tbuckley/cabot-search huggingface dataset:
Abstract 3054: CD47 signaling regulates a DNA damage response pathway by suppressing the expression of Schlafen-11 (SLFN11)
Authors: Anthony L. Schwartz, Sukhbir Kaur, Sai-Wen Tang, Yves Pommier, David D. Roberts
Journal: Cancer Research (2016)

Abstract Schlafen-11 (SLFN11) expression was recently shown to determine the sensitivity of human cancer cells to DNA damaging agents including topoisomerase inhibitors, DNA alkylating agents, and DNA synthesis inhibitors. High expression of SLFN11 in cancer cell lines results in increased sensitivity to these agents, whereas depletion of SLFN11 induces cellular protection. In addition, high expression of SHFN11 is associated with greater overall survival than low SLFN11 expression in ovarian patients treated with cisplatin. These observations suggest that SLFN11 may be an integral part of a critical DNA repair pathway. However, the pathways that regulate SLFN11 expression have not been reported. CD47 is an integrin-associated protein widely expressed on mammalian cells and frequently elevated in cancers. Its ligand, thrombospondin-1 (TSP1) induces CD47 signaling that regulates some growth factor receptors, cell fate, viability, and responses to cellular stresses such as radiation and chemotherapy. Our laboratory has previously shown that CD47 deficiency results in protection of nontransformed cells, whereas high CD47 expression sensitizes the same cells to ionizing radiation and DNA-damaging chemotherapy. We identified SLFN11 expression as a potential target of CD47 signaling by microarray analysis of a CD47-deficient mutant cell line and found that CD47 expression also correlates with that of SLFN11 in some human cancers. Thus, we sought to investigate the possible regulation of SLFN11 by CD47 by treating various cell lines with the function-modifying CD47 antibody B6H12 or its physiological ligands TSP1 and signal regulatory protein-α (SIRPα). qRT-PCR analysis revealed significant decreases in SLFN11 expression at 3 and 6 hours post-B6H12 treatment. Furthermore, treatment with TSP1 significantly decreased SHFN11 mRNA expression at the same time points, but SIRPα-Fc did not. Conversely, transient re-expression of CD47 in deficient cells elevated SLFN11 expression. These data demonstrate that pharmacological and physiological modulation of CD47 signaling acutely alters SLFN11 expression and suggests a potential mechanism by which CD47 modulates cellular sensitivity to DNA damaging chemotherapy agents. SLFN11 may in turn be a functional target and useful biomarker for the therapeutic CD47 antibodies currently in clinical trials. Citation Format: Anthony L. Schwartz, Sukhbir Kaur, Sai-Wen Tang, Yves Pommier, David D. Roberts. CD47 signaling regulates a DNA damage response pathway by suppressing the expression of Schlafen-11 (SLFN11). [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3054.
Abstract 4118: Honokiol inhibits lung cancer brain metastasis through inhibition of STAT3 signaling pathway
Authors: Yongik Lee, Jing Pan, Qi Zhang, Yian Wang, Ming You
Journal: Cancer Research (2016)

Abstract Lung cancer is the leading cause of cancer death in the United States, and metastasis to lymph-node (LN) and distal organs especially brain leads to sever complications and are the major cause of death. Preventing lung cancer development and metastases is important strategy to reduce lung cancer mortality. Honokiol (HNK), a natural compound present in magnolia bark extracts, has a good bioavailability profile and recently has also been shown to readily cross both the blood-brain barrier (BBB). We previously demonstrated that HNK can prevent and inhibit squamous lung cancer cell carcinoma both in-vitro and in-vivo. In the current study, we evaluated the anti-metastatic effects of HNK in both LN and brain murine models of lung tumor metastasis. The H2030-BrM3 (BR-brain seeking) lung tumor cells stably transfected with luciferase and GFP were orthotopically injected into lung for LN metastases, or directly to the left ventricle of mouse heart for brain metastases, LN or brain metastasis was monitored using a non-invasive IVIS bio-luminescent imaging system. To test the efficacy of HNK in preventing tumor cells migrating to LN or brain, mice were given 10 mg/kg per body weight HNK by aerosol (for lung to LN metastasis model) or oral gavage starting the day after tumor cell injection, our results reveal that HNK significantly prevented the metastasis of lung cancer cells to LN and brain. Our results demonstrate that HNK decreased LN metastases incidence to 30% compare to 100% in control mice, and inhibited brain metastasis near 70% compare to control. Furthermore, analysis of HNK's mechanism of action by utilizing both RNA sequencing and receptor tyrosine kinase assay suggests that its effect is primarily mediated by inhibiting STAT3 pathway. HNK specifically inhibits STAT3 phosphorylation, and knock-down STAT3 totally abrogated the anti-metastasis effects of HNK in brain metastatic lung cancer cell lines, PC9-BrM3 and H2030-BrM3. These finding suggest that HNK could provide novel chemopreventive or therapeutic options for preventing both lung tumor progression and lung cancer brain metastasis. Citation Format: Yongik Lee, Jing Pan, Qi Zhang, Yian Wang, Ming You. Honokiol inhibits lung cancer brain metastasis through inhibition of STAT3 signaling pathway. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4118.
Abstract 4405: Over-expression of PARP is associated with an aggressive phenotype and can be synergistically targeted using combination of PARP and XIAP inhibitors in breast cancer
Authors: Maqbool Ahmed, Azhar R. Hussain, Shaham Beg, Saravanan Thangavel, Rafia Begum, Dahish Ajarim, Fouad Al-Dayel, Abdul Khalid Siraj K. Siraj, Khawla S. Al-kuraya
Journal: Cancer Research (2016)

Abstract Breast cancer is the most common cancer in females and despite improvement in treatment modality with the introduction of hormonal targeted therapy, these cancers still remains a major cause of morbidity and mortality in females. Poly ADP ribose polymerase (PARP) is an enzyme which plays a critical role for repairing single-strand breaks. The main function of PARP1 is dependent upon cellular stress responses and directs cells towards DNA repair based on the strength of the stress stimulus. PARP has been found to be over-expressed in various tumors including ovarian cancer; breast cancer and lung cancer, however, its role in the pathogenesis of breast cancer of Middle Eastern origin have not been completely elucidated. Therefore, we examined the expression of PARP in a large cohort of more than 1000 breast cancer by IHC in a tissue microarray format and found PARP was over expressed in 44.7% (451/1008) and was found to be significantly associated with aggressive markers such as Triple negative phenotype, high grade tumors, large tumor size, stage 4 disease and had a poor 5 year overall survival of 72.6 months as compared to 85.4 months (p = 0.0005). Interestingly PARP expression was also found to be significantly associated with aggressive molecular markers such as activated AKT, XIAP and proliferative marker; ki67. Next, in vitro effect of inactivation of PARP was evaluated using a PARP inhibitor; olaparib on a panel of BC cell lines. Olaparib treatment alone did not affect the cell viability and apoptosis at doses up to 10μM concentration. However, when BC cells were treated with sub-optimal dose of Olaparib (1μM) and Embelin (XIAP inhibitor)(5μM) in combination for 48 hours, there was appreciable inhibition of cell viability via induction of apoptosis. Combination of Olaparib and Embelin induced apoptosis via activation and cleavage of caspases-9, -3 and PARP in BC cells. These studies highlight the importance of targeting PARP in combination with either small molecular inhibitors or chemotherapeutic agents in BC can improve the management and survival of this aggressive disease. Citation Format: Maqbool Ahmed, Azhar R. Hussain, Shaham Beg, Saravanan Thangavel, Rafia Begum, Dahish Ajarim, Fouad Al-Dayel, Abdul Khalid Siraj K. Siraj, Khawla S. Al-kuraya. Over-expression of PARP is associated with an aggressive phenotype and can be synergistically targeted using combination of PARP and XIAP inhibitors in breast cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4405.
Graduated Driver Licensing Night Driving Restrictions and Drivers Aged 16 or 17 Years Involved in Fatal Night Crashes — United States, 2009–2014
Authors: Ruth A. Shults, Allan F. Williams
Journal: MMWR Morbidity and Mortality Weekly Report (2016)

Fatal crash risk is higher at night for all drivers, but especially for young, inexperienced drivers (1). To help address the increased crash risk for beginner teen drivers, 49 states and the District of Columbia include a night driving restriction (NDR) in their Graduated Driver Licensing (GDL) system. NDRs have been shown to reduce crashes among newly licensed teens, with higher reductions associated with NDRs starting at 10:00 p.m. or earlier (2-3). However, in 23 states and the District of Columbia, NDRs begin at 12:00 a.m. or later, times when most teen drivers subject to GDL are not driving. CDC analyzed 2009-2014 national and state-level data from the Fatality Analysis Reporting System (FARS) to determine the proportion of drivers aged 16 or 17 years involved in fatal crashes who crashed at night (9:00 p.m.-5:59 a.m.) and the proportion of these drivers who crashed before 12:00 a.m. Nationwide, among 6,104 drivers aged 16 or 17 years involved in fatal crashes during 2009-2014, 1,865 (31%) were involved in night crashes. Among drivers involved in night crashes, 1,054 (57%) crashed before 12:00 a.m. State-level analyses revealed an approximately twofold variation among states in both the proportions of drivers aged 16 or 17 years involved in fatal crashes that occurred at night and the proportions of night fatal crash involvements that occurred before 12:00 a.m. Because nearly all of the night driving trips taken by drivers aged 16 or 17 years end before 12:00 a.m., NDRs beginning at 12:00 a.m. or later provide minimal protection. States could consider updating their NDR coverage to include earlier nighttime hours. This descriptive report summarizes the characteristics of NDRs, estimates the extent to which drivers aged 16 or 17 years drive at night, and describes their involvement in fatal nighttime crashes during 2009-2014. The effects of NDRs on crashes were not evaluated because of the small state-level sample sizes during the 6-year study period.
Abstract 2370: Therapeutic nano-DC vaccine For HER2 positive breast cancer
Authors: Haifa Shen, Xiaojun Xia
Journal: Cancer Research (2016)

Abstract Harnessing a patient's own immune capacity to eradicate malignant cells is a promising approach for cancer treatment, and therapeutic vaccine represents an important arm of cancer immunotherapy. Our research aims to develop a potent therapeutic cancer vaccine for breast cancer which is traditionally considered as poorly immunogenic. We have recently shown that porous silicon microparticles (PSMs) can stimulate type I interferon (IFN) expression in dendritic cells (DCs), and thus serve as a potent adjuvant for a therapeutic cancer vaccine (Xia et al: Cell Reports 2015, 11:957-966). This action is mediated by the TRIF/MAVS pathways, and is independent of the cell surface or endosomal Toll-like receptors. In addition, the nanometer-size pores in PSMs can serve as a reservoir for sustained antigen release. We have assembled a Nano-DC vaccine comprising of bone marrow-derived DCs internalized with HER2 antigen peptide-loaded PSMs. Treatment of murine models of HER2 positive breast cancer with this Nano-DC vaccine not only activates and expands antigen-specific CD8+ T cells, but also promotes a Th2-to-Th1 transition in the tumor microenvironment to favor anti-tumor activity. Thus, our result supports the development of a therapeutic Nano-DC vaccine for breast cancer. Citation Format: Haifa Shen, Xiaojun Xia. Therapeutic nano-DC vaccine For HER2 positive breast cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2370.
Improving the applicability of guidelines on nonmelanoma skin cancer in frail older adults: a multidisciplinary expert consensus and systematic review of current guidelines
Authors: S.F.K. Lubeek, R.J. Borgonjen, L.J. van Vugt, M.G. Olde Rikkert, P.C.M. van de Kerkhof, M.J.P. Gerritsen
Journal: British Journal of Dermatology (2016)

Balancing treatment decisions in frail older adults with nonmelanoma skin cancer (NMSC) can be challenging. Clinical practice guidelines (CPGs) could provide assistance.To collect and prioritize items related to frail older adults with NMSC for integration into CPGs and to assess the current extent of this integration.Items were collected and prioritized by a multidisciplinary working group (29 members) using a modified Delphi procedure and a five-point Likert scale. To assess current integration of these items in CPGs, a systematic review was subsequently performed by two independent reviewers using five medical databases (PubMed, Embase, Cochrane Library, SUMsearch and Trip Database), websites of guideline developers/databases, and (inter)national dermatological societies.Prioritization of a final 13-item list showed that 'limited life expectancy' (4·5 ± 0·9) and 'treatment goals other than cure' (4·4 ± 0·7) were most desired to be integrated into CPGs; both were included in six (46%) of the CPGs found (n = 13). Attention to 'tumour characteristics' and 'comorbidities' were included in CPGs most often (100% and 77%, respectively).More attention to items related to frail older adults in NMSC CPGs is broadly desired, but CPG integration of these items is currently limited. More integration might stimulate more holistic, personalized and patient-centred care in frail older adults.
Abstract LB-288: Investigation on the interaction between human beta defensin type 3 (hBD-3) and ectodomain of EphA2 receptor using molecular dynamics simulation method
Authors: Liqun Zhang
Journal: Cancer Research (2016)

Abstract Defensins are a family of cationic cysteine-rich small molecules. In general, human beta defensins (hBD) are produced by epithelial cells, and they are important to the human innate immune system. Experimental results showed that defensins can directly bind with receptors such as chemokine receptors and act through several mechanisms that may trigger antitumor immunity or facilitate the host's immune response (or evasion) and promote tumor progression. hBD type 3 (hBD-3) is newly discovered and is unique that it has a net charge density much higher than other family members, and has the ability to undergo oligomerization. On the other hand, EPH receptors and their corresponding ligands (ephrins) are membrane-bound proteins that require direct cell-cell interactions for the activation of the receptors. Eph-ephrin system plays a critical role in tumor and vascular functions during carcinogenesis. Once EPH receptor A2 (EphA2) is ligand-independent, it can over-express itself in many types of tumors, and behave like an oncogene. Besides, many studies suggested that mutations that affect EPH receptor function play a role in cancer initiation or progression. Therefore, the EphA2-ephrin5 system can be a novel target for the development of anti-tumorigenic and anti-angiogenic therapies, and understanding its interaction with other molecules is important to demystify the cancer mechanism. Both EphA2 ectodomain (ECD) and hBD-3 exist outside of the cell membrane. In order to find out the interaction mechanism of hBD-3 with EphA2 receptor, initially blind docking using Cluspro software was performed to predict all the possible binding sites between hBD-3 oligomer and EphA2 ECD in the free and bound forms. After that, all atom molecular dynamics CHARMM simulations were performed to find out the most probable binding interfaces between hBD-3 oligomer and EphA2 ECD. It was found that hBD-3 has multiple stable binding sites on the EphA2 ECD, and its binding on the ligand-binding domain (LBD) of EphA2 could influence the binding of ephrin5 with EphA2. Those suggest the hBD-3 could play a role in cancer initiation. Citation Format: Liqun Zhang. Investigation on the interaction between human beta defensin type 3 (hBD-3) and ectodomain of EphA2 receptor using molecular dynamics simulation method. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr LB-288.
Lentiviral vector-mediated overexpression of mutant ataxin-7 recapitulates SCA7 pathology and promotes accumulation of the FUS/TLS and MBNL1 RNA-binding proteins
Authors: Sandro Alves, Thibaut Marais, Maria-Grazia Biferi, Denis Furling, Martina Marinello, Khalid El Hachimi, Nathalie Cartier, Merle Ruberg, Giovanni Stevanin, Alexis Brice, Martine Barkats, Annie Sittler
Journal: Molecular Neurodegeneration (2016)

We used lentiviral vectors (LVs) to generate a new SCA7 animal model overexpressing a truncated mutant ataxin-7 (MUT ATXN7) fragment in the mouse cerebellum, in order to characterize the specific neuropathological and behavioral consequences of the genetic defect in this brain structure. LV-mediated overexpression of MUT ATXN7 into the cerebellum of C57/BL6 adult mice induced neuropathological features similar to that observed in patients, such as intranuclear aggregates in Purkinje cells (PC), loss of synaptic markers, neuroinflammation, and neuronal death. No neuropathological changes were observed when truncated wild-type ataxin-7 (WT ATXN7) was injected. Interestingly, the local delivery of LV-expressing mutant ataxin-7 (LV-MUT-ATXN7) into the cerebellum of wild-type mice also mediated the development of an ataxic phenotype at 8 to 12 weeks post-injection. Importantly, our data revealed abnormal levels of the FUS/TLS, MBNL1, and TDP-43 RNA-binding proteins in the cerebellum of the LV-MUT-ATXN7 injected mice. MUT ATXN7 overexpression induced an increase in the levels of the pathological phosphorylated TDP-43, and a decrease in the levels of soluble FUS/TLS, with both proteins accumulating within ATXN7-positive intranuclear inclusions. MBNL1 also co-aggregated with MUT ATXN7 in most PC nuclear inclusions. Interestingly, no MBNL2 aggregation was observed in cerebellar MUT ATXN7 aggregates. Immunohistochemical studies in postmortem tissue from SCA7 patients and SCA7 knock-in mice confirmed SCA7-induced nuclear accumulation of FUS/TLS and MBNL1, strongly suggesting that these proteins play a physiopathological role in SCA7. This study validates a novel SCA7 mouse model based on lentiviral vectors, in which strong and sustained expression of MUT ATXN7 in the cerebellum was found sufficient to generate motor defects.
Abstract 4870: A novel potential target for cancer immunotherapy
Authors: Susanna Campagnoli, Matteo Parri, Alberto Grandi, Elisa De Camilli, Giuseppe Viale, Renata Maria Grifantini, Piero Pileri
Journal: Cancer Research (2016)

Abstract Suppression of the host's immune system plays a major role in cancer progression. The tumor microenvironment (TME) not only plays a pivotal role during cancer progression and metastasis but also has profound effects on therapeutic efficacy. Immune checkpoint therapy, which targets regulatory pathways in T cells to enhance antitumor immune responses, has led to important clinical advances and provided a new weapon against cancer. This therapy has elicited durable clinical responses and, in a fraction of patients, long-term remissions. Several immune checkpoint inhibitors have been approved by the Food and Drug Administration (FDA), whose therapeutic effect is due to blocking the activity of proteins expressed in T lymphocytes (CTLA4, PD-1) and the interaction with surface protein expressed on tumor cells (PD-L1 and PD-L2). In our recent research activities we have identified 89 tumor-associated proteins by systematic immunohistochemistry analysis of tissue microarray (TMA) representing breast, colon, lung ovary and prostate cancer by using a large collection of polyclonal antibodies (approximately 1600) raised against membrane-associated and secreted proteins only marginally characterized. Among them, an interesting protein, which decorated the plasma membrane of breast cancer cells, was selected. This protein has been described to interact with the CD270/BTLA/CD160 pathway that regulates T-cell activation. It has also the capability to interfere with T-cell mediated allo-responses. Our characterization data showed that the protein is localized on the surface of several cancer cell lines. Moreover, it has the ability to stimulate cytokine production and secretion in PBMC from healthy donors. Several monoclonal antibodies have been generated in our lab against this protein and selected for the ability to bind the surface of cancer cells. Moreover, the ability of these monoclonal antibodies to interfere with the immune cells activity and to interfere with tumor growth in animal models is under evaluation. Results will be provided during the meeting. The currently approved therapeutic targets regimens for triple negative breast cancer and ovarian cancer have limited efficacy. Therefore, the identification of other tumor-associated proteins targetable by specific mAbs is essential to improve patient survival. Citation Format: Susanna Campagnoli, Matteo Parri, Alberto Grandi, Elisa De Camilli, Giuseppe Viale, Renata Maria Grifantini, Piero Pileri. A novel potential target for cancer immunotherapy. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4870.