bluuebunny/crossref_metadata_2025_split huggingface dataset:
Basic Fibroblast Growth Factor-Mediated Overexpression of Vascular Endothelial Growth Factor in 1F6 Human Melanoma Cells is Regulated by Activation of PI-3K and p38 MAPK
Authors: Fontijn Dennis , Bosch Linda J. W. , Duyndam Monique C. A. , van Berkel Maria P. A. , Janmaat Maarten L. , Boven Epie 
Published: January 2021

Background: 1F6 human melanoma xenografts overexpressing either the 18 kD (18kD) form or all (ALL) forms of human basic fibroblast growth factor (bFGF) demonstrate an abundant number of microvessels and accelerated growth. We now examined whether bFGF mediates vascular endothelial growth factor (VEGF) expression.Methods: Quantitative RT-PCR was used to determine bFGF and VEGF mRNA, VEGF protein secretion was measured by ELISA and VEGF promoter activation was assessed by a dual luciferase activity assay. Western blot was carried out to detect phosphorylation of bFGF-regulated target proteins.Results: In 1F6-18kD and 1F6-ALL clones VEGF mRNA was increased 4- to 5-fold and VEGF protein secretion was highly stimulated due to activation of the VEGF promotor. PI-3K, p38 MAPK and ERK1/2 MAPK pathways were activated, while inhibition of PI-3K or p38 resulted in, respectively, 55% and up to 70% reduction of VEGF mRNA overexpression. A concurrent 60% decrease in VEGF protein secretion was mostly apparent upon inhibition of PI-3K. Inhibition of ERK1/2 hardly affected VEGF mRNA or protein secretion. Two unselected human melanoma cell lines with high metastatic potential contained high bFGF and VEGF, while three non- or sporadically metastatic cell lines displayed low bFGF and VEGF.Conclusion: These data indicate that stimulation of VEGF protein secretion in response to bFGF overexpression may contribute to increased vascularization and enhanced aggressiveness in melanoma.
Prognostic Relevance of Promoter Hypermethylation of Multiple Genes in Breast Cancer Patients
Authors: Sharma Gayatri , Mirza Sameer , Yang Yi-Hsin , Parshad Rajinder , Hazrah Priya , Gupta Siddartha Datta , Ralhan Ranju 
Published: January 2021

Background: Methylation-mediated suppression of detoxification, DNA repair and tumor suppressor genes has been implicated in cancer development. This study was designed to investigate the impact of concurrent methylation of multiple genes in breast tumors on disease prognosis.Methods: Methylation specific PCR was carried out to analyze the methylation status of seven genes in archived breast tissues and determine the effect of aberrant methylation of multiple genes on disease prognosis and patients’ survival.Results: Promoter hypermethylation was observed in PRB 67%, ERα 64%, RASSF1A 63%, p16INK4A 51%, PRBβ2 22%, GSTP1 25% and BRCA1 27% of the breast cancers, respectively. Concurrent methylation of BRCA1, ERα, GSTP1 and RARβ2, was observed in a large proportion of breast cancers analyzed, suggesting that these genes do not appear to be methylated alone. Patients with high methylation indices had poor prognosis (p < 0.001, Hazards ratio = 14.58). Cox regression analysis showed RARβ2 promoter methylation to be an independent important determinant of breast cancer prognosis.Conclusions: Our results suggest that methylation of multiple genes plays an important role in prognosis of breast cancer. Our study not only describes the association of methylation mediated silencing of multiple genes with the severity of disease, but also drives to speculate the molecular crosstalk between genes or genetic pathways regulated by them individually.
Cutaneous Human Papillomavirus E7 Type-Specific Effects on Differentiation and Proliferation of Organotypic Skin Cultures
Authors: Westphal K. , Akgül B. , Storey A. , Nindl I. 
Published: January 2021

Background: A role for cutaneous human β-papillomavirus (HPV) types as co-factors in the development of non-melanoma skin cancer has been postulated. Here we have investigated the effects of E7 expression on keratinocyte differentiation, proliferation and cell-cycle proteins in organotypic skin cultures.Methods: Recombinant retroviruses containing the E7 genes from cutaneous HPV types 1, 4, 5, 8, 20, 38 and RTRX7 were produced that include types associated with benign and malignant lesions. Adult human primary keratinocytes were transduced with these recombinant retroviruses and differentiated into skin-equivalents using de-epidermalised human dermis.Results: Expression patterns of the basal keratinocyte marker cytokeratin 14 (CK14) were not altered by any of the viral E7 types analysed. However, expression of the early and late differentiation markers CK10 and involucrin were markedly altered in HPV 1, 4 and 38 cultures. The highest proliferation rates in basal cell layers, as judged by BrdU and Ki67 staining, were observed in HPV 1, 4 and 38 cultures. Interestingly, co-expression of cyclin E and p16INK4a within the same cell of the suprabasal cell layers was observed only in cultures generated using E7 of HPV 5 or HPV 8.Conclusion: HPV types associated with either benign or malignant lesions perturb keratinocyte proliferation and differentiation in different ways. Moreover, expression of E7 from HPV 5 or HPV 8 seem able to overcome p16INK4a induced cell cycle arrest in a subset of keratinocytes.
The Prognostic Value of the Proliferation Marker Phosphohistone H3 (PPH3) in Luminal, Basal-Like and Triple Negative Phenotype Invasive Lymph Node-Negative Breast Cancer
Authors: Skaland Ivar , Janssen Emiel A. M. , Gudlaugsson Einar , Guo Lydia Hui Ru , Baak Jan P. A. 
Published: January 2021

Purpose: Prognostic comparison of phosphohistone-H3 (PPH3) with Cytokeratin 5/6 and/or 14 positive (= basal-CK), triple (ER, PR, HER2)-negative (= TNP) and basal-like (= TNP and basal-CK positive) phenotype in invasive breast cancers.Patients and Methods: Classical variables, PPH3, ER, PR, basal-CK and HER2 in 240 T1–2N0M0 patients under 71 years.Results: TNP and basal-like cancers had higher PPH3 expression than the other cancers (mean 48 versus 11, P < 0.001). Fifteen percent of the patients in the whole group, but 32–38% of TNP and basal-like cancers recurred.With multivariate analysis, PPH3 < 13 (n = 156) versus ≥ 13 (n = 84 = 35% of all cases) was the strongest and only prognosticator (10-year survival 96% and 64%, P ≤ 0.001, Hazard ratio = 9.0).Conclusion: PPH3 is the strongest prognosticators in luminal, Triple negative and basal-like T1–2N0M0 invasive breast cancers.
Expression of ERα, ERβ and Co-Regulator PELP1/MNAR in Colorectal Cancer: Prognostic Significance and Clinicopathologic Correlations
Authors: Grivas Petros D. , Tzelepi Vassiliki , Sotiropoulou-Bonikou Georgia , Kefalopoulou Zinovia , Papavassiliou Athanasios G. , Kalofonos Haralabos 
Published: January 2021

Background: Estrogen receptor β (ERβ) is abundantly expressed in colorectal tissue, but its role in colorectal carcinogenesis remains elusive. ER novel co-regulator, proline-, glutamic acid- and leucine-rich protein 1 (PELP1/MNAR) has been characterized, but its expression in colorectal carcinomas has not been investigated.Methods: ERα, ERβ and PELP1/MNAR protein expression were evaluated by immunohistochemistry in colorectal normal mucosa, adenomas and adenocarcinomas from 113 patients with colorectal cancer.Results: ERα expression is extremely rare in colorectal tissue and its expression does not appear to be associated with colorectal carcinogenesis. ERβ and PELP1/MNAR were detected in the nucleus of epithelial, endothelial, inflammatory, smooth muscle cells and myofibroblasts. When intensity of staining was taken into account, the expression of both proteins was significantly increased in epithelial cells of carcinomas compared to normal mucosa. ERβ expression in epithelial cells was correlated with decreased disease progression – free survival. PELP1/MNAR overexpression in epithelial cells was found to be an independent favorable prognostic factor. Additionally, the expression of both proteins was significantly increased in stromal myofibroblasts of carcinomas compared to adenomas and normal mucosa.Conclusion: ERβ and PELP1/MNAR appear to be involved in colorectal tumorigenesis and might have prognostic significance.
Functional Implication of Netrin Expression in Malignant Melanoma
Authors: Kaufmann Simone , Kuphal Silke , Schubert Thomas , Bosserhoff Anja K. 
Published: January 2021

Background: Malignant melanoma cells are known to have altered expression of genes supporting proliferation and invasion, however, the expression of molecules of the Netrin family of repellent factors has not been analyzed in melanomas until now.Results: Here, we show that Netrin-1 expression is strongly induced in melanoma cells compared to melanocytes in vivo and in vitro controlled at the transcriptional level via ETS-1. In addition, the expression of the netrin receptor UNC5B was induced and that of UNC5C was reduced in the tumor cells. In order to determine the functional relevance of Netrin-1 expression in malignant melanoma, Netrin expression in melanoma cells was reduced by siRNA attempts and primary human melanocytes were treated with recombinant Netrin-1. The cells showed no changes in proliferation or apoptosis, however, a strong reduction of migratory properties was observed in the melanoma cells after reduction of Netrin expression whereas melanocyte migration was strongly induced by treatment with Netrin.Conclusions: Our study suggests that Netrin-1 promotes melanoma cell invasion and migration and therefore has an important role in the progression of malignant melanoma.
PI3K-AKT-mTOR Pathway is Dominant over Androgen Receptor Signaling in Prostate Cancer Cells
Authors: Kaarbø Mari , Mikkelsen Øyvind Løveseter , Malerød Lene , Qu Su , Lobert Viola H. , Akgul Gulcan , Halvorsen Thomas , Mælandsmo Gunhild M. , Saatcioglu Fahri 
Published: January 2021

Background: Androgen receptor (AR) and the phosphatidylinositol-3 kinase (PI3K) signaling are two of the most important pathways implicated in prostate cancer. Previous work has shown that there is crosstalk between these two pathways; however, there are conflicting findings and the molecular mechanisms are not clear. Here we studied the AR–PI3K pathway crosstalk in prostate cancer cells in vitro as well as in vivo.Methods: Quantitative PCR, Western analysis, reporter assays, and proliferation analyses in vitro and in vivo were used to evaluate the effect of PI3K pathway inhibition on AR signaling and cell growth.Results: Transcriptional activity of AR was increased when the PI3K pathway was inhibited at different levels. In the androgen responsive prostate cancer cell line LNCaP, androgen and the mTOR inhibitor rapamycin synergistically activated androgen target genes. Despite increased androgen signaling, rapamycin treatment reduced LNCaP cell growth; the AR antagonist bicalutamide potentiated this effect. Furthermore, the rapamycin derivative CCI-779 reduced the growth of CWR22 prostate cancer xenografts while increasing AR target gene expression.Conclusions: These findings suggest that inhibition of the PI3K pathway activates AR signaling. Despite the increase in AR signaling which has proliferative effects, the result of PI3K pathway inhibition is antiproliferative. These findings suggest that the PI3K pathway is dominant over AR signaling in prostate cancer cells which should be considered in developing novel therapeutic strategies for prostate cancer.
Expression Profile of Tyrosine Phosphatases in HER2 Breast Cancer Cells and Tumors
Authors: Lucci Maria Antonietta , Orlandi Rosaria , Triulzi Tiziana , Tagliabue Elda , Balsari Andrea , Villa-Moruzzi Emma 
Published: January 2021

Background: HER2-overexpression promotes malignancy by modulating signalling molecules, which include PTPs/DSPs (protein tyrosine and dual-specificity phosphatases). Our aim was to identify PTPs/DSPs displaying HER2-associated expression alterations.Methods: HER2 activity was modulated in MDA-MB-453 cells and PTPs/DSPs expression was analysed with a DNA oligoarray, by RT-PCR and immunoblotting. Two public breast tumor datasets were analysed to identify PTPs/DSPs differentially expressed in HER2-positive tumors.Results: In cells (1) HER2-inhibition up-regulated 4 PTPs (PTPRA, PTPRK, PTPN11, PTPN18) and 11 DSPs (7 MKPs [MAP Kinase Phosphatases], 2 PTP4, 2 MTMRs [Myotubularin related phosphatases]) and down-regulated 7 DSPs (2 MKPs, 2 MTMRs, CDKN3, PTEN, CDC25C); (2) HER2-activation with EGF affected 10 DSPs (5 MKPs, 2 MTMRs, PTP4A1, CDKN3, CDC25B) and PTPN13; 8 DSPs were found in both groups. Furthermore, 7 PTPs/DSPs displayed also altered protein level. Analysis of 2 breast cancer datasets identified 6 differentially expressed DSPs: DUSP6, strongly up-regulated in both datasets; DUSP10 and CDC25B, up-regulated; PTP4A2, CDC14A and MTMR11 down-regulated in one dataset.Conclusions: Several DSPs, mainly MKPs and, unexpectedly, MTMRs, were altered following HER2-modulation in cells and 3 DSPs (DUSP6, CDC25B and MTMR11) were altered in both cells and tumors. Among these, DUSP6, strongly up-regulated in HER2-positive tumors, would deserve further investigation as tumor marker or potential therapy target.
The Pan-Deacetylase Inhibitor Panobinostat Inhibits Growth of Hepatocellular Carcinoma Models by Alternative Pathways of Apoptosis
Authors: Di Fazio Pietro , Schneider-Stock Regine , Neureiter Daniel , Okamoto Kinya , Wissniowski Till , Gahr Susanne , Quint Karl , Meissnitzer Matthias , Alinger Beate , Montalbano Roberta , Sass Gabriele , Hohenstein Bernd , Hahn Eckhart G. , Ocker Matthias 
Published: January 2021

Inhibition of deacetylases represents a new treatment option for human cancer diseases. We applied the novel and potent pan-deacetylase inhibitor panobinostat (LBH589) to human hepatocellular carcinoma models and investigated by which pathways tumor cell survival is influenced.HepG2 (p53wt) and Hep3B (p53null) responded to panobinostat treatment with a reduction of cell proliferation and a significant increase in apoptotic cell death at low micromolar concentrations. Apoptosis was neither mediated by the extrinsic nor the intrinsic pathway but quantitative RT-PCR showed an upregulation of CHOP, a marker of the unfolded protein response and endoplasmic reticulum stress with subsequent activation of caspase 12. Dependent on the p53 status, a transcriptional upregulation of p21cip1/waf1, an increased phosphorylation of H2AX, and an activation of the MAPK pathway were observed. In a subcutaneous xenograft model, daily i.p. injections of 10 mg/kg panobinostat lead to a significant growth delay with prolonged overall survival, mediated by reduced tumor cell proliferation, increased apoptosis and reduced angiogenesis in tumor xenografts. Panobinostat increased the acetylation of histones H3 and H4.Panobinostat is a well tolerated new treatment option for HCC that activates alternative pathways of apoptosis, also in p53-deficient tumors.
Translational Regulation of Cancer Metastasis
Authors: Micalizzi Douglas S. , Ebright Richard Y. , Haber Daniel A. , Maheswaran Shyamala 
Published: January 2021

Abstract
Deregulation of the mRNA translational process has been observed during tumorigenesis. However, recent findings have shown that deregulation of translation also contributes specifically to cancer cell spread. During metastasis, cancer cells undergo changes in cellular state, permitting the acquisition of features necessary for cell survival, dissemination, and outgrowth. In addition, metastatic cells respond to external cues, allowing for their persistence under significant cellular and microenvironmental stresses. Recent work has revealed the importance of mRNA translation to these dynamic changes, including regulation of cell states through epithelial-to-mesenchymal transition and tumor dormancy and as a response to external stresses such as hypoxia and immune surveillance. In this review, we focus on examples of altered translation underlying these phenotypic changes and responses to external cues and explore how they contribute to metastatic progression. We also highlight the therapeutic opportunities presented by aberrant mRNA translation, suggesting novel ways to target metastatic tumor cells.
The Genetic Evolution of Treatment-Resistant Cutaneous, Acral, and Uveal Melanomas
Authors: Makohon-Moore Alvin P. , Lipson Evan J. , Hooper Jody E. , Zucker Amanda , Hong Jungeui , Bielski Craig M. , Hayashi Akimasa , Tokheim Collin , Baez Priscilla , Kappagantula Rajya , Kohutek Zachary , Makarov Vladimir , Riaz Nadeem , Postow Michael A. , Chapman Paul B. , Karchin Rachel , Socci Nicholas D. , Solit David B. , Chan Timothy A. , Taylor Barry S. , Topalian Suzanne L. , Iacobuzio-Donahue Christine A. 
Published: January 2021

AbstractPurpose:Melanoma is a biologically heterogeneous disease composed of distinct clinicopathologic subtypes that frequently resist treatment. To explore the evolution of treatment resistance and metastasis, we used a combination of temporal and multilesional tumor sampling in conjunction with whole-exome sequencing of 110 tumors collected from 7 patients with cutaneous (n = 3), uveal (n = 2), and acral (n = 2) melanoma subtypes.Experimental Design:Primary tumors, metastases collected longitudinally, and autopsy tissues were interrogated. All but 1 patient died because of melanoma progression.Results:For each patient, we generated phylogenies and quantified the extent of genetic diversity among tumors, specifically among putative somatic alterations affecting therapeutic resistance.Conclusions:In 4 patients who received immunotherapy, we found 1–3 putative acquired and intrinsic resistance mechanisms coexisting in the same patient, including mechanisms that were shared by all tumors within each patient, suggesting that future therapies directed at overcoming intrinsic resistance mechanisms may be broadly effective.
Development and Validation of a Simplified Probability Assessment Score Integrated With Age‐Adjusted
d
‐Dimer for Diagnosis of Acute Aortic Syndromes
Authors: Morello Fulvio , Bima Paolo , Pivetta Emanuele , Santoro Marco , Catini Elisabetta , Casanova Barbara , Leidel Bernd A. , de Matos Soeiro Alexandre , Nestelberger Thomas , Mueller Christian , Grifoni Stefano , Lupia Enrico , Nazerian Peiman 
Published: January 2021

Background

When acute aortic syndromes (AASs) are suspected, pretest clinical probability assessment and
d
‐dimer (DD) testing are diagnostic options allowing standardized care. Guidelines suggest use of a 12‐item/3‐category score (aortic dissection detection) and a DD cutoff of 500 ng/mL. However, a simplified assessment tool and a more specific DD cutoff could be advantageous.

Methods and Results

In a prospective derivation cohort (n=1848), 6 items identified by logistic regression (thoracic aortic aneurysm, severe pain, sudden pain, pulse deficit, neurologic deficit, hypotension), composed a simplified score (AORTAs) assigning 2 points to hypotension and 1 to the other items. AORTAs≤1 and ≥2 defined low and high clinical probability, respectively. Age‐adjusted DD was calculated as years/age × 10 ng/mL (minimum 500). The AORTAs score and AORTAs≤1/age‐adjusted DD rule were validated in 2 patient cohorts: a high‐prevalence retrospective cohort (n=1035; 22% AASs) and a low‐prevalence prospective cohort (n=447; 11% AASs) subjected to 30‐day follow‐up. The AUC of the AORTAs score was 0.729 versus 0.697 of the aortic dissection detection score (
P
=0.005). AORTAs score assessment reclassified 16.6% to 25.1% of patients, with significant net reclassification improvement of 10.3% to 32.7% for AASs and −8.6 to −17% for alternative diagnoses. In both cohorts, AORTAs≥2 had superior sensitivity and slightly lower specificity than aortic dissection detection ≥2. In the prospective validation cohort, AORTAs≤1/age‐adjusted DD had a sensitivity of 100%, a specificity of 48.6%, and an efficiency of 43.3%.

Conclusions
AORTAs is a simplified score with increased sensitivity, improved AAS classification, and minor trade‐off in specificity, amenable to integration with age‐adjusted DD for diagnostic rule‐out.
Staging model for amyotrophic lateral sclerosis in Singapore
Authors: Tay Yuan Teck , Chai Josiah YH , Jabin Kamilah Bte Shekh , Ang Kexin 
Published: January 2021

Abstract

Introduction:
A clinical-based staging model would guide physicians in the prompt management of the evolving symptoms and functional needs of patients with amyotrophic lateral sclerosis (ALS).

Methods:
We aimed to delineate the clinical trajectory of ALS in Singapore and test the degree of congruity of King’s College staging for ALS (King’s staging) among Singapore patients. In this retrospective cohort study, clinical milestones used for staging were identical to King’s staging: stage 1 corresponded to symptom onset; stage 2A corresponded to diagnosis; stage 2B corresponded to two central nervous system (CNS) regions; stage 3B corresponded to three CNS regions; stage 4A corresponded to requirement of supportive enteric feeding; and stage 4B corresponded to requirement of non-invasive ventilation, of which bulbar, diaphragmatic, upper and lower limb pyramidal involvements each constituted one CNS region. Standardised timings from disease onset (0) to death (1) among Singapore patients with ALS were measured.

Results:
46 patients with ALS were reviewed. Results were largely congruous with King’s staging. Results for patients with limb-onset. ALS were: diagnosis (0.35); two CNS region involvement (0.42); three CNS region involvement (0.63); diaphragmatic involvement (0.81); and bulbar involvement (0.73). Results for patients with bulbar-onset. ALS were: diagnosis (0.14); two CNS region involvement (0.28); three CNS region involvement (0.42); diaphragmatic involvement (0.62); and bulbar involvement (0.67).

Conclusion:
King’s staging can be used to model ALS trajectory in Singapore due to the large degree of congruity seen. Easily remembered and accessible knowledge of ALS staging will allow prompt management of the evolving needs of patients with ALS.
Elevation of preoperative cystatin C as an early predictor of contrast-induced nephropathy in patients receiving percutaneous coronary intervention
Authors: Gu Guoqiang , Yu Ningning , Zhou Yaqing , Cui Wei 
Published: January 2021

Abstract

Introduction:
Contrast-induced nephropathy (CIN) is a serious complication of percutaneous coronary intervention (PCI). The most important predictor of CIN is renal function before PCI. Serum creatinine (SCr) is a commonly used biomarker of renal function, but an elevation in SCr lags behind the onset of kidney injury and is not viable for early detection of CIN after PCI. Our primary objective was to investigate whether preoperative cystatin C (CysC) before PCI was an early predictor of postoperative CIN. The secondary objective was to evaluate associations between preoperative CysC and renal biomarkers.

Methods:
From December 2014 to December 2015, 341 patients with normal renal function were enrolled into the study at our medical centre. All patients were apportioned to normal CysC (≤1.03 mg/L) or high CysC (>1.03 mg/L) groups before PCI and were hydrated from four hours prior to PCI to 24 hours after it. Renal function was monitored at 48 hours after PCI. Clinical parameters were recorded before and after PCI.

Results:
There was no significant difference in preoperative SCr between the CIN and non-CIN groups. However, preoperative CysC demonstrated significant difference between the two groups (p <0.01). Logistic regression analysis showed that elevated CysC before PCI was a risk factor for CIN (p = 0.013). Furthermore, the linear regression models identified an association between CysC before PCI and renal function after PCI.

Conclusion:
CysC before PCI was viable as a biomarker of renal function after PCI and high preoperative CysC was able to predict CIN earlier than SCr.