tbuckley/cabot-search huggingface dataset:
Analysis of somatic mutations in kappa transgenes.
Authors: J Hackett, B J Rogerson, R L O'Brien, U Storb
Journal: The Journal of Experimental Medicine (1990)

We have examined the nature and localization of somatic mutations in three kappa transgenes cloned from IgG-secreting hybridomas. All of the mutations identified were single base substitutions. Mutations were localized to the variable (V) region and its flanking sequences. In every case, the nuclear matrix association region, kappa enhancer, and C gene were spared. These data indicate that the rearranged kappa gene contains the necessary sequences for targeting of the mutation process, and suggest that the observed localization of mutations to the V region reflects the inherent specificity of this mutation process.
Oxidized Low-Density Lipoproteins Activate CD4+ T Cell Apoptosis in Patients with End-Stage Renal Disease through Fas Engagement
Authors: Pascal Meier, Franc[COMBINING CEDILLA]ois Spertini, Edouard Blanc, Michel Burnier
Journal: Journal of the American Society of Nephrology (2006)

Oxidized LDL (oxLDL) are cytotoxic to vascular cells, but their possible toxic action on T cells from patients with ESRD has not been evaluated. oxLDL concentrations were measured and compared in patients who were on long-term hemodialysis (HD), in patients who had ESRD and were on continuous ambulatory peritoneal dialysis, in nondialyzed patients with chronic kidney disease, and in age- and gender-matched control subjects. In parallel, the proliferative capacity of CD69+/CD4+ T cells and their rate of apoptosis, IL-2 expression, and intracellular expression of Bcl-2 and Bax were determined in vitro. The oxLDL concentrations were significantly higher in HD patients (all P = 0.001). Upon phytohemagglutinin stimulation, CD69+/CD4+ T cells from HD patients proliferated significantly less than those from the other patients' group (both P < 0.001). oxLDL but not the native LDL were led to CD69+/CD4+ T cells' program cell death in a dosage- and time-dependent manner through Fas pathway (P = 0.001). Cell surface Fas expression was followed by DNA fragmentation when CD69+/CD4+ T cells from HD patients or control subjects were cultured with oxLDL (200 microg/ml; 31 +/- 3 versus 25 +/- 3%; P = 0.001). In the presence of oxLDL, CD69+/CD4+ T cells from HD patients expressed significantly lower IL-2 levels, which strongly correlated with a decrease in the antiapoptotic Bcl-2 and conversely with an increase in the proapoptotic Bax expression. In conclusion, these data suggest that, in HD patients, exposure of activated CD4+ T cells to oxLDL leads to Fas-mediated apoptosis in association with inhibition of IL-2 expression. Subsequently, this may favor activation of mitochondria-dependent apoptotic pathways, leading to activated CD4+ T cell dysfunction.
Epithelial and dendritic cells in the thymic medulla promote CD4+Foxp3+ regulatory T cell development via the CD27–CD70 pathway
Authors: Jonathan M. Coquet, Julie C. Ribot, Nikolina Bąbała, Sabine Middendorp, Gerda van der Horst, Yanling Xiao, Joana F. Neves, Diogo Fonseca-Pereira, Heinz Jacobs, Daniel J. Pennington, Bruno Silva-Santos, Jannie Borst
Journal: The Journal of Experimental Medicine (2013)

CD4(+)Foxp3(+) regulatory T cells (Treg cells) are largely autoreactive yet escape clonal deletion in the thymus. We demonstrate here that CD27-CD70 co-stimulation in the thymus rescues developing Treg cells from apoptosis and thereby promotes Treg cell generation. Genetic ablation of CD27 or its ligand CD70 reduced Treg cell numbers in the thymus and peripheral lymphoid organs, whereas it did not alter conventional CD4(+)Foxp3(-) T cell numbers. The CD27-CD70 pathway was not required for pre-Treg cell generation, Foxp3 induction, or mature Treg cell function. Rather, CD27 signaling enhanced positive selection of Treg cells within the thymus in a cell-intrinsic manner. CD27 signals promoted the survival of thymic Treg cells by inhibiting the mitochondrial apoptosis pathway. CD70 was expressed on Aire(-) and Aire(+) medullary thymic epithelial cells (mTECs) and on dendritic cells (DCs) in the thymic medulla. CD70 on both mTECs and DCs contributed to Treg cell development as shown in BM chimera experiments with CD70-deficient mice. In vitro experiments indicated that CD70 on the CD8α(+) subset of thymic DCs promoted Treg cell development. Our data suggest that mTECs and DCs form dedicated niches in the thymic medulla, in which CD27-CD70 co-stimulation rescues developing Treg cells from apoptosis, subsequent to Foxp3 induction by TCR and CD28 signals.
Liver transplantation and de novo hepatitis B Infection
Authors: M.A. Aldersley, R.E. Eglin, J.G. O'Grady, D. Mortiboy, S. Davison, R.H. George, L. Theilmann, J. Arnold, U. Töx, K. Datsis, G. Otto, W. Hofmann, J. Köck, H.J. Schlicht
Journal: The Lancet (1994)
Prognostic Validity of a Novel American Joint Committee on Cancer Staging Classification for Pancreatic Neuroendocrine Tumors
Authors: Jonathan R. Strosberg, Asima Cheema, Jill Weber, Gang Han, Domenico Coppola, Larry K. Kvols
Journal: Journal of Clinical Oncology (2011)

Purpose The American Joint Committee on Cancer (AJCC) staging manual (seventh edition) has introduced its first TNM staging classification for pancreatic neuroendocrine tumors (NETs) derived from the staging algorithm for exocrine pancreatic adenocarcinomas. This classification has not yet been validated. Methods Patients with pancreatic NETs treated at the H. Lee Moffitt Cancer Center between 1999 and 2010 were assigned a stage (I to IV) based on the new AJCC classification. Kaplan-Meier analyses for overall survival (OS) were performed based on age, race, histologic grade, incidental diagnosis, and TNM staging (European Neuroendocrine Tumors Society [ENETS] v AJCC) using log-rank tests. Survival time was measured from time of initial diagnosis to date of last contact or date of death. Multivariate modeling was performed using Cox proportional hazards regression. Weighted Cohen's κ coefficient was computed to evaluate the agreement of ENETS and AJCC classifications. Results We identified 425 patients with pancreatic NETs. On the basis of histopathologic grade, 5-year survival rates for low-, intermediate-, and high-grade tumors were 75%, 62%, and 7%, respectively (P &lt; .001). When using the ENETS classification, 5-year OS rates for stages I, II, III, and IV were 100%, 88%, 85%, and 57%, respectively (P &lt; .001). Subsequently, using the AJCC classification, 5-year OS rates for stages I, II, III, and IV were 92%, 84%, 81%, and 57%, respectively (P &lt; .001). Both the novel AJCC classification and the ENETS classification were highly prognostic for survival. Conclusion The AJCC TNM classification for pancreatic NETs is prognostic for OS and can be adopted in clinical practice.
Transient Neonatal Diabetes, <i>ZFP57</i>, and Hypomethylation of Multiple Imprinted Loci
Authors: Susanne E. Boonen, Deborah J.G. Mackay, Johanne M.D. Hahnemann, Louise Docherty, Karen Grønskov, Anna Lehmann, Lise G. Larsen, Andreas P. Haemers, Yves Kockaerts, Lutgarde Dooms, Dũng Chí Vũ, C.T. Bich Ngoc, Phuong Bich Nguyen, Olga Kordonouri, Frida Sundberg, Pinar Dayanikli, Vijith Puthi, Carlo Acerini, Ahmed F. Massoud, Zeynep Tümer, I. Karen Temple
Journal: Diabetes Care (2012)

Transient neonatal diabetes mellitus 1 (TNDM1) is the most common cause of diabetes presenting at birth. Approximately 5% of the cases are due to recessive ZFP57 mutations, causing hypomethylation at the TNDM locus and other imprinted loci (HIL). This has consequences for patient care because it has impact on the phenotype and recurrence risk for families. We have determined the genotype, phenotype, and epigenotype of the first 10 families to alert health professionals to this newly described genetic subgroup of diabetes.The 10 families (14 homozygous/compound heterozygous individuals) with ZFP57 mutations were ascertained through TNDM1 diagnostic testing. ZFP57 was sequenced in probands and their relatives, and the methylation levels at multiple maternally and paternally imprinted loci were determined. Medical and family histories were obtained, and clinical examination was performed.The key clinical features in probands were transient neonatal diabetes, intrauterine growth retardation, macroglossia, heart defects, and developmental delay. However, the finding of two homozygous relatives without diabetes and normal intelligence showed that the phenotype could be very variable. The epigenotype always included total loss of methylation at the TNDM1 locus and reproducible combinations of differential hypomethylation at other maternally imprinted loci, including tissue mosaicism.There is yet no clear genotype-epigenotype-phenotype correlation to explain the variable clinical presentation, and this results in difficulties predicting the prognosis of affected individuals. However, many cases have a more severe phenotype than seen in other causes of TNDM1. Further cases and global epigenetic testing are needed to clarify this.
Belotecan, new camptothecin analogue, is active in patients with small-cell lung cancer: results of a multicenter early phase II study
Authors: D.H. Lee, S.-W. Kim, C. Suh, J.-S. Lee, J.H. Lee, S.-J. Lee, B.Y. Ryoo, K. Park, J.S. Kim, D.S. Heo, N.K. Kim
Journal: Annals of Oncology (2007)
The significance of the nuclear and cytoplasmic localization of metallothionein in human liver and tumor cells.
Authors: M G Cherian
Journal: Environmental Health Perspectives (1994)

Metallothioneins are a group of low-molecular-weight intracellular proteins present in high levels in fetal mammalian livers, bound to zinc and copper. They are also present in two major isoforms in low basal levels in various organs of adults in several species. Although a number of functions have been proposed for metallothioneins, their major biological roles may be in the storage of zinc and copper during rapid growth and development, and also in the detoxification of certain toxic metals. In adult liver, metallothionein is mainly localized in the cytoplasm, it is localized also in the hepatocyte nuclei in human fetal liver and fetal and neonatal rat liver, as determined by immunohistochemical staining with a specific metallothionein antibody. Because of its high expression in fetal development, the potential role of metallothioneins in human tumors was investigated. The cellular localization of metallothionein was demonstrated in various human tumors such as thyroid tumors, testicular germ cell carcinoma, bladder transitional cell carcinomas, and salivary gland tumors. In most of these tumor tissues, metallothioneins were found in high levels in nucleus and cytoplasm in both benign and malignant tumors, although the proliferating edge of the malignant tumors showed most intense metallothionein staining. The expression of metallothionein is not universal to all tumor growth; its presence may depend on various factors, such as the type of tumor, cellular origin, morphological heterogeneity, or stage of growth. Human testicular seminomas, which are well differentiated, showed little expression of metallothionein irrespective of the staging, as compared to less well-differentiated embryonal carcinomas.(ABSTRACT TRUNCATED AT 250 WORDS)
Reduced nuclear factor-κB repressing factor: a link toward systemic inflammation in COPD
Authors: Kang-Yun Lee, Shu-Chuan Ho, Yao-Fei Chan, Chun-Hua Wang, Chien-Da Huang, Wen-Te Liu, Shu-Min Lin, Yu-Lun Lo, Ya-Ling Chang, Lu-Wei Kuo, Han-Pin Kuo
Journal: European Respiratory Journal (2012)

Chronic systemic inflammation is implicated in the systemic manifestations and, probably, the excess mortality risk of chronic obstructive pulmonary disease (COPD). The role of nuclear factor (NF)-κB repressing factor (NRF), a DNA-binding, protein-inhibiting NF-κB response gene, in human diseases has not been explored. We hypothesised that the NRF-negative regulatory mechanism is impaired in COPD peripheral blood mononuclear cells (PBMCs) leading to excessive interleukin (IL)-8/CXCL8 production. NRF expression, NF-κB activation, IL-8/CXCL8 release and intracellular oxidative stress were assessed in PBMCs of normal subjects and stable COPD patients. Primary PBMCs with NRF overexpression, NRF knockdown and exposure to H 2 O 2 were used to elucidate the mechanisms. Stable COPD patients, especially those with severe COPD, showed decreased NRF expression, enhanced NF-κB activation and increased IL-8/CXCL8 release in PBMCs compared with normal subjects. This was associated with reduced NRF and increased RNA polymerase II occupancy at the IL-8/CXCL8 promoter. NRF knockdown enhanced IL-8/CXCL8 production in normal PBMCs, whilst NRF overexpression attenuated IL-8/CXCL8 production. Intracellular oxidative stress was increased in COPD PBMCs. H 2 O 2 -decreased NRF expression and -enhanced IL-8/CXCL8 production was augmented in COPD PBMCs. NRF expression is reduced in PBMCs of stable COPD patients, probably through oxidative stress, leading to increased production of IL-8/CXCL8 and potentially chronic systemic inflammation.
Injury risk factors, screening tests and preventative strategies: a systematic review of the evidence that underpins the perceptions and practices of 44 football (soccer) teams from various premier leagues
Authors: Alan McCall, Chris Carling, Michael Davison, Mathieu Nedelec, Franck Le Gall, Serge Berthoin, Gregory Dupont
Journal: British Journal of Sports Medicine (2015)

To systematically review the scientific level of evidence for the 'Top 3' risk factors, screening tests and preventative exercises identified by a previously published survey of 44 premier league football (soccer) teams. Also, to provide an overall scientific level of evidence and graded recommendation based on the current research literature.A systematic literature search (Pubmed [MEDLINE], SportDiscus, PEDRO and Cochrane databases). The quality of the articles was assessed and a level of evidence (1++ to 4) was assigned. Level 1++ corresponded to the highest level of evidence available and 4, the lowest. A graded recommendation (A: strong, B: moderate, C: weak, D: insufficient evidence to assign a specific recommendation) for use in the practical setting was given.Fourteen studies were analysed. The overall level of evidence for the risk factors previous injury, fatigue and muscle imbalance were 2++, 4 and 'inconclusive', respectively. The graded recommendation for functional movement screen, psychological questionnaire and isokinetic muscle testing were all 'D'. Hamstring eccentric had a weak graded 'C' recommendation, and eccentric exercise for other body parts was 'D'. Balance/proprioception exercise to reduce ankle and knee sprain injury was assigned a graded recommendation 'D'.The majority of perceptions and practices of premier league teams have a low level of evidence and low graded recommendation. This does not imply that these perceptions and practices are not important or not valid, as it may simply be that they are yet to be sufficiently validated or refuted by research.
Lenalidomide after Stem-Cell Transplantation for Multiple Myeloma
Authors: Philip L. McCarthy, Kouros Owzar, Craig C. Hofmeister, David D. Hurd, Hani Hassoun, Paul G. Richardson, Sergio Giralt, Edward A. Stadtmauer, Daniel J. Weisdorf, Ravi Vij, Jan S. Moreb, Natalie Scott Callander, Koen Van Besien, Teresa Gentile, Luis Isola, Richard T. Maziarz, Don A. Gabriel, Asad Bashey, Heather Landau, Thomas Martin, Muzaffar H. Qazilbash, Denise Levitan, Brian McClune, Robert Schlossman, Vera Hars, John Postiglione, Chen Jiang, Elizabeth Bennett, Susan Barry, Linda Bressler, Michael Kelly, Michele Seiler, Cara Rosenbaum, Parameswaran Hari, Marcelo C. Pasquini, Mary M. Horowitz, Thomas C. Shea, Steven M. Devine, Kenneth C. Anderson, Charles Linker
Journal: New England Journal of Medicine (2012)

Data are lacking on whether lenalidomide maintenance therapy prolongs the time to disease progression after autologous hematopoietic stem-cell transplantation in patients with multiple myeloma.
Novel agents for chronic lymphocytic leukemia
Authors: Mei Wu, Akintunde Akinleye, Xiongpeng Zhu
Journal: Journal of Hematology & Oncology (2013)

Abstract Chronic lymphocytic leukemia (CLL) is a heterogeneous group of B-cell neoplasm. CLL is typically sensitive to a variety of cytotoxic agents, but relapse frequently occurs with conventional approaches. The treatment of CLL is evolving rapidly with the introduction of novel drugs, such as bendamustine, ofatumumab, lenalidomide, ibrutinib, idelalisib, veltuzumab, XmAb5574, navitoclax, dasatinib, alvespimycin, and TRU-016. This review summarizes the most current clinical experiences with these agents in the treatment of CLL.
Systolic Improvement and Mechanical Resynchronization Does Not Require Electrical Synchrony in the Dilated Failing Heart With Left Bundle-Branch Block
Authors: Christophe Leclercq, Owen Faris, Richard Tunin, Jennifer Johnson, Ritsuchi Kato, Frank Evans, Julio Spinelli, Henry Halperin, Elliot McVeigh, David A. Kass
Journal: Circulation (2002)

Biventricular (BiV) and left ventricular (LV) pacing similarly augment systolic function in left bundle-branch block (LBBB)-failing hearts despite different electrical activation. We tested whether electrical synchrony is required to achieve mechanical synchronization and functional benefit from pacing.Epicardial mapping, tagged MRI, and hemodynamics were obtained in dogs with LBBB-failing hearts during right atrial, LV, and BiV stimulation. BiV and LV both significantly improved chamber hemodynamics (eg, 25% increase in dP/dt(max) and aortic pulse pressure) compared with atrial pacing-LBBB, and this improvement correlated with mechanical resynchronization. Electrical dispersion, however, decreased 13% with BiV but increased 23% with LV pacing (P<0.01).Improved mechanical synchrony and function do not require electrical synchrony. Mechanical coordination plays the dominant role in global systolic improvement with either pacing approach.
cGMP-Dependent and -Independent Inhibition of a K+ Conductance by Natriuretic Peptides
Authors: JOCHEN R. HIRSCH, MARKUS MEYER, HANS-JURGEN MÄGERT, WOLF-GEORG FORSSMANN, STEEN MOLLERUP, PETER HERTER, GERHARD WEBER, RAINER CERMAK, IEVA ANKORINA-STARK, EBERHARD SCHLATTER, MOGENS KRUHØFFER
Journal: Journal of the American Society of Nephrology (1999)

Abstract. In immortalized human kidney epithelial (IHKE-1) cells derived from proximal tubules, two natriuretic peptide receptors (NPR) were identified. In addition to NPR-A, which is bound by atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP), and urodilatin (URO), a novel form of NPR-B that might be bound by C-type natriuretic peptide (CNP) was identified using PCR. This novel splice variant of NPR-B (NPR-Bi) was also found in human kidney. Whereas ANP, BNP, and URO increased intracellular cGMP levels in IHKE-1 cells in a concentration-dependent manner, CNP had no effect on cGMP levels. To determine the physiologic responses to these agonists in IHKE-1 cells, the membrane voltage ( V m ) was monitored using the slow whole-cell patch-clamp technique. ANP (10 nM), BNP (10 nM), and URO (16 nM) depolarized these cells by 3 to 4 mV ( n = 47, 7, and 16, respectively), an effect that could be mimicked by 0.1 mM 8-Br-cGMP ( n = 15). The effects of ANP and 8-Br-cGMP were not additive ( n = 4). CNP (10 nM) also depolarized these cells, by 3 ± 1 mV ( n = 28), despite the absence of an increase in cellular cGMP levels, indicating a cGMP-independent mechanism. In the presence of CNP, 8-Br-cGMP further depolarized V m significantly, by 1.6 ± 0.3 mV ( n = 5). The depolarizations by ANP were completely abolished in the presence of Ba 2+ (1 mM, n = 4) and thus can be related to inhibition of a K + conductance in the luminal membrane of IHKE-1 cells. The depolarizations attributable to CNP were completely blocked when genistein (10 μM, n = 6), an inhibitor of tyrosine kinases, was present. These findings indicate that natriuretic peptides regulate electrogenic transport processes via cGMP-dependent and -independent pathways that influence the V m of IHKE-1 cells.
Strategies for modern biomarker and drug development in oncology
Authors: Alan D Smith, Desam Roda, Timothy A Yap
Journal: Journal of Hematology & Oncology (2014)

Technological advancements in the molecular characterization of cancers have enabled researchers to identify an increasing number of key molecular drivers of cancer progression. These discoveries have led to multiple novel anticancer therapeutics, and clinical benefit in selected patient populations. Despite this, the identification of clinically relevant predictive biomarkers of response continues to lag behind. In this review, we discuss strategies for the molecular characterization of cancers and the importance of biomarkers for the development of novel antitumor therapeutics. We also review critical successes and failures in oncology, and detail the lessons learnt, which may aid in the acceleration of anticancer drug development and biomarker discovery.
A new Fc receptor on mouse macrophages binding IgG3.
Authors: B Diamond, D E Yelton
Journal: The Journal of Experimental Medicine (1981)

Monoclonal antibodies to sheep erythrocytes (SRBC) have proved useful in identifying two Fc receptors on mouse macrophages, one for IgG2a, and one for IgG1 and IgG2b. We have used monoclonal IgG3 anti-SRBC to identify a third Fc receptor on mouse macrophages which binds IgG3 uniquely. This receptor is present on primary resident and thioglycolate-induced peritoneal macrophages and on some macrophage cell lines. The binding of IgG3-coated SRBC is inhibited by aggregated byt not monomeric IgG3, and not by IgG1, IgG2a, and IgG2b aggregates. It is unaffected by treating the macrophages with trypsin or cytochalasin B and occurs at both 4 degrees and 37 degrees C. IgG3, like all other IgG subclasses, mediates phagocytosis. We have also generated a variant macrophage line which bears the receptors for IgG1 and IgG2b and for IgG2a, but not for IgG3.
Nuclear Factor-κB–Dependent Mechanisms in Breast Cancer Cells Regulate Tumor Burden and Osteolysis in Bone
Authors: Andrew H. Gordon, Regis J. O'Keefe, Edward M. Schwarz, Randy N. Rosier, J. Edward Puzas
Journal: Cancer Research (2005)

A central mediator of a wide host of target genes, the nuclear factor-kappaB (NF-kappaB) family of transcription factors, has emerged as a molecular target in cancer and diseases associated with bone destruction. To evaluate how NF-kappaB signaling in tumor cells regulates processes associated with osteolytic bone tumor burden, we stably infected the bone-seeking MDA-MB-231 breast cancer cell line with a dominant-negative mutant IkappaB that prevents phosphorylation of IkappaBalpha and associated nuclear translocation of NF-kappaB. Blockade of NF-kappaB signaling in MDA-MB-231 cells by the mutant IkappaB decreased in vitro cell proliferation, expression of the proinflammatory, bone-resorbing cytokine interleukin-6, and in vitro bone resorption by tumor/osteoclast cocultures while reciprocally up-regulating production of the proapoptotic enzyme caspase-3. Suppression of NF-kappaB transcription in these breast cancer cells also reduced incidence of in vivo tumor-mediated osteolysis after intratibial injection of tumor cells in female athymic nude mice. Immunohistochemistry showed that the cancerous lesions formed in bone by MDA-MB-231 cells express both interleukin-6 and the p65 subunit of NF-kappaB at the bone-tumor interface. NF-kappaB signaling in breast cancer cells therefore promotes bone tumor burden and tumor-mediated osteolysis through combined control of tumor proliferation, cell survival, and bone resorption. These findings imply that NF-kappaB and its associated genes may be relevant therapeutic targets in osteolytic tumor burden.