bluuebunny/crossref_metadata_2025_split huggingface dataset:
HER2 Signaling Drives DNA Anabolism and Proliferation through SRC-3 Phosphorylation and E2F1-Regulated Genes
Authors: Nikolai Bryan C. , Lanz Rainer B. , York Brian , Dasgupta Subhamoy , Mitsiades Nicholas , Creighton Chad J. , Tsimelzon Anna , Hilsenbeck Susan G. , Lonard David M. , Smith Carolyn L. , O'Malley Bert W. 
Published: February 2016

Abstract
Approximately 20% of early-stage breast cancers display amplification or overexpression of the ErbB2/HER2 oncogene, conferring poor prognosis and resistance to endocrine therapy. Targeting HER2+ tumors with trastuzumab or the receptor tyrosine kinase (RTK) inhibitor lapatinib significantly improves survival, yet tumor resistance and progression of metastatic disease still develop over time. Although the mechanisms of cytosolic HER2 signaling are well studied, nuclear signaling components and gene regulatory networks that bestow therapeutic resistance and limitless proliferative potential are incompletely understood. Here, we use biochemical and bioinformatic approaches to identify effectors and targets of HER2 transcriptional signaling in human breast cancer. Phosphorylation and activity of the Steroid Receptor Coactivator-3 (SRC-3) is reduced upon HER2 inhibition, and recruitment of SRC-3 to regulatory elements of endogenous genes is impaired. Transcripts regulated by HER2 signaling are highly enriched with E2F1 binding sites and define a gene signature associated with proliferative breast tumor subtypes, cell-cycle progression, and DNA replication. We show that HER2 signaling promotes breast cancer cell proliferation through regulation of E2F1-driven DNA metabolism and replication genes together with phosphorylation and activity of the transcriptional coactivator SRC-3. Furthermore, our analyses identified a cyclin-dependent kinase (CDK) signaling node that, when targeted using the CDK4/6 inhibitor palbociclib, defines overlap and divergence of adjuvant pharmacologic targeting. Importantly, lapatinib and palbociclib strictly block de novo synthesis of DNA, mostly through disruption of E2F1 and its target genes. These results have implications for rational discovery of pharmacologic combinations in preclinical models of adjuvant treatment and therapeutic resistance. Cancer Res; 76(6); 1463–75. ©2016 AACR.
IgG Glycome in Colorectal Cancer
Authors: Vučković Frano , Theodoratou Evropi , Thaçi Kujtim , Timofeeva Maria , Vojta Aleksandar , Štambuk Jerko , Pučić-Baković Maja , Rudd Pauline M. , Đerek Lovorka , Servis Dražen , Wennerström Annika , Farrington Susan M. , Perola Markus , Aulchenko Yurii , Dunlop Malcolm G. , Campbell Harry , Lauc Gordan 
Published: February 2016

AbstractPurpose: Alternative glycosylation has significant structural and functional consequences on IgG and consequently also on cancer immunosurveillance. Because of technological limitations, the effects of highly heritable individual variations and the differences in the dynamics of changes in IgG glycosylation on colorectal cancer were never investigated before.Experimental Design: Using recently developed high-throughput UPLC technology for IgG glycosylation analysis, we analyzed IgG glycome composition in 760 patients with colorectal cancer and 538 matching controls. Effects of surgery were evaluated in 28 patients sampled before and three times after surgery. A predictive model was built using regularized logistic regression and evaluated using a 10-cross validation procedure. Furthermore, IgG glycome composition was analyzed in 39 plasma samples collected before initial diagnosis of colorectal cancer.Results: We have found that colorectal cancer associates with decrease in IgG galactosylation, IgG sialylation and increase in core-fucosylation of neutral glycans with concurrent decrease of core-fucosylation of sialylated glycans. Although a model based on age and sex did not show discriminative power (AUC = 0.499), the addition of glycan variables into the model considerably increased the discriminative power of the model (AUC = 0.755). However, none of these differences were significant in the small set of samples collected before the initial diagnosis.Conclusions: Considering the functional relevance of IgG glycosylation for both tumor immunosurveillance and clinical efficacy of therapy with mAbs, individual variation in IgG glycosylation may turn out to be important for prediction of disease course or the choice of therapy, thus warranting further, more detailed studies of IgG glycosylation in colorectal cancer. Clin Cancer Res; 22(12); 3078–86. ©2016 AACR.
Targeting the Nuclear Import Receptor Kpnβ1 as an Anticancer Therapeutic
Authors: van der Watt Pauline J. , Chi Alicia , Stelma Tamara , Stowell Catherine , Strydom Erin , Carden Sarah , Angus Liselotte , Hadley Kate , Lang Dirk , Wei Wei , Birrer Michael J. , Trent John O. , Leaner Virna D. 
Published: February 2016

AbstractKaryopherin beta 1 (Kpnβ1) is a nuclear transport receptor that imports cargoes into the nucleus. Recently, elevated Kpnβ1 expression was found in certain cancers and Kpnβ1 silencing with siRNA was shown to induce cancer cell death. This study aimed to identify novel small molecule inhibitors of Kpnβ1, and determine their anticancer activity. An in silico screen identified molecules that potentially bind Kpnβ1 and Inhibitor of Nuclear Import-43, INI-43 (3-(1H-benzimidazol-2-yl)-1-(3-dimethylaminopropyl)pyrrolo[5,4-b]quinoxalin-2-amine) was investigated further as it interfered with the nuclear localization of Kpnβ1 and known Kpnβ1 cargoes NFAT, NFκB, AP-1, and NFY and inhibited the proliferation of cancer cells of different tissue origins. Minimum effect on the proliferation of noncancer cells was observed at the concentration of INI-43 that showed a significant cytotoxic effect on various cervical and esophageal cancer cell lines. A rescue experiment confirmed that INI-43 exerted its cell killing effects, in part, by targeting Kpnβ1. INI-43 treatment elicited a G2–M cell-cycle arrest in cancer cells and induced the intrinsic apoptotic pathway. Intraperitoneal administration of INI-43 significantly inhibited the growth of subcutaneously xenografted esophageal and cervical tumor cells. We propose that Kpnβ1 inhibitors could have therapeutic potential for the treatment of cancer. Mol Cancer Ther; 15(4); 560–73. ©2016 AACR.
Dissecting Therapeutic Resistance to ERK Inhibition
Authors: Jha Sharda , Morris Erick J. , Hruza Alan , Mansueto My Sam , Schroeder Gottfried K. , Arbanas Jaren , McMasters Daniel , Restaino Clifford R. , Dayananth Priya , Black Stuart , Elsen Nathaniel L. , Mannarino Anthony , Cooper Alan , Fawell Stephen , Zawel Leigh , Jayaraman Lata , Samatar Ahmed A. 
Published: February 2016

Abstract
The MAPK pathway is frequently activated in many human cancers, particularly melanomas. A single-nucleotide mutation in BRAF resulting in the substitution of glutamic acid for valine (V600E) causes constitutive activation of the downstream MAPK pathway. Selective BRAF and MEK inhibitor therapies have demonstrated remarkable antitumor responses in BRAFV600E-mutant melanoma patients. However, initial tumor shrinkage is transient and the vast majority of patients develop resistance. We previously reported that SCH772984, an ERK 1/2 inhibitor, effectively suppressed MAPK pathway signaling and cell proliferation in BRAF, MEK, and concurrent BRAF/MEK inhibitor-resistant tumor models. ERK inhibitors are currently being evaluated in clinical trials and, in anticipation of the likelihood of clinical resistance, we sought to prospectively model acquired resistance to SCH772984. Our data show that long-term exposure of cells to SCH772984 leads to acquired resistance, attributable to a mutation of glycine to aspartic acid (G186D) in the DFG motif of ERK1. Structural and biophysical studies demonstrated specific defects in SCH772984 binding to mutant ERK. Taken together, these studies describe the interaction of SCH772984 with ERK and identify a novel mechanism of ERK inhibitor resistance through mutation of a single residue within the DFG motif. Mol Cancer Ther; 15(4); 548–59. ©2016 AACR.
Novel Mps1 Kinase Inhibitors with Potent Antitumor Activity
Authors: Wengner Antje M. , Siemeister Gerhard , Koppitz Marcus , Schulze Volker , Kosemund Dirk , Klar Ulrich , Stoeckigt Detlef , Neuhaus Roland , Lienau Philip , Bader Benjamin , Prechtl Stefan , Raschke Marian , Frisk Anna-Lena , von Ahsen Oliver , Michels Martin , Kreft Bertolt , von Nussbaum Franz , Brands Michael , Mumberg Dominik , Ziegelbauer Karl 
Published: February 2016

Abstract
Monopolar spindle 1 (Mps1) has been shown to function as the key kinase that activates the spindle assembly checkpoint (SAC) to secure proper distribution of chromosomes to daughter cells. Here, we report the structure and functional characterization of two novel selective Mps1 inhibitors, BAY 1161909 and BAY 1217389, derived from structurally distinct chemical classes. BAY 1161909 and BAY 1217389 inhibited Mps1 kinase activity with IC50 values below 10 nmol/L while showing an excellent selectivity profile. In cellular mechanistic assays, both Mps1 inhibitors abrogated nocodazole-induced SAC activity and induced premature exit from mitosis (“mitotic breakthrough”), resulting in multinuclearity and tumor cell death. Both compounds efficiently inhibited tumor cell proliferation in vitro (IC50 nmol/L range). In vivo, BAY 1161909 and BAY 1217389 achieved moderate efficacy in monotherapy in tumor xenograft studies. However, in line with its unique mode of action, when combined with paclitaxel, low doses of Mps1 inhibitor reduced paclitaxel-induced mitotic arrest by the weakening of SAC activity. As a result, combination therapy strongly improved efficacy over paclitaxel or Mps1 inhibitor monotreatment at the respective MTDs in a broad range of xenograft models, including those showing acquired or intrinsic paclitaxel resistance. Both Mps1 inhibitors showed good tolerability without adding toxicity to paclitaxel monotherapy. These preclinical findings validate the innovative concept of SAC abrogation for cancer therapy and justify clinical proof-of-concept studies evaluating the Mps1 inhibitors BAY 1161909 and BAY 1217389 in combination with antimitotic cancer drugs to enhance their efficacy and potentially overcome resistance. Mol Cancer Ther; 15(4); 583–92. ©2016 AACR.
Chemical Inhibition of Wild-Type p53-Induced Phosphatase 1 (WIP1/PPM1D) by GSK2830371 Potentiates the Sensitivity to MDM2 Inhibitors in a p53-Dependent Manner
Authors: Esfandiari Arman , Hawthorne Thomas A. , Nakjang Sirintra , Lunec John 
Published: February 2016

Abstract
Sensitivity to MDM2 inhibitors is widely different among responsive TP53 wild-type cell lines and tumors. Understanding the determinants of MDM2 inhibitor sensitivity is pertinent for their optimal clinical application. Wild-type p53-inducible phosphatase-1 (WIP1) encoded by PPM1D, is activated, gained/amplified in a range of TP53 wild-type malignancies, and is involved in p53 stress response homeostasis. We investigated cellular growth/proliferation of TP53 wild-type and matched mutant/null cell line pairs, differing in PPM1D genetic status, in response to Nutlin-3/RG7388 ± a highly selective WIP1 inhibitor, GSK2830371. We also assessed the effects of GSK2830371 on MDM2 inhibitor-induced p53Ser15 phosphorylation, p53-mediated global transcriptional activity, and apoptosis. The investigated cell line pairs were relatively insensitive to single-agent GSK2830371. However, a non–growth-inhibitory dose of GSK2830371 markedly potentiated the response to MDM2 inhibitors in TP53 wild-type cell lines, most notably in those harboring PPM1D-activating mutations or copy number gain (up to 5.8-fold decrease in GI50). Potentiation also correlated with significant increase in MDM2 inhibitor–induced cell death endpoints that were preceded by a marked increase in a WIP1 negatively regulated substrate, phosphorylated p53Ser15, known to increase p53 transcriptional activity. Microarray-based gene expression analysis showed that the combination treatment increases the subset of early RG7388-induced p53 transcriptional target genes. These findings demonstrate that potent and selective WIP1 inhibition potentiates the response to MDM2 inhibitors in TP53 wild-type cells, particularly those with PPM1D activation or gain, while highlighting the mechanistic importance of p53Ser15 and its potential use as a biomarker for response to this combination regimen. Mol Cancer Ther; 15(3); 379–91. ©2016 AACR.
The Role of CD44 in Glucose Metabolism in Prostatic Small Cell Neuroendocrine Carcinoma
Authors: Li Wei , Cohen Alexa , Sun Yin , Squires Jill , Braas Daniel , Graeber Thomas G. , Du Lin , Li Gang , Li Zhen , Xu Xiang , Chen Xufeng , Huang Jiaoti 
Published: February 2016

Abstract
While prostatic adenocarcinomas are relatively indolent, some patients with advanced adenocarcinomas recur with small cell neuroendocrine carcinoma which is highly aggressive and lethal. Because glycolysis is a feature of malignancy and the degree of glycolysis generally correlates with tumor aggressiveness, we wanted to compare the metabolic differences and the molecular mechanisms involved between the two tumor types. In this study, and based on previous characterization, LNCaP and PC-3 prostate cancer cell lines were selected as models of prostatic adenocarcinoma and small cell neuroendocrine carcinoma, respectively. In addition to measuring glucose consumption, lactate secretion, and reactive oxygen species (ROS) levels, we performed metabolic profiling in these two model systems. The role of CD44 was studied by RNAi and lentivirus-mediated overexpression. Expression of key enzymes in glycolysis was studied using human tissue microarrays containing benign prostate, adenocarcinoma, and small cell neuroendocrine carcinoma. Results showed that glycolytic features of PC-3 cells were higher than that of LNCaP cells. PFKFB4 was overexpressed in human small cell carcinoma tissue versus adenocarcinoma tissue. CD44 regulated glucose metabolism, intracellular ROS, and cell proliferation in PC-3 cells. Inhibition of CD44 also sensitized PC-3 cells to carboplatin. In conclusion, this study suggests different pathways of glucose metabolism contribute to the disparate biologic behaviors of these two tumor types.
Implications: CD44 is an important regulator of glucose metabolism in small cell neuroendocrine carcinoma and may be an important therapeutic target. Mol Cancer Res; 14(4); 344–53. ©2016 AACR.
The Complex Role of Neutrophils in Tumor Angiogenesis and Metastasis
Authors: Liang Wei , Ferrara Napoleone 
Published: February 2016

Abstract
Chronic inflammation fosters cancer development and progression and also modulates tumor responses to anticancer therapies. Neutrophils are key effector cells in innate immunity and are known to play a critical role in various inflammatory disorders. However, the functions of neutrophils in cancer pathogenesis have been largely neglected until recently and still remain poorly characterized compared with other immune cells in the tumor microenvironment. We highlight recent findings on the mechanisms by which tumor cells, in cooperation with tumor-associated stromal cells, induce expansion, recruitment, and polarization of neutrophils. We also review the multifaceted roles that neutrophils play in different aspects of cancer development and progression, with an emphasis on tumor angiogenesis and metastasis. Cancer Immunol Res; 4(2); 83–91. ©2016 AACR.
Microhabitat Influence on Growth Distribution Pattern of Ramin (Gonystylus bancanus) in Siak, Riau Province
Authors: Pribadi Didit Okta , Kusuma Yayan Wahyu C. 
Published: February 2016

Plant growth distribution patterns are influenced by distribution of habitat characteristics, capacity of adaptation, and association with other plant species or animals. Global climate change has serious impact on the changing habitat which eventually threat plants. This study has objectives: (1) to measure plant growth dependence on their microhabitat; (2) to define microhabitat variables that influence growth significantly; and (3) to formulate suitable conservation efforts for certain species.Â Gonystylus bancanus is one of major timber species that has been facing high exploitation in Indonesia. This species is usually found on specific â€œpeat swampsâ€ ecosystem. Data were collected through primary surveys in Riau Province.Â Data analyses were peformed by clustering the adult base on variable of height and width of basalt area, and describing distribution pattern of the cluster. Then, Discriminant Function Analysis was used to overlay the cluster with the distribution of microhabitat characteristic consisting of altitude, slope, soil humidity, soil pH, peat depth and percentage of canopy cover. The result shows, distribution of microhabitat match with 67.4% of height distribution and 78.3% of width distribution of basalt area.Â Altitude and canopy cover percentage have significant correlation with height distribution (Î±=0.05).Â Meanwhile, altitude, canopy cover, and slope have significant correlation with width distribution of basalt area (Î±=0.1).Â However, peat depth variable shows interesting pattern since shallower peat depth are followed by wider of basalt area. High correlation between plant growth and its microhabitat suggests that in-situ conservation is better strategy than ex-situ conservation and this is particularly true for Gonystylus bancanus conservation management
Dissociable Effects of Dopamine on the Initial Capture and the Reactive Inhibition of Impulsive Actions in Parkinson's Disease
Authors: van Wouwe Nelleke C. , Kanoff Kristen E. , Claassen Daniel O. , Spears Charis A. , Neimat Joseph , van den Wildenberg Wery P. M. , Wylie Scott A. 
Published: February 2016

Abstract
Dopamine plays a key role in a range of action control processes. Here, we investigate how dopamine depletion caused by Parkinson disease (PD) and how dopamine restoring medication modulate the expression and suppression of unintended action impulses. Fifty-five PD patients and 56 healthy controls (HCs) performed an action control task (Simon task). PD patients completed the task twice, once withdrawn from dopamine medications and once while taking their medications. PD patients experienced similar susceptibility to making fast errors in conflict trials as HCs, but PD patients were less proficient compared with HCs at suppressing incorrect responses. Administration of dopaminergic medications had no effect on impulsive error rates but significantly improved the proficiency of inhibitory control in PD patients. We found no evidence that dopamine precursors and agonists affected action control in PD differently. Additionally, there was no clear evidence that individual differences in baseline action control (off dopamine medications) differentially responded to dopamine medications (i.e., no evidence for an inverted U-shaped performance curve). Together, these results indicate that dopamine depletion and restoration therapies directly modulate the reactive inhibitory control processes engaged to suppress interference from the spontaneously activated response impulses but exert no effect on an individual's susceptibility to act on impulses.
Upper Beta Band Oscillations in Human Premotor Cortex Encode Subjective Choices in a Vibrotactile Comparison Task
Authors: Herding Jan , Spitzer Bernhard , Blankenburg Felix 
Published: February 2016

AbstractComparisons of sequentially presented vibrotactile frequencies have been extensively studied using electrophysiological recordings in nonhuman primates. Although neural signatures for working memory aspects of such tasks were recently also identified in human oscillatory EEG activity, homologue correlates of the comparison process are yet unknown. Here, we recorded EEG activity while participants decided which of two sequentially presented vibrotactile stimuli had a higher frequency. Because choices in this type of task are known to be systematically biased by the time-order effect, we applied Bayesian modeling to account for individual choice behavior. Using model-based EEG analysis, we found that upper beta band amplitude (∼20–30 Hz) was modulated by participants' choices. The modulation emerged ∼750 msec before a behavioral response was given and was source-localized to premotor areas.Importantly, the choice-dependent modulation of beta band amplitude was invariant to different motor response mappings and reflected the categorical outcome of the subjective comparison between the two frequencies. Consistently, this pattern was evident for both correct and incorrect trials, indicating that the beta band amplitude mirrors the internal representation of the comparison outcome. Our data complement previous findings in nonhuman primates and corroborate that the beta band activity in premotor areas reflects the categorical outcome of a sensory comparison prior to translation into an effector-specific motor command.
The Lost Map of Matteo de’ Pasti: Cartography, Diplomacy, and Espionage in the Renaissance Adriatic
Authors: Roberts Sean 
Published: February 2016

The sculptor Matteo de’ Pasti left Rimini in 1461 bound for Ottoman Sultan Mehmed ii’s court at Constantinople with gifts from Sigismondo Malatesta. When his ship stopped in Crete, Matteo was detained by the island’s Venetian authorities on charges of espionage. Contemporaries report that he carried with him a map, now lost, but assumed to be a strategically valuable one of the Adriatic. Discussions of Matteo’s mission claim that it attempted to supply the sultan with essential intelligence for an invasion of Italy.
Yet, this spy story finds little confirmation in historical sources. Indeed, our knowledge of the map’s very existence derives from the reports of Sigismondo’s enemies. I examine this prominent embassy as a means to reconsider attitudes toward the utility of maps in the scholarly imagination and the role of art and artists in early modern diplomacy. Revisiting documentary evidence and the claims scholars have grounded therein, I explore how we have told the tale of this journey in ways that conform to our own shifting expectations, sometimes at the expense of fidelity to the sources at hand. Overwhelming focus on the absent map has obscured both Matteo’s role as envoy and the distinctive place of evidently skillful and delightful visual culture in this attempted exchange.