bluuebunny/crossref_metadata_2025_split huggingface dataset:
Frequent HIN-1 Promoter Methylation and Lack of Expression in Multiple Human Tumor Types
Authors: Krop Ian , Player Audrey , Tablante Ana , Taylor-Parker Michele , Lahti-Domenici Jaana , Fukuoka Junya , Batra Surinder K. , Papadopoulos Nickolas , Richards William G. , Sugarbaker David J. , Wright Renee L. , Shim Judy , Stamey Thomas A. , Sellers William R. , Loda Massimo , Meyerson Matthew , Hruban Ralph , Jen Jin , Polyak Kornelia 
Published: May 2022

Abstract
HIN-1 (high in normal-1) is a candidate tumor suppressor identified as a gene silenced by methylation in the majority of breast carcinomas. HIN-1 is highly expressed in the mammary gland, trachea, lung, prostate, pancreas, and salivary gland, and in the lung, its expression is primarily restricted to bronchial epithelial cells. In this report, we show that, correlating with the secretory nature of HIN-1, high levels of HIN-1 protein are detected in bronchial lavage, saliva, plasma, and serum. To determine if, similar to breast carcinomas, HIN-1 is also silenced in tumors originating from other organs with high HIN-1 expression, we analyzed its expression and promoter methylation status in lung, prostate, and pancreatic carcinomas. Nearly all prostate and a significant fraction of lung and pancreatic carcinomas showed HIN-1 hypermethylation, and the majority of lung and prostate tumors lacked HIN-1 expression. In lung carcinomas, the degree of HIN-1 methylation differed among tumor subtypes (P = 0.02), with the highest level of HIN-1 methylation observed in squamous cell carcinomas and the lowest in small cell lung cancer. In lung adenocarcinomas, the expression of HIN-1 correlated with cellular differentiation status. Hypermethylation of the HIN-1 promoter was also frequently observed in normal tissue adjacent to tumors but not in normal tissue from noncancer patients, implying that HIN-1 promoter methylation may be a marker of premalignant changes. Thus, silencing of HIN-1 expression and methylation of its promoter occurs in multiple human cancer types, suggesting that elimination of HIN-1 function may contribute to several forms of epithelial tumorigenesis.
Inhibin Resistance Is Associated with Aggressive Tumorigenicity of Ovarian Cancer Cells
Authors: Steller Michael D. , Shaw Tanya J. , Vanderhyden Barbara C. , Ethier Jean-François 
Published: May 2022

Abstract
Malignant ovarian epithelial tumors have been shown to have decreased inhibin production relative to activin production compared with normal ovarian surface epithelial (OSE) cells and nonmalignant ovarian tumors. Activin stimulates proliferation of many ovarian cancer cell lines. Inhibin antagonizes the action of activin, and inhibin-deficient mice develop gonadal tumors, suggesting that inhibin may be a tumor suppressor. However, its effects on OSE and ovarian cancer cells are unknown. We hypothesize that activin and inhibin are important regulators of biological activity in ovarian cancers. We found that inhibin A decreased murine OSE proliferation, whereas activin A had no effect. Activin A increased the proliferation of four of eight ovarian cancer cell lines (SKOV3, OCC1, OVCAR3, and A2780-s). Inhibin A decreased the proliferation of SKOV3, A2780-s, and OVCAR3 but had no effect on OCC1, ES-2, HEY, A2780-cp, and OVCA429 cells. When injected into nude mice, the inhibin-resistant cancer cell lines resulted in shorter survival time compared with the inhibin-responsive cells. Further investigations on SKOV3 and OCC1 cells showed that activin A increased invasion through Matrigel. Inhibin A decreased both basal and activin-induced proliferation and invasion of SKOV3 but had no effect on OCC1 cells. Reverse transcription-PCR analyses showed that the SKOV3 and OCC1 cells produced activin, but only SKOV3 produced inhibin. Analysis of the activin/inhibin signaling pathways indicated that Smad anchor for receptor activation was elevated in SKOV3 and OCC1 cells and that an up-regulation of the activin receptor expression may explain the inhibin resistance of OCC1 cells. Our results suggest that activin responsiveness may be gained during transformation of OSE cells and that inhibin resistance may contribute to the aggressive behavior of ovarian cancer cells.
EphA2 Induction of Fibronectin Creates a Permissive Microenvironment for Malignant Cells
Authors: Hu Min , Carles-Kinch Kelly L. , Zelinski Daniel P. , Kinch Michael S. 
Published: May 2022

Abstract
Normal and metastatic cells continuously exchange information with the surrounding tissue environment, and this communication governs many aspects of cell behavior. In particular, the physical placement or adhesions of cells within their environment are increasingly understood to facilitate this communication. Classically, cell-cell and cell-extracellular matrix adhesions have been viewed as separable events that are independently controlled. This simple view is changing, as evidence emerges of coordinated regulation of cellular adhesions. Here, we show that the EphA2 tyrosine kinase, which is overexpressed in many aggressive cancers, regulates a fine balance of cell-cell and cell-extracellular matrix adhesions in epithelial cells. EphA2 selectively inhibits cell-cell adhesions by increasing cell attachment and up-regulating the extracellular matrix protein fibronectin. We also show that fibronectin can contribute to important aspects of malignant character. Antibody-based targeting of EphA2 inhibits malignant cell growth by decreasing fibronectin and thereby inducing apoptotic death. Our findings strengthen a concept that cancer progression is regulated by a bidirectional communication between tumor cells and their surrounding microenvironment.
HER-2/neuOverexpression Increases the Viable Hypoxic Cell Population within Solid Tumors without Causing Changes in Tumor Vascularization
Authors: Dragowska Wieslawa H. , Warburton Corinna , Yapp Donald T.T. , Minchinton Andrew I. , Hu Yanping , Waterhouse Dawn N. , Gelmon Karen , Skov Kirsten , Woo Janet , Masin Dana , Huxham Lynsey A. , Kyle Alastair H. , Bally Marcel B. 
Published: May 2022

AbstractThe effects of HER-2/neu overexpression on the tumor microenvironment in an aggressive breast cancer xenograft model were investigated. These studies focused on tumors derived following the subcutaneous injection of MDA-MB-435/LCC6 cells transfected with human c-erbB2 (LCC6HER-2) into SCID-Rag2M mice. LCC6HER-2 tumors were more viable (H&E-stained tumor sections) than isogenic vector control tumors (LCC6Vector). Correspondingly, a 2.7-fold increase in trypan blue–excluding cells (P = 0.00056) and a 4.8-fold increase in clonogenic cells (P = 0.00146) were noted in cell suspensions derived from disaggregated LCC6HER-2 versus LCC6Vector tumors. Tumor sections stained with the antibody detecting 2-(2-nitro-1H-imidazol-1-yl)-N-(2,2,3,3,3-pentafluoropropyl)-acetamide (EF5), a marker of hypoxia, showed a greater fraction of hypoxic tissue in LCC6HER-2 tumors compared with control tumors. Flow cytometric analyses based on viable tumor cells (DNA content ≥ 2N) in cell suspensions from disaggregated tumors confirmed that there were significantly more EF5-positive cells (i.e., hypoxic) in LCC6HER-2 than in LCC6Vector tumors (16.41 ± 8.1% and 5.96 ± 4.1%, respectively; P = 0.0015). Protein levels of phosphorylated (Ser536) nuclear factor-κB p65 were significantly elevated in LCC6HER-2 tumors (P = 0.00048), and a trend in increased hypoxia-inducible factor-1α protein levels was observed in LCC6HER-2 compared with LCC6Vector tumors. Despite the substantial viable hypoxic cell fraction and a 1.7-fold increase of vascular endothelial growth factor protein (P = 0.05) in LCC6HER-2 tumors, no significant differences were found (P &gt; 0.05) between LCC6HER-2 and LCC6Vector vasculature (CD31 staining and Hoechst 33342 perfusion). These results suggest that HER-2/neu overexpression may be linked with overall increased tumor viability and a significant increase in the population of viable hypoxic cells, which is not due to differences in tumor vascularization.
Bad-Dependent Rafts Alteration Is a Consequence of an Early Intracellular Signal Triggered by Interleukin-4 Deprivation
Authors: Fleischer Aarne , Ghadiri Ata , Dessauge Frédéric , Duhamel Marianne , Cayla Xavier , Garcia Alphonse , Rebollo Angelita 
Published: May 2022

Abstract
Many molecules are inducibly localized in lipid rafts, and their alteration inhibits early activation events, supporting a critical role for these domains in signaling. Using confocal microscopy and cellular fractionation, we have shown that the pool of Bad, attached to lipid rafts in proliferating cells, is released when cells undergo apoptosis. Kinetic studies indicate that rafts alteration is a consequence of an intracellular signal triggered by interleukin-4 deprivation. Growth factor deprivation in turn induces PP1α phosphatase activation, responsible for cytoplasmic Bad dephosphorylation as well as caspase-9 and caspase-3 activation. Caspases translocate to rafts and induce their modification followed by translocation of Bad from rafts to mitochondria, which correlates with apoptosis. Taken together, our results suggest that alteration of lipid rafts is an early event in the apoptotic cascade indirectly induced by interleukin-4 deprivation via PP1α activation, dephosphorylation of cytoplasmic Bad, and caspase activation.
Histone Deacetylase Inhibitors Up-Regulate the Expression of Tight Junction Proteins
Authors: Bordin Mauro , D'Atri Fabio , Guillemot Laurent , Citi Sandra 
Published: May 2022

Abstract
Histone deacetylase (HDAC) inhibitors promote cell maturation, differentiation, and apoptosis through changes in gene expression. Differentiated epithelial cells are characterized by apical tight junctions (TJ), which play a role in cell-cell adhesion, polarity, and the permeability barrier function of epithelia. The relationship between cellular differentiation and expression of TJ-associated proteins is not known. Here, we investigated whether HDAC inhibitors affect the expression of TJ proteins in cultured cells by immunoblotting, immunofluorescence, and quantitative real-time, reverse transcription-PCR. We find that the HDAC inhibitor sodium butyrate significantly up-regulates the protein levels of cingulin, ZO-1, and ZO-2 in Rat-1 fibroblasts, cingulin in COS-7 cells, and cingulin and occludin in HeLa cells. Levels of mRNA for cingulin, ZO-1, and ZO-2 are also increased in sodium butyrate–treated Rat-1 fibroblasts. Up-regulation of cingulin is reversible and dose dependent and requires de novo protein synthesis and protein kinase activity, because it is inhibited by cycloheximide and by the protein kinase inhibitor H-7. Up-regulation of TJ proteins by sodium butyrate is linked to the ability of sodium butyrate to inhibit HDAC activity, because suberoylanilide hydroxamic acid, a HDAC inhibitor of a different structural class, also up-regulates cingulin, ZO-1, and ZO-2 expression in Rat-1 fibroblasts. These results indicate that cellular differentiation correlates with kinase-dependent up-regulation of the expression of specific TJ proteins.
Screening of
ABCG5
and
ABCG8
Genes for Sitosterolemia in a Familial Hypercholesterolemia Cascade Screening Program
Authors: Tada Mauricio Teruo , Rocha Viviane Zorzanelli , Lima Isabella Ramos , Oliveira Théo Gremen Mimary , Chacra Ana Paula , Miname Marcio Hiroshi , Nunes Valéria Sutti , Nakandakare Edna Regina , Costa Gurgel Castelo Maria Helane , Jannes Cinthia Elim , Santos Raul D. , Krieger José Eduardo , Pereira Alexandre Costa 
Published: May 2022

Background:

Sitosterolemia is a rare autosomal recessive disorder caused by homozygous or compound heterozygous variants in
ABCG5/ABCG8
. The disease is characterized by increased plasma plant sterols. Small case series suggest that patients with sitosterolemia have wide phenotypic heterogeneity with great variability on either plasma cholesterol levels or development of atherosclerotic cardiovascular disease. The present study aims to characterize the prevalence and clinical features of sitosterolemia participating in a familial hypercholesterolemia genetic cascade screening program.

Methods:

From 443 familial hypercholesterolemia index cases, 260 were negative for familial hypercholesterolemia genes and were sequenced for the
ABCG5/8
genes. Clinical and laboratory characteristics of affected individuals were determined.

Results:

Eight (3.1%) index cases were found to be homozygous or compound heterozygous variant for
ABCG5/ABCG8
genes, confirming the genetic diagnosis of sitosterolemia. Screening their relatives led to the identification of 6 additional confirmed sitosterolemia cases (3 homozygous and 3 compound heterozygous variant) and 18 carriers (heterozygous). The mean age of identified sitosterolemia cases (n=14) was 37.2±19.8 years, 50% were females, and 78.6% (all adults) presented either clinical or subclinical atherosclerotic cardiovascular disease. As expected, affected individuals presented elevated plasma plant sterol levels (mean β-Sitosterol and campesterol, respectively, 160.3±107.1 and 32.0±19.6 µg/mL) and the highest plasma LDL (low-density lipoprotein)-cholesterol was 269.0±120.0 mg/dL (range: 122–521 mg/dL). LDL-cholesterol mean reduction with therapy among cases was 65%. Eighty-three percent (83%) of identified sitosterolemia patients presented hematologic abnormalities.

Conclusions:
Testing genes associated with sitosterolemia in the molecular routine workflow of a familial hypercholesterolemia cascade screening program allowed the precise diagnosis of sitosterolemia in a substantial number of patients with varying LDL-C levels and high incidence of early atherosclerotic cardiovascular disease and hematologic abnormalities.
Genetic Basis of Left Ventricular Noncompaction
Authors: Rojanasopondist Pakdee , Nesheiwat Leigh , Piombo Sebastian , Porter George A. , Ren Mindong , Phoon Colin K.L. 
Published: May 2022

Background:
Left ventricular noncompaction (LVNC) is the third most common pediatric cardiomyopathy characterized by a thinned myocardium and prominent trabeculations. Next-generation genetic testing has led to a rapid increase in the number of genes reported to be associated with LVNC, but we still have little understanding of its pathogenesis. We sought to grade the strength of the gene-disease relationship for all genes reported to be associated with LVNC and identify molecular pathways that could be implicated.

Methods:
Following a systematic PubMed review, all genes identified with LVNC were graded using a validated, semi-quantitative system based on all published genetic and experimental evidence created by the Clinical Genome Resource (ClinGen). Genetic pathway analysis identified molecular processes and pathways associated with LVNC.

Results:
We identified 189 genes associated with LVNC: 11 (6%) were classified as definitive, 21 (11%) were classified as moderate, and 140 (74%) were classified as limited, but 17 (9%) were classified as no evidence. Of the 32 genes classified as definitive or moderate, the most common gene functions were sarcomere function (n=11; 34%), transcriptional/translational regulator (n=6; 19%), mitochondrial function (n=3; 9%), and cytoskeletal protein (n=3; 9%). Furthermore, 18 (56%) genes were implicated in noncardiac syndromic presentations. Lastly, 3 genetic pathways (cardiomyocyte differentiation via BMP receptors, factors promoting cardiogenesis in vertebrates, and Notch signaling) were found to be unique to LVNC and not overlap with pathways identified in dilated cardiomyopathy and hypertrophic cardiomyopathy.

Conclusions:
LVNC is a genetically heterogeneous cardiomyopathy. Distinct from dilated or hypertrophic cardiomyopathies, LVNC appears to arise from abnormal developmental processes.
The Nuclear Balance Is What States Make of It
Authors: Logan David C. 
Published: May 2022

Abstract
Does nuclear superiority offer states political or military benefits? And do those benefits accrue beyond acquiring a secure second-strike capability? International relations theory has long held that nuclear superiority does not confer significant advantages, a conclusion supported by much of the qualitative literature on bargaining and crisis interactions between nuclear-armed states. New work by scholars using statistical methods to analyze data on nuclear crises, interstate disputes, and compellent threats has sought to answer these questions, producing conflicting results. Despite the contributions of these recent works, this line of research has assumed that warhead counts are an appropriate measure of nuclear capabilities and that states possess accurate information about the material balance. Instead, states use multiple quantitative and qualitative characteristics to evaluate the nuclear balance, and they often have inaccurate or incomplete information about the size, composition, and configuration of other states' nuclear forces. Using new data, replications of two prominent recent works show that results are sensitive to how the nuclear balance is operationalized. Drawing on archival and interview data from the United States and the Soviet Union during the Cold War, findings show how states and leaders often understand and respond to the nuclear balance in inconsistent, asymmetric, and subjective ways.
Chaenomeles japonica (Maleae, Amygdaloideae, Rosaceae): validation of six Alberts Tīcs’ cultivar names and two new synonyms for the species
Authors: STALAŽS ARTURS , SVIĶE SILGA , VECKALNE AIGA 
Published: May 2022

Chaenomeles is a rosaceous genus of Asian origin with eight species, including four artificially created hybrids. Several species of this genus are used in many countries for ornamental plants and fruit production. As a result of many years of breeding work in Latvia, Alberts Tīcs selected six Chaenomeles japonica (Japanese quince) cultivars. Unfortunately, when publishing the descriptions of his cultivars, he does not comply with the requirements of the International Code of Nomenclature for cultivated plants because the names of newly introduced cultivars are not validly published. In his publications on the cultivation of Chaenomeles, Tīcs has introduced new scientific names, which have been published without complying with the requirements of the International Code of Nomenclature for algae, fungi, and plants. The validation of Tīcs’ cultivar names has been performed here, and the names—Chaenomeles maulei f. pomifera-inermis nom. nud. and Chaenomeles ×pomoidea nom. nud.—have been recognized as new synonyms of Chaenomeles japonica. Descriptions have been provided for all Alberts Tīcs’ cultivars.
Coupling length: a generalized gleno-acetabular distance measurement for interpreting the size and gait of quadrupedal trackmakers
Authors: Stevens Kent A. , Ernst Scott , Marty Daniel 
Published: May 2022

AbstractThe gleno-acetabular distance DGA, a conventional proxy for the size of a quadrupedal trackmaker, is often estimated as the distance GA between the midpoint between a left and right pair of pes tracks and the midpoint between a selected pair of left and right manus tracks. While frequently used to estimate trackmaker size from fossil trackways, the relationship between GA and DGA depends upon the gait (which is unknown for extinct trackmakers), and is subject to multiple additional sources of uncertainty including which specific pair of manus tracks to associate with a given pair of pes tracks. Here a generalization is introduced, termed coupling length, which does not require any presumption about trackmaker gait of the degree of overstepping. On the contrary, a systematic analysis of a trackway in terms of coupling length can permit estimation of both the size and the gait with which the trackmaker progressed. Coupling length can be computed at successive points along a trackway, allowing exploration of a range of hypothetical gaits and body sizes for the trackmaker responsible. A fitness function quantifying persistent variation in coupling length along a trackway is used to indicate whether a given trackway could have been created by a fairly consistent gait, and if so, a range of high-fitness solution gaits and their associated DGA. The method was applied to selected quasi-regular sauropod trackways and a solution found for a narrow range of gaits with limb phase of about 0.3 and DGA = 1.6 ± 0.2 m. This is the first estimation of sauropod trackmaker gait, and introduces a novel method by which irregularity along a trackway is used as a source of information to constrain inferences of trackmaker behavior. The computed DGA for this sauropod suggests significantly smaller trackmakers than conventional estimations based on track dimensions and hip height estimates. Size estimation by this approach offers greatly reduced uncertainty compared to conventional estimates.
Prediction of lung cancer using gene expression and deep learning with KL divergence gene selection
Authors: Liu Suli , Yao Wu 
Published: May 2022

AbstractBackgroundLung cancer is one of the cancers with the highest mortality rate in China. With the rapid development of high-throughput sequencing technology and the research and application of deep learning methods in recent years, deep neural networks based on gene expression have become a hot research direction in lung cancer diagnosis in recent years, which provide an effective way of early diagnosis for lung cancer. Thus, building a deep neural network model is of great significance for the early diagnosis of lung cancer. However, the main challenges in mining gene expression datasets are the curse of dimensionality and imbalanced data. The existing methods proposed by some researchers can’t address the problems of high-dimensionality and imbalanced data, because of the overwhelming number of variables measured (genes) versus the small number of samples, which result in poor performance in early diagnosis for lung cancer.MethodGiven the disadvantages of gene expression data sets with small datasets, high-dimensionality and imbalanced data, this paper proposes a gene selection method based on KL divergence, which selects some genes with higher KL divergence as model features. Then build a deep neural network model using Focal Loss as loss function, at the same time, we use k-fold cross validation method to verify and select the best model, we set the value of k is five in this paper.ResultThe deep learning model method based on KL divergence gene selection proposed in this paper has an AUC of 0.99 on the validation set. The generalization performance of model is high.ConclusionThe deep neural network model based on KL divergence gene selection proposed in this paper is proved to be an accurate and effective method for lung cancer prediction.