bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3433: Identification of potential salivary response biomarkers in subjects practicing yogic breathing
Authors: Balasubramanian Sundaravadivel , Janech Michael G. , Warren Graham W. 
Published: August 2015

Abstract
Yogic Breathing (YB; Pranayama) is a form of Yoga technique practiced since ancient times for healthy living. In the United States, the practice of Yoga has markedly increased in recent years. Recent data suggest that adjunctive Yoga in cancer patients may help patients with symptom management. Whereas there are data on Asana (Postures) that involve physical movements in cancer patients, there are limited data on YB. Considering the ease of practice when compared to Asana, YB might benefit patients who are already physically overwhelmed with symptom burden. Current data measure the outcomes of Yoga using subjective measures, but biomarkers in an easily accessible biospecimen might provide key information as to the effects of YB among practitioners. We hypothesized that YB stimulates alterations in the salivary biomarker expression. We conducted an Institutional Review Board approved pilot randomized controlled trial in 20 subjects (n = 10 in each group) to compare the salivary expression of biomarkers between a 20 min YB group vs. Attention Control (AC) group. The YB group performed two exercises (Pranava Pranayama, and Thirumoolar Pranayama) each for 10 min, and the AC group read a scientific article for the same amount of time. Tandem Mass Spectrometric (LC-LC-MS-MS), Multiplex, and Western blot analysis showed the differential expression of 22 salivary proteins associated with immune response, stress and cancer. As compared with the AC group, YB increased Deleted in Malignant Brain Tumor 1 (DMBT1) as early as 5 min and maintained significantly high levels in all time points tested. In contrast, YB reduced IL-1beta (at 10, 15 and 20 min) and IL-8 levels (at 5, 10, 15 and 20 min) in participants when compared to AC controls. Further analysis of salivary lipidomic profiles demonstrated marginal reductions in sphingosine and sphingosine-1-phosphate levels in YB group. Collectively, our data provide the first evidence that YB could alter salivary biomarkers associated with cancer, inflammation, and stress. These markers may be useful to evaluate symptom management via stress reduction and immune regulation.
Citation Format: Sundaravadivel Balasubramanian, Michael G. Janech, Graham W. Warren. Identification of potential salivary response biomarkers in subjects practicing yogic breathing. [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 3433. doi:10.1158/1538-7445.AM2015-3433
Abstract 3860: USP7 deubiquitinase promotes ubiquitin-dependent DNA damage signaling by stabilizing RNF168
Authors: Zhu Qianzheng , Sharma Nidhi , He Jingshan , Wani Gulzar , Wani Altaf A. 
Published: August 2015

Abstract
In DNA damage response (DDR), histone ubiquitination by RNF168 is a critical event, which orchestrates the recruitment of downstream DDR factors, e.g. BRCA1 and 53BP1. Here, we report USP7 deubiquitinase regulates the stability of RNF168. We showed that USP7 disruption impairs the monoubiquitination of H2A (uH2A) and ultraviolet radiation (UVR)-induced monoubiquitination of γH2AX, and decreases the levels of pBmi1, Bmi1, RNF168, pChk1 and BRCA1. USP7 silencing by siRNA reduces uH2A and UVR-induced monoubiquititination of γH2AX, as well as the levels of Ring1B, Bmi1, RNF168 and BRCA1, recapitulating the chronic USP7 deficiency. USP7 disruption also compromises the formation of UVR-induced foci (UVRIF) and ionizing radiation-induced foci (IRIF) of uH2A, poly-K63-ubiquititination and BRCA1, but does not affect UVRIF and IRIF of 53BP1. USP7 was shown to physically bind RNF168 in vitro and in vivo. Overexpression of wild-type USP7, but not its catalytic-inactive or interaction-defective mutants, prevents UVR-induced RNF168 degradation. Both USP7 mutants are unable to cleave Ub-conjugates of RNF168 in vivo. Furthermore, ectopic expression of RNF168, or both RNF8 and RNF168 together, rescue the formation of UVRIF and IRIF of poly-K63-ubiquititination and BRCA1. Taken together, these findings reveal an important role of USP7 in regulating ubiquitin-dependent signaling via stabilization of RNF168.
Note: This abstract was not presented at the meeting.
Citation Format: Qianzheng Zhu, Nidhi Sharma, Jingshan He, Gulzar Wani, Altaf A. Wani. USP7 deubiquitinase promotes ubiquitin-dependent DNA damage signaling by stabilizing RNF168. [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 3860. doi:10.1158/1538-7445.AM2015-3860
Abstract 4018: The role of c-MET/HGF signaling as a critical mediator of an invasive and resistant phenotype in colorectal cancer
Authors: Bradley Conor A. , Dunne Philip , McArt Darragh , Arthur Ken , McQuaid Stephen , Salto-Tellez Manuel , Johnston Patrick , Van Schaeybroeck Sandra 
Published: August 2015

Abstract
The c-MET proto-oncogene is frequently overexpressed (50-60%), amplified (5-10%), and mutated (5%) in colorectal cancer (CRC). Hepatocyte growth factor (HGF)-induced c-MET activation has been linked with migration, survival, invasion, and resistance to targeted therapy, and has been suggested as a possible prognostic biomarker for CRC. We are currently investigating the role of c-MET and microenvironment derived HGF in the acquisition of an invasive and migratory phenotype, and resistance to targeted therapy in CRC.
In order to model CRC tumour cell invasion and metastasis, we have generated invasive subpopulations from CRC cells using Boyden Invasion chambers. Invasive cell lines were characterised for protein expression/activity by Western blotting, and analysed for migratory and invasive potential using the xCELLigence System (Roche). To model the CRC microenvironment, we have utilised a range of co-culture techniques with CRC cell lines and colon fibroblasts. c-MET expression in FFPE tissues was measured using IHC in a tissue microarray (TMA) derived from early stage CRC patients.
HCT116 and LoVo invasive subpopulations showed an EMT-like, mesenchymal, migratory/invasive phenotype. In addition, increased expression and activation levels of c-MET were found in these sublines, which was determined to be ligand independent. Inhibition of c-MET using RNAi abrogated both basal and HGF-induced migration and invasion in CRC cell lines. Co-culture of CRC cells with HGF-expressing colon-derived fibroblasts leads to activation of c-MET, inducing CRC migration, invasion, and resistance to MEK inhibition, and this phenotype could be diminished using a HGF neutralising antibody. Significant increased expression levels of c-MET were also found in a CRC TMA compared to matched normal tissues, and also at the invasive edge of some CRC tumours, where it may be driving invasive biology.
The identification of key pathways driving metastasis has a huge potential to change treatment strategies in CRC. We intend to further investigate the role of c-MET in regulation of migration, invasion, and resistance to therapy in CRC. We hypothesise that patients with high tumoural c-MET at the invasive front may benefit in particular from anti- c-MET therapies.
Citation Format: Conor A. Bradley, Philip Dunne, Darragh McArt, Ken Arthur, Stephen McQuaid, Manuel Salto-Tellez, Patrick Johnston, Sandra Van Schaeybroeck. The role of c-MET/HGF signaling as a critical mediator of an invasive and resistant phenotype in colorectal 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 4018. doi:10.1158/1538-7445.AM2015-4018
Abstract 451: The vigorous immune microenvironment of microsatellite instable colon cancer is balanced by multiple counter-inhibitory checkpoints
Authors: Llosa Nicolas Jose , Cruise Michael , Tam Ada , Wick Elizabeth , Hechenbleikner Elizabeth , Taube Janis , Blosser Lee , Fan Hongni , Wang Hao , Zhang Ming , Luber Brandon , Papadopoulos Nickolas , Kinzler Kenneth , Vogelstein Bert , Sears Cynthia , Anders Robert , Pardoll Drew , Housseau Franck 
Published: August 2015

Abstract
We examined the immune microenvironment of primary colorectal cancer (CRC) using immunohistochemistry, laser capture microdissection/qRT-PCR, flow cytometry and functional analysis of tumor infiltrating lymphocytes. A subset of CRC displayed high infiltration with activated CD8+ CTL as well as activated Th1 cells characterized by IFN-γ production and the Th1 transcription factor Tbet. Parallel analysis of tumor genotypes revealed that virtually all of the tumors with this active Th1/CTL microenvironment had defects in mismatch repair, as evidenced by microsatellite instability (MSI). Counterbalancing this active Th1/CTL microenvironment, MSI tumors selectively demonstrated highly up-regulated expression of multiple immune checkpoints, including five - PD-1, PD-L1, CTLA-4, LAG-3 and IDO - currently being targeted clinically with inhibitors. These findings link tumor genotype with the immune microenvironment, and explain why MSI tumors are not naturally eliminated despite a hostile Th1/CTL microenvironment. They further suggest that blockade of specific checkpoints may be selectively efficacious in the MSI subset of CRC.
Significance. The findings reported in this article are the first to demonstrate a link between a genetically defined subtype of cancer and its corresponding expression of immune checkpoints in the tumor microenvironment. The mismatch repair defective subset of CRC selectively up-regulates at least 5 checkpoint molecules that are targets of inhibitors currently being clinically tested.
Citation Format: Nicolas Jose Llosa, Michael Cruise, Ada Tam, Elizabeth Wick, Elizabeth Hechenbleikner, Janis Taube, Lee Blosser, Hongni Fan, Hao Wang, Ming Zhang, Brandon Luber, Nickolas Papadopoulos, Kenneth Kinzler, Bert Vogelstein, Cynthia Sears, Robert Anders, Drew Pardoll, Franck Housseau. The vigorous immune microenvironment of microsatellite instable colon cancer is balanced by multiple counter-inhibitory checkpoints. [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 451. doi:10.1158/1538-7445.AM2015-451
Abstract 5315: Hydroxychloroquine inhibits proliferation and S6 phosphorylation in human renal carcinoma cells
Authors: Lee Hyung-Ok , Mustafa Aladdin , Hudes Gary R. , Kruger Warren D. 
Published: August 2015

Abstract
mTOR inhibitors are used to treat metastatic renal cell cancer (RCC), but most patients eventually become resistant. One possible mechanism for resistance is upregulation of autophagy, a pathway which helps recycle intracellular proteins and promotes cell survival. Hydroxychloroquine (HCQ), a potent autophagy inhibitor used to treat malaria and autoimmune disorders, is currently being studied in the context of cancer treatment. Here, we have investigated the effects of HCQ on three different renal carcinoma derived cell lines. We found that HCQ treatment inhibits RCC cell growth, promotes apoptosis, inhibits mitochondrial oxygen consumption, and increases glycolysis rates. To understand the molecular mechanism behind these effects, we examined various nodes in the mTOR pathway and compared the effects of HCQ with the effects of the mTOR inhibitor RAD001. A key downstream readout of the pathway, phospho-S6 protein, was inhibited by both HCQ and RAD001. However, the upstream kinase, P70S6K, was only inhibited by RAD001 and not HCQ, suggesting that the block by HCQ was downstream of the p70S6K. Treatment with the proteasome inhibitor bortezomib, restored phospho-S6 levels, suggesting that the reduction of phospho S6 is caused by increased degradation of phospho, but not total S6. Surprisingly, depletion of the key autophagy regulator Atg7 did not mimic the effects of HCQ, indicating that HCQ regulates S6 phosphorylation by ATG7-independent mechanism. Our finding suggests that HCQ may be useful in the treatment of renal cell carcinoma.
Citation Format: Hyung-Ok Lee, Aladdin Mustafa, Gary R. Hudes, Warren D. Kruger. Hydroxychloroquine inhibits proliferation and S6 phosphorylation in human renal carcinoma cells. [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 5315. doi:10.1158/1538-7445.AM2015-5315
Abstract 953: An anti-CD38 antibody drug conjugate for the treatment of diverse hematologic malignancies
Authors: Prudent James R. , Marshall David J. , Murphy John , Malavasi Fabio 
Published: August 2015

Abstract
Purpose:
The CD38 cell surface antigen is expressed in diverse hematologic malignancies including multiple myeloma, acute promyelocytic leukemia (PML), B-cell non-Hodgkin lymphoma (NHL), B-cell acute lymphoblastic leukemia (ALL), B-cell chronic lymphocytic leukemia (B-CLL),and T-cell ALL. Here, we assessed the antitumor activity of novel extracellular drug conjugates composed of anti-CD38 monoclonal antibodies conjugated to various steroidal derivatives via flexible stable linkers.
Experimental Design:
Activity of EDC8 was examined on lymphoma, leukemia and multiple myeloma cell lines and a B-cell lymphoma xenograft model in immunodeficient mice.
Results:
We identified that multiple anti-CD38 antibodies when conjugated to a novel small molecule steroids through long stable linkers could provide picomolar apoptotic activity independent of effector functions. These antibody drug conjugates, termed EDC8s, inhibited cytotoxic activity through a mechanism that was dependent on CD38 expression, as CD38 induction by ATRA could turn EDC8 resistant cells, sensitive, and naked anti-CD38 antibodies could compete with the EDC8s rendering them inactive. The activity of the EDC8s was also dependent on linker length and steroid chemistry. In vivo, EDC8 was active on a B-cell lymphoma CD38+ tumor xenograft model. Results from one of the EDC8s demonstrated in vivo tumor regression and cures when 5mgs/kg of the conjugate was administered and this anti-CD38 antibody drug conjugate had impressive single-agent activity greatly surpassing the activity of CHOP.
Conclusion:
These results support efforts to further evaluate these unique CD38-targeting antibody drug conjugates and may lead to phase I clinical trials in patients with certain CD38+ malignancies.
Citation Format: James R. Prudent, David J. Marshall, John Murphy, Fabio Malavasi. An anti-CD38 antibody drug conjugate for the treatment of diverse hematologic malignancies. [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 953. doi:10.1158/1538-7445.AM2015-953
Abstract 995: Regulation of radiation by autophagic modulator
Authors: Lee Keun Ho , Lee Yoon Kyung 
Published: August 2015

Abstract
Introduction: On account of limited therapeutic options for advanced and recurrent cervical cancer, novel therapeutic modalities are being investigated based on translational research. Among the promising topics is autophagy. Autophagy can be refered to as a double edged sword in a way that it is known to play a role in both tumor cell suppression and survival. This study was carried out to determine the effect of autophagy in treatment of cervical cancer cells with radiation alone and with autophagy inducer or inhibitor.
Methods: Human cervical cancer cells, Hela and Caski were used. Western blot was implemented to detect protein expression. Fluorescence microscopy and inverted microscopy guided inspection confimed autophagy. Hela and Caski cells were irradiated with r-rays (2 Gy / min) and again each time after treatment with autophagy inducer (Rapamycin) and inhibitor (3-MA). Expression of LC3 and cell deaths in two cell preparations were examined.
Results: Notable increment of LC3 expression were detected after radiation in both cell lines by western blot and microscope analyses. Radiation of pre-Rapamycin treated cells showed further increased LC3 expression and pre-3-MA treated cells, less increased LC3 expression than radiation alone compared to non-treated, not radiated cells. Cell viability decreased to 75% in Hela cells and 79% in Caski cells after radiation. When treated with Rapamycin, cell viabilities were 59% and 65%, and with 3-MA, 65% and 70% in each cell lines.
Discussion: Radiation induces autophagy in cervical cancer cell lines. Autophagy induced by radiation could be modified when treated with Rapamycin / 3-MA which leads to more cell deaths. Further investigations are needed to identify the specific pathways mediating post-IR induced autophagy in order to confirm the functional link between autophagy and radiation treatment. Inhibition of autophagy seems to promote more cells to undergo apoptosis, however, the relationship between autophagy and apoptosis with IR treatment in cervical cancer cells remain to be enlightened. Induction of autophagy may interfere with the mechanism of homeostasis that is originally preserved by autophagy itself, and leads to cell death possibly altogether with apoptosis. The pathway via which this process conducts also waits to be distinguished.
Citation Format: Keun Ho Lee, Yoon Kyung Lee. Regulation of radiation by autophagic modulator. [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 995. doi:10.1158/1538-7445.AM2015-995
Abstract LB-064: Characterization of the tumor suppressor function of the lysine-specific methyltransferase KMT2D in follicular lymphoma
Authors: Ortega-Molina Ana , Boss Isaac , Pan Heng , Jiang Yanwen , Hu Deqing , Gao Xin , Shaknovich Rita , Shilatifard Ali , Melnick Ari M. , Wendel Hans-Guido 
Published: August 2015

Abstract
Follicular lymphoma (FL) is a common and incurable form indolent B-cell lymphoma. Genomic studies have now catalogued many recurrent mutations in FL. Epigenetic regulators have emerged as the most common targets of somatic point mutations. For example, the histone methyltransferase KMT2D (MLL4/MLL2) is the most frequently mutated gene in FL with reported mutational frequencies of up to 84%. However, the transcriptional and biological consequences of KMT2D loss of function are currently unknown.
Using a well-described murine model of FL, we showed that deficiency of KMT2D promotes the initiation of indolent FL in vivo. To explore the mechanism of KMT2D-mediated tumor suppression we used cross species comparisons of gene expression, histone H3K4 methylation marks and KMT2D genomic occupancy. These analyses converge on a relatively small group of conserved target genes. Strikingly, they include bona fide tumor suppressors and regulators of B-cell proliferation (e.g. TNFAIP3/A20, SOCS3, ARID1A, and TNFRSF14). Our results indicate that KMT2D restrains FL development through simultaneous effects on multiple key regulators of B-cell behavior.
Note: This abstract was not presented at the meeting.
Citation Format: Ana Ortega-Molina, Isaac Boss, Heng Pan, Yanwen Jiang, Deqing Hu, Xin Gao, Rita Shaknovich, Ali Shilatifard, Ari M. Melnick, Hans-Guido Wendel. Characterization of the tumor suppressor function of the lysine-specific methyltransferase KMT2D in follicular lymphoma. [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-064. doi:10.1158/1538-7445.AM2015-LB-064
Abstract LB-080: Reactivating RBL2/p130 oncosuppressive function as a new, possible antitumoral strategy
Authors: Pentimalli Francesca , Esposito Luca , Forte Iris Maria , Iannuzzi Carmelina Antonella , Rizzolio Flavio , Tuccinardi Tiziano , Indovina Paola , Boffo Silvia , Giordano Antonio 
Published: August 2015

Abstract
Deregulation of cell cycle control is the leading cause of cancer. The retinoblastoma (Rb) family members, including RB1/p105, RBL1/p107 and RBL2/p130, are crucial to restrain cell cycle progression and their inactivation, either direct or indirect, is a hallmark of most human tumors. In particular, RBL2/p130 emerging role in senescence and apoptosis, seems to contribute importantly to its tumor suppressor function. Furthermore, many studies largely contributed to establish RBL2/p130 as an important cancer target, which is inactivated by cell cycle kinases and whose deregulation underlies various cancer types. In this regard, we set out to restore RBL2/p130 function in tumors and exploit its tumor suppressive potential for cancer therapy. In particular, we have identified, through computational chemistry and molecular modeling studies, a small molecule able to act as a specific inhibitor of the CDK2-CycA complex and to reactivate the tumor suppressive function of RBL2/p130 in cancer.
We analyzed by MTS assay the cytotoxic effect of our compound on a panel of different tumor cell lines and determined its IC50 values. We evaluated its effects on cell cycle and apoptosis by FACS and dissected its molecular mechanism of action by Western blot and RT-PCR.
We found that our compound effectively inhibited proliferation of lung cancer and mesothelioma cell lines by specifically inhibiting CDK2-CycA activity towards RBL2/p130. The decrease in RBL2/p130 phosphorylation led to stabilization of its complex with the E2F4 transcriptional factor and consequent repression of their targets necessary for cell cycle progression, including CDK2 itself. Consistently, our compound arrested cell cycle and triggered apoptosis. Interestingly, apoptosis seemed to be mediated by RBL2/p130 itself because it was repressed in RBL2/p130-silenced cells. Furthermore, our compound proved to be active in an A549 xenograft model of lung cancer.
Overall our findings indicate that the pharmacological reactivation of RBL2/p130 induces its cell-cycle restraining and pro-apoptotic functions, the latter being still largely unexplored, and identify a new possible therapeutic strategy for cancer treatment.
Citation Format: Francesca Pentimalli, Luca Esposito, Iris Maria Forte, Carmelina Antonella Iannuzzi, Flavio Rizzolio, Tiziano Tuccinardi, Paola Indovina, Silvia Boffo, Antonio Giordano. Reactivating RBL2/p130 oncosuppressive function as a new, possible antitumoral strategy. [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-080. doi:10.1158/1538-7445.AM2015-LB-080