bluuebunny/crossref_metadata_2025 huggingface dataset:
A Novel Higher‐Order Shear and Normal Deformable Plate Theory for the Static, Free Vibration and Buckling Analysis of Functionally Graded Plates
Authors: Yi Shi-Chao , Yao Lin-Quan , Tang Bai-Jian
Published: January 2017

Closed‐form solution of a special higher‐order shear and normal deformable plate theory is presented for the static situations, natural frequencies, and buckling responses of simple supported functionally graded materials plates (FGMs). Distinguished from the usual theories, the uniqueness is the differentia of the new plate theory. Each individual FGM plate has special characteristics, such as material properties and length‐thickness ratio. These distinctive attributes determine a set of orthogonal polynomials, and then the polynomials can form an exclusive plate theory. Thus, the novel plate theory has two merits: one is the orthogonality, where the majority of the coefficients of the equations derived from Hamilton’s principle are zero; the other is the flexibility, where the order of the plate theory can be arbitrarily set. Numerical examples with different shapes of plates are presented and the achieved results are compared with the reference solutions available in the literature. Several aspects of the model involving relevant parameters, length‐to‐thickness, stiffness ratios, and so forth affected by static and dynamic situations are elaborate analyzed in detail. As a consequence, the applicability and the effectiveness of the present method for accurately computing deflection, stresses, natural frequencies, and buckling response of various FGM plates are demonstrated.
Inference of Gene Regulatory Networks Using Bayesian Nonparametric Regression and Topology Information
Authors: Fan Yue , Wang Xiao , Peng Qinke
Published: January 2017

Gene regulatory networks (GRNs) play an important role in cellular systems and are important for understanding biological processes. Many algorithms have been developed to infer the GRNs. However, most algorithms only pay attention to the gene expression data but do not consider the topology information in their inference process, while incorporating this information can partially compensate for the lack of reliable expression data. Here we develop a Bayesian group lasso with spike and slab priors to perform gene selection and estimation for nonparametric models. B-spline basis functions are used to capture the nonlinear relationships flexibly and penalties are used to avoid overfitting. Further, we incorporate the topology information into the Bayesian method as a prior. We present the application of our method on DREAM3 and DREAM4 datasets and two real biological datasets. The results show that our method performs better than existing methods and the topology information prior can improve the result.
Detection ofAeromonas hydrophilaUsing Fiber Optic Microchannel Sensor
Authors: Gauri Samla , Abidin Zurina Zainal , Kamuri Mohd Firdaus , Mahdi Mohd Adzir , Md Yunus Nurul Amziah
Published: January 2017

This research focuses on the detection ofAeromonas hydrophilausing fiber optic microchannel biosensor. Microchannel was fabricated by photolithography method. The fiber optic was chosen as signal transmitting medium and light absorption characteristic of different microorganisms was investigated for possible detection. Experimental results showed thatAeromonas hydrophilacan be detected at the region of UV-Vis spectra between 352 nm and 354 nm which was comparable to measurement provided by UV spectrophotometer and also theoretical calculation by Beer-Lambert Absorption Law. The entire detection can be done in less than 10 minutes using a total volume of 3 μL only.This result promises good potential of this fiber optic microchannel sensor as a reliable, portable, and disposable sensor.
A Subdermal Osteochondroma in a Young Girl
Authors: Cole Heather A. , Correa Hernan , Schoenecker Jonathan G.
Published: January 2017

Osteochondromas are common benign tumors of cartilage and bone. They are usually found as contiguous bone with a cartilage cap at the end of the growth plate of long bones. Similar to structure are extraskeletal osteochondromas. However, unlike typical osteochondromas, extraskeletal osteochondromas are noncontinuous with bone. To our knowledge, all reported extraskeletal osteochondromas have been contained within fascial compartments. Here we present the case of a 5-year-old female who had a slow growing mass of the anterior distal right thigh. Imaging studies revealed an ossified mass extending from dermal layer of the subcutaneous tissue with no connection to the underlying deep fascia. An excisional biopsy was performed and proved to be a subdermal extraskeletal osteochondroma.
IL-7 Induces an Epitope Masking ofγc Protein in IL-7 Receptor Signaling Complex
Authors: Goh Tae Sik , Jo Yuna , Lee Byunghyuk , Kim Geona , Hwang Hyunju , Ko Eunhee , Kang Seung Wan , Oh Sae-Ock , Baek Sun-Yong , Yoon Sik , Lee Jung Sub , Hong Changwan
Published: January 2017

IL-7 signaling via IL-7Rαand commonγ-chain (γc) is necessary for the development and homeostasis of T cells. Although the delicate mechanism in which IL-7Rαdownregulation allows the homeostasis of T cell with limited IL-7 has been well known, the exact mechanism behind the interaction between IL-7Rαandγc in the absence or presence of IL-7 remains unclear. Additionally, we are still uncertain as to how only IL-7Rαis separately downregulated by the binding of IL-7 from the IL-7Rα/γc complex. We demonstrate here that 4G3, TUGm2, and 3E12 epitope masking ofγc protein are induced in the presence of IL-7, indicating that the epitope alteration is induced by IL-7 binding to the preassembled receptor core. Moreover, the epitope masking ofγc protein is inversely correlated with the expression of IL-7Rαupon IL-7 binding, implying that the structural alteration ofγc might be involved in the regulation of IL-7Rαexpression. The conformational change inγc upon IL-7 binding may contribute not only to forming the functional IL-7 signaling complex but also to optimally regulating the expression of IL-7Rα.
A Fast Detection Algorithm for the X‐Ray Pulsar Signal
Authors: Liang Hao , Zhan Yafeng
Published: January 2017

The detection of the X‐ray pulsar signal is important for the autonomous navigation system using X‐ray pulsars. In the condition of short observation time and limited number of photons for detection, the noise does not obey the Gaussian distribution. This fact has been little considered extant. In this paper, the model of the X‐ray pulsar signal is rebuilt as the nonhomogeneous Poisson distribution and, in the condition of a fixed false alarm rate, a fast detection algorithm based on maximizing the detection probability is proposed. Simulation results show the effectiveness of the proposed detection algorithm.
Abstract A06: Combination of TRAIL and Chal-24 synergistically induces autophagy-mediated apoptosis in lung cancer cells
Authors: Xu Xiuling , Xu Jennings , Shi Shaoqing , Wang Qiong , Saxton Bryanna , Xing Chengguo , Lin Yong
Published: January 2017

Combination chemotherapy is an effective strategy for increasing anticancer efficacy, reducing side effects and alleviating drug resistance. Here we report that combination of the recently identified novel chalcone derivative, chalcone-24 (Chal-24), and TNF-related apoptosis-inducing ligand (TRAIL) significantly increases cytotoxicity in lung cancer cells. Chal-24 treatment significantly enhanced TRAIL-induced activation of caspase-8 and caspase-3, and the cytotoxicity induced by combination of these agents was effectively suppressed by the pan-caspase inhibitor z-VAD-fmk. Chal-24 and TRAIL combination suppressed expression of cellular FLICE (FADD-like IL-1β-converting enzyme)-inhibitory protein large (c-FLIPL) and cellular inhibitor of apoptosis proteins (c-IAPs), and ectopic expression of c-FLIPL and c-IAPs inhibited the potentiated cytotoxicity. In addition, TRAIL and Chal-24 cooperatively activated autophagy. Suppression of autophagy effectively attenuated cytotoxicity induced by the combination of Chal-24 and TRAIL, which was associated with attenuation of c-FLIPL and c-IAPs degradation. Altogether, these results suggest that Chal-24 potentiates the anticancer activity of TRAIL through autophagy-mediated degradation of c-FLIPL and c-IAPs, and that combination of Chal-24 and TRAIL could be an effective approach in improving chemotherapy efficacy.

Citation Format: Xiuling Xu, Jennings Xu, Shaoqing Shi, Qiong Wang, Bryanna Saxton, Chengguo Xing, Yong Lin. Combination of TRAIL and Chal-24 synergistically induces autophagy-mediated apoptosis in lung cancer cells. [abstract]. In: Proceedings of the AACR Precision Medicine Series: Targeting the Vulnerabilities of Cancer; May 16-19, 2016; Miami, FL. Philadelphia (PA): AACR; Clin Cancer Res 2017;23(1_Suppl):Abstract nr A06.
Abstract A18: Targeting the MNK kinases for the treatment of NF1-mutant cancers
Authors: Lock Rebecca , Ingraham Rachel , Maertens Ophélia , Konicek Bruce , Yan Sau-chi , Graff Jeremy , Cichowski Karen
Published: January 2017

NF1 mutant cancers are driven by excessive Ras signaling; however, there are currently no effective therapies for these or other Ras-dependent tumors. While MEK inhibitors promote regression of NF1-deficient premalignant lesions, they are ineffective in advanced cancers. Our lab and others have shown that the addition of a PI3K/AKT/mTORC1 inhibitor can co-operate with MEK inhibition to elicit tumor regression in pre-clinical Ras-driven tumor models; however, one concern is that these combinations might not be tolerated in the clinic due to toxicity. Therefore our goal has been to identify more refined, cancer-specific signaling nodes within these pathways. Here we find that eIF4E, a key downstream effector of mTORC1, is constitutively phosphorylated by the MAP kinase-interacting kinases (MNK1 and 2) in NF1 mutant malignant peripheral nerve sheath tumors (MPNSTs). Moreover, we find that combined genetic or chemical suppression of MNK kinases can cooperate with MEK inhibition to reduce cell viability to a similar extent as broad mTOR inhibition. Surprisingly, we find that the MNK kinases are important, previously unrecognized direct targets of the receptor tyrosine kinase inhibitor cabozantinib. Furthermore, we find that cabozantinib but not a more selective MET inhibitor kills NF1-deficient tumor cells when combined with MEK inhibition, and does so in part via eIF4E phosphorylation inhibition. Finally, we show that combining cabozantinib and MEK inhibitors triggers dramatic tumor regression in an aggressive genetically engineered mouse model of MPNSTs. Together, these results identify MNK/eIF4E as a targetable signaling axis when combined with MEK inhibition in these Ras-driven tumors and highlight the utility of both drug repurposing and developing more specific MNK inhibitors for these and other malignancies.

Citation Format: Rebecca Lock, Rachel Ingraham, Ophélia Maertens, Bruce Konicek, Sau-chi Yan, Jeremy Graff, Karen Cichowski. Targeting the MNK kinases for the treatment of NF1-mutant cancers. [abstract]. In: Proceedings of the AACR Precision Medicine Series: Targeting the Vulnerabilities of Cancer; May 16-19, 2016; Miami, FL. Philadelphia (PA): AACR; Clin Cancer Res 2017;23(1_Suppl):Abstract nr A18.
Abstract A19: Identification of Heregulin (HRG) expression as a driver of a difficult-to-treat cancer phenotype and development of a companion diagnostic for the HRG-ErbB3 targeting drug seribantumab
Authors: Mathews Sara , Finn Gregory , Kudla Arthur J. , Rimkunas Victoria , Laivins Peter , MacBeath Gavin , Czibere Akos , Baum Jason
Published: January 2017

Heregulin (HRG) is the cognate ligand of the ErbB3 receptor and has been identified as a potent driver of a distinct tumor cell phenotype characterized by enhanced survival that appears to be inherently more resistant to standard of care therapies. Seribantumab (MM-121) is a fully human monoclonal antibody designed to block HRG from binding to ErbB3 and to prevent the establishment of HRG-driven cancer cell survival in response to cytotoxic therapies. Clinical evidence from randomized studies suggests that patients who receive standard therapy have shorter progression-free survival (PFS) when their tumors are positive for HRG RNA expression compared to patients receiving standard therapy with HRG-negative tumors. The addition of seribantumab was able to enhance the anti-tumor effect of these respective standard therapies and prolong PFS in patients with HRG-positive tumors. Profiling data indicates that positive HRG expression can be found in more than a third of most solid tumors identifying a high unmet medical need. In order to identify HRG-driven tumors with a more difficult-to-treat phenotype, an RNA in situ hybridization (ISH) diagnostic assay has been developed. Details will be presented illustrating the benefits of RNA ISH over alternate detection methods for HRG. This includes the visualization of tumor cell HRG expression with high sensitivity and specificity in small tissue specimens such as fine needle aspirates and core needle biopsies. This assay is currently being used to select patients for inclusion into diagnostic-driven clinical studies.

Citation Format: Sara Mathews, Gregory Finn, Arthur J. Kudla, Victoria Rimkunas, Peter Laivins, Gavin MacBeath, Akos Czibere, Jason Baum. Identification of Heregulin (HRG) expression as a driver of a difficult-to-treat cancer phenotype and development of a companion diagnostic for the HRG-ErbB3 targeting drug seribantumab. [abstract]. In: Proceedings of the AACR Precision Medicine Series: Targeting the Vulnerabilities of Cancer; May 16-19, 2016; Miami, FL. Philadelphia (PA): AACR; Clin Cancer Res 2017;23(1_Suppl):Abstract nr A19.
Abstract A28: Targeting the epigenetic state regulating cancer cell vulnerability to proteasome inhibition
Authors: Tsvetkov Peter , Sokol Ethan , Jin Dexter , Gupta Piyush , Santagata Sandro , Whitesell Luke , Lindquist Susan
Published: January 2017

The proteasome is a central regulator of protein homeostasis in all eukaryotes. Targeted pharmaceutical inhibition of the proteasome complex has been implemented as a successful therapeutic strategy to treat several cancers including multiple myeloma. Unfortunately, many of the cancers show intrinsic resistance to proteasome inhibitors, and those that are initially responsive eventually develop resistance by a poorly understood mechanism. We have recently performed genome-wide screens for mutations that allowed cells to survive in the presence of two distinct proteasome inhibitors (bortezomib and MG132). Counter to expectation, we have shown that reducing any one of the many of the subunits of the regulatory cap complex (19S) is sufficient to alter both the levels and ratio of the 26S/20S proteasome complex and induce increased resistance to proteasome inhibition. These findings motivated us to establish a cell-based screening strategy to identify molecules that specifically target the proteasome inhibitor (PI)-resistant state. We further exploited the Genomics of Drug Sensitivity in Cancer (GDSC) database to analyze the efficacy of PIs across 315 cancer cell lines for which we also had matched gene expression data. This analysis revealed that a significant decrease in the gene expression of one component of the 19S complex is both naturally occurring (in almost 6-8% of cells examined) and is sufficient to predict resistance to PIs. We termed these cells, proteasome HYDRA (Hypo expression Yielding Drug Resistance Ability) cancer cells. Further exploring the HYDRA cells utilizing the Cancer Cell Line Encyclopedia (CCLE) dataset revealed that the loss of expression of the proteasome subunit is not associated with a loss of gene copy number but rather is an epigenetic mechanism of reduced gene expression. We show here a novel cellular epigenetic switch utilized by many cancer cells that renders them resistant to proteotoxic stress. Our findings enable prediction of cancer cell vulnerability to proteasome function perturbation and also facilitate the specific targeting of this unique epigenetic state by selective drug treatment.

Citation Format: Peter Tsvetkov, Ethan Sokol, Dexter Jin, Piyush Gupta, Sandro Santagata, Luke Whitesell, Susan Lindquist. Targeting the epigenetic state regulating cancer cell vulnerability to proteasome inhibition. [abstract]. In: Proceedings of the AACR Precision Medicine Series: Targeting the Vulnerabilities of Cancer; May 16-19, 2016; Miami, FL. Philadelphia (PA): AACR; Clin Cancer Res 2017;23(1_Suppl):Abstract nr A28.
Abstract A36: TP53 loss creates therapeutic vulnerability in colorectal cancer
Authors: Liu Yunhua , Lu Xiongbin
Published: January 2017

TP53, a well-known tumor suppressor gene, is frequently inactivated by mutation or deletion in a majority of human tumors. A tremendous effort has been made to restore p53 activity in cancer therapies. However, no effective p53-based therapy has been successfully translated into clinical cancer treatment due to the complexity of p53 regulators and their poor drugability. Here, we demonstrate that genomic deletion of TP53 frequently encompasses neighboring essential genes, rendering cancer cells with hemizygous TP53 deletion vulnerable to further suppression of such genes. POLR2A is identified as such an essential house-keeping gene that is virtually co-deleted with TP53 in many types of human cancer. It encodes the largest and catalytic subunit of RNA polymerase II complex, which is specifically inhibited by α-amanitin. Our analysis of clinical samples and cancer cell lines in The Cancer Genome Atlas (TCGA) and Cancer Cell Line Encyclopedia (CCLE) reveals that POLR2A expression levels are tightly correlated with its gene copy numbers in human colorectal tumors. Suppression of POLR2A with α-amanitin or short-hairpin RNAs, selectively inhibits proliferation, survival and tumorigenic potential of colorectal cancer cells with hemizygous TP53 loss in a p53-independent manner. Previous clinical applications of α-amanitin have been limited due to its liver toxicity. However, we found that α-amanitin-based antibody drug conjugates (ADCs) are highly effective therapeutic agents with dramatically reduced toxicity. Here, we show that low doses of α-amanitin-conjugated anti-EpCAM (Epithelial Cell Adhesion Molecule) antibody lead to complete tumor regression in murine models of human colorectal cancer with hemizygous deletion of POLR2A. We anticipate that inhibiting POLR2A will be a novel therapeutic approach for cancers harboring such common genomic alterations.

Note: This abstract was not presented at the conference.

Citation Format: Yunhua Liu, Xiongbin Lu. TP53 loss creates therapeutic vulnerability in colorectal cancer. [abstract]. In: Proceedings of the AACR Precision Medicine Series: Targeting the Vulnerabilities of Cancer; May 16-19, 2016; Miami, FL. Philadelphia (PA): AACR; Clin Cancer Res 2017;23(1_Suppl):Abstract nr A36.
Abstract A39: A small molecule inhibitor of the Notch transcriptional activation complex
Authors: Astudillo Luisana , Capobianco Anthony J.
Published: January 2017

Deregulation of the Notch pathway underlies many aspects of cancer physiology depending on cell type and context. In many human cancers, aberrant Notch activity has been demonstrated to play a role in the initiation and maintenance of the neoplastic phenotype. Notch also plays a central role in cancer stem cells, which may underlie a role in metastasis and resistance to therapy. The important and diverse role played by Notch in cancer makes it an exceedingly attractive target for anti-neoplastic therapeutics. However, the full range of potential targets in the pathway have been under-explored. To date, there are no small molecule inhibitors that directly target the intracellular Notch pathway or the assembly of the transcriptional activation complex. We have developed an in vitro assay that quantitatively measures the assembly of the Notch transcriptional complex on DNA. Through computer-aided drug design we explored potential ligand binding sites and screened for compounds that could disrupt the assembly of the Notch transcriptional activation complex. Herein we report the identification and characterization of a small molecule inhibitor of the Notch transcriptional activation complex, termed Inhibitor of Mastermind Recruitment-1 (IMR-1). We demonstrate that IMR-1 disrupts the recruitment of Mastermind-like 1 (Maml1) to the Notch transcriptional activation complex on chromatin and thereby causes a decrease in Notch target gene transcription. Furthermore, IMR-1 inhibits the growth of Notch-dependent cell lines and significantly abrogates the growth of patient-derived tumor xenografts. Therefore, our data suggest that a novel class of Notch inhibitors targeting the transcriptional activation complex may represent a new paradigm for Notch-based anticancer therapeutics.

Citation Format: Luisana Astudillo, Anthony J. Capobianco. A small molecule inhibitor of the Notch transcriptional activation complex. [abstract]. In: Proceedings of the AACR Precision Medicine Series: Targeting the Vulnerabilities of Cancer; May 16-19, 2016; Miami, FL. Philadelphia (PA): AACR; Clin Cancer Res 2017;23(1_Suppl):Abstract nr A39.
Abstract B04: Synthetic lethal targeting of E-cadherin-deficient cancers
Authors: Guilford Parry J. , Chen Augustine , Telford Bryony , Single Andrew , Beetham Henry , Godwin Tanis
Published: January 2017

Germline mutation of the E-cadherin gene (CDH1) genetically defines the inherited cancer syndrome hereditary diffuse gastric cancer (HDGC). HDGC is characterized by highly penetrant diffuse gastric cancer (DGC) and an elevated rate of lobular breast cancer (LBC). Somatic CDH1 mutations also occur frequently in the sporadic forms of these cancers. We propose that the loss of E-cadherin, a tumor suppressor gene, creates vulnerabilities in the cancer cell that can be exploited with drugs (“synthetic lethal” interactions). We are particularly interested in identifying drugs that can be used for the chemoprevention of advanced disease in HDGC family members by targeting the multifocal precursor lesions that occur in stomach and breast tissue. In the stomach, these early lesions are mucosally-confined stage T1a signet ring cell carcinomas. Up to 400 independent foci have been identified in the stomachs of CDH1 mutation carriers; these foci are genetically homogenous and are likely to only require the 2nd CDH1 hit for their initiation. To identify the vulnerabilities created by E-cadherin loss, we have conducted a genome-wide siRNA knockdown screen, a 4000 compound known drug screen and a 114,000 compound library screen in isogenic MCF10a breast cell lines with and without E-cadherin expression. The functional screen has shown that GPCR signaling proteins are highly enriched amongst the candidate synthetic lethal proteins, as well as many protein classes associated cell signaling and cytoskeletal function. Drugs that show increased activity against the E-cadherin-deficient cells include the JAK inhibitor LY2784544, the c-SRC inhibitor saracatanib, the beta-2 adrenoreceptor (GPCR) agonist formoterol, several HDAC inhibitors and statins. Detail on synergistic combinations involving many of these drugs is provided in the abstract entitled “Statins show synthetic lethality in E-cadherin-deficient cells and are synergistic with SRC and HDAC inhibitors”. To identify mechanisms associated with E-cadherin synthetic lethality, we used the cell viability data from the siRNA screen to examine the distributions of cell viabilities for the genes that make up the major KEGG signaling pathways. Using the Kolomogorov-Smirnof method to test for significance, we identified the PI3K-AKT survival pathway as being central to E-cadherin's synthetic lethal associations. These findings pave the way for the development of rationally designed drug combinations for the chemoprevention and treatment of E-cadherin-negative cancers.

Citation Format: Parry J. Guilford, Augustine Chen, Bryony Telford, Andrew Single, Henry Beetham, Tanis Godwin. Synthetic lethal targeting of E-cadherin-deficient cancers. [abstract]. In: Proceedings of the AACR Precision Medicine Series: Targeting the Vulnerabilities of Cancer; May 16-19, 2016; Miami, FL. Philadelphia (PA): AACR; Clin Cancer Res 2017;23(1_Suppl):Abstract nr B04.
Abstract B11: HER2 regulates PARP-1 expression via the let-7a microRNA in HER2+ breast cancer
Authors: Wielgos Monicka , Rajbhandari Rajani , Nozell Susan , Wei Shi , Yang Eddy S.
Published: January 2017

Background: HER2+ breast cancers are sensitive to PARP inhibition and express elevated levels of the PARP-1 protein. However, the mode of regulation of PARP-1 expression by HER2 is not well understood. In this study, we report that the let-7a microRNA is regulating PARP-1 expression at the post-transcriptional level in HER2+ breast cancer cells.

Methods: Human HER2+ breast cancer cell lines BT-474 and SKBR3 were used in this study. MDA-MB-231 (non-HER2 expressing breast cancer cells) were also stably transfected with a HER2 wild-type plasmid (231 HER2) or the vector control (231 NEO). Further, to identify candidate microRNAs regulated by HER2 overexpression we used the nCounter miRNA Expression Assay. MicroRNA and mRNA expression were validated via qRT-PCR analysis in breast cancer cell lines or patient primary tumors. Cells were also transfected with a HER2 siRNA, a let-7a mimic, and an inhibitor of let-7a as well as their respective controls. Western blot analysis and firefly luciferase assays were used to determine whether the 3'UTR of PARP1 was being directly targeted by the let-7a microRNA.

Results: HER2 did not regulate PARP-1 at the mRNA level but increased PARP-1 protein in HER2+ breast cancer cells. Specifically, ectopic HER2 overexpression correlated with increased PARP-1 protein levels in the 231 HER2 cell line. Conversely, silencing HER2 reduced PARP-1 protein levels in the BT-474 and SKBR3 cell lines. NanoString nCounter analysis revealed that the HER2+ breast cancer cell lines expressed low levels of the let-7a microRNA. Further, let-7a expression was upregulated after HER2 knockdown in the two native HER2+ breast cancer cell lines. The let-7a mimic also reduced both PARP1 protein expression and luciferase activity in the 231 HER2 and BT-474 cell lines, whereas the let-7a inhibitor reversed these effects in the 231 NEO cell line. Importantly, HER2+ breast tumors expressed higher levels of PARP-1 and lower levels of let-7a; whereas, the HER2- breast tumors expressed lower levels of PARP-1 and higher levels of let-7a.

Conclusions: These results suggest that let-7a regulates PARP-1 expression in HER2+ breast tumors. Let-7a may also be a potential therapeutic target and predictive biomarker of PARPi sensitivity in HER2+ breast cancer patients.

Citation Format: Monicka Wielgos, Rajani Rajbhandari, Susan Nozell, Shi Wei, Eddy S. Yang. HER2 regulates PARP-1 expression via the let-7a microRNA in HER2+ breast cancer. [abstract]. In: Proceedings of the AACR Precision Medicine Series: Targeting the Vulnerabilities of Cancer; May 16-19, 2016; Miami, FL. Philadelphia (PA): AACR; Clin Cancer Res 2017;23(1_Suppl):Abstract nr B11.
Abstract B19: Targeting dependencies within apoptotic pathways through inhibition of BET bromodomains
Authors: Conery Andrew R. , Centore Richard C. , Spillane Kerry L. , Follmer Nicole E. , Bommi-Reddy Archana , Hatton Charlie , Bryant Barbara M. , Greninger Patricia , Amzallag Arnaud , Benes Cyril H. , Mertz Jennifer A. , Sims Robert J.
Published: January 2017

Cancer is driven in large part by dysregulated transcriptional programs that allow for the acquisition of the many ‘Hallmarks of Cancer.' Multiple regulatory factors are essential for the establishment and maintenance of these cancer-specific transcriptional programs, and this dependence creates vulnerabilities that can be therapeutically targeted. Here we describe a selective dependence on the bromodomain and extraterminal (BET) family of proteins for the reprogramming of apoptotic signaling networks and demonstrate how this dependence can be predicted prior to therapeutic intervention. We demonstrate in phenotypically sensitive cell lines that BET inhibition results in a rapid and robust transcriptional response among regulators of apoptosis, and that this transcriptional response is correlated with changes in the apoptotic threshold of target cells and subsequent apoptosis. We show that the robustness of the apoptotic response, and not that of the cytostatic response, predicts phenotypic sensitivity to BETi. Consistent with this, we observed that acquired BETi tolerance in two disparate cellular models is driven by dysregulated expression of anti-apoptotic BCL2 family proteins, and that genetic or pharmacological manipulation of apoptotic signaling can modify the phenotypic response to BETi. We further demonstrate that the basal expression levels of a set of apoptotic factors significantly predict preclinical response to BETi, and in particular note that BETi preferentially targets those cells that are dependent on BCL2 for survival. Our findings suggest that tumor cells have acquired a dependence on BET bromodomain function to evade apoptosis, and highlight opportunities to exploit this dependence in the clinic through rational patient selection and drug combination strategies.

Citation Format: Andrew R. Conery, Richard C. Centore, Kerry L. Spillane, Nicole E. Follmer, Archana Bommi-Reddy, Charlie Hatton, Barbara M. Bryant, Patricia Greninger, Arnaud Amzallag, Cyril H. Benes, Jennifer A. Mertz, Robert J. Sims, III. Targeting dependencies within apoptotic pathways through inhibition of BET bromodomains. [abstract]. In: Proceedings of the AACR Precision Medicine Series: Targeting the Vulnerabilities of Cancer; May 16-19, 2016; Miami, FL. Philadelphia (PA): AACR; Clin Cancer Res 2017;23(1_Suppl):Abstract nr B19.
Abstract B23: Crucial deubiquitinases in cancer cell survival
Authors: Kategaya Lorna , Cuellar Trinna , Haley Ben , Liu Jinfeng , Tran Andy , Cao Yi , Stokoe David , McCleland Mark , Blackwood Beth , Yee Sharon , Drobnick Joy , Drummond Jake , Ernst James , Kwok Michael , Ly Cuong , Pastor Richard , Lello Paola Di , Ndubaku Chudi , Blake Robert , Tsui Vickie , Murray Jeremy , Maurer Till , Wertz Ingrid
Published: January 2017

Deubiquitinases (DUBs) are enzymes that proteolytically cleave ubiquitin from substrates. Substrates include oncogenes, tumor suppressors and polyubiquitinated proteins marked for degradation by the proteasome. Ubiquitin specific peptidase-7 (USP7) deubiquitinates MDM2 (an oncogene). MDM2 is a ligase that ubiquitinates p53 (a tumor suppressor protein), targeting it for proteosomal degradation. As such, USP7 is a promising cancer target because its inhibition stabilizes p53 and thereby promotes apoptosis and cell cycle arrest, processes that are often deregulated in tumors (Nicholson and Suresh Kumar, 2011). We found that USP7 was selectively druggable following a fragment-based lead discovery effort to obtain USP7 antagonists. Cellular and xenograft studies confirm that inhibiting USP7 activity stabilized p53 levels and p53-downstream target, p21. Additionally, normal primary and p53-null cells were less sensitive than the corresponding p53-WT cancer cells to USP7 inhibition.

To investigate whether other DUBs are involved in cancer cell survival, we carried out a drop-out CRISPR screen using a pooled DUB library in HCT116 and A549 cells. Out of the approximately 100 DUBs targeted, nine, including USP7, were found to affect cell viability. These hits were validated using siRNA-mediated knockdown in cancer cell lines (A549, HCT116, MCF7). Three DUBs that robustly decreased cell proliferation were further tested in normal cells (Human Mammary Epithelial Cells and Human Bronchial Epithelial Cells). DUB protein expression levels and activity were also determined. In general, DUB expression levels, activity and knockdown efficiency were higher in cancer cells compared to normal cells. Collectively, our studies support the hypothesis that USP7 inhibition may be an efficacious strategy to promote cancer cell death. Furthermore, there are other DUBs that should be considered as novel cancer targets.

Citation Format: Lorna Kategaya, Trinna Cuellar, Ben Haley, Jinfeng Liu, Andy Tran, Yi Cao, David Stokoe, Mark McCleland, Beth Blackwood, Sharon Yee, Joy Drobnick, Jake Drummond, James Ernst, Michael Kwok, Cuong Ly, Richard Pastor, Paola Di Lello, Chudi Ndubaku, Robert Blake, Vickie Tsui, Jeremy Murray, Till Maurer, Ingrid Wertz. Crucial deubiquitinases in cancer cell survival. [abstract]. In: Proceedings of the AACR Precision Medicine Series: Targeting the Vulnerabilities of Cancer; May 16-19, 2016; Miami, FL. Philadelphia (PA): AACR; Clin Cancer Res 2017;23(1_Suppl):Abstract nr B23.
Myeloid-Derived Suppressor Cells
Authors: Gabrilovich Dmitry I.
Published: January 2017

Myeloid cells developed evolutionarily as a major mechanism to protect the host. They evolved as a critical barrier against infections and are important contributors to tissue remodeling. However, in cancer, myeloid cells are largely converted to serve a new master—tumor cells. This process is epitomized by myeloid-derived suppressor cells (MDSC). These cells are closely related to neutrophils and monocytes. MDSCs are not present in the steady state of healthy individuals and appear in cancer and in pathologic conditions associated with chronic inflammation or stress. These cells have emerged as an important contributor to tumor progression. Ample evidence supports a key role for MDSCs in immune suppression in cancer, as well as their prominent role in tumor angiogenesis, drug resistance, and promotion of tumor metastases. MDSCs have a fascinating biology and are implicated in limiting the effects of cancer immunotherapy. Therefore, targeting these cells may represent an attractive therapeutic opportunity. Cancer Immunol Res; 5(1); 3–8. ©2016 AACR.
Changes in Intestinal Motility and Gut Microbiota Composition in a Rat Stress Model
Authors: Murakami Takaaki , Kamada Kazuhiro , Mizushima Katsura , Higashimura Yasuki , Katada Kazuhiro , Uchiyama Kazuhiko , Handa Osamu , Takagi Tomohisa , Naito Yuji , Itoh Yoshito
Published: January 2017

Background: Irritable bowel syndrome (IBS) causes chronic abdominal pain and abnormal bowel movements. The etiology involves complicated interactions among visceral hypersensitivity, disorders related to bowel movements, and stress. Changes in the microbiota affect the IBS pathophysiology. We investigated changes in colorectal motility, structure, and microbiota in response to stress due to maternal separation (MS) and corticotropin-releasing hormone (CRH) administration in rats. Summary: Neonatal rats were separated from their mothers for 3 h daily from postnatal day (PND) 2 to PND14. The control group included rats of the same age that were not separated. After MS, the rats were undisturbed for 5 weeks. At 8 weeks of age, 10 µg of CRH or saline was intravenously administered to MS and control groups. Two hours later, the number of fecal pellets was counted. Three hours after CRH or saline administration, the rats were sacrificed and colorectal tissue samples and cecal contents were collected to analyze the fecal microbiota. The number of fecal pellets was significantly greater in MS with the CRH group. Both stressors altered the microbiota composition. Key Messages: Among rats that received CRH, MS increased the colorectal motility. Stress due to MS altered the gut microbiota composition.
Short- and Long-Term Outcomes of Infliximab Treatment for Steroid-Refractory Ulcerative Colitis and Related Prognostic Factors: A Single-Center Retrospective Study
Authors: Nasuno Masanao , Miyakawa Maki , Tanaka Hiroki , Motoya Satoshi
Published: January 2017

Background/Aims: The aim of this study was to analyze the short- and long-term outcomes of infliximab (IFX) treatment to cure steroid-refractory ulcerative colitis (UC) and related prognostic factors. Methods: Retrospective data were collected from 125 patients with steroid-refractory UC who received IFX treatment at our center from July 2005 to November 2013. The Lichtiger clinical activity index score was calculated at baseline, 2 weeks, 6 weeks, and 1 year, and the cumulative non-colectomy rate following IFX administration was estimated. Remission rate prognostic factors and the cumulative colectomy rate prognostic factors were evaluated using multivariate logistic regression analysis and multivariate Cox regression analysis, respectively. Results: Remission rates at 2 weeks, 6 weeks, and 1 year were 46, 58, and 45%, respectively. The 1-, 3-, and 5-year cumulative non-colectomy rates were 80, 78, and 75%, respectively. Previous treatment with calcineurin inhibitors was a significant prognostic factor for lower remission and cumulative non-colectomy rates, whereas concomitant immunomodulators was a significant prognostic factor for the higher remission rate. Gender (female) was a prognostic factor for higher remission rate at 1 year and higher cumulative non-colectomy rate. Conclusions: This study revealed good short- and long-term outcomes of IFX treatment in patients with steroid-refractory UC. Previous treatment with calcineurin inhibitors was a prognostic factor for poor outcomes of IFX treatment, whereas concomitant immunomodulators and gender (female) were prognostic factors for good outcomes.
Observational Study of Switching from Natalizumab to Immunomodulatory Drugs
Authors: Villaverde-González Ramón , Gracia Gil Julia , Pérez Sempere Angel , Millán Pascual Jorge , Marín Marín José , Carcelén Gadea María , Gabaldón Torres Laura , Moreno Escribano Antonio , Candeliere Merlicco Antonio
Published: January 2017

Objective: To determine the effect of disease-modifying drugs (DMDs) on disease activity rebound in patients discontinuing natalizumab (NTZ). Methods: Twenty-one patients with relapsing-remitting multiple sclerosis (RRMS) treated with NTZ for ≥1 year and who switched to DMDs (glatiramer acetate [GA] or interferon) were followed up for 12 months in clinical practice. Clinical outcomes after NTZ cessation were assessed every 3 months for 1 year and MRI was performed at 12 months. Results: Twelve months after switching from NTZ to DMDs, there were no significant differences in the annualized relapse rate (ARR) compared to the days that NTZ was used (0.3 vs. 0.1; p = 0.083); and the ARR never reached similar values to those prior to NTZ use (1.61; p < 0.001). The percentage of relapse-free patients after switching from NTZ was 71.4%. These patients did not have lower disease activity before NTZ compared with those with clinical relapses (1.3 vs. 1.7; p = 0.302), but they had lower Expanded Disability Status Scale scores (3.4 vs. 5.7; p = 0.001). DMDs had beneficial effects on MRI parameters, as 10 of 16 patients (62.5%) presented no evidence of radiological activity 12 months after NTZ discontinuation. Conclusions: Patients with RRMS and moderate disability who discontinued NTZ for safety reasons may benefit from the DMDs GA and interferon with no known risk for progressive multifocal leukoencephalopathy.
Characterization of Conversion Chemotherapy for Secondary Surgical Resection in Colorectal Cancer Patients with Lung Metastases
Authors: Nozawa Hiroaki , Ishihara Soichiro , Kawai Kazushige , Hata Keisuke , Kiyomatsu Tomomichi , Tanaka Toshiaki , Nishikawa Takeshi , Otani Kensuke , Yasuda Koji , Sasaki Kazuhito , Murono Koji , Nakajima Jun , Watanabe Toshiaki
Published: January 2017

Objective: Clinical trials demonstrated that 6-37% of the patients with colorectal liver-limited metastases underwent surgical resection after first-line chemotherapy. However, limited information is available on the conversion of colorectal cancer patients with lung metastases to resection by systemic chemotherapy. Methods: We retrospectively investigated 156 patients with unresectable colorectal cancer who received oxaliplatin- or irinotecan-based first-line systemic chemotherapy with or without antibodies in our department between January 2007 and December 2015. The conversion rate to surgery and chemotherapeutic regimens and periods were analyzed with respect to the target organ. Results: In addition to 4 patients who achieved complete response, 73 exhibited tumor shrinkage of any extent. Twenty patients underwent secondary surgery, all of whom received targeting antibodies. In 75 patients with liver metastases, 18 (24%) were converted to resection after chemotherapy for a median of 110 days. In contrast, 4 (7%) out of 56 patients with lung metastases underwent resection after chemotherapy for a median of 449 days. Conversion was an independent prognostic factor in patients with lung metastases. Conclusion: The conversion rate to resection was lower for colorectal cancer patients with lung metastasis by systemic chemotherapy, which required a longer duration than for those with liver metastases.
Comparison of Three Screening Questionnaires for Chronic Obstructive Pulmonary Disease in the Primary Care
Authors: Spyratos Dionisios , Haidich Anna-Bettina , Chloros Diamantis , Michalopoulou Dionisia , Sichletidis Lazaros
Published: January 2017

Background: Even though the diagnosis of chronic obstructive pulmonary disease (COPD) is easy and based mainly on spirometry and symptoms, the prevalence of underdiagnosis is extremely high. The use of simple screening tools (e.g., questionnaires, hand-held spirometers) has been proved to be a simple method for case finding of COPD. Nevertheless the most appropriate target group of the general population has not been specified yet. Objectives: The aim of the present study was to compare 3 screening questionnaires among smokers aged >40 years in the primary care setting. Methods: We excluded all subjects with a previous medical diagnosis of bronchial asthma or chronic pulmonary disease other than COPD. All participants were in a stable clinical condition, filled in the International Primary Care Airways Group (IPAG) questionnaire, the COPD Population Screener (COPD-PS) questionnaire, and the Lung Function Questionnaire (LFQ) and underwent spirometry. Medical diagnosis of COPD was established by an experienced pulmonologist. Results: We studied 3,234 subjects during a 3.5-year period. COPD prevalence was 10.9% (52.1% underdiagnosis). All 3 questionnaires showed extremely high negative predictive values (94-96%), so in this case the diagnosis of COPD could be safely excluded. The area under the curve was similar across the 3 questionnaires (AUCROC: 0.794-0.809). The COPD-PS questionnaire demonstrated the highest positive predictive value (41%) compared to the other 2. On the other hand, the IPAG questionnaire and LFQ demonstrated higher sensitivities than COPD-PS resulting in lower percentages of missed cases. Conclusions: Three validated screening questionnaires for COPD demonstrated different diagnostic characteristics.
Impaction and Prediction: Does Ureteral Wall Thickness Affect the Success of Medical Expulsive Therapy in Pediatric Ureteral Stones?
Authors: Tuerxun Aierken , Batuer Abudukahaer , Erturhan Sakip , Eryildirim Bilal , Camur Emre , Sarica Kemal
Published: January 2017

Objective: The study aimed to evaluate the predictive value of ureteral wall thickness (UWT) and stone-related parameters for medical expulsive therapy (MET) success with an alpha blocker in pediatric upper ureteral stones. Patients and Methods: A total of 35 children receiving MET ureteral stones (<10 mm) were evaluated. Patients were divided into 2 subgroups where MET was successful in 18 children (51.4%) and unsuccessful in 17 children (48.6%). Prior to management, stone size, stone density (in Hounsfield unit), degree of hydronephrosis, and UWT were evaluated with patient demographics and recorded. The possible predictive value of these parameters in success rates and time to stone expulsion were evaluated in a comparative manner between the 2 groups. Results: The overall mean patient age and stone size values were 5.40 ± 0.51 years and 6.24 ± 0.28 mm, respectively. Regarding the predictive values of these parameters for the success of MET, while stone size and UWT were found to be highly predictive for MET success, patients age, body mass index, stone density, and degree of hydronephrosis had no predictive value on this aspect. Conclusions: Our findings indicated that some stone and anatomical factors may be used to predict the success of MET in pediatric ureteral stones in an effective manner. With this approach, unnecessary use of these drugs that may cause a delay in removing the stone will be avoided, and the possible adverse effects of obstruction as well as stone-related clinical symptoms could be minimized.
In vitro Dermal Absorption of Hydroquinone: Protocol Validation and Applicability on Illegal Skin-Whitening Cosmetics
Authors: Desmedt Bart , Ates Gamze , Courselle Patricia , De Beer Jacques O. , Rogiers Vera , Hendrickx Benoit , Deconinck Eric , De Paepe Kristien
Published: January 2017

In Europe, hydroquinone is a forbidden cosmetic ingredient. It is, however, still abundantly used because of its effective skin-whitening properties. The question arises as to whether the quantities of hydroquinone used become systemically available and may cause damage to human health. Dermal absorption studies can provide this information. In the EU, dermal absorption has to be assessed in vitro since the Cosmetic Regulation 1223/2009/EC forbids the use of animals. To obtain human-relevant data, a Franz diffusion cell protocol was validated using human skin. The results obtained were comparable to those from a multicentre validation study. The protocol was applied to hydroquinone and the dermal absorption ranged between 31 and 44%, which is within the range of published in vivo human values. This shows that a well-validated in vitro dermal absorption study using human skin provides relevant human data. The validated protocol was used to determine the dermal absorption of illegal skin-whitening cosmetics containing hydroquinone. All samples gave high dermal absorption values, rendering them all unsafe for human health. These results add to our knowledge of illegal cosmetics on the EU market, namely that they exhibit a negative toxicological profile and are likely to induce health problems.
Princípios e recomendações para o manejo de pastagens
Authors:   Universidade de São Paulo. Faculdade de Zootecnia e Engenharia de Alimentos, Pereira Lilian Elgalise Techio , Polizel Guilherme Henrique Gebim ,   Universidade de São Paulo. Faculdade de Zootecnia e Engenharia de Alimentos
Published: January 2017

O objetivo desta publicação é contribuir para a melhoria dos sistemas de produção baseados em pastagens, apresentando os princípios de manejo para as principais espécies forrageiras utilizadas. As recomendações aqui propostas são resultados de anos de esforços conjuntos e trabalhos de campo realizados em diversas Instituições de Pesquisa e Universidades de todo o país. Aos produtores, por meio da informação,esperamos auxiliar no planejamento da propriedade e facilitar a adoção das ferramentas de manejo aqui propostas.