bluuebunny/crossref_metadata_2025 huggingface dataset:
Data from Selective Role of an NH2-Terminal WxxLF Motif for Aberrant Androgen Receptor Activation in Androgen Depletion–Independent Prostate Cancer Cells
Authors: Dehm Scott M. , Regan Kevin M. , Schmidt Lucy J. , Tindall Donald J.
Published: March 2023

Abstract
Systemic prostate cancer therapy requires androgen ablation, which inhibits the production or action of androgens. Prostate cancer ultimately relapses during androgen ablation, and an androgen depletion-independent (ADI) phenotype emerges. Aberrant androgen receptor (AR) activation underlies therapy resistance at this stage of the disease, and mounting evidence implicates the large and highly disordered AR NH2-terminal domain (NTD) as a key mediator of this activity. In this study, we investigated the role of the NTD transactivation unit 5 (TAU5) domain in mediating AR transcriptional activity in cell-based models of prostate cancer progression. AR replacement and Gal4-based promoter tethering experiments revealed that AR TAU5 had a dichotomous function, inhibiting ligand-dependent AR activity in androgen-dependent prostate cancer cells, while enhancing ligand-independent AR activity in ADI prostate cancer cells. Molecular dissection of TAU5 showed that a WxxLF motif was fully responsible for its ligand-independent activity. Mechanistically, WxxLF did not rely on an interaction with the AR ligand-binding domain to mediate ligand-independent AR activity. Rather, WxxLF functioned as an autonomous transactivation domain. These data show that ligand-dependent and ligand-independent AR activation rely on fundamentally distinct mechanisms, and define WxxLF as the major transactivation motif within the AR TAU5 domain. [Cancer Res 2007;67(20):10067–77]
Data from Up-regulation of Mcl-1 Is Critical for Survival of Human Melanoma Cells upon Endoplasmic Reticulum Stress
Authors: Jiang Chen Chen , Lucas Keryn , Avery-Kiejda Kelly A. , Wade Margaret , deBock Charles E. , Thorne Rick F. , Allen John , Hersey Peter , Zhang Xu Dong
Published: March 2023

Abstract
We have previously shown that most melanoma cell lines are insensitive to endoplasmic reticulum (ER) stress–induced apoptosis, and this involves activation of the mitogen-activated protein/extracellular signal-regulated kinase (MEK)/ERK signaling pathway and expression of the apoptosis repressor with caspase recruitment domain (ARC) protein in the cells. In the present study, we show that up-regulation of the antiapoptotic Bcl-2 family member Mcl-1 is another mechanism critical for protection of melanoma cells against ER stress–induced apoptosis. Inhibition of Mcl-1 by small interference RNA (siRNA) rendered melanoma cells sensitive to apoptosis induced by the ER stress inducers thapsigargin and tunicamycin, but this sensitization was partially reversed by siRNA knockdown of PUMA or Noxa, as shown in Mcl-1–deficient melanoma cells. Both PUMA and Noxa were increased by ER stress through transcriptional up-regulation, but only up-regulation of Noxa was dependent on p53, whereas up-regulation of PUMA seemed to be mediated by a p53-independent mechanism(s). Up-regulation of Mcl-1 was also due to increased transcription that involved the IRE1α and activating transcription factor 6 signaling pathways of the unfolded protein response. In addition, activation of the MEK/ERK signaling pathway seemed to be necessary for optimal up-regulation of Mcl-1. Taken together, these results reveal the mechanisms of resistance of melanoma cells to apoptosis induction mediated by BH3-only proteins upon ER stress, and identify Mcl-1 as a target for the treatment of melanoma in combination with therapeutics that induce ER stress. [Cancer Res 2008;68(16):6708–17]
Data from Integrin αvβ3 Controls Activity and Oncogenic Potential of Primed c-Src
Authors: Huveneers Stephan , van den Bout Iman , Sonneveld Petra , Sancho Ana , Sonnenberg Arnoud , Danen Erik H.J.
Published: March 2023

Abstract
Increased activity of the proto-oncogene c-Src and elevated levels of integrin αvβ3 are found in melanomas and multiple carcinomas. Regulation of c-Src involves “priming” through disruption of intramolecular interactions followed by “activation” through phosphorylation in the kinase domain. Interactions with overexpressed receptor tyrosine kinases or mutations in the SRC gene can induce priming of c-Src in cancer. Here, we show that αvβ3 promotes activation of primed c-Src, causing enhanced phosphorylation of established Src substrates, survival, proliferation, and tumor growth. The β3 cytoplasmic tail is required and sufficient for integrin-mediated stimulation of all these events through a mechanism that is independent of β3 tyrosine phosphorylation. Instead, experiments using Src variants containing the v-Src Src homology 3 (SH3) domain and using mutant β3 subunits indicate that a functional interaction of the β3 cytoplasmic tail with the c-Src SH3 domain is required. These findings delineate a novel integrin-controlled oncogenic signaling cascade and suggest that the interaction of αvβ3 with c-Src may represent a novel target for therapeutic intervention. [Cancer Res 2007;67(6):2693–700]
Data from Inhibition of RAS-Mediated Transformation and Tumorigenesis by Targeting the Downstream E3 Ubiquitin Ligase Seven in Absentia Homologue
Authors: Schmidt Rebecca L. , Park Cheol Hong , Ahmed Atique U. , Gundelach Justin H. , Reed Nanette R. , Cheng Shen , Knudsen Bruce E. , Tang Amy H.
Published: March 2023

Abstract
Constitutively active RAS small GTPases promote the genesis of human cancers. An important goal in cancer biology is to identify means of countervailing activated RAS signaling to reverse malignant transformation. Oncogenic K-RAS mutations are found in virtually all pancreatic adenocarcinomas, making the RAS pathway an ideal target for therapeutic intervention. How to best contravene hyperactivated RAS signaling has remained elusive in human pancreatic cancers. Guided by the Drosophila studies, we reasoned that a downstream mediator of RAS signals might be a suitable anti-RAS target. The E3 ubiquitin ligase seven in absentia (SINA) is an essential downstream component of the Drosophila RAS signal transduction pathway. Thus, we determined the roles of the conserved human homologues of SINA, SIAHs, in mammalian RAS signaling and RAS-mediated tumorigenesis. We report that similar to its Drosophila counterpart, human SIAH is also required for oncogenic RAS signaling in pancreatic cancer. Inhibiting SIAH-dependent proteolysis blocked RAS-mediated focus formation in fibroblasts and abolished the tumor growth of human pancreatic cancer cells in soft agar as well as in athymic nude mice. Given the high level of conservation of RAS and SIAH function, our study provides useful insights into altered proteolysis in the RAS pathway in tumor initiation, progression, and oncogenesis. By targeting SIAH, we have found a novel means to contravene oncogenic RAS signaling and block RAS-mediated transformation/tumorigenesis. Thus, SIAH may offer a novel therapeutic target to halt tumor growth and ameliorate RAS-mediated pancreatic cancer. [Cancer Res 2007;67(24):11798–810]
Data from Phosphoinositide-3-Kinase Signaling Controls S-Phase Kinase–Associated Protein 2 Transcription via E2F1 in Pancreatic Ductal Adenocarcinoma Cells
Authors: Reichert Maximilian , Saur Dieter , Hamacher Rainer , Schmid Roland M. , Schneider Günter
Published: March 2023

Abstract
The phosphoinositide-3-kinase (PI3K)/AKT signaling pathway controls fundamental processes of cancer cell biology like proliferation and cell survival. The PI3K/AKT pathway is activated in pancreatic ductal adenocarcinoma (PDAC) cells. The molecular mechanisms linking PI3K signaling to the cell cycle machinery in PDAC cells are not investigated in detail. Using the PI3K inhibitor Ly294002 as well as small interfering RNA targeting AKT1 expression, we show that PI3K controls the proliferation and G1 phase progression of PDAC cells. Gene profiling revealed several important regulators of G1-S phase progression controlled by PI3K signaling like p21Cip1, S-phase kinase–associated protein 2 (SKP2), CDC25a, cyclin A, cyclin D2, CDK2, and cyclin E. We show that the F-box protein SKP2, an oncogene up-regulated in PDAC, is transcriptionally regulated by the PI3K/AKT1 pathway in PDAC cells. At the molecular level, the control of the SKP2 gene by PI3K is due to the regulation of E2F1 binding to the proximal SKP2 gene promoter. The complex and profound connection of PI3K/AKT1 signaling to the cell cycle qualifies this pathway as a suitable target for therapeutic intervention in PDAC. [Cancer Res 2007;67(9):4149–56]
Data from Osteopontin Promotes Vascular Endothelial Growth Factor–Dependent Breast Tumor Growth and Angiogenesis via Autocrine and Paracrine Mechanisms
Authors: Chakraborty Goutam , Jain Shalini , Kundu Gopal C.
Published: March 2023

Abstract
Angiogenesis is the hallmark of cancer, and development of aggressiveness of primary tumor depends on de novo angiogenesis. Here, using multiple in vitro and in vivo models, we report that osteopontin (OPN) triggers vascular endothelial growth factor (VEGF)–dependent tumor progression and angiogenesis by activating breast tumor kinase (Brk)/nuclear factor–inducing kinase/nuclear factor-κB (NF-κB)/activating transcription factor-4 (ATF-4) signaling cascades through autocrine and paracrine mechanisms in breast cancer system. Our results revealed that both exogenous and tumor-derived OPN play significant roles in VEGF-dependent tumor angiogenesis. Clinical specimen analysis showed that OPN and VEGF expressions correlate with levels of neuropilin-1, Brk, NF-κB, and ATF-4 in different grades of breast cancer. Consequently, OPN plays essential role in two key aspects of tumor progression: VEGF expression by tumor cells and VEGF-stimulated neovascularization. Thus, targeting OPN and its regulated signaling network could be a novel strategy to block tumor angiogenesis and may develop an effective therapeutic approach for the management of breast cancer. [Cancer Res 2008;68(1):152–61]
Data from Estrogen Induces Repression of the Breast Cancer and Salivary Gland Expression Gene in an Estrogen Receptor α–Dependent Manner
Authors: Bretschneider Nancy , Brand Heike , Miller Nicola , Lowery Aoife J. , Kerin Michael J. , Gannon Frank , Denger Stefanie
Published: March 2023

Abstract
The focus of this study is on the expression and regulation of the estrogen-regulated breast cancer and salivary gland expression (BASE) gene that may function as a breast cancer marker. In MCF7 cells, BASE is repressed by estrogen in an estrogen receptor α (ERα)-dependent manner. Promoter analysis of the BASE gene led to the identification of a 2-kb upstream enhancer that harbors binding sites for ERα and FoxA1. The recruitment of both ERα and FoxA1 to this region was shown by chromatin immunoprecipitation analysis. Furthermore, mutation studies and knockdown experiments show a clear separation between gene expression mediated by FoxA1 and ERα-dependent gene regulation. Additionally, we provide information on BASE expression in human breast tumor samples. [Cancer Res 2008;68(1):106–14]
Data from Differing Phenotypes between Intraepithelial and Stromal Lymphocytes in Early-Stage Tongue Cancer
Authors: Katou Fuminori , Ohtani Haruo , Watanabe Yoshiko , Nakayama Takashi , Yoshie Osamu , Hashimoto Kenji
Published: March 2023

Abstract
The significance of tumor-infiltrating lymphocytes (TIL) has attracted much attention in relation to the prognosis of patients. We herein examined the activation status of the TILs in relation to the tumor microenvironment. By using frozen sections of human early-stage tongue cancers (n = 22), the TILs in the cancer nests and those in the cancer stroma were compared for the expression of PD-1, NKG2A, NKG2D, CD69, and Ki-67. The lymphocytes in oral lichen planus, an active immune response-mediated mucosal disease, were also analyzed for comparison purposes. All of the cancer specimens were abundantly infiltrated by CD8+ T cells and CD56+ natural killer (NK) cells in the stroma, as well as in the tumor nest. The tumor nest–infiltrating (intraepithelial) CD8+ T cells frequently expressed PD-1, an inhibitory receptor, in sharp contrast to those in the stroma or in the lichen planus. Conversely, the intraepithelial CD8+ T cells only infrequently expressed NKG2D, an activating receptor, in contrast to those in the stroma or in the lichen planus. No intraepithelial CD8+ T cells expressed Ki-67, a proliferation-associated marker, whereas those in the stroma frequently expressed it. Furthermore, the intraepithelial NK cells expressed NKG2A, an inhibitory receptor, more frequently than those in the stroma or the lichen planus. Collectively, the intraepithelial CD8+ T cells and NK cells are phenotypically inactivated, whereas stromal counterparts are phenotypically just as active as those in the lichen planus. These results suggest the first-step occurrence of an immune evasion mechanism in the tumor nest of oral squamous cell carcinoma. [Cancer Res 2007;67(23):11195–201]
Data from Promoter Hypermethylation of the PALB2 Susceptibility Gene in Inherited and Sporadic Breast and Ovarian Cancer
Authors: Potapova Anna , Hoffman Amanda M. , Godwin Andrew K. , Al-Saleem Tahseen , Cairns Paul
Published: March 2023

Abstract
The partner and localizer of BRCA2 (PALB2) gene was recently identified as a BRCA2-interacting protein and subsequently shown to be a Fanconi anemia gene (FANCN). Disease-associated point mutations resulting in protein truncation have been found in BRCA1/2 mutation–negative breast cancer families identifying PALB2 as a susceptibility gene for breast cancer. Aberrant promoter hypermethylation is a mechanism of inactivation of many tumor suppressor genes, including BRCA1 and p16INK4a, in breast and ovarian cancer. We therefore investigated the methylation status of a 1512 bp typical CpG island located in the promoter and exon 1 region of the PALB2 gene in 130 sporadic and familial breast and ovarian primary tumors, 9 cell lines, and 10 normal cell specimens. We found two primary breast tumors from BRCA2 mutation carriers, four sporadic primary breast tumors, and four sporadic primary ovarian tumors showed hypermethylation of the core promoter region of PALB2. All 10 normal tissue DNA had an unmethylated PALB2 promoter region. Quantitative real-time reverse transcription-PCR showed PALB2 expression to be reduced 28-fold in primary breast tumor with PALB2 promoter hypermethylation compared with matched normal breast tissue RNA. Aberrant promoter hypermethylation of PALB2 is more frequent than the reported level of PALB2 point mutations in breast tumors from BRCA1/2-negative families and is similar to the frequency of BRCA1 hypermethylation in inherited and sporadic breast and ovarian cancers. [Cancer Res 2008;68(4):998–1002]
Data from NO Signaling Confers Cytoprotectivity through the Survivin Network in Ovarian Carcinomas
Authors: Engels Knut , Knauer Shirley K. , Loibl Sibylle , Fetz Verena , Harter Philipp , Schweitzer Andrea , Fisseler-Eckhoff Annette , Kommoss Friedrich , Hanker Lars , Nekljudova Valentina , Hermanns Iris , Kleinert Hartmut , Mann Wolf , du Bois Andreas , Stauber Roland H.
Published: March 2023

Abstract
Despite considerable success in the treatment of epithelial ovarian cancer (EOC), therapy resistance counteracts improvement of long-term survival. The dual role of survivin as an apoptosis inhibitor and mitotic regulator has been associated with disease outcome. However, the molecular mechanisms involved in the deregulated expression in EOC of survivin need further investigation. Here, we show that high amounts of the nitric oxide (NO) donors, S-nitroso-N-acetyl-penicillamine (SNAP) and sodium nitroprusside (SNP) or strong overexpression of the inducible nitric oxide synthase (iNOS) suppressed survivin levels via the p38MAPK pathway and triggered apoptosis in ovarian cancer cell lines (OCC). Importantly, low NO concentrations conferred resistance against carboplatin/paclitaxel-induced apoptosis. Cytoprotection was mediated by survivin because we observed its up-regulation subsequent to low SNAP/SNP doses or ectopic expression of low amounts of iNOS. Also, RNAi-mediated depletion of survivin blocked the antiapoptotic effects of NO signaling. Induction of survivin involves activation of the phosphatidylinositol-3-kinase (PI3K)/Akt pathway, which was antagonized by the PI3K-inhibitor, LY294002. Interestingly, application of the iNOS-inhibitor 1400W together with RNAi-mediated survivin down-regulation cooperatively enhanced drug-induced apoptosis in OCCs. The iNOS/survivin interdependencies seem to be also of clinical relevance because immunohistochemistry revealed that low iNOS levels correlate with survivin expression (P < 0.01) in carboplatin/paclitaxel-treated EOC patients with minimal postoperative residual tumor (n = 54). Also, iNOS and survivin expression were associated with increased risk for disease progression. Our study uncovers a novel molecular mechanism of how NO signaling may contribute to therapy resistance in EOC by modulating survivin expression. Pharmacogenetic iNOS/survivin-targeting strategies may hence be pursued to complement current treatment modalities in EOC. [Cancer Res 2008;68(13):5159–65]
Data from AXL Is a Potential Target for Therapeutic Intervention in Breast Cancer Progression
Authors: Zhang Yi-Xiang , Knyazev Peter G. , Cheburkin Yuri V. , Sharma Kirti , Knyazev Yuri P. , Őrfi László , Szabadkai István , Daub Henrik , Kéri György , Ullrich Axel
Published: March 2023

Abstract
Protein kinases play important roles in tumor development and progression. A variety of members of this family of signal transduction enzymes serve as targets for therapeutic intervention in cancer. We have identified the receptor tyrosine kinase (RTK) AXL as a potential mediator of motility and invasivity of breast cancer cells. AXL is expressed in most highly invasive breast cancer cells, but not in breast cancer cells of low invasivity. Ectopic expression of AXL was sufficient to confer a highly invasive phenotype to weakly invasive MCF7 breast cancer cells. Experimental inhibition of AXL signaling by a dominant-negative AXL mutant, an antibody against the extracellular domain of AXL, or short hairpin RNA knockdown of AXL decreased motility and invasivity of highly invasive breast cancer cells. To selectively interfere with cancer cell properties defining the rate of disease progression, we identified 3-quinolinecarbonitrile compounds, which displayed potent inhibitory activity against AXL and showed strong interference with motility and invasivity of breast cancer cells. Our findings validated the RTK AXL as a critical element in the signaling network that governs motility and invasivity of breast cancer cells, and allowed the identification of experimental anti-AXL small molecular inhibitors that represent lead substances for the development of antimetastatic breast cancer therapy. [Cancer Res 2008;68(6):1905–15]
Data from Quantitative Analysis of DNA Methylation Profiles in Lung Cancer Identifies Aberrant DNA Methylation of Specific Genes and Its Association with Gender and Cancer Risk Factors
Authors: Vaissière Thomas , Hung Rayjean J. , Zaridze David , Moukeria Anush , Cuenin Cyrille , Fasolo Virginie , Ferro Gilles , Paliwal Anupam , Hainaut Pierre , Brennan Paul , Tost Jörg , Boffetta Paolo , Herceg Zdenko
Published: March 2023

Abstract
The global increase in lung cancer burden, together with its poor survival and resistance to classical chemotherapy, underscores the need for identification of critical molecular events involved in lung carcinogenesis. Here, we have applied quantitative profiling of DNA methylation states in a panel of five cancer-associated genes (CDH1, CDKN2A, GSTP1, MTHFR, and RASSF1A) to a large case-control study of lung cancer. Our analyses revealed a high frequency of aberrant hypermethylation of MTHFR, RASSF1A, and CDKN2A in lung tumors as compared with control blood samples, whereas no significant increase in methylation levels of GSTP1 and CDH1 was observed, consistent with the notion that aberrant DNA methylation occurs in a tumor-specific and gene-specific manner. Importantly, we found that tobacco smoking, sex, and alcohol intake had a strong influence on the methylation levels of distinct genes (RASSF1A and MTHFR), whereas folate intake, age, and histologic subtype had no significant influence on methylation states. We observed a strong association between MTHFR hypermethylation in lung cancer and tobacco smoking, whereas methylation levels of CDH1, CDKN2A, GSTP1, and RASSF1A were not associated with smoking, indicating that tobacco smoke targets specific genes for hypermethylation. We also found that methylation levels in RASSF1A, but not the other genes under study, were influenced by sex, with males showing higher levels of methylation. Together, this study identifies aberrant DNA methylation patterns in lung cancer and thus exemplifies the mechanism by which environmental factors may interact with key genes involved in tumor suppression and contribute to lung cancer. [Cancer Res 2009;69(1):243–52]
Data from Different Roles of Estrogen Receptors α and β in the Regulation of E-Cadherin Protein Levels in a Mouse Mammary Epithelial Cell Line
Authors: Helguero Luisa A. , Lindberg Karolina , Gardmo Cissi , Schwend Thomas , Gustafsson Jan-Åke , Haldosén Lars-Arne
Published: March 2023

Abstract
Two estrogen receptors (ERα and ERβ) are found throughout the mammary gland. Evidence indicates that, while ERα transduces proliferation signals, ERβ opposes this effect and is necessary for epithelial differentiation. Using mouse mammary epithelial cells, we have previously shown that activation of ERβ opposes ERα-induced proliferation and increases apoptosis. Furthermore, stable knockdown of ERβ resulted in loss of growth contact inhibition. In this work, we report that loss of ERβ is associated with a decrease of E-cadherin protein levels through different posttranscriptional regulatory mechanisms. Ligand activation of ERα induced E-cadherin extracellular shedding and internalization only in the absence of ERβ, followed by lysosomal degradation. Loss of ERβ also led to an increase of E-cadherin uptake in a ligand-independent manner through mechanisms that required caveolae formation. Proteasome activity was necessary for both mechanisms to operate. Increased E-cadherin internalization correlated with the up-regulation of β-catenin transcriptional activity and impaired morphogenesis on Engelbreth-Holm-Swarm matrix. Taken together, these results emphasize the role of epithelial ERβ in maintaining cell adhesion and a differentiated phenotype and highlight the potential importance of ERβ for the design of specific agonists for use in breast cancer therapy. [Cancer Res 2008;68(21):8695–704]
Supplementary Methods S2 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

supplementary methods: Detailed laboratory methods
Supplementary Figure S1 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

Endpoint titers of plasma antibodies at week 12 amongst vaccine responders
Supplementary Data from The Road to Personalized Myeloma Medicine: Patient-specific Single-domain Antibodies for Anti-idiotypic Radionuclide Therapy
Authors: Puttemans Janik , Stijlemans Benoit , Keyaerts Marleen , Vander Meeren Sam , Renmans Wim , Fostier Karel , Debie Pieterjan , Hanssens Heleen , Rodak Magdalena , Pruszynski Marek , De Veirman Kim , Vanderkerken Karin , Lahoutte Tony , Morgenstern Alfred , Bruchertseifer Frank , Devoogdt Nick , D'Huyvetter Matthias
Published: March 2023

Supplementary Data
Data 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

Abstract
The interaction between neoplastic and stromal cells within a tumor mass plays an important role in cancer biology. However, it is challenging to distinguish between tumor and stromal cells in mesenchymal tumors since lineage-specific cell surface markers typically used in other cancers do not distinguish between the different cell subpopulations. Desmoid tumors consist of mesenchymal fibroblast-like cells driven by mutations stabilizing beta-catenin. Here we aimed to identify surface markers that can distinguish mutant cells from stromal cells to study tumor-stroma interactions. We analyzed colonies derived from single cells from human desmoid tumors using a high throughput surface antigen screen, to characterize the mutant and non-mutant cells. We found that CD142 is highly expressed by the mutant cell populations and correlates with beta-catenin activity. CD142-based cell sorting isolated the mutant population from heterogeneous samples, including one where no mutation was previously detected by traditional Sanger sequencing. We then studied the secretome of mutant and non-mutant fibroblastic cells. PTX3 is one stroma-derived secreted factor that increases mutant cell proliferation via STAT6 activation. These data demonstrate a sensitive method to quantify and distinguish neoplastic from stromal cells in mesenchymal tumors. It identifies proteins secreted by non-mutant cells that regulate mutant cell proliferation that could be therapeutically.
Association of Circulating Procoagulant Microvesicles with Painful Vaso-Occlusive Crisis in Sickle Cell Disease
Authors: Hashemi Tayer Akbar , Ranjbaran Reza , Kamravan Maryam , Abbasi Mojdeh , Zareian Reyhaneh
Published: March 2023

Introduction: Thrombotic complication is one of the features of sickle cell disease (SCD), characterized by appearance of phosphatidylserine on the outer membrane of sickle-shaped red blood cells and most abundantly on membrane protrusions called microvesicles (MVs). However, the exact mechanism by which MVs may enhance coagulant activity in SCD patients has not been fully addressed. The aim of this study was to further investigate the procoagulant activity of circulating MVs in sickle cell crises. Materials and Methods: Subjects included in this cross-sectional study were 47 patients with SCD and 25 normal subjects with written informed consent obtained from all the participants. MV analysis was conducted by using CD61, CD235α, and Annexin-V monoclonal antibodies. The coagulant activity of MVs was determined by an ELISA-based procoagulant activity assay. Results: The majority of MVs were originated from platelets (CD61+) and erythrocytes (CD235+). These MVs demonstrated significantly enhanced levels during the painful crisis when compared with the steady-state period (p < 0.001) and controls (p < 0.001). Also, the procoagulant activity of MVs was significantly higher in crisis compared to those of steady state (p < 0.001) and positively correlated with the number of Annexin-V+ MVs (p < 0.001). Significant correlations were found between erythrocyte-derived MVs with hemolysis marker (r = 0.51, p < 0.001) and the hemoglobin level (r = −0.63, p < 0.001). Conclusion: The numbers of platelet- and erythrocyte-derived MVs are related to painful crisis, and their quantification in SCD may be helpful for identifying cases at increased risk of thrombotic complications.
Supervised, Self-Administered Tablet-Based Cognitive Assessment in Neurodegenerative Disorders and Stroke
Authors: Sloane Kelly L. , Fabian Rachel , Wright Amy , Saxena Sadhvi , Kim Kevin , Stein Colin M. , Keser Zafer , Glenn Shenly , Hillis Argye E.
Published: March 2023

Introduction: As the population ages, the prevalence of cognitive impairment is expanding. Given the recent pandemic, there is a need for remote testing modalities to assess cognitive deficits in individuals with neurological disorders. Self-administered, remote, tablet-based cognitive assessments would be clinically valuable if they can detect and classify cognitive deficits as effectively as traditional in-person neuropsychological testing. Methods: We tested whether the Miro application, a tablet-based neurocognitive platform, measured the same cognitive domains as traditional pencil-and-paper neuropsychological tests. Seventy-nine patients were recruited and then randomized to either undergo pencil-and-paper or tablet testing first. Twenty-nine age-matched healthy controls completed the tablet-based assessments. We identified Pearson correlations between Miro tablet-based modules and corresponding neuropsychological tests in patients and compared scores of patients with neurological disorders with those of healthy controls using t tests. Results: Statistically significant Pearson correlations between the neuropsychological tests and their tablet equivalents were found for all domains with moderate (r > 0.3) or strong (r > 0.7) correlations in 16 of 17 tests (p < 0.05). All tablet-based subtests differentiated healthy controls from neurologically impaired patients by t tests except for the spatial span forward and finger tapping modules. Participants reported enjoyment of the tablet-based testing, denied that it provoked anxiety, and noted no preference between modalities. Conclusions: This tablet-based application was found to be widely acceptable to participants. This study supports the validity of these tablet-based assessments in the differentiation of healthy controls from patients with neurocognitive deficits in a variety of cognitive domains and across multiple neurological disease etiologies.
The Not-So-Distant Future or Just Hype? Utilizing Machine Learning to Predict 30-Day Post-Operative Complications in Laparoscopic Colectomy Patients
Authors: Velmahos Constantine S. , Paschalidis Aris , Paranjape Charudutt N.
Published: March 2023

Background

Complex machine learning (ML) models have revolutionized predictions in clinical care. However, for laparoscopic colectomy (LC), prediction of morbidity by ML has not been adequately analyzed nor compared against traditional logistic regression (LR) models.

Methods

All LC patients, between 2017 and 2019, in the National Surgical Quality Improvement Program (NSQIP) were identified. A composite outcome of 17 variables defined any post-operative morbidity. Seven of the most common complications were additionally analyzed. Three ML models (Random Forests, XGBoost, and L1-L2-RFE) were compared with LR.

Results

Random Forests, XGBoost, and L1-L2-RFE predicted 30-day post-operative morbidity with average area under the curve (AUC): .709, .712, and .712, respectively. LR predicted morbidity with AUC = .712. Septic shock was predicted with AUC ≤ .9, by ML and LR.

Conclusion

There was negligible difference in the predictive ability of ML and LR in post-LC morbidity prediction. Possibly, the computational power of ML cannot be realized in limited datasets.
Commercialization Strategies of Large-Scale and Distributed Open Innovation: The Case of Open-Source Hardware
Authors: Rayna Thierry , Striukova Ludmila , Fauchart Emmanuelle
Published: March 2023

The ability to commercialize products based on distributed innovation is one of the critical challenges of large-scale open innovation. While this issue has been largely investigated in relation to open-source software (OSS), the literature on commercialization strategies of open-source hardware (OSHW) is comparatively scarce, despite OSHW commercialization being more complex. Based on a multi-method exploratory study, this article shows that with OSHW, firms may strategically leverage a “gray area” between closeness and openness to take advantage of OSWH community innovations.
Growth and Potential of Intra-Industry Trade of India in Agriculture among the BIMSTEC Nations
Authors: Bhardwaj Mandeep , Mahapatra Sushanta Kumar , Dutta Tanima , Bhangu Jyotsana
Published: March 2023

The unification and development of crawling Asian countries is the burning issue after the declaration of failure of the SAARC (South Asian Association for Regional Cooperation) region. Besides, a small bubble in the ocean of agreements is ‘BIMSTEC’ (Bay of Bengal Initiative for Multi-Sectoral Technical and Economic Cooperation), which has not been flourishing to date due to the lack of interest of a dominating country like India, whose focus is on other successful regional blocs. However, recent studies have shown that though it starts late but contributing significantly towards the trade among BIMSTEC countries. And, second, almost all the countries have shared similar cultures, languages and levels of per-capita income except Myanmar and Thailand, which will favour the trade among the region. Thus, the main focus of the study is to analyse the revealed comparative advantage of countries in BIMSTEC, their trade competitiveness and contribution made to the country’s growth before and after formation by the region. Under the study, it was observed that the intra-industry trades of India in Agriculture among the BIMSTEC nations have shown very less potential for trade in all 24 agriculture chapters. Thus, economies need to reframe the policies as required and identify the potential products in agricultural-related goods that can significantly improve the trade balance of the countries.

JEL Codes: F14, F15, F19, F53
Effectiveness of Interventions on Death Anxiety and Fear in Adults with Chronic Disease: A Systematic Review and Meta-Analysis of Randomized Controlled Trials
Authors: Gulbahar Eren Merve , Üçgül Kübra , Sert Havva
Published: March 2023

This systematic review and meta-analysis aimed to synthesize the outcomes of various interventions to alleviate death anxiety and fear. Studies published between January 2010 and June 2022 were searched in the ScienceDirect, Scopus, Web of Science, PubMed, Cochrane Library, and CHINAL databases. The Preferred Reporting Items for Systematic Reviews and Meta-analyses statement guidelines were used in this meta-analysis. The results were examined using 95% confidence intervals, p-values, and fixed- or random-effects models based on the heterogeneity test. Sixteen studies involving 1262 participants were included in this systematic review. Interventions in seven studies using the Templer Death Anxiety Scale (TDAS) significantly decreased death anxiety levels in the intervention groups compared to the control groups (z = −4.47; p < 0.001; 95% CI: −3.36 to −1.31). This meta-analysis provides insights into implementing logotherapy, cognitive behavioral therapy, spirituality-based care, and educational interventions for death anxiety and the fear experienced by patients with chronic diseases.
Navigating the Risks of Party Rape in Historically White Greek Life at an Elite College: Women’s Accounts
Authors: Ispa-Landa Simone , Thomas Sara E.
Published: March 2023

Landmark research from before the 2010s shows that college women rarely held institutions responsible for allowing rape-prone party contexts to persist and failing to support survivors. Yet the college landscape has changed profoundly since these studies were published, with prominent anti-rape campaigns and new guidelines to Title IX policy. To update a research stream that has provided the basis for theorizing about sexual violence in college peer cultures, we examine 121 intensive interviews with 68 women who are at heightened risk of party rape because of their involvement in historically White sororities. Several key findings emerged. First, women were highly invested in the Greek party circuit. Second, participants blamed institutions for failing to do more to keep them safe. Reflecting their focus on institutions, women also proposed that institutional authorities change their policies so sororities could move parties out of fraternity houses and into sorority houses. Third, women took on the labor of trying to protect themselves and other women at parties by designating monitors. However, they reported that with this system, other women could be deemed responsible, not for being assaulted but for failing to prevent rape. Finally, women found ways to identify and exclude men they deemed “rapey” from Greek gatherings. However, boycotting an entire fraternity was more controversial and harder to sustain. Overall, women’s preferred prevention strategies reflect a strong desire to avoid disturbing the Greek party scene. Implications for research and policy on gender and sexual violence prevention in higher education are discussed.
Beyond the pale: Fencing off parks for festivals
Authors: Smith Andrew
Published: March 2023

Pale is the Old English word for fence, and the phrase ‘to go beyond the pale’ means to stray beyond the limits of acceptable action. In this critical commentary I discuss whether the installation of temporary fencing in public parks to secure ticketed festivals is now beyond the pale. Fences restrict access but they also affect how park spaces are perceived, used and managed. I use photographs taken in three different London parks to illustrate the materiality of these temporary structures, but also their aesthetic impact, symbolic significance and lasting legacies. I argue that temporary fences have enduring effects on parks and public spaces by discouraging everyday use, by preparing the ground for future incursions, and by normalising and festivalising barriers that restrict access. My commentary highlights the often overlooked importance of fences and illustrates the splintered and sequestered nature of contemporary cities – where citizens are increasingly fenced off.
The impact of social media marketing on the dissemination of mini program in social network with different community structure
Authors: Tian Tian , Zhao Narisa
Published: March 2023

Mini program has become an important infrastructure for the Internetisation of traditional brands. Previous studies have mostly explored the design and development of mini program, but little research has been conducted on the mini program dissemination process. Studying the impact of social media marketing on the mini program dissemination process has important theoretical and applicable value for the in-depth discovery of the mini program dissemination mechanism and the marketing strategies improvement for mini program operators. Based on the classical Susceptible–Infected–Recovered (SIR) epidemic dissemination dynamic model and combined with the Sense, Interest and Interactive, Connect and Diffusion, Action and Share user behaviour consumption model, we propose a mini program propagation model considering social media marketing and community structure, and establish a set of differential equations reflecting the mini program propagation rules. The validity of the model and experimental results are verified through the comparison among the simulation, actual data and numerical experimental results. The experimental results show that the improvement of social media marketing can considerably promote the dissemination of mini program. Surprisingly, with the same social media marketing investment, the dissemination effect of mini program in a weak community is better than that in a strong community. The reason for this is that the higher clustering coefficient fails to offset the negative impact of high modularity on marketing information dissemination. Consequently, compared with the marketing needs of the weak community structure, more social media marketing efforts need to be invested in the strong community structure. Improving social media marketing in the early stages of dissemination can maximise the marketing effect. Moreover, the effect of combining of advertising marketing and interactive marketing in social media marketing is better than that of a single marketing strategy.
“You Hide Pieces of Yourself”: Navigating White Spaces as U.S. Missionaries of Color
Authors: Huang Lindsey A. , Blandón Norlan Josué Hernández
Published: March 2023

While extensive research has been conducted on the experiences of racial and ethnic minorities in predominately white institutions (PWIs) in the United States, there has been little research that examines the experiences of U.S. racial and ethnic minorities that serve for religious reasons with PWIs in international settings. Therefore, the purpose of this study was to understand how race shapes the relationship of long-term U.S. missionaries of color with their missions organization and teammates. Semi-structured, in-depth interviews were conducted with sixteen long-term U.S. missionaries of color serving internationally. The findings point to a number of ways that race shapes the experiences of these missionaries and have important implications for cross-cultural workers of diverse backgrounds as well as cross-cultural work teams and sending organizations. The results also point to the need for more research on diverse work teams in international settings.
Improving masticatory and swallowing ability of postoperative oral and maxillofacial tumor patients by telerehabilitation—A randomized controlled trial
Authors: Pang Pai , Lin Shanfeng , Chen Haiwei , Shan Yubo , Sun Changfu
Published: March 2023

Objective

To evaluate the effect of telerehabilitation on oral function of oral and maxillofacial tumor patients.

Design

Unicentral, single-blind, randomized controlled trial.

Setting

Community.

Subjects

Patients with primary oral and maxillofacial tumor receiving surgical treatment.

Interventions

Telerehabilitation guidance from therapists.

Main measures

At the beginning of training (T0) and 1 month (T1), 3 months (T2) and 6 months (T3) after training, patients’ masticatory ability (mastication efficiency—masticatory performance evaluating gum, maximum bite force and mouth opening) and swallowing ability (water swallowing test) was measured. Modified Sato questionnaire and MD Anderson dysphagia inventory (MDADI) were used for self-evaluation of masticatory and swallowing ability.

Results

A total of 64 participants (intervention: 33; control: 31) were included. The masticatory efficiency scores of the intervention group were significantly better than those of the control group at T2 (intervention: 3.67 (0.48); control: 3.03 (0.85)) and T3 (intervention: 4.20 (0.30); control: 3.50 (0.79)); and maximum mouth opening was better at T2 (intervention: 3.18 (0.59); control: 2.77 (0.54)) and T3 (intervention: 3.54 (0.58); control: 3.09 (0.41)). In water swallowing test, the intervention group had better scores at T2 and T3. The scores of MDADI scale in intervention group were better than those in the control group after 3 months of training. In subgroup analysis, the intervention group of oral cancer patients had better swallowing function at T2 and T3, but no significant difference was found in the subgroup of oropharyngeal cancer.

Conclusions

Telerehabilitation could greatly improve the long-term (3–6 months) training effect under the condition of greatly saving medical resources and reducing personnel contact.
A pilot study of lymphoscintigraphy with tracer injection into the human brain
Authors: Coxon Andrew T , Desai Rupen , Patel Pujan R , Vellimana Ananth K , Willie Jon T , Dowling Joshua L , Leuthardt Eric C , Kim Albert H , Johanns Tanner M , Siegel Barry A , Dunn Gavin P
Published: March 2023

Many groups have reported lymphatic and glymphatic structures in animal and human brains, but tracer injection into the human brain to demonstrate real-time lymphatic drainage and mapping has not been described. We enrolled patients undergoing standard-of-care resection or stereotactic biopsy for suspected intracranial tumors. Patients received peritumoral injections of 99mTc-tilmanocept followed by planar or tomographic imaging. Fourteen patients with suspected brain tumors were enrolled. One was excluded from analysis because of tracer leakage during injection. There was no drainage of 99mTc-tilmanocept to regional lymph nodes in any of the patients. On average, after correcting for radioactive decay, 70.7% (95% CI: 59.9%, 81.6%) of the tracer in the injection site and 78.1% (95% CI: 71.1%, 85.1%) in the whole-head on the day of surgery remained the morning after, with variable radioactivity in the subarachnoid space. The retained fraction was much greater than expected based on the clearance rate from non-brain injection sites. In this pilot study, the lymphatic tracer 99mTc-tilmanocept was injected into the brain parenchyma, and there was no drainage outside the brain to the cervical lymph nodes. Our work demonstrates an inefficiency of drainage from peritumoral brain parenchyma and highlights a therapeutic opportunity to improve immunosurveillance of the brain.
How low can we go? CT dose reduction in the assessment of the medial clavicular epiphysis in forensic age estimation: a prospective postmortem CT study
Authors: Mehnert Silke , Berger Nicole , Flach Patricia M , Thali Michael J , Ampanozi Garyfalia , Franckenberg Sabine
Published: March 2023

Background

Projection radiography and, more recently, computed tomography (CT) play an important role in forensic age estimation. Both in terms of general criminal responsibility and government regulations concerning refugee care, it is important to differentiate correctly between youths and adults. A disadvantage of age estimation in CT is the ionizing radiation exposure.

Purpose

To investigate how far the CT dose can be reduced without losing diagnostic confidence in assessing the different stages of ossification of the medial clavicle.

Material and Methods

We prospectively scanned 25 postmortem cases with a fixed parameters protocol (FPP) and a care dose modulation protocol (CDMP) for different scan parameters. Two radiologists assessed the diagnostic image quality using a 5-point Likert scale. Inter-reader agreement was evaluated with Cohen's kappa. Differences in doses between FPP and CDMP were assessed with the one-tailed t-test.

Results

The best combination of diagnostic image quality and lowest radiation dose was obtained using a CDMP with 100 kV and 40 mAs and an FPP with 100 kV and 30 mAs. Doses for 120 kV were significantly higher (one-tailed P < 0.001). The diagnostic image quality for 80 kV was insufficient overall.

Discussion

Our results confirm that CT imaging at 100 kV allows a sufficient image quality that is diagnostic for age estimation in the ossification of the medial clavicle.