tbuckley/cabot-search huggingface dataset:
Eicosapentaenoic acid reduces rectal polyp number and size in familial adenomatous polyposis
Authors: N. J. West, S. K. Clark, R. K. S. Phillips, J. M. Hutchinson, R. J. Leicester, A. Belluzzi, M. A. Hull
Journal: Gut (2010)

<h3>Objective</h3> The omega-3 polyunsaturated fatty acid eicosapentaenoic acid (EPA) has anticolorectal cancer activity in vitro and in preclinical models. The present study tested whether a novel, enteric-coated formulation of EPA, as the free fatty acid (EPA-FFA), has chemopreventative efficacy in patients with familial adenomatous polyposis (FAP), in a randomised, double-blind, placebo-controlled trial. <h3>Methods</h3> Patients undergoing endoscopic surveillance of their retained rectum postcolectomy were randomised to EPA-FFA (SLA Pharma) 2 g daily or placebo for 6 months. The number and size of polyps in an area of mucosa defined by a tattoo were determined before and after intervention. Global rectal polyp burden was scored (−1, 0, +1) by examination of video endoscopy records. Mucosal fatty acid content was measured by gas chromatography–mass spectrometry. <h3>Results</h3> 55 patients with FAP were evaluated by an intention-to-treat analysis (EPA-FFA 28, placebo 27). Treatment with EPA-FFA for 6 months was associated with a mean 22.4% (95% CI 5.1% to 39.6%) reduction in polyp number (p=0.012) and a 29.8% (3.6% to 56.1%) decrease in the sum of polyp diameters (p=0.027). Global polyp burden worsened over 6 months in the placebo group (−0.34) unlike the EPA-FFA group (+0.09, difference 0.42 (0.10–0.75), p=0.011). EPA-FFA treatment led to a mean 2.6-fold increase in mucosal EPA levels (p=0.018 compared with placebo). EPA-FFA was well tolerated with an incidence of adverse events similar to placebo. <h3>Conclusions</h3> EPA-FFA has chemopreventative efficacy in FAP, to a degree similar to that previously observed with selective cyclo-oxygenase-2 inhibitors. EPA holds promise as a colorectal cancer chemoprevention agent with a favourable safety profile. <h3>Clinical trial number</h3> NCT00510692.
Human NK Cells Are Alerted to Induction of p53 in Cancer Cells by Upregulation of the NKG2D Ligands ULBP1 and ULBP2
Authors: Sonja Textor, Nathalie Fiegler, Annette Arnold, Angel Porgador, Thomas G. Hofmann, Adelheid Cerwenka
Journal: Cancer Research (2011)

Abstract Natural killer (NK) cells are immune cells sensing and eliminating foreign, stressed, transformed, and senescent cells through specialized surface receptors, such as NKG2D, that interacts with several virus- or stress-inducible ligands, including ULBP1 and -2, which are expressed on target cell surfaces. For example, induction of DNA damage or cellular senescence pathways in tumor cells led to upregulation of NKG2D ligands that activate NK cells. Although, both pathways activate p53, the relationship of p53 activation to upregulation of NKG2D ligands has not been addressed. In this study, we report that induction of wild-type p53, but not mutant p53, strongly upregulated mRNA and cell surface expression of ULBP1 and -2, whereas expression of other NK cell ligands was not affected. We defined intronic p53-responsive elements in these two novel p53 target genes. Coculture of wild-type p53-induced human tumor cells with primary human NK cells enhanced NKG2D-dependent degranulation and IFN-γ production by NK cells. Accordingly, treatment of certain wild-type p53-expressing tumor cell lines with the p53-reactivating small molecular compound RITA resulted in upregulation of ULBP2 mRNA and cell surface protein expression. Taken together, our findings define the involvement of p53 in the regulation of specific NKG2D ligands that enhance NK cell–mediated target recognition. One implication of our work is that activating p53 after adoptive transfer of NK cells might constitute an effective combinatorial strategy of NK cell–based immunochemotherapy in cancers in which wild-type p53 function is preserved. Cancer Res; 71(18); 5998–6009. ©2011 AACR.
Renal impairment in chronic cigarette smokers.
Authors: G Gambaro, F Verlato, A Budakovic, D Casara, G Saladini, D Del Prete, G Bertaglia, M Masiero, S Checchetto, B Baggio
Journal: Journal of the American Society of Nephrology (1998)

To determine the effect of chronic cigarette smoking on renal function, a cross-sectional study was carried out with 30 subjects who had no known vascular disease risk factor other than cigarette smoking, and 24 age- and sex-matched controls without any vascular risk factor including cigarette smoking. Renal function by radionuclide studies of renal plasma flow, GFR, and plasma endothelin-1 concentration was determined. Compared with nonsmokers, smokers had a renal function impairment characterized by a normal GFR and a significant reduction in renal plasma flow as reflected by MAG3 clearance (199.20 +/- 58.85 ml/min per 1.73 m2 versus 256.54 +/- 60.14 ml/min per 1.73 m2; t = 3.52, P < 0.001). MAG3 clearance was significantly correlated with age and smoking. The renal dysfunction was associated with an increase in plasma endothelin-1 concentration (21.56 +/- 1.15 pmol/L versus 25.01 +/- 3.21 pmol/L; t = 5.00, P < 0.001). Former smokers as well had similar, although milder, abnormalities. In conclusion, cigarette smokers manifest an impairment of renal function, suggesting that smoke may have a detrimental effect on renal function.
Long-term persistence of molecular disease after histological remission in low-grade gastric MALT lymphoma treated with H. pylori eradication. Lack of association with translocation t(11;18): a 10-year updated follow-up of a prospective study
Authors: C. Montalban, A. Santón, C. Redondo, M. García-Cosio, D. Boixeda, E. Vazquez-Sequeiros, F. Norman, C.M. de Argila, I. Alvarez, V. Abraira, C. Bellas
Journal: Annals of Oncology (2005)
Intravital two-photon imaging: a versatile tool for dissecting the immune system
Authors: T. Ishii, M. Ishii
Journal: Annals of the Rheumatic Diseases (2011)

During the past decade, multi-photon or 'two-photon' excitation microscopy has launched a new era in the field of biological imaging. The near-infrared excitation laser for two-photon microscopy can penetrate thicker specimens, enabling the visualisation of living cell behaviour deep within tissues and organs without thin sectioning. The minimised photobleaching and toxicity enables the visualisation of live and intact specimens for extended periods. In this brief review, recent findings in intravital two-photon imaging for the physiology and pathology of the immune system are discussed. The immune system configures highly dynamic networks, where many cell types actively travel throughout the body and interact with each other in specific areas. Hence, real-time intravital imaging may be a powerful tool for dissecting the mechanisms of this dynamic system. The most unique characteristic of the immune system is its highly dynamic nature. A variety of cell types, such as lymphocytes, macrophages and dendritic cells (DCs), are continuously circulating throughout the body, migrating through the peripheral tissues and interacting with each other in their respective niches. Conventional methodologies in immunology, such as flow cytometry, cell or tissue culture, biochemistry and histology, have brought tremendous achievement within this field, although the dynamics of immune cells in an entire animal remain less clear. Technological progress of fluorescence microscopy has enabled us to visualise the intact biological phenomenon that has been uninvestigated. Among the advancements, the recent emergence and prevalence of two-photon, excitation-based, laser microscopy has revolutionised the research field, such that the dynamic behaviour of cells deep inside living organs can be visualised and analysed.
Immunopathogenesis and Immunotherapy of Type 1 Diabetes
Authors: Kim Wilson, George S. Eisenbarth
Journal: Annual Review of Medicine (1990)

Research in recent years has elucidated more clearly the genetic and immunopathogenic basis as well as the natural history of Type 1 diabetes mellitus. The development of Type 1 diabetes can be conceptually divided into stages, beginning in part with a human leukocyte antigen (HLA)-restricted genetic susceptibility. In some genetically susceptible subjects, a triggering event activates both cellular and humoral autoimmunity. Glucose-stimulated insulin secretion and beta cell mass diminish as anti-islet autoimmunity progresses. This process culminates in overt diabetes when only residual beta cell mass (estimated to be less than 10%) remains. Complete beta cell destruction follows within months to years of diagnosis. Most attempts at interrupting beta cell destruction have taken the form of broad immunosuppressive therapy begun at diagnosis when beta cell destruction is nearly complete. Greater understanding of early immune mediators and refinement of techniques to identify subjects at risk for Type 1 diabetes have set the stage for more specific immunomodulation targeted earlier in the course of the disease. We will review these recent advances in understanding the immunopathogenesis of Type 1 diabetes as they pertain to current and future trials of immunotherapy.
Claudin-4-targeted optical imaging detects pancreatic cancer and its precursor lesions
Authors: Albrecht Neesse, Anke Hahnenkamp, Heidi Griesmann, Malte Buchholz, Stefan A Hahn, Abdelouahid Maghnouj, Volker Fendrich, Janine Ring, Bence Sipos, David A Tuveson, Christoph Bremer, Thomas M Gress, Patrick Michl
Journal: Gut (2012)

<h3>Objectives</h3> Novel imaging methods based on specific molecular targets to detect both established neoplasms and their precursor lesions are highly desirable in cancer medicine. Previously, we identified claudin-4, an integral constituent of tight junctions, as highly expressed in various gastrointestinal tumours including pancreatic cancer. Here, we investigate the potential of targeting claudin-4 with a naturally occurring ligand to visualise pancreatic cancer and its precursor lesions in vitro and in vivo by near-infrared imaging approaches. <h3>Design</h3> A non-toxic C-terminal fragment of the claudin-4 ligand <i>Clostridium perfringens</i> enterotoxin (C-CPE) was labelled with a cyanine dye (Cy5.5). Binding of the optical tracer was analysed on claudin-4 positive and negative cells in vitro, and tumour xenografts in vivo. In addition, two genetically engineered mouse models for pancreatic intraepithelial neoplasia (PanIN) and pancreatic cancer were used for in vivo validation. Optical imaging studies were conducted using 2D planar fluorescence reflectance imaging (FRI) technology and 3D fluorescence-mediated tomography (FMT). <h3>Results</h3> In vitro, the peptide-dye conjugate showed high binding affinity to claudin-4 positive CAPAN1 cells, while claudin-4 negative HT1080 cells revealed little or no fluorescence. In vivo, claudin-4 positive tumour xenografts, endogenous pancreatic tumours, hepatic metastases, as well as preinvasive PanIN lesions, were visualised by FRI and FMT up to 48 h after injection showing a significantly higher average of fluorochrome concentration as compared with claudin-4 negative xenografts and normal pancreatic tissue. <h3>Conclusions</h3> C-CPE-Cy5.5 combined with novel optical imaging methods enables non-invasive visualisation of claudin-4 positive murine pancreatic tumours and their precursor lesions, representing a promising modality for early diagnostic imaging.
THE CULTIVATION OF HUMAN TISSUE IN VITRO
Authors: Joseph R. Losee, Albert H. Ebeling
Journal: The Journal of Experimental Medicine (1914)

A strain of human connective tissue was kept in a condition of active life in vitro for more than two months. When a medium has been devised the composition of which is more constant, it is reasonable to suppose that human connective tissue can be cultivated in vitro for an indefinite period.
Increased risk of tuberculosis in patients with rheumatoid arthritis in Japan
Authors: T Yamada, A Nakajima, E Inoue, E Tanaka, M Hara, T Tomatsu, N Kamatani, H Yamanaka
Journal: Annals of the Rheumatic Diseases (2006)

<b>Objective:</b> To determine the risk for tuberculosis infection in patients with rheumatoid arthritis before the anti-cytokine era in Japan. <b>Patients and methods:</b> A database of a single-institute-based large observational cohort study for rheumatoid arthritis at the Institute of Rheumatology, Tokyo Women's Medical University, Tokyo, Japan, was analysed. Information on the history of tuberculosis infection was collected by patient self-reporting during April and October 2003. The age-adjusted incidence rate and relative risk for tuberculosis infection were investigated. <b>Results:</b> Among 5044 patients with rheumatoid arthritis, 483 (9.6%) patients claimed to have a history of tuberculosis infection before October 2002. The frequency of history of tuberculosis increased according to the age of the patient. Four cases of new-onset tuberculosis were identified among 5544 patients with rheumatoid arthritis during 1 year. The age-adjusted incidence of tuberculosis was 42.4/100 000 patients. The relative risk for tuberculosis was 3.21 (95% confidence interval (CI) 1.21 to 8.55), and that of men and women was 10.59 (95% CI 3.42 to 32.78) and 1.41 (95% CI 0.2 to 10), respectively. <b>Conclusion:</b> There was an increased risk of tuberculosis infection in Japanese patients with rheumatoid arthritis, especially in male patients before the introduction of anti-tumour necrosis factor treatment. These data should form the basis for the risk management of anti-cytokine treatment in Japan.
Declining β-Cell Function Relative to Insulin Sensitivity With Increasing Fasting Glucose Levels in the Nondiabetic Range in Children
Authors: Hala Tfayli, SoJung Lee, Silva Arslanian
Journal: Diabetes Care (2010)

OBJECTIVE In adults, higher fasting plasma glucose (FPG) levels, even within the normoglycemic range, are associated with increased diabetes risk. This investigation tested the hypothesis that β-cell function relative to insulin sensitivity decreases with increasing FPG in youth. RESEARCH DESIGN AND METHODS A total of 223 youth with FPG &amp;lt;126 mg/dl underwent evaluation of first- and second-phase insulin secretion during a 2-h hyperglycemic (∼225 mg/dl) clamp, insulin sensitivity during a 3-h hyperinsulinemic-euglycemic clamp, body composition, and abdominal adiposity with dual-energy X-ray absorptiometry and computed tomographic scan. β-Cell function relative to insulin sensitivity was calculated as the product of first-phase insulin and insulin sensitivity, i.e., glucose disposition index (GDI). The subjects were divided into three FPG categories: ≤90, &amp;gt;90–&amp;lt;100, and ≥100–&amp;lt;126 mg/dl. RESULTS GDI decreased significantly across the three categories as FPG increased (1,086 ± 192 vs. 814 ± 67 and 454 ± 57 mg/kg/min, P = 0.002). This decline remained significant after adjustment for race, sex, BMI, and percent body fat or visceral fat. Within each FPG category, GDI declined with increasing BMI percentiles. CONCLUSIONS The impairment in β-cell function relative to insulin sensitivity is apparent even within the nondiabetic FPG range in children. At the current cutoff of 100 mg/dl for impaired fasting glucose (IFG), there is an ∼49% decline in the GDI independent of obesity and race. This observation may reflect a heightened risk of β-cell dysfunction and progression to diabetes in these children. Considering the near doubling of IFG prevalence among youth between National Health and Nutrition Examination Survey 1999–2000 and 2005–2006, our findings have important public health implications.
Stent Thrombosis in the Modern Era
Authors: Donald E. Cutlip, Donald S. Baim, Kalon K. L. Ho, Jeffrey J. Popma, Alexandra J. Lansky, David J. Cohen, Joseph P. Carrozza, Manish S. Chauhan, Orlando Rodriguez, Richard E. Kuntz
Journal: Circulation (2001)

There are limited studies of stent thrombosis in the modern era of second-generation stents, high-pressure deployment, and current antithrombotic regimens.
Impaired glucose tolerance is a risk factor for cardiovascular disease, but not impaired fasting glucose. The Funagata Diabetes Study.
Authors: M Tominaga, H Eguchi, H Manaka, K Igarashi, T Kato, A Sekikawa
Journal: Diabetes Care (1999)

To determine whether the new category of impaired fasting glucose (IFG) recently proposed by the Expert Committee of the American Diabetes Association is a risk factor for cardiovascular disease.Death certificates and residence transfer documents from the cohort population consisting of participants of the diabetes prevalence study in Funagata, Yamagata prefecture, Japan, 1990-1992, were analyzed up through the end of 1996. First, the cohort population was classified into three groups: normal glucose tolerance (NGT) (n = 2,016), impaired glucose tolerance (IGT) (n = 382), and diabetic (n = 253). Then the same population was reclassified into normal fasting glucose (NFG), IFG, and diabetic. The cumulative survival rates among the groups were compared using the classical life-table method, and age-adjusted analyses, the person-year method, and Cox's proportional hazard model were adopted.At the end of seven observed years, the cumulative survival rates from cardiovascular disease of IGT and diabetes were 0.962 and 0.954, respectively, both significantly lower than that of NGT (0.988). The Cox's proportional hazard model analysis showed that the hazard ratio of IGT to NGT on death from cardiovascular disease was 2.219 (95% CI 1.076-4.577). However, the cumulative survival rate of IFG from cardiovascular disease was 0.977, not significantly lower than that of NFG (0.985). The Cox's hazard ratio of IFG to NFG on death from cardiovascular disease was 1.136 (0.345-3.734), which was not significant either.IGT was a risk factor for cardiovascular disease, but IFG was not.
Phase I Trial and Pharmacokinetic Study of Ixabepilone Administered Daily for 5 Days in Children and Adolescents With Refractory Solid Tumors
Authors: Brigitte C. Widemann, Wendy Goodspeed, Anne Goodwin, Tito Fojo, Frank M. Balis, Elizabeth Fox
Journal: Journal of Clinical Oncology (2008)

The objectives of this phase I trial were to determine the maximum-tolerated dose (MTD), toxicity profile, dose-limiting toxicities (DLTs), pharmacokinetics, and preliminary response rate for ixabepilone, a microtubule-stabilizing agent, administered intravenously daily for 5 days in children and adolescents.Patients >or= 2 and <or= 18 years with relapsed or refractory solid tumors were enrolled onto sequential cohorts to the following five dose levels: 3.0 (n = 3), 4.5 (n = 4), 6.0 (n = 3), 8.0 (n = 6), and 10 (n = 3) mg/m(2)/d. Eligibility criteria, dose levels, definitions of DLT and MTD, and pharmacokinetic sampling times were designed to be as similar as possible to the adult phase I trial of ixabepilone on the same schedule.Nineteen children (median age, 10 years; range, 2 to 18 years) were enrolled, and 18 (12 with sarcomas) were assessable for toxicity. DLTs (grade 4 neutropenia for > 5 days and grade 3 fatigue) were observed in two of three patients receiving 10 mg/m(2)/d. The MTD of ixabepilone administered daily for 5 days every 21 days was 8 mg/m(2)/d. Myelosuppression, GI, and hepatic toxicities were common non-DLTs. Peripheral neuropathy was uncommon. Ixabepilone clearance was 475 +/- 247 mL/min/m(2), volume of distribution at steady-state was 12.2 +/- 5.4 L/kg, and half-life was 14 hours.The recommended dose of ixabepilone for phase II trials in solid tumors is 8 mg/m(2)/d daily for 5 days every 21 days. This dose is 33% higher than the MTD in adults receiving the same dosing schedule. Pharmacokinetic parameters in children and adolescents were highly variable but similar to adults.
Overexpression of Acid Ceramidase Protects from Tumor Necrosis Factor–Induced Cell Death
Authors: Astrid Strelow, Katussevani Bernardo, Sabine Adam-Klages, Thomas Linke, Konrad Sandhoff, Martin Krönke, Dieter Adam
Journal: The Journal of Experimental Medicine (2000)

Tumor necrosis factor (TNF) signals cell death and simultaneously induces generation of ceramide. To evaluate the contribution of ceramide to TNF-dependent cell death, we generated clones of the TNF-sensitive cell line L929 that constitutively overexpress human acid ceramidase (AC). Ceramidase, in concert with sphingosine kinase, metabolizes ceramide to sphingosine-1-phosphate (SPP), an inducer of proliferation. In response to TNF, parental L929 cells display a significant increase in intracellular ceramide correlated with an "atypical apoptosis" characterized by membrane blebbing, DNA fragmentation and degradation of poly(ADP-ribose) polymerase despite a lack of caspase activity. These features are strongly reduced or absent in AC-overexpressing cells. Pharmacological suppression of AC with N-oleoylethanolamine restored the accumulation of intracellular ceramide as well as the sensitivity of the transfectants to TNF, implying that an enhanced metabolization of intracellular ceramide by AC shifts the balance between intracellular ceramide and SPP levels towards cell survival. Correspondingly, inhibition of ceramide production by acid sphingomyelinase also increased survival of TNF-treated L929 cells.
Prevalence of FOXP3+ Regulatory T Cells Increases During the Progression of Pancreatic Ductal Adenocarcinoma and Its Premalignant Lesions
Authors: Nobuyoshi Hiraoka, Kaoru Onozato, Tomoo Kosuge, Setsuo Hirohashi
Journal: Clinical Cancer Research (2006)

Antitumor immune response changes drastically during the progression of cancers. Established cancers often escape from the host immune system, although specific immune surveillance operates in the early stages of tumorigenesis in murine models. CD4+CD25+ regulatory T cells (TR) play a central role in self-tolerance and suppress effective antitumor immune responses. The aim of this study was to investigate the clinical significance and roles of TR in the progression and multistep carcinogenesis of pancreatic ductal adenocarcinoma.We raised anti-FOXP3 antibodies and used them in immunohistochemical studies of the prevalence of FOXP3+CD4+CD25+ TR in the CD4+ T cells, which infiltrated in tissue and draining lymph nodes of 198 pancreatic ductal adenocarcinomas, their premalignant lesions (84 lesions of pancreatic intraepithelial neoplasias and 51 intraductal papillary-mucinous neoplasms), and 15 nonneoplastic pancreatic lesions.The prevalence of TR was significantly increased in the ductal adenocarcinomas compared with that in the stroma of nonneoplastic inflammation (P<0.0001). The increased prevalence of T(R) was significantly correlated with certain clinicopathologic factors. A better prognosis was observed in patients with a low prevalence of T(R), and this was independent of other survival factors (P<0.0001). Infiltration of intraepithelial CD8+TIA-1+ cytotoxic T cells in pancreatic ducts was marked in low-grade premalignant lesions but diminished during the progression of both pancreatic intraepithelial neoplasias and intraductal papillary-mucinous neoplasms. Conversely, the prevalence of TR increased significantly during the progression of premalignant lesions.T(R) play a role in controlling the immune response against pancreatic ductal carcinoma from the premalignant stage to established cancer. In pancreatic ductal carcinoma, a high prevalence of TR seems to be a marker of poor prognosis.