tbuckley/cabot-search huggingface dataset:
TCR-based lineage tracing: no evidence for conversion of conventional into regulatory T cells in response to a natural self-antigen in pancreatic islets
Authors: Jamie Wong, Diane Mathis, Christophe Benoist
Journal: The Journal of Experimental Medicine (2007)

Foxp3-expressing regulatory T (T reg) cells derive primarily from selection in the thymus. Yet conversion of mature conventional CD4+ T (T conv) cell lymphocytes can be achieved in several conditions, such as transforming growth factor β treatment, homeostatic expansion, or chronic exposure to low-dose antigen. Such conversion might provide a means to generate peripheral tolerance by “converting” potentially damaging T cells that react to self-antigens. We tested this hypothesis in mice transgenic for the BDC2.5 T cell receptor (TCR), which is representative of a diabetogenic specificity that is naturally present in NOD mice and reactive against a pancreatic self-antigen. In the thymus, before any exposure to antigen, clonotype-positive T reg and T conv cells express a second TCRα chain derived from endogenous loci. High-throughput single-cell sequencing of secondary TCRs of the Vα2 family showed their joining CDR3α regions to be very different in T reg and T conv cell thymocytes. These specific CDR3α motifs, thus, provided a “tag” with which to test the actual impact of T conv to T reg cell conversion in response to peripheral self-antigen; should the autoreactive clonotypic TCR induce T conv to T reg cell conversion upon encounter of cognate antigen in the pancreas or draining lymph node, one would expect to detect tag CDR3α motifs from T conv cells in the T reg cell populations. Sequencing large numbers of peripheral BDC+Vα2+ cells showed that little to no conversion occurs in response to this pancreatic autoantigen.
Anticolorectal cancer activity of the omega-3 polyunsaturated fatty acid eicosapentaenoic acid
Authors: Andrew J Cockbain, Milene Volpato, Amanda D Race, Alessandra Munarini, Chiara Fazio, Andrea Belluzzi, Paul M Loadman, Giles J Toogood, Mark A Hull
Journal: Gut (2014)

Oral administration of the omega-3 fatty acid eicosapentaenoic acid (EPA), as the free fatty acid (FFA), leads to EPA incorporation into, and reduced growth of, experimental colorectal cancer liver metastases (CRCLM).We performed a Phase II double-blind, randomised, placebo-controlled trial of EPA-FFA 2 g daily in patients undergoing liver resection surgery for CRCLM. The patients took EPA-FFA (n=43) or placebo (n=45) prior to surgery. The primary end-point was the CRCLM Ki67 proliferation index (PI). Secondary end-points included safety and tolerability of EPA-FFA, tumour fatty acid content and CD31-positive vascularity. We also analysed overall survival (OS) and disease-free survival (DFS).The median (range) duration of EPA-FFA treatment was 30 (12-65) days. Treatment groups were well matched with no significant difference in disease burden at surgery or preoperative chemotherapy. EPA-FFA treatment was well tolerated with no excess of postoperative complications. Tumour tissue from EPA-FFA-treated patients demonstrated a 40% increase in EPA content (p=0.0008), no difference in Ki67 PI, but reduced vascularity in 'EPA-naïve' individuals (p=0.075). EPA-FFA also demonstrated antiangiogenic activity in vitro. In the first 18 months after CRCLM resection, EPA-FFA-treated individuals obtained OS benefit compared with placebo, although early CRC recurrence rates were similar.EPA-FFA therapy is safe and well tolerated in patients with advanced CRC undergoing liver surgery. EPA-FFA may have antiangiogenic properties. Remarkably, limited preoperative treatment may provide postoperative OS benefit. Phase III clinical evaluation of prolonged EPA-FFA treatment in CRCLM patients is warranted.ClinicalTrials.gov NCT01070355.
Miscarriage but not fecundity is associated with progression of joint destruction in rheumatoid arthritis
Authors: F M van Dunne
Journal: Annals of the Rheumatic Diseases (2004)

To determine whether reproductive history before disease onset is associated with severity of joint destruction in rheumatoid arthritis.A special early arthritis clinic (EAC) was established at the department of rheumatology of Leiden University Medical Centre. General practitioners were encouraged to refer patients with joint complaints to this clinic, where the diagnosis of rheumatoid arthritis was made by a rheumatologist. In all, 113 female patients with definite rheumatoid arthritis were included in this study. A structured questionnaire was administered and joint damage was assessed by sequential x rays of the hands and feet, using the modified Sharp score.The length of time of unprotected intercourse until first pregnancy (fecundity) was comparable with data from earlier studies, with 16% of the patients reporting a time to first pregnancy of more than 12 months. Fecundity did not reflect the extent of joint damage over time. The miscarriage rate was 15% per pregnancy, comparable to population figures (12-15%). A significant increase in joint damage over a two year follow up was found in patients with rheumatoid arthritis who had experienced at least one miscarriage compared with those who had never had a miscarriage (mean modified Sharp scores at 2 years, 24 (95% confidence interval, 15 to 32) and 16 (10 to 23), respectively; p<0.05). At baseline, the Sharp scores were similar in the two subgroups.Miscarriage before disease onset but not fecundity is associated with the progression of joint damage in rheumatoid arthritis.
Diagnostic Accuracy of Multidetector Computed Tomography Coronary Angiography in Patients With Dilated Cardiomyopathy
Authors: Daniele Andreini, Gianluca Pontone, Mauro Pepi, Giovanni Ballerini, Antonio L. Bartorelli, Alessandra Magini, Carlo Quaglia, Enrica Nobili, Piergiuseppe Agostoni
Journal: Journal of the American College of Cardiology (2007)
Chromium Picolinate Supplementation Attenuates Body Weight Gain and Increases Insulin Sensitivity in Subjects With Type 2 Diabetes
Authors: Julie Martin, Zhong Q. Wang, Xian H. Zhang, Deborah Wachtel, Julia Volaufova, Dwight E. Matthews, William T. Cefalu
Journal: Diabetes Care (2006)

Chromium picolinate (CrPic) supplementation has been suggested to improve glycemia, but there are conflicting reports on efficacy. We sought to determine the effect of CrPic on insulin sensitivity, glycemic control, and body composition in subjects with type 2 diabetes.Thirty-seven subjects with type 2 diabetes were evaluated. After baseline, subjects were placed on a sulfonylurea (glipizide gastrointestinal therapeutic system 5 mg/day) with placebo for 3 months. Subjects were then randomized in a double-blind fashion to receive either the sulfonylurea plus placebo (n = 12) or the sulfonylurea plus 1,000 microg Cr as CrPic (n = 17) for 6 months. Body composition, insulin sensitivity, and glycemic control were determined at baseline, end of the 3-month single-blind placebo phase, and end of study.Subjects randomized to sulfonylurea/placebo, as opposed to those randomized to sulfonylurea/CrPic, had a significant increase in body weight (2.2 kg, P < 0.001 vs. 0.9 kg, P = 0.11), percent body fat (1.17%, P < 0.001 vs. 0.12%, P = 0.7), and total abdominal fat (32.5 cm(2), P < 0.05 vs. 12.2 cm(2), P < 0.10) from baseline. Subjects randomized to sulfonylurea/CrPic had significant improvements in insulin sensitivity corrected for fat-free mass (28.8, P < 0.05 vs. 15.9, P = 0.4), GHb (-1.16%, P < 0.005 vs. -0.4%, P = 0.3), and free fatty acids (-0.2 mmol/l, P < 0.001 vs. -0.12 mmol/l, P < 0.03) as opposed to sulfonylurea/placebo.This study demonstrates that CrPic supplementation in subjects with type 2 diabetes who are taking sulfonylurea agents significantly improves insulin sensitivity and glucose control. Further, CrPic supplementation significantly attenuated body weight gain and visceral fat accumulation compared with the placebo group.
Angiotensin II Activates Na <sup>+</sup> -Independent Cl <sup>−</sup> -HCO <sub>3</sub> <sup>−</sup> Exchange in Ventricular Myocardium
Authors: María C. Camilión de Hurtado, Bernardo V. Alvarez, Néstor G. Pérez, Irene L. Ennis, Horacio E. Cingolani
Journal: Circulation Research (1998)

Abstract —The effect of angiotensin II (Ang II) on the activity of the cardiac Na + -independent Cl − -HCO 3 − exchanger (anionic exchanger [AE]) was explored in cat papillary muscles. pH i was measured by epifluorescence with BCECF-AM. Ang II (500 nmol/L) induced a 5-( N -ethyl- N -isopropyl)amiloride–sensitive increase in pH i in the absence of external HCO 3 − (HEPES buffer), consistent with its stimulatory action on Na + -H + exchange (NHE). This alkalinizing effect was not detected in the presence of a CO 2 -HCO 3 − buffer (pH i 7.07±0.02 and 7.08±0.02 before and after Ang II, respectively; n=17). Moreover, in Na + -free HCO 3 − –buffered medium, in which neither NHE nor Na + -HCO 3 − cotransport are acting, Ang II decreased pH i , and this effect was canceled by previous treatment with SITS. These findings suggested that the Ang II–induced activation of NHE was masked, in the presence of the physiological buffer, by a HCO 3 − -dependent acidifying mechanism, probably the AE. This hypothesis was confirmed on papillary muscles bathed with HCO 3 − buffer that were first exposed to 1 μmol/L S20787, a specific inhibitor of AE activity in cardiac tissue, and then to 500 nmol/L Ang II (n=4). Under this condition, Ang II increased pH i from 7.05±0.05 to 7.22±0.05 ( P &lt;.05). The effect of Ang II on AE activity was further explored by measuring the velocity of myocardial pH i recovery after the imposition of an intracellular alkali load in a HCO 3 − -containing solution either with or without Ang II. The rate of myocardial pH i recovery was doubled in the presence of Ang II, suggesting a stimulatory effect on AE. The enhancement of the activity of this exchanger by Ang II was also detected when the AE activity was reversed by the removal of extracellular Cl − in a Na + -free solution. Under this condition, the rate of intracellular alkalinization increased from 0.053±0.016 to 0.108±0.026 pH unit/min (n=6, P &lt;.05) in the presence of Ang II. This effect was canceled either by the presence of the AT 1 receptor antagonist, losartan, or by the previous inhibition of protein kinase C with chelerythrine or calphostin C. The above results allow us to conclude that Ang II, in addition to its stimulatory effect on alkaline loading mechanisms, activates the AE in ventricular myocardium and that the latter effect is mediated by a protein kinase C–dependent regulatory pathway linked to the AT 1 receptors.
The Epidemiology of Severe Sepsis in Children in the United States
Authors: R. Scott Watson, Joseph A. Carcillo, Walter T. Linde-Zwirble, Gilles Clermont, Jeffrey Lidicker, Derek C. Angus
Journal: American Journal of Respiratory and Critical Care Medicine (2003)

Despite extensive research into the etiology and treatment of severe sepsis, little is known about its epidemiology in children. We sought to determine the age- and sex-adjusted incidence, outcome, and associated hospital costs of severe sepsis in United States children using 1995 hospital discharge and population data from seven states (24% of the United States population). Of 1,586,253 hospitalizations in children who were 19 years old or less, 9,675 met International Classification of Diseases, 9th revision, clinical modification-based severe sepsis criteria or 42,364 cases of pediatric severe sepsis per year nationally (0.56 cases per 1,000 population per year). The incidence was the highest in infants (5.16 per 1,000), fell dramatically in older children (0.20 per 1,000 in 10 to 14 year olds), and was 15% higher in boys than in girls (0.60 versus 0.52 per 1,000, p < 0.001). Hospital mortality was 10.3%, or 4,383 deaths nationally (6.2 per 100,000 population). Half of the cases had underlying disease (49.0%), and over one-fifth (22.9%) were low-birth-weight newborns. Respiratory infections (37%) and primary bacteremia (25%) were the most common infections. The mean length of stay and cost were 31 days and $40,600, respectively. Estimated annual total costs were 1.97 billion US dollars nationally. Severe sepsis is a significant health problem in children and is associated with the use of extensive healthcare resources. Infants are at highest risk, especially those with a low birth weight.
Positive Feedback Activation of Estrogen Receptors by the CXCL12-CXCR4 Pathway
Authors: Karine Sauvé, Julie Lepage, Mélanie Sanchez, Nikolaus Heveker, André Tremblay
Journal: Cancer Research (2009)

Induction of estrogen-regulated gene transcription by estrogen receptors ERalpha and ERbeta plays an important role in breast cancer development and growth. High expression of the chemokine receptor CXCR4 and its ligand CXCL12/stromal cell-derived factor 1 (SDF-1) has also been correlated with aggressive breast tumor phenotypes. Here, we describe a positive regulatory loop between the CXCR4/SDF-1 signaling pathway and ER transcriptional competence in human breast cancer cells. Treatment of breast carcinoma MCF-7 cells with SDF-1 increased ER transcriptional activity and expression of ER target genes, including SDF-1 itself. These effects were blocked by the antiestrogen ICI-182780 and by CXCR4 silencing and, conversely, estrogen-induced gene expression and growth of MCF-7 cells were impaired on CXCR4 inhibition. Both ERalpha and ERbeta were activated by SDF-1 in the presence of CXCR4 and by overexpression of a constitutively active CXCR4, indicating that CXCR4 signals to both receptors. In particular, ERbeta was able to translate the effects of SDF-1 on its own expression, as well as enhance activator protein 1 (AP-1) containing genes cyclin D1 and c-Myc in the presence of tamoxifen. This correlated with an increased ERbeta occupancy of responsive promoters at both estrogen-responsive and AP-1 elements. Ser-87, a conserved mitogen-activated protein kinase site in ERbeta, was highly phosphorylated by SDF-1, revealing an essential role of the AF-1 domain in response to CXCR4 activation. These results identify a complete autocrine loop between the CXCR4/SDF-1 and ERalpha/ERbeta signaling pathways that dictates ER-dependent gene expression and growth of breast cancer cells.
Immunochemical and Biological Characterization of a Mugwort (<i>Artemisia vulgaris</i>) Pollen Extract
Authors: H. Ipsen, H. Formgren, H. Løswenstein, L. Ingemann
Journal: Allergy (1985)

A reference extract of mugwort pollen ( Artemisia vulgaris ) was characterized by crossed immunoelectrophoresis (CIE), crossed radio immunoelectrophoresis (CRIE) and quantitative skin prick test (QSPT). CIE revealed that the extract contained at least 42 distinct antigens of which 24 migrated towards the anode and 18 towards the cathode at pH 8.6. A CRIE analysis of the crude mugwort pollen extract, performed with sera from 29 mugwort‐allergic patients, showed that 10 antigens may be considered allergens; one was classified as a major allergen, five as intermediate allergens, and four as minor allergens. The QSPT performed on the same 29 allergic patients established that 17.4 μg lyophilised reference mugwort pollen extract per ml had a biological potency of 1 HEP (histamine equivalent by prick test).
Age-related CD8 T Cell Clonal Expansions Constrict CD8 T Cell Repertoire and Have the Potential to Impair Immune Defense
Authors: Ilhem Messaoudi, Joël LeMaoult, Jose A. Guevara-Patino, Beatrix M. Metzner, Janko Nikolich-Žugich
Journal: The Journal of Experimental Medicine (2004)

Peripheral T cell diversity is virtually constant in the young, but is invariably reduced in aged mice and humans. CD8+ T cell clonal expansions (TCE) are the most drastic manifestation of, and possible contributors to, this reduced diversity. We show that the presence of TCE results in reduced CD8+, but not CD4+, T cell diversity, and in functional inability to mobilize parts of the CD8+ T cell repertoire affected by TCE. In the model of herpes simplex virus (HSV)-1 infection of B6 mice, &amp;gt;90% of the responding CD8+ T cells use Vβ10 or Vβ8 and are directed against a single glycoprotein B (gB498-505) epitope, gB-8p. We found that old animals bearing CD8+ TCE within Vβ10 or Vβ8 families failed to mount an effective immune response against HSV-1, as judged by reduced numbers of peptide-major histocompatibility complex tetramer+ CD8 T cells and an absence of antiviral lytic function. Furthermore, Vβ8 TCE experimentally introduced into young mice resulted in lower resistance to viral challenge, whereas Vβ5+ TCE induced in a similar fashion did not impact viral resistance. These results demonstrate that age-related TCE functionally impair the efficacy of antiviral CD8+ T cell immunity in an antigen-specific manner, strongly suggesting that TCE are not the mere manifestation of, but are also a contributing factor to, the immunodeficiency of senescence.
FDG-PET and PET-CT Imaging of Head and Neck Cancers
Authors: Y. Menda, M. M. Graham
Journal: Clinical Nuclear Medicine (2008)

Head and neck cancers are generally defined as cancers involving all regions of the head and neck, except for the thyroid and central nervous system. Most of these cancers are squamous cell carcinomas. The most common sites are larynx, tongue, floor of the mouth, lip, tonsils, and salivary glands, although these carcinomas can arise at almost any location in the nasopharynx, oropharynx, or hypopharynx. Thyroid cancers and tumors of the central nervous system are usually not included in head and neck cancer classification. The estimated number of new cases in the United States for 2005 is 39,000, with approximately 11,000 deaths (American Cancer Society 2005). The male:female ratio is about 2:1. Primary risk factors for virtually all head and neck cancers are alcohol and tobacco use. Early stage head and neck tumors are treated with either surgery or radiotherapy with excellent prognosis. Locally advanced tumors without distant metastasis are typically treated with surgery and postoperative radiation and hemotherapy or with definitive combination chemoradiation therapy. If chemoradiation is used as the initial treatment, salvage surgery is performed if there is evidence of residual disease. Patients with distant metastatic disease have very poor prognosis and are usually referred for palliative chemotherapy or radiation
ITGBL1 Is a Runx2 Transcriptional Target and Promotes Breast Cancer Bone Metastasis by Activating the TGFβ Signaling Pathway
Authors: Xiao-Qing Li, Xin Du, Dong-Mei Li, Peng-Zhou Kong, Yan Sun, Pei-Fang Liu, Qing-Shan Wang, Yu-Mei Feng
Journal: Cancer Research (2015)

Abstract Bone metastasis affects more than 70% of advanced breast cancer patients, but the molecular mechanisms of this process remain unclear. Here, we present clinical and experimental evidence to clarify the role of the integrin β-like 1 (ITGBL1) as a key contributor to bone metastasis of breast cancer. In an in vivo model system and in vitro experiments, ITGBL1 expression promoted formation of osteomimetic breast cancers, facilitating recruitment, residence, and growth of cancer cells in bone microenvironment along with osteoclast maturation there to form osteolytic lesions. Mechanistic investigations identified the TGFβ signaling pathway as a downstream effector of ITGBL1 and the transcription factor Runx2 as an upstream activator of ITGBL1 expression. In support of these findings, we also found that ITGBL1 was an essential mediator of Runx2-induced bone metastasis of breast cancer. Overall, our results illuminate how bone metastasis occurs in breast cancer, and they provide functional evidence for new candidate biomarkers and therapeutic targets to identify risk, to prevent, and to treat this dismal feature of advanced breast cancer. Cancer Res; 75(16); 3302–13. ©2015 AACR.
15-Hydroxy-5,8,11,13-eicosatetraenoic acid inhibits human vascular cyclooxygenase. Potential role in diabetic vascular disease.
Authors: B N Setty, M J Stuart
Journal: Journal of Clinical Investigation (1986)

Human umbilical arteries converted arachidonic acid to three hydroxyeicosatetraenoic acids (HETEs) as well as prostaglandins. The mono-HETEs have been identified by reverse-phase high pressure liquid chromatography and gas chromatography-mass spectroscopy as 15-HETE and 11-HETE. 15-HETE in arterial segments appears to be derived mainly via the 15-lipoxygenase pathway, whereas 11-HETE, and the presumed di-HETE(s) were products of cyclooxygenase. Nordihydroguaiaretic acid, a lipoxygenase inhibitor, stimulated prostanoid production with a concomitant inhibition of 15-HETE formation. These results suggested that 15-HETE may function as an endogenous regulator of prostacyclin. In human umbilical arterial microsomes, 15-HETE was found to inhibit 6-keto-prostaglandin F1 alpha and total prostanoid production in a concentration-dependent manner (median inhibition constant [IC50] of 52 +/- 3 and 63 +/- 4 microM respectively). The relative distribution of prostaglandins, however, remained unaffected, indicating that the site of action was cyclooxygenase. Kinetic analysis revealed that 15-HETE was a competitive inhibitor of the enzyme. Although no changes in maximum velocity occurred, the apparent Km was significantly different (9.3 +/- 6.9 microM [1 SD] for control vs. 37.6 +/- 17.7 microM for the 15-HETE-treated enzyme). Furthermore, the inhibitory effect of 15-HETE on prostacyclin production was confirmed using cultured bovine endothelial cells. In this cell system, not only did 15-HETE inhibit endogenous prostacyclin production, but also the conversion of exogenous [1-14C]arachidonic acid to prostacyclin (IC50 of 40 +/- 17 microM). No effect on arachidonic acid release was noted. To investigate whether our in vitro finding that 15-HETE inhibited prostacyclin production could be relevant to the in vivo situation, our final studies were performed on vasculature obtained from the diabetic milieu. We found that the production of 15-HETE was significantly increased in vasculature obtained from the infant of the diabetic mother (1.14 +/- 0.26 pmol/mg) when compared to control neonates (0.77 +/- 0.22; P less than 0.01). A concomitant decrease in prostacyclin production was seen (51.6 +/- 12.6 pmol/mg in infants of diabetic mothers vs. 71 +/- 22.3 in controls). Moreover, an inverse correlation between these two eicosanoids was also noted. Our results suggest a potential in vivo regulatory role for 15-HETE on prostacyclin production.