bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract B55: Role of HSF1 in chemotherapy-induced autophagy and endoplasmic reticulum stress response in breast cancer
Authors: Desai Shruti , Tan Ming
Published: May 2016

Heat Shock Factor 1 (HSF1), a master regulator of heat shock response, plays an important role in tumorigenesis. In this study we demonstrate that HSF1 is required for chemotherapeutic agents induced cytoprotective autophagy and Endoplasmic Reticulum (ER) stress response. HSF1 can transcriptionally regulate autophagy related gene ATG7 and ER membrane protein IRE1α. Interestingly, most of this regulation is independent of HSF1's heat shock function.

Treatment of cancer cells with FDA approved chemotherapeutic agent induced autophagy which was significantly decreased upon HSF1 knockdown. Mechanistic studies revealed that HSF1 regulates autophagy by directly binding to the ATG7 promoter and transcriptionally upregulating its expression. HSF1 also may play a role in regulating autophagy by modulating levels of phosphorylated AMPK, a key protein that can trigger autophagy. Thus HSF1 regulates the process of autophagy in a multi-pronged manner, through regulation of key autophagy protein as well as regulation of key inducer of autophagy. Furthermore, a strong positive correlation was observed between levels of HSF1 and ATG7 in breast cancer patient samples, thus validating our in vitro findings. Similarly, knockdown of HSF1 reduced the induction of ER stress response by chemotherapeutic agents. Mechanistic studies have revealed that HSF1 regulated cytoprotective ER stress response by directly regulating IRE1α expression and sustained activation. IRE1α, a resident ER protein, is a key sensor of ER stress. It activates Xbp1 leading to expression of protein chaperone genes that help alleviate the ER stress response. This HSF1/IRE1α pathway was further validated in cancer patients by immunohistochemistry staining of breast cancer patient tissue array.

This study identifies a critical role for HSF1 in controlling cytoprotective stress response pathways of autophagy and ER stress response in tumor cells. HSF1 does this by not only regulating transcription of key proteins required in these pathways but also by regulating activation of key inducers of these pathways. The findings from this study can be further used to design more robust treatment strategies for breast cancer patients thus improving their prognosis.

Citation Format: Shruti Desai, Ming Tan. Role of HSF1 in chemotherapy-induced autophagy and endoplasmic reticulum stress response in breast cancer. [abstract]. In: Proceedings of the AACR Special Conference: Metabolism and Cancer; Jun 7-10, 2015; Bellevue, WA. Philadelphia (PA): AACR; Mol Cancer Res 2016;14(1_Suppl):Abstract nr B55.
Abstract B68: Calorie restriction normalizes global microRNA expression by preventing the loss of Dicer expression during mammary tumorigenesis
Authors: Devlin Kaylyn L. , Sanford Tiffany , Mambo Elizabeth , Hursting Stephen D.
Published: May 2016

MicroRNA (miRNAs) are small, post-transcriptional regulators that play an integral role in maintenance of cellular functions and whose dysregulation has been shown to promote many types of cancer, including breast cancer. Global downregulation of miRNAs has emerged as a common theme in human breast tumors and has been shown to contribute to oncogenesis. One of the primary mechanisms through which miRNAs are globally dysregulated is downregulation of enzymes involved in miRNA biogenesis. We aim to establish how calorie restriction (CR), which potently inhibits breast cancer progression, regulates global miRNA expression and the expression of miRNA biogenesis enzymes in mammary tumors. To address these questions, 100 female Sprague Dawley rats were administered either dimethylbenz(a)anthracene (DMBA) or vehicle control at 50 days of age, then randomized to receive either control (AIN-76A) diet ad-libitum (n=40) or a 30% CR diet regiment (n=60). Resultant mammary tumors were allowed to develop for 12 weeks. Calorie restriction significantly increased survival to study endpoint relative to control diet (75% vs 35%, respectively) (p=0.0047). Furthermore, of the animals that developed tumors, CR significantly decreased median tumor area by 56% compared to control diet (109.4 mm2 vs 250.9 mm2, respectively) (p=0.0286). Global miRNA expression was analyzed by miRNA-specific sequencing. Calorie restriction had a broad effect on miRNA expression, illustrated by the fact that of all the miRNAs with a greater than two-fold expression difference between CR and control, 80% are overexpressed in CR tumors compared to control tumors. These results can be explained by the additional finding that CR was able to prevent the loss of Dicer expression, a key miRNA biogenesis enzyme, observed in control-fed mammary tumor tissue compared to normal tissue. This important finding suggests that global miRNA normalization through the retention of Dicer expression during cancer progression could be a contributing mechanism to CR's anticancer effects. We are further investigating these findings by exogenously overexpressing Dicer in Rama25 cells (derived from a DMBA-induced mammary tumor in a Sprague Dawley rat) and MCF7 cells, and analyzing the resultant tumorigenic potential in vitro and in vivo. The results obtained will provide insights into the mechanisms of breast cancer progression and how CR inhibits progression through microRNA modulation.

Citation Format: Kaylyn L. Devlin, Tiffany Sanford, Elizabeth Mambo, Stephen D. Hursting. Calorie restriction normalizes global microRNA expression by preventing the loss of Dicer expression during mammary tumorigenesis. [abstract]. In: Proceedings of the AACR Special Conference: Metabolism and Cancer; Jun 7-10, 2015; Bellevue, WA. Philadelphia (PA): AACR; Mol Cancer Res 2016;14(1_Suppl):Abstract nr B68.
Abstract IA03: Metabolic heterogeneity in cancer cells and tumors
Authors: DeBerardinis Ralph J.
Published: May 2016

Most diseases are accompanied by altered metabolism at the cellular level. In cancer, metabolic reprogramming that is, the regulated alteration of metabolism as a consequence of tumorigenic mutations and other factors is viewed as an essential component of malignant transformation. Research in cancer metabolism is motivated in part by the hope that understanding the basis of metabolic reprogramming will stimulate the development of new approaches in cancer imaging and therapy, both of which have historically capitalized on the altered metabolic states of tumors. Over the past decade, a large number of mechanisms by which oncogene-directed perturbations of signal transduction regulate intermediary metabolism have been defined. Conversely, it has also become apparent that metabolites themselves influence gene expression and signaling in ways that appear to promote malignancy. However, there is still little agreement as to the breadth of metabolic programs that can support cancer cell survival and growth, and more importantly, about which of the myriad metabolic activities observed in culture are relevant to bona fide tumor metabolism in vivo. I will discuss approaches to address these two challenges. First, I will discuss efforts to link functional metabolic pathway choices with oncogenotypes, gene expression networks and therapeutic sensitivities using a systematic analysis of a large panel of lung cancer cell lines. In these studies, cell-autonomous metabolic phenotypes were scored using a set of quantitative features (nutrient consumption, nutrient addiction, 13C labeling patterns), then cross-referenced against a rich set of orthogonal databases to identify genotype-phenotype connections and novel relationships between metabolism and therapeutic sensitivities. Second, I will describe efforts to probe metabolism in human tumors using methods that report on both cell-autonomous and non-cell autonomous influences. We have developed clinical studies involving a combination of pre-surgical imaging and intra-operative 13C infusions to assess metabolic heterogeneity between individual non-small cell lung cancers in human patients, and to characterize the extent of metabolic heterogeneity within individual tumors. Together, these efforts identify a complex but finite set of metabolic phenotypes that support cell growth and may predict therapeutic vulnerabilities. They also underscore the potential for both existing and novel imaging approaches to inform about metabolic phenotypes in vivo.

Citation Format: Ralph J. DeBerardinis. Metabolic heterogeneity in cancer cells and tumors. [abstract]. In: Proceedings of the AACR Special Conference: Metabolism and Cancer; Jun 7-10, 2015; Bellevue, WA. Philadelphia (PA): AACR; Mol Cancer Res 2016;14(1_Suppl):Abstract nr IA03.
Abstract IA20: Hypoxia, metabolism, and tumor progression
Authors: Simon Marie Celeste
Published: May 2016

Clear cell renal cell carcinoma (ccRCC) is the most common form of kidney malignancy. It is both chemotherapy and radiation resistant and current treatment options for this disease are limited, particularly because 1 out of 4 patients are diagnosed at a disseminated, metastatic disease state. Underlying these clinical characteristics are a number of changes at the molecular level, the most pronounced of which are metabolic alterations that promote malignancy. One of these modifications is to the urea cycle, which is the second most underexpressed metabolic pathway in ccRCC. The urea cycle occurs in the kidney and is involved in detoxification of free ammonia species. Two key enzymes in this cycle are arginase II (ARG2) and argininosuccinate synthase 1 (ASS1); ARG2 is included on chromosome 14q and loss of this region correlates with high malignancy grade and a poorer prognosis in ccRCC. Data from nearly 500 primary ccRCC tumors in The Cancer Genome Atlas (TCGA) dataset demonstrates that ARG2 exhibits copy number loss in 40% of ccRCC and is underexpressed at the mRNA level, whereas ASS1 is significantly underexpressed, but not deleted, in ccRCC compared to normal kidney tissue. In preliminary experiments, we have demonstrated that re-expressing these enzymes in ccRCC cell lines suppresses proliferation in vitro and in vivo during xenograft tumor growth. Furthermore, re-expression of ARG2 and ASS1 reduces glycolytic flux and decreases mTOR activity. The central hypothesis of our work is that ARG2 and ASS1 act as tumor suppressors by modulating urea cycle and glycolytic metabolism and by repressing mTORC1 dependent growth pathways. The objective is to define the molecular mechanisms by which ARG2 and ASS1 loss alters cellular metabolism to promote ccRCC tumor growth. Delineating these mechanisms will provide new therapeutic avenues to target in this disease.

Citation Format: Marie Celeste Simon. Hypoxia, metabolism, and tumor progression. [abstract]. In: Proceedings of the AACR Special Conference: Metabolism and Cancer; Jun 7-10, 2015; Bellevue, WA. Philadelphia (PA): AACR; Mol Cancer Res 2016;14(1_Suppl):Abstract nr IA20.
Abstract A33: Dual loss of the SWI/SNF complex ATPases SMARCA4/BRG1 and SMARCA2/BRM is highly sensitive and specific for small cell carcinoma of the ovary, hypercalcemic type.
Authors: Karnezis Anthony N. , Wang Yemin , Ramos Pilar , Hendricks William , Yin Holly , Oliva Esther , D'Angelo Emanuela , Prat Jaime , Nucci Marisa R. , Nielsen Torsten O. , Weissman Bernard E. , Trent Jeffrey M. , Gilks C Blake , Huntsman David G.
Published: May 2016

Small cell carcinoma of the ovary, hypercalcemic type (SCCOHT) is a lethal and sometimes familial ovarian tumor of young women and children. We and others recently discovered that over 90% of SCCOHT harbor inactivating mutations in the chromatin remodeling gene SMARCA4 with concomitant loss of its encoded protein SMARCA4 (BRG1), one of two mutually-exclusive ATPases of the SWI/SNF chromatin remodeling complex. To determine the specificity of SMARCA4 loss for SCCOHT, we examined the expression of SMARCA4 by immunohistochemistry (IHC) in more than 3000 primary gynecologic tumors. Among ovarian tumors, it was only absent in clear cell carcinoma (15 of 360, 4%). In the uterus, it was absent in endometrial stromal sarcomas (4 of 52, 8%) and high-grade endometrioid carcinomas (2 of 338, 1%). Recent studies have shown that SMARCA2 (BRM), the other mutually exclusive ATPase of the SWI/SNF complex, is necessary for survival of tumor cells lacking SMARCA4. Therefore, we examined SMARCA2 expression and discovered that all SMARCA4-negative SCCOHTs also lacked SMARCA2 protein by IHC, including the SCCOHT cell lines BIN67 and SCCOHT1. Among ovarian tumors, the SMARCA4/SMARCA2 dual loss phenotype appears completely specific for SCCOHT. SMARCA2 loss was not due to mutation but rather from an absence of mRNA expression, which was restored by treatment with the histone deacetylase (HDAC) inhibitor trichostatin A. Treatment with HDAC inhibitors or re-expression of either SMARCA4 or SMARCA2 potently inhibited the growth of BIN67 and SCCOHT1 cell lines. Our results indicate that SMARCA4 loss, either alone or with SMARCA2 loss, is the first highly sensitive and specific diagnostic immunohistochemical marker of SCCOHT, and that HDAC inhibitors are promising agents to explore for the treatment of SCCOHT.

Citation Format: Anthony N. Karnezis, Yemin Wang, Pilar Ramos, William Hendricks, Holly Yin, Esther Oliva, Emanuela D'Angelo, Jaime Prat, Marisa R. Nucci, Torsten O. Nielsen, Bernard E. Weissman, Jeffrey M. Trent, C Blake Gilks, David G. Huntsman. Dual loss of the SWI/SNF complex ATPases SMARCA4/BRG1 and SMARCA2/BRM is highly sensitive and specific for small cell carcinoma of the ovary, hypercalcemic type. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research: Exploiting Vulnerabilities; Oct 17-20, 2015; Orlando, FL. Philadelphia (PA): AACR; Clin Cancer Res 2016;22(2 Suppl):Abstract nr A33.
Abstract A73: CDK4/6 inhibition as maintenance therapy in ovarian cancer.
Authors: Iyengar Mangala , Coffman Lan , Buckanovich Ronald
Published: May 2016

Over 70% of patients with ovarian cancer who achieve a clinical remission with initial surgery and chemotherapy will relapse and die of their disease. Effective maintenance therapies that can improve the survival of ovarian cancer patients are clearly needed. CDK4/6 inhibitors have been studied as maintenance therapy in hematologic and breast malignancies. CDK4/6 inhibition prevents the G1-S cell cycle phase transition in retinoblastoma (RB1) wild-type cells, causing G0/G1 arrest. Thus, CDK4/6 inhibitor therapy could significantly slow the growth of residual cancer cells after chemotherapy and improve outcomes. Indeed, the CDK4/6 inhibitor palbociclib doubled progression-free survival from 10 to 20 months in late-stage breast cancer.

CDK4/6 inhibitors remain untested in ovarian cancer. TCGA analysis shows that almost 40% of ovarian cancer patients bear mutations or dysregulation of genes in the CDK4/6 pathway that could sensitize them to CDK4/6 inhibition. We therefore investigated the CDK4/6 inhibitor LEE-011 (Novartis) in serous ovarian cancer. As expected, LEE-011 treatment led to a dose-dependent delay in the growth of multiple RbWT cell lines. Growth arrest was associated with an increase in the number of cells in the G1/G0 phase of the cell cycle and a decrease in the number of cells in S/M phases of the cell cycle. By contrast, LEE-011 did not produce these effects in the Rbnull COV362 cell line. LEE-011 treatment produced a significant, dose-dependent increase in senescence associated β-galactosidase. Despite significant expression of senescence-associated markers, cells could regrow after termination of LEE-011 therapy, suggesting a potential pseudo-senescent state. Finally, LEE-011 treatment concurrent with cisplatin therapy significantly inhibited the re-growth of RbWT ovarian cancer cells. LEE-011 maintenance therapy after cisplatin treatment led to growth arrest in vitro. Interestingly, although LEE-011 alone failed to show an effect on the Rbnull COV362 cells, LEE-011 maintenance therapy following cisplatin decreased COV362 cell regrowth. This was associated with a dose-dependent decrease in the percentage of ALDH+ cancer stem-like cells.

Taken together, these data suggest that LEE-011 may be an effective maintenance therapy for ovarian cancer in not only RbWT cells but potentially even in Rbnull cells. In vivo studies confirming these results are ongoing.

Citation Format: Mangala Iyengar, Lan Coffman, Ronald Buckanovich. CDK4/6 inhibition as maintenance therapy in ovarian cancer. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research: Exploiting Vulnerabilities; Oct 17-20, 2015; Orlando, FL. Philadelphia (PA): AACR; Clin Cancer Res 2016;22(2 Suppl):Abstract nr A73.
Understanding Intratumoral Heterogeneity: Lessons from the Analysis of At-Risk Tissue and Premalignant Lesions in the Colon
Authors: Sievers Chelsie K. , Leystra Alyssa A. , Clipson Linda , Dove William F. , Halberg Richard B.
Published: May 2016

Advances in DNA sequencing have created new opportunities to better understand the biology of cancers. Attention is currently focused on precision medicine: does a cancer carry a mutation that is targetable with already available drugs? But, the timing at which multiple, targetable mutations arise during the adenoma to carcinoma sequence remains unresolved. Borras and colleagues identified mutations and allelic imbalance in at-risk mucosa and early polyps in the human colon. Their analyses indicate that mutations in key genes can arise quite early during tumorigenesis and that polyps are often multiclonal with at least two clones. These results are consistent with the “Big Bang” model of tumorigenesis, which postulates that intratumoral heterogeneity is a consequence of a mutational burst in the first few cell divisions following initiation that drives divergence from a single founder with unique but related clones coevolving. Emerging questions center around the ancestry of the tumor and impact of early intratumoral heterogeneity on tumor establishment, growth, progression, and most importantly, response to therapeutic intervention. Additional sequencing studies in which samples, especially at-risk tissue and premalignant neoplasms, are analyzed from animal models and humans will further our understanding of tumorigenesis and lead to more effective strategies for prevention and treatment. Cancer Prev Res; 9(8); 638–41. ©2016 AACR.

See related article by Borras, et al., Cancer Prev Res 2016;9(6):417–427
Abstract A152: The macrophage migration inhibitory factor promotes breast cancer metastasis through interaction with the host immune response
Authors: Balogh Kristen N. , Cross Janet V.
Published: May 2016

The Macrophage Migration Inhibitory Factor (MIF) is an inflammatory cytokine that has been well-characterized as a mediator of numerous inflammatory disease processes, including in the setting of breast cancer. Ongoing research has shown that increased levels of MIF in breast cancer patient serum and biopsy samples are a marker of poor prognosis. We have previously demonstrated that expression of MIF in the primary tumor is required for spontaneous pulmonary metastasis in the 4T1 murine model of breast cancer. We hypothesized that MIF, as a cytokine, would promote metastasis by controlling some aspect of the interaction between the tumor and the host immune system. This was supported by our observation that MIF expression was no longer required for metastasis in an immunodeficient host lacking T, B, and NK cells. Using flow cytometry, we discovered that MIF expression in the primary tumor increased the abundance of a subset of myeloid-derived suppressor cells (MDSCs) in the tumor microenvironment. Furthermore, systemic depletion of MDSCs from tumor-bearing mice prevented spontaneous metastasis, suggesting that the MIF-induced increase in MDSCs is likely mediating the enhanced metastasis. These observations support a model in which MIF and MDSCs may be cooperating to protect the tumor cells from immune attack not only in the primary tumor, but also at sites of metastasis. Therefore, we hypothesize that MIF and MDSCs are functioning together to promote formation of a “metastatic niche” in the lung. Our ongoing studies aim to determine if MIF expression in the primary tumor drives matrix remodeling and/or establishment of an immunosuppressive microenvironment in the lungs of tumor-bearing mice, as well as whether inhibiting MIF pharmacologically can interrupt the process of niche formation. A more complete understanding of the role MIF plays in breast cancer development and metastasis will support deployment of MIF-targeted therapeutic interventions, as well as providing critical support for studies of how MIF inhibition might be combined with other immune-targeted therapies to enhance patient survival.

Citation Format: Kristen N. Balogh, Janet V. Cross. The macrophage migration inhibitory factor promotes breast cancer metastasis through interaction with the host immune response. [abstract]. In: Proceedings of the CRI-CIMT-EATI-AACR Inaugural International Cancer Immunotherapy Conference: Translating Science into Survival; September 16-19, 2015; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(1 Suppl):Abstract nr A152.
Effects of Polybrominated Diphenyl Ethers on Rat and Human 11β-Hydroxysteroid Dehydrogenase 1 and 2 Activities
Authors: Chen Xiaomin , Dong Yaoyao , Cao Shuyan , Li Xiaoheng , Wang Zhe , Chen Ruijie , Ge Ren-Shan
Published: May 2016

Polybrominated diphenyl ethers (PBDEs) are a class of brominated flame retardants. PBDEs have been widely used in textiles, flexible polyurethane foams, electronic components, electrical components, and plastics. 11β-Hydroxysteroid dehydrogenases, isoform 1 (HSD11B1) and isoform 2 (HSD11B2), have been demonstrated to be the regulators of local glucocorticoid levels. In this study, the potencies of 4 different PBDEs (BDE-3, BDE-47, BDE-100, and BDE-153) with 1-6 bromine atoms attached in inhibition of rat and human HSD11B1 and HSD11B2 activities were compared to 4-bromobiphenyl (BBP), a structurally similar compound. All 4 PBDEs and BBP did not inhibit rat and human HSD11B1. BDE-3 and BDE-47 potently inhibited rat HSD11B2, and BDE-47 and BDE-153 potently inhibited human HSD11B2, with the half maximal inhibitory concentration values of 12.42, 5.95, 11.97, and 4.41 µmol/l, respectively. All PBDEs noncompetitively inhibited HSD11B2 when a steroid substrate was used. However, PBDEs exerted uncompetitive inhibition when the cofactor NAD+ was used. In conclusion, some PBDEs are selective inhibitors of HSD11B2, possibly causing excessive glucocorticoid action in local tissues.
Prevalência dos tipos sangüíneos A, B e AB em gatos domésticos mestiços da cidade de Porto Alegre, Rio Grande do Sul, Brasil
Authors: Lacerda Luciana De Almeida , Oliveira Simone Tostes de , Guerra Tatiana Amaral , Stein Gisele Guiomara , González Félix Hilario Díaz
Published: May 2016

O presente estudo teve como objetivo determinar a prevalência dos tipos sangüíneos em felinos domésticos, mestiços, da cidade de Porto Alegre, Rio Grande do Sul, Brasil. Foram selecionados aleatoriamente 100 gatos, clinicamente saudáveis, mestiços e sem parentesco entre si. Amostras de sangue foram coletadas da veia jugular e a tipagem sangüínea foi realizada através do teste RapidVet H Feline (DMS Laboratories, Flemington, USA) e do teste hemaglutinação em tubo de ensaio. A tipagem reversa foi realizada para confirmar o tipo e a presença de aloanticorpos naturais. No presente estudo encontrou-se prevalência de 97% e 3% de gatos do tipo A e B, respectivamente. Não foram encontrados gatos do tipo AB. Os resultados indicam que no sul do Brasil há uma alta prevalência de gatos domésticos mestiços do tipo A, entretanto a prevalência de gatos do tipo B encontrada no trabalho é mais alta do que aquelas relatadas em alguns países. O conhecimento da prevalência dos tipos sangüíneos da população de gatos de uma região pode auxiliar na determinação dos riscos de reações transfusionais e de ocorrência de isoeritrólise neonatal, e estes podem ser prevenidos através de tipagem sangüínea e teste de compatibilidade sangüínea.
Validação laboratorial e fisiológica de conjunto comercial para a quantificação de corticóides fecais em chimpanzé (Pan troglodytes) e orangotango (Pongo pygmaeus), cativos e submetidos a enriquecimentos ambientais
Authors: Pizzutto Cristiane Schilbach , Sgai Manuela Gonçalves Fraga Geronymo , Viau Priscila , Chelini Marie Odile Monier , Oliveira Cláudio Alvarenga de , Guimarães Marcelo Alcindo de Barros Vaz
Published: May 2016

Neste trabalho foi realizado estudo comparativo dos níveis de corticóides fecais (CF) de chimpanzé (Pan troglodytes) e orangotango (Pongo pygmaeus). Foram analisadas amostras coletadas em duas fases distintas, relacionadas com a introdução de técnicas de enriquecimento ambiental, a saber: Base (antes da introdução) e Habituação (imediatamente após). Realizamos as validações do conjunto comercial para radioimunoensaio ImmunuChemTM Double Antibody Corticosterone da MP Biomedicals, para mensuração de CF. A validação laboratorial dos conjuntos diagnósticos para uso em extrato fecal de primatas foi realizada pelo método de paralelismo, no qual, para cada espécie, concentrações conhecidas de corticosterona foram adicionadas a um pool de extratos fecais, sendo estas amostras analisadas em seguida. As inclinações das curvas obtidas nestes ensaios e da curva padrão do ensaio foram então comparadas. Os resultados obtidos para chimpanzé e orangotango, foram respectivamente, Y= 17,23+1,31*X;R^2=0,98 e Y=11,14+1,29*X; R^2=0,99. Para a validação fisiológica, foi utilizada a introdução de técnicas de enriquecimento ambiental como causador de aumento dos níveis de CF, conseqüentes à indução de resposta do tipo estresse. Os resultados foram expressos em médias e erros-padrão da média. As concentrações médias destes corticóides foram: chimpanzés: Base (5,90 +/-2,41x10³ ng/g de fezes), Habituação (14,92 +/- 4,66x10³ ng/g de fezes) e para o orangotango: Base (91,1 +/- 30,0x10³ ng/g de fezes), Habituação (185,1 +/- 57x10³ng/g de fezes). Houve diferença significativa (P<0,05) para os valores destes CF para ambas as espécies entre as duas fases estudadas.
Quantificação do interferon-tau durante o reconhecimento materno da gestação em fêmeas bovinas Bos taurus indicus
Authors: Giassetti Mariana Ianello , Pontes Eduardo Oliveira , Niemeyer Claudia , Siqueira Adriano Felipe Perez , Fedozzi Filipe , Lima Marcelo Cardoso , Marques Vanessa Belentani , Bertan Claudia Maria , Miglino Maria Angélica , Arruda Rubens Paes , Papa Paula Carvalho , Binelli Mario
Published: May 2016

Durante o período crítico do reconhecimento materno, compreendido entre o 15º e 19º dias da gestação, o concepto deve sintetizar competentemente moléculas capazes de bloquear a síntese de prostaglandina F2α (PGF2α) e a luteólise. Em bovinos, a principal macromolécula protéica envolvida em tal bloqueio é o interferon-tau (IFN-τ). Durante o período crítico, falhas neste reconhecimento determinam à mortalidade embrionária em até 40% das fêmeas inseminadas. Informações sobre o IFN-τ em animais Bos taurus indicus, ainda são restritas. Este estudo objetivou uma avaliação quantitativa do IFN-τ durante o período crítico do reconhecimento materno, em lavados uterinos obtidos por sonda de Foley (dias 14, 16 e 18 pósestro) ou post-mortem (dia 18 pós-estro). Para tanto, foram utilizadas fêmeas multíparas azebuadas (Bos taurus indicus), cíclicas ou prenhes, nos dias 14, 16 e 18 pós-estro. Para a obtenção dos lavados, os úteros foram infundidos com solução de Ringer Simples. Os lavados foram concentrados por ultra-filtração e liofilizados. As macromoléculas protéicas foram separadas por Eletroforese Unidimensional SDSPAGE, em gel com 15% de poliacrilamida. A quantificação do IFN-τ nos lavados uterinos foi realizada por Western-Blotting e densitometria. Tanto nos lavados obtidos por sonda de Foley quanto nos post-mortem foi possível observar bandas de proteínas que apresentaram reação cruzada com os anticorpos utilizados no Western-Blotting. O IFN-τ foi detectado apenas nos lavados uterinos post-mortem de vacas prenhes (P<0,05). A densidade óptica não foi afetada pelo dia do período crítico, estado (cíclico ou prenhe) ou interação dia x estado. Nos lavados post-mortem não houve efeito de peso do concepto ou concentração de progesterona plasmática no dia do lavado na densidade da banda protéica referente ao IFN-τ . Concluiu-se que a detecção e quantificação do IFN-τ no ambiente uterino de vacas azebuadas, nestas condições experimentais, é possível apenas em lavados uterinos obtidos post-mortem.
Calmodulin Mediates Ca
2+
-Dependent Inhibition of Tie2 Signaling and Acts as a Developmental Brake During Embryonic Angiogenesis
Authors: Yang Chansik , Ohk Jiyeon , Lee Ji Yeun , Kim Eun Jin , Kim Jiyoon , Han Sangyeul , Park Dongeun , Jung Hosung , Kim Chungho
Published: May 2016

Objective—

Angiogenesis, the process of building complex vascular structures, begins with sprout formation on preexisting blood vessels, followed by extension of the vessels through proliferation and migration of endothelial cells. Based on the potential therapeutic benefits of preventing angiogenesis in pathological conditions, many studies have focused on the mechanisms of its initiation as well as control. However, how the extension of vessels is terminated remains obscure. Thus, we investigated the negative regulation mechanism.

Approach and Results—

We report that increased intracellular calcium can induce dephosphorylation of the endothelial receptor tyrosine kinase Tie2. The calcium-mediated dephosphorylation was found to be dependent on Tie2–calmodulin interaction. The Tyr1113 residue in the C-terminal end loop of the Tie2 kinase domain was mapped and found to be required for this interaction. Moreover, mutation of this residue into Phe impaired both the Tie2-calmodulin interaction and calcium-mediated Tie2 dephosphorylation. Furthermore, expressing a mutant Tie2 incapable of binding to calmodulin or inhibiting calmodulin function in vivo causes unchecked growth of the vasculature in
Xenopus
. Specifically, knockdown of Tie2 in
Xenopus
embryo retarded the sprouting and extension of intersomitic veins. Although human Tie2 expression in the Tie2-deficient animals almost completely rescued the retardation, the Tie2(Y1113F) mutant caused overgrowth of intersomitic veins with strikingly complex and excessive branching patterns.

Conclusions—

We propose that the calcium/calmodulin-dependent negative regulation of Tie2 can be used as an inhibitory signal for vessel growth and branching to build proper vessel architecture during embryonic development.
Survival Analysis After Extracorporeal Membrane Oxygenation in Critically Ill Adults
Authors: Chang Chia-Hsuin , Chen Hsi-Chieh , Caffrey James L. , Hsu Jiun , Lin Jou-Wei , Lai Mei-Shu , Chen Yih-Sharng
Published: May 2016

Background—

Extracorporeal membrane oxygenation (ECMO) provides circulatory and respiratory support for patients with severe acute cardiopulmonary failure. The objective of this study was to examine the survival outcomes for patients who received ECMO.

Methods and Results—

Adult patients who received ECMO from September 1, 2002, to December 31, 2012, were identified from the Taiwan National Health Insurance Database associated with coronary artery bypass graft surgery, myocardial infarction/cardiogenic shock, injury, and infection/septic shock. A Cox regression model was used to determine hazard ratios and to compare 30-day and 1-year survival rates with the myocardial infarction/cardiogenic shock group used as the reference. The mean±SD age of the 4227-patient cohort was 57±17 years, and 72% were male. The overall mortalities were 59.8% and 76.5% at 1 month and 1 year. Survival statistics deteriorated sharply when ECMO was required for >3 days. Acute (30-day) survival was more favorable in the infection/septic shock (n=1076; hazard ratio, 0.61; 95% confidence interval, 0.55–0.67), coronary artery bypass graft surgery (n=1077; hazard ratio, 0.68; 95% confidence interval, 0.61–0.75), and injury (n=369, hazard ratio, 0.82; 95% confidence interval, 0.70–0.95) groups. The extended survival rapidly approached an asymptote near 20% for the infection/septic shock, myocardial infarction/cardiogenic shock (n=1705), and coronary artery bypass graft surgery groups. The pattern of survival for the injury group was somewhat better, exceeding 30% at year-end.

Conclusions—

Regardless of initial pathology, patients requiring ECMO were critically ill with similar guarded prognoses. Those in the trauma group had somewhat better outcomes. Determining the efficacy and cost-effectiveness of ECMO should be a critical future goal.
Mediators of Tradition – Embodiments of Doctrine in Rural Swedish Parish Life
Authors: Ideström Jonas
Published: May 2016

The aim of this article is to analyse how doctrines are embodied in local church life and how they mediate tradition in a local church and community. The article draws on a larger research project focusing on questions concerning ecclesial identity in rural areas of northern Sweden. The ecclesiological analysis and approach is inspired by Actor-Network Theory. The material embodiments of theological doctrines in the Eucharistic liturgy are interpreted as mediators of tradition within the thick fabric of the liturgy and the ecclesial context. The analysis results in a picture of the thick ecclesial fabric in which doctrines are mediated and given meaning in parish life. The article also shows how doctrines can be mediated and translated on a personal level in relation to the liturgy.
Praxis or Talk about Praxis? The Concept of Praxis in Ecclesiology
Authors: Schmiedel Ulrich
Published: May 2016

Churches are in crisis. The turn to praxis in ecclesiology appears to attend to the current crisis; yet, the appearance might be deceptive. Since post-liberal ecclesiologies – such as John Milbank’s – consider neither quantitative-empirical nor qualitative-empirical accounts of concrete churches, the turn might be assessed as a turn to talk about praxis instead of a turn to praxis. Confronting Milbank’s concept of praxis with the ecclesiology of Ernst Troeltsch (1865–1923), I argue that Troeltsch allows for accounts of concrete churches since he conceptualises the identity of Christianity not as a proposition but as a project. Hence, praxis is the criterion for the evaluation of concepts of identity. Both churches and reflections on churches are to be ‘elasticised’ in order to attend to the current crisis.
Lectotypification of Bauhinia monandra (Fabaceae: Caesalpinioideae)
Authors: BANDYOPADHYAY SUBIR
Published: May 2016

The name Bauhinia monandra is lectotypified here.
Olifantiella elisabethiana, a new raphid diatom species (Bacillariophyta) observed in the Port of Antwerp (Belgium)
Authors: VAN DE VIJVER BART , MERTENS ADRIENNE , VAN DAM HERMAN
Published: May 2016

During an extensive analysis of the diatom flora of the Port of Antwerp (Belgium) in 2008, an unknown naviculoid taxon was observed. Detailed morphological investigations using light, scanning electron and transmission electron microscopy resulted in the description of this unknown taxon as Olifantiella elisabethiana Van de Vijver sp. nov. This new small-celled, biraphid species is characterized in having a typical internal process named buciniportula, opening externally by a pore or slit, unseriate striae composed of one single transapically elongated areola and a siliceous hymenous velum extending internally from the valve mantle to halfway the valve margin and the axial area. The morphological observations allowed to precise the characterization of the genus Olifantiella. A modification of the original description is proposed with regard to the internal structure. The presence of this Olifantiella species in the northern hemisphere is briefly discussed as all other known taxa of this genus have only been found in the tropical coastal waters of the Indian and Pacific Ocean.
Passiflora creuci-caetanoae a new species of Passiflora L. supersection Tacsonia (Passifloraceae) from Colombia
Authors: BONILLA MORALES MIGUEL MACGAYVER , AGUIRRE-MORALES CAROLINA , CARDENAS JULIAN
Published: May 2016

A new species of Passiflora from the Andes of Cundinamarca and Meta regions (Colombian Eastern Cordillera) is described and illustrated. P. creuci-caetanoae is morphologically similar to the species of the section Colombianae ser. Colombianae, in particular with P. cuatrecasasii and P. adulterina. P. creuci-caetanoae is characterized by its straight trichomes, ovate-lanceolate leaves with truncate base, ensiform stipules and obovate petals. In addition, an improved key to section Colombiana ser. Colombiane for Colombia is provided, and information about ecology, distribution, and conservation status of P. creuci-caetanoae are discussed.
Distribution of two species of Nephropsis Wood-Mason, 1872 (Crustacea, Decapoda, Nephropidae) from northeastern Brazil
Authors: ALVES-JÚNIOR FLAVIO DE ALMEIDA , ARAÚJO MARINA DE SÁ LEITÃO CÂMARA DE , SOUZA-FILHO JESSER F.
Published: May 2016

The genus Nephropsis Wood-Mason, 1872 has been reported from Brazil by Tavares (1998), Tavares & Young (2002), Silva et al. (2003), Dall´Occo et al. (2007) and Serejo et al. (2007), recording Nephropsis aculeata Smith, 1881, N. rosea Bate, 1888 and N. agassizii A. Milne-Edwards, 1880, the last of which occurs in both northeastern and southeastern of Brazil.
Modulation of Daily Rainfall in Southern Vietnam by the Madden–Julian Oscillation and Convectively Coupled Equatorial Waves
Authors: van der Linden Roderick , Fink Andreas H. , Pinto Joaquim G. , Phan-Van Tan , Kiladis George N.
Published: May 2016

Rainfall extremes have a large socioeconomic relevance for southern Vietnam. More than 30 million people live in this low-lying, flood-prone region in Southeast Asia. In this study the influence of the Madden–Julian oscillation (MJO) and convectively coupled equatorial waves on the modulation of daily rainfall during the rainy season (May–October) is evaluated and quantified using an extensive station database and the gridded Asian Precipitation–Highly Resolved Observational Data Integration Toward Evaluation of Water Resources (APHRODITE) product for different phases of the equatorial waves.

The MJO, Kelvin, and equatorial Rossby (ER) waves significantly modulate daily rainfall in Vietnam south of 16°N. The MJO shows the most coherent signals across the region, followed by ER waves, whose influence is strongest in central Vietnam; Kelvin waves only affect the southern parts of Vietnam. For all waves, the frequency of occurrence of intense daily rainfall larger than 25 mm is significantly enhanced during wet phases, whereas the magnitude of rainfall anomalies is related to the wave’s amplitude only in the MJO and ER cases. A novel wave interference diagram reveals strong positive interferences of dry and wet anomalies when the MJO occurs concurrently with Kelvin and ER waves. In terms of causes of rainfall anomalies, the waves modulate tropospheric moisture convergence over the region, but a strong influence on the depth of the monsoon flow and the vertical wind shear is discernible from radiosonde data only for the MJO. The results suggest new opportunities for submonthly prediction of dry and wet spells in Indochina.
Enhanced Diapycnal Mixing due to Near-Inertial Internal Waves Propagating through an Anticyclonic Eddy in the Ice-Free Chukchi Plateau
Authors: Kawaguchi Yusuke , Nishino Shigeto , Inoue Jun , Maeno Katsuhisa , Takeda Hiroki , Oshima Kazuhiro
Published: May 2016

The Arctic Ocean is known to be quiescent in terms of turbulent kinetic energy (TKE) associated with internal waves. To investigate the current state of TKE in the seasonally ice-free Chukchi Plateau, Arctic Ocean, this study performed a 3-week, fixed-point observation (FPO) using repeated microstructure, hydrographic, and current measurements in September 2014. During the FPO program, the microstructure observation detected noticeable peaks of TKE dissipation rate ε during the transect of an anticyclonic eddy moving across the FPO station. Particularly, ε had a significant elevation in the lower halocline layer, near the critical level, reaching the order of 10−8 W kg−1. The ADCP-measured current displayed energetic near-inertial internal waves (NIWs) propagating via the stratification at the top and bottom of the anticyclone. According to spectral analyses of horizontal velocity, the waves had almost downward energy propagation, and its current amplitude reached ~10 cm s−1. The WKB scaling, incorporating vertical variations of relative vorticity, suggests that increased wave energy near the two pycnoclines was associated with diminishing group velocity at the corresponding depths. The finescale parameterization using observed near-inertial velocity and buoyancy frequency successfully reproduced the characteristics of observed ε, supporting that the near-inertial kinetic energy can be effectively dissipated into turbulence near the critical layer. According to a mixed layer slab model, a rapidly moving storm that has passed over in the first week likely delivered the bulk of NIW kinetic energy, eventually captured by the vortex, into the surface water.
Differentiation in key learning areas for gifted students in regular classes
Authors: Yuen Mantak , Chan Serene , Chan Cheri , Fung Dennis CL , Cheung Wai Ming , Kwan Tammy , Leung Frederick KS
Published: May 2016

Gifted students usually require much less time spent in practising and revising basic skills; instead, they benefit greatly from opportunities to work through the curriculum at a faster pace (acceleration). Teachers currently working with mixed-ability classes do not always find it easy to differentiate their teaching approach in this way, so there is a need to facilitate in-service professional development to provide teachers with practical strategies for implementing effective differentiation for gifted learners. In response, a project for primary school teachers was organized by a university in Hong Kong. The purposes of the project were (a) to enhance the confidence of teachers in planning and delivering differentiated lessons in specific key learning areas (KLAs) with particular reference to gifted students; (b) to empower teachers with knowledge and strategies necessary for designing and implementing a differentiated curriculum in KLA domains and (c) to establish a professional development practice that connects local academics with schools and teachers. The project was implemented by inviting curriculum leaders, panel chairpersons and subject teachers from primary schools to attend a 3-hour lecture and a 6-hour workshop in which differentiation practices were explored. The project was later evaluated based on feedback from participants and university consultants. Overall, the feedback was positive, but suggestions are provided here for enhancing future projects of a similar nature.
Biocompatibility and cellular uptake mechanisms of poly(N-isopropylacrylamide) in different cells
Authors: Guo Zhong , Li Sha , Wang Changyong , Xu Jiake , Kirk Brett , Wu Jianping , Liu Zonghua , Xue Wei
Published: May 2016

Thermosensitive poly( N-isopropylacrylamide) is widely used in various biomedical applications including drug delivery systems, gene delivery systems, switching devices, sensors, and diagnostic assays. To promote these clinical applications, it is essential to have a comprehensive understanding of the biosafety of poly( N-isopropylacrylamide) and the interaction of poly( N-isopropylacrylamide) with different cell lines, which has little research until now. In this work, we evaluated the biocompatibility of poly( N-isopropylacrylamide) including cell viability, nitric oxide production, and apoptosis of macrophages RAW264.7, human bronchial epithelial cells, A549, and human umbilical vein endothelial cells in the presence of poly( N-isopropylacrylamide). We have also examined the cellular uptake mechanisms of poly( N-isopropylacrylamide) using endocytic inhibitors and insighted into the intracellular co-localization of poly( N-isopropylacrylamide) using confocal laser scanning microscope. The results showed that poly( N-isopropylacrylamide) had good biocompatibility and could be internalized by these cells. It is macropinocytosis that poly( N-isopropylacrylamide) could be internalized in RAW264.7 cells and caveolae-mediated endocytosis in human bronchial epithelial cells, A549, and human umbilical vein endothelial cells. In addition, we also evidenced that intracellular poly( N-isopropylacrylamide) was co-localized with lysosome. The study provided important information for the development and clinical applications of poly( N-isopropylacrylamide) in the biomedical field.
Variable dimensional chain of stroke-related mechanical assemblies
Authors: Hu Min , Ma Junxu , Zhao Wanhua
Published: May 2016

In traditional assembly dimensional chain theory, actual geometrical features are obtained by translating or rotating from the nominal geometrical features. Thus, the deviation stack-up function is irrelevant with the machining stroke. In order to solve this problem, a model describing the variation in the dimensional chain of stroke-related mechanical assemblies is proposed. The geometrical features of assembly parts are discretized as a set of coordinate points, and the traditional geometrical dimensional chain is equivalently replaced by several linear dimensional chains. For every linear dimensional chain, the assembly datum of two parts is deformed due to gravity or thermal effect and so on, resulting in the non-closure of dimensional chain. In this article, the closure of the dimensional chain is guaranteed by replacing the assembly datum by the plane determined by three highest points. Finally, an experiment was carried out to verify the necessity of constructing the variable dimensional chain and its accuracy. Combining this new model with Monte Carlo simulation method, the influence of gravity on tolerance analysis was analyzed, and the results show that the variation in the dimensional chain induced by working conditions cannot be ignored in the tolerance design stage.
Buprenorphine Versus Methadone for Opioid Dependence in Pregnancy
Authors: Noormohammadi Arezo , Forinash Alicia , Yancey Abigail , Crannage Erica , Campbell Kristin , Shyken Jaye
Published: May 2016

Objective: To evaluate maternal and neonatal safety outcomes for methadone and buprenorphine in the obstetric population. Data Sources: A literature search of PubMed (1966 to March 2016) and EMBASE (1973 to March 2016) was completed using the search terms buprenorphine, methadone, pregnancy, opioid, and neonatal abstinence syndrome. Priority was given to randomized controlled trials and trials directly comparing buprenorphine and methadone during pregnancy. The bibliographies were reviewed for other relevant articles. Study Selection and Data Extraction: All human studies published in English, that compared methadone and buprenorphine use in pregnancy were evaluated. Because of the limited number of obstetric studies, only 5 critical studies were found. Data Synthesis: Buprenorphine significantly improved or had similar outcomes to methadone for development of neonatal abstinence syndrome (NAS), percentage of infants requiring treatment for NAS (20%-47% vs 45.5%-57%, respectively), total amount of morphine used to treat NAS (0.472-3.4 vs 1.862-10.4 mg, respectively), duration of NAS (4.1-5.6 vs 5.3-9.9 days, respectively), peak NAS (3.9-11 vs 4.9-12.8 score, respectively), infant hospital stay (6.8-10.6 vs 8.1-17.5 days, respectively), and gestational age at delivery (38.8-39.7 vs 37.9-38.8 weeks, respectively). No difference was found with other neonatal or maternal outcomes. Conclusions: Both methadone and buprenorphine are effective agents, with improved safety compared with continued nonmedical opioid use during pregnancy. There is evidence to suggest that buprenorphine should be considered as an equivalent option to methadone for use in pregnancy; however, larger studies are still needed to fully evaluate buprenorphine safety and advantages over methadone in the obstetric population.