bluuebunny/crossref_metadata_2025_split huggingface dataset:
Potential Mechanisms for Thrombocytopenia Development with Trastuzumab Emtansine (T-DM1)
Authors: Uppal Hirdesh , Doudement Estelle , Mahapatra Kaushiki , Darbonne Walter C. , Bumbaca Daniela , Shen Ben-Quan , Du Xiaoyan , Saad Ola , Bowles Kristin , Olsen Steve , Lewis Phillips Gail D. , Hartley Dylan , Sliwkowski Mark X. , Girish Sandhya , Dambach Donna , Ramakrishnan Vanitha 
Published: November 2014

AbstractPurpose: Trastuzumab-emtansine (T-DM1) is an antibody–drug conjugate (ADC) comprising the cytotoxic agent DM1 conjugated to trastuzumab with a stable linker. Thrombocytopenia was the dose-limiting toxicity in the phase I study, and grade ≥3 thrombocytopenia occurred in up to 13% of patients receiving T-DM1 in phase III studies. We investigated the mechanism of T-DM1–induced thrombocytopenia.Experimental Design: The effect of T-DM1 on platelet function was measured by aggregometry, and by flow cytometry to detect the markers of activation. The effect of T-DM1 on differentiation and maturation of megakaryocytes (MK) from human hematopoietic stem cells was assessed by flow cytometry and microscopy. Binding, uptake, and catabolism of T-DM1 in MKs, were assessed by various techniques including fluorescence microscopy, scintigraphy to detect T-[H3]-DM1 and 125I-T-DM1, and mass spectrometry. The role of FcγRIIa was assessed using blocking antibodies and mutant constructs of trastuzumab that do not bind FcγR.Results: T-DM1 had no direct effect on platelet activation and aggregation, but it did markedly inhibit MK differentiation via a cytotoxic effect. Inhibition occurred with DM1-containing ADCs but not with trastuzumab demonstrating a role for DM1. MKs internalized these ADCs in a HER2-independent, FcγRIIa-dependent manner, resulting in intracellular release of DM1. Binding and internalization of T-DM1 diminished as MKs matured; however, prolonged exposure of mature MKs to T-DM1 resulted in a disrupted cytoskeletal structure.Conclusions: These data support the hypothesis that T-DM1–induced thrombocytopenia is mediated in large part by DM1-induced impairment of MK differentiation, with a less pronounced effect on mature MKs. Clin Cancer Res; 21(1); 123–33. ©2014 AACR.
Tasquinimod Modulates Suppressive Myeloid Cells and Enhances Cancer Immunotherapies in Murine Models
Authors: Shen Li , Sundstedt Anette , Ciesielski Michael , Miles Kiersten Marie , Celander Mona , Adelaiye Remi , Orillion Ashley , Ciamporcero Eric , Ramakrishnan Swathi , Ellis Leigh , Fenstermaker Robert , Abrams Scott I. , Eriksson Helena , Leanderson Tomas , Olsson Anders , Pili Roberto 
Published: November 2014

Abstract
A major barrier for cancer immunotherapy is the presence of suppressive cell populations in patients with cancer, such as myeloid-derived suppressor cells (MDSC) and tumor-associated macrophages (TAM), which contribute to the immunosuppressive microenvironment that promotes tumor growth and metastasis. Tasquinimod is a novel antitumor agent that is currently at an advanced stage of clinical development for treatment of castration-resistant prostate cancer. A target of tasquinimod is the inflammatory protein S100A9, which has been demonstrated to affect the accumulation and function of tumor-suppressive myeloid cells. Here, we report that tasquinimod provided a significant enhancement to the antitumor effects of two different immunotherapeutics in mouse models of cancer: a tumor vaccine (SurVaxM) for prostate cancer and a tumor-targeted superantigen (TTS) for melanoma. In the combination strategies, tasquinimod inhibited distinct MDSC populations and TAMs of the M2-polarized phenotype (CD206+). CD11b+ myeloid cells isolated from tumors of treated mice expressed lower levels of arginase-1 and higher levels of inducible nitric oxide synthase (iNOS), and were less immunosuppressive ex vivo, which translated into a significantly reduced tumor-promoting capacity in vivo when these cells were coinjected with tumor cells. Tumor-specific CD8+ T cells were increased markedly in the circulation and in tumors. Furthermore, T-cell effector functions, including cell-mediated cytotoxicity and IFNγ production, were potentiated. Taken together, these data suggest that pharmacologic targeting of suppressive myeloid cells by tasquinimod induces therapeutic benefit and provide the rationale for clinical testing of tasquinimod in combination with cancer immunotherapies. Cancer Immunol Res; 3(2); 136–48. ©2014 AACR.
Shared Molecular Pathways and Gene Networks for Cardiovascular Disease and Type 2 Diabetes Mellitus in Women Across Diverse Ethnicities
Authors: Chan Kei Hang K. , Huang Yen-Tsung , Meng Qingying , Wu Chunyuan , Reiner Alexander , Sobel Eric M. , Tinker Lesley , Lusis Aldons J. , Yang Xia , Liu Simin 
Published: November 2014

Background—
Although cardiovascular disease (CVD) and type 2 diabetes mellitus (T2D) share many common risk factors, potential molecular mechanisms that may also be shared for these 2 disorders remain unknown.

Methods and Results—

Using an integrative pathway and network analysis, we performed genome-wide association studies in 8155 blacks, 3494 Hispanic American, and 3697 Caucasian American women who participated in the national Women’s Health Initiative single-nucleotide polymorphism (SNP) Health Association Resource and the Genomics and Randomized Trials Network. Eight top pathways and gene networks related to cardiomyopathy, calcium signaling, axon guidance, cell adhesion, and extracellular matrix seemed to be commonly shared between CVD and T2D across all 3 ethnic groups. We also identified ethnicity-specific pathways, such as cell cycle (specific for Hispanic American and Caucasian American) and tight junction (CVD and combined CVD and T2D in Hispanic American). In network analysis of gene–gene or protein–protein interactions, we identified key drivers that included
COL1A1, COL3A1
, and
ELN
in the shared pathways for both CVD and T2D. These key driver genes were cross-validated in multiple mouse models of diabetes mellitus and atherosclerosis.

Conclusions—
Our integrative analysis of American women of 3 ethnicities identified multiple shared biological pathways and key regulatory genes for the development of CVD and T2D. These prospective findings also support the notion that ethnicity-specific susceptibility genes and process are involved in the pathogenesis of CVD and T2D.
Stent Coverage and Neointimal Proliferation in Bare Metal Stents Postdilated With a Paclitaxel-Eluting Balloon Versus Everolimus-Eluting Stents
Authors: Poerner Tudor C. , Otto Sylvia , Gassdorf Johannes , Nitsche Kristina , Janiak Florian , Scheller Bruno , Goebel Björn , Jung Christian , Figulla Hans R. 
Published: November 2014

Background—
In this randomized trial, strut coverage and neointimal proliferation of a therapy of bare metal stents (BMSs) postdilated with the paclitaxel drug-eluting balloon (DEB) was compared with everolimus drug-eluting stents (DESs) at 6-month follow-up using optical coherence tomography. We hypothesized sufficient stent coverage at follow-up.

Methods and Results—

A total of 105 lesions in 90 patients were treated with either XIENCE V DES (n=51) or BMS postdilated with the SeQuent Please DEB (n=54). At follow-up, comparable results on the primary optical coherence tomography end point (percentage uncovered struts 5.64±9.65% in BMS+DEB versus 4.93±9.29% in DES;
P
=0.366) were found. Thus, BMS+DEB achieved the prespecified noninferiority margin of 5% uncovered struts versus DES (difference between treatment means, 0.71%; one-sided upper 95% confidence interval, 4.14%; noninferiority
P
=0.04). Optical coherence tomography analysis showed significantly more global neointimal proliferation in the BMS+DEB group (15.7±7.8 versus 11.0±5.2 mm
3
proliferation volume/cm stent length;
P
=0.002). No significant focal in-stent stenosis analyzed with angiography (percentage diameter stenosis at follow-up, 22.8±11.9 versus 16.9±10.4;
P
=0.014) and optical coherence tomography (peak local area stenosis, 39.5±13.8% versus 36.8±15.6%;
P
=0.409) was found.

Conclusions—
Good stent strut coverage of >94% was found in both therapy groups. Despite greater suppression of global neointimal growth in DES, both DES and BMS+DEB effectively prevented clinically relevant focal restenosis at 6-month follow-up.

Clinical Trial Registration—

URL:
http://www.clinicaltrials.gov
. Unique identifier: NCT01056744.
Worsening of Renal Function During 1 Year After Hospital Discharge Is a Strong and Independent Predictor of All‐Cause Mortality in Acute Decompensated Heart Failure
Authors: Ueda Tomoya , Kawakami Rika , Sugawara Yu , Okada Sadanori , Nishida Taku , Onoue Kenji , Soeda Tsunenari , Okayama Satoshi , Takeda Yukiji , Watanabe Makoto , Kawata Hiroyuki , Uemura Shiro , Saito Yoshihiko 
Published: November 2014

Background

Renal impairment is a common comorbidity and the strongest risk factor for poor prognosis in acute decompensated heart failure (
ADHF
). In clinical practice, renal function is labile during episodes of
ADHF
, and often worsens after discharge. The significance of worsening of renal function (
WRF
) after discharge has not been investigated as extensively as baseline renal function at admission or
WRF
during hospitalization.

Methods and Results

Among 611 consecutive patients with ADHF emergently admitted to our hospital, 233 patients with 3 measurements of serum creatinine (SCr) level measurements (on admission, at discharge, and 1 year after discharge) were included in the present study. Patients were divided into 2 groups according to the presence or absence of WRF at 1 year after discharge (1y‐WRF), defined as an absolute increase in SCr >0.3 mg/
dL
(>26.5 μmol/L) plus a ≥25% increase in SCr at 1 year after discharge compared to the SCr value at discharge. All‐cause and cardiovascular mortality were assessed as adverse outcomes. During a mean follow‐up of 35.4 months, 1y‐
WRF
occurred in 48 of 233 patients. There were 66 deaths from all causes. All‐cause and cardiovascular mortality were significantly higher in patients with 1y‐
WRF
(log‐rank
P
<0.0001 and
P
<0.0001, respectively) according to Kaplan–Meier analysis. In a multivariate Cox proportional hazards model, 1y‐
WRF
was a strong and independent predictor of all‐cause and cardiovascular mortality. Hemoglobin and B‐type natriuretic peptide at discharge, as well as left ventricular ejection fraction <50%, were independent predictors of 1y‐
WRF
.

Conclusions

In patients with
ADHF
, 1y‐
WRF
is a strong predictor of all‐cause and cardiovascular mortality.
Reproductive potential and stock recruitment of the Caribbean and Brazilian metapopulations of the spiny lobster, Panulirus argus (Latreille, 1804)
Authors: Cruz Raúl , Silva Katia C. A. , Santana João V. M. , Gaeta Juliana C. , Cintra Israel H. A. 
Published: November 2014

The spiny lobsterPanulirus argus(Latreille, 1804) is the most important commercial fishing resource in the western central Atlantic and Brazil. Field studies covering the waters off southwestern Cuba and northern Brazil have improved our understanding of the variations in the reproductive potential (number of eggs), stock recruitment and reproductive efficiency of spiny lobsters according to location, depth and size class. Using the spawner-recruitment model, the reproductive potential index was correlated with the index of subsequent recruitment based on field sampling. Spiny lobster habitats in deeper waters need special attention in order to protect the species from overfishing of the recruitment. Considering the longevity and absence of reproductive senility in spiny lobsters, management strategies should ideally include the creation of spawner sanctuaries (marine protected areas) capable of restoring and maintaining the biomass of the spawning stock and the establishment of a maximum catch size of 135 mm (CL) for both sexes along the entire Brazilian coast. Based on our findings, we propose to establish spiny lobster sanctuaries (50-100 m) on the continental shelf off northern Brazil, from Amapá (5°25′N 51°0′W) to the western reaches of the coast of Pará (1°11′N 46°27′W, 0°42′N 46°45′W), covering a total surface area of 64 230 km2.
A null model to study community structure of microcrustacean assemblages in north Patagonian urban wetlands (39-41°S, Chile)
Authors: De los Ríos-Escalante Patricio , Muñoz-Pedreros Andrés , Möller Patricia 
Published: November 2014

The inland water bodies of northern Chilean Patagonia (38-41°S) have many lakes, wetlands and ponds with different littoral and zooplanktonic crustacean assemblages. This study presents field observations of species associations sampled from shallow wetlands located in the urban zones of Valdivia (39°S) and Puerto Montt (41°S). A species presence-absence matrix was created for calculating the Jaccard Index of community similarity and for testing null models of species associations, with the aim of determining whether species associations are random or not. The results of the Jaccard Index calculations indicated the existence of non-defined groups. The results of the null model analysis denoted the presence of regulating factors for Valdivia wetlands, whereas for Puerto Montt wetlands no such factors could be demonstrated. The outcomes of both the Jaccard Index and the significant null model analysis agree with previous ecological descriptions of changes in trophic status as a consequence of changes in the surrounding basin as a determinant of species associations. The ecology of these communities is also discussed.
Niche segregation between two closely similar gammarids (Peracarida, Amphipoda) — native vs. naturalized non-native species
Authors: Mauchart Péter , Bereczki Csaba , Ortmann-Ajkai Adrienne , Csabai Zoltán , Szivák Ildikó 
Published: November 2014

Closely similar species may occupy similar niches, but usually divergence can be found in one or more traits when they inhabit the same habitat. In this study, we examined how two co-occurring gammarids — the nativeGammarus fossarumand the naturalizedG. roeselii — are distributed among microhabitats, depending on their sympatric or allopatric distribution. We hypothesized that the larger body-sized species (G. roeselii), exploiting their advantages in competition, restrict smaller species to microhabitats with smaller particle sizes. Four headwaters were sampled in the Mecsek Mountains (SW Hungary) in May, July and October 2009, and 37 local scale environmental variables at each site were measured. AlthoughG. fossarumis smaller in size, significantly more individuals were collected from the more favourable lithal and biotic microhabitats, whereas a strong negative association was observed between the two species.Gammarus roeseliioccurred at sites characterized by degraded riparian vegetation, which indicates stronger anthropogenic impacts, but still has a disadvantage in competition in mountainous streams under anthropogenic influence.
Reproduction and growth of the spiny lebbeid shrimp, Lebbeus groenlandicus (Fabricius, 1775) (Caridea, Hippolytidae) in the East Sea of Korea
Authors: Bae Ho Jin , Oh Chul-Woong 
Published: November 2014

Reproduction and growth of the spiny lebbeid shrimp, Lebbeus groenlandicus (Fabricius, 1775), were investigated based on samples in the East Sea of Korea [= Sea of Japan], from January 2012 to April 2013. We collected 2964 shrimp samples during the study period, which included significantly more females than males (male : female ratio, 1.0 : 1.17). The females were generally larger than the males, and significant differences in the linear-regression slopes of carapace length (CL) versus body weight between the sexes indicate sex-specific differences in allometric growth. The gonadosomatic index (GSI) varied monthly, reaching a maximum in November 2012 (10.28) and a minimum in March 2013 (2.15). The proportion of ovigerous females varied from month to month. The highest values of the GSI coincided with the breeding period, and there was a significant difference between the mean GSI of females with non-eyed and those with eyed eggs, indicating that L. groenlandicus is a consecutive breeder. There was a significant correlation between CL and the number of eggs (EN) in the early egg stages. There was also a significant difference in the slopes of the regressions of CL versus EN between females carrying non-eyed and eyed egg stages. Based on the dry weights in the early egg stages, reproductive output was determined to be 0.18 ± 0.006. The Von Bertalanffy growth function parameters were CL∞ = 38.80 mm, year−1, , and WP = 0.4 for males, and CL∞ = 43.64 mm, year−1, , and WP = 0.6 for females. The growth performance index () was 2.86 for males and 2.89 for females.
Description of the ‘stargazer mysid’ Mysidopsis zsilaveczi sp. nov. (Mysida, Mysidae, Leptomysinae) from the Cape Peninsula, South Africa
Authors: Wittmann K. J. , Griffiths C. L. 
Published: November 2014

Mysidopsis zsilaveczi sp. nov. shows colour patterns on the eye that mislead the observer in thinking that the eyes are facing upwards, largely irrespective of their actual orientation, and have resulted in local divers naming these animals ‘stargazer mysids’. To date, only males of the new species could be sampled. Within the species-rich genus Mysidopsis G. O. Sars, 1864 the males of M. zsilaveczi are characterized, besides their unique colour patterns, by a subdivided antennal scale; by a small, mid-dorsal protuberance on the carapace; by endopods of all pleopods having a large, expanded, plate-like exite on the basal segment; by the comparatively large, two-segmented endopod of pleopod 1; by uropodal endopods that extend well beyond the telson; and by having a linguiform telson with spines all along its lateral margins. The new species also shows diverse, very small, lobe-like structures on basis and dactylus of thoracic endopods 3-8. Closely similar structures were for the first time also found in Mediterranean material of M. angusta G. O. Sars, 1864 and M. gibbosa G. O. Sars, 1864. This new species raises the number of southern African Mysidopsis species to nine, confirming the coastal waters of this subcontinent as being one of the major hotspots of diversity in this genus. An updated key to the Mysidopsis species from southern Africa (Namibia plus South Africa) is provided.
An Official Image of the World for the Hispanic Monarchy
Authors: Sánchez Antonio 
Published: November 2014

This paper discusses the Padrón Real (Royal Pattern Chart or master sea chart), an official class of maps of the world instituted by the Spanish monarchy and produced by Seville’s Casa de la Contratación (House of Trade) from 1508 onwards, in a political context dominated by the dispute between the two largest expansionist empires in Europe – Portugal and Castile – which was heightened following the signing of the Treaty of Tordesillas in 1494. The Padrón Real became a model for European cartographers and its history sheds light on the development of map-making practices at the Casa in the Crown’s attempt to regulate cosmography for its own political ends.
The Padrón Real was unprecedented for its time and, together with the question of how to determine longitude, reflected what were the most important cartographic challenges facing the early modern world: how to represent a three-dimensional body – the globe – on a flat surface and how to provide reliable geographic maps when they were subject to constant revision.
The Characterization of Ice Hydrometeor Gamma Size Distributions as Volumes in N0–λ–μ Phase Space: Implications for Microphysical Process Modeling
Authors: McFarquhar Greg M. , Hsieh Tsung-Lin , Freer Matt , Mascio Jeana , Jewett Brian F. 
Published: November 2014

Abstract
Gamma distributions represent particle size distributions (SDs) in mesoscale and cloud-resolving models that predict one, two, or three moments of hydrometeor species. They are characterized by intercept (N0), slope (λ), and shape (μ) parameters prognosed by such schemes or diagnosed based on fits to SDs measured in situ in clouds. Here, ice crystal SDs acquired in arctic cirrus during the Indirect and Semi-Direct Aerosol Campaign (ISDAC) and in hurricanes during the National Aeronautic and Space Administration (NASA) African Monsoon Multidisciplinary Analyses (NAMMA) are fit to gamma distributions using multiple algorithms. It is shown that N0, λ, and μ are not independent parameters but rather exhibit mutual dependence. Although N0, λ, and μ are not highly dependent on choice of fitting routine, they are sensitive to the tolerance permitted by fitting algorithms, meaning a three-dimensional volume in N0–λ–μ phase space is required to represent a single SD. Depending on the uncertainty in the measured SD and on how well a gamma distribution matches the SD, parameters within this volume of equally realizable solutions can vary substantially, with N0, in particular, spanning several orders of magnitude. A method to characterize a family of SDs as an ellipsoid in N0–λ–μ phase space is described, with the associated scatter in N0–λ–μ for such families comparable to scatter in N0, λ, and μ observed in prior field campaigns conducted in different conditions. Ramifications for the development of cloud parameterization schemes and associated calculations of microphysical process rates are discussed.
Evaluating the Performance of Hydrological Models via Cross-Spectral Analysis: Case Study of the Thames Basin, United Kingdom
Authors: Weedon Graham P. , Prudhomme Christel , Crooks Sue , Ellis Richard J. , Folwell Sonja S. , Best Martin J. 
Published: November 2014

AbstractNine distributed hydrological models, forced with common meteorological inputs, simulated naturalized daily discharge from the Thames basin for 1963–2001. While model-dependent evaporative losses are critical for modeling mean discharge, multiple physical processes at many time scales influence the variability and timing of discharge. Here the use of cross-spectral analysis is advocated to measure how the average amplitude—and independently, the average phase—of modeled discharge differ from observed discharge at daily to decadal time scales. Simulation of the spectral properties of the model discharge via numerical manipulation of precipitation confirms that modeled transformation involves runoff generation and routing that amplify the annual cycle, while subsurface storage and routing of runoff between grid boxes introduces most of the autocorrelation and delays. Too much or too little modeled evaporation affects discharge variability, as do the capacity and time constants of modeled stores. Additionally, the performance of specific models would improve if four issues were tackled: 1) nonsinusoidal annual variations in model discharge (prolonged low base flow and shortened high base flow; three models), 2) excessive attenuation of high-frequency variability (three models), 3) excessive short-term variability in winter half years but too little variability in summer half years (two models), and 4) introduction of phase delays at the annual scale only during runoff generation (three models) or only during routing (one model). Cross-spectral analysis reveals how reruns of one model using alternative methods of runoff generation—designed to improve performance at the weekly to monthly time scales—degraded performance at the annual scale. The cross-spectral approach facilitates hydrological model diagnoses and development.