bluuebunny/crossref_metadata_2025_split huggingface dataset:
Protocol for the avatar acceptability study: a multiperspective cross-sectional study evaluating the acceptability of using patient-derived xenografts to guide personalised cancer care in Australia and New Zealand
Authors: Wakefield Claire E , Doolan Emma L , Fardell Joanna E , Signorelli Christina , Quinn Veronica F , Tucker Kathy F , Patenaude Andrea F , Marshall Glenn M , Lock Richard B , Georgiou Gabrielle , Cohn Richard J 
Published: August 2018

IntroductionPatient-derived xenografts (PDXs) have the potential to transform personalised cancer care, however, little is known about the acceptability of using PDXs to guide treatment decision-making. Given that patient and community preferences can influence satisfaction with care as well as the success of new technologies, we will evaluate the acceptability of PDXs in individuals affected by cancer and community comparisons.Methods and analysisThis comparative cross-sectional study will recruit 323 individuals affected by cancer (cancer survivors (of childhood or adult cancer) and parents of childhood cancer survivors) and 323 community comparisons (adults and parents). We will collect data via structured interviews and questionnaires. To determine the acceptability of PDXs, we will assess five domains: willingness to use PDXs when/if diagnosed with cancer, perceived advantages and disadvantages of PDXs, maximum acceptable out-of-pocket costs per patient, maximum acceptable turnaround time to receive results and maximum acceptable number of mice sacrificed per patient. The primary endpoint will be participants’ decisional balance ratio (calculated as participants’ advantages ratings divided by perceived disadvantages ratings).Ethics and disseminationThe study protocol has been approved by the South Eastern Sydney Local Health District Human Research Ethics Committee (HREC:12/173) and UNSW Sydney (HC15773). The results will be disseminated in peer-reviewed journals and at scientific conferences. A lay summary will be published on the Behavioural Sciences Unit website.
Long-term outcomes of His bundle pacing in patients with heart failure with left bundle branch block
Authors: Huang Weijian , Su Lan , Wu Shengjie , Xu Lei , Xiao Fangyi , Zhou Xiaohong , Mao Guangyun , Vijayaraman Pugazhendhi , Ellenbogen Kenneth A 
Published: August 2018

ObjectivesHis bundle pacing (HBP) can potentially correct left bundle branch block (LBBB). We aimed to assess the efficacy of HBP to correct LBBB and long-term clinical outcomes with HBP in patients with heart failure (HF).MethodsThis is an observational study of patients with HF with typical LBBB who were indicated for pacing therapy and were consecutively enrolled from one centre. Permanent HBP leads were implanted if the LBBB correction threshold was <3.5V/0.5 ms or 3.0 V/1.0 ms. Pacing parameters, left ventricular ejection fraction (LVEF), left ventricular end-systolic volume (LVESV) and New York Heart Association (NYHA) Class were assessed during follow-up.ResultsIn 74 enrolled patients (69.6±9.2 years and 43 men), LBBB correction was acutely achieved in 72 (97.3%) patients, and 56 (75.7%) patients received permanent HBP (pHBP) while 18 patients did not receive permanent HBP (non-permanent HBP), due to no LBBB correction (n=2), high LBBB correction thresholds (n=10) and fixation failure (n=6). The median follow-up period of pHBP was 37.1 (range 15.0–48.7) months. Thirty patients with pHBP had completed 3-year follow-up, with LVEF increased from baseline 32.4±8.9% to 55.9±10.7% (p<0.001), LVESV decreased from a baseline of 137.9±64.1 mL to 52.4±32.6 mL (p<0.001) and NYHA Class improvement from baseline 2.73±0.58 to 1.03±0.18 (p<0.001). LBBB correction threshold remained stable with acute threshold of 2.13±1.19 V/0.5 ms to 2.29±0.92 V/0.5 ms at 3-year follow-up (p>0.05).ConclusionspHBP improved LVEF, LVESV and NYHA Class in patients with HF with typical LBBB.
Low but not high frequency of intermittent hypoxia suppresses endothelium-dependent, oxidative stress-mediated contractions in carotid arteries of obese mice
Authors: Lee Mary Y. K. , Ge Grace , Fung M. L. , Vanhoutte Paul M. , Mak Judith C. W. , Ip Mary S. M. 
Published: August 2018

Obstructive sleep apnea is characterized by intermittent hypoxia (IH) during sleep and predisposes to endothelial dysfunction. Obesity is a major risk factor for the occurrence of sleep apnea. The present study compared the functional impact of low- (IH10; 10 hypoxic events/h) and high-frequency (IH60; 60 hypoxic events/h) IH for 4 wk on endothelial function in male C57BL/6 mice with or without high-fat (HF) diet-induced obesity. Mean arterial blood pressure (tail cuff method) was increased in obese mice after IH60 exposure, i.e., HF + IH60 group. The serum levels of the oxidative stress marker malondialdehyde were augmented in lean IH60 and HF groups, with a further increase in HF + IH60 but a reduction in HF + IH10 mice compared with the HF group. Vascular responsiveness was assessed as changes in isometric tension in isolated arteries. Relaxations to the endothelium-dependent vasodilator acetylcholine were impaired in HF + IH60 aortae. Endothelium-dependent contractions (EDC; response to acetylcholine in the presence of the nitric oxide synthase inhibitor l-NAME) in carotid arteries were augmented in the HF group, but this HF-induced augmentation was suppressed by low-frequency IH exposure. The addition of apocynin (antioxidant) reduced EDC in HF and HF + IH60 groups but not in HF + IH10 group. In conclusion, these findings suggest that exposure of obese mice to mild IH exerts preconditioning-like suppression of endothelium-dependent and oxidative stress-mediated contractions. When IH severity increases, this suppression diminishes and endothelial dysfunction accelerates. NEW & NOTEWORTHY The present study demonstrates, for the first time, that low-frequency intermittent hypoxia may exert a preconditioning-like suppression of oxidative stress-induced endothelium-dependent contractions in mice with diet-induced obesity. This relative suppression was diminished as intermittent hypoxia became more severe, and a deleterious effect on endothelial function emerged.
Single-Cell Analyses of Prostate Cancer Liquid Biopsies Acquired by Apheresis
Authors: Lambros Maryou B. , Seed George , Sumanasuriya Semini , Gil Veronica , Crespo Mateus , Fontes Mariane , Chandler Rob , Mehra Niven , Fowler Gemma , Ebbs Berni , Flohr Penny , Miranda Susana , Yuan Wei , Mackay Alan , Ferreira Ana , Pereira Rita , Bertan Claudia , Figueiredo Ines , Riisnaes Ruth , Rodrigues Daniel Nava , Sharp Adam , Goodall Jane , Boysen Gunther , Carreira Suzanne , Bianchini Diletta , Rescigno Pasquale , Zafeiriou Zafeiris , Hunt Joanne , Moloney Deirdre , Hamilton Lucy , Neves Rui P. , Swennenhuis Joost , Andree Kiki , Stoecklein Nikolas H. , Terstappen Leon W.M.M. , de Bono Johann S. 
Published: August 2018

AbstractPurpose: Circulating tumor cells (CTCs) have clinical relevance, but their study has been limited by their low frequency.Experimental Design: We evaluated liquid biopsies by apheresis to increase CTC yield from patients suffering from metastatic prostate cancer, allow precise gene copy-number calls, and study disease heterogeneity.Results: Apheresis was well tolerated and allowed the separation of large numbers of CTCs; the average CTC yield from 7.5 mL of peripheral blood was 167 CTCs, whereas the average CTC yield per apheresis (mean volume: 59.5 mL) was 12,546 CTCs. Purified single CTCs could be isolated from apheresis product by FACS sorting; copy-number aberration (CNA) profiles of 185 single CTCs from 14 patients revealed the genomic landscape of lethal prostate cancer and identified complex intrapatient, intercell, genomic heterogeneity missed on bulk biopsy analyses.Conclusions: Apheresis facilitated the capture of large numbers of CTCs noninvasively with minimal morbidity and allowed the deconvolution of intrapatient heterogeneity and clonal evolution. Clin Cancer Res; 24(22); 5635–44. ©2018 AACR.
Role of the RANK/RANKL Pathway in Multiple Myeloma
Authors: Raje Noopur S. , Bhatta Sumita , Terpos Evangelos 
Published: August 2018

AbstractReceptor activator of nuclear factor-kappa B (RANK) and its ligand, RANKL, are expressed in a variety of tissues throughout the body; their primary role is in the regulation of bone remodeling and development of the immune system. Consistent with these functions, evidence exists for a role of RANK/RANKL in all stages of tumorigenesis, from cell proliferation and carcinogenesis to epithelial–mesenchymal transition to neoangiogenesis and intravasation to metastasis to bone resorption and tumor growth in bone. Results from current studies also point to a role of RANK/RANKL signaling in patients with multiple myeloma, who have increased serum levels of soluble RANKL and an imbalance in RANKL and osteoprotegerin. Current therapies for patients with multiple myeloma demonstrate that RANKL may be released by tumor cells or osteoprogenitor cells. This article will review currently available evidence supporting a role for RANK/RANKL signaling in tumorigenesis, with a focus on patients with multiple myeloma.
The BTK Inhibitor ARQ 531 Targets Ibrutinib-Resistant CLL and Richter Transformation
Authors: Reiff Sean D. , Mantel Rose , Smith Lisa L. , Greene J.T. , Muhowski Elizabeth M. , Fabian Catherine A. , Goettl Virginia M. , Tran Minh , Harrington Bonnie K. , Rogers Kerry A. , Awan Farrukh T. , Maddocks Kami , Andritsos Leslie , Lehman Amy M. , Sampath Deepa , Lapalombella Rosa , Eathiraj Sudharshan , Abbadessa Giovanni , Schwartz Brian , Johnson Amy J. , Byrd John C. , Woyach Jennifer A. 
Published: August 2018

Abstract
Targeted inhibition of Bruton tyrosine kinase (BTK) with the irreversible inhibitor ibrutinib has improved outcomes for patients with hematologic malignancies, including chronic lymphocytic leukemia (CLL). Here, we describe preclinical investigations of ARQ 531, a potent, reversible inhibitor of BTK with additional activity against Src family kinases and kinases related to ERK signaling. We hypothesized that targeting additional kinases would improve global inhibition of signaling pathways, producing more robust responses. In vitro treatment of patient CLL cells with ARQ 531 decreases BTK-mediated functions including B-cell receptor (BCR) signaling, viability, migration, CD40 and CD86 expression, and NF-κB gene transcription. In vivo, ARQ 531 was found to increase survival over ibrutinib in a murine Eμ-TCL1 engraftment model of CLL and a murine Eμ-MYC/TCL1 engraftment model resembling Richter transformation. Additionally, ARQ 531 inhibits CLL cell survival and suppresses BCR-mediated activation of C481S BTK and PLCγ2 mutants, which facilitate clinical resistance to ibrutinib.
Significance: This study characterizes a rationally designed kinase inhibitor with efficacy in models recapitulating the most common mechanisms of acquired resistance to ibrutinib. Reversible BTK inhibition is a promising strategy to combat progressive CLL, and multikinase inhibition demonstrates superior efficacy to targeted ibrutinib therapy in the setting of Richter transformation. Cancer Discov; 8(10); 1300–15. ©2018 AACR.
This article is highlighted in the In This Issue feature, p. 1195
Repotrectinib (TPX-0005) Is a Next-Generation ROS1/TRK/ALK Inhibitor That Potently Inhibits ROS1/TRK/ALK Solvent- Front Mutations
Authors: Drilon Alexander , Ou Sai-Hong Ignatius , Cho Byoung Chul , Kim Dong-Wan , Lee Jeeyun , Lin Jessica J. , Zhu Viola W. , Ahn Myung-Ju , Camidge D. Ross , Nguyen Judy , Zhai Dayong , Deng Wei , Huang Zhongdong , Rogers Evan , Liu Juliet , Whitten Jeff , Lim John K. , Stopatschinskaja Shanna , Hyman David M. , Doebele Robert C. , Cui J. Jean , Shaw Alice T. 
Published: August 2018

Abstract
The use of tyrosine kinase inhibitors (TKI) with activity against ALK, ROS1, or TRKA–C can result in significant clinical benefit in patients with diverse tumors harboring ALK, ROS1, or NTRK1–3 rearrangements; however, resistance invariably develops. The emergence of on-target kinase domain mutations represents a major mechanism of acquired resistance. Solvent-front substitutions such as ALKG1202R, ROS1G2032R or ROS1D2033N, TRKAG595R, and TRKCG623R are among the most recalcitrant of these mechanisms. Repotrectinib (TPX-0005) is a rationally designed, low-molecular-weight, macrocyclic TKI that is selective and highly potent against ROS1, TRKA–C, and ALK. Importantly, repotrectinib exhibits activity against a variety of solvent-front substitutions in vitro and in vivo. As clinical proof of concept, in an ongoing first-in-human phase I/II trial, repotrectinib achieved confirmed responses in patients with ROS1 or NTRK3 fusion–positive cancers who had relapsed on earlier-generation TKIs due to ROS1 or TRKC solvent-front substitution-mediated resistance.
Significance: Repotrectinib (TPX-0005), a next-generation ROS1, pan-TRK, and ALK TKI, overcomes resistance due to acquired solvent-front mutations involving ROS1, NTRK1–3, and ALK. Repotrectinib may represent an effective therapeutic option for patients with ROS1-, NTRK1–3-, or ALK-rearranged malignancies who have progressed on earlier-generation TKIs. Cancer Discov; 8(10); 1227–36. ©2018 AACR.
This article is highlighted in the In This Issue feature, p. 1195
Factors Associated with Stroke Misdiagnosis in the Emergency Department: A Retrospective Case-Control Study
Authors: Venkat Abhay , Cappelen-Smith Cecilia , Askar Shabeel , Thomas Peter R. , Bhaskar Sonu , Tam Amanda , McDougall Alan J. , Hodgkinson Suzanne J. , Cordato Dennis J. 
Published: August 2018

<b><i>Background:</i></b> Failure to recognise acute stroke may result in worse outcomes due to missed opportunity for acute stroke therapies. Our study examines factors associated with stroke misdiagnosis in patients admitted to a large comprehensive stroke centre. <b><i>Methods:</i></b> Retrospective review comparing 156 consecutive stroke patients misdiagnosed in emergency department (ED) with 156 randomly selected stroke controls matched for age, gender, language spoken and stroke subtype for the period 2014–2016. <b><i>Results:</i></b> There were 141 ischemic and 15 hemorrhagic misdiagnosed strokes (median age: 77 years, male:female = 1.3: 1). Symptom resolution, altered mental status, nausea/vomiting, dizziness and vertigo favored misdiagnosis (<i>p</i> &#x3c; 0.05). Hemiparesis and dysarthria favored an accurate diagnosis (<i>p</i> &#x3c; 0.05). Misdiagnosed patients were more commonly triaged into a lower ED category (62 vs. 42%, <i>p</i> = 0.001), clinically assessed as Face, Arm, Speech and Time (FAST) – negative (78 vs. 22%, <i>p</i> &#x3c; 0.001) and underwent delayed CT imaging (median 4.1 vs. 1.5 h, <i>p</i> &#x3c; 0.001). Misdiagnosed patients were more likely to have posterior circulation stroke (PCS; 39 vs. 22%, <i>p </i>= 0.01) and be admitted under non-neurological services (35 vs. 11%, <i>p</i> &#x3c; 0.001) with worse discharge outcomes including increased mortality. <b><i>Conclusions:</i></b> Patients with stroke misdiagnosis were commonly FAST-negative with nonspecific symptoms including altered mental status, dizziness and nausea/vomiting often associated with PCS. Improved diagnostic accuracy may increase access to acute therapies.
Order of Treatment Matters in Ischemic Stroke: Mechanical Thrombectomy First, Then Carotid Artery Stenting for Tandem Lesions of the Anterior Circulation
Authors: Maus Volker , Borggrefe Jan , Behme Daniel , Kabbasch Christoph , Abdullayev Nuran , Barnikol Utako Birgit , Yeo Leonard Leong Litt , Brouwer Patrick A. , Söderman Michael , Möhlenbruch Markus , Liebig Thomas , Fink Gereon Rudolf , Mpotsaris Anastasios 
Published: August 2018

<b><i>Background:</i></b> One endovascular treatment option of acute ischemic stroke due to tandem occlusion (TO) comprises intracranial thrombectomy and acute extracranial carotid artery stenting (CAS). In this setting, the order of treatment may impact the clinical outcome in this stroke subtype. <b><i>Methods:</i></b> Retrospective analysis was performed on data prospectively collected in 4 international stroke centers between 2013 and 2017. One hundred sixty-five patients with anterior TO were treated by endovascular therapy. Clinical and procedural data were evaluated. Favorable clinical outcome was defined as modified Rankin Scale (mRS) ≤2 at 90 days. Propensity score matching was performed for different treatment strategies. <b><i>Results:</i></b> Patients’ mean age was 65 ± 11 years and 118 were male (69%). The median admission National Institutes of Health Stroke Scale was 15 (interquartile range 8). In 59% of the patients (<i>n</i> = 101), the antegrade strategy (first stenting, then thrombectomy) was ­performed, in 41% (<i>n</i> = 70) retrograde treatment (first thrombectomy, then stenting). Successful reperfusion (mTICI ≥2b) was achieved in 128 patients (75%). Fifty-nine patients (39%) showed a favorable clinical outcome after 90 days. After propensity score matching, data of 100 patients could be analyzed. Analysis revealed that the retrograde strategy yielded a significantly higher rate of successful reperfusion compared to the antegrade strategy (92 vs. 56%; <i>p</i> &#x3c; 0.001). The rate of favorable clinical outcome after 90 days (mRS ≤2) was consistently higher (44 vs. 30%; <i>p</i> &#x3c; 0.05) in the retrograde strategy group. <b><i>Conclusion:</i></b> Mechanical thrombectomy prior to acute CAS in TO is a predictive factor for favorable clinical outcome at 90 days.
Rochas intrusivas básicas no sudeste do Cinturão Dom Feliciano, RS: petrografia e geoquímica das associações I e II
Authors: Barbosa Laércio Dal Olmo , Koester Edinei , Gastal Maria do Carmo Pinto 
Published: August 2018

Intrusões dioríticas, gabroicas e outras rochas máficas-ultramáficas registram tanto os processos de extração e transporte de magmas do manto, resultando na acresção vertical de material à crosta, quanto os processos de interação entre esses dois componentes. Recentemente, essas rochas têm sido apontadas como importantes marcadores petrogenéticos, quando associadas ao magmatismo intermediário a ácido, em ambientes orogênicos a pós-colisionais. Na porção sudeste do Cinturão Dom Feliciano, no Rio Grande do Sul, constituído majoritariamente por granitoides, ocorrem intrusões dioríticas e gabroicas de pequeno porte e caráter dominantemente básico, na região compreendida entre Pinheiro Machado e Pedro Osório. Este artigo apresenta a caracterização geológica, mineralógica, petrográfica e geoquímica dessas rochas, propondo assim a separação de duas associações principais. A Associação I (AI), constituída por rochas gabroicas, comumente cumuladas e por vezes estratificadas, engloba os corpos do Passo da Fabiana, Passo da Olaria, Arroio Santa Fé e Desvio Herval. A Associação II (AII), diorítica a gabroica, compreende rochas maciças a localmente foliadas, nas ocorrências do Alto Alegre, Passo dos Machados e Campo Bonito. As duas associações são subalcalinas, com afinidade cálcio-alcalina médio-K (AI) e médio a alto-K (AII), com altos teores de alumina (Al2O3 > 17%), mesmo para os termos não cumulados. Diferenças quanto aos elementos maiores (CaO, Mg# e álcalis), menores e traços (P2O5, Zr, Nb, Y, total e padrões de ETR) referendam a separação proposta. As assinaturas magnéticas sugerem o controle no posicionamento das intrusões por descontinuidades litosféricas, que teriam possibilitado a ascensão e a colocação desses magmas em níveis superiores da crosta. Processos petrogenéticos envolvendo a participação de líquidos derivados do manto em reservatórios supracrustais e a sua evolução nas deep crustal hot zones são propostos.
Concentração de elementos traços, terras raras e escândio em perfil de intemperismo de rocha metaultramáfica (Bom Jesus da Penha, Minas Gerais)
Authors: Faria Júnior Ilio Rodarte , Luvizotto George Luiz , Rosolen Vania Silvia 
Published: August 2018

O processo de formação dos horizontes lateríticos é responsável pela reorganização química e mineralógica dos litotipos preexistentes. Esse arranjo é controlado pela mineralogia primária da rocha e pelas características de desenvolvimento do processo intempérico. Este artigo apresenta um estudo em um clorita-anfibólio xisto, a partir do qual se desenvolveram dois horizontes de intemperismo. No topo se observou solo caulinítico vermelho argiloso, enquanto abaixo se desenvolve um horizonte saprolítico verde com plintitas de cor ocre, o qual contém montmorillonita neoformada. Os elementos químicos analisados tiveram variações nos teores ao longo desse perfil, sendo que todos os metais tiveram, em determinadas amostras, picos de acúmulos superiores a 100% em relação à rocha. Al2O3, U, Th, Zr e TiO2 mostram concentração residual no topo do horizonte de solos, junto a caulinita e óxidos e hidróxidos de ferro; Fe2O3, V e Co tiveram maior acúmulo na base do horizonte de solos, próximo à transição para o saprolito; Mn, Cr2O3, Ni, Zn, Cu e elementos terras raras (ETR) apresentaram máximos de enriquecimento no horizonte plintificado, junto a montmorillonita; CaO, MgO e SiO2 tiveram redução dos teores ao longo de todo o perfil estudado. Tomando o litotipo metaultramáfico, destacam-se os enriquecimentos dos elementos terras raras e ítrio (ETRY) e escândio (Sc) no perfil de intemperismo, os quais são compatíveis com modelos de mineralização laterítica.
Ground Penetrating Radar digital imaging and modeling of microbialites from the Salitre Formation, Northeast Brazil
Authors: Lima Rebeca Seabra de , Teixeira Washington Luiz Evangelista , Albuquerque Filipe Ramos de , Lima-Filho Francisco Pinheiro 
Published: August 2018

Thanks to the discovery of new giant oil fields in the South Hemisphere in the last decades, named Pre-salt, there has been a considerable interest in the geometrical and sedimentological characterization of microbial deposits, coquinas, and collapsed caves, which represent a considerable part of these reservoirs. It is known that exposures analogous to oil reservoirs are an important source of information at the sub-seismic scale, as this information is helpful in parametrizing and modeling reservoirs, especially microbial reservoirs. This scenario is more favorable when the Ground Penetrating Radar (GPR) method is used in analogous exposures located in arid regions with scarce or no soil, such as the Fazenda Arrecife, in the Chapada Diamantina (Salitre Formation), Northeastern Brazil. Although rarely mentioned in the literature on microbialite geophysical imaging, GPR has been used in microbial deposits associated with the Neoproterozoic storm deposits of the Salitre Formation. The results of 3D imaging of a microbial colony, using the 200 MHz antenna, with both conventional processing and processing using geophysical attributes, are presented in this study. The conventional processing produced a 3D digital model that allowed the geometrical characterization and parametrization of the imaged microbial colony. The use of four geophysical attributes yielded good results, establishing the contact between the microbial colony and tempestite deposits, and determining the internal geometry of microbial deposits. The processing with “instantaneous amplitude” and “Hilbert trace with energy” highlighted the contact between the microbialite colony (low amplitude) and tempestite deposits (high amplitude), whereas the processing with the “energy” attribute provided a better visualization of the internal lamination of columnar microbialites, result similar to that obtained in the processing with “Hilbert trace with similarity”. GPR obtained images of up to 10 m in depth, with excellent resolution for microbial deposits and tempestites associated with them. The processing using geophysical attributes achieved considerably better results when compared to conventional processing, allowing a better visualization of the internal and external geometry of the imaged colony.