransferase, and HA synthase expression. Androgen-dependent and androgen-independent human prostate cancer cell lines were used to test the effects of UGDH manipulation on tumor cell growth, HA production, and androgen glucuronidation. Dihydrotestosterone (DHT) increased UGDH expression ∼2.5-fold in androgen-dependent cells. However, up-regulation of UGDH did not affect HA synthase expression or enhance HA production. Mass spectrometric analysis showed that DHT was converted to a glucuronide, DHT-G, at a 6-fold higher level in androgen-dependent cells relative to androgen-independent cells. The increased solubilization and elimination of DHT corresponded to slower cellular growth kinetics, which could be reversed in androgen-dependent cells by treatment with a UDP-glucuronate scavenger. Collectively, these results suggest that dysregulated expression of UGDH could promote the development of androgen-independent tumor cell growth by increasing available levels of intracellular androgen. [Cancer Res 2009;69(6):2332–9]
Survival after rectal cancer: differences between hospital catchment areas. A nationwide study in Sweden
Authors: P Blomqvist, A Ekbom, O Nyren, U B Krusemo, R Bergstrom, H-O Adami
Journal: Gut (1999)

The quality of rectal cancer surgery at small units has been debated. No national studies of this issue have been undertaken and most studies have been based on insufficient data to clarify the controversy. It has been claimed that observed differences in outcomes between specialised centres and smaller hospitals are confounded by differences in stage/severity.To compare survival after rectal cancer between hospital catchment areas.All patients with rectal cancer notified to the Swedish Cancer Register in 1973-1992 (n = 30 811) were followed up by record linkage to the nationwide Death Register.Relative survival-that is, ratio of observed to expected survival-was computed as a measure of excess mortality attributable to rectal cancer. Multivariate analysis was then performed to estimate the independent effects of hospital catchment area categories and age, year of diagnosis, and duration of follow up.One year relative survival among rectal cancer patients residing in catchment areas of large regional hospitals was 76%, compared with 72% for small local hospitals (p<0.001). A difference was already noted after 30 days and remained five years after diagnosis. Relative survival improved considerably overall, but the differences between catchment area categories persisted. These were not reduced by adjustment for age, time after diagnosis, or time period in multivariate models.The differences in outcome between catchment area categories could not be explained by differences in age, time period, or duration of follow up after diagnosis. They are unlikely to be explained by differences between catchment area populations with regard to the average stage of the disease at which symptoms lead to diagnosis. The differences may therefore be attributable to different strategies for diagnosing and managing patients with rectal cancer.
In vivo priming of two distinct antitumor effector populations: the role of MHC class I expression.
Authors: H I Levitsky, A Lazenby, R J Hayashi, D M Pardoll
Journal: The Journal of Experimental Medicine (1994)

Downregulation of major histocompatibility complex (MHC) class I expression is an important mechanism by which tumors evade classical T cell-dependent immune responses. Therefore, a system was designed to evaluate parameters for active immunization against MHC class I- tumors. Mice were capable of rejecting a MHC class I- tumor challenge after immunization with an irradiated granulocyte/macrophage colony-stimulating factor (GM-CSF) transduced MHC class I- tumor vaccine. This response was critically dependent on CD4+ T cells and natural killer (NK) cells, but minimally on CD8+ T cells. A strong protective response against MHC class I+ variants of the tumor could be elicited when mice were immunized with irradiated MHC class I+ GM-CSF-secreting tumor cells. This response required CD4+ and CD8+ T cells, and in addition, elimination of NK cells resulted in outgrowth of tumors that had lost expression of at least one MHC class I gene. Finally, class I MHC expression on the vaccinating cells inhibited the response generated against a MHC class I- tumor challenge. These results demonstrate that the host is capable of being immunized against a tumor that has lost MHC class I expression and reveal conditions under which distinct effector cells play a role in the systemic antitumor immune response.
dCLIP: a computational approach for comparative CLIP-seq analyses
Authors: Tao Wang, Yang Xie, Guanghua Xiao
Journal: Genome biology (2014)

Abstract Although comparison of RNA-protein interaction profiles across different conditions has become increasingly important to understanding the function of RNA-binding proteins (RBPs), few computational approaches have been developed for quantitative comparison of CLIP-seq datasets. Here, we present an easy-to-use command line tool, dCLIP, for quantitative CLIP-seq comparative analysis. The two-stage method implemented in dCLIP, including a modified MA normalization method and a hidden Markov model, is shown to be able to effectively identify differential binding regions of RBPs in four CLIP-seq datasets, generated by HITS-CLIP, iCLIP and PAR-CLIP protocols. dCLIP is freely available at http://qbrc.swmed.edu/software/ .
Recombination or Mutational Hot Spots in Human mtDNA?
Authors: Hideki Innan, Magnus Nordborg
Journal: Molecular Biology and Evolution (2002)

Awadalla, Eyre-Walker, and Maynard Smith (1999) recently argued that there might be recombination in human mitochondrial DNA (mtDNA). Their claim was based on their observation of decaying linkage disequilibrium (LD) as a function of physical distance. Their study was much criticized, and follow-up studies have failed to find any evidence for recombination. We argue that the criticisms levied, even if correct, could not possibly explain the findings of Awadalla, Eyre-Walker, and Maynard Smith (1999) . Nonetheless, the test proposed by Awadalla, Eyre-Walker, and Maynard Smith (1999 ) is not robust because recombination is not the only explanation for decay of LD. We show that such a pattern can be caused by mutational hot spots as well. However, a closer look at the data suggests that the pattern observed was not caused by mutational hot spots but rather by chance. Thus, there appears to be no evidence for recombination in the mtDNA polymorphism data. In conclusion, we discuss the possibility of detecting recombination in mtDNA and the implications of its existence.
Thyroid autoimmunity and hypothyroidism before and during pregnancy
Authors: Kris Poppe, Daniel Glinoer
Journal: Human Reproduction Update (2003)

In the present review, an attempt was made to describe current knowledge and concepts concerning the complex relationships that link thyroid autoimmunity (TAI) and hypothyroidism with female and male infertility, as well as abnormalities occurring during pregnancy, such as pregnancy loss and maternal and fetal repercussions associated with hypothyroidism. In the case of infertility, although the clinical relevance of TAI is somewhat controversial, when all available information is considered the results strongly suggest that when infertility is due to well-defined female causes, autoimmunity is involved and TAI constitutes a useful marker of the underlying immune abnormality, independently of thyroid function disorders. In the case of pregnancy loss, the vast majority of available studies clearly establish that TAI (even with no overt thyroid dysfunction) is associated with a significant increase in miscarriage risk. To find an association, however, does not imply a causal relationship, and the aetiology of increased pregnancy loss associated with TAI remains presently not completely understood. With regard to maternal repercussions during gestation, the main risk associated with TAI is the occurrence of hypothyroidism and obstetric complications (premature birth, pre-eclampsia, etc.). Thus, systematic screening of TAI and hypothyroidism during early pregnancy, monitoring of thyroid function with/without L-thyroxine treatment and follow-up during post-partum have proved helpful and important in order to manage these patients adequately. Finally, with regard to potential repercussions affecting the offspring, recent evidence suggests that thyroid maternal underfunction, even when considered mild (or subclinical), may be associated with an impairment of fetal brain development. When present only during the first half of gestation, maternal hypothyroxinaemia is a risk factor for impaired fetal brain development, due to insufficient transfer of maternal thyroid hormones to the feto-placental unit. When hypothyroidism is not restricted to the first trimester and worsens as gestation progresses (as in untreated hypothyroidism), the fetus may also be deprived of adequate amounts of thyroid hormones during later neurological maturation and development, leading to poorer school performance and lower IQ.
A time-limited, six month program of community-based disease management, support and education following hospital admission for AECOPD: Outcomes from a pilot study
Authors: Myra Stern, Helen Broomfield, Angela Williamson, Catherine Potter, Claire Yeramesu
Journal: European Respiratory Journal (2011)

Introduction:  Our specialist multidisciplinary respiratory team (MDRT) can successfully support COPD patients following AECOPD admission (>1000 bed-days saved/year). Patient-dependency has made discharge difficult. The aim of this pilot was to determine the efficacy/suitability of a time-limited (6/12) support program, focused on self-management.   Method:  Patients admitted with AECOPD >2/year or first time with no previous diagnosis/education, were referred. Disease severity, anxiety/depression and admission frequency (year before/year after) were documented. A pre-determined program of self-management skills was assessed by the Bristol Questionaire (BQ).   Results:  23 COPD patients, (mean (±SD) age 73.3±0.02 years; FEV 1  0.79±0.07; MRCDS 4.1±0.1) were under MDRT for 6.4±0.9 months (mean±SE). 11/23 were discharged appropriately; 2 died; 8/23 required ongoing support. There was no significant difference in disease severity or HADS between those discharged and those requiring ongoing support. Admission rate significantly (p   Conclusion:  A time-limited program focused on self management is appropriate for about 50% patients admitted with severe COPD. Further work needs to be done to determine specific factors that can predict which patients are suitable for this intervention.
Population kinetics of rat peripheral B cells.
Authors: D Gray
Journal: The Journal of Experimental Medicine (1988)

Currently available estimates of B cell life span vary from 4 d to 6 wk. The discrepancy may have arisen out of the selective effects of stress and drug cytotoxicity on short-lived populations. In this report, bromodeoxyuridine (BUdR), a drug that incorporates into the DNA of dividing cells, has been fed to rats in their drinking water, eliminating stressful injection procedures. Labeled cells in the recirculating B cell pool are identified in tissue sections using an mAb to BUdR. BUdR is shown to have no cytostatic effects at the dose used. Over a 5-d period of infusion, only 20% of the peripheral recirculating pool incorporate label (approximately 4% per day); labeling over various periods indicates that the peripheral B cell pool turns over in approximately 4 wk. To distinguish between turnover due to incorporation of new B cells into the peripheral pool and division of antigen-activated B cells rats underwent two consecutive periods of labeling, first with [3H]thymidine for 5 d and then with BUdR for a further 5 d. Virgin B cells newly derived from dividing precursors in the bone marrow do not continue to proliferate in the periphery, while activated cells undergo several rounds of division during both labeling periods. The results indicate that 3-4% of the peripheral pool is replaced by new B cells each day, while 0.3-0.6% become part of activated clones every day. Assuming that the peripheral pool of the rat contains 10(9) B cells, then 3-4 X 10(7) new B cells become stably incorporated per day. This represents approximately 10% of the putative output of the bone marrow.
<i>Enterococcus faecalis</i> Induces Aneuploidy and Tetraploidy in Colonic Epithelial Cells through a Bystander Effect
Authors: Xingmin Wang, Toby D. Allen, Randal J. May, Stanley Lightfoot, Courtney W. Houchen, Mark M. Huycke
Journal: Cancer Research (2008)

Abstract Intestinal commensals are potential important contributors to the etiology of sporadic colorectal cancer, but mechanisms by which bacteria can initiate tumors remain uncertain. Herein, we describe mechanisms that link Enterococcus faecalis, a bacterium known to produce extracellular superoxide, to the acute induction of chromosomal instability. Immortalized human and nontransformed murine colonic epithelial cells, along with a mouse colonic ligation model, were used to assess the effect of E. faecalis on genomic DNA stability and damage. We found that this human intestinal commensal generated aneuploidy, tetraploidy, and γH2AX foci in HCT116, RKO, and YAMC cells. In addition, direct exposure of E. faecalis to these cells induced a G2 cell cycle arrest. Similar observations were noted by exposing cells to E. faecalis–infected macrophages in a dual-chamber coculture system for detecting bystander effects. Manganese superoxide dismutase, catalase, and tocopherols attenuated, and caffeine and inhibitors of glutathione synthase exacerbated, the aneugenic effects and linked the redox-active phenotype of this intestinal commensal to potentially transforming events. These findings provide novel insights into mechanisms by which E. faecalis and intestinal commensals can contribute to cellular transformation and tumorigenesis. [Cancer Res 2008;68(23):9909–17]