bluuebunny/crossref_metadata_2025_split huggingface dataset:
Global Earthquake Forecasting System (GEFS): The challenges ahead
Authors: Mignan A. , Ouillon G. , Sornette D. , Freund F. 
Published: January 2021

AbstractWe conclude this special issue on the Global Earthquake Forecasting System (GEFS) by briefly reviewing and analyzing the claims of non-seismic precursors made in the present volume, and by reflecting on the current limitations and future directions to take. We find that most studies presented in this special volume, taken individually, do not provide strong enough evidence of non-seismic precursors to large earthquakes. The majority of the presented results are hampered by the fact that the task at hand is susceptible to potential biases in data selection and possible overfitting. The most encouraging results are obtained for ground-based geoelectric signals, although the probability gain is likely small compared to an earthquake clustering baseline. The only systematic search on satellite data available so far, those of the DEMETER mission, did not find a robust precursory pattern. The conclusion that we can draw is that the overall absence of convincing evidence is likely due to a deficit in systematically applying robust statistical methods and in integrating scientific knowledge of different fields. Most authors are specialists of their field while the study of earthquake precursors requires a system approach combined with the knowledge of many specific characteristics of seismicity. Relating non-seismic precursors to earthquakes remains a challenging multidisciplinary field of investigation. The plausibility of these precursors predicted by models of lithosphere-atmosphere-ionosphere coupling, together with the suggestive evidence collected here, call for further investigations. The primary goal of the GEFS is thus to build a global database of candidate signals, which could potentially improve earthquake predictability (if the weak signals observed are real and false positives sufficiently uncorrelated between different data sources). Such a stacking of disparate and voluminous data will require big data storage and machine learning pipelines, which has become feasible only recently. This special issue compiled an eclectic list of non-seismic precursor candidates, which is in itself a valuable source of information for seismologists, geophysicists and other scientists who may not be familiar with such types of investigations. It also forms the foundation for a coherent, multi-disciplinary collaboration on earthquake prediction.
The sun as a significant agent provoking earthquakes
Authors: Anagnostopoulos G. , Spyroglou I. , Rigas A. , Preka-Papadema P. , Mavromichalaki H. , Kiosses I. 
Published: January 2021

AbstractIn this paper we provide significant evidence that the sun is a principal agent provoking seismic activity. In particular the aim of the studies presented is to examine the possible relation of the coronal hole (CH) driven high speed solar wind streams (HSSs) with seismicity We performed several statistical studies of solar space and seismological data between 1980 and 2017 as well as a study for a long time interval from the year 1900 until the year 2017. (A1) Concerning the period 1980–2017 among other results we found that the earthquakes (EQs) withM ≥ 83 between 2010–2017 (including the catastrophic earthquakes of Japan 2011 (M91) Sumatra 2012 (M86) and Chile 2015 (M83)) occurred during times of large coronal holes as seen by the Solar Dynamics Observatory (SDO) satellite and were related with CH-driven HSSs observed by the ACE spacecraft several weeks or a few months before the EQ occurrences. (A2) Further research on the hypothesis of the possible HSS-EQ relationship revealed a surprising novel finding: a power spectrum analysis suggests that during the decay phase of the SCC22 and SC23 and at the maximum of SC23 the values of the global seismic (M ≥ 6) energy output shows a periodic variation of ~27 days, which is the mean rotational period of the Sun. (A3) Moderate (not strong) storms in general precede the great EQs. (B) The study of the data for the time interval 1900–2017 revealed that: (1) all of the giant (M ≥ 85) EQs occurred during the decay minimum and the rising phase of the solar cycle or in the maximum phase but at times of a strong reduction of the monthly averaged sunspot number: Chile M95 1960 EQ – Alaska M92 1964 EQ – Sumatra M91 2004 EQ (decay phase) Japan M91 2011 EQ (rising phase of the "strange" SC24) (2) the global energy release of all EQs with magnitudesM ≥ 55 show the highest values during the decay phase of the solar cycle and in particular three years after the solar maximum and (3) a very significant negative correlation (rS = −042p < 10−4) was found between the SSN and the number of earthquakes withM ≥ 7 during the period 1930–2010 during times of moderate and high amplitude solar cycles. (C) Another result of our study is that the comparison of the yearly numbers of great (M ≥ 7) EQs with the SSN fails to provide correct statistical results whereas this is possible for the global seismic energy or the giant EQs. (D) Finally we infer that the case and statistical studies presented in this paper strongly suggest a close relation between CH-associated HSSs and seismic activity. We present some observational evidence that most probably Alfvèn waves mediate the interaction of CH-driven HSSs with seismicity.
It's Better To Be Lucky Than Smart
Authors: Kaback H.R. 
Published: January 2021

Bacterial cytoplasmic membrane vesicles provide a unique experimental system for studying active transport. Vesicles are prepared by lysis of osmotically sensitized cells (i.e., protoplasts or spheroplasts) and comprise osmotically intact, unit-membrane-bound sacs that are approximately 0.5–1.0 μm in diameter and devoid of internal structure. Their metabolic activities are restricted to those provided by the enzymes of the membrane itself, and each vesicle is functional. The energy source for accumulation of a particular substrate can be determined by studying which compounds or experimental conditions drive solute accumulation, and metabolic conversion of the transported substrate or the energy source is minimal. These properties of the vesicle system constitute a considerable advantage over intact cells, as the system provides clear definition of the reactions involved in the transport process. This discussion is not intended as a general review but is concerned with respiration-dependent active transport in membrane vesicles from Escherichia coli. Emphasis is placed on experimental observations demonstrating that respiratory energy is converted primarily into work in the form of a solute concentration gradient that is driven by a proton electrochemical gradient, as postulated by the chemiosmotic theory of Peter Mitchell.
HCC Heterogeneity: Molecular Pathogenesis and Clinical Implications
Authors: Fransvea Emilia , Paradiso Angelo , Antonaci Salvatore , Giannelli Gianluigi 
Published: January 2021

Background: Hepatocellular carcinoma (HCC) poses a major challenge because of the extreme variability of the clinical outcome, which makes it difficult to properly stage the disease and thereby estimate the prognosis. There is growing evidence that this heterogeneous clinical behavior is attributable to several different biological pathways. A novel approach to mapping these differences is by investigating the epigenetics associated with certain clinical aspects.Design: Herein, the relevance of these molecular differences in combination with the biological and molecular pathways regulating the clinical outcome will be discussed. Use of a mechanistic and pathogenic approach to clarify the natural history of HCC is not just an academic speculation but should help to develop new therapies and to tailor these therapies to each individual patient.Conclusion: New biological therapies targeting components of the tumoral or peritumoral microenvironment are crucial to the fight against HCC. However, biological redundancies and the presence of several growth factors, hormones, cytokines, etc., potentially involved in HCC tumor progression make it difficult to assess the best target. Sorafenib, a multi-tyrosine kinase inhibitor, blocks the functions of different growth factors present in the tissue microenvironment. The use of Sorafenib in patients with HCC offers a new approach to the therapy of this disease, stimulating research focusing on the development of drugs based on new molecular and pathogenic insights.
Comparison between Real-Time Quantitative PCR Detection of HER2 mRNA Copy Number in Peripheral Blood and ELISA of Serum HER2 Protein for Determining HER2 Status in Breast Cancer Patients
Authors: Savino Maria , Parrella Paola , Copetti Massimiliano , Barbano Raffaela , Murgo Roberto , Fazio Vito Michele , Valori Vanna Maria , Carella Massimo , Garrubba Maria , Santini Stefano Angelo 
Published: January 2021

Background: The development of non-invasive procedure to determine HER2 status may represent a powerful method for monitoring disease progression and response to the treatment.Methods: Serum samples and RNA from peripheral blood were evaluated in 85 breast cancer patients (49 HER2 positive and 36 HER2 negative) and 22 healthy controls. HER2 mRNA levels were measured by real-time quantitative PCR (QPCR) and serum HER2 protein by immunoenzimatic assay (EIA). ROC curve analyses were used to determine the optimal cut off values.Results: A statistically significant difference was detected for both QPCR and EIA in HER2 positive patients as compared with both healthy controls and HER2 negative tumours. QPCR showed a 91% (CI95%: 84%–98%) specificity and a 78% (CI95%: 68%–88%) sensitivity for an optimal cut off value of 4.74. The optimal cut off value for EIA was 22 ng/ml yielding a 95% (CI95%: 90%–100%) specificity and a 59% (CI95%: 48%–70%) sensitivity. The QPCR assay was slightly less specific than EIA in discriminating HER2 positive breast cancers from HER2 negative tumours (78% CI95%: 69%–87% versus 86% CI95%: 79%–93%), but it was more sensitive (76% CI95%: 67%–85% versus 55% CI95%: 44%–66%).Conclusions: Our results indicate that QPCR performs better than EIA in the determination of HER2 status of breast cancer patients and could be useful in monitoring the disease during follow up.
Pla2g2a Attenuates Colon Tumorigenesis in Azoxymethane-Treated C57BL/6 Mice; Expression Studies Reveal Pla2g2a Target Genes and Pathways
Authors: Fijneman Remond J. A. , Bade Lindsey K. , Peham Johannes R. , van de Wiel Mark A. , van Hinsbergh Victor W. M. , Meijer Gerrit A. , O’Sullivan Michael G. , Cormier Robert T. 
Published: January 2021

Background: The group IIA secretory phospholipase A2 gene, Pla2g2a, confers resistance to intestinal tumorigenesis in the ApcMin/+ mouse model. However, it is unclear how Pla2g2a exerts its tumor-suppressive effects and whether its mode of action depends on Apc-germline mutations.Methods: We tested whether expression of a Pla2g2a transgene provides protection against carcinogen-induced colon tumors, and examined whether the normal colon microenvironment is modulated by Pla2g2a expression.Results: Pla2g2a strongly inhibited colon tumorigenesis in mice following treatment with the DNA alkylating agent azoxymethane (AOM). Moreover, AOM-induced duodenal tumors were also attenuated by Pla2g2a expression. These tumors demonstrated upregulation of β-catenin, indicative of involvement of the Wnt signaling pathway. Comparison of genome-wide microarray expression profiles of healthy (non-pathologic) colon tissues from Pla2g2a-transgenic to non-transgenic mice revealed 382 genes that were differentially expressed, comprising clusters of genes involved in inflammation and microbial defense, cell signaling and cell cycle, transactivation, apoptosis and mitochondrial function, DNA repair, and lipid and energy metabolism. Pathway analysis using Gene Set Enrichment Analysis (GSEA) indicated that Pla2g2a suppresses the expression of interferon-induced genes.Conclusion: Our results demonstrate that Pla2g2a attenuates colon tumorigenesis independent of Apc-germline mutations, and reveal Pla2g2a target genes and pathways in non-pathologic colon microenvironment that influence conditions for colorectal cancer development.
Multiple Localization of Endogenous MARK4L Protein in Human Glioma
Authors: Magnani Ivana , Novielli Chiara , Bellini Melissa , Roversi Gaia , Bello Lorenzo , Larizza Lidia 
Published: January 2021

Background: We have previously shown that the sustained expression of MARK4L transcripts in glioma and neural progenitors (NHNPs) declines after exposure to antisense MARK4L oligonucleotides in glioblastoma cell lines. Array-CGH confirmed the genomic duplication of MARK4L identified by FISH in a glioblastoma cell line. This background together with literature data on the exogenous association of MARK4 with interphase centrosome prompted us to investigate the sub-cellular localization of the endogenous MARK4L protein aiming at achieving insights on its possible role in the pathomechanisms of glioma.Methods: Immunodetection was carried out to validate the specificity of MARK4L antibody in gliomas and NHNPs. Mass spectrometry was applied for MARK4L protein identification in a representative glioblastoma cell line. Combined biochemical fractionation and immunodetection analyses were performed to confirm the sub-cellular localization of MARK4L achieved by immunofluorescence in glioma cell lines.Results: By assigning MARK4L protein within the band immunoprecipitated by the specific antibody we validated our anti-MARK4L antibody. We demonstrated that the endogenous MARK4L: (i) colocalizes with centrosomes at all mitotic stages and resides in centrosome-enriched fractions; (ii) associates with the nucleolus and the midbody and respective fractions, and (iii) co-stains the aberrant centrosome configurations observed in glioma cell lines.Conclusions: The overall data merge on the multiplex entry of MARK4L into the cell cycle and link it to the aberrant centrosomes in glioma cell lines suggesting a possible role of this kinase in the abnormal mitotic processes of human glioma.
A Panel of High Resolution Melting (HRM) Technology-Based Assays with Direct Sequencing Possibility for Effective Mutation Screening of EGFR and K-ras Genes
Authors: Heideman D. A. M. , Thunnissen F. B. , Doeleman M. , Kramer D. , Verheul H. M. , Smit E. F. , Postmus P. E. , Meijer C. J. L. M. , Meijer G.A. , Snijders P. J. F. 
Published: January 2021

Background: Increasing data from clinical trials support EGFR and K-ras mutation status as predictive markers of tumour response to EGFR-targeted therapies. Consequently, rapid and reliable mutation screening assays are demanded to guide rational use of EGFR-targeted therapies.Methods: In this study, we describe the development of high resolution melting (HRM) technology-based assays with direct sequencing confirmation possibility for mutation screening of the EGFR gene (exons 19, 20 and 21) in routine diagnostic specimens, and compared assay findings to those of conventional nested-PCR following cycle-sequencing.Results: In reconstruction experiments, each HRM assay following sequencing demonstrated a sensitivity of ≤5% of mutated DNA in a background of wild-type DNA. The panel of EGFR HRM assays following sequencing applied to a series of genomic DNA samples isolated from 68 FFPE NSCLC specimens correctly identified all EGFR mutations that were previously found by nested-PCR following cycle-sequencing. The HRM approach additionally scored two mutations not detected by the conventional assay.Complementary HRM following sequencing for K-ras revealed three mutations. EGFR and K-ras mutations were mutually exclusive.Conclusions: The panel of designed HRM assays with direct reflex sequencing possibility provides an effective method for mutation screening of EGFR and K-ras genes in routine diagnostic specimens, thereby allowing the selection of the treatment of choice in clinical practice.
TGF-β Repressors SnoN and Ski Are Implicated in Human Colorectal Carcinogenesis
Authors: Bravou Vasiliki , Antonacopoulou Anna , Papadaki Helen , Floratou Konstantina , Stavropoulos Michalis , Episkopou Vasso , Petropoulou Chariklia , Kalofonos Haralabos 
Published: January 2021

Background: The TGF-β signaling repressors SnoN and Ski have been critically implicated in human cancer.Methods: To explore the role of SnoN and Ski in the development and progression of colorectal cancer we examined their protein expression profile by immunohistochemistry in a series of human colorectal adenomas, carcinomas and lymph node metastases. The mRNA expression of SnoN was also quantified by Real-Time RT-PCR.Results: SnoN and Ski were overexpressed both in adenomas with severe dysplasia and colorectal carcinomas. Protein expression was cytoplasmic and nuclear with predominant cytoplasmic localization. The subcellular localization was related differently to pathologic variables of colorectal carcinomas. Although there was no significant association of protein levels with tumor invasion and metastasis, a significant correlation of nuclear SnoN and Ski with β-catenin pathway was observed. Moreover, SnoN mRNA did not differ in carcinomas as compared to normal control and there was no correlation between SnoN protein and mRNA levels.Conclusion: Our findings suggest that SnoN and Ski exert oncogenic effects in human colorectal carcinogenesis and their overexpression is implicated in early stage disease.
Different Subcellular Localization of ALCAM Molecules in Neuroblastoma: Association with Relapse
Authors: Corrias Maria Valeria , Gambini Claudio , Gregorio Andrea , Croce Michela , Barisione Gaia , Cossu Claudia , Rossello Armando , Ferrini Silvano , Fabbi Marina 
Published: January 2021

Background: The Activated Leukocyte Cell Adhesion Molecule (ALCAM/CD), involved in nervous system development, has been linked to tumor progression and metastasis in several tumors. No information is available on ALCAM expression in neuroblastoma, a childhood neoplasia originating from the sympathetic nervous system.Methods: ALCAM expression was analysed by immunofluorescence and immunohistochemistry on differentiated neuroblastoma cell lines and on archival specimens of stroma-poor, not MYCN amplified, resectable neuroblastoma tumors, respectively.Results: ALCAM is variously expressed in neuroblastoma cell lines, is shed by metalloproteases and is cleaved by ADAM17/TACE in vitro. ALCAM is expressed in neuroblastoma primary tumors with diverse patterns of subcellular localization and is highly expressed in the neuropil area in a subgroup of cases. Tumor specimens showing high expression of ALCAM at the membrane of the neuroblast body or low levels in the neuropil area are associated with relapse (P = 0.044 and P < 0.0001, respectively). In vitro differentiated neuroblastoma cells show strong ALCAM expression on neurites, suggesting that ALCAM expression in the neuropil is related to a differentiated phenotype.Conclusions: Assessment of ALCAM localization by immunohistochemistry may help to identify patients who, in the absence of negative prognostic factors, are at risk of relapse and require a more careful follow-up.
Microarray Analysis of Suppression Subtracted Hybridisation Libraries Identifies Genes Associated with Breast Cancer Progression
Authors: Barraclough Dong Liu , Sewart Susan , Rudland Philip S. , Shoker Balvinder S. , Sibson D. Ross , Barraclough Roger , Davies Michael P. A. 
Published: January 2021

Background: A major challenge of cancer research is to identify key molecules which are responsible for the development of the malignant metastatic phenotype, the major cause of cancer death.Methods: Four subtracted cDNA libraries were constructed representing mRNAs differentially expressed between benign and malignant human breast tumour cells and between micro-dissected breast carcinoma in situ and invasive carcinoma. Hundreds of differentially expressed cDNAs from the libraries were micro-arrayed and screened with mRNAs from human breast tumor cell lines and clinical specimens. Gene products were further examined by RT-PCR and correlated with clinical data.Results: The combination of subtractive hybridisation and microarray analysis has identified a panel of 15 cDNAs which shows strong correlations with estrogen receptor status, malignancy or relapse. This panel included S100P, which was associated with aneuploidy in cell lines and relapse/death in patients, and AGR2 which was associated with estrogen receptor and with patient relapse. X-box binding protein-1 is also an estrogen-dependent gene and is associated with better survival for breast cancer patients.Conclusions: The combination of subtracted cDNA libraries and microarray analysis has thus identified potential diagnostic/prognostic biomarkers and targets for cancer therapy, which have not been identified from common prognostic gene signatures.
Validation of a Fully Automated HER2 Staining Kit in Breast Cancer
Authors: Moelans Cathy B. , Kibbelaar Robby E. , van den Heuvel Marius C. , Castigliego Domenico , de Weger Roel A. , van Diest Paul J. 
Published: January 2021

Background: Testing for HER2 amplification and/or overexpression is currently routine practice to guide Herceptin therapy in invasive breast cancer. At present, HER2 status is most commonly assessed by immunohistochemistry (IHC). Standardization of HER2 IHC assays is of utmost clinical and economical importance. At present, HER2 IHC is most commonly performed with the HercepTest which contains a polyclonal antibody and applies a manual staining procedure. Analytical variability in HER2 IHC testing could be diminished by a fully automatic staining system with a monoclonal antibody.Materials and Methods: 219 invasive breast cancers were fully automatically stained with the monoclonal antibody-based Oracle HER2 Bond IHC kit and manually with the HercepTest. All cases were tested for amplification with chromogenic in situ hybridization (CISH).Results: HercepTest yielded an overall sharper membrane staining, with less cytoplasmic and stromal background than Oracle in 17% of cases. Overall concordance between both IHC techniques was 89% (195/219) with a kappa value of 0.776 (95% CI 0.698–0.854), indicating a substantial agreement. Most (22/24) discrepancies between HercepTest and Oracle showed a weaker staining for Oracle. Thirteen of the 24 discrepant cases were high-level HER2 amplified by CISH, and in 12 of these HercepTest IHC better reflected gene amplification status. All the 13 HER2 amplified discrepant cases were at least 2+ by HercepTest, while 10/13 of these were at least 2+ for Oracle. Considering CISH as gold standard, sensitivity of HercepTest and Oracle was 91% and 83%, and specificity was 94% and 98%, respectively. Positive and negative predictive values for HercepTest and Oracle were 90% and 95% for HercepTest and 96% and 91% for Oracle, respectively.Conclusion: Fully-automated HER2 staining with the monoclonal antibody in the Oracle kit shows a high level of agreement with manual staining by the polyclonal antibody in the HercepTest. Although Oracle shows in general some more cytoplasmic staining and may be slightly less sensitive in picking up HER2 amplified cases, it shows a higher specificity and may be considered as an alternative method to evaluate the HER2 expression in breast cancer with potentially less analytical variability.