tbuckley/cabot-search huggingface dataset:
A Human Minor Histocompatibility Antigen Resulting from Differential Expression due to a Gene Deletion
Authors: Makoto Murata, Edus H. Warren, Stanley R. Riddell
Journal: The Journal of Experimental Medicine (2003)

Minor histocompatibility antigens (minor H antigens) are targets of graft-versus-host disease and graft-versus-leukemia responses after allogeneic human leukocyte antigen identical hematopoietic stem cell transplantation. Only a few human minor H antigens have been molecularly characterized and in all cases, amino acid differences between homologous donor and recipient proteins due to nucleotide polymorphisms in the respective genes were responsible for immunogenicity. Here, we have used cDNA expression cloning to identify a novel human minor H antigen encoded by UGT2B17, an autosomal gene in the multigene UDP-glycosyltransferase 2 family that is selectively expressed in liver, intestine, and antigen-presenting cells. In contrast to previously defined human minor H antigens, UGT2B17 is immunogenic because of differential expression of the protein in donor and recipient cells as a consequence of a homozygous gene deletion in the donor. Deletion of individual members of large gene families is a common form of genetic variation in the population and our results provide the first evidence that differential protein expression as a consequence of gene deletion is a mechanism for generating minor H antigens in humans.
Antisense suppression of transferrin receptor gene expression in a human hepatoma cell (HuH‐7) line
Authors: Katsunori Sasaki, Olga Zak, Philip Aisen
Journal: American Journal of Hematology (1993)

Abstract A recombinant plasmid carrying human transferrin receptor cDNA in reverse orientation downstream from the human cytomegalovirus immediate early promoter/enhancer element was introduced into the HuH‐7 human hepatoma cell line by lipofection. Cell surface transferrin binding and iron uptake from transferrin each decreased by about 50% in stable transfectants bearing integrated antisense DNA expression vector. Northern blot analysis indicated that the abundance of target transferrin receptor message was not altered by antisense RNA. These results suggest that the antisense transcript interferes with expression of the endogenous transferrin receptor gene at the level of translation. © 1993 Wiley‐Liss, Inc.
Intraindividual Comparison of Selective Arterial versus Venous 68Ga-DOTATOC PET/CT in Patients with Gastroenteropancreatic Neuroendocrine Tumors
Authors: Clemens Kratochwil, Frederik L. Giesel, Ruben López-Benítez, Nadine Schimpfky, Kirsten Kunze, Michael Eisenhut, Hans-Ulrich Kauczor, Uwe Haberkorn
Journal: Clinical Cancer Research (2010)

Abstract Purpose: Therapy with the somatostatin analogue DOTA-(0)-Phe(1)-Tyr(3)-octreotide (DOTATOC) labeled with a β-(DOTA-Phe-Tyr-Octreotide) emitter such as 90Y or 177Lu is accepted for the palliative treatment of unresectable neuroendocrine cancer. However, the optimal route of administration has not been determined. Using positron-emission tomography (PET)-labeled 68Ga-DOTATOC, we compared selective tumoral uptake on PET/computed tomography (CT) after arterial or venous administration of the agent in patients with gastroenteropancreatic neuroendocrine tumor. Experimental Design: Fifteen patients with neuroendocrine cancer were examined with 68Ga-DOTATOC PET/CT after intravenous (i.v.) and intraarterial (i.a.) administration within 4 weeks of each other and without any intervening therapy. Eleven patients had multifocal metastases, six were considered to have unresectable primary tumor. The intraarterial catheter was placed in the vessel supplying the main tumor burden. The standard uptake value (SUV) was used to compare intratumoral concentrations of 68Ga-DOTATOC. Results: Compared with i.v. infusion, the i.a. infusion resulted in an increased SUV in 117 of 122 (96%) liver metastases. The average increase in SUV was 3.75-fold higher with i.a. administration. The increase in uptake for the primary tumors was dependent on the selectivity of the catheter placement, resulting in variable increases in SUV after i.a. injection (1.44- to 7.8-fold higher). Conclusions: This study showed that uptake of DOTATOC is commonly several fold higher after selective i.a. administration in comparison with i.v. injection in both the primary tumor as well as in liver metastases of neuroendocrine cancer. Therefore, intraarterial DOTATOC is a promising drug for regionally intensified radiopeptide therapy. Clin Cancer Res; 16(10); 2899–905. ©2010 AACR.
An Interference Phenomenon Associated With Resistance to Infection With Mouse Mammary Tumor Virus&lt;xref ref-type="fn" rid="FN2"&gt;2&lt;/xref&gt;
Authors: Satyabrata Nandi, Kenneth B. DeOme
Journal: JNCI Journal of the National Cancer Institute (1965)

A recently developed mammary noduligenesis test for the detection of the mammary tumor virus (MTV) was used to 1) determine the susceptibility of BALB/c and C3Hf mice of various ages and physiological states to infection with MTV, and 2) determine whether the age of the host or that of the mammary tissues is responsible for the resistance of older mice to MTV. MTV-containing extracts from A or C3H tissues were administered to BALB/c and C3Hf mice of various ages and, in a second experiment, mammary tissues from BALB/c and C3Hf animals of different ages were transplanted into mammary gland-free fat pads of 3-week-old MTV-carrying isologous hosts. MTV infection of intact hosts or of mammary transplants was judged on the basis of the noduligenic test. The results indicated that BALB/c mice of all ages are susceptible to MTV, but that the incidence of MTV infection decreases with increasing age. Transplanted mammary tissues from BALB/c mice of all ages were equally susceptible to infection, however. It was concluded that age resistance to MTV in this strain is systemically mediated. C3Hf mice under 18 days of age, and also their transplanted mammary tissues, were susceptible to MTV infection. However, C3Hf mice 18 days or older and their mammary transplants were refractory to MTV infection. It is suggested that resistance to MTV in C3Hf mice over 18 days of age is due to the presence of an MTV-interfering agent in their mammary tissues. The possibility is discussed that this interfering agent is equivalent to the recently postulated nodule-inducing virus (NIV), an agent immunologically related to MTV. Both NIV and the MTV-interfering agent occur in C3Hf animals, while neither activity is present in mice of the BALB/c strain.
Pathophysiological aspects of thyroid hormone disorders/thyroid peroxidase autoantibodies and reproduction
Authors: R. Vissenberg, V.D. Manders, S. Mastenbroek, E. Fliers, G.B. Afink, C. Ris-Stalpers, M. Goddijn, P.H. Bisschop
Journal: Human Reproduction Update (2015)

BACKGROUNDThyroid hormone disorders and thyroid peroxidase autoantibodies (TPO-Ab) in women are associated with subfertility and early pregnancy loss. Here, we aim to provide a comprehensive overview of the literature on the pathophysiology of these associations.
Coordinate Direct Input of Both KRAS and IGF1 Receptor to Activation of PI3 kinase in <i>KRAS</i>-Mutant Lung Cancer
Authors: Miriam Molina-Arcas, David C. Hancock, Clare Sheridan, Madhu S. Kumar, Julian Downward
Journal: Cancer Discovery (2013)

Abstract Using a panel of non–small cell lung cancer (NSCLC) lines, we show here that MAP-ERK kinase (MEK) and RAF inhibitors are selectively toxic for the KRAS-mutant genotype, whereas phosphoinositide 3-kinase (PI3K), AKT, and mTOR inhibitors are not. IGF1 receptor (IGF1R) tyrosine kinase inhibitors also show selectivity for KRAS-mutant lung cancer lines. Combinations of IGF1R and MEK inhibitors resulted in strengthened inhibition of KRAS-mutant lines and also showed improved effectiveness in autochthonous mouse models of Kras-induced NSCLC. PI3K pathway activity is dependent on basal IGF1R activity in KRAS-mutant, but not wild-type, lung cancer cell lines. KRAS is needed for both MEK and PI3K pathway activity in KRAS-mutant, but not wild-type, lung cancer cells, whereas acute activation of KRAS causes stimulation of PI3K dependent upon IGF1R kinase activity. Coordinate direct input of both KRAS and IGF1R is thus required to activate PI3K in KRAS-mutant lung cancer cells. Significance: It has not yet been possible to target RAS proteins directly, so combined targeting of effector pathways acting downstream of RAS, including RAF/MEK and PI3K/AKT, has been the most favored approach to the treatment of RAS-mutant cancers. This work sheds light on the ability of RAS to activate PI3K through direct interaction, indicating that input is also required from a receptor tyrosine kinase, IGF1R in the case of KRAS-mutant lung cancer. This suggests potential novel combination therapeutic strategies for NSCLC. Cancer Discov; 3(5); 548–63. ©2013 AACR. See related commentary by Chen and Sweet-Cordero, p. 491 This article is highlighted in the In This Issue feature, p. 471
Effect of Low-Dose Tamoxifen on Steroid Receptor Coactivator 3/Amplified in Breast Cancer 1 in Normal and Malignant Human Breast Tissue
Authors: Line L. Haugan Moi, Marianne Hauglid Flågeng, Sara Gandini, Aliana Guerrieri-Gonzaga, Bernardo Bonanni, Matteo Lazzeroni, Jennifer Gjerde, Ernst A. Lien, Andrea De Censi, Gunnar Mellgren
Journal: Clinical Cancer Research (2010)

Nuclear receptor coactivator expression and activity may partly explain the complex agonist/antagonist effects of tamoxifen at clinical level. In a preoperative trial, dose reduction from 20 to 1 mg tamoxifen was associated with retained antiproliferative effect on breast cancer. Here, we assessed the gene expression of the steroid receptor coactivators SRC-1, SRC-2/transcription intermediary factor 2, and SRC-3/amplified in breast cancer 1 (AIB1) and the growth factor receptor HER-2/neu under three tamoxifen dose regimens.Surgical specimens from estrogen receptor-positive breast cancer and adjacent normal breast tissue from 64 patients treated 4 weeks preoperatively with 20, 5, or 1 mg/d tamoxifen and 28 nontreated breast cancer controls were analyzed for coactivator and HER-2/neu mRNA expression using real-time reverse transcription-PCR. The gene expression levels were related to immunohistochemical expression of Ki67, serum levels of insulin-like growth factor I and sex hormone binding globulin, other prognostic factors, and clinical outcome.The coactivators and HER-2/neu mRNA levels were higher in malignant compared with normal tissue (P < 0.001). Tamoxifen significantly increased the expression of coactivators in normal and malignant tissue irrespective of dose, especially for SRC-3/AIB1 (P < 0.001 tamoxifen-treated versus nontreated subjects). SRC-3/AIB1 and HER-2/neu mRNA levels were positively correlated (P = 0.016), but the coactivators could not explain the variability of Ki67, insulin-like growth factor I, and sex hormone binding. Although not significant, SRC-3/AIB1 tended to be higher in subjects with poor clinical outcome and unfavorable prognostic factors.Increased coactivator mRNA levels seem to be an early response to tamoxifen without dose-response relationship in the 1- to 20-mg range. Clinical and molecular effects of low-dose tamoxifen should be further explored.
Maximizing the Renal Cyclic 3′-5′-Guanosine Monophosphate System with Type V Phosphodiesterase Inhibition and Exogenous Natriuretic Peptide
Authors: Horng H. Chen, Brenda K. Huntley, John A. Schirger, Alessandro Cataliotti, John C. Burnett
Journal: Journal of the American Society of Nephrology (2006)

Type V phosphodiesterase (PDE V) metabolizes cyclic guanosine monophosphate (cGMP) and is abundant in the kidney and vasculature and was found recently in the heart. Sildenafil is a PDE V inhibitor that is used clinically for erectile dysfunction. Brain natriuretic peptide (BNP) is a cardiac peptide with vasodilating, lusitropic, and natriuretic properties that are mediated via cGMP. It was hypothesized that chronic inhibition of PDE V (PDE VI) will enhance the renal actions of exogenous BNP by potentiating the renal cGMP. The cardiorenal and humoral function was determined at baseline in two groups of dogs with pacing-induced overt chronic heart failure (CHF; 240 bpm for 10 d): Group 1 (n = 6) received Sildenafil 50 mg orally three times daily during the 10 d of pacing, and group 2 (n = 5) received no PDE V inhibitor. The response to acute subcutaneous BNP (5 microg/kg) administration also was compared in both groups on day 11. The GFR was assessed by inulin clearance (P < 0.05). There was no improvement of renal function in group 1 after 10 d of PDE VI as compared with group 2, despite having higher cardiac output (P < 0.05). Group 1 had significantly higher plasma (44 +/- 2 versus 21 +/- 3 pmol/ml; P < 0.05) and urinary cGMP (4219 +/- 900 versus 1954 +/- 300 pmol/min; P < 0.05) as compared with group 2. With acute subcutaneous BNP administration, group 1 had a natriuretic and diuretic response that was associated with an increase in GFR (30 +/- 6 to 45 +/- 6 ml/min; P < 0.05) and that was not observed in group 2 (25 +/- 6 to 29 +/- 4 ml/min). Plasma BNP increased to a similar extent in both groups with subcutaneous BNP. In contrast, group 1 had a much greater urinary cGMP excretion (4219 +/- 900 to 8600 +/- 1600 pmol/min; P < 0.05) as compared with group 2 (1954 +/- 300 to 3580 +/- 351 pmol/min; P < 0.05). In experimental overt CHF, chronic administration of PDE V inhibitor did not enhance renal function despite an improvement in cardiac output. However, chronic PDE VI significantly enhanced the renal hemodynamic and excretory responses to exogenous BNP. This study supports a role for PDE V as contributing to renal maladaptation in a model of experimental overt CHF and the strategy of maximizing the renal cGMP system by combined PDE VI and natriuretic peptides in CHF to improve renal function.
A Possible Explanation of Statistical Interaction, With Application to the Effects of Soluble Thrombomodulin and Soluble Intercellular Adhesion Molecule-1 on Coronary Heart Disease
Authors: T. Paul Hutchinson
Journal: Circulation (2003)

Adhesion Molecule-1 on Coronary Heart DiseaseWu et al 1 estimated the relative risks of coronary heart disease (CHD), according to tertile of soluble thrombomodulin (sTM) and tertile of soluble intercellular adhesion molecule-1 (sICAM).High sTM and low sICAM were associated with lower risk, but there was an important interaction.The logarithms of the relative risks in the 9 groups are shown in Table 1.(The logarithm has been used because a relative risk is a ratio, and thus 0.5 is as far away from 1 as 2 is.)An interaction is a difference of differences, eg, the difference between the "Middle" and "Upper" columns is different in the "Upper" row (0.48) from what it is in the "Lower" row (Ϫ0.34).I suggest this interaction may arise from additivity plus nonlinearity, as follows.(1) Contributions from sTM and sICAM add together to give a total quantity x of the important independent variable.(2) Risk does not steadily decrease with x or steadily increase with x.Rather, it depends on x nonlinearlythere is an optimal level of x at which risk is a minimum, with increased risk associated with both lower and higher x.Let us give scores of Ϫ1, 0, and ϩ1 to the lower, middle, and upper tertiles of sTM, and scores of Ϫa, 0, and ϩa to the lower, middle, and upper tertiles of sICAM, with a being an unknown that we will fit to the data.The total x for any combination of sTM level and sICAM level will be the sum of the appropriate two components.The dependent variable (logarithm of relative risk) will be assumed to have a quadratic dependence on this, ie, b 0 ϩb 1 xϩb 2 x 2 , where the bs are unknowns that we will fit to the data.What are the best-fitting values of a, b 0 , b 1 , and b 2 ?How well do they reproduce the data?I found the best-fitting values were, respectively, Ϫ0.69, Ϫ0.07, Ϫ0.29, and 0.14.That a is negative means there is less of x (whatever this is) when sICAM is high.Or, putting this another way, the difference between sTM and sICAM, with these each being in appropriately scaled units, is what is important for the risk, not the sum.A difference suggests a chemical combination of an active molecule with a reagent to form an inactive product (and knowledge of the relative molecular weights would enable the number of one molecule that combine with the other to be estimated), but this is only speculation.The predicted values are shown in Table 2.The model has successfully reproduced the general features of the data.(If the scores for the tertiles of sTM and for the tertiles of sICAM are permitted to be unequally spaced, the fit is only slightly better.)At best, the results suggest the scientific mechanism through which interaction arises.And at the least, they are a concise description of the interaction (there is only a single parameter more than with a noninteraction model).
Folate treatment and unbalanced methylation and changes of allelic expression induced by hyperhomocysteinaemia in patients with uraemia
Authors: Diego Ingrosso, Amelia Cimmino, Alessandra F Perna, Lucia Masella, Natale G De Santo, Maria Luigia De Bonis, Marcella Vacca, Maurizio D'Esposito, Michele D'Urso, Patrizia Galletti, Vincenzo Zappia
Journal: The Lancet (2003)
Nanoliposomal ceramide prevents in vivo growth of hepatocellular carcinoma
Authors: H. R. S. Tagaram, N. A. DiVittore, B. M. Barth, J. M. Kaiser, D. Avella, E. T. Kimchi, Y. Jiang, H. C. Isom, M. Kester, K. F. Staveley-O'Carroll
Journal: Gut (2010)

<h3>Background and objectives</h3> Hepatocellular carcinoma (HCC) affects an increasing number of people worldwide. The poor survival rate of patients with HCC is manifested by an aggressive and metastatic phenotype, as well as a poor response to common therapeutic strategies. The purpose of this study was to evaluate the efficacy of nanoliposomal C6-ceramide as an antineoplastic agent in an in vivo model of human HCC. <h3>Methods</h3> The growth-arresting and pro-apoptotic properties of nanoliposomal C6-ceramide were first evaluated in vitro in human SK-HEP-1 cells by assessing cellular viability, caspase 3/7 activity, annexin-V expression, DNA fragmentation, cell cycle distribution and AKT phosphorylation. SK-HEP-1 cells were then engrafted subcutaneously into athymic nude mice and nanoliposomal C6-ceramide was administered by tail vein injection. Tumour size was monitored over time, followed by excision of tumours to evaluate tumour vascularisation, proliferation, apoptosis and cellular signalling. <h3>Results</h3> Nanoliposomal C6-ceramide, but not ghost (no ceramide) nanoliposomes, induced apoptotic cell death of SK-HEP-1 cells in vitro, concomitant with an accumulation of cells in the G<sub>2</sub> phase of the cell cycle and decreased phosphorylation of AKT. Systemic administration of nanoliposomal C6-ceramide to mice engrafted with SK-HEP-1 tumours reduced tumour vascularisation and proliferation, induced tumour cell apoptosis, decreased phosphorylation of AKT and ultimately blocked tumour growth. <h3>Conclusions</h3> These studies show that nanoliposomal ceramide is an efficacious antineoplastic agent for the treatment of in vitro and in vivo models of human HCC.
Indeterminate 1-2-cm nodules found on hepatocellular carcinoma surveillance: Biopsy for all, some, or none?
Authors: Korosh Khalili, Tae Kyoung Kim, Hyun-Jung Jang, Leyla Kochak Yazdi, Maha Guindi, Morris Sherman
Journal: Hepatology (2010)

Abstract In the latest hepatocellular carcinoma (HCC) management guidelines by the American Association for the Study of Liver Diseases, biopsy is advocated for all nodules deemed indeterminate after imaging work-up by contrast-enhanced scans. However, the latest guidelines' imaging work-up algorithm has been shown to improve sensitivity of characterization of HCC for 1-2-cm nodules, decreasing the proportion of HCCs that remain indeterminate after imaging work-up. We undertook a study of 1-2-cm indeterminate nodules to determine what proportions are malignant and which variables can be used to limit biopsy to a subset of nodules at higher risk of malignancy. Eighty consecutive patients with 93 indeterminate nodules were included. Final diagnosis was established in 85 nodules, with 13 malignant (9 by biopsy, 4 by growth) and 72 benign (stability of ≥18 months). Cause of liver disease, ethnicity, size, arterial hypervascularity, venous hypoenhancement, and presence of synchronous typical HCC were analyzed by univariate logistic analysis to determine significant predictors of malignancy. Rate of malignancy among indeterminate 1-2-cm nodules was found to be 14%-23%. Only arterial hypervascularity [odds ratio (OR), 3.7) and presence of synchronous HCC (OR, 7.1) were significant predictors of malignancy. A strategy of limiting biopsy to nodules that had either feature would result in 23 biopsies and potentially detect 8 of 13 malignant nodules, yielding a sensitivity of 62% and specificity of 79%. Conclusion: The prevalence of malignancy among 1-2-cm indeterminate nodules is low (14%-23%), and biopsy of all such nodules results in many negative results. Limiting biopsy to nodules with arterial hypervascularity or in the presence of a synchronous typical HCC would detect the majority of HCCs while substantially reducing the number of biopsies. (Hepatology 2011)
Regions of the T cell receptor alpha and beta chains that are responsible for interactions with CD3.
Authors: L Tan, J Turner, A Weiss
Journal: The Journal of Experimental Medicine (1991)

The T cell antigen receptor consists of the Ti alpha/beta heterodimer which recognizes antigen, and the associated CD3 chains, thought to be involved in signal transduction. To understand the nature of the interaction between Ti and CD3, chimeric molecules which included the COOH-terminal segments of Ti alpha or beta linked to the extracellular segment of CD8, were transfected into a mutant T cell deficient in Ti beta chain expression and cell surface CD3. Both chimeric chains were required to express the chimeric Ti and to restore CD3 surface expression. CD8/Ti and CD3 cointernalized and coimmunoprecipitated. Stimulation of the chimeric receptor induced transmembrane signaling events and cell activation. These results demonstrate that the Ti alpha and beta COOH termini containing the transmembrane domains are sufficient for structural and functional coupling of Ti to CD3.
Double-blind vaccine-controlled randomised efficacy trial of an investigational Shigella sonnei conjugate vaccine in young adults
Authors: Dani Cohen, Shai Ashkenazi, Manfred S Green, Michael Gdalevich, Guy Robin, Raphael Slepon, Miri Yavzori, Nadav Orr, Colin Block, Isaac Ashkenazi, Joshua Shemer, David N Taylor, Thomas L Hale, Jerald C Sadoff, Danka Pavliakova, Rachel Schneerson, John B Robbins
Journal: The Lancet (1997)