tbuckley/cabot-search huggingface dataset:
CD1d-restricted Human Natural Killer T Cells Are Highly Susceptible to Human Immunodeficiency Virus 1 Infection
Authors: Alison Motsinger, David W. Haas, Aleksandar K. Stanic, Luc Van Kaer, Sebastian Joyce, Derya Unutmaz
Journal: The Journal of Experimental Medicine (2002)

Human natural killer (NK) T cells are unique T lymphocytes that express an invariant T cell receptor (TCR) Vα24-Vβ11 and have been implicated to play a role in various diseases. A subset of NKT cells express CD4 and hence are potential targets for human immunodeficiency virus (HIV)-1 infection. We demonstrate that both resting and activated human Vα24+ T cells express high levels of the HIV-1 coreceptors CCR5 and Bonzo (CXCR6), but low levels of CCR7, as compared with conventional T cells. Remarkably NKT cells activated with α-galactosylceramide (α-GalCer)-pulsed dendritic cells were profoundly more susceptible to infection with R5-tropic, but not X4-tropic, strains of HIV-1, compared with conventional CD4+ T cells. Furthermore, resting CD4+ NKT cells were also more susceptible to infection. After initial infection, HIV-1 rapidly replicated and depleted the CD4+ subset of NKT cells. In addition, peripheral blood NKT cells were markedly and selectively depleted in HIV-1 infected individuals. Although the mechanisms of this decline are not clear, low numbers or absence of NKT cells may affect the course of HIV-1 infection. Taken together, our findings indicate that CD4+ NKT cells are directly targeted by HIV-1 and may have a potential role during viral transmission and spread in vivo.
Suppressing Orthotopic Pancreatic Tumor Growth with a Fiber-Modified Adenovector Expressing the <b> <i>TRAIL</i> </b> Gene from the Human Telomerase Reverse Transcriptase Promoter
Authors: Dietmar Jacob, John Davis, Hongbo Zhu, Lidong Zhang, Fuminori Teraishi, Shuhong Wu, Frank C. Marini, Bingliang Fang
Journal: Clinical Cancer Research (2004)

An adenoviral vector with RGD-modified fibers and expressing the human tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) gene from the human telomerase reverse transcriptase (hTERT) promoter (designated Ad/TRAIL-F/RGD) was constructed, and its antitumor activity was evaluated in vitro and in vivo. An in vitro study showed that treatment with Ad/TRAIL-F/RGD elicited a high rate of apoptosis in human pancreatic and colon cancer cell lines that were either susceptible or resistant to conventional adenovectors. In vivo study showed that direct administration of Ad/TRAIL-F/RGD to an orthotopic implantation tumor model established in the pancreatic tails of nu/nu mice significantly suppressed tumor growth: tumors in the animals treated with Ad/TRAIL-F/RGD were approximately eight times smaller than those in animals treated with a control vector. We also evaluated hTERT promoter activity and the effect of Ad/TRAIL-F/RGD on mesenchymal stem cells. Our results showed that transgene expression from the hTERT promoter in human bone marrow mesenchymal stem cells was minimal. No adverse effect was observed in mesenchymal stem cells treated with Ad/TRAIL-F/RGD. Together, our results suggest that Ad/TRAIL-F/RGD could become a potent therapeutic agent for the management of pancreatic cancer.
Extensive Gene Conversion Drives the Concerted Evolution of Paralogous Copies of the SRY Gene in European Rabbits
Authors: A. Geraldes, T. Rambo, R. A. Wing, N. Ferrand, M. W. Nachman
Journal: Molecular Biology and Evolution (2010)

The human Y chromosome consists of ampliconic genes, which are located in palindromes and undergo frequent gene conversion, and single-copy genes including the primary sex-determining locus, SRY. Here, we demonstrate that SRY is duplicated in a large palindrome in the European rabbit (Oryctolagus cuniculus). Furthermore, we show through comparative sequencing that orthologous palindrome arms have diverged 0.40% between rabbit subspecies over at least 2 My, but paralogous palindrome arms have remained nearly identical. This provides clear evidence of gene conversion on the rabbit Y chromosome. Together with previous observations in humans, these results suggest that gene conversion is a general feature of the evolution of the mammalian Y chromosome.
Immunoprophylactic trial with combined Mycobacterium Leprae/BCG vaccine against leprosy: preliminary results
Authors: J. Convit, C. Sampson, M. Zúñiga, J. Plata, J. Silva, J. Molina, M.E. Pinardi, A. Salgado, P.G. Smith, B.R. Bloom
Journal: The Lancet (1992)
Concealed arrhythmogenic syndromes: the hidden substrate of idiopathic ventricular fibrillation?
Authors: S Priori
Journal: Cardiovascular Research (2001)

In ∼6–10% of survivors of cardiac arrest no cardiac abnormality can be identified despite extensive clinical evaluation. Autopsy data confirm that in a similar percentage of victims of sudden death no structural heart disease can be identified at post mortem evaluation. Occurrence of cardiac arrest in the absence of a substrate is defined 'idiopathic ventricular fibrillation' thus admitting that the cause for the arrhythmic event has remained unknown. We present data supporting the hypothesis that incompletely penetrant genetic defects may underlie at least some of these unexplained deaths.
Statins Enhance Migratory Capacity by Upregulation of the Telomere Repeat-Binding Factor TRF2 in Endothelial Progenitor Cells
Authors: Ioakim Spyridopoulos, Judith Haendeler, Carmen Urbich, Tim H. Brummendorf, Hidemasa Oh, Michael D. Schneider, Andreas M. Zeiher, Stefanie Dimmeler
Journal: Circulation (2004)

Background— Cultivation of endothelial progenitor cells (EPCs) leads to premature replicative senescence, limiting ex vivo expansion for potential clinical cell therapy. Recent studies have linked senescence to the dysfunction of telomeres, the “ends” of chromosomes, via the so-called mitotic clock or culture-induced stress. The purpose of this study was to elucidate a possible role of telomere biology in the functional augmentation of EPCs by statins. Methods and Results— Human EPCs were isolated from peripheral blood. Using flow cytometry after fluorescence in situ hybridization with a telomere-specific (C 3 TA 2 ) 3 peptide nucleic acid probe (Flow-FISH), we found mean telomere length in untreated EPCs from healthy subjects to range between 8.5±0.2 and 11.1±0.5 kb with no change over 6 days of culture, excluding telomere erosion as one cause for premature senescence. Although mean telomere length did not differ between statin-treated and untreated EPCs, atorvastatin (0.1 μmol/L) and mevastatin (1.0 μmol/L) both led to a more than 3-fold increase in the expression of the telomere capping protein TRF2 (telomere repeat-binding factor), as shown by immunoblotting, whereas quantitative reverse transcription–polymerase chain reaction demonstrated no increase in TRF2 mRNA. Telomere dysfunction of EPCs was also paralleled by a 4-fold increase in the DNA damage checkpoint-kinase 2 (Chk2). Conversely, statin cotreatment or overexpression of TRF2 completely suppressed Chk2 induction. Finally, overexpression of a dominant negative mutant of the TRF2 protein abrogated statin-induced enhancement of migratory activity down to baseline values. Conclusions— Ex vivo culturing of EPCs leads to “uncapping” of telomeres, indicated by the loss of TRF2. Statin cotreatment of EPCs prevents impairment of their functional capacity by a TRF2-dependent, posttranscriptional mechanism. This is the first time a beneficial effect of statins on telomere biology has been described.
Stabilizing Selection on Behavior and Morphology Masks Positive Selection on the Signal in a Salamander Pheromone Signaling Complex
Authors: R. A. Watts
Journal: Molecular Biology and Evolution (2004)

Natural selection maintains the integration and coordination of sets of phenotypic characters that collectively perform a task. In functional complexes in which characters span molecular to behavioral levels of organization, we might then expect similar modes of selection to produce similar patterns in evolutionary divergence at each level. To test this expectation, we diagnosed selection at behavioral, morphological, and molecular levels for courtship pheromone signaling by plethodontid salamanders. At the levels of morphology and behavior tens of millions of years of stasis (stabilizing selection) occur on each side of a transition from vaccination to olfactory delivery modes. As a proxy for the molecular level, we used plethodontid receptivity factor (PRF), a protein that is an active component of the pheromone. We cloned PRF from 12 Plethodon spp. spanning the delivery transition and obtained multiple alleles from each individual surveyed. Analyses of 61 alleles for PRF identified elevated nonsynonymous over synonymous substitution rates along lineages in a molecular phylogeny, and at 8% of sites in the protein, indicating that positive (directional) selection has acted on this vertebrate pheromone gene. Structural models showed PRF is in a family of cytokines characterized by a four–α-helix bundle. Positive selection in PRF was associated with receptor binding sites that are under purifying selection in other cytokines of that family. The evolutionary dynamics of the plethodontid pheromone delivery complex consists of stabilizing selection on morphological and behavioral aspects of signal delivery but positive selection on the signal mediated by receptors. Thus, different selection modes prevail at different levels in this reproductive functional complex. Evolutionary studies of integrated sets of characters therefore require separate analyses of selective action at each level.
Imatinib mesylate in the treatment of c-kit–positive acute myeloid leukemia: is this the real target?
Authors: Michele Malagola, Giovanni Martinelli, Michela Rondoni, Stefania Paolini, Stavrula Gaitani, Mario Arpinati, Pier Paolo Piccaluga, Marilina Amabile, Constanza Basi, Emanuela Ottaviani, Anna Candoni, Enrico Gottardi, Daniela Cilloni, Monica Bocchia, Giuseppe Saglio, Francesco Lauria, Renato Fanin, Giuseppe Visani, Maria Carla Marrè, Michela Maderna, Francesca Rancati, Vincenza Vinaccia, Domenico Russo, Michele Baccarani
Journal: Blood (2005)
Molecular imaging of VEGF in gastrointestinal cancer in vivo using confocal laser endomicroscopy
Authors: S. Foersch, R. Kiesslich, M. J. Waldner, P. Delaney, P. R. Galle, M. F. Neurath, M. Goetz
Journal: Gut (2010)

<h3>Background</h3> Vascular endothelial growth factor (VEGF) is a therapeutic target in gastrointestinal cancer (GiC). However, its in vivo visualisation could not be achieved to date with endoscopic techniques. Confocal laser endomicroscopy (CLE) is a novel imaging technique for gastrointestinal endoscopy providing in vivo microscopy at subcellular resolution. The aim of the study was to evaluate CLE for in vivo molecular imaging of VEGF in GiC. <h3>Methods</h3> Molecular imaging of tumours in APCmin mice, in xenograft models and in surgical specimens of patients with colorectal cancer (CRC) was achieved after application of labelled antibodies. The tumour sites were scanned with the probe for the strongest specific fluorescent signal. From all tumour sites examined with CLE in vivo, targeted specimens were obtained for histology, immunohistochemistry (IHC) and fluorescence microscopy. <h3>Results</h3> A VEGF-specific signal was visualised in vivo in 13/15 APCmin mice and in 9/10 xenograft tumours. CLE enabled the cytoplasmatic distribution of VEGF to be displayed due to its subcellular resolution. In human tissue, a VEGF-specific signal was observed in 12/13 malignant specimens and in 10/11 samples from healthy mucosa from the patients (p&lt;0.03). CLE findings correlated well with ex vivo microscopy. <h3>Conclusion</h3> In vivo molecular imaging with specific targeting of VEGF is possible in murine tumours, human xenografts and tissue specimens using CLE. CLE with similar probes can be performed in human colonoscopy. Therefore—from a technical point of view—in vivo molecular imaging is transferable to stratification of patients with CRC during endoscopy even today. CLE could contribute to the identification of lesions at risk and potentially predict response to targeted treatment.
Predictors of New-Onset Diastolic and Systolic Hypertension
Authors: Stanley S. Franklin, Jose R. Pio, Nathan D. Wong, Martin G. Larson, Eric P. Leip, Ramachandran S. Vasan, Daniel Levy
Journal: Circulation (2005)

Factors leading differentially to the development of isolated diastolic (IDH), systolic-diastolic (SDH), and isolated systolic (ISH) hypertension are poorly understood. We examined the relations of blood pressure (BP) and clinical risk factors to the new onset of the 3 forms of hypertension.Participants in the Framingham Heart Study were included if they had undergone 2 biennial examinations between 1953 and 1957 and were free of antihypertensive therapy and cardiovascular disease. Compared with optimal BP (SBP <120 and DBP <80 mm Hg), the adjusted hazard ratios (HRs) for developing new-onset IDH over the ensuing 10 years were 2.75 for normal BP, 3.29 for high-normal BP (both P<0.0001), 1.31 (P=0.40) for SDH, and 0.61 (P=0.36) for ISH. The HRs of developing new-onset SDH were 3.32, 7.96, 7.10, and 23.12 for the normal BP, high-normal BP, ISH, and IDH groups, respectively (all P<0.0001). The HRs of developing ISH were 3.26 for normal and 4.82 for high-normal BP (both P<0.0001), 1.39 (P=0.24) for IDH, and 1.69 (P<0.01) for SDH. Increased body mass index (BMI) during follow-up predicted new-onset IDH and SDH. Other predictors of IDH were younger age, male sex, and BMI at baseline. Predictors of ISH included older age, female sex, and increased BMI during follow-up.Given the propensity for increased baseline BMI and weight gain to predict new-onset IDH and the high probability of IDH to transition to SDH, it is likely that IDH is not a benign condition. ISH arises more commonly from normal and high-normal BP than from "burned-out" diastolic hypertension.
Levetiracetam enhances p53-mediated MGMT inhibition and sensitizes glioblastoma cells to temozolomide
Authors: George C. Bobustuc, Cheryl H. Baker, Arati Limaye, Wayne D. Jenkins, Gary Pearl, Nicholas G. Avgeropoulos, Santhi D. Konduri
Journal: Neuro-Oncology (2010)

Antiepileptic drugs (AEDs) are frequently used to treat seizures in glioma patients. AEDs may have an unrecognized impact in modulating O6-methylguanine-DNA methyltransferase (MGMT), a DNA repair protein that has an important role in tumor cell resistance to alkylating agents. We report that levetiracetam (LEV) is the most potent MGMT inhibitor among several AEDs with diverse MGMT regulatory actions. In vitro, when used at concentrations within the human therapeutic range for seizure prophylaxis, LEV decreases MGMT protein and mRNA expression levels. Chromatin immunoprecipitation analysis reveals that LEV enhances p53 binding on the MGMT promoter by recruiting the mSin3A/histone deacetylase 1 (HDAC1) corepressor complex. However, LEV does not exert any MGMT inhibitory activity when the expression of either p53, mSin3A, or HDAC1 is abrogated. LEV inhibits malignant glioma cell proliferation and increases glioma cell sensitivity to the monofunctional alkylating agent temozolomide. In 4 newly diagnosed patients who had 2 craniotomies 7–14 days apart, prior to the initiation of any tumor-specific treatment, samples obtained before and after LEV treatment showed the inhibition of MGMT expression. Our results suggest that the choice of AED in patients with malignant gliomas may have an unrecognized impact in clinical practice and research trial design.
Rationing Resources While Improving Quality
Authors: S. Clark Newhall
Journal: JAMA (1995)

<h3>To the Editor.</h3> —After reading the article by Dr Eddy,<sup>1</sup>I was left with an uneasy feeling that the cost-benefit analyses he describes might not meet the requirements of peer review usually applied to validate the results of other scientific assertions. Accordingly, a decision to change one's practice based on a cost-benefit analysis conducted at the behest of an insurer may not be the best decision a physician can make for his or her patient. I entertain these doubts at the risk of being thought a backward curmudgeon of the "just to be on the safe side" school. I suggest that cost-benefit analyses such as Eddy describes should be published in the peer-reviewed medical literature, just as other scientific studies are. Further, it seems appropriate that insurers restrain themselves from creating "complementary coverage policies or guidelines" until the particular cost-benefit analysis and its assumptions can be considered in the
TLR-independent anti-inflammatory function of intestinal epithelial TRAF6 signalling prevents DSS-induced colitis in mice
Authors: Katerina Vlantis, Apostolos Polykratis, Patrick-Simon Welz, Geert van Loo, Manolis Pasparakis, Andy Wullaert
Journal: Gut (2015)

<h3>Objective</h3> The gut microbiota modulates host susceptibility to intestinal inflammation, but the cell types and the signalling pathways orchestrating this bacterial regulation of intestinal homeostasis remain poorly understood. Here, we investigated the function of intestinal epithelial toll-like receptor (TLR) responses in the dextran sodium sulfate (DSS)-induced mouse model of colitis. <h3>Design</h3> We applied an in vivo genetic approach allowing intestinal epithelial cell (IEC)-specific deletion of the critical TLR signalling adaptors, MyD88 and/or TIR-domain-containing adapter-inducing interferon-β (TRIF), as well as the downstream ubiquitin ligase TRAF6 in order to reveal the IEC-intrinsic function of these TLR signalling molecules during DSS colitis. <h3>Results</h3> Mice lacking TRAF6 in IECs showed exacerbated DSS-induced inflammatory responses that ensued in the development of chronic colon inflammation. Antibiotic pretreatment abolished the increased DSS susceptibility of these mice, showing that epithelial TRAF6 signalling pathways prevent the gut microbiota from driving excessive colitis. However, in contrast to epithelial TRAF6 deletion, blocking epithelial TLR signalling by simultaneous deletion of MyD88 and TRIF specifically in IECs did not affect DSS-induced colitis severity. This in vivo functional comparison between TRAF6 and MyD88/TRIF deletion in IECs shows that the colitis-protecting effects of epithelial TRAF6 signalling are not triggered by TLRs. <h3>Conclusions</h3> Intestinal epithelial TRAF6-dependent but MyD88/TRIF-independent and, thus, TLR-independent signalling pathways are critical for preventing propagation of DSS-induced colon inflammation by the gut microbiota. Moreover, our experiments using mice with dual MyD88/TRIF deletion in IECs unequivocally show that the gut microbiota trigger non-epithelial TLRs rather than epithelial TLRs to restrict DSS colitis severity.
Vanilloids in pancreatic cancer: potential for chemotherapy and pain management
Authors: M Hartel
Journal: Gut (2005)

Success of chemotherapy and alleviation of pain are frequently less than optimal in pancreatic cancer patients, leading to increasing interest in new pharmacological substances, such as vanilloids. Our study addressed the question of whether vanilloids influence pancreatic cancer cell growth, and if vanilloids could be used for pain treatment via the vanilloid 1 receptor (VR1) in pancreatic cancer patients.In vitro, the effect of resiniferatoxin (vanilloid analogue) on apoptosis and cell growth in pancreatic cancer cells--either alone, combined with 5-fluorouracil (5-FU), or combined with gemcitabine--was determined by annexin V staining, FACS analysis, and MTT assay, respectively. VR1 expression was evaluated on RNA and protein level by quantitative polymerase chain reaction and immunohistochemistry in human pancreatic cancer and chronic pancreatitis. Patient characteristics--especially pain levels--were registered in a prospective database and correlated with VR1 expression.Resiniferatoxin induced apoptosis by targeting mitochondrial respiration and decreased cell growth in pancreatic cancer cells without showing synergistic effects with 5-FU or gemcitabine. Expression of VR1 was significantly upregulated in human pancreatic cancer and chronic pancreatitis. VR1 expression was related to the intensity of pain reported by cancer patients but not to the intensity of pain reported by patients with chronic pancreatitis.Resiniferatoxin induced apoptosis in pancreatic cancer cells indicates that vanilloids may be useful in the treatment of human pancreatic cancer. Furthermore, vanilloid might be a novel and effective treatment option for neurogenic pain in patients with pancreatic cancer.
Sleep disorders in children.
Authors: G Stores
Journal: BMJ (1990)

hepatocellular carcinoma, and indeed this tumour occurs about 200 times more frequently in such patients than in the general population.'416Niederau et al found that patients receiving treatment before cirrhosis appeared did not develop hepatocellular carcinoma later.'4The case is, therefore, convincing.Individual people with the genetic predisposition to develop hereditary haemochromatosis seem to be relatively common (at least in white populations), and early venesection treatment prevents progression of hepatic disease to cirrhosis and may consequently prevent the complication of hepatocellular carcinoma.We should therefore aim at diagnosing hereditary haemochromatosis as early as possible, and screen- ing for this condition would probably benefit more patients than many tests done routinely on blood taken from patients in hospital.
TRAF-interacting protein (TRIP) negatively regulates IFN-β production and antiviral response by promoting proteasomal degradation of TANK-binding kinase 1
Authors: Meng Zhang, Lijuan Wang, Xueying Zhao, Kai Zhao, Hong Meng, Wei Zhao, Chengjiang Gao
Journal: The Journal of Experimental Medicine (2012)

TANK-binding kinase 1 (TBK1) plays an essential role in Toll-like receptor (TLR)- and retinoic acid-inducible gene I (RIG-I)-mediated induction of type I interferon (IFN; IFN-α/β) and host antiviral responses. How TBK1 activity is negatively regulated remains largely unknown. We report that TNF receptor-associated factor (TRAF)-interacting protein (TRIP) promotes proteasomal degradation of TBK1 and inhibits TLR3/4- and RIG-I-induced IFN-β signaling. TRIP knockdown resulted in augmented activation of IFN regulatory factor 3 (IRF3) and enhanced expression of IFN-β in TLR3/4- and RIG-I-activated primary peritoneal macrophages, whereas overexpression of TRIP had opposite effects. Consistently, TRIP impaired Sendai virus (SeV) infection-induced IRF3 activation and IFN-β production and promoted vesicular stomatitis virus (VSV) replication. As an E3 ubiquitin ligase, TRIP negatively regulated the cellular levels of TBK1 by directly binding to and promoting K48-linked polyubiquitination of TBK1. Therefore, we identified TRIP as a negative regulator in TLR3/4- and RIG-I-triggered antiviral responses and suggested TRIP as a potential target for the intervention of diseases with uncontrolled IFN-β production.