bluuebunny/crossref_metadata_2025 huggingface dataset:
Bivalent Chromatin Domains in Glioblastoma Reveal a Subtype-Specific Signature of Glioma Stem Cells
Authors: Hall Amelia Weber , Battenhouse Anna M. , Shivram Haridha , Morris Adam R. , Cowperthwaite Matthew C. , Shpak Max , Iyer Vishwanath R.
Published: March 2018

Glioblastoma multiforme (GBM) can be clustered by gene expression into four main subtypes associated with prognosis and survival, but enhancers and other gene-regulatory elements have not yet been identified in primary tumors. Here, we profiled six histone modifications and CTCF binding as well as gene expression in primary gliomas and identified chromatin states that define distinct regulatory elements across the tumor genome. Enhancers in mesenchymal and classical tumor subtypes drove gene expression associated with cell migration and invasion, whereas enhancers in proneural tumors controlled genes associated with a less aggressive phenotype in GBM. We identified bivalent domains marked by activating and repressive chromatin modifications. Interestingly, the gene interaction network from common (subtype-independent) bivalent domains was highly enriched for homeobox genes and transcription factors and dominated by SHH and Wnt signaling pathways. This subtype-independent signature of early neural development may be indicative of poised dedifferentiation capacity in glioblastoma and could provide potential targets for therapy.

Significance: Enhancers and bivalent domains in glioblastoma are regulated in a subtype-specific manner that resembles gene regulation in glioma stem cells. Cancer Res; 78(10); 2463–74. ©2018 AACR.
Phase I Study of Single-Agent Utomilumab (PF-05082566), a 4-1BB/CD137 Agonist, in Patients with Advanced Cancer
Authors: Segal Neil H. , He Aiwu R. , Doi Toshihiko , Levy Ronald , Bhatia Shailender , Pishvaian Michael J. , Cesari Rossano , Chen Ying , Davis Craig B. , Huang Bo , Thall Aron D. , Gopal Ajay K.
Published: March 2018

Purpose: Utomilumab (PF-05082566) is an agonistic mAb that engages the immune costimulatory molecule 4-1BB/CD137. In this first-in-human, phase I, open-label, multicenter, multiple-dose study (NCT01307267) we evaluated safety, tolerability, pharmacokinetics, preliminary clinical activity, and pharmacodynamics of single-agent utomilumab in patients with advanced malignancies.

Experimental Design: Dose escalation was based on a standard 3+3 design for doses of utomilumab from 0.006 to 0.3 mg/kg every 4 weeks and a time-to-event continual reassessment method for utomilumab 0.6 to 10 mg/kg every 4 weeks. The primary study endpoint was dose-limiting toxicity (DLT) in the first two cycles.

Results: Utomilumab demonstrated a well-tolerated safety profile (N = 55). None of the patients experienced a DLT at the dose levels evaluated. The most common treatment-related adverse events were fatigue, pyrexia, decreased appetite, dizziness, and rash (<10% of patients). Only one (1.8%) patient experienced a grade 3–4 treatment-related adverse event (fatigue), and no clinically relevant elevations in transaminases were noted. Utomilumab demonstrated linear pharmacokinetics at doses ranging from 0.006 to 10 mg/kg, with similar safety and pharmacokinetics in anti-drug antibody (ADA)-negative and ADA-positive patients. The overall objective response rate was 3.8% (95% CI, 0.5%–13.0%) in patients with solid tumors and 13.3% in patients with Merkel cell carcinoma, including a complete response and a partial response. Circulating biomarkers support 4-1BB/CD137 engagement by utomilumab and suggest that circulating lymphocyte levels may influence probability of clinical benefit.

Conclusions: The favorable safety profile and preliminary antitumor activity demonstrated by utomilumab warrant further evaluation in patients with advanced malignancies. Clin Cancer Res; 24(8); 1816–23. ©2018 AACR.
Dual Inhibition of IGF-1R and ErbB3 Enhances the Activity of Gemcitabine and Nab-Paclitaxel in Preclinical Models of Pancreatic Cancer
Authors: Camblin Adam J. , Pace Emily A. , Adams Sharlene , Curley Michael D. , Rimkunas Victoria , Nie Lin , Tan Gege , Bloom Troy , Iadevaia Sergio , Baum Jason , Minx Charlene , Czibere Akos , Louis Chrystal U. , Drummond Daryl C. , Nielsen Ulrik B. , Schoeberl Birgit , Pipas J. Marc , Straubinger Robert M. , Askoxylakis Vasileios , Lugovskoy Alexey A.
Published: March 2018

Purpose: Insulin-like growth factor receptor 1 (IGF-1R) is critically involved in pancreatic cancer pathophysiology, promoting cancer cell survival and therapeutic resistance. Assessment of IGF-1R inhibitors in combination with standard-of-care chemotherapy, however, failed to demonstrate significant clinical benefit. The aim of this work is to unravel mechanisms of resistance to IGF-1R inhibition in pancreatic cancer and develop novel strategies to improve the activity of standard-of-care therapies.

Experimental Design: Growth factor screening in pancreatic cancer cell lines was performed to identify activators of prosurvival PI3K/AKT signaling. The prevalence of activating growth factors and their receptors was assessed in pancreatic cancer patient samples. Effects of a bispecific IGF-1R and ErbB3 targeting antibody on receptor expression, signaling, cancer cell viability and apoptosis, spheroid growth, and in vivo chemotherapy activity in pancreatic cancer xenograft models were determined.

Results: Growth factor screening in pancreatic cancer cells revealed insulin-like growth factor 1 (IGF-1) and heregulin (HRG) as the most potent AKT activators. Both growth factors reduced pancreatic cancer cell sensitivity to gemcitabine or paclitaxel in spheroid growth assays. Istiratumab (MM-141), a novel bispecific antibody that blocks IGF-1R and ErbB3, restored the activity of paclitaxel and gemcitabine in the presence of IGF-1 and HRG in vitro. Dual IGF-1R/ErbB3 blocking enhanced chemosensitivity through inhibition of AKT phosphorylation and promotion of IGF-1R and ErbB3 degradation. Addition of istiratumab to gemcitabine and nab-paclitaxel improved chemotherapy activity in vivo.

Conclusions: Our findings suggest a critical role for the HRG/ErbB3 axis and support the clinical exploration of dual IGF-1R/ErbB3 blocking in pancreatic cancer. Clin Cancer Res; 24(12); 2873–85. ©2018 AACR.
Tetrandrine (TET) Induces Death Receptors Apo Trail R1 (DR4) and Apo Trail R2 (DR5) and Sensitizes Prostate Cancer Cells to TRAIL-Induced Apoptosis
Authors: Shishodia Gauri , Koul Sweaty , Dong Qin , Koul Hari K.
Published: March 2018

TNF-related apoptosis-inducing ligand (TRAIL) selectively induces apoptosis in cancer cells, but not in normal cells; as such, it is a promising therapeutic agent. However, therapeutic resistance limits its clinical use in many malignancies, including prostate cancer. Strategies to sensitize cancer cells to TRAIL are urgently needed. We demonstrate here that small-molecule tetrandrine (TET) potentially sensitizes previously resistant (LNCaP and C4-2B cells) and mildly sensitive (PC3 cells) prostate cancer cells to TRAIL-induced apoptosis, and they do so by upregulating mRNA expression and protein levels of death receptors Apo Trail R1 (DR4) and Apo Trail R2 (DR5). Using shRNA knockdown, we show critical requirement of DR4 and DR5 in sensitization of prostate cancer cells to TRAIL. We show that double knockdown of DR4 and DR5 abrogated the apoptotic effects of TET and TRAIL. We also demonstrate that TET-induced DR4 and DR5 expression is independent of p53 status. Given that loss of p53 is associated with progression of prostate cancer to CRPC and NEPC, our results show that TET, by acting as a TRAIL-sensitizing agent in prostate cancer, could serve as a potential therapeutic agent in CRPC and NEPC, for which there is no cure to date. Mol Cancer Ther; 17(6); 1217–28. ©2018 AACR.
The DNA-PK Inhibitor VX-984 Enhances the Radiosensitivity of Glioblastoma Cells Grown In Vitro and as Orthotopic Xenografts
Authors: Timme Cindy R. , Rath Barbara H. , O'Neill John W. , Camphausen Kevin , Tofilon Philip J.
Published: March 2018

Radiotherapy is a primary treatment modality for glioblastomas (GBM). Because DNA-PKcs is a critical factor in the repair of radiation-induced double strand breaks (DSB), this study evaluated the potential of VX-984, a new DNA-PKcs inhibitor, to enhance the radiosensitivity of GBM cells. Treatment of the established GBM cell line U251 and the GBM stem-like cell (GSC) line NSC11 with VX-984 under in vitro conditions resulted in a concentration-dependent inhibition of radiation-induced DNA-PKcs phosphorylation. In a similar concentration-dependent manner, VX-984 treatment enhanced the radiosensitivity of each GBM cell line as defined by clonogenic analysis. As determined by γH2AX expression and neutral comet analyses, VX-984 inhibited the repair of radiation-induced DNA double-strand break in U251 and NSC11 GBM cells, suggesting that the VX-984-induced radiosensitization is mediated by an inhibition of DNA repair. Extending these results to an in vivo model, treatment of mice with VX-984 inhibited radiation-induced DNA-PKcs phosphorylation in orthotopic brain tumor xenografts, indicating that this compound crosses the blood–brain tumor barrier at sufficient concentrations. For mice bearing U251 or NSC11 brain tumors, VX-984 treatment alone had no significant effect on overall survival; radiation alone increased survival. The survival of mice receiving the combination protocol was significantly increased as compared with control and as compared with radiation alone. These results indicate that VX-984 enhances the radiosensitivity of brain tumor xenografts and suggest that it may be of benefit in the therapeutic management of GBM. Mol Cancer Ther; 17(6); 1207–16. ©2018 AACR.
New Proposal to Define the Fascial System
Authors: Bordoni Bruno , Marelli Fabiola , Morabito Bruno , Castagna Roberto , Sacconi Beatrice , Mazzucco Paul
Published: March 2018

At the beginning of the third millennium, we still do not have a definition of ‘fascia' recognized as valid by every researcher. This article attempts to give a new definition of the fascial system, including the epidermis, by comparing the mechanical-metabolic characteristics of the connective tissue and the skin. In fact, according to the latest classification deriving from the Fascia Nomenclature Committee, the outer skin layer is not considered as part of the fascial continuum. This article highlights the reasons for taking the functional characteristics of the tissue into consideration, rather than its mere structure. A brief discussion will address the questions as to what is considered as fascial tissue and from which embryonic germ layer the epidermis is formed. The notion that all the layers intersect will be highlighted, demonstrating that quoting precise definitions of tissue stratification in the living organism probably does not correspond to what happens in vivo. What we propose as a definition is not to be regarded as a point of arrival but as another departure.
Red Blood Cell Transfusion in Preterm Infants: Current Evidence and Controversies
Authors: Howarth Claire , Banerjee Jayanta , Aladangady Narendra
Published: March 2018

The current evidence regarding the indication, advantages and risks of red blood cell transfusion (RBCT) for preterm infants is discussed. This is an important area in Neonatology to be examined given that 90% of extremely low birth weight infants receive RBCT and many controversies remain regarding when to transfuse and the risks of RBCT. The various treatment thresholds and guidelines used are presented and we compare the short-term clinical benefits of liberal and restrictive RBCT in preterm infants; the majority of these are equivocal and sadly long-term outcome data is limited. The latest evidence on how anaemia and blood transfusion affect organ perfusion in preterm infants is presented. This is important when trying to establish the optimal trigger threshold for RBCT in preterm infants, especially because the knowledge about the adaptive physiological responses to anaemia in very low birth weight infants and the effects of RBCT at various levels of anaemia is also inadequate. Further research into the physiological adaptive response to anaemia of varying degrees and to RBCT at different levels of anaemia in preterm infants of different gestational and post-natal ages is needed before we can conclusively guide the optimal timing and trigger thresholds for RBCT in preterm infants.
The Role of Epithelial Stat3 in Amelogenesis during Mouse Incisor Renewal
Authors: Zhang Bin , Meng Bo , Viloria Edward , Naveau Adrien , Ganss Bernhard , Jheon Andrew H.
Published: March 2018

The aim of this study was to evaluate the role of epithelial signal transducer and activator of transcription 3 (STAT3) in mouse incisor amelogenesis. Since Stat3 is expressed in the epithelial component of developing and adult mouse teeth, we generated and analyzed Krt14Cre/+;Stat3fl/fl mutant mice in which Stat3 was inactivated in epithelia including ameloblast progenitors and ameloblasts, the cells responsible for enamel formation. Histological analysis showed little enamel matrix in mutant incisors compared to controls. Delayed incisor enamel mineralization was demonstrated using micro-computed X-ray tomography analysis and was supported by an increase in the pre-expression distance of enamel-enriched proteins such as amelogenin, ameloblastin, and kallikrein-4. Lastly, scanning electron microscopy analysis showed little enamel mineralization in mutant incisors underneath the mesial root of the 1st molar; however, the micro-architecture of enamel mineralization was similar in the erupted portion of control and mutant incisors. Taken together, our findings demonstrate for the first time that the absence of epithelial Stat3 in mice leads to delayed incisor amelogenesis.
Evaluation of a Prognostic Homeopathic Questionnaire for Women with Premenstrual Disorders
Authors: Klein-Laansma Christien T. , Rutten Alexander L.B. , Jansen Jean Pierre C.H. , van Wietmarschen Herman , Jong Miek C.
Published: March 2018

Background/Aims: Validation of treatments with individually prescribed homeopathic medicines is a challenging task. A prognostic homeopathic patient questionnaire containing 140 keynote symptoms (highly characteristic of a specific homeopathic medicine) and an electronic algorithm to process the answers were used in 2 clinical studies. The algorithm outcome, based on total symptom scores, indicated 1 of 11 pre-selected homeopathic medicines for women with premenstrual syndrome and premenstrual dysphoric disorder (PMS/PMDD). Aims were (1) to estimate the prognostic values of keynote symptoms and (2) to evaluate the reliability of the homeopathic medicine ranking in the algorithm outcome. Methods: The prevalence of specific keynote symptoms was calculated in 145 women diagnosed with PMS/PMDD and in 40 included women with favorable outcomes using 1 of the 11 homeopathic medicines. Likelihood ratios (LRs) of the keynote symptoms were calculated. Pearson's correlations were calculated between 2 sets of total algorithm scores for 11 homeopathic medicines, obtained at 2 time points. Results: (1) A positive prognostic value (LR ≥ 1.5) was found in 34 keynote symptoms with a prevalence of 10-40%, with 10 symptoms already being connected to the corresponding homeopathic medicine in the algorithm. For example, the symptom ‘common cold of the nose before menstruation' indicated Magnesium carbonicum with LR = 7.47 (confidence interval (CI) 3.90-14.28). (2) Pearson's correlations for the reliability evaluation varied from 0.69 to 0.84. Conclusions: Recommendations can be made to improve the PMS algorithm with more accurate keynote symptoms. The prognostic questionnaire proved a reliable tool to rank 11 homeopathic medicines by total scores, based on keynote symptoms. This PMS algorithm can be used for the treatment of PMS/PMDD in clinical practice.
Effects of Kudingcha Nanoparticles in Hyperlipidaemic Rats Induced by a High Fat Diet
Authors: Zhang Hongliang , Zou Xiaoqin , Huang Qiuyan , Zhong Xiaobin , Huang Zhenguang
Published: March 2018

Background/Aims: The herbal medicine Kudingcha has a bitter taste and low bioavailability for lipid reduction. To improve the bioavailability and ameliorate the compliance, we prepared Kudingcha nanoparticles and investigated their effect in hyperlipidaemic rats. In addition, the safety and lipid-lowering mechanism of the Kudingcha nanoparticles were examined. Methods: Kudingcha nanoparticles were prepared by ionotropic gelation and spray-drying. Seventy rats were randomly assigned into eight groups: a normal fat diet group (NF), a high-fat group (HF), a spontaneous recovery group (SR), a Kudingcha group (KDC), a blank nanoparticle group (B-N), and a Kudingcha nanoparticle groups (low, medium and high doses). All groups (except for the normal fat diet group) were fed a high-fat diet to establish hyperlipidaemia. Different interventions were administered to the treatment groups for four weeks. Serum lipids were measured using commercially available kits according to the recommended protocols. Liver morphology and histopathology were examined by a light microscope. The mRNA and protein levels of TLR4 and NF-κB were determined by RT-PCR and Western blotting, respectively. In addition, acute toxicity was evaluated by the LD50 test. Results: The Kudingcha nanoparticles were spherical and had a smooth surface. The size distribution of the nanoparticles was 100-600 nm. Acute toxicity results revealed that the Kudingcha nanoparticles were a non-toxic substance. Compared with regular Kudingcha, TG and TC decreased distinctly in the Kudingcha nanoparticles, especially for the moderate and high dose groups (p<0.05). Moreover, the Kudingcha nanoparticles were superior in lowering body, liver and adipose tissue weights compared to Kudingcha (p<0.05). With respect to antioxidant properties, the nanoparticles also revealed an outstanding impact on serum SOD and MDA. In addition, liver morphology and histology in the moderate and high dose nanoparticle groups were similar to those in the normal group. Finally, the mRNA and protein expression levels of TLR4 and NF-κB in the liver tissue of the nanoparticle groups were significantly upregulated compared with the KDC group (p<0.05). Conclusions: Based on these results, we conclude that Kudingcha nanoparticles are a potent lipid-lowering agent and may have a potential role in the treatment of hyperlipidaemia and fatty liver disease.
Sumoylation of EphB1 Suppresses Neuroblastoma Tumorigenesis via Inhibiting PKCγ Activation
Authors: Chen Qin , Deng Rong , Zhao Xian , Yuan Haihua , Zhang Hailong , Dou Jinzhuo , Chen Ran , Jin Hui , Wang Yanli , Huang Jian , Yu Jianxiu
Published: March 2018

Background/Aims: An increasing number of studies have linked erythropoietin-producing hepatocellular carcinoma (Eph) family receptor tyrosine kinases to cancer progression. However, little knowledge is available about the regulation of their functions in cancer. Methods: SUMOylation was analyzed by performing Ni2+-NTA pull-down assay and immunoprecipitation. Cell proliferation, anchorage-independent growth, and tumorigenesis in vivo were examined by cell counting kit-8, soft agar colony formation assay, and a xenograft tumor mouse model, respectively. Results: We found that EphB1 was post-translationally modified by the small ubiquitin-like modifier (SUMO) protein at lysine residue 785. Analysis of wild-type EphB1 and SUMOylation-deficient EphB1 K785R mutant revealed that SUMOylation of EphB1 suppressed cell proliferation, anchorage-independent cell growth, and xenograft tumor growth. Mechanistic study showed that SUMOylation of EphB1 repressed activation of its downstream signaling molecule PKCγ, and consequently inhibited tumorigenesis. A reciprocal regulatory loop between PKCγ and SUMOylation of EphB1 was also characterized. Conclusion: Our findings identify SUMO1 as a novel key regulator of EphB1-mediated tumorigenesis.
Phosphodiesterase 4 Inhibitor Roflumilast Protects Rat Hippocampal Neurons from Sevoflurane Induced Injury via Modulation of MEK/ERK Signaling Pathway
Authors: Peng Sheng , Yan Hong-Zhu , Liu Pei-Rong , Shi Xiao-Wei , Liu Chun-Liang , Liu Qi , Zhang Yu
Published: March 2018

Background/Aims: Sevoflurane, a commonly used volatile anesthetic, recently has been found has neurotoxicity in the central nervous system of neonatal rodents. This study aimed to reveal whether phosphodiesterase 4 (PDE-4) inhibitor roflumilast has protective functions in sevoflurane-induced nerve damage. Methods: Hippocampal neurons were isolated from juvenile rats, and were exposed to sevoflurane with or without roflumilast treatment. Cell viability and apoptosis were respectively assessed by CCK-8 and flow cytometry. Western blot analysis was performed to detect the protein expressions of apoptosis-related factors, and core factors in MEK/ERK and mTOR signaling pathways. Results: Toxic effects of sevoflurane on hippocampal neurons were observed, as cell viability was reduced, apoptotic cell rate was increased, Bcl-2 was down-regulated, and Bax, cleaved caspase-3 and -9 were up-regulated after 1% sevoflurane exposure for 16 h. Sevoflurane exhibited a temporarily (less than 16 h) inhibitory effect on MEK/ERK pathway, but has no impact on mTOR pathway. Roflumilast promoted the release of cAMP and down-regulated the protein expression of PDE-4. Roflumilast (1 µM) alone has no impact on viability and apoptosis of hippocampal neurons. However, roflumilast increased cell viability and deceased apoptosis in sevoflurane-injured neurons. Besides, roflumilast could recover sevoflurane-induced deactivation of MEK/ERK pathway. Conclusion: To conclude, this study demonstrated a neuroprotective role of roflumilast in sevoflurane-induced nerve damage. Roflumilast promoted hippocampal neurons viability, and reduced apoptosis possibly via modulation of MEK/ERK signaling pathway.
Consolidation Chemotherapy Prevents Relapse by Indirectly Regulating Bone Marrow Adipogenesis in Patients with Acute Myeloid Leukemia
Authors: Liu Haiyan , Zhai Yuanmei , Zhao Wenli , Wan Yun , Lu Wei , Yang Shaoxin , Yu Yehua , Wei Yanyu , Li Zhiqiang , Shi Jun
Published: March 2018

Background/Aims: Chemotherapy is still the main strategy used to prevent the relapse of acute myeloid leukaemia (AML). As the most abundant stromal component in bone marrow (BM), marrow adipocytes have been previously shown to promote leukaemogenesis. The present study was designed to further validate whether marrow adipocytes exert synergistic effects on strengthening chemotherapeutic efficacy and evaluate the underlying mechanism. Methods: A retrospective study of BM biopsies from 80 patients with AML in remission and 71 control subjects was applied to quantitatively analyse the marrow adipocyte volume. Toxicity tests were used to assess the effect of chemotherapy drugs on BM cells. The possible mechanisms by which chemotherapy regulated the reduced marrow adipocyte content were investigated using antibody neutralization experiments, with an emphasis on growth differentiation factor 15 (GDF15). Results: In our study, the marrow adipocyte content was obviously reduced in the AML- complete remission (CR) group compared with the control group (P<0.001). Moreover, patients with a reduced adipocyte content exhibited longer relapse-free survival (RFS) (P<0.001). We also confirmed that GDF15 was overexpressed in mononuclear cells (MNCs) after treatment with chemotherapy drugs and partially blocked mesenchymal stem cells (MSCs) adipogenesis. Intriguingly, this inhibitory effect on adipogenesis was rescued by treatment with a neutralizing anti-GDF15 antibody. Conclusion: Chemotherapy indirectly inhibited adipogenesis by promoting GDF15 secretion from BM MNCs, subsequently strengthening the efficacy of consolidation chemotherapy in patients with AML during CR.
Prevalência de síndrome metabólica em pacientes curados de câncer pediátrico
Authors: Saragiotto Barbara , Neves Gustavo Ribeiro , Cliquet Marcelo Gil , Murazawa Marina Mayumi , Felipe Thiago Cardona
Published: March 2018

O câncer atinge cerca de doze mil crianças por ano no Brasil. Parte delas, quando submetida a tratamento, tende a possuir maiores chances de desenvolver Síndrome Metabólica. Introdução: As crianças e adolescentes tratadas de câncer tendem a desenvolver a síndrome metabólica devido a alterações que os radioterápicos e quimioterápicos propiciam. Essas disfunções acometem os tecidos: adiposo, osteomuscular, endotelial; o trato gastrointestinal e o fígado. Objetivos: Analisar a prevalência de síndrome metabólica em crianças curadas de câncer e comparar as variáveis estudadas. Materiais e Métodos: Avaliamos trinta e oito pacientes do Hospital GPACI que tenham terminado o tratamento de câncer há, no mínimo, cinco anos. Foram investigadas variáveis como: glicemia, pressão arterial, circunferência abdominal, HDL, triglicerídeos, tipo de câncer, tipo de tratamento e histórico familiar. Como grupo controle, utilizamos 20 irmãos dos pacientes analisados sob os mesmos parâmetros. Resultados: Sobreviventes tiveram maior chance de desenvolver síndrome metabólica (RR 2,1 Mid-p 0,27). Tanto no grupo controle quanto no grupo de curados, o HDL foi o índice que teve mais alterações, estando abaixo ou igual a 45mg/dL em 46% dos voluntários. Comparando o grupo estudado com o grupo controle, a circunferência abdominal foi o fator de maior relevância (RR 5,2 Mid-p 0,02). Discussão: Contrastamos a prevalência de síndrome metabólica encontrada nos curados de câncer tanto com seus irmãos quanto com crianças e adolescentes dos Estados Unidos da América. Em ambas as comparações, a prevalência no grupo estudado foi maior, o que é semelhante a outras pesquisas realizadas. Conclusão: A circunferência abdominal foi o fator que apresentou significância estatística e maior risco de acometer os sobreviventes de câncer infantil. Diferentemente de outros estudos, os outros índices não tiveram significância estatística, provavelmente pelo tamanho da amostra.
O circuito produtivo dos agrocombustíveis no Brasil sob a ordem do liberalismo transnacional: do controle estatal à hegemonia corporativa
Authors: Freitas Elisa Pinheiro de , Queirós Margarida Maria
Published: March 2018

Tomando o circuito produtivo dos agrocombustíveis no Brasil como caso de estudo, o propósito deste artigo é o de demonstrar as dinâmicas vinculadas ao seu processo de modernização e internacionalização, em particular, como as empresas transnacionais (ETN) que operam nesse circuito produtivo fomentando a produção de etanol de cana-de-açúcar e mais recentemente de milho têm: (i) condicionado os rumos das políticas estatais do Brasil, concentrando, por meio de subsídios e financiamentos, grande parte dos recursos públicos; (ii) influenciado a expansão de culturas e a organização do território brasileiro. Na primeira seção, abordam-se as políticas estatais brasileiras que tornaram possível a modernização do circuito agroenergético e, na segunda, o processo de internacionalização do circuito, intensificado sobretudo na primeira década do novo milênio e o papel impulsionador do Estado nesse processo. Por fim, é identificada a atuação das ETN nos (des)arranjos socioterritoriais a partir da expansão das culturas voltadas para a produção dos agrocombustíveis.
Território e saúde: circuitos da economia urbana dos equipamentos médicos no estado de São Paulo, de Virna Carvalho David
Authors: Creuz Villy
Published: March 2018

Lançado em 2016 pela editora Humanitas em parceria com a Fapesp, o livro analisa o território usado por diferentes agentes do sistema produtivo de equipamentos médico-hospitalares no estado de São Paulo, em particular, a partir de situações geográficas em Campinas, Ribeirão Preto e São José do Rio Preto. Oferece uma leitura sobre o papel complementar da participação de agentes pouco capitalizados que se relacionam com os serviços de saúde no país.
Gentrificação, preservação patrimonial e turismo: os novos sentidos da paisagem urbana na renovação das cidades
Authors: Paes Maria Tereza Duarte
Published: March 2018

A gentrificação constituiu-se em um processo de natureza dinâmica, seja em sua concepção conceitual ou em sua forma de expressão no espaço. Desde os anos 1990, a preservação de sítios históricos urbanos no Brasil e na América Latina serviu de âncora para a refuncionalização turística e a ascensão econômica de inúmeras cidades, articulou-se às estratégias políticas e econômicas de renovação urbana e ganhou inúmeras denominações a partir de visões teóricas ou técnicas, interesses políticos e escalas diferenciadas. Esses temas serão abordados aqui a partir de apontamentos de pesquisa teórico-conceitual e de argumentos empíricos de algumas cidades brasileiras e centros históricos da América Latina, fundamentando a reflexão sobre a gentrificação global e os seus processos inerentes de injustiça social na produção de novas paisagens e na apropriação seletiva do espaço urbano.
A inserção do Brasil no sistema-Terra, na totalidade-mundo e na economia mundial, segundo a geografia regional: de Vidal de la Blache a Pierre Monbeig (1911-1957)
Authors: Lira Larissa Alves de
Published: March 2018

Nesse artigo, o Brasil é visto como um espaço no qual se concebem uma visão naturalista do capitalismo e uma renovação epistemológica da geografia regional em direção a uma visão sistêmica, tendo como base as obras e os comentários de Vidal de la Blache, Albert Demangeon e Pierre Monbeig sobre o “país novo”. O território é visto como inserido num sistema-Terra, numa totalidade-mundo e numa economia mundial. A partir desses conceitos, propomos uma reflexão sobre como uma visão naturalista ou uma geo-história do capitalismo tardio pode ajudar a pensar os caminhos do desenvolvimento do país.
Mobilidade geográfica e acessibilidade: uma proposição teórica
Authors: Castillo Ricardo Abid
Published: March 2018

mobilidade geográfia e acessibilidade: uma proposição teórica
Socioeconomic Disparities in Adherence and Outcomes After Heart Transplant
Authors: Wayda Brian , Clemons Autumn , Givens Raymond C. , Takeda Koji , Takayama Hiroo , Latif Farhana , Restaino Susan , Naka Yoshifumi , Farr Maryjane A. , Colombo Paolo C. , Topkara Veli K.
Published: March 2018

Background:

There is mixed evidence of racial and socioeconomic disparities in heart transplant outcomes. Their underlying cause—and whether individual- or community-level traits are most influential—remains unclear. The current study aimed to characterize socioeconomic disparities in outcomes and identify time trends and mediators of these disparities.

Methods and Results:

We used United Network for Organ Sharing registry data and included 33 893 adult heart transplant recipients between 1994 and 2014. Socioeconomic status (SES) indicators included insurance, education, and neighborhood SES measured using a composite index. Black race and multiple indicators of low SES were associated with the primary outcome of death or retransplant, independent of baseline clinical characteristics. Blacks had lower HLA and race matching, but further adjustment for these and other graft characteristics only slightly attenuated the association with black race (HR, 1.25 after adjustment). This and the associations with neighborhood SES (HR, 1.19 for lowest versus highest decile), Medicare (HR, 1.17), Medicaid (HR, 1.29), and college education (HR, 0.90) remained significant after full adjustment. When comparing early (1994–2000) and late (2001–2014) cohorts, the disparities associated with the middle (second and third) quartiles significantly decreased over time, but those associated with lowest SES quartile and black race persisted. Low neighborhood SES was also associated with higher risks of noncompliance (HR, 1.76), rejection (HR, 1.28), hospitalization (HR, 1.13), and infection (HR, 1.10).

Conclusions:

Racial and socioeconomic disparities exist in heart transplant outcomes, but the latter may be narrowing over time. These disparities are not explained by differences in clinical or graft characteristics.
Longitudinal Assessment of Vascular Function With Sunitinib in Patients With Metastatic Renal Cell Carcinoma
Authors: Catino Anna B. , Hubbard Rebecca A. , Chirinos Julio A. , Townsend Ray , Keefe Stephen , Haas Naomi B. , Puzanov Igor , Fang James C. , Agarwal Neeraj , Hyman David , Smith Amanda M. , Gordon Mary , Plappert Theodore , Englefield Virginia , Narayan Vivek , Ewer Steven , ElAmm Chantal , Lenihan Daniel , Ky Bonnie
Published: March 2018

Background:

Sunitinib, used widely in metastatic renal cell carcinoma, can result in hypertension, left ventricular dysfunction, and heart failure. However, the relationships between vascular function and cardiac dysfunction with sunitinib are poorly understood.

Methods and Results:

In a multicenter prospective study of 84 metastatic renal cell carcinoma patients, echocardiography, arterial tonometry, and BNP (B-type natriuretic peptide) measures were performed at baseline and at 3.5, 15, and 33 weeks after sunitinib initiation, correlating with sunitinib cycles 1, 3, and 6. Mean change in vascular function parameters and 95% confidence intervals were calculated. Linear regression models were used to estimate associations between vascular function and left ventricular ejection fraction, longitudinal strain, diastolic function (E/e′), and BNP. After 3.5 weeks of sunitinib, mean systolic blood pressure increased by 9.5 mm Hg (95% confidence interval, 2.0–17.1;
P
=0.02) and diastolic blood pressure by 7.2 mm Hg (95% confidence interval, 4.3–10.0;
P
<0.001) across all participants. Sunitinib resulted in increases in large artery stiffness (carotid–femoral pulse wave velocity) and resistive load (total peripheral resistance and arterial elastance; all
P
<0.05) and changes in pulsatile load (total arterial compliance and wave reflection). There were no statistically significant associations between vascular function and systolic dysfunction (left ventricular ejection fraction and longitudinal strain). However, baseline total peripheral resistance, arterial elastance, and aortic impedance were associated with worsening diastolic function and filling pressures over time.

Conclusions:

In patients with metastatic renal cell carcinoma, sunitinib resulted in early, significant increases in blood pressure, arterial stiffness, and resistive and pulsatile load within 3.5 weeks of treatment. Baseline vascular function parameters were associated with worsening diastolic but not systolic function.
Bleeding Severity After Percutaneous Coronary Intervention
Authors: Redfors Björn , Généreux Philippe , Witzenbichler Bernhard , Kirtane Ajay J. , McAndrew Thomas , Weisz Giora , Stuckey Thomas D. , Henry Timothy D. , Maehara Akiko , Mehran Roxana , Stone Gregg W.
Published: March 2018

Background—

In-hospital bleeding after percutaneous coronary intervention is associated with increased mortality. We studied the impact of bleeding severity, defined as magnitude of Hgb (hemoglobin) reduction from baseline (ΔHgb), on the risk of death and other adverse events.

Methods and Results—

We studied the association between ΔHgb, baseline characteristics, and outcomes among 7608 patients in the ADAPT-DES registry (Assessment of Dual Antiplatelet Therapy With Drug-Eluting Stents) who had information on Hgb values before and after they underwent successful percutaneous coronary intervention. Post-percutaneous coronary intervention, 5985 (78.7%) patients had a drop in Hgb, with 2684 patients (35.3%) having a ΔHgb <1.0 g/dL, 2338 (30.7%) ≥1.0 to <2.0 g/dL, 745 (9.8%) ≥2.0 to <3.0 g/dL, 145 (1.9%) ≥3.0 to <4.0 g/dL, and 73 (1.0%) ≥4.0 g/dL. The risk of dying within 2 years was 3.3% with <1.0 g/dL ΔHgb, 3.4% with ΔHgb ≥1.0 to <2.0 g/dL, 3.7% with ΔHgb ≥2.0 to <3.0 g/dL, 4.1% with ΔHgb ≥3.0 to <4.0 g/dL, and 9.8% with ΔHgb ≥4.0 g/dL (
P
=0.03). The risk of major adverse cardiac events (defined as cardiac death, myocardial infarction, or stent thrombosis) was higher for patients with ΔHgb ≥4.0 g/dL (adjusted hazard ratio, 3.39; 95% confidence interval, 1.97–5.83;
P
<0.001) and for patients with ΔHgb ≥3.0 to <4.0 g/dL (adjusted hazard ratio, 2.17; 95% confidence interval, 1.34–3.53;
P
=0.002).

Conclusions—

Among patients who undergo successful percutaneous coronary intervention, bleeding events that result in ΔHgb ≥4.0 g/dL are associated with a considerably increased risk of dying.

Clinical Trial Registration—

URL:
https://www.clinicaltrials.gov
. Unique identifier: NCT00638794.
Clinical Outcomes and Prognosis Markers of Patients With Liver Disease Undergoing Transcatheter Aortic Valve Replacement
Authors: Tirado-Conte Gabriela , Rodés-Cabau Josep , Rodríguez-Olivares Ramón , Barbanti Marco , Lhermusier Thibault , Amat-Santos Ignacio , Toggweiler Stefan , Cheema Asim N. , Muñoz-García Antonio J. , Serra Vicenc , Giordana Francesca , Veiga Gabriela , Jiménez-Quevedo Pilar , Campelo-Parada Francisco , Loretz Lucca , Todaro Denise , del Trigo María , Hernández-García José M. , García del Blanco Bruno , Bruno Francesco , de la Torre Hernández José M. , Stella Pieter , Tamburino Corrado , Macaya Carlos , Nombela-Franco Luis
Published: March 2018

Background—

Chronic liver disease is a known risk factor for perioperative morbidity and mortality in patients undergoing cardiac surgery. Very little data exist about such patients treated with transcatheter aortic valve replacement (TAVR). Our objective was to evaluate early and late clinical outcomes in a large cohort of patients with liver disease undergoing TAVR and to determine predictive factors of mortality among these patients.

Methods and Results—

This multicenter study collected data from 114 patients with chronic liver disease who underwent TAVR in 12 institutions. Perioperative and long-term outcomes were compared with a cohort of 1118 patients without liver disease after a propensity score–matching analysis (114 matched pairs). In-hospital mortality and vascular and bleeding complications were similar between matched groups. Acute kidney injury was more common in liver disease group (30.8% versus 13.5%;
P
=0.010). Although cardiovascular mortality was similar between groups (9.4% versus 6.5%;
P
=0.433) at 2-year follow-up, noncardiac mortality was higher in the liver group (26.4% versus 14.8%;
P
=0.034). Lower glomerular filtration rate (hazard ratio, 1.10, for each decrease of 5 mL/min in estimated glomerular filtration rate; 95% confidence interval, 1.03–1.17;
P
=0.005) and Child-Pugh class B or C (hazard ratio, 3.11; 95% confidence interval, 1.47–6.56;
P
=0.003) were the predictors of mortality in patients with chronic liver disease, with a mortality rate of 83.2% at 2-year follow-up in patients with both factors (estimated glomerular filtration rate <60 mL/min and Child-Pugh B or C).

Conclusions—

These findings suggested that TAVR is a feasible treatment for severe aortic stenosis in patients with early-stage liver disease or as bridge therapy before a curative treatment of the hepatic condition. Patients with Child-Pugh class B-C, especially in combination with renal impairment, had a very low survival rate, and TAVR should be carefully considered to avoid a futile treatment. These results may contribute to improve the clinical decision-making process and management in patients with liver disease.
Risk Factors for Poststroke Cognitive Decline
Authors: Levine Deborah A. , Wadley Virginia G. , Langa Kenneth M. , Unverzagt Frederick W. , Kabeto Mohammed U. , Giordani Bruno , Howard George , Howard Virginia J. , Cushman Mary , Judd Suzanne E. , Galecki Andrzej T.
Published: March 2018

Background and Purpose—

Poststroke cognitive decline causes disability. Risk factors for poststroke cognitive decline independent of survivors’ prestroke cognitive trajectories are uncertain.

Methods—

Among 22 875 participants aged ≥45 years without baseline cognitive impairment from the REGARDS cohort (Reasons for Geographic and Racial Differences in Stroke), enrolled from 2003 to 2007 and followed through September 2015, we measured the effect of incident stroke (n=694) on changes in cognitive functions and cognitive impairment (Six-Item Screener score <5) and tested whether patient factors modified the effect. Median follow-up was 8.2 years.

Results—

Incident stroke was associated with acute declines in global cognition, new learning, verbal memory, and executive function. Acute declines in global cognition after stroke were greater in survivors who were black (
P
=0.04), men (
P
=0.04), and had cardioembolic (
P
=0.001) or large artery stroke (
P
=0.001). Acute declines in executive function after stroke were greater in survivors who had <high school education versus college graduates (
P
=0.01). Incident stroke was associated with faster declines in global cognition and executive function but not new learning or verbal memory compared with prestroke slopes. Faster declines in global cognition over years after stroke were greater in survivors who were older (
P
<0.01), resided outside the Stroke Belt (
P
=0.005), or had cardioembolic stroke (
P
=0.01). Faster declines in executive function over years after stroke were greater in survivors who were older (
P
<0.01) or lacked hypertension (
P
=0.03).

Conclusions—

Incident stroke alters a patient’s cognitive trajectory, and this effect is greater with increasing age and cardioembolic stroke. Race, sex, geography, and hypertension status may modify the risk of poststroke cognitive decline.
Time From Imaging to Endovascular Reperfusion Predicts Outcome in Acute Stroke
Authors: Tsai Jenny P. , Mlynash Michael , Christensen Soren , Kemp Stephanie , Kim Sun , Mishra Nishant K. , Federau Christian , Nogueira Raul G. , Jovin Tudor G. , Devlin Thomas G. , Akhtar Naveed , Yavagal Dileep R. , Bammer Roland , Straka Matus , Zaharchuk Gregory , Marks Michael P. , Albers Gregory W. , Lansberg Maarten G.
Published: March 2018

Background and Purpose—

This study aims to describe the relationship between computed tomographic (CT) perfusion (CTP)-to-reperfusion time and clinical and radiological outcomes, in a cohort of patients who achieve successful reperfusion for acute ischemic stroke.

Methods—

We included data from the CRISP (Computed Tomographic Perfusion to Predict Response in Ischemic Stroke Project) in which all patients underwent a baseline CTP scan before endovascular therapy. Patients were included if they had a mismatch on their baseline CTP scan and achieved successful endovascular reperfusion. Patients with mismatch were categorized into target mismatch and malignant mismatch profiles, according to the volume of their Tmax >10s lesion volume (target mismatch, <100 mL; malignant mismatch, >100 mL). We investigated the impact of CTP-to-reperfusion times on probability of achieving functional independence (modified Rankin Scale, 0–2) at day 90 and radiographic outcomes at day 5.

Results—

Of 156 included patients, 108 (59%) had the target mismatch profile, and 48 (26%) had the malignant mismatch profile. In patients with the target mismatch profile, CTP-to-reperfusion time showed no association with functional independence (
P
=0.84), whereas in patients with malignant mismatch profile, CTP-to-reperfusion time was strongly associated with lower probability of functional independence (odds ratio, 0.08;
P
=0.003). Compared with patients with target mismatch, those with the malignant mismatch profile had significantly more infarct growth (90 [49–166] versus 43 [18–81] mL;
P
=0.006) and larger final infarct volumes (110 [61–155] versus 48 [21–99] mL;
P
=0.001).

Conclusions—

Compared with target mismatch patients, those with the malignant profile experience faster infarct growth and a steeper decline in the odds of functional independence, with longer delays between baseline imaging and reperfusion. However, this does not exclude the possibility of treatment benefit in patients with a malignant profile.
Rescue Stenting for Failed Mechanical Thrombectomy in Acute Ischemic Stroke
Authors: Chang Yoonkyung , Kim Byung Moon , Bang Oh Young , Baek Jang-Hyun , Heo Ji Hoe , Nam Hyo Suk , Kim Young Dae , Yoo Joonsang , Kim Dong Joon , Jeon Pyoung , Baik Seung Kug , Suh Sang Hyun , Lee Kyung-Yul , Kwak Hyo Sung , Roh Hong Gee , Lee Young-Jun , Kim Sang Heum , Ryu Chang-Woo , Ihn Yon-Kwon , Kim Byungjun , Jeon Hong Jun , Kim Jin Woo , Byun Jun Soo , Suh Sangil , Park Jeong Jin , Lee Woong Jae , Roh Jieun , Shin Byoung-Soo , Kim Jeong-Min
Published: March 2018

Background and Purpose—

Effective rescue treatment has not yet been suggested in patients with mechanical thrombectomy (MT) failure. This study aimed to test whether rescue stenting (RS) improved clinical outcomes in MT-failed patients.

Methods—

This is a retrospective analysis of the cohorts of the 16 comprehensive stroke centers between September 2010 and December 2015. We identified the patients who underwent MT but failed to recanalize intracranial internal carotid artery or middle cerebral artery M1 occlusion. Patients were dichotomized into 2 groups: patients with RS and without RS after MT failure. Clinical and laboratory findings and outcomes were compared between the 2 groups. It was tested whether RS is associated with functional outcome.

Results—

MT failed in 148 (25.0%) of the 591 patients with internal carotid artery or middle cerebral artery M1 occlusion. Of these 148 patients, 48 received RS (RS group) and 100 were left without further treatment (no stenting group). Recanalization was successful in 64.6% (31 of 48 patients) of RS group. Compared with no stenting group, RS group showed a significantly higher rate of good outcome (modified Rankin Scale score, 0–2; 39.6% versus 22.0%;
P
=0.031) without increasing symptomatic intracranial hemorrhage (16.7% versus 20.0%;
P
=0.823) or mortality (12.5% versus 19.0%;
P
=0.360). Of the RS group, patients who had recanalization success had 54.8% of good outcome, which is comparable to that (55.4%) of recanalization success group with MT. RS remained independently associated with good outcome after adjustment of other factors (odds ratio, 3.393; 95% confidence interval, 1.192–9.655;
P
=0.022). Follow-up vascular imaging was available in the 23 (74.2%) of 31 patients with recanalization success with RS. The stent was patent in 20 (87.0%) of the 23 patients. Glycoprotein IIb/IIIa inhibitor was significantly associated with stent patency but not with symptomatic intracranial hemorrhage.

Conclusions—

RS was independently associated with good outcomes without increasing symptomatic intracranial hemorrhage or mortality. RS seemed considered in MT-failed internal carotid artery or middle cerebral artery M1 occlusion.
Ischemic Stroke Alters the Expression of the Transcribed Ultraconserved Regions of the Genome in Rat Brain
Authors: Mehta Suresh L. , Vemuganti Raghu
Published: March 2018

Background and Purpose—

Human and rodent genomes diverged ≈75 million years ago. However, 481 regions of their genomes (200–779 nucleotide each) remained absolutely conserved and form noncoding RNAs known as transcribed ultraconserved regions (T-UCRs). The functional significance of T-UCRs is not apparent, but their altered expression is associated with many diseases, and thus thought to be critical for life. We presently investigated the poststroke temporal changes in the expression of T-UCRs with potential functional significance.

Methods—

Male, spontaneously hypertensive rats were subjected to transient middle cerebral artery occlusion. Expression profile of T-UCRs was determined at 3, 6, and 12 hours of reperfusion using microarrays and real-time polymerase chain reaction in the peri-infarct cortex. The putative functional significance of stroke-responsive T-UCRs was identified by bioinformatics.

Results—

Ischemia altered expression of 69 T-UCRs at ≥1 time points of reperfusion compared with sham. Poststroke expression of the intragenic T-UCRs is independent of the expression of their parent gene mRNAs. Bioinformatics showed that the upstream/downstream and the parent genes of the T-UCRs modulate several biological and molecular functions, including metabolism, response to stimuli, cell communication, protein and nucleic acid binding.

Conclusions—

This first report shows that ischemic stroke temporally alters the noncoding ultraconserved RNAs in spontaneously hypertensive rats, but their functional significance is yet to be evaluated.