bluuebunny/crossref_metadata_2025 huggingface dataset:
Developmental changes in motor unit activity patterns: child-adult comparison using discrete motor unit analysis
Authors: Woods Stacey , McKiel Andrew , Herda Trent , Klentrou Panagiota , Holmes Michael , Gabriel David , Falk Bareket
Published: March 2024

Using global surface electromyography (sEMG) and the sEMG threshold it has been suggested that children activate their type-II motor unit (MU) to a lesser extent compared with adults. However, when age-related differences in discrete MU activation are examined using sEMG decomposition this phenomenon is not observed. Furthermore, findings from these studies are inconsistent and conflicting. Therefore, the purpose of this study was to examine differences in discrete MU activation of the vastus lateralis (VL) between boys and men during moderate-intensity knee extensions. Seventeen boys and 20 men completed two laboratory sessions. Following a habituation session, maximal voluntary isometric knee extension (MVIC) torque was determined before completing trapezoidal contractions at 70% MVIC. sEMG of the VL was captured and mathematically decomposed into individual MU action potential trains. Motor unit action potential amplitude (MUAPamp), recruitment threshold (RT), and MU firing rates (MUFR) were calculated. We observed that MUAPamp–RT slope was steeper in men compared with boys ( p < 0.05) even after accounting for fat thickness and quadriceps muscle depth. The mean MUFR and y-intercept of the MUFR–RT relationship were significantly ( p < 0.001) lower in boys than in men. The slope of the MUFR–RT relationship tended to be steeper in men, but the differences did not reach statistical significance ( p = 0.056). Overall, our results suggest that neural strategies used to produce torque are different among boys and men. Such differences may be related, in part, to boys’ lower MUFR and lesser ability to activate their higher-threshold MUs. Although, other factors (e.g., muscle composition) likely also play a role.
The dynamical behavior of the capacitively coupled argon plasma driven by very high frequency
Authors: Yin Guiqin , Jiang Yongbo , Yuan Qianghua
Published: March 2024

The dynamical behavior of the capacitively coupled Ar plasma driven by four frequencies (54, 80, 94 and 100[Formula: see text]MHz) at fixed pressure are simulated by the particle-in-cell/Monte-Carlo collisions (PIC/MCC) model based on the electromagnetic field. The magnetic field is generated by plasma current itself. The results show that the electron density, charge density, and electron temperature increase with the frequency increase when radio frequency (RF) power is 40[Formula: see text]W. The electron heating rate and argon ion heating rate near the sheath increase with the frequency increase. The high-energy electron density ([Formula: see text] [Formula: see text]eV) varies nonlinearly with the frequency increase. The high-energy electron density is highest at 80[Formula: see text]MHz among the four frequencies. The electron density, charge density, and high-energy electron density increase with RF power (30, 45, 60, and 75[Formula: see text]W) increase at 80[Formula: see text]MHz. The electron temperature decreases with RF power increase at 80[Formula: see text]MHz. The electron heating rate and argon ion heating rate near the sheath have no change with RF power increase at 80[Formula: see text]MHz. The electron energy probability distributions (EEPF) show that the number of high-energy electrons ([Formula: see text] [Formula: see text]eV) is highest at 80[Formula: see text]MHz. The reason may be the electron resonant heating that occurs in the plasma when the electron cyclotron frequency equals source frequency at 80[Formula: see text]MHz. The electron dynamics of capacitively coupled plasma is important for microelectronics etching and membrane deposition.
Scalable deposition of MASnI2Br-based perovskite solar cells via ultrasonic spray pyrolysis
Authors: Aldemir Durmuş Ali , Lapa Havva Elif , Şen Esra , Kaleli Murat
Published: March 2024

All layers of MASnI2Br-based perovskite solar cells (PSCs) were deposited by ultrasonic spray pyrolysis method. The depositions of the layers were carried out in a large area. The perovskite thin film deposited on FTO/TiO2 had large grains. The crystallite size of the film was calculated as 90[Formula: see text]nm from the XRD pattern. The bandgap of 1.54[Formula: see text]eV was determined from the UV-visible measurement of MASnI2Br thin film. The PSCs with the different active areas (0.3[Formula: see text]cm2 and 3.18[Formula: see text]cm2) were fabricated. The champion cells’ power conversion efficiencies were recorded at 0.181% and 0.120% for 0.3[Formula: see text]cm2 and 3.18[Formula: see text]cm2, respectively.
Effect of impurities and carrier concentration on conductivity of bilayer graphene double layer system in different dielectric environments
Authors: Vyas Harsh T. , Shah Tejas R. , Patel Digish K. , Ambavale Sagar K.
Published: March 2024

The electronic transport properties of the bilayer graphene double layer (BLGDL) system at [Formula: see text][Formula: see text]K using the Boltzmann transport equation are reported here. The conductivity of the BLGDL system has been calculated with varying parameters as relative carrier concentration [Formula: see text], short-range (point defect) and long-range (Coulomb charge) impurity concentration, relative dielectric constant [Formula: see text] and interlayer distance [Formula: see text]. The maximum conductivity has been achieved in the absence of short-range impurity. The short-range impurity plays a non-trivial meaningful role in high dielectric and high carrier concentration regimes and limits the conductivity. For higher [Formula: see text] and higher [Formula: see text] values, the nature of the conductivity curve turns out to be of a sublinear nature, while in all other cases, it shows a superlinear trend. Suitable selection of relative dielectric constants, relative carrier concentration and interlayer distance helps to improve the conductivity of the BLGDL system. If the dielectric constant of the spacer is higher than the substrate material, the thickness of the spacer material helps remarkably in enhancing conductivity. Moreover, a comparison of BLGDL with our previously reported MLG–MLG double layer graphene system (DLGS) confirms that higher conductivity is achieved in the case of BLG–BLG system compared to DLGS.
Entropy-based analysis of hemodynamics in elliptical arterial flows with non-Newtonian Rabinowitsch fluid
Authors: Shahzad Muhammad Hasnain , Nadeem Sohail , Ahmad Hijaz , Hussein Mohamed , Awan Aziz Ullah , Alroobaea Roobaea , Allahyani Seham Ayesh
Published: March 2024

This research concerns examining the non-Newtonian blood flow behavior through an artery of elliptic cross-section, affected by several stenoses. The Rabinowitsch fluid model is used to investigate the non-Newtonian behavior of the blood for uniform and nonuniform shapes of stenosis. The mathematical equations have been converted into a dimensionless form, and their nonlinearity is reduced by applying the assumptions of mild stenosis. The resulting differential equations are solved by using analytical techniques. A new polynomial of degree eight is introduced to complete the solutions of mathematical equations. The entropy generation is studied mathematically to analyze the irreversibility effects. The detailed graphical examination delineates the physical aspects of mathematical results. The flow velocity is higher for uniform shape than for nonuniform stenosis. The rising percentage of stenosis significantly enhances the flow velocity of the stenotic region. The entropy is enormous near the stenotic wall and has small values near the centerline, which assures the smooth flow in this region. Further, the streamlines are plotted to find the position of stenosis and assess the flow nature for the growing height of stenosis and rising flow rate.
A first-principle study on the pressure-dependent structural, electronic, and optical properties of 4-Hydrazine Benzene Sulfonamide
Authors: Zhang Chao , Chen Limin , Gong Zhicheng , Liu Chunsheng
Published: March 2024

This study utilizes first-principle density functional theory (DFT) to explore the high-pressure behavior of 4-hydrazine benzene sulfonamide. Our investigation, spanning pressures from 0 to 300[Formula: see text]GPa, delves into diverse properties of the crystal (C6H9N3O2S), encompassing the crystal structure, band gap, density of states, permittivity, and conductivity. Under increasing pressure, intriguing observations emerge. Distortions in the molecular structure manifest notably at 70, 130, and 270[Formula: see text]GPa, accompanied by distinctive anisotropic behavior in lattice constants. Notably, our scrutiny of the band gap and density of states exposes a transition from a semiconductor to a metallic state and back to a semiconductor state, illuminating the profound influence of pressure on the material’s electronic structure. At 0[Formula: see text]GPa, the real part of permittivity registers negative values within the 15.6–20.2[Formula: see text]eV energy range, suggesting the crystal’s inability to propagate light and its manifestation of metallic reflection properties. Conversely, at 270[Formula: see text]GPa, the imaginary part of permittivity indicates metallic characteristics within the electronic structure, alongside a substantial energy loss in the crystal’s real part of conductivity. Moreover, the imaginary part of conductivity unveils pronounced energy conversion between the driving electric field and current excitation, hinting at structural instability under this extreme pressure. This research contributes vital insights into the behavior of hydrocarbons under high pressure, filling crucial gaps in our understanding of their properties.
Hearty Mart: Democratizing Corporate Entrepreneurship
Authors: Ghura Amarpreet Singh , Abhishek
Published: March 2024

Nadeem Jafri (Jafri), the founder of Hearty Mart Enterprise Private Limited (HMEPL), was based in Juhapura, Ahmedabad India. HMEPL catered to Hotel, Restaurant, and Café (HoReCa) segment. In 2017, Jafri started practicing corporate entrepreneurship at HMEPL with a dedicated team and later democratized the same for all employees of HMEPL. In the last quarter of 2022, HMEPL acquired four businesses and exercised organization restructuring which led to seven business entities with diverse backgrounds, were based in remote locations and had resource constraints when compared with HMEPL. Jafri wondered about a mechanism to successfully implement the innovation and entrepreneurship culture in the newly restructured entity HMEPL and across other seven businesses. The case provides an opportunity for students to step into the shoes of Jafri and plan a way to implement entrepreneurial and innovation culture in the newly restructured HMEPL and across other seven businesses. In doing so, students should take into consideration the data regarding the existing processes and teams at HMEPL that helped it to innovate, and make assumptions to analyze the feasibility of implementing entrepreneurial and innovation culture in newly restructured HMEPL and across seven other businesses.

Nadeem Jafri (Jafri), the founder of Hearty Mart Enterprise Private Limited (HMEPL), was sitting in his Juhapura office in Ahmedabad on 18th July 2023 and reflecting on the integration of new business ventures within HMEPL. Jafri started HMEPL in Ahmedabad, India, and catered to Hotel, Restaurant, and Café (HoReCa) segment. In 2017, Jafri started practicing corporate entrepreneurship in HMEPL with the leadership team and later democratized the same for all the employees of HMEPL. In the last quarter of 2022, HMEPL acquired four businesses and post the acquisition, went through organizational restructuring leading to seven business units operating under HMEPL. Jafri was wondering about the mechanism to implement the innovation and corporate entrepreneurship culture in the newly restructured HMEPL and across the seven business units which had diverse businesses. Many questions remained unanswered during the early phase of implementing innovation and entrepreneurship culture in the newly restructured HMEPL and across the seven business units. He grappled with questions like, ‘do we need to implement corporate entrepreneurship in all the businesses or do a pilot in one of the business units,’ ‘are all the business units ready as each one of them is based in a remote location and is also facing resource constraints,’ and ‘will the employees agree?’ Despite such skepticism, Jafri had to share the way forward about the idea of implementing the innovation and corporate entrepreneurship culture in the next leadership meeting on the coming weekend. The business of HMEPL had gained momentum and had crossed pre-COVID levels by early June 2023. Jafri had to ensure that he made the right choices which ensured continued growth for HMEPL.
CARBON RISK HEDGING: REDUCING PORTFOLIO CARBON RISK USING A BETA HEDGE RATIO
Authors: LEIFHELM MATHIS , SCHOLZ PETER
Published: March 2024

In response to the global transition to a low-carbon economy, carbon risk reduction in diversified portfolios has become imperative. We develop a new hedge approach to mitigate carbon risk, quantified as the carbon beta using a multi-factor model. By calculating a novel hedge ratio, investors are provided with an optimal allocation to a hedge asset, facilitating the effective reduction of carbon beta within their portfolios. Our findings highlight the effectiveness of this approach, which leads to carbon beta reductions without significant losses in risk-adjusted returns, implying that investors and fund managers can adopt this hedge strategy to moderate their carbon risk exposure. Compared to other carbon risk hedge methods, our approach only requires an investment in one more asset, making real-world applications relatively straightforward.
Application of a Surface Waveguide in Microwave Drying Units of the Agribusiness Industry
Authors: Ritter Ekaterina , Savostin Alexey , Ritter Dmitry , Savostina Galina , Smirnov Andrey , Moldakhmetov Sayat
Published: March 2024

In the last two decades, the electromagnetic field of the microwave range has been successfully introduced into various branches of the agribusiness industry as one of the most promising and advanced technologies for drying manufactured products. In this regard, the article proposes a new microwave irradiation technique for drying various objects based on a surface waveguide’s properties. The paper analyses the main links that make up the surface waveguide as a microwave irradiation system and shows the ways of their implementation. The article describes the advantages of applying a vibratory device for exciting a surface wave, using a re-emitting antenna array, and operating a single conductor with a dielectric coating as a surface waveguide. Such advantages make it possible to introduce microwave drying units with the required distribution of electromagnetic field energy along the irradiated material, small dimensions, high drying quality, and low price.
Perioperative Treatment with Rivaroxaban and Dabigatran on Changes of Coagulation and Platelet Activation Biomarkers following Left Atrial Appendage Closure
Authors: Yao Yao , Li Yanli , Jin Qinchun , Li Xiaoye , Zhang Xiaochun , Lv Qianzhou
Published: March 2024

Insufficient data exist regarding the investigation of the impact of novel oral anticoagulants (NOACs) on coagulation activation biomarkers in the context of left atrial appendage closure (LAAC) and device‐related thrombosis (DRT). The study was designed to investigate the changes and presence of coagulation activation biomarkers between different antithrombotic strategies following LAAC. A total of 120 nonvalvular atrial fibrillation patients intolerant of long‐term anticoagulants, who underwent successful WATCHMAN closure implantation, were enrolled (rivaroxaban, n = 82; dabigatran, n = 38). Blood samples were obtained from left atrium (LA) and left atrial appendage (LAA) during the operation and fasting blood samples on the same day of LAAC and 45 days after discharge. The biochemical indicators, thrombin‐antithrombin complex (TAT), soluble P‐selectin (sP‐selectin), von Willebrand factor (vWF), and CD40 ligand (CD40L), were measured by enzyme‐linked immunosorbent assay. The primary endpoints of this study were the efficacy and safety characteristics of different antithrombotic strategies, including DRT incidence, stroke or transient ischemic attack, systemic embolism, and clinical major and nonmajor bleeding complications during the follow‐up of 180 days. The results revealed that TAT, vWF, sP‐selectin, and CD40L levels in vein were significantly reduced by 2.4% (p = 0.043), 5.0% (p < 0.001), 8.7% (p < 0.001), and 2.5% (p = 0.043) from their baseline levels after rivaroxaban treatment. Conversely, no significant changes were detected in the dabigatran group. Furthermore, the plasma levels of platelet activation biomarkers (CD40L and sP‐selectin) in both LA and LAA groups were significantly lower after anticoagulation with rivaroxaban, as compared to dabigatran treatment (CD40L: 554.62 ± 155.54 vs. 445.02 ± 130.04 for LA p = 0.0013, 578.51 ± 156.28 vs. 480.13 ± 164.37 for LAA p = 0.0052; sP‐selectin: 2849.07 ± 846.69 vs. 2225.54 ± 799.96 for LA p = 0.0105, 2915.52 ± 1402.40 vs. 2203.41 ± 1061.67 for LAA p = 0.0022). Notably, the present study suggests that rivaroxaban may be more effective in the prevention of DRT for patients undergoing LAAC.
The Therapeutic Effect of Ginsenoside Rb1 against Mechanical Trauma in a Rat Model of Postpartum Stress Urinary Incontinence
Authors: Chen Shaohui , Wei Bingyan , Zhang Sanyuan , li Hongmei , Huang Rui
Published: March 2024

Aims. The aim of this study was to confirm the repairing effect of ginsenoside Rb1 (GS‐Rb1) on mechanical trauma to periurethral tissues caused by childbirth and to explore its potential preventive mechanisms for mechanical trauma‐induced stress urinary incontinence. Methods. 48 healthy adult female Sprague–Dawley (SD) rats were randomly divided into four groups: normal control, SUI groups, L‐GS‐Rb1 groups, and H‐GS‐Rb1 groups, with 12 rats in each group. The histopathological examinations of the urethral were performed to detect the morphological changes after repair of periurethral traumatic tissue. The TGF‐β1/Smad and NRF2/ARE signaling pathways related to periurethral tissue trauma repair were determined by RT‐PCR and western blot. The bladder capacity and LPP were examined in rats. Results. GS‐Rb1 significantly decreased the number of fragmented and disorganized elastic and muscle fibers in the urethra and anterior vaginal wall of SUI rats. GS‐Rb1 also increased the collagen content and reduced damage to the structural integrity of the periurethral myofibers. Furthermore, GS‐Rb1 promoted expressions of TGF‐β1, Smad2, Smad3, Smad7, p‐Smad3, p‐Smad2, and collagens I and III. It also increased the protein levels of Nrf2, GPX1, and MnSOD. The bladder capacity and LPP of rats in the L‐GS‐Rb1 group were close to those of rats in the normal groups. Conclusions. Ginsenoside Rb1 promotes the repair of periurethral tissue trauma in the postpartum period and has a preventive effect on the occurrence of stress urinary incontinence.
In‐Plane Dynamic Cushioning Performance of Concave Hexagonal Honeycomb Cores
Authors: Liu Miao , Cao Yan , Sun De-Qiang , Nie Chao-Rui , Wang Zhi-Jie
Published: March 2024

In order to further study the cushioning performance of concave hexagonal cores (CHCs) and expand their application range, the in‐plane finite element model of CHCs is established in this paper. A dynamic cushioning coefficient method was proposed to characterize the cushioning performance of CHCs. The dynamic cushioning coefficient curve and minimum dynamic cushioning coefficient (MDCC) of CHCs with different impact velocities and structural parameters are obtained. The influence rules of structural parameters and impact velocities on the MDCC are analyzed; the deformation mode and transformation empirical formula are also obtained. The results show that when other parameters are constant, the MDCC of CHCs decreases with the increase of impact velocity, increases with the increase of wall thickness and side length ratio, and decreases with the increase of expansion angle. The theoretical analysis is consistent with the finite element results, which further verifies the reliability of the model. This paper provides a solid theoretical basis for the industrial application of the cushioning performance of CHCs and forms a key technical support.
Data from Local Radiotherapy Induces Homing of Hematopoietic Stem Cells to the Irradiated Bone Marrow
Authors: Bastianutto Carlo , Mian Asim , Symes Julie , Mocanu Joseph , Alajez Nehad , Sleep Gillian , Shi Wei , Keating Armand , Crump Michael , Gospodarowicz Mary , Medin Jeff , Minden Mark , Liu Fei-Fei
Published: March 2024

Abstract
Local breast radiation therapy (RT) is associated with a 3-fold increased risk of secondary acute myeloid leukemia. As a first step in determining the mechanism(s) underlying this observation, we investigated the role of RT in mediating the active recruitment of hematopoietic stem cells (HSC) to the site of RT. Our results show in a mouse model that local RT delivered to the left leg causes preferential accumulation of bone marrow mononuclear cells to the irradiated site, with maximum signal intensity observed at 7 days post-RT. This is associated with a 4-fold higher number of donor-derived HSC present in the left leg, demonstrating recruitment of HSC to the site of RT. SDF-1, matrix metalloproteinase 2 (MMP-2), and MMP-9 expression is significantly increased in the irradiated bone marrow, and their inhibition significantly reduced HSC recruitment to the irradiated bone marrow. Our data show that local RT has significant systemic effects by recruiting HSC to the irradiated bone marrow site, a process mediated by SDF-1, MMP-2, and MMP-9. These results raise the possibility that the exposure of increased numbers of HSC at a local site to fractionated irradiation may increase the risk of leukemogenesis. Our data also suggest some opportunities for leukemia prevention in breast cancer patients undergoing RT. [Cancer Res 2007;67(21):10112–6]
Data from Delta-like 4 Notch Ligand Regulates Tumor Angiogenesis, Improves Tumor Vascular Function, and Promotes Tumor Growth In vivo
Authors: Li Ji-Liang , Sainson Richard C.A. , Shi Wen , Leek Russell , Harrington Laura S. , Preusser Matthias , Biswas Swethajit , Turley Helen , Heikamp Emily , Hainfellner Johannes A. , Harris Adrian L.
Published: March 2024

Abstract
The vascular endothelial growth factor (VEGF) plays a key role in tumor angiogenesis. However, clinical trials targeting the VEGF pathway are often ineffective, suggesting that other factors/pathways are also important in tumor angiogenesis. We have previously shown that the Notch ligand Delta-like 4 (DLL4) is up-regulated in tumor vasculature. Here, we show that DLL4, when expressed in tumor cells, functions as a negative regulator of tumor angiogenesis by reducing the number of blood vessels in all five types of xenografts, but acts as a positive driver for tumor growth in two of them (human glioblastoma and prostate cancer). The growth of in vivo models was not related to the effects on growth in vitro. DLL4 expressed in the tumor cells activated Notch signaling in host stromal/endothelial cells, increased blood vessel size, and improved vascular function within tumors. The promotion of tumor growth was, to some extent, due to a reduction of tumor hypoxia and apoptosis. DLL4-expressing tumor cells responded to anti-VEGF therapy with bevacizumab. A soluble form of DLL4 (D4ECD-Fc) blocked tumor growth in both bevacizumab-sensitive and bevacizumab-resistant tumors by disrupting vascular function despite increased tumor vessel density. In addition, we show that DLL4 is up-regulated in tumor cells and tumor endothelial cells of human glioblastoma. Our findings provide a rational basis for the development of novel antiangiogenic strategies via blockade of DLL4/Notch signaling and suggest that combined approaches for interrupting both DLL4 and VEGF pathways may improve antiangiogenic therapy. [Cancer Res 2007;67(23):11244–53]
Data from Gene Alterations Identified by Expression Profiling in Tumor-Associated Endothelial Cells from Invasive Ovarian Carcinoma
Authors: Lu Chunhua , Bonome Tomas , Li Yang , Kamat Aparna A. , Han Liz Y. , Schmandt Rosemarie , Coleman Robert L. , Gershenson David M. , Jaffe Robert B. , Birrer Michael J. , Sood Anil K.
Published: March 2024

Abstract
Therapeutic strategies based on antiangiogenic approaches are beginning to show great promise in clinical studies. However, full realization of these approaches requires identification of key differences in gene expression between endothelial cells from tumors versus their normal counterparts. Here, we examined gene expression differences in purified endothelial cells from 10 invasive epithelial ovarian cancers and 5 normal ovaries using Affymetrix U133 Plus 2.0 microarrays. More than 400 differentially expressed genes were identified in tumor-associated endothelial cells. We selected and validated 23 genes that were overexpressed by 3.6- to 168-fold using real-time reverse transcription-PCR and/or immunohistochemistry. Among these, the polycomb group protein enhancer of Zeste homologue 2 (EZH2), the Notch ligand Jagged1, and PTK2 were elevated 3- to 4.3-fold in tumor-associated endothelial cells. Silencing these genes individually with small interfering RNA blocked endothelial cell migration and tube formation in vitro. The present study shows that tumor and normal endothelium differ at the molecular level, which may have significant implications for the development of antiangiogenic therapies. [Cancer Res 2007;67(4):1757–68]
Data from Cancer Cell Lines as Genetic Models of Their Parent Histology: Analyses Based on Array Comparative Genomic Hybridization
Authors: Greshock Joel , Nathanson Katherine , Martin Anne-Marie , Zhang Lin , Coukos George , Weber Barbara L. , Zaks Tal Z.
Published: March 2024

Abstract
Tumor-derived cell lines are used as in vitro cancer models, but their ability to accurately reflect the phenotype and genotype of the parental histology remains questionable, given the prevalence of documented cell line–specific cytogenetic changes. We have addressed the issue of whether copy number alterations seen in tumor-derived cell lines reflect those observed in studies of fresh tissue by carrying out a meta-analysis of array-based comparative genomic hybridization data that considers both copy number alteration frequencies and the occurrence of cancer gene amplifications and homozygous deletions. Pairwise correlation comparisons between the data sets of seven diagnosis-specific matched tumor and cell line groups indicate that the trends in aberration frequencies are highly correlated between tumors and cell line sets of matched cancer histology relative to unmatched pairings. Despite their similarities, cell lines showed uniformly higher locus-specific alteration frequencies (P = 0.004) and several recurring cell line–specific alterations emerged. These include the previously documented losses of 13q and 9p and gains of 20q, as well as additional undescribed cell line–specific gains of 5p, 7p, and 17q and losses of 18q and 4q. These results indicate that, on average, cell lines preserve in vitro the genetic aberrations that are unique to the parent histology from which they were derived while acquiring additional locus-specific alterations. These data may enable a more predictive understanding of individual cell lines as in vitro models of cancer biology and therapy. [Cancer Res 2007;67(8):3594–600]
Data from Discovery of Epigenetically Silenced Genes by Methylated DNA Immunoprecipitation in Colon Cancer Cells
Authors: Jacinto Filipe V. , Ballestar Esteban , Ropero Santiago , Esteller Manel
Published: March 2024

Abstract
CpG island promoter hypermethylation of tumor suppressor genes is a common hallmark of human cancer, and new large-scale epigenomic technologies might be useful in our attempts to define the complete DNA hypermethylome of tumor cells. Here, we report a functional search for hypermethylated CpG islands using the colorectal cancer cell line HCT-116, in which two major DNA methyltransferases, DNMT1 and DNMT3b, have been genetically disrupted (DKO cells). Using methylated DNA immunoprecipitation methodology in conjunction with promoter microarray analyses, we found that DKO cells experience a significant loss of hypermethylated CpG islands. Further characterization of these candidate sequences shows CpG island promoter hypermethylation and silencing of genes with potentially important roles in tumorigenesis, such as the Ras guanine nucleotide-releasing factor (RASGRF2), the apoptosis-associated basic helix-loop transcription factor (BHLHB9), and the homeobox gene (HOXD1). Hypermethylation of these genes occurs in premalignant lesions and accumulates during tumorigenesis. Thus, our results show the usefulness of DNMT genetic disruption strategies combined with methylated DNA immunoprecipitation in searching for unknown hypermethylated candidate genes in human cancer that might aid our understanding of the biology of the disease and be of potential translational use. [Cancer Res 2007;67(24):11481–6]
Data from Epithelial to Mesenchymal Transition in Human Breast Epithelial Cells Transformed by 17β-Estradiol
Authors: Huang Yong , Fernandez Sandra V. , Goodwin Shirlean , Russo Patricia A. , Russo Irma H. , Sutter Thomas R. , Russo Jose
Published: March 2024

Abstract
The estrogen dependence of breast cancer has long been recognized; however, the role of 17β-estradiol (E2) in cancer initiation was not known until we showed that it induces complete neoplastic transformation of the human breast epithelial cells MCF-10F. E2 treatment of MCF-10F cells progressively induced high colony efficiency and loss of ductulogenesis in early transformed (trMCF) cells and invasiveness in Matrigel invasion chambers. The cells that crossed the chamber membrane were collected and identified as bsMCF; their subclones were designated bcMCF; and the cells harvested from carcinoma formation in severe combined immunodeficient mice were designated caMCF. These phenotypes correlated with gene dysregulation during the progression of the transformation. The highest number of dysregulated genes was observed in caMCF, being slightly lower in bcMCF, and lowest in trMCF. This order was consistent with the extent of chromosome aberrations (caMCF > bcMCF >>> trMCF). Chromosomal amplifications were found in 1p36.12-pter, 5q21.1-qter, and 13q21.31-qter. Losses of the complete chromosome 4 and 8p11.21-23.1 were found only in tumorigenic cells. In tumor-derived cell lines, additional losses were found in 3p12.1-14.1, 9p22.1-pter, and 18q11.21-qter. Functional profiling of dysregulated genes revealed progressive changes in the integrin signaling pathway, inhibition of apoptosis, acquisition of tumorigenic cell surface markers, and epithelial-mesenchymal transition. In tumorigenic cells, the levels of E-cadherin, epithelial membrane antigen, and various keratins were low and CD44E/CD24 were negative, whereas SNAI2, vimentin, S100A4, FN1, HRAS, transforming growth factor β1, and CD44H were high. The phenotypic and genomic changes triggered by estrogen exposure that lead normal cells to tumorigenesis confirm the role of this steroid hormone in cancer initiation. [Cancer Res 2007;67(23):11147–57]
Data from Chemoprevention of Familial Adenomatous Polyposis by Natural Dietary Compounds Sulforaphane and Dibenzoylmethane Alone and in Combination in ApcMin/+ Mouse
Authors: Shen Guoxiang , Khor Tin Oo , Hu Rong , Yu Siwang , Nair Sujit , Ho Chi-Tang , Reddy Bandaru S. , Huang Mou-Tuan , Newmark Harold L. , Kong Ah-Ng Tony
Published: March 2024

Abstract
Cancer chemopreventive agent sulforaphane (SFN) and dibenzoylmethane (DBM) showed antitumorigenesis effects in several rodent carcinogenesis models. In this study, we investigated the cancer chemopreventive effects and the underlying molecular mechanisms of dietary administration of SFN and DBM alone or in combination in the ApcMin/+ mice model. Male ApcMin/+ mice (12 per group) at age of 5 weeks were given control AIN-76A diet, diets containing 600 ppm SFN and 1.0% DBM, or a combination of 300 ppm SFN and 0.5% DBM for 10 weeks. Mice were then sacrificed, and tumor numbers and size were examined. Microarray analysis, Western blotting, ELISA, and immunohistochemical staining were done to investigate the underlying molecular mechanisms of cancer chemopreventive effects of SFN and DBM. Dietary administrations of SFN and DBM alone or in combination significantly inhibited the development of intestinal adenomas by 48% (P = 0.002), 50% (P = 0.001), and 57% (P < 0.001), respectively. Dietary administration of 600 ppm SFN and 1.0% DBM also reduced colon tumor numbers by 80% (P = 0.016) and 60% (P = 0.103), respectively, whereas the combination of SFN and DBM treatment blocked the colon tumor development (P = 0.002). Both SFN and DBM treatments resulted in decreased levels of prostaglandin E2 or leukotriene B4 in intestinal polyps or apparently normal mucosa. Treatments also led to the inhibition of cell survival and growth-related signaling pathways (such as Akt and extracellular signal-regulated kinase) or biomarkers (such as cyclooxygenase-2, proliferating cell nuclear antigen, cleaved caspases, cyclin D1, and p21). In conclusion, our results showed that both SFN and DBM alone as well as their combination are potent natural dietary compounds for chemoprevention of gastrointestinal cancers. [Cancer Res 2007;67(20):9937–44]
Data from Common and Distinct Genomic Events in Sporadic Colorectal Cancer and Diverse Cancer Types
Authors: Martin Eric S. , Tonon Giovanni , Sinha Raktim , Xiao Yonghong , Feng Bin , Kimmelman Alec C. , Protopopov Alexei , Ivanova Elena , Brennan Cameron , Montgomery Kate , Kucherlapati Raju , Bailey Gerald , Redston Mark , Chin Lynda , DePinho Ronald A.
Published: March 2024

Abstract
Colorectal cancer (CRC) is a major cause of cancer morbidity and mortality, and elucidation of its underlying genetics has advanced diagnostic screening, early detection, and treatment. Because CRC genomes are characterized by numerous non-random chromosomal structural alterations, we sought to delimit regions of recurrent amplifications and deletions in a collection of 42 primary specimens and 37 tumor cell lines derived from chromosomal instability neoplasia and microsatellite instability neoplasia CRC subtypes and to compare the pattern of genomic aberrations in CRC with those in other cancers. Application of oligomer-based array-comparative genome hybridization and custom analytic tools identified 50 minimal common regions (MCRs) of copy number alterations, 28 amplifications, and 22 deletions. Fifteen were highly recurrent and focal (<12 genes) MCRs, five of them harboring known CRC genes including EGFR and MYC with the remaining 10 containing a total of 65 resident genes with established links to cancer. Furthermore, comparisons of these delimited genomic profiles revealed that 22 of the 50 CRC MCRs are also present in lung cancer, glioblastoma, and/or multiple myeloma. Among 22 shared MCRs, nine do not contain genes previously shown genetically altered in cancer, whereas the remaining 13 harbor 35 known cancer genes, of which only 14 have been linked to CRC pathogenesis. Together, these observations point to the existence of many yet-to-be discovered cancer genes driving CRC development, as well as other human cancers, and show the utility of high-resolution copy number analysis in the identification of genetic events common and specific to the development of various tumor types. [Cancer Res 2007;67(22):10736–43]
Data from A Cell Proliferation and Chromosomal Instability Signature in Anaplastic Thyroid Carcinoma
Authors: Salvatore Giuliana , Nappi Tito Claudio , Salerno Paolo , Jiang Yuan , Garbi Corrado , Ugolini Clara , Miccoli Paolo , Basolo Fulvio , Castellone Maria Domenica , Cirafici Anna Maria , Melillo Rosa Marina , Fusco Alfredo , Bittner Michael L. , Santoro Massimo
Published: March 2024

Abstract
Here, we show that the anaplastic thyroid carcinoma (ATC) features the up-regulation of a set of genes involved in the control of cell cycle progression and chromosome segregation. This phenotype differentiates ATC from normal tissue and from well-differentiated papillary thyroid carcinoma. Transcriptional promoters of the ATC up-regulated genes are characterized by a modular organization featuring binding sites for E2F and NF-Y transcription factors and cell cycle–dependent element (CDE)/cell cycle gene homology region (CHR) cis-regulatory elements. Two protein kinases involved in cell cycle regulation, namely, Polo-like kinase 1 (PLK1) and T cell tyrosine kinase (TTK), are part of the gene set that is up-regulated in ATC. Adoptive overexpression of p53, p21 (CIP1/WAF1), and E2F4 down-regulated transcription from the PLK1 and TTK promoters in ATC cells, suggesting that these genes might be under the negative control of tumor suppressors of the p53 and pRB families. ATC, but not normal thyroid, cells depended on PLK1 for survival. RNAi-mediated PLK1 knockdown caused cell cycle arrest associated with 4N DNA content and massive mitotic cell death. Thus, thyroid cell anaplastic transformation is accompanied by the overexpression of a cell proliferation/genetic instability-related gene cluster that includes PLK1 kinase, which is a potential molecular target for ATC treatment. [Cancer Res 2007;67(21):10148–57]
Data from Association of Matrix Metalloproteinase-8 Gene Variation with Breast Cancer Prognosis
Authors: Decock Julie , Long Ji-Rong , Laxton Ross C. , Shu Xiao-Ou , Hodgkinson Conrad , Hendrickx Wouter , Pearce Eve G. , Gao Yu-Tang , Pereira Andresa C. , Paridaens Robert , Zheng Wei , Ye Shu
Published: March 2024

Abstract
Animal and cell studies indicate an inhibitory effect of matrix metalloproteinase-8 (MMP8) on tumorigenesis and metastasis. We investigated whether MMP8 gene variation was associated with breast cancer metastasis and prognosis in humans. We first studied nine tagging single nucleotide polymorphisms (SNP) in the MMP8 gene in 140 clinically and pathologically well-characterized breast cancer patients. Four of the SNPs were found to be associated with lymph node metastasis, the most pronounced being a promoter SNP (rs11225395) with its minor allele (T) associating with reduced susceptibility to lymph node metastasis (P = 0.02). This SNP was further evaluated for association with cancer relapse and survival among a cohort of ∼1,100 breast cancer patients who had been followed for cancer recurrence and mortality for a median of 7.1 years. The T allele was associated with reduced cancer relapse and greater survival, particularly among patients with earlier stage cancer. Among patients of tumor-node-metastasis stage 0 to II, the adjusted hazard ratio of disease-free survival was 0.7 [95% confidence interval (95% CI), 0.5–0.9] for patients carrying T allele compared with those homozygous for the C allele (P = 0.02). In vitro experiments showed that the T allele had higher promoter activity than the C allele in breast cancer cells. Electrophoretic mobility shift assays showed binding of nuclear proteins to the DNA sequence at the SNP site of the T allele but not that of the C allele. The data suggest that MMP8 gene variation may influence breast cancer prognosis and support the notion that MMP8 has an inhibitory effect on cancer metastasis. [Cancer Res 2007;67(21):10214–21]
Data from An Actin-Binding Protein Girdin Regulates the Motility of Breast Cancer Cells
Authors: Jiang Ping , Enomoto Atsushi , Jijiwa Mayumi , Kato Takuya , Hasegawa Taisaku , Ishida Maki , Sato Tomoko , Asai Naoya , Murakumo Yoshiki , Takahashi Masahide
Published: March 2024

Abstract
Girdin (girders of actin filaments) is a novel actin-binding Akt substrate that plays an important role in actin organization and Akt-dependent cell motility in fibroblasts. Here, we find that Girdin is expressed in a variety of cancer cell lines, including the breast cancer cell line MDA-MB-231, and is phosphorylated by the stimulation of insulin-like growth factor (IGF-I). In vitro migration and invasion assays showed that Girdin is required for the IGF-I–dependent cell movement of MDA-MB-231 cells. Short hairpin interfering RNA directed against Girdin markedly inhibited the metastasis of s.c. transplanted MDA-MB-231 cells in nude mice. In addition, Girdin is highly expressed in a variety of human malignant tissues, including breast, colon, lung, and uterine cervical carcinomas. These findings highlight the important role of Girdin in tumor progression in which the Akt signaling pathway is aberrantly activated. [Cancer Res 2008;68(5):1310–8]
Data from Direct Evidence for Epithelial-Mesenchymal Transitions in Breast Cancer
Authors: Trimboli Anthony J. , Fukino Koichi , de Bruin Alain , Wei Guo , Shen Lei , Tanner Stephan M. , Creasap Nicholas , Rosol Thomas J. , Robinson Michael L. , Eng Charis , Ostrowski Michael C. , Leone Gustavo
Published: March 2024

Abstract
We developed stromal- and epithelial-specific cre-transgenic mice to directly visualize epithelial-mesenchymal transition (EMT) during cancer progression in vivo. Using three different oncogene-driven mouse mammary tumor models and cell-fate mapping strategies, we show in vivo evidence for the existence of EMT in breast cancer and show that myc can specifically elicit this process. Hierarchical cluster analysis of genome-wide loss of heterozygosity reveals that the incidence of EMT in invasive human breast carcinomas is rare, but when it occurs it is associated with the amplification of MYC. These data provide the first direct evidence for EMT in breast cancer and suggest that its development is favored by myc-initiated events. [Cancer Res 2008;68(3):937–45]
Data from ODC1 Is a Critical Determinant of MYCN Oncogenesis and a Therapeutic Target in Neuroblastoma
Authors: Hogarty Michael D. , Norris Murray D. , Davis Kimberly , Liu Xueyuan , Evageliou Nicholas F. , Hayes Candace S. , Pawel Bruce , Guo Rong , Zhao Huaqing , Sekyere Eric , Keating Joanna , Thomas Wayne , Cheng Ngan Ching , Murray Jayne , Smith Janice , Sutton Rosemary , Venn Nicola , London Wendy B. , Buxton Allen , Gilmour Susan K. , Marshall Glenn M. , Haber Michelle
Published: March 2024

Abstract
Neuroblastoma is a frequently lethal childhood tumor in which MYC gene deregulation, commonly as MYCN amplification, portends poor outcome. Identifying the requisite biopathways downstream of MYC may provide therapeutic opportunities. We used transcriptome analyses to show that MYCN-amplified neuroblastomas have coordinately deregulated myriad polyamine enzymes (including ODC1, SRM, SMS, AMD1, OAZ2, and SMOX) to enhance polyamine biosynthesis. High-risk tumors without MYCN amplification also overexpress ODC1, the rate-limiting enzyme in polyamine biosynthesis, when compared with lower-risk tumors, suggesting that this pathway may be pivotal. Indeed, elevated ODC1 (independent of MYCN amplification) was associated with reduced survival in a large independent neuroblastoma cohort. As polyamines are essential for cell survival and linked to cancer progression, we studied polyamine antagonism to test for metabolic dependence on this pathway in neuroblastoma. The Odc inhibitor α-difluoromethylornithine (DFMO) inhibited neuroblast proliferation in vitro and suppressed oncogenesis in vivo. DFMO treatment of neuroblastoma-prone genetically engineered mice (TH-MYCN) extended tumor latency and survival in homozygous mice and prevented oncogenesis in hemizygous mice. In the latter, transient Odc ablation permanently prevented tumor onset consistent with a time-limited window for embryonal tumor initiation. Importantly, we show that DFMO augments antitumor efficacy of conventional cytotoxics in vivo. This work implicates polyamine biosynthesis as an arbiter of MYCN oncogenesis and shows initial efficacy for polyamine depletion strategies in neuroblastoma, a strategy that may have utility for this and other MYC-driven embryonal tumors. [Cancer Res 2008;68(23):9735–45]
Data from Stromal Transforming Growth Factor-β Signaling Mediates Prostatic Response to Androgen Ablation by Paracrine Wnt Activity
Authors: Placencio Veronica R. , Sharif-Afshar Ali-Reza , Li Xiaohong , Huang Hongxia , Uwamariya Consolate , Neilson Eric G. , Shen Michael M. , Matusik Robert J. , Hayward Simon W. , Bhowmick Neil A.
Published: March 2024

Abstract
Mechanisms of androgen dependence of the prostate are critical to understanding prostate cancer progression to androgen independence associated with disease mortality. Transient elevation of transforming growth factor-β (TGF-β) occurs after androgen ablation. To determine the role of TGF-β on prostate response to androgen ablation, conditional TGF-β type II receptor knockout mouse models of the epithelia (Tgfbr2NKX3.1KO) and stromal fibroblasts (Tgfbr2fspKO) were used. After castration, the prostates of Tgfbr2NKX3.1KO mice had apoptosis levels similar to those expected for control Tgfbr2floxE2/floxE2 mice. Prostates of Tgfbr2fspKO mice, however, had reduced regression and high levels of proliferation associated with canonical Wnt activity throughout the glandular epithelia regardless of androgen status. In contrast, Tgfbr2floxE2/floxE2 prostates had epithelial canonical Wnt activity only in the surviving proximal ducts after castration. In vitro studies showed that androgen antagonist, bicalutamide, transiently elevated both Tgfbr2floxE2/floxE2 and Tgfbr2fspKO stromal expression of Wnt-2, Wnt-3a, and Wnt-5a. The neutralization of Wnt signaling by the expression of secreted frizzled related protein-2 (SFRP-2) resulted in decreased LNCaP prostate epithelial cell proliferation in stromal conditioned media transfer experiments. In vivo tissue recombination studies using Tgfbr2fspKO prostatic stromal cells in combination with wild-type or SV40 large T antigen expressing epithelia resulted in prostates that were refractile to androgen ablation. The expression of SFRP-2 restored the Tgfbr2fspKO-associated prostate responsiveness to androgen ablation. These studies reveal a novel TGF-β, androgen, and Wnt paracrine signaling axis that enables prostatic regression of the distal ducts after androgen ablation while supporting proximal duct survival. [Cancer Res 2008;68(12):4709–18]