bluuebunny/crossref_metadata_2025_split huggingface dataset:
Targeted Destruction of c-Myc by an Engineered Ubiquitin Ligase Suppresses Cell Transformation and Tumor Formation
Authors: Hatakeyama Shigetsugu , Watanabe Masashi , Fujii Yo , Nakayama Keiichi I. 
Published: July 2017

Abstract
Given that expression of c-Myc is up-regulated in many human malignancies, targeted inactivation of this oncoprotein is a potentially effective strategy for cancer treatment. The ubiquitin-proteasome pathway of protein degradation is highly specific and can be engineered to achieve the elimination of undesirable proteins such as oncogene products. We have now generated a fusion protein (designated Max-U) that is composed both of Max, which forms a heterodimer with c-Myc, and of CHIP, which is a U box-type ubiquitin ligase (E3). Max-U physically interacted with c-Myc in transfected cells and promoted the ubiquitylation of c-Myc in vitro. It also reduced the stability of c-Myc in vivo, resulting in suppression of transcriptional activity dependent on c-Myc. Expression of Max-U reduced both the abundance of endogenous c-Myc in and the proliferation rate of a Burkitt lymphoma cell line. Furthermore, expression of Max-U but not that of a catalytically inactive mutant thereof markedly inhibited both the anchorage-independent growth in vitro of NIH 3T3 cells that overexpress c-Myc as well as tumor formation by these cells in nude mice. These findings indicate that the targeted destruction of c-Myc by an artificial E3 may represent an effective therapeutic strategy for certain human malignancies.
Somatic Mutations of the Protein Kinase Gene Family in Human Lung Cancer
Authors: Davies Helen , Hunter Chris , Smith Raffaella , Stephens Philip , Greenman Chris , Bignell Graham , Teague Jon , Butler Adam , Edkins Sarah , Stevens Claire , Parker Adrian , O'Meara Sarah , Avis Tim , Barthorpe Syd , Brackenbury Lisa , Buck Gemma , Clements Jody , Cole Jennifer , Dicks Ed , Edwards Ken , Forbes Simon , Gorton Matthew , Gray Kristian , Halliday Kelly , Harrison Rachel , Hills Katy , Hinton Jonathon , Jones David , Kosmidou Vivienne , Laman Ross , Lugg Richard , Menzies Andrew , Perry Janet , Petty Robert , Raine Keiran , Shepherd Rebecca , Small Alexandra , Solomon Helen , Stephens Yvonne , Tofts Calli , Varian Jennifer , Webb Anthony , West Sofie , Widaa Sara , Yates Andrew , Brasseur Francis , Cooper Colin S. , Flanagan Adrienne M. , Green Anthony , Knowles Maggie , Leung Suet Y. , Looijenga Leendert H.J. , Malkowicz Bruce , Pierotti Marco A. , Teh Bin T. , Yuen Siu T. , Lakhani Sunil R. , Easton Douglas F. , Weber Barbara L. , Goldstraw Peter , Nicholson Andrew G. , Wooster Richard , Stratton Michael R. , Futreal P. Andrew 
Published: July 2017

Abstract
Protein kinases are frequently mutated in human cancer and inhibitors of mutant protein kinases have proven to be effective anticancer drugs. We screened the coding sequences of 518 protein kinases (∼1.3 Mb of DNA per sample) for somatic mutations in 26 primary lung neoplasms and seven lung cancer cell lines. One hundred eighty-eight somatic mutations were detected in 141 genes. Of these, 35 were synonymous (silent) changes. This result indicates that most of the 188 mutations were “passenger” mutations that are not causally implicated in oncogenesis. However, an excess of ∼40 nonsynonymous substitutions compared with that expected by chance (P = 0.07) suggests that some nonsynonymous mutations have been selected and are contributing to oncogenesis. There was considerable variation between individual lung cancers in the number of mutations observed and no mutations were found in lung carcinoids. The mutational spectra of most lung cancers were characterized by a high proportion of C:G &gt; A:T transversions, compatible with the mutagenic effects of tobacco carcinogens. However, one neuroendocrine cancer cell line had a distinctive mutational spectrum reminiscent of UV-induced DNA damage. The results suggest that several mutated protein kinases may be contributing to lung cancer development, but that mutations in each one are infrequent.
CIB2 Negatively Regulates Oncogenic Signaling in Ovarian Cancer via Sphingosine Kinase 1
Authors: Zhu Wenying , Jarman Kate E. , Lokman Noor A. , Neubauer Heidi A. , Davies Lorena T. , Gliddon Briony L. , Taing Houng , Moretti Paul A.B. , Oehler Martin K. , Pitman Melissa R. , Pitson Stuart M. 
Published: July 2017

Abstract
Sphingosine kinase 1 (SK1) is a key regulator of the cellular balance between proapoptotic and prosurvival sphingolipids. Oncogenic signaling by SK1 relies on its localization to the plasma membrane, which is mediated by the calcium and integrin binding protein CIB1 via its Ca2+-myristoyl switch function. Here we show that another member of the CIB family, CIB2, plays a surprisingly opposite role to CIB1 in the regulation of SK1 signaling. CIB2 bound SK1 on the same site as CIB1, yet it lacks the Ca2+-myristoyl switch function. As a result, CIB2 blocked translocation of SK1 to the plasma membrane and inhibited its subsequent signaling, which included sensitization to TNFα-induced apoptosis and inhibition of Ras-induced neoplastic transformation. CIB2 was significantly downregulated in ovarian cancer and low CIB2 expression was associated with poor prognosis in ovarian cancer patients. Notably, reintroduction of CIB2 in ovarian cancer cells blocked plasma membrane localization of endogenous SK1, reduced in vitro neoplastic growth and tumor growth in mice, and suppressed cell motility and invasiveness both in vitro and in vivo. Consistent with the in vitro synergistic effects between the SK1-specific inhibitor SK1-I and standard chemotherapeutics, expression of CIB2 also sensitized ovarian cancer cells to carboplatin. Together, these findings identify CIB2 as a novel endogenous suppressor of SK1 signaling and potential prognostic marker and demonstrate the therapeutic potential of SK1 in this gynecologic malignancy. Cancer Res; 77(18); 4823–34. ©2017 AACR.
Overexpressed P-Cadherin/CDH3 Promotes Motility of Pancreatic Cancer Cells by Interacting with p120ctn and Activating Rho-Family GTPases
Authors: Taniuchi Keisuke , Nakagawa Hidewaki , Hosokawa Masayo , Nakamura Toru , Eguchi Hidetoshi , Ohigashi Hiroaki , Ishikawa Osamu , Katagiri Toyomasa , Nakamura Yusuke 
Published: July 2017

Abstract
P-Cadherin/CDH3 belongs to the family of classic cadherins that are engaged in various cellular activities including motility, invasion, and signaling of tumor cells, in addition to cell adhesion. However, the biological roles of P-cadherin itself are not fully characterized. Based on information derived from a previous genome-wide cDNA microarray analysis of microdissected pancreatic ductal adenocarcinoma (PDAC), we focused on P-cadherin as one of the genes most strongly overexpressed in the great majority of PDACs. To investigate the consequences of overexpression of P-cadherin in terms of pancreatic carcinogenesis and tumor progression, we used a P-cadherin–deficient PDAC cell line, Panc-1, to construct a cell line (Panc1-CDH3) that stably overexpressed P-cadherin. Induction of P-cadherin in Panc1-CDH3 increased the motility of the cancer cells, but a blocking antibody against P-cadherin suppressed the motility in vitro. Overexpression of P-cadherin was strongly associated with cytoplasmic accumulation of one of the catenins, p120ctn, and cadherin switching in PDAC cells. Moreover, P-cadherin–dependent activation of cell motility was associated with activation of Rho GTPases, Rac1 and Cdc42, through accumulation of p120ctn in cytoplasm and cadherin switching. These findings suggest that overexpression of P-cadherin is likely to be related to the biological aggressiveness of PDACs; blocking of P-cadherin activity or its associated signaling could be a novel therapeutic approach for treatment of aggressive pancreatic cancers.
Magnetic Resonance Spectroscopy Monitoring of Mitogen-Activated Protein Kinase Signaling Inhibition
Authors: Beloueche-Babari Mounia , Jackson L. Elizabeth , Al-Saffar Nada M.S. , Workman Paul , Leach Martin O. , Ronen Sabrina M. 
Published: July 2017

AbstractSeveral mitogen-activated protein kinase (MAPK) signaling inhibitors are currently undergoing clinical trial as part of novel mechanism-based anticancer treatment strategies. This study was aimed at detecting biomarkers of MAPK signaling inhibition in human breast and colon carcinoma cells using magnetic resonance spectroscopy. We investigated the effect of the prototype MAPK kinase inhibitor U0126 on the 31P-MR spectra of MDA-MB-231, MCF-7 and Hs578T breast, and HCT116 colon carcinoma cells. Treatment of MDA-MB-231 cells with 50 μmol/L U0126 for 2, 4, 8, 16, 24, 32, and 40 hours caused inhibition of extracellular signal–regulated kinases (ERK1/2) phosphorylation from 2 hours onwards. 31P-MR spectra of extracted cells indicated that this was associated with a significant drop in phosphocholine levels to 78 ± 8% at 8 hours, 74 ± 8% at 16 hours, 66 ± 7% at 24 hours, 71 ± 10% at 32 hours, and 65 ± 10% at 40 hours post-treatment. In contrast, the lower concentration of 10 μmol/L U0126 for 40 hours had no significant effect on either P-ERK1/ 2 or phosphocholine levels in MDA-MB-231 cells. Depletion of P-ERK1/2 in MCF-7 and Hs578T cells with 50 μmol/L U0126 also produced a drop in phosphocholine levels to 51 ± 17% at 40 hours and 23 ± 12% at 48 hours, respectively. Similarly, in HCT116 cells, inhibition with 30 μmol/L U0126 caused depletion of P-ERK1/2 and a decrease in phosphocholine levels to 80 ± 9% at 16 hours and 61 ± 4% at 24 hours post-treatment. The reduction in phosphocholine in MDA-MB-231 and HCT116 cells correlated positively with the drop in P-ERK1/2 levels. Our results show that MAPK signaling inhibition with U0126 is associated with a time-dependent decrease in cellular phosphocholine levels. Thus, phosphocholine has potential as a noninvasive pharmacodynamic marker for monitoring MAPK signaling blockade.
Decitabine Priming Enhances Mucin 1 Inhibition Mediated Disruption of Redox Homeostasis in Cutaneous T-Cell Lymphoma
Authors: Jain Salvia , Washington Abigail , Leaf Rebecca Karp , Bhargava Parul , Clark Rachael A. , Kupper Thomas S. , Stroopinsky Dina , Pyzer Athalia , Cole Leandra , Nahas Myrna , Apel Arie , Rosenblatt Jacalyn , Arnason Jon , Kufe Donald , Avigan David 
Published: July 2017

Abstract
Cutaneous T-cell lymphoma (CTCL) is a heterogeneous neoplasm and patients with relapsed/refractory disease exhibit resistance to standard therapies. We have previously demonstrated that the Mucin 1 C-terminal subunit (MUC1-C) plays a critical role in protection from oxidative stress in CTCL cells. Targeting of MUC1-C with a pharmacologic inhibitor, GO-203, was associated with apoptosis in CTCL. However, disease responses were incomplete underscoring the need for combinatorial strategies that could exploit the vulnerability of CTCL cells to oxidative signals. Cell lines, primary samples, and xenograft models of CTCL were used to assess synergy of GO-203 with decitabine, a hypomethylating agent. Present studies demonstrate that exposure of CTCL cells to decitabine in combination with GO-203, increased the generation of reactive oxygen species (ROS) levels and decreased levels of scavenger molecules, NADP, NADPH, glutathione, and TIGAR, critical to intracellular redox homeostasis. Dual exposure to GO-203 and decitabine resulted in marked downregulation of DNA methyl transferases demonstrating significant synergy of these agents in inducing global and gene specific hypomethylation. Accordingly, treatment with decitabine and GO-203 upregulated the ROS generating enzymes, NADPH oxidase 4 and dual oxidase 2 potentially due to their effect on epigenomic regulation of these proteins. In concert with these findings, exposure to decitabine and GO-203 resulted in heightened apoptotic death in CTCL cell lines, patient-derived primary samples and in a murine xenograft model. These findings indicate that decitabine intensifies MUC1-C inhibition induced redox imbalance and provides a novel combination of targeted and epigenetic agents for patients with CTCL. Mol Cancer Ther; 16(10); 2304–14. ©2017 AACR.
JAK1/STAT3 Activation through a Proinflammatory Cytokine Pathway Leads to Resistance to Molecularly Targeted Therapy in Non–Small Cell Lung Cancer
Authors: Shien Kazuhiko , Papadimitrakopoulou Vassiliki A. , Ruder Dennis , Behrens Carmen , Shen Li , Kalhor Neda , Song Juhee , Lee J. Jack , Wang Jing , Tang Ximing , Herbst Roy S. , Toyooka Shinichi , Girard Luc , Minna John D. , Kurie Jonathan M. , Wistuba Ignacio I. , Izzo Julie G. 
Published: July 2017

Abstract
Molecularly targeted drugs have yielded significant therapeutic advances in oncogene-driven non–small cell lung cancer (NSCLC), but a majority of patients eventually develop acquired resistance. Recently, the relation between proinflammatory cytokine IL6 and resistance to targeted drugs has been reported. We investigated the functional contribution of IL6 and the other members of IL6 family proinflammatory cytokine pathway to resistance to targeted drugs in NSCLC cells. In addition, we examined the production of these cytokines by cancer cells and cancer-associated fibroblasts (CAF). We also analyzed the prognostic significance of these molecule expressions in clinical NSCLC samples. In NSCLC cells with acquired resistance to targeted drugs, we observed activation of the IL6–cytokine pathway and STAT3 along with epithelial-to-mesenchymal transition (EMT) features. In particular, IL6 family cytokine oncostatin-M (OSM) induced a switch to the EMT phenotype and protected cells from targeted drug-induced apoptosis in OSM receptors (OSMRs)/JAK1/STAT3–dependent manner. The cross-talk between NSCLC cells and CAFs also preferentially activated the OSM/STAT3 pathway via a paracrine mechanism and decreased sensitivity to targeted drugs. The selective JAK1 inhibitor filgotinib effectively suppressed STAT3 activation and OSMR expression, and cotargeting inhibition of the oncogenic pathway and JAK1 reversed resistance to targeted drugs. In the analysis of clinical samples, OSMR gene expression appeared to be associated with worse prognosis in patients with surgically resected lung adenocarcinoma. Our data suggest that the OSMRs/JAK1/STAT3 axis contributes to resistance to targeted drugs in oncogene-driven NSCLC cells, implying that this pathway could be a therapeutic target. Mol Cancer Ther; 16(10); 2234–45. ©2017 AACR.
Vessel-Targeted Chemophototherapy with Cationic Porphyrin-Phospholipid Liposomes
Authors: Luo Dandan , Geng Jumin , Li Nasi , Carter Kevin A. , Shao Shuai , Atilla-Gokcumen G. Ekin , Lovell Jonathan F. 
Published: July 2017

Abstract
Cationic liposomes have been used for targeted drug delivery to tumor blood vessels, via mechanisms that are not fully elucidated. Doxorubicin (Dox)-loaded liposomes were prepared that incorporate a cationic lipid; 1,2-dioleoyl-3-trimethylammonium-propane (DOTAP), along with a small amount of porphyrin-phospholipid (PoP). Near-infrared (NIR) light caused release of entrapped Dox via PoP-mediated DOTAP photo-oxidation. The formulation was optimized to enable extremely rapid NIR light-triggered Dox release (i.e., in 15 seconds), while retaining reasonable serum stability. In vitro, cationic PoP liposomes readily bound to both MIA PaCa-2 human pancreatic cancer cells and human vascular endothelial cells. When administered intravenously, cationic PoP liposomes were cleared from circulation within minutes, with most accumulation in the liver and spleen. Fluorescence imaging revealed that some cationic PoP liposomes also localized at the tumor blood vessels. Compared with analogous neutral liposomes, strong tumor photoablation was induced with a single treatment of cationic PoP liposomes and laser irradiation (5 mg/kg Dox and 100 J/cm2 NIR light). Unexpectedly, empty cationic PoP liposomes (lacking Dox) induced equally potent antitumor phototherapeutic effects as the drug loaded ones. A more balanced chemo- and phototherapeutic response was subsequently achieved when antitumor studies were repeated using higher drug dosing (7 mg/kg Dox) and a low fluence phototreatment (20 J/cm2 NIR light). These results demonstrate the feasibility of vessel-targeted chemophototherapy using cationic PoP liposomes and also illustrate synergistic considerations. Mol Cancer Ther; 16(11); 2452–61. ©2017 AACR.
Inclusion of a Genetic Risk Score into a Validated Risk Prediction Model for Colorectal Cancer in Japanese Men Improves Performance
Authors: Iwasaki Motoki , Tanaka-Mizuno Sachiko , Kuchiba Aya , Yamaji Taiki , Sawada Norie , Goto Atsushi , Shimazu Taichi , Sasazuki Shizuka , Wang Hansong , Marchand Loïc Le , Tsugane Shoichiro 
Published: July 2017

Abstract
We previously developed and validated a risk prediction model for colorectal cancer in Japanese men using modifiable risk factors. To further improve risk prediction, we evaluated the degree of improvement obtained by adding a genetic risk score (GRS) using genome-wide association study (GWAS)-identified risk variants to our validated model. We examined the association between 36 risk variants identified by GWAS and colorectal cancer risk using a weighted Cox proportional hazards model in a nested case–control study within the Japan Public Health Center-based Prospective Study. GRS was constructed using six variants associated with risk in this study of the 36 tested. We assessed three models: a nongenetic model that included the same variables used in our previously validated model; a genetic model that used GRS; and an inclusive model, which included both. The c-statistic, integrated discrimination improvement (IDI), and net reclassification improvement (NRI) were calculated by the 5-fold cross-validation method. We estimated 10-year absolute risks for developing colorectal cancer. A statistically significant association was observed between the weighted GRS and colorectal cancer risk. The mean c-statistic for the inclusive model (0.66) was slightly greater than that for the nongenetic model (0.60). Similarly, the mean IDI and NRI showed improvement when comparing the nongenetic and inclusive models. These models for colorectal cancer were well calibrated. The addition of GRS using GWAS-identified risk variants to our validated model for Japanese men improved the prediction of colorectal cancer risk. Cancer Prev Res; 10(9); 535–41. ©2017 AACR.
Tumor Evolution as a Therapeutic Target
Authors: Amirouchene-Angelozzi Nabil , Swanton Charles , Bardelli Alberto 
Published: July 2017

Abstract
Recent technological advances in the field of molecular diagnostics (including blood-based tumor genotyping) allow the measurement of clonal evolution in patients with cancer, thus adding a new dimension to precision medicine: time. The translation of this new knowledge into clinical benefit implies rethinking therapeutic strategies. In essence, it means considering as a target not only individual oncogenes but also the evolving nature of human tumors. Here, we analyze the limitations of targeted therapies and propose approaches for treatment within an evolutionary framework.
Significance: Precision cancer medicine relies on the possibility to match, in daily medical practice, detailed genomic profiles of a patient's disease with a portfolio of drugs targeted against tumor-specific alterations. Clinical blockade of oncogenes is effective but only transiently; an approach to monitor clonal evolution in patients and develop therapies that also evolve over time may result in improved therapeutic control and survival outcomes. Cancer Discov; 7(8); 805–17. ©2017 AACR.
Superenhancer Analysis Defines Novel Epigenomic Subtypes of Non-APL AML, Including an RARα Dependency Targetable by SY-1425, a Potent and Selective RARα Agonist
Authors: McKeown Michael R. , Corces M. Ryan , Eaton Matthew L. , Fiore Chris , Lee Emily , Lopez Jeremy T. , Chen Mei Wei , Smith Darren , Chan Steven M. , Koenig Julie L. , Austgen Kathryn , Guenther Matthew G. , Orlando David A. , Lovén Jakob , Fritz Christian C. , Majeti Ravindra 
Published: July 2017

Abstract
We characterized the enhancer landscape of 66 patients with acute myeloid leukemia (AML), identifying 6 novel subgroups and their associated regulatory loci. These subgroups are defined by their superenhancer (SE) maps, orthogonal to somatic mutations, and are associated with distinct leukemic cell states. Examination of transcriptional drivers for these epigenomic subtypes uncovers a subset of patients with a particularly strong SE at the retinoic acid receptor alpha (RARA) gene locus. The presence of a RARA SE and concomitant high levels of RARA mRNA predisposes cell lines and ex vivo models to exquisite sensitivity to a selective agonist of RARα, SY-1425 (tamibarotene). Furthermore, only AML patient-derived xenograft (PDX) models with high RARA mRNA were found to respond to SY-1425. Mechanistically, we show that the response to SY-1425 in RARA-high AML cells is similar to that of acute promyelocytic leukemia treated with retinoids, characterized by the induction of known retinoic acid response genes, increased differentiation, and loss of proliferation.
Significance: We use the SE landscape of primary human AML to elucidate transcriptional circuitry and identify novel cancer vulnerabilities. A subset of patients were found to have an SE at RARA, which is predictive for response to SY-1425, a potent and selective RARα agonist, in preclinical models, forming the rationale for its clinical investigation in biomarker-selected patients. Cancer Discov; 7(10); 1136–53. ©2017 AACR.
See related commentary by Wang and Aifantis, p. 1065..
This article is highlighted in the In This Issue feature, p. 1047
Femoral Artery Atherosclerosis Is Associated With Physical Function Across the Spectrum of the Ankle‐Brachial Index: The San Diego Population Study
Authors: Wassel Christina L. , Ellis Alicia M. , Suder Natalie C. , Barinas‐Mitchell Emma , Rifkin Dena E. , Forbang Nketi I. , Denenberg Julie O. , Marasco Antoinette M. , McQuaide Belinda J. , Jenny Nancy S. , Allison Matthew A. , Ix Joachim H. , Criqui Michael H. 
Published: July 2017

Background
The ankle‐brachial index (ABI) is inadequate to detect early‐stage atherosclerotic disease, when interventions to prevent functional decline may be the most effective. We determined associations of femoral artery atherosclerosis with physical functioning, across the spectrum of the ABI, and within the normal ABI range.

Methods and Results

In 2007–2011, 1103 multiethnic men and women participated in the San Diego Population Study, and completed all components of the summary performance score. Using Doppler ultrasound, superficial and common femoral intima media thickness and plaques were ascertained. Logistic regression was used to assess associations of femoral atherosclerosis with the summary performance score and its individual components. Models were adjusted for demographics, lifestyle factors, comorbidities, lipids, and kidney function. In adjusted models, among participants with a normal‐range ABI (1.00–1.30), the highest tertile of superficial intima media thickness was associated with lower odds of a perfect summary performance score of 12 (odds ratio=0.56 [0.36, 0.87],
P
=0.009), and lower odds of a 4‐m walk score of 4 (0.34 [0.16, 0.73],
P
=0.006) and chair rise score of 4 (0.56 [0.34, 0.94],
P
=0.03). Plaque presence (0.53 [0.29, 0.99],
P
=0.04) and greater total plaque burden (0.61 [0.43, 0.87],
P
=0.006) were associated with worse 4‐m walk performance in the normal‐range ABI group. Higher superficial intima media thickness was associated with lower summary performance score in all individuals (
P
=0.02).

Conclusions
Findings suggest that use of femoral artery atherosclerosis measures may be effective in individuals with a normal‐range ABI, especially, for example, those with diabetes mellitus or a family history of peripheral artery disease, when detection can lead to earlier intervention to prevent functional declines and improve quality of life.