bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract LB-303: Identification of a mammalian sterile-20 like kinase 4 (MST4) inhibitor to target pituitary tumorigenesis
Authors: Xiong Weipeng , Matheson Chris , Backos Donald S. , Xu Mei , Kiseljak-Vassiliades Katja , Salian-Mehta Smita , Reigan Philip , Wierman Margaret E.
Published: August 2015

Pituitary tumors of the gonadotrope lineage are often large and invasive, resulting in hypopituitarism. There are no medical treatments currently available. Using a combined genetic and genomic screen of human pituitary tumor samples, we identified the Mammalian sterile-20 like kinase 4 (MST4) as a pro-tumorigenic effector, driving increased pituitary cell proliferation and survival in response to a hypoxic microenvironment. MST4 is a member of the germinal center kinase III subfamily of Ste-20 kinases with limited data available concerning its role in tumorigenesis. To identify selective inhibitors of the MST4 kinase, computational-based virtual library screening was employed to dock the commercially available SelleckChem kinase inhibitor library into the ATP binding site of the MST4 crystal structure. Several candidate MST4 kinase inhibitors were identified with the potential to bind with high affinity. Using a newly developed TRFRET in vitro kinase assay, one of the small molecule compounds exhibited a potent inhibition of the MST4 kinase (IC50 = 6.18 nM +/- 2.2 nM). To determine the ability of this inhibitor to antagonize MST4 actions, a hypoxic LβT2 gonadotrope pituitary cell model was used. Under chronic hypoxia (5% O2), cells stably overexpressing MST4 showed an increased rate of proliferation (at 7 days, 3.16-fold, p = 0.006) compared to vector control cells as assessed by BrdU staining. These effects were completely blocked by the inhibitor at 50nM (-2.61-fold, p = 0.01, NS from controls). Similarly, MST4 protection from hypoxia induced apoptosis under 1% O2 for 17h was also inhibited at the same dose as assessed by TUNEL staining (-2.72-fold, p<0.001, NS from controls). Analysis of transfectants expressing wildtype and Mst4-mutants (K53E-kinase dead, T178A-loss of autophosphorylation, and C-terminus deletion) confirmed the inhibitory effect was dependent on the kinase sequence. Together, these data identify a potent inhibitor of the MST4 kinase with the capacity to selectively block pituitary cell growth under a hypoxic microenvironment and support future studies of its ability to modulate pituitary tumor growth in rodent models.

Citation Format: Weipeng Xiong, Chris Matheson, Donald S. Backos, Mei Xu, Katja Kiseljak-Vassiliades, Smita Salian-Mehta, Philip Reigan, Margaret E. Wierman. Identification of a mammalian sterile-20 like kinase 4 (MST4) inhibitor to target pituitary tumorigenesis. [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 LB-303. doi:10.1158/1538-7445.AM2015-LB-303
Abstract SY01-04: Chloroquine derivatives as anticancer agents
Authors: Amaravadi Ravi K.
Published: August 2015

Mouse models of cancer have demonstrated that therapy-induced autophagy in advanced cancer can promote tumor cell survival and resistance to therapy. Chloroquine derivatives impair autophagy by impairing lysosomal function. Preclinical studies in many, but not all, cancer models have shown that combining chloroquine derivatives with other anticancer agents produces autophagic vesicle accumulation followed by enhanced cancer cell death. Based on these results, clinical trials involving the hydroxychloroquine (HCQ) have been launched for patients with refractory malignancies. The results of the first 6 HCQ clinical trials (5 in humans, 1 in dogs) represent the first deliberate attempt to modulate autophagy therapeutically in patients. These studies indicate that autophagy can be modulated therapeutically with HCQ in patients. While the majority of patients did not experience unexpected toxicity, specific HCQ- chemotherapy combinations did produce enhanced myelosuppression, indicating treatment with HCQ and other chloroquine derivatives should continue to only be considered in the context of clinical trials. Encouraging antitumor activity of HCQ based combinations was observed in patients with melanoma, colon cancer, renal cell carcinoma, and in pet dogs, but randomized studies will be needed to determine if the activity can be attributed to the addition of HCQ. Preliminary results of currently enrolling or more recently completed clinical trials involving hydroxychloroquine will be highlighted. A serum-based approach based on secretome analysis of melanoma cells grown in three dimensional culture has identified potential quantitative biomarkers of low and high tumor cell autophagy. This approach could potentially lead to predictive and pharmacodynamic assays of response to autophagy modulation. To improve the potency of chloroquine derivatives against cancer we have previously reported a dimeric chloroquine Lys05, which is being evaluated for clinical development. Based on analysis of 70 new derivatives of Lys05, compounds which localize to the lysosome, inhibit autophagy and exhibit nanomolar cytotoxicity profiles have been identified. Finally we will discuss ongoing efforts to develop a more detailed understanding of the mechanism of action chloroquine as an anticancer agent.

Citation Format: Ravi K. Amaravadi. Chloroquine derivatives as anticancer agents. [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 SY01-04. doi:10.1158/1538-7445.AM2015-SY01-04
Abstract SY10-04: Histone tail alterations in cellular senescence
Authors: Duarte Luis F. , Young Andrew R. J. , Wang Zichen , Wu Hsan-Au , Panda Taniya , Kou Yan , Kapoor Avnish , Hasson Dan , Mills Nicholas R. , Ma'ayan Avi , Narita Masashi , Bernstein Emily
Published: August 2015

The process of cellular senescence generates a repressive chromatin environment, however, the role of histone tail modifications, histone variants and histone proteolytic cleavage in senescence remains unclear. Using well-characterized senescence models in human primary lung fibroblasts and melanocytes, we are investigating how chromatin alterations contribute to the senescence phenotype. Here we report novel histone H3 tail cleavage events in oncogene-induced and replicative senescence models mediated by the protease Cathepsin L. We find that cleaved forms of H3 are nucleosomal and that H3.3 is the preferred cleaved form of H3 - an H3 histone variant that is deposited independent of DNA replication. Ectopic expression of H3.3 and its cleavage product (H3.3cs1), which lacks the first twenty-one amino acids of the H3 tail, is sufficient to induce senescence. Furthermore, we find that chromatin incorporation of H3.3cs1 is mediated by the HUCA (HIRA/UBN1/CABIN1/ASF1a) histone chaperone complex. Genome-wide transcriptional profiling revealed that H3.3cs1 facilitates transcriptional silencing of cell cycle regulators including RB/E2F target genes, likely via the permanent removal of H3K4me3. Collectively, our studies have identified histone H3.3 and its proteolytically processed forms as key regulators of cellular senescence.

Citation Format: Luis F. Duarte, Andrew R. J. Young, Zichen Wang, Hsan-Au Wu, Taniya Panda, Yan Kou, Avnish Kapoor, Dan Hasson, Nicholas R. Mills, Avi Ma'ayan, Masashi Narita, Emily Bernstein. Histone tail alterations in cellular senescence. [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 SY10-04. doi:10.1158/1538-7445.AM2015-SY10-04
Abstract SY11-04: Genetics of immune escape
Authors: Hacohen Nir
Published: August 2015

How the genomic landscape of a tumor shapes and is shaped by anti-tumor immunity has not been systematically explored. Using large-scale genomic datasets of solid tissue tumor biopsies, we quantified the cytolytic activity of the local immune infiltrate and identified associated properties across 18 tumor types. The number of predicted MHC Class I-associated neoantigens was correlated with cytolytic activity and was lower than expected in colorectal and other tumors, suggesting immune-mediated elimination. We identified recurrently mutated genes that showed positive association with cytolytic activity, including beta-2-microglobulin (B2M), HLA-A, -B and -C and Caspase 8 (CASP8), highlighting loss of antigen presentation and blockade of extrinsic apoptosis as key strategies of resistance to cytolytic activity. Genetic amplifications were also associated with high cytolytic activity, including immunosuppressive factors such as PDL1/2 and ALOX12B/15B. Our genetic findings thus provide evidence for immunoediting in tumors and uncover mechanisms of tumor-intrinsic resistance to cytolytic activity.

Citation Format: Nir Hacohen. Genetics of immune escape. [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 SY11-04. doi:10.1158/1538-7445.AM2015-SY11-04
Abstract SY12-03: Obesity, inflammation and breast cancer
Authors: Dannenberg Andrew J.
Published: August 2015

Obesity is a risk factor for the development of hormone receptor-positive breast cancer in postmenopausal women. In addition to its impact on breast cancer risk, obesity has been recognized as a poor prognostic factor among breast cancer survivors. Obesity causes subclinical inflammation in visceral and subcutaneous white adipose tissue, characterized by macrophages surrounding dead or dying adipocytes forming crown-like structures (CLS). Estrogen synthesis is catalyzed by aromatase, which is encoded by CYP19. Several pro-inflammatory mediators including PGE2 and TNF-alpha are known inducers of aromatase. Utilizing a combination of preclinical models and human breast tissue samples, we demonstrated that obesity was associated with increased numbers of CLS in the breast (CLS-B), activation of the NF-κB transcription factor, increased levels of pro-inflammatory mediators and elevated aromatase expression. These findings raise the possibility that the obesity-inflammation-aromatase axis is important for understanding the link between obesity and hormone receptor-positive breast cancer in postmenopausal women. To further explore the potential clinical significance of breast adipose inflammation, a retrospective study was carried out to investigate the relationship between CLS-B and breast cancer recurrence. The presence of CLS-B at the time of index mastectomy was associated with shortened recurrence free survival in women who develop recurrent breast cancer. Whether white adipose inflammation promotes the progression of breast cancer via local effects, systemic mechanisms, e.g., hyperinsulinemia or both is uncertain. Given the apparent significance of white adipose inflammation (CLS-B) in the pathogenesis of disease, a blood-based biomarker discovery effort has been initiated. Elevated levels of CRP, IL-6 and insulin as well as altered levels of numerous metabolites correlate with the presence of breast white adipose inflammation. Finally, the connection between obesity, adipose inflammation and cancer provides a strong rationale for attempting to develop effective anti-inflammatory interventions. This will be illustrated with findings from a recent preclinical study that utilized caloric restriction to reverse adipose inflammation and related molecular changes in the mammary glands of obese mice.

Citation Format: Andrew J. Dannenberg. Obesity, inflammation and breast 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 SY12-03. doi:10.1158/1538-7445.AM2015-SY12-03
Abstract SY18-03: Therapeutically targeting the p53 pathway using miRNA-based approaches in mouse models of cancer
Authors: Flores Elsa R.
Published: August 2015

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

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

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 >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

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

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

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
Inference-Based Approach versus Cognitive Behavioral Therapy in the Treatment of Obsessive-Compulsive Disorder with Poor Insight: A 24-Session Randomized Controlled Trial
Authors: Visser Henny A. , van Megen Harold , van Oppen Patricia , Eikelenboom Merijn , Hoogendorn Adriaan W. , Kaarsemaker Maarten , van Balkom Anton J.
Published: August 2015

Objective: Obsessive-compulsive disorder (OCD) with poor insight has severe consequences for patients; nonetheless, no randomized controlled trial has ever been performed to evaluate the effectiveness of any treatment specifically for poor-insight OCD. A new psychotherapy for OCD, the inference-based approach (IBA), targets insight in OCD by strengthening normal sensory-driven reality testing. The goal of the present study is to compare the effectiveness of this new treatment to the effectiveness of cognitive behavior therapy (CBT) for patients with OCD with poor insight. Method: A randomized controlled trial was conducted, in which 90 patients with OCD with poor insight received either 24 CBT sessions or 24 IBA sessions. The primary outcome measure was the Yale-Brown Obsessive Compulsive Scale (YBOCS). Secondary outcome measures were level of insight, anxiety and depressive symptoms, and quality of life. Mixed-effects models were used to determine the treatment effect. Results: In both conditions, a significant OCD symptom reduction was reached, but no condition effects were established. Post hoc, in a small subgroup of patients with the worst insight (n = 23), it was found that the patients treated with the IBA reached a significantly higher OCD symptom reduction than the patients treated with CBT [estimated marginal mean = -7.77, t(219.45) = -2.4, p = 0.017]. Conclusion: Patients with OCD with poor insight improve significantly after psychological treatment. The results of this study suggest that both CBT and the IBA are effective treatments for OCD with poor insight. The IBA might be more promising than CBT for patients with more extreme poor insight.
Hypnotics and Triazolobenzodiazepines - Best Predictors of High-Dose Benzodiazepine Use: Results from the Luxembourg National Health Insurance Registry
Authors: Cloos Jean-Marc , Bocquet Valéry , Rolland-Portal Isabelle , Koch Paul , Chouinard Guy
Published: August 2015

Background: Benzodiazepines are not all the same concerning their risk of high-dose use. Methods: We studied benzodiazepine use from the Luxembourg national records of all insured. We calculated the 12-year prevalence from 1995 to 2007. Benzodiazepine users were divided into 3 groups, short-term with no longer than 3-month intake, intermediate with multiple administration with at least a 1-year interruption, and continuous who never stopped. A high-dose user (HDU) was defined as a patient who received a higher dose than the yearly maximum usual therapeutic dose. Results: An average of 16.0% of the adult insured population received at least 1 benzodiazepine annually, 42.9% were older than 50, 55.9% were women, and 5.4% were HDUs. We found that 32.6% were short-term users, 49.0% intermediate and 18.4% continuous. Compared to diazepam, hypnotics had higher risks for high-dose use in at least 1 age group at first-benzodiazepine intake, the risks being greater in elderly subjects and women, the highest risks being with triazolam (adjusted odds ratio = 215.85; 95% confidence interval = 133.75-348.35) in the 69- to 105-year-old group at first-benzodiazepine intake. Anxiolytics had a low risk except for alprazolam and prazepam in the 69- to 105-year-old group at first-benzodiazepine intake, clonazepam and clobazam had the lowest risk in 18- to 43-year-olds at first-benzodiazepine intake. Alprazolam had dispensed volumes increased by threefold over the 12-year period. Conclusion: All hypnotics had higher risks for high-dose use compared to diazepam in continuous users. Two anxiolytics, clonazepam and clobazam, had the lowest risks. Hypnotics and the triazolobenzodiazepines alprazolam and triazolam were most problematic. Elderly subjects and women are at greater risks.
Predictive Factors for Time to Progression after Hyperthermic Mitomycin C Treatment for High-Risk Non-Muscle Invasive Urothelial Carcinoma of the Bladder: An Observational Cohort Study of 97 Patients
Authors: Sooriakumaran Prasanna , Chiocchia Virginia , Dutton Susan , Pai Aakash , Ayres Benjamin E. , Le Roux Pieter , Swinn Michael , Bailey Michael , Perry Matthew J.A. , Issa Rami
Published: August 2015

Introduction: Hyperthermic mitomycin (HM) is a novel treatment modality for selected patients with high-risk non-muscle invasive bladder cancer (NMIBC). We sought to determine predictors of response to this therapy. Patients and Methods: A longitudinal, cohort study of 97 patients with high-risk NMIBC treated with ≥4 HM instillations on a prophylactic schedule was conducted. The primary outcome was time-to-progression survival; secondary outcomes were overall survival, cancer-specific survival, and adverse events. Descriptive statistics, Kaplan-Meier survival analyses, Cox proportional hazards modelling, and univariate and multivariable regression were performed. Results: The presence of initial complete response (CR; no evidence of disease at first check video-cystoscopy and urine cytology) post-HM treatment was an independent predictor of good response to HM. Female patients and those without carcinoma in situ (CIS) also appeared to respond better to the intervention. The overall bladder preservation rate at a median of 27 months was 81.4%; 17/97 (17.5%) patients died during the course of the study. Conclusions: High-risk NMIBC patients can be safely treated with HM and have good oncological outcome. However, those without an initial CR have a poor prognosis and should be counselled towards adopting other treatment methodologies such as cystectomy. Female gender and lack of CIS may be good prognostic indicators for response to HM.
Bilateral Truncal Ligation of the Inferior Thyroid Artery during Bilateral Subtotal Thyroidectomy Causes a Decrease in Parathormone without Clinically Manifest Hypoparathyroidism: A Randomized Clinical Trial
Authors: Kebsch Astrid , Settmacher Utz , Lesser Thomas
Published: August 2015

Background: Bilateral truncal ligation (BTL) of the inferior thyroid artery (ITA) is frequently used during subtotal thyroidectomy to reduce the risk of post-operative bleeding as well as to reduce the blood loss intra-operatively. However, its effect on parathyroid function has not been evaluated in relation to age, residual and resected thyroid volume. Methods: A total of 83 patients were randomized to receive non-BTL or BTL. After bilateral resection, the residual thyroid tissue on each side was measured by intra-operative ultrasonography. Laboratory and clinical examinations were performed the day before operation, intra-operatively and on post-operative days 2 and 5. The primary outcome measure was the difference in intact parathormone (PTHi) on post-operative day 5. Secondary outcomes were laboratory-diagnosed hypocalcaemia or hypoparathyroidism and clinically manifest hypoparathyroidism, respectively. Results: PTHi on post-operative day 5 was significantly lower in the BTL group (29.4 vs. 34.7 ng/l in the non-BTL group, p = 0.033), especially in 61- to 80-year-old patients (0 vs. -7.91 ng/l, p = 0.029). The biggest decline in PTHi was found in the BTL group (-14.067 ng/l PTH, p = 0.018) with a residual thyroid volume of 0.5-1.9 ml. There were two cases of asymptomatic hypoparathyroidism in each group (5.1 vs. 4.8%, respectively, p = 1.000). The only case of clinically manifest hypoparathyroidism was in a BTL group patient aged 64 years (2.4%, p = 1.000). Conclusion: BTL of the ITA during subtotal thyroidectomy causes a larger decrease in PTH but does not lead to a significantly higher rate of clinically manifest hypoparathyroidism. BTL of the ITA, age >61 years, and a very small thyroid remnant (<2 ml) may be risk factors for post-operative hypoparathyroidism.
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.
A Commentary on Two Scientific Studies of the ruma (רומא) Jar from Qumran
Authors: Yellin Joseph
Published: August 2015

Two chemical studies of the ruma jar from Qumran Cave 7 are examined. It is shown that these researches, seemingly at odds, have more in common than not. It is argued that the evidence from both studies point to Jerusalem as the origin of the ruma jar although one of the studies concludes that the ruma jar was locally made in Qumran from local clay. The data from both studies are consistent but the interpretations differ.
The Oral-Written Textuality of Stichographic Poetry in the Dead Sea Scrolls
Authors: Miller Shem
Published: August 2015

Textuality in antiquity differs significantly from that of modern Western culture in which the text exists as a fixed, idealized abstraction. In antiquity reading was speaking, and stichography is a visual representation of this interface between speech and writing. Stichography’s spatialization displays scribes’ perception of the spoken text including the concomitants of oral performance. Stichography also reflects scribes’ attentiveness to the readership’s experience with the performed or inscribed text. Scribes interacted with compositions as authors, adapting them according to the exigencies of specific performance events. As a result, the transmission of a specific written layout can supersede parallelismus membrorum; nevertheless, parallelism is a constitutive device in the majority of stichographic texts. The demarcation of sense units elicits two symbiotic social uses, both of which are also implied by the content of the canon. Stichographic texts provide a formatted reference point that is styled to facilitate oral performance and pedagogy.
Hopkins’s Sermons and “Felix Randal”
Authors: Marshall Elaine F.
Published: August 2015

Since Alfred Thomas’s discovery in 1971 that Hopkins had entered the death of his parishioner, Felix Spencer, in St. Francis Xavier’s church record book, scholars have interpreted Hopkins’s sonnet, “Felix Randal,” in the context of his ministerial experience in Victorian Liverpool. This paper aims to add to existing research on “Felix Randal” by analyzing some of the sonnet’s underlying themes in the light of Hopkins’s Bedford Leigh and Liverpool sermons, and sources on Felix Spencer and his environment that have not yet received attention by critics. These sources include The Gore’s Directory, contemporary newspapers, and material on Felix Spencer’s burial. The investigation will reveal that, despite the differences between Hopkins’s sermons and “Felix Randal,” some of the teachings in his sermons, together with information on the social conditions in his urban parishes, can help the reader to probe the obscurities in the sonnet, and offer additional interpretations of its meaning.
Healing Vibrations through Visionary Art
Authors: Atkinson Maggie
Published: August 2015

Nineteenth-century visionary artist Georgiana Houghton believed in the healing qualities of her art, and she educated religious teachers and clergy about the nature of her spiritual images. This article examines Houghton’s mediumistic paintings and seeks to demonstrate how her experimentation with vibrant colors and manipulation of form prefigured early modernist painting techniques. In addition, this analysis expands on how Houghton transformed her knowledge of the tenets of Spiritualism, which she amalgamated with her understanding of the science of botany to produce flower form spiritual portraits that she later developed into complex visionary abstracted pictures.
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.
Mosses of Cook Islands
Authors: O'Shea Brian J.
Published: August 2015

checklist of the mosses of the Cook Islands group is provided, together with a brief introduction to the islands and a history of bryophyte collecting in the area. A total of 62 mosses are listed, an addition of 11 mosses to previously published information.
Name changes for 13 African mosses with invalid names
Authors: O'Shea Brian J.
Published: August 2015

Thirteen taxa currently listed on the sub-Saharan moss checklist have invalid names, mostly as homonyms. Each of these are reviewed and appropriate valid names are given.
Additions to the Bolivian Bryophyte Flora
Authors: Churchill Steven P. , Sanjines A. Ninel N. , Fuentes C. Alfredo , Lozano Reinaldo
Published: August 2015

Eleven hepatics and seven mosses are newly recorded for Bolivia. New generic records include Cronisia, Nowellia, Pleurozia (hepatics), and Meiothecium (mosses). Additional records for 21 bryophytes that were previously little known in Bolivia, including several from the isolated Chiquitano low mountain ranges, are given. Papillaria tenella Herzog and the name Papillaria diversifolia Herzog nom. nud. are identical to Toloxis imponderosa (Taylor) W.R. Buck
The first pagurapseudid species (Peracarida: Tanaidacea) from New Zealand with remarks on paguridean (Decapoda: Paguridea) and pagurapseudid convergence and competition
Authors: BIRD GRAHAM J. , WEBBER W. RICHARD
Published: August 2015

A new species of pagurapseudid, Macrolabrum maui, is described from the lower eulittoral rocky shore on the East Coast of the North Island, New Zealand. It is similar to M. haikung from Bass Strait, Australia and M. distonyx from New Caledonia. Males and females show little dimorphism. Typical of the subfamily Pagurapseudinae, M. maui inhabits shells of micro-molluscs such as the gastropods Eatoniella, Merelina, and Pisinna. A dichotomous key to the species of Macrolabrum is given. Possible competition for micro-mollusc shells between small pagurideans, notably their glaucothoe stage, and pagurapseudids is considered based on their convergent morphologies and on body sizes.
Cacoheterotanais rogerbamberi, a new genus and species of leptocheliid Tanaidacea (Crustacea: Peracarida) from shelf-waters of the Gulf of Mexico
Authors: MORALES-NÚÑEZ ANDRÉS G. , HEARD RICHARD W.
Published: August 2015

A new leptocheliid tanaidacean, Cacoheterotanais rogerbamberi gen. et sp. n., is described from the Continental Shelf of the eastern Gulf of Mexico at depths ranging from 10 to 30 m. The new monotypic genus and species is distinguished from the other genera within the Pseudonototanais complex, or genus-group, (Cocotanais, Heterotanais, Makassaritanais, Ogleus, and Pseudonototanais) by a combination of characters, including the (1) male antennule with three peduncular and three flagella articles, (2) male and female both having three articles in the uropodal endopod, (3) basis of the female maxilliped with three pairs of long distal setae, and (4) differences in the morphology, setation and shape of the male cheliped. A key and table are presented to further distinguish C. rogerbamberi from the genera and species within the Pseudonototanais complex.
First record of Tanaidacea (Crustacea) from a deep-sea coral reef in the Gulf of Guinea
Authors: Jakiel Aleksandra , Stępień Anna , Jóźwiak Piotr , Serigstad Bjørn , Błażewicz-Paszkowycz Magdalena
Published: August 2015

Four undescribed species of Tanaidacea were discovered during a baseline monitoring program conducted off the coast of Ghana. The specimens came from a deep-water reef largely composed of the ahermatypic coral, Lophelia pertusa. The tanaidacean material was collected during November 2012 onboard the RV Dr Fridtjof Nansen using a van Veen grab in depths of between 375 and 386 m. Three of the new species described herein are tanaidomorphans belonging to the genera Bathyleptochelia (Leptocheliidae), Pseudotanais (Pseudotanaidae) and Cryptocopoides (Cryptocopidae). The fourth species, an apseudomorphan, belongs to Calozodion (Metapseudidae), a genus hitherto known only from shallow waters (<200 m). This report constitutes the first records of tanaidaceans from a deep-sea Lophelia reef.