bluuebunny/crossref_metadata_2025 huggingface dataset:
Optimising the surveillance of Aedes aegypti in Brazil by selecting smaller representative areas within an endemic city
Authors: Leandro André de Souza , Pires‐Vieira Lara Helena , Lopes Renata Defante , Rivas Açucena Veleh , Amaral Caroline , Silva Isaac , Maciel‐de‐Freitas Rafael , Chiba de Castro Wagner A.
Published: March 2024

Objectives

Arboviruses, such as dengue (DENV), zika (ZIKV), and chikungunya (CHIKV), constitute a growing urban public health threat. Focusing on Aedes aegypti mosquitoes, their primary vectors, is crucial for mitigation. While traditional immature‐stage mosquito surveillance has limitations, capturing adult mosquitoes through traps yields more accurate data on disease transmission. However, deploying traps presents logistical and financial challenges, demonstrating effective temporal predictions but lacking spatial accuracy. Our goal is to identify smaller representative areas within cities to enhance the early warning system for DENV outbreaks.

Methods

We created Sentinel Geographic Units (SGUs), smaller areas of 1 km2 within each stratum, larger areas, with the aim of aligning the Trap Positivity Index (TPI) and Adult Density Index (ADI) with their respective strata. We conducted a two‐step evaluation of SGUs. First, we examined the equivalence of TPI and ADI between SGUs and strata from January 2017 to July 2022. Second, we assessed the ability of SGU's TPI and ADI to predict DENV outbreaks in comparison to Foz do Iguaçu's Early‐Warning System, which forecasts outbreaks up to 4 weeks ahead. Spatial and temporal analyses were carried out, including data interpolation and model selection based on Akaike information criteria (AIC).

Results

Entomological indicators produced in small SGUs can effectively replace larger sentinel areas to access dengue outbreaks. Based on historical data, the best predictive capability is achieved 2 weeks after infestation verification. Implementing the SGU strategy with more frequent sampling can provide more precise space–time estimates and enhance dengue control.

Conclusions

The implementation of SGUs offers an efficient way to monitor mosquito populations, reducing the need for extensive resources. This approach has the potential to improve dengue transmission management and enhance the public health response in endemic cities.
An h$h$‐principle for embeddings transverse to a contact structure
Authors: Cardona Robert , Presas Francisco
Published: March 2024

Given a class of embeddings into a contact or a symplectic manifold, we give a sufficient condition, that we call isocontact or isosymplectic realization, for this class to satisfy a general ‐principle. The flexibility follows from the ‐principles for isocontact and isosymplectic embeddings, it provides a framework for classical results, and we give two new applications. Our main result is that embeddings transverse to a contact structure satisfy a full ‐principle in two cases: if the complement of the embedding is overtwisted, or when the intersection of the image of the formal derivative with the contact structure is strictly contained in a proper symplectic subbundle. We illustrate the general framework on symplectic manifolds by studying the universality of Hamiltonian dynamics on regular level sets via a class of embeddings.
Influence of Walking Over Unexpected Uneven Terrain on Joint Loading for Individuals With Transtibial Amputation
Authors: Stewart Kristen M. , Klute Glenn K. , Neptune Richard R.
Published: March 2024

Individuals with transtibial amputation (TTA) experience asymmetric lower-limb loading which can lead to joint pain and injuries. However, it is unclear how walking over unexpected uneven terrain affects their loading patterns. This study sought to use modeling and simulation to determine how peak joint contact forces and impulses change for individuals with unilateral TTA during an uneven step and subsequent recovery step and how those patterns compare to able-bodied individuals. We expected residual limb loading during the uneven step and intact limb loading during the recovery step would increase relative to flush walking. Further, individuals with TTA would experience larger loading increases compared to able-bodied individuals. Simulations of individuals with TTA showed during the uneven step, changes in joint loading occurred at all joints except the prosthetic ankle relative to flush walking. During the recovery step, intact limb joint loading increased in early stance relative to flush walking. Simulations of able-bodied individuals showed large increases in ankle joint loading for both surface conditions. Overall, increases in early stance knee joint loading were larger for those with TTA compared to able-bodied individuals during both steps. These results suggest that individuals with TTA experience altered joint loading patterns when stepping on uneven terrain. Future work should investigate whether an adapting ankle-foot prosthesis can mitigate these changes to reduce injury risk.
Inflow Conditions and the Flow Behavior of Submerged Annular Viscoplastic Non-Newtonian Jets
Authors: Hammad Khaled J.
Published: March 2024

Submerged annular viscoplastic jet flows were studied numerically within the steady laminar flow regime. The impacts of inner-to-outer annular nozzle diameter ratio, and yield number, for uniform and fully-developed inflow conditions, were investigated. The extent of the outer recirculation region and recirculation intensities of both the central and outer regions were found to substantially diminish with the yield number, resulting in the elimination of recirculation throughout the whole flow field at high yield numbers. The axial penetration of the jet decreases with both the yield number and the annular diameter ratio. The impact of inflow conditions on the flow structure and decay characteristics of the jet are more pronounced at low yield numbers.
Desert diversity: genome sequence of
Gordonia rubripertincta
cluster DJ phage Mossy and cluster DV phage Erutan
Authors: Barnes October , Workman Christopher J. , Patterson Noah C. , Oesch Riley , Johnson Katie L. , Goncz Kaarin , Sharbrough Joel , DeVeaux Linda C.
Published: March 2024

Lytic bacteriophages Mossy and Erutan were directly isolated from desert soil on
Gordonia rubripertincta
and characterized by their morphologies and genomes. Mossy, part of the DJ cluster of Actinobacteriophage, has a genome of 61,183 bp. The genome of Erutan, part of the DV cluster, is 66,957 bp.
Impact of post-procedure stenosis on outcomes of patients with severe intracranial stenosis treated with intracranial stent placement
Authors: Nunna Ravi S , Ma Xiaoyu , Genovese Sabrina , Lodhi Abdullah , Bains Navpreet K , Cohen David , Smith Caitlyn , Ortiz Michael J , Siddiq Farhan , Gomez Camilo R , Qureshi Adnan I
Published: March 2024

Background

The optimal target post-procedure stenosis after percutaneous angioplasty and stent placement (PTAS) for intracranial stenosis is unknown. We determined the effect of post-procedure stenosis after intracranial PTAS on subsequent clinical events in patients with severe symptomatic intracranial stenosis.

Methods

We categorized the severity of post-procedure stenosis as ‘<30%’, ‘30–49%’, and ‘≥50%’ among 207 patients who underwent PTAS in a multicenter randomized clinical trial. Outcomes included stroke or death within 72 hours and within 30 days, ipsilateral stroke beyond 30 days of treatment, and stroke or death within 30 days or stroke in the qualifying artery beyond 30 days (primary endpoint of the trial). Cox proportional hazards analysis was performed with adjustments for age, initial severity of stenosis, location of stenosis, and qualifying event. Kaplan-Meier curves were generated for the primary endpoint stratified by post-procedure stenosis with log-rank analysis.

Results

The severity of post-procedure stenosis was categorized as <30%, 30–49%, and ≥50% in 112, 73, and 22 patients, respectively. Compared with patients with post-procedure stenosis <30%, there was no difference in the risk of primary endpoint among patients with post-procedure stenoses of 30–49% (hazards ratio (HR) 0.85, 95% confidence interval (95% CI) 0.64 to 1.15) or those with ≥50% (HR 0.91, 95% CI 0.57 to 1.43). Log-rank analysis did not demonstrate a difference in rates of primary endpoint between groups stratified by post-procedure stenosis (P=0.70).

Conclusion

In the absence of any benefit on short- and long-term outcomes, strategies to achieve a low severity of post-procedure stenosis among patients with severe intracranial stenosis may not be warranted.
Effects of liquid nicotine concentration and flavour on the acceptability of electronic nicotine delivery systems (ENDS) among people who smoke participating in a randomised controlled trial to reduce cigarette consumption
Authors: Yingst Jessica , Midya Vishal , White Augustus , Foulds Jonathan , Cobb Caroline O , Veldheer Susan , Yen Miao-Shan , Eissenberg Thomas
Published: March 2024

Background

Research is needed to understand the acceptability of electronic nicotine delivery systems (ENDS) as a smoking reduction aid. This study examines the acceptability of ENDS by liquid nicotine concentration and flavour among people who smoke using ENDS to reduce their smoking.

Methods

People who smoke cigarettes but were naïve to ENDS participated in a double-blind randomised controlled trial to reduce conventional cigarette smoking. Participants were randomised to either a control cigarette substitute (CS) or one of three ENDS groups; 0 mg/mL, 8 mg/mL or 36 mg/mL nicotine concentration. ENDS flavour was chosen by the participant (tobacco or menthol). Participants reported their CS, ENDS and cigarettes per day (CPD) from the past 7 days at 1-month, 3-month and 6-month follow-up visits. Participants also reported side effects and measures of satisfaction, psychological reward, aversion and craving relief. Outcome variables were modelled using linear mixed effects by the following groups: liquid nicotine concentration, flavour and a flavour-nicotine concentration interaction.

Results

Participants (n=520) were 41.2% male, 67.3% white, had a mean age of 46.2 years and smoked a mean of 18.6 CPD (SD=7.74) at baseline. All flavour and concentration groups decreased CPD from baseline to all follow-up visits with the 36 mg/mL experiencing the greatest reduction, compared with the 0 mg/mL and 8 mg/mL groups. All groups except the 36 mg/mL group decreased their product use over time. The use of menthol flavour was associated with fewer side effects at 3 months (p=0.02) and lesser aversion at 1 month (p=0.03) compared with tobacco-flavoured ENDS. The 36 mg/mL group experienced the greatest craving relief and greatest aversion compared with other groups.

Conclusions

Both nicotine concentration and flavour appear to have independent, as well as interactive, effects that influence ENDS acceptability among people who use cigarettes.
Force convective heat transfer simulation in a rectangular channel with multiple square obstacles via finite element method
Authors: Ashraf Muhammad Waqas , Haider Jamil Abbas , Ghazwani Hassan Ali , Ahmad Shahbaz , Zheng Zhoushun , Gul Sana
Published: March 2024

This study investigated fluid flow and forced convective heat transfer in rectangular microchannels with square barriers, as illustrated in Fig.  1 . In the first situation, three obstacles were positioned along the microchannel’s top wall. In the second scenario, obstacles were positioned along the microchannel’s bottom wall. In the final example, three square obstacles are placed symmetrically on either side of the microchannel wall. With the help of the Finite Element Method (FEM), we investigate the physicochemical behavior of the microchannel. The development of computer code within COMSOL multiphysics made it possible to simulate heat transport and fluid flow. The results include the implications of the rarefaction effect on fluid flow and heat transmission and decisions regarding the location of barriers and the shape of obstacles in squares. In addition, with the lowest value in skin friction and a lower Nusselt number, the third example, which has barriers on both sides, provides a valuable method for reducing the fluid temperature at the exit of the microchannel. This is because it has barriers on both sides. In the section under “Results and Discussion,” we provide an in-depth analysis of the numerical data derived from the microchannel.

• Objective: This study aims to numerically investigate forced convective heat transfer in a rectangular channel featuring multiple square obstacles. The simulation employs the FEM to model fluid flow and temperature distribution. • Geometry and complexity: The channel geometry incorporates square obstacles, introducing geometric complexity. The FEM is chosen for its capability to handle intricate geometries accurately.
Detection of fat concentration milk using TMDC-based surface plasmon resonance sensor
Authors: Karki Bhishma , Trabelsi Youssef , Uniyal Arun , Pal Amrindra , Bharos Yadav Ram
Published: March 2024

In this paper, a TMDC-based surface plasmon resonance (SPR) sensor for detecting fat concentration milk, incorporating an Ag-Pt (bimetallic) layer, is presented. The Pt (Platinum) layer provides chemical stability and increases sensitivity with the TMDC layer. Compared to the conventional SPR sensor, the maximum sensitivity, detection accuracy (DA), and figure of merit (FoM) of 314∘/RIU, 0.142/degree, and FoM 44.05/RIU are achieved with the WS2 layer. The sensor’s increased sensitivity is due to the increased field intensity and depth of penetration into the sensor layer, resulting in a larger interaction volume. The presence of the WS2 layer, with its significant imaginary part of the dielectric constant, helps improve sensitivity and broadens the SPR curves. This broadening SPR curve ultimately affects the DA and FoM of the sensor. The capability of the proposed sensor to detect various biological analytes with a refractive index (1.3452–1.3657) can be demonstrated.
Electro-optic and transport properties with stability parameters of cubic KMgX (X = P, As, Sb, and Bi) half-Heusler materials: Appropriate for green energy applications
Authors: Menaria Ghanshyam Lal , Rani Upasana , Kamlesh Peeyush Kumar , Singh Rashmi , Rani Monika , Singh Nihal , Sharma Dinesh C. , Verma Ajay Singh
Published: March 2024

Due to their distinct characteristics and prospective uses in several disciplines, half-Heusler (HH) materials are a family of intermetallic compounds that have garnered a lot of attention. HH compounds have a cubic crystal structure and exhibit a wide range of electronic, optical, mechanical and thermoelectric characteristics. Direct bandgap acquired by the WC-GGA (TB[Formula: see text][Formula: see text][Formula: see text]mBJ) approach is 1.07[Formula: see text]eV (2.26[Formula: see text]eV), 0.61[Formula: see text]eV (1.71[Formula: see text]eV), 0.76[Formula: see text]eV (1.68[Formula: see text]eV), and 0[Formula: see text]eV (0.78[Formula: see text]eV) for KMgP, KMgAs, KMgSb, and KMgBi, respectively. Threshold power [Formula: see text] of KMgX ([Formula: see text], As, Sb, and Bi), starts from 2.218, 1.701, 1.674, and 0.776[Formula: see text]eV, so they exhibit the distinct peaks at 4.014, 3.742, 3.388, and 3.197[Formula: see text]eV, correspondingly. Among these materials, the maximum value of Seebeck coefficient (S) has been attained at 300[Formula: see text]K. Specifically, KMgP achieves the highest value of S at 3.134[Formula: see text]mV/K, followed by KMgAs at 2.947[Formula: see text]mV/K, KMgSb at 2.893[Formula: see text]mV/K, and KMgBi at 1.431[Formula: see text]mV/K, all in their respective p-type configurations. In order to determine the compound’s stability, we will explore the elastic and thermodynamic properties. We will also discuss their possible applications in photovoltaic and thermoelectric devices.
Automatic Lyric Transcription and Automatic Music Transcription from Multimodal Singing
Authors: Gu Xiangming , Ou Longshen , Zeng Wei , Zhang Jianan , Wong Nicholas , Wang Ye
Published: March 2024

Automatic lyric transcription (ALT) refers to transcribing singing voices into lyrics, while automatic music transcription (AMT) refers to transcribing singing voices into note events, i.e., musical MIDI notes. Despite these two tasks having significant potential for practical application, they are still nascent. This is because the transcription of lyrics and note events solely from singing audio is notoriously difficult due to the presence of noise contamination, e.g., musical accompaniment, resulting in a degradation of both the intelligibility of sung lyrics and the recognizability of sung notes. To address this challenge, we propose a general framework for implementing multimodal ALT and AMT systems. Additionally, we curate the first multimodal singing dataset, comprising N20EMv1 and N20EMv2, which encompasses audio recordings and videos of lip movements, together with ground truth for lyrics and note events. For model construction, we propose adapting self-supervised learning models from the speech domain as acoustic encoders and visual encoders to alleviate the scarcity of labeled data. We also introduce a residual cross-attention mechanism to effectively integrate features from the audio and video modalities. Through extensive experiments, we demonstrate that our single-modal systems exhibit state-of-the-art performance on both ALT and AMT tasks. Subsequently, through single-modal experiments, we also explore the individual contributions of each modality to the multimodal system. Finally, we combine these and demonstrate the effectiveness of our proposed multimodal systems, particularly in terms of their noise robustness.
Wavelet Coherence Analysis of Plasma Beta, Alfven Mach Number, and Magnetosonic Mach Number during Different Geomagnetic Storms
Authors: Giri Ashutosh , Adhikari Binod , Baral Rabin , Idosa Uga Chali , Calabia Andres
Published: March 2024

We study the variation in plasma beta, Alfven Mach number, and magnetosonic Mach number during different geomagnetic storms of solar cycles 23, 24, and 25. In addition, we employ measurements of the solar wind’s flow pressure, proton density, interplanetary magnetic field (IMF) along the z-direction (Bz), temperature, velocity, and geomagnetic index SYM-H. Here, the wavelet coherence (WTC) approach of plasma beta, the Alfven Mach number, and the magnetosonic Mach number have been used with the symmetrical H component (SYM-H) index, which are critical indicators of the plasma behavior and magnetic field interactions. A solar CME or, much less severely, a corotating interaction region (CIR), which is formed at the leading edge of a high-speed stream, is the source of the magnetic storm. The key objective of this study is to reveal the possible dependencies of the geomagnetic indices on whether a storm is driven by a CME or CIR. For CIR-associated storms, large amplitude waves occur preferentially with the rising Alfven Mach number and plasma beta. At the same time, the magnetosonic Mach number lacks variability during the storms caused by shock on the arrival of Earth’s environment. This is different for CME-driven storms, where the variations of the magnetosonic Mach number do not show much fluctuation compared to the Alfven Mach number and plasma beta. WTC between SYM-H and our derived parameters indicates periodicities between 64 and 512 minutes and noticeable regions of significantly enhanced power on November 07–09, 2004, and June 21–23, 2015. However, the magnetosonic Mach number showed a noticeable coherence with SYM-H between 64 and 250 minutes on September 06–08, 2017. Although, during March 19–21, 2021, both the Alfven Mach number and magnetosonic Mach number showed a noticeable coherence with SYM-H, plasma beta showed none. These parameters can be used in the prediction of geomagnetic storms of the category above G3.
Whole‐Exome Sequencing Analysis Identifies Risk Genes in Atlantoaxial Dislocation Patients with Sandwich Fusion
Authors: Gao Guodong , Tian Yinglun , Hung Kan-Lin , Fan Dongwei , Xu Nanfang , Wang Shenglin
Published: March 2024

Sandwich fusion of Klippel‐Feil syndrome (KFS), which is a rare congenital disorder involving the fusion of cervical vertebrae, poses significant challenges in the diagnosis and treatment of atlantoaxial dislocation (AAD). While the disorder’s genetic basis is not well‐understood, the rarity of the sandwich fusion makes it difficult to study. Whole‐exome sequencing (WES) was conducted on 68 unrelated Chinese patients with sandwich fusion. The study compared their genetic data with a control group of 219 individuals without musculoskeletal disorders. Various analyses, including mutational burden assessments, were employed to identify potential pathogenic genes. The study identified significant genetic variations in patients with sandwich fusion, highlighting genes like KMT5A, HYDIN, and PCDHB4 as potential contributors. Notably, severe cases exhibited oligogenic effects, with mutations in genes like MEOX1 associated with the severity of spinal issues. These findings offer critical insights into the genetic basis of sandwich fusion and provide a foundation for future research and therapeutic development.
Transformer‐Enhanced Traffic Load Simulation for Wear Evaluation of Bridge Expansion Joint
Authors: Dong Yiqing , Pan Yue , Wang Dalei , Chen Airong
Published: March 2024

Timely wear evaluation is crucial in maintaining the functionality of bridge expansion joints (BEJs), ultimately ensuring the safety of bridges. Despite the significance of traffic load simulation (TLS) in simulation‐based evaluation methods, existing TLS approaches face challenges in accurately modeling in situ traffic flow at a high fidelity. This paper presents a novel methodology and its application for evaluating the wear performance of BEJs, employing a Transformer‐enhanced TLS approach. Initially, a tailored dataset is crafted for data‐driven car‐following modeling, leveraging an established spatial‐temporal traffic load monitoring system. High‐fidelity TLS with a mean absolute error (MAE) of 0.1738 m/s is then achieved using Transformer modules equipped with an attention mechanism. To evaluate the final wear life of BEJs, transient dynamic analysis and a calibrated finite element model of the bridge are employed to extract cumulative displacement. Additionally, a surrogate model is developed to depict the relationship between the hourly traffic weight on the entire bridge deck and the cumulative displacement of BEJs, yielding an impressive R‐squared value of 0.96619. Comparative results demonstrate the superior performance of our proposed TLS approach over other data‐driven approaches, with the linear model derived from our TLS approach outperforming the model generated by the conventional Monte Carlo‐based TLS approach. To conclude, our proposed TLS emerges as a comprehensive and precise methodology for the wear evaluation of BEJs.
Research on the Factors Influencing the Seismic Performance of Grouting Sleeve Assembled Double-Column Piers
Authors: Li Sheng , Yao Zewen , Wang Li , Ma Li , He Yongze , Ban Xuefeng
Published: March 2024

The present study investigated the influence of key design parameters on the seismic performance of prefabricated precast assembled piers’ connection parts to better adapt to the industrialized construction of prefabricated precast assembled pier connected using grouting sleeves. Relying on a prefabricated assembled bridge in the actual project, the ABAQUS software was used to establish a refined solid finite element model of prefabricated assembled piers connected with grouting sleeves. Numerical simulation analysis was conducted for the piers with low circumferential reciprocating loading. The seismic performance of the prefabricated assembled piers was evaluated in terms of hysteresis characteristics, dissipation characteristics, and damage development. The effects of the length of the grouting sleeve and the diameter of the longitudinal reinforcement on the seismic performance were also investigated. The maximum error between the numerical simulation results and the test results was 5.7%, and the plastic region of the precast assembled pier obtained from the numerical simulation was consistent with the test results, indicating that the numerical simulation method is accurate and reliable. When the length of the grouting sleeve increased from 0.6 to 1.2 m, the yield load, peak load, and dissipation of energy of prefabricated assembled piers increased by 11.6%, 10.9%, and 11.4%, respectively; no significant change in residual displacement; ductility coefficient decreased by a small amount. When the longitudinal reinforcement diameter increased from 20 to 50 mm, prefabricated assembled piers yield load, peak load, and dissipation increased by 99.6%, 89.3%, and 218.9%, respectively, whereas the residual displacement increased by 137.3%, and the ductility coefficient decreased more. Increasing the length of the grouting sleeve or increasing the diameter of longitudinal reinforcement improved the stiffness of the piers, causing the piers to displace less and damage less under the same force, but the residual displacement would increase.
Data from A Novel Splice Variant of GLI1 That Promotes Glioblastoma Cell Migration and Invasion
Authors: Lo Hui-Wen , Zhu Hu , Cao Xinyu , Aldrich Amy , Ali-Osman Francis
Published: March 2024

Abstract
The family of GLI zinc finger transcription factors regulates the expression of genes involved in many important cellular processes, notably embryonal development and cellular differentiation. The glioma-associated oncogene homologue 1 (GLI1) isoform, in particular, has attracted much attention because of its frequent activation in many human cancers and its interactions with other signaling pathways, such as those mediated by K-RAS, transforming growth factor-β, epidermal growth factor receptor, and protein kinase A. Here, we report the identification of a novel truncated GLI1 splice variant, tGLI1, with an in-frame deletion of 123 bases (41 codons) spanning the entire exon 3 and part of exon 4 of the GLI1 gene. Expression of tGLI1 is undetectable in normal cells but is high in glioblastoma multiforme (GBM) and other cancer cells. Although tGLI1 undergoes nuclear translocalization and transactivates GLI1-binding sites similar to GLI1, unlike GLI1, it is associated with increased motility and invasiveness of GBM cells. Using microarray analysis, we showed >100 genes to be differentially expressed in tGLI1-expressing compared with GLI1-expressing GBM cells, although both cell types expressed equal levels of known GLI1-regulated genes, such as PTCH1. We further showed one of the tGLI1 up-regulated genes, CD24, an invasion-associated gene, to be required for the migratory and invasive phenotype of GBM cells. These data provide conclusive evidence for a novel gain-of-function GLI1 splice variant that promotes migration and invasiveness of GBM cells and open up a new research paradigm on the role of the GLI1 pathway in malignancy. [Cancer Res 2009;69(17):6790–8]
Data from The Decline in U.S. Cancer Mortality in People Born since 1925
Authors: Kort Eric J. , Paneth Nigel , Vande Woude George F.
Published: March 2024

Abstract
The conventional practice of analyzing overall age-adjusted cancer mortality rates heavily emphasizes the experience of older, higher mortality age groups. This may conceal shifts in lifetime cancer mortality experience emerging first in younger age groups. We examined age-specific cancer mortality rates and birth cohort–specific cancer mortality rates in U.S. mortality data recorded since 1955 to assess the effects of age, period, and cohort in secular mortality trends. Cancer mortality and population data were obtained from WHO Statistical Information System. Age-specific cancer mortality rates have been steadily declining in the United States since the early 1950s, beginning with children and young adults and now including all age groups. During the second half of the 20th century, each successive decade of births from 1925 to 1995 experienced a lower risk of cancer death than its predecessor at virtually every age for which such a comparison can be made. A major decline in cancer mortality has been occurring in the United States for the past 50 years, affecting birth cohorts born as long as 80 years ago. Excepting lung cancer, much of this decline has occurred despite relatively stable cancer incidence. These findings suggest that improvements in cancer detection, treatment, and/or prevention have reduced the risk of cancer death across the life span for individuals born in the last three quarters of the 20th century. [Cancer Res 2009;69(16):6500–5]
Data from The CD4+ T-Cell Response of Melanoma Patients to a MAGE-A3 Peptide Vaccine Involves Potential Regulatory T Cells
Authors: François Violaine , Ottaviani Sabrina , Renkvist Nicolina , Stockis Julie , Schuler Gerold , Thielemans Kris , Colau Didier , Marchand Marie , Boon Thierry , Lucas Sophie , van der Bruggen Pierre
Published: March 2024

Abstract
Melanoma patients were injected with various vaccines containing a MAGE-A3 peptide presented by HLA-DP4. Anti–MAGE-A3.DP4 T cells were not detectable in the blood before vaccination, but their frequencies after vaccination ranged from 2 × 10−6 to 2 × 10−3 among the CD4+ blood T lymphocytes of the patients. The CD4+ blood T lymphocytes that stained ex vivo with HLA-DP4 tetramers folded with the MAGE-A3 peptide were selected by flow cytometry and amplified under clonal conditions. About 5% of the CD4+ T-cell clones that recognized the MAGE-A3.DP4 antigen had a CD25+ phenotype in the resting state. These CD25+ clones had a high capacity to suppress the proliferation of another T-cell clone after peptide stimulation in vitro. Most of them had high FOXP3 expression in the resting state and an unmethylated FOXP3 intron 1. They produced active transforming growth factor-β but none of cytokines IFN-γ, interleukin-2 (IL-2), IL-4, IL-5, and IL-10. About 20% of CD25− clones had a significant but lower suppressive activity. Most of the CD25− clonal populations contained cells that expressed FOXP3 in the resting state, but FOXP3 demethylation was not observed. We conclude that MAGE-A3.DP4 vaccination can produce CD4+ T cells that may exert regulatory T-cell function in vivo. [Cancer Res 2009;69(10):4335–45]
Data from Interleukin-27 Activates Natural Killer Cells and Suppresses NK-Resistant Head and Neck Squamous Cell Carcinoma through Inducing Antibody-Dependent Cellular Cytotoxicity
Authors: Matsui Masahiro , Kishida Tsunao , Nakano Hiroshi , Yoshimoto Koichiro , Shin-Ya Masaharu , Shimada Taketoshi , Nakai Shigeru , Imanishi Jiro , Yoshimoto Takayuki , Hisa Yasuo , Mazda Osam
Published: March 2024

Abstract
Interleukin (IL)-27 is an IL-12 family cytokine playing a pivotal role in the induction of Th1 immune responses, although its action on natural killer (NK) cells has not been fully elucidated. Here, we show that IL-27 is capable of inducing phosphorylation of signal transducers and activators of transcription 1 and 3, as well as expression of T-bet and granzyme B in murine DX-5+ NK cells. IL-27 also enhances cytotoxic activity of NK cells both in vitro and in vivo, while the in vitro viability of NK cells is also improved by this cytokine. Therapeutic administration of the IL-27 gene drastically suppressed the growth of NK-unsusceptible SCCVII tumors that had been preestablished in syngenic mice, resulting in significant prolongation of the survival of the animals. This can likely be ascribed to the antibody-dependent cellular cytotoxicity machinery because IL-27 successfully induced tumor-specific IgG in the sera of the tumor-bearing mice, and supplementation of the sera enabled IL-27–activated NK cells to kill SCCVII cells in an Fcγ receptor III–dependent manner. These findings strongly suggest that IL-27 may offer a powerful immunotherapeutic tool to eradicate head and neck squamous cell carcinoma and other poorly immunogenic neoplasms through activating NK cells and inducing tumor-specific immunoglobulin that may cooperatively elicit antibody-dependent cellular cytotoxicity activity. [Cancer Res 2009;69(6):2523–30]
Data from Oxidation Status of Human OGG1-S326C Polymorphic Variant Determines Cellular DNA Repair Capacity
Authors: Bravard Anne , Vacher Monique , Moritz Eva , Vaslin Laurence , Hall Janet , Epe Bernd , Radicella J. Pablo
Published: March 2024

Abstract
The hOGG1 gene encodes the DNA glycosylase that removes the mutagenic lesion 7,8-dihyro-8-oxoguanine (8-oxoG) from DNA. A frequently found polymorphism resulting in a serine to cysteine substitution at position 326 of the OGG1 protein has been associated in several molecular epidemiologic studies with cancer development. To investigate whether the variant allele encodes a protein with altered OGG1 function, we compared the 8-oxoG repair activity, both in vivo and in cell extracts, of lymphoblastoid cell lines established from individuals carrying either Ser/Ser or Cys/Cys genotypes. We show that cells homozygous for the Cys variant display increased genetic instability and reduced in vivo 8-oxoG repair rates. Consistently, their extracts have an almost 2-fold lower basal 8-oxoG DNA glycosylase activity when compared with the Ser variant. Treatment with reducing agents of either the Cys variant cells directly or of protein extracts from these cells increases the repair capacity to the level of the Ser variant, whereas it does not affect the activity in cells or extracts from the latter. Furthermore, the DNA glycosylase activity of cells carrying the Cys/Cys alleles is more sensitive to inactivation by oxidizing agents when compared with that of the Ser/Ser cells. Analysis of the redox status of the OGG1 protein in the cells confirms that the lower activity of OGG1-Cys326 is associated with the oxidation of Cys326 to form a disulfide bond. Our findings support the idea that individuals homozygous for the OGG1-Cys variant could more readily accumulate mutations under conditions of oxidative stress. [Cancer Res 2009;69(8):3642–9]
Data from A CreER-Based Random Induction Strategy for Modeling Translocation-Associated Sarcomas in Mice
Authors: Haldar Malay , Hedberg Matthew L. , Hockin Matthew F. , Capecchi Mario R.
Published: March 2024

Abstract
Previously, we reported modeling synovial sarcomas in mice by conditionally expressing the human t(X;18) translocation–derived SYT-SSX2 fusion protein in Myf5-expressing myoblasts. Using a tamoxifen-inducible CreER system in mice, we show here that sporadic expression of SYT-SSX2 across multiple tissue types leads to exclusive formation of synovial sarcoma–like tumors, whereas its widespread expression is lethal. Certain clinical and histologic features of tumors in this new model suggest additional nonmyoblast origin for synovial sarcoma. CreER-based sporadic expression both avoids the severe early developmental phenotypes associated with widespread SYT-SSX2 expression and better models natural pathogenesis of cancers in which transformed cells usually arise within an environment of largely normal cells. Furthermore, this strategy may recapitulate multiple potential cellular origins within a single model system. [Cancer Res 2009;69(8):3657–64]
Data from Imatinib Mesylate Induces Cisplatin Hypersensitivity in Bcr-Abl+ Cells by Differential Modulation of p53 Transcriptional and Proapoptotic Activity
Authors: Skorta Ioanna , Oren Moshe , Markwardt Christiane , Gutekunst Matthias , Aulitzky Walter E. , van der Kuip Heiko
Published: March 2024

Abstract
Imatinib is highly effective in inducing remission in chronic myelogenous leukemia (CML). However, complete eradication of the malignant clone by imatinib is rare. We investigated the efficacy of combining imatinib with cisplatin. Inhibition of Bcr-Abl by imatinib induced a hypersensitive phenotype both in Bcr-Abl+ cell lines and in CD34+ cells from CML patients. Importantly, cisplatin sensitivity of leukemic cells harboring an inactive Bcr-Abl greatly exceeded that of Bcr-Abl− parental cells. The cisplatin response of Bcr-Abl+ cells treated with imatinib was characterized by an impaired G2-M arrest and by rapid induction of mitochondrial cell death after the first passage through G2. Imatinib abrogated ATM activation on cisplatin selectively in Bcr-Abl+ cells. As a consequence, phosphorylation of p53 on Ser15 and its activity as a transcription factor was significantly diminished. Furthermore, p53 accumulated predominantly in the cytoplasm in Bcr-Abl+ cells treated with imatinib and cisplatin. Silencing of p53 significantly reduced sensitivity to cisplatin in imatinib-treated Bcr-Abl+ cells, indicating that p53 retains its proapoptotic activity. Simultaneous downregulation of Bcl-xL was an additional requirement for cisplatin hypersensitivity, as p53-dependent cell death could be antagonized by exogenous Bcl-xL. We conclude that imatinib sensitizes Bcr-Abl+ cells to cisplatin by simultaneous inhibition of p53 transactivation, induction of p53 accumulation predominantly in the cytoplasm, and reduction of Bcl-xL. [Cancer Res 2009;69(24):9337–45]
Data from MicroRNA Regulation of DNA Repair Gene Expression in Hypoxic Stress
Authors: Crosby Meredith E. , Kulshreshtha Ritu , Ivan Mircea , Glazer Peter M.
Published: March 2024

Abstract
Genetic instability is a hallmark of cancer; the hypoxic tumor microenvironment has been implicated as a cause of this phenomenon. MicroRNAs (miR) are small nonprotein coding RNAs that can regulate various cellular pathways. We report here that two miRs, miR-210 and miR-373, are up-regulated in a hypoxia-inducible factor-1α–dependent manner in hypoxic cells. Bioinformatics analyses suggested that these miRs could regulate factors implicated in DNA repair pathways. Forced expression of miR-210 was found to suppress the levels of RAD52, which is a key factor in homology-dependent repair (HDR); the forced expression of miR-373 led to a reduction in the nucleotide excision repair (NER) protein, RAD23B, as well as in RAD52. Consistent with these results, both RAD52 and RAD23B were found to be down-regulated in hypoxia, but in both cases, the hypoxia-induced down-regulation could be partially reversed by antisense inhibition of miR-210 and miR-373. Importantly, luciferase reporter assays indicated that miR-210 is capable of interacting with the 3′ untranslated region (UTR) of RAD52 and that miR-373 can act on the 3′ UTR of RAD23B. These results indicate that hypoxia-inducible miR-210 and miR-373 play roles in modulating the expression levels of key proteins involved in the HDR and NER pathways, providing new mechanistic insight into the effect of hypoxia on DNA repair and genetic instability in cancer. [Cancer Res 2009;69(3):1221–9]
Data from Caspase-8 Association with the Focal Adhesion Complex Promotes Tumor Cell Migration and Metastasis
Authors: Barbero Simone , Mielgo Ainhoa , Torres Vicente , Teitz Tal , Shields David J. , Mikolon David , Bogyo Matthew , Barilà Daniela , Lahti Jill M. , Schlaepfer David , Stupack Dwayne G.
Published: March 2024

Abstract
Caspase-8 is a proapoptotic protease that suppresses neuroblastoma metastasis by inducing programmed cell death. Paradoxically, caspase-8 can also promote cell migration among nonapoptotic cells; here, we show that caspase-8 can promote metastasis when apoptosis is compromised. Migration is enhanced by caspase-8 recruitment to the cellular migration machinery following integrin ligation. Caspase-8 catalytic activity is not required for caspase-8–enhanced cell migration; rather, caspase-8 interacts with a multiprotein complex that can include focal adhesion kinase and calpain 2 (CPN2), enhancing cleavage of focal adhesion substrates and cell migration. Caspase-8 association with CPN2/calpastatin disrupts calpastatin-mediated inhibition of CPN2. In vivo, knockdown of either caspase-8 or CPN2 disrupts metastasis among apoptosis-resistant tumors. This unexpected molecular collaboration provides an explanation for the continued or elevated expression of caspase-8 observed in many tumors. [Cancer Res 2009;69(9):3755–63]
Data from Androgen-Stimulated UDP-Glucose Dehydrogenase Expression Limits Prostate Androgen Availability without Impacting Hyaluronan Levels
Authors: Wei Qin , Galbenus Robert , Raza Ashraf , Cerny Ronald L. , Simpson Melanie A.
Published: March 2024

Abstract
UDP-glucose dehydrogenase (UGDH) oxidizes UDP-glucose to UDP-glucuronate, an essential precursor for production of hyaluronan (HA), proteoglycans, and xenobiotic glucuronides. High levels of HA turnover in prostate cancer are correlated with aggressive progression. UGDH expression is high in the normal prostate, although HA accumulation is virtually undetectable. Thus, its normal role in the prostate may be to provide precursors for glucuronosyltransferase enzymes, which inactivate and solubilize androgens by glucuronidation. In this report, we quantified androgen dependence of UGDH, glucuronosyltransferase, and HA synthase expression. Androgen-dependent and androgen-independent human prostate cancer cell lines were used to test the effects of UGDH manipulation on tumor cell growth, HA production, and androgen glucuronidation. Dihydrotestosterone (DHT) increased UGDH expression ∼2.5-fold in androgen-dependent cells. However, up-regulation of UGDH did not affect HA synthase expression or enhance HA production. Mass spectrometric analysis showed that DHT was converted to a glucuronide, DHT-G, at a 6-fold higher level in androgen-dependent cells relative to androgen-independent cells. The increased solubilization and elimination of DHT corresponded to slower cellular growth kinetics, which could be reversed in androgen-dependent cells by treatment with a UDP-glucuronate scavenger. Collectively, these results suggest that dysregulated expression of UGDH could promote the development of androgen-independent tumor cell growth by increasing available levels of intracellular androgen. [Cancer Res 2009;69(6):2332–9]
Data from Strong Smooth Muscle Differentiation Is Dependent on Myocardin Gene Amplification in Most Human Retroperitoneal Leiomyosarcomas
Authors: Pérot Gaëlle , Derré Josette , Coindre Jean-Michel , Tirode Franck , Lucchesi Carlo , Mariani Odette , Gibault Laure , Guillou Louis , Terrier Philippe , Aurias Alain
Published: March 2024

Abstract
Myocardin (MYOCD), a serum response factor (SRF) transcriptional cofactor, is essential for cardiac and smooth muscle development and differentiation. We show here by array-based comparative genomic hybridization, fluorescence in situ hybridization, and expression analysis approaches that MYOCD gene is highly amplified and overexpressed in human retroperitoneal leiomyosarcomas (LMS), a very aggressive well-differentiated tumor. MYOCD inactivation by shRNA in a human LMS cell line with MYOCD locus amplification leads to a dramatic decrease of smooth muscle differentiation and strongly reduces cell migration. Moreover, forced MYOCD expression in three undifferentiated sarcoma cell lines and in one liposarcoma cell line confers a strong smooth muscle differentiation phenotype and increased migration abilities. Collectively, these results show that human retroperitoneal LMS differentiation is dependent on MYOCD amplification/overexpression, suggesting that in these well-differentiated LMS, differentiation could be a consequence of an acquired genomic alteration. In this hypothesis, these tumors would not necessarily derive from cells initially committed to smooth muscle differentiation. These data also provide new insights on the cellular origin of these sarcomas and on the complex connections between oncogenesis and differentiation in mesenchymal tumors. [Cancer Res 2009;69(6):2269–78]
Data from A Novel Human AlkB Homologue, ALKBH8, Contributes to Human Bladder Cancer Progression
Authors: Shimada Keiji , Nakamura Mitsutoshi , Anai Satoshi , De Velasco Marco , Tanaka Motoyoshi , Tsujikawa Kazutake , Ouji Yukiteru , Konishi Noboru
Published: March 2024

Abstract
We recently identified a novel human AlkB homologue, ALKBH8, which is expressed in various types of human cancers including human urothelial carcinomas. In examining the role and function of ALKBH8 in human bladder cancer development in vitro, we found that silencing of ALKBH8 through small interfering RNA transfection reduced reactive oxygen species (ROS) production via down-regulation of NAD(P)H oxidase-1 (NOX-1) and induced apoptosis through subsequent activation of c-jun NH2-terminal kinase (JNK) and p38. However, we also found that JNK and p38 activation resulted in phosphorylation of H2AX (γH2AX), a variant of mammalian histone H2A, which contributes to the apoptosis induced by silencing ALKBH8 and NOX-1. Silencing of ALKBH8 significantly suppressed invasion, angiogenesis, and growth of bladder cancers in vivo as assessed both in the chorioallantoic membrane assay and in an orthotopic mouse model using green fluorescent protein–labeled KU7 human urothelial carcinoma cells. Immunohistochemical examination showed high expression of ALKBH8 and NOX-1 proteins in high-grade, superficially and deeply invasive carcinomas (pT1 and >pT2) as well as in carcinoma in situ, but not in low-grade and noninvasive phenotypes (pTa). These findings indicate an essential role for ALKBH8 in urothelial carcinoma cell survival mediated by NOX-1–dependent ROS signals, further suggesting new therapeutic strategies in human bladder cancer by inducing JNK/p38/γH2AX–mediated cell death by silencing of ALKBH8. [Cancer Res 2009;69(7):3157–64]
Data from E2F7 Can Regulate Proliferation, Differentiation, and Apoptotic Responses in Human Keratinocytes: Implications for Cutaneous Squamous Cell Carcinoma Formation
Authors: Endo-Munoz Liliana , Dahler Alison , Teakle Ngari , Rickwood Danny , Hazar-Rethinam Mehlika , Abdul-Jabbar Ibtissam , Sommerville Scott , Dickinson Ian , Kaur Pritinder , Paquet-Fifield Sophie , Saunders Nicholas
Published: March 2024

Abstract
The E2F family of transcription factors plays a crucial role in the regulation of genes involved in cell proliferation, differentiation, and apoptosis. In keratinocytes, the inhibition of E2F is a key step in the control and initiation of squamous differentiation. Because the product of the recently identified E2F7a/E2F7b gene has been shown to repress E2F-regulated promoters, and to be abundant in skin, we examined its role in the epidermis. Our results indicate that E2F7b mRNA expression is selectively associated with proliferation-competent keratinocytes. Moreover, E2F7 was able to antagonize E2F1-induced proliferation and apoptosis. In contrast, although E2F7 was able to inhibit proliferation and initiate differentiation, it was unable to antagonize the differentiation suppression induced by E2F1. These data indicate that E2F7-mediated suppression of proliferation and apoptosis acts through E2F1-dependent pathways, whereas E2F7-induced differentiation acts through an E2F1-independent pathway. These data also suggest that proliferation, differentiation, and survival of primary human keratinocytes can be controlled by the relative ratio of E2F1 to E2F7. Because deregulated proliferation, differentiation, and apoptosis are hallmarks of cancer, we examined the expression levels of E2F1 and E2F7 in cutaneous squamous cell carcinomas (CSCC). We found that both genes were overexpressed in CSCCs compared with normal epidermis. Furthermore, inhibition of E2F7 in a SCC cell line sensitized the cells to UV-induced apoptosis and doxorubicin-induced apoptosis. Combined, these data suggest that the selected disruption of E2F1 and E2F7 in keratinocytes is likely to contribute to CSCC formation and may prove to be a viable therapeutic target. [Cancer Res 2009;69(5):1800–9]