bluuebunny/crossref_metadata_2025 huggingface dataset:
Data from Manganese Superoxide Dismutase Enhances the Invasive and Migratory Activity of Tumor Cells
Authors: Connor Kip M. , Hempel Nadine , Nelson Kristin K. , Dabiri Ganary , Gamarra Aldo , Belarmino James , Van De Water Livingston , Mian Badar M. , Melendez J. Andres
Published: March 2023

Abstract
Clinically significant elevations in the expression of manganese superoxide dismutase (Sod2) are associated with an increased frequency of tumor invasion and metastasis in certain cancers. The aim of this study was to examine whether increases in Sod2 activity modulate the migratory potential of tumor cells, contributing to their enhanced metastatic behavior. Overexpression of Sod2 in HT-1080 fibrosarcoma cells significantly enhanced their migration 2-fold in a wound healing assay and their invasive potential 3-fold in a transwell invasion assay. Severity of invasion was directly correlated to Sod2 expression levels and this invasive phenotype was similarly observed in 253J bladder tumor cells, in which Sod expression resulted in a 3-fold increase in invasion compared with controls. Further, migration and invasion of the Sod2-expressing cells was inhibited following overexpression of catalase, indicating that the promigratory/invasive phenotype of Sod2-expressing cells is H2O2 dependent. Sod2 overexpression was associated with a loss of vinculin-positive focal adhesions that were recovered in cells coexpressing catalase. Tail vein injections of Sod2-GFP–expressing HT-1080 cells in NCR nude mice led to the development of pulmonary metastatic nodules displaying high Sod2-GFP expression. Isolated tumors were shown to retain high Sod2 activity in culture and elevated levels of the matrix degrading protein matrix metalloproteinase-1, and a promigratory phenotype was observed in a population of cells growing out from the tumor nodule. These findings suggest that the association between increased Sod2 activity and poor prognosis in cancer can be attributed to alterations in their migratory and invasive capacity. [Cancer Res 2007;67(21):10260–67]
Data from Adaptor Protein LAPF Recruits Phosphorylated p53 to Lysosomes and Triggers Lysosomal Destabilization in Apoptosis
Authors: Li Nan , Zheng Yuanyuan , Chen Wei , Wang Chunmei , Liu Xingguang , He Weigang , Xu Hongmei , Cao Xuetao
Published: March 2023

Abstract
Evidence suggests a functional association between the tumor suppressor p53 and apoptosis-involved organelle lysosome; however, the detailed mechanisms remain poorly understood. We recently reported that a lysosome-targeting protein, LAPF (lysosome-associated and apoptosis-inducing protein containing PH and FYVE domains), could initiate apoptosis of L929 cells through a lysosomal-mitochondrial pathway. In this study, we show that LAPF specifically interacted with phosphorylated p53 (Ser15/18) both in vitro and in vivo, which could be enhanced by apoptotic stimuli, such as tumor necrosis factor α (TNF-α) and ionizing irradiation. The PH domain of LAPF and the transactivation domain of p53 mediated the interaction between both molecules. Phosphorylated p53 (Ser15/18) could translocate to lysosomes before lysosomal membrane permeabilization (LMP) in LAPF-initiated and TNF-induced apoptosis. Silencing of LAPF expression abrogated lysosomal translocation of phosphorylated p53 (Ser15/18), whereas silencing of p53 expression had no effect on lysosomal translocation of LAPF. Similar to that of LAPF silencing, silencing of endogenous p53 expression in L929 cells could significantly impair TNF-α–induced LMP and apoptosis. However, reexpression of wild-type p53, p53S15D (substitution of Ser15 to Asp that mimics a phosphorylated state), and p53R175H (a transcription-deficient mutant) in p53-knockdown L929 cells could rescue the decrease in TNF-induced apoptosis. The data suggest that phosphorylated p53 (Ser15/18) might translocate to lysosome via forming complexes with adaptor protein LAPF and subsequently result in LMP and apoptosis, which might be in a transcription-independent manner. [Cancer Res 2007;67(23):11176–85]
Data from Molecular Imaging of the Efficacy of Heat Shock Protein 90 Inhibitors in Living Subjects
Authors: Chan Carmel T. , Paulmurugan Ramasamy , Gheysens Olivier S. , Kim Joungnam , Chiosis Gabriela , Gambhir Sanjiv Sam
Published: March 2023

Abstract
Heat shock protein 90α (Hsp90α)/p23 and Hsp90β/p23 interactions are crucial for proper folding of proteins involved in cancer and neurodegenerative diseases. Small molecule Hsp90 inhibitors block Hsp90α/p23 and Hsp90β/p23 interactions in part by preventing ATP binding to Hsp90. The importance of isoform-selective Hsp90α/p23 and Hsp90β/p23 interactions in determining the sensitivity to Hsp90 was examined using 293T human kidney cancer cells stably expressing split Renilla luciferase (RL) reporters. Interactions between Hsp90α/p23 and Hsp90β/p23 in the split RL reporters led to complementation of RL activity, which was determined by bioluminescence imaging of intact cells in cell culture and living mice using a cooled charge-coupled device camera. The three geldanamycin-based and seven purine-scaffold Hsp90 inhibitors led to different levels of inhibition of complemented RL activities (10–70%). However, there was no isoform selectivity to both classes of Hsp90 inhibitors in cell culture conditions. The most potent Hsp90 inhibitor, PU-H71, however, led to a 60% and 30% decrease in RL activity (14 hr) in 293T xenografts expressing Hsp90α/p23 and Hsp90β/p23 split reporters respectively, relative to carrier control–treated mice. Molecular imaging of isoform-specific Hsp90α/p23 and Hsp90β/p23 interactions and efficacy of different classes of Hsp90 inhibitors in living subjects have been achieved with a novel genetically encoded reporter gene strategy that should help in accelerating development of potent and isoform-selective Hsp90 inhibitors. [Cancer Res 2008;68(1):216–26]
Data from p70 S6 Kinase Promotes Epithelial to Mesenchymal Transition through Snail Induction in Ovarian Cancer Cells
Authors: Pon Yuen L. , Zhou Hong Y. , Cheung Annie N.Y. , Ngan Hextan Y.S. , Wong Alice S.T.
Published: March 2023

Abstract
p70 S6 kinase (p70S6K) is a downstream effector of phosphatidylinositol 3-kinase and is frequently activated in human ovarian cancer. Here we show that p70S6K functions in epithelial to mesenchymal transition (EMT) responsible for the acquisition of invasiveness during tumor progression. This tumorigenic activity is associated with the ability of p70S6K to repress E-cadherin through the up-regulation of Snail. p70S6K activation induced phenotypic changes consistent with EMT in ovarian cancer cells: The cells lost epithelial cell morphology, acquired fibroblast-like properties, and showed reduced intercellular adhesion. Western blot showed that p70S6K activation led to decreased expression of the epithelial marker E-cadherin and increased expression of mesenchymal markers N-cadherin and vimentin. Inhibition of p70S6K by a specific inhibitor or small interfering RNA reversed the shift of EMT markers. Importantly, p70S6K activation also stimulated the expression of Snail, a repressor of E-cadherin and an inducer of EMT, but not other family members such as Slug. This induction of Snail was regulated at multiple levels by increasing transcription, inhibiting protein degradation, and enhancing nuclear localization of Snail. RNA interference–mediated knockdown of Snail suppressed p70S6K-induced EMT, confirming that the effect was Snail specific. Furthermore, phospho (active)-p70S6K staining correlated with higher tumor grade. We also showed a significant positive correlation between p70S6K activation and Snail expression in ovarian cancer tissues. These results indicate that p70S6K may play a critical role in tumor progression in ovarian cancer through the induction of EMT. Targeting p70S6K may thus be a useful strategy to impede cancer cell invasion and metastasis. [Cancer Res 2008;68(16):6524–32]
Data from Pten Inactivation Accelerates Oncogenic K-ras–Initiated Tumorigenesis in a Mouse Model of Lung Cancer
Authors: Iwanaga Kentaro , Yang Yanan , Raso Maria Gabriela , Ma Lijiang , Hanna Amy E. , Thilaganathan Nishan , Moghaddam Seyed , Evans Christopher M. , Li Huaiguang , Cai Wei-Wen , Sato Mitsuo , Minna John D. , Wu Hong , Creighton Chad J. , Demayo Francesco J. , Wistuba Ignacio I. , Kurie Jonathan M.
Published: March 2023

Abstract
Phosphatase and tensin homologue deleted from chromosome 10 (Pten) is expressed aberrantly in non–small cell lung cancer cells, but the role of Pten in lung neoplasia has not been fully elucidated. In this study, we used a genetic approach to inactivate Pten in the bronchial epithelium of mice. Although, by itself, Pten inactivation had no discernible effect on bronchial epithelial histology, it accelerated lung tumorigenesis initiated by oncogenic K-ras, causing more rapid lethality than that induced by oncogenic K-ras alone (8 weeks versus 24 weeks of median duration of survival, respectively). Lung tumors arose in K-ras mutant, Pten-deficient mice that rapidly obstructed bronchial lumina and replaced alveolar spaces. Relative to K-ras mutant tumors, the K-ras mutant, Pten-deficient tumors exhibited more advanced histologic severity and more prominent inflammation and vascularity. Thus, Pten inactivation cooperated with oncogenic K-ras in promoting lung tumorigenesis. [Cancer Res 2008;68(4):1119–27]
Data from Effect of Ablation or Inhibition of Stromal Matrix Metalloproteinase-9 on Lung Metastasis in a Breast Cancer Model Is Dependent on Genetic Background
Authors: Martin Michelle D. , Carter Kathy J. , Jean-Philippe Sharon R. , Chang Mayland , Mobashery Shahriar , Thiolloy Sophie , Lynch Conor C. , Matrisian Lynn M. , Fingleton Barbara
Published: March 2023

Abstract
Matrix metalloproteinases (MMP) are a family of enzymes with a myriad of functions. Lately, we have come to realize that broad-spectrum inhibition of these enzymes, as was tried unsuccessfully in multiple phase III trials in cancer patients, is likely unwise given the protumorigenic and antitumorigenic functions of various family members. Here, we used the multistage mammary tumor model MMTV-PyVT to investigate roles for either MMP7 or MMP9 in tumor progression. We found no effect of genetic ablation of MMP7 or MMP9 on the multifocal tumors that developed in the mammary glands. Lack of MMP7 also had no effect on the development of lung metastases, suggesting that MMP7 is irrelevant in this model. In contrast, MMP9 deficiency was associated with an 80% decrease in lung tumor burden. The predominant cellular source of MMP9 was myeloid cells, with neutrophils being the largest contributor in tumor-bearing lungs. Experimental metastasis assays corroborated the role of host-derived MMP9 in lung metastasis and also facilitated determination of a time frame most relevant for the MMP9-mediated effect. The lung tumors from MMP9-deficient mice showed decreased angiogenesis. Surprisingly, the antimetastatic outcome of MMP9 ablation seemed to be dependent on strain. Only mice that had genetic background derived from C57BL/6 showed reduced metastasis, whereas mice fully of the FVB/N background showed no significant effect. These strain-specific responses were also observed in a study using a highly selective pharmacologic inhibitor of MMP9 and thus suggest that responses to MMP inhibition are controlled by genetic differences. [Cancer Res 2008;68(15):6251–9]
Data from p53-Dependent and p53-Independent Activation of Autophagy by ARF
Authors: Abida Wassim M. , Gu Wei
Published: March 2023

Abstract
The ARF tumor suppressor is a crucial component of the cellular response to hyperproliferative signals, including oncogene activation, and functions by inducing a p53-dependent cell growth arrest and apoptosis program. It has recently been reported that the ARF mRNA can produce a smARF isoform that lacks the NH2-terminal region required for p53 activation. Overexpression of this isoform can induce autophagy, a cellular process characterized by the formation of cytoplasmic vesicles and the digestion of cellular content, independently of p53. However, the level of this isoform is extremely low in cells, and it remains unclear whether the predominant form of ARF, the full-length protein, is able to activate autophagy. Here, we show that full-length ARF can induce autophagy in 293T cells where p53 is inactivated by viral proteins, and, notably, expression of the NH2-terminal region alone, which is required for nucleolar localization, is sufficient for autophagy activation, independently of p53. Given the reported ability of p53 to induce autophagy, we also investigated the role of p53 in ARF-mediated autophagy induction. We found that full-length ARF expression induces p53 activation and promotes autophagy in a p53-positive cell line, and that ARF-mediated autophagy can be abrogated, at least in part, by RNAi-mediated knockdown of p53 in this cellular context. Thus, our findings modify the current view regarding the mechanism of autophagy induction by ARF and suggest an important role for autophagy in tumor suppression via full-length ARF in both p53-dependent and p53-independent manners, depending on cellular context. [Cancer Res 2008;68(2):352–7]
Data from Genetic Instability Caused by Loss of MutS Homologue 3 in Human Colorectal Cancer
Authors: Haugen Astrid C. , Goel Ajay , Yamada Kanae , Marra Giancarlo , Nguyen Thuy-Phuong , Nagasaka Takeshi , Kanazawa Shinsaku , Koike Junichi , Kikuchi Yoshinori , Zhong Xiaoling , Arita Michitsune , Shibuya Kazutoshi , Oshimura Mitsuo , Hemmi Hiromichi , Boland C. Richard , Koi Minoru
Published: March 2023

Abstract
Microsatellite instability (MSI) is a hallmark of mismatch repair (MMR) deficiency. High levels of MSI at mononucleotide and dinucleotide repeats in colorectal cancer (CRC) are attributed to inactivation of the MMR genes, hMLH1 and hMSH2. CRC with low levels of MSI (MSI-L) exists; however, its molecular basis is unclear. There is another type of MSI—elevated microsatellite alterations at selected tetranucleotide repeats (EMAST)—where loci containing [AAAG]n or [ATAG]n repeats are unstable. EMAST is frequent in non-CRCs; however, the incidence of EMAST and its cause in CRC is not known. Here, we report that MutS homologue 3 (MSH3) knockdown or MSH3-deficient cells exhibit the EMAST phenotype and low levels of mutations at dinucleotide repeats. About 60% of 117 sporadic CRC cases exhibit EMAST. All of the cases defined as MSI-H (16 cases) exhibited high levels of EMAST. Among 101 non–MSI-H cases, all 19 cases of MSI-L and 35 of 82 cases of MSS exhibited EMAST. Although non–MSI-H CRC tissues contained MSH3-negative tumor cells ranging from 2% to 50% of the total tumor cell population, the tissues exhibiting EMAST contained more MSH3-negative cells (average, 31.5%) than did the tissues not exhibiting EMAST (8.4%). Taken together, our results support the concept that MSH3 deficiency causes EMAST or EMAST with low levels of MSI at loci with dinucleotide repeats in CRC. [Cancer Res 2008;68(20):8465–72]
Data from Lack of Hypoxic Response in Uterine Leiomyomas despite Severe Tissue Hypoxia
Authors: Mayer Arnulf , Höckel Michael , Wree Alexander , Leo Cornelia , Horn Lars-Christian , Vaupel Peter
Published: March 2023

Abstract
Hypoxia is now established as a key factor influencing the pathophysiology of malignant growth. Among other effects, hypoxia modulates the expression of a multitude of genes through the induction of hypoxia-inducible transcription factors. This differential gene expression favors angiogenesis, cell survival, an invasive/metastatic phenotype, and resistance to anticancer therapies. Because benign tumors do not exhibit these traits, one might expect these entities to be neither hypoxic nor to induce the genetic hypoxia response program. To test this hypothesis, an investigation of the oxygenation status of 17 leiomyomas and 1 leiomyosarcoma of the uterus using polarographic needle electrodes (Eppendorf pO2 sensor) and the expression of hypoxia-related markers in biopsy specimens of the same tumors was carried out. Marker expression in eight additional archival leiomyosarcomas was also assessed. Leiomyoma tissue was generally found to be severely hypoxic, with median oxygen (O2) partial pressure values ranging from 1 to 5 mm Hg. In contrast, none of the hypoxia-related markers hypoxia-inducible factor (HIF)–1α, HIF-2α, glucose transporter-1, or carbonic anhydrase IX were expressed in any leiomyoma. Larger intercapillary distances were correlated with a poorer oxygenation status. Conversely, the expression of hypoxia-related markers was abundant in the leiomyosarcomas and they also exhibited a high-turnover phenotype (significantly increased proliferation and apoptosis). Uterine leiomyoma might therefore represent a state of oxygen-limited proliferation. Malignancy in the same organ system is associated with growth and metabolism beyond tissue-inherent limitations leading to the induction of hypoxia-related markers, thereby contributing to a self-perpetuating aggressive phenotype. [Cancer Res 2008;68(12):4719–26]
Data from Transforming Growth Factor-β Suppresses the Ability of Ski to Inhibit Tumor Metastasis by Inducing Its Degradation
Authors: Le Scolan Erwan , Zhu Qingwei , Wang Long , Bandyopadhyay Abhik , Javelaud Delphine , Mauviel Alain , Sun LuZhe , Luo Kunxin
Published: March 2023

Abstract
c-Ski is an important corepressor of transforming growth factor-β (TGF-β) signaling through its ability to bind to and repress the activity of the Smad proteins. It was initially identified as an oncogene that promotes anchorage-independent growth of chicken and quail embryo fibroblasts when overexpressed. Although increased Ski expression is detected in many human cancer cells, the roles of Ski in mammalian carcinogenesis have yet to be defined. Here, we report that reducing Ski expression in breast and lung cancer cells does not affect tumor growth but enhances tumor metastasis in vivo. Thus, in these cells, Ski plays an antitumorigenic role. We also showed that TGF-β, a cytokine that is often highly expressed in metastatic tumors, induces Ski degradation through the ubiquitin-dependent proteasome in malignant human cancer cells. On TGF-β treatment, the E3 ubiquitin ligase Arkadia mediates degradation of Ski in a Smad-dependent manner. Although Arkadia interacts with Ski in the absence of TGF-β, binding of phosphorylated Smad2 or Smad3 to Ski is required to induce efficient degradation of Ski by Arkadia. Our results suggest that the ability of TGF-β to induce degradation of Ski could be an additional mechanism contributing to its protumorigenic activity. [Cancer Res 2008;68(9):3277–85]
Data from Vascular Endothelial Cadherin Promotes Breast Cancer Progression via Transforming Growth Factor β Signaling
Authors: Labelle Myriam , Schnittler Hans J. , Aust Daniela E. , Friedrich Katrin , Baretton Gustavo , Vestweber Dietmar , Breier Georg
Published: March 2023

Abstract
Epithelial-to-mesenchymal transition (EMT) is an important event during carcinoma progression and leads to increased tumor cell malignancy. Here, we show that vascular endothelial (VE)-cadherin is induced during EMT in mammary tumor cells and is aberrantly expressed in invasive human breast carcinomas. VE-cadherin enhanced the capacity of fibroblastoid tumor cells to proliferate, form cord-like invasive structures, and adhere to endothelial cells, characteristics that are key contributors to their increased malignancy and metastatic potential. Consistently, VE-cadherin expression in malignant fibroblastoid tumor cells promoted the growth of experimental mammary carcinomas in vivo. Analysis of the signaling mechanisms involved revealed that VE-cadherin expression influences the levels of Smad2 phosphorylation and expression of target genes of transforming growth factor-β (TGF-β), a major mediator of advanced tumor progression and malignant tumor cell proliferation. VE-cadherin might thus promote tumor progression not only by contributing to tumor angiogenesis but also by enhancing tumor cell proliferation via the TGF-β signaling pathway. This article provides evidence for a novel function of VE-cadherin in tumor progression and reveals a previously unknown molecular link between VE-cadherin expression and TGF-β signaling. Our findings may have important implications for the clinical application of anti–VE-cadherin strategies. [Cancer Res 2008;68(5):1388–97]
Data from Cyclooxygenase-2 Expression during Immortalization and Breast Cancer Progression
Authors: Zhao Xiangshan , Goswami Monica , Pokhriyal Nidhi , Ma Hui , Du Hongyan , Yao Jun , Victor Thomas A. , Polyak Kornelia , Sturgis Charles D. , Band Hamid , Band Vimla
Published: March 2023

Abstract
Identification of molecular aberrations in premalignant human mammary epithelial cells (hMEC), the precursors for breast cancers, is a central goal in breast cancer biology. Recent studies implicated expression of cyclooxygenase 2 (COX-2) as a marker to identify precursor cells for breast cancer. In this study, we analyzed COX-2 expression in preselection and postselection hMEC cells and observed similar COX-2 levels in both cells. Interestingly, immortalization of postselection cells using various methods leads to a dramatic decrease in COX-2 expression. Similar to immortal cells, the majority of breast cancer cell lines expressed low levels of COX-2 protein. Finally, analyses of COX-2 expression in a series of specimens from reduction mammoplasty, adenosis, ductal carcinoma in situ, and infiltrating ductal carcinoma showed down-regulation of COX-2 expression during tumor progression. Importantly, down-regulation of COX-2 using small interfering RNA in cells showed no effect on cell proliferation, anchorage-independent growth, migration, or invasion. These results show that (a) COX-2 overexpression does not seem to predict a breast cancer precursor cell and does not provide advantage for the cell to be transformed; (b) inhibition of COX-2 does not affect hMEC growth and oncogenic behavior in the conditions analyzed; and (c) COX-2 expression is decreased in breast cancer cell lines and cancer specimens as compared with normal mammary epithelial cells. [Cancer Res 2008;68(2):467–75]
Data from Cell Lineage Analysis of a Mouse Tumor
Authors: Frumkin Dan , Wasserstrom Adam , Itzkovitz Shalev , Stern Tomer , Harmelin Alon , Eilam Raya , Rechavi Gideon , Shapiro Ehud
Published: March 2023

Abstract
Revealing the lineage relations among cancer cells can shed light on tumor growth patterns and metastasis formation, yet cell lineages have been difficult to come by in the absence of a suitable method. We previously developed a method for reconstructing cell lineage trees from genomic variability caused by somatic mutations. Here, we apply the method to cancer and reconstruct, for the first time, a lineage tree of neoplastic and adjacent normal cells obtained by laser microdissection from tissue sections of a mouse lymphoma. Analysis of the reconstructed tree reveals that the tumor initiated from a single founder cell, ∼5 months before diagnosis, that the tumor grew in a physically coherent manner, and that the average number of cell divisions accumulated in cancerous cells was almost twice than in adjacent normal lung epithelial cells but slightly less than the expected figure for normal B lymphocytes. The cells were also genotyped at the TP53 locus, and neoplastic cells were found to share a common mutation, which was most likely present in a heterozygous state. Our work shows that the ability to obtain data regarding the physical appearance, precise anatomic position, genotypic profile, and lineage position of single cells may be useful for investigating cancer development, progression, and interaction with the microenvironment. [Cancer Res 2008;68(14):5924–31]
Data from The Nuclear Factor-κB Pathway Controls the Progression of Prostate Cancer to Androgen-Independent Growth
Authors: Jin Ren Jie , Lho Yongsoo , Connelly Linda , Wang Yongqing , Yu Xiuping , Saint Jean Leshana , Case Thomas C. , Ellwood-Yen Katharine , Sawyers Charles L. , Bhowmick Neil A. , Blackwell Timothy S. , Yull Fiona E. , Matusik Robert J.
Published: March 2023

Abstract
Typically, the initial response of a prostate cancer patient to androgen ablation therapy is regression of the disease. However, the tumor will progress to an “androgen-independent” stage that results in renewed growth and spread of the cancer. Both nuclear factor-κB (NF-κB) expression and neuroendocrine differentiation predict poor prognosis, but their precise contribution to prostate cancer progression is unknown. This report shows that secretory proteins from neuroendocrine cells will activate the NF-κB pathway in LNCaP cells, resulting in increased levels of active androgen receptor (AR). By blocking NF-κB signaling in vitro, AR activation is inhibited. In addition, the continuous activation of NF-κB signaling in vivo by the absence of the IκBα inhibitor prevents regression of the prostate after castration by sustaining high levels of nuclear AR and maintaining differentiated function and continued proliferation of the epithelium. Furthermore, the NF-κB pathway was activated in the ARR2PB-myc-PAI (Hi-myc) mouse prostate by cross-breeding into a IκBα+/− haploid insufficient line. After castration, the mouse prostate cancer continued to proliferate. These results indicate that activation of NF-κB is sufficient to maintain androgen-independent growth of prostate and prostate cancer by regulating AR action. Thus, the NF-κB pathway may be a potential target for therapy against androgen-independent prostate cancer. [Cancer Res 2008;68(16):6762–9]
Data from Curcumin Blocks RON Tyrosine Kinase–Mediated Invasion of Breast Carcinoma Cells
Authors: Narasimhan Madhusudhanan , Ammanamanchi Sudhakar
Published: March 2023

Abstract
We have recently shown that macrophage-stimulating protein (MSP) promotes the invasion of recepteur d'origine nantais (RON), a tyrosine kinase receptor–positive MDA-MB-231, MDA-MB-468 breast cancer cells, and also identified the regulatory elements required for RON gene expression. In this report, we have analyzed the efficacy of a chemopreventive agent, curcumin, in blocking RON tyrosine kinase–mediated invasion of breast cancer cells. Reverse transcription-PCR and Western analysis indicated the down-regulation of the RON message and protein, respectively, in MDA-MB-231 and MDA-MB-468 cells. Significantly, curcumin-mediated inhibition of RON expression resulted in the blockade of RON ligand, MSP-induced invasion of breast cancer cells. We have identified two putative nuclear factor-κB p65 subunit binding sites on the RON promoter. Using chromatin immunoprecipitation analysis and site-directed mutagenesis of the RON promoter, we have confirmed the binding of p65 to the RON promoter. Our data show that curcumin reduces RON expression by affecting p65 protein expression and transcriptional activity. Treatment of MDA-MB-231 cells with pyrrolidine dithiocarbamate, an inhibitor of p65, or small interfering RNA knockdown of p65, blocked RON gene expression and MSP-mediated invasion of MDA-MB-231 cells. This is the first report showing the regulation of human RON gene expression by nuclear factor-κB and suggests a potential therapeutic role for curcumin in blocking RON tyrosine kinase–mediated invasion of carcinoma cells. [Cancer Res 2008;68(13):5185–92]
Data from Skewing the T-Cell Repertoire by Combined DNA Vaccination, Host Conditioning, and Adoptive Transfer
Authors: Jorritsma Annelies , Bins Adriaan D. , Schumacher Ton N.M. , Haanen John B.A.G.
Published: March 2023

Abstract
Approaches for T-cell–based immunotherapy that have shown substantial effects in clinical trials are generally based on the adoptive transfer of high numbers of antigen-specific cells, and the success of these approaches is thought to rely on the high magnitude of the tumor-specific T-cell responses that are induced. In this study, we aimed to develop strategies that also yield a T-cell repertoire that is highly skewed toward tumor recognition but do not rely on ex vivo generation of tumor-specific T cells. To this end, the tumor-specific T-cell repertoire was first expanded by DNA vaccination and then infused into irradiated recipients. Subsequent vaccination of the recipient mice with the same antigen resulted in peak CD8+ T-cell responses of ∼50%. These high T-cell responses required the presence of antigen-experienced tumor-specific T cells within the graft because only mice that received cells of previously vaccinated donor mice developed effective responses. Tumor-bearing mice treated with this combined therapy showed a significant delay in tumor outgrowth, compared with mice treated by irradiation or vaccination alone. Furthermore, this antitumor effect was accompanied by an increased accumulation of activated and antigen-specific T cells within the tumor. In summary, the combination of DNA vaccination with host conditioning and adoptive transfer generates a marked, but transient, skewing of the T-cell repertoire toward tumor recognition. This strategy does not require ex vivo expansion of cells to generate effective antitumor immunity and may therefore easily be translated to clinical application. [Cancer Res 2008;68(7):2455–62]
Supplementary Table S3 from Randomized, Double-Blind, Placebo-Controlled Trial of MUC1 Peptide Vaccine for Prevention of Recurrent Colorectal Adenoma
Authors: Schoen Robert E. , Boardman Lisa A. , Cruz-Correa Marcia , Bansal Ajay , Kastenberg David , Hur Chin , Dzubinski Lynda , Kaufman Sharon F. , Rodriguez Luz M. , Richmond Ellen , Umar Asad , Szabo Eva , Salazar Andres , McKolanis John , Beatty Pamela , Pai Reetesh K. , Singhi Aatur D. , Jacqueline Camille M. , Bao Riuye , Diergaarde Brenda , McMurray Ryan P. , Strand Carrie , Foster Nathan R. , Zahrieh David M. , Limburg Paul J. , Finn Olivera J.
Published: March 2023

Adverse Events: Grade 1
Supplementary Figures S1-S6, Figure Legends, and Table Legends from Blocking Genomic Instability Prevents Acquired Resistance to MAPK Inhibitor Therapy in Melanoma
Authors: Dharanipragada Prashanthi , Zhang Xiao , Liu Sixue , Lomeli Shirley H. , Hong Aayoung , Wang Yan , Yang Zhentao , Lo Kara Z. , Vega-Crespo Agustin , Ribas Antoni , Moschos Stergios J. , Moriceau Gatien , Lo Roger S.
Published: March 2023

Supplementary Figure S1. Associations of CGRs and ecDNAs with ploidy, expression, and enhancers. Supplementary Figure S2. Analysis of chromothripsis, ecDNAs, and CGRs in MAPKi-sensitive/-naïve versus -resistant melanoma. Supplementary Figure S3. Inferring double-stranded DNA break repair pathways underlying ecDNA and CGR breakpoint junctions. Supplementary Figure S4. Single-agent inhibitory potencies in human melanoma, PDAC, and NSCLC clonogenic growth assays. Supplementary Figure S5. DNA-PKi and/or PARPi co-treatment prevents acquired MAPKi-resistance in human melanoma cell lines. Supplementary Figure S6. In vivo impacts of DNA-PKi when combined with MAPKi.
Supplementary Figure 7 from Persistence of Drug-Resistant Leukemic Stem Cells and Impaired NK Cell Immunity in CML Patients Depend on MIR300 Antiproliferative and PP2A-Activating Functions
Authors: Silvestri Giovannino , Trotta Rossana , Stramucci Lorenzo , Ellis Justin J. , Harb Jason G. , Neviani Paolo , Wang Shuzhen , Eisfeld Ann-Kathrin , Walker Christopher J. , Zhang Bin , Srutova Klara , Gambacorti-Passerini Carlo , Pineda Gabriel , Jamieson Catriona H. M. , Stagno Fabio , Vigneri Paolo , Nteliopoulos Georgios , May Philippa C. , Reid Alistair G. , Garzon Ramiro , Roy Denis-Claude , Moutuou Moutuaata M. , Guimond Martin , Hokland Peter , Deininger Michael W. , Fitzgerald Garrett , Harman Christopher , Dazzi Francesco , Milojkovic Dragana , Apperley Jane F. , Marcucci Guido , Qi Jianfei , Polakova Katerina Machova , Zou Ying , Fan Xiaoxuan , Baer Maria R. , Calabretta Bruno , Perrotti Danilo
Published: March 2023

Figure S7. Bioinformatic analysis of TUG1-sponged miRNAs and mRNA targets in CML. A, (left) Integration of validated TUG1-sponged miRNAs with RNAseq data (heatmaps) from BM CD34+CD38- and CD34+CD38+ CML (CP and BC) and NBM (n=3/group). Effect of TUG1-sponged miRNA on PP2A inhibitors (Venn diagram); Functional integration of TUG1-sponged miRNAs and their mRNA targets into regulatory network KEGG/GO analysis; (right) Circular diagrams show top 4 pathways affected by TUG1-sponged miRNAs. B, Predicted effect of MIR300 and of TUG1-sponged miRNAs on Pluripotent Stem Cell Signaling pathways.
Supplementary Figure 3 from Persistence of Drug-Resistant Leukemic Stem Cells and Impaired NK Cell Immunity in CML Patients Depend on MIR300 Antiproliferative and PP2A-Activating Functions
Authors: Silvestri Giovannino , Trotta Rossana , Stramucci Lorenzo , Ellis Justin J. , Harb Jason G. , Neviani Paolo , Wang Shuzhen , Eisfeld Ann-Kathrin , Walker Christopher J. , Zhang Bin , Srutova Klara , Gambacorti-Passerini Carlo , Pineda Gabriel , Jamieson Catriona H. M. , Stagno Fabio , Vigneri Paolo , Nteliopoulos Georgios , May Philippa C. , Reid Alistair G. , Garzon Ramiro , Roy Denis-Claude , Moutuou Moutuaata M. , Guimond Martin , Hokland Peter , Deininger Michael W. , Fitzgerald Garrett , Harman Christopher , Dazzi Francesco , Milojkovic Dragana , Apperley Jane F. , Marcucci Guido , Qi Jianfei , Polakova Katerina Machova , Zou Ying , Fan Xiaoxuan , Baer Maria R. , Calabretta Bruno , Perrotti Danilo
Published: March 2023

Figure S3. MIR300 acts as master PP2A activator and inhibitor of G1/S transition. A, (left) Additional effects of MIR300 on SET, CCND2 and CDK6 expression; (right) KEGG/GO analysis of MIR300 effects on signal transduction pathways. B, CSmiRTar (filters: bone marrow normal and myeloid leukemia cells) and miRDIP-ComiR integrated analyses show functional clustering of predicted/validated MIR300 targets.
Supplementary Figure 1 from Persistence of Drug-Resistant Leukemic Stem Cells and Impaired NK Cell Immunity in CML Patients Depend on MIR300 Antiproliferative and PP2A-Activating Functions
Authors: Silvestri Giovannino , Trotta Rossana , Stramucci Lorenzo , Ellis Justin J. , Harb Jason G. , Neviani Paolo , Wang Shuzhen , Eisfeld Ann-Kathrin , Walker Christopher J. , Zhang Bin , Srutova Klara , Gambacorti-Passerini Carlo , Pineda Gabriel , Jamieson Catriona H. M. , Stagno Fabio , Vigneri Paolo , Nteliopoulos Georgios , May Philippa C. , Reid Alistair G. , Garzon Ramiro , Roy Denis-Claude , Moutuou Moutuaata M. , Guimond Martin , Hokland Peter , Deininger Michael W. , Fitzgerald Garrett , Harman Christopher , Dazzi Francesco , Milojkovic Dragana , Apperley Jane F. , Marcucci Guido , Qi Jianfei , Polakova Katerina Machova , Zou Ying , Fan Xiaoxuan , Baer Maria R. , Calabretta Bruno , Perrotti Danilo
Published: March 2023

Figure S1. MIR300 activity in quiescent leukemic stem and progenitor cells. CFC-replating assays shows effects of lentiviral-mediated ectopic MIR300 expression, 250 nM and 500 nM CpG-miR-300 on serial replating activity (2nd replating) of leukemic chronic and acute CML and normal UCB CD34+CD38- HSC-enriched cell fractions. Infection with lentiviral empty vector and treatment with CpG-anti-MIR300 and CpG-scramble served as controls.
Supplementary Figure S6 from Predictive and Prognostic Implications of Circulating CX3CR1+ CD8+ T Cells in Non–Small Cell Lung Cancer Patients Treated with Chemo-Immunotherapy
Authors: Abdelfatah Eihab , Long Mark D. , Kajihara Ryutaro , Oba Takaaki , Yamauchi Takayoshi , Chen Hongbin , Sarkar Joy , Attwood Kristopher , Matsuzaki Junko , Segal Brahm H. , Dy Grace K. , Ito Fumito
Published: March 2023

Supplementary Figure 6. Related to Fig. 2 and Supplementary Table 5A, B. Heat map showing the top 10 top significantly enriched pathways found in each T-cell cluster. Gene sets from Reactome (A) and Gene Ontology-Biological Processes (GO-BP) (B) are shown separately. Only gene sets with Benjamini-Hochberg-adjusted p < 0.05 were considered as significantly enriched.
Supplementary Figure S5 from Predictive and Prognostic Implications of Circulating CX3CR1+ CD8+ T Cells in Non–Small Cell Lung Cancer Patients Treated with Chemo-Immunotherapy
Authors: Abdelfatah Eihab , Long Mark D. , Kajihara Ryutaro , Oba Takaaki , Yamauchi Takayoshi , Chen Hongbin , Sarkar Joy , Attwood Kristopher , Matsuzaki Junko , Segal Brahm H. , Dy Grace K. , Ito Fumito
Published: March 2023

Supplementary Figure 5. Related to Figure 2 and Supplementary Table 4. Analysis of peripheral blood CD45+CD19–CD3+CD56– cells by scRNA/TCR-seq. Heatmap of all cells showing the expression levels of the 10 most discriminative genes per cell type (in rows) across all the identified cell populations (in columns). Gene expression in each clusters are also listed in Supplementary Table 4. Color-code layout: scale of purple to yellow; from lowest expression to highest expression.
Supplementary Figure S3 from Predictive and Prognostic Implications of Circulating CX3CR1+ CD8+ T Cells in Non–Small Cell Lung Cancer Patients Treated with Chemo-Immunotherapy
Authors: Abdelfatah Eihab , Long Mark D. , Kajihara Ryutaro , Oba Takaaki , Yamauchi Takayoshi , Chen Hongbin , Sarkar Joy , Attwood Kristopher , Matsuzaki Junko , Segal Brahm H. , Dy Grace K. , Ito Fumito
Published: March 2023

Supplementary Figure 3. An increase of the CX3CR1 score is associated with better survival in NSCLC patients undergoing chemo-immunotherapy. Related to Fig. 1E Progression free survival (PFS) and overall survival (OS) for high (≥ 20%) versus low (< 20%) CX3CR1 score. P values were calculated by a log-rank (Mantel-Cox) test.
Supplementary Fig. S7 from The PARP1 Inhibitor AZD5305 Impairs Ovarian Adenocarcinoma Progression and Visceral Metastases in Patient-derived Xenografts Alone and in Combination with Carboplatin
Authors: Dellavedova Giulia , Decio Alessandra , Formenti Laura , Albertella Mark R. , Wilson Joanne , Staniszewska Anna D. , Leo Elisabetta , Giavazzi Raffaella , Ghilardi Carmen , Bani Maria Rosa
Published: March 2023

Fig. S7 shows the effect of the combination on OC-PDX HOC84
Figure S4 from IL1β Expression Driven by Androgen Receptor Absence or Inactivation Promotes Prostate Cancer Bone Metastasis
Authors: DiNatale Anthony , Worrede Asurayya , Iqbal Waleed , Marchioli Michael , Toth Allison , Sjöström Martin , Zhu Xiaolin , Corey Eva , Feng Felix Y. , Zhou Wanding , Fatatis Alessandro
Published: March 2023

PC3-ML cells show no difference in luciferase activity between the wild-type promoter and the AREΔ IL-1β promoter, in which the ARE half-site located at -576 was removed.
Figure S3 from IL1β Expression Driven by Androgen Receptor Absence or Inactivation Promotes Prostate Cancer Bone Metastasis
Authors: DiNatale Anthony , Worrede Asurayya , Iqbal Waleed , Marchioli Michael , Toth Allison , Sjöström Martin , Zhu Xiaolin , Corey Eva , Feng Felix Y. , Zhou Wanding , Fatatis Alessandro
Published: March 2023

PC3-ML cells transduced with an inducible AR-overexpression construct showed strong mitigation of IL-1β expression (a) and secretion (b), as compared to both wild type, non-transduced cells and transduced cells without doxycycline exposure.
Supplementary Fig. S2 from The PARP1 Inhibitor AZD5305 Impairs Ovarian Adenocarcinoma Progression and Visceral Metastases in Patient-derived Xenografts Alone and in Combination with Carboplatin
Authors: Dellavedova Giulia , Decio Alessandra , Formenti Laura , Albertella Mark R. , Wilson Joanne , Staniszewska Anna D. , Leo Elisabetta , Giavazzi Raffaella , Ghilardi Carmen , Bani Maria Rosa
Published: March 2023

Figure S2 shows the response of the OC-PDXs to platinum and olaparib
Supplementary Fig. S1 from The PARP1 Inhibitor AZD5305 Impairs Ovarian Adenocarcinoma Progression and Visceral Metastases in Patient-derived Xenografts Alone and in Combination with Carboplatin
Authors: Dellavedova Giulia , Decio Alessandra , Formenti Laura , Albertella Mark R. , Wilson Joanne , Staniszewska Anna D. , Leo Elisabetta , Giavazzi Raffaella , Ghilardi Carmen , Bani Maria Rosa
Published: March 2023

Figure S1 shows absence of drug-related toxicity
Supplementary Table S5 from CD142 identifies neoplastic desmoid tumor cells, uncovering interactions between neoplastic and stromal cells that drive proliferation
Authors: Al-Jazrawe Mushriq , Xu Steven , Poon Raymond , Wei Qingxia , Przybyl Joanna , Varma Sushama , van de Rijn Matt , Alman Benjamin
Published: March 2023

Primers used in real-time quantitative PCR experiments.
Supplementary Table S4 from CD142 identifies neoplastic desmoid tumor cells, uncovering interactions between neoplastic and stromal cells that drive proliferation
Authors: Al-Jazrawe Mushriq , Xu Steven , Poon Raymond , Wei Qingxia , Przybyl Joanna , Varma Sushama , van de Rijn Matt , Alman Benjamin
Published: March 2023

Summary of double-color cell sorting experiments.
Supplementary Table S3 from CD142 identifies neoplastic desmoid tumor cells, uncovering interactions between neoplastic and stromal cells that drive proliferation
Authors: Al-Jazrawe Mushriq , Xu Steven , Poon Raymond , Wei Qingxia , Przybyl Joanna , Varma Sushama , van de Rijn Matt , Alman Benjamin
Published: March 2023

CD142 immunohistochemical analysis in scar tissue cores. Results from duplicate cores per do are shown when available.
Supplementary Table S1 from CD142 identifies neoplastic desmoid tumor cells, uncovering interactions between neoplastic and stromal cells that drive proliferation
Authors: Al-Jazrawe Mushriq , Xu Steven , Poon Raymond , Wei Qingxia , Przybyl Joanna , Varma Sushama , van de Rijn Matt , Alman Benjamin
Published: March 2023

Cell surface profiling data of mutant and non-mutant desmoid tumor-derived colonies. Name of the sample indicates the mutation status (mutant (MUT) or wildtype (WT)) of the pooled colonies and the genotype (T41A or S45F) of the original primary sample.
Supplementary Figure S7 from CD142 identifies neoplastic desmoid tumor cells, uncovering interactions between neoplastic and stromal cells that drive proliferation
Authors: Al-Jazrawe Mushriq , Xu Steven , Poon Raymond , Wei Qingxia , Przybyl Joanna , Varma Sushama , van de Rijn Matt , Alman Benjamin
Published: March 2023

Morphological differences in mutant and non-mutant cells isolated by FACS sorting
Supplementary Figure S6 from CD142 identifies neoplastic desmoid tumor cells, uncovering interactions between neoplastic and stromal cells that drive proliferation
Authors: Al-Jazrawe Mushriq , Xu Steven , Poon Raymond , Wei Qingxia , Przybyl Joanna , Varma Sushama , van de Rijn Matt , Alman Benjamin
Published: March 2023

Correlation between estimated mutation frequency from Sanger sequencing and percent CD142-positive cells in heterogeneous desmoid tumor samples
Supplementary Figure S12 from CD142 identifies neoplastic desmoid tumor cells, uncovering interactions between neoplastic and stromal cells that drive proliferation
Authors: Al-Jazrawe Mushriq , Xu Steven , Poon Raymond , Wei Qingxia , Przybyl Joanna , Varma Sushama , van de Rijn Matt , Alman Benjamin
Published: March 2023

Representative gating strategy
Data from IL1β Expression Driven by Androgen Receptor Absence or Inactivation Promotes Prostate Cancer Bone Metastasis
Authors: DiNatale Anthony , Worrede Asurayya , Iqbal Waleed , Marchioli Michael , Toth Allison , Sjöström Martin , Zhu Xiaolin , Corey Eva , Feng Felix Y. , Zhou Wanding , Fatatis Alessandro
Published: March 2023

We report the inverse association between the expression of androgen receptor (AR) and IL1β in a cohort of patients with metastatic castration-resistant prostate cancer. We also discovered that AR represses the IL1β gene by binding an androgen response element half-site located within the promoter, which explains the IL1β expression in AR-negative (ARNEG) cancer cells. Consistently, androgen depletion or AR-pathway inhibitors (ARI) derepressed IL1β in AR-positive cancer cells, both in vitro and in vivo. The AR transcriptional repression is sustained by histone deacetylation at the H3K27 mark in the IL1β promoter. Notably, patients’ data suggest that DNA methylation prevents IL1β expression, even if the AR-signaling axis is inactive. Our previous studies show that secreted IL1β supports metastatic progression in mice by altering the transcriptome of tumor-associated bone stroma. Thus, in patients with prostate cancer harboring ARNEG tumor cells or treated with androgen-deprivation therapy/ARIs, and with the IL1β gene unmethylated, IL1β could condition the metastatic microenvironment to sustain disease progression.
Significance:
IL1β plays a crucial role in promoting skeletal metastasis. The current standard of care for patients with prostate cancer inhibits the AR-signaling axis in tumor cells and will consequently unleash IL1β production. Thus, hormonal deprivation and AR inhibitors should be combined with targeting IL1β signaling, and screening for DNA methylation on the IL1β locus will identify patients that benefit the most from this approach.
Stroke After SARS-CoV-2 mRNA Vaccine: A Nationwide Registry Study
Authors: Ihle-Hansen Håkon , Bøås Håkon , Tapia German , Hagberg Guri , Ihle-Hansen Hege , Berild Jacob Dag , Selmer Randi , Karlstad Øystein , Gulseth Hanne Løvdal , Ariansen Inger
Published: March 2023

Background:

Whether the SARS-CoV-2 mRNA vaccines may cause a transient increased stroke risk is uncertain.

Methods:

In a registry-based cohort of all adult residents at December 27, 2020, in Norway, we linked individual-level data on COVID-19 vaccination, positive SARS-CoV-2 test, hospital admissions, cause of death, health care worker status, and nursing home resident status extracted from the Emergency Preparedness Register for COVID-19 in Norway. The cohort was followed for incident intracerebral bleeding, ischemic stroke, and subarachnoid hemorrhage within the first 28 days after the first/second or third dose of mRNA vaccination until January 24, 2022. Stroke risk after vaccination relative to time not exposed to vaccination was assessed by Cox proportional hazard ratio, adjusted for age, sex, risk groups, health care personnel, and nursing home resident.

Results:

The cohort included 4 139 888 people, 49.8% women, and 6.7% were ≥80 years of age. During the first 28 days after an mRNA vaccine, 2104 people experienced a stroke (82% ischemic stroke, 13% intracerebral hemorrhage, and 5% subarachnoid hemorrhage). Adjusted hazard ratios (95% CI) after the first/second and after the third mRNA vaccine doses were 0.92 (0.85–1.00) and 0.89 (0.73–1.08) for ischemic stroke, 0.81 (0.67–0.98) and 1.05 (0.64–1.71) for intracerebral hemorrhage, and 0.64 (0.46–0.87) and 1.12 (0.57–2.19) for subarachnoid hemorrhage, respectively.

Conclusions:

We did not find increased risk of stroke during the first 28 days after an mRNA SARS-CoV-2 vaccine.
Enerji Korkusunun Temiz Enerji ETF Volatilitesi Üzerine Etkisi: TVP-VAR Uygulaması
Authors: ÖZDEMİR HÖL Arife , GÜLCAN Nazlıgül , BOYACIOĞLU Namıka
Published: March 2023

Son dönemlerde hem küresel ısınmadan kaynaklı iklim değişikliğiyle mücadele eylem planları kapsamında hem de ekonomilerine katkıda bulunmak amacıyla tüm dünyada temiz enerjiye olan ilgi artmıştır. Temiz enerji sektöründe yer alan yatırımcılara yol gösterici olması açısından bu çalışmada enerji korkusunun temiz enerji yatırım fonları (ETF) volatilitesine etkisi araştırılmaktadır. Araştırmada enerji korkusunu temsilen CBOE Ham Petrol Volatilite Endeksi (OVX) ile CBOE Enerji Sektörü ETF Volatilite Endeksi (VXXLE), temiz enerji ETF’lerini temsilen de iShares Global Clean Energy ETF (ICLN), First Trust NASDAQ Clean Edge Green Energy ETF (QCLN), Invesco WilderHill Clean Energy ETF (PBW) dikkate alınmıştır. Araştırma kapsamı 02.01.2015-11.02.2022 dönemi volatilite serilerinden oluşmaktadır. Antonakakis vd. (2019a) tarafından geliştirilen TVP-VAR yönteminin kullanıldığı çalışma sonucunda PBW temiz enerji ETF ve VXXLE’nin volatiliteyi yaydığı, ICLN, QCLN temiz enerji ETF’i ve OVX’in ise volatiliteyi aldığı, temiz enerji ETF’lerini tek etkileyen korku endeksinin VXXLE olduğu, OVX’in ise temiz enerji ETF’lerini etkilemediği sonucuna ulaşılmıştır. Ayrıca korku endekslerinin varyansında meydana gelen değişmelerin büyük çoğunluğunun kendileri tarafından açıklandığı ve korku endekslerinin birbirlerini etkileme güçlerinin daha fazla olduğu, temiz enerji ETF’lerinin varyansında meydana gelen değişmelerin büyük çoğunluğunun diğer temiz enerji ETF’leri tarafından açıklandığı belirlenmiştir.