bluuebunny/crossref_metadata_2025_split huggingface dataset:
Functional Analysis of Serum Long Noncoding RNAs in Patients with Atrial Fibrillation
Authors: Zhang Qi , Wang Jun , Wang Ying , Yang Ji-Meng , Dong Hai-Cui , Xu Di 
Published: May 2022

Objectives. Long noncoding RNAs (lncRNAs) are closely related to diverse diseases. However, its role in atrial fibrillation (AF) pathogenesis needs further exploration. Design. We performed microarray analysis on the serum samples from 70 healthy volunteers and 70 AF patients. This study was aimed at detecting the levels of serum lncRNAs and mRNAs and bioinformatically analyze them to establish potential marker(s) for AF diagnosis. Receiver operating curve (ROC) and area under the curve (AUC) were employed to address the AF diagnostic power of lncRNAs. Results. In the AF serum samples, 753 lncRNAs and 802 mRNAs (

p
≤
0.05

;

fold

change
≥
2

) were upregulated, and 315 lncRNAs and 153 mRNAs were downregulated, as opposed to healthy serum samples. Using bioinformatic analysis, we analyzed the top 4 differentially expressed (DE) lncRNAs, namely, NR-001587, NR-015407, NR-038455, and NR-038894, and found that the PI3K-AKT cell proliferation signaling pathway was most affected. This was in accordance with our functional analysis of DE mRNAs and adjacent lncRNAs. Notably, the elevated serum NR-001587 levels were strongly associated with AF incidence. Conclusions. Our work highlights the role of lncRNAs in AF pathogenesis and provides a novel serum biomarker for AF diagnosis.
Suicidal Ideation in Long-Term Adult Cancer Survivors: Findings of a Nationwide Cross-Sectional Study
Authors: Hwang In Cheol , Ahn Hong Yup , Suh Heuy Sun 
Published: May 2022

Abstract

Background:
Cancer survivors suffer substantial psychologic distress, but little is known about their vulnerabilities to suicidal ideation more than 5 years after diagnosis.

Methods:
We compared suicidal ideation among 1,033 adult cancer survivors, who had received a diagnosis of cancer more than 5 years previously, with that among individuals without a cancer history using nationwide survey data. Logistic regression models were used to evaluate suicidal ideation in cancer survivors.

Results:
Cancer survivors did not have a significantly higher suicidal ideation rate than those without a cancer history, regardless of depressive mood.

Conclusions:
A cancer history of 5 years or greater is not associated with suicidal ideation.

Impact:
A large Korean study considering depressive mood affirm no association between long-term cancer survivorship and suicidal ideation.
Adverse Urinary System Diagnoses among Older Women with Endometrial Cancer
Authors: Anderson Chelsea , Olshan Andrew F. , Park Jihye , Bae-Jump Victoria L. , Brewster Wendy R. , Lund Jennifer L. , Nichols Hazel B. 
Published: May 2022

Abstract

Background:
Endometrial cancer and its treatment may impact urinary system function, but few large-scale studies have examined urinary diagnoses among endometrial cancer survivors. We investigated the risk of several urinary outcomes among older women with endometrial cancer compared with similar women without a cancer history.

Methods:
Women aged 66+ years with an endometrial cancer diagnosis during 2004–2017 (N = 44,386) and women without a cancer history (N = 221,219) matched 1:5 on exact age, race/ethnicity, and state were identified in the Surveillance, Epidemiology, and End Results-Medicare linked data. ICD-9 and -10 diagnosis codes were used to define urinary outcomes in the Medicare claims. HRs for urinary outcomes were estimated using multivariable Cox proportional hazards regression models.

Results:
Relative to women without cancer, endometrial cancer survivors were at an increased risk of several urinary system diagnoses, including lower urinary tract infection [HR, 2.36; 95% confidence interval (CI), 2.32–2.40], urinary calculus (HR, 2.22; 95% CI, 2.13–2.31), renal failure (HR, 2.28; 95% CI, 2.23–2.33), and chronic kidney disease (HR, 1.85; 95% CI, 1.81–1.90). Similar associations were observed in sensitivity analyses limited to 1+ and 5+ years after endometrial cancer diagnosis. Black race, higher comorbidity index, higher stage or grade cancer, non-endometrioid histology, and treatment with chemotherapy and/or radiation were often significant predictors of urinary outcomes among endometrial cancer survivors.

Conclusions:
Our results suggest that, among older women, the risk of urinary outcomes is elevated after endometrial cancer.

Impact:
Monitoring for urinary diseases may be a critical part of long-term survivorship care for older women with an endometrial cancer history.
The V5 Domain of Protein Kinase C Plays a Critical Role in Determining the Isoform-Specific Localization, Translocation, and Biological Function of Protein Kinase C-δ and -ε
Authors: Wang Qiming Jane , Lu Ganwei , Schlapkohl Walter A. , Goerke Axel , Larsson Christer , Mischak Harald , Blumberg Peter M. , Mushinski J. Frederic 
Published: May 2022

Abstract
The catalytic domain of overexpressed protein kinase C (PKC)-δ mediates phorbol 12-myristate 13-acetate (PMA)-induced differentiation or apoptosis in appropriate model cell lines. To define the portions of the catalytic domain that are critical for these isozyme-specific functions, we constructed reciprocal chimeras, PKC-δ/εV5 and -ε/δV5, by swapping the V5 domains of PKC-δ and -ε. PKC-δ/εV5 failed to mediate PMA-induced differentiation of 32D cells, showing the essential nature of the V5 domain for PKC-δ's functionality. The other chimera, PKC-ε/δV5, endowed inactive PKC-ε with nearly all PKC-δ's apoptotic ability, confirming the importance of PKC-δ in this function. Green fluorescent protein (GFP)-tagged PKC-δV5 and -ε/δV5 in A7r5 cells showed substantial basal nuclear localization, while GFP-tagged PKC-ε and -δ/εV5 showed significantly less, indicating that the V5 region of PKC-δ contains determinants critical to its nuclear distribution. PKC-ε/δV5-GFP showed much slower kinetics of translocation to membranes in response to PMA than parental PKC-ε, implicating the PKC-εV5 domain in membrane targeting. Thus, the V5 domain is critical in several of the isozyme-specific functions of PKC-δ and -ε.
A Simple Epigenetic Method for the Diagnosis and Classification of Brain Tumors
Authors: Zukiel Ryszard , Nowak Stanislaw , Barciszewska Anna-Maria , Gawronska Iwona , Keith Gerard , Barciszewska Miroslawa Z. 
Published: May 2022

Abstract
The new, simple, and reliable method for the diagnosis of brain tumors is described. It is based on a TLC quantitative determination of 5-methylcytosine (m5C) in relation to its damage products of DNA from tumor tissue. Currently, there is evidence that oxidative stress through reactive oxygen species (ROS) plays an important role in the etiology and progression of several human diseases. Oxidative damage of DNA, lipids, and proteins is deleterious for the cell. m5C, along with other basic components of DNA, is the target for ROS, which results in the appearance of new modified nucleic acid bases. If so, m5C residue constitutes a mutational hotspot position, whether it occurs within a nucleotide sequence of a structural gene or a regulatory region. Here, we show the results of the analysis of 82 DNA samples taken from brain tumor tissues. DNA was isolated and hydrolyzed into nucleotides, which, after labeling with [γ-32P]ATP, were separated on TLC. Chromatograms were evaluated using PhosphorImager and the amounts of 5-methyldeoxycytosine (m5dC) were calculated as a ratio (R) of m5dC to m5dC + deoxycytosine + deoxythymidine spot intensities. The R value could not only be a good diagnostic marker for brain tumors but also a factor differentiating low-grade and high-grade gliomas. Therefore, DNA methylation pattern might be a useful tool to give a primary diagnosis of a brain tumor or as a marker for the early detection of the relapse of the disease. This method has several advantages over those existing nowadays.
A Naturally Occurring Soluble Form of Vascular Endothelial Growth Factor Receptor 2 Detected in Mouse and Human Plasma
Authors: Ebos John M.L. , Bocci Guido , Man Shan , Thorpe Philip E. , Hicklin Daniel J. , Zhou Danielle , Jia Xiaohong , Kerbel Robert S. 
Published: May 2022

Abstract
Angiogenesis and vasculogenesis are regulated in large part by several different growth factors and their associated receptor tyrosine kinases (RTKs). Foremost among these is the vascular endothelial growth factor (VEGF) family including VEGF receptor (VEGFR)-2 and -1. VEGFR ligand binding and biological activity are regulated at many levels, one of which is by a soluble, circulating form of VEGFR-1 (sVEGFR-1). This sVEGFR-1 can act as a competitive inhibitor of its ligand, serve as a possible biomarker, and play important roles in cancer and other diseases such as preeclampsia. Recombinant forms of sVEGFR-2 have been shown to have antiangiogenic activity, but a naturally occurring sVEGFR-2 has not been described previously. Here, we report such an entity. Having a molecular weight of ∼160 kDa, sVEGFR-2 can be detected in mouse and human plasma with several different monoclonal and polyclonal anti-VEGFR-2 antibodies using both ELISA and immunoprecipitation techniques. In vitro studies have determined that the sVEGFR-2 fragment can be found in the conditioned media of mouse and human endothelial cells, thus suggesting that it may be secreted, similar to sVEGFR-1, or proteolytically cleaved from the cell. Potential biological activity of this protein was inferred from experiments in which mouse sVEGFR-2 could bind to VEGF-coated plates. Similar to sVEGFR-1 and other soluble circulating RTKs, sVEGFR-2 may have regulatory consequences with respect to VEGF-mediated angiogenesis as well as potential to serve as a quantitative biomarker of angiogenesis and antiangiogenic drug activity, particularly for drugs that target VEGF or VEGFR-2.
AND-34 Activates Phosphatidylinositol 3-Kinase and Induces Anti-Estrogen Resistance in a SH2 and GDP Exchange Factor–Like Domain-Dependent Manner
Authors: Felekkis Kyriacos N. , Narsimhan Radha P. , Near Richard , Castro Ariel F. , Zheng Yi , Quilliam Lawrence A. , Lerner Adam 
Published: May 2022

AbstractAND-34, a 95-kDa protein with modest homology to Ras GDP exchange factors, associates with the focal adhesion protein p130Cas. Overexpression of AND-34 confers anti-estrogen resistance in breast cancer cell lines, a property linked to its ability to activate Rac. Here, we show that both the GDP exchange factor–like domain and the SH2 domain of AND-34 are required for Rac activation and for resistance to the estrogen receptor (ER) antagonist ICI 182,780. As phosphatidylinositol 3-kinase (PI3K) signaling can regulate Rac activation, we examined the effects of AND-34 on PI3K. Overexpression of AND-34 in MCF-7 cells increased PI3K activity and augmented Akt Ser473 phosphorylation and kinase activity. Inhibition of PI3K with LY294002 or a dominant-negative p85 construct blocked AND-34-mediated Rac and Akt activation. Although R-Ras can activate PI3K, transfection with constitutively active R-Ras failed to induce Rac activation and AND-34 overexpression failed to induce R-Ras activation. Treatment of either vector-only or AND-34-transfected ZR-75-1 cells with ICI 182,780 markedly diminished ERα levels, suggesting that AND-34-induced anti-estrogen resistance is likely to occur by an ERα-independent mechanism. Treatment of a ZR-75-1 breast cancer cell line stably transfected with AND-34 plus 2 μmol/L LY294002 or 10 μmol/L NSC23766, a Rac-specific inhibitor, abrogated AND-34-induced resistance to ICI 182,780. Our studies suggest that AND-34-mediated PI3K activation induces Rac activation and anti-estrogen resistance in human breast cancer cell lines.
Inhibition of IκBα Nuclear Export as an Approach to Abrogate Nuclear Factor-κB–Dependent Cancer Cell Survival
Authors: O'Connor Shelby , Shumway Stuart , Miyamoto Shigeki 
Published: May 2022

Abstract
Deregulation of the transcription factor nuclear factor-κB (NF-κB) leading to its constitutive activation is frequently observed in human cancer. Because altered NF-κB activities often promote the survival of malignant cells, its inhibition is regarded as a promising anticancer strategy. Because activation of the latent cytoplasmic NF-κB complex can be induced by a wide variety of different stimuli, its deregulation may occur by an equally large number of distinct mechanisms. This diversity raises a conundrum in conceptualizing general approaches to attenuate NF-κB activity in cancer. Here, we provide evidence that inhibition of IκBα nuclear export is a viable target to generally abrogate constitutive NF-κB activity in different cancer cell types. We show that inhibition of IκBα nuclear export has an important course of events in cancer cells harboring constitutive NF-κB activity—an initial increase in the pool of stable nuclear NF-κB/IκBα complexes that leads to a reduction of constitutive NF-κB activity and subsequent induction of apoptosis. Importantly, similar effects on multiple different cancer cell types indicate that inhibition of nuclear export of IκBα leads to broad inhibition of constitutive NF-κB activation regardless of various deregulated, upstream events involved.
Somatic Mitochondrial DNA Mutations in Neurofibromatosis Type 1-Associated Tumors
Authors: Kurtz Andreas , Lueth Maria , Kluwe Lan , Zhang Tingguo , Foster Rosemary , Mautner Victor-Felix , Hartmann Melanie , Tan Duan-Jun , Martuza Robert L. , Friedrich Reinhard E. , Driever Pablo Hernáiz , Wong Lee-Jun C. 
Published: May 2022

Abstract
Neurofibromatosis type 1 is an autosomal dominantly inherited disease predisposing to a multitude of tumors, most characteristically benign plexiform neurofibromas and diffuse cutaneous neurofibromas. We investigated the presence and distribution of somatic mitochondrial DNA (mtDNA) mutations in neurofibromas and in nontumor tissue of neurofibromatosis type 1 patients. MtDNA alterations in the entire mitochondrial genome were analyzed by temporal temperature gradient gel electrophoresis followed by DNA sequencing. Somatic mtDNA mutations in tumors were found in 7 of 19 individuals with cutaneous neurofibromas and in 9 of 18 patients with plexiform neurofibromas. A total of 34 somatic mtDNA mutations were found. All mutations were located in the displacement loop region of the mitochondrial genome. Several plexiform neurofibromas from individual patients had multiple homoplasmic mtDNA mutations. In cutaneous neurofibromas, the same mtDNA mutations were always present in tumors from different locations of the same individual. An increase in the proportion of the mutant mtDNA was always found in the neurofibromas when compared with nontumor tissues. The somatic mtDNA mutations were present in the Schwann cells of the analyzed multiple cutaneous neurofibromas of the same individual. The observed dominance of a single mtDNA mutation in multiple cutaneous neurofibromas of individual patients indicates a common tumor cell ancestry and suggests a replicative advantage rather than random segregation for cells carrying these mutated mitochondria.
Molecular Characterization of the Transition to Malignancy in a Genetically Engineered Mouse-Based Model of Ductal Carcinoma In situ
Authors: Namba Ruria , Maglione Jeannie E. , Young Lawrence J.T. , Borowsky Alexander D. , Cardiff Robert D. , MacLeod Carol L. , Gregg Jeffrey P. 
Published: May 2022

Abstract
A transplantable model of human ductal carcinoma in situ that progresses to invasive carcinoma was developed from a genetically engineered mouse (GEM). Additional lines were established using early mammary premalignant lesions from transgenic MMTV-PyV-mT mice. These lines were verified to be premalignant and transplanted repeatedly to establish stable and predictable properties. Here, we report the first in-depth molecular analysis of neoplastic progression occurring in one premalignant transplantable GEM-derived line. Oligonucleotide microarrays showed that many genes are differentially expressed between the quiescent and prelactating mammary gland and the premalignant GEM outgrowth. In contrast, a small but consistent group of genes was associated with the transformation from premalignancy to tumor. This suggests that the majority of gene expression changes occur during the premalignant transition from normal to premalignancy, whereas many fewer changes occur during the malignant transition from premalignancy to invasive carcinoma. The premalignant transition is associated with several cell cycle–related genes and the up-regulation of oncogenes is associated with various cancers (Ccnd11, Cdk4, Myb, and Ect2). The changes identified in the malignant transition included genes previously associated with human breast cancer progression. Misregulation of the insulin-like growth factor and transforming growth factor-β signaling pathways and the stromal-epithelial interaction were implicated. Our results suggest that this transplantable GEM-based model recapitulates human ductal carcinoma in situ at both histologic and molecular levels. With consistent tumor latency and molecular profiles, this model provides an experimental platform that can be used to assess functional genomics and molecular pharmacology and to test promising chemoprevention strategies.
Mad 1 Inhibits Cell Growth and Proliferation but Does Not Promote Differentiation or Overall Survival in Human U-937 Monoblasts
Authors: Hultquist Anne , Cetinkaya Cihan , Wu Siqin , Castell Alina , Erlandsson Anna , Larsson Lars-Gunnar 
Published: May 2022

Abstract
The Mad family proteins are transcriptional repressors belonging to the basic region/helix-loop-helix/leucine zipper family. They share a common obligatory dimerization partner, Max, with the oncoprotein c-Myc and antagonize the function of Myc to activate transcription. The Myc/Max/Mad network has therefore been suggested to function as a molecular switch that regulates cell growth and differentiation by controlling a common set of genes. To study the biological consequences of Mad1 expression for hematopoietic cell growth and differentiation, we used the U-937 monocytic differentiation model to generate cells with inducible Mad1 expression using the reversed tetracycline-controlled transactivator system. The elevated expression of Mad1 in these cells resulted in increased Mad1/Max heterodimer formation correlating with reduced expression of the Myc/Mad target gene ODC. Mad1-expressing U-937 cells in suspension culture proliferated slower and exhibited an increased number of cells in the G1 phase of the cell cycle. Further, growth in semisolid medium was almost completely inhibited. Mad1-expression, however, neither enforced spontaneous differentiation nor enhanced differentiation induced by the phorbol ester 12-O-tetradecanoylphorbol-13-acetate, retinoic acid (RA), or vitamin D3 but rather led to delayed RA-stimulated differentiation. Mad1-expressing cells were further found to be reduced in cell size in all phases of the cells cycle and particularly in response to RA-induced differentiation. Unexpectedly, whereas Fas-induced apoptosis was slightly attenuated in Mad1-expressing U-937 cells, Mad1 sensitized the cells to tumor necrosis factor–α-induced apoptosis. These results suggest that Mad1 primarily regulates cell growth and proliferation in these cells, whereas its role in cellular differentiation and survival seems to be more complex.
Topoisomerase I and II Inhibitors Control Caspase-2 Pre-Messenger RNA Splicing in Human Cells
Authors: Solier Stéphanie , Lansiaux Amélie , Logette Emmanuelle , Wu Jane , Soret Johann , Tazi Jamal , Bailly Christian , Desoche Lydie , Solary Eric , Corcos Laurent 
Published: May 2022

Abstract
We have recently shown that the topoisomerase II inhibitor, etoposide (VP16), could trigger caspase-2 pre-mRNA splicing in human leukemic cell lines. This leads to increased inclusion of exon 9, which is specifically inserted into the short caspase-2S isoform mRNA and absent from the long caspase-2L isoform mRNA. One of the consequences of this alternative splicing is a decrease in the total amount of the mature form of caspase-2L mRNA and protein. In this study, we analyzed the effects of several representative molecules of various classes of cytotoxic agents on caspase-2 pre-mRNA splicing in both U937 leukemic cells and in HeLa cervix carcinoma cells. Very strikingly, both topoisomerase I (camptothecin and homocamptothecin derivatives) and II (VP16, amsacrine, doxorubicin, mitoxantrone) inhibitors induced exon 9 inclusion. DNA intercalating glycosyl indolocarbazole derivatives as well as DNA alkylating agents, such as cisplatin and melphalan, antimetabolites like 5-fluorouracil, and mitotic spindle poisons like vinblastine had no effect. Therefore, both classes of DNA topoisomerases can control pre-mRNA splicing of the caspase-2 transcript. In addition, the splicing reaction brought about by camptothecin was hampered in human CEM/C2 and in murine P388-45R leukemic deficient in topoisomerase I activity. Conversely, VP16 did not trigger caspase-2 alternative splicing in human HL60/MX2 leukemic cells harboring a mutant topoisomerase II. Minigene transfection analysis revealed that topoisomerase inhibitors did not change the splicing profile when cis-acting elements in intron-9, reported to control exon 9 inclusion independently of drug treatment, were removed. Rather, our experiments suggest that exon 9 inclusion induced by topoisomerase inhibitors reflects the activity exerted by topoisomerase I or II on proteins that control splicing reactions, or their direct involvement in pre-mRNA splicing.
In vivo Recombination After Chronic Damage Exposure Falls to Below Spontaneous Levels in “Recombomice”
Authors: Kovalchuk Olga , Hendricks Carrie A. , Cassie Scott , Engelward Andrew J. , Engelward Bevin P. 
Published: May 2022

Abstract
All forms of cancer are initiated by heritable changes in gene expression. Although point mutations have been studied extensively, much less is known about homologous recombination events, despite its role in causing sequence rearrangements that contribute to tumorigenesis. Although transgenic mice that permit detection of point mutations have provided a fundamental tool for studying point mutations in vivo, until recently, transgenic mice designed specifically to detect homologous recombination events in somatic tissues in vivo did not exist. We therefore created fluorescent yellow direct repeat mice, enabling automated detection of recombinant cells in vivo for the first time. Here, we show that an acute dose of ionizing radiation induces recombination in fluorescent yellow direct repeat mice, providing some of the first direct evidence that ionizing radiation induces homologous recombination in cutaneous tissues in vivo. In contrast, the same total dose of radiation given under chronic exposure conditions suppresses recombination to levels that are significantly below those of unexposed animals. In addition, global methylation is suppressed and key DNA repair proteins are induced in tissues from chronically irradiated animals (specifically AP endonuclease, polymerase β, and Ku70). Thus, increased clearance of recombinogenic lesions may contribute to suppression of homologous recombination. Taken together, these studies show that fluorescent yellow direct repeat mice provide a rapid and powerful assay for studying the recombinogenic effects of both short-term and long-term exposure to DNA damage in vivo and reveal for the first time that exposure to ionizing radiation can have opposite effects on genomic stability depending on the duration of exposure.