bluuebunny/crossref_metadata_2025 huggingface dataset:
CXCL-8/IL8 Produced by Diffuse Large B-cell Lymphomas Recruits Neutrophils Expressing a Proliferation-Inducing Ligand APRIL
Authors: Manfroi Benoit , McKee Thomas , Mayol Jean Francois , Tabruyn Sebastien , Moret Sebastien , Villiers Christian , Righini Christian , Dyer Martin , Callanan Mary , Schneider Pascal , Tzankov Alexandar , Matthes Thomas , Sturm Nathalie , Huard Bertrand
Published: December 2016

Tumor-infiltrating neutrophils have been implicated in malignant development and progression, but mechanisms are ill defined. Neutrophils produce a proliferation-inducing ligand APRIL/TNFSF13, a factor that promotes development of tumors from diverse origins, including diffuse large B-cell lymphoma (DLBCL). High APRIL expression in DLBCL correlates with reduced patient survival, but the pathway(s) dictating APRIL expression are not known. Here, we show that all blood neutrophils constitutively secrete APRIL, and inflammation-associated stimuli, such as TNF, further upregulate APRIL. In a significant fraction of DLBCL patients, tumor cells constitutively produced the ELC-CXC chemokine CXCL-8 (IL8), enabling them to recruit APRIL-producing blood neutrophils. CXCL-8 production in DLBCL was unrelated to the cell of origin, as APRIL-producing neutrophils infiltrated CXCL-8+ DLBCL from both germinal center (GC) and non-GC subtypes. Rather, CXCL-8 production implied events affecting DNA methylation and acetylation. Overall, our results showed that chemokine-mediated recruitment of neutrophils secreting the tumor-promoting factor APRIL mediates DLBCL progression. Cancer Res; 77(5); 1097–107. ©2016 AACR.
ESE3 Inhibits Pancreatic Cancer Metastasis by Upregulating E-Cadherin
Authors: Zhao Tiansuo , Jiang Wenna , Wang Xiuchao , Wang Hongwei , Zheng Chen , Li Yang , Sun Yan , Huang Chongbiao , Han Zhi-bo , Yang Shengyu , Jia Zhiliang , Xie Keping , Ren He , Hao Jihui
Published: December 2016

The ETS family transcription factor ESE3 is a crucial element in differentiation and development programs for many epithelial tissues. Here we report its role as a tumor suppressor in pancreatic cancer. We observed drastically lower ESE3 expression in pancreatic ductal adenocarcinomas (PDAC) compared with adjacent normal pancreatic tissue. Reduced expression of ESE3 in PDAC correlated closely with an increase in lymph node metastasis and vessel invasion and a decrease in relapse-free and overall survival in patients. In functional experiments, downregulating the expression of ESE3 promoted PDAC cell motility and invasiveness along with metastasis in an orthotopic mouse model. Mechanistic studies in PDAC cell lines, the orthotopic mouse model, and human PDAC specimens demonstrated that ESE3 inhibited PDAC metastasis by directly upregulating E-cadherin expression at the level of its transcription. Collectively, our results establish ESE3 as a negative regulator of PDAC progression and metastasis by enforcing E-cadherin upregulation. Cancer Res; 77(4); 874–85. ©2016 AACR.
Therapeutic Activity of Anti-AXL Antibody against Triple-Negative Breast Cancer Patient-Derived Xenografts and Metastasis
Authors: Leconet Wilhem , Chentouf Myriam , du Manoir Stanislas , Chevalier Clément , Sirvent Audrey , Aït-Arsa Imade , Busson Muriel , Jarlier Marta , Radosevic-Robin Nina , Theillet Charles , Chalbos Dany , Pasquet Jean-Max , Pèlegrin André , Larbouret Christel , Robert Bruno
Published: December 2016

Purpose: AXL receptor tyrosine kinase has been described as a relevant molecular marker and a key player in invasiveness, especially in triple-negative breast cancer (TNBC).

Experimental Design: We evaluate the antitumor efficacy of the anti-AXL monoclonal antibody 20G7-D9 in several TNBC cell xenografts or patient-derived xenograft (PDX) models and decipher the underlying mechanisms. In a dataset of 254 basal-like breast cancer samples, genes correlated with AXL expression are enriched in EMT, migration, and invasion signaling pathways.

Results: Treatment with 20G7-D9 inhibited tumor growth and bone metastasis formation in AXL-positive TNBC cell xenografts or PDX, but not in AXL-negative PDX, highlighting AXL role in cancer growth and invasion. In vitro stimulation of AXL-positive cancer cells by its ligand GAS6 induced the expression of several EMT-associated genes (SNAIL, SLUG, and VIM) through an intracellular signaling implicating the transcription factor FRA-1, important in cell invasion and plasticity, and increased their migration/invasion capacity. 20G7-D9 induced AXL degradation and inhibited all AXL/GAS6–dependent cell signaling implicated in EMT and in cell migration/invasion.

Conclusions: The anti-AXL antibody 20G7-D9 represents a promising therapeutic strategy in TNBC with mesenchymal features by inhibiting AXL-dependent EMT, tumor growth, and metastasis formation. Clin Cancer Res; 23(11); 2806–16. ©2016 AACR.
Osimertinib for the Treatment of Metastatic EGFR T790M Mutation–Positive Non–Small Cell Lung Cancer
Authors: Khozin Sean , Weinstock Chana , Blumenthal Gideon M. , Cheng Joyce , He Kun , Zhuang Luning , Zhao Hong , Charlab Rosane , Fan Ingrid , Keegan Patricia , Pazdur Richard
Published: December 2016

On November 13, 2015, the FDA granted accelerated approval to osimertinib (TAGRISSO; AstraZeneca), a breakthrough therapy-designated drug for the treatment of patients with metastatic EGFR T790M mutation–positive non–small cell lung cancer, as detected by an FDA-approved test, with progression on or after EGFR tyrosine kinase inhibitor therapy. Approval was based on durable tumor response rates in two single-arm, multicenter trials: the dose extension cohort of a first-in-human trial (FIH; AURA extension; n = 201) and a fixed-dose, activity-estimating trial (AURA2; n = 210). Osimertinib was administered at 80 mg orally once daily. The objective response rates (ORR) per blinded independent committee review were 57% [95% confidence interval (CI), 50–64) in AURA extension and 61% (95% CI, 54–68) in AURA2. Median duration of response (DOR) could not be estimated. Supportive efficacy data from 63 patients in the dose-finding part of the FIH trial demonstrated an ORR of 51% (95% CI, 38–64), with a median DOR of 12.4 months. Common adverse events (AE) evaluated in 411 patients included diarrhea (42%), rash (41%), dry skin (31%), and nail toxicity (25%). Grade 3 to 4 AEs occurred in 28% of patients, and 5.6% discontinued treatment due to AEs. Clin Cancer Res; 23(9); 2131–5. ©2016 AACR.
Whole-Exome Sequencing Validates a Preclinical Mouse Model for the Prevention and Treatment of Cutaneous Squamous Cell Carcinoma
Authors: Knatko Elena V. , Praslicka Brandon , Higgins Maureen , Evans Alan , Purdie Karin J. , Harwood Catherine A. , Proby Charlotte M. , Ooi Aikseng , Dinkova-Kostova Albena T.
Published: December 2016

Cutaneous squamous cell carcinomas (cSCC) are among the most common and highly mutated human malignancies. Solar UV radiation is the major factor in the etiology of cSCC. Whole-exome sequencing of 18 microdissected tumor samples (cases) derived from SKH-1 hairless mice that had been chronically exposed to solar-simulated UV (SSUV) radiation showed a median point mutation (SNP) rate of 155 per Mb. The majority (78.6%) of the SNPs are C.G>T.A transitions, a characteristic UVR-induced mutational signature. Direct comparison with human cSCC cases showed high overlap in terms of both frequency and type of SNP mutations. Mutations in Trp53 were detected in 15 of 18 (83%) cases, with 20 of 21 SNP mutations located in the protein DNA-binding domain. Strikingly, multiple nonsynonymous SNP mutations in genes encoding Notch family members (Notch1-4) were present in 10 of 18 (55%) cases. The histopathologic spectrum of the mouse cSCC that develops in this model resembles very closely the spectrum of human cSCC. We conclude that the mouse SSUV cSCCs accurately represent the histopathologic and mutational spectra of the most prevalent tumor suppressors of human cSCC, validating the use of this preclinical model for the prevention and treatment of human cSCC. Cancer Prev Res; 10(1); 67–75. ©2016 AACR.
Rational Selection of Syngeneic Preclinical Tumor Models for Immunotherapeutic Drug Discovery
Authors: Mosely Suzanne I.S. , Prime John E. , Sainson Richard C.A. , Koopmann Jens-Oliver , Wang Dennis Y.Q. , Greenawalt Danielle M. , Ahdesmaki Miika J. , Leyland Rebecca , Mullins Stefanie , Pacelli Luciano , Marcus Danielle , Anderton Judith , Watkins Amanda , Coates Ulrichsen Jane , Brohawn Philip , Higgs Brandon W. , McCourt Matthew , Jones Hazel , Harper James A. , Morrow Michelle , Valge-Archer Viia , Stewart Ross , Dovedi Simon J. , Wilkinson Robert W.
Published: December 2016

Murine syngeneic tumor models are critical to novel immuno-based therapy development, but the molecular and immunologic features of these models are still not clearly defined. The translational relevance of differences between the models is not fully understood, impeding appropriate preclinical model selection for target validation, and ultimately hindering drug development. Across a panel of commonly used murine syngeneic tumor models, we showed variable responsiveness to immunotherapies. We used array comparative genomic hybridization, whole-exome sequencing, exon microarray analysis, and flow cytometry to extensively characterize these models, which revealed striking differences that may underlie these contrasting response profiles. We identified strong differential gene expression in immune-related pathways and changes in immune cell–specific genes that suggested differences in tumor immune infiltrates between models. Further investigation using flow cytometry showed differences in both the composition and magnitude of the tumor immune infiltrates, identifying models that harbor “inflamed” and “non-inflamed” tumor immune infiltrate phenotypes. We also found that immunosuppressive cell types predominated in syngeneic mouse tumor models that did not respond to immune-checkpoint blockade, whereas cytotoxic effector immune cells were enriched in responsive models. A cytotoxic cell–rich tumor immune infiltrate has been correlated with increased efficacy of immunotherapies in the clinic, and these differences could underlie the varying response profiles to immunotherapy between the syngeneic models. This characterization highlighted the importance of extensive profiling and will enable investigators to select appropriate models to interrogate the activity of immunotherapies as well as combinations with targeted therapies in vivo. Cancer Immunol Res; 5(1); 29–41. ©2016 AACR.
Human Dendritic Cells Mitigate NK-Cell Dysfunction Mediated by Nonselective JAK1/2 Blockade
Authors: Curran Shane A. , Shyer Justin A. , St. Angelo Erin T. , Talbot Lillian R. , Sharma Sneh , Chung David J. , Heller Glenn , Hsu Katharine C. , Betts Brian C. , Young James W.
Published: December 2016

Janus kinase (JAK) inhibitors have achieved positive responses in myeloproliferative neoplasms, but at the expense of decreased natural killer (NK) cell numbers and compromised function. Selective JAK2 inhibition may also have a role in preventing and treating graft-versus-host disease after allogeneic hematopoietic stem cell transplantation. Although JAK inhibitors can impair monocyte-derived dendritic cell (moDC) activation and function and suppress effector T-cell responses, the effects on NK cells and the relevant mechanisms remain undefined. Using common γc cytokines and distinct human dendritic cell (DC) subtypes, we compared the effects of a JAK2-specific (TG101348) with a less selective JAK1/2 (ruxolitinib) inhibitor on NK-cell activation and function. Ruxolitinib treatment completely blocked IL2, IL15, and DC-mediated STAT5 phosphorylation, along with the capacity of NK cells to secrete IFNγ or lyse NK cell–sensitive targets. Only NK-cell proliferation stimulated by moDCs resisted ruxolitinib treatment. In contrast, TG101348 treatment of stimulated NK cells resulted in far less functional compromise. TG101348 completely inhibited only soluble IL15-mediated STAT5 phosphorylation, which Langerhans-type DCs (LCs), presenting membrane-bound IL15 in trans, could salvage. These results demonstrate that ruxolitinib's nonselective inhibition of JAK1/2 results in profound NK-cell dysfunction by blocking downstream pSTAT5, hence providing a persuasive rationale for the development of selective JAK2 inhibitors for immunotherapeutic applications. Cancer Immunol Res; 5(1); 52–60. ©2016 AACR.
Differential Expression of Bcl-2 in the Cochlea and Auditory Cortex of a Mouse Model of Age-Related Hearing Loss
Authors: Huang Qiuhong , Xiong Hao , Yang Haidi , Ou Yongkang , Zhang Zhigang , Chen Suijun , Ye Yongyi , Zheng Yiqing
Published: December 2016

Bcl-2, the first gene shown to be involved in apoptosis, is a potent regulator of cell survival and known to have protective effects against a variety of age-related diseases. However, the possible relationship between hearing and Bcl-2 expression in the cochlea or auditory cortex of C57BL/6 mice, a mouse model of age-related hearing loss, is still unknown. Using RT-PCR, immunohistochemistry, and Western blot analysis, our results show that Bcl-2 is strongly expressed in the inner hair cells and spiral ganglion neurons of young mice. In addition, moderate Bcl-2 expression is also detected in the outer hair cells and in the neurons of the auditory cortex. A significant reduction of Bcl-2 expression in the cochlea or auditory cortex is also associated with elevated hearing thresholds and hair cell loss during aging. The expression pattern of Bcl-2 in the peripheral and central auditory systems suggests that Bcl-2 may play an important role in auditory function serving as a protective molecule against age-related hearing loss.
Dexamethasone Implant in Chronic Diabetic Macular Edema Resistant to Intravitreal Ranibizumab Treatment
Authors: Yucel Ozlem Eski , Can Ertugrul , Ozturk Hilal Eser , Birinci Hakki , Sullu Yuksel
Published: December 2016

Purpose: The aim of this study was to assess the efficacy of a single intravitreal dexamethasone implant (IDI) over 6 months in eyes with chronic diabetic macular edema (DME) that were resistant to intravitreal ranibizumab (IR) treatment. Methods: This retrospective study was conducted at the Ondokuz Mayis University Hospital, Samsun, Turkey. Efficacy outcomes were considered as the change from baseline in best corrected visual acuity (BCVA) and central macular thickness (CMT). Results: Thirty eyes of 20 patients with a mean age of 61.6 ± 8.8 (45-85) years were included in the study. The mean BCVA significantly increased from 0.68 ± 0.27 to 0.56 ± 0.30 logMAR (p = 0.001) and 0.57 ± 0.30 logMAR (p = 0.002) at months 1 and 2, respectively. The proportion of patients who gained 3 or more lines in BCVA was 20%. The mean CMT significantly decreased from 578.93 ± 17.95 µm at baseline to 282.10 ± 21.42, 292.26 ± 19.69, 371.70 ± 21.23, and 463.60 ± 23.16 µm at months 1, 2, 3, and 4, respectively (p = 0.001). Intraocular pressure (IOP) increase occurred in 5 (16.7%) eyes. Cataract surgery was required in 3 (13%) out of 23 phakic eyes. Conclusion: IDI provides significant benefits in visual acuity gains and anatomic improvements in eyes with chronic DME that are resistant to IR treatment. Increases in IOP and cataract progression can be observed in IDI-treated patients. However, its safety profile is acceptable.
Detection and Phylogenetic Analysis of Torque Teno Virus in Salivary and Tumor Biopsy Samples from Head and Neck Carcinoma Patients
Authors: Hettmann Andrea , Demcsák Anett , Bach Ádám , Decsi Gábor , Dencs Ágnes , Pálinkó Dóra , Rovó László , Nagy Katalin , Minarovits Janos , Takács Mária
Published: December 2016

Objectives: Because torque teno virus (TTV) has been implicated in tumorigenesis as a cocarcinogen, we studied TTV prevalence in saliva and biopsy samples from head and neck cancer (HNCC) patients, patients with premalignant lesions of oral cancer, and controls. We also wished to determine the TTV genotypes in HNCC patients. Methods: A seminested polymerase chain reaction (PCR) amplifying the N22 region of the TTV genome, as well as direct sequencing of PCR fragments, was used. Results: TTV prevalence was higher in HNCC patients (saliva: 27/71, 38%; tumor biopsy: 22/74, 30%) than in controls (saliva: 8/56, 14%; oral mucosa: 1/19, 5%). TTV prevalence was also high in patients with premalignant lesions of oral carcinoma (saliva: 9/18, 50%; biopsy: 5/21, 24%). By phylogenetic analysis, TTV belonging mostly to genotypes 1 and 2 was found in HNCC patients. In most of the cases, identical TTV strains were present in the biopsy and salivary sample of the same HNCC patient. In addition, the same TTV strain was detected in 2 laryngeal carcinoma biopsies obtained from 2 independent patients. Conclusions: Our data are compatible with the idea that TTV might act as a cocarcinogen in certain cases of HNCC. Alternatively, HNCC may facilitate either TTV replication or TTV entry into the saliva.
Dermoscopic Findings of Scalp Aplasia Cutis Congenita
Authors: Damiani Leandro , Aguiar Fernanda Musa , da Silva Mariana Vale Scribel , Miteva Mariya I. , Pinto Giselle Martins
Published: December 2016

Aplasia cutis congenita (ACC) is a rare disease characterized by congenital absence of skin, affecting preferentially the scalp. Diagnosis is made clinically; however, recent studies have shown that dermoscopy can be a useful tool for the diagnosis and differentiation from sebaceous nevus. The clinical findings include a shiny atrophic alopecic patch associated with dermoscopic findings of absent follicular openings, thicker vessels and a distinct collar hypertrichosis. We report 2 cases of alopecia presenting from birth. At dermoscopy, the absence of follicular openings and the increase in the caliber of vessels led us to establish the diagnosis of ACC.
Necroptosis Induced by Ad-HGF Activates Endogenous C-Kit+ Cardiac Stem Cells and Promotes Cardiomyocyte Proliferation and Angiogenesis in the Infarcted Aged Heart
Authors: Liu Jiabao , Wu Peng , Wang Hao , Wang Yunle , Du Yingqiang , Cheng Weili , Xu Zhihui , Zhou Ningtian , Wang Liansheng , Yang Zhijian
Published: December 2016

Background/Aims: The discovery of c-kit+ cardiac stem cells (CSCs) provided us with new therapeutic targets to repair the damaged heart. However, the precise mechanisms regulating CSC proliferation and differentiation in the aged heart remained elusive. Necroptosis, a type of regulated cell death, has recently been shown to occur following myocardial infarction (MI); however, its effect on c-kit+ CSCs remains unknown. We investigated the effects of hepatocyte growth factor (HGF) and necroptosis on the proliferation and differentiation of endogenous c-kit+ CSCs in aged rat hearts following MI. Methods: The c-kit+ CSCs and HGF/p-Met expression levels in neonatal, adult and aged rats were compared using immunofluorescence and Western blotting. Immediately after MI, adenovirus carrying the HGF gene (Ad-HGF) was injected into the left ventricular wall surrounding the infarct areas of the aged rat heart. The proliferation and differentiation of the endogenous c-kit+ CSCs were studied using immunofluorescence. The signalling pathways were analysed via Western blotting and ELISA. Results: HGF/p-Met expression levels and c-kit+ CSC abundance gradually decreased with age. Ad-HGF promoted c-kit+ CSC differentiation into precursor cells of cardiomyocyte, endothelial and smooth muscle cell lineages and enhanced cardiomyocyte proliferation and angiogenesis in aged rats; these effects were reversed by the inhibition of necroptosis. Ad-HGF administration induced necroptosis by increasing the expression of receptor interacting protein kinase (RIP) 1 and receptor interacting protein kinase (RIP) 3 proteins in the infarcted heart. Moreover, Ad-HGF-induced necroptosis increased high-mobility group box 1 protein (HMGB1) levels and enhanced the abundance of c-kit+ cells in the bone marrow, which may partly account for the beneficial effect of necroptosis on the c-kit+ CSCs. Conclusion: Ad-HGF-induced necroptosis facilitated aged heart repair after MI by promoting c-kit+ CSC proliferation and differentiation. These findings may lead to the development of new methods for the treatment of ischaemic heart disease in aged populations.
PD-1 and PD-L1 Immune Checkpoint Blockade to Treat Breast Cancer
Authors: Hartkopf Andreas D. , Taran Florin-Andrei , Wallwiener Markus , Walter Christina B. , Krämer Bernhard , Grischke Eva-Maria , Brucker Sara Y.
Published: December 2016

Immune checkpoint inhibition represents a major recent breakthrough in the treatment of malignant diseases including breast cancer. Blocking the programmed death receptor-1 (PD-1) and its ligand, PD-L1, has shown impressive antitumor activity and may lead to durable long-term disease control, especially in the triple-negative subtypes of breast cancer (TNBC). Although immune checkpoint blockade is generally well tolerated, specific immune-related adverse events (irAEs) may occur. This review summarizes the clinical efficacy, perspectives, and future challenges of using PD-1/PD-L1-directed antibodies in the treatment of breast cancer.
Valores intermediários de BNP são capazes de predizer eventos em pacientes com síndrome coronária aguda?
Authors: Soeiro Alexandre De Matos , Roque Eduardo A. de Castro , Póvoa Priscila Galvão , Bossa Aline Siqueira , Zullino Cindel Nogueira , Soeiro Maria Carolina Feres de Almeida , Leal Tatiana De Carvalho Andreucci Torres , Jardim Yuri Justi , Sinigaglia Mariana Marques , Silva Alex França da , Muntaneli Bruna , Serrano Junior Carlos V. , Oliveira Junior Múcio Tavares de
Published: December 2016

Introdução: Diversos estudos na literatura têm relacionado valores elevados de peptídeo natriurético cerebral (BNP) com pior prognóstico em pacientes com síndrome coronária aguda (SCA). No entanto, valores entre 100 pg/mL e 400 pg/mL são considerados limítrofes e ainda questionados em relação à diagnóstico e ocorrência de eventos. Métodos: Trata-se de estudo retrospectivo observacional com objetivo de avaliar se o valor intermediário de BNP na admissão hospitalar é capaz de predizer prognóstico intrahospitalar. Os pacientes foram divididos em dois grupos: grupo I: BNP < 100 pg/mL; grupo II: 100 < BNP < 400 pg/mL. Foram incluídos 405 pacientes (235 no grupo I e 170 no grupo II) com SCA. Obtiveram-se dados referentes à comorbidades e medicações utilizadas. Análise estatística: O desfecho primário foi mortalidade por todas as causas. O desfecho secundário foi eventos combinados (choque cardiogênico, reinfarto, morte, acidente vascular cerebral e sangramento). A comparação entre grupos foi realizada através de Q-quadrado e ANOVA. A análise multivariada foi realizada por regressão logística, sendo considerado significativo p < 0,05. Resultados: Na comparação entre os grupos I e II, observaram-se diferenças em relação à prevalência de diabetes mellitus e angioplastia coronária prévia. Na análise multivariada, observaram-se diferenças significativas entre os grupos I e II em relação à ocorrência de choque cardiogênico (2,55% x 10,59%, OR = 4,09, p = 0,01), respectivamente. Conclusão: Valores intermediários de BNP não foram capazes de predizer mortalidade em pacientes com SCA. No entanto, observou-se uma maior incidência de choque cardiogênico.
Análise da expressão de PD-L1 no microambiente do câncer de pulmão de não pequenas células e de seu papel como potencial marcador preditivo
Authors: Kalkaslief de Souza Rachel , Kadekaru Marina Yuri , Lemos-Santos Maria Clara , Castro Júnior Gilberto De , Ramos Rodrigo Nalio
Published: December 2016

Objective: To analyse the recent findings regarding programmed-death ligand 1(PD-L1) expression on tumor infiltrating immune cells in NSCLC and its potential role as a predictive biomarker for clinical outcomes and for successful PD-1/PD-L1 blocking immunotherapy. Methods: 5 databases were accessed for search: PubMed, Web of Science, Scopus, Lilacs, and Clinical Trials.gov. Articles were selected if written in English, Portuguese or Spanish and if available via institutional access. Results: 15 articles were selected. PD-L1 expression was found to be related to the presence of immature DCs and had also constitutive expression on fibroblasts derived from NSCLC specimens. PD-L1 expression in tumor infiltrating immune cells was observed to be correlated with overall survival benefit and improved tumor response after atezolizumab therapy. A significant correlation between PD-L1 expression in peripheral T cells and clinical outcomes was also detected, besides the finding of significant correlation between an increased PD-L1 expression and clinical benefits in anti-PD-1 therapy. Discussion: Preliminary observations showed that PD-L1 expression in immune cells is related to an immunosuppressive milieu in NSCLC and to clinical benefits of immunotherapy.
A viabilidade da utilização de drogas epigenéticas como tratamento de pacientes com sepse – uma perspectiva translacional
Authors: Costa Thamara Rodrigues da , Bonizzio Carolina Reis , Luz Maria Clara Andrade da , Soriano Francisco Garcia
Published: December 2016

Sepsis is a serious and potentially lethal clinical condition characterized by dysregulated immune and systemic inflammatory responses (SIRS) to an infection. Although sepsis has a high mortality rate (reaching 25% in Europe and North America), the clinical interventions available are still limited. In the bottom of this exacerbation of the immune response, that evolves to immunosuppression and immune paralysis, lies epigenetic mechanisms. In sepsis, the balance between activated and repressed immune related genes is at lost, and to recover that epigenetic based drugs promises to be the future of sepsis treatment. Histone deacetylase inhibitors (HDAC’s inhibitors) are drugs based in the epigenetic mechanism of acetylation and deacetylation of histones, and they have already been tested - phases three and four of clinical trials - as treatment for other diseases, such as multiple myeloma, and cutaneous t-cell lymphoma. Furthermore, experimental studies in sepsis models shows that HDAC’s inhibitors are a promising suppressor of the exacerbated inflammatory response. Therefore, as the recent works shows, epigenetic drugs should be considered a viable sepsis therapy in the future. The focus of this review is to present the most recent scientific advances in the basic and clinical areas of epigenetic as a sepsis treatment, opening opportunities for the use of epigenetic in treating this condition.
Mulheres pela perspectiva masculina na literatura japonesa: As protagonistas-narradoras de Dazai
Authors: Kawana Karen Kazue
Published: December 2016

Na literatura japonesa, homens escrevem como mulheres ao menos desde o século X, portanto, o fato de Dazai Osamu (1909-1948) escrever contos com narradoras na segunda metade do século XX não é algo novo, entretanto, neste artigo, procuramos mostrar que elas possuem características peculiares que as distinguem das figuras femininas presentes nas obras de contemporâneos como Kawabata Yasunari e Tanizaki Jun’ichirô.
Characterization of the Changes in Cardiac Structure and Function in Mice Treated With Anthracyclines Using Serial Cardiac Magnetic Resonance Imaging
Authors: Farhad Hoshang , Staziaki Pedro V. , Addison Daniel , Coelho-Filho Otavio R. , Shah Ravi V. , Mitchell Richard N. , Szilveszter Balint , Abbasi Siddique A. , Kwong Raymond Y. , Scherrer-Crosbie Marielle , Hoffmann Udo , Jerosch-Herold Michael , Neilan Tomas G.
Published: December 2016

Background—

Anthracyclines are cardiotoxic; however, there are limited data characterizing the serial changes in cardiac structure and function after anthracyclines. The aim of this study was to use cardiac magnetic resonance to characterize anthracycline-induced cardiotoxicity in mice.

Methods and Results—

This was a longitudinal cardiac magnetic resonance and histological study of 45 wild-type male mice randomized to doxorubicin (n=30, 5 mg/kg of doxorubicin/week for 5 weeks) or placebo (n=15). A cardiac magnetic resonance was performed at baseline and at 5, 10, and 20 weeks after randomization. Measures of primary interest included left ventricular ejection fraction, myocardial edema (multiecho short-axis spin-echo acquisition), and myocardial fibrosis (Look-Locker gradient echo). In doxorubicin-treated mice versus placebo, there was an increase in myocardial edema at 5 weeks (T2 values of 32±4 versus 21±3 ms;
P
<0.05), followed by a reduction in left ventricular ejection fraction (54±6 versus 63±5%;
P
<0.05) and an increase in myocardial fibrosis (extracellular volume of 0.34±0.03 versus 0.27±0.03;
P
<0.05) at 10 weeks. There was a strong association between the early (5 weeks) increase in edema and the subacute (10 weeks) increase in fibrosis (
r
=0.90;
P
<0.001). Both the increase in edema and fibrosis predicted the late doxorubicin-induced mortality in mice (
P
<0.001).

Conclusions—

Our data suggest that, in mice, anthracycline-induced cardiotoxicity is associated with an early increase in cardiac edema and a subsequent increase in myocardial fibrosis. The early increase in edema and subacute increase in fibrosis are strongly linked and are both predictive of late mortality.
Lifestyle Interventions to Prevent Cardiovascular Events After Stroke and Transient Ischemic Attack
Authors: Deijle Inger A. , Van Schaik Sander M. , Van Wegen Erwin E.H. , Weinstein Henry C. , Kwakkel Gert , Van den Berg-Vos Renske M.
Published: December 2016

Background and Purpose—

Patients with a transient ischemic attack or ischemic stroke have an increased risk of subsequent cardiovascular events. The purpose of this systematic review and meta-analysis was to determine whether lifestyle interventions focusing on behaviorally modifiable risk factors with or without an exercise program are effective in terms of (1) preventing recurrent cardiovascular events, (2) reducing mortality, and (3) improving modifiable risk factors associated with cardiovascular disease in patients after a transient ischemic attack or ischemic stroke.

Methods—

For this systematic review and meta-analysis, we systematically searched PubMed, Embase, PsycInfo, and the Cochrane Library from the start of the database to May 7, 2015. Subgroup analyses were conducted to explore the influence of therapy-related factors.

Results—

Twenty-two randomized controlled trials were identified with a total of 2574 patients. Pooling showed a significant reduction in systolic blood pressure by the lifestyle interventions applied, compared with usual care (mean difference, −3.6 mm Hg; 95% confidence interval, −5.6 to −1.6,
I
2
=33%). No significant effect was found on cardiovascular events, mortality, diastolic blood pressure, or cholesterol. In the subgroup analyses, the trials with cardiovascular fitness interventions, trials with an intervention that lasted longer than 4 months, and interventions that used >3 behavior change techniques were more effective in reducing systolic blood pressure.

Conclusions—

We found that lifestyle interventions are effective in lowering systolic blood pressure. About other end points, this systematic review found no effect of lifestyle interventions on cardiovascular event rate mortality, diastolic blood pressure, or total cholesterol.
Increased Stroke Burdens Among the Low-Income Young and Middle Aged in Rural China
Authors: Ning Xianjia , Sun Jian , Jiang Rongcai , Lu Hongyan , Bai Lingling , Shi Min , Tu Jun , Wu Yanan , Wang Jinghua , Zhang Jianning
Published: December 2016

Background and Purpose—

Although stroke in the young and middle aged accounts for 31% of all strokes in China, the disease burden is unknown. We aimed to determine the secular trends in stroke incidence and the transition of subtypes in rural China over a 24-year period.

Methods—

In 1992, 14 920 residents were recruited to participate in the Tianjin Brain Study. Stroke events and all deaths were registered annually. We assessed the trends in incidence of first-ever stroke, including intracerebral hemorrhage and ischemic stroke, among adults aged 35 to 64 years during 1992 to 1999, 2000 to 2007, and 2008 to 2015. The annual proportion of change in stroke incidence was evaluated from 1992 to 2015.

Results—

The age-standardized incidence of first-ever stroke per 100 000 person-years increased significantly, from 122 in 1992 to 1999, to 215.8 in 2000 to 2007, to 471.8 in 2008 to 2015. The incidence of first-ever stroke increased annually by 11.9% overall (12.4% in men, 9.0% in women, 8.7% for intracerebral hemorrhage, and 10.7% for ischemic stroke;
P
<0.001). The greatest increases were observed in adults aged 55 to 64 years, with an annual increase of 11.6% for ischemic stroke (10.8% in men and 6.9% in women). However, the proportion of intracerebral hemorrhage has not changed over the past 24 years.

Conclusions—

In contrast with that in developed countries, the burden of stroke in China originates primarily from young and middle-aged adults. Thus, control of risk factors in this population is required to reduce the future burden of stroke in China.
A Note on Meccan Women in the Fifteenth Century
Authors: Al-Fassi Hatoon Ajwad
Published: December 2016

The history of women in Arabia is a relatively new and unexplored area of research and the place of women in Mecca (Makkah), Islam’s holiest city, is particularly shrouded in darkness. From the fifteenth century, however, there has been a stream of biographical works (tabaqat) that shed much light on the women of the city. This note turns scholarly attention on such fifteenth and sixteenth century works as Taqi al-Din al-Fassi’s (d. 1429) eight volumeAl-‘Iqd al-Thamin fi Tarikh al-Balad al-Amin, which dedicates a volume to women, in an effort to continue the scholarly appraisal of women’s lives in Muslim societies. Reading such important sources shows how women actively participated in the public life of the city, including its intellectual circles, contrary to Orientalist stereotypes. By exploring the multiple roles of Meccan women in the fifteenth century, the hope is to prompt further study of their significance and its historical implications.
Recognition of Indigenous Land Rights in Norway and Canada
Authors: Ravna Øyvind , Bankes Nigel
Published: December 2016

Many states offer constitutional protection to the traditional lands of indigenous peoples. International treaties protecting ethnic minorities and indigenous peoples also require protection of the rights of indigenous communities with respect to traditional territories. States have followed different routes in identifying the ownership and resource rights of indigenous communities. In Norway, the Courts have traditionally applied the rules on prescription and immemorial usage, developed through centuries in the farming societies of Scandinavia. The legislature has chosen to follow the same approach in the Finnmark area of Norway under the terms of the Finnmark Act (2005). By contrast, in Canada, a settled colony with an English common law tradition, the Courts have developed a sui generis approach to the recognition of Aboriginal title. This article examines the rules for identifying and legally recognising the traditional lands of indigenous people in Norway and Canada with a view to reflecting on similarities and differences.
The Practice of International Criminal Law. Some Reflections from an icty Prosecutor
Authors: Jarvis Michelle
Published: December 2016

In this article, the author reflects back over fifteen years working at the International Criminal Tribunal for the former Yugoslavia (icty) to describe the practice of international criminal law. Written from a prosecutor’s perspective, the article explores some of the challenges international justice practitioners face as well as the many rewards that come with working in this field. The article also highlights the rapidly changing contours of international justice as a career path and possible future directions for those working within it, as well as the need for more collaboration between international justice practitioners and the academic community in the future.
Rome’s Legacy: Negotiating the Reparations Mandate of the International Criminal Court
Authors: Sperfeldt Christoph
Published: December 2016

This article examines the negotiations that led to the incorporation of reparations provisions into the legal framework of the International Criminal Court (icc). Building upon a review of the travaux préparatoires and interviews, it traces the actors and main debates during the lead-up to the Rome Conference and the drafting of the Rules of Procedure and Evidence, explaining how and why reparations were included into the Rome Statute. In doing so, the article shows how the reparations mandate was produced at the intersection of a set of different agendas and actors. From this account, it identifies a number of key themes that were at the centre of the negotiations and often galvanised contestations among delegations or with ngos. The article concludes with a fresh perspective on the origin of victim reparations in the Rome Statute and its relevance for understanding many of today’s debates around reparations in international criminal justice.
The Philippine Claim Against China
Authors: Pinto M. Christopher W.
Published: December 2016

China was excluded by its Declaration of 2006 from application of unclos compulsory procedures in “all categories of disputes referred to in paragraph 1(a), (b), and (c) of Article 298,” notably “any dispute that necessarily involves the concurrent consideration of any unsettled dispute concerning sovereignty or other rights over continental or insular land territory.” The implications of sovereignty over land territory considered in relation to maritime rights make it extremely difficult to make distinctions isolating the latter from the parent concept of “sovereignty.” The Tribunal, when assuming jurisdiction over the Philippine claim made an admirable effort to do so, and the reader may evaluate its success. China, on the other hand, did not merely “fail to appear” or “fail to present its case,” but chose instead to rely on its exclusionary Declaration of 2006 in publicly denying the competence of an Annex vii Tribunal to assume jurisdiction. Nor was China invited to withdraw its 2006 Declaration or to enter into a special agreement to submit a dispute excluded by its Declaration, as contemplated by paragraph 2 of Article 298. In the author’s view, China’s Declaration of 2006 deprived the Convention’s procedures of the essential element of a State’s consent to jurisdiction.
The Meaning of the Supreme Court’s Decision on the Rejection of an Establishment Application for the Migrants’ Trade Union
Authors: Lee Seokwoo , Cho Youngkwan
Published: December 2016

A group of 91 migrant workers, including undocumented workers, working in Seoul, Incheon and Gyeonggi Province organized the Migrants’ Trade Union (“mtu”) which is in the form of regional trade union on April 24, 2005. On May 3 of the same year, it submitted an establishment application for labor union accompanied by its bylaws to the Minister of Labor (now the Minister of Employment and Labor).

This mtu case, which has been pending before the Supreme Court for eight years was decided to “dismiss the defendant’s appeal.” This case will probably be named as the longest pending case of the Supreme Court.
Jericho-off-the-Record: Tracing ‘New’ Records of the 1950s Excavations at Tell es-Sultan
Authors: Wagemakers Bart
Published: December 2016

During the last few years the Non-Professional Archaeological Photographs project (npaph) has gathered and digitised numerous forgotten non-professional photographs and slides from past archaeological excavations (1950–1980), which were subsequently ingested and processed at dans. The term ‘non-professional’ refers to participants of excavations who were not part of the trained staff but who supported the dig as part of their continuous education or out of interest. Secondly, this category of documentation also includes private photographs, slides and films made at the excavation by the archaeological staff and which are not stored in official archives. Several npaph publications have previously demonstrated that this category of records is of significance to current archaeological research. The npaph has recently initiated a new project: Jericho-off-the-Record. This project aims to gather not only visual non-professional documentation of the second British campaign to Tell es-Sultan (ancient Jericho) but also to collect written and oral records of the renowned excavation, which was conducted by Kathleen Kenyon from 1952 till 1958. This article provides an update of the situation regarding the current project of which an initial data deposit has been made accessible in
easy
, the dans online archiving system.
A critical checklist of the woody flora of Tuscany (Italy)
Authors: ROMA-MARZIO FRANCESCO , BEDINI GIANNI , MÜLLER JONAS V. , Peruzzi Lorenzo
Published: December 2016

A comprehensive checklist of the Tuscan woody flora providing sub-regional details is presented. This checklist comprises 412 taxa, of which 264 are native and 148 are non-native. Nine taxa new for the region were found, and eleven taxa were excluded from the regional flora. The native taxa belong to 109 genera and 53 families. Rosaceae is the family richest in taxa, with Rosa being the genus with the highest number of species. On the provincial level, the province of Grosseto is the province with the highest number of native taxa, followed by the provinces of Lucca and Florence. The lowest number of taxa was documented in the provinces of Pistoia and Prato. With regard to the non-native woody flora, the highest number of non-native taxa can be found in the province of Livorno, whereas the lowest number occurs in the provinces of Arezzo and Siena. At regional level, 9% of non-native taxa are invasive, 45% naturalized and 46% casual. Asia and North America are the most common native ranges of those taxa. After an extensive herbarium study, the taxonomy and distribution of Acer opalus, Cornus sanguinea, Juniperus deltoides, Oreoherzogia alpina, Pyrus communis, Quercus crenata, Salix elaeagnos, and Sorbus aria are discussed in more detail.
Recent Advances in Satellite Data Rescue
Authors: Poli Paul , Dee Dick P. , Saunders Roger , John Viju O. , Rayer Peter , Schulz Jörg , Holmlund Kenneth , Coppens Dorothee , Klaes Dieter , Johnson James E. , Esfandiari Asghar E. , Gerasimov Irina V. , Zamkoff Emily B. , Al-Jazrawi Atheer F. , Santek David , Albani Mirko , Brunel Pascal , Fennig Karsten , Schröder Marc , Kobayashi Shinya , Oertel Dieter , Döhler Wolfgang , Spänkuch Dietrich , Bojinski Stephan
Published: December 2016

To better understand the impacts of climate change, environmental monitoring capabilities must be enhanced by deploying additional and more accurate satellite- and ground-based (including in situ) sensors. In addition, reanalysis of observations collected decades ago but long forgotten can unlock precious information about the recent past. Historical, in situ observations mainly cover densely inhabited areas and frequently traveled routes. In contrast, large selections of early meteorological satellite data, waiting to be exploited today, provide information about remote areas unavailable from any other source. When initially collected, these satellite data posed great challenges to transmission and archiving facilities. As a result, data access was limited to the main teams of scientific investigators associated with the instruments. As archive media have aged, so have the mission scientists and other pioneers of satellite meteorology, who sometimes retired in possession of unique and unpublished information.

This paper presents examples of recently recovered satellite data records, including satellite imagery, early infrared hyperspectral soundings, and early microwave humidity soundings. Their value for climate applications today can be realized using methods and techniques that were not yet available when the data were first collected, including efficient and accurate observation simulators and data assimilation into reanalyses. Modern technical infrastructure allows serving entire mission datasets online, enabling easy access and exploration by a broad range of users, including new and old generations of climate scientists.
An Investigation of the Influences of Mesoscale Ocean Eddies on Tropical Cyclone Intensities
Authors: Ma Zhanhong , Fei Jianfang , Liu Lei , Huang Xiaogang , Li Yan
Published: December 2016

The impact of mesoscale ocean eddies on tropical cyclone intensities is investigated based on a combination of observations and atmosphere–ocean coupling simulations. A statistical analysis reveals that the tropical cyclone–eddy interactions occur at very high frequencies; over 90% of the recorded tropical cyclones over the western North Pacific have encountered ocean eddies from 2002 to 2011. The chances of confronting a cold core eddy (CCE) are slightly larger than confronting a warm core eddy (WCE). The observational sea surface temperature data have statistically evidenced that CCEs tend to promote the sea surface temperature decrease caused by tropical cyclones while WCEs tend to restrain such ocean responses. The roles of CCEs are statistically more significant than those of WCEs in modulating the sea surface temperature response. It is therefore proposed that CCEs should be paid no less attention than WCEs during the TC–ocean interaction process. The CCE-induced changes in sea surface temperature decreases are observed to be more remarkable for more intense and slower-moving tropical cyclones and for thinner depth of mixed layers. A set of numerical experiments reveal that the effects of ocean eddies are positively related to their strengths and storm intensities, and the eddy feedback is less pronounced when the eddy is located at one side of storm tracks than right below the tropical cyclone center. The eddy-induced moisture disequilibrium sooner vanishes after the departure of tropical cyclones. The intensity recoveries last for 1–2 days because of the dependence of surface enthalpy fluxes on surface winds.
Prior Familiarization With Takeover Requests Affects Drivers’ Takeover Performance and Automation Trust
Authors: Hergeth Sebastian , Lorenz Lutz , Krems Josef F.
Published: December 2016

Objective:

The objective for this study was to investigate the effects of prior familiarization with takeover requests (TORs) during conditional automated driving on drivers’ initial takeover performance and automation trust.

Background:

System-initiated TORs are one of the biggest concerns for conditional automated driving and have been studied extensively in the past. Most, but not all, of these studies have included training sessions to familiarize participants with TORs. This makes them hard to compare and might obscure first-failure-like effects on takeover performance and automation trust formation.

Method:

A driving simulator study compared drivers’ takeover performance in two takeover situations across four prior familiarization groups (no familiarization, description, experience, description and experience) and automation trust before and after experiencing the system.

Results:

As hypothesized, prior familiarization with TORs had a more positive effect on takeover performance in the first than in a subsequent takeover situation. In all groups, automation trust increased after participants experienced the system. Participants who were given no prior familiarization with TORs reported highest automation trust both before and after experiencing the system.

Conclusion:

The current results extend earlier findings suggesting that prior familiarization with TORs during conditional automated driving will be most relevant for takeover performance in the first takeover situation and that it lowers drivers’ automation trust.

Application:

Potential applications of this research include different approaches to familiarize users with automated driving systems, better integration of earlier findings, and sophistication of experimental designs.