bluuebunny/crossref_metadata_2025_split huggingface dataset:
Broadened population-level frequency tuning in the auditory cortex of tinnitus patients
Authors: Sekiya Kenichi , Takahashi Mariko , Murakami Shingo , Kakigi Ryusuke , Okamoto Hidehiko 
Published: January 2017

Tinnitus is a phantom auditory perception without an external sound source and is one of the most common public health concerns that impair the quality of life of many individuals. However, its neural mechanisms remain unclear. We herein examined population-level frequency tuning in the auditory cortex of unilateral tinnitus patients with similar hearing levels in both ears using magnetoencephalography. We compared auditory-evoked neural activities elicited by a stimulation to the tinnitus and nontinnitus ears. Objective magnetoencephalographic data suggested that population-level frequency tuning corresponding to the tinnitus ear was significantly broader than that corresponding to the nontinnitus ear in the human auditory cortex. The results obtained support the hypothesis that pathological alterations in inhibitory neural networks play an important role in the perception of subjective tinnitus. NEW & NOTEWORTHY Although subjective tinnitus is one of the most common public health concerns that impair the quality of life of many individuals, no standard treatment or objective diagnostic method currently exists. We herein revealed that population-level frequency tuning was significantly broader in the tinnitus ear than in the nontinnitus ear. The results of the present study provide an insight into the development of an objective diagnostic method for subjective tinnitus.
Synaptic control of the shape of the motoneuron pool input-output function
Authors: Powers Randall K. , Heckman Charles J. 
Published: January 2017

Although motoneurons have often been considered to be fairly linear transducers of synaptic input, recent evidence suggests that strong persistent inward currents (PICs) in motoneurons allow neuromodulatory and inhibitory synaptic inputs to induce large nonlinearities in the relation between the level of excitatory input and motor output. To try to estimate the possible extent of this nonlinearity, we developed a pool of model motoneurons designed to replicate the characteristics of motoneuron input-output properties measured in medial gastrocnemius motoneurons in the decerebrate cat with voltage-clamp and current-clamp techniques. We drove the model pool with a range of synaptic inputs consisting of various mixtures of excitation, inhibition, and neuromodulation. We then looked at the relation between excitatory drive and total pool output. Our results revealed that the PICs not only enhance gain but also induce a strong nonlinearity in the relation between the average firing rate of the motoneuron pool and the level of excitatory input. The relation between the total simulated force output and input was somewhat more linear because of higher force outputs in later-recruited units. We also found that the nonlinearity can be increased by increasing neuromodulatory input and/or balanced inhibitory input and minimized by a reciprocal, push-pull pattern of inhibition. We consider the possibility that a flexible input-output function may allow motor output to be tuned to match the widely varying demands of the normal motor repertoire. NEW & NOTEWORTHY Motoneuron activity is generally considered to reflect the level of excitatory drive. However, the activation of voltage-dependent intrinsic conductances can distort the relation between excitatory drive and the total output of a pool of motoneurons. Using a pool of realistic motoneuron models, we show that pool output can be a highly nonlinear function of synaptic input but linearity can be achieved through adjusting the time course of excitatory and inhibitory synaptic inputs.
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

Abstract
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

Abstract
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

Abstract
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

Abstract
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

Abstract
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

Abstract
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

Abstract
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

Abstract
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.