bluuebunny/crossref_metadata_2025_split huggingface dataset:
BCR-ABL1expression, RT-qPCR and treatment decisions in chronic myeloid leukaemia
Authors: Latham Susan , Bartley Paul A , Budgen Bradley , Ross David M , Hughes Elizabeth , Branford Susan , White Deborah , Hughes Timothy P , Morley Alexander A 
Published: February 2016

AimsRT-qPCR is used to quantify minimal residual disease (MRD) in chronic myeloid leukaemia (CML) in order to make decisions on treatment, but its results depend on the level ofBCR-ABL1expression as well as leukaemic cell number. The aims of the study were to quantify inter-individual differences in expression level, to determine the relationship between expression level and response to treatment, and to investigate the effect of expression level on interpretation of the RT-qPCR result.MethodsBCR-ABL1expression was studied in 248 samples from 65 patients with CML by determining the difference between MRD quantified by RT-qPCR and DNA-qPCR. The results were analysed statistically and by simple indicative modelling.ResultsInter-individual levels of expression approximated a normal distribution with an SD of 0.36 log. Expression at diagnosis correlated with expression during treatment. Response to treatment, as measured by the number of leukaemic cells after 3, 6 or 12 months of treatment, was not related to the level of expression. Indicative modelling suggested that interpretation of RT-qPCR results in relation to treatment guidelines could be affected by variation in expression when MRD was around 10% at 3 months and by both expression variation and Poisson variation when MRD was around or below the limit of detection of RT-qPCR.ConclusionsVariation between individuals in expression ofBCR-ABL1can materially affect interpretation of the RT-qPCR when this test is used to make decisions on treatment.
Hypoxia-Induced Epithelial-to-Mesenchymal Transition in Hepatocellular Carcinoma Induces an Immunosuppressive Tumor Microenvironment to Promote Metastasis
Authors: Ye Long-Yun , Chen Wei , Bai Xue-Li , Xu Xing-Yuan , Zhang Qi , Xia Xue-Feng , Sun Xu , Li Guo-Gang , Hu Qi-Da , Fu Qi-Han , Liang Ting-Bo 
Published: February 2016

Abstract
Portal vein tumor thrombosis (PVTT) is a significant risk factor for metastasis in hepatocellular carcinoma (HCC) patients and is therefore associated with poor prognosis. The presence of PVTT frequently accompanies substantial hypoxia within the tumor microenvironment, which is suggested to accelerate tumor metastasis, but it is unclear how this occurs. Recent evidence has shown that the hypoxia-inducible factor HIF-1α induces epithelial-to-mesenchymal transition (EMT) in tumor cells to facilitate metastasis. In this study, we investigated whether hypoxia-induced EMT in cancer cells also affects immune cells in the tumor microenvironment to promote immunosuppression. We found that hypoxia-induced EMT increased the expression of the CCL20 cytokine in hepatoma cells. Furthermore, coculture of monocyte-derived macrophages with hypoxic hepatoma cells revealed that the expression of indoleamine 2, 3-dioxygenase (IDO) was induced in monocyte-derived macrophages in a CCL20-dependent manner. In turn, these IDO-expressing monocyte-derived macrophages suppressed T-cell proliferation and promoted the expansion of immunosuppressive regulatory T cells. Moreover, high CCL20 expression in HCC specimens was associated with PVTT and poor patient survival. Collectively, our findings suggest that the HIF-1α/CCL20/IDO axis in hepatocellular carcinoma is important for accelerating tumor metastasis through both the induction of EMT and the establishment of an immunosuppressive tumor microenvironment, warranting further investigation into the therapeutic effects of blocking specific nodes of this signaling network. Cancer Res; 76(4); 818–30. ©2016 AACR.
Phytoestrogen Suppresses Efflux of the Diagnostic Marker Protoporphyrin IX in Lung Carcinoma
Authors: Fujita Hirofumi , Nagakawa Keisuke , Kobuchi Hirotsugu , Ogino Tetsuya , Kondo Yoichi , Inoue Keiji , Shuin Taro , Utsumi Toshihiko , Utsumi Kozo , Sasaki Junzo , Ohuchi Hideyo 
Published: February 2016

Abstract
One promising method to visualize cancer cells is based on the detection of the fluorescent photosensitizer protoporphyrin IX (PpIX) synthesized from 5-aminolevulinic acid (ALA), but this method cannot be used in cancers that exhibit poor PpIX accumulation. PpIX appears to be pumped out of cancer cells by the ABC transporter G2 (ABCG2), which is associated with multidrug resistance. Genistein is a phytoestrogen that appears to competitively inhibit ABCG2 activity. Therefore, we investigated whether genistein can promote PpIX accumulation in human lung carcinoma cells. Here we report that treatment of A549 lung carcinoma cells with genistein or a specific ABCG2 inhibitor promoted ALA-mediated accumulation of PpIX by approximately 2-fold. ABCG2 depletion and overexpression studies further revealed that genistein promoted PpIX accumulation via functional repression of ABCG2. After an extended period of genistein treatment, a significant increase in PpIX accumulation was observed in A549 cells (3.7-fold) and in other cell lines. Systemic preconditioning with genistein in a mouse xenograft model of lung carcinoma resulted in a 1.8-fold increase in accumulated PpIX. Long-term genistein treatment stimulated the expression of genes encoding enzymes involved in PpIX synthesis, such as porphobilinogen deaminase, uroporphyrinogen decarboxylase, and protoporphyrinogen oxidase. Accordingly, the rate of PpIX synthesis was also accelerated by genistein pretreatment. Thus, our results suggest that genistein treatment effectively enhances ALA-induced PpIX accumulation by preventing the ABCG2-mediated efflux of PpIX from lung cancer cells and may represent a promising strategy to improve ALA-based diagnostic approaches in a broader set of malignancies. Cancer Res; 76(7); 1837–46. ©2016 AACR.
Galectin-3 Cleavage Alters Bone Remodeling: Different Outcomes in Breast and Prostate Cancer Skeletal Metastasis
Authors: Nakajima Kosei , Kho Dhong Hyo , Yanagawa Takashi , Harazono Yosuke , Hogan Victor , Chen Wei , Ali-Fehmi Rouba , Mehra Rohit , Raz Avraham 
Published: February 2016

Abstract
Management of bone metastasis remains clinically challenging and requires the identification of new molecular target(s) that can be therapeutically exploited to improve patient outcome. Galectin-3 (Gal-3) has been implicated as a secreted factor that alters the bone microenvironment. Proteolytic cleavage of Gal-3 may also contribute to malignant cellular behaviors, but has not been addressed in cancer metastasis. Here, we report that Gal-3 modulates the osteolytic bone tumor microenvironment in the presence of RANKL. Gal-3 was localized on the osteoclast cell surface, and its suppression by RNAi or a specific antagonist markedly inhibited osteoclast differentiation markers, including tartrate-resistant acid phosphatase, and reduced the number of mature osteoclasts. Structurally, the 158–175 amino acid sequence in the carbohydrate recognition domain (CRD) of Gal-3 was responsible for augmented osteoclastogenesis. During osteoclast maturation, Gal-3 interacted and colocalized with myosin-2A along the surface of cell–cell fusion. Pathologically, bone metastatic cancers expressed and released an intact form of Gal-3, mainly detected in breast cancer bone metastases, as well as a cleaved form, more abundant in prostate cancer bone metastases. Secreted intact Gal-3 interacted with myosin-2A, leading to osteoclastogenesis, whereas a shift to cleaved Gal-3 attenuated the enhancement in osteoclast differentiation. Thus, our studies demonstrate that Gal-3 shapes the bone tumor microenvironment through distinct roles contingent on its cleavage status, and highlight Gal-3 targeting through the CRD as a potential therapeutic strategy for mitigating osteolytic bone remodeling in the metastatic niche. Cancer Res; 76(6); 1391–402. ©2016 AACR.
Activated KRAS Cooperates with MLL-AF4 to Promote Extramedullary Engraftment and Migration of Cord Blood CD34+ HSPC But Is Insufficient to Initiate Leukemia
Authors: Prieto Cristina , Stam Ronald W. , Agraz-Doblas Antonio , Ballerini Paola , Camos Mireia , Castaño Julio , Marschalek Rolf , Bursen Aldeheid , Varela Ignacio , Bueno Clara , Menendez Pablo 
Published: February 2016

Abstract
The MLL–AF4 (MA4) fusion gene is the genetic hallmark of an aggressive infant pro–B-acute lymphoblastic leukemia (B-ALL). Our understanding of MA4-mediated transformation is very limited. Whole-genome sequencing studies revealed a silent mutational landscape, which contradicts the aggressive clinical outcome of this hematologic malignancy. Only RAS mutations were recurrently detected in patients and found to be associated with poorer outcome. The absence of MA4-driven B-ALL models further questions whether MA4 acts as a single oncogenic driver or requires cooperating mutations to manifest a malignant phenotype. We explored whether KRAS activation cooperates with MA4 to initiate leukemia in cord blood–derived CD34+ hematopoietic stem/progenitor cells (HSPC). Clonogenic and differentiation/proliferation assays demonstrated that KRAS activation does not cooperate with MA4 to immortalize CD34+ HSPCs. Intrabone marrow transplantation into immunodeficient mice further showed that MA4 and KRASG12V alone or in combination enhanced hematopoietic repopulation without impairing myeloid–lymphoid differentiation, and that mutated KRAS did not cooperate with MA4 to initiate leukemia. However, KRAS activation enhanced extramedullary hematopoiesis of MA4-expressing cell lines and CD34+ HSPCs that was associated with leukocytosis and central nervous system infiltration, both hallmarks of infant t(4;11)+ B-ALL. Transcriptional profiling of MA4-expressing patients supported a cell migration gene signature underlying the mutant KRAS-mediated phenotype. Collectively, our findings demonstrate that KRAS affects the homeostasis of MA4-expressing HSPCs, suggesting that KRAS activation in MA4+ B-ALL is important for tumor maintenance rather than initiation. Cancer Res; 76(8); 2478–89. ©2016 AACR.
Stomach-Specific Activation of Oncogenic KRAS and STAT3-Dependent Inflammation Cooperatively Promote Gastric Tumorigenesis in a Preclinical Model
Authors: Thiem Stefan , Eissmann Moritz F. , Elzer Joachim , Jonas Anna , Putoczki Tracy L. , Poh Ashleigh , Nguyen Paul , Preaudet Adele , Flanagan Dustin , Vincan Elizabeth , Waring Paul , Buchert Michael , Jarnicki Andrew , Ernst Matthias 
Published: February 2016

Abstract
About 5% to 10% of human gastric tumors harbor oncogenic mutations in the KRAS pathway, but their presence alone is often insufficient for inducing gastric tumorigenesis, suggesting a requirement for additional mutagenic events or microenvironmental stimuli, including inflammation. Assessing the contribution of such events in preclinical mouse models requires Cre recombinase–mediated conditional gene expression in stem or progenitor cells of normal and transformed gastric epithelium. We therefore constructed a bacterial artificial chromosome containing transgene (Tg), comprising the regulatory elements of the trefoil factor 1 (Tff1) gene and the tamoxifen-inducible Cre recombinase (CreERT2)–coding sequence. The resulting Tg(Tff1-CreERT2) mice were crossed with mice harboring conditional oncogenic mutations in Kras or Braf. The administration of tamoxifen to the resulting adult Tg(Tff1-CreERT2);KrasLSL-G12D/+ and Tg(Tff1-CreERT2);BrafLSL-V600E/+ mice resulted in gastric metaplasia, inflammation, and adenoma development, characterized by excessive STAT3 activity. To assess the contribution of STAT3 to the spontaneously developing gastric adenomas in gp130F/F mice, which carry a knockin mutation in the Il6 signal transducer (Il6st), we generated Tg(Tff1-CreERT2);Stat3fl/fl;gp130F/F mice that also harbor a conditional Stat3 knockout allele and found that tamoxifen administration conferred a significant reduction in their tumor burden. Conversely, excessive Kras activity in Tg(Tff1-CreERT2);KrasLSL-G12D/+;gp130F/F mice promoted more extensive gastric inflammation, metaplastic transformation, and tumorigenesis than observed in Tg(Tff1-CreERT2);KrasLSL-G12D/+ mice. Collectively, our findings demonstrate that advanced gastric tumorigenesis requires oncogenic KRAS or BRAF in concert with aberrant STAT3 activation in epithelial precursor cells of the glandular stomach, providing a new conditional model of gastric cancer in which to investigate candidate therapeutic targets and treatment strategies. Cancer Res; 76(8); 2277–87. ©2016 AACR.
Intermittent High-Dose Scheduling of AZD8835, a Novel Selective Inhibitor of PI3Kα and PI3Kδ, Demonstrates Treatment Strategies forPIK3CA-Dependent Breast Cancers
Authors: Hudson Kevin , Hancox Urs J. , Trigwell Cath , McEwen Robert , Polanska Urszula M. , Nikolaou Myria , Morentin Gutierrez Pablo , Avivar-Valderas Alvaro , Delpuech Oona , Dudley Phillippa , Hanson Lyndsey , Ellston Rebecca , Jones Alys , Cumberbatch Marie , Cosulich Sabina C. , Ward Lara , Cruzalegui Francisco , Green Stephen 
Published: February 2016

AbstractThe PIK3CA gene, encoding the p110α catalytic unit of PI3Kα, is one of the most frequently mutated oncogenes in human cancer. Hence, PI3Kα is a target subject to intensive efforts in identifying inhibitors and evaluating their therapeutic potential. Here, we report studies with a novel PI3K inhibitor, AZD8835, currently in phase I clinical evaluation. AZD8835 is a potent inhibitor of PI3Kα and PI3Kδ with selectivity versus PI3Kβ, PI3Kγ, and other kinases that preferentially inhibited growth in cells with mutant PIK3CA status, such as in estrogen receptor–positive (ER+) breast cancer cell lines BT474, MCF7, and T47D (sub-μmol/L GI50s). Consistent with this, AZD8835 demonstrated antitumor efficacy in corresponding breast cancer xenograft models when dosed continuously. In addition, an alternative approach of intermittent high-dose scheduling (IHDS) was explored given our observations that higher exposures achieved greater pathway inhibition and induced apoptosis. Indeed, using IHDS, monotherapy AZD8835 was able to induce tumor xenograft regression. Furthermore, AZD8835 IHDS in combination with other targeted therapeutic agents further enhanced antitumor activity (up to 92% regression). Combination partners were prioritized on the basis of our mechanistic insights demonstrating signaling pathway cross-talk, with a focus on targeting interdependent ER and/or CDK4/6 pathways or alternatively a node (mTOR) in the PI3K-pathway, approaches with demonstrated clinical benefit in ER+ breast cancer patients. In summary, AZD8835 IHDS delivers strong antitumor efficacy in a range of combination settings and provides a promising alternative to continuous dosing to optimize the therapeutic index in patients. Such schedules merit clinical evaluation. Mol Cancer Ther; 15(5); 877–89. ©2016 AACR.
Ética: origens e distinção da moral
Authors: Figueiredo Antônio Macena 
Published: February 2016

<span style="font-family: HelveticaLTStd-Roman; font-size: xx-small;"><span style="font-family: HelveticaLTStd-Roman; font-size: xx-small;"><p>Ética e moral são termos freqüentemente utilizados no cotidiano, porém, definir o que significam, não é tarefa fácil. Basta perguntar se existe alguma distinção entre esses vocábulos para constatarmos que as pessoas se vêem em dificuldade ao tentar explicar. Este artigo tem como objetivo apresentar alguns esclarecimentos teórico-filosóficos sobre a origem das divergências conceituais. Parte de uma breve revisão sobre as origens etimológicas dos termos</p></span></span><em><span style="font-family: HelveticaLTStd-Obl; font-size: xx-small;"><em><span style="font-family: HelveticaLTStd-Obl; font-size: xx-small;"><em><span style="font-family: HelveticaLTStd-Obl; font-size: xx-small;">ethos </span></em></span></em></span></em><span style="font-family: HelveticaLTStd-Roman; font-size: xx-small;"><span style="font-family: HelveticaLTStd-Roman; font-size: xx-small;">e </span></span><em><span style="font-family: HelveticaLTStd-Obl; font-size: xx-small;"><em><span style="font-family: HelveticaLTStd-Obl; font-size: xx-small;">mos. </span></em></span></em><span style="font-family: HelveticaLTStd-Roman; font-size: xx-small;"><span style="font-family: HelveticaLTStd-Roman; font-size: xx-small;">São apresentados os diversos sentidos em que esses vocábulos podem ser empregados, conceitos utilizados e finaliza com uma reflexão sobre a compreensão da ética como ciência específica ou como ramo de estudo da filosofia.</span><p> </p></span>
Processos movidos contra cirurgiões-dentistas no Conselho Regional de Odontologia - seção Pará - nos últimos sete anos
Authors: Oliveira Clarissa Mendes Lobato de , Bezerra Erika Seabra Martins , Lobato Isabella Haber , Nobre Rafaela Moutinho , Machado Sissy Mendes , Barroso Regina Feio 
Published: February 2016

<span style="color: #221e1f; font-size: xx-small;"><span style="color: #221e1f; font-size: xx-small;"><span style="color: #221e1f; font-size: xx-small;"><span style="color: #221e1f; font-size: xx-small;"><span style="color: #221e1f; font-size: xx-small;"><font size="1" color="#221e1f"><p>O crescente número de processos cíveis e criminais envolvendo profissionais da área da saúde no Brasil,</p></font></span></span><span style="font-family: Helvetica,Helvetica; color: #221e1f; font-size: xx-small;"><span style="font-family: Helvetica,Helvetica; color: #221e1f; font-size: xx-small;"><span style="font-family: Helvetica,Helvetica; color: #221e1f; font-size: xx-small;">inclusive cirurgiões-dentistas, motivou o presente estudo, voltado a pesquisar e analisar processos instaurados contra cirurgiões-dentistas no período de 2003 até 2009 no Conselho Regional de Odontologia do Pará (CRO-PA). A amostra constou de 57 processos cujos dados permitiram inferir que a propaganda ilegal foi a principal causa para a abertura </span></span></span><span style="color: #221e1f; font-size: xx-small;"><span style="color: #221e1f; font-size: xx-small;">de processos (10%), seguida por intercorrências no tratamento cirúrgico (10,5%). Dentre os processos finalizados, </span></span><span style="font-family: Helvetica,Helvetica; color: #221e1f; font-size: xx-small;"><span style="font-family: Helvetica,Helvetica; color: #221e1f; font-size: xx-small;"><span style="font-family: Helvetica,Helvetica; color: #221e1f; font-size: xx-small;">57,6% foram arquivados e 42,4% foram julgados, mostrando que na maior parte das vezes ocorreu o entendimento entre as partes envolvidas.</span></span></span></span></span></span><span style="font-family: Helvetica,Helvetica; color: #221e1f; font-size: xx-small;"><span style="font-family: Helvetica,Helvetica; color: #221e1f; font-size: xx-small;"> </span><p> </p></span><p> </p>
Medicina legal, criminologia e punição: aspectos da trajetória intelectual e profissional de Flamínio Fávero (1895-1982)
Authors: Alvarez Marcos César , Salla Fernando , Alves Kelly Ludkiewicz 
Published: February 2016

O artigo discute aspectos da trajetória intelectual e profissional do médico Flamínio Fávero (1895-1982). Formado pela Faculdade de Medicina de São Paulo, Fávero teve importante atuação no campo da Medicina Legal e das discussões criminológicas no período, bem como atuou no sistema penitenciário do estado. O estudo dessa e de outras trajetórias abre possibilidade de compreensão do papel das elites e de suas representações no que diz respeito ao controle do crime e às práticas e instituições de punição na história da sociedade brasileira.
Distribuição das perícias médicas realizadas no Instituto de Medicina Social e de Criminologia do Estado de São Paulo (IMESC) segundo o tipo de ação judicial
Authors: Wild Camila Lúcia Dedivitis Tiossi 
Published: February 2016

<p>O Instituto de Medicina Social e de Criminologia do Estado de São Paulo (IMESC) presta auxílio ao judiciário em ações cíveis, elaborando laudos periciais para subsidiar o juiz em discussões que esbarram em matéria médica. No presente trabalho foram analisadas retrospectivamente 1131 perícias médicas na área clínica realizadas no IMESC, por um mesmo perito, no período de abril 2009 a novembro 2012. A perícia médica mais prevalente foi a ação de interdição (30,5%), seguida da securitária (25%) e indenizatória (17%). Foi observada uma variedade de temas que a perícia judicial civil aborda, fazendo com que o perito médico necessite de amplo conhecimento nas diversas questões de litígio para que possa auxiliar o juízo.</p>
O uso do DNA barcoding para identificar barbatanas de tubarão comercializadas ilegalmente no Brasil.
Authors: Carvalho CBV , Freitas JM 
Published: February 2016

A demanda por barbatanas de tubarão tem aumentado nos últimos anos, estimulando o comércio ilegal e técnicas de captura predatórias que ameaçam a sobrevivência das populações naturais. As barbatanas de tubarão são normalmente removidas imediatamente após a captura e o corpo do animal é jogado de volta ao mar, o que impede a identiﬁ cação morfológica da espécie. Quando a identiﬁ cação morfológica está comprometida, a identiﬁ cação genética pode ser usada para associar amostras desconhecidas com amostras de referência por meio da comparação de sequências de genes mitocondriais. Neste estudo, nós usamos sequências de 650 pares de base da subunidade I do gene citocromo c oxidase (COI) associadas com o Barcode of Life Database (BOLD) para identiﬁ car uma carga de barbatanas de tubarão apreendidas pela Polícia Federal do Brasil em 2011. Nós conseguimos associar com sucesso 25 das 26 amostras encaminhadas para o laboratório com três espécies diferentes, sendo elas Prionace glauca, Isurus oxyrinchus e Sphyrna zygaena. Embora as três espécies não estejam atualmente protegidas pelas leis brasileiras, este estudo reforça a utilidade da ferramenta do DNA barcoding na casuística forense.
Análise de polimorfismos do gene MC1R associados a fenótipos humanos de pigmentação na população brasileira.
Authors: Marano LA , Simões AL , Donadi EA , Mendes-Junior CT 
Published: February 2016

Dentre os genes conhecidos por inﬂ uenciarem a variação normal de pigmentação de olhos, pele e cabelos em humanos, o gene MC1R (receptor de melanocortina 1) é o mais bem caracterizado até o momento. A atuação do MC1R ocorre pela produção de uma proteína transmembrana nos melanócitos, responsável pela regulação da produção de melanina nos mesmos. Sabe-se que a atuação do MC1R determina a proporção entre eumelanina (coloração castanha/preta) e feomelanina (amarela/vermelha) presente nos melanócitos. O presente trabalho tem como objetivo analisar os SNPs conhecidos do gene MC1R com o propósito de se avaliar a inﬂ uência da diversidade deste gene em características como a presença de sardas e variação da pigmentação dos olhos, pele e cabelos em humanos. Foram analisados 29 SNPs conhecidos da região codiﬁ cadora do gene MC1R em 296 indivíduos da região de Ribeirão Preto, SP. A extração do DNA foi feita pela técnica de salting-out. A região codiﬁ cadora do gene MC1R (951pb) foi ampliﬁ cada em uma única reação de PCR, a qual foi sequenciada em um analisador genético ABI-PRISM 310 por eletroforese capilar, utilizando-se os mesmos primers empregados para a ampliﬁ cação. Dos 29 SNPs avaliados, 22 deles mostraram variação nas amostras estudadas, sendo que metade deles demonstrou estar associados a características de pigmentação. Observou-se um conjunto de SNPs associados claramente à fenótipos relacionados à feomelanina (+1645 A, +1831 T,+1858 T e +2260 C), enquanto outros se relacionam à ocorrência de eumelanina (+1558 G, +2322 G, +2346 A). O presente trabalho apresenta associações signiﬁ cativas entre SNPs individuais e pigmentação de olhos, cabelos e pele, sendo que nosso dados conﬁ rmam que tal gene também desempenha papel relevante na variação de pigmentação na população Brasileira.