tbuckley/cabot-search huggingface dataset:
The link between antibodies to OxLDL and natural protection against pneumococci depends on DH gene conservation
Authors: Andre M. Vale, Pratibha Kapoor, Greg A. Skibinski, Ada Elgavish, Tamer I. Mahmoud, Cosima Zemlin, Michael Zemlin, Peter D. Burrows, Alberto Nobrega, John F. Kearney, David E. Briles, Harry W. Schroeder
Journal: The Journal of Experimental Medicine (2013)

Selection and physiological production of protective natural antibodies (NAbs) have been associated with exposure to endogenous antigens. The extent to which this association depends on germline NAb sequence is uncertain. Here we show that alterations in germline D(H) sequence can sever the association between the production of self-reactive NAbs and NAbs that afford protection against a pathogen. In unmanipulated hosts, the availability of the evolutionarily conserved DFL16.1 gene segment sequence profoundly affected the serum levels of NAbs against bacterial phosphorylcholine but not oxidized low-density lipoprotein. Mice with partially altered DFL16.1 sequence could use N nucleotides to recreate the amino acid sequence associated with the classical protective T15 idiotype–positive NAbs, whereas those without DFL16.1 could not. DFL16.1 gene-deficient mice proved more susceptible to challenge with live Streptococcus pneumoniae. Our findings indicate that although production of self-reactive NAbs can be independent of germline D(H) sequence, their capacity to provide protection against pathogens cannot. The potential relevance of these findings for the rational design of vaccines is discussed.
Do We Need a Different Set of Response Assessment Criteria for Tumor Immunotherapy?
Authors: Antoni Ribas, Bartosz Chmielowski, John A. Glaspy
Journal: Clinical Cancer Research (2009)

Tumor shrinkage induced by tumor immunotherapy may be preceded by inflammatory changes. This confounds the assessment of response rates to tumor immunotherapy. In this issue of Clinical Cancer Research, Wolchok et al. attempt to address this peculiarity by proposing a new set of criteria termed immune-related response criteria.
The role of apoptosis in the pathogenesis and treatment of diseases
Authors: E Solary, L Dubrez, B Eymin
Journal: European Respiratory Journal (1996)

In adult multicellular organisms, homeostasis is determined in each cell lineage by a balance between cell death and cell growth. Dysregulation of cell death mechanisms is involved in the pathogenesis of an increasing number of diseases. Defective apoptosis can participate in malignant transformation, viral latency and autoimmune diseases. Excessive apoptotic cell death is involved in CD4+ T-cell depletion observed in acquired immune deficiency syndrome, in fulminant hepatitis associated with infection by hepatitis B and C viruses, in some neurodegenerative disorders and haematological diseases, in polycystic kidney disease and ischaemia. Three steps can be distinguished in the pathway that leads to cell death. The first step involves interactions between the extracellular and intracellular signals that decide whether a cell should live or die. When death is chosen, a common pathway that involves at least the Bcl-2- family of proteins and the interleukin-1 beta (IL-1 beta)-converting enzyme-related cysteine proteases confirms whether or not the cell should die. Finally, if death is allowed to occur, the apoptotic process itself is characterized by deoxyribonucleic acid (DNA) fragmentation, proteolysis and morphological changes that precede the engulfment of apoptotic cells by neighbouring cells and phagocytes. Several inducers and inhibitors of apoptosis acting on one or several of these three steps that characterize the apoptotic process have been identified in vitro. Their potential usefulness in improving the current therapeutic strategies and designing new strategies in several different diseases is discussed.
Generation of cytolytic T lymphocytes in thymectomized, irradiated, and bone marrow-reconstituted mice.
Authors: V Duprez, B Hamilton, S J Burakoff
Journal: The Journal of Experimental Medicine (1982)

A model system has been developed to study extrathymic T cell differentiation. Mice have been thymectomized, lethally irradiated, and reconstituted with bone marrow cells depleted of Thy-1-positive cells. After 8 wk, the spleen cells of these 5athymic, bone marrow-reconstituted chimeras contain Thy-1-positive pre-cytolytic T lymphocytes (CTL) that are able to respond to antigen only when exogenous interleukin 2 is added to culture.. The phenotype of these pre-CTL is similar to that of thymocytes, suggesting that they may be an immature T cell. Initial evaluation of the CTL repertoire of these athymic mice demonstrates that the CTL generated to trinitrophenyl-modified syngeneic cells are H-2 restricted and that the CTL generated to alloantigens have many of the cross-reactivities observed in normal but not in nude mice. The discrepancies observed in the CTL repertoire between these thymectomized chimeras and nude mice are discussed.
Noninvasive Magnetic Resonance Spectroscopic Pharmacodynamic Markers of the Choline Kinase Inhibitor MN58b in Human Carcinoma Models
Authors: Nada M.S. Al-Saffar, Helen Troy, Ana Ramírez de Molina, Laura E. Jackson, Basetti Madhu, John R. Griffiths, Martin O. Leach, Paul Workman, Juan C. Lacal, Ian R. Judson, Yuen-Li Chung
Journal: Cancer Research (2006)

Abstract MN58b is a novel anticancer drug that inhibits choline kinase, resulting in inhibition of phosphocholine synthesis. The aim of this work was to develop a noninvasive and robust pharmacodynamic biomarker for target inhibition and, potentially, tumor response following MN58b treatment. Human HT29 (colon) and MDA-MB-231 (breast) carcinoma cells were examined by proton (1H) and phosphorus (31P) magnetic resonance spectroscopy (MRS) before and after treatment with MN58b both in culture and in xenografts. An in vitro time course study of MN58b treatment was also carried out in MDA-MB-231 cells. In addition, enzymatic assays of choline kinase activity in cells were done. A decrease in phosphocholine and total choline levels (P &amp;lt; 0.05) was observed in vitro in both cell lines after MN58b treatment, whereas the inactive analogue ACG20b had no effect. In MDA-MB-231 cells, phosphocholine fell significantly as early as 4 hours following MN58b treatment, whereas a drop in cell number was observed at 48 hours. Significant correlation was also found between phosphocholine levels (measured by MRS) and choline kinase activities (r2 = 0.95, P = 0.0008) following MN58b treatment. Phosphomonoesters also decreased significantly (P &amp;lt; 0.05) in both HT29 and MDA-MB-231 xenografts with no significant changes in controls. 31P-MRS and 1H-MRS of tumor extracts showed a significant decrease in phosphocholine (P ≤ 0.05). Inhibition of choline kinase by MN58b resulted in altered phospholipid metabolism both in cultured tumor cells and in vivo. Phosphocholine levels were found to correlate with choline kinase activities. The decrease in phosphocholine, total choline, and phosphomonoesters may have potential as noninvasive pharmacodynamic biomarkers for determining tumor response following treatment with choline kinase inhibitors. (Cancer Res 2006; 66(1): 427-34)
O6-methylguanine methyltransferase in colorectal cancers: detection of mutations, loss of expression, and weak association with G:C&gt;A:T transitions
Authors: S Halford
Journal: Gut (2005)

O(6)-methylguanine methyltransferase (MGMT) repairs inappropriately methylated guanine in DNA. MGMT mutations have not previously been reported in cancers, but in colorectal tumours MGMT promoter methylation is common and has been associated with increased G:C>A:T transitions, a high frequency of K-ras mutations, and low level microsatellite instability (MSI low). However, some have suggested that MGMT changes are background or secondary events, with little importance for tumorigenesis.We have analysed fresh frozen colorectal cancers and colorectal cancer cell lines for MGMT changes: mutations, allelic loss, and protein expression.Six of 113 cancers harboured somatic missense MGMT mutations, at least three of which probably caused reduced MGMT function and were accompanied by silencing or loss of the wild-type allele. Cancers with pathogenic MGMT mutations tended to harbour G:C>A:T somatic mutations at other loci. Overall, MGMT expression was reduced or lost in more than half of the cancers. We found no association between MGMT expression and the somatic mutation spectrum at APC, beta-catenin, K-ras, or p53, but decreased MGMT expression was weakly associated with the presence of a G:C>A:T change at any one of these loci. Reduced MGMT expression was not however associated with an increased frequency of K-ras mutations or with MSI low.In summary, we found that mutation of MGMT contributes to decreased protein function. Our findings provide good evidence to show that MGMT changes, including methylation, are selected rather than background events, at least in some cases. Decreased MGMT expression or function probably has a weak or moderate effect on the mutation spectrum in colorectal cancers.
INTENSIVE THERAPY FOR CHILDREN WITH ACUTE LYMPHOBLASTIC LEUKAEMIA AND UNFAVOURABLE PRESENTING FEATURES
Authors: PaulS. Gaynon, W.Archie Bleyer, VincentC. Albo, NeilJ. Grossman, LouisT. Novak, GregoryH. Reaman, PeterG. Steinherz, ArthurR. Ablin, JerryZ. Finklestein, PhilipS. Littman, AllanF. Pyesmany, HarlandN. Sather, G.Denman Hammond
Journal: The Lancet (1988)
Dopaminergic Modulation of Neuronal Excitability in the Striatum and Nucleus Accumbens
Authors: Saleem M. Nicola, D. James Surmeier, Robert C. Malenka
Journal: Annual Review of Neuroscience (2000)

The striatum and its ventral extension, the nucleus accumbens, are involved in behaviors as diverse as motor planning, drug seeking, and learning. Invariably, these striatally mediated behaviors depend on intact dopaminergic innervation. However, the mechanisms by which dopamine modulates neuronal function in the striatum and nucleus accumbens have been difficult to elucidate. Recent electrophysiological studies have revealed that dopamine alters both voltage-dependent conductances and synaptic transmission, resulting in state-dependent modulation of target cells. These studies make clear predictions about how dopamine, particularly via D 1 receptor activation, should alter the responsiveness of striatal neurons to extrinsic excitatory synaptic activity.
SECOND TRIMESTER CHORIONIC VILLUS (PLACENTAL) BIOPSY
Authors: Bjorn Gustavii, Heléne Edvall, Elisabeth Svalenius, Kerstin Dahlander, Connie Jorgensen, J.P. Cook, I.D. Young, D. Maxwell, B. Modell, M. Petrou, R.H.T. Ward
Journal: The Lancet (1986)
Nitric oxide–mediated regulation of ferroportin-1 controls macrophage iron homeostasis and immune function in <i>Salmonella</i> infection
Authors: Manfred Nairz, Ulrike Schleicher, Andrea Schroll, Thomas Sonnweber, Igor Theurl, Susanne Ludwiczek, Heribert Talasz, Gerald Brandacher, Patrizia L. Moser, Martina U. Muckenthaler, Ferric C. Fang, Christian Bogdan, Günter Weiss
Journal: The Journal of Experimental Medicine (2013)

Nitric oxide (NO) generated by inducible NO synthase 2 (NOS2) affects cellular iron homeostasis, but the underlying molecular mechanisms and implications for NOS2-dependent pathogen control are incompletely understood. In this study, we found that NO up-regulated the expression of ferroportin-1 (Fpn1), the major cellular iron exporter, in mouse and human cells. Nos2(-/-) macrophages displayed increased iron content due to reduced Fpn1 expression and allowed for an enhanced iron acquisition by the intracellular bacterium Salmonella typhimurium. Nos2 gene disruption or inhibition of NOS2 activity led to an accumulation of iron in the spleen and splenic macrophages. Lack of NO formation resulted in impaired nuclear factor erythroid 2-related factor-2 (Nrf2) expression, resulting in reduced Fpn1 transcription and diminished cellular iron egress. After infection of Nos2(-/-) macrophages or mice with S. typhimurium, the increased iron accumulation was paralleled by a reduced cytokine (TNF, IL-12, and IFN-γ) expression and impaired pathogen control, all of which were restored upon administration of the iron chelator deferasirox or hyperexpression of Fpn1 or Nrf2. Thus, the accumulation of iron in Nos2(-/-) macrophages counteracts a proinflammatory host immune response, and the protective effect of NO appears to partially result from its ability to prevent iron overload in macrophages.
Selecting Drug Combinations Based on Total Equivalent Dose (Dose Intensity)
Authors: R. Simon, E. L. Korn
Journal: JNCI Journal of the National Cancer Institute (1990)

We describe a mathematical model for selecting cytotoxic drugs and dosages for a combination regimen based on the antitumor activities of the drugs given as single agents and their organ-specific maximum tolerated doses. The regimen defined maximizes an approximate measure of antitumor effect subject to constraints on combined toxicity. This approach does not assume that the underlying dose-response curve is steep; nor does it assume that maximally dose-intense regimens are clinically appropriate in all situations. Whether the identified regimen is superior to standard treatments should be determined by prospective, randomized clinical trials. Determining which drugs to combine and in what proportions to combine them offers combinatorially huge numbers of possibilities. The method described here offers one approach to identifying combinations worthy of evaluation in prospective trials.
Opposite evolution in incidence of Crohn's disease and ulcerative colitis in Northern France (1988-1999)
Authors: F Molinie
Journal: Gut (2004)

<b>Background:</b> Northern France was characterised by a high incidence of Crohn's disease (CD) and a low incidence of ulcerative colitis (UC) according to the first inquiry undertaken in the late 1980s. <b>Aims:</b> To assess the trends in the incidence of inflammatory bowel disease (IBD) over a 12 year period (1988–1999) in the same area of Northern France. <b>Patients:</b> Patients living in Northern France (Nord, Pas-de-Calais, Somme, and Seine Maritime—total of 5 790 526 inhabitants) between 1988 and 1999 were included in the study. Case ascertainment was established according to methodology previously described. <b>Methods:</b> Trends in incidence were studied using a Poisson regression model in four three year periods (1988–90, 1991–93, 1994–96, and 1997–99) adjusted for age at diagnosis and sex. Incidence rates were standardised for age with the European standard population. <b>Results:</b> During 1988–99, 7066 cases of IBD were recorded (56.8% CD, 37.7% UC, and 5.5% indeterminate colitis). Mean annual incidence rate of CD increased from 5.2/100 000 inhabitants in 1988–90 to 6.4 in 1997–99 (adjusted p for trend &lt;0.001). In contrast, the incidence of UC decreased from 4.2 to 3.5 (adjusted p for trend &lt;0.001). The ileocolonic subtype of CD increased by 25% even though median age at diagnosis and frequency of digestive investigations were not different. <b>Conclusions:</b> Contrary to what has been reported in other countries in Northern Europe, the incidence of CD increased by 23% in 12 years in Northern France while that of UC decreased by 17% during the same period. This indicates that some factors which influence IBD frequency (in both directions) are still at work in this area of Europe, and that further studies aimed at identifying these should be performed. The rising incidence of CD could enhance the burden of this disease on the public health system in France.
Magnetic Resonance Imaging of Lung Water Content and Distribution in Term and Preterm Infants
Authors: Eleri W. Adams, Serena J. Counsell, Joseph V. Hajnal, Peter N. Cox, Nigel L. Kennea, Anna S. Thornton, A. Charles Bryan, A. David Edwards
Journal: American Journal of Respiratory and Critical Care Medicine (2002)

An increase in lung liquid may contribute to respiratory disease in preterm infants. Uneven distribution of lung liquid may cause heterogeneity in the lung disease seen in these infants. We used magnetic resonance imaging to investigate lung water content and distribution in 16 preterm (24–31 weeks) and 9 term infants in the first week of life. Images of lung parenchyma were examined and relative proton density quantified to give an index of lung water. Lung water content and distribution were compared between preterm and term infants, and in preterm infants regional signal distribution between dependent and nondependent lung on T1 weighted images was also compared after turning between prone and supine positions. Relative proton density was higher in preterm than in term lung (p < 0.008) and greater in dependent than in nondependent regions, particularly in the preterm (p < 0.001). Repositioning preterm infants rapidly redistributed signal intensities, with more even distribution lying prone than supine (p < 0.001). Small, low-signal regions were seen in the lung parenchyma in preterm but not in term infants, which may indicate peribronchial fluid or overdistension of compliant lung units. We conclude that lung water content is higher in preterm than in term infants and is associated with gravity-related changes consistent with dependent atelectasis.
Antibody raised against soluble CD4-rgp120 complex recognizes the CD4 moiety and blocks membrane fusion without inhibiting CD4-gp120 binding.
Authors: F Celada, C Cambiaggi, J Maccari, S Burastero, T Gregory, E Patzer, J Porter, C McDanal, T Matthews
Journal: The Journal of Experimental Medicine (1990)

We studied the humoral response of mice immunized with soluble CD4-rgp120 complex, testing polyclonal and monoclonal antibodies (mAbs) with the aim of identifying molecular changes that take place after the first interaction between human immunodeficiency virus and the cell surface. The antisera had a paradoxically high syncytia-blocking titer associated with anti-CD4 specificity, while their capacity to inhibit CD4-gp120 binding was relatively modest. One of the mAbs produced from these responders blocks syncytia formation but does not inhibit CD4 interaction with gp120. Apparently, this mAb interacts with the CD4 moiety of CD4-gp120 complex and prevents a post-binding event necessary for membrane fusion and viral infection.
Mycotic aneurysm caused by Burkholderia pseudomallei: report of a Brazilian strain genetically related to Thai strains
Authors: J.J.C. Sidrim, M.F.G. Rocha, T.J.P.G. Bandeira, R.A. Cordeiro, B.M. Carvalho, T.B. Grangeiro, M.A. Holanda, R.A.C. Lima, L.G.A. Valente, A.K.F. Costa, R.S.N. Brilhante
Journal: Clinical Microbiology and Infection (2010)
Beyond TNF, Th1 and Th2 in inflammatory bowel disease
Authors: M. Shale, S. Ghosh
Journal: Gut (2008)

The last decade has seen rapid developments in the field of biological therapy for inflammatory bowel disease (IBD). Understanding the immunopathogenesis of IBD has led to identification of distinct immunological targets. Such targeted therapy with antitumour necrosis factor (TNF) monoclonal antibodies is now in widespread use for both Crohn’s disease (CD) and ulcerative colitis (UC). Beyond this, therapies with other anticytokines are in various stages of development, including antibodies against interleukin 6 (IL6), IL12/23 and interferon γ (IFNγ).

The rationale for targeting these cytokines is largely derived from observations regarding the cytokine profile in intestinal tissues from patients with generally long-standing IBD, and from experiments utilising animal models of the disease. Analysis of the mucosal T cell phenotype had until recently largely supported the concept of CD as a Th1 disease, driven by IL12 and characterised by the production of the signature cytokine, IFNγ, and UC as an atypical Th2 disease characterised by production of cytokines such as IL13. More recently, the discovery of the Th17 lineage, driven by IL23 (as well as IL6 and transforming growth factor β) and characterised by IL17 production has led to a re-evaluation, and the realisation that a number of inflammatory conditions in which Th1 was previously considered central, may actually be Th17 dependent. Amongst these are several experimental models of colitis, and there is emerging evidence of CD as a Th17 disease. To add to the complexity, in contrast to mice, in humans a significant proportion of Th17 cells also secrete IFNγ, thus displaying a mixed Th17/Th1 cytokine phenotype, particularly in the gut.1 Furthermore, a number of observations regarding Th17 cells challenge our concepts of terminal T cell lineage commitment, with the demonstration that regulatory T cells can differentiate into inflammatory Th17 cells.2 A number of …
Long-term effects of intrauterine growth restriction on cardiac metabolism and susceptibility to ischaemia/reperfusion
Authors: Christian F. Rueda-Clausen, Jude S. Morton, Gary D. Lopaschuk, Sandra T. Davidge
Journal: Cardiovascular Research (2010)

AimsAdult offspring who are born intrauterine growth restricted (IUGR) are at risk of developing cardiovascular diseases during adulthood. Additionally, several cardiac diseases are associated with changes in myocardial energy metabolism. However, the potential long-term effects of being born IUGR on cardiac energetics are unknown. The aim of this study was to assess the long-term effect of IUGR on cardiac performance and energy metabolism under aerobic conditions and after ischaemia/reperfusion (IR) injury.
Latino Immigrants, Acculturation, and Health: Promising New Directions in Research
Authors: Ana F. Abraído-Lanza, Sandra E. Echeverría, Karen R. Flórez
Journal: Annual Review of Public Health (2015)

This article provides an analysis of novel topics emerging in recent years in research on Latino immigrants, acculturation, and health. In the past ten years, the number of studies assessing new ways to conceptualize and understand how acculturation-related processes may influence health has grown. These new frameworks draw from integrative approaches testing new ground to acknowledge the fundamental role of context and policy. We classify the emerging body of evidence according to themes that we identify as promising directions--intrapersonal, interpersonal, social environmental, community, political, and global contexts, cross-cutting themes in life course and developmental approaches, and segmented assimilation--and discuss the challenges and opportunities each theme presents. This body of work, which considers acculturation in context, points to the emergence of a new wave of research that holds great promise in driving forward the study of Latino immigrants, acculturation, and health. We provide suggestions to further advance the ideologic and methodologic rigor of this new wave.