bluuebunny/crossref_metadata_2025_split huggingface dataset:
Modulation of Ribosomal Frameshifting Frequency and Its Effect on the Replication of Rous Sarcoma Virus
Authors: Nikolić Emily I. C. , King Louise M. , Vidakovic Marijana , Irigoyen Nerea , Brierley Ian 
Published: August 2012

ABSTRACT

Programmed −1 ribosomal frameshifting is widely used in the expression of RNA virus replicases and represents a potential target for antiviral intervention. There is interest in determining the extent to which frameshifting efficiency can be modulated before virus replication is compromised, and we have addressed this question using the alpharetrovirus Rous sarcoma virus (RSV) as a model system. In RSV, frameshifting is essential in the production of the Gag-Pol polyprotein from the overlapping
gag
and
pol
coding sequences. The frameshift signal is composed of two elements, a heptanucleotide slippery sequence and, just downstream, a stimulatory RNA structure that has been proposed to be an RNA pseudoknot. Point mutations were introduced into the frameshift signal of an infectious RSV clone, and virus replication was monitored following transfection and subsequent infection of susceptible cells. The introduced mutations were designed to generate a range of frameshifting efficiencies, yet with minimal impact on encoded amino acids. Our results reveal that point mutations leading to a 3-fold decrease in frameshifting efficiency noticeably reduce virus replication and that further reduction is severely inhibitory. In contrast, a 3-fold stimulation of frameshifting is well tolerated. These observations suggest that small-molecule inhibitors of frameshifting are likely to have potential as agents for antiviral intervention. During the course of this work, we were able to confirm, for the first time
in vivo
, that the RSV stimulatory RNA is indeed an RNA pseudoknot but that the pseudoknot
per se
is not absolutely required for virus viability.
Intensity and correlates of multidimensional problems in HIV patients receiving integrated palliative care in sub-Saharan Africa
Authors: Harding Richard , Selman Lucy , Agupio Godfrey , Dinat Natalya , Downing Julia , Gao Wei , Gwyther Liz , Mashao Thandi , Mmoledi Keletso , Moll Anthony , Mpanga Sebuyira Lydia , Ikin Barbara , Higginson Irene J 
Published: August 2012

BackgroundDespite global clinical guidance that HIV patients should have multidimensional care integrated into their management, there has been very limited data to guide practice since the advent of treatment. This study aimed to determine the three-day period intensity of problems (physical, psychological, social and spiritual) among HIV patients receiving integrated palliative care in sub-Saharan Africa, and to identify associations with problem severity.MethodsA sample of 230 consecutive adult patients attending five sites in South Africa and Uganda gave self-report data using a well-validated outcome scale. Multivariable regression models determine the association of patient characteristics with intensity of three scale factors.ResultsThe most burdensome problems were (in descending order) pain, worry, symptoms, and adequate information to plan for the future. Interestingly, CD4 counts were available on file for only 59.1% of patients. In multivariate analyses, being cared for at home was associated with poorer physical/psychological factor score (B=−0.192, 95% CI −2.566 -0.464, p=0.005), while being on ART was associated with better factor score (B=0.187, 95% CI=0.424 23.80, p=0.005). For the existential/spiritual factor, being cared for at home was associated with a worse factor score (B=−0.306, 95% CI −2.776 −1.128, p<0.001). ART use was not associated with either the interpersonal or spiritual/existential factors.DiscussionThese self-report data reveal a high burden of both physical and psychological problems, and that communication from professionals is insufficient. Patients receiving home care may require additional support to enhance wellbeing, and treatment may not affect interpersonal and existential/spiritual wellbeing.
Lurbinectedin (PM01183), a New DNA Minor Groove Binder, Inhibits Growth of Orthotopic Primary Graft of Cisplatin-Resistant Epithelial Ovarian Cancer
Authors: Vidal August , Muñoz Clara , Guillén María-José , Moretó Jemina , Puertas Sara , Martínez-Iniesta María , Figueras Agnés , Padullés Laura , García-Rodriguez Francisco J. , Berdiel-Acer Mireia , Pujana Miguel A. , Salazar Ramón , Gil-Martin Marta , Martí Lola , Ponce Jordi , Molleví David G. , Capella Gabriel , Condom Enric , Viñals Francesc , Huertas Dori , Cuevas Carmen , Esteller Manel , Avilés Pablo , Villanueva Alberto 
Published: August 2012

Abstract
Purpose: Epithelial ovarian cancer (EOC) is the fifth leading cause of death in women diagnosed with gynecologic malignancies. The low survival rate is because of its advanced-stage diagnosis and either intrinsic or acquired resistance to standard platinum-based chemotherapy. So, the development of effective innovative therapeutic strategies to overcome cisplatin resistance remains a high priority.
Experimental Design: To investigate new treatments in in vivo models reproducing EOCs tumor growth, we generated a preclinical model of ovarian cancer after orthotopic implantation of a primary serous tumor in nude mice. Further, matched model of acquired cisplatin-resistant tumor version was successfully derived in mice. Effectiveness of lurbinectedin (PM01183) treatment, a novel marine-derived DNA minor groove covalent binder, was assessed in both preclinical models as a single and a combined-cisplatin agent.
Results: Orthotopically perpetuated tumor grafts mimic the histopathological characteristics of primary patients' tumors and they also recapitulate in mice characteristic features of tumor response to cisplatin treatments. We showed that single lurbinectedin or cisplatin-combined therapies were effective in treating cisplatin-sensitive and cisplatin-resistant preclinical ovarian tumor models. Furthermore, the strongest in vivo synergistic effect was observed for combined treatments, especially in cisplatin-resistant tumors. Lurbinectedin tumor growth inhibition was associated with reduced proliferation, increased rate of aberrant mitosis, and subsequent induced apoptosis.
Conclusions: Taken together, preclinical orthotopic ovarian tumor grafts are useful tools for drug development, providing hard evidence that lurbinectedin might be a useful therapy in the treatment of EOC by overcoming cisplatin resistance. Clin Cancer Res; 18(19); 5399–411. ©2012 AACR.
Antitumor Activity of Triolimus: A Novel Multidrug-Loaded Micelle Containing Paclitaxel, Rapamycin, and 17-AAG
Authors: Hasenstein Jason R. , Shin Ho-Chul , Kasmerchak Kelsey , Buehler Darya , Kwon Glen S. , Kozak Kevin R. 
Published: August 2012

AbstractTriolimus is a first-in-class, multidrug-loaded micelle containing paclitaxel, rapamycin, and 17-AAG. In this study, we examine the antitumor mechanisms of action, efficacy, and toxicity of Triolimus in vitro and in vivo. In vitro cytotoxicity testing of Triolimus was conducted using two aggressive adenocarcinomas including the lung cancer cell line, A549, and breast cancer cell line, MDA-MB-231. The three-drug combination of paclitaxel, rapamycin, and 17-AAG displayed potent cytotoxic synergy in both A549 and MDA-MB-231 cell lines. Mechanistically, the drug combination inhibited both the Ras/Raf/mitogen-activated protein kinase and PI3K/Akt/mTOR pathways. Triolimus was advanced into tumor xenograft models for assessment of efficacy, toxicity, and mechanisms of action. In vivo, a three-infusion schedule of Triolimus inhibited A549 and MDA-MB-231 tumor growth far more potently than paclitaxel-containing micelles and effected tumor cures in MDA-MB-231 tumor-bearing animals. Tumor growth delays resulted from a doubling in tumor cell apoptosis and a 50% reduction in tumor cell proliferation compared with paclitaxel-containing micelles. Enhanced antitumor efficacy was achieved without clinically significant increases in acute toxicity. Thus, Triolimus displays potent synergistic activity in vitro and antitumor activity in vivo with comparable toxicity to paclitaxel. These observations provide strong support for further development of Triolimus and an important proof of concept for safe, effective nanoparticle-based delivery of three complementary anticancer agents. Mol Cancer Ther; 11(10); 2233–42. ©2012 AACR.
In Situ Vaccination with CD204 Gene-Silenced Dendritic Cell, not Unmodified Dendritic Cell, Enhances Radiation Therapy of Prostate Cancer
Authors: Guo Chunqing , Yi Huanfa , Yu Xiaofei , Zuo Daming , Qian Jie , Yang Gary , Foster Barbara A. , Subjeck John R. , Sun Xiaolei , Mikkelsen Ross B. , Fisher Paul B. , Wang Xiang-Yang 
Published: August 2012

Abstract
Given the complexity of prostate cancer progression and metastasis, multimodalities that target different aspects of tumor biology, for example, radiotherapy in conjunction with immunotherapy, may provide the best opportunities for promoting clinical benefits in patients with high-risk localized prostate cancer. Here, we show that intratumoral administration of unmodified dendritic cells (DC) failed to synergize with fractionated radiotherapy. However, ionizing radiation combined with in situ vaccination with DCs, in which the immunosuppressive scavenger receptor A (SRA/CD204) has been downregulated by lentivirus-mediated gene silencing, profoundly suppressed the growth of two mouse prostate cancers (e.g., RM1 and TRAMP-C2) and prolonged the lifespan of tumor-bearing animals. Treatment of subcutaneous tumors with this novel combinatorial radioimmunotherapeutic regimen resulted in a significant reduction in distant experimental metastases. SRA/CD204-silenced DCs were highly efficient in generating antigen or tumor-specific T cells with increased effector functions (e.g., cytokine production and tumoricidal activity). SRA/CD204 silencing-enhanced tumor cell death was associated with elevated IFN-γ levels in tumor tissue and increased tumor-infiltrating CD8+ cells. IFN-γ neutralization or depletion of CD8+ cells abrogated the SRA/CD204 downregulation-promoted antitumor efficacy, indicating a critical role of IFN-γ–producing CD8+ T cells. Therefore, blocking SRA/CD204 activity significantly enhances the therapeutic potency of local radiotherapy combined with in situ DC vaccination by promoting a robust systemic antitumor immunity. Further studies are warranted to test this novel combinatorial approach for translating into improved clinical outcomes in patients with prostate cancer. Mol Cancer Ther; 11(11); 2331–41. ©2012 AACR.
Regulation of Inflammatory Breast Cancer Cell Invasion through Akt1/PKBα Phosphorylation of RhoC GTPase
Authors: Lehman Heather L. , Van Laere Steven J. , van Golen Cynthia M. , Vermeulen Peter B. , Dirix Luc Y. , van Golen Kenneth L. 
Published: August 2012

Abstract
With a 42% and 18% 5- and 10-year respective disease-free survival rate, inflammatory breast cancer (IBC) is arguably the deadliest form of breast cancer. IBC invades the dermal lymphatic vessels of the skin overlying the breast and as a consequence nearly all women have lymph node involvement and ∼1/3 have gross distant metastases at the time of diagnosis. One year after diagnosis ∼90% of patients have detectable metastases, making IBC a paradigm for lymphovascular invasion. Understanding the underlying mechanisms of the IBC metastatic phenotype is essential for new therapies. Work from our laboratory and others show distinct molecular differences between IBC and non-IBCs (nIBCs). Previously we showed that RhoC GTPase is a metastatic switch responsible for the invasive phenotype of IBC. In this study we integrate observations made in IBC patients with in vitro analysis. We show that the PI3K/Akt signaling pathway is crucial in IBC invasion. Key molecules involved in cytoskeletal control and cell motility are specifically upregulated in IBC patients compared with stage and cell-type-of-origin matched nIBCs patients. Distinctively, RhoC GTPase is a substrate for Akt1 and its phosphorylation is absolutely essential for IBC cell invasion. Further our data show that Akt3, not Akt1 has a role in IBC cell survival. Together our data show a unique and targetable pathway for IBC invasion and survival. Mol Cancer Res; 10(10); 1306–18. ©2012 AACR.
Energy Balance Modulates Mouse Skin Tumor Promotion through Altered IGF-1R and EGFR Crosstalk
Authors: Moore Tricia , Beltran Linda , Carbajal Steve , Hursting Stephen D. , DiGiovanni John 
Published: August 2012

Abstract
Obesity, an established risk factor for epithelial cancers, remains prevalent in the United States and many other countries. In contrast to positive energy balance states (overweight, obesity), calorie restriction (CR) has been shown to act as a universal inhibitor of tumorigenesis in multiple animal models of human cancer. Unfortunately, the mechanisms underlying the enhancing effects of obesity or the inhibitory effects of CR on cancer etiology remain elusive. Here, we evaluated the impact of dietary energy balance manipulation on epithelial carcinogenesis and identified several potential mechanisms that may account for the differential effects of obesity and CR on cancer. Obesity enhanced tumor promotion during epithelial carcinogenesis, in part, due to altered insulin-like growth factor-1 receptor (IGF-1R)/EGF receptor (EGFR) crosstalk and downstream signaling to effectors such as Akt/mTOR. Obesity-induced changes in cellular signaling subsequently led to altered levels of cell-cycle proteins that favored enhanced epidermal proliferation during tumor promotion. In contrast, CR reduced susceptibility to tumor promotion, attenuated IGF-1R/EGFR crosstalk and downstream signaling, and altered levels of cell-cycle proteins that favored reduced epidermal proliferation during tumor promotion. Collectively, these findings suggest potential targets for the prevention of epithelial cancers, as well as for reversal of obesity-mediated cancer development and progression. Cancer Prev Res; 5(10); 1236–46. ©2012 AACR.
Dose–Response Relationship of Robot-Assisted Stroke Motor Rehabilitation
Authors: Hsieh Yu-wei , Wu Ching-yi , Lin Keh-chung , Yao Grace , Wu Kuen-yuh , Chang Ya-ju 
Published: August 2012

Background and Purpose—
The increasing availability of robot-assisted therapy (RT), which provides quantifiable, reproducible, interactive, and intensive practice, holds promise for stroke rehabilitation, but data on its dose–response relation are scanty. This study used 2 different intensities of RT to examine the treatment effects of RT and the effect on outcomes of the severity of initial motor deficits.

Methods—
Fifty-four patients with stroke were randomized to a 4-week intervention of higher-intensity RT, lower-intensity RT, or control treatment. The primary outcome, the Fugl-Meyer Assessment, was administered at baseline, midterm, and posttreatment. Secondary outcomes included the Medical Research Council scale, the Motor Activity Log, and the physical domains of the Stroke Impact Scale.

Results—

The higher-intensity RT group showed significantly greater improvements on the Fugl-Meyer Assessment than the lower-intensity RT and control treatment groups at midterm (
P
=0.003 and
P
=0.02) and at posttreatment (
P
=0.04 and
P
=0.02). Within-group gains on the secondary outcomes were significant, but the differences among the 3 groups did not reach significance. Recovery rates of the higher-intensity RT group were higher than those of the lower-intensity RT group, particularly on the Fugl-Meyer Assessment. Scatterplots with curve fitting showed that patients with moderate motor deficits gained more improvements than those with severe or mild deficits after the higher-intensity RT.

Conclusions—
This study demonstrated the higher treatment intensity provided by RT was associated with better motor outcome for patients with stroke, which may shape further stroke rehabilitation.

Clinical Trial Registration—

URL:
http://clinicaltrials.gov
. Unique identifier: NCT00917605.
Trends in U.S. Surface Humidity, 1930–2010
Authors: Brown Paula J. , DeGaetano Arthur T. 
Published: August 2012

AbstractU.S. hourly surface observations are examined at 145 stations to identify annual and seasonal changes in temperature, dewpoint, relative humidity, and specific humidity since 1930. Because of numerous systematic instrument changes that have occurred, a homogeneity assessment was performed on temperatures and dewpoints. Dewpoints contained higher breakpoint detection rates associated with instrumentation changes than did temperatures. Temperature trends were tempered by adjusting the data, whereas dewpoints were unaffected. The effects were the same whether the adjustments were based on statistically detected or fixed-year breakpoints. Average long-term trends (1930–2010) indicate that temperature has warmed but that little change has occurred in dewpoint and specific humidity. Warming is strongest in spring. There is evidence of inhomogeneity in the relative humidity record that primarily affects data from prior to 1950. Therefore, long-term decreases in relative humidity, which are strongest in winter, need to be viewed with caution. Trends since 1947 indicate that the warming of temperatures has coincided with increases in dewpoints and a moistening of specific humidity. This moistening is especially pronounced during the summer in the Midwest. For the nation, trends in relative humidity show little change for the period 1947–2010, during which these data are more homogeneous. Moistening has occurred throughout the central United States while other regions have experienced drying. Urban-related warming and drying trends are present in the data, but their effect is minimal. Regional changes in land use and moisture availability are likely influencing trends in atmospheric moisture.
Saturated Pseudoadiabats—A Noniterative Approximation
Authors: Bakhshaii Atoossa , Stull Roland 
Published: August 2012

AbstractTwo noniterative approximations are presented for saturated pseudoadiabats (also known as moist adiabats). One approximation determines which moist adiabat passes through a point of known pressure and temperature, such as through the lifting condensation level on a skew T or tephigram. The other approximation determines the air temperature at any pressure along a known moist adiabat, such as the final temperature of a rising cloudy air parcel. The method used to create these statistical regressions is a relatively new variant of genetic programming called gene-expression programming. The correlation coefficient between the resulting noniterative approximations and the iterated data such as plotted on thermodynamic diagrams is over 99.97%. The mean absolute error is 0.28°C, and the root mean square error is 0.44 within a thermodynamic domain bounded by −30° < θw ≤ 40°C, P > 20 kPa, and −60° ≤ T ≤ 40°C, where θw, P, and T are wet-bulb potential temperature, pressure, and air temperature.
Calculation of Air Temperatures above the Urban Canopy Layer from Measurements at a Rural Operational Weather Station
Authors: Bueno Bruno , Hidalgo Julia , Pigeon Grégoire , Norford Leslie , Masson Valery 
Published: August 2012

AbstractUrban canopy models (UCMs) are being used as urban-climate prediction tools for different applications including outdoor thermal comfort and building energy consumption. To take advantage of their low computational cost, UCMs are often forced offline without being coupled to mesoscale atmospheric simulations, which requires access to meteorological information above the urban canopy layer. This limits the use of UCMs by other scientific and professional communities, such as building engineers and urban planners, who are interested in urban-climate prediction but may not have access to mesoscale simulation results or experimental meteorological data. Furthermore, the conventional offline use of UCMs neglects the fact that the urban boundary layer can be affected by the surface and that the same forcing conditions may not be suitable for studying different urban scenarios. This paper presents a physically based and computationally efficient methodology to calculate forcing air temperatures for UCMs from meteorological data measured at operational weather stations. Operational weather stations are available for most cities in the world and are usually located in open areas outside the cities. The proposed methodology is satisfactorily evaluated against mesoscale atmospheric simulations and field data from Basel, Switzerland, and Toulouse, France.
Origin of the Intraseasonal Variability over the North Pacific in Boreal Summer*
Authors: Wang Lu , Li Tim , Zhou Tianjun , Rong Xinyao 
Published: August 2012

Abstract
The spatial structure and temporal evolution of the intraseasonal oscillation (ISO) in boreal summer over the midlatitude North Pacific Ocean are investigated, through the diagnosis of NCEP reanalysis data. It is found that the midlatitude ISO has an equivalent-barotropic structure, with maximum amplitude at 250 hPa. Initiated near 120°W, the ISO perturbation propagates westward at a phase speed of about 2.4 m s−1 and reaches a maximum amplitude at 150°W. A diagnosis of barotropic energy conversion shows that the ISO gains energy from the summer mean flow in the ISO activity region. A center-followed column-averaged vorticity budget analysis shows that the nonlinear eddy meridional vorticity transport plays a major role in the growth of the ISO perturbation. There is a two-way interaction between ISO flows and synoptic eddies. While a cyclonic (anticyclonic) ISO flow causes synoptic-scale eddies to tilt toward the northwest–southeast (northeast–southwest) direction, the tilted synoptic eddies then exert a positive feedback to reinforce the ISO cyclonic (anticyclonic) flow through eddy vorticity transport. The reanalysis data and numerical simulations show that the midlatitude ISO is primarily driven by local processes and the tropical forcing accounts for about 20% of total intraseasonal variability in midlatitudes. However, 20% might be an underestimate given that the tropical intraseasonal forcing is not fully included in the current observational analysis and modeling experiment.
A 39-Yr Survey of Cloud Changes from Land Stations Worldwide 1971–2009: Long-Term Trends, Relation to Aerosols, and Expansion of the Tropical Belt
Authors: Eastman Ryan , Warren Stephen G. 
Published: August 2012

Abstract
An archive of land-based, surface-observed cloud reports has been updated and now spans 39 years from 1971 through 2009. Cloud-type information at weather stations is available in individual reports or in long-term, seasonal, and monthly averages. A shift to a new data source and the automation of cloud reporting in some countries has reduced the number of available stations; however, this dataset still represents most of the global land area.
Global-average trends of cloud cover suggest a small decline in total cloud cover, on the order of 0.4% per decade. Declining clouds in middle latitudes at high and middle levels appear responsible for this trend. An analysis of zonal cloud cover changes suggests poleward shifts of the jet streams in both hemispheres. The observed displacement agrees with other studies.
Changes seen in cloud types associated with the Indian monsoon are consistent with previous work suggesting that increased pollution (black carbon) may be affecting monsoonal precipitation, causing drought in northern India. A similar analysis over northern China does not show an obvious aerosol connection.
Past reports claiming a shift from stratiform to cumuliform cloud types over Russia were apparently partially based on spurious data. When the faulty stations are removed, a trade-off of stratiform and cumuliform cloud cover is still observed, but muted, over much of northern Eurasia.