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[PMID]: 29176764 [Au] Autor: Gregersen I; Sandanger Ø; Askevold ET; Sagen EL; Yang K; Holm S; Pedersen TM; Skjelland M; Krohg-Sørensen K; Hansen TV; Dahl TB; Otterdal K; Espevik T; Aukrust P; Yndestad A; Halvorsen B [Ad] Endereço: Research Institute of Internal Medicine, Oslo University Hospital Rikshospitalet,Oslo, Norway. [Ti] Título: Interleukin 27 is increased in carotid atherosclerosis and promotes NLRP3 inflammasome activation. [So] Source: PLoS One;12(11):e0188387, 2017. [Is] ISSN: 1932-6203 [Cp] País de publicação: United States [La] Idioma: eng [Ab] Resumo: AIM: Interleukin-27 (IL-27) is involved in different inflammatory diseases; however, its role in atherosclerosis is unclear. In this study we investigated the expression of IL-27 and its receptor in patients with carotid atherosclerosis and if IL-27 could modulate the inflammatory effects of the NLRP3 inflammasome in vitro. METHODS: Plasma IL-27 was measured by enzyme immunoassay in patients with carotid stenosis (n = 140) and in healthy controls (n = 19). Expression of IL-27 and IL-27R was analyzed by quantitative PCR and immunohistochemistry in plaques from patients and in non-atherosclerotic vessels. THP-1 monocytes, primary monocytes and peripheral blood mononuclear cells (PBMCs) were used to study effects of IL-27 in vitro. RESULTS: Our main findings were: (i) Plasma levels of IL-27 were significantly elevated in patients with carotid atherosclerotic disease compared to healthy controls. (ii) Gene expression of IL-27 and IL-27R was significantly elevated in plaques compared to control vessels, and co-localized to macrophages. (iii) In vitro, IL-27 increased NLRP3 inflammasome activation in monocytes with enhanced release of IL-1 ß. CONCLUSIONS: We demonstrate increased levels of IL-27 and IL-27R in patients with carotid atherosclerosis. Our in vitro findings suggest an inflammatory role for IL-27, which can possibly be linked to atherosclerotic disease development. [Mh] Termos MeSH primário: Doenças das Artérias Carótidas/metabolismo Inflamassomos/metabolismo Interleucina-27/metabolismo Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo [Mh] Termos MeSH secundário: Idoso Antígenos CD/metabolismo Apirase/metabolismo Doenças das Artérias Carótidas/sangue Doenças das Artérias Carótidas/genética Doenças das Artérias Carótidas/patologia Feminino Regulação da Expressão Gênica Seres Humanos Interleucina-1beta/metabolismo Interleucina-27/sangue Interleucina-27/genética Interleucinas/metabolismo Lipopolissacarídeos Macrófagos/metabolismo Masculino Antígenos de Histocompatibilidade Menor/metabolismo Monócitos/metabolismo Placa Aterosclerótica/metabolismo Placa Aterosclerótica/patologia Receptores de Citocinas/genética Receptores de Citocinas/metabolismo Fatores de Transcrição STAT/metabolismo Transdução de Sinais Fator de Necrose Tumoral alfa/metabolismo Regulação para Cima/genética [Pt] Tipo de publicação: JOURNAL ARTICLE [Nm] Nome de substância: 0 (Antigens, CD); 0 (EBI3 protein, human); 0 (Inflammasomes); 0 (Interleukin-1beta); 0 (Interleukin-27); 0 (Interleukins); 0 (Lipopolysaccharides); 0 (Minor Histocompatibility Antigens); 0 (NLR Family, Pyrin Domain-Containing 3 Protein); 0 (Receptors, Cytokine); 0 (STAT Transcription Factors); 0 (Tumor Necrosis Factor-alpha); EC 3.6.1.5 (Apyrase); EC 3.6.1.5 (CD39 antigen) [Em] Mês de entrada: 1712 [Cu] Atualização por classe: 171219 [Lr] Data última revisão: 171219 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 171128 [St] Status: MEDLINE [do] DOI: 10.1371/journal.pone.0188387

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[PMID]: 28927768 [Au] Autor: Park S; Park Y; Son SH; Lee K; Jung YW; Lee KY; Jeon YH; Byun Y [Ad] Endereço: College of Pharmacy, Korea University, 2511 Sejong-ro, Sejong 30019, South Korea. [Ti] Título: Synthesis and biological evaluation of peptide-derived TSLP inhibitors. [So] Source: Bioorg Med Chem Lett;27(20):4710-4713, 2017 10 15. [Is] ISSN: 1464-3405 [Cp] País de publicação: England [La] Idioma: eng [Ab] Resumo: Thymic stromal lymphopoietin (TSLP) is a type II cytokine which is associated with most inflammatory allergic disorders in humans. It is produced mainly by epithelial cells with important role in the development of chronic inflammatory diseases by activating T-helper cell type-2 (T 2) pathways. In this study, a total of 16 peptides were prepared by solid phase peptide synthesis based on amino acid sequences of the interface between TSLP and TSLP receptor. Their TSLP inhibition activities were determined by ELISA assay. Among them, three peptides (6-8) exhibited >50% inhibition at concentration of 0.3mM. They can be used as hit compounds for developing peptide-based TSLP inhibitors. [Mh] Termos MeSH primário: Citocinas/antagonistas & inibidores Peptídeos/metabolismo [Mh] Termos MeSH secundário: Sequência de Aminoácidos Citocinas/metabolismo Ensaio de Imunoadsorção Enzimática Seres Humanos Ligantes Peptídeos/química Ligação Proteica Receptores de Citocinas/química Receptores de Citocinas/metabolismo Células Th2/citologia Células Th2/metabolismo [Pt] Tipo de publicação: JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T [Nm] Nome de substância: 0 (CRLF2 protein, human); 0 (Cytokines); 0 (Ligands); 0 (Peptides); 0 (Receptors, Cytokine); 0 (thymic stromal lymphopoietin) [Em] Mês de entrada: 1711 [Cu] Atualização por classe: 171125 [Lr] Data última revisão: 171125 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 170921 [St] Status: MEDLINE

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[PMID]: 28866095 [Au] Autor: Sadras T; Heatley SL; Kok CH; Dang P; Galbraith KM; McClure BJ; Muskovic W; Venn NC; Moore S; Osborn M; Revesz T; Moore AS; Hughes TP; Yeung D; Sutton R; White DL [Ad] Endereço: Cancer Theme, South Australian Health & Medical Research Institute, Adelaide, SA, Australia; Discipline of Medicine, University of Adelaide, Adelaide, SA, Australia. [Ti] Título: Differential expression of MUC4, GPR110 and IL2RA defines two groups of CRLF2-rearranged acute lymphoblastic leukemia patients with distinct secondary lesions. [So] Source: Cancer Lett;408:92-101, 2017 Nov 01. [Is] ISSN: 1872-7980 [Cp] País de publicação: Ireland [La] Idioma: eng [Ab] Resumo: CRLF2-rearrangements (CRLF2-r) occur frequently in Ph-like B-ALL, a high-risk ALL sub-type characterized by a signaling profile similar to Ph + ALL, however accumulating evidence indicates genetic heterogeneity within CRLF2-r ALL. We performed thorough genomic characterization of 35 CRLF2-r cases (P2RY8-CRLF2 n = 18; IGH-CRLF2 n = 17). Activating JAK2 mutations were present in 34% of patients, and a CRLF2-F232C mutation was identified in an additional 17%. IKZF1 deletions were detected in 63% of cases. The majority of patients (26/35) classified as Ph-like, and these were characterized by significantly higher levels of MUC4, GPR110 and IL2RA/CD25. In addition, Ph-like CRLF2-r samples were significantly enriched for IKZF1 deletions, JAK2/CRLF2 mutations and increased expression of JAK/STAT target genes (CISH, SOCS1), suggesting that mutation-driven CRLF2/JAK2 activation is more frequent in this sub-group. Less is known about the genomics of CRLF2-r cases lacking JAK2-pathway mutations, but KRAS/NRAS mutations were identified in 4/9 non-Ph-like samples. This work highlights the heterogeneity of secondary lesions which may arise and influence intracellular-pathway activation in CRLF2-r patients, and importantly presents distinct therapeutic targets within a group of patients harboring identical primary translocations, for whom efficient directed therapies are currently lacking. [Mh] Termos MeSH primário: Regulação Leucêmica da Expressão Gênica Rearranjo Gênico Subunidade alfa de Receptor de Interleucina-2/metabolismo Mucina-4/metabolismo Proteínas Oncogênicas/metabolismo Leucemia-Linfoma Linfoblástico de Células Precursoras/patologia Receptores de Citocinas/genética Receptores Acoplados a Proteínas-G/metabolismo [Mh] Termos MeSH secundário: Feminino Seres Humanos Subunidade alfa de Receptor de Interleucina-2/genética Janus Quinase 2/genética Janus Quinase 2/metabolismo Mucina-4/genética Mutação/genética Proteínas Oncogênicas/genética Cromossomo Filadélfia Leucemia-Linfoma Linfoblástico de Células Precursoras/genética Leucemia-Linfoma Linfoblástico de Células Precursoras/metabolismo Prognóstico Receptores Acoplados a Proteínas-G/genética Células Tumorais Cultivadas [Pt] Tipo de publicação: JOURNAL ARTICLE [Nm] Nome de substância: 0 (CRLF2 protein, human); 0 (GPR110 protein, human); 0 (IL2RA protein, human); 0 (Interleukin-2 Receptor alpha Subunit); 0 (MUC4 protein, human); 0 (Mucin-4); 0 (Oncogene Proteins); 0 (Receptors, Cytokine); 0 (Receptors, G-Protein-Coupled); EC 2.7.10.2 (JAK2 protein, human); EC 2.7.10.2 (Janus Kinase 2) [Em] Mês de entrada: 1711 [Cu] Atualização por classe: 171101 [Lr] Data última revisão: 171101 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 170904 [St] Status: MEDLINE

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[PMID]: 28846084 [Au] Autor: Broggi A; Tan Y; Granucci F; Zanoni I [Ad] Endereço: Harvard Medical School and Division of Gastroenterology, Boston Children's Hospital, Boston, Massachusetts, USA. [Ti] Título: IFN-λ suppresses intestinal inflammation by non-translational regulation of neutrophil function. [So] Source: Nat Immunol;18(10):1084-1093, 2017 Oct. [Is] ISSN: 1529-2916 [Cp] País de publicação: United States [La] Idioma: eng [Ab] Resumo: Interferon-λ (IFN-λ) is a central regulator of mucosal immunity; however, its signaling specificity relative to that of type I interferons is poorly defined. IFN-λ can induce antiviral interferon-stimulated genes (ISGs) in epithelia, while the effect of IFN-λ in non-epithelial cells remains unclear. Here we report that neutrophils responded to IFN-λ. We found that in addition to inducing ISG transcription, IFN-λ (but not IFN-ß) specifically activated a translation-independent signaling pathway that diminished the production of reactive oxygen species and degranulation in neutrophils. In mice, IFN-λ was elicited by enteric viruses and acted on neutrophils to decrease oxidative stress and intestinal damage. Thus, IFN-λ acted as a unique immunomodulatory agent by modifying transcriptional and non-translational neutrophil responses, which might permit a controlled development of the inflammatory process. [Mh] Termos MeSH primário: Gastroenterite/etiologia Gastroenterite/metabolismo Interferon gama/metabolismo Intestinos/imunologia Intestinos/metabolismo Neutrófilos/imunologia Neutrófilos/metabolismo [Mh] Termos MeSH secundário: Animais Análise por Conglomerados Modelos Animais de Doenças Gastroenterite/patologia Expressão Gênica Perfilação da Expressão Gênica Regulação da Expressão Gênica Predisposição Genética para Doença Seres Humanos Mucosa Intestinal/imunologia Mucosa Intestinal/metabolismo Mucosa Intestinal/microbiologia Mucosa Intestinal/patologia Intestinos/patologia Camundongos Camundongos Knockout Microbiota Estresse Oxidativo Receptores de Citocinas/genética Receptores de Citocinas/metabolismo [Pt] Tipo de publicação: JOURNAL ARTICLE [Nm] Nome de substância: 0 (Receptors, Cytokine); 82115-62-6 (Interferon-gamma) [Em] Mês de entrada: 1710 [Cu] Atualização por classe: 171126 [Lr] Data última revisão: 171126 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 170829 [St] Status: MEDLINE [do] DOI: 10.1038/ni.3821

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[PMID]: 28730733 [Au] Autor: Xu W; Xu L; Deng B; Leng J; Tang N; Zhao LC; Zhou HH; Zhao ZZ; Yang ZJ; Xiao TT; Tian XY; Ho AHM; Chan NWK; Chow YL; Chow CY; Xu M [Ad] Endereço: Hong Kong Baptist University, Kowloon Tong, Hong Kong. [Ti] Título: The Potential Impact of Radix Paeoniae Alba in Embryonic Development of Mice. [So] Source: Phytother Res;31(9):1376-1383, 2017 Sep. [Is] ISSN: 1099-1573 [Cp] País de publicação: England [La] Idioma: eng [Ab] Resumo: Although Radix Paeoniae Alba (RPA) has been ranked as one of the top 6 herbs used frequently to prevent and treat miscarriages clinically, there is no clear evidence regarding its safety in embryonic development. This study aims to evaluate the potential impacts of RPA on embryonic stem cells (ESCs) and pregnant mice. Cytotoxicity assays of the extract were performed in ESCs and 3T3 cells. Pregnant ICR mice were orally treated with RPA extracts at dosages of 0 (G1 group as negative controls), 2, 8 and 32 g/kg/day (G2, G3 and G4 groups) respectively from the gestation day (Gd) 6-15. On Gd 18, there was no significant difference in the IC values between ESCs and 3T3 cells (p > 0.05). There was no significant difference in the maternal and fetal evaluations among four groups (p > 0.05). Fetal IL-2, IL-2r, TNF-α, TNF-αr, IL-4, IL-4r, IL-10r, IL-17 and IL-17r of G4 group were significantly lower than G1 group (p < 0.05). In conclusion, RPA at dosage of 32 g/kg/day (16-folds of human daily dosage) did not cause adverse impact in cultured ESCs and pregnant mice. RPA might down-regulate fetal Th1/Th2/Th17 cytokines and receptors maybe beneficial to embryonic survival and development. Copyright © 2017 John Wiley & Sons, Ltd. [Mh] Termos MeSH primário: Medicamentos de Ervas Chinesas/farmacologia Desenvolvimento Embrionário/efeitos dos fármacos Células-Tronco Embrionárias/efeitos dos fármacos Paeonia/química [Mh] Termos MeSH secundário: Células 3T3 Animais Citocinas/metabolismo Feminino Feto/efeitos dos fármacos Camundongos Camundongos Endogâmicos ICR Gravidez Receptores de Citocinas/metabolismo [Pt] Tipo de publicação: JOURNAL ARTICLE [Nm] Nome de substância: 0 (Cytokines); 0 (Drugs, Chinese Herbal); 0 (Receptors, Cytokine) [Em] Mês de entrada: 1710 [Cu] Atualização por classe: 171010 [Lr] Data última revisão: 171010 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 170722 [St] Status: MEDLINE [do] DOI: 10.1002/ptr.5864

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[PMID]: 28709134 [Au] Autor: Boer JM; den Boer ML [Ad] Endereço: Research Laboratory of Pediatric Oncology, Erasmus MC - Sophia Children's Hospital, Rotterdam, The Netherlands. Electronic address: j.m.boer@erasmusmc.nl. [Ti] Título: BCR-ABL1-like acute lymphoblastic leukaemia: From bench to bedside. [So] Source: Eur J Cancer;82:203-218, 2017 Sep. [Is] ISSN: 1879-0852 [Cp] País de publicação: England [La] Idioma: eng [Ab] Resumo: Acute lymphoblastic leukaemia (ALL) occurs in approximately 1:1500 children and is less frequently found in adults. The most common immunophenotype of ALL is the B cell lineage and within B cell precursor ALL, specific genetic aberrations define subtypes with distinct biological and clinical characteristics. With more advanced genetic analysis methods such as whole genome and transcriptome sequencing, novel genetic subtypes have recently been discovered. One novel class of genetic aberrations comprises tyrosine kinase-activating lesions, including translocations and rearrangements of tyrosine kinase and cytokine receptor genes. These newly discovered genetic aberrations are harder to detect by standard diagnostic methods such as karyotyping, fluorescent in situ hybridisation (FISH) or polymerase chain reaction (PCR) because they are diverse and often cryptic. These lesions involve one of several tyrosine kinase genes (among others, v-abl Abelson murine leukaemia viral oncogene homologue 1 (ABL1), v-abl Abelson murine leukaemia viral oncogene homologue 2 (ABL2), platelet-derived growth factor receptor beta polypeptide (PDGFRB)), each of which can be fused to up to 15 partner genes. Together, they compose 2-3% of B cell precursor ALL (BCP-ALL), which is similar in size to the well-known fusion gene BCR-ABL1 subtype. These so-called BCR-ABL1-like fusions are mutually exclusive with the sentinel translocations in BCP-ALL (BCR-ABL1, ETV6-RUNX1, TCF3-PBX1, and KMT2A (MLL) rearrangements) and have the promising prospect to be sensitive to tyrosine kinase inhibitors similar to BCR-ABL1. In this review, we discuss the types of tyrosine kinase-activating lesions discovered, and the preclinical and clinical evidence for the use of tyrosine kinase inhibitors in the treatment of this novel subtype of ALL. [Mh] Termos MeSH primário: Proteínas de Fusão bcr-abl/genética Terapia de Alvo Molecular/métodos Leucemia-Linfoma Linfoblástico de Células Precursoras Inibidores de Proteínas Quinases/uso terapêutico [Mh] Termos MeSH secundário: Antineoplásicos Seres Humanos Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico Leucemia-Linfoma Linfoblástico de Células Precursoras/genética Proteínas Tirosina Quinases/antagonistas & inibidores Proteínas Tirosina Quinases/metabolismo Receptores de Citocinas/metabolismo [Pt] Tipo de publicação: JOURNAL ARTICLE; REVIEW [Nm] Nome de substância: 0 (Antineoplastic Agents); 0 (Protein Kinase Inhibitors); 0 (Receptors, Cytokine); EC 2.7.10.1 (Protein-Tyrosine Kinases); EC 2.7.10.2 (Fusion Proteins, bcr-abl) [Em] Mês de entrada: 1709 [Cu] Atualização por classe: 170907 [Lr] Data última revisão: 170907 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 170715 [St] Status: MEDLINE

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[PMID]: 28701507 [Au] Autor: Han M; Rajput C; Hong JY; Lei J; Hinde JL; Wu Q; Bentley JK; Hershenson MB [Ad] Endereço: Department of Pediatrics and Communicable Diseases, University of Michigan Medical School, Ann Arbor, MI 48109; and. [Ti] Título: The Innate Cytokines IL-25, IL-33, and TSLP Cooperate in the Induction of Type 2 Innate Lymphoid Cell Expansion and Mucous Metaplasia in Rhinovirus-Infected Immature Mice. [So] Source: J Immunol;199(4):1308-1318, 2017 Aug 15. [Is] ISSN: 1550-6606 [Cp] País de publicação: United States [La] Idioma: eng [Ab] Resumo: Early-life respiratory viral infection is a risk factor for asthma development. Rhinovirus (RV) infection of 6-d-old mice, but not mature mice, causes mucous metaplasia and airway hyperresponsiveness that are associated with the expansion of lung type 2 innate lymphoid cells (ILC2s) and are dependent on IL-13 and the innate cytokine IL-25. However, contributions of the other innate cytokines, IL-33 and thymic stromal lymphopoietin (TSLP), to the observed asthma-like phenotype have not been examined. We reasoned that IL-33 and TSLP expression are also induced by RV infection in immature mice and are required for maximum ILC2 expansion and mucous metaplasia. We inoculated 6-d-old BALB/c (wild-type) and TSLP receptor-knockout mice with sham HeLa cell lysate or RV. Selected mice were treated with neutralizing Abs to IL-33 or recombinant IL-33, IL-25, or TSLP. ILC2s were isolated from RV-infected immature mice and treated with innate cytokines ex vivo. RV infection of 6-d-old mice increased IL-33 and TSLP protein abundance. TSLP expression was localized to the airway epithelium, whereas IL-33 was expressed in epithelial and subepithelial cells. RV-induced mucous metaplasia, ILC2 expansion, airway hyperresponsiveness, and epithelial cell IL-25 expression were attenuated by anti-IL-33 treatment and in TSLP receptor-knockout mice. Administration of intranasal IL-33 and TSLP was sufficient for mucous metaplasia. Finally, TSLP was required for maximal ILC2 gene expression in response to IL-25 and IL-33. The generation of mucous metaplasia in immature RV-infected mice involves a complex interplay among the innate cytokines IL-25, IL-33, and TSLP. [Mh] Termos MeSH primário: Citocinas/imunologia Interleucina-33/imunologia Interleucinas/imunologia Ativação Linfocitária Linfócitos/fisiologia Metaplasia/imunologia Infecções por Picornaviridae/imunologia Rhinovirus/imunologia [Mh] Termos MeSH secundário: Fatores Etários Animais Asma/imunologia Asma/virologia Citocinas/genética Células Epiteliais/imunologia Células Epiteliais/metabolismo Células Epiteliais/virologia Imunoglobulinas/genética Imunoglobulinas/imunologia Imunoglobulinas/metabolismo Interleucina-33/genética Interleucinas/genética Linfócitos/imunologia Metaplasia/patologia Metaplasia/virologia Camundongos Camundongos Knockout Membrana Mucosa/imunologia Membrana Mucosa/patologia Infecções por Picornaviridae/virologia Receptores de Citocinas/genética Receptores de Citocinas/imunologia Receptores de Citocinas/metabolismo Hipersensibilidade Respiratória/imunologia Hipersensibilidade Respiratória/metabolismo Hipersensibilidade Respiratória/virologia [Pt] Tipo de publicação: JOURNAL ARTICLE [Nm] Nome de substância: 0 (Cytokines); 0 (D17Wsu104e protein, mouse); 0 (Il33 protein, mouse); 0 (Immunoglobulins); 0 (Interleukin-33); 0 (Interleukins); 0 (Receptors, Cytokine); 0 (Tslpr protein, mouse); 0 (thymic stromal lymphopoietin) [Em] Mês de entrada: 1710 [Cu] Atualização por classe: 171016 [Lr] Data última revisão: 171016 [Sb] Subgrupo de revista: AIM; IM [Da] Data de entrada para processamento: 170714 [St] Status: MEDLINE [do] DOI: 10.4049/jimmunol.1700216

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[PMID]: 28640909 [Au] Autor: Carvallo L; Lopez L; Fajardo JE; Jaureguiberry-Bravo M; Fiser A; Berman JW [Ad] Endereço: Department of Pathology, Albert Einstein College of Medicine, Bronx, New York, United States of America. [Ti] Título: HIV-Tat regulates macrophage gene expression in the context of neuroAIDS. [So] Source: PLoS One;12(6):e0179882, 2017. [Is] ISSN: 1932-6203 [Cp] País de publicação: United States [La] Idioma: eng [Ab] Resumo: Despite the success of cART, greater than 50% of HIV infected people develop cognitive and motor deficits termed HIV-associated neurocognitive disorders (HAND). Macrophages are the major cell type infected in the CNS. Unlike for T cells, the virus does not kill macrophages and these long-lived cells may become HIV reservoirs in the brain. They produce cytokines/chemokines and viral proteins that promote inflammation and neuronal damage, playing a key role in HIV neuropathogenesis. HIV Tat is the transactivator of transcription that is essential for replication and transcriptional regulation of the virus and is the first protein to be produced after HIV infection. Even with successful cART, Tat is produced by infected cells. In this study we examined the role of the HIV Tat protein in the regulation of gene expression in human macrophages. Using THP-1 cells, a human monocyte/macrophage cell line, and their infection with lentivirus, we generated stable cell lines that express Tat-Flag. We performed ChIP-seq analysis of these cells and found 66 association sites of Tat in promoter or coding regions. Among these are C5, CRLF2/TSLPR, BDNF, and APBA1/Mint1, genes associated with inflammation/damage. We confirmed the association of Tat with these sequences by ChIP assay and expression of these genes in our THP-1 cell lines by qRT-PCR. We found that HIV Tat increased expression of C5, APBA1, and BDNF, and decreased CRLF2. The K50A Tat-mutation dysregulated expression of these genes without affecting the binding of the Tat complex to their gene sequences. Our data suggest that HIV Tat, produced by macrophage HIV reservoirs in the brain despite successful cART, contributes to neuropathogenesis in HIV-infected people. [Mh] Termos MeSH primário: Complexo AIDS Demência/imunologia Regulação da Expressão Gênica Macrófagos/metabolismo Produtos do Gene tat do Vírus da Imunodeficiência Humana/metabolismo [Mh] Termos MeSH secundário: Complexo AIDS Demência/metabolismo Proteínas Adaptadoras de Transdução de Sinal/metabolismo Substituição de Aminoácidos Fator Neurotrófico Derivado do Encéfalo/metabolismo Diferenciação Celular Linhagem Celular Complemento C5/metabolismo Seres Humanos Macrófagos/citologia Macrófagos/virologia Proteínas do Tecido Nervoso/metabolismo Receptores de Citocinas/metabolismo Produtos do Gene tat do Vírus da Imunodeficiência Humana/química Produtos do Gene tat do Vírus da Imunodeficiência Humana/genética [Pt] Tipo de publicação: JOURNAL ARTICLE [Nm] Nome de substância: 0 (APBA1 protein, human); 0 (Adaptor Proteins, Signal Transducing); 0 (Brain-Derived Neurotrophic Factor); 0 (CRLF2 protein, human); 0 (Complement C5); 0 (Nerve Tissue Proteins); 0 (Receptors, Cytokine); 0 (tat Gene Products, Human Immunodeficiency Virus) [Em] Mês de entrada: 1709 [Cu] Atualização por classe: 170918 [Lr] Data última revisão: 170918 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 170623 [St] Status: MEDLINE [do] DOI: 10.1371/journal.pone.0179882

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[PMID]: 28605290 [Au] Autor: Bond J; Graux C; Lhermitte L; Lara D; Cluzeau T; Leguay T; Cieslak A; Trinquand A; Pastoret C; Belhocine M; Spicuglia S; Lheritier V; Leprêtre S; Thomas X; Huguet F; Ifrah N; Dombret H; Macintyre E; Boissel N; Asnafi V [Ad] Endereço: Jonathan Bond, Ludovic Lhermitte, Agata Cieslak, Amélie Trinquand, Elizabeth Macintyre, and Vahid Asnafi, Hôpital Necker-Enfants Malades; Jonathan Bond, Ludovic Lhermitte, Agata Cieslak, Amélie Trinquand, Elizabeth Macintyre, and Vahid Asnafi, Institut National de la santé et de la recherche médical [Ti] Título: Early Response-Based Therapy Stratification Improves Survival in Adult Early Thymic Precursor Acute Lymphoblastic Leukemia: A Group for Research on Adult Acute Lymphoblastic Leukemia Study. [So] Source: J Clin Oncol;35(23):2683-2691, 2017 Aug 10. [Is] ISSN: 1527-7755 [Cp] País de publicação: United States [La] Idioma: eng [Ab] Resumo: Purpose Early thymic precursor (ETP) acute lymphoblastic leukemia (ALL) is an immunophenotypically defined subgroup of T-cell ALL (T-ALL) associated with high rates of intrinsic treatment resistance. Studies in children have shown that the negative prognostic impact of chemotherapy resistance is abrogated by the implementation of early response-based intensification strategies. Comparable data in adults are lacking. Patients and Methods We performed comprehensive clinicobiologic, genetic, and survival analyses of a large cohort of 213 adult patients with T-ALL, including 47 patients with ETP-ALL, treated in the GRAALL (Group for Research on Adult Acute Lymphoblastic Leukemia) -2003 and -2005 studies. Results Targeted next-generation sequencing revealed that the genotype of immunophenotypically defined adult T-ALL is similar to the pediatric equivalent, with high rates of mutations in factors involved in cytokine receptor and RAS signaling (62.2%), hematopoietic development (29.7%), and chemical modification of histones (48.6%). In contrast to pediatric cases, mutations in DNA methylation factor genes were also common (32.4%). We found that despite expected high levels of early bone marrow chemotherapy resistance (87%), the overall prognosis for adults with ETP-ALL treated using the GRAALL protocols was not inferior to that of the non-ETP-ALL group (5-year overall survival: ETP, 59.6%; 95% CI, 44.2% to 72.0% v non-ETP, 66.5%; 95% CI, 58.7% to 73.2%; P = 0.33) and that allogeneic stem-cell transplantation had a beneficial effect in a large proportion of patients with ETP-ALL. Conclusion Our results suggest that the use of response-based risk stratification and therapy intensification abrogates the poor prognosis of adult ETP-ALL. [Mh] Termos MeSH primário: Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem Transplante de Células-Tronco Hematopoéticas Leucemia-Linfoma Linfoblástico de Células T Precursoras/genética Leucemia-Linfoma Linfoblástico de Células T Precursoras/terapia Neoplasias do Timo/genética Neoplasias do Timo/terapia [Mh] Termos MeSH secundário: Adulto Ciclofosfamida/administração & dosagem Metilação de DNA/genética Análise Mutacional de DNA Resistência a Medicamentos Antineoplásicos Feminino Genótipo Hematopoese/genética Histonas/química Seres Humanos Imunofenotipagem Masculino Prognóstico Receptores de Citocinas/genética Transdução de Sinais/genética Taxa de Sobrevida Transplante Homólogo Proteínas ras/genética Proteínas ras/metabolismo [Pt] Tipo de publicação: CLINICAL TRIAL, PHASE II; CLINICAL TRIAL, PHASE III; JOURNAL ARTICLE; MULTICENTER STUDY; RANDOMIZED CONTROLLED TRIAL [Nm] Nome de substância: 0 (Histones); 0 (Receptors, Cytokine); 8N3DW7272P (Cyclophosphamide); EC 3.6.5.2 (ras Proteins) [Em] Mês de entrada: 1709 [Cu] Atualização por classe: 170908 [Lr] Data última revisão: 170908 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 170613 [St] Status: MEDLINE [do] DOI: 10.1200/JCO.2016.71.8585

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[PMID]: 28557976 [Au] Autor: Forero-Castro M; Robledo C; Benito R; Bodega-Mayor I; Rapado I; Hernández-Sánchez M; Abáigar M; Maria Hernández-Sánchez J; Quijada-Álamo M; María Sánchez-Pina J; Sala-Valdés M; Araujo-Silva F; Kohlmann A; Luis Fuster J; Arefi M; de Las Heras N; Riesco S; Rodríguez JN; Hermosín L; Ribera J; Camos Guijosa M; Ramírez M; de Heredia Rubio CD; Barragán E; Martínez J; Ribera JM; Fernández-Ruiz E; Hernández-Rivas JM [Ad] Endereço: IBSAL, IBMCC, University of Salamanca, CSIC, Cancer Research Center, Campus Miguel de Unamuno, Salamanca 37007, Spain. [Ti] Título: Mutations in TP53 and JAK2 are independent prognostic biomarkers in B-cell precursor acute lymphoblastic leukaemia. [So] Source: Br J Cancer;117(2):256-265, 2017 Jul 11. [Is] ISSN: 1532-1827 [Cp] País de publicação: England [La] Idioma: eng [Ab] Resumo: BACKGROUND: In B-cell precursor acute lymphoblastic leukaemia (B-ALL), the identification of additional genetic alterations associated with poor prognosis is still of importance. We determined the frequency and prognostic impact of somatic mutations in children and adult cases with B-ALL treated with Spanish PETHEMA and SEHOP protocols. METHODS: Mutational status of hotspot regions of TP53, JAK2, PAX5, LEF1, CRLF2 and IL7R genes was determined by next-generation deep sequencing in 340 B-ALL patients (211 children and 129 adults). The associations between mutation status and clinicopathological features at the time of diagnosis, treatment outcome and survival were assessed. Univariate and multivariate survival analyses were performed to identify independent prognostic factors associated with overall survival (OS), event-free survival (EFS) and relapse rate (RR). RESULTS: A mutation rate of 12.4% was identified. The frequency of adult mutations was higher (20.2% vs 7.6%, P=0.001). TP53 was the most frequently mutated gene (4.1%), followed by JAK2 (3.8%), CRLF2 (2.9%), PAX5 (2.4%), LEF1 (0.6%) and IL7R (0.3%). All mutations were observed in B-ALL without ETV6-RUNX1 (P=0.047) or BCR-ABL1 fusions (P<0.0001). In children, TP53mut was associated with lower OS (5-year OS: 50% vs 86%, P=0.002) and EFS rates (5-year EFS: 50% vs 78.3%, P=0.009) and higher RR (5-year RR: 33.3% vs 18.6% P=0.037), and was independently associated with higher RR (hazard ratio (HR)=4.5; P=0.04). In adults, TP53mut was associated with a lower OS (5-year OS: 0% vs 43.3%, P=0.019) and a higher RR (5-year RR: 100% vs 61.4%, P=0.029), whereas JAK2mut was associated with a lower EFS (5-year EFS: 0% vs 30.6%, P=0.035) and a higher RR (5-year RR: 100% vs 60.4%, P=0.002). TP53mut was an independent risk factor for shorter OS (HR=2.3; P=0.035) and, together with JAK2mut, also were independent markers of poor prognosis for RR (TP53mut: HR=5.9; P=0.027 and JAK2mut: HR=5.6; P=0.036). CONCLUSIONS: TP53mut and JAK2mut are potential biomarkers associated with poor prognosis in B-ALL patients. [Mh] Termos MeSH primário: Biomarcadores Tumorais/genética Janus Quinase 2/genética Leucemia-Linfoma Linfoblástico de Células Precursoras/genética Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia Proteína Supressora de Tumor p53/genética [Mh] Termos MeSH secundário: Adolescente Adulto Idoso Idoso de 80 Anos ou mais Linfócitos B/patologia Criança Pré-Escolar Intervalo Livre de Doença Feminino Regulação Neoplásica da Expressão Gênica Sequenciamento de Nucleotídeos em Larga Escala Seres Humanos Lactente Masculino Meia-Idade Mutação Leucemia-Linfoma Linfoblástico de Células Precursoras/patologia Prognóstico Receptores de Citocinas/biossíntese Resultado do Tratamento [Pt] Tipo de publicação: JOURNAL ARTICLE [Nm] Nome de substância: 0 (Biomarkers, Tumor); 0 (CRLF2 protein, human); 0 (Receptors, Cytokine); 0 (TP53 protein, human); 0 (Tumor Suppressor Protein p53); EC 2.7.10.2 (JAK2 protein, human); EC 2.7.10.2 (Janus Kinase 2) [Em] Mês de entrada: 1708 [Cu] Atualização por classe: 170817 [Lr] Data última revisão: 170817 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 170531 [St] Status: MEDLINE [do] DOI: 10.1038/bjc.2017.152

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