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[PMID]: 25843670
[Au] Autor:Andemariam B; Adami AJ; Singh A; McNamara JT; Secor ER; Guernsey LA; Thrall RS
[Ad] Address:Division of Hematology-Oncology, Lea Center for Hematologic Disorders, Adult Sickle Cell Center, University of Connecticut Health Center, Farmington, Conn. Electronic address: andemariam@uchc.edu....
[Ti] Title:The sickle cell mouse lung: proinflammatory and primed for allergic inflammation.
[So] Source:Transl Res;166(3):254-68, 2015 Sep.
[Is] ISSN:1878-1810
[Cp] Country of publication:United States
[La] Language:eng
[Ab] Abstract:Comorbid asthma in sickle cell disease (SCD) confers higher rates of vaso-occlusive pain and mortality, yet the physiological link between these two distinct diseases remains puzzling. We used a mouse model of SCD to study pulmonary immunology and physiology before and after the induction of allergic airway disease (AAD). SCD mice were sensitized with ovalbumin (OVA) and aluminum hydroxide by the intraperitoneal route followed by daily, nose-only OVA-aerosol challenge to induce AAD. The lungs of naive SCD mice showed signs of inflammatory and immune processes: (1) histologic and cytochemical evidence of airway inflammation compared with naive wild-type mice; (2) bronchoalveolar lavage (BAL) fluid contained increased total lymphocytes, %CD8+ T cells, granulocyte-colony stimulating factor, interleukin 5 (IL-5), IL-7, and chemokine (C-X-C motif) ligand (CXCL)1; and (3) lung tissue and hilar lymph node (HLN) had increased CD4+, CD8+, and regulatory T (Treg) cells. Furthermore, SCD mice at AAD demonstrated significant changes compared with the naive state: (1) BAL fluid with increased %CD4+ T cells and Treg cells, lower %CD8+ T cells, and decreased interferon gamma, CXCL10, chemokine (C-C motif) ligand 2, and IL-17; (2) serum with increased OVA-specific immunoglobulin E, IL-6, and IL-13, and decreased IL-1α and CXCL10; (3) no increase in Treg cells in the lung tissue or HLN; and (4) hyporesponsiveness to methacholine challenge. In conclusion, SCD mice have an altered immunologic pulmonary milieu and physiological responsiveness. These findings suggest that the clinical phenotype of AAD in SCD mice differs from that of wild-type mice and that individuals with SCD may also have a unique, divergent phenotype perhaps amenable to a different therapeutic approach.
[Pt] Publication type:JOURNAL ARTICLE
[Em] Entry month:1508
[Cu] Class update date: 150815
[Lr] Last revision date:150815
[Js] Journal subset:AIM; IM
[St] Status:In-Data-Review

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[PMID]: 25829398
[Au] Autor:Cervantes-Gomez F; Lamothe B; Woyach JA; Wierda WG; Keating MJ; Balakrishnan K; Gandhi V
[Ad] Address:Department of Experimental Therapeutics, MD Anderson Cancer Center, Houston, Texas....
[Ti] Title:Pharmacological and Protein Profiling Suggests Venetoclax (ABT-199) as Optimal Partner with Ibrutinib in Chronic Lymphocytic Leukemia.
[So] Source:Clin Cancer Res;21(16):3705-15, 2015 Aug 15.
[Is] ISSN:1078-0432
[Cp] Country of publication:United States
[La] Language:eng
[Ab] Abstract:PURPOSE: Bruton's tyrosine kinase (BTK) is a critical enzyme in the B-cell receptor pathway and is inhibited by ibrutinib due to covalent binding to the kinase domain. Though ibrutinib results in impressive clinical activity in chronic lymphocytic leukemia (CLL), most patients achieve only partial remission due to residual disease. We performed a pharmacologic profiling of residual circulating CLL cells from patients receiving ibrutinib to identify optimal agents that could induce cell death of these lymphocytes. EXPERIMENTAL DESIGN: Ex vivo serial samples of CLL cells from patients on ibrutinib were obtained prior and after (weeks 2, 4, and 12) the start of treatment. These cells were incubated with PI3K inhibitors (idelalisib or IPI-145), bendamustine, additional ibrutinib, or BCL-2 antagonists (ABT-737 or ABT-199), and cell death was measured. In vitro investigations complemented ex vivo studies. Immunoblots for BTK signaling pathway and antiapoptotic proteins were performed. RESULTS: The BCL-2 antagonists, especially ABT-199, induced high cell death during ex vivo incubations. In concert with the ex vivo data, in vitro combinations also resulted in high cytotoxicity. Serial samples of CLL cells obtained before and 2, 4, 12, or 36 weeks after the start of ibrutinib showed inhibition of BTK activity and sensitivity to ABTs. Among the three BCL-2 family antiapoptotic proteins that are overexpressed in CLL, levels of MCL-1 and BCL-XL were decreased after ibrutinib while ABT-199 selectively antagonizes BCL-2. CONCLUSIONS: Our biologic and molecular results suggest that ibrutinib and ABT-199 combination should be tested clinically against CLL. Clin Cancer Res; 21(16); 3705-15. ©2015 AACR.
[Pt] Publication type:JOURNAL ARTICLE
[Em] Entry month:1508
[Cu] Class update date: 150815
[Lr] Last revision date:150815
[Js] Journal subset:IM
[St] Status:In-Data-Review
[do] DOI:10.1158/1078-0432.CCR-14-2809

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[PMID]: 26234156
[Au] Autor:Teng G; Maman Y; Resch W; Kim M; Yamane A; Qian J; Kieffer-Kwon KR; Mandal M; Ji Y; Meffre E; Clark MR; Cowell LG; Casellas R; Schatz DG
[Ad] Address:Department of Immunobiology, Yale University School of Medicine, 300 Cedar Street, Box 208011, New Haven, CT 06520-8011, USA....
[Ti] Title:RAG Represents a Widespread Threat to the Lymphocyte Genome.
[So] Source:Cell;162(4):751-65, 2015 Aug 13.
[Is] ISSN:1097-4172
[Cp] Country of publication:United States
[La] Language:eng
[Ab] Abstract:The RAG1 endonuclease, together with its cofactor RAG2, is essential for V(D)J recombination but is a potent threat to genome stability. The sources of RAG1 mis-targeting and the mechanisms that have evolved to suppress it are poorly understood. Here, we report that RAG1 associates with chromatin at thousands of active promoters and enhancers in the genome of developing lymphocytes. The mouse and human genomes appear to have responded by reducing the abundance of "cryptic" recombination signals near RAG1 binding sites. This depletion operates specifically on the RSS heptamer, whereas nonamers are enriched at RAG1 binding sites. Reversing this RAG-driven depletion of cleavage sites by insertion of strong recombination signals creates an ectopic hub of RAG-mediated V(D)J recombination and chromosomal translocations. Our findings delineate rules governing RAG binding in the genome, identify areas at risk of RAG-mediated damage, and highlight the evolutionary struggle to accommodate programmed DNA damage in developing lymphocytes.
[Pt] Publication type:JOURNAL ARTICLE
[Em] Entry month:1508
[Cu] Class update date: 150815
[Lr] Last revision date:150815
[Js] Journal subset:IM
[St] Status:In-Data-Review

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[PMID]: 26269722
[Au] Autor:Casulari LA; Dondi D; Celotti F; da Silva FV; Reis CE; da Costa TH
[Ad] Address:Unit of Endocrinology, University Hospital Brasilia, University of Brasilia, Brasilia, Brazil ; CLINEN - Clínica de Neurologia e Endocrinologia. SCN quadra 1, bloco F, Ed. America Office Tower, sala 1111, Brasília, DF 70711-905 Brazil....
[Ti] Title:Effects of caloric restriction and low glycemic index diets associated with metformin on glucose metabolism and cortisol response in overweight/obese subjects: a case series study.
[So] Source:Diabetol Metab Syndr;7:65, 2015.
[Is] ISSN:1758-5996
[Cp] Country of publication:England
[La] Language:eng
[Ab] Abstract:BACKGROUND: To determine whether cortisol secretion and glucocorticoid receptors in lymphocytes and monocytes are altered in patients with impaired glucose tolerance, and whether treatment with a hypocaloric diet and metformin could interfere with these aspects. METHODS: This is an analytical, interventional, case series study. Patients with impaired glucose tolerance were included. They received 500 mg of metformin twice daily and followed a low glycemic index diet for 16 weeks. Cortisol levels were assessed at 8:00 A.M. before and after use of 0.25 mg of dexamethasone at 11:00 P.M. the day before. RESULTS: Sixteen subjects (9 men) were included. Normal basal levels of cortisol and adequate responses to the low dose of dexamethasone were observed before and after treatment. There was no significant correlation between the parameters evaluated and cortisol levels. Nevertheless, there was a strong correlation between the number of glucocorticoid receptors, BMI (r = 0.88; p = 0.02), and insulin AUC (r = 0.94; p = 0.005) before treatment; after treatment, all these associations ceased to exist. CONCLUSION: The cortisol secretion remained normal in the group of patients with impaired glucose tolerance. Treatment with metformin and diet did not change this condition. However, glucocorticoid receptor number had a strong correlation with insulin, due to insulin resistance, but this characteristic was lost after treatment.
[Pt] Publication type:JOURNAL ARTICLE
[Em] Entry month:1508
[Cu] Class update date: 150815
[Lr] Last revision date:150815
[Da] Date of entry for processing:150813
[St] Status:PubMed-not-MEDLINE
[do] DOI:10.1186/s13098-015-0057-9

  5 / 455367 MEDLINE  
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[PMID]: 26269765
[Au] Autor:Teng F; Mu D; Meng X; Kong L; Zhu H; Liu S; Zhang J; Yu J
[Ad] Address:Department of Radiation Oncology, Shandong Cancer Hospital and Institute, Shandong University Jinan, China....
[Ti] Title:Tumor infiltrating lymphocytes (TILs) before and after neoadjuvant chemoradiotherapy and its clinical utility for rectal cancer.
[So] Source:Am J Cancer Res;5(6):2064-74, 2015.
[Is] ISSN:2156-6976
[Cp] Country of publication:United States
[La] Language:eng
[Ab] Abstract:BACKGROUNDS: Radiotherapy (RT) and chemotherapy (CT) can potentiate systemic antitumor immune effect. However, immunomodulation during RT or CT and their clinical implications in rectal cancer have not been thoroughly investigated. METHODS: We investigated alterations in the densities of tumor infiltrating lymphocytes (TILs) during chemoradiation and their clinical utilities in patients with rectal cancer. We analyzed 136 rectal cancer patients who underwent neoadjuvant RT, CT or chemoradiotherapy (CRT), followed by radical resection retrospectively. Pretreatment biopsy specimens and posttreatment resected specimens of all patients were immunostained for CD3 and CD8. The predictive value of TILs to neoadjuvant treatment and prognosis were examined. RESULTS: Densities of CD3+ and CD8+TILs in posttreatment specimens after RT, CT or CRT were all significantly higher than those in pretreatment specimens. There were no significant differences between each two of these three groups. High pretreatment CD3+ and CD8+TILs were associated with good response (TRG ≥ 3) after neoadjuvant treatments (P = 0.033 and 0.021). High CD3+TILs and CD8+TILs in pretreatment biopsy specimens were significantly associated with favorable disease free survival (DFS) (P = 0.010 and P = 0.022) and overall survival (OS) (P = 0.019 and P = 0.003). CONCLUSIONS: We may, thus, conclude that chemoradiation can enhance local immune response by increased TILs. High TILs densities before treatment are associated with good response to neoadjuvant chemoradiotherapy and a favorable prognosis.
[Pt] Publication type:JOURNAL ARTICLE
[Em] Entry month:1508
[Cu] Class update date: 150815
[Lr] Last revision date:150815
[Da] Date of entry for processing:150813
[St] Status:PubMed-not-MEDLINE

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[PMID]: 25884392
[Au] Autor:Charehsaz M; Sipahi H; Celep E; Üstündag A; Cemiloglu Ülker Ö; Duydu Y; Aydin A; Yesilada E
[Ad] Address:Faculty of Pharmacy, Department of Toxicology, Yeditepe University, 34755, Atasehir, Istanbul, Turkey. mohammad.saz@yeditepe.edu.tr....
[Ti] Title:The fruit extract of Berberis crataegina DC: exerts potent antioxidant activity and protects DNA integrity.
[So] Source:Daru;23:24, 2015.
[Is] ISSN:2008-2231
[Cp] Country of publication:England
[La] Language:eng
[Ab] Abstract:BACKGROUND: Dried fruits of Berberis crataegina (Berberidaceae) have been frequently consumed as food garniture in Turkish cuisine, while its fruit paste has been used to increase stamina and in particular to prevent from cardiovascular dysfunctions in Northeastern Black Sea region of Turkey. This study investigated this folkloric information in order to explain the claimed healing effects as well as to evaluate possible risks. METHODS: Total phenolic, flavonoid and proanthocyanidin contents and antioxidant capacity of the methanolic fruit extract were evaluated through several in vitro assays. The cytotoxic and genotoxic effects of B. crataegina fruit extract were also assessed in both cervical cancer cell line (HeLa) and human peripheral blood lymphocytes. RESULTS: The extract showed protective effects against ferric-induced oxidative stress and had a relatively good antioxidant activity. It also ameliorated the H2O2 mediated DNA damage in lymphocytes, suggesting the protective effect against oxidative DNA damage. CONCLUSION: The methanolic extract of B. crataegina fruits may be a potential antioxidant nutrient and also may exert a protective role against lipid peroxidation as well as oxidative DNA damage.
[Pt] Publication type:JOURNAL ARTICLE
[Em] Entry month:1508
[Cu] Class update date: 150804
[Lr] Last revision date:150804
[Js] Journal subset:IM
[St] Status:In-Process
[do] DOI:10.1186/s40199-015-0108-7

  7 / 455367 MEDLINE  
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[PMID]: 26129855
[Au] Autor:Wang Z; Metcalf B; Kasheta M; Kasala-Hallinan C; Tran D; Johnson RP; Else JG; Karl J; O'Connor D; Apetrei C; Kaur A
[Ad] Address:Division of Immunology, Harvard Medical School, New England Primate Research Center, One Pine Hill Drive, Southborough, MA, 01772-9102, USA.
[Ti] Title:Characterization of MHC class I alleles in sooty mangabeys as a tool for evaluating cellular immunity in natural hosts of SIV infection.
[So] Source:Immunogenetics;67(8):447-61, 2015 Aug.
[Is] ISSN:1432-1211
[Cp] Country of publication:United States
[La] Language:eng
[Ab] Abstract:Although immune pressure exerted by MHC class I-restricted cytotoxic T lymphocytes (CTL) are an important determinant of outcome in pathogenic HIV and SIV infection, lack of data on MHC class I genes has hampered study of its role in natural hosts with nonpathogenic SIV infection. In this study, we cloned and characterized full-length MHC class I genes derived from the cDNA library of two unrelated naturally infected sooty mangabeys (Cercocebus atys) in whom SIV-specific CTL epitopes were previously mapped. Twenty one full-length MHC class I alleles consisting of five MHC-A (Ceat-A), 13 MHC-B (Ceat-B), and three MHC-E (Ceat-E) alleles were identified. Sequence-specific primers (SSP) for high-throughput screening of genomic DNA by PCR were developed for 16 of the 18 Ceat-A and Ceat-B alleles. Screening of 62 SIV-negative and 123 SIV-infected sooty mangabeys at the Yerkes National Primate Research Center (YNPRC) revealed the presence of up to four MHC-A and eight MHC-B alleles in individual mangabeys, indicating that similar to macaque species, mangabeys have at least two duplications of the MHC-A locus and four duplications of the MHC-B locus in the absence of an MHC-C locus. Using stable transfectants of Ceat MHC Class I alleles in the MHC-null 721.221 cell line, we identified Ceat-B*12:01 as the restricting allele of a previously reported Nef20-28 CTL epitope. Ceat-B*1201/Nef20-28 tetramers identified tetramer-positive CD8+ T lymphocytes in Ceat-B*1201-positive SIV-infected mangabeys. This study has laid the groundwork for comprehensive analysis of CTL and SIV evolution in a natural host of SIV infection.
[Pt] Publication type:JOURNAL ARTICLE
[Em] Entry month:1507
[Cu] Class update date: 150815
[Lr] Last revision date:150815
[Js] Journal subset:IM
[St] Status:In-Data-Review
[do] DOI:10.1007/s00251-015-0853-2

  8 / 455367 MEDLINE  
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[PMID]: 26034288
[Au] Autor:Weigelin B; Bolaños E; Teijeira A; Martinez-Forero I; Labiano S; Azpilikueta A; Morales-Kastresana A; Quetglas JI; Wagena E; Sánchez-Paulete AR; Chen L; Friedl P; Melero I
[Ad] Address:Department of Cell Biology, Radboud University Nijmegen Medical Center, 6525 GA Nijmegen, The Netherlands;...
[Ti] Title:Focusing and sustaining the antitumor CTL effector killer response by agonist anti-CD137 mAb.
[So] Source:Proc Natl Acad Sci U S A;112(24):7551-6, 2015 Jun 16.
[Is] ISSN:1091-6490
[Cp] Country of publication:United States
[La] Language:eng
[Ab] Abstract:Cancer immunotherapy is undergoing significant progress due to recent clinical successes by refined adoptive T-cell transfer and immunostimulatory monoclonal Ab (mAbs). B16F10-derived OVA-expressing mouse melanomas resist curative immunotherapy with either adoptive transfer of activated anti-OVA OT1 CTLs or agonist anti-CD137 (4-1BB) mAb. However, when acting in synergistic combination, these treatments consistently achieve tumor eradication. Tumor-infiltrating lymphocytes that accomplish tumor rejection exhibit enhanced effector functions in both transferred OT-1 and endogenous cytotoxic T lymphocytes (CTLs). This is consistent with higher levels of expression of eomesodermin in transferred and endogenous CTLs and with intravital live-cell two-photon microscopy evidence for more efficacious CTL-mediated tumor cell killing. Anti-CD137 mAb treatment resulted in prolonged intratumor persistence of the OT1 CTL-effector cells and improved function with focused and confined interaction kinetics of OT-1 CTL with target cells and increased apoptosis induction lasting up to six days postadoptive transfer. The synergy of adoptive T-cell therapy and agonist anti-CD137 mAb thus results from in vivo enhancement and sustainment of effector functions.
[Pt] Publication type:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Em] Entry month:1506
[Cu] Class update date: 150627
[Lr] Last revision date:150627
[Js] Journal subset:IM
[St] Status:In-Process
[do] DOI:10.1073/pnas.1506357112

  9 / 455367 MEDLINE  
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[PMID]: 25824598
[Au] Autor:Kumar A; Samant M; Misra P; Khare P; Sundar S; Garg R; Dube A
[Ad] Address:Division of Parasitology, Central Drug Research Institute (CDRI-CSIR), Lucknow, India....
[Ti] Title:Immunostimulatory potential and proteome profiling of Leishmania donovani soluble exogenous antigens.
[So] Source:Parasite Immunol;37(7):368-75, 2015 Jul.
[Is] ISSN:1365-3024
[Cp] Country of publication:England
[La] Language:eng
[Ab] Abstract:Isolation of the soluble exogenous antigens (SEAgs), its immune response study and proteome profiling is an essential prerequisite for understanding the molecular pathogenesis of Leishmania donovani. The immunostimulatory potential of L. donovani SEAgs, purified from culture of L. donovani clinical isolate, was evaluated for their ability to induce cellular responses in treated/cured hamsters. SEAgs induced significant proliferative responses in lymphocytes (SI 5.6 ± 2.3; P < 0.01) isolated from cured hamster. In addition, significant NO production in response to SEAgs was also noticed in macrophages of hamsters, mouse and human cell lines (J774A-1 and THP1). Western blot analyses with antibodies against proteophosphoglycan (PPG; surface-expressed and secreted molecule) of L. donovani revealed that PPG molecules are also present in L. donovani SEAgs. Mass spectrometry (MS)-based proteome analysis of 12 protein bands of SEAgs through MALDI-TOF/TOF endorsed the identification of some Th1-stimulatory immunogenic proteins. These immunogenic proteins may offer increased hope for the discovery of new promising vaccine candidates against visceral leishmaniasis (VL). The overall results suggest that immunostimulatory molecules are present in the SEAgs, which may be further exploited, for developing a subunit vaccine against VL a fatal human disease.
[Pt] Publication type:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Em] Entry month:1506
[Js] Journal subset:IM
[St] Status:In-Process
[do] DOI:10.1111/pim.12189

  10 / 455367 MEDLINE  
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[PMID]: 25833958
[Au] Autor:Biswas M; Sarkar D; Kumar SR; Nayak S; Rogers GL; Markusic DM; Liao G; Terhorst C; Herzog RW
[Ad] Address:Department of Pediatrics, University of Florida, Gainesville, FL; and....
[Ti] Title:Synergy between rapamycin and FLT3 ligand enhances plasmacytoid dendritic cell-dependent induction of CD4+CD25+FoxP3+ Treg.
[So] Source:Blood;125(19):2937-47, 2015 May 7.
[Is] ISSN:1528-0020
[Cp] Country of publication:United States
[La] Language:eng
[Ab] Abstract:CD4(+)CD25(+)FoxP3(+) regulatory T cells (Treg) are critical elements for maintaining immune tolerance, for instance to exogenous antigens that are introduced during therapeutic interventions such as cell/organ transplant or gene/protein replacement therapy. Coadministration of antigen with rapamycin simultaneously promotes deletion of conventional CD4(+) T cells and induction of Treg. Here, we report that the cytokine FMS-like receptor tyrosine kinase ligand (Flt3L) enhances the in vivo effect of rapamycin. This occurs via selective expansion of plasmacytoid dendritic cells (pDCs), which further augments the number of Treg. Whereas in conventional DCs, rapamycin effectively blocks mammalian target of rapamycin (mTOR) 1 signaling induced by Flt3L, increased mTOR1 activity renders pDCs more resistant to inhibition by rapamycin. Consequently, Flt3L and rapamycin synergistically promote induction of antigen-specific Treg via selective expansion of pDCs. This concept is supported by the finding that Treg induction is abrogated upon pDC depletion. The combination with pDCs and rapamycin is requisite for Flt3L/antigen-induced Treg induction because Flt3L/antigen by itself fails to induce Treg. As co-administering Flt3L, rapamycin, and antigen blocked CD8(+) T-cell and antibody responses in models of gene and protein therapy, we conclude that the differential effect of rapamycin on DC subsets can be exploited for improved tolerance induction.
[Mh] MeSH terms primary: CD4-Positive T-Lymphocytes/immunology
Dendritic Cells/immunology
Forkhead Transcription Factors/metabolism
Interleukin-2 Receptor alpha Subunit/metabolism
Membrane Proteins/metabolism
Sirolimus/pharmacology
T-Lymphocytes, Regulatory/immunology
[Mh] MeSH terms secundary: Animals
Antibiotics, Antineoplastic/pharmacology
Apoptosis/drug effects
Blotting, Western
CD4-Positive T-Lymphocytes/drug effects
CD4-Positive T-Lymphocytes/metabolism
Cells, Cultured
Cytokines
Dendritic Cells/drug effects
Dendritic Cells/metabolism
Drug Synergism
Flow Cytometry
Humans
Immune Tolerance/immunology
Male
Mice
Mice, Inbred BALB C
Mice, Inbred C57BL
Mice, Transgenic
Phosphorylation
Signal Transduction
T-Lymphocytes, Regulatory/drug effects
T-Lymphocytes, Regulatory/metabolism
TOR Serine-Threonine Kinases/metabolism
[Pt] Publication type:JOURNAL ARTICLE; RESEARCH SUPPORT, N.I.H., EXTRAMURAL
[Nm] Name of substance:0 (Antibiotics, Antineoplastic); 0 (Cytokines); 0 (Forkhead Transcription Factors); 0 (Foxp3 protein, mouse); 0 (Interleukin-2 Receptor alpha Subunit); 0 (Membrane Proteins); 0 (flt3 ligand protein); EC 2.7.1.1 (TOR Serine-Threonine Kinases); W36ZG6FT64 (Sirolimus)
[Em] Entry month:1507
[Cu] Class update date: 150815
[Lr] Last revision date:150815
[Js] Journal subset:AIM; IM
[Da] Date of entry for processing:150508
[St] Status:MEDLINE
[do] DOI:10.1182/blood-2014-09-599266


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