bluuebunny/crossref_metadata_2025_split huggingface dataset:
Neuregulin Autocrine Signaling Promotes Self-Renewal of Breast Tumor-Initiating Cells by Triggering HER2/HER3 Activation
Authors: Lee Cleo Yi-Fang , Lin Yuan , Bratman Scott V. , Feng Weiguo , Kuo Angera H. , Scheeren Ferenc A. , Engreitz Jesse M. , Varma Sushama , West Robert B. , Diehn Maximilian 
Published: November 2013

Abstract
Currently, only patients with HER2-positive tumors are candidates for HER2-targeted therapies. However, recent clinical observations suggest that the survival of patients with HER2-low breast cancers, who lack HER2 amplification, may benefit from adjuvant therapy that targets HER2. In this study, we explored a mechanism through which these benefits may be obtained. Prompted by the hypothesis that HER2/HER3 signaling in breast tumor-initiating cells (TIC) promotes self-renewal and survival, we obtained evidence that neuregulin 1 (NRG1) produced by TICs promotes their proliferation and self-renewal in HER2-low tumors, including in triple-negative breast tumors. Pharmacologic inhibition of EGFR, HER2, or both receptors reduced breast TIC survival and self-renewal in vitro and in vivo and increased TIC sensitivity to ionizing radiation. Through a tissue microarray analysis, we found that NRG1 expression and associated HER2 activation occurred in a subset of HER2-low breast cancers. Our results offer an explanation for why HER2 inhibition blocks the growth of HER2-low breast tumors. Moreover, they argue that dual inhibition of EGFR and HER2 may offer a useful therapeutic strategy to target TICs in these tumors. In generating a mechanistic rationale to apply HER2-targeting therapies in patients with HER2-low tumors, this work shows why these therapies could benefit a considerably larger number of patients with breast cancer than they currently reach. Cancer Res; 74(1); 341–52. ©2013 AACR.
Integrative Genomic Analysis of Temozolomide Resistance in Diffuse Large B-Cell Lymphoma
Authors: Leshchenko Violetta V. , Kuo Pei-Yu , Jiang Zewei , Thirukonda Venu K. , Parekh Samir 
Published: November 2013

Abstract
Purpose: Despite advances, there is an urgent need for effective therapeutics for relapsed diffuse large B-cell lymphoma, particularly in elderly patients and primary central nervous system (CNS) lymphoma. Temozolomide (TMZ), an oral DNA-alkylating agent routinely used in the therapy of glioblastoma multiforme, is active in patients with primary CNS lymphoma but the response rates are low. The mechanisms contributing to TMZ resistance are unknown.
Experimental Design: We undertook an unbiased and genome-wide approach to understand the genomic methylation and gene expression profiling differences associated with TMZ resistance in diffuse large B-cell lymphoma cell lines and identify mechanisms to overcome TMZ resistance.
Results: TMZ was cytotoxic in a subset of diffuse large B-cell lymphoma cell lines, independent of MGMT promoter methylation or protein expression. Using Connectivity Map (CMAP), we identified several compounds capable of reversing the gene expression signature associated with TMZ resistance. The demethylating agent decitabine (DAC) is identified by CMAP as capable of reprogramming gene expression to overcome TMZ resistance. Treatment with DAC led to increased expression of SMAD1, a transcription factor involved in TGF-β/bone morphogenetic protein (BMP) signaling, previously shown to be epigenetically silenced in resistant diffuse large B-cell lymphoma. In vitro and in vivo treatment with a combination of DAC and TMZ had greater antilymphoma activity than either drug alone, with complete responses in TMZ-resistant diffuse large B-cell lymphoma murine xenograft models.
Conclusions: Integrative genome-wide methylation and gene expression analysis identified novel genes associated with TMZ resistance and demonstrate potent synergy between DAC and TMZ. The evidence from cell line and murine experiments supports prospective investigation of TMZ in combination with demethylating agents in diffuse large B-cell lymphoma. Clin Cancer Res; 20(2); 382–92. ©2013 AACR.
Proteasome Proteolysis Supports Stimulated Platelet Function and Thrombosis
Authors: Gupta Nilaksh , Li Wei , Willard Belinda , Silverstein Roy L. , McIntyre Thomas M. 
Published: November 2013

Objective—
Proteasome inhibitors used in the treatment of hematologic cancers also reduce thrombosis. Whether the proteasome participates in platelet activation or function is unclear because little is known of the proteasome in these terminally differentiated cells.

Approach and Results—

Platelets displayed all 3 primary proteasome protease activities, which MG132 and bortezomib (Velcade) inhibited. Proteasome substrates are marked by ubiquitin, and platelets contained a functional ubiquitination system that modified the proteome by monoubiquitination and polyubiquitination. Systemic MG132 strongly suppressed the formation of occlusive, platelet-rich thrombi in FeCl
3
-damaged carotid arteries. Transfusion of platelets treated ex vivo with MG132 and washed before transfusion into thrombocytopenic mice also reduced carotid artery thrombosis. Proteasome inhibition reduced platelet aggregation by low thrombin concentrations and ristocetin-stimulated agglutination through the glycoprotein Ib-IX-V complex. This receptor was not appropriately internalized after proteasome inhibition in stimulated platelets, and spreading and clot retraction after MG132 exposure also were decreased. The effects of proteasome inhibitors were not confined to a single receptor as MG132 suppressed thrombin-stimulated, ADP-stimulated, and lipopolysaccharide-stimulated microparticle shedding. Proteasome inhibition increased ubiquitin decoration of cytoplasmic proteins, including the cytoskeletal proteins Filamin A and Talin-1. Mass spectrometry revealed a single MG132-sensitive tryptic cleavage after R
1745
in an extended Filamin A loop, which would separate its actin-binding domain from its carboxy terminal glycoprotein Ibα–binding domain.

Conclusions—
Platelets contain a ubiquitin/proteasome system that marks cytoskeletal proteins for proteolytic modification to promote productive platelet–platelet and platelet–wall interactions.
Clinical Effectiveness of Cardiac Resynchronization and Implantable Cardioverter-Defibrillator Therapy in Men and Women With Heart Failure
Authors: Wilcox Jane E. , Fonarow Gregg C. , Zhang Yan , Albert Nancy M. , Curtis Anne B. , Gheorghiade Mihai , Heywood J. Thomas , Mehra Mandeep R. , O’Connor Christopher M. , Reynolds Dwight , Walsh Mary Norine , Yancy Clyde W. 
Published: November 2013

Background—
Many clinical trials have demonstrated a benefit for cardiac resynchronization (CRT) and implantable cardioverter-defibrillator (ICD) therapies in patients with heart failure and reduced ejection fraction, yet questions have been raised with regard to the benefit of ICDs for women. The purpose of this study was to determine the clinical effectiveness of CRT and ICD therapy as a function of sex in outpatients with heart failure and reduced ejection fraction (≤35%).

Methods and Results—

Data from the Registry to Improve the Use of Evidence-Based Heart Failure Therapies in the Outpatient Setting (IMPROVE HF) were analyzed by device status and sex among guideline-eligible patients for vital status (alive/dead) at 24 months. Multivariate generalized estimating equation analyses were conducted adjusting for baseline patient and practice characteristics. In the ICD/CRT-defibrillator (CRT-D) eligible cohort (n=7748), there were 5485 (71%) men and 2261 (29%) women. In the CRT-pacemaker (CRT-P)/CRT-D eligible cohort (n=1188), there were 824 (69%) men and 364 (31%) women. The clinical benefit associated with ICD/CRT-D therapy was similar in both men and women (men adjusted odds ratio, 0.71; 95% confidence interval, 0.57–0.87;
P
=0.0012; and women adjusted odds ratio, 0.65; 95% confidence interval, 0.49–0.85;
P
=0.0019). For CRT-P/CRT-D, the associated benefits showed no significant heterogeneity (men adjusted odds ratio, 0.59; 95% confidence interval, 0.33–1.06;
P
=0.0793; and women adjusted odds ratio, 0.44; 95% confidence interval, 0.22–0.90;
P
=0.0243). The device-by-sex interactions were not significant (
P
=0.4441 for CRT-P/CRT-D and
P
=0.5966 for ICD/CRT-D).

Conclusions—
The use of guideline-directed CRT and ICD therapy was associated with substantially reduced 24-month mortality in eligible men and women with heart failure and reduced ejection fraction. Device therapies should be offered to all eligible patients with heart failure, without modification based on sex.
Syvertsenia iberica (Cymatosiraceae): a new estuarine diatom genus characterized by the position of its process
Authors: GOMES ANA , WITKOWSKI ANDRZEJ , DĄBEK PRZEMYSŁAW , BOSKI TOMASZ , MOURA DELMINDA , SZKORNIK KATIE , KURZYDŁOWSKI KRZYSZTOF 
Published: November 2013

Diatom assemblages were studied along an intertidal transect in the lower Guadiana River Estuary (South-Eastern Portugal). The analyses of the assemblages by means of light and scanning electron microscope revealed a new diatom genus and species, Syvertsenia iberica. Syvertsenia was found in three out of eighteen of the samples analysed in the transect. The proposed new genus belongs to the family Cymatosiraceae, which is characterized by the presence of two distinct ocelluli. In common with other genera belonging to the subfamily Cymatosiroideae, the new genus shows heterovalvy and morphological similarity to Cymatosira, Campylosira and Plagiogrammopsis. In terms of ultrastructure, the features which identify these diatoms as a new genus are its linear valve outline, protracted to distinctly set off apices and also the distribution pattern of areola. Furthermore the position of the tubular process on a valve mantle extension, allows an easy distinction from other Cymatosiroideae. Syvertsenia iberica is a benthic epipsammic diatom whose ecological and geographical distribution requires more investigation.
Gravity Currents in Confined Channels with Environmental Shear
Authors: Bryan George H. , Rotunno Richard 
Published: November 2013

AbstractThis study examines properties of gravity currents in confined channels with sheared environmental flow. Under the assumptions of steady and inviscid flow, two-dimensional analytic solutions are obtained for a wide range of shear values. The slope of a gravity current interface just above the surface increases as environmental shear α increases, which is consistent with previous studies, although here it is shown that the interface slope can exceed 80° for nondimensional shear α &gt; 2. Then the inviscid-flow analytic solutions are compared with two- and three-dimensional numerical model simulations, which are turbulent and thus have dissipation. The simulated current depths are systematically lower, compared to a previous study, apparently because of different numerical techniques in this study that allow for a faster transition to turbulence along the gravity current interface. Furthermore, simulated gravity current depths are 10%–40% lower than the inviscid analytic values. To explain the model-produced current depths, a steady analytic theory with energy dissipation is revisited. It is shown that the numerical model current depths are close to values associated with the maximum possible dissipation rate in the simplest form of the analytic model for all values of α examined in this study. A primary conclusion is that dissipation plays an important and nonnegligible role in gravity currents within confined channels, with or without environmental shear.
Climatic Impacts of Land-Use Change due to Crop Yield Increases and a Universal Carbon Tax from a Scenario Model*
Authors: Davies-Barnard T. , Valdes P. J. , Singarayer J. S. , Jones C. D. 
Published: November 2013

Abstract
Future land cover will have a significant impact on climate and is strongly influenced by the extent of agricultural land use. Differing assumptions of crop yield increase and carbon pricing mitigation strategies affect projected expansion of agricultural land in future scenarios. In the representative concentration pathway 4.5 (RCP4.5) from phase 5 of the Coupled Model Intercomparison Project (CMIP5), the carbon effects of these land cover changes are included, although the biogeophysical effects are not. The afforestation in RCP4.5 has important biogeophysical impacts on climate, in addition to the land carbon changes, which are directly related to the assumption of crop yield increase and the universal carbon tax. To investigate the biogeophysical climatic impact of combinations of agricultural crop yield increases and carbon pricing mitigation, five scenarios of land-use change based on RCP4.5 are used as inputs to an earth system model [Hadley Centre Global Environment Model, version 2–Earth System (HadGEM2-ES)]. In the scenario with the greatest increase in agricultural land (as a result of no increase in crop yield and no climate mitigation) there is a significant −0.49 K worldwide cooling by 2100 compared to a control scenario with no land-use change. Regional cooling is up to −2.2 K annually in northeastern Asia. Including carbon feedbacks from the land-use change gives a small global cooling of −0.067 K. This work shows that there are significant impacts from biogeophysical land-use changes caused by assumptions of crop yield and carbon mitigation, which mean that land carbon is not the whole story. It also elucidates the potential conflict between cooling from biogeophysical climate effects of land-use change and wider environmental aims.
Cloud Feedbacks, Rapid Adjustments, and the Forcing–Response Relationship in a Transient CO2 Reversibility Scenario
Authors: Andrews Timothy , Ringer Mark A. 
Published: November 2013

AbstractThe Hadley Centre Global Environment Model, version 2–Earth System (HadGEM2-ES) climate model is forced by a 1% yr−1 compound increase in atmospheric CO2 for 140 years, followed by a 1% yr−1 CO2 decrease back to the starting level. Analogous atmosphere-only simulations are performed to diagnose the component of change associated with the effective radiative forcing and rapid adjustments. The residual change is associated with radiative feedbacks that are shown to be linearly related to changes in global-mean surface air temperature and are found to be reversible under this experimental design, even for regional cloud feedback changes. The cloud adjustment is related to changes in cloud amount, with little indication of any large-scale changes in cloud optical depth. Plant physiological forcing plays a significant role in determining the cloud adjustment in this model and is the dominant contribution to the low-level cloud changes over land. Low-level cloud adjustments are associated with changes in surface turbulent fluxes and lower tropospheric stability, with significant adjustments in boundary layer cloud types and in the depth of the boundary layer itself. The linearity of simple forcing–response frameworks are examined and found to be generally applicable. Small regional departures from linearity occur during the early part of the ramp-down phase, where the Southern Ocean and eastern tropical Pacific continue to warm for a few decades, despite the reversal in radiative forcing and global temperatures. The importance of considering time-varying patterns of warming and regional phenomena when diagnosing and understanding feedbacks in a coupled atmosphere–ocean framework is highlighted.
Coastal-Trapped Waves in the East China Sea Observed by a Mooring Array in Winter 2006
Authors: Yin Liping , Qiao Fangli , Zheng Quanan 
Published: November 2013

Abstract
Using five mooring array observations in the coastal water of the East China Sea (ECS) in winter 2006, the authors identify three kinds of low-frequency waves using the ensemble empirical mode decomposition (EEMD) method. The analysis indicates that the periods of the waves varied from 2 to 10 days, which are consistent with coastal-trapped wave (CTW) modes: the Kelvin wave (KW) mode, the first shelf wave (SW1) mode, and the second shelf wave (SW2) mode. An analytical model is established and the dispersion relation of the waves from the analytical method agrees well with the observations. The wind-forced, coastal-trapped wave theory is then applied. The calculation shows that over a wide shelf, the forcing term of wind stress curl plays an important role in shaping the CTW. Numerical solutions reproduce the sea level variation and the alongshore current. The results show that the sea level variation mainly resulted from the KW mode, but the alongshore current resulted from both the KW and SW1 modes.
One- and Two-Dimensional Wind Speed Models for Ka-Band Altimetry
Authors: Lillibridge John , Scharroo Remko , Abdalla Saleh , Vandemark Doug 
Published: November 2013

abstract
SARAL—the Satellite with ARgos and ALtiKa—is the first satellite radar altimetry mission to fly a Ka-band instrument (AltiKa). Ocean backscatter measurements in the Ka band suffer larger signal attenuation due to water vapor and atmospheric liquid water than those from Ku-band altimeters. An attenuation algorithm is provided, based on radar propagation theory, which is a function of atmospheric pressure, temperature, water vapor, and liquid water content. Because of the nature of the air–sea interactions between wind and surface gravity waves, the shorter wavelength Ka-band backscatter exhibits a different relationship with wind speed than at Ku band, particularly at moderate to high wind speeds. This paper presents a new one-dimensional wind speed model, as a function of backscatter only, and a two-dimensional model, as a function of backscatter and significant wave height, tuned to AltiKa’s backscatter measurements. The performance of these new Ka-band altimeter wind speed models is assessed through validation with independent ocean buoy wind speeds. The results indicate wind measurement accuracy comparable to that observed at Ku band with only slightly elevated noise in the wind estimates.
The Advantages of a Mixed-Band Radar Network for Severe Weather Operations: A Case Study of 13 May 2009
Authors: Mahale Vivek N. , Brotzge Jerald A. , Bluestein Howard B. 
Published: November 2013

Abstract
Adding a mix of X- or C-band radars to the current Weather Surveillance Radar-1988 Doppler (WSR-88D) network could address several limitations of the network, including improvements to spatial gaps in low-level coverage and temporal sampling of volume scans. These limitations can result in missing critical information in highly dynamic events, such as tornadoes and severe straight-line wind episodes. To evaluate the potential value of a mixed-band radar network for severe weather operations, a case study is examined using data from X- and S-band radars. On 13 May 2009, a thunderstorm complex associated with a cold front moved southward into southwest Oklahoma. A tornado rapidly developed from an embedded supercell within the complex. The life cycle of the tornado and subsequent wind event was sampled by the experimental Collaborative Adaptive Sensing of the Atmosphere (CASA) radar testbed of four X-band radars as well as two operational WSR-88Ds. In this study, the advantages of a mixed-band radar network are demonstrated through a chronological analysis of the event. The two radar networks provided enhanced overall situational awareness. Data from the WSR-88Ds provided 1) clear-air sensitivity, 2) a broad overview of the storm complex, 3) a large maximum unambiguous range, and 4) upper-level scans up to 19.5°. Data from the CASA radars provided 1) high-temporal, 1-min updates; 2) overlapping coverage for dual-Doppler analysis; and 3) dense low-level coverage. The combined system allowed for detailed, dual- and single-Doppler observations of a wind surge, a mesocyclone contraction, and a downburst.
Effects of an aquatic therapy approach (Halliwick-Therapy) on functional mobility in subacute stroke patients: a randomized controlled trial
Authors: Tripp Florian , Krakow Karsten 
Published: November 2013

Objective: To evaluate the effects of an aquatic physiotherapy method (Halliwick-Therapy) upon mobility in the post-acute phase of stroke rehabilitation. Design: Randomized controlled trial. Setting: Hospital for neurological rehabilitation. Participants: Adult patients after first-ever stroke in post-acute inpatient rehabilitation at least two weeks after the onset of stroke ( n = 30). Interventions: In the Halliwick-Therapy group ( n = 14) the treatment over a period of two weeks included 45 minutes of aquatic therapy three times per week and a conventional physiotherapeutic treatment twice a week. Subjects in the control group ( n = 16) received conventional physiotherapeutic treatment over a period of two weeks five times per week. Outcome measures: The primary outcome variable was postural stability (Berg Balance Scale). Secondary outcome variables were functional reach, functional gait ability and basic functional mobility. Results: Compared to the control group, significantly more subjects in the Halliwick-Therapy group (83.3% versus 46.7%) attained significant improvement of the Berg Balance Scale ( P < 0.05). Improvement of the functional gait ability was significantly higher in the Halliwick-Therapy group (mean (SD) 1.25(0.86)) than in the control group (mean (SD) 0.73 (0.70)) ( P < 0.1). The mean differences of improvements in functional reach and basic functional mobility were not statistically significant between groups. Conclusions: This study indicates that Halliwick-Therapy is safe and well tolerated in stroke patients in post-acute rehabilitation and has positive effects upon some aspects of mobility.
Aquatic therapy improves pain, disability, quality of life, body composition and fitness in sedentary adults with chronic low back pain. A controlled clinical trial
Authors: Baena-Beato Pedro Ángel , Artero Enrique G , Arroyo-Morales Manuel , Robles-Fuentes Alejandro , Gatto-Cardia María Claudia , Delgado-Fernández Manuel 
Published: November 2013

Objective: To determine the effects of a two-month intensive aquatic therapy programme on back pain, disability, quality of life, body composition and health-related fitness in sedentary adults with chronic low back pain. Design: Controlled clinical trial. Setting: Community. Subjects: Forty-nine sedentary patients with chronic low back pain. Interventions: Patients were allocated into active group ( n = 24, two months, five times/week) or waiting list, control group ( n = 25) according to space on the programme. Main measures: Outcomes variables were pain (visual analogue scale), disability (Oswestry Disability Index), quality of life (Quality Short-Form Health Survey 36), body composition (weight, body mass index, body fat percentage and skeletal muscle mass) and health-related fitness (sit-and-reach, handgrip strength, curl-up, Rockport 1-mile test). Results: The active group significantly improved low back pain (–3.83 ± 0.35 mm on the visual analogue scale ), disability (–12.7 ± 1.3 points for the Oswestry Disability Index) and the standardized physical component (10.3 ± 1.4 points for the Quality Short-Form Health Survey 36) of quality-of-life domains ( P < 0.001), with no significant changes on the standardized mental component ( P = 0.114). In relation to body composition and fitness, the active group showed significant improvements (all P-values < 0.01). The control group presented no significant change in any parameter. Conclusions: A two-month intensive aquatic therapy programme of high-frequency (five times/week) decreases levels of back pain and disability, increases quality of life, and improves body composition and health-related fitness in sedentary adults with chronic low back pain.