tbuckley/cabot-search huggingface dataset:
Mesenchymal stem cell therapy of Crohn's disease: are the far-away hills getting closer?
Authors: J. Panes, D. Benitez-Ribas, A. Salas
Journal: Gut (2011)

Persistence of unmet therapeutic needs in patients with Crohn's disease with luminal or perianal refractory disease has fostered the interest in innovative cellular immunoregulatory and regenerative medicines. Apart from autologous haematopoietic stem cell transplant, in which efficacy has been suggested in small series of patients and is now being evaluated in controlled trials, various groups have undertaken initiatives to determine the potential of mesenchymal stromal cell (MSC)-based therapy in Crohn's disease.

Bone marrow MSCs were first identified by Friedenstein, who described an adherent fibroblast-like population able to differentiate into bone. He referred to these cells as osteogenic precursor cells.1 Subsequent studies demonstrated that these cells have the ability to differentiate into various other mesodermal cell lineages, including chondrocytes, tenocytes and myoblasts. Based on this multilineage differentiation capacity, the term ‘mesenchymal stem cells’ was introduced.2 Although MSCs at a population level fulfil stem-cell criteria (ie, self-renewal and the capacity for multi-lineage differentiation), it remains questionable whether the qualification ‘stem cell’ is legitimate for MSCs at the single-cell level. It was therefore recently proposed that the term ‘multipotent mesenchymal stromal cells’ (with the abbreviation MSCs) should be used to describe fibroblast-like plastic-adherent cells.3

Although, originally, MSCs were isolated from bone marrow, similar populations have been isolated from other tissues, including adipose tissue, placenta, amniotic fluid and fetal tissues such as fetal lung and blood.2 To date, the isolation of MSCs still relies on their adherence to plastic, resulting in a heterogeneous population of adherent cells. No specific marker or combination of markers has been identified that specifically defines MSCs. Phenotypically, ex vivo expanded MSCs express a number of non-specific markers, including CD105 (SH2 or endoglin), CD73 (SH3 or SH4), CD90, CD166, CD44, and CD29, and are devoid …
INJURY TO THE INTERNAL EAR PRESENTING SOME UNUSUAL FEATURES
Authors: H. L. Whale
Journal: BMJ (1916)

JouaXand teriiiinal peritonitis all point to tllis.The case, however, presents imany problems of interest.It started wtlh tonsillitis probably of streptococcal origin, and at that timne tlhere -:as no albuiminuria.Tlle question arises, then, Did the tonsillitis pass on to a septicaemia, and cause a strepto- coccal interstitial neplhritis, or did the toxin circulating in the blood from thle focus in the throat cause tlle kidney trouble, leading to a general lowering of resistance, which allowed the streptococcus to get a footing in the general circulation ?In other words, was this nephritis of pyaemic or toxic origin ?Personally I am inclined to the former view.I admit that no organism -was denionstrable in the section:s, and the fact of its growing from the kidney pulp can be explained by a general blooI infection.I support my case eintirely on the microscopical abscesses in the interstitial tissue of the kidney, and on the clinical course of the case.My thanks armdue to Captain McLeod, R.A.M.C., who did the bacteriological work, and to Dr. Amecielle, of the Frenclh medical service, wlho got the tissues sectioned for me, and gave mne his valuable opinion on tllem.
Smokers commonly misperceive that nicotine is a major carcinogen: National survey data
Authors: N. Wilson, J. Peace, R. Edwards, D. Weerasekera
Journal: Thorax (2010)

In vitro testing has shown that nicotine may play a role in making cancers more aggressive,1 but the currently available evidence does not suggest that nicotine in itself induces cancer.2 Despite this, many smokers believe that nicotine does cause cancer. For example, in a USA-based study it was found that 65% of smokers believed nicotine causes lung cancer and 71% believed it caused oral cancer.3 Furthermore, some smokers regard nicotine replacement therapy (NRT) as also being carcinogenic.4 These findings are concerning since misperceptions about nicotine may result in underutilisation of NRT. Therefore, we aimed to assess these views in New Zealand (NZ) smokers, with the context being …
CD54/intercellular adhesion molecule 1 and major histocompatibility complex II signaling induces B cells to express interleukin 2 receptors and complements help provided through CD40 ligation.
Authors: J Poudrier, T Owens
Journal: The Journal of Experimental Medicine (1994)

We have examined signaling roles for CD54 intercellular adhesion molecule 1 and major histocompatibility complex (MHC) II as contact ligands during T help for B cell activation. We used a T helper 1 (Th1)-dependent helper system that was previously shown to be contact as well as interleukin 2 (IL-2) dependent to demonstrate the relative roles of CD54, MHC II, and CD40 signaling in the events leading to the induction of B cell proliferation and responsiveness to IL-2. Paraformaldehyde-fixed activated Th1-induced expression of IL-2R alpha, IL-2R beta, and B7, and upregulated MHC II and CD54 on B cells. Anti-CD54 and MHC II mAbs as well as a CD8 alpha-CD40 ligand (L) soluble construct inhibited both the T-dependent induction of Ig secretion, and B cell phenotypic changes. We then compared the effects of activated Th1 cells with that of cross-linking these molecules. Cross-linking of CD54 and MHC II resulted in the upregulated expression of MHC II and of CD54 and B7, respectively, analogous to the effect of fixed activated Th1 cells. B7 expression was further enhanced by co-cross-linking CD54 and MHC II. Cross-linking of CD40 achieved comparable effects. Strikingly, cross-linking ligation of CD54 and MHC II in the presence of IL-5 induced expression of a functional IL-2R on small resting B cells. By contrast CD40 ligation, which induced B cell proliferation, did not induce IL-2 responsiveness. These data show that CD40 ligation is necessary but may not be sufficient for B cell differentiation and identify CD54 and MHC II as contact ligands that can complement CD40 signaling in the generation of T-dependent B cell responses to IL-2.
Bcl-2 Suppresses Sarcoplasmic/Endoplasmic Reticulum Ca<sup>2+</sup>-ATPase Expression in Cystic Fibrosis Airways
Authors: Shama Ahmad, Aftab Ahmad, Elena S. Dremina, Victor S. Sharov, Xiaoling Guo, Tara N. Jones, Joan E. Loader, Jason R. Tatreau, Anne-Laure Perraud, Christian Schöneich, Scott H. Randell, Carl W. White
Journal: American Journal of Respiratory and Critical Care Medicine (2009)

Modulation of the activity of sarcoendoplasmic reticulum calcium ATPase (SERCA) can profoundly affect Ca(2+) homeostasis. Although altered calcium homeostasis is a characteristic of cystic fibrosis (CF), the role of SERCA is unknown.This study provides a comprehensive investigation of expression and activity of SERCA in CF airway epithelium. A detailed study of the mechanisms underlying SERCA changes and its consequences was also undertaken.Lung tissue samples (bronchus and bronchiole) from subjects with and without CF were evaluated by immunohistochemistry. Protein and mRNA expression in primary non-CF and CF cells was determined by Western and Northern blots.SERCA2 expression was decreased in bronchial and bronchiolar epithelia of subjects with CF. SERCA2 expression in lysates of polarized tracheobronchial epithelial cells from subjects with CF was decreased by 67% as compared with those from subjects without CF. Several non-CF and CF airway epithelial cell lines were also probed. SERCA2 expression and activity were consistently decreased in CF cell lines. Adenoviral expression of mutant F508 cystic fibrosis transmembrane regulator gene (CFTR), inhibition of CFTR function pharmacologically (CFTR(inh)172), or stable expression of antisense oligonucleotides to inhibit CFTR expression caused decreased SERCA2 expression. In CF cells, SERCA2 interacted with Bcl-2, leading to its displacement from caveolae-related domains of endoplasmic reticulum membranes, as demonstrated in sucrose density gradient centrifugation and immunoprecipitation studies. Knockdown of SERCA2 using siRNA enhanced epithelial cell death due to ozone, hydrogen peroxide, and TNF-alpha.Reduced SERCA2 expression may alter calcium signaling and apoptosis in CF. These findings decrease the likelihood of therapeutic benefit of SERCA inhibition in CF.
Mercaptopurine Therapy Intolerance and Heterozygosity at the Thiopurine S-Methyltransferase Gene Locus
Authors: M. V. Relling, M. L. Hancock, G. K. Rivera, J. T. Sandlund, R. C. Ribeiro, E. Y. Krynetski, C.-H. Pui, W. E. Evans
Journal: JNCI Journal of the National Cancer Institute (1999)

BACKGROUND: Patients with acute lymphoblastic leukemia are often treated with 6-mercaptopurine, and those with homozygous deficiency in thiopurine S -methyltransferase (TPMT) enzyme activity have an extreme sensitivity to this drug as a result of the accumulation of higher cellular concentrations of thioguanine nucleotides. We studied the metabolism, dose requirements, and tolerance of 6-mercaptopurine among patients with different TPMT phenotypes. METHODS: We compared, by use of statistical modeling, 6-mercaptopurine pharmacology and tolerance in 180 patients who achieved remission on St. Jude Children's Research Hospital Protocol Total XII composed of weekly methotrexate (40 mg/m 2 ) and daily oral 6-mercaptopurine (75 mg/m 2 ) given for 2.5 years, interrupted every 6 weeks during the first year for treatment with either high-dose methotrexate or teniposide plus cytarabine. Statistical tests were two-sided. RESULTS: Erythrocyte concentrations of thioguanine nucleotides (pmol/8 × 10 8 erythrocytes) were inversely related to TPMT enzyme activity ( P <.01), with averages (± standard deviations) of 417 (±179), 963 (±752), and 3565 (±1282) in TPMT homozygous wild-type (n = 161), heterozygous (n = 17), and homozygous-deficient (n = 2) patients, respectively. There was complete concordance between TPMT genotype and phenotype in a subset of 28 patients for whom TPMT genotype was determined. There were no sex differences in thioguanine nucleotide concentrations ( P = .24), TPMT enzyme activity ( P = .22), or average weekly prescribed dose of 6-mercaptopurine ( P = .49). The cumulative incidence of 6-mercaptopurine dose reductions due to toxicity was highest among patients homozygous for mutant TPMT (100%), intermediate among heterozygous patients (35%), and lowest among wild-type patients (7%) ( P <.001), with average (± standard deviation) final weekly 6-mercaptopurine doses of 72 (±60), 449 (±160), and 528 (±90) mg/m 2 , respectively. Lowering doses of 6-mercaptopurine in TPMT heterozygotes and in deficient patients allowed administration of full protocol doses of other chemotherapy while maintaining high thioguanine nucleotide concentrations. CONCLUSION: We conclude that genetic polymorphism in TPMT is an important determinant of mercaptopurine toxicity, even among patients who are heterozygous for this trait.
The evaluation of lung function measured by impulse oscillometry method in very low birth weight born children at preschool age
Authors: Meral Oruc, Ayla Gunlemez, Zeynep Seda Uyan, Ayse Sevim Gokalp, Nazan Kavas, Gulcan Turker, Ayse Engin Arisoy
Journal: European Respiratory Journal (2012)

Introduction: Chronic lung disease is one of the most important complications of prematurity and results in short and long-term morbidity. Survival of more prematurely born babies leads to an increase in the incidence of bronchopulmonary dysplasia (BPD).  Aim: To evaluate the lung function of babies who were born under birth weight of 1500 grams using impulse oscillometry in preschool age.  Methods: Eighty-six children who were 3-6 years old and followed in our neonatology clinic (born under birth weight of 1500 grams) were enrolled in the study as the patient group and 40 term-born healthy children as the control group. The demographic data of the patients, duration of mechanical ventilation and oxygen therapy and presence of BPD were recorded. After routine physical examination, lung functions of children were measured by impulse oscillometry. The data were evaluated by SPSS 16 program.  Results: Forty-nine (57%) of 86 patients were non-BPD, 20 were mild BPD, 14 were moderate BPD and 3 were severe BPD. Weight and height of premature and control groups were similar. There was a statistically significant difference between the two groups in terms of resistance (R5,R10,R20), reactance (X5,X10,X20) and resonant frequency (fres). The airway resistance was significantly higher and reactance was significantly lower in the premature group. However, there was no difference between BPD and non-BPD groups.  Conclusion: Although premature babies can catch-up their peers at 3-4 years old in terms of their body percentiles, their lungs still reflect the traces of prematurity.
Acute myeloid leukemia fusion proteins deregulate genes involved in stem cell maintenance and DNA repair
Authors: Myriam Alcalay, Natalia Meani, Vania Gelmetti, Anna Fantozzi, Marta Fagioli, Annette Orleth, Daniela Riganelli, Carla Sebastiani, Enrico Cappelli, Cristina Casciari, Maria Teresa Sciurpi, Angela Rosa Mariano, Simone Paolo Minardi, Lucilla Luzi, Heiko Muller, Pier Paolo Di Fiore, Guido Frosina, Pier Giuseppe Pelicci
Journal: Journal of Clinical Investigation (2003)

Acute myelogenous leukemias (AMLs) are genetically heterogeneous and characterized by chromosomal rearrangements that produce fusion proteins with aberrant transcriptional regulatory activities. Expression of AML fusion proteins in transgenic mice increases the risk of myeloid leukemias, suggesting that they induce a preleukemic state. The underlying molecular and biological mechanisms are, however, unknown. To address this issue, we performed a systematic analysis of fusion protein transcriptional targets. We expressed AML1/ETO, PML/RAR, and PLZF/RAR in U937 hemopoietic precursor cells and measured global gene expression using oligonucleotide chips. We identified 1,555 genes regulated concordantly by at least two fusion proteins that were further validated in patient samples and finally classified according to available functional information. Strikingly, we found that AML fusion proteins induce genes involved in the maintenance of the stem cell phenotype and repress DNA repair genes, mainly of the base excision repair pathway. Functional studies confirmed that ectopic expression of fusion proteins constitutively activates pathways leading to increased stem cell renewal (e.g., the Jagged1/Notch pathway) and provokes accumulation of DNA damage. We propose that expansion of the stem cell compartment and induction of a mutator phenotype are relevant features underlying the leukemic potential of AML-associated fusion proteins.
Ataxia Telangiectasia Mutated Down-regulates Phospho-Extracellular Signal-Regulated Kinase 1/2 via Activation of MKP-1 in Response to Radiation
Authors: Mukesh K. Nyati, Felix Y. Feng, Divya Maheshwari, Sooryanarayana Varambally, Steven P. Zielske, Aarif Ahsan, Patrick Y. Chun, Vinay A. Arora, Mary A. Davis, Mira Jung, Mats Ljungman, Christine E. Canman, Arul M. Chinnaiyan, Theodore S. Lawrence
Journal: Cancer Research (2006)

Abstract Ataxia telangiectasia mutated (ATM) kinase plays a crucial role in the cellular response to DNA damage and in radiation resistance. Although much effort has focused on the relationship between ATM and other nuclear signal transducers, little is known about interactions between ATM and mitogenic signaling pathways. In this study, we show a novel relationship between ATM kinase and extracellular signal-regulated kinase 1/2 (ERK1/2), a key mitogenic stimulator. Activation of ATM by radiation down-regulates phospho-ERK1/2 and its downstream signaling via increased expression of mitogen-activated protein kinase phosphatase MKP-1 in both cell culture and tumor models. This dephosphorylation of ERK1/2 is independent of epidermal growth factor receptor (EGFR) activity and is associated with radioresistance. These findings show a new function for ATM in the control of mitogenic pathways affecting cell signaling and emphasize the key role of ATM in coordinating the cellular response to DNA damage. (Cancer Res 2006; 66(24): 11554-9)
Amplification of TRIM44: Pairing a Prognostic Target With Potential Therapeutic Strategy
Authors: Chin-Ann Johnny Ong, Nicholas B. Shannon, Caryn S. Ross-Innes, Maria O’Donovan, Oscar M. Rueda, De-en Hu, Mikko I. Kettunen, Christina Elaine Walker, Ayesha Noorani, Richard H. Hardwick, Carlos Caldas, Kevin Brindle, Rebecca C. Fitzgerald
Journal: JNCI Journal of the National Cancer Institute (2014)

Many prognostic biomarkers have been proposed recently. However, there is a lack of therapeutic strategies exploiting novel prognostic biomarkers. We aimed to propose therapeutic options in patients with overexpression of TRIM44, a recently identified prognostic gene. Genomic and transcriptomic data of epithelial cancers (n = 1932), breast cancers (BCs; n = 1980) and esophago-gastric cancers (EGCs; n = 163) were used to identify genomic aberrations driving TRIM44 overexpression. The driver gene status of TRIM44 was determined using a small interfering RNA (siRNA) screen of the 11p13 amplicon. Integrative analysis was applied across multiple datasets to identify pathway activation and potential therapeutic strategies. Validation of the in silico findings were performed using in vitro assays, xenografts, and patient samples (n = 160). TRIM44 overexpression results from genomic amplification in 16.1% of epithelial cancers, including 8.1% of EGCs and 6.1% of BCs. This was confirmed using fluorescent in situ hybridization. The siRNA screen confirmed TRIM44 to be a driver of the amplicon. In silico analysis revealed an association between TRIM44 and mTOR signalling, supported by a decrease in mTOR signalling after siRNA knockdown of TRIM44 in cell lines and colocalization of TRIM44 and p-mTOR in patient samples. In vitro inhibition studies using an mTOR inhibitor (everolimus) decreased cell viability in two TRIM44-amplified cells lines by 88% and 70% compared with 35% in the control cell line. These findings were recapitulated in xenograft models. Genomic amplification drives TRIM44 overexpression in EGCs and BCs. Targeting the mTOR pathway provides a potential therapeutic option for TRIM44-amplified tumors.
Alopecia areata regrowth induced by Primula obconica
Authors: E.L. Rhodes, W. Dolman, C. Kennedy, R.R. Taylor
Journal: British Journal of Dermatology (1981)

Journal Article Alopecia areata regrowth induced by Primula obconica Get access E.L. Rhodes, E.L. Rhodes Department of Dermatology, Kingston and St Helier Hospitals Dr E.L. Rhodes, St Helier Hospital, Carshalton, Surrey. Search for other works by this author on: Oxford Academic Google Scholar W. Dolman, W. Dolman Department of Dermatology, Kingston and St Helier Hospitals Search for other works by this author on: Oxford Academic Google Scholar C. Kennedy, C. Kennedy Department of Dermatology, Kingston and St Helier Hospitals Search for other works by this author on: Oxford Academic Google Scholar R.R. Taylor R.R. Taylor Department of Dermatology, Kingston and St Helier Hospitals Search for other works by this author on: Oxford Academic Google Scholar British Journal of Dermatology, Volume 104, Issue 3, 1 March 1981, Pages 339–400, https://doi.org/10.1111/j.1365-2133.1981.tb00959.x Published: 01 March 1981
Redefining cognitive psychology
Authors: John Jonides, Patricia Reuter-Lorenz
Journal: Behavioral and Brain Sciences (1995)

Abstract Posner &amp; Raichle illustrate how neuroimaging blends profitably with neuropsychology and electrophysiology to advance cognitive theory. Recognizing that there are limitations to each of these techniques, we nonetheless argue that their confluence has fundamentally changed the way cognitive psychologists think about problems of the mind.
Phase II study of E7070 in patients with metastatic melanoma
Authors: J.F. Smyth, S. Aamdal, A. Awada, C. Dittrich, F. Caponigro, P. Schöffski, M. Gore, T. Lesimple, N. Djurasinovic, B. Baron, M. Ravic, P. Fumoleau, C.J.A. Punt
Journal: Annals of Oncology (2004)
IL-15 and Type I Interferon Are Required for Activation of Tumoricidal NK Cells by Virus-Infected Dendritic Cells
Authors: Jeanette E. Boudreau, Kyle B. Stephenson, Fuan Wang, Ali A. Ashkar, Karen L. Mossman, Laurel L. Lenz, Kenneth L. Rosenthal, Jonathan L. Bramson, Brian D. Lichty, Yonghong Wan
Journal: Cancer Research (2011)

There is increasing evidence that natural killer (NK) cells play an important role in antitumor immunity following dendritic cell (DC) vaccination. Little is known, however, about the optimal stimulation of DCs that favors NK activation in tumor-bearing hosts. In this study, we demonstrate that treatment with toll-like receptor (TLR) ligands and infection with a mutant vesicular stomatitis virus (VSV-ΔM51) both induced DC maturation. Further, inoculation of these DCs led to robust NK-mediated protection against tumor challenge. Strikingly, only VSV-ΔM51-infected DCs were capable of suppressing the growth of established tumors, suggesting that additional signals provided by viral infection may be required to activate tumoricidal NK cells in tumor-bearing hosts. VSV-ΔM51 infection of DCs induced greater type I interferon (IFN I) production than TLR ligand treatment, and disruption of the IFN I pathway in DCs eliminated their ability to induce NK activation and tumor protection. However, further studies indicated that IFN I alone was not sufficient to activate NK cells, especially in the presence of a tumor, and DC-derived IL-15 was additionally required for tumoricidal NK activation. These results suggest that induction of IFN I by VSV-ΔM51 allows DCs to overcome tumor-associated immunosuppression and facilitate IL-15-mediated priming of tumoricidal NK cells. Thus, the mode of DC maturation should be carefully considered when designing DC-based cancer immunotherapies.
Loss of Protein Inhibitors of Activated STAT-3 Expression in Glioblastoma Multiforme Tumors: Implications for STAT-3 Activation and Gene Expression
Authors: Emily C. Brantley, L. Burton Nabors, G. Yancey Gillespie, Youn-Hee Choi, Cheryl Ann Palmer, Keith Harrison, Kevin Roarty, Etty N. Benveniste
Journal: Clinical Cancer Research (2008)

Abstract Purpose: STATs activate transcription in response to numerous cytokines, controlling proliferation, gene expression, and apoptosis. Aberrant activation of STAT proteins, particularly STAT-3, is implicated in the pathogenesis of many cancers, including GBM, by promoting cell cycle progression, stimulating angiogenesis, and impairing tumor immune surveillance. Little is known about the endogenous STAT inhibitors, the PIAS proteins, in human malignancies. The objective of this study was to examine the expression of STAT-3 and its negative regulator, PIAS3, in human tissue samples from control and GBM brains. Experimental Design: Control and GBM human tissues were analyzed by immunoblotting and immunohistochemistry to determine the activation status of STAT-3 and expression of the PIAS3 protein. The functional consequence of PIAS3 inhibition by small interfering RNA or PIAS3 overexpression in GBM cells was determined by examining cell proliferation, STAT-3 transcriptional activity, and STAT-3 target gene expression. This was accomplished using [3H]TdR incorporation, STAT-3 dominant-negative constructs, reverse transcription-PCR, and immunoblotting. Results and Conclusions: STAT-3 activation, as assessed by tyrosine and serine phosphorylation, was elevated in GBM tissue compared with control tissue. Interestingly, we observed expression of PIAS3 in control tissue, whereas PIAS3 protein expression in GBM tissue was greatly reduced. Inhibition of PIAS3 resulted in enhanced glioblastoma cellular proliferation. Conversely, PIAS3 overexpression inhibited STAT-3 transcriptional activity, expression of STAT-3–regulated genes, and cell proliferation. We propose that the loss of PIAS3 in GBM contributes to enhanced STAT-3 transcriptional activity and subsequent cell proliferation.