bluuebunny/crossref_metadata_2025_split huggingface dataset:
Post-stroke mRNA expression profile of MMPs: effect of genetic deletion of MMP-12
Authors: Nalamolu Koteswara Rao , Chelluboina Bharath , Magruder Ian B , Fru Diane N , Mohandass Adithya , Venkatesh Ishwarya , Klopfenstein Jeffrey D , Pinson David M , Boini Krishna M , Veeravalli Krishna Kumar 
Published: March 2018

Background and purposeRecent reports from our laboratory demonstrated the post-ischaemic expression profile of various matrix metalloproteinases (MMPs) in rats and the detrimental role of MMP-12 in post-stroke brain damage. We hypothesise that the post-stroke dysregulation of MMPs is similar across species and that genetic deletion of MMP-12 would not affect the post-stroke expression of other MMPs. We tested our hypothesis by determining the pre-ischaemic and post-ischaemic expression profile of MMPs in wild-type and MMP-12 knockout mice.MethodsFocal cerebral ischaemia was induced in wild-type and MMP-12 knockout mice by middle cerebral artery occlusion procedure by insertion of a monofilament suture. One hour after ischaemia, reperfusion was initiated by removing the monofilament. One day after reperfusion, ischaemic brain tissues from various groups of mice were collected, and total RNA was isolated and subjected to cDNA synthesis followed by PCR analysis.ResultsAlthough the post-stroke expression profile of MMPs in the ischaemic brain of mice is different from rats, there is a clear species similarity in the expression of MMP-12, which was found to be predominantly upregulated in both species. Further, the post-stroke induction or inhibition of various MMPs in MMP-12 knockout mice is different from their respective expression profile in wild-type mice. Moreover, the brain mRNA expression profile of various MMPs in MMP-12 knockout mice under normal conditions is also different to their expression in wild-type mice.ConclusionsIn the ischaemic brain, MMP-12 upregulates several fold higher than any other MMP. Mice derived with the genetic deletion of MMP-12 are constitutive and have altered MMP expression profile both under normal and ischaemic conditions.
Timing and spatial patterns of Cretaceous and Cenozoic inversion in the Southern Permian Basin
Authors: Kley Jonas 
Published: March 2018

Abstract
Mesozoic extensional basins of the Southern Permian Basin (SPB) System became inverted from Late Cretaceous time onwards. Following a first Cretaceous ‘Subhercynian’ pulse of contractional deformation and basin uplift, several distinct inversion events of Cenozoic age were often described. The oldest of these is the ‘Laramide’ event of Paleocene age which coincides with the termination of chalk deposition and widespread regression around the North Sea Basin, whose axial part continued to subside. The spatial extent of these effects is too wide to be compatible with inversion by folding and reverse faulting. The width of the uplifting and subsiding regions was also too large to be consistent with folding of the entire lithosphere under tangential compression. There appears to be no unequivocal evidence of discrete structures formed or reactivated in the Laramide event. By contrast, well-documented younger inversion of approximately Late Eocene to Late Oligocene–(Miocene?) age affected the region from the Celtic Sea to the western Netherlands. The associated deformation is weaker than that of the Late Cretaceous event and spatially overlaps with it only in the Southern North Sea. Structural inversion of the SPB thus comprised only two events separated in time and mostly also in space.
Activation of the Receptor Tyrosine Kinase AXL Regulates the Immune Microenvironment in Glioblastoma
Authors: Sadahiro Hirokazu , Kang Kyung-Don , Gibson Justin T. , Minata Mutsuko , Yu Hai , Shi Junfeng , Chhipa Rishi , Chen Zhihong , Lu Songjian , Simoni Yannick , Furuta Takuya , Sabit Hemragul , Zhang Suojun , Bastola Soniya , Yamaguchi Shinobu , Alsheikh Hebaallah , Komarova Svetlana , Wang Jun , Kim Sung-Hak , Hambardzumyan Dolores , Lu Xinghua , Newell Evan W. , DasGupta Biplab , Nakada Mitsutoshi , Lee L. James , Nabors Burt , Norian Lyse A. , Nakano Ichiro 
Published: March 2018

Abstract
Glioblastoma (GBM) is a lethal disease with no effective therapies available. We previously observed upregulation of the TAM (Tyro-3, Axl, and Mer) receptor tyrosine kinase family member AXL in mesenchymal GBM and showed that knockdown of AXL induced apoptosis of mesenchymal, but not proneural, glioma sphere cultures (GSC). In this study, we report that BGB324, a novel small molecule inhibitor of AXL, prolongs the survival of immunocompromised mice bearing GSC-derived mesenchymal GBM-like tumors. We show that protein S (PROS1), a known ligand of other TAM receptors, was secreted by tumor-associated macrophages/microglia and subsequently physically associated with and activated AXL in mesenchymal GSC. PROS1-driven phosphorylation of AXL (pAXL) induced NFκB activation in mesenchymal GSC, which was inhibited by BGB324 treatment. We also found that treatment of GSC-derived mouse GBM tumors with nivolumab, a blocking antibody against the immune checkpoint protein PD-1, increased intratumoral macrophages/microglia and activation of AXL. Combinatorial therapy with nivolumab plus BGB324 effectively prolonged the survival of mice bearing GBM tumors. Clinically, expression of AXL or PROS1 was associated with poor prognosis for patients with GBM. Our results suggest that the PROS1–AXL pathway regulates intrinsic mesenchymal signaling and the extrinsic immune microenvironment, contributing to the growth of aggressive GBM tumors.
Significance: These findings suggest that development of combination treatments of AXL and immune checkpoint inhibitors may provide benefit to patients with GBM. Cancer Res; 78(11); 3002–13. ©2018 AACR.
Transducin-Like Enhancer of Split 3 (TLE3) Expression Is Associated with Taxane Sensitivity in Nonserous Ovarian Carcinoma in a Three-Cohort Study
Authors: Ring Brian Z. , Murali Rajmohan , Soslow Robert A. , Bowtell David D.L. , Fereday Sian , deFazio Anna , Traficante Nadia , Kennedy Catherine J. , Brand Alison , Sharma Raghwa , Harnett Paul , Samimi Goli 
Published: March 2018

Abstract
Background: Chemoresistance is a major challenge in ovarian cancer treatment, resulting in poor survival rates. Identifying markers of treatment response is imperative for improving outcome while minimizing unnecessary side effects. We have previously demonstrated that expression of transducin-like enhancer of split 3 (TLE3) is associated with favorable progression-free survival in taxane-treated ovarian cancer patients with nonserous histology. The purpose of this study was to perform an independent evaluation of the association of TLE3 expression with response to taxane-based chemotherapy in nonserous ovarian cancer, to validate its role as a potential therapeutic response marker for taxane-based chemotherapy.
Methods: We performed immunohistochemical staining of TLE3 on ovarian cancer specimens from the Australian Ovarian Cancer Study, the Westmead Gynaecological Oncology Biobank, and Memorial Sloan Kettering Cancer Center. Progression-free survival and overall survival were assessed to validate an association between TLE3 expression and response to taxane therapy that we previously observed in a smaller study.
Results: Expression of TLE3 was associated with favorable outcome only in patients who had received paclitaxel as part of their treatment regimen for both 3-year progression-free survival (n = 160; HR, 0.56; P = 0.03) and 5-year overall survival (HR, 0.53; P = 0.04). Further analysis revealed that the predictive association between TLE3 expression and outcome was strongest in tumors with clear cell histology.
Conclusions: The association between high TLE3 expression and a favorable response to taxane-containing chemotherapy regimens was validated in patients with nonserous ovarian cancer.
Impact: TLE3 expression may serve as a marker of chemosensitivity in taxane-treated patients with nonserous histologies. Cancer Epidemiol Biomarkers Prev; 27(6); 680–8. ©2018 AACR.
Concurrent Alterations in EGFR-Mutant Lung Cancers Associated with Resistance to EGFR Kinase Inhibitors and Characterization of MTOR as a Mediator of Resistance
Authors: Yu Helena A. , Suzawa Ken , Jordan Emmet , Zehir Ahmet , Ni Ai , Kim Ryan , Kris Mark G. , Hellmann Matthew D. , Li Bob T. , Somwar Romel , Solit David B. , Berger Michael F. , Arcila Maria , Riely Gregory J. , Ladanyi Marc 
Published: March 2018

Abstract
Purpose: To identify molecular factors that determine duration of response to EGFR tyrosine kinase inhibitors and to identify novel mechanisms of drug resistance, we molecularly profiled EGFR-mutant tumors prior to treatment and after progression on EGFR TKI using targeted next-generation sequencing.
Experimental Design: Targeted next-generation sequencing was performed on 374 consecutive patients with metastatic EGFR-mutant lung cancer. Clinical data were collected and correlated with somatic mutation data. Erlotinib resistance due to acquired MTOR mutation was functionally evaluated by in vivo and in vitro studies.
Results: In 200 EGFR-mutant pretreatment samples, the most frequent concurrent alterations were mutations in TP53, PIK3CA, CTNNB1, and RB1 and focal amplifications in EGFR, TTF1, MDM2, CDK4, and FOXA1. Shorter time to progression on EGFR TKI was associated with amplification of ERBB2 (HR = 2.4, P = 0.015) or MET (HR = 3.7, P = 0.019), or mutation in TP53 (HR = 1.7, P = 0.006). In the 136 posttreatment samples, we identified known mechanisms of acquired resistance: EGFR T790M (51%), MET (7%), and ERBB2 amplifications (5%). In the 38 paired samples, novel acquired alterations representing putative resistance mechanisms included BRAF fusion, FGFR3 fusion, YES1 amplification, KEAP1 loss, and an MTOR E2419K mutation. Functional studies confirmed the contribution of the latter to reduced sensitivity to EGFR TKI in vitro and in vivo.
Conclusions: EGFR-mutant lung cancers harbor a spectrum of concurrent alterations that have prognostic and predictive significance. By utilizing paired samples, we identified several novel acquired alterations that may be relevant in mediating resistance, including an activating mutation in MTOR further validated functionally. Clin Cancer Res; 24(13); 3108–18. ©2018 AACR.
Lipidomic Profiling Links the Fanconi Anemia Pathway to Glycosphingolipid Metabolism in Head and Neck Cancer Cells
Authors: Zhao Xueheng , Brusadelli Marion G. , Sauter Sharon , Butsch Kovacic Melinda , Zhang Wujuan , Romick-Rosendale Lindsey E. , Lambert Paul F. , Setchell Kenneth D.R. , Wells Susanne I. 
Published: March 2018

Abstract
Purpose: Mutations in Fanconi anemia (FA) genes are common in sporadic squamous cell carcinoma of the head and neck (HNSCC), and we have previously demonstrated that FA pathway depletion in HNSCC cell lines stimulates invasion. The goal of our studies was to use a systems approach in order to define FA pathway–dependent lipid metabolism and to extract lipid-based signatures and effectors of invasion in FA-deficient cells.
Experimental Design: We subjected FA-isogenic HNSCC keratinocyte cell lines to untargeted and targeted lipidomics analyses to discover novel biomarkers and candidate therapeutic targets in FA-deficient cells. Cellular invasion assays were carried out in the presence and absence of N-butyldeoxynojirimycin (NB-DNJ), a biosynthetic inhibitor of the newly identified class of gangliosides, to investigate the requirement of ganglioside upregulation in FA-deficient HNSCC cells.
Results: The most notable element of the lipid profiling results was a consistent elevation of glycosphingolipids, and particularly the accumulation of gangliosides. Conversely, repression of this same class of lipids was observed upon genetic correction of FA patient–derived HNSCC cells. Functional studies demonstrate that ganglioside upregulation is required for HNSCC cell invasion driven by FA pathway loss. The motility of nontransformed keratinocytes in response to FA loss displayed a similar dependence, thus supporting early and late roles for the FA pathway in controlling keratinocyte invasion through lipid regulation.
Conclusions: Elevation of glycosphingolipids including the ganglioside GM3 in response to FA loss stimulates invasive characteristics of immortalized and transformed keratinocytes. An inhibitor of glycosphingolipid biosynthesis NB-DNJ attenuates invasive characteristics of FA-deficient HNSCC cells. Clin Cancer Res; 24(11); 2700–9. ©2018 AACR.
ABCC1-Exported Sphingosine-1-phosphate, Produced by Sphingosine Kinase 1, Shortens Survival of Mice and Patients with Breast Cancer
Authors: Yamada Akimitsu , Nagahashi Masayuki , Aoyagi Tomoyoshi , Huang Wei-Ching , Lima Santiago , Hait Nitai C. , Maiti Aparna , Kida Kumiko , Terracina Krista P. , Miyazaki Hiroshi , Ishikawa Takashi , Endo Itaru , Waters Michael R. , Qi Qianya , Yan Li , Milstien Sheldon , Spiegel Sarah , Takabe Kazuaki 
Published: March 2018

Abstract
Sphingosine-1-phosphate (S1P), a bioactive sphingolipid mediator, has been implicated in regulation of many processes important for breast cancer progression. Previously, we observed that S1P is exported out of human breast cancer cells by ATP-binding cassette (ABC) transporter ABCC1, but not by ABCB1, both known multidrug resistance proteins that efflux chemotherapeutic agents. However, the pathologic consequences of these events to breast cancer progression and metastasis have not been elucidated. Here, it is demonstrated that high expression of ABCC1, but not ABCB1, is associated with poor prognosis in breast cancer patients. Overexpression of ABCC1, but not ABCB1, in human MCF7 and murine 4T1 breast cancer cells enhanced S1P secretion, proliferation, and migration of breast cancer cells. Implantation of breast cancer cells overexpressing ABCC1, but not ABCB1, into the mammary fat pad markedly enhanced tumor growth, angiogenesis, and lymphangiogenesis with a concomitant increase in lymph node and lung metastases as well as shorter survival of mice. Interestingly, S1P exported via ABCC1 from breast cancer cells upregulated transcription of sphingosine kinase 1 (SPHK1), thus promoting more S1P formation. Finally, patients with breast cancers that express both activated SPHK1 and ABCC1 have significantly shorter disease-free survival. These findings suggest that export of S1P via ABCC1 functions in a malicious feed-forward manner to amplify the S1P axis involved in breast cancer progression and metastasis, which has important implications for prognosis of breast cancer patients and for potential therapeutic targets.
Implication: Multidrug resistant transporter ABCC1 and activation of SPHK1 in breast cancer worsen patient's survival by export of S1P to the tumor microenvironment to enhance key processes involved in cancer progression. Mol Cancer Res; 16(6); 1059–70. ©2018 AACR.
Nucleoside Diphosphate Kinase-3 (NME3) Enhances TLR5-Induced NFκB Activation
Authors: Flentie Kelly , Gonzalez Caleb , Kocher Brandon , Wang Yue , Zhu Hongtu , Marasa Jayne , Piwnica-Worms David 
Published: March 2018

Abstract
Bacterial flagellin is a potent activator of NFκB signaling, inflammation, and host innate immunity, and recent data indicate that flagellin represents a novel antitumor ligand acting through toll-like receptor 5 (TLR5) and the NFκB pathway to induce host immunity and aid in the clearance of tumor xenografts. To identify innate signaling components of TLR5 responsible for these antitumor effects, a loss-of-function high-throughput screen was employed utilizing carcinoma cells expressing a dynamic NFκB bioluminescent reporter stimulated by Salmonella typhimurium expressing flagellin. A live cell screen of a siRNA library targeting 691 known and predicted human kinases to identify novel tumor cell modulators of TLR5-induced NFκB activation uncovered several interesting positive and negative candidate regulators not previously recognized, including nucleoside diphosphate kinase 3 (NME3), characterized as an enhancer of signaling responses to flagellin. Targeted knockdown and overexpression assays confirmed the regulatory contribution of NME3 to TLR5-mediated NFκB signaling, mechanistically downstream of MyD88. Furthermore, Kaplan–Meier survival analysis showed that NME3 expression correlated highly with TLR5 expression in breast, lung, ovarian, and gastric cancers, and furthermore, high-level expression of NME3 increased overall survival for patients with breast, lung, and ovarian cancer, but the opposite in gastric cancer. Together, these data identify a previously unrecognized proinflammatory role for NME3 in signaling downstream of TLR5 that may potentiate cancer immunotherapies.
Implications: Proinflammatory signaling mediated by innate immunity engagement of flagellin-activated TLR5 in tumor cells results in antitumor effects through NME3 kinase, a positive downstream regulator of flagellin-mediated NFκB signaling, enhancing survival for several human cancers. Mol Cancer Res; 16(6); 986–99. ©2018 AACR.
FoxO3a Mediates the Inhibitory Effects of the Antiepileptic Drug Lamotrigine on Breast Cancer Growth
Authors: Pellegrino Michele , Rizza Pietro , Nigro Alessandra , Ceraldi Rosangela , Ricci Elena , Perrotta Ida , Aquila Saveria , Lanzino Marilena , Andò Sebastiano , Morelli Catia , Sisci Diego 
Published: March 2018

Abstract
Breast cancer is a complex and heterogeneous disease, with distinct histologic features dictating the therapy. Although the clinical outcome of breast cancer patients has been considerably improved, the occurrence of resistance to common endocrine and chemotherapy treatments remains the major cause of relapse and mortality. Thus, efforts in identifying new molecules to be employed in breast cancer therapy are needed. As a “faster” alternative to reach this aim, we evaluated whether lamotrigine, a broadly used anticonvulsant, could be “repurposed” as an antitumoral drug in breast cancer. Our data show that lamotrigine inhibits the proliferation, the anchorage-dependent, and independent cell growth in breast cancer cells (BCC), including hormone-resistant cell models. These effects were associated with cell-cycle arrest and modulation of related proteins (cyclin D1, cyclin E, p27Kip1, and p21Waf1/Cip1), all target genes of FoxO3a, an ubiquitous transcription factor negatively regulated by AKT. Lamotrigine also increases the expression of another FoxO3a target, PTEN, which, in turn, downregulates the PI3K/Akt signaling pathway, with consequent dephosphorylation, thus activation, of FoxO3a. Moreover, lamotrigine induces FoxO3a expression by increasing its transcription through FoxO3a recruitment on specific FHRE located on its own promoter, in an autoregulatory fashion. Finally, lamotrigine significantly reduced tumor growth in vivo, increasing FoxO3a expression.
Implications: The anticonvulsant drug lamotrigine shows strong antiproliferative activity on breast cancer, both in vitro and in vivo. Thus, drug repurposing could represent a valuable option for a molecularly targeted therapy in breast cancer patients. Mol Cancer Res; 16(6); 923–34. ©2018 AACR.
Identification of Cdk1–LATS–Pin1 as a Novel Signaling Axis in Anti-tubulin Drug Response of Cancer Cells
Authors: Yeung Benjamin , Khanal Prem , Mehta Virja , Trinkle-Mulcahy Laura , Yang Xiaolong 
Published: March 2018

Abstract
The Hippo pathway is a signaling cascade that plays important roles in organ size control, tumorigenesis, metastasis, stress response, stem cell differentiation, and renewal during development and tissue homeostasis and mechanotransduction. Recently, it has been observed that loss of the Hippo pathway core component LATS (large tumor suppressor) or overexpression of its downstream targets YAP and its paralog TAZ causes resistance of cancer cells to anti-tubulin drugs. However, YAP and TAZ mediates anti-tubulin drug-induced apoptosis independent of its upstream regulator LATS and the Hippo pathway. Thus, the underlying molecular mechanism of how LATS is involved in the anti-tubulin drug response remains unknown. Proteomic approaches, SILAC and BioID, were used to identify the isomerase Pin1 as a novel LATS-interacting protein after anti-tubulin drug treatment. Treatment with anti-tubulin drugs activated cyclin-dependent kinase 1 (CDK1), which phosphorylates LATS2 at five S/T-P motifs that functionally interact with the WW domain of Pin1 and inhibit its antiapoptotic function. Thus, these data identify Cdk1 and Pin1 as a novel upstream regulator and downstream mediator, respectively, of LATS in antitubulin drug response. Further studies on this novel Cdk1–LATS–Pin1 signaling axis will be important for understanding the molecular mechanisms of drug resistance and will provide useful information for targeting of this pathway in the future.
Implications: This study provides new insight on the molecular mechanism of anti-tubulin drug resistance and suggests novel therapeutic targets for drug-resistant cancers. Mol Cancer Res; 16(6); 1035–45. ©2018 AACR.
Long-Term Cognitive Decline After Newly Diagnosed Heart Failure
Authors: Hammond Christa A. , Blades Natalie J. , Chaudhry Sarwat I. , Dodson John A. , Longstreth W.T. , Heckbert Susan R. , Psaty Bruce M. , Arnold Alice M. , Dublin Sascha , Sitlani Colleen M. , Gardin Julius M. , Thielke Stephen M. , Nanna Michael G. , Gottesman Rebecca F. , Newman Anne B. , Thacker Evan L. 
Published: March 2018

Background:
Heart failure (HF) is associated with cognitive impairment. However, we know little about the time course of cognitive change after HF diagnosis, the importance of comorbid atrial fibrillation, or the role of ejection fraction. We sought to determine the associations of incident HF with rates of cognitive decline and whether these differed by atrial fibrillation status or reduced versus preserved ejection fraction.

Methods and Results:

Participants were 4864 men and women aged ≥65 years without a history of HF and free of clinical stroke in the CHS (Cardiovascular Health Study)—a community-based prospective cohort study in the United States, with cognition assessed annually from 1989/1990 through 1998/1999. We identified 496 participants with incident HF by review of hospital discharge summaries and Medicare claims data, with adjudication according to standard criteria. Global cognitive ability was measured by the Modified Mini-Mental State Examination. In adjusted models, 5-year decline in model-predicted mean Modified Mini-Mental State Examination score was 10.2 points (95% confidence interval, 8.6–11.8) after incident HF diagnosed at 80 years of age, compared with a mean 5-year decline of 5.8 points (95% confidence interval, 5.3–6.2) from 80 to 85 years of age without HF. The association was stronger at older ages than at younger ages, did not vary significantly in the presence versus absence of atrial fibrillation (
P
=0.084), and did not vary significantly by reduced versus preserved ejection fraction (
P
=0.734).

Conclusions:
Decline in global cognitive ability tends to be faster after HF diagnosis than without HF. Clinical and public health implications of this finding warrant further attention.