bluuebunny/crossref_metadata_2025_split huggingface dataset:
Hypolipidaemia among patients with PMM2-CDG is associated with low circulating PCSK9 levels: a case report followed by observational and experimental studies
Authors: Chong Michael , Yoon Grace , Susan-Resiga Delia , Chamberland Ann , Cheillan David , Paré Guillaume , Seidah Nabil G 
Published: August 2019

BackgroundProprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors are novel therapeutics for reducing low-density lipoprotein cholesterol (LDLc). While serious side-effects have not been observed in short-term clinical trials, there remain concerns that long-term PCSK9 inhibition may cause neurocognitive side-effects.Methods and resultsAn adult male with childhood-onset global developmental delay, cerebellar atrophy and severe hypolipidaemia underwent extensive biochemical and genetic investigations. Initial testing revealed low circulating PCSK9 levels and a common loss-of-function PCSK9 polymorphism, but these findings did not fully account for severe hypolipidaemia. Whole-exome sequencing was subsequently performed and identified two pathogenic phosphomannose mutase 2 (PMM2) variants (p.Arg141His and p.Pro69Ser) known to cause PMM2-associated congenital disorder of glycosylation (PMM2-CDG). A diagnosis of PMM2-CDG was consistent with the proband’s neurological symptoms and severe hypolipidaemia. Given that PMM2-CDG is characterised by defective protein N-glycosylation and that PCSK9 is a negative regulator of LDLc, we postulated that loss of PCSK9 N-glycosylation mediates hypolipidaemia among patients with PMM2-CDG. First, in an independent cohort of patients with PMM2-CDG (N=8), we verified that circulating PCSK9 levels were significantly lower in patients than controls (p=0.0006). Second, we conducted in vitro experiments in hepatocyte-derived cells to evaluate the effects of PCSK9 N-glycosylation loss on LDL receptor (LDLR) activity. Experimental results suggest that defective PCSK9 N-glycosylation reduces the ability of circulating PCSK9 to degrade LDLR.ConclusionLife-long exposure to genetically lower PCSK9 per se is unlikely to cause neurocognitive impairment. Both observational and experimental findings suggest that hypolipidaemia in PMM2-CDG may be partially mediated by loss of PCSK9 N-glycosylation and/or its regulators.
Factors associated with rehoming and time until rehoming for horses listed with an equine charity
Authors: Rosanowski Sarah , Verheyen Kristien 
Published: August 2019

The number of unwanted horses in the UK has increased in recent years. It is therefore important to identify factors that indicate whether a horse can be rehomed and how long it takes to be rehomed. Data from 1 January 2013 until 30 March 2014 were extracted from an equine rehoming charity's database. Exposure variables were examined using multivariable logistic and Cox regression. In total, 791 horses were included in the study and 410 (51.8%) were rehomed during the study period. Median time until rehomed was 39 days (IQR 24–75). Horses whose owner was prepared to transfer ownership were nearly three times more likely to be rehomed than those available for loan. Horses deemed suitable for beginner riders had higher odds of finding a new home, compared with those needing an advanced rider. Horses that were only suitable as unridden companions took longer to find a new home than rideable horses. A restricted rehoming radius (<50 miles) also resulted in longer time to rehoming. Findings from this study can be used to inform rehoming strategies but also to identify horses less likely to be rehomed, and thus where alternative options should be considered.
Fault zone architecture and its scaling laws: where does the damage zone start and stop?
Authors: Torabi A. , Ellingsen T. S. S. , Johannessen M. U. , Alaei B. , Rotevatn A. , Chiarella D. 
Published: August 2019

Abstract

Damage zones of different fault types are investigated in siliciclastics (Utah, USA), carbonates (Majella Mountain, Italy) and metamorphic rocks (western Norway). The study was conducted taking measurements of deformation features such as fractures and deformation bands on multiple 1D scanlines along fault walls. The resulting datasets are used to plot the frequency distribution of deformation features and to constrain the geometrical width of the damage zone for the studied faults. The damage-zone width of a single fault is constrained by identifying the changes in the slope of cumulative plots made on the frequency data. The cumulative plot further shows high deformation frequency by a steep slope (inner damage zone) and less deformation as a gentle slope (outer damage zone). Statistical distributions of displacement and damage-zone width and their relationship are improved, and show two-slope power-law distributions with a break point at
c.
100 m displacement. Bleached sandstones in the studied siliciclastic rocks of Utah are associated with a higher frequency of deformation bands and a wider damage zone compared to the unbleached zone of similar lithology. Fault damage zones in the carbonate rocks of Majella are often host to open fractures (karst), demonstrating that they can also be conductive to fluid flow.
Cerebral peak alpha frequency reflects average pain severity in a human model of sustained, musculoskeletal pain
Authors: Furman Andrew J. , Thapa Tribikram , Summers Simon J. , Cavaleri Rocco , Fogarty Jack S. , Steiner Genevieve Z. , Schabrun Siobhan M. , Seminowicz David A. 
Published: August 2019

Heightened pain sensitivity, the amount of pain experienced in response to a noxious event, is a known risk factor for development of chronic pain. We have previously reported that pain-free, sensorimotor peak alpha frequency (PAF) is a reliable biomarker of pain sensitivity for thermal, prolonged pains lasting tens of minutes. To test whether PAF can provide information about pain sensitivity occurring over clinically relevant timescales (i.e., weeks), EEG was recorded before and while participants experienced a long-lasting pain model, repeated intramuscular injection of nerve growth factor (NGF), that produces progressively developing muscle pain for up to 21 days. We demonstrate that pain-free, sensorimotor PAF is negatively correlated with NGF pain sensitivity; increasingly slower PAF is associated with increasingly greater pain sensitivity. Furthermore, PAF remained stable following NGF injection, indicating that the presence of NGF pain for multiple weeks is not sufficient to induce the PAF slowing reported in chronic pain. In total, our results demonstrate that slower pain-free, sensorimotor PAF is associated with heightened sensitivity to a long-lasting musculoskeletal pain and also suggest that the apparent slowing of PAF in chronic pain may reflect predisease pain sensitivity. NEW & NOTEWORTHY Pain sensitivity, the intensity of pain experienced after injury, has been identified as an important risk factor in the development of chronic pain. Biomarkers of pain sensitivity have the potential to ease chronic pain burdens by preventing disease emergence. In the current study, we demonstrate that the speed of pain-free, sensorimotor peak alpha frequency recorded during resting-state EEG predicts pain sensitivity to a clinically-relevant, human model of prolonged pain that persists for weeks.
Mutant IDH Sensitizes Gliomas to Endoplasmic Reticulum Stress and Triggers Apoptosis via miR-183-Mediated Inhibition of Semaphorin 3E
Authors: Zhang Ying , Pusch Stefan , Innes James , Sidlauskas Kastytis , Ellis Matthew , Lau Joanne , El-Hassan Tedani , Aley Natasha , Launchbury Francesca , Richard-Loendt Angela , deBoer Jasper , Chen Sheng , Wang Lei , von Deimling Andreas , Li Ningning , Brandner Sebastian 
Published: August 2019

AbstractHuman astrocytomas and oligodendrogliomas are defined by mutations of the metabolic enzymes isocitrate dehydrogenase (IDH) 1 or 2, resulting in the production of the abnormal metabolite D-2 hydroxyglutarate. Here, we studied the effect of mutant IDH on cell proliferation and apoptosis in a glioma mouse model. Tumors were generated by inactivating Pten and p53 in forebrain progenitors and compared with tumors additionally expressing the Idh1 R132H mutation. Idh-mutant cells proliferated less in vitro and mice with Idh-mutant tumors survived significantly longer compared with Idh-wildtype mice. Comparison of miRNA and RNA expression profiles of Idh-wildtype and Idh-mutant cells and tumors revealed miR-183 was significantly upregulated in IDH-mutant cells. Idh-mutant cells were more sensitive to endoplasmic reticulum (ER) stress, resulting in increased apoptosis and thus reduced cell proliferation and survival. This was mediated by the interaction of miR-183 with the 5′ untranslated region of semaphorin 3E, downregulating its function as an apoptosis suppressor. In conclusion, we show that mutant Idh1 delays tumorigenesis and sensitizes tumor cells to ER stress and apoptosis. This may open opportunities for drug treatments targeting the miR-183–semaphorin axis.Significance:The pathologic metabolite 2-hydroxyglutarate, generated by IDH-mutant astrocytomas, sensitizes tumor cells to ER stress and delays tumorigenesis.
Abstract 1002: An association between Annexin A1 (ANXA1) and loss of progesterone receptor expression in estrogen receptor-positive breast cancer
Authors: Ahn Sung Gwe , Bae Soong June , Cha Chihwan , Yoon Chang Ik , Park So Eun , Jeong Joon 
Published: August 2019

Abstract
Purpose: There is a strong body of evidence that low expression of progesterone receptor has a negative prognostic value in estrogen receptor (ER)-positive breast cancer. To discover key factors associated with PR-loss in ER-positive cancer, we conducted cell line experiments and investigated clinical samples.
Methods: We generated PR knock-down MCF7 and T47D cell lines using lentiviral transfection with PR shRNA. Gene expression microarray analyses were performed using Illumina Chip. Annexin A1 (ANXA1) was evaluated for tissue microarray (TMA) using HER2-negative human breast carcinoma.
Results: When PR-intact and PR-knockdown cells were compared using gene-expression profiles, ANXA1 was commonly identified as a molecule associated PR-knockdown in both MCF7 and T47D cell lines. Further, the mRNA expression of ANXA1 was elevated by PR-knockdown in both cell lines. In HER2-negative patients (n=370), ANXA1-positive tumors were associated with a lack of PR expression (P&lt;0.001). The patients with ANXA1-positivity had a poor survival outcome in terms of overall survival and metastasis-free survival.
Conclusions: Our findings inform that ANXA1 may act a role in tumor progression of PR-lacking breast cancer.
Citation Format: Sung Gwe Ahn, Soong June Bae, Chihwan Cha, Chang Ik Yoon, So Eun Park, Joon Jeong. An association between Annexin A1 (ANXA1) and loss of progesterone receptor expression in estrogen receptor-positive breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1002.
Abstract 1013: Role of mitochondria and glutamine metabolism in therapy resistance: Combined targeting of estrogen receptor alpha and exportin 1 in endocrine resistant breast cancers
Authors: Cotul Eylem Kulkoyluoglu , Smith Brandi Patrice , Chang Hua , Landesman Yosef , Duong Kevin , Erdogan Zeynep Madak 
Published: August 2019

Abstract
Majority of breast cancer specific deaths in women with ERα (+) tumor occur due to metastases that are resistant to endocrine therapy. There is a critical need for novel therapeutic approaches to prevent or delay recurrence of ERα (+) tumors. The objective of this study was to elucidate the role of mitochondrial pathways that are activated in the presence of single therapies and undermine therapy effectiveness in ER (+) breast cancers. In our previous studies, we identified Exportin 1 (XPO1), a nuclear export protein, as an important player in endocrine resistance progression. Selinexor (SXR), an XPO1 antagonist, has been evaluated in multiple later stage clinical trials in patients with relapsed and /or refractory hematological and solid tumor malignancies. Using a combination of transcriptomics, kinase arrays, metabolomics and metabolic flux experiments, we identified glutamine metabolism pathways to be rewired during endocrine resistance. In limited media conditions mimicking nutrient deprived tumor microenvironment, endocrine resistant cells were more dependent on mitochondria for energy production. Their glucose and fatty acid dependency decreased in the presence of SXR and cells were more dependent on glutamine. The effect of glutamine was dependent on conversion of the glutamine to glutamate and mitochondrial complex 1 activity. In order to examine metabolites that might result in the observed phenotype we performed GC/MS whole metabolite profiling and identified aminoacid metabolism pathways to be upregulated when cells were treated with SXR. We demonstrated that combined targeting of XPO1 and ERα rewires metabolic pathways and shuts down both glycolytic and mitochondrial pathways that would eventually lead to autophagy. Remodeling metabolic pathways to regenerate new vulnerabilities in endocrine-resistant breast tumors is novel, and given the need for better strategies for improving therapy response of relapsed ERα (+) tumors, our findings show great promise for uncovering the role ERα-XPO1 crosstalk plays in reducing cancer recurrences.
Citation Format: Eylem Kulkoyluoglu Cotul, Brandi Patrice Smith, Hua Chang, Yosef Landesman, Kevin Duong, Zeynep Madak Erdogan. Role of mitochondria and glutamine metabolism in therapy resistance: Combined targeting of estrogen receptor alpha and exportin 1 in endocrine resistant breast cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1013.
Abstract 1016: The androgen receptor splice variant AR-V7 associates with the glucocorticoid receptor following androgen blockade
Authors: Bueter Eric , Hosfield David , McAuley Erin , Selman Phillip , Greene Geoffrey , Conzen Suzanne D. , Szmulewitz Russell Z. 
Published: August 2019

Abstract
Expression of the constitutively active androgen receptor splice variant AR-V7 is associated with resistance to anti-androgen therapies and worse clinical outcomes in prostate cancer. Dimerization is a requirement for AR-V7 transcriptional activity, but whether that occurs through homodimerization or heterodimerization remains poorly understood. Because NR3C-family nuclear hormone receptors rely on a highly conserved D-box motif within the DNA-binding domain to mediate dimerization, we hypothesized that AR-V7 can heterodimerize with other NR3C-family nuclear hormone receptors, with a particular interest in the glucocorticoid receptor (GR). Like AR-V7, GR is upregulated in prostate cancer following androgen blockade, regulates canonical AR target genes, and is associated with resistance to anti-androgen therapies. Using NanoBRET technology in HEK293 cells, we found that AR-V7 interacts with liganded NR3C-family nuclear hormone receptors, including the full-length androgen receptor, the progesterone receptor, the mineralocorticoid receptor, and, most notably, GR. Using co-immunoprecipitation and proximity ligation assays, we demonstrate that AR-V7 associates with GR following androgen blockade in both the VCaP cell line and the CWR-22RV1 cell line, two models of prostate cancer that express endogenous AR-V7 and GR. Preliminary ChIP-Seq experiments in these cell lines suggest AR-V7 and GR chromatin occupancy at the same genomic sites in a ligand-dependent manner. Taken altogether, this data suggests AR-V7 can utilize GR as an alternative binding partner to initiate heterodimerization and transcriptional activation.
Citation Format: Eric Bueter, David Hosfield, Erin McAuley, Phillip Selman, Geoffrey Greene, Suzanne D. Conzen, Russell Z. Szmulewitz. The androgen receptor splice variant AR-V7 associates with the glucocorticoid receptor following androgen blockade [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1016.
Abstract 1018: GnRH antagonists have direct inhibitory effects on castration-resistant prostate cancer via intracrine androgen and AR-V7 expression
Authors: Cucchiara Vito , Yang Joy C. , Liu Chengfei , Adomat Hans , Guns Emma , Gleave Martin E. , Gao Allen C. , Evans Christopher P. 
Published: August 2019

Abstract
Hormone therapy is currently the mainstay in the management of locally advanced and metastatic prostate cancer (PCa). Degarelix (Firmagon, Deg), a GnRH receptor antagonist demonstrated some advantages over the LHRH agonist Leuprolide (Leup) by avoiding “testosterone flare” and lower FSH levels. We compared the effect of Deg and Leup on prostate cancer (PC) cell progression in vitro and in vivo. GnRHR2 was readily detectable in PC cells. AR transcriptional activity reported by PSA-Luc assay was modulated by both Leup and Deg. In LNCaP and C4-2B MDVR cells, 20µM Deg significantly reduced the cell viability (p&lt;0.01). GnRH-antagonist (alone or in combination with AA or Enza) counteracted the transactivation activity of AR by reducing AR-FL and AR variants at the protein level. In C4-2BMDVR cells, Deg reduced AR-V7 protein expression by 26 to 40% alone or combined with AA and Enza compared to control. Leup, however, enhanced variant expression. Deg reduced AR-variant levels from 17 to 41% in monotherapy or combinations compared to control. In mice, Leup slightly suppressed tumor growth compared to controls (p&gt;0.05). However, tumors in Deg-treated group were 1.5-fold smaller than Leup-treated group but 1.7-fold bigger than surgical castration-group. Ki67 IHC staining confirmed the difference in tumor proliferation among groups. Measurements of intratumoral steroids by LC-MS from tumors, serum samples or cell pellets confirmed that Deg decreased the levels of testosterone and steroidogenesis pathway intermediates, comparable to surgical castration; while Leup had no inhibitory effect. Our results suggest a selective mechanism of action of Deg against AR-variants. The present study provides additional molecular insights regarding the mechanism of Deg compared to GnRH agonist therapy which may have clinical implications.
Citation Format: Vito Cucchiara, Joy C. Yang, Chengfei Liu, Hans Adomat, Emma Guns, Martin E. Gleave, Allen C. Gao, Christopher P. Evans. GnRH antagonists have direct inhibitory effects on castration-resistant prostate cancer via intracrine androgen and AR-V7 expression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1018.
Abstract 1032: Establishing an in vitro model of lipopolysaccharide-induced tumorospheres formation of prostate epithelial cells for drug screening
Authors: Jiang Jiajia , Lian Xueqi , Tang Sijie , Li Xiaohua 
Published: August 2019

Abstract
Tumorospheres forming assay not only was utilized to enrich cancer stem cell from bulk cancer cells, also was widely used to analyze the ability of clonogenic growth and self-renewal capability of cancer stem cells. Meanwhile, chronic inflammation-induced epithelial transformation has been documented in a broad range of cells. However, the effect of chronic inflammatory agent on tumorosphere formation has never been tested. In current study, the classic pro-inflammatory agent lipopolysaccharide was utilized to establish an in vitro model through inducing prostate tumoroshpere formation. Then, trichostatin A, a panel inhibitor of histone deacetylases, was tested in this model for its anti-tumor effect. The results showed that treatment with lipopolysaccharide stimulated prostate cancer DU145 and PC3 cells undergoing migration and invasion with decreased the ratio of CK8 and CK18 versus vimentin. It also induced tumorospheres formation in suspension culture with increased a panel of tumor stem cell markers transcription (e.g. CD44, α-intergrin, nestin etc) and promoted phosphorylation of Stat3 (p-Stat3) and pro-oncogene c-Myc expression in vitro. Treatment with trichostatin A showed to restrain the above lipopolysaccharide-induced EMT and tumorosphere formation with decreasing the level of p-Stat3, p-Erk, p-c-jun, c-Myc, CD44 and SOX-2. Finally, blocking Stat3 signaling pathway by treatment with trichostatin A and/or small molecule compound Stattic, an inhibitor of p-Stat3, abrogated LPS-induced cancer stem-like tumorosphere formation. Taken together, our data demonstrated that lipopolysaccharide induced cancer stem-like tumorospheres formation successfully, which could be served as a simple and easy handling in vitro model for anti-tumor drug screening.
Citation Format: Jiajia Jiang, Xueqi Lian, Sijie Tang, Xiaohua Li. Establishing an in vitro model of lipopolysaccharide-induced tumorospheres formation of prostate epithelial cells for drug screening [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1032.
Abstract 1038: Metformin inhibits epithelial-mesenchymal transition in human pancreatic cancer cell lines
Authors: Yoshida Juichiro , Ishikawa Takeshi , Endo Yuki , Matsumura Shinya , Ohta Takayuki , Mizushima Katsura , Hirai Yasuko , Okayama Tetsuya , Sakamoto Naoyuki , Inoue Ken , Katada Kazuhiro , Kamada Kazuhiro , Uchiyama Kazuhiko , Takagi Tomohisa , Naito Yuji , Itoh Yoshito 
Published: August 2019

Abstract
Background: Epithelial-mesenchymal transition (EMT) is considered to be a crucial event in the development of cancer metastasis. Metformin is an antidiabetic drug used in treatment of type 2 diabetes. Recently, increasing evidence has indicated that metformin can inhibit tumor growth, however, effect of metformin on EMT remains still well unknown.
Methods: We investigated whether metformin inhibits EMT in the human pancreatic cancer cell lines (PANC-1, BXPC-3, and MIAPaCa-2). Pancreatic cancer cells were stimulated TGF-β1 (10ng/ml) with or without metformin(10mM). After 48h, we evaluated for EMT-related factors using western blot analyses, immunocytochemistry and RT-PCR. Wound healing assay was performed to determine cell migration.
Results: The cells stimulated TGF-β1 acquired elongated and fusiform morphology, and metformin inhibited the TGF-β1-induced morphological changes in PANC-1 and BXPC-3 cells. Wound healing assay of PANC-1 and MIAPaCa-2 cells showed that significant wound healing was seen after 24h in cells treated with TGF-β1 compared with the control, and metformin inhibited wound closure. E-cadherin expression weakened after exposure to TGF-β1, but it was reversed by metformin in these cell lines. Metformin treatment reduced the expression of mesenchymal markers (Vimentin, N-cadherin and αSMA) induced by TGF-β1 in these cell lines. Exposure of cells to TGF-β1 resulted in the phosphorylation of mTOR, and exposure of cells to metformin resulted in the phosphorylation of AMPK and blocked the phosphorylation of mTOR in BXPC-3 cells. Furthermore, cell viability was no significantly change between exposing metformin or not.
Discussion: Our results indicate that metformin inhibits TGF-β1 induced EMT in human pancreatic cancer cells. Moreover, our results suggest that metformin induces the phosphorylation of AMPK and inhibits TGF-β1 induced mTOR activation in BXPC-3 cells.
Citation Format: Juichiro Yoshida, Takeshi Ishikawa, Yuki Endo, Shinya Matsumura, Takayuki Ohta, Katsura Mizushima, Yasuko Hirai, Tetsuya Okayama, Naoyuki Sakamoto, Ken Inoue, Kazuhiro Katada, Kazuhiro Kamada, Kazuhiko Uchiyama, Tomohisa Takagi, Yuji Naito, Yoshito Itoh. Metformin inhibits epithelial-mesenchymal transition in human pancreatic cancer cell lines [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1038.