bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract SY18-03: Therapeutically targeting the p53 pathway using miRNA-based approaches in mouse models of cancer
Authors: Flores Elsa R. 
Published: August 2015

Abstract
The tumor suppressor gene, p53, is commonly mutated or lost in human cancer, and p53 reactivation has been shown to suppress tumors in-vivo. This strategy has proven difficult to implement therapeutically. One alternative strategy to overcome p53 loss is to manipulate the p53 family members, p63 and p73, which interact with p53 extensively to suppress tumorigenesis. Both p63 and p73 are composed of multiple isoforms. The isoforms can be placed into two groups: the TA isoforms, which structurally resemble p53 and act as tumor suppressors, and the ΔN isoforms, which bind to p53, TAp63, and TAp73 and inhibit their function, thus acting as oncogenes. Many current therapeutic strategies to target p53 focus on p53 solely, ignoring the existence of the other p53 family members. Over the last decade, we have learned that this family of genes acts together to suppress tumorigenesis and metastasis; therefore, a clear understanding of the cross talk between the p53 family as a whole is needed to effectively treat cancers with alterations in the p53 family of genes. Recently, my laboratory has shown that in vivo inactivation of ΔNp63 or ΔNp73 in the p53-deficient mouse model of thymic lymphoma leads to massive tumor regression and increased survival through upregulation of TAp63 and TAp73 and subsequent transactivation of a large network of genes and miRNAs identified through RNA sequencing (Venkatanarayan et al., Nature, 2014 Nov 17, doi: 10.1038/nature13910). Importantly, we have previously shown that Dicer and DGCR8 are transcriptional targets of p63 (Su et al., Nature, 2010 Oct 21;467(7318):986-90 and Chakravarti et al., Proc Natl Acad Sci U S A, 2014 Feb 4;111(5):E572-81. doi: 10.1073/pnas.1319743111). To identify inhibitors of ΔNp63 or ΔNp73 as a means to identify compounds that may be used to target the p53 pathway therapeutically, we screened a drug library of more than 850 FDA approved compounds. We found several small molecules that were able to reduce ΔNp63 protein stability and a specific set of miRNAs essential for the effectiveness of the drugs. In vivo analyses of these compounds as well as of these miRNA inhibitors have shown their efficacy in counteracting tumor formation and progression in genetically engineered mouse models deficient for p53 and in patient derived xenograft (PDX) mouse models with tumors that have p53 mutations. In summary, we have now identified multiple modalities to therapeutically target the p53 pathway through manipulation of p63 and p73.
Citation Format: Elsa R. Flores. Therapeutically targeting the p53 pathway using miRNA-based approaches in mouse models of cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr SY18-03. doi:10.1158/1538-7445.AM2015-SY18-03
Abstract SY21-04: Starting an immune response against pancreatic cancer: Getting past the stroma
Authors: Vonderheide Robert H. 
Published: August 2015

Abstract
Pancreatic ductal adenocarcinoma (PDA) is a highly aggressive and lethal cancer which is poorly responsive to standard therapies. Although the PDA tumor microenvironment is considered especially immunosuppressive, recent data mostly from genetically engineered and other mouse models of the disease suggest that novel immunotherapeutic approaches hold promise. Here, both laboratory and clinical efforts to target the CD40 pathway for immunotherapy in PDA will be described. Findings suggest that CD40 agonists can mediate both T-cell-dependent and T-cell-independent immune mechanisms of tumor regression in mice and patients. T-cell-independent mechanisms are associated with macrophage activation and the destruction of PDA tumor stroma, but these effects are transient. T cell-dependent mechanisms can be elicited with novel chemotherapy combinations and further extended by checkpoint blockade (with anti-PD-1 and/or anti-CTLA4). In the absence of anti-CD40 agonist antibody, neither chemotherapy nor checkpoint blockade can achieve meaningful tumor regressions nor long-term remissions, but inclusion of anti-CD40 can establish immune memory and cures in murine models. Overall, immune
modulation of the PDA tumor microenvironment represents a useful approach in cancer immunotherapy.
Citation Format: Robert H. Vonderheide. Starting an immune response against pancreatic cancer: Getting past the stroma. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr SY21-04. doi:10.1158/1538-7445.AM2015-SY21-04
Abstract SY35-01: The next generation of ADCs
Authors: Drachman Jonathan G. 
Published: August 2015

Abstract
The concept of an antibody-drug conjugate (ADC) is deceptively simple: a monoclonal antibody against a tumor-specific antigen delivers a potent cytotoxic payload directly to the malignant cells, resulting in targeted killing. However, this apparent simplicity belies a complex product with multiple interacting components. Working to optimize these components, we have identified three important concepts that impact the therapeutic potential of ADCs.
First, we have learned that stability of an ADC can vary according to the specific conjugation site on the antibody. During the development of engineered cysteine antibodies (EC-mAbs), we evaluated various cysteine substitutions and found that S239C on the IgG heavy chain is particularly stable when conjugated using standard maleimide chemistry. Alternatively, we have devised a method for producing stable conjugation to native cysteine residues by designing maleimides that catalyze their own ring-opening after coupling to the antibody. These modifications in ADC stability appear to result in both improved activity and decreased toxicity in preclinical models.
Second, we have observed that modulation of ADC hydrophobicity results in profound changes in both biodistribution and antitumor activity. When utilizing typical drug-linkers, ADCs with a high drug-to-antibody ratio (DAR &gt;4) appear to be cleared from circulation more rapidly by reticuloendothelial cells. By reducing drug-linker hydrophobicity, we can circumvent this clearance pathway and it becomes possible to increase the DAR, resulting in more potent ADCs that retain desirable pharmacokinetic properties. We have achieved a similar result with the use of short, discrete PEG oligomers to mask the drug linker, thereby reducing the apparent hydrophobicity of the ADC.
Finally, the chemical properties of the released payload have a major impact on both efficacy and toxicity. The difference between polar and nonpolar payloads will be discussed, including bystander activity, potential mechanisms of resistance, and adverse events observed in clinical trials.
A new class of DNA crosslinking payloads is represented by the pyrrolobenzodiazepines (PBD) dimer, which is several logs more potent than auristatins and has the ability to overcome multi-drug resistance phenotypes.
These examples demonstrate how rapidly the ADC field is evolving and provide hope that the next generation of ADCs will be even more effective and well-tolerated in the fight against cancer.
Citation Format: Jonathan G. Drachman. The next generation of ADCs. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr SY35-01. doi:10.1158/1538-7445.AM2015-SY35-01
Abstract SY39-03: Radiation-mediated DNA sensing pathway for immunity and tumor regression
Authors: Fu Yang-xin 
Published: August 2015

Abstract
It is thought that ablative radiotherapy (RT), used for rapid control tumor growth, induces genotoxic stress and mitosis crisis leading to prolonged dormancy of irradiated tumor at local and distal site in most patients. We have unexpectedly observed that initial reduction of tumor burden following ablative RT also depends largely on type I IFN for CTL. Targeting tumor with IFN can control tumor growth through initiating a coordinated innate and adaptive immune attack against tumor cells. However, the mechanism for radiation-mediated type I IFN induction remains unclear. Here, we demonstrated that STING, but not MYD88, was required for type I IFN-dependent antitumor effects of radiation. STING in dendritic cells (DCs) controlled radiation-mediated IFN-β induction and was activated by irradiated-tumor cells. The cytosolic DNA sensor cyclic GMP-AMP synthase (cGAS) mediated DCs sensing of irradiated-tumor cells. Moreover, STING was essential for radiation-induced adaptive immune responses, which relied on type I IFN signaling on DCs. Exogenous IFN-β treatment rescued cGAS/STING-deficient immune responses. Accordingly, enhancing STING signaling by cGAMP administration promoted antitumor efficacy of radiation. Our results reveal that the molecular mechanism of radiation-mediated antitumor immunity depends on a proper cytosolic DNA-sensing pathway, pointing towards a new understanding of radiation and host interactions. Furthermore, we uncover a new strategy to improve radiotherapy by cGAMP treatment. RT induced IFN can also upregulate PD-L1 that suppress T cell-mediated damage and develop radiation resistance for relapse over time. Anti-PDL-1 antibody can greatly reduce radiation resistance leading to complete tumor regression. Furthermore, our study challenges the rationale for current radio/chemotherapy strategies and highlights the importance of immune activation in preventing tumor relapse.
Citation Format: Yang-xin Fu. Radiation-mediated DNA sensing pathway for immunity and tumor regression. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr SY39-03. doi:10.1158/1538-7445.AM2015-SY39-03
Abstract SY43-01: Stereochemistry matters: L-2HG as a tumor response to hypoxia
Authors: Thompson Craig B. , Intlekofer Andrew M. , Dematteo Raymond G. , Venneti Sriram , Finley Lydia W. S. , Lu Chao , Rustenburg Ariën S. , Grinaway Patrick B. , Chodera John D. , Cross Justin R. , Judkins Alexander R. 
Published: August 2015

Abstract
Somatic mutations in isocitrate dehydrogenase 1 or 2 (IDH1/2) contribute to the pathogenesis of cancer via production of the ‘oncometabolite’ D-2-hydroxyglutarate (D-2HG). Elevated D-2HG can block differentiation of malignant cells by functioning as a competitive inhibitor of alpha-ketoglutarate (alpha-KG) dependent enzymes, including Jumonji family histone lysine demethylases. 2HG is a chiral molecule that can exist in either the D- or L- enantiomer. Although cancer-associated IDH1/2 mutations exclusively produce D-2HG, biochemical studies have demonstrated that L-2HG functions as a more potent inhibitor of alpha-KG-dependent enzymes. Here we report that under conditions of oxygen limitation, mammalian cells selectively produce L-2HG via enzymatic reduction of alpha-KG. Hypoxia-induced L-2HG is not mediated by IDH1 or IDH2, but instead results from promiscuous substrate usage by lactate dehydrogenase A (LDHA). During hypoxia, the resulting increase in L-2HG is necessary and sufficient for the induction of increased methylation of histone repressive marks, including histone 3 lysine 9 (H3K9me3). Thus, L-2HG appears to function as a metabolic signaling intermediate, translating information about oxygen availability into epigenetic modifications that can influence gene expression and cellular differentiation.
Citation Format: Craig B. Thompson, Andrew M. Intlekofer, Raymond G. Dematteo, Sriram Venneti, Lydia W. S. Finley, Chao Lu, Ariën S. Rustenburg, Patrick B. Grinaway, John D. Chodera, Justin R. Cross, Alexander R. Judkins. Stereochemistry matters: L-2HG as a tumor response to hypoxia. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr SY43-01. doi:10.1158/1538-7445.AM2015-SY43-01
Abstract SY44-03: Proteogenomic and phosphoproteomic analysis of ovarian cancer
Authors: Rodland Karin D. 
Published: August 2015

Abstract
A comprehensive molecular level view of cancer is desirable for understanding the underlying causes of disease, for predicting prognosis, and ultimately guiding treatment. The Cancer Genome Atlas (TCGA) conducted an extensive genomic and transcriptomic characterization of ovarian high-grade serous carcinoma (HGSC) with the objective of informing prognosis and the development of targeted therapies for this highly lethal gynecologic malignancy1. However, proteins are likely closer to biological and disease phenotypes, often not well correlated with their transcripts, and their characterization is expected to provide insights not evident from genomic studies. Therefore, to obtain a more comprehensive assessment of the complex HGSC phenotype, the Clinical Proteomic Tumor Analysis Consortium (CPTAC) conducted an extensive proteomic and phosphoproteomic characterization of the HGSC tumors previously characterized by TCGA, providing quantitative measurements for 10,030 proteins across 174 tumors, and 25,598 phosphosites from 6,769 phosphoproteins. Novel insights into ovarian cancer biology arising from these proteogenomic studies include: 1) a substantial trans-regulation of protein abundances by copy number alterations (CNAs), which when analyzed at a pathway level converged on the cancer-associated processes of proliferation, cell motility/invasion, and immune regulation; 2) identification of five proteomic subtypes in the TCGA cohort, with two subtypes showing robust concordance with the mesenchymal and proliferative subtypes, and tumors from transcript assigned differentiated and immunoreactive subtypes not robustly segregating into distinct clusters, demonstrating their proteomic heterogeneity; 3) identification of specific post-translational modifications associated with homologous repair deficiency; and 4) phosphoproteomic data revealing a consistent novel set of activated pathways associated with patient survival, including up-regulation of VEGFR signaling in patients with poor outcomes, and suggesting a strategy for selecting anti-angiogenesis therapies. This study will inform future use of protein markers to stratify patients who may benefit from anti-angiogenesis or PARP inhibitor therapy, predicting development of platinum resistant disease, identifying immunoregulatory networks that can be exploited for cancer immunotherapy, and determining the clinical phenotypes based upon proteomic ovarian cancer subtypes.
Citation Format: Karin D. Rodland. Proteogenomic and phosphoproteomic analysis of ovarian cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr SY44-03. doi:10.1158/1538-7445.AM2015-SY44-03
Low-Versus Standard-Dose Alteplase for Ischemic Strokes Within 4.5 Hours
Authors: Kim Beom Joon , Han Moon-Ku , Park Tai Hwan , Park Sang-Soon , Lee Kyung Bok , Lee Byung-Chul , Yu Kyung-Ho , Oh Mi Sun , Cha Jae Kwan , Kim Dae-Hyun , Lee Jun , Lee Soo Joo , Ko Youngchai , Park Jong-Moo , Kang Kyusik , Cho Yong-Jin , Hong Keun-Sik , Kim Joon-Tae , Choi Jay Chol , Kim Dong-Eog , Shin Dong-Ick , Kim Wook-Joo , Lee Juneyoung , Lee Ji Sung , Yoon Byung-Woo , Gorelick Philip B. , Bae Hee-Joon 
Published: August 2015

Background and Purpose—
The low-dose (0.6 mg/kg) alteplase strategy to treat acute ischemic stroke patients became widespread in East Asian countries, without rigorous testing against standard-dose (0.9 mg/kg) alteplase treatment. Our aim was to investigate the comparative effectiveness and safety of the low-dose versus standard-dose intravenous alteplase strategy.

Methods—
A total of 1526 acute ischemic stroke patients who qualified for intravenous alteplase and treated within 4.5 hours were identified from a prospective, multicenter, and nationwide stroke registry database. Primary outcomes were a modified Rankin scale score of 0 to 1 at 3 months after stroke and occurrence of symptomatic hemorrhagic transformation. Inverse probability of low-dose alteplase weighting by propensity scores was used to remove baseline imbalances between the 2 groups, and variation among centers were also accounted using generalized linear mixed models with a random intercept.

Results—
Low-dose intravenous alteplase was given to 450 patients (29.5%) and standard-dose intravenous alteplase to 1076 patients (70.5%). Low-dose alteplase treatment was comparable to standard-dose therapy according to the following adjusted outcomes and odds ratios (95% confidence intervals): modified Rankin scale score 0 to 1 at 3 months and 0.95 (0.68–1.32); modified Rankin scale 0 to 2 at 3 months and 0.84 (0.62–1.15); symptomatic hemorrhagic transformation and 1.05 (0.65–1.70); and 3-month mortality and 0.54 (0.35–0.83). The associations were unchanged when the analysis was limited to those without endovascular recanalization.

Conclusions—
The low-dose alteplase strategy was comparable to the standard-dose treatment in terms of the effectiveness and safety.
Combined Approach to Lysis Utilizing Eptifibatide and Recombinant Tissue-Type Plasminogen Activator in Acute Ischemic Stroke-Full Dose Regimen Stroke Trial
Authors: Adeoye Opeolu , Sucharew Heidi , Khoury Jane , Vagal Achala , Schmit Pamela A. , Ewing Irene , Levine Steven R. , Demel Stacie , Eckerle Bryan , Katz Brian , Kleindorfer Dawn , Stettler Brian , Woo Daniel , Khatri Pooja , Broderick Joseph P. , Pancioli Arthur M. 
Published: August 2015

Background and Purpose—
The Combined Approach to Lysis Utilizing Eptifibatide and Recombinant Tissue-Type Plasminogen Activator (r-tPA; CLEAR) in Acute Ischemic Stroke (AIS) and CLEAR-Enhanced Regimen (CLEAR-ER) trials demonstrated safety of reduced dose r-tPA plus the glycoprotein 2b/3a inhibitor, eptifibatide, in AIS compared with r-tPA alone. The objective of the CLEAR-Full Dose Regimen (CLEAR-FDR) trial was to estimate the rate of symptomatic intracerebral hemorrhage (sICH) in AIS patients treated with the combination of full-dose r-tPA plus eptifibatide.

Methods—
CLEAR-FDR was a single-arm, prospective, open-label, multisite study. Patients aged 18 to 85 years treated with 0.9 mg/kg IV r-tPA within 3 hours of symptom onset were enrolled. After obtaining consent, eptifibatide (135 μg/kg bolus and 2-hour infusion at 0.75 μg/kg per minute) was administered. The primary end point was the proportion of patients who experienced sICH within 36 hours. An independent clinical monitor adjudicated if an sICH had occurred and an independent neuroradiologist reviewed all images. The stopping rule was 3 sICHs within the first 19 patients or 4 sICHs within 29 patients.

Results—
From October 2013 to December 2014, 27 patients with AIS were enrolled. Median age was 73 years (range, 34–85; interquartile range, 65–80) and median National Institute of Health stroke scale score was 12 (range, 6–26; interquartile range, 9–16). One sICH (3.7%; 95% confidence interval, 0.7%–18%) was observed.

Conclusions—
These results demonstrate comparable safety of full-dose r-tPA plus eptifibatide with historical rates of sICH with r-tPA alone and support proceeding with a phase 3 trial evaluating full-dose r-tPA combined with eptifibatide to improve outcomes after AIS.
Literary Catholicity
Authors: Fischer Benjamin , Derbesy Philip C. 
Published: August 2015

The influence of G. K. Chesterton on the outlook and work of C. S. Lewis has long been a passing note for critics of Lewis. While some have admired Lewis’s adaptation of Chestertonian insights, others have made his mimesis the grounds for a general dismissal. None of these critics, however, have directly examined the nature of this influence itself. This essay addresses this critical omission by establishing the ways in which Lewis purposefully imitated his predecessor’s particular way of being a Christian who writes. From Chesterton, Lewis borrowed an approach to literary influence that not only rejects originality as an ultimate measure but also elevates deliberate literary imitation of earlier insights as necessary to Christian writing. In doing so, both writers drew on a common tradition, reworking and rearticulating it, and thereby contributed their own voices and insights to it.
New Prototrochus species of sea cucumber from Australia (Echinodermata: Holothuroidea: Synaptida: Myriotrochidae)
Authors: O’LOUGHLIN P MARK , MACINTOSH HUGH 
Published: August 2015

The case put by Alexey Smirnov in 2012 is accepted and the order name Synaptida Cuénot is adopted in place of Apodida Brandt. Two new Myriotrochidae Théel species from the continental slope of Australia are described: Prototrochus robbinsae sp. nov. and Prototrochus roniae sp. nov. A key to the six Australasian species of Prototrochus Beljaev & Mironov and a distribution and depth map are provided.
A new species of Pycnogonum Brünnich, 1764 (Arthropoda, Pycnogonida) from Flemish Cap (Northwest Atlantic Ocean)
Authors: MUNILLA TOMÁS , MURILLO FRANCISCO JAVIER , SOLER-MEMBRIVES ANNA 
Published: August 2015

A new pycnogonid species of the genus Pycnogonum is described from Flemish Cap (Northwest Atlantic Ocean) at 1453–1462 m depth. Pycnogonum bamberi sp. nov. is compared with its congeners, from which it can be distinguished by the combination of a glans-shaped proboscis, the low, transverse ridges that lie on the dorsodistal surfaces of the first coxae and femora of all legs and the distinctive conical tubercle on the mid-dorsal surface of the fourth segment of the trunk.
Horizontal Transition of Turbulent Cascade in the Near-Surface Layer of Tropical Cyclones
Authors: Tang Jie , Byrne David , Zhang Jun A. , Wang Yuan , Lei Xiao-tu , Wu Dan , Fang Ping-zhi , Zhao Bing-ke 
Published: August 2015

Abstract
Tropical cyclones (TC) consist of a large range of interacting scales from hundreds of kilometers to a few meters. The energy transportation among these different scales—that is, from smaller to larger scales (upscale) or vice versa (downscale)—may have profound impacts on TC energy dynamics as a result of the associated changes in available energy sources and sinks. From multilayer tower measurements in the low-level (&lt;120 m) boundary layer of several landing TCs, the authors found there are two distinct regions where the energy flux changes from upscale to downscale as a function of distance to the storm center. The boundary between these two regions is approximately 1.5 times the radius of maximum wind. Two-dimensional turbulence (upscale cascade) occurs more typically at regions close to the inner-core region of TCs, while 3D turbulence (downscale cascade) mostly occurs at the outer-core region in the surface layer.