bluuebunny/crossref_metadata_2025_split huggingface dataset:
Protease-Activated Receptors (PAR1 and PAR2) Contribute to Tumor Cell Motility and Metastasis
Authors: Shi Xiaoli , Gangadharan Beena , Brass Lawrence F. , Ruf Wolfram , Mueller Barbara M. 
Published: May 2022

Abstract
The effects of the pleiotropic serine protease thrombin on tumor cells are commonly thought to be mediated by the thrombin receptor protease-activated receptor 1 (PAR1). We demonstrate here that PAR1 activation has a role in experimental metastasis using the anti-PAR1 antibodies ATAP2 and WEDE15, which block PAR1 cleavage and activation. Thrombin also stimulates chemokinesis of human melanoma cells toward fibroblast conditioned media and soluble matrix proteins. Thrombin-enhanced migration is abolished by anti-PAR1 antibodies, demonstrating that PAR1 cleavage and activation are required. The PAR1-specific agonist peptide TFLLRNPNDK, however, does not stimulate migration, indicating that PAR1 activation is not sufficient. In contrast, a combination of TFLLRNPNDK and the PAR2 agonist peptide SLIGRL mimics the thrombin effect on migration, whereas PAR2 agonist alone has no effect. Agonist peptides for the thrombin receptors PAR3 and PAR4 used alone or with PAR1 agonist also have no effect. Similarly, activation of PAR1 and PAR2 also enhances chemokinesis of prostate cancer cells. Desensitization with PAR2 agonist abolishes thrombin-enhanced cell motility, demonstrating that thrombin acts through PAR2. PAR2 is cleaved by proteases with trypsin-like specificity but not by thrombin. Thrombin enhances migration in the presence of a cleavage-blocking anti-PAR2 antibody, suggesting that thrombin activates PAR2 indirectly and independent of receptor cleavage. Treatment of melanoma cells with trypsin or PAR2 agonist peptide enhances experimental metastasis. Together, these data confirm a role for PAR1 in migration and metastasis and demonstrate an unexpected role for PAR2 in thrombin-dependent tumor cell migration and in metastasis.
Interleukin-10 Induced Activating Transcription Factor 3 Transcriptional Suppression of Matrix Metalloproteinase-2 Gene Expression in Human Prostate CPTX-1532 Cells
Authors: Stearns Mark E. , Kim Greg , Garcia Fernando , Wang Min 
Published: May 2022

AbstractAberrant expression of the 72-kDa type IV collagenase [matrix metalloproteinase (MMP)-2] is implicated in the invasion and angiogenesis process of malignant tumors. We investigated the effects of interleukin (IL)-10 on MMP-2 expression in CPTX-1532 human prostate tumor cells. Our results demonstrate that IL-10 significantly inhibited MMP-2 transcription and protein expression induced by a phorbol ester, phorbol 12-myristate 13-acetate. The inhibitory effects of IL-10 on MMP-2 expression correlated with the suppression of MMP-2 promoter activity. To determine the mechanism of IL-10 action, we examined IL-10–dependent promoter activity with luciferase constructs from a 2-kbp promoter region of the human MMP-2 gene. We functionally characterized the promoter fragments by transient transfection experiments with CPTX-1532 cells. The experiments revealed that a cAMP responsive element binding protein (CREB) consensus domain was identified upstream of the 5′ transcriptional start site, which was highly responsive to IL-10–dependent down-regulation of promoter luciferase activity. Electrophoretic mobility shift assays combined with antibody “supershift assays” confirmed the data from the luciferase assays. Immunoblot assays of activating transcription factor (ATF) 3 immunoprecipitates with tyrosine specific antibodies revealed that IL-10 stimulated tyrosine phosphorylation of ATF3 to activate binding to the CREB domain and suppress MMP-2 expression. Studies with stable, IL-10 transfected CPTX-1532 subclones further showed that IL-10 failed to suppress MMP-2 expression in ATF3-deficient CPTX-1532 cells, where the ATF3 mRNA was destroyed with a DNAzyme oligonucleotide targeting the 5′ region of the mRNA. Finally, reconstitution of ATF3 successfully restored the inhibitory effects of IL-10 on MMP-2 gene expression. Taken together, these data demonstrate the critical role of tyrosine phosphorylated ATF3 and the CREB consensus domain in IL-10 suppression of MMP-2 gene expression in primary human prostate tumor cells.
Polo-Like Kinase 1 Inactivation Following Mitotic DNA Damaging Treatments Is Independent of Ataxia Telangiectasia Mutated Kinase
Authors: Yuan Jin-Hui , Feng Yang , Fisher Rebecca H. , Maloid Sharon , Longo Dan L. , Ferris Douglas K. 
Published: May 2022

AbstractPolo-like kinase 1 (Plk1) is an important regulator of several events during mitosis. Recent reports show that Plk1 is involved in both G2 and mitotic DNA damage checkpoints. Ataxia telangiectasia mutated kinase (ATM) is an important enzyme involved in G2 phase cell cycle arrest following interphase DNA damage, and inhibition of Plk1 by DNA damage during G2 occurs in an ATM-/ATM-Rad3–related kinase (ATR)–dependent fashion. However, it is unclear how Plk1 is regulated in response to M phase DNA damage. We found that treatment of mitotic cells with DNA damaging agents inhibits Plk1 activity primarily through dephosphorylation of Plk1, which occurred in both p53 wild-type and mutant cells. Inhibition of Plk1 is not prevented by caffeine pretreatment that inhibits ATM activity and also occurs in ATM mutant cell lines. Furthermore, ATM mutant cell lines, unlike wild-type cells, fail to arrest after mitotic DNA damaging treatments. The phosphatidylinositol 3-kinase (PI3K) inhibitor, LY294002, reduces Plk1 dephosphorylation following mitotic DNA damaging treatments, suggesting that the PI3K pathway may be involved in regulating Plk1 activity. Earlier studies showed that inhibition of Plk1 by G2 DNA damage occurs in an ATM-dependent fashion. Our results extend the previous studies by showing that ATM is not required for dephosphorylation and inhibition of Plk1 activity following mitotic DNA damage, and also suggest that Plk1 is not a principal regulator or mediator of the mitotic DNA damage response.
ERβ Sensitizes Breast Cancer Cells to Retinoic Acid: Evidence of Transcriptional Crosstalk
Authors: Rousseau Caroline , Nichol Jessica N. , Pettersson Filippa , Couture Marie-Claude , Miller Wilson H. 
Published: May 2022

Abstract
The ability of retinoids to inhibit breast cancer cell growth correlates with estrogen receptor (ER) α status, as shown by the antiproliferative effects of retinoids in ERα-positive breast cancer cells and their use as chemopreventive agents in premenopausal women. The discovery of ERβ, also present in breast cancer cells, has added a new level of complexity to this malignancy. To determine the retinoid response in ERβ-expressing breast cancer cells, we used retroviral transduction of ERβ in ER-negative MDA-MB-231 cells. Western blot and immunofluorescence confirmed expression and nuclear localization of ERβ, whereas functionality was shown using an estrogen response element–containing reporter. A significant retinoic acid (RA)–mediated growth inhibition was observed in the transduced ERβ-positive cells as shown by proliferation assays. Addition of estradiol, tamoxifen, or ICI 182,780 had no effect on cell growth and did not alter RA sensitivity. We observed that retinoids altered ERβ-mediated transcriptional activity from an estrogen response element, which was confirmed by decreased expression of the pS2 gene, and from an activator protein response element. Conversely, the expression of ERβ altered RA receptor (RAR) β expression, resulting in greater induction of RARβ gene expression on RA treatment, without altered expression of RARα. Our data provide evidence of transcriptional crosstalk between ERβ and RAR in ERβ-positive breast cancer cells that are growth inhibited by RA.
Hypermethylation of the Death-Associated Protein Kinase Promoter Attenuates the Sensitivity to Tumor Necrosis Factor-Related Apoptosis-Inducing Ligand-Induced Apoptosis in Human Non–Small Cell Lung Cancer Cells
Authors: Tang Ximing , Wu Weiguo , Sun Shi-yong , Wistuba Ignacio I. , Hong Waun Ki , Mao Li 
Published: May 2022

AbstractDeath-associated protein (DAP) kinase plays an important role in IFN-γ, tumor necrosis factor (TNF)-α, or Fas–ligand induced apoptosis. TNF-related apoptosis-inducing ligand (TRAIL) is a member of the TNF ligand family and can induce caspase-dependent apoptosis in cancer cells while sparing most of the normal cells. However, some of the cancer cell lines are insensitive to TRAIL, and such resistance cannot be explained by the dysfunction of TRAIL receptors or their known downstream targets. We reported previously that DAP kinase promoter is frequently methylated in non-small cell lung cancer (NSCLC), and such methylation is associated with a poor clinical outcome. To determine whether DAP kinase promoter methylation contributes to TRAIL resistance in NSCLC cells, we measured DAP kinase promoter methylation and its gene expression status in 11 NSCLC cell lines and correlated the methylation/expression status with the sensitivity of cells to TRAIL. Of the 11 cell lines, 1 had a completely methylated DAP kinase promoter and no detectable DAP kinase expression, 4 exhibited partial promoter methylation and substantially decreased gene expression, and the other 6 cell lines showed no methylation in the promoter and normal DAP kinase expression. Therefore, the amount of DAP kinase expression amount was negatively correlated to its promoter methylation (r = −0.77; P = 0.003). Interestingly, the cell lines without the DAP kinase promoter methylation underwent substantial apoptosis even in the low doses of TRAIL, whereas those with DAP kinase promoter methylation were resistant to the treatment. The resistance to TRAIL was reciprocally correlated to DAP kinase expression in 10 of the 11 cell lines at 10 ng/mL concentration (r = 0.91; P = 0.001). We treated cells resistant to TRAIL with 5-aza-2′-deoxycytidine, a demethylating reagent, and found that these cells expressed DAP kinase and became sensitive to TRAIL. These results suggest that DAP kinase is involved in TRAIL-mediated cell apoptosis and that a demethylating agent may have a role in enhancing TRAIL-mediated apoptosis in some NSCLC cells by reactivation of DAP kinase.
Vav Transformation Requires Activation of Multiple GTPases and Regulation of Gene Expression
Authors: Palmby Todd R. , Abe Karon , Karnoub Antoine E. , Der Channing J. 
Published: May 2022

AbstractAlthough Vav can act as a guanine nucleotide exchange factor for RhoA, Rac1, and Cdc42, its transforming activity has been ascribed primarily to its ability to activate Rac1. However, because activated Vav, but not Rac-specific guanine nucleotide exchange factors, exhibits very potent focus-forming transforming activity when assayed in NIH 3T3 cells, Vav transforming activity must also involve activation of Rac-independent pathways. In this study, we determined the involvement of other Rho family proteins and their signaling pathways in Vav transformation. We found that RhoA, Rac1, and Cdc42 functions are all required for Vav transforming activity. Furthermore, we determined that Vav activation of nuclear factor-κB and the Jun NH2-terminal kinase mitogen-activated protein kinase (MAPK) is necessary for full transformation by Vav, whereas p38 MAPK does not seem to play an important role. We also determined that Vav is a weak activator of Elk-1 via a Ras- and MAPK/extracellular signal-regulated kinase kinase–dependent pathway, and this activity was essential for Vav transformation. Thus, we conclude that full Vav transforming activation is mediated by the activation of multiple small GTPases and their subsequent activation of signaling pathways that regulate changes in gene expression. Because Vav is activated by the epidermal growth factor receptor and other tyrosine kinases involved in cancer development, defining the role of aberrant Vav signaling may identify activities of receptor tyrosine kinases important for human oncogenesis.
Induction of Apoptosis by Antisense CK2 in Human Prostate Cancer Xenograft Model
Authors: Slaton Joel W. , Unger Gretchen M. , Sloper Daniel T. , Davis Alan T. , Ahmed Khalil 
Published: May 2022

Abstract
Protein serine/threonine kinase CK2 (formerly casein kinase 2) is a ubiquitous protein kinase that plays key roles in cell growth, proliferation, and survival. We have shown previously that its molecular down-regulation induces apoptosis in cancer cells in culture. Here, we have employed a xenograft model of prostate cancer to extend these studies to determine whether antisense CK2α evokes a similar response in vivo. A single dose of antisense CK2α oligodeoxynucleotide given directly into the PC3-LN4 xenograft tumor in nude mouse induced a dose- and time-dependent tumor cell death in vivo. The tumor was completely resolved at the higher tested dose of the antisense. Cell death was due to apoptosis and correlated with a potent down-regulation of the CK2α message and loss of CK2 from the nuclear matrix in the xenograft tissue as well as in cancer cells in culture. These observations accorded with several of the earlier studies indicating that loss of CK2 from the nuclear matrix is associated with induction of apoptosis. Comparison of the effects of antisense CK2α oligodeoxynucleotide on cancer versus normal or noncancer cells showed that the concentration of antisense CK2α that elicited extensive apoptosis in tumor cells in culture or xenograft tumors in vivo had a relatively small or minimal effect on noncancer cells in culture or on normal prostate gland subjected to orthotopic injection of antisense oligodeoxynucleotide in vivo. The basis for the difference in sensitivity of cancer versus noncancer cells to antisense CK2α is unknown at this time; however, this differential response under similar conditions of treatment may be significant in considering the potential feasibility of targeting the CK2 signal for induction of apoptosis in cancer cells in vivo. Although much further work will be needed to establish the feasibility of targeting CK2 for cancer therapy, to our knowledge, this is the first report to provide important new evidence as an initial “proof of principle” for the potential application of antisense CK2α in cancer therapy, paving the way for future detailed studies of approaches to targeting CK2 in vivo to induce cancer cell death.
Regulation of Polyamine Analogue Cytotoxicity by c-Jun in Human MDA-MB-435 Cancer Cells
Authors: Huang Yi , Keen Judith C. , Hager Erin , Smith Renee , Hacker Amy , Frydman Benjamin , Valasinas Aldonia L. , Reddy Venodhar K. , Marton Laurence J. , Casero Robert A. , Davidson Nancy E. 
Published: May 2022

Abstract
Several polyamine analogues have efficacy against a variety of epithelial tumor models including breast cancer. Recently, a novel class of polyamine analogues designated as oligoamines has been developed. Here, we demonstrate that several representative oligoamine compounds inhibit in vitro growth of human breast cancer MDA-MB-435 cells. The activator protein-1 (AP-1) transcriptional factor family members, c-Jun and c-Fos, are up-regulated by oligoamines in MDA-MB-435 cells, suggesting a possible AP-1-dependent induction of apoptosis. However, the use of a novel c-Jun NH2-terminal kinase (JNK) inhibitor, SP600125, suggests that inhibition of c-Jun activity sensitized tumor cells to oligoamine-induced cell death. To directly test this hypothesis, cells were stably transfected with the dominant-negative mutant c-Jun (TAM67), which lacks the NH2-terminal transactivation domain. Cells overexpressing TAM67 exhibit normal growth kinetics but demonstrate a significantly increased sensitivity to oligoamine cytotoxicity and attenuated colony formation after oligoamine treatment. Furthermore, oligoamine treatment leads to more profound caspase-3 activation and poly(ADP-ribose) polymerase cleavage in TAM67 transfectants, suggesting that c-Jun acts as an antiapoptosis factor in MDA-MB-435 cells in response to oligoamine treatment. These findings indicate that oligoamine-inducible AP-1 plays a prosurvival role in oligoamine-treated MDA-MB-435 cells and that JNK/AP-1 might be a potential target for enhancing the therapeutic efficacy of polyamine analogues in human breast cancer.
Mdm2 in the Response to Radiation
Authors: Perry Mary Ellen 
Published: May 2022

Abstract
Murine double minute 2 (Mdm2) is a critical component of the responses to both ionizing and UV radiation. The level of Mdm2 expression determines the extent to which radiation induces an increase in the activity of the p53 tumor suppressor. Mdm2 acts as a survival factor in many cell types by limiting the apoptotic function of p53. In addition, expression of mdm2 is induced in response to DNA damage, and the resulting high levels of Mdm2 protein are thought to shorten the length of the cell cycle arrest established by p53 in the radiation response. Increased levels of Mdm2 appear to ensure that the activity of p53 returns to its low basal levels in surviving cells. Decreased levels of Mdm2 sensitize cells to ionizing radiation. Thus, Mdm2 is a potential target for therapeutic intervention because its inhibition may radiosensitize the subset of human tumors expressing wild-type p53 such that radiotherapy is more efficacious.
Abstract 156: Insights From Meta-analysis Of Studies Using Machine Learning To Predict Mortality, Readmission, Or Other Outcomes Among Heart Failure Patients
Authors: Zhang Zhenwei , Ahmed Md Ashfaq , McGranaghan Peter , Rubens Muni , Ramamoorthy Venkataraghavan , Saxena Anshul , Chaparro Sandra , Jimenez Javier , Veledar Emir 
Published: May 2022

Developing and implementing analytical models for predicting mortality or readmission related outcomes among heart failure (HF) patients are challenging. In this study, we used meta-analyses of reported predictive models to assess what machine learning (ML) has been able to accomplish in this field, by evaluating the ML model performance for studies in HF.
We performed a literature search using Google Scholar, Web of Science and PubMed. The studies reporting AUC and 95% CI for various models were included. In addition, total participants, year of publication, type of analytical method (logistic regression, RF, etc.) and type of outcome (mortality, readmission, etc.) were extracted. We combined effect sizes using random effects (RF) model, and tested for heterogeneity, and publication bias.
12 studies were included in the analysis (patients= 123,832; AUC=15, with outcome mortality =17,471, readmission=15,703, hospitalization=67,523). Combined mean AUC was 0.77 (95% CI: 0.72, 0.82). Test of heterogeneity showed high variation between studies (I2=98.9%). Egger’s test intercept was 5.2 (95% CI: -4.2, 14.7, p > .25) indicating no small study effects/bias. Meta regression showed newer publications provide better AUC values (p < 0.03). In subgroup analysis, the pooled AUC for readmission, hospitalization, and mortality groups were 0.71, 0.80, and 0.78 respectively. The highest individual AUC was from neural networks (NN) predicting hospitalization with AUC 0.96 and lowest was from RF predicting readmission with AUC 0.65.
Presented models were diverse, ranking in quality from fair to very good, and being varied for different clinical outcomes among HF patients. Situation known from studies using classical statistical methods holds also for methods using ML, with better predictive values for hospitalizations, and lower for other outcomes. Methods using NN and methods using higher numbers of variables performed very well and had highest predictive power.
Coastal Trapped Waves: Normal Modes, Evolution Equations, and Topographic Generation
Authors: Kelly Samuel M. , Ogbuka Sebastine 
Published: May 2022

Abstract
Coastal trapped waves (CTWs) transport energy along coastlines and drive coastal currents and upwelling. CTW modes are nonorthogonal when frequency is treated as the eigenvalue, preventing the separation of modal energy fluxes and quantification of longshore topographic scattering. Here, CTW modes are shown to be orthogonal with respect to energy flux (but not energy) when the longshore wavenumber is the eigenvalue. The modal evolution equation is a simple harmonic oscillator forced by longshore bathymetric variability, where downstream distance is treated like time. The energy equation includes an expression for modal topographic scattering. The eigenvalue problem is carefully discretized to produce numerically orthogonal modes, allowing CTW amplitudes, energy fluxes, and generation to be precisely quantified in numerical simulations. First, a spatially uniform K1 longshore velocity is applied to a continental slope with a Gaussian bump in the coastline. Mode-1 CTW generation increases quadratically with the amplitude of the bump and is maximum when the bump’s length of coastline matches the natural wavelength of the CTW mode, as predicted by theory. Next, a realistic K1 barotropic tide is applied to the Oregon coast. The forcing generates mode-1 and mode-2 CTWs with energy fluxes of 6 and 2 MW, respectively, which are much smaller than the 80 MW of M2 internal-tide generation in this region. CTWs also produce 1-cm sea surface displacements along the coast, potentially complicating the interpretation of future satellite altimetry. Prospects and challenges for quantifying the global geography of CTWs are discussed.
The Sensitivity of Downstream Ridge Building Forecasts to Upstream Warm Conveyor Belt Forecast Uncertainty Using MPAS
Authors: Berman Jeremy D. , Torn Ryan D. 
Published: May 2022

Abstract
One potential way to improve the skill of medium-range weather forecasts is to improve the evolution of Rossby waves, which largely modulate extratropical weather. Recent research has hypothesized that the predictability of downstream Rossby waves may be limited by forecast uncertainty linked to upstream diabatic processes such as latent heat release within the warm conveyor belt (WCB) of extratropical cyclones. This hypothesis is evaluated using Model for Prediction Across Scales (MPAS) ensemble forecasts for two events characterized by highly amplified flow over the North Atlantic associated with cyclogenesis. The source of variability in ridge forecasts is diagnosed using the ensemble-sensitivity technique and a potential vorticity (PV) tendency budget, which quantifies the contribution from individual physical processes toward subsequent ridge amplification. Before the onset of ridge amplitude differences for both events, ensemble forecasts with a more amplified ridge are associated with greater negative PV advection by the irrotational wind. The importance of PV advection by the irrotational wind suggests that PV changes are modulated by diabatic heating, which is confirmed by the sensitivity of ridge amplitude to earlier diabatic heating and lower-tropospheric moisture within an upstream WCB. After the onset of ridge amplitude differences, PV advection by the nondivergent wind becomes the primary driver of downstream forecast differences. Initial condition perturbations within the sensitive areas of the WCB confirm that increasing the initial lower-tropospheric moisture results in a more amplified ridge. This suggests that more accurate initial conditions near the WCB could lead to better downstream forecasts.