bluuebunny/crossref_metadata_2025_split huggingface dataset:
Incidence and serotype characterisation ofStreptococcus agalactiaein a Portuguese hospital
Authors: Pinto Ana Mafalda , Pereira Tamegão Aires , Alves Valquíria , Araújo António , Lage Olga Maria 
Published: November 2017

AimsStreptococcus agalactiae,commonly known as group BStreptococcus(GBS), has been recognised as a worldwide causative pathogenic agent of neonatal sepsis, meningitis and pneumonia. To better understand the behaviour ofS. agalactiaein pregnant women from a hospital from the North of Portugal, retrospective analyses were performed to describe epidemiological, clinical and microbiological characteristics of the isolates obtained.MethodsBased on laboratorial records and the hospital’s patient files, a 6-year retrospective study was performed to analyseS. agalactiaeisolates from screened pregnant women between 35 and 37 weeks of gestation and hospitalised neonates from pregnant women between 24 and 41 weeks of gestation admitted in Hospital Pedro Hispano. Serotype characterisation was also performed in 67 GBS strains.ResultsIn 6692 pregnant women between 35 and 37 weeks of gestation screened between 2011 and 2016, a total of 1377S. agalactiaeisolates (21%) were found. A high percentage (40%) of unknown colonisation status among hospitalised neonates from pregnant women between 24 and 41 weeks of gestations was also found. The incidence of neonatal sepsis was 8.7 (95% CI 7.0 to 10.8) cases per 1000 live births. Regarding serotype characterisation, serotype III (22.4%) was the most frequent, followed by serotype Ia (19.4%) and serotypes Ib and V (both with 17.9%).ConclusionHigh epidemiological values of GBS colonisation and incidence were found in this study. In Portugal studies on the epidemiology and behaviour ofS. agalactiaeremain limited, reinforcing the importance and need forS. agalactiaescreening across the country.
CEBPAmutational analysis in acute myeloid leukaemia by a laboratory-developed next-generation sequencing assay
Authors: Ng Christopher Wai Siong , Kosmo Bustamin , Lee Peak-Ling , Lee Chun Kiat , Guo Jingxue , Chen Zhaojin , Chiu Lily , Lee Hong Kai , Ho Sherry , Zhou Jianbiao , Lin Mingxuan , Tan Karen M L , Ban Kenneth H K , Tan Tin Wee , Chng Wee Joo , Yan Benedict 
Published: November 2017

AimThe presence of biallelicCEBPAmutations is a favourable prognostic feature in acute myeloid leukaemia (AML).CEBPAmutations are currently identified through conventional capillary sequencing (CCS). With the increasing adoption of next-generation sequencing (NGS) platforms, challenges with regard to amplification efficiency ofCEBPAdue to the high GC content may be encountered, potentially resulting in suboptimal coverage. Here, the performance of an amplicon-based NGS method using a laboratory-developedCEBPA-specific Nextera XT (CEBNX) was evaluated.MethodsMutational analyses of theCEBPAgene of 137 AML bone marrow or peripheral blood retrospective specimens were performed by the amplification of theCEBPAgene using the Expand Long Range dNTPack and the amplicons processed by CCS and NGS.CEBPA-specific libraries were then constructed using the Nextera XT V.2 kit. All FASTQ files were then processed with the MiSeq Reporter V.2.6.2.3 using the PCR Amplicon workflow via the customisedCEBPA-specific manifest file. The variant calling format files were analysed using the Illumina Variant Studio V.2.2.ResultsA coverage per base of 3631X to 28184X was achieved. 22 samples (16.1%) were found to containCEBPAmutations, with variant allele frequencies (VAF) ranging from 3.8% to 58.2%. Taking CCS as the ‘gold standard’, sensitivity and specificity of 97% and 97% was achieved. For the transactivation domain 2 polymorphism (c.584_589dupACCCGC/p.His195_Pro196dup), the CEBNX achieved 100% sensitivity and 100% specificity relative to CCS.ConclusionsOur laboratory-developed CEBNX workflow shows high coverage and thus overcomes the challenges associated with amplification efficiency and low coverage ofCEBPA.Therefore, our assay is suitable for deployment in the clinical laboratory.
miR-139-5p Modulates Radiotherapy Resistance in Breast Cancer by Repressing Multiple Gene Networks of DNA Repair and ROS Defense
Authors: Pajic Marina , Froio Danielle , Daly Sheridan , Doculara Louise , Millar Ewan , Graham Peter H. , Drury Alison , Steinmann Angela , de Bock Charles E. , Boulghourjian Alice , Zaratzian Anaiis , Carroll Susan , Toohey Joanne , O’Toole Sandra A. , Harris Adrian L , Buffa Francesca M. , Gee Harriet E. , Hollway Georgina E. , Molloy Timothy J. 
Published: November 2017

Abstract
Radiotherapy is essential to the treatment of most solid tumors and acquired or innate resistance to this therapeutic modality is a major clinical problem. Here we show that miR-139-5p is a potent modulator of radiotherapy response in breast cancer via its regulation of genes involved in multiple DNA repair and reactive oxygen species defense pathways. Treatment of breast cancer cells with a miR-139-5p mimic strongly synergized with radiation both in vitro and in vivo, resulting in significantly increased oxidative stress, accumulation of unrepaired DNA damage, and induction of apoptosis. Several miR-139-5p target genes were also strongly predictive of outcome in radiotherapy-treated patients across multiple independent breast cancer cohorts. These prognostically relevant miR-139-5p target genes were used as companion biomarkers to identify radioresistant breast cancer xenografts highly amenable to sensitization by cotreatment with a miR-139-5p mimetic.
Significance: The microRNA described in this study offers a potentially useful predictive biomarker of radiosensitivity in solid tumors and a generally applicable druggable target for tumor radiosensitization. Cancer Res; 78(2); 501–15. ©2017 AACR.
A Potent, Metabolically Stable Tubulin Inhibitor Targets the Colchicine Binding Site and Overcomes Taxane Resistance
Authors: Arnst Kinsie E. , Wang Yuxi , Hwang Dong-Jin , Xue Yi , Costello Terry , Hamilton David , Chen Qiang , Yang Jinliang , Park Frank , Dalton James T. , Miller Duane D. , Li Wei 
Published: November 2017

Abstract
Antimitotics that target tubulin are among the most useful chemotherapeutic drugs, but their clinical activity is often limited by the development of multidrug resistance. We recently discovered the novel small-molecule DJ101 as a potent and metabolically stable tubulin inhibitor that can circumvent the drug efflux pumps responsible for multidrug resistance of existing tubulin inhibitors. In this study, we determined the mechanism of action of this drug. The basis for its activity was illuminated by solving the crystal structure of DJ101 in complex with tubulin at a resolution of 2.8Å. Investigations of the potency of DJ101 in a panel of human metastatic melanoma cell lines harboring major clinically relevant mutations defined IC50 values of 7–10 nmol/L. In cells, DJ101 disrupted microtubule networks, suppressed anchorage-dependent melanoma colony formation, and impaired cancer cell migration. In melanoma-bearing mice, DJ101 administration inhibited tumor growth and reduced lung metastasis in the absence of observable toxicity. DJ101 also completely inhibited tumor growth in a paclitaxel-resistant xenograft mouse model of human prostate cancer (PC-3/TxR), where paclitaxel was minimally effective. Our findings offer preclinical proof of concept for the continued development of DJ101 as a next-generation tubulin inhibitor for cancer therapy.
Significance: These findings offer preclinical proof of concept for the continued development of DJ101 as a next-generation antitubulin drug for cancer therapy. Cancer Res; 78(1); 265–77. ©2017 AACR.
YAP1 and COX2 Coordinately Regulate Urothelial Cancer Stem-like Cells
Authors: Ooki Akira , Del Carmen Rodriguez Pena Maria , Marchionni Luigi , Dinalankara Wikum , Begum Asma , Hahn Noah M. , VandenBussche Christopher J. , Rasheed Zeshaan A. , Mao Shifeng , Netto George J. , Sidransky David , Hoque Mohammad O. 
Published: November 2017

Abstract
Overcoming acquired drug resistance remains a core challenge in the clinical management of human cancer, including in urothelial carcinoma of the bladder (UCB). Cancer stem-like cells (CSC) have been implicated in the emergence of drug resistance but mechanisms and intervention points are not completely understood. Here, we report that the proinflammatory COX2/PGE2 pathway and the YAP1 growth-regulatory pathway cooperate to recruit the stem cell factor SOX2 in expanding and sustaining the accumulation of urothelial CSCs. Mechanistically, COX2/PGE2 signaling induced promoter methylation of let-7, resulting in its downregulation and subsequent SOX2 upregulation. YAP1 induced SOX2 expression more directly by binding its enhancer region. In UCB clinical specimens, positive correlations in the expression of SOX2, COX2, and YAP1 were observed, with coexpression of COX2 and YAP1 particularly commonly observed. Additional investigations suggested that activation of the COX2/PGE2 and YAP1 pathways also promoted acquired resistance to EGFR inhibitors in basal-type UCB. In a mouse xenograft model of UCB, dual inhibition of COX2 and YAP1 elicited a long-lasting therapeutic response by limiting CSC expansion after chemotherapy and EGFR inhibition. Our findings provide a preclinical rationale to target these pathways concurrently with systemic chemotherapy as a strategy to improve the clinical management of UCB.
Significance: These findings offer a preclinical rationale to target the COX2 and YAP1 pathways concurrently with systemic chemotherapy to improve the clinical management of UCB, based on evidence that these two pathways expand cancer stem-like cell populations that mediate resistance to chemotherapy. Cancer Res; 78(1); 168–81. ©2017 AACR.
ERα Binding by Transcription Factors NFIB and YBX1 Enables FGFR2 Signaling to Modulate Estrogen Responsiveness in Breast Cancer
Authors: Campbell Thomas M. , Castro Mauro A. A. , de Oliveira Kelin Gonçalves , Ponder Bruce A. J. , Meyer Kerstin B. 
Published: November 2017

Abstract
Two opposing clusters of transcription factors (TF) have been associated with the differential risks of estrogen receptor positive or negative breast cancers, but the mechanisms underlying the opposing functions of the two clusters are undefined. In this study, we identified NFIB and YBX1 as novel interactors of the estrogen receptor (ESR1). NFIB and YBX1 are both risk TF associated with progression of ESR1-negative disease. Notably, they both interacted with the ESR1-FOXA1 complex and inhibited the transactivational potential of ESR1. Moreover, signaling through FGFR2, a known risk factor in breast cancer development, augmented these interactions and further repressed ESR1 target gene expression. We therefore show that members of two opposing clusters of risk TFs associated with ESR1-positive and -negative breast cancer can physically interact. We postulate that this interaction forms a toggle between two developmental pathways affected by FGFR2 signaling, possibly offering a junction to exploit therapeutically.
Significance: Binding of the transcription factors NFIB and YBX1 to the estrogen receptor can promote an estrogen-independent phenotype that can be reverted by inhibiting FGFR2 signaling. Cancer Res; 78(2); 410–21. ©2017 AACR.
Small-Molecule Inhibition of Axl Targets Tumor Immune Suppression and Enhances Chemotherapy in Pancreatic Cancer
Authors: Ludwig Kathleen F. , Du Wenting , Sorrelle Noah B. , Wnuk-Lipinska Katarzyna , Topalovski Mary , Toombs Jason E. , Cruz Victoria H. , Yabuuchi Shinichi , Rajeshkumar N.V. , Maitra Anirban , Lorens James B. , Brekken Rolf A. 
Published: November 2017

Abstract
Activation of the receptor tyrosine kinase Axl is associated with poor outcomes in pancreatic cancer (PDAC), where it coordinately mediates immune evasion and drug resistance. Here, we demonstrate that the selective Axl kinase inhibitor BGB324 targets the tumor–immune interface to blunt the aggressive traits of PDAC cells in vitro and enhance gemcitibine efficacy in vivo. Axl signaling stimulates the TBK1–NFκB pathway and innate immune suppression in the tumor microenvironment. In tumor cells, BGB324 treatment drove epithelial differentiation, expression of nucleoside transporters affecting gemcitabine response, and an immune stimulatory microenvironment. Our results establish a preclinical mechanistic rationale for the clinical development of Axl inhibitors to improve the treatment of PDAC patients.
Significance: These results establish a preclinical mechanistic rationale for the clinical development of AXL inhibitors to improve the treatment of PDAC patients. Cancer Res; 78(1); 246–55. ©2017 AACR.
Perioperative, Spatiotemporally Coordinated Activation of T and NK Cells Prevents Recurrence of Pancreatic Cancer
Authors: Brooks Jennifer , Fleischmann-Mundt Bettina , Woller Norman , Niemann Julia , Ribback Silvia , Peters Kristin , Demir Ihsan Ekin , Armbrecht Nina , Ceyhan Guralp O. , Manns Michael P. , Wirth Thomas C. , Kubicka Stefan , Bernhardt Gunter , Smyth Mark J. , Calvisi Diego F. , Gürlevik Engin , Kühnel Florian 
Published: November 2017

Abstract
Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal and disseminating cancer resistant to therapy, including checkpoint immunotherapies, and early tumor resection and (neo)adjuvant chemotherapy fails to improve a poor prognosis. In a transgenic mouse model of resectable PDAC, we investigated the coordinated activation of T and natural killier (NK) cells in addition to gemcitabine chemotherapy to prevent tumor recurrence. Only neoadjuvant, but not adjuvant treatment with a PD-1 antagonist effectively supported chemotherapy and suppressed local tumor recurrence and improved survival involving both NK and T cells. Local T-cell activation was confirmed by increased tumor infiltration with CD103+CD8+ T cells and neoantigen-specific CD8 T lymphocytes against the marker neoepitope LAMA4-G1254V. To achieve effective prevention of distant metastases in a complementary approach, we blocked the NK-cell checkpoint CD96, an inhibitory NK-cell receptor that binds CD155, which was abundantly expressed in primary PDAC and metastases of human patients. In gemcitabine-treated mice, neoadjuvant PD-1 blockade followed by adjuvant inhibition of CD96 significantly prevented relapse of PDAC, allowing for long-term survival. In summary, our results show in an aggressively growing transgenic mouse model of PDAC that the coordinated activation of both innate and adaptive immunity can effectively reduce the risk of tumor recurrence after surgery, facilitating long-term remission of this lethal disease.
Significance: Coordinated neoadjuvant and adjuvant immunotherapies reduce the risk of disease relapse after resection of murine PDAC, suggesting this concept for future clinical trials. Cancer Res; 78(2); 475–88. ©2017 AACR.
Honokiol Radiosensitizes Squamous Cell Carcinoma of the Head and Neck by Downregulation of Survivin
Authors: Wang Xu , Beitler Jonathan J. , Huang Wen , Chen Guo , Qian Guoqing , Magliocca Kelly , Patel Mihir R. , Chen Amy Y. , Zhang Jun , Nannapaneni Sreenivas , Kim Sungjin , Chen Zhengjia , Deng Xingming , Saba Nabil F. , Chen Zhuo Georgia , Arbiser Jack L. , Shin Dong M. 
Published: November 2017

Abstract
Purpose: Previous studies revealed diverging results regarding the role of survivin in squamous cell carcinoma of the head and neck (SCCHN). This study aimed to evaluate the clinical significance of survivin expression in SCCHN; the function of survivin in DNA-damage repair following ionizing radiation therapy (RT) in SCCHN cells; and the potential of honokiol to enhance RT through downregulation of survivin.
Experimental Design: Expression of survivin in SCCHN patient primary tumor tissues (n = 100) was analyzed and correlated with clinical parameters. SCCHN cell lines were used to evaluate the function of survivin and the effects of honokiol on survivin expression in vitro and in vivo.
Results: Overexpression of survivin was significantly associated with lymph nodes' metastatic status (P = 0.025), worse overall survival (OS), and disease-free survival (DFS) in patients receiving RT (n = 65, OS: P = 0.024, DFS: P = 0.006) and in all patients with SCCHN (n = 100, OS: P = 0.002, DFS: P = 0.003). In SCCHN cells, depletion of survivin led to increased DNA damage and cell death following RT, whereas overexpression of survivin increased clonogenic survival. RT induced nuclear accumulation of survivin and its molecular interaction with γ-H2AX and DNA-PKCs. Survivin specifically bound to DNA DSB sites induced by I-SceI endonuclease. Honokiol (which downregulates survivin expression) in combination with RT significantly augmented cytotoxicity in SCCHN cells with acquired radioresistance and inhibited growth in SCCHN xenograft tumors.
Conclusions: Survivin is a negative prognostic factor and is involved in DNA-damage repair induced by RT. Targeting survivin using honokiol in combination with RT may provide novel therapeutic opportunities. Clin Cancer Res; 24(4); 858–69. ©2017 AACR.
Cell-Free DNA and Circulating Tumor Cells: Comprehensive Liquid Biopsy Analysis in Advanced Breast Cancer
Authors: Rossi Giovanna , Mu Zhaomei , Rademaker Alfred W. , Austin Laura K. , Strickland Kimberly S. , Costa Ricardo Lima Barros , Nagy Rebecca J. , Zagonel Vittorina , Taxter Timothy J. , Behdad Amir , Wehbe Firas H. , Platanias Leonidas C. , Gradishar William J. , Cristofanilli Massimo 
Published: November 2017

Abstract
Purpose: Liquid biopsy provides a real-time assessment of metastatic breast cancer (MBC). We evaluated the utility of combining circulating tumor cells (CTC) and circulating tumor DNA (ctDNA) to predict prognosis in MBC.
Experimental Design: We conducted a retrospective study of 91 patients with locally advanced breast cancer and MBC. CTCs were enumerated by CellSearch; the plasma-based assay was performed utilizing Guardant360 and the survival analysis using Kaplan–Meier curves.
Results: Eighty-four patients had stage IV cancer, and 7 patients had no metastases. Eighty patients had CTC analysis: median number 2 (0–5,612). Blood samples [232 of 277 (84%)] had mutations. The average ctDNA fraction was 4.5% (0–88.2%) and number of alterations 3 (0–27); the most commonly mutated genes were TP53 (52%), PIK3CA (40%), and ERBB2 (20%). At the time of analysis, 36 patients (39.6%) were dead. The median follow-up for CTCs was 9 months; for ctDNA, it was 9.9 months. For CTCs and ctDNA, respectively, progression-free survival (PFS) was 4.2 and 5.2 months and overall survival (OS) was 18.7 and 21.5 months. There was a statistically significant difference in PFS and OS for baseline CTCs &lt; 5 versus CTCs ≥ 5 (P = 0.021 and P = 0.0004, respectively); %ctDNA &lt; 0.5 versus ≥ 0.5 (P = 0.003 and P = 0.012); number of alterations &lt; 2 versus ≥ 2 (P = 0.059 borderline and P = 0.0015). A significant association by Fisher exact test was found between the number of alterations and the %ctDNA in the baseline sample (P &lt; 0.0001).
Conclusions: The study demonstrated that liquid biopsy is an effective prognostic tool. Clin Cancer Res; 24(3); 560–8. ©2017 AACR.
Idades U-Pb de zircão detrítico da sequência metassedimentar superior na região do Greenstone Belt de Guarinos, Goiás
Authors: Silva Alex Joaquim Choupina Andrade , Simões Luiz Sérgio Amarante 
Published: November 2017

Na porção norte do Bloco Arqueano de Goiás ocorrem dois greenstone belts (Guarinos e Pilar de Goiás) cobertos por uma sequência metassedimentar, atribuída por diversos autores ao Grupo Araxá e por outros ao Grupo Serra da Mesa/Serra Dourada e, ainda, referida por alguns simplesmente como uma Sequência Mesoproterozoica. Embora ocorram semelhanças litoestratigráficas entre os grupos Araxá e Serra da Mesa, trabalhos mais recentes têm mostrado que a evolução dessas bacias e as suas idades de sedimentação possuem peculiaridades que as diferenciam entre si. Este trabalho apresenta dados geocronológicos U-Pb em zircão detríticos obtidos pelo método ablação a laser (LA-MC-ICP-MS) em amostras de quartzitos dessa sequência metassedimentar. O zircão mais jovem encontrado apresenta idade de 1405 ± 10 Ma, marcando o limite máximo de deposição e indicando área-fonte com rochas do Mesoproterozoico. As amostras apresentam maior frequência de cristais paleoproterozoicos, entre 1796 e 2472 Ma, e populações mais antigas, de idade mesoneoarqueana, entre 2672 e 3112 Ma. Enquanto os detritos paleoproterozoicos a arqueanos podem ser provenientes das rochas que constituem o Bloco Arqueano de Goiás, a fonte para o conjunto mesoproterozoico é duvidosa; talvez esteja relacionada a rochas da Província Estanífera de Goiás, ou equivalentes.
Front San Diablo na região de Miraflores, Faixa Sunsás, Bolívia: implicações tectônicas e estratigráficas
Authors: Nedel Ingrid Moerschberger , Ruiz Amarildo Salina , Matos-Salinas Gerardo Ramiro , Sousa Maria Zélia Aguiar de , Pimentel Marcio Martins , Pavanetto Pamela 
Published: November 2017

O Front San Diablo trata-se de uma megaestrutura tectônica desenvolvida nas rochas do Terreno Paraguá e pela cobertura metassedimentar do Grupo Sunsás. Os dados geológicos e geocronológicos obtidos neste trabalho permitiram correlacionar os litotipos descritos na região estudada a três unidades litoestratigráficas: o Complexo Chiquitania, formado por biotita gnaisses de composição monzogranítica a granodiorítica; a Suíte Intrusiva Pensamiento, representada pelo Granito Colmena, um corpo intrusivo milonitizado de composição monzogranítica, localizado na zona de maior deformação do front; e o Grupo Sunsás, formado por micaxistos e metarenitos. Foram identificadas três fases de deformação: F1 gerou o bandamento gnáissico S1 com trend N-S nas rochas do Complexo Chiquitania; F2 promoveu a transposição do bandamento S1, e deu origem a dobras e à foliação S2 segundo o trend regional E-W; F3 foi marcada por dobras suaves e foliações espaçadas do tipo crenulação (S3) ortogonais ao trend geral das estruturas. Os dados geocronológicos U-Pb (SHRIMP) indicaram idade de cristalização em 1.685 ± 4,9 Ma e provável idade de metamorfismo em 1.111 ± 10 Ma para o gnaisse do Complexo Chiquitania; já os dados U-Pb (LA-ICP-MS) obtidos a partir de zircões detríticos sugerem idade máxima de sedimentação em torno de 1,2 Ga para o Grupo Sunsás, com fontes de idade paleo e mesoproterozoicas. Os dados estruturais caracterizam o Front San Diablo como uma larga zona de cisalhamento com direção NE e movimento direcional destral, gerada durante a Orogênese Sunsás em torno de 1,0 Ga, como indicam os dados K-Ar prévios. A partir dos dados apresentados, sugere-se que o Front San Diablo não se trata de um limite tectônico entre os terrenos alóctones Paraguá e San Pablo, mas sim de uma larga faixa de cisalhamento desenvolvida no Toniano, responsável pela justaposição por meio de movimentos direcionais de blocos crustais no interior do Terreno Paraguá.