tbuckley/cabot-search huggingface dataset:
Abstract 1951: Role of mitochondrial peptide Humanin in the response of experimental breast cancer to chemotherapy
Authors: Camila Zuccato, Mariela A. Moreno Ayala, Maria F. Gottardo, Matias Luis Pidre, Antonela S. Asad, Alejandro J. Nicola Candia, Victor Romanowski, Adriana Seilicovich, Marianela Candolfi
Journal: Cancer Research (2018)

Abstract Humanin (HN) is a mitochondrial-derived peptide with potent cytoprotective effect in many cell types. Administration of HN has been proposed as a therapeutic approach for several chronic diseases, such as diabetes, neurodegenerative conditions and cardiovascular diseases. Although HN has been shown to protect normal tissues against the toxic effects of chemotherapy, its role in tumor chemoresistance is poorly understood. Here, we aimed to elucidate the role of HN in the progression and cytotoxic response of experimental triple negative breast cancer (TNBC). We detected HN expression in murine and human TNBC cells, which was upregulated in the presence of chemotherapeutic drugs, i.e. Doxorubicin (DOXO) and Cisplatin, as assessed by flow cytometry. Addition of HN protected TNBC cells from various cytotoxic insults, such as serum deprivation, proapoptotic cytokine TNF-α or chemotherapy with DOXO. We next evaluated the role of endogenous HN in the apoptotic response of TNBC cells, using a plasmid encoding a short hairpin RNA to inhibit HN expression (pUC.shHN). To readily assess transduction efficiency, the plasmid also encodes the red fluorescent protein dTomato as a reporter gene. Transfection of TNBC 4T1 tumor cells with pUC.shHN increased the percentage of apoptotic cells when compared to cells transfected with control plasmid, as assessed by flow cytometry after staining with propidium iodide. When transfected 4T1 cells were incubated with different concentrations of DOXO, pUC.shHN reduced their clonogenic capacity. We also evaluated the effect of HN in the progression of experimental mouse 4T1 TNBC treated with DOXO. HN was readily detected in tumor samples and lung metastases. Systemic administration of HN reduced tumor apoptotic rate, accelerated tumor progression and increased the development of lung metastases. In addition, administration of HN impaired the antitumor and antimetastatic effect of chemotherapy. In summary, our findings suggest that HN inhibits the response of TNBC cells to cytotoxic stimuli, facilitating tumor progression and chemoresistance. Thus, blockade of HN could constitute a therapeutic strategy to improve the efficacy of chemotherapy in breast cancer. Citation Format: Camila Zuccato, Mariela A. Moreno Ayala, Maria F. Gottardo, Matias Luis Pidre, Antonela S. Asad, Alejandro J. Nicola Candia, Victor Romanowski, Adriana Seilicovich, Marianela Candolfi. Role of mitochondrial peptide Humanin in the response of experimental breast cancer to chemotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1951.
Abstract 14706: Cardiac Phenotype in Children Undergoing Screening for Familial Hypertrophic Cardiomyopathy: Is it Time to Change Screening Guidelines?
Authors: Laura Zahavich, Jacob Mathew, Judith Wilson, Kristen George, Sarah Bowdin, Leland N Benson, Seema Mital
Journal: Circulation (2015)

Introduction: Current hypertrophic cardiomyopathy (HCM) screening guidelines recommend that clinical and/or genetic screening of children with family history of HCM be initiated from age 10 years (European Society of Cardiology 2014) or 12 years (American Heart Association 2011) onward and earlier only in the presence of malignant family history, presence of symptoms and/or participation in competitive sports. We assessed the proportion of asymptomatic children undergoing HCM screening that developed HCM phenotype or major adverse cardiac events (MACE) prior to age 12 years. Methods: This was a single centre retrospective study of HCM kindreds referred for screening to our cardiomyopathy clinic. Index cases with HCM, and cases with secondary cardiomyopathy (metabolic, neuromuscular, syndromic) were excluded. Genotype and phenotype status at initial screening and last follow-up were analyzed. MACE was defined as occurrence of death, transplant, resuscitated cardiac arrest, implantation of ICD or myectomy. Results: From 2005-2014, 427 children were referred for cardiac screening secondary to a family history of HCM. Of these, 379 (88.8%) had first-degree relatives with HCM and 146 (34.1%) had a family history of sudden cardiac death. The median age at first screening was 7.4 years (range 1 day-17 years), and median follow-up duration was 3 years. 45% (13/29 tested) phenotype-positive children, and 53% (32/60 tested) phenotype-negative children has positive genetic testing. 27/427 (6.3%) were phenotype-positive (maximal LV wall thickness Z-score &gt;2.0) at initial screening and an additional 13 (3%) became phenotype-positive during follow-up. The median age at positive phenotypic diagnosis of HCM was 8 years (range 5 days-17 years) with 24 children being &lt;12 years old (5.6%). 11/427 (2.6%) suffered a MACE during follow-up. Median age at MACE occurrence was 10.9 years (range 6-15 years) with 6 children being &lt;12 years old at occurrence of MACE (1.4%). Conclusion: Overall, more than 5% children being screened for HCM were phenotype-positive and 1.4% suffered a MACE before 12 years of age. These data suggest the importance of revising existing guidelines to recommend clinical and/or genetic screening of HCM of all family members independent of age.
Abstract LB-373: Comprehensive analysis of cancer stemness
Authors: Tathiane M. Malta, Artem Sokolov, Andrew J. Gentles, Tomasz Burzykowski, Laila Poisson, John Weinstein, Bożena Kamińska, Joerg Huelsken, Larsson Omberg, Olivier Gevaert, Antonio Colaprico, Patrycja Czerwińska, Sylwia Mazurek, Lopa Mishra, Holger Heyn, Alex Krasnitz, Andrew K. Godwin, Alexander J. Lazar, The Cancer Genome Atlas Research Network, Joshua M. Stuart, Katherine Hoadley, Peter W. Laird, Houtan Noushmehr, Maciej Wiznerowicz
Journal: Cancer Research (2018)

Abstract Cancer progression involves the gradual loss of a differentiated phenotype and acquisition of progenitor and stem cell-like features. Here, we provide new stemness indices for assessing the degree of oncogenic dedifferentiation. We took advantage of an innovative one-class logistic regression machine learning algorithm (OCLR) to extract transcriptomic and epigenetic feature sets derived from non-transformed pluripotent stem cells and their differentiated progenies. Using OCLR, we were able to sort TCGA tumor samples by stemness phenotype and identify previously undiscovered biological mechanisms associated with the dedifferentiated oncogenic state. Analyses of tumor microenvironment revealed the correlation of cancer stemness with immune checkpoint expression and infiltrating immune system cells not previously anticipated. We have shown the de-differentiated oncogenic phenotype increased in the metastatic tumor that further justify their more aggressive phenotype. Application of our stemness indices reveals features of intra-tumor heterogeneity in molecular profiles obtained from the single-cell analyses. Finally, the machine learning-based indices allowed for the identification of chemical compounds and novel targets for the cancer therapies aiming at tumor differentiation. Our findings provide new prognostic signatures that enable cancer biologists and oncologists to quantify the impact of tumor stemness on outcome across cancer types and may help to pave the way for progress in treatment strategies for cancer patients. Citation Format: Tathiane M. Malta, Artem Sokolov, Andrew J. Gentles, Tomasz Burzykowski, Laila Poisson, John Weinstein, Bożena Kamińska, Joerg Huelsken, Larsson Omberg, Olivier Gevaert, Antonio Colaprico, Patrycja Czerwińska, Sylwia Mazurek, Lopa Mishra, Holger Heyn, Alex Krasnitz, Andrew K. Godwin, Alexander J. Lazar, The Cancer Genome Atlas Research Network, Joshua M. Stuart, Katherine Hoadley, Peter W. Laird, Houtan Noushmehr, Maciej Wiznerowicz. Comprehensive analysis of cancer stemness [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr LB-373.
Abstract 5615: Antibodies targeting TIP1 enhance the efficacy of radiotherapy in lung cancer and glioblastoma
Authors: Vaishali Kapoor, Abhay K. Singh, David Dadey, Kelly Hoye, Andrea Collins, Dinesh Thotala, Dennis Hallahan
Journal: Cancer Research (2018)

Abstract Antigens that are over-expressed in cancer in response to radiation are being used as novel targets. We showed tax interacting protein 1 (TIP-1) to be radiation-inducible that translocated to the surface of the cancer cell following irradiation. TIP-1, which consists of a single PDZ domain plays an important role in cell signaling, cancer development, and progression. TIP-1's involvement in various survival pathways makes it an attractive target for anticancer therapeutics. We used antibodies specific to this PDZ domain to determine its role in cancer cell survival. We monitored the proliferation of lung cancer (A549 and H460) and glioblastoma (D54 and U251) cells after 24, 48, 72 and 96h treatment with the anti-PDZ antibody. We observed a time-dependent proliferation arrest with anti-PDZ antibody treatment which was associated with increased apoptosis. The anti-PDZ antibody, when combined with radiation (3Gy), led to reduced proliferation and colony formation. Anti-PDZ antibody had no effect on the proliferation of normal lung (MRC-5) and endothelial (HUVEC) cells. Cells treated with anti-PDZ antibody showed decreased levels of the phosphorylated forms of AKT, mTOR, and a downstream substrate of mTOR, 4EBP1. Anti-PDZ antibody treatment also led to an overall reduction in basal levels of AKT, mTOR, and 4EBP1. Further, we evaluated the effect of the anti-PDZ antibody on tumor growth in heterotopic mouse models of lung cancer (A549) and glioma (U251). We observed significant growth delay in mice treated with anti-PDZ antibody treatment when compared to mice treated with the isotype control. The combination of the anti-PDZ antibody with radiation showed an additive effect. Immunoblot analysis of tumor tissues also showed downregulation of phosphorylated and total levels of AKT, mTOR and 4EBP1 in the tumors treated with anti-PDZ antibody. Overall, our results suggest that TIP-1 is a promising therapeutic target for treatment of lung cancer and glioblastoma. Antibodies specific to the PDZ domain of TIP-1 enhance the efficacy of radiotherapy. The anti-PDZ antibodies need to be optimized further before translating it into the clinic. Citation Format: Vaishali Kapoor, Abhay K. Singh, David Dadey, Kelly Hoye, Andrea Collins, Dinesh Thotala, Dennis Hallahan. Antibodies targeting TIP1 enhance the efficacy of radiotherapy in lung cancer and glioblastoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5615.
Abstract 3139: Innate immune cells expressing myeloperoxidase directly inhibit tumor NF-κB transcriptional activation during tumor initiation
Authors: Tracy W. Liu, Seth T. Gammon, David Piwnica-Worms
Journal: Cancer Research (2018)

Abstract Neutrophils are considered the primary defenders of the innate immune system. However, in the context of cancer, the role of neutrophils is complex where they can be host protecting or pro-tumorigenic. For example, myeloperoxidase (MPO), the major protein in neutrophils, produces reactive oxygen species (ROS); ROS can lead to tumor regression from cell cytotoxicity or cause DNA-damage resulting in genetic mutations triggering tumor initiation/progression. Using the melanoma cell lines, B16F10, stably expressing a NF-κB-driven Firefly luciferase (FLuc) reporter or an IκBα-FLuc fusion reporter gene, co-culture studies in vitro with bone marrow-isolated-neutrophils from C57BL/6 animals demonstrated inhibition of NF-κB transcriptional activation in a MPO activity-dependent manner. Using bioluminescence imaging with luminol, neutrophils pre-stimulated with 50uM phorbol myristate acetate (PMA) demonstrated an increase in MPO activity by 20.3 ± 2.4 fold over unstimulated neutrophils. When B16F10 reporter cells were co-cultured with PMA pre-stimulated neutrophils, we observed inhibition of IκBα degradation by 33.0% ± 11.9%, resulting in a decrease in NF-κB transcriptional activation compared to co-culture studies with unstimulated neutrophils. The role of neutrophils during B16F10 tumor initiation and growth was compared in C57BL/6 and syngeneic MPO-null mice. Utilizing intravital imaging with skinfold window chamber animal models and imaging reporters, we evaluated in real-time, the recruitment of MPO-expressing cells and tumor NF-κB activation in vivo. Mean NF-κB transcriptional activation within the tumor compartment in MPO-null mice was 42.2% ± 1.6% greater compared to wild type animals. Tumor growth and survival curves demonstrated that B16F10 tumors grew slower in wild-type animals (mean survival of 26.8 days) compared to MPO-null animals (mean survival time of 23.4 days). Using an MPO inhibitor, 4-aminobenzoic acid hydrazide (4-ABAH), we pharmacologically mimicked the MPO-null phenotype in C57BL/6 animals (40mg/kg intraperitoneal injection twice daily). B16F10 tumors grew slower in C57BL/6 animals treated with 4-ABAH (mean survival of 23.8 days) compared to wild type animals. Taken together, these data demonstrated that MPO-expressing cells contribute to host protection during tumor initiation in a NF-κB-dependent manner. Citation Format: Tracy W. Liu, Seth T. Gammon, David Piwnica-Worms. Innate immune cells expressing myeloperoxidase directly inhibit tumor NF-κB transcriptional activation during tumor initiation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3139.
Growth Factor Therapy and Autologous Lymph Node Transfer in Lymphedema
Authors: MarkkuLähteenvuo, KristaHonkonen, TomiTervala, TuomasTammela, ErkkiSuominen, JohannaLähteenvuo, IvanaKholová, KariAlitalo, SeppoYlä-Herttuala, AnneSaaristo
Journal: Circulation (2011)

Background—Lymphedema after surgery, infection, or radiation therapy is a common and often incurable problem. Application of lymphangiogenic growth factors has been shown to induce lymphangiogenesis and to reduce tissue edema. The therapeutic effect of autologous lymph node transfer combined with adenoviral growth factor expression was evaluated in a newly established porcine model of limb lymphedema. Methods and Results—The lymphatic vasculature was destroyed within a 3-cm radius around an inguinal lymph node. Lymph node grafts and adenovirally (Ad) delivered vascular endothelial growth factor (VEGF)-C (n=5) or VEGF-D (n=9) were used to reconstruct the lymphatic network in the inguinal area; AdLacZ (β-galactosidase; n=5) served as a control. Both growth factors induced robust growth of new lymphatic vessels in the defect area, and postoperative lymphatic drainage was significantly improved in the VEGF-C/D–treated pigs compared with controls. The structure of the transferred lymph nodes was best preserved...
Abstract B14: IGF axis proteins are the main carcinogens in ovulatory follicular fluid: Evidences from a mammary fat pad tumorigenesis model
Authors: Hsuan-Shun Huang, Sung-Chao Chu, Tang-Yuan Chu
Journal: Clinical Cancer Research (2018)

Abstract Ovarian high-grade serous carcinoma (HGSC) is the most devastating gynecologic cancer with elusive etiology and poor prognosis. Previous studies have disclosed that TP53 mutation is the universal and earliest genetic hit in its origin in the fallopian tube fimbriae. We and others have reported that ROS in ovulatory follicular fluid (FF) is the main mutagen that induces DNA double-strand breaks in fimbrial epithelial cells. However, ROS alone could not explain the transformation activity of FF found by our early study. In parallel studies (abstract by Chu TY et al.), we disclosed the presence of inactive IGF axis proteins in FF, including IGFBP-bonded IGFs and the GAG-free PAPP-A cleaving enzyme. Upon docking to the cell membrane at GAG sites, PAPP-A cleaves IGFBP, frees IGF to bind with IGF-1R, activates the downstream PI3K/Akt/mTOR signaling pathway, and results in the full transformation of the p53/Rb-null immortalized fimbrial epithelial cells. In this study, we established a tumorigenesis induction model in Trp53-/- mice to study the carcinogenic activity of FF. Upon repeated injection of ROS-high FF into the mammary fat pad of Trp53-/- mice, 10 of the 18 (56%) mice grew tumor around the injection site within 8 weeks. The histology showed small and mature B cell non-Hodgkin lymphoma. In contrast, no tumor growth was noted by 16 weeks when FF was injected subcutaneously or when mice were castrated. When IGF2 was depleted from the FF by monoclonal antibody, there was no tumor growth 8 weeks after the same repeated fat pad injections. By contrast, repeated injection of 100ng/ml IGF2 resulted in tumorigenesis in 33% (2/6) of the mice. The study provides in vivo evidence showing that other than ROS, IGF axis proteins are the main carcinogen in ovulatory follicular fluid. Citation Format: Hsuan-Shun Huang, Sung-Chao Chu, Tang-Yuan Chu. IGF axis proteins are the main carcinogens in ovulatory follicular fluid: Evidences from a mammary fat pad tumorigenesis model. [abstract]. In: Proceedings of the AACR Conference: Addressing Critical Questions in Ovarian Cancer Research and Treatment; Oct 1-4, 2017; Pittsburgh, PA. Philadelphia (PA): AACR; Clin Cancer Res 2018;24(15_Suppl):Abstract nr B14.
Novel simultaneous endoscopic ultrasound-guided hepaticoduodenostomy and hepaticogastrostomy for recurrent hepatic hilar obstruction
Authors: Susumu Hijioka, Yasunari Sakamoto, Akihiro Ohba, Yuta Maruki, Justin C. Y. Chan, Takuji Okusaka, Yutaka Saito
Journal: Endoscopy (2018)

We present the case of a 46-year-old man who had undergone percutaneous side-by-side multi-stent drainage for hepatic hilar obstructive jaundice due to colorectal liver metastases ([Fig. 1]). Six months later, obstructive jaundice was again noted. Contrast-enhanced computed tomography (CT) revealed recurrent hilar obstruction due to tumor ingrowth into the stent.
Endothelial Vasodilator Function Is Preserved at the Spastic/Inflammatory Coronary Lesions in Pigs
Authors: KenjiMiyata, HiroakiShimokawa, TohruYamawaki, IkukoKunihiro, XuchenZhou, TaikiHigo, ErikoTanaka, NaokiKatsumata, KensukeEgashira, AkiraTakeshita
Journal: Circulation (1999)

Background—The question of whether or not endothelial vasodilator function in the spastic coronary artery is preserved is still controversial. We recently developed a porcine model in which long-term and local treatment with interleukin-1β (IL-1β) from the adventitial site causes coronary arteriosclerotic changes and vasospastic responses to autacoids. The aim of this study was to examine the endothelial vasodilator function in our new porcine model of the spasm both in vivo and in vitro. Methods and Results—A segment of the porcine coronary artery was aseptically wrapped with cotton mesh that held absorbed IL-1β–bound microbeads. Two weeks after the procedure, intracoronary administration of serotonin caused coronary vasospasm at the IL-1β–treated site (n=10). Coronary vasodilatation to bradykinin, substance P, or an increase in coronary blood flow was preserved at the spastic site. Vasodilator responses to 3-morpholinosydnonimine (an NO donor) and nitroglycerin also were comparable between the 2 sites. ...
Abstract 3097: Chemo prevention effect of Withaferin A, a natural compound, on mouse models of colorectal carcinogenesis
Authors: Deeksha Pal, Balaji Chandrasekaran, Becca Von Baby, Houda Alatassi, Murali Ankem, Chendil Damodaran
Journal: Cancer Research (2018)

Abstract Introduction: Colorectal cancer (CRC) is the most common cancer and one of the leading causes of cancer-related deaths in United States as well as worldwide. Development of sporadic CRC takes an average of 15-20 years, so establishing preventive measures are possible. We are interested in a dietary compound, Withaferin-A (WA), which possesses both chemotherapeutic and chemopreventive properties. WA's effect was studied on both colitis-mediated colon and spontaneous-intestinal carcinogenesis mouse models. Methods: In the present study, two animal models of colon cancer were used to study the chemo- preventive effect of WA. In intestinal tumorigenesis model C57BL/6-ApcMin/+ , mice at six weeks of age were orally fed with the vehicle or WA (4mg/kg body weight of mice) for five days per week for 12-14 weeks. The other model used was AOM/DSS (Azoxymethane/dextran sulfate sodium), which induces gut inflammation and tumorigenesis. Intraperitoneal injection of AOM (8mg/kg) was followed by three cycles of DSS. WA (3mg/kg body weight of mice) was administered five times per week for 8-10 weeks. After completion of the studies, the tumor tissues were subjected to histopathological and molecular analysis. An unpaired Student's t-test was used for statistical analysis. Results: Oral administration of WA to ApcMin/+ mice leads to a significant decrease in the number of intestinal polyps and colon tumors (colon: 42%, p=0.025), proximal: 53%, p=0.0063, middle: 27.84%, p= 0.28, distal: 32.8, p= 0.001) when compared to vehicle-treated mice. Similarly, in AOM/DSS, oral administration of WA reduced polyp multiplicity by 40% (p= 0.02) compared to vehicle-treated controls. Moreover, the treatment group of both colon cancer models showed inhibition of pro-survival signaling markers (Notch1, pAKT and NFκB) as well as a decrease in proliferative markers. Conclusion: Our results suggest that WA effectively suppresses intestinal polyp development and colitis-mediated colon carcinogenesis, suggesting a preventive and therapeutic role in colon cancer models. These findings warrant further investigation to develop novel strategies to achieve maximum benefit of dietary agents for cancer chemoprevention. Citation Format: Deeksha Pal, Balaji Chandrasekaran, Becca Von Baby, Houda Alatassi, Murali Ankem, Chendil Damodaran. Chemo prevention effect of Withaferin A, a natural compound, on mouse models of colorectal carcinogenesis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3097.