bluuebunny/crossref_metadata_2025_split huggingface dataset:
Autophagy Induced by Conventional Chemotherapy Mediates Tumor Cell Sensitivity to Immunotherapy
Authors: Ramakrishnan Rupal , Huang Chun , Cho Hyun-Il , Lloyd Mark , Johnson Joseph , Ren Xiubao , Altiok Soner , Sullivan Daniel , Weber Jeffrey , Celis Esteban , Gabrilovich Dmitry I. 
Published: September 2012

Abstract
Autophagy attenuates the efficacy of conventional chemotherapy but its effects on immunotherapy have been little studied. Here, we report that chemotherapy renders tumor cells more susceptible to lysis by CTL in vivo. Moreover, bystander tumor cells that did not express antigen were killed by CTL. This effect was mediated by transient but dramatic upregulation of the mannose-6-phosphate receptor (MPR) on the tumor cell surface. Antitumor effects of combined treatment related to the kinetics of MPR upregulation and abrogation of this event abolished the combined effect of immunotherapy and chemotherapy. MPR accumulation on the tumor cell surface during chemotherapy was observed in different mouse tumor models and in patients with multiple myeloma. Notably, this effect was the result of redistribution of the receptor caused by chemotherapy-inducible autophagy. Together, our findings reveal one molecular mechanism through which the antitumor effects of conventional cancer chemotherapy and immunotherapy are realized. Cancer Res; 72(21); 5483–93. ©2012 AACR.
Breakdown of the FLT3-ITD/STAT5 Axis and Synergistic Apoptosis Induction by the Histone Deacetylase Inhibitor Panobinostat and FLT3-Specific Inhibitors
Authors: Pietschmann Kristin , Bolck Hella Anna , Buchwald Marc , Spielberg Steffi , Polzer Harald , Spiekermann Karsten , Bug Gesine , Heinzel Thorsten , Böhmer Frank-Dietmar , Krämer Oliver H. 
Published: September 2012

Abstract
Activating mutations of the class III receptor tyrosine kinase FLT3 are the most frequent molecular aberration in acute myeloid leukemia (AML). Mutant FLT3 accelerates proliferation, suppresses apoptosis, and correlates with poor prognosis. Therefore, it is a promising therapeutic target. Here, we show that RNA interference against FLT3 with an internal tandem duplication (FLT3-ITD) potentiates the efficacy of the histone deacetylase inhibitor (HDACi) panobinostat (LBH589) against AML cells expressing FLT3-ITD. Similar to RNA interference, tyrosine kinase inhibitors (TKI; AC220/cpd.102/PKC412) in combination with LBH589 exhibit superior activity against AML cells. Median dose–effect analyses of drug-induced apoptosis rates of AML cells (MV4-11 and MOLM-13) revealed combination index (CI) values indicating strong synergism. AC220, the most potent and FLT3-specific TKI, shows highest synergism with LBH589 in the low nanomolar range. A 4-hour exposure to LBH589 + AC220 already generates more than 50% apoptosis after 24 hours. Different cell lines lacking FLT3-ITD as well as normal peripheral blood mononuclear cells are not significantly affected by LBH589 + TKI, showing the specificity of this treatment regimen. Immunoblot analyses show that LBH589 + TKI induce apoptosis via degradation of FLT3-ITD and its prosurvival target STAT5. Previously, we showed the LBH589-induced proteasomal degradation of FLT3-ITD. Here, we show that activated caspase-3 also contributes to the degradation of FLT3-ITD and that STAT5 is a direct target of this protease. Our data strongly emphasize HDACi/TKI drug combinations as promising modality for the treatment of FLT3-ITD–positive AMLs. Mol Cancer Ther; 11(11); 2373–83. ©2012 AACR.
Plasmacytoid Dendritic Cells Play a Key Role in Promoting Atherosclerosis in Apolipoprotein E–Deficient Mice
Authors: MacRitchie Neil , Grassia Gianluca , Sabir Suleman R. , Maddaluno Marcella , Welsh Paul , Sattar Naveed , Ialenti Armando , Kurowska-Stolarska Mariola , McInnes Iain B. , Brewer James M. , Garside Paul , Maffia Pasquale 
Published: August 2012

Objective—
Clinical studies have identified that reduced numbers of circulating plasmacytoid dendritic cells (pDCs) act as a predictor of cardiovascular events in coronary artery disease and that pDCs are detectable in the shoulder region of human atherosclerotic plaques, where rupture is most likely to occur. Results from animal models are controversial, with pDCs seen to inhibit or promote lesion development depending on the experimental settings. Here, we investigated the role of pDCs in atherosclerosis in apolipoprotein E−deficient mice.

Methods and Results—

We demonstrated that the aorta and spleen of both apolipoprotein E−deficient and C57BL/6 mice displayed similar numbers of pDCs, with similar activation status. In contrast, assessment of antigen uptake/presentation using the Eα/Y-Ae system revealed that aortic pDCs in apolipoprotein E−deficient
-
mice were capable of presenting in vivo systemically administered antigen. Continuous treatment of apolipoprotein E−deficient mice with anti−mouse plasmacytoid dendritic cell antigen 1 (mPDCA-1) antibody caused specific depletion of pDCs in the aorta and spleen and significantly reduced atherosclerosis formation in the aortic sinus (by 46%;
P
<0.001). Depletion of pDCs also reduced macrophages (by 34%;
P
<0.05) and increased collagen content (by 41%;
P
<0.05) in aortic plaques, implying a more stable plaque phenotype. Additionally, pDC depletion reduced splenic T-cell activation and inhibited interleukin-12, chemokine (C-X-C motif) ligand 1, monokine induced by interferon-γ, interferon γ−induced protein 10, and vascular endothelium growth factor serum levels.

Conclusion—
These results identify a critical role for pDCs in atherosclerosis and suggest a potential role for pDC targeting in the control of the pathology.
Hepatocyte Growth Factor Inhibits Lipopolysaccharide-Induced Oxidative Stress via Epithelial Growth Factor Receptor Degradation
Authors: Shimizu Kazutaka , Taniyama Yoshiaki , Sanada Fumihiro , Azuma Junya , Iwabayashi Masaaki , Iekushi Kazuma , Rakugi Hiromi , Morishita Ryuichi 
Published: August 2012

Objective—
Lipopolysaccharide (LPS) triggers sepsis and systemic inflammatory response syndrome, which results in multiple organ failure. Our recent reports demonstrated that hepatocyte growth factor (HGF) attenuated angiotensin II–induced oxidative stress via epithelial growth factor receptor (EGFR) degradation in vascular smooth muscle cells. Here, we examined whether HGF can protect against systemic inflammatory response syndrome induced by LPS and investigated the mechanism.

Methods and Results—
HGF inhibited the increase in the expression of vascular cell adhesion molecule-1 and EGFR by LPS in vitro. HGF inhibited colocalization of EGFR and Src homology domain 2–containing inositol 5′-phosphatase 2. Furthermore, HGF inhibited reactive oxygen species production. We also injected LPS into HGF transgenic mice with increased HGF serum concentration and their littermates. HGF transgenic mice reduced LPS-induced vascular cell adhesion molecule-1 and reactive oxygen species compared with control, accompanied by significant EGFR degradation. Furthermore, HGF transgenic mice significantly improved survival in the LPS injection model.

Conclusion—
The present study revealed inhibition of LPS-induced vascular cell adhesion molecule-1 expression by HGF via the degradation of EGFR. We demonstrated that HGF regulated Src homology domain 2–containing inositol 5′-phosphatase 2 recruitment to EGFR and inhibited LPS-induced inflammation via EGFR degradation. This effect of HGF may be useful for the treatment of inflammatory disease.
Elevated Levels of the Mediator of Catabolic Bone Remodeling RANKL in the Bone Marrow Environment Link Chronic Heart Failure with Osteoporosis
Authors: Leistner David M. , Seeger Florian H. , Fischer Ariane , Röxe Tino , Klotsche Jens , Iekushi Kazuma , Seeger Timon , Assmus Birgit , Honold Jörg , Karakas Mahir , Badenhoop Klaus , Frantz Stefan , Dimmeler Stefanie , Zeiher Andreas M. 
Published: September 2012

Background—
Chronic heart failure (CHF) is associated with a 4-fold increased risk for osteoporotic fractures. Therefore, we sought to identify the pathophysiological link between chronic heart failure and catabolic bone remodeling.

Methods and Results—

In a total cohort of 153 subjects (123 patients with CHF, 30 patients with coronary artery disease and preserved cardiac function) as well as mice with heart failure, bone marrow (BM) plasma levels of the catabolic receptor activator of NF-κB ligand (RANKL), and its antagonist, osteoprotegerin were measured. The osteoclast inducing activity of BM plasma was tested in cell culture. BM plasma levels of RANKL and of the ratio RANKL/osteoprotegerin were significantly elevated in patients with CHF. On multivariate regression analysis, parameters of severity and duration of heart failure were independent determinants of elevated BM plasma RANKL levels. BM plasma levels of RANKL were directly correlated with the systemic marker of bone turnover C-telopeptide of type 1 collagen (
r
=0.6;
P
<0.001). Alterations in BM plasma levels of RANKL/osteoprotegerin were confirmed in a mouse model of postinfarction heart failure. Stimulation of human mesenchymal cells with BM plasma obtained from CHF patients increased the formation of osteoclasts, and this effect was blocked by the RANKL inhibition.

Conclusions—
CHF is associated with a profound and selective elevation of the bone resorption stimulating RANKL within the BM microenvironment. These data for the first time disclose a direct pathophysiological pathway linking CHF with catabolic bone remodeling associated with an increased osteoporotic fracture risk.

Clinical Trial Registration—

URL:
http://www.clinicaltrials.gov
. Unique identifiers: NCT 00289822, NCT 00284713, NCT 00326989, NCT 00962364.
Short Sleep Duration Is Associated With Carotid Intima-Media Thickness Among Men in the Coronary Artery Risk Development in Young Adults (CARDIA) Study
Authors: Sands Megan R. , Lauderdale Diane S. , Liu Kiang , Knutson Kristen L. , Matthews Karen A. , Eaton Charles B. , Linkletter Crystal D. , Loucks Eric B. 
Published: August 2012

Background and Purpose—
Carotid intima-media thickness (CIMT) is a subclinical marker of cardiovascular disease. Recent studies suggest that shorter sleep duration is a risk factor for cardiovascular disease, but there is limited evidence regarding this association using high-quality, objective assessments of sleep. The aim of this study is to determine whether sleep duration is associated with CIMT.

Methods—
The study used an observational cohort consisting of 617 black and white middle-aged healthy participants (37–52 years; 58% female) in the Coronary Artery Risk Development in Young Adults (CARDIA) Study. Multivariable-adjusted linear regression analyses were performed. Sleep duration was measured using wrist actigraphy monitors. CIMT was calculated using the average of 20 measurements of the mean common carotid, bulb, and internal CIMT, which was assessed using ultrasound images.

Results—

After adjusting for covariates, 1 hour of longer sleep duration was associated with 0.026 mm less CIMT among men (
P
=0.02; 95% CI, −0.047 to −0.005) and 0.001 mm less CIMT among women (
P
=0.91; 95% CI, −0.020 to 0.022). Segment-specific analyses indicated that the carotid bulb was a key driver of the observed association.

Conclusions—
Shorter objectively assessed sleep duration was associated with greater CIMT among men but not women.
Long-Term Rate of Change in Memory Functioning Before and After Stroke Onset
Authors: Wang Qianyi , Capistrant Beatrix D. , Ehntholt Amy , Glymour M. Maria 
Published: August 2012

Background and Purpose—
Memory impairment is a predictor and a consequence of stroke, but memory decline is common even in healthy elderly individuals. We compared the long-term trajectory of memory functioning before and after stroke with memory change in stroke-free elderly individuals.

Methods—
Health and Retirement Study participants aged 50 years and older (n=17 340) with no stroke history at baseline were interviewed biennially up to 10 years for first self-reported or proxy-reported stroke (n=1574). Age-, sex-, and race-adjusted segmented linear regression models were used to compare annual rates of change in a composite memory score before and after stroke among 3 groups: 1189 stroke survivors; 385 stroke decedents; and 15 766 cohort members who remained stroke-free.

Results—

Before stroke onset, individuals who later survived stroke had significantly (
P
<0.001) faster average annual rates of memory decline (−0.143 points per year) than those who remained stroke-free throughout follow-up (−0.101 points per year). Stroke decedents had even faster prestroke memory decline (−0.212 points per year). At stroke onset, memory declined an average of −0.369 points among stroke survivors, comparable with 3.7 years of age-related decline in stroke-free cohort members. After stroke, memory in stroke survivors continued to decline at −0.142 points per year, similar to their prestroke rates (
P
=0.93). Approximately 50% of the memory difference between stroke survivors soon after stroke and age-matched stroke-free individuals was attributable to prestroke memory.

Conclusions—
Although stroke onset induced large decrements in memory, memory differences were apparent years before stroke. Memory declines before stroke, especially among those who did not survive the stroke, were faster than declines among stroke-free adults.
30-Day Risk-Standardized Mortality and Readmission Rates After Ischemic Stroke in Critical Access Hospitals
Authors: Lichtman Judith H. , Leifheit-Limson Erica C. , Jones Sara B. , Wang Yun , Goldstein Larry B. 
Published: August 2012

Background and Purpose—
The critical access hospital (CAH) designation was established to provide rural residents with local access to emergency and inpatient care. CAHs, however, have poorer short-term outcomes for pneumonia, heart failure, and myocardial infarction compared with other hospitals. We assessed whether 30-day risk-standardized mortality rates (RSMRs) and risk-standardized readmission rates (RSRRs) after ischemic stroke differ between CAHs and non-CAHs.

Methods—

The study included all fee-for-service Medicare beneficiaries 65 years of age or older with a primary discharge diagnosis of ischemic stroke (
International Classification of Diseases,
9th revision codes 433, 434, 436) in 2006. Hierarchical generalized linear models calculated hospital-level RSMRs and RSRRs, adjusting for patient demographics, medical history, and comorbid conditions. Non-CAHs were categorized by hospital volume quartiles and the RSMR and RSRR posterior probabilities in comparison with CAHs were determined using linear regression with Markov chain Monte Carlo simulation.

Results—

There were 10 267 ischemic stroke discharges from 1165 CAHs and 300 114 discharges from 3381 non-CAHs. The RSMRs of CAHs were higher than non-CAHs (11.9%±1.4% vs 10.9%±1.7%;
P
<0.001), but the RSRRs were comparable (13.7%±0.6% vs 13.7%±1.4%;
P
=0.3). The RSMRs for the 2 higher volume quartiles of non-CAHs were lower than CAHs (posterior probability of RSMRs higher than CAHs=0.007 for quartile 3;
P
<0.001 for quartile 4), but there were no differences for lower volume hospitals; RSRRs did not vary by annual hospital volume.

Conclusions—
CAHs had higher RSMRs compared with non-CAHs, but readmission rates were similar. The observed differences may be partly explained by patient characteristics and annual hospital volume.
Indications of Stratified Turbulence in a Mechanistic GCM
Authors: Brune Sebastian , Becker Erich 
Published: September 2012

Abstract
The horizontal kinetic energy spectrum and its budget are analyzed on the basis of a general circulation model with simplistic parameterizations of radiative and latent heating. A spectral truncation at total wavenumber 330 is combined with a level spacing of either ~200 m or ~1.5 km from the midtroposphere to the lower stratosphere. The subgrid-scale parameterization consists of a Smagorinsky-type anisotropic diffusion scheme that is scaled by a Richardson criterion for dynamic instability and combined with a stress-tensor-based hyperdiffusion that acts only on the very smallest resolved scales. Simulations with both vertical resolutions show a transition from the synoptic −3 to the mesoscale slope in the upper-tropospheric kinetic energy spectrum. Analysis of the spectral budget indicates that the mesoscale slope can be interpreted as stratified turbulence, as has been proposed in recent works of Lindborg and others, only when a high vertical resolution is applied. In this case, the mesoscale kinetic energy around 300–150 hPa is dominated by the nonrotational flow, and the forward horizontal energy cascade is accompanied by an equally strong forward spectral flux due to adiabatic conversion. This adiabatic conversion mainly results from a vertical potential energy flux that originates in the midtroposphere, where the mesoscale adiabatic conversion is negative. For a conventionally coarse vertical resolution, however, the mesoscale slope in the troposphere is dominated by the rotational flow, and the spectral flux due to adiabatic conversion is not comparable to that associated with horizontal advection.
The Effect of Phase-Correlated Returns and Spatial Smoothing on the Accuracy of Radar Refractivity Retrievals
Authors: Nicol J. C. , Illingworth A. J. 
Published: September 2012

Abstract
Radar refractivity retrievals have the potential to accurately capture near-surface humidity fields from the phase change of ground clutter returns. In practice, phase changes are very noisy and the required smoothing will diminish large radial phase change gradients, leading to severe underestimates of large refractivity changes (ΔN). To mitigate this, the mean refractivity change over the field (〈ΔN〉field) must be subtracted prior to smoothing. However, both observations and simulations indicate that highly correlated returns (e.g., when single targets straddle neighboring gates) result in underestimates of 〈ΔN〉field when pulse-pair processing is used. This may contribute to reported differences of up to 30 N units between surface observations and retrievals. This effect can be avoided if 〈ΔN〉field is estimated using a linear least squares fit to azimuthally averaged phase changes. Nevertheless, subsequent smoothing of the phase changes will still tend to diminish the all-important spatial perturbations in retrieved refractivity relative to 〈ΔN〉field; an iterative estimation approach may be required. The uncertainty in the target location within the range gate leads to additional phase noise proportional to ΔN, pulse length, and radar frequency. The use of short pulse lengths is recommended, not only to reduce this noise but to increase both the maximum detectable refractivity change and the number of suitable targets. Retrievals of refractivity fields must allow for large ΔN relative to an earlier reference field. This should be achievable for short pulses at S band, but phase noise due to target motion may prevent this at C band, while at X band even the retrieval of ΔN over shorter periods may at times be impossible.
A numerical approach for nonsmooth ordinary differential equations
Authors: Erfanian Hamid Reza , Skandari MH Noori , Kamyad AV 
Published: September 2012

In this paper, the authors proposed an approach for solving nonsmooth continuous and discontinuous ordinary differential equations which is based on a generalization of the Taylor expansion. First is considered a generalized derivative for nonsmooth functions with a single variable which is proposed by Kamyad et al. Then, the generalized Taylor expansion of nonsmooth functions is introduced and used to state an approach. Finally, some numerical examples of nonsmooth ordinary differential equations are solved.
A Retrospective Comparison of First Metatarsophalangeal Joint Arthrodesis Using a Locked Plate and Compression Screw Technique
Authors: Hyer Christopher F. , Scott Ryan T. , Swiatek Michael 
Published: September 2012

Introduction: The historic primary treatment for end-stage first metatarsophalangeal (MTP) joint arthritis has been fusion. Traditionally, this has been accomplished by metaphyseal apposition between the proximal phalanx and metatarsal using crossed compression screws. Recently, locked plates have been introduced that help support this technique by offering added stability. We present our experience with 45 first MTP fusions in 45 feet using a locked plate and compression screw. Methods: A retrospective review of 45 patients who met the study criteria with a hallux rigidus correction using a locked plate with a compression screw was performed. Charts and radiographs were independently reviewed by 2 authors not involved in the index procedures to assess outcomes. Results: There was a 93% fusion rate (42/45 feet) with 3 nonunions. The mean time to union was 51.1 days (range = 29-116 days, SD = 24.4). The mean patient age was 58.1 years (range = 29-80 years, SD = 10.1). The mean time to partial weight bearing was 7.0 days (range = 0-53 days, SD = 13.8) and the mean time to full weight bearing was 62.0 days (range = 29-57 days, SD = 17.9). Discussion: We report on the results of first MTP fusion using a compression screw and locked plate technique. The results show that this is an effective means of creating a first MTP joint arthrodesis. Levels of Evidence: Therapeutic, Level IV, Case series
Absence of LTB4/BLT1 axis facilitates generation of mouse GM-CSF–induced long-lasting antitumor immunologic memory by enhancing innate and adaptive immune systems
Authors: Yokota Yosuke , Inoue Hiroyuki , Matsumura Yumiko , Nabeta Haruka , Narusawa Megumi , Watanabe Ayumi , Sakamoto Chika , Hijikata Yasuki , Iga-Murahashi Mutsunori , Takayama Koichi , Sasaki Fumiyuki , Nakanishi Yoichi , Yokomizo Takehiko , Tani Kenzaburo 
Published: August 2012

Abstract
BLT1 is a high-affinity receptor for leukotriene B4 (LTB4) that is a potent lipid chemoattractant for myeloid leukocytes. The role of LTB4/BLT1 axis in tumor immunology, including cytokine-based tumor vaccine, however, remains unknown. We here demonstrated that BLT1-deficient mice rejected subcutaneous tumor challenge of GM-CSF gene-transduced WEHI3B (WGM) leukemia cells (KO/WGM) and elicited robust antitumor responses against second tumor challenge with WEHI3B cells. During GM-CSF–induced tumor regression, the defective LTB4/BLT1 signaling significantly reduced tumor-infiltrating myeloid-derived suppressor cells, increased the maturation status of dendritic cells in tumor tissues, enhanced their CD4+ T-cell stimulation capacity and migration rate of dendritic cells that had phagocytosed tumor-associated antigens into tumor-draining lymph nodes, suggesting a positive impact on GM-CSF–sensitized innate immunity. Furthermore, KO/WGM mice displayed activated adaptive immunity by attenuating regulatory CD4+ T subsets and increasing numbers of Th17 and memory CD44hiCD4+ T subsets, both of which elicited superior antitumor effects as evidenced by adoptive cell transfer. In vivo depletion assays also revealed that CD4+ T cells were the main effectors of the persistent antitumor immunity. Our data collectively underscore a negative role of LTB4/BLT1 signaling in effective generation and maintenance of GM-CSF–induced antitumor memory CD4+ T cells.