bluuebunny/crossref_metadata_2025 huggingface dataset:
Data from Antifolate Activity of Pyrimethamine Enhances Temozolomide-Induced Cytotoxicity in Melanoma Cells
Authors: Chen Ming , Osman Iman , Orlow Seth J.
Published: April 2023

Abstract
Most metastatic melanoma patients fail to respond to available therapy, underscoring the need to develop more effective treatments. We screened 2,000 compounds from the Spectrum Library in human melanoma cell lines to identify compounds that enhanced the cytotoxic effect of temozolomide, a drug used to treat metastatic melanoma.

Screening was done with the temozolomide-resistant melanoma cell line SK-MEL-19, and six compounds were identified that had little or no inherent cytotoxicity but significantly enhanced growth-inhibition by temozolomide. These compounds were tested in five additional melanoma cell lines. Cell proliferation and death assays were used to compare the efficacy of single agent temozolomide versus combination treatments. Effects of combination treatment on levels of DNA double-strand breaks, the DNA repair protein O6-methylguanine-DNA-methyltransferase, apoptosis [measured by cleaved caspase-3 and poly(ADP-ribose) polymerase], and cell cycle were examined. Pyrimethamine, an antiparasitic, sensitized melanoma cells to temozolomide. Temozolomide combined with Pyrimethamine synergistically inhibited cell proliferation in melanoma cells with combination index values of 0.7 or less. In addition, combination treatment induced cell cycle arrest and increased both DNA damage and apoptosis. The increase in cell death due to combination treatment was rescued by leucovorin. Other folate antagonists were also effective enhancers of temozolomide-induced cytotoxicity, and the effects of antifolates were also evident in gliomas. Our screening approach led to the identification of Pyrimethamine, an orally available drug that efficiently crosses the blood-brain barrier, as a potent enhancer of the efficacy of temozolomide as an antineoplastic agent via inhibition of folate metabolism. (Mol Cancer Res 2009;7(5):703–12)
Data from Aldehyde Dehydrogenase 1 Is a Tumor Stem Cell-Associated Marker in Lung Cancer
Authors: Jiang Feng , Qiu Qi , Khanna Abha , Todd Nevins W. , Deepak Janaki , Xing Lingxiao , Wang Huijun , Liu Zhenqiu , Su Yun , Stass Sanford A. , Katz Ruth L.
Published: April 2023

Abstract
Tumor contains small population of cancer stem cells (CSC) that are responsible for its maintenance and relapse. Analysis of these CSCs may lead to effective prognostic and therapeutic strategies for the treatment of cancer patients. We report here the identification of CSCs from human lung cancer cells using Aldefluor assay followed by fluorescence-activated cell sorting analysis. Isolated cancer cells with relatively high aldehyde dehydrogenase 1 (ALDH1) activity display in vitro features of CSCs, including capacities for proliferation, self-renewal, and differentiation, resistance to chemotherapy, and expressing CSC surface marker CD133. In vivo experiments show that the ALDH1-positive cells could generate tumors that recapitulate the heterogeneity of the parental cancer cells. Immunohistochemical analysis of 303 clinical specimens from three independent cohorts of lung cancer patients and controls show that expression of ALDH1 is positively correlated with the stage and grade of lung tumors and related to a poor prognosis for the patients with early-stage lung cancer. ALDH1 is therefore a lung tumor stem cell-associated marker. These findings offer an important new tool for the study of lung CSCs and provide a potential prognostic factor and therapeutic target for treatment of the patients with lung cancer. (Mol Cancer Res 2009;7(3):330–8)
Data from Ablation of Sphingosine Kinase-2 Inhibits Tumor Cell Proliferation and Migration
Authors: Gao Peng , Smith Charles D.
Published: April 2023

Abstract
Sphingosine kinases (SK) regulate the balance between proapoptotic ceramides and mitogenic sphingosine-1-phosphate (S1P); however, the functions of the two isoenzymes (SK1 and SK2) in tumor cells are not well defined. Therefore, RNA interference was used to assess the individual roles of SK1 and SK2 in tumor cell sphingolipid metabolism, proliferation, and migration/invasion. Treatment of A498, Caki-1, or MDA-MB-231 cells with siRNAs specific for SK1 or SK2 effectively suppressed the expression of the target mRNA and protein. Ablation of SK1 did not affect mRNA or protein levels of SK2 and reduced intracellular levels of S1P while elevating ceramide levels. In contrast, ablation of SK2 elevated mRNA, protein, and activity levels of SK1 and increased cellular S1P levels. Interestingly, cell proliferation and migration/invasion were suppressed more by SK2-selective ablation than by SK1-selective ablation, showing that the increased S1P does not rescue these phenotypes. Similarly, exogenous S1P did not rescue the cells from the antiproliferative or antimigratory effects of the siRNAs. Consistent with these results, differential effects of SK1- and SK2-selective siRNAs on signaling proteins, including p53, p21, ERK1, ERK2, FAK, and VCAM1, indicate that SK1 and SK2 have only partially overlapping functions in tumor cells. Overall, these data indicate that loss of SK2 has stronger anticancer effects than does suppression of SK1. Consequently, selective inhibitors of SK2 may provide optimal targeting of this pathway in cancer chemotherapy. Mol Cancer Res; 9(11); 1509–19. ©2011 AACR.
Data from Lrig1 Is an Estrogen-Regulated Growth Suppressor and Correlates with Longer Relapse-Free Survival in ERα-Positive Breast Cancer
Authors: Krig Sheryl R. , Frietze Seth , Simion Catalina , Miller Jamie K. , Fry Will H.D. , Rafidi Hanine , Kotelawala Lakmal , Qi Lihong , Griffith Obi L. , Gray Joe W. , Carraway Kermit L. , Sweeney Colleen
Published: April 2023

Abstract
Lrig1 is the founding member of the Lrig family and has been implicated in the negative regulation of several oncogenic receptor tyrosine kinases including ErbB2. Lrig1 is expressed at low levels in several cancer types but is overexpressed in some prostate and colorectal tumors. Given this heterogeneity, whether Lrig1 functions to suppress or promote tumor growth remains a critical question. Previously, we found that Lrig1 was poorly expressed in ErbB2-positive breast cancer, suggesting that Lrig1 has a growth-inhibitory role in this tumor type. However, breast cancer is a complex disease, with ErbB2-positive tumors accounting for just 25% of all breast cancers. To gain a better understanding of the role of Lrig1 in breast cancer, we examined its expression in estrogen receptor α (ERα)-positive disease which accounts for the majority of breast cancers. We find that Lrig1 is expressed at significantly higher levels in ERα-positive disease than in ERα-negative disease. Our study provides a molecular rationale for Lrig1 enrichment in ERα-positive disease by showing that Lrig1 is a target of ERα. Estrogen stimulates Lrig1 accumulation and disruption of this induction enhances estrogen-dependent tumor cell growth, suggesting that Lrig1 functions as an estrogen-regulated growth suppressor. In addition, we find that Lrig1 expression correlates with prolonged relapse-free survival in ERα-positive breast cancer, identifying Lrig1 as a new prognostic marker in this setting. Finally, we show that ErbB2 activation antagonizes ERα-driven Lrig1 expression, providing a mechanistic explanation for Lrig1 loss in ErbB2-positive breast cancer. This work provides strong evidence for a growth-inhibitory role for Lrig1 in breast cancer. Mol Cancer Res; 9(10); 1406–17. ©2011 AACR.
Data from Rictor Phosphorylation on the Thr-1135 Site Does Not Require Mammalian Target of Rapamycin Complex 2
Authors: Boulbes Delphine , Chen Chien-Hung , Shaikenov Tattym , Agarwal Nitin K. , Peterson Timothy R. , Addona Terri A. , Keshishian Hasmik , Carr Steven A. , Magnuson Mark A. , Sabatini David M. , Sarbassov Dos D.
Published: April 2023

Abstract
In animal cells, growth factors coordinate cell proliferation and survival by regulating the phosphoinositide 3-kinase/Akt signaling pathway. Deregulation of this signaling pathway is common in a variety of human cancers. The PI3K-dependent signaling kinase complex defined as mammalian target of rapamycin complex 2 (mTORC2) functions as a regulatory Ser-473 kinase of Akt. We find that activation of mTORC2 by growth factor signaling is linked to the specific phosphorylation of its component rictor on Thr-1135. The phosphorylation of this site is induced by the growth factor stimulation and expression of the oncogenic forms of ras or PI3K. Rictor phosphorylation is sensitive to the inhibition of PI3K, mTOR, or expression of integrin-linked kinase. The substitution of wild-type rictor with its specific phospho-mutants in rictor null mouse embryonic fibroblasts did not alter the growth factor–dependent phosphorylation of Akt, indicating that the rictor Thr-1135 phosphorylation is not critical in the regulation of the mTORC2 kinase activity. We found that this rictor phosphorylation takes place in the mTORC2-deficient cells, suggesting that this modification might play a role in the regulation of not only mTORC2 but also the mTORC2-independent function of rictor. Mol Cancer Res; 8(6); 896–906. ©2010 AACR.
Data from HuR-Mediated Control of C/EBPβ mRNA Stability and Translation in ALK-Positive Anaplastic Large Cell Lymphomas
Authors: Bergalet Julie , Fawal Mohamad , Lopez Celine , Desjobert Cecile , Lamant Laurence , Delsol Georges , Morello Dominique , Espinos Estelle
Published: April 2023

Abstract
The CCAAT/enhancer-binding protein β (C/EBPβ) plays a major role in the pathogenesis of anaplastic large cell lymphomas (ALCL) that express the nucleophosmin-anaplastic lymphoma kinase (NPM-ALK) tyrosine kinase (ALK+). Although ALK-mediated C/EBPβ transcriptional activation has been reported, C/EBPβ mRNA possesses U- and AU-rich domains in its 3′-untranslated region (3′-UTR) that might be privileged targets for posttranscriptional control in ALK+ ALCLs. The purpose of this study was to explore this possibility. By using human ALCL-derived cells and a murine model of ALK-transformed cells, we show that the AU-binding protein HuR binds to the 3′-UTR of C/EBPβ mRNA, as previously reported in adipocytes, and that NPM-ALK enhances this interaction. Interaction between HuR and C/EBPβ mRNA impacts on C/EBPβ gene expression at both the mRNA and protein levels. Indeed, C/EBPβ mRNA stability following HuR silencing is reduced and reaches the value observed in ALK-inactivated cells. Remarkably, HuR expression is not modified by NPM-ALK, but its association with actively translating polysomes is dramatically increased in ALK+ cells. HuR/polysomes association diminishes when NPM-ALK activity is inhibited and is accompanied by a concomitant decrease of C/EBPβ mRNA translation. Finally, we show that HuR and NPM-ALK colocalized in cytoplasmic granules and HuR is phosphroylated on tyrosine residues in ALK+ ALCL cells. Our study thus demonstrates that C/EBPβ is indeed regulated at the posttranscriptional level by HuR in ALK+ cells, leading us to propose that part of NPM-ALK oncogenic properties relies on its ability to modify HuR properties in the cytoplasm and hence to alter expression of key actors of transformation. Mol Cancer Res; 9(4); 485–96. ©2011 AACR.
Data from Functional Inactivation of Endogenous MDM2 and CHIP by HSP90 Causes Aberrant Stabilization of Mutant p53 in Human Cancer Cells
Authors: Li Dun , Marchenko Natalia D. , Schulz Ramona , Fischer Victoria , Velasco-Hernandez Talia , Talos Flaminia , Moll Ute M.
Published: April 2023

Abstract
The tight control of wild-type p53 by mainly MDM2 in normal cells is permanently lost in tumors harboring mutant p53, which exhibit dramatic constitutive p53 hyperstabilization that far exceeds that of wild-type p53 tumors. Importantly, mutant p53 hyperstabilization is critical for oncogenic gain of function of mutant p53 in vivo. Current insight into the mechanism of this dysregulation is fragmentary and largely derived from ectopically constructed cell systems. Importantly, mutant p53 knock-in mice established that normal mutant p53 tissues have sufficient enzymatic reserves in MDM2 and other E3 ligases to maintain full control of mutant p53. We find that in human cancer cells, endogenous mutant p53, despite its ability to interact with MDM2, suffers from a profound lack of ubiquitination as the root of its degradation defect. In contrast to wild-type p53, the many mutant p53 proteins which are conformationally aberrant are engaged in complexes with the HSP90 chaperone machinery to prevent its aggregation. In contrast to wild-type p53 cancer cells, we show that in mutant p53 cancer cells, this HSP90 interaction blocks the endogenous MDM2 and CHIP (carboxy-terminus of Hsp70-interacting protein) E3 ligase activity. Interference with HSP90 either by RNA interference against HSF1, the transcriptional regulator of the HSP90 pathway, or by direct knockdown of Hsp90 protein or by pharmacologic inhibition of Hsp90 activity with 17AAG (17-allylamino-17-demethoxygeldanamycin) destroys the complex, liberates mutant p53, and reactivates endogenous MDM2 and CHIP to degrade mutant p53. Of note, 17AAG induces a stronger viability loss in mutant p53 than in wild-type p53 cancer cells. Our data support the rationale that suppression of mutant p53 levels in vivo in established cancers might achieve clinically significant effects. Mol Cancer Res; 9(5); 577–88. ©2011 AACR.
Data from Mutant p53 (G199V) Gains Antiapoptotic Function through Signal Transducer and Activator of Transcription 3 in Anaplastic Thyroid Cancer Cells
Authors: Kim Tae-Hyun , Lee Sang Yull , Rho Jee Hyun , Jeong Na Young , Soung Young Hwa , Jo Wol Soon , Kang Do-Young , Kim Sung-Heun , Yoo Young Hyun
Published: April 2023

Abstract
In the present study, we identified a missense mutation (G199V) in KAT-18 cell line established from primary cultures of anaplastic thyroid cancer (ATC). Notably, knockdown of this mutant (mt) p53 reduced cell viability and exerted antitumor activity equivalent to high doses of several chemotherapeutic agents. We showed that p53 knockdown had an antitumor effect via the induction of apoptosis. We further examined the underlying mechanism by which mt p53 (G199V) gains antiapoptotic function in KAT-18 cells. Microarray analysis revealed that p53 knockdown modified the expression of numerous apoptosis-related genes. Importantly, p53 knockdown led to downregulation of signal transducer and activator of transcription-3 (STAT3) gene expression. We further observed that p53 knockdown induced the downregulation of STAT3 protein. We also observed that a STAT3 inhibitor augmented the reduction of cell viability induced by p53 knockdown, whereas interleukin-6 treatment alleviated this effect. In addition, overexpression of STAT3 protected ATC cells against cell death induced by p53 knockdown. Taken together, these data show that mt p53 (G199V) gains antiapoptotic function mediated by STAT3 in ATC cells. Inhibition of the function of mt p53 (G199V) could be a novel and useful therapeutic strategy for decreasing the extent and severity of toxicity due to chemotherapeutic agents. (Mol Cancer Res 2009;7(10):1645–54)
Data from PU.1 Activation Relieves GATA-1–Mediated Repression of Cebpa and Cbfb during Leukemia Differentiation
Authors: Burda Pavel , Curik Nikola , Kokavec Juraj , Basova Petra , Mikulenkova Dana , Skoultchi Arthur I. , Zavadil Jiri , Stopka Tomas
Published: April 2023

Abstract
Hematopoietic transcription factors GATA-1 and PU.1 bind each other on DNA to block transcriptional programs of undesired lineage during hematopoietic commitment. Murine erythroleukemia (MEL) cells that coexpress GATA-1 and PU.1 are blocked at the blast stage but respond to molecular removal (downregulation) of PU.1 or addition (upregulation) of GATA-1 by inducing terminal erythroid differentiation. To test whether GATA-1 blocks PU.1 in MEL cells, we have conditionally activated a transgenic PU.1 protein fused with the estrogen receptor ligand-binding domain (PUER), resulting in activation of a myeloid transcriptional program. Gene expression arrays identified components of the PU.1-dependent transcriptome negatively regulated by GATA-1 in MEL cells, including CCAAT/enhancer binding protein α (Cebpa) and core-binding factor, β subunit (Cbfb), which encode two key hematopoietic transcription factors. Inhibition of GATA-1 by small interfering RNA resulted in derepression of PU.1 target genes. Chromatin immunoprecipitation and reporter assays identified PU.1 motif sequences near Cebpa and Cbfb that are co-occupied by PU.1 and GATA-1 in the leukemic blasts. Significant derepression of Cebpa and Cbfb is achieved in MEL cells by either activation of PU.1 or knockdown of GATA-1. Furthermore, transcriptional regulation of these loci by manipulating the levels of PU.1 and GATA-1 involves quantitative increases in a transcriptionally active chromatin mark: acetylation of histone H3K9. Collectively, we show that either activation of PU.1 or inhibition of GATA-1 efficiently reverses the transcriptional block imposed by GATA-1 and leads to the activation of a myeloid transcriptional program directed by PU.1. (Mol Cancer Res 2009;7(10):1693–703)
Data from Poly(ADP-Ribose) Polymerase 1 Promotes Tumor Cell Survival by Coactivating Hypoxia-Inducible Factor-1–Dependent Gene Expression
Authors: Elser Michael , Borsig Lubor , Hassa Paul O. , Erener Suheda , Messner Simon , Valovka Taras , Keller Stephan , Gassmann Max , Hottiger Michael O.
Published: April 2023

Abstract
Hypoxia-inducible factor 1 (HIF-1) is the key transcription factor regulating hypoxia-dependent gene expression. Lack of oxygen stabilizes HIF-1, which in turn modulates the gene expression pattern to adapt cells to the hypoxic environment. Activation of HIF-1 is also detected in most solid tumors and supports tumor growth through the expression of target genes that are involved in processes like cell proliferation, energy metabolism, and oxygen delivery. Poly(ADP-ribose) polymerase 1 (PARP1) is a chromatin-associated protein, which was shown to regulate transcription. Here we report that chronic myelogenous leukemia cells expressing small interfering RNA against PARP1, which were injected into wild-type mice expressing PARP1, showed tumor growth with increased levels of necrosis, limited vascularization, and reduced expression of GLUT-1. Of note, PARP1-deficient cells showed a reduced HIF-1 transcriptional activation that was dependent on PARP1 enzymatic activity. PARP1 neither influenced binding of HIF-1 to its hypoxic response element nor changed HIF-1α protein levels in hypoxic cells. However, PARP1 formed a complex with HIF-1α through direct protein interaction and coactivated HIF-1α–dependent gene expression. These findings provide convincing evidence that wild-type mice expressing PARP1 cannot compensate for the loss of PARP1 in tumor cells and strengthen the importance of the role of PARP1 as a transcriptional coactivator of HIF-1–dependent gene expression during tumor progression. (Mol Cancer Res 2008;6(2):282–90)
Data from Interferon Regulatory Factors IRF5 and IRF7 Inhibit Growth and Induce Senescence in Immortal Li-Fraumeni Fibroblasts
Authors: Li Qunfang , Tang Lin , Roberts Paul Christopher , Kraniak Janice M. , Fridman Aviva Levine , Kulaeva Olga I. , Tehrani Omid S. , Tainsky Michael A.
Published: April 2023

Abstract
Cellular immortalization is one of the prerequisite steps in carcinogenesis. By gene expression profiling, we have found that genes in the interferon (IFN) pathway were dysregulated during the spontaneous cellular immortalization of fibroblasts from Li-Fraumeni syndrome (LFS) patients with germ-line mutations in p53. IFN signaling pathway genes were down-regulated by epigenetic silencing during immortalization, and some of these same IFN-regulated genes were activated during replicative senescence. Bisulfite sequencing of the promoter regions of two IFN regulatory transcription factors (IRF5 and IRF7) revealed that IRF7, but not IRF5, was epigenetically silenced by methylation of CpG islands in immortal LFS cells. The induction of IRF7 gene by IFNα in immortal LFS cells was potentiated by pretreatment with the demethylation agent 5-aza-2′-deoxycytidine. Overexpression of IRF5 and IRF7 revealed that they can act either alone or in tandem to activate other IFN-regulated genes. In addition, they serve to inhibit the proliferation rate and induce a senescence-related phenotype in immortal LFS cells. Furthermore, polyinosinic:polycytidylic acid treatment of the IRF-overexpressing cells showed a more rapid induction of several IFN-regulated genes. We conclude that the epigenetic inactivation of the IFN pathway plays a critical role in cellular immortalization, and the reactivation of IFN-regulated genes by transcription factors IRF5 and/or IRF7 is sufficient to induce cellular senescence. The IFN pathway may provide valuable molecular targets for therapeutic interventions at early stages of cancer development. (Mol Cancer Res 2008;6(5):770–84)
Data from HOP/OB1/NECC1 Promoter DNA Is Frequently Hypermethylated and Involved in Tumorigenic Ability in Esophageal Squamous Cell Carcinoma
Authors: Yamashita Keishi , Kim Myoung Sook , Park Hannah Lui , Tokumaru Yutaka , Osada Motonobu , Inoue Hiroshi , Mori Masaki , Sidransky David
Published: April 2023

Abstract
Promoter DNA hypermethylation with gene silencing is a common feature of human cancer, and cancer-prone methylation is believed to be a landmark of tumor suppressor genes (TSG). Identification of novel methylated genes would not only aid in the development of tumor markers but also elucidate the biological behavior of human cancers. We identified several epigenetically silenced candidate TSGs by pharmacologic unmasking of esophageal squamous cell carcinoma (ESCC) cell lines by demethylating agents (5-aza-2′-deoxycitidine and trichostatin A) combined with ESCC expression profiles using expression microarray. HOP/OB1/NECC1 was identified as an epigenetically silenced candidate TSG and further examined for (a) expression status, (b) methylation status, and (c) functional involvement in cancer cell lines. (a) The HOP gene encodes two putative promoters (promoters A and B) associated with two open reading frames (HOPα and HOPβ, respectively), and HOPα and HOPβ were both down-regulated in ESCC independently. (b) Promoter B harbors dense CpG islands, in which we found dense methylation in a cancer-prone manner (55% in tumor tissues by TaqMan methylation-specific PCR), whereas promoter A does not harbor CpG islands. HOPβ silencing was associated with DNA methylation of promoter B in nine ESCC cell lines tested, and reactivated by optimal conditions of demethylating agents, whereas HOPα silencing was not reactivated by such treatments. Forced expression of HOP suppressed tumorigenesis in soft agar in four different squamous cell carcinoma cell lines. More convincingly, RNA interference knockdown of HOP in TE2 cells showed drastic restoration of the oncogenic phenotype. In conclusion, HOP is a putative TSG that harbors tumor inhibitory activity, and we for the first time showed that the final shutdown process of HOP expression is linked to promoter DNA hypermethylation under the double control of the discrete promoter regions in cancer. (Mol Cancer Res 2008;6(1):31–41)
Data from Fbw7 Isoform Interaction Contributes to Cyclin E Proteolysis
Authors: Zhang Wei , Koepp Deanna M.
Published: April 2023

Abstract
The ubiquitin proteasome system plays important roles in regulating cell growth and proliferation. Many proteins that function in ubiquitin-mediated destruction have been linked to tumorigenesis. The putative tumor-suppressor protein Fbw7 (hAgo/hCdc4) is a specificity factor for the Skp1-Cul1-F-box protein ubiquitin ligase complex and targets a number of proto-oncogene products for ubiquitin-mediated destruction, including the cell cycle regulator cyclin E. In mammals, there are three splice variants of Fbw7 that use distinct first exons, resulting in proteins that have unique NH2 termini but are otherwise identical. Here, we show that the Fbw7 splice variants interact with each other through an NH2-terminal region common to all of the Fbw7 isoforms. Other F-box proteins have been shown to regulate substrate binding or turnover by forming homodimeric or heterodimeric complexes, which are dependent on a sequence motif called the D domain. Fbw7 and its orthologues exhibit significant sequence similarity to such F-box proteins, including the D domain. Fbw7 mutants that lack the region encompassing the D domain fail to bind other Fbw7 isoforms, despite being properly localized and binding both cyclin E and Skp1. Finally, we show the functional significance of this region as mutants lacking the NH2-terminal region involved in Fbw7 binding exhibit reduced rates of cyclin E protein turnover, indicating that Fbw7 isoform interaction is important for the efficiency of cyclin E turnover. Overall, this study contributes to the current understanding of the regulation of the Fbw7 tumor-suppressor protein. (Mol Cancer Res 2006;4(12):935–43)
Data from Comprehensive Profiling of 8p11-12 Amplification in Breast Cancer
Authors: Gelsi-Boyer Véronique , Orsetti Béatrice , Cervera Nathalie , Finetti Pascal , Sircoulomb Fabrice , Rougé Carole , Lasorsa Laurence , Letessier Anne , Ginestier Christophe , Monville Florence , Esteyriès Séverine , Adélaïde José , Esterni Benjamin , Henry Catherine , Ethier Stephen P. , Bibeau Frédéric , Mozziconacci Marie-Joëlle , Charafe-Jauffret Emmanuelle , Jacquemier Jocelyne , Bertucci François , Birnbaum Daniel , Theillet Charles , Chaffanet Max
Published: April 2023

Abstract
In human carcinomas, especially breast cancer, chromosome arm 8p is frequently involved in complex chromosomal rearrangements that combine amplification at 8p11-12, break in the 8p12-21 region, and loss of 8p21-ter. Several studies have identified putative oncogenes in the 8p11-12 amplicon. However, discrepancies and the lack of knowledge on the structure of this amplification lead us to think that the actual identity of the oncogenes is not definitively established. We present here a comprehensive study combining genomic, expression, and chromosome break analyses of the 8p11-12 region in breast cell lines and primary breast tumors. We show the existence of four amplicons at 8p11-12 using array comparative genomic hybridization. Gene expression analysis of 123 samples using DNA microarrays identified 14 genes significantly overexpressed in relation to amplification. Using fluorescence in situ hybridization analysis on tissue microarrays, we show the existence of a cluster of breakpoints spanning a region just telomeric to and associated with the amplification. Finally, we show that 8p11-12 amplification has a pejorative effect on survival in breast cancer. (Mol Cancer Res 2005;3(12):655–67)
Finasteride and Prostate Cancer: New York Times Article from Finasteride Does Not Increase the Risk of High-Grade Prostate Cancer: A Bias-Adjusted Modeling Approach
Authors: Redman Mary W. , Tangen Catherine M. , Goodman Phyllis J. , Lucia M. Scott , Coltman Charles A. , Thompson Ian M.
Published: April 2023

Finasteride and Prostate Cancer: New York Times Article from Finasteride Does Not Increase the Risk of High-Grade Prostate Cancer: A Bias-Adjusted Modeling Approach
Perspective from Increased Susceptibility of Nrf2 Knockout Mice to Colitis-Associated Colorectal Cancer
Authors: Khor Tin Oo , Huang Mou-Tuan , Prawan Auemduan , Liu Yue , Hao Xingpei , Yu Siwang , Cheung William Ka Lung , Chan Jefferson Y. , Reddy Bandaru S. , Yang Chung S. , Kong Ah-Ng
Published: April 2023

Perspective from Increased Susceptibility of Nrf2 Knockout Mice to Colitis-Associated Colorectal Cancer
Dor em pediatria
Authors: Okada Massako , Teixeira Manoel Jacobsen , Tengan Sérgio K. , Bezerra Simone Lopes , Ramos Carolina Anunciação
Published: April 2023

Dor é comum em todas as faixas etárias pediátricas. É provável que se manifeste também durante a vida fetal. Osinstrumentos para a avaliação da dor em pediatria, fisiológicas, comportamentais, ou de auto-relatos devem ser adaptados a fase do desenvolvimento. As condições álgicas agudas mais prevalentes são relacionadas aos traumatismos de causa externa ou interna, as cefaléias e as síndromes dolorosas músculo-esqueléticas e viscerais são mais relacionadas à dor crônica ou recidivantes.
Tratamento da dor em pediatria
Authors: Okada Massako , Teixeira Manoel Jacobsen , Miyagi Karina Takesaki
Published: April 2023

Várias evidências sugerem que além do aspecto humanístico, o tratamento da dor em pediatria previne numerosascomplicações de ordem, física e psicocomportamental. A avaliação adequada da condição dolorosa e a eliminação dos fatores causais biopsicossociais são atitudes necessárias para o tratamento da dor. Em concomitância com esta atitude, o uso de analgésicos antiinflamatórios não esteroidais, opióides e adjuvantes são recomendáveis para aplicação nas diferentes faixas etárias dos doentes pediátricos. Os procedimentos de medicina física e reabilitação e de medicina psicocomportamental são indicados especialmente durante a fase reabilitacional e como formas de treinamento das crianças para enfrentar as condições álgicas agudas e crônicas. Os procedimentos neuroanestésicos e neurocirúrgicos são indicados em condições especiais.
Modern childhood and preschool education protecting the rights of child: to the 75th anniversary of E.O. Smirnova’s birth
Authors: Karabanova Olga A.
Published: April 2023

Background. Xe relevance of the article is determined by the need to consider the socio-cultural situation of modern childhood and child subculture, as well as the need to Ynd ways to resolve the crisis of childhood. In a convergent environment of development and information socialization, the analysis of the role of game and toys, of watching animated Ylms and playing computer games in the development of a preschooler allows us to outline a strategy to overcome the crisis by modernizing the system of preschool education. Objective. Xe aim of the work is to analyse the scientiYc heritage of Doctor in, Professor E.O. Smirnova, in whose works an original concept of play activity and toys was developed. Xe concept considers play at preschool age in the conditions of modern childhood on theoretical, methodological and practice-oriented levels. Results. It is maintained that play is a source for autonomy and initiative of the child, indicating the development of personality in childhood. Xe characteristics of the children’s subculture, reZecting the crisis of childhood, are highlighted. Special attention is paid to the trends in the transformation of toys and the role of cartoons and computer games in a convergent development environment. Xe causes of the crisis of childhood are considered. Xese causes are associated with violation of the intermediary mission of an adult when transmitting socio-cultural experience, with break in motivation and modes of action of a child, with alienation of meaning in activity, with blocking creative independent activity and initiative of a child, with reduction of development to the “knowledge-ability-skill” learning paradigm. Xe goals and objectives of psychological expertise are deYned. Criteria for expert evaluation of toys and cartoons are developed. Xe requirements for computer games, reZecting the social demand for the content to provide developing, safe information environment, are formulated. Conclusion. Xe necessary condition for overcoming the crisis of childhood is the strategy of constructing a safe developing convergent environment for child’s mental development in preschool age. Xis strategy is based on the psychological examination of toys, cartoons, and computer games. Xe progress of personality development is determined by the support for the autonomy and initiative in typical activities of preschool age children: play, cognition, perception of animated Ylms in cooperation with adults and peers.
New species and records of Heterospio (Annelida, Longosomatidae) from continental shelf, slope and abyssal depths of the Atlantic Ocean, Pacific Ocean, Indian Ocean and adjacent seas
Authors: BLAKE JAMES A. , MACIOLEK NANCY J.
Published: April 2023

Nineteen species of the rare polychaete genus Heterospio are reported, 15 of which are new to science. The status of H. longissima Ehlers, 1874, the type-species, is reviewed. The specimens examined are from several locations in the North Atlantic Ocean, Gulf of Mexico, Caribbean Sea, off Br azil, the Indian Ocean, the Pacific Ocean off California, New Zealand, Australia, and the South China Sea. Deep-water samples from the western North Atlantic Ocean collected by the late Drs. H.L. Sanders and R.R. Hessler that were reported by Hartman as H. longissima were re-examined and referred to two new species, H. hartmanae n. sp. (abyssal depths, New England to Bermuda transect) and H. guiana n. sp. (bathyal depths off Suriname). Other materials from the Sanders/Hessler North Atlantic collections were also examined and referred to two additional species, H. canariensis n. sp. (deep water off Canary Islands) and H. southwardorum n. sp. (Bay of Biscay) as well as H. cf. reducta from off SW Ireland in bathyal depths. New collections from the North Atlantic region include additional materials of H. hartmanae n. sp. (deep water off the Mid-Atlantic and SE USA), H. aruba n. sp. (Caribbean Sea), H. bathyala n. sp. (deep water off SE USA), and H. dibranchiata n. sp. (deep water, Gulf of Mexico). Heterospio paulolanai n. sp. is from shelf depths off southeastern Brazil. Heterospio knoxi n. sp. is from the North Island of New Zealand, H. ehlersi n. sp. is from the Gulf of Thailand, in the South China Sea, H. bidentata n. sp. is described from deep water in the Coral Sea off eastern Australia, and H. alata n. sp. and H. brunei n. sp. are described from deep water off the Island of Borneo in the South China Sea. Heterospio africana n. sp. and H. antonbruunae n. sp. are described from off east Africa in the Mozambique Channel. New records and descriptions of H. catalinensis, H. indica, and H. peruana are presented. The 15 new species reported here nearly triple the number of previously known species of Heterospio, with 23 species now recognized. All known species are tabulated and compared.
Wspomnienie o Profesor Irenie Kwileckiej (20 lutego 1925 – 11 lipca 2022)
Authors: Łuczak Arleta
Published: April 2023

In Memoriam: Professor Irena Kwilecka (20 February 1925 – 11 July 2022)This article is an in memoriam to Professor Irena Kwilecka, a renowned scholar studying Old Polish Bible translations and sixteenth-century vocabularies. Professor Kwilecka worked at the Adam Mickiewicz University in Poznań (1953–1964) and the Institute of Slavic Studies, Polish Academy of Sciences (from 1964).Wspomnienie o Profesor Irenie Kwileckiej (20 lutego 1925 – 11 lipca 2022)Wspomnienie o Profesor Irenie Kwileckiej, wybitnej badaczce staropolskich przekładów Biblii i szesnastowiecznych wokabularzy. Pracowała na Uniwersytecie im. Adama Mickiewicza w Poznaniu (lata 1953–1964) i w Instytucie Slawistyki Polskiej Akademii Nauk (od 1964 roku).
Supportive Care Needs Among Head and Neck Cancer Patients Prior to Oncologic Treatment: A Prospective, Nested Cross-Sectional Qualitative Analysis
Authors: Day Andrew T. , Sood Anubha , Emmet Thomas R. , Eary Rebecca L. , Prestwood Courtney A. , Salley Jordan , Huffman Alexandra , Doenges Jacquelyn , Mayfield Arnold Elizabeth , Tiro Jasmin A. , Lee Simon Craddock
Published: April 2023

Objectives:

To qualitatively characterize pretreatment head and neck cancer (HNC) patients’ supportive care (SC) needs, attitudes toward SC, and barriers to SC utilization.

Materials and Methods:

A prospective, nested, bi-institutional, cross-sectional pilot study design was employed. Participants were sub-selected from a representative sample of 50 patients newly diagnosed with mucosal or salivary gland HNC or sarcoma of the head and neck. Eligibility criteria included reporting ≥2 unmet needs (according to the Supportive Care Needs Survey—Short Form 34) or clinically-significant distress (National Comprehensive Cancer Network Distress Thermometer score ≥4). Semi-structured interviews were performed prior to initiation of oncologic treatment. Audio-recorded interviews were transcribed and thematically analyzed using NVivo 12.0 (QSR Australia). Thematic findings and representative quotes were interpreted by the entire research team.

Results:

Twenty-seven patients were interviewed. One-third were treated at the county safety-net hospital and the remainder were treated at the university health system. An equal proportion of patients presented with oral cavity, oropharyngeal, and laryngeal or other tumors. Two significant findings were identified on semi-structured interviews. First, patients did not perceive the relevance of SC prior to treatment. Second, anxiety surrounding the HNC diagnosis and impending treatment dominated in the pretreatment phase.

Conclusion:

Improved HNC patient education about the relevance and importance of SC in the pretreatment setting is needed. Integration of social work or psychological services in HNC clinics is warranted to address patients’ cancer-related worry—a discrete, dominant pretreatment SC need.
Credit Claiming by Labeling
Authors: Oliveros Virginia , Weitz-Shapiro Rebecca , Winters Matthew S.
Published: April 2023

We examine a phenomenon we call “credit claiming by labeling” in which a sitting politician places her name on a project, program, or policy with the goal of claiming credit for it. While the prevalence of this practice suggests that many politicians believe that credit claiming by labeling will aid their careers, there is little existing evidence on this question. We examine the effects of credit claiming by labeling with a survey experiment in Argentina. We find that it has a negative, though small, effect on respondents’ attitudes. Descriptive data suggests that these results stem from the perceived pervasiveness of the practice. We then use evidence from an additional treatment on the (un)biased selection of program beneficiaries to show that respondents actually reward politicians who neither label nor manipulate programs. These results suggest substantial obstacles to overturning citizens’ negative baseline beliefs about the politicized implementation of government programs.
Resisting racism in school
Authors: Johnson Darius O. , Markoff Briana , Carter Andrews Dorinda J.
Published: April 2023

Darius O. Johnson, Briana Markoff, and Dorinda J. Carter Andrews examined data from focus groups conducted with more than 60 Black boys in midwestern high schools to learn how teachers and schools can refuse antiblackness and reimagine futures for Black boys in school. Black boys and young men want safe school environments and will create safe communal spaces when needed. They seek teachers who are culturally relevant; they want to be able to trust their teachers; and they want to be their full, authentic selves at school. Findings show how educators can work within antiblack institutions toward reducing in-school suffering while working to create better futures for Black boys in school.
On Leadership: What should students learn?
Authors: Starr Joshua P.
Published: April 2023

Despite significant societal changes, the high school experience hasn’t changed much in recent decades. Joshua P. Starr reflects on his own high school experiences and that of his son and considers how schools might change their focus away from requiring students to learn specific facts and toward having them develop skills as they engage in rich content that interests them and their teachers.
Career Confidential: Math teacher wants to help risk-averse male students
Authors: Fagell Phyllis L.
Published: April 2023

Phyllis Fagell advises teachers and a principal who are dealing with their students’ and their own anxiety. A middle school math teacher is finding that more boys than girls in her class are risk-averse when it comes to math. A high school teacher has noticed that a lot of her students are getting sick and missing class when there’s a test. And a principal who’s made some hard calls and gotten blowback wonders if he’s in the right job.
Advanced Placement Gatekeeping and Racialized Tracking
Authors: Hirschl Noah , Smith Christian Michael
Published: April 2023

Racialized tracking is central to sociological explanations for racially stratified educational outcomes. However, school officials’ decision-making is of debated importance for explaining racialized tracking. We contribute to this literature by examining the effects of schools’ enrollment policies for Advanced Placement (AP) courses. Using a unique combination of school survey data and administrative data from Wisconsin, we examine what happens to racial inequality in AP participation when school officials enforce performance-based selection criteria, which we call “course gatekeeping.” We find that course gatekeeping has racially disproportionate effects. Although racialized differences in prior achievement partially explain the especially large negative effects among students of color, course gatekeeping producesBlack-white and Hispanic-white disparities in participation even among students with similar, relatively low prior achievement. We further find that course gatekeeping has longer-run effects, particularly discouraging Black and Asian or Pacific Islander students from attending highly selective four-year colleges.
The Human Rights Crisis in Mexico: Human Trafficking and Information Management
Authors: Veloz Adriana González , Pinto Luis Gabriel Arango
Published: April 2023

An analysis of news items on human trafficking in Mexico published in digital newspaper portals and electronic versions of newspapers with national circulation concludes that the issue is of little interest to the media; the dissemination of information on the topic is limited and superficial and lacking in new data. The media reproduce vague perceptions of the phenomenon of human trafficking because they essentially reflect disagreements over the concepts, methodologies, and figures as handled by specialists. The reproduction of human rights violations in the journalistic items themselves (such as the mediatic display of the people involved in an event) is also noticeable.

Un análisis de las noticias sobre la trata de personas en México publicadas en portales de periódicos digitales y versiones electrónicas de periódicos con circulación nacional concluye que el tema es de poco interés para los medios de comunicación. La difusión de información sobre el tema es limitada y superficial y carece de nuevos datos. Los medios de comunicación reproducen percepciones vagas en torno al fenómeno de la trata de personas porque esencialmente reflejan desacuerdos sobre los conceptos, metodologías y cifras manejadas por especialistas. La reproducción de violaciones a los derechos humanos en los propios artículos periodísticos (por ejemplo, la exhibición mediática de las personas involucradas en un evento) también es de notar.
The relative effectiveness of overlapping international institutions: European Union versus United Nations regulations of air pollution
Authors: Tveit Andreas Kokkvoll , Tørstad Vegard
Published: April 2023

Which types of international institutions display higher ability to change states’ behaviour? This article assesses the relative environmental effectiveness of a management-based (‘soft’) and an enforcement-based (‘hard’) international agreement: the United Nations Sofia Protocol and a European Union directive. Using difference-in-differences analysis, we find that the European Union directive is more effective in inducing emissions reductions than the United Nation’s Sofia Protocol. We propose that the European Union’s enforcement capacity is a likely driver of the directive’s effectiveness. The article makes two contributions to existing literature. First, we provide causal evidence on the relative importance of overlapping international institutions in regulating environmental policy outcomes, elucidating how an apparent emissions-reducing effect of a ‘soft’ United Nations Protocol is in fact driven by the existence of overlapping ‘hard’ European Union regulation. Second, we demonstrate how states’ enthusiasm for emissions regulations can explain the relative effectiveness of soft and hard law institutions.
Iconic gestures support novel word learning in multilingual students with SLCN in classrooms
Authors: Frey Nathalie , Lüke Carina
Published: April 2023

Learning academic vocabulary is a crucial task for all students, but especially challenging for students with speech, language, and communication needs (SLCN) and those who are multilingual. Following a participatory research strategy, we analyze whether iconic gestures can be integrated in teaching routines in an inclusive elementary school and whether the presentation of iconic gestures supports novel word learning over the period of four math lessons. One hundred and sixteen students (44% boys), the majority (91%) with SLCN, participated in the study. We conducted a control group design in eight classes with pre- and post-testing of a target academic vocabulary on the topic “Geometric surfaces and solids.” Results show a significant increase in the acquisition of the receptive and expressive target academic vocabulary for all students, but a predominance of expressive learning performance in favor of students who observed iconic gestures during lessons. Iconic gestures can be easily implemented into teaching, improve novel word learning in students with SLCN and serve as a cuing strategy for naming words in students with severe SLCN.
Determinants of motivation in world-class musicians and Olympic athletes: Exploring the front and the back side of the medallion
Authors: Hatfield Johannes Lunde
Published: April 2023

The aim of the present case study was to obtain an in-depth understanding of the long-term motivation in four world-class musicians and two Olympic athletes. One part of the sample (Case 1) included three world famous musicians and one Olympic champion who all currently enjoy busy successful careers. These individuals are referred to as High Performing Stayers (HPS). The other part of the sample (Case 2) included one highly gifted musician and one Olympic athlete who both decided to put an end to their highly successful careers. These individuals are referred to as High Performing Quitters (HPQ). The performers’ perceptions of underlying driving forces and motivational impediments on their journey toward excellence were investigated through the lens of Self-Determination Theory. Semi-structured interviews revealed conspicuous and contrasting motivational patterns throughout the development of the six performers. All the four HPS were largely driven by autonomous forms of motivation such a self-initiative, passion, curiosity and a desire for endless discovery and aspiration. In contrast, despite reaching the highest international level, the two HPQ turned out to be driven by controlled coercive forms of motivation throughout their journey toward excellence. Educational implications are discussed in relation to the main findings.