bluuebunny/crossref_metadata_2025_split huggingface dataset:
G0S2 Suppresses Oncogenic Transformation by Repressing a MYC-Regulated Transcriptional Program
Authors: Yim Christina Y. , Sekula David J. , Hever-Jardine Mary P. , Liu Xi , Warzecha Joshua M. , Tam Janice , Freemantle Sarah J. , Dmitrovsky Ethan , Spinella Michael J. 
Published: February 2016

Abstract
Methylation-mediated silencing of G0–G1 switch gene 2 (G0S2) has been detected in a variety of solid tumors, whereas G0S2 induction is associated with remissions in patients with acute promyelocytic leukemia, implying that G0S2 may possess tumor suppressor activity. In this study, we clearly demonstrate that G0S2 opposes oncogene-induced transformation using G0s2-null immortalized mouse embryonic fibroblasts (MEF). G0s2-null MEFs were readily transformed with HRAS or EGFR treatment compared with wild-type MEFs. Importantly, restoration of G0S2 reversed HRAS-driven transformation. G0S2 is known to regulate fat metabolism by attenuating adipose triglyceride lipase (ATGL), but repression of oncogene-induced transformation by G0S2 was independent of ATGL inhibition. Gene expression analysis revealed an upregulation of gene signatures associated with transformation, proliferation, and MYC targets in G0s2-null MEFs. RNAi-mediated ablation and pharmacologic inhibition of MYC abrogated oncogene-induced transformation of G0s2-null MEFs. Furthermore, we found that G0S2 was highly expressed in normal breast tissues compared with malignant tissue. Intriguingly, high levels of G0S2 were also associated with a decrease in breast cancer recurrence rates, especially in estrogen receptor–positive subtypes, and overexpression of G0S2 repressed the proliferation of breast cancer cells in vitro. Taken together, these findings indicate that G0S2 functions as a tumor suppressor in part by opposing MYC activity, prompting further investigation of the mechanisms by which G0S2 silencing mediates MYC-induced oncogenesis in other malignancies. Cancer Res; 76(5); 1204–13. ©2016 AACR.
Pharmacological Inhibition of the Histone Lysine Demethylase KDM1A Suppresses the Growth of Multiple Acute Myeloid Leukemia Subtypes
Authors: McGrath John P. , Williamson Kaylyn E. , Balasubramanian Srividya , Odate Shobu , Arora Shilpi , Hatton Charlie , Edwards Thomas M. , O'Brien Thomas , Magnuson Steven , Stokoe David , Daniels Danette L. , Bryant Barbara M. , Trojer Patrick 
Published: February 2016

Abstract
Lysine-specific demethylase 1 (KDM1A) is a transcriptional coregulator that can function in both the activation and repression of gene expression, depending upon context. KDM1A plays an important role in hematopoiesis and was identified as a dependency factor in leukemia stem cell populations. Therefore, we investigated the consequences of inhibiting KDM1A in a panel of cell lines representing all acute myelogenous leukemia (AML) subtypes using selective, reversible and irreversible KDM1A small-molecule inhibitors. Cell models of AML, CML, and T-ALL were potently affected by KDM1A inhibition, and cells bearing RUNX1-RUNX1T1 (AML1-ETO) translocations were especially among the most sensitive. RNAi-mediated silencing of KDM1A also effectively suppressed growth of RUNX1-RUNX1T1–containing cell lines. Furthermore, pharmacologic inhibition of KDM1A resulted in complete abrogation of tumor growth in an AML xenograft model harboring RUNX1–RUNX1T1 translocations. We unexpectedly found that KDM1A-targeting compounds not only inhibited the catalytic activity of the enzyme, but evicted KDM1A from target genes. Accordingly, compound-mediated KDM1A eviction was associated with elevated levels of local histone H3 lysine 4 dimethylation, and increased target gene expression, which was further accompanied by cellular differentiation and induction of cell death. Finally, our finding that KDM1A inhibitors effectively synergize with multiple conventional as well as candidate anti-AML agents affords a framework for potential future clinical application. Cancer Res; 76(7); 1975–88. ©2016 AACR.
Antagonizing the Hedgehog Pathway with Vismodegib Impairs Malignant Pleural Mesothelioma Growth In Vivo by Affecting Stroma
Authors: Meerang Mayura , Bérard Karima , Felley-Bosco Emanuela , Lauk Olivia , Vrugt Bart , Boss Andreas , Kenkel David , Broggini-Tenzer Angela , Stahel Rolf A. , Arni Stephan , Weder Walter , Opitz Isabelle 
Published: February 2016

Abstract
An autocrine-driven upregulation of the Hedgehog (Hh) signaling pathway has been described in malignant pleural mesothelioma (MPM), in which the ligand, desert Hh (DHH), was produced from tumor cells. However, our investigation revealed that the Hh pathway is activated in both tumor and stroma of MPM tumor specimens and an orthotopic immunocompetent rat MPM model. This was demonstrated by positive immunohistochemical staining of Glioma-associated oncogene 1 (GLI1) and Patched1 (PTCH1) in both tumor and stromal fractions. DHH was predominantly expressed in the tumor fractions. To further investigate the role of the Hh pathway in MPM stroma, we antagonized Hh signaling in the rat model of MPM using a Hh antagonist, vismodegib, (100 mg/kg orally). Daily treatment with vismodegib efficiently downregulated Hh target genes Gli1, Hedgehog Interacting Protein (Hhip), and Ptch1, and caused a significant reduction of tumor volume and tumor growth delay. Immunohistochemical analyses revealed that vismodegib treatment primarily downregulated GLI1 and HHIP in the stromal compartment along with a reduced expression of previously described fibroblast Hh-responsive genes such as Fibronectin (Fn1) and Vegfa. Primary cells isolated from the rat model cultured in 3% O2 continued to express Dhh but did not respond to vismodegib in vitro. However, culture supernatant from these cells stimulated Gli1, Ptch1, and Fn1 expression in mouse embryonic fibroblasts, which was suppressed by vismodegib. Our study provides new evidence regarding the role of Hh signaling in MPM stroma in the maintenance of tumor growth, emphasizing Hh signaling as a treatment target for MPM. Mol Cancer Ther; 15(5); 1095–105. ©2016 AACR.
KLF4 Suppresses Tumor Formation in Genetic and Pharmacological Mouse Models of Colonic Tumorigenesis
Authors: Ghaleb Amr M. , Elkarim Enas A. , Bialkowska Agnieszka B. , Yang Vincent W. 
Published: February 2016

Abstract
The zinc finger transcription factor Krüppel-like factor 4 (KLF4) is frequently downregulated in colorectal cancer. Previous studies showed that KLF4 is a tumor suppressor in the intestinal tract and plays an important role in DNA damage-repair mechanisms. Here, the in vivo effects of Klf4 deletion were examined from the mouse intestinal epithelium (Klf4ΔIS) in a genetic or pharmacological setting of colonic tumorigenesis: ApcMin/+ mutation or carcinogen treatment with azoxymethane (AOM), respectively. Klf4ΔIS/ApcMin/+ mice developed significantly more colonic adenomas with 100% penetrance as compared with ApcMin/+ mice with intact Klf4 (Klf4fl/fl/ApcMin/+). The colonic epithelium of Klf4ΔIS/ApcMin/+ mice showed increased mTOR pathway activity, together with dysregulated epigenetic mechanism as indicated by altered expression of HDAC1 and p300. Colonic adenomas from both genotypes stained positive for γH2AX, indicating DNA double-strand breaks. In Klf4ΔIS/ApcMin/+ mice, this was associated with reduced nonhomologous end joining (NHEJ) repair and homologous recombination repair (HRR) mechanisms as indicated by reduced Ku70 and Rad51 staining, respectively. In a separate model, following treatment with AOM, Klf4ΔIS mice developed significantly more colonic tumors than Klf4fl/fl mice, with more Klf4ΔIS mice harboring K-Ras mutations than Klf4fl/fl mice. Compared with AOM-treated Klf4fl/fl mice, adenomas of treated Klf4ΔIS mice had suppressed NHEJ and HRR mechanisms, as indicated by reduced Ku70 and Rad51 staining. This study highlights the important role of KLF4 in suppressing the development of colonic neoplasia under different tumor-promoting conditions.
Implications: The study demonstrates that KLF4 plays a significant role in the pathogenesis of colorectal neoplasia. Mol Cancer Res; 14(4); 385–96. ©2016 AACR.
A importância do laudo pericial médico na formação do entendimento do juízo: análise de casos de suposta má prática médica em cirurgia geral
Authors: Leal Lucas Pedroso Fernandes Ferreira , Milagres Antônio 
Published: February 2016

Atualmente, no Brasil, têm aumentado enormemente as demandas jurídicas impetradas por paciente contra seus médicos. A má prática médica é conceituada como a conduta inadequada, que supõe inobservância técnica, capaz de produzir dano à vida ou agravo à saúde de outrém, mediante imperícia, imprudência ou negligência. A ausência de conhecimento técnico em medicina faz com que a autoridade judicial se utilize da perícia médica para apuração da responsabilidade civil dos envolvidos. O objetivo deste trabalho foi avaliar a importância do laudo pericial médico na formação do entendimento da autoridade judicial em casos de alegada má prática médica na especialidade de cirurgia geral e verificar o impacto da perícia médica na formação de seu convencimento. Estudaram-se os laudos oficiais e as decisões judiciais do ano de 2009 de 100 processos cíveis referentes à má prática médica na especialidade de cirurgia geral, propostas no estado de São Paulo, até a primeira instância. Observaram-se os elementos do laudo pericial e a fundamentação da sentença. Determinaram-se a concordância e a discordância entre os entendimentos médico e jurídico em cada caso. Em todos os julgados mencionou-se a prova pericial médica. Em 96% dos casos o laudo médico-legal influenciou a decisão judicial. 80% das sentenças foi desfavorável aos autores. Em 84% dos casos, o perito não estabeleceu nexo de causalidade. Houve, em 16% das perícias realizadas, elementos que permitiram concluir pela ocorrência de má prática médica. A concordância deu-se, especificamente, em 75% quanto à conduta médica inadequada e em 100% quando se considerou a assistência prestada adequada. Constatou-se que a perícia médica é o principal meio de prova nas ações que versam sobre má prática médica. Demonstrou-se a grande influência do laudo pericial na decisão pela procedência, ou não, das ações. O fornecimento adequado à autoridade competente de esclarecimentos sobre a matéria em tela, com base em conhecimentos científicos, é responsável pela formação do convencimento do magistrado, contribuindo para que se faça justiça.
O gene rbcL como barcode para identificação forense de Cannabis sativa
Authors: Ribeiro ASD , Dias VHG , Mello ICT , Silva R , Sabino BD , Garrido RG , Seldin L , Moura-Neto Rodrigo S 
Published: February 2016

<em>Cannabis sativa</em> é uma das espécies mais antigas de plantas domesticadas e permanece como uma das culturas mais amplamente difundida e a droga ilícita mais consumida no mundo. Há uma grande diﬁ culdade em identiﬁ car e individualizar as amostras de Cannabis sp, diﬁ cultando a correlação a prováveis locais de plantações ilegais, o que permitiria revelar rotas de tráﬁ co, relacionar grupos criminosos e distinguir amostras legais daquelas comercializadas como droga, onde o cultivo é permitido. A principal ﬁ nalidade do DNA Barcode é o de proporcionar uma rápida e precisa identiﬁ cação de organismos a partir de uma pequena região padronizada do genoma que ajuda a caracterizar e distinguir espécies e indivíduos não identiﬁ cados para atribuir à espécie. Um dos genes candidatos é o ribulose-1,5-bisfosfato carboxilase/oxigenase (rbcL), utilizado como um sistema de DNA Barcode e presente no DNA dos cloroplastos das plantas, sendo o responsável pela produção subunidade maior da que converte dióxido de carbono e água em carboidratos.Nosso objetivo é o desenvolvimento de um protocolo eﬁ ciente de extração de DNA e de sequenciamento do gene rbcL para análise forense de amostras apreendidas da Polícia Judiciária. DNA de amostras de Cannabis sativa,caracterizadas no ICCE/DGPTC/PCERJ, foi extraído utilizandoo Mini DNeasy Plant (Qiagen)no IPPGF/DGPTC/PCERJ. O material foi transferido para o LabFor/UFRJe um fragmento de 735 pb do gene rbcL foi ampliﬁ cado através de um par de iniciadores descritos na literatura como universais para plantas.O fragmento foi sequenciado, com o protocolo do BigDye v3.1, usando ABI 3500 (Life Technologies). As comparações das sequências foram realizadas no software Geneious (Biomatters). A nossa sequência consenso de 559 pb foi comparada às seqüências que correspondem às regiões rbcL em <em>Cannabis sativa</em> depositadas no GenBank, e observamos a ocorrência de polimorﬁ smos (SNPs) entre as amostras dos Estados unidos, Reino Unido e China, sugerindo que se trata de uma assinatura genética para análise forense.
INÍCIO DA VIDA: AS FRONTEIRAS DO CONCEITO
Authors: ALMEIDA Marcos De , MUÑOZ Daniel Romero 
Published: February 2016

<span style="font-family: Arial; font-size: xx-small;"><span style="font-family: Arial; font-size: xx-small;"><p>O s autores discutem o conceito do início da vida contrapondo-o à questão do que torna a vida humana <span style="font-family: Arial; font-size: xx-small;">mais valiosa que outras formas de vida? Colocam que a vida é um “</span></p></span></span><em><span style="font-family: Arial; font-size: xx-small;"><em><span style="font-family: Arial; font-size: xx-small;">continuum</span></em></span></em><span style="font-family: Arial; font-size: xx-small;"><span style="font-family: Arial; font-size: xx-small;">” e que a emergência do indivíduo ocorre gradualmente até tornar-se o elemento vivo de maior significado moral: a pessoa. E buscam na conceituação de Locke os atributos que a tornam tão importante.</span><p> </p></span><p> </p>
Incident Cerebral Microbleeds in a Cohort of Intracerebral Hemorrhage
Authors: Pasquini Marta , Benedictus Marije R. , Boulouis Grégoire , Rossi Costanza , Dequatre-Ponchelle Nelly , Cordonnier Charlotte 
Published: February 2016

Background and Purpose—
We aimed to identify prognostic and associated factors of incident cerebral microbleeds (CMBs) in intracerebral hemorrhage (ICH) survivors.

Methods—
Observational prospective cohort of 168 ICH survivors who underwent 1.5T magnetic resonance imaging at ICH onset and during follow-up (median scan interval, 3.4; interquartile range, 1.4–4.7) years. We used logistic regression adjusted for age, sex, and scan interval. Analyses were stratified according to the index ICH location (58 lobar ICH, 103 nonlobar ICH, excluding patients with multiple or unclassifiable ICH).

Results—
Eighty-nine (53%) patients had CMBs at ICH onset, and 80 (48%) exhibited incident CMBs during follow-up. Predictors of incident CMBs at ICH onset were ≥1 CMBs (adjusted odds ratio [aOR], 2.27; 95% confidence interval [CI], 1.18–4.35), old radiological macrohemorrhage (aOR, 6.78; 95% CI, 2.76–16.68), and CMBs in mixed location (aOR, 3.73; 95% CI, 1.67–8.31). When stratifying by ICH location, incident CMBs were associated in nonlobar ICH with incident lacunes (aOR, 2.86; 95% CI, 1.04–7.85) and with the use of antiplatelet agents (aOR, 2.89; 95% CI, 1.14–7.32). In lobar ICH, incident CMBs were associated with incident radiological macrohemorrhage (aOR, 9.76; 95% CI, 1.07–88.77).

Conclusions—
Prognostic and associated factors of incident CMBs differed according to the index ICH location. Whereas in lobar ICH, incident CMBs were associated with hemorrhagic biomarkers, in nonlobar ICH, ischemic burden also increased. CMBs may be interesting biomarkers to monitor in randomized trials on restarting antithrombotic drugs after ICH.
Endothelial Cells Lining Sporadic Cerebral Cavernous Malformation Cavernomas Undergo Endothelial-to-Mesenchymal Transition
Authors: Bravi Luca , Malinverno Matteo , Pisati Federica , Rudini Noemi , Cuttano Roberto , Pallini Roberto , Martini Maurizio , Larocca Luigi Maria , Locatelli Marco , Levi Vincenzo , Bertani Giulio Andrea , Dejana Elisabetta , Lampugnani Maria Grazia 
Published: February 2016

Background and Purpose—

Cerebral cavernous malformation (CCM) is characterized by multiple lumen vascular malformations in the central nervous system that can cause neurological symptoms and brain hemorrhages. About 20% of CCM patients have an inherited form of the disease with ubiquitous loss-of-function mutation in any one of 3 genes
CCM1
,
CCM2
, and
CCM3
. The rest of patients develop sporadic vascular lesions histologically similar to those of the inherited form and likely mediated by a biallelic acquired mutation of
CCM
genes in the brain vasculature. However, the molecular phenotypic features of endothelial cells in CCM lesions in sporadic patients are still poorly described. This information is crucial for a targeted therapy.

Methods—
We used immunofluorescence microscopy and immunohistochemistry to analyze the expression of endothelial-to-mesenchymal transition markers in the cavernoma of sporadic CCM patients in parallel with human familial cavernoma as a reference control.

Results—
We report here that endothelial cells, a cell type critically involved in CCM development, undergo endothelial-to-mesenchymal transition in the lesions of sporadic patients. This switch in endothelial phenotype has been described only in genetic CCM patients and in murine models of the disease. In addition, TGF-β/p-Smad- and β-catenin-dependent signaling pathways seem activated in sporadic cavernomas as in familial ones.

Conclusions—
Our findings support the use of common therapeutic strategies for both sporadic and genetic CCM malformations.
Documentation of Improved Outcomes for Intracranial Aneurysm Management Over a 15-Year Interval
Authors: Chua Michelle H. , Griessenauer Christoph J. , Stapleton Christopher J. , He Lucy , Thomas Ajith J. , Ogilvy Christopher S. 
Published: February 2016

Background and Purpose—
Despite rapid advancements in intracranial aneurysm management, there is no evidence as of yet that this has translated into improvement in overall prognosis.

Methods—
We compared 2 periods of aneurysm management, 1998 to 2003 (n=1023 aneurysms) and 2007 to 2013 (n=1499 aneurysms), at a single, high-volume neurovascular center. Our outcome of interest was low or moderate disability (Glasgow Outcome Scale score of 4 or 5) at 6 months or more post treatment.

Results—

There were significant improvements in outcome for surgical, endovascular, and overall treatment of unruptured (adjusted odds ratio [OR], 2.33;
P
=0.0091; adjusted OR, 4.40;
P
=0.0271; and adjusted OR, 2.58;
P
=0.0008, respectively) and ruptured (adjusted OR, 3.18;
P
=0.0004; adjusted OR, 3.54;
P
=0.0001; and adjusted OR, 3.11;
P
<0.0001, respectively) aneurysms from the first to the second time period. In 2007 to 2013, the proportion of cases with low or moderate disability at 6 months post subarachnoid hemorrhage was 75.6% for surgical clipping and 76.6% for endovascular therapy.

Conclusions—
We report significantly improved outcomes over time for overall aneurysm management and for multiple patient subgroups, associated with increased usage of endovascular therapy.
Taxonomic assessment of fossil Holocene coralline red algae (Rhodophyta, Corallinales, Hapalidiales) from southwestern Atlantic
Authors: Tâmega Frederico Tapajós de Souza , De Oliveira Paula Spotorno , Coutinho Ricardo , Bassi Davide 
Published: February 2016

Holocene shallow-water carbonate and mixed siliciclastic-carbonate deposits from the Arraial do Cabo Bay, Brazil, southwestern Atlantic, contain well-preserved coralline red algae. These comprise four species of three genera representing the subfamilies Lithophylloideae, Mastophoroideae and Melobesioideae: Lithophyllum pustulatum, Spongites fruticulosus, Spongites yendoi, Mesophyllum engelharti. Geniculate corallines are present as algal debris. This study represents the first fossil record of these species in southwestern Atlantic Ocean. They inhabited the studied area since at least 13.000 years and are still thriving in the present-day assemblages. Only L. pustulatum and S. fruticulosus have old fossil records traced back into the Oligocene from the Mediterranean region. From ca. 3.000 years ago these species thrive in intertidal settings along the southwestern Atlantic Ocean coasts, which have been characterized by a regressive sea-level trend.
On the Potential for Abrupt Arctic Winter Sea Ice Loss
Authors: Bathiany S. , Notz D. , Mauritsen T. , Raedel G. , Brovkin V. 
Published: February 2016

Abstract
The authors examine the transition from a seasonally ice-covered Arctic to an Arctic Ocean that is sea ice free all year round under increasing atmospheric CO2 levels. It is shown that in comprehensive climate models, such loss of Arctic winter sea ice area is faster than the preceding loss of summer sea ice area for the same rate of warming. In two of the models, several million square kilometers of winter sea ice are lost within only one decade. It is shown that neither surface albedo nor cloud feedbacks can explain the rapid winter ice loss in the climate model MPI-ESM by suppressing both feedbacks in the model. The authors argue that the large sensitivity of winter sea ice area in the models is caused by the asymmetry between melting and freezing: an ice-free summer requires the complete melt of even the thickest sea ice, which is why the perennial ice coverage decreases only gradually as more and more of the thinner ice melts away. In winter, however, sea ice areal coverage remains high as long as sea ice still forms, and then drops to zero wherever the ocean warms sufficiently to no longer form ice during winter. The loss of basinwide Arctic winter sea ice area, however, is still gradual in most models since the threshold mechanism proposed here is reversible and not associated with the existence of multiple steady states. As this occurs in every model analyzed here and is independent of any specific parameterization, it is likely to be relevant in the real world.
Which Aspects of CO2 Forcing and SST Warming Cause Most Uncertainty in Projections of Tropical Rainfall Change over Land and Ocean?
Authors: Chadwick Robin 
Published: February 2016

Abstract
The sources of intermodel uncertainty in regional tropical rainfall projections are examined using a framework of atmosphere-only experiments. Uncertainty is dominated by model disagreement on shifts in convective regions, but the drivers of this uncertainty differ between land and ocean. Over the tropical oceans SST pattern uncertainty plays a substantial role, although it is not the only cause of uncertainty. Over land SST pattern uncertainty appears to be much less influential, and the largest source of uncertainty comes from the response to uniform SST warming, with a secondary contribution from the response to direct CO2 forcing. This may be because a larger number of processes can cause rainfall change in response to uniform SST warming than direct CO2 forcing, and so there is more potential for models to disagree. However, new experiments designed to more accurately decompose the regional climate responses of coupled models, combined with results from high-resolution climate modeling, are needed before these results can be considered robust. The pattern of present-day rainfall does not in general provide emergent constraints on future regional rainfall change. Correlations between relative humidity (RH) change and spatial shifts in convection over many land regions suggest that a proposed causal influence of RH change on dynamical rainfall change is plausible, although causality is not demonstrated here.