bluuebunny/crossref_metadata_2025_split huggingface dataset:
Screening and functional exploration of prothrombin Arg596 related mutations in Chinese venous thromboembolism patients
Authors: Wu Xi , Li Lei , Ding Qiulan , Wang Xuefeng , Wu Fang , Wu Wenman 
Published: January 2018

AimsDysfunctional prothrombin residue Arg596 associated mutation has been found to precipitate venous thromboembolism (VTE). In the current study we investigated the prevalence of Arg596 associated mutations in Chinese patients with VTE and explored the functional impact of Arg596Gln mutation on coagulation function in affected patients.MethodsProthrombin clotting activity was measured in 267 unrelated patients with unprovoked VTE. Patients with moderately decreased activities underwent further analysis of theF2gene. Prothrombin amidolytic activity and antigen levels were detected in mutation carriers. Specific family members were investigated about their VTE histories and clinical phenotypes. The thrombin generation test (TGT) was used to evaluate thrombin function and antithrombin resistance assay was applied to assess the extent of impaired antithrombin inhibition of mutation carriers.ResultsTwo heterozygous mutation carriers of prothrombin Arg596Gln were identified, both of whom had moderately decreased clotting activities but normal amidolytic activities and antigen levels. Among the families of the two probands, nine out of 13 mutation carriers experienced episodes of VTE. TGTs showed that patients had elevated endogenous thrombin potential and prolonged start tail time. Thrombin generation could be inhibited in the presence of thrombomodulin. The thrombin Arg596Gln variant in patients’ plasma presented strong resistance to antithrombin inhibition.ConclusionProthrombin Arg596Gln mutation is a risk factor for Chinese patients with VTE due to its moderately decreased clotting activity but strong resistance to antithrombin inhibition. Prothrombin clotting activity screening and its encoding gene sequencing should be considered in patients with VTE when other established risk factors are absent.
Examining the utility of cystatin C as a confirmatory test of chronic kidney disease across the age range in middle-aged and older community-dwelling adults
Authors: Canney Mark , Sexton Donal J , O’Leary Neil , Healy Martin , Kenny Rose Anne , Little Mark A , O’Seaghdha Conall M 
Published: January 2018

BackgroundCystatin C has been proposed as a confirmatory test of chronic kidney disease (CKD). This is most applicable to older individuals with CKD, the majority of whom have a creatinine-based estimated glomerular filtration rate (eGFR) of 45–59 mL/min/1.73 m2(CKD stage 3a). We sought to examine the utility of cystatin C as a confirmatory test of CKD across the age range in the general population of older adults.MethodsCross-sectional analysis of 5386 participants from The Irish Longitudinal Study on Ageing, a cluster-sampled national cohort of community-dwelling adults aged ≥50 years. Cystatin C and creatinine were measured simultaneously using standardised assays. Using generalised additive models, we modelled the distributions of creatinine and cystatin C per year of age from four distributional parameters: location, dispersion, skewness, kurtosis. Among participants with CKD stage 3a, we estimated the predicted probability of cystatin C eGFR <60 mL/min/1.73 m2(‘confirmed CKD’) as a function of age.ResultsMedian age was 62 years, 53% were female and median cystatin C eGFR was 80 mL/min/1.73 m2. We observed progressive variability in cystatin C with increasing age. Compared with creatinine, cystatin C levels rose sharply beyond the age of 65. Among participants with CKD stage 3a (n=463), the predicted probability of ‘confirmed CKD’ increased steadily with age, from 15% at age 50 to 80% at age 80.ConclusionsThe clinical utility of cystatin C may be maximised in middle-aged individuals, in whom the distribution of cystatin C is less variable than older adults, and the pretest probability of confirming CKD is lower.
Global evidence on the effect of point-of-sale display bans on smoking prevalence
Authors: He Yanyun , Shang Ce , Huang Jidong , Cheng Kai-Wen , Chaloupka Frank J 
Published: January 2018

BackgroundSince Iceland became the first country to impose a ban on point-of-sale (POS) tobacco product displays in 2001, 20 countries have implemented POS display bans as of 2016. This study examined the effect that POS display bans have on smoking prevalence.MethodsData were sourced from Euromonitor International and the WHO MPOWER package for 2007–2014 from 77 countries worldwide. generalised linear models with country and year fixed effects were estimated to analyse the effect of POS display bans on smoking prevalence.ResultsHaving a POS display ban reduced overall adult daily smoking, male smoking and female smoking by about 7%, 6% and 9%, respectively.ConclusionsHaving a POS display ban is likely to reduce smoking prevalence and generate public health benefits.
Response of growth, yield, and quality of pea shoots to supplemental light-emitting diode lighting during winter greenhouse production
Authors: Kong Yun , Llewellyn Dave , Zheng Youbin 
Published: January 2018

Low natural light levels during the winter months are a major limiting factor for greenhouse production in northern regions. To determine the effects of supplemental lighting (SL) on winter greenhouse production of pea shoots, crop growth, yield, and quality were investigated under the treatments of supplemental photosynthetic photon flux density (PPFD) of 50, 80, 110, and 140 μmol m−2 s−1, all with a 16 h photoperiod, plus a no-SL control treatment, inside a Canadian greenhouse from December to March. Light-emitting diodes with a red to blue PPFD ratio of 4:1 and peak wavelengths at 665 and 440 nm were used for the lighting treatment. During the trial period, the average natural daily light integral (DLI) inside the greenhouse was 5.3 mol m−2 d−1 and the average daily temperature was around 13 °C. Compared with the no-SL control, SL of 50–140 μmol m−2 s−1 increased stem length and leaf number before the first harvest and promoted the cumulative yield (kg m−2) of pea shoots throughout the five harvest times. The total yield (kg m−2) of five harvests and weekly average stem extension rate were proportional to supplemental PPFD within the range of 0–140 μmol m−2 s−1; however, SL of 50–80 μmol m−2 s−1, corresponding to total (natural + supplemental) DLI of 8.1–9.8 mol m−2 d−1, resulted in the best integrated quality based on the evaluation of individual fresh mass, soluble solids content, succulence, and firmness. Therefore, a total DLI ranging between 8.1 and 9.8 mol m−2 d−1 can be suggested as a target for winter greenhouse production of pea shoots under conditions similar to this trial.
Agonist-induced CXCR4 and CB2 Heterodimerization Inhibits Gα13/RhoA-mediated Migration
Authors: Scarlett Kisha A. , White El-Shaddai Z. , Coke Christopher J. , Carter Jada R. , Bryant Latoya K. , Hinton Cimona V. 
Published: January 2018

Abstract
G-protein–coupled receptor (GPCR) heterodimerization has emerged as a means by which alternative signaling entities can be created; yet, how receptor heterodimers affect receptor pharmacology remains unknown. Previous observations suggested a biochemical antagonism between GPCRs, CXCR4 and CB2 (CNR2), where agonist-bound CXCR4 and agonist-bound CB2 formed a physiologically nonfunctional heterodimer on the membrane of cancer cells, inhibiting their metastatic potential in vitro. However, the reduced signaling entities responsible for the observed functional outputs remain elusive. This study now delineates the signaling mechanism whereby heterodimeric association between CXCR4 and CB2, induced by simultaneous agonist treatment, results in decreased CXCR4-mediated cell migration, invasion, and adhesion through inhibition of the Gα13/RhoA signaling axis. Activation of CXCR4 by its cognate ligand, CXCL12, stimulates Gα13 (GNA13), and subsequently, the small GTPase RhoA, which is required for directional cell migration and the metastatic potential of cancer cells. These studies in prostate cancer cells demonstrate decreased protein expression levels of Gα13 and RhoA upon simultaneous CXCR4/CB2 agonist stimulation. Furthermore, the agonist-induced heterodimer abrogated RhoA-mediated cytoskeletal rearrangement resulting in the attenuation of cell migration and invasion of an endothelial cell barrier. Finally, a reduction was observed in the expression of integrin α5 (ITGA5) upon heterodimerization, supported by decreased cell adhesion to extracellular matrices in vitro. Taken together, the data identify a novel pharmacologic mechanism for the modulation of tumor cell migration and invasion in the context of metastatic disease.
Implications: This study investigates a signaling mechanism by which GPCR heterodimerization inhibits cancer cell migration. Mol Cancer Res; 16(4); 728–39. ©2018 AACR.
Centriole Overduplication is the Predominant Mechanism Leading to Centrosome Amplification in Melanoma
Authors: Denu Ryan A. , Shabbir Maria , Nihal Minakshi , Singh Chandra K. , Longley B. Jack , Burkard Mark E. , Ahmad Nihal 
Published: January 2018

Abstract
Centrosome amplification (CA) is common in cancer and can arise by centriole overduplication or by cell doubling events, including the failure of cell division and cell–cell fusion. To assess the relative contributions of these two mechanisms, the number of centrosomes with mature/mother centrioles was examined by immunofluorescence in a tissue microarray of human melanomas and benign nevi (n = 79 and 17, respectively). The centrosomal protein 170 (CEP170) was used to identify centrosomes with mature centrioles; this is expected to be present in most centrosomes with cell doubling, but on fewer centrosomes with overduplication. Using this method, it was determined that the majority of CA in melanoma can be attributed to centriole overduplication rather than cell doubling events. As Polo-like kinase 4 (PLK4) is the master regulator of centriole duplication, the hypothesis that PLK4 overexpression contributes to centriole overduplication was evaluated. PLK4 is significantly overexpressed in melanoma compared with benign nevi and in a panel of human melanoma cell lines (A375, Hs294T, G361, WM35, WM115, 451Lu, and SK-MEL-28) compared with normal human melanocytes. Interestingly, although PLK4 expression did not correlate with CA in most cases, treatment of melanoma cells with a selective small-molecule PLK4 inhibitor (centrinone B) significantly decreased cell proliferation. The antiproliferative effects of centrinone B were also accompanied by induction of apoptosis.
Implications: This study demonstrates that centriole overduplication is the predominant mechanism leading to centrosome amplification in melanoma and that PLK4 should be further evaluated as a potential therapeutic target for melanoma treatment. Mol Cancer Res; 16(3); 517–27. ©2018 AACR.
Characterization and Evidence of the miR-888 Cluster as a Novel Cancer Network in Prostate
Authors: Hasegawa Tsuyoshi , Glavich Garrison J. , Pahuski Mary , Short Aleena , Semmes O. John , Yang Lifang , Galkin Vitold , Drake Richard , Esquela-Kerscher Aurora 
Published: January 2018

Abstract
Prostate cancer afflicts 1 in 7 men and is the second leading cause of male cancer-related deaths in the United States. MicroRNAs (miRNAs), an extensive class of approximately 22 nucleotide noncoding RNAs, are often aberrantly expressed in tissues and fluids from prostate cancer patients, but the mechanisms of how specific miRNAs regulate prostate tumorigenesis and metastasis are poorly understood. Here, miR-888 was identified as a novel prostate factor that promotes proliferation and migration. miR-888 resides within a genomic cluster of 7 miRNA genes (mir-892c, mir-890, mir-888, mir-892a, mir-892b, mir-891b, mir-891a) on human chromosome Xq27.3. Moreover, as miR-888 maps within HPCX1, a locus associated with susceptibility and/or hereditary prostate cancer, it was hypothesized that additional miRNA cluster members also play functional roles in the prostate. Expression analysis determined that cluster members were similarly elevated in metastatic PC3-ML prostate cells and their secreted exosomes, as well as enriched in expressed prostatic secretions urine-derived exosomes obtained from clinical patients with high-grade prostate cancer. In vitro assays revealed that miR-888 cluster members selectively modulated PC3-derived and LNCaP cell proliferation, migration, invasion, and colony formation. Mouse xenograft studies verified miR-888 and miR-891a as pro-oncogenic factors that increased prostate tumor growth in vivo. Further analysis validated RBL1, KLF5, SMAD4, and TIMP2 as direct miR-888 targets and that TIMP2 is also coregulated by miR-891a. This study provides the first comprehensive analysis of the entire miR-888 cluster and reveals biological insight.
Implications: This work reveals a complex noncoding RNA network in the prostate that could be developed as effective diagnostic and therapeutic tools for advanced prostate cancer. Mol Cancer Res; 16(4); 669–81. ©2018 AACR.
BRCA1 through Its E3 Ligase Activity Regulates the Transcription Factor Oct1 and Carbohydrate Metabolism
Authors: Vázquez-Arreguín Karina , Maddox Jessica , Kang Jinsuk , Park Dongju , Cano Reuben R. , Factor Rachel E. , Ludwig Thomas , Tantin Dean 
Published: January 2018

Abstract
The tumor suppressor BRCA1 regulates the DNA damage response (DDR) and other processes that remain incompletely defined. Among these, BRCA1 heterodimerizes with BARD1 to ubiquitylate targets via its N-terminal E3 ligase activity. Here, it is demonstrated that BRCA1 promotes oxidative metabolism by degrading Oct1 (POU2F1), a transcription factor with proglycolytic and tumorigenic effects. BRCA1 E3 ubiquitin ligase mutation skews cells toward a glycolytic metabolic profile while elevating Oct1 protein. CRISPR-mediated Oct1 deletion reverts the glycolytic phenotype. RNA sequencing (RNAseq) confirms deregulation of metabolic genes downstream of Oct1. BRCA1 mediates Oct1 ubiquitylation and degradation, and mutation of two ubiquitylated Oct1 lysines insulates the protein against BRCA1-mediated destabilization. Oct1 deletion in MCF-7 breast cancer cells does not perturb growth in standard culture, but inhibits growth in soft agar and xenograft assays. In primary breast cancer clinical specimens, Oct1 protein levels correlate positively with tumor aggressiveness and inversely with BRCA1. These results identify BRCA1 as an Oct1 ubiquitin ligase that catalyzes Oct1 degradation to promote oxidative metabolism and restrict tumorigenicity. Mol Cancer Res; 16(3); 439–52. ©2018 AACR.
Novel Intergenically Spliced Chimera, NFATC3-PLA2G15, Is Associated with Aggressive T-ALL Biology and Outcome
Authors: Bond Jonathan , Tran Quang Christine , Hypolite Guillaume , Belhocine Mohamed , Bergon Aurélie , Cordonnier Gaëlle , Ghysdael Jacques , Macintyre Elizabeth , Boissel Nicolas , Spicuglia Salvatore , Asnafi Vahid 
Published: January 2018

Abstract
Leukemias are frequently characterized by the expression of oncogenic fusion chimeras that normally arise due to chromosomal rearrangements. Intergenically spliced chimeric RNAs (ISC) are transcribed in the absence of structural genomic changes, and aberrant ISC expression is now recognized as a potential driver of cancer. To better understand these potential oncogenic drivers, high-throughput RNA sequencing was performed on T-acute lymphoblastic leukemia (T-ALL) patient specimens (n = 24), and candidate T-ALL–related ISCs were identified (n = 55; a median of 4/patient). In-depth characterization of the NFATC3-PLA2G15 chimera, which was variably expressed in primary T-ALL, was performed. Functional assessment revealed that the fusion had lower activity than wild-type NFATC3 in vitro, and T-ALLs with elevated NFATC3-PLA2G15 levels had reduced transcription of canonical NFAT pathway genes in vivo. Strikingly, high expression of the NFATC3-PLA2G15 chimera correlated with aggressive disease biology in murine patient-derived T-ALL xenografts, and poor prognosis in human T-ALL patients. Mol Cancer Res; 16(3); 470–5. ©2018 AACR.
Epigenetic Reprogramming of Pericentromeric Satellite DNA in Premalignant and Malignant Lesions
Authors: Brückmann Nadine Heidi , Pedersen Christina Bøg , Ditzel Henrik Jørn , Gjerstorff Morten Frier 
Published: January 2018

Abstract
Repression of repetitive DNA is important for maintaining genomic stability, but is often perturbed in cancer. For instance, the megabase satellite domain at chromosome 1q12 is a common site of genetic rearrangements, such as translocations and deletions. Polycomb-group proteins can be observed as large subnuclear domains called polycomb bodies, the composition and cellular function of which has remained elusive. This study demonstrates that polycomb bodies are canonical subunits of the multiprotein polycomb repressive complex 1 deposited on 1q12 pericentromeric satellite DNA, which are normally maintained as constitutive heterochromatin by other mechanisms. Furthermore, the data reveal that polycomb bodies are exclusive to premalignant and malignant cells, being absent in normal cells. For instance, polycomb bodies are present in melanocytic cells of nevi and conserved in primary and metastatic melanomas. Deposition of polycomb on the 1q12 satellite DNA in melanoma development correlated with reduced DNA methylation levels. In agreement with this, inhibition of DNA methyltransferases, with the hypomethylating agent guadecitabine (SGI-110), was sufficient for polycomb body formation on pericentromeric satellites in primary melanocytes. This suggests that polycomb bodies form in cancer cells with global DNA demethylation to control the stability of pericentromeric satellite DNA. These results reveal a novel epigenetic perturbation specific to premalignant and malignant cells that may be used as an early diagnostic marker for detection of precancerous changes and a new therapeutic entry point.
Implications: Pericentromeric satellite DNA is epigenetically reprogrammed into polycomb bodies as a premalignant event with implications for transcriptional activity and genomic stability. Mol Cancer Res; 16(3); 417–27. ©2018 AACR.
Foxo-dependent Par-4 Upregulation Prevents Long-term Survival of Residual Cells Following PI3K–Akt Inhibition
Authors: Damrauer Jeffrey S. , Phelps Stephanie N. , Amuchastegui Katie , Lupo Ryan , Mabe Nathaniel W. , Walens Andrea , Kroger Benjamin R. , Alvarez James V. 
Published: January 2018

Abstract
Tumor recurrence is a leading cause of death and is thought to arise from a population of residual cells that survive treatment. These residual cancer cells can persist, locally or at distant sites, for years or decades. Therefore, understanding the pathways that regulate residual cancer cell survival may suggest opportunities for targeting these cells to prevent recurrence. Previously, it was observed that the proapoptotic protein (PAWR/Par-4) negatively regulates residual cell survival and recurrence in mice and humans. However, the mechanistic underpinnings on how Par-4 expression is regulated are unclear. Here, it is demonstrated that Par-4 is transcriptionally upregulated following treatment with multiple drugs targeting the PI3K–Akt–mTOR signaling pathway, and identify the Forkhead family of transcription factors as mediators of this upregulation. Mechanistically, Foxo3a directly binds to the Par-4 promoter and activates its transcription following inhibition of the PI3K–Akt pathway. This Foxo-dependent Par-4 upregulation limits the long-term survival of residual cells following treatment with therapeutics that target the PI3K–Akt pathway. Taken together, these results indicate that residual breast cancer tumor cell survival and recurrence requires circumventing Foxo-driven Par-4 upregulation and suggest that approaches to enforce Par-4 expression may prevent residual cell survival and recurrence. Mol Cancer Res; 16(4); 599–609. ©2018 AACR.
Differential Regulation of LET-7 by LIN28B Isoform–Specific Functions
Authors: Mizuno Rei , Chatterji Priya , Andres Sarah , Hamilton Kathryn , Simon Lauren , Foley Shawn W. , Jeganathan Arjun , Gregory Brian D. , Madison Blair , Rustgi Anil K. 
Published: January 2018

Abstract
The RNA-binding protein LIN28B plays an important role in development, stem cell biology, and tumorigenesis. LIN28B has two isoforms: the LIN28B-long and -short isoforms. Although studies have revealed the functions of the LIN28B-long isoform in tumorigenesis, the role of the LIN28B-short isoform remains unclear and represents a major gap in the field. The LIN28B-long and -short isoforms are expressed in a subset of human colorectal cancers and adjacent normal colonic mucosa, respectively. To elucidate the functional and mechanistic aspects of these isoforms, colorectal cancer cells (Caco-2 and LoVo) were generated to either express no LIN28B or the -short or -long isoform. Interestingly, the long isoform suppressed LET-7 expression and activated canonical RAS/ERK signaling, whereas the short isoform did not. The LIN28B-long isoform–expressing cells demonstrated increased drug resistance to 5-fluorouracil and cisplatin through the upregulation of ERCC1, a DNA repair gene, in a LET-7–dependent manner. The LIN28B-short isoform preserved its ability to bind pre-let-7, without inhibiting the maturation of LET-7, and competed with the LIN28B-long isoform for binding to pre-let-7. Coexpression of the short isoform in the LIN28B-long isoform–expressing cells rescued the phenotypes induced by the LIN28B-long isoform.
Implications: This study demonstrates the differential antagonistic functions of the LIN28B-short isoform against the LIN28B-long isoform through an inability to degrade LET-7, which leads to the novel premise that the short isoform may serve to counterbalance the long isoform during normal colonic epithelial homeostasis, but its downregulation during colonic carcinogenesis may reveal the protumorigenic effects of the long isoform. Mol Cancer Res; 16(3); 403–16. ©2018 AACR.
Dual Inhibition of CDK4 and CDK2 via Targeting p27 Tyrosine Phosphorylation Induces a Potent and Durable Response in Breast Cancer Cells
Authors: Patel Priyank , Tsiperson Vladislav , Gottesman Susan R.S. , Somma Jonathan , Blain Stacy W. 
Published: January 2018

AbstractCyclin-dependent kinase 4/6 (CDK4/6)-specific inhibitors, such as palbociclib, have shown clinical efficacy, but primary or secondary resistance has emerged as a problem. To develop more effective therapeutic approaches, investigation is needed into the mechanisms of resistance or adaption. Here, it is demonstrated that CDK2 compensates for loss of CDK4 activity to rescue palbociclib-arrested breast cancer cells, suggesting that inhibition of both kinases is required to achieve durable response. In addition, a novel strategy is described to inhibit tyrosine phosphorylation of p27Kip1 (CDKN1B) and simultaneously inhibit both CDK2 and CDK4. p27Kip1 is a required assembly factor for cyclin–CDK4 complexes, but it must be phosphorylated on residue Y88 to open or activate the complex. The Brk-SH3 peptide, ALT, blocks p27 Y88 phosphorylation, inhibiting CDK4. Nonphosphorylated p27 is no longer a target for ubiquitin-mediated degradation and this stabilized p27 now also inhibits CDK2 activity. Thus, ALT induction inhibits both the kinase that drives proliferation (CDK4) and the kinase that mediates resistance (CDK2), causing a potent and long-lasting cell-cycle arrest. ALT arrests growth of all breast cancer subgroups and synergizes with palbociclib to increase cellular senescence and to cause tumor regression in breast cancer xenograft models. The use of ALT demonstrates that both CDK4 and CDK2 need to be inhibited if long-term efficacy is to be achieved and represents a novel modality to inhibit breast cancer cells.Implications: Modulating tyrosine phosphorylation of p27 impacts both proliferative (CDK4) and resistance (CDK2) mechanisms in breast cancer and suggests that phospho-p27 status may serve as a biomarker for patients that are responsive to CDK4/6 inhibition. Mol Cancer Res; 16(3); 361–77. ©2018 AACR.