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[PMID]: 29331379 [Au] Autor: Shinagawa-Kobayashi Y; Kamimura K; Goto R; Ogawa K; Inoue R; Yokoo T; Sakai N; Nagoya T; Sakamaki A; Abe S; Sugitani S; Yanagi M; Fujisawa K; Nozawa Y; Koyama N; Nishina H; Furutani-Seiki M; Sakaida I; Terai S [Ad] Endereço: Division of Gastroenterology and Hepatology, Graduate School of Medical and Dental Sciences, Niigata University, Niigata, Niigata, Japan. [Ti] Título: Effect of histidine on sorafenib-induced vascular damage: Analysis using novel medaka fish model. [So] Source: Biochem Biophys Res Commun;496(2):556-561, 2018 02 05. [Is] ISSN: 1090-2104 [Cp] País de publicação: United States [La] Idioma: eng [Ab] Resumo: BACKGROUND: Sorafenib (SFN) is an anti-angiogenic chemotherapeutic that prolongs survival of patients with hepatocellular carcinoma (HCC); its side effects, including vascular damages such as hand-foot syndrome (HFS), are a major cause of therapy discontinuation. We previously reported that maintenance of peripheral blood flow by intake of dried bonito broth (DBB) significantly prevented HFS and prolonged the administration period. The amino acids contained in DBB probably contribute to its effects, but the mechanism has not been clarified. We hypothesized that histidine, the largest component among the amino acids contained in DBB, has effects on SFN-induced vascular damage, and evaluated this possibility using a novel medaka fish model. METHODS: The fli::GFP transgenic medaka fish model has a fluorescently visible systemic vasculature. We fed the fish with SFN with and without histidine to compare blood flow and vascular structure among the differently fed models. The vascular cross-sectional area of each fish was measured to determine vascular diameter changes. RESULTS: Our results demonstrated that SFN-fed medaka developed a narrower vascular diameter. In addition, this narrowing was counteracted by addition of histidine to the medaka diet. We observed no positive effect of histidine on regeneration of cut vessels or on cell growth of endothelial cells and HCC cell lines. CONCLUSION: We proved the efficacy of the medaka model to assess vascular changes after administration of specific chemicals. And our results suggest that SFN causes vascular damage by narrowing peripheral vessel diameter, and that histidine effectively counteracts these changes to maintain blood flow. [Mh] Termos MeSH primário: Antineoplásicos/efeitos adversos Velocidade do Fluxo Sanguíneo/efeitos dos fármacos Vasos Sanguíneos/efeitos dos fármacos Vasos Sanguíneos/patologia Histidina/farmacologia Niacinamida/análogos & derivados Compostos de Fenilureia/efeitos adversos [Mh] Termos MeSH secundário: Animais Carcinoma Hepatocelular/tratamento farmacológico Seres Humanos Neoplasias Hepáticas/tratamento farmacológico Niacinamida/efeitos adversos Oryzias [Pt] Tipo de publicação: JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T [Nm] Nome de substância: 0 (Antineoplastic Agents); 0 (Phenylurea Compounds); 25X51I8RD4 (Niacinamide); 4QD397987E (Histidine); 9ZOQ3TZI87 (sorafenib) [Em] Mês de entrada: 1803 [Cu] Atualização por classe: 180309 [Lr] Data última revisão: 180309 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 180115 [St] Status: MEDLINE

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[PMID]: 29249005 [Au] Autor: Trevisani F; Brandi G; Garuti F; Barbera MA; Tortora R; Casadei Gardini A; Granito A; Tovoli F; De Lorenzo S; Inghilesi AL; Foschi FG; Bernardi M; Marra F; Sacco R; Di Costanzo GG [Ad] Endereço: Department of Medical and Surgical Sciences, Medical Semeiotics, University of Bologna, via Albertoni 15, 40138, Bologna, Italy. franco.trevisani@unibo.it. [Ti] Título: Metronomic capecitabine as second-line treatment for hepatocellular carcinoma after sorafenib discontinuation. [So] Source: J Cancer Res Clin Oncol;144(2):403-414, 2018 Feb. [Is] ISSN: 1432-1335 [Cp] País de publicação: Germany [La] Idioma: eng [Ab] Resumo: PURPOSE: Metronomic capecitabine (MC) is a well-tolerated systemic treatment showing promising results in one retrospective study, as second-line therapy after sorafenib failure, in patients with hepatocellular carcinoma (HCC). METHODS: 117 patients undergoing MC were compared to 112 patients, eligible for this treatment, but undergoing best supportive care (BSC) after sorafenib discontinuation for toxicity or HCC progression. The two groups were compared for demographic and clinical features. A multivariate regression analysis was conducted to detect independent prognostic factors. To balance confounding factors between the two groups, a propensity score model based on independent prognosticators (performance status, neoplastic thrombosis, causes of sorafenib discontinuation and pre-sorafenib treatment) was performed. RESULTS: Patients undergoing MC showed better performance status, lower tumor burden, lower prevalence of portal vein thrombosis, and better cancer stage. Median (95% CI) post-sorafenib survival (PSS) was longer in MC than in BSC patients [9.5 (7.5-11.6) vs 5.0 (4.2-5.7) months (p < 0.001)]. Neoplastic thrombosis, cause of sorafenib discontinuation, pre-sorafenib treatment and MC were independent prognosticators. The benefit of capecitabine was confirmed in patients after matching with propensity score [PSS: 9.9 (6.8-12.9) vs. 5.8 (4.8-6.8) months, (p = 0.001)]. MC lowered the mortality risk by about 40%. MC achieved better results in patients who stopped sorafenib for adverse events than in those who progressed during it [PSS: 17.3 (10.5-24.1) vs. 7.8 (5.2-10.1) months, (p = 0.035)]. Treatment toxicity was low and easily manageable with dose modulation. CONCLUSIONS: MC may be an efficient and safe second-line systemic therapy for HCC patients who discontinued sorafenib for toxicity or tumor progression. [Mh] Termos MeSH primário: Capecitabina/administração & dosagem Carcinoma Hepatocelular/tratamento farmacológico Neoplasias Hepáticas/tratamento farmacológico Niacinamida/análogos & derivados Compostos de Fenilureia/administração & dosagem [Mh] Termos MeSH secundário: Administração Metronômica Idoso Antimetabólitos Antineoplásicos/administração & dosagem Feminino Seres Humanos Masculino Niacinamida/administração & dosagem Niacinamida/efeitos adversos Compostos de Fenilureia/efeitos adversos Inibidores de Proteínas Quinases/administração & dosagem Inibidores de Proteínas Quinases/efeitos adversos Estudos Retrospectivos Taxa de Sobrevida [Pt] Tipo de publicação: JOURNAL ARTICLE [Nm] Nome de substância: 0 (Antimetabolites, Antineoplastic); 0 (Phenylurea Compounds); 0 (Protein Kinase Inhibitors); 25X51I8RD4 (Niacinamide); 6804DJ8Z9U (Capecitabine); 9ZOQ3TZI87 (sorafenib) [Em] Mês de entrada: 1803 [Cu] Atualização por classe: 180308 [Lr] Data última revisão: 180308 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 171218 [St] Status: MEDLINE [do] DOI: 10.1007/s00432-017-2556-6

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[PMID]: 27771613 [Au] Autor: Gyawali B; Shimokata T; Ando M; Honda K; Ando Y [Ad] Endereço: Department of Clinical Oncology and Chemotherapy, Nagoya University Graduate School of Medicine, Nagoya. [Ti] Título: Risk of serious adverse events and fatal adverse events with sorafenib in patients with solid cancer: a meta-analysis of phase 3 randomized controlled trials†. [So] Source: Ann Oncol;28(2):246-253, 2017 02 01. [Is] ISSN: 1569-8041 [Cp] País de publicação: England [La] Idioma: eng [Ab] Resumo: Background: Sorafenib is a multikinase-tyrosine kinase inhibitor commonly used in a variety of cancers. There are concerns about the increased risk of serious adverse events (SAEs) and fatal adverse events (FAEs) with sorafenib. We performed an up-to-date meta-analysis of all phase 3 randomized controlled trials (RCTs) of sorafenib to quantify the increased risk of SAEs and FAEs. Patients and methods: We carried out a systematic search of electronic databases for studies published from inception to February 2016 without any restrictions. Eligibility criteria included phase 3 RCTs of solid tumors comparing sorafenib, alone or in combination with nontargeted chemotherapy (Sorafenib arm) versus placebo or nontargeted chemotherapy (control arm). Data on SAEs and FAEs for both the arms were extracted from each study and pooled to determine the overall incidence, relative risks (RRs) and 95% Confidence Intervals (CIs). Results: Of 471 studies identified, a total of 12 phase 3 RCTs involving 6797 solid cancer patients comparing sorafenib with control met the eligibility criteria and were included. The overall incidence of SAEs and FAEs with sorafenib were 26.4% (95% CI, 18.0-36.9%) and 1.3% (95% CI: 0.8-2.2%), respectively. Compared with control, sorafenib use significantly increased the risk of both SAEs (RR: 1.49, 95% CI: 1.18-1.89, P = 0.001) and FAEs (RR: 1.82, 95% CI: 1.05-3.14, P = 0.033). This association varied significantly with cancer types (P < 0.001) and approval status (P = 0.012) for SAEs but no evidence of heterogeneity was found for FAEs. Conclusions: This meta-analysis of phase 3 RCTs demonstrates an increased risk of both SAEs and FAEs with sorafenib use in adult patients with solid cancers. This quantification of increased risks of SAEs and FAEs will be important in considering the trade-off of sorafenib treatment during shared decision-making. [Mh] Termos MeSH primário: Antineoplásicos/efeitos adversos Neoplasias/tratamento farmacológico Niacinamida/análogos & derivados Compostos de Fenilureia/efeitos adversos [Mh] Termos MeSH secundário: Ensaios Clínicos Fase III como Assunto Seres Humanos Neoplasias/mortalidade Niacinamida/efeitos adversos Modelos de Riscos Proporcionais Risco [Pt] Tipo de publicação: JOURNAL ARTICLE; META-ANALYSIS; RESEARCH SUPPORT, NON-U.S. GOV'T [Nm] Nome de substância: 0 (Antineoplastic Agents); 0 (Phenylurea Compounds); 25X51I8RD4 (Niacinamide); 9ZOQ3TZI87 (sorafenib) [Em] Mês de entrada: 1712 [Cu] Atualização por classe: 180308 [Lr] Data última revisão: 180308 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 161025 [St] Status: MEDLINE [do] DOI: 10.1093/annonc/mdw549

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[PMID]: 28746590 [Au] Autor: Campregher PV; Mattos VRP; Salvino MA; Santos FPS; Hamerschlak N [Ad] Endereço: Hospital Israelita Albert Einstein, São Paulo, SP, Brazil. [Ti] Título: Successful treatment of post-transplant relapsed acute myeloid leukemia with FLT3 internal tandem duplication using the combination of induction chemotherapy, donor lymphocyte infusion, sorafenib and azacitidine. Report of three cases. [So] Source: Einstein (Sao Paulo);15(3):355-358, 2017 Jul-Sep. [Is] ISSN: 2317-6385 [Cp] País de publicação: Brazil [La] Idioma: eng; por [Ab] Resumo: Acute myeloid leukemia is a hematopoietic stem cell neoplastic disease associated with high morbidity and mortality. The presence of FLT3 internal tandem duplication mutations leads to high rates of relapse and decreased overall survival. Patients with FLT3 internal tandem duplication are normally treated with hematopoietic stem cell transplantation in first complete remission. Nevertheless, the incidence of post-transplant relapse is considerable in this group of patients, and the management of this clinical condition is challenging. The report describes the outcomes of patients with FLT3 internal tandem duplication positive acute myeloid leukemia who relapsed after allogeneic hematopoietic stem cell transplantation and were treated with the combination of re-induction chemotherapy, donor lymphocyte infusion, sorafenib and azacitidine. Three cases are described and all patients achieved prolonged complete remission with the combined therapy. The combination of induction chemotherapy followed by donor lymphocyte infusion, and the maintenance with azacitidine and sorafenib can be effective approaches in the treatment of post-hematopoietic stem cell transplant and relapsed FLT3 internal tandem duplication positive acute myeloid leukemia patients. This strategy should be further explored in the context of clinical trials. [Mh] Termos MeSH primário: Antineoplásicos/administração & dosagem Azacitidina/administração & dosagem Quimioterapia de Indução Leucemia Mieloide Aguda/terapia Transfusão de Linfócitos Niacinamida/análogos & derivados Compostos de Fenilureia/administração & dosagem Tirosina Quinase 3 Semelhante a fms/genética [Mh] Termos MeSH secundário: Adulto Idoso Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico Terapia Combinada/métodos Feminino Seres Humanos Leucemia Mieloide Aguda/genética Masculino Meia-Idade Recidiva Local de Neoplasia/terapia Niacinamida/administração & dosagem Recidiva Resultado do Tratamento [Pt] Tipo de publicação: CASE REPORTS [Nm] Nome de substância: 0 (Antineoplastic Agents); 0 (Phenylurea Compounds); 25X51I8RD4 (Niacinamide); 9ZOQ3TZI87 (sorafenib); EC 2.7.10.1 (FLT3 protein, human); EC 2.7.10.1 (fms-Like Tyrosine Kinase 3); M801H13NRU (Azacitidine) [Em] Mês de entrada: 1712 [Cu] Atualização por classe: 180227 [Lr] Data última revisão: 180227 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 170727 [St] Status: MEDLINE

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[PMID]: 28470518 [Au] Autor: Chen D; Eyupoglu IY; Savaskan N [Ad] Endereço: Translational Cell Biology and Neurooncology Laboratory of the Universitätsklinikum Erlangen (UKER), Friedrich-Alexander University of Erlangen - Nürnberg (FAU), and Department of Neurosurgery of the Universitätsklinikum Erlangen, Universitätsklinikum Erlangen (UKER), Friedrich-Alexander University [Ti] Título: Ferroptosis and Cell Death Analysis by Flow Cytometry. [So] Source: Methods Mol Biol;1601:71-77, 2017. [Is] ISSN: 1940-6029 [Cp] País de publicação: United States [La] Idioma: eng [Ab] Resumo: Cell death and its recently discovered regulated form ferroptosis are characterized by distinct morphological, electrophysiological, and pharmacological features. In particular ferroptosis can be induced by experimental compounds and clinical drugs (i.e., erastin, sulfasalazine, sorafenib, and artesunate) in various cell types and cancer cells. Pharmacologically, this cell death process can be inhibited by iron chelators and lipid peroxidation inhibitors. Relevance of this specific cell death form has been found in different pathological conditions such as cancer, neurotoxicity, neurodegeneration, and ischemia. Distinguishing cell viability and cell death is essential for experimental and clinical applications and a key component in flow cytometry experiments. Dead cells can compromise the integrity of the data by nonspecific binding of antibodies and dyes. Therefore it is essential that dead cells are robustly and reproducibly identified and characterized by means of cytometry application. Here we describe a procedure to detect and quantify cell death and its specific form ferroptosis based on standard flow cytometry techniques. [Mh] Termos MeSH primário: Apoptose/efeitos dos fármacos Citometria de Fluxo/métodos Ferro/metabolismo [Mh] Termos MeSH secundário: Animais Antineoplásicos/farmacologia Linhagem Celular Tumoral Sobrevivência Celular/efeitos dos fármacos Dactinomicina/análogos & derivados Dactinomicina/química Seres Humanos Indicadores e Reagentes/química Necrose Niacinamida/análogos & derivados Niacinamida/farmacologia Compostos de Fenilureia/farmacologia Piperazinas/farmacologia Propídio/química Ratos [Pt] Tipo de publicação: JOURNAL ARTICLE [Nm] Nome de substância: 0 (Antineoplastic Agents); 0 (Indicators and Reagents); 0 (Phenylurea Compounds); 0 (Piperazines); 0 (erastin); 1CC1JFE158 (Dactinomycin); 25X51I8RD4 (Niacinamide); 36015-30-2 (Propidium); 7240-37-1 (7-aminoactinomycin D); 9ZOQ3TZI87 (sorafenib); E1UOL152H7 (Iron) [Em] Mês de entrada: 1802 [Cu] Atualização por classe: 180219 [Lr] Data última revisão: 180219 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 170505 [St] Status: MEDLINE [do] DOI: 10.1007/978-1-4939-6960-9_6

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[PMID]: 28675895 [Au] Autor: Labenz C; Prenosil V; Koch S; Huber Y; Marquardt JU; Schattenberg JM; Galle PR; Weinmann A; Wörns MA [Ad] Endereço: Department of Internal Medicine I, University Medical Center of the Johannes Gutenberg-University, Mainz, Germany. [Ti] Título: Impact of Individual Components of the Metabolic Syndrome on the Outcome of Patients with Advanced Hepatocellular Carcinoma Treated with Sorafenib. [So] Source: Dig Dis;36(1):78-88, 2018. [Is] ISSN: 1421-9875 [Cp] País de publicação: Switzerland [La] Idioma: eng [Ab] Resumo: BACKGROUND/AIM: Individual components of the metabolic syndrome (MS) such as obesity or diabetes mellitus impair the prognosis of patients with hepatocellular carcinoma (HCC) following curative treatment approaches or transarterial therapies. The aim of this retrospective study was to assess the impact of these factors on the overall survival (OS) of patients with advanced HCC treated with sorafenib. METHODS: Univariate and multivariate analyses were performed to assess the impact of individual components of the MS on the OS of 152 consecutive patients with advanced HCC treated with sorafenib. RESULTS: The presence of overweight/obesity, type 2 diabetes mellitus, hypertension, dyslipidemia, and of the MS itself did not impair the median OS. Multivariate analysis showed that Eastern Cooperative Oncology Group Performance Status ≥1 (hazards ratio [HR] 2.03), presence of macrovascular invasion (HR 1.71), Child-Pugh score B/C (HR 2.19), tumor grading G3 (HR 2.17), no prior HCC treatment (HR 2.34), and the presence of 2 or more out of 5 individual components of the MS (HR 0.65) were independent prognostic factors regarding the median OS. CONCLUSIONS: Our investigations do not confirm a negative prognostic role of individual components of the MS or the MS itself for patients with advanced HCC treated with sorafenib. [Mh] Termos MeSH primário: Carcinoma Hepatocelular/complicações Carcinoma Hepatocelular/tratamento farmacológico Neoplasias Hepáticas/complicações Neoplasias Hepáticas/tratamento farmacológico Síndrome Metabólica/complicações Niacinamida/análogos & derivados Compostos de Fenilureia/uso terapêutico [Mh] Termos MeSH secundário: Adulto Idoso Idoso de 80 Anos ou mais Antineoplásicos/uso terapêutico Carcinoma Hepatocelular/patologia Diabetes Mellitus Tipo 2/complicações Feminino Seres Humanos Neoplasias Hepáticas/patologia Masculino Meia-Idade Análise Multivariada Estadiamento de Neoplasias Niacinamida/uso terapêutico Prognóstico Modelos de Riscos Proporcionais Estudos Retrospectivos Análise de Sobrevida Resultado do Tratamento Adulto Jovem [Pt] Tipo de publicação: JOURNAL ARTICLE [Nm] Nome de substância: 0 (Antineoplastic Agents); 0 (Phenylurea Compounds); 25X51I8RD4 (Niacinamide); 9ZOQ3TZI87 (sorafenib) [Em] Mês de entrada: 1802 [Cu] Atualização por classe: 180216 [Lr] Data última revisão: 180216 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 170705 [St] Status: MEDLINE [do] DOI: 10.1159/000477578

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[PMID]: 29304116 [Au] Autor: Lange A; Jaskula E; Lange J; Dworacki G; Nowak D; Simiczyjew A; Mordak-Domagala M; Sedzimirska M [Ad] Endereço: L. Hirszfeld Institute of Immunology and Experimental Therapy, Polish Academy of Sciences, Wroclaw, Poland. [Ti] Título: The sorafenib anti-relapse effect after alloHSCT is associated with heightened alloreactivity and accumulation of CD8+PD-1+ (CD279+) lymphocytes in marrow. [So] Source: PLoS One;13(1):e0190525, 2018. [Is] ISSN: 1932-6203 [Cp] País de publicação: United States [La] Idioma: eng [Ab] Resumo: We studied three FLT3 ITD acute myeloid leukemia (AML) patients who relapsed after allogeneic haematopoietic stem cell transplantation (alloHSCT) and received multikinase inhibitor (MKI) sorafenib as part of salvage therapy. MKI was given to block the effect of FLT3 ITD mutation which powers proliferation of blast cells. However, the known facts that sorafenib is more effective in patents post alloHSCT suggested that this MKI can augment the immune system surveillance on leukaemia. In the present study, we investigated in depth the effect of sorafenib on the alloreactivity seen post-transplant including that on leukaemia. The patients (i) responded to the treatment with cessation of blasts which lasted 1, 17 and 42+ months, (ii) developed skin lesions with CD3+ cell invasion of the epidermis, (iii) had marrow infiltrated with CD8+ lymphocytes which co-expressed PD-1 (programmed cell death protein 1 receptor, CD279) in higher proportions than those in the blood (163±32 x103 cells/µl vs 38±8 x103 cells/µl, p<0.001). The Lymphoprep fraction of marrow cells investigated for the expression of genes involved in lymphocyte activation showed in the patients with long lasting complete remission (CR) a similar pattern characterized by (i) a low expression of nitric oxide synthase 2 (NOS2) and colony stimulating factor 2 (CSF2) as well as that of angiopoietin-like 4 (ANGPTL4) (supporting the immune response and anti-angiogenic) genes, and (ii) higher expression of fibroblast growth factor 1 (FGF1) and collagen type IV alpha 3 chain (COL4A3) as well as toll like receptor 9 (TLR9) and interleukin-12 (IL-12) (pro-inflammatory expression profile) genes as compared with the normal individual. The positive effect in one patient hardly justified the presence of unwanted effects (progressive chronic graft-versus-host disease (cGvHD) and avascular necrosis of the femur), which were in contrast negligible in the other patient. The anti-leukemic and unwanted effects of sorafenib do not rely on each other. [Mh] Termos MeSH primário: Antineoplásicos/uso terapêutico Células da Medula Óssea/imunologia Antígenos CD8/imunologia Transplante de Células-Tronco Hematopoéticas/efeitos adversos Leucemia Mieloide Aguda/cirurgia Linfócitos/imunologia Niacinamida/análogos & derivados Compostos de Fenilureia/uso terapêutico Receptor de Morte Celular Programada 1/imunologia [Mh] Termos MeSH secundário: Feminino Seres Humanos Leucemia Mieloide Aguda/imunologia Masculino Meia-Idade Niacinamida/uso terapêutico Recidiva Transplante Homólogo [Pt] Tipo de publicação: JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T [Nm] Nome de substância: 0 (Antineoplastic Agents); 0 (CD8 Antigens); 0 (PDCD1 protein, human); 0 (Phenylurea Compounds); 0 (Programmed Cell Death 1 Receptor); 25X51I8RD4 (Niacinamide); 9ZOQ3TZI87 (sorafenib) [Em] Mês de entrada: 1802 [Cu] Atualização por classe: 180215 [Lr] Data última revisão: 180215 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 180106 [St] Status: MEDLINE [do] DOI: 10.1371/journal.pone.0190525

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[PMID]: 29174347 [Au] Autor: Pinkerton AB; Sergienko E; Bravo Y; Dahl R; Ma CT; Sun Q; Jackson MR; Cosford NDP; Millán JL [Ad] Endereço: Conrad Prebys Center for Chemical Genomics, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037, USA. Electronic address: apinkerton@sbpdiscovery.org. [Ti] Título: Discovery of 5-((5-chloro-2-methoxyphenyl)sulfonamido)nicotinamide (SBI-425), a potent and orally bioavailable tissue-nonspecific alkaline phosphatase (TNAP) inhibitor. [So] Source: Bioorg Med Chem Lett;28(1):31-34, 2018 01 01. [Is] ISSN: 1464-3405 [Cp] País de publicação: England [La] Idioma: eng [Ab] Resumo: Tissue-nonspecific alkaline phosphatase (TNAP) is an ectoenzyme crucial for bone matrix mineralization via its ability to hydrolyze extracellular inorganic pyrophosphate (ePP ), a potent mineralization inhibitor, to phosphate (P ). By the controlled hydrolysis of ePP , TNAP maintains the correct ratio of P to ePP and therefore enables normal skeletal and dental calcification. In other areas of the body low ePP levels lead to the development of pathological soft-tissue calcification, which can progress to a number of disorders. TNAP inhibitors have been shown to prevent these processes via an increase of ePP . Herein we describe the use of a whole blood assay to optimize a previously described series of TNAP inhibitors resulting in 5-((5-chloro-2-methoxyphenyl)sulfonamido)nicotinamide (SBI-425), a potent, selective and oral bioavailable compound that robustly inhibits TNAP in vivo. [Mh] Termos MeSH primário: Fosfatase Alcalina/antagonistas & inibidores Inibidores Enzimáticos/química Niacinamida/análogos & derivados Niacinamida/química Sulfonamidas/química [Mh] Termos MeSH secundário: Administração Oral Fosfatase Alcalina/metabolismo Animais Avaliação Pré-Clínica de Medicamentos Inibidores Enzimáticos/metabolismo Inibidores Enzimáticos/farmacocinética Meia-Vida Concentração Inibidora 50 Camundongos Niacinamida/metabolismo Niacinamida/farmacocinética Relação Estrutura-Atividade Sulfonamidas/metabolismo Sulfonamidas/farmacocinética [Pt] Tipo de publicação: JOURNAL ARTICLE; RESEARCH SUPPORT, N.I.H., EXTRAMURAL [Nm] Nome de substância: 0 (Enzyme Inhibitors); 0 (SBI-425); 0 (Sulfonamides); 25X51I8RD4 (Niacinamide); EC 3.1.3.1 (Alkaline Phosphatase) [Em] Mês de entrada: 1801 [Cu] Atualização por classe: 180212 [Lr] Data última revisão: 180212 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 171128 [St] Status: MEDLINE

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[PMID]: 29374686 [Au] Autor: Song HY; Rellinger EJ; Park SH; Paul P; Qiao J; Vasilopoulos A; Ozden O; Gius D; Chung DH [Ad] Endereço: Robert H. Lurie Comprehensive Cancer Center, Northwestern University Medical Center, Chicago, IL, U.S.A. [Ti] Título: Inhibition of Sirtuin 6 Induces Neuroblastoma Differentiation. [So] Source: Anticancer Res;38(2):647-654, 2018 02. [Is] ISSN: 1791-7530 [Cp] País de publicação: Greece [La] Idioma: eng [Ab] Resumo: BACKGROUND/AIM: Sirtuins (SIRTs) play crucial roles in various signaling pathways that modulate differentiation and proliferation. We sought to elucidate the role of SIRTs in differentiation and proliferation of human neuroblastoma (NB). MATERIALS AND METHODS: NB cells were treated with nicotinamide (NAM), a non-specific SIRT inhibitor, SIRT-targeted short hairpin RNAs, and retinoic acid to assess cell growth and differentiation. RESULTS: SIRTs are involved in proliferation and differentiation using NAM in BE(2)-C cells. Specifically, SIRT6 knockdown in BE(2)-C cells reduced cell proliferation, induced neurite extension, corresponding with induction of p21 expression and G cell-cycle arrest. These effects were rescued by forced re-overexpression of SIRT6. SIRT6 expression was reduced in differentiated human NB sections, and RA-induced differentiation in BE(2)-C cells. CONCLUSION: SIRTs have important oncogenic properties in NB beyond its established functions in aging and genome stability. SIRT6 may represent a novel target for developing future therapeutics for the treatment of aggressive NBs. [Mh] Termos MeSH primário: Diferenciação Celular/efeitos dos fármacos Neuroblastoma/tratamento farmacológico Neuroblastoma/metabolismo Sirtuínas/antagonistas & inibidores [Mh] Termos MeSH secundário: Linhagem Celular Tumoral Proliferação Celular/efeitos dos fármacos Relação Dose-Resposta a Droga Técnicas de Silenciamento de Genes Seres Humanos Neuroblastoma/patologia Niacinamida/farmacologia RNA Interferente Pequeno/farmacologia Sirtuínas/genética Tretinoína/administração & dosagem Tretinoína/farmacologia [Pt] Tipo de publicação: JOURNAL ARTICLE [Nm] Nome de substância: 0 (RNA, Small Interfering); 25X51I8RD4 (Niacinamide); 5688UTC01R (Tretinoin); EC 3.5.1.- (SIRT6 protein, human); EC 3.5.1.- (Sirtuins) [Em] Mês de entrada: 1802 [Cu] Atualização por classe: 180208 [Lr] Data última revisão: 180208 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 180129 [St] Status: MEDLINE

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MEDLINE

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[PMID]: 29369224 [Au] Autor: Kaplan DE; Mehta R; D'Addeo K; Valderrama A; Taddei TH; Sorafenib for Hepatocellular carcinomA in VEterans (SHAVE) Study Investigators [Ad] Endereço: Department of Medicine, University of Pennsylvania. [Ti] Título: Sorafenib prescribed by gastroenterologists and hepatologists for hepatocellular carcinoma: A retrospective, multi-institutional cohort study. [So] Source: Medicine (Baltimore);97(4):e9757, 2018 Jan. [Is] ISSN: 1536-5964 [Cp] País de publicação: United States [La] Idioma: eng [Ab] Resumo: Sorafenib is the only Food and Drug Administration (FDA)-approved first-line therapy shown to have survival benefit for patients with advanced hepatocellular carcinoma (HCC). Patients with advanced HCC are often but not exclusively transferred from non-oncologists to oncologists to initiate systemic therapy. The objective of this study was to assess whether sorafenib prescribing by non-oncologists has any impact on utilization, adverse effects, cost or outcome.This was a retrospective cohort study utilizing data from patients prescribed sorafenib for HCC within Veterans Health Administration hospitals with 100% chart abstraction to confirm HCC diagnosis, identify prescribing provider specialty (oncology versus gastroenterology/hepatology), and obtain data required for cancer staging by the Barcelona Clinic Liver Cancer (BCLC) system. The primary outcome was overall survival from the time of sorafenib prescription.A total of 4903 patients who prescribed sorafenib for HCC were identified, for whom 340 patients (6.9%) were prescribed drug by a non-oncologist (Onc). BCLC Stage, age, Child-Turcotte-Pugh score, and comorbidity indices were similar between patients prescribed sorafenib by oncologists and non-oncologists. Oncologists more often discontinued sorafenib due to progression, whereas non-oncologists were more likely to continue sorafenib until death resulting in greater pill utilization and cost. Overall survival in both unadjusted and multivariable models showed no significant impact of prescriber type on survival (222 vs 217 days, P = .96), confirmed with propensity-matched subcohorts.Similar survival outcomes were observed for patients with HCC prescribed sorafenib by non-oncologists and oncologists, suggesting that non-oncologists with expertise in the management of HCC can safely and effectively administer sorafenib. [Mh] Termos MeSH primário: Antineoplásicos/uso terapêutico Carcinoma Hepatocelular/tratamento farmacológico Neoplasias Hepáticas/tratamento farmacológico Niacinamida/análogos & derivados Compostos de Fenilureia/uso terapêutico Padrões de Prática Médica/estatística & dados numéricos [Mh] Termos MeSH secundário: Idoso Antineoplásicos/economia Custos de Medicamentos Prescrições de Medicamentos/estatística & dados numéricos Feminino Gastroenterologistas/estatística & dados numéricos Seres Humanos Masculino Oncologia/estatística & dados numéricos Meia-Idade Niacinamida/economia Niacinamida/uso terapêutico Compostos de Fenilureia/economia Estudos Retrospectivos Estados Unidos [Pt] Tipo de publicação: EVALUATION STUDIES; JOURNAL ARTICLE; MULTICENTER STUDY [Nm] Nome de substância: 0 (Antineoplastic Agents); 0 (Phenylurea Compounds); 25X51I8RD4 (Niacinamide); 9ZOQ3TZI87 (sorafenib) [Em] Mês de entrada: 1802 [Cu] Atualização por classe: 180208 [Lr] Data última revisão: 180208 [Sb] Subgrupo de revista: AIM; IM [Da] Data de entrada para processamento: 180126 [St] Status: MEDLINE [do] DOI: 10.1097/MD.0000000000009757

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