bluuebunny/crossref_metadata_2025_split huggingface dataset:
The Power of Negative Thinking: Which Cells Limit Tumor Immunity?
Authors: Tang Siuwah , Lotze Michael T. 
Published: August 2012

Abstract
Why human tumors grow infiltrated by specific antitumor T cells has been a mystery attributed to negative factors released directly by the tumor or indirectly through immune intermediaries. The frequency and phenotype of myeloid-derived suppressor cells in the peripheral blood of melanoma patients and healthy donors are surprisingly similar. Clin Cancer Res; 18(19); 5157–9. ©2012 AACR.
Sorafenib-Induced Hepatocellular Carcinoma Cell Death Depends on Reactive Oxygen Species ProductionIn VitroandIn Vivo
Authors: Coriat Romain , Nicco Carole , Chéreau Christiane , Mir Olivier , Alexandre Jérôme , Ropert Stanislas , Weill Bernard , Chaussade Stanislas , Goldwasser François , Batteux Frédéric 
Published: August 2012

AbstractSorafenib is presently the only effective therapy in advanced hepatocellular carcinoma (HCC). Because most anticancer drugs act, at least in part, through the generation of reactive oxygen species, we investigated whether sorafenib can induce an oxidative stress. The effects of sorafenib on intracellular ROS production and cell death were assessed in vitro in human (HepG2) and murine (Hepa 1.6) HCC cell lines and human endothelial cells (HUVEC) as controls. In addition, 26 sera from HCC patients treated by sorafenib were analyzed for serum levels of advanced oxidation protein products (AOPP). Sorafenib significantly and dose-dependently enhanced in vitro ROS production by HCC cells. The SOD mimic MnTBAP decreased sorafenib-induced lysis of HepG2 cells by 20% and of Hepa 1.6 cells by 75% compared with HCC cells treated with 5 mg/L sorafenib alone. MnTBAP significantly enhanced by 25% tumor growth in mice treated by sorafenib. On the other hand, serum levels of AOPP were higher in HCC patients treated by sorafenib than in sera collected before treatment (P &lt; 0.001). An increase in serum AOPP concentration ≥0.2 μmol/L chloramine T equivalent after 15 days of treatment is a predictive factor for sorafenib response with higher progression free survival (P &lt; 0.05) and overall survival rates (P &lt; 0.05). As a conclusion, sorafenib dose-dependently induces the generation of ROS in tumor cells in vitro and in vivo. The sera of Sorafenib-treated HCC patients contain increased AOPP levels that are correlated with the clinical effectiveness of sorafenib and can be used as a marker of effectiveness of the drug. Mol Cancer Ther; 11(10); 2284–93. ©2012 AACR.
PI3K Inhibition Impairs BRCA1/2 Expression and Sensitizes BRCA-Proficient Triple-Negative Breast Cancer to PARP Inhibition
Authors: Ibrahim Yasir H. , García-García Celina , Serra Violeta , He Lei , Torres-Lockhart Kristine , Prat Aleix , Anton Pilar , Cozar Patricia , Guzmán Marta , Grueso Judit , Rodríguez Olga , Calvo Maria Teresa , Aura Claudia , Díez Orland , Rubio Isabel T. , Pérez José , Rodón Jordi , Cortés Javier , Ellisen Leif W. , Scaltriti Maurizio , Baselga José 
Published: August 2012

Abstract
PARP inhibitors are active in tumors with defects in DNA homologous recombination (HR) due to BRCA1/2 mutations. The phosphoinositide 3-kinase (PI3K) signaling pathway preserves HR steady state. We hypothesized that in BRCA-proficient triple-negative breast cancer (TNBC), PI3K inhibition would result in HR impairment and subsequent sensitization to PARP inhibitors. We show in TNBC cells that PI3K inhibition leads to DNA damage, downregulation of BRCA1/2, gain in poly-ADP-ribosylation, and subsequent sensitization to PARP inhibition. In TNBC patient–derived primary tumor xenografts, dual PI3K and PARP inhibition with BKM120 and olaparib reduced the growth of tumors displaying BRCA1/2 downregulation following PI3K inhibition. PI3K-mediated BRCA downregulation was accompanied by extracellular signal–regulated kinase (ERK) phosphorylation. Overexpression of an active form of MEK1 resulted in ERK activation and downregulation of BRCA1, whereas the MEK inhibitor AZD6244 increased BRCA1/2 expression and reversed the effects of MEK1. We subsequently identified that the ETS1 transcription factor was involved in the ERK-dependent BRCA1/2 downregulation and that knockdown of ETS1 led to increased BRCA1/2 expression, limiting the sensitivity to combined BKM120 and olaparib in 3-dimensional culture.
Significance: Treatment options are limited for patients with TNBCs. PARP inhibitors have clinical activity restricted to a small subgroup of patients with BRCA mutations. Here, we show that PI3K blockade results in HR impairment and sensitization to PARP inhibition in TNBCs without BRCA mutations, providing a rationale to combine PI3K and PARP inhibitors in this indication. Our findings could greatly expand the number of patients with breast cancer that would benefit from therapy with PARP inhibitors. On the basis of our findings, a clinical trial with BKM120 and olaparib is being initiated in patients with TNBCs. Cancer Discov; 2(11); 1036–47. ©2012 AACR.
Read the Commentary on this article by Rehman et al., p. 982.
This article is highlighted in the In This Issue feature, p. 961
Modeling Supravalvular Aortic Stenosis Syndrome With Human Induced Pluripotent Stem Cells
Authors: Ge Xin , Ren Yongming , Bartulos Oscar , Lee Min Young , Yue Zhichao , Kim Kun-Yong , Li Wei , Amos Peter J. , Bozkulak Esra Cagavi , Iyer Amulya , Zheng Wei , Zhao Hongyu , Martin Kathleen A. , Kotton Darrell N. , Tellides George , Park In-Hyun , Yue Lixia , Qyang Yibing 
Published: August 2012

Background—

Supravalvular aortic stenosis (SVAS) is caused by mutations in the elastin (
ELN
) gene and is characterized by abnormal proliferation of vascular smooth muscle cells (SMCs) that can lead to narrowing or blockage of the ascending aorta and other arterial vessels. Having patient-specific SMCs available may facilitate the study of disease mechanisms and development of novel therapeutic interventions.

Methods and Results—

Here, we report the development of a human induced pluripotent stem cell (iPSC) line from a patient with SVAS caused by the premature termination in exon 10 of the
ELN
gene resulting from an exon 9 four-nucleotide insertion. We showed that SVAS iPSC-derived SMCs (iPSC-SMCs) had significantly fewer organized networks of smooth muscle α-actin filament bundles, a hallmark of mature contractile SMCs, compared with control iPSC-SMCs. The addition of elastin recombinant protein or enhancement of small GTPase RhoA signaling was able to rescue the formation of smooth muscle α-actin filament bundles in SVAS iPSC-SMCs. Cell counts and BrdU analysis revealed a significantly higher proliferation rate in SVAS iPSC-SMCs than control iPSC-SMCs. Furthermore, SVAS iPSC-SMCs migrated at a markedly higher rate to the chemotactic agent platelet-derived growth factor compared with the control iPSC-SMCs. We also provided evidence that elevated activity of extracellular signal-regulated kinase 1/2 is required for hyperproliferation of SVAS iPSC-SMCs. The phenotype was confirmed in iPSC-SMCs generated from a patient with deletion of elastin owing to Williams-Beuren syndrome.

Conclusions—
SVAS iPSC-SMCs recapitulate key pathological features of patients with SVAS and may provide a promising strategy to study disease mechanisms and to develop novel therapies.
Seedability of Winter Orographic Clouds
Authors: Hill Geoffrey E. 
Published: August 2012

Abstract
This article is a review of work on the subject of seedability of winter orographic clouds for increasing precipitation. Various aspects of seedability are examined in the review, including definitions, distribution of supercooled liquid water, related meteorological factors, relationship of supercooled liquid water to storm stage, factors governing seedability, and the use of seeding criteria.
Of particular interest is the conclusion that seedability is greatest when supercooled liquid water concentrations are large and at the same time precipitation rates are small. Such a combination of conditions is favored if the cloud-top temperature is warmer than a limiting value and as the cross-barrier wind speed at mountaintop levels increases.
It is also suggested that cloud seeding is best initiated in accordance with direct measurements of supercooled liquid water, precipitation, and cross-barrier wind speed. However, in forecasting these conditions or in continuation of seeding previously initiated, the cloud-top temperature and cross-barrier wind speed are the most useful quantities.
Leeside Boundary Layer Confluence and Afternoon Thunderstorms over Mayaguez, Puerto Rico
Authors: Jury Mark R. , Chiao Sen 
Published: August 2012

AbstractThe midsummer boundary layer (BL) circulation and afternoon thunderstorm convection on the lee side of Puerto Rico is studied using observations and high-resolution models. Satellite infrared data help to identify cases on 5 and 14 June 2010 when midday surface temperatures show a 2°C gradient between land and sea and afternoon cloud-top temperatures <−60°C. Acoustic sounder profiles are analyzed for climatology, wind shear, turbulence, and diurnal cycles in the 40–300-m layer. Weather Research and Forecasting (WRF) model simulations indicate that sea-breeze flow is entrained into convective cells near Mayaguez, Puerto Rico. The simulated BL wind shear is too weak (0.5 × 10−2 s−1) in comparison with the acoustic sounder (2 × 10−2 s−1). Model 900-hPa winds are southeasterly and spread simulated convection too far north in comparison with radar. The pattern of near-surface winds in the island wake triggers afternoon thunderstorms near Mayaguez. A feature of the confluent circulation around Puerto Rico is opposing shear zones on the leeward corners of the island and a sea breeze of 5 m s−1 over the west coast during midday.
Contributions of Lake-Effect Periods to the Cool-Season Hydroclimate of the Great Salt Lake Basin
Authors: Yeager Kristen N. , Steenburgh W. James , Alcott Trevor I. 
Published: August 2012

AbstractAlthough smaller lakes are known to produce lake-effect precipitation, their influence on the precipitation climatology of lake-effect regions remains poorly documented. This study examines the contribution of lake-effect periods (LEPs) to the 1998–2009 cool-season (16 September–15 May) hydroclimate in the region surrounding the Great Salt Lake, a meso-β-scale hypersaline lake in northern Utah. LEPs are identified subjectively from radar imagery, with precipitation (snow water equivalent) quantified through the disaggregation of daily (i.e., 24 h) Cooperative Observer Program (COOP) and Snowpack Telemetry (SNOTEL) observations using radar-derived precipitation estimates. An evaluation at valley and mountain stations with reliable hourly precipitation gauge observations demonstrates that the disaggregation method works well for estimating precipitation during LEPs. During the study period, LEPs account for up to 8.4% of the total cool-season precipitation in the Great Salt Lake basin, with the largest contribution to the south and east of the Great Salt Lake. The mean monthly distribution of LEP precipitation is bimodal, with a primary maximum from October to November and a secondary maximum from March to April. LEP precipitation is highly variable between cool seasons and is strongly influenced by a small number of intense events. For example, at a lowland (mountain) station in the lake-effect-precipitation belt southeast of the Great Salt Lake, just 12 (13) events produce 50% of the LEP precipitation. Although these results suggest that LEPs contribute modestly to the hydroclimate of the Great Salt Lake basin, infrequent but intense events have a profound impact during some cool seasons.
Chronic Bartonellosis in Cats
Authors: Stützer Bianca , Hartmann Katrin 
Published: August 2012

Practical relevance: Bartonellae are small, vector-transmitted Gram-negative intracellular bacteria that are well adapted to one or more mammalian reservoir hosts. Cats are the natural reservoir for Bartonella henselae, which is a (re-)emerging bacterial pathogen. It can cause cat scratch disease in humans and, in immunocompromised people, may lead to severe systemic diseases, such as bacillary angiomatosis. Cats bacteraemic with B henselae constitute the main reservoir from which humans become infected. Most cats naturally infected with B henselae show no clinical signs themselves, but other Bartonella species for which cats are accidental hosts appear to have more pathogenicity. Global importance: Several studies have reported a prevalence of previous or current Bartonella species infection in cats of up to 36%. B henselae is common in cats worldwide, and bacteraemia can be documented by blood culture in about a quarter of healthy cats. The distribution of B henselae to various parts of the world has largely occurred through humans migrating with their pet cats. The pathogen is mainly transmitted from cat to cat by fleas, and the majority of infected cats derive from areas with high flea exposure. No significant difference in B henselae prevalence has been determined between male and female cats. In studies on both naturally and experimentally infected cats, chronic bacteraemia has mainly been found in cats under the age of 2 years, while those over 2 years of age are rarely chronically bacteraemic. Evidence base: This article reviews published studies and case reports on bartonellosis to explore the clinical significance of the infection in cats and its impact on humans. The article also discusses possible treatment options for cats and means of minimising the zoonotic potential.
Feline Physiotherapy and Rehabilitation
Authors: Sharp Brian 
Published: August 2012

Practical relevance: Physiotherapy is highly valued within human medicine and relatively well established for canine patients. Despite a popular misconception that feline patients will not cooperate with such treatment, physiotherapy is now increasingly being performed with cats. With cat ownership increasing in many countries, and an emergence of specialist physiotherapy practitioners, there is demand for effective postoperative and post-injury rehabilitation for any cat with compromised physical function due to injury, surgery or disease. Clinical challenges: While physiotherapy and rehabilitation are potentially beneficial for cats, due to their independent nature feline patients certainly present a greater challenge in the pursuit of effective therapy than their canine counterparts. Audience: This two-part review article is directed at the primary care veterinary team. The benefits of physiotherapy and the various treatment modalities available to the qualified veterinary physiotherapist, as well as the non-specialist veterinarian and veterinary nurse or technician, are examined in this first part. Evidence base: The benefits of human physiotherapeutic intervention are well documented, and there is good evidence for the effectiveness of most treatment modalities. Animal studies are still in their infancy, although some preliminary studies in dogs have shown good results.
Feline Physiotherapy and Rehabilitation
Authors: Sharp Brian 
Published: August 2012

Practical relevance: There is an increasing demand for effective postoperative and post-injury rehabilitation for any cat with compromised physical function due to injury, surgery or disease. Clinical challenges: The design of a suitable rehabilitation programme that will assist the recovery process, as well as ensure the return of neuromusculoskeletal control to the highest levels of function possible, requires a good understanding of feline behaviour, accurate assessment of the cat’s condition and the correct implementation of a range of physiotherapeutic modalities. Audience: This two-part review article is directed at the primary care veterinary team. The clinical application of a variety of physiotherapeutic modalities in the rehabilitation of cats is examined in this second part. Evidence base: Although evidence supporting the benefits of physiotherapy and rehabilitation with cats is sparse, many techniques, treatments and rehabilitation regimens successfully used on human patients are being readily adapted for animal use. Treatment recommendations described in this review are primarily based on the author’s experience, and that of colleagues, except where specific reference is made to published evidence.
Examining the Relationship Between Work/Life Conflict and Life Satisfaction in Executives
Authors: McMillan Heather S. , Morris Michael Lane 
Published: August 2012

The Problem Determining “what” and “how” people are satisfied personally and with work has become an ongoing stream of research for both academics and practitioners. Yet research has contributed to confusing the issue and has not been able to provide any distinct answers to this problem. The Solution This study goes beyond current research by examining how problem-focused coping resources are used to ameliorate the negative relationship between work/life conflict and life satisfaction. Based on a sample of 491 executives, structural equation modeling (SEM) was used to test the mediational ability of problem-solving coping. Problem-solving coping was found to partially mediate the negative relationship between work/life conflict and life satisfaction. The Stakeholders Human resource development (HRD) scholars and practitioners interested in researching and reducing work/life conflict. A discussion of the importance of HRD interventions targeting problem-focused coping skills is included.
Readiness, Trust, and Adherence
Authors: Grimes Richard M. , Grimes Deanna E. 
Published: August 2012

Objective: This paper examines the scientific bases for the recommendations on readiness, trust, and adherence that were contained in 5 HIV treatment guidelines. Methods: The authors reviewed the treatment guidelines of 5 internationally recognized expert panels, and 5 review articles on readiness, trust, and adherence to determine the evidence for the guidelines' recommendations. These review articles were assessed to determine whether they contained: 1) a definition of the concept, 2) a measure that predicted outcomes, or 3) evidence that a replicable intervention altered outcomes. Results: There is no good definition, measure, or evidence that readiness predicts adherence. There were no interventions that improved readiness in a clinically useful way. There was no good definition or measure of trust, nor was there evidence that patient trust predicts adherence or that interventions improve trust. It is not clear whether trust is a cause or an effect of clinical outcomes. There is agreement that adherence is defined as taking medications as prescribed. Six measures of adherence were found, and several studies showed that they correlated poorly when applied to the same sample of patients. Adherence interventions have had some success but are poorly described and idiosyncratic such that it is difficult to replicate them in other settings. Conclusion: Research on readiness and trust are unlikely to yield useful results. Systematic, long term research on clinician-based adherence interventions must be done. A life-long process such as adherence to antiretroviral treatment is unlikely to be understood without having a long-term study of a cohort of patients taking these medications.
The angiogenesis inhibitor vasostatin is regulated by neutrophil elastase–dependent cleavage of calreticulin in AML patients
Authors: Mans Sarah , Banz Yara , Mueller Beatrice U. , Pabst Thomas 
Published: August 2012

AbstractThe calcium-binding protein calreticulin (CRT) regulates protein folding in the endoplasmic reticulum (ER) and is induced in acute myeloid leukemia (AML) cells with activation of the unfolded protein response. Intracellular CRT translocation to the cell surface induces immunogenic cell death, suggesting a role in tumor suppression. In this study, we investigated CRT regulation in the serum of patients with AML. We found that CRT is not only exposed by exocytosis on the outer cell membrane after treatment with anthracyclin but also ultimately released to the serum in vitro and in AML patients during induction therapy. Leukemic cells of 113 AML patients showed increased levels of cell-surface CRT (P < .0001) and N-terminus serum CRT (P < .0001) compared with normal myeloid cells. Neutrophil elastase was identified to cleave an N-terminus CRT peptide, which was characterized as vasostatin and blocked ATRA-triggered differentiation. Levels of serum vasostatin in patients with AML inversely correlated with bone marrow vascularization, suggesting a role in antiangiogenesis. Finally, patients with increased vasostatin levels had longer relapse-free survival (P = .04) and specifically benefited from autologous transplantation (P = .006). Our data indicate that vasostatin is released from cell-surface CRT and impairs differentiation of myeloid cells and vascularization of the bone marrow microenvironment.
Association of Fcγ receptor IIIa genotype with the rate of HIV infection after gp120 vaccination
Authors: Forthal Donald N. , Gabriel Erin E. , Wang Angela , Landucci Gary , Phan Tran B. 
Published: August 2012

AbstractWe determined whether polymorphisms in Fcγ receptor (FcγR) IIa or FcγRIIIa genes were associated with outcomes in Vax004, a trial testing recombinant gp120 vaccination in preventing sexually acquired HIV infection. Male subjects (n = 1725), including infected and uninfected vaccinees and placebo recipients, were genotyped. We observed no association between FcγRIIa genotype and infection rate in vaccinees or placebo recipients. However, FcγRIIIa genotype was associated with infection rate among vaccinees (P = .035). Exploratory analyses revealed that vaccinees homozygous for the FcγRIIIa V allele in the lowest behavioral risk group had a greater rate of infection than low risk vaccinees with at least 1 F allele (hazard ratio [HR] = 3.52; P = .002). No such association was seen among vaccinees with high-risk behaviors or among placebo recipients in either risk stratum. Vaccinated low-risk VV subjects had a greater infection rate than low-risk VV placebo recipients (HR = 4.51; P = .17) or low-risk placebo recipients with any genotype (HR = 4.72; P = .002). Moreover, low-risk VV vaccinees had infection rates similar to individuals with high behavioral risk, irrespective of genotype. Our results generate the hypothesis that recombinant gp120 vaccine may have increased the likelihood of acquiring HIV infection in individuals with the VV genotype (present in ∼ 10% of the population) at low behavioral risk of infection.