bluuebunny/crossref_metadata_2025 huggingface dataset:
Mitochondrial Damage Mediates Genotoxicity of Arsenic in Mammalian Cells
Authors: Liu Su-Xian , Davidson Mercy M. , Tang Xiuwei , Walker Winsome F. , Athar Mohammad , Ivanov Vladimir , Hei Tom K.
Published: July 2017

Arsenic is an important environmental carcinogen that affects millions of people worldwide through contaminated water supplies. For decades, arsenic was considered a nongenotoxic carcinogen. Using the highly sensitive AL mutation assay, we previously showed that arsenic is, indeed, a potent gene and chromosomal mutagen and that its effects are mediated through the induction of reactive oxygen species. However, the origin of these radicals and the pathways involved are not known. Here we show that mitochondrial damage plays a crucial role in arsenic mutagenicity. Treatment of enucleated cells with arsenic followed by rescue fusion with karyoplasts from controls resulted in significant mutant induction. In contrast, treatment of mitochondrial DNA–depleted (ρ0) cells produced few or no mutations. Mitochondrial damage can lead to the release of superoxide anions, which then react with nitric oxide to produce the highly reactive peroxynitrites. The mutagenic damage was dampened by the nitric oxide synthase inhibitor, NG-methyl-l-arginine. These data illustrate that mitochondria are a primary target in arsenic-induced genotoxic response and that a better understanding of the mutagenic/carcinogenic mechanism of arsenic should provide a basis for better interventional approach in both treatment and prevention of arsenic-induced cancer.
New Genetic Tactics to Model Alveolar Rhabdomyosarcoma in the Mouse
Authors: Keller Charles , Capecchi Mario R.
Published: July 2017

Using conditional knock-in and knock-out techniques, we designed a mouse model of the childhood muscle cancer alveolar rhabdomyosarcoma (ARMS) that is driven by the chromosomal translocation product, Pax3:Fkhr. Tumors that closely recapitulate the spectrum of molecular markers and histology seen in human ARMS are exclusively produced in this model. Unexpectedly, expression of Pax3:Fkhr in muscle satellite cells did not produce tumors, but it did in differentiating myofibers. Expression of Pax3:Fkhr in muscle is necessary but not sufficient to initiate tumorigenesis at high frequency. This model offers new insight into the roots of alveolar rhabdomyosarcoma and illustrates the utility of Cre-loxP technology for studying otherwise inaccessible cancers in the mouse.
A Validated Mathematical Model of Cell-Mediated Immune Response to Tumor Growth
Authors: de Pillis Lisette G. , Radunskaya Ami E. , Wiseman Charles L.
Published: July 2017

Mathematical models of tumor-immune interactions provide an analytic framework in which to address specific questions about tumor-immune dynamics. We present a new mathematical model that describes tumor-immune interactions, focusing on the role of natural killer (NK) and CD8+ T cells in tumor surveillance, with the goal of understanding the dynamics of immune-mediated tumor rejection. The model describes tumor-immune cell interactions using a system of differential equations. The functions describing tumor-immune growth, response, and interaction rates, as well as associated variables, are developed using a least-squares method combined with a numerical differential equations solver. Parameter estimates and model validations use data from published mouse and human studies. Specifically, CD8+ T-tumor and NK-tumor lysis data from chromium release assays as well as in vivo tumor growth data are used. A variable sensitivity analysis is done on the model. The new functional forms developed show that there is a clear distinction between the dynamics of NK and CD8+ T cells. Simulations of tumor growth using different levels of immune stimulating ligands, effector cells, and tumor challenge are able to reproduce data from the published studies. A sensitivity analysis reveals that the variable to which the model is most sensitive is patient specific, and can be measured with a chromium release assay. The variable sensitivity analysis suggests that the model can predict which patients may positively respond to treatment. Computer simulations highlight the importance of CD8+ T-cell activation in cancer therapy.
Functional Implications of Altered Subcellular Localization of PELP1 in Breast Cancer Cells
Authors: Vadlamudi Ratna K. , Manavathi Bramanandam , Balasenthil Seetharaman , Nair Sujit S. , Yang Zhibo , Sahin Aysegul A. , Kumar Rakesh
Published: July 2017

It is increasingly accepted that steroidal receptor coregulators may also function in the cytoplasmic compartment. Proline-, glutamic acid–, and leucine-rich protein-1 (PELP1) is a novel coregulator that plays a role in both the genomic and extranuclear actions of estrogen receptors (ER) in hormonally responsive tissues. In this study using breast tumor arrays, we found that PELP1 was localized only in the cytoplasm in 58% of the PELP1-positive breast tumors. To help explain the significance of the cytoplasmic localization of PELP1 in human breast tumors, we created a mutant protein that was expressed only in the cytoplasm (PELP1-cyto) and then generated a model system wherein MCF-7 breast cancer cells were engineered to specifically express this mutant. We found that PELP1-cyto cells were hypersensitive to estrogen but resistant to tamoxifen. PELP1-cyto cells, but not parental MCF-7 cells, formed xenograft tumors in nude mice. In addition, PELP1-cyto cells exhibited increased association of PELP1 with Src, enhanced mitogen-activated protein kinase (MAPK) activation, and constitutive activation of AKT. The altered localization of PELP1 was sufficient to trigger the interaction of PELP1 with the p85 subunit of phosphatidylinositol-3-kinase (PI3K), leading to PI3K activation. In addition, PELP1 interacted with epidermal growth factor receptors and participated in growth factor–mediated ER transactivation functions. Our results suggest that the altered localization of PELP1 modulates sensitivity to antiestrogens, potentiates tumorigenicity, presumably via the stimulation of extranuclear estrogen responses, such as the activation of MAPK and AKT, and also enhance cross-regulation of ER transactivation activity by growth factors.
Penetratin Improves Tumor Retention of Single-Chain Antibodies: A Novel Step toward Optimization of Radioimmunotherapy of Solid Tumors
Authors: Jain Maneesh , Chauhan Subhash C. , Singh Ajay P. , Venkatraman Ganesh , Colcher David , Batra Surinder K.
Published: July 2017

Single-chain Fv (scFv) antibody fragments exhibit improved pharmacokinetics and biodistribution compared with intact IgG. The tumor uptake of scFvs is rapid, and the serum half-life is shorter than IgG. However, scFvs exhibit lower net dose deposition in the tumor due to a shorter residence time that limits their use in radioimmunotherapy. To improve the tumor uptake and retention of scFvs, we investigated the utility of cell-penetrating peptides, penetratin and transactivator of transcription (TAT). Biodistribution studies were done in LS174T tumor-bearing mice with divalent scFv derived from anti–tumor-associated glycoprotein 72 monoclonal antibody (mAb) CC49. Penetratin increased the tumor retention of scFvs without affecting the peak dose accumulation. The percentage of doses retained in tumors at 24 hours postadministration with a control (no peptide), penetratin, and TAT were 27.25%, 79.84%, and 48.55%, respectively, of that accumulated at 8 hours postinjection. The tumor-to-blood ratios at 24 hours postadministration were 7.14, 19.53, and 16.48 with control, penetratin, and TAT treatment, respectively, whereas the pharmacokinetics were unaltered. Coinjection with TAT, however, resulted in increased uptake of the radioconjugate by the lungs. Autoradiography of the excised tumors indicated a more homogenous distribution of the radiolabeled scFv with both penetratin and TAT in comparison with the control treatment. Real-time whole-body imaging of the live animals confirmed improved tumor localization with penetratin without any increase in the uptake by normal tissues. In conclusion, a significant improvement in the tumor retention of sc(Fv)2 was achieved by administration of penetratin. Therefore, the combination of penetratin and scFvs has the potential of improving the utility of mAb-based radiopharmaceuticals.
Adverse Effect of Adjuvant Tamoxifen in Premenopausal Breast Cancer with Cyclin D1 Gene Amplification
Authors: Jirström Karin , Stendahl Maria , Rydén Lisa , Kronblad Åsa , Bendahl Pär-Ola , Stål Olle , Landberg Göran ,   The South Swedish and Southeast Swedish Breast Cancer Groups.
Published: July 2017

Cyclins D1 and A2 are cell cycle regulators that also have the ability to interact with the estrogen receptor (ER) and consequently interfere with antiestrogen treatment in breast cancer. Experimental data support this concept, but the clinical relevance needs to be further established. In this study, we evaluated cyclin D1 and A2 protein expression by immunohistochemistry and cyclin D1 gene (CCND1) amplification by fluorescence in situ hybridization in 500 primary breast cancers arranged in tissue microarrays. Patients had been randomized to 2 years of adjuvant tamoxifen or no treatment with a median follow-up of 14 years, allowing for subgroup analysis of treatment response defined by cyclin status. We found that both cyclin D1 and A2 protein overexpression was associated with an impaired tamoxifen response, although not significant in multivariate interaction analyses, whereas tamoxifen-treated patients with CCND1-amplified tumors had a substantially increased risk for disease recurrence after tamoxifen treatment in univariate analyses [relative risk (RR), 2.22; 95% confidence interval (95% CI), 0.94-5.26; P = 0.06] in contrast to nonamplified tumors (RR, 0.39; 95% CI, 0.23-0.65; P < 0.0001). Consequently, a highly significant interaction between tamoxifen treatment and CCND1 amplification could be shown regarding both recurrence-free survival (RR, 6.38; 95% CI, 2.29-17.78; P < 0.001) and overall survival (RR, 5.34; 95% CI, 1.84-15.51; P = 0.002), suggesting an agonistic effect of tamoxifen in ER-positive tumors. In node-positive patients, the disparate outcome according to gene amplification status was even more accentuated. In summary, our data implicate that despite a significant correlation to cyclin D1 protein expression, amplification status of the CCND1 gene seems a strong independent predictor of tamoxifen response, and possibly agonism, in premenopausal breast cancer.
Conditional Expression of the CTCF-Paralogous Transcriptional Factor BORIS in Normal Cells Results in Demethylation and Derepression of MAGE-A1 and Reactivation of Other Cancer-Testis Genes
Authors: Vatolin Sergei , Abdullaev Ziedulla , Pack Svetlana D. , Flanagan Patrick T. , Custer Mary , Loukinov Dmitri I. , Pugacheva Elena , Hong Julie A. , Morse Herbert , Schrump David S. , Risinger John I. , Barrett J. Carl , Lobanenkov Victor V.
Published: July 2017

Brother of the Regulator of Imprinted Sites (BORIS) is a mammalian CTCF paralog with the same central 11Zn fingers (11ZF) that mediate specific interactions with varying ∼50-bp target sites. Regulated in vivo occupancy of such sites may yield structurally and functionally distinct CTCF/DNA complexes involved in various aspects of gene regulation, including epigenetic control of gene imprinting and X chromosome inactivation. The latter functions are mediated by meCpG-sensitive 11ZF binding. Because CTCF is normally present in all somatic cells, whereas BORIS is active only in CTCF- and 5-methylcytosine–deficient adult male germ cells, switching DNA occupancy from CTCF to BORIS was suggested to regulate site specificity and timing of epigenetic reprogramming. In addition to 11ZF-binding paternal imprinting control regions, cancer-testis gene promoters also undergo remethylation during CTCF/BORIS switching in germ cells. Only promoters of cancer testis genes are normally silenced in all somatic cells but activated during spermatogenesis when demethylated in BORIS-positive germ cells and are found aberrantly derepressed in various tumors. We show here that BORIS is also expressed in multiple cancers and is thus itself a cancer-testis gene and that conditional expression of BORIS in normal fibroblasts activates cancer-testis genes selectively. We tested if replacement of CTCF by BORIS on regulatory DNA occurs in vivo on activation of a prototype cancer-testis gene, MAGE-A1. Transition from a hypermethylated/silenced to a hypomethylated/activated status induced in normal cells by 5-aza-2′-deoxycytidine (5-azadC) was mimicked by conditional input of BORIS and is associated with complete switching from CTCF to BORIS occupancy at a single 11ZF target. This site manifested a novel type of CTCF/BORIS 11ZF binding insensitive to CpG methylation. Whereas 5-azadC induction of BORIS takes only few hours, derepression of MAGE-A1 occurred 1 to 2 days later, suggesting that BORIS mediates cancer-testis gene activation by 5-azadC. Indeed, infection of normal fibroblasts with anti-BORIS short hairpin RNA retroviruses before treatment with 5-azadC blocked reactivation of MAGE-A1. We suggest that BORIS is likely tethering epigenetic machinery to a novel class of CTCF/BORIS 11ZF target sequences that mediate induction of cancer-testis genes.
A Novel Method for Viral Gene Delivery in Solid Tumors
Authors: Wang Yong , Liu Shanling , Li Chuan-Yuan , Yuan Fan
Published: July 2017

Intratumoral infusion is the most commonly used method for viral gene delivery in clinical trials for cancer treatment. However, a potential problem in this approach is that viral vectors may disseminate from tumor to normal tissues during and after the infusion. To reduce the dissemination, we developed a novel method based on a biocompatible polymer, poloxamer 407, which could significantly increase the viscosity of virus suspension when the temperature was changed from 4°C to 37°C. With this method, we could significantly increase transgene expression in solid tumors and reduce virus dissemination by 2 orders of magnitude after intratumoral infusion of adenoviral vectors. The mechanism of reduction was likely to be that the viscous poloxamer solution blocked convection of viral vectors in the interstitial space and the lumen of microvessels in the vicinity of the infusion site. This method has a potential to be used in the clinic for enhancing efficacy and reducing toxicity in viral gene therapy.
Galectin-3 Inhibits Tumor Necrosis Factor–Related Apoptosis-Inducing Ligand–Induced Apoptosis by Activating Akt in Human Bladder Carcinoma Cells
Authors: Oka Natsuo , Nakahara Susumu , Takenaka Yukinori , Fukumori Tomoharu , Hogan Victor , Kanayama Hiro-omi , Yanagawa Takashi , Raz Avraham
Published: July 2017

The antiapoptotic molecule galectin-3 was previously shown to regulate CD95, a member of the tumor necrosis factor (TNF) family of proteins in the apoptotic signaling pathway. Here, we question the generality of the phenomenon by studying a different member of this family of proteins [e.g., TNF-related apoptosis-inducing ligand (TRAIL), which induces apoptosis in a wide variety of cancer cells]. Overexpression of galectin-3 in J82 human bladder carcinoma cells rendered them resistant to TRAIL-induced apoptosis, whereas phosphatidylinositol 3-kinase (PI3K) inhibitors (wortmannin and LY-294002) blocked the galectin-3 protecting effect. Because Akt is a major downstream PI3K target reported to play a role in TRAIL-induced apoptosis, we questioned the possible relationship between galectin-3 and Akt. Parental J82 and the control vector–transfected J82 cells (barely detectable galectin-3) exhibit low level of constitutively active Akt, resulting in sensitivity to TRAIL. On the other hand, J82 cells overexpressing galectin-3 cells expressed a high level of constitutively active Akt and were resistant to TRAIL. Moreover, the blockage of TRAIL-induced apoptosis in J82 cells seemed to be mediated by Akt through the inhibition of BID cleavage. These results suggest that galectin-3 involves Akt as a modulator molecule in protecting bladder carcinoma cells from TRAIL-induced apoptosis.
Insertion of Myc into Igh Accelerates Peritoneal Plasmacytomas in Mice
Authors: Park Sung Sup , Shaffer Arthur L. , Kim Joong Su , duBois Wendy , Potter Michael , Staudt Louis M. , Janz Siegfried
Published: July 2017

Gene-targeted mice that contain a His6-tagged mouse c-Myc cDNA, MycHis, inserted head to head into different sites of the mouse immunoglobulin heavy-chain locus, Igh, mimic the chromosomal T(12;15)(Igh-Myc) translocation that results in the activation of Myc in the great majority of mouse plasmacytomas. Mice carrying MycHis just 5′ of the intronic heavy-chain enhancer Eμ (strain iMycEμ) provide a specific model of the type of T(12;15) found in a subset (∼20%) of plasmacytomas that develop “spontaneously” in the gut-associated lymphoid tissue (GALT) of interleukin-6 transgenic BALB/c (C) mice. Here we show that the transfer of the iMycEμ transgene from a mixed genetic background of segregating C57BL/6 × 129/SvJ alleles to the background of C increased the incidence of GALT plasmacytomas by a factor of 2.5 in first-generation backcross mice (C.iMycEμ N1). Third-generation backcross mice (C.iMycEμ N3, ∼94% C alleles) were hypersusceptible to inflammation-induced peritoneal plasmacytomas (tumor incidence, 100%; mean tumor onset, 86 ± 28 days) compared with inbred C mice (tumor incidence, 5% on day 150 after tumor induction). Peritoneal plasmacytomas of C.iMycEμ N3 mice overexpressed MycHis, produced monoclonal immunoglobulin, and exhibited a unique plasma cell signature upon gene expression profiling on mouse Lymphochip cDNA microarrays. These findings indicated that the iMycEμ transgene accelerates plasmacytoma development by collaborating with tumor susceptibility alleles of strain C and circumventing the requirement for tumor precursors to acquire deregulated Myc by chromosomal translocation.
Mitochondrial DNA G10398A Polymorphism and Invasive Breast Cancer in African-American Women
Authors: Canter Jeffrey A. , Kallianpur Asha R. , Parl Fritz F. , Millikan Robert C.
Published: July 2017

Mitochondria generate oxygen-derived free radicals that damage mitochondrial DNA (mtDNA) as well as nuclear DNA and in turn promote carcinogenesis. The mtDNA G10398A polymorphism alters the structure of Complex I in the mitochondrial electron transport chain, an important site of free radical production. This polymorphism is associated with several neurodegenerative disorders. We hypothesized that the 10398A allele is also associated with breast cancer susceptibility. African mitochondria harbor the 10398A allele less frequently than Caucasian mitochondria, which predominantly carry this allele. Mitochondrial genotypes at this locus were therefore determined in two separate populations of African-American women with invasive breast cancer and in controls. A preliminary study at Vanderbilt University (48 cases, 54 controls) uncovered an association between the 10398A allele and invasive breast cancer in African-American women, [odds ratio (OR), 2.90; 95% confidence interval (95% CI), 0.61-18.3; P = 0.11]. We subsequently validated this finding in a large, population-based, case-control study of breast cancer, the Carolina Breast Cancer Study at the University of North Carolina (654 cases, 605 controls). African-American women in this study with the 10398A allele had a significantly increased risk of invasive breast cancer (OR, 1.60; 95% CI, 1.10-2.31; P = 0.013). The 10398A allele remained an independent risk factor after adjustment for other well-accepted breast cancer risk factors. No association was detectable in white women (879 cases, 760 controls; OR, 1.03; 95% CI, 0.81-1.31; P = 0.81). This study provides novel epidemiologic evidence that the mtDNA 10398A allele influences breast cancer susceptibility in African-American women. mtDNA polymorphisms may be underappreciated factors in breast carcinogenesis.
An Essential Role for the Tumor-Suppressor Merlin in Regulating Fatty Acid Synthesis
Authors: Stepanova Dina S. , Semenova Galina , Kuo Yin-Ming , Andrews Andrew J. , Ammoun Sylwia , Hanemann C. Oliver , Chernoff Jonathan
Published: July 2017

Neurofibromatosis type 2 (NF2) is an autosomal dominant disorder characterized by the development of multiple tumors in the central nervous system, most notably schwannomas, and meningiomas. Mutational inactivation of the NF2 gene encoding the protein Merlin is found in most sporadic and inherited schwannomas, but the molecular mechanisms underlying neoplastic changes in schwannoma cells remain unclear. We report here that Nf2-deficient cells display elevated expression levels of key enzymes involved in lipogenesis and that this upregulation is caused by increased activity of Torc1. Inhibition or knockdown of fatty acid synthase (FASN), the enzyme that catalyzes the formation of palmitic acid from malonyl-CoA, drove NF2-deficient cells into apoptosis. Treatment of NF2-mutant cells with agents that inhibit the production of malonyl-CoA reduced their sensitivity to FASN inhibitors. Collectively, these results suggest that the altered lipid metabolism found in NF2-mutant cells renders them sensitive to elevated levels of malonyl-CoA, as occurs following blockade of FASN, suggesting new targeted strategies in the treatment of NF2-deficient tumors. Cancer Res; 77(18); 5026–38. ©2017 AACR.
MYC-Regulated Mevalonate Metabolism Maintains Brain Tumor–Initiating Cells
Authors: Wang Xiuxing , Huang Zhi , Wu Qiulian , Prager Briana C. , Mack Stephen C. , Yang Kailin , Kim Leo J.Y. , Gimple Ryan C. , Shi Yu , Lai Sisi , Xie Qi , Miller Tyler E. , Hubert Christopher G. , Song Anne , Dong Zhen , Zhou Wenchao , Fang Xiaoguang , Zhu Zhe , Mahadev Vaidehi , Bao Shideng , Rich Jeremy N.
Published: July 2017

Metabolic dysregulation drives tumor initiation in a subset of glioblastomas harboring isocitrate dehydrogenase (IDH) mutations, but metabolic alterations in glioblastomas with wild-type IDH are poorly understood. MYC promotes metabolic reprogramming in cancer, but targeting MYC has proven notoriously challenging. Here, we link metabolic dysregulation in patient-derived brain tumor–initiating cells (BTIC) to a nexus between MYC and mevalonate signaling, which can be inhibited by statin or 6-fluoromevalonate treatment. BTICs preferentially express mevalonate pathway enzymes, which we find regulated by novel MYC-binding sites, validating an additional transcriptional activation role of MYC in cancer metabolism. Targeting mevalonate activity attenuated RAS-ERK–dependent BTIC growth and self-renewal. In turn, mevalonate created a positive feed-forward loop to activate MYC signaling via induction of miR-33b. Collectively, our results argue that MYC mediates its oncogenic effects in part by altering mevalonate metabolism in glioma cells, suggesting a therapeutic strategy in this setting. Cancer Res; 77(18); 4947–60. ©2017 AACR.
Mathematical Modeling of Tumor–Tumor Distant Interactions Supports a Systemic Control of Tumor Growth
Authors: Benzekry Sebastien , Lamont Clare , Barbolosi Dominique , Hlatky Lynn , Hahnfeldt Philip
Published: July 2017

Interactions between different tumors within the same organism have major clinical implications, especially in the context of surgery and metastatic disease. Three main explanatory theories (competition, angiogenesis inhibition, and proliferation inhibition) have been proposed, but precise determinants of the phenomenon remain poorly understood. Here, we formalized these theories into mathematical models and performed biological experiments to test them with empirical data. In syngeneic mice bearing two simultaneously implanted tumors, growth of only one of the tumors was significantly suppressed (61% size reduction at day 15, P < 0.05). The competition model had to be rejected, whereas the angiogenesis inhibition and proliferation inhibition models were able to describe the data. Additional models including a theory based on distant cytotoxic log-kill effects were unable to fit the data. The proliferation inhibition model was identifiable and minimal (four parameters), and its descriptive power was validated against the data, including consistency in predictions of single tumor growth when no secondary tumor was present. This theory may also shed new light on single cancer growth insofar as it offers a biologically translatable picture of how local and global action may combine to control local tumor growth and, in particular, the role of tumor-tumor inhibition. This model offers a depiction of concomitant resistance that provides an improved theoretical basis for tumor growth control and may also find utility in therapeutic planning to avoid postsurgery metastatic acceleration. Cancer Res; 77(18); 5183–93. ©2017 AACR.
Insurance Clearance for Early-Phase Oncology Clinical Trials Following the Affordable Care Act
Authors: Kehl Kenneth L. , Fullmer Cheryl P. , Fu Siqing , George Goldy C. , Hess Kenneth R. , Janku Filip , Karp Daniel D. , Kato Shumei , Kizer Cynthia K. , Kurzrock Razelle , Naing Aung , Pant Shubham , Piha-Paul Sarina A. , Subbiah Vivek , Tsimberidou Apostolia M. , Hong David S.
Published: July 2017

Purpose: The Affordable Care Act (ACA) required that private insurance plans allow clinical trial participation and cover standard-of-care costs, but the impact of this provision has not been well-characterized. We assessed rates of insurance clearance for trial participation within our large early-phase clinical trials program, before and after implementation of the requirement.

Experimental Design: We analyzed the departmental database for the Clinical Center for Targeted Therapy (CCTT) at MD Anderson Cancer Center (Houston, TX). Among patients referred for sponsored trials, we described rates of insurance clearance and prolonged time to clearance (at least 14 days) from July 2012 to June 2013 (baseline), July 2013–December 2013 (following CCTT staffing changes in July 2103), and January 2014–June 2015 (following implementation of the ACA). We used multivariable logistic regression models to compare rates across these time periods.

Results: We identified 2,404 referrals for insurance clearance. Among privately insured patients, insurance clearance rates were higher for those referred from January 2014 to June 2015 than for those referred from July 2012 to June 2013 (OR, 4.72; 95% CI, 2.96–7.51). There was no association between referral period and clearance rates for Medicare/Medicaid patients (P = 0.25). Referral from January 2014 to June 2015 was associated with lower rates of prolonged clearance among both privately insured (OR 0.57; 95% CI, 0.38–0.86) and Medicare/Medicaid patients (OR 0.39; 95% CI, 0.19–0.83).

Conclusions: Within our large early-phase clinical trials program, insurance clearance rates among privately insured patients improved following implementation of the ACA's requirement for coverage of standard-of-care costs. Clin Cancer Res; 23(15); 4155–62. ©2017 AACR.
Quercetin Targets hnRNPA1 to Overcome Enzalutamide Resistance in Prostate Cancer Cells
Authors: Tummala Ramakumar , Lou Wei , Gao Allen C. , Nadiminty Nagalakshmi
Published: July 2017

Prostate cancer remains dependent on androgen receptor signaling even after castration. Aberrant androgen receptor signaling in castration-resistant prostate cancer is mediated by mechanisms such as alterations in the androgen receptor and activation of interacting signaling pathways. Clinical evidence confirms that resistance to the next-generation antiandrogen, enzalutamide, may be mediated to a large extent by alternative splicing of the androgen receptor to generate constitutively active splice variants such as AR-V7. The splice variants AR-V7 and ARv567es have been implicated in the resistance to not only enzalutamide, but also to abiraterone and other conventional therapeutics such as taxanes. Numerous studies, including ours, suggest that splicing factors such as hnRNPA1 promote the generation of AR-V7, thus contributing to enzalutamide resistance in prostate cancer cells. In the present study, we discovered that quercetin, a naturally occurring polyphenolic compound, reduces the expression of hnRNPA1, and consequently, that of AR-V7. The suppression of AR-V7 by quercetin resensitizes enzalutamide-resistant prostate cancer cells to treatment with enzalutamide. Our results indicate that quercetin downregulates hnRNPA1 expression, downregulates the expression of AR-V7, antagonizes androgen receptor signaling, and resensitizes enzalutamide-resistant prostate cancer cells to enzalutamide treatment in vivo in mouse xenografts. These findings demonstrate that suppressing the alternative splicing of the androgen receptor may have important implications in overcoming the resistance to next-generation antiandrogen therapy. Mol Cancer Ther; 16(12); 2770–9. ©2017 AACR.
Autophagy Inhibition Improves Sunitinib Efficacy in Pancreatic Neuroendocrine Tumors via a Lysosome-dependent Mechanism
Authors: Wiedmer Tabea , Blank Annika , Pantasis Sophia , Normand Lea , Bill Ruben , Krebs Philippe , Tschan Mario P. , Marinoni Ilaria , Perren Aurel
Published: July 2017

Increasing the efficacy of approved systemic treatments in metastasized pancreatic neuroendocrine tumors (PanNET) is an unmet medical need. The antiangiogenic tyrosine kinase inhibitor sunitinib is approved for PanNET treatment. In addition, sunitinib is a lysosomotropic drug and such drugs can induce lysosomal membrane permeabilization as well as autophagy. We investigated sunitinib-induced autophagy as a possible mechanism of PanNET therapy resistance. Sunitinib accumulated in lysosomes and induced autophagy in PanNET cell lines. Adding the autophagy inhibitor chloroquine reduced cell viability in cell lines and in primary cells isolated from PanNET patients. The same treatment combination reduced tumor burden in the Rip1Tag2 transgenic PanNET mouse model. The combination of sunitinib and chloroquine reduced recovery and induced apoptosis in vitro, whereas single treatments did not. Knockdown of key autophagy proteins in combination with sunitinib showed similar effect as chloroquine. Sunitinib also induced lysosomal membrane permeabilization, which further increased in the presence of chloroquine or knockdown of lysosome-associated membrane protein (LAMP2). Both combinations led to cell death. Our data indicate that chloroquine increases sunitinib efficacy in PanNET treatment via autophagy inhibition and lysosomal membrane permeabilization. We suggest that adding chloroquine to sunitinib treatment will increase efficacy of PanNET treatment and that such patients should be included in respective ongoing clinical trials. Mol Cancer Ther; 16(11); 2502–15. ©2017 AACR.
The IGF1R/INSR Inhibitor BI 885578 Selectively Inhibits Growth of IGF2-Overexpressing Colorectal Cancer Tumors and Potentiates the Efficacy of Anti-VEGF Therapy
Authors: Sanderson Michael P. , Hofmann Marco H. , Garin-Chesa Pilar , Schweifer Norbert , Wernitznig Andreas , Fischer Stefan , Jeschko Astrid , Meyer Reiner , Moll Jürgen , Pecina Thomas , Arnhof Heribert , Weyer-Czernilofsky Ulrike , Zahn Stephan K. , Adolf Günther R. , Kraut Norbert
Published: July 2017

Clinical studies of pharmacologic agents targeting the insulin-like growth factor (IGF) pathway in unselected cancer patients have so far demonstrated modest efficacy outcomes, with objective responses being rare. As such, the identification of selection biomarkers for enrichment of potential responders represents a high priority for future trials of these agents. Several reports have described high IGF2 expression in a subset of colorectal cancers, with focal IGF2 amplification being responsible for some of these cases. We defined a novel cut-off value for IGF2 overexpression based on differential expression between colorectal tumors and normal tissue samples. Analysis of two independent colorectal cancer datasets revealed IGF2 to be overexpressed at a frequency of 13% to 22%. An in vitro screen of 34 colorectal cancer cell lines revealed IGF2 expression to significantly correlate with sensitivity to the IGF1R/INSR inhibitor BI 885578. Furthermore, autocrine IGF2 constitutively activated IGF1R and Akt phosphorylation, which was inhibited by BI 885578 treatment. BI 885578 significantly delayed the growth of IGF2-high colorectal cancer xenograft tumors in mice, while combination with a VEGF-A antibody increased efficacy and induced tumor regression. Besides colorectal cancer, IGF2 overexpression was detected in more than 10% of bladder carcinoma, hepatocellular carcinoma and non-small cell lung cancer patient samples. Meanwhile, IGF2-high non-colorectal cancer cells lines displayed constitutive IGF1R phosphorylation and were sensitive to BI 885578. Our findings suggest that IGF2 may represent an attractive patient selection biomarker for IGF pathway inhibitors and that combination with VEGF-targeting agents may further improve clinical outcomes. Mol Cancer Ther; 16(10); 2223–33. ©2017 AACR.
A LITERATURA NAS SOMBRAS AS EDIÇÕES EM PORTUGUÊS E OS TRADUTORES DA ATALÁ DE CHATEAUBRIAND NA CRISE DO ANTIGO REGIME LUSO- BRASÍLICO (1810-1820)
Authors: Magalhães Pablo Iglesias
Published: July 2017

Esse artigo discute a circulação de quatro edições em português da novela Atala (1801), impressas em Lisboa, Londres e Salvador (1810-1820), sendo a primeira proibida pelo Santo Ofício em 1812. Por meio de extensa pesquisa, foi possível localizar exemplares únicos e identificar os três anônimos tradutores da referida novela, revelando que aqueles personagens, ligados por amizade e pela maçonaria, atuaram contra o absolutismo e em prol dos projetos constitucionalistas nos dois lados do Atlântico.
RASGAR EL ARCHIVO: NOSOTROS LOS SALVADOS DE JACQUELINE GOLDBERG
Authors: Kanzepolsky Adriana
Published: July 2017

Nosso trabalho se pergunta sobre a relação entre poema, arquivo, testemunho e autoria em Nosotros los salvados de Jacqueline Goldberg, livro que recupera e apaga simultaneamente uma serie de depoimentos de sobreviventes da Shoa, destinados à Survivors of the Shoa Visual History Foundation de Steven Spielberg. Isto é, focamos na relação paradoxal que os poemas estabelecem com o arquivo que está na sua origem.
ENTRE O IMPERATIVO DA RESISTÊNCIA E A CONSCIÊNCIA DA DERROTA: A LITERATURA BRASILEIRA DURANTE O REGIME MILITAR
Authors: Napolitano Marcos
Published: July 2017

Este artigo propõe uma cartografia geral para situar a literatura brasileira (prosa e poesia) dentro do campo mais amplo da chamada “resistência cultural” ao regime militar implantado em 1964. No plano da memória social, a literatura é pouco lembrada dentro do campo das artes, se compararmos aos papeis ocupados pelo teatro, música popular e cinema na constituição da identidade de oposição ao regime. Entretanto, a literatura deve ser analisada a partir de sua capacidade de adensamento das relações entre a linguagem reflexiva e a matéria histórica, menos comprometida com imposições de mercado ou de grande público. Neste sentido, há um corpus essencial de autores e de obras que desempenharam um papel importante tanto na reconstrução de subjetividades diante da experiência da derrota e do autoritarismo, quanto no escrutínio da nova realidade social e política imposta pelo regime militar.
LÍRICA, MEMÓRIA E HISTÓRIA: BREVE PERCURSO POR ROMANCEIRO DA INCONFIDÊNCIA DE CECÍLIA MEIRELES E OS “POEMAS DO HOLOCAUSTO” DE ROSE AUSLÄNDER
Authors: Irrgang Sílvia Nauroski
Published: July 2017

Este ensaio tem como objetivo estudar a presença da violência e do trauma em Romanceiro da Inconfidência de Cecília Meireles, assim como na produção lírica da poeta judia de expressão alemã Rose Ausländer a partir de seu confinamento no gueto de Czernowitz em 1941. Também irá refletir sobre as contribuições da literatura, sobretudo em relação às futuras gerações, como instrumento de rememoração e na aquisição de uma consciência histórica.
ÓDIO E PODER
Authors: Mathias Dionei
Published: July 2017

Este artigo pretende analisar a conexão entre ódio e poder no romance Die Klavierspielerin (A pianista), escrita por Elfriede Jelinek. Após uma introdução que discute a questão do poder, como entendido para os fins deste artigo, o texto reflete sobre (1) as práticas maternas de poder, (2) a reprodução dos modelos de socialização e (3) o corpo e o aluno Klemmer como duas fontes do ódio e do poder.
CETP (Cholesteryl Ester Transfer Protein) Inhibition With Anacetrapib Decreases Production of Lipoprotein(a) in Mildly Hypercholesterolemic Subjects
Authors: Thomas Tiffany , Zhou Haihong , Karmally Wahida , Ramakrishnan Rajasekhar , Holleran Stephen , Liu Yang , Jumes Patricia , Wagner John A. , Hubbard Brian , Previs Stephen F. , Roddy Thomas , Johnson-Levonas Amy O. , Gutstein David E. , Marcovina Santica M. , Rader Daniel J. , Ginsberg Henry N. , Millar John S. , Reyes-Soffer Gissette
Published: July 2017

Objective—

Lp(a) [lipoprotein (a)] is composed of apoB (apolipoprotein B) and apo(a) [apolipoprotein (a)] and is an independent risk factor for cardiovascular disease and aortic stenosis. In clinical trials, anacetrapib, a CETP (cholesteryl ester transfer protein) inhibitor, causes significant reductions in plasma Lp(a) levels. We conducted an exploratory study to examine the mechanism for Lp(a) lowering by anacetrapib.

Approach and Results—

We enrolled 39 participants in a fixed-sequence, double-blind study of the effects of anacetrapib on the metabolism of apoB and high-density lipoproteins. Twenty-nine patients were randomized to atorvastatin 20 mg/d, plus placebo for 4 weeks, and then atorvastatin plus anacetrapib (100 mg/d) for 8 weeks. The other 10 subjects were randomized to double placebo for 4 weeks followed by placebo plus anacetrapib for 8 weeks. We examined the mechanisms of Lp(a) lowering in a subset of 12 subjects having both Lp(a) levels >20 nmol/L and more than a 15% reduction in Lp(a) by the end of anacetrapib treatment. We performed stable isotope kinetic studies using
2
H
3
-leucine at the end of each treatment to measure apo(a) fractional catabolic rate and production rate. Median baseline Lp(a) levels were 21.5 nmol/L (interquartile range, 9.9–108.1 nmol/L) in the complete cohort (39 subjects) and 52.9 nmol/L (interquartile range, 38.4–121.3 nmol/L) in the subset selected for kinetic studies. Anacetrapib treatment lowered Lp(a) by 34.1% (
P
≤0.001) and 39.6% in the complete and subset cohort, respectively. The decreases in Lp(a) levels were because of a 41% reduction in the apo(a) production rate, with no effects on apo(a) fractional catabolic rate.

Conclusions—

Anacetrapib reduces Lp(a) levels by decreasing its production.

Clinical Trial Registration—

URL:
http://www.clinicaltrials.gov
. Unique identifier: NCT00990808.
Action, Not Just Words: The Practical Implications of Human Rights Law for the Use of Force and Firearms by Law Enforcement Officials
Authors: Bienert Anja
Published: July 2017

The author discusses the areas to be addressed if international human rights rules and standards applicable to the use of force and firearms are not to remain merely a theoretical concept, but are to be implemented in daily policing practice. These areas are the domestic legislation that must be formulated in conformity with international human rights law and the operational framework to be established by the command leadership of a law enforcement agency, including: operational policies and instructions for the use of force and firearms; the appropriate choice for equipment and weapons including instructions as to their use; practical scenario-based training of law enforcement officials that must seek to develop the skills and competencies required for daily policing work; and an effective system of accountability, in particular for unlawful use of force.
Where are the Women? The Missing Question in the un’s Response to Sexual Abuse in Peacekeeping Operations
Authors: Díaz Pablo Castillo
Published: July 2017

The role of gender equality considerations, including the gender balance of peacekeeping operations, has been underplayed as a potential solution to the un’s recurrent problems with sexual exploitation and abuse by blue helmets. This article explores 3 elements related to gender equality that have been neglected in responding to this issue: the presence of women in peacekeeping operations, the voice and opinion of women’s organizations, and the assistance to victims of such violations. The connection between women’s leadership and participation, on the one hand, and better outcomes for women and girls on the other, has been evident in many related policy areas, and should be applied more forcefully in addressing sexual exploitation and abuse by un peacekeepers.
Silencing the Nagorno-Karabakh Conflict and Challenges of the Four-Day War
Authors: Bayramov Agha
Published: July 2017

The Four-Day War of 2016 once again exposed the danger that the Nagorno-Karabakh conflict poses in the Caucasus. However, despite its military scale and human losses, Russia has raised only general statements from other co-chairs of the osce (Organization for Security and Co-operation in Europe) Minsk Group, from the United States and France, and from other international actors such as the United Nations Security Council. In an attempt to stimulate debate about this lack of engagement, this paper claims that the external actors involved aim to cast silence over the Nagorno-Karabakh conflict beyond the region. While this approach may serve to remove the political impact of the conflict from the international arena, it unwittingly also enhances the aggressiveness of both Armenia and Azerbaijan in the regional arena. The main aim of this paper is, then, to explain why the conflict is being silenced, how this is made possible and what the regional effects of this approach are. By drawing on the Four-Day War of 2016, the paper intends to show how the recent violence has challenged the silencing of external actors.
Administrative Measures in Counter-terrorism and the Protection of Human Rights
Authors: Boutin Bérénice
Published: July 2017

This article analyses the increasing use of administrative measures, such as travel bans and control orders, in the counter-terrorism context. On the basis of a review of the use of these measures in three selected states (the United Kingdom, France, and the Netherlands), the paper provides a critical assessment of the use of administrative measures in counter-terrorism. It identifies situations in which the use of administrative measures might be justified, and assesses the impact of the use of these measures on the protection of human rights. In conclusion, the paper recommends that limits and safeguards be established around the use of administrative measures in counter-terrorism.
Access to Justice 4 Known or Potential Extremists?
Authors: Eijkman Quirine , Roodnat Josien
Published: July 2017

This article discusses, from the local professional perspective, access to justice for person-specific interventions to prevent or counter (violent) extremism in Europe. Using a Dutch case study it focusses on legal protection for hand-tailored interferences that are part of a wider-ranging counter-terrorism policy. While the so-called person-specific interventions, carried out by professionals, target designated high-risk individuals and groups, it is primarily the municipal authority that coordinates these criminal –, administrative – or social based measures. Furthermore, although researchers and human rights advocates have repeatedly sounded the alarm over access to justice for those affected, little research has been done into how those responsible for implementation perceive the necessity of legal protection. Also, the potential side-effects such as executive arbitrariness are modestly reflected in the literature. Henceforth, by reviewing policy documents and conducting semi-structured interviews, this exploratory study concludes that as far as legal protection for hand-tailored interferences are concerned, local professionals have faith in the checks and balances of the criminal justice system. Yet from their perspective this was less self-evident in cases of administrative – or social measures. Therefore, one may wonder if legal protections for person-specific interventions that deal with (potential) extremists are sufficient in practice.
icct Report, December 2016: Foreign Terrorist Fighters
Authors: Mehra Tanya
Published: July 2017

This article is based on a paper which was developed for the Global Counterterrorism Forum’s Foreign Terrorist Fighters (ftf) Working Group. It takes stock of the current trends and dynamics related to the ftf phenomenon and identifies some of the gaps that still need to be addressed. The distinction between home-grown terrorists and (returning) ftfs is fading, the difference between isil/Da’esh inspired or directed terrorist attacks is becoming more fluid and the nexus between terrorism and crime is more prominent, which clearly indicates that terrorism can manifest itself in many different ways. The involvement of returning ftfs in some terrorist attacks is a stark reminder of the potential threat returning ftfs pose. The data also indicates a demographic change with a more prominent role of female ftfs and children being recruited and used in hostilities or involved in terrorist attacks. The current trends underline the need for a comprehensive, tailored and multidisciplinary approach including the involvement of stakeholders at the local level to adequately address the evolving aspects of the ftf phenomenon. This paper provides a short overview of policy responses which can broadly be grouped into preventive, criminal, administrative and rehabilitative measures. The ftf related responses could have several human rights implications and states are encouraged to develop a comprehensive approach to address the ftf phenomenon in full respect of human rights.
‘Wandering’ Scholars in the Beginning of Printing
Authors: Müller Jan-Dirk
Published: July 2017

The dissemination of humanism depends on personal contacts between individuals. In the fourteenth and fifteenth centuries there was an intense exchange between Germany and the Italian universities. German princes recruited administrators, counselors, and diplomats among Italian humanists. Italian teachers of rhetoric or art tried to make their fortunes north of the Alps. Apollon himself and with him the studia humanitatis are imagined as crossing the mountains.
Cosmic Dreams
Authors: Schneider Christian
Published: July 2017

Kepler’s Somnium (1634), Kircher’s Iter exstaticum (1656), and Cyrano’s Voyage dans la Lune
(1657) use elements of dream and fiction as literary strategies for imparting new cosmological knowledge. This essay argues that it is above all the heuristic potential inherent in metaphorical and analogical operations that fuels the recourse to fiction in Kepler, Cyrano, and Kircher. By utilizing fiction and metaphor as a heuristic faculty of the human imagination, Kepler’s Somnium establishes the epistemological counterpart to the Copernican revolution.
Going Far – Staying Near
Authors: Williams Gerhild Scholz
Published: July 2017

For some time, the interaction between the Ottoman and German Empires has been narrated as a “clash of civilizations”. This was centered on the conviction that early modern Christian Europe and the Islamic Ottoman Empire faced each other across an insurmountable cultural and religious divide, an enmity calmed only briefly by cease-fires or short term peace treaties. During these times of Waffenruhe, the opposing powers engaged in a multifaceted cultural conversation carried out in chapbooks, sermons, broadsheets, woodcuts, novels, histories, and newsprint. The image of the Turk that emerged was complicated, and constantly in motion. Merchants, soldiers, sailors, captives, and slaves populate contemporary narratives. The distance covered by these mobile members of otherwise rather sedentary societies and cultures is commensurate with the diversity of experiences and contacts, many of them providing the stuff of news eagerly consumed back home.