bluuebunny/crossref_metadata_2025_split huggingface dataset:
Impacts of past and future coastal changes on the Yukon coast — threats for cultural sites, infrastructure, and travel routes
Authors: Irrgang Anna M. , Lantuit Hugues , Gordon Richard R. , Piskor Ashley , Manson Gavin K. 
Published: February 2019

Yukon’s Beaufort coast, Canada, is a highly dynamic landscape. Cultural sites, infrastructure, and travel routes used by the local population are particularly vulnerable to coastal erosion. To assess threats to these phenomena, rates of shoreline change for a 210 km length of the coast were analyzed and combined with socioeconomic and cultural information. Rates of shoreline change were derived from aerial and satellite imagery from the 1950s, 1970s, 1990s, and 2011. Using these data, conservative (S1) and dynamic (S2) shoreline projections were constructed to predict shoreline positions for the year 2100. The locations of cultural features in the archives of a Parks Canada database, the Yukon Archaeological Program, and as reported in other literature were combined with projected shoreline position changes. Between 2011 and 2100, approximately 850 ha (S1) and 2660 ha (S2) may erode, resulting in a loss of 45% (S1) to 61% (S2) of all cultural features by 2100. The last large, actively used camp area and two nearshore landing strips will likely be threatened by future coastal processes. Future coastal erosion and sedimentation processes are expected to increasingly threaten cultural sites and influence travelling and living along the Yukon coast.
A Phase I, Open-Label, Multicenter, Dose-escalation Study of the Oral Selective FGFR Inhibitor Debio 1347 in Patients with Advanced Solid Tumors Harboring FGFR Gene Alterations
Authors: Voss Martin H. , Hierro Cinta , Heist Rebecca S. , Cleary James M. , Meric-Bernstam Funda , Tabernero Josep , Janku Filip , Gandhi Leena , Iafrate A. John , Borger Darrell R. , Ishii Nobuya , Hu Youyou , Kirpicheva Yulia , Nicolas-Metral Valerie , Pokorska-Bocci Anna , Vaslin Chessex Anne , Zanna Claudio , Flaherty Keith T. , Baselga Jose 
Published: February 2019

Abstract

Purpose:
To investigate tolerability, efficacy, and pharmacokinetics/pharmacodynamics of Debio 1347, a selective FGFR inhibitor.

Patients and Methods:
This was a first-in-human, multicenter, open-label study in patients with advanced solid tumors harboring FGFR1–3 gene alterations. Eligible patients received oral Debio 1347 at escalating doses once daily until disease progression or intolerable toxicity. Dose-limiting toxicities (DLT) were evaluated during the first 4 weeks on treatment, pharmacokinetics/pharmacodynamics postfirst dose and after 4 weeks.

Results:
A total of 71 patients were screened and 58 treated with Debio 1347 at doses from 10 to 150 mg/day. Predominant tumor types were breast and biliary duct cancer, most common gene alterations were FGFR1 amplifications (40%) and mutations in FGFR2 (12%) and FGFR3 (17%); 12 patients (21%) showed FGFR fusions. Five patients at three dose levels had six DLTs (dry mouth/eyes, hyperamylasemia, hypercalcemia, hyperbilirubinemia, hyperphosphatemia, and stomatitis). The maximum tolerated dose was not reached, but dermatologic toxicity became sometimes dose limiting beyond the DLT period at ≥80 mg/day. Adverse events required dose modifications in 52% of patients, mostly due to dose-dependent, asymptomatic hyperphosphatemia (22%). RECIST responses were seen across tumor types and mechanisms of FGFR activation. Six patients, 3 with FGFR fusions, demonstrated partial responses, 10 additional patients' tumor size regressions of ≤30%. Plasma half-life was 11.5 hours. Serum phosphate increased with Debio 1347 plasma levels and confirmed target engagement at doses ≥60 mg/day.

Conclusions:
Preliminary efficacy was encouraging and tolerability acceptable up to 80 mg/day, which is now used in an extension part of the study.
Bad to the Bone: The Role of the Insulin-Like Growth Factor Axis in Osseous Metastasis
Authors: Rieunier Guillaume , Wu Xiaoning , Macaulay Valentine M. , Lee Adrian V. , Weyer-Czernilofsky Ulrike , Bogenrieder Thomas 
Published: February 2019

AbstractBone metastases are a frequent complication of cancer that are associated with considerable morbidity. Current treatments may temporarily palliate the symptoms of bone metastases but often fail to delay their progression. Bones provide a permissive environment because they are characterized by dynamic turnover, secreting factors required for bone maintenance but also stimulating the establishment and growth of metastases. Insulin-like growth factors (IGF) are the most abundant growth factors in bone and are required for normal skeletal development and function. Via activation of the IGF-1 receptors (IGF-1R) and variant insulin receptors, IGFs promote cancer progression, aggressiveness, and treatment resistance. Of specific relevance to bone biology, IGFs contribute to the homing, dormancy, colonization, and expansion of bone metastases. Furthermore, preclinical evidence suggests that tumor cells can be primed to metastasize to bone by a high IGF-1 environment in the primary tumor, suggesting that bone metastases may reflect IGF dependency. Therapeutic targeting of the IGF axis may therefore provide an effective method for treating bone metastases. Indeed, anti–IGF-1R antibodies, IGF-1R tyrosine kinase inhibitors, and anti–IGF-1/2 antibodies have demonstrated antitumor activity in preclinical models of prostate and breast cancer metastases, either alone or in combination with other agents. Several studies suggest that such treatments can inhibit bone metastases without affecting growth of the primary tumor. Although previous trials of anti–IGF-1R drugs have generated negative results in unselected patients, these considerations suggest that future clinical trials of IGF-targeted agents may be warranted in patients with bone metastases.
Molecular Characterization of Prostate Cancer with Associated Gleason Score Using Mass Spectrometry Imaging
Authors: Randall Elizabeth C. , Zadra Giorgia , Chetta Paolo , Lopez Begona G.C. , Syamala Sudeepa , Basu Sankha S. , Agar Jeffrey N. , Loda Massimo , Tempany Clare M. , Fennessy Fiona M. , Agar Nathalie Y.R. 
Published: February 2019

AbstractDiagnosis of prostate cancer is based on histologic evaluation of tumor architecture using a system known as the “Gleason score.” This diagnostic paradigm, while the standard of care, is time-consuming, shows intraobserver variability, and provides no information about the altered metabolic pathways, which result in altered tissue architecture. Characterization of the molecular composition of prostate cancer and how it changes with respect to the Gleason score (GS) could enable a more objective and faster diagnosis. It may also aid in our understanding of disease onset and progression. In this work, we present mass spectrometry imaging for identification and mapping of lipids and metabolites in prostate tissue from patients with known prostate cancer with GS from 6 to 9. A gradient of changes in the intensity of various lipids was observed, which correlated with increasing GS. Interestingly, these changes were identified in both regions of high tumor cell density, and in regions of tissue that appeared histologically benign, possibly suggestive of precancerous metabolomic changes. A total of 31 lipids, including several phosphatidylcholines, phosphatidic acids, phosphatidylserines, phosphatidylinositols, and cardiolipins were detected with higher intensity in GS (4+3) compared with GS (3+4), suggesting they may be markers of prostate cancer aggression. Results obtained through mass spectrometry imaging studies were subsequently correlated with a fast, ambient mass spectrometry method for potential use as a clinical tool to support image-guided prostate biopsy.Implications:In this study, we suggest that metabolomic differences between prostate cancers with different Gleason scores can be detected by mass spectrometry imaging.
Therapeutic Targeting of CD146/MCAM Reduces Bone Metastasis in Prostate Cancer
Authors: Zoni Eugenio , Astrologo Letizia , Ng Charlotte K.Y. , Piscuoglio Salvatore , Melsen Janine , Grosjean Joël , Klima Irena , Chen Lanpeng , Snaar-Jagalska Ewa B. , Flanagan Kenneth , van der Pluijm Gabri , Kloen Peter , Cecchini Marco G. , Kruithof-de Julio Marianna , Thalmann George N. 
Published: February 2019

AbstractProstate Cancer is the most common cancer and the second leading cause of cancer-related death in males. When prostate cancer acquires castration resistance, incurable metastases, primarily in the bone, occur. The aim of this study is to test the applicability of targeting melanoma cell adhesion molecule (MCAM; CD146) with a mAb for the treatment of lytic prostate cancer bone metastasis. We evaluated the effect of targeting MCAM using in vivo preclinical bone metastasis models and an in vitro bone niche coculture system. We utilized FACS, cell proliferation assays, and gene expression profiling to study the phenotype and function of MCAM knockdown in vitro and in vivo. To demonstrate the impact of MCAM targeting and therapeutic applicability, we employed an anti-MCAM mAb in vivo. MCAM is elevated in prostate cancer metastases resistant to androgen ablation. Treatment with DHT showed MCAM upregulation upon castration. We investigated the function of MCAM in a direct coculture model of human prostate cancer cells with human osteoblasts and found that there is a reduced influence of human osteoblasts on human prostate cancer cells in which MCAM has been knocked down. Furthermore, we observed a strongly reduced formation of osteolytic lesions upon bone inoculation of MCAM-depleted human prostate cancer cells in animal model of prostate cancer bone metastasis. This phenotype is supported by RNA sequencing (RNA-seq) analysis. Importantly, in vivo administration of an anti-MCAM human mAb reduced the tumor growth and lytic lesions. These results highlight the functional role for MCAM in the development of lytic bone metastasis and suggest that MCAM is a potential therapeutic target in prostate cancer bone metastasis.Implications:This study highlights the functional application of an anti-MCAM mAb to target prostate cancer bone metastasis.
Immune Profiling and Quantitative Analysis Decipher the Clinical Role of Immune-Checkpoint Expression in the Tumor Immune Microenvironment of DLBCL
Authors: Xu-Monette Ziju Y. , Xiao Min , Au Qingyan , Padmanabhan Raghav , Xu Bing , Hoe Nicholas , Rodríguez-Perales Sandra , Torres-Ruiz Raul , Manyam Ganiraju C. , Visco Carlo , Miao Yi , Tan Xiaohong , Zhang Hongwei , Tzankov Alexandar , Wang Jing , Dybkær Karen , Tam Wayne , You Hua , Bhagat Govind , Hsi Eric D. , Ponzoni Maurilio , Ferreri Andrés J.M. , Møller Michael B. , Piris Miguel A. , van Krieken J. Han , Winter Jane N. , Westin Jason R. , Pham Lan V. , Medeiros L. Jeffrey , Rassidakis George Z. , Li Yong , Freeman Gordon J. , Young Ken H. 
Published: February 2019

Abstract
PD-1/L1 and CTLA-4 blockade immunotherapies have been approved for 13 types of cancers and are being studied in diffuse large B-cell lymphoma (DLBCL), the most common aggressive B-cell lymphoma. However, whether both PD-1 and CTLA-4 checkpoints are active and clinically significant in DLBCL is unknown. Whether PD-1 ligands expressed by tumor cells or by the microenvironment of DLBCL are critical for the PD-1 immune checkpoint is unclear. We performed immunophenotypic profiling for 405 patients with de novo DLBCL using a MultiOmyx immunofluorescence platform and simultaneously quantitated expression/coexpression of 13 immune markers to identify prognostic determinants. In both training and validation cohorts, results demonstrated a central role of the tumor immune microenvironment, and when its functionality was impaired by deficiency in tumor-infiltrating T cells and/or natural killer cells, high PD-1 expression (but not CTLA-4) on CD8+ T cells, or PD-L1 expression on T cells and macrophages, patients had significantly poorer survival after rituximab–CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) immunochemotherapy. In contrast, tumor-cell PD-L2 expression was associated with superior survival, as well as PD-L1+CD20+ cells proximal (indicates interaction) to PD-1+CD8+ T cells in patients with low PD-1+ percentage of CD8+ T cells. Gene-expression profiling results suggested the reversibility of T-cell exhaustion in PD-1+/PD-L1+ patients with unfavorable prognosis and implication of LILRA/B, IDO1, CHI3L1, and SOD2 upregulation in the microenvironment dysfunction with PD-L1 expression. This study comprehensively characterized the DLBCL immune landscape, deciphered the differential roles of various checkpoint components in rituximab–CHOP resistance in DLBCL patients, and suggests targets for PD-1/PD-L1 blockade and combination immunotherapies.
Análise da resposta cartesiana acerca de como pode a alma mover o corpo na Correspondência com Elisabeth
Authors: Laporta Beatriz 
Published: February 2019

Trata-se de abordar uma das questões com mais desdobramentos que já foram dirigidas à filosofia cartesiana, a saber, como pode a alma mover o corpo, na carta endereçada a Elisabeth de 21 de maio de 1643. Issoexige uma reflexão sobre como Descartes estabeleceu com tanta segurança a ordem das razões nas Meditações, e como colocou a união substancial dentro dela, pois na Correspondência afirmou-se que essa união não pode ser entendida pela razão.
Direct Visualization of the His Bundle Pacing Lead Placement by 3-Dimensional Electroanatomic Mapping
Authors: Orlov Michael V. , Koulouridis Ioannis , Monin AJ , Casavant David , Maslov Mikhail , Erez Aharon , Hicks Amy , Aoun Joe , Wylie John V. 
Published: February 2019

Background:
His bundle pacing (HBP) remains technically challenging and is currently guided by electrograms and 2-dimensional fluoroscopy. Our objective was to describe a new technique for HBP directly guided by electroanatomic mapping (EAM).

Methods:
Twenty-eight patients were included. The atrioventricular septum was mapped via EAM, and His bundle (HB) electrograms, selective, and nonselective HB capture sites were tagged. Pacing leads were connected to EAM, navigated to tagged HB target sites and deployed. Intracardiac electrograms and pacing parameters were recorded. Lead location was tagged on the cloud of HB sites, which was divided into 3 arbitrary segments. In 5 patients, atrioventricular nodal ablation was performed with direct visualization of the HBP lead by EAM.

Results:

Reproducible navigation of the pacing lead to predetermined HBP locations guided by EAM was achieved in all patients. The lead was successfully deployed in 25 patients. HB cloud area was 360 (212) mm
2
. There was no correlation between HBP threshold and lead location on the His cloud. The intracardiac electrograms atrial/ventricular ratio at the lead deployment site correlated with its EAM position on the His cloud (
P
=0.045). Procedure, fluoroscopy, and mapping times were 116.0 (38.8), 8.6 (6.3), and 9.0 (11.4) minutes, respectively. HBP threshold at implant was 1.5 (2.3) V at 1.5 (1.0) ms. Distance between HB lead and ablation sites was 10.0 (1.3) mm in patients undergoing atrioventricular nodal ablation.

Conclusions:
Direct guidance of HBP by EAM allows for direct visualization of the pacing lead on the HB cloud and reproducible navigation to predetermined HB capture sites. Intracardiac electrograms atrial/ventricular ratio at the lead deployment site correlates with His cloud location. EAM can be applied during standard HBP procedures or combined with atrioventricular nodal ablation.
Characterization of Regional Wind Patterns Using Self-Organizing Maps: Impact on Dallas–Fort Worth Long-Term Ozone Trends
Authors: Kotsakis Alexander , Choi Yunsoo , Souri Amir H. , Jeon Wonbae , Flynn James 
Published: February 2019

AbstractThis study analyzes wind patterns in the Dallas–Fort Worth (DFW) area to gain a clearer understanding of meteorological patterns that have historically led to ozone exceedances in this region. Using a clustering algorithm called “self-organizing maps,” we analyzed five notable characteristic regional wind patterns that occurred between April and October in 2000–14. A regional-scale high pressure system, cluster 2, produced weak southeast winds over DFW and accounted for 35.2% of ozone exceedances. Clusters 1 and 5, characterized by southwesterly winds over the DFW area, were together associated with one-third of total ozone exceedances and show quantifiable impacts of the Barnett Shale region on downwind ozone production. Cluster 3, associated with Bermuda-high conditions, had relatively lower ozone in DFW (45.3 ppbv) resulting from transport of lower background ozone from the Gulf of Mexico. For clusters that produce southeasterly or southwesterly winds over Houston, ozone values in DFW were always larger than those in Houston. Further, to determine the potential impact of Houston pollution on DFW ozone, a sensitivity simulation with no Houston emissions and a base simulation were performed. The difference between the simulations revealed ozone enhancements of 1–2 ppbv and coincident enhancements in NOy under south-southeasterly wind conditions. From these results, we conclude that downwind pollution from Houston and the Barnett Shale area exacerbates DFW ozone concentrations, underscoring the impacts of specific wind patterns on air quality in DFW.
Characteristics of the Sea-Breeze Circulation in the Pearl River Delta Region and Its Dynamical Diagnosis
Authors: You Cheng , Chi-Hung Fung Jimmy 
Published: February 2019

AbstractThe Pearl River delta (PRD) region has experienced rapid economic development since the 1980s and has become one of the world’s largest industrial zones and metropolitan areas. Previous studies have shown that the sea-breeze circulation can contribute to pollutant transportation and convective initiation, so it is useful to study the dynamic structure of the sea-breeze circulation in the PRD region. Many researchers have focused on the effects of environmental factors, such as topography, urbanization, and background wind, on the sea breeze, but most focused only on case studies and did not quantify the characteristics of the sea-breeze circulation climatologically. In this study, a sea-breeze identification metric was defined to identify sea-breeze events from WRF simulation data of 2012 and quantify their characteristics, including their start time, end time, strength, height, frequency, pumping ability, and inland-penetrating distance. The results indicate that this method works well to identify and quantify the sea-breeze events of 2012. It is found that the solenoid term, the largest positive contributor to vorticity acceleration, is mostly modulated by the temperature gradient. Therefore, the frontogenesis of the sea-breeze front is discussed in this study. The result shows that offshore background wind that increases frontogenesis is favorable to the development of the sea breeze, but it also prevents it from propagating vertically and horizontally.
Fasting of male mice – Effects of time point of initiation and duration on clinical chemistry parameters and animal welfare
Authors: Jensen Tanja L , Kiersgaard Maria K , Mikkelsen Lars F , Sørensen Dorte B 
Published: February 2019

Fasting of mice is a common procedure, which can affect the outcome of the study as well as animal welfare. In this study, we assess the effects of fasting, fasting duration and fasting initiation time in relation to light schedule and present suggestions for optimization of fasting. Male C57BL/6NCrl mice were fasted for 0, 3, 6, 12, 18 and 24 hours initiated either in the light period (photophase) or the dark period (scotophase). Body weight, gastric content, body temperature, corticosterone and 19 routine clinical chemistry parameters were evaluated. Fasting caused significant changes in most of the measured parameters. Increasing duration of fasting resulted in increasing physiological changes. Fasting initiated in the scotophase caused more significant changes than fasting initiated in the photophase. To cause the least physiological changes in mice and increase animal welfare, mice should preferably be fasted in the photophase and for the shortest possible period allowed by the experimental purpose of fasting.
The Risk of Acute Kidney Injury in Critically Ill Patients Receiving Concomitant Vancomycin With Piperacillin–Tazobactam or Cefepime
Authors: Molina Kyle C. , Barletta Jeffrey F. , Hall Scott T. , Yazdani Cyrus , Huang Vanthida 
Published: February 2019

Purpose: The objective of this study was to compare the incidence of acute kidney injury (AKI) among critically ill patients receiving combination therapy with vancomycin plus piperacillin–tazobactam (VPT) against patients receiving vancomycin plus cefepime (VC). Methods: A retrospective cohort study of adult patients admitted to an intensive care unit between September 2012 and December 2016 was conducted. Patients were included if they received combination therapy with VPT or VC for ≥48 hours. Patients were excluded if creatinine clearance was <60 mL/min or received renal replacement therapy prior to the initiation of therapy. The primary end point was AKI, as defined by the Acute Kidney Injury Network classification, during or within 48 hours of completion of therapy. The incidence of AKI was compared between groups and multivariate analysis was performed to control for relevant confounders. Results: A total of 394 patients received either VPT (n = 258) or VC (n = 136). There were no differences in baseline serum creatinine (0.8 [0.3]mg/dL vs 0.7 [0.3] mg/dL, P = 0.207), use of vasopressors (44% vs 38%, P = 0.255), mechanical ventilation (45% vs 40%, P = 0.350), or initial vancomycin trough (11.2 [5] mg/L vs 11 [4.8] mg/L, P = 0.668) between VPT and VC groups, respectively. The incidence of AKI was 28.7% for VPT patients versus 21.3% for VC patients ( P = 0.114). Multivariate analysis revealed vancomycin trough >20 mg/L (odds ratio, OR [95% confidence interval, CI] = 2.69 [1.62-4.47]), baseline SCr (OR [95% CI] = 3.34 [1.43-7.80]), vasopressors (OR [95% CI] = 1.77 [1.04-3.04]), and duration of combination therapy (OR [95% CI] = 1.009 [1.003-1.015]) as independent risk factors for AKI. Conclusion: The risk of AKI was similar between VPT and VC groups in critically ill patients. Risk factors for AKI were related to baseline renal function, duration of combination therapy, supratherapeutic vancomycin troughs, and severity of illness.