tbuckley/cabot-search huggingface dataset:
Abstract LB-171: Potential chemopreventative treatments in Fanconi anemia related HNSCC
Authors: Kimberly A. Miller, Beverly R. Wuertz, Anna M. Haynes, David A. Potter, Frank G. Ondrey
Journal: Cancer Research (2018)

Abstract Fanconi anemia (FA) is a DNA repair mechanism genetic disorder which leads to bone marrow failure and cancer. Risk of solid tumor malignancy in FA patients occurs decades earlier and at a rate several hundred-fold higher than the general population, necessitating regular cancer surveillance. Development of an adjunct therapy or preventative survival-enhancing therapy with a minimal side effect profile will benefit this population in which chemotherapy and radiation are particularly damaging. To this end, we established a cell line from a post bone marrow transplant FA patient with a T2N2bM0 oral SCC grown as an adherent monolayer culture. We tested pioglitazone, metformin, and N1-hexyl-N5-benzyl-biguanide (HBB), emerging chemopreventative therapies for head and neck squamous carcinoma, for growth inhibition in head and neck cancer cell lines, including our FA SCC cell line. Additional cell lines include UMSCC 11A (laryngeal squamous cell carcinoma), CA 9-22 (oral squamous cell carcinoma), Beas2B (SV40 immortalized normal bronchial epithelium), and MSK Leuk1 (oral leukoplakia cell line). All cell lines are HPV negative. MTT assays determined cell viability after 1, 2, and 3 days of treatment. Pioglitazone at all concentrations (5, 10, 20, 40 μM) decreases cell proliferation compared to solvent controls (P&amp;lt;0.0001). Metformin (1 μM - 1 mM) unexpectedly increased cell proliferation or was otherwise equal in growth with the controls, and at higher doses (10 mM - 100 mM) metformin decreased cell proliferation or resulted in cytotoxicity (P&amp;lt;0.0001). Pioglitazone (10 μM) and metformin (above 1 mM) resulted in larger, cell line dependent, decreases in cell proliferation than either agent alone. In the FA cell line, pioglitazone and HBB resulted in increased efficacy. HBB treatment resulted in decreases in proliferation and percent live cells at 20 μM equivalent to the effect of 10 to 100 mM metformin. Combining HBB with 10 μM pioglitazone decreased cell proliferation and percent live cells over pioglitazone alone. HBB also caused S phase blockade in a pilot FA cell cycle experiment. Pioglitazone combined with HBB appears to be a promising chemopreventative adjunct treatment for HNSCC in FA patients. Further studies are underway to evaluate the relative contribution of HBB to decreased cell proliferation versus apoptotic mechanisms. Recent studies of HBB in breast cancer indicate cytochrome P450 arachidonic acid epoxygenase activity as an HBB target and suggest further exploration of this target in head and neck squamous cell carcinoma. Citation Format: Kimberly A. Miller, Beverly R. Wuertz, Anna M. Haynes, David A. Potter, Frank G. Ondrey. Potential chemopreventative treatments in Fanconi anemia related HNSCC [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-171.
Abstract LB-278: In vivo evaluation model of human T cell activation by immune checkpoint inhibitors using human PBMC-transferred NOG mouse
Authors: Chiyoko Nishime, Ikumi Katano, Eiko Nishinaka, Kenji Kawai, Ryoji Ito, Jun-ichi Hata, Taichi Yamamoto
Journal: Cancer Research (2018)

Abstract Within the past decade, immune checkpoint inhibitors, such as anti-programmed death (PD)-1 antibodies (e.g. pembrolizumab; Keytruda and Nivolumab: OPDIVO), treatment has become one of the most advancing therapeutic options in oncology. The PD-1/PD-L1 pathway plays a crucial role in mediating self tolerance and controlling self damage to suppress effector/self-reactive T cells and protects against autoimmune reactions. Therapeutic treatment of anti-PD-1 antibodies clearly suppresses tumor growth and induces T cell activation in cancer patients by blockade of the PD-1/PD-L1 pathway, but over activation of T cells exhibits immune-related adverse effects with exacerbation of autoimmune reactions. A human peripheral blood mononuclear cells (hPBMC) transferred humanized NOG mouse has been used to evaluate the efficacy and safety of therapeutic antibodies due to the efficient engraftment of human T cells in the mice. The human T cells were spontaneously activated in the mice because of xenogenic-reaction and the mice frequently died of graft-versus-host disease (GVHD) (Ito R et al., Transplantation, 2009). In the present study, we evaluate the potential adverse effects of 2 therapeutic antibodies, Keytruda and OPDIVO by using conventional NOG mice transferred with hPBMC. These mice showed a weight loss, wasting, rough fur, and skin thickening suggesting of GVHD symptoms. These changes exacerbated in either antibody treated hPBMC-NOG mice with increase of activation marker for T cells, and they died earlier than saline-treated group. By immune-cytoloical analysis, human T cells was significantly decreased in number in hPBMC-NOG mice even though the antibodies were treated. These results demonstrated the hPBMC-NOG mice might become powerful preclinical tools to analyze human T cells activated by therapeutic immune checkpoint inhibitors. Citation Format: Chiyoko Nishime, Ikumi Katano, Eiko Nishinaka, Kenji Kawai, Ryoji Ito, Jun-ichi Hata, Taichi Yamamoto. In vivo evaluation model of human T cell activation by immune checkpoint inhibitors using human PBMC-transferred NOG mouse [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-278.
Abstract 18099: Cardiac-Specific NF-κB Inhibition Protects Against Cardiomyocyte Senescence and Age-Related Cardiac Dysfunction
Authors: Sheng Ye, Guangming Cheng, Jiafeng Lin, Xing Chen, Lin Zhao, Anweshan Samanta, Magdy Girgis, Arash Davani, Anja Browning, Yanjuan Yang, Jeryl Hauptman, Robert Vincent, Buddhadeb Dawn
Journal: Circulation (2016)

Introduction: Increasing evidence indicates that progressive cardiomyocyte aging contributes to the development of cardiac dysfunction in the elderly. The role of NF-κB, a central component of cell...
Abnormal Extracellular Matrix Protein Transport Associated With Increased Apoptosis of Vascular Smooth Muscle Cells in Marfan Syndrome and Bicuspid Aortic Valve Thoracic Aortic Aneurysm
Authors: MariaNataatmadja, MalcolmWest, JennyWest, KimSummers, PhilipWalker, MichioNagata, TeruoWatanabe
Journal: Circulation (2003)

Background— Marfan syndrome (MS) is a genetic disorder caused by a mutation in the fibrillin gene FBN1. Bicuspid aortic valve (BAV) is a congenital heart malformation of unknown cause. Both conditions are associated with ascending aortic aneurysm and premature death. This study examined the relationship among the secretion of extracellular matrix proteins fibrillin, fibronectin, tenascin, and vascular smooth muscle cell (VSMC) apoptosis. The role of matrix metalloproteinase (MMP)-2 in VSMC apoptosis was studied in MS aneurysm. Methods and Results— Aneurysm tissue was obtained from patients undergoing surgery (MS: 4 M, 1 F, age 27–45 years; BAV: 3 M, 2 F, age 28–65 years). Normal aorta from subjects with nonaneurysm disease was also collected (4 M, 1 F, age 23–93 years). MS and BAV aneurysm histology showed areas of cystic medial necrosis (CMN) without inflammatory infiltrate. Immunohistochemical study of cultured MS and BAV VSMC showed intracellular accumulation and reduction of extracellular distribution...
The impact on case findings by transferring clinical breast examination skills to female community health volunteers in limited resources country like Nepal.
Authors: Sanjiv Kumar Hyoju
Journal: Journal of Clinical Oncology (2012)

e11094 Background: In limited resources countries, patients with breast cancer present to the hospital in the late stage because of lack of awareness, screening program. Clinical Breast Examination (CBE) may be the only means of detecting the breast cancer early in countries with limited resources since mammography is less likely to be cost effective approach and CBE by surgeons are also not possible because of limited health care facility. Hence CBE by FCHVs seems to be more feasible. This study was conducted to observe the skill transfer to FCHVs for detection of clinical abnormalities in breast by determining kappa agreement, sensitivity, specificity, positive predictive value and negative predictive value of CBE by FCHVs considering CBE by the Surgeon as gold standard. Methods: It is a cross-sectional study conducted in Eastern Nepal for period of one year from June 2008 to May 2009. Total 1238 women were examined by both a FCHV and the Surgeon. The results were analyzed to find out interobserver kappa agreement, sensitivity, specificity, positive predictive value and negative predictive value for detection of clinical abnormalities in breast following CBE by FCHVs considering CBE by the Surgeon as gold standard. Results: Total 1238 women received CBE by both a FCHV and the Surgeon. The interobserver kappa agreement for the detection of clinical abnormalities in breast was 67% indicating a good agreement exists between the FCHVs and the Surgeon’s CBE Sensitivity, specificity, positive predictive value and negative predictive values of “FCHVs’ CBE” to detect clinical abnormalities in breast in comparison to “the Surgeon’s CBE” as gold standard were 70%, 95%, 74% and 94% respectively. Conclusions: In view of good CBE skills transfer to FCHVs for detection of clinical abnormalities in breast, the effective training of FCHVs may diagnose and refer the women with clinical breast abnormalities to the hospital for further investigation and treatment.
Enhanced Generation of Reactive Oxygen Species in the Limb Skeletal Muscles From a Murine Infarct Model of Heart Failure
Authors: HiroyukiTsutsui, TomomiIde, ShunjiHayashidani, NobuhiroSuematsu, TetsuyaShiomi, JingWen, Kei-ichiroNakamura, KazuhiroIchikawa, HideoUtsumi, AkiraTakeshita
Journal: Circulation (2001)

Background— The generation of reactive oxygen species (ROS) is enhanced in the failing myocardium. We hypothesized that ROS were also increased in the limb skeletal muscles in heart failure. Methods and Results— Myocardial infarction (MI) was created in mice by ligating the left coronary artery. After 4 weeks, the left ventricle was dilated and contractility was diminished by echocardiography. Left ventricular end-diastolic pressure was elevated after MI in association with an increase in lung weight/body weight and the presence of pleural effusion. The generation of ROS in the limb muscles, including the soleus and gastrocnemius muscles, which were excised after MI, was measured by electron spin resonance spectroscopy with 4-hydroxy-2,2,6,6-tetramethyl-piperidine-N-oxyl (hydroxy-TEMPO). Overall, generation was increased, but it was attenuated in the presence of dimethylthiourea or 4,5-dihydroxy-1,2-benzenedisulfonic disodium salt in the reaction mixture, indicating increased generation of hydroxyl radica...
Abstract 16456: Regulation of Vascular Smooth Muscle Phenotypic Switch and Suppression of Atherosclerosis by c-Kit/SCF Expression in Hyperlipidemic Mice
Authors: Lei Song, Annia Mesa, Natasha Fernandez, Guillermo Selman, Nieves Santos, Keith A Webster, Roberto I Vazquez-Padron
Journal: Circulation (2015)

Introduction: This study provides our novel evidence that stem cell factor (SCF) receptor c-Kit regulates vascular smooth muscle cell (SMC) phenotype and is potently anti-atherogenic. Methods and Results: Atherosclerotic plaque was quantified in transgenic mice deficient for c-Kit (c-Kit W/Wv ApoE -/- ) or SCF (c-Kitl sl /+ ApoE -/- ) after 16 weeks of high fat diet (HFD). Both mutant strains displayed substantially greater atherosclerosis compared with control (ApoE -/- ) littermates ( p &lt;0.01 and &lt;0.05 respectively). Transplantation of c-Kit positive bone marrow into c-Kit W/Wv ApoE -/- mice failed to rescue the atherogenic phenotype indicating that increased atherosclerosis was associated with reduced arterial c-Kit. To investigate the mechanism, SMC organization and morphology were analyzed in aorta by histopathology and electron microscopy. Remarkably, SMCs were more abundant, disorganized and vacuolated in aortas of c-Kit mutant mice compared with controls ( p &lt;0.05). Markers of the “contractile” SMC phenotype (Calponin, SM22α) were downregulated in parallel with decreased c-Kit ( p &lt;0.05). Reconstitution of c-Kit in synthetic cultured SMCs conferred increased spindle-shaped morphology, reduced proliferation and elevated levels of contractile markers Calponin and SM22α, each characteristic of a resumed contractile phenotype ( p &lt;0.05). Conversely, aortas of c-Kit W/Wv ApoE -/- accumulated more pro-inflammatory cytokines (MCP-1, RANTES, MIP-1β, G-CSF, p &lt;0.01) and elevated monocytes compared with control mice treated equivalently. Additionally, quantitative mRNA screening and western blot analysis revealed elevated levels of atherosclerotic and inflammatory biomarkers Toll Like Receptors (TLR4, 6, 9) and TNF-α in cultures of c-Kit W/Wv VS c-Kit +/+ SMC. Conclusion: c-Kit/SCF expression prevents phenotypic switching of contractile SMC to the pro-inflammatory, synthetic phenotype and markedly suppresses atherosclerosis in this murine model.
Emergence of Localized Serogroup W Meningococcal Disease in the United States — Georgia, 2006–2016
Authors: Ashley E. Moore, Jessica R. MacNeil, Xin Wang, Sandeep J. Joseph, Lauren Lorentzson, Stepy Thomas, Amy Tunali, Tonia Parrott, Monica M. Farley, Melissa Tobin-D’Angelo
Journal: MMWR Morbidity and Mortality Weekly Report (2018)

Several countries in Europe and Australia are reporting an increasing incidence of Neisseria meningitidis serogroup W (NmW) as a consequence of the rapid expansion of a single NmW clone belonging to clonal complex 11 (1-5). Because this clone is reported to be associated with more severe disease, unusual clinical presentations, and a high case fatality ratio (CFR), it is considered a hypervirulent strain (1,6). In the United States, NmW accounts for approximately 5% of meningococcal disease reported each year, and this proportion has remained stable for several years (7). However, localized increases in NmW have been reported, most notably in Florida during 2008-2009 (8). In Georgia, NmW accounted for only 3% of meningococcal disease cases reported during 2006-2013; however, between January 2014 and December 2016, 42% of all reported cases were NmW. Surveillance data from Georgia were analyzed to describe the epidemiology and clinical characteristics of NmW cases, and whole-genome sequencing of NmW isolates was performed for comparison with NmW strains circulating in the United States and worldwide. These data indicate that the U.S. NmW strains might have evolved from the same ancestor as the hypervirulent strain that is circulating globally. Genetic analysis demonstrates that these strains are closely related, which would suggest that genetic variation led to the rise of different strains from the same ancestor. Given the recent global expansion of this potentially hypervirulent NmW lineage, clinicians and public health officials need to remain vigilant in obtaining isolates to monitor changes in circulating strains.
Abstract 137: Pharmacologic activation of integrin CD11b as a novel therapeutic strategy against lung cancer
Authors: Terese Geraghty, Anugraha Rajagopalan, Samia Khan, Judith Varner, Vineet Gupta
Journal: Cancer Research (2018)

Abstract Lung cancer is the leading cause of cancer related deaths in the United States. With a 5-year survival rate of 18%, lung cancer patients are in immediate need of new therapeutic options. A major problem facing immunotherapy for cancer is the active immune suppression by the tumor. Tumors show presence of large numbers of tumor associated macrophages (TAMs), which suppress the adaptive immune response, increase neo-vascularization to the tumor, and promote tumor survival. Integrin CD11b is highly expressed on TAMs and is essential for their recruitment and biological functions. Reasoning that CD11b activity is important for controlling tumor growth, we developed a novel small molecule agonist called leuhadherin-1 (LA1), which activates CD11b. We found that CD11b activation by LA1 significantly reduced tumor growth in wild type mice bearing Lewis Lung Carcinoma (LLC) tumors as early as one week post treatment. Conversely, LLC tumors grew at a faster rate in CD11b-/- mice, compared to wild type mice, showing that CD11b is important for controlling tumor growth. Importantly, LA1 treatment in tumor bearing CD11b-/- mice did not show any efficacy, demonstrating the specificity of LA1 to CD11b. These data suggest that CD11b activation via LA1 modulates TAMs in tumors and is a novel therapeutic strategy against cancer. Citation Format: Terese Geraghty, Anugraha Rajagopalan, Samia Khan, Judith Varner, Vineet Gupta. Pharmacologic activation of integrin CD11b as a novel therapeutic strategy against lung cancer [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 137.
Abstract 2463: Long noncoding RNAs in tumor responses toward lovastatin
Authors: Entkhab M. Alanisi, Jiuhui Wang, Yande Guo, Daotai Nie
Journal: Cancer Research (2018)

Abstract Background: Lovastatin is one of FDA-approved drugs used to treat hypercholesterolemia to reduce cardiovascular diseases. It is a compound of the statin family derived from type of species of Aspergillus terruses. Lovastatin targets hepatocytes and blocks the cholesterol synthesis pathway by inhibiting the rate-limiting enzyme 3-hydroxy-3-methyl glutaryl CoA reductase (HMG-CoA reductase). This leads to decreased production of cholesterol and many other biochemical end products, including ubiquinone and dolichol. These biochemical end products are important for cancer progression. When lovastatin blocks their production, it leads to increased apoptosis of cancer cells. Therefore, lovastatin has promising anticancer activities but the detailed mechanisms remain poorly understood. Long noncoding RNAs are originally thought as nonfunctional. Emerging evidence suggest that lncRNAs have crucial roles in many biologic functions like apoptosis and cell cycle, translation control, epigenetic regulation and splicing regulation. In this study, we set out to identify and determine Lnc-RNAs that can regulate tumor cell responses towards lovastatin treatment. Methods: PC3, Heya8, HCT116 cells were obtained from ATCC. HCT116 p53-/- cells were gifts from Dr. Yin-Yuan Mo. The cytotoxic effects of lovastatin on those cell lines were evaluated by several approaches like MTS assays and morphologic changes. The qPCR array was used to identify lncRNAs whose levels are changed by lovastatin treatment. The regulation of lncRNA by lovastatin was further confirmed in multiple cell lines. Results and Conclusion: Lovastatin treatment had cytotoxic effects in multiple cell lines we evaluated. Through profiling array, we have identified NEAT1, MALAT1, and RMST as a responder to lovastatin. The lncRNAs identified had a significant increase in the expression compared to the nontreated cells in a dose- and time-dependent manner. The RMST mRNA expression in the HCT116 p53-/- cell line was about 25-fold more than its level in the HCT116 wild-type cells after treatment of 20 μM lovastatin for 48 hours, suggesting a role of tumor suppressor p53 gene in regulating the RMST expression. We knocked out RMST using CRISPR-Cas9 approach and found that RMST is an important mediator for lovastatin to downregulate mTOR activities and reduce colony formation. Taken together, our data suggest that lncRNAs can be stimulated by lovastatin to elicit cellular responses. Citation Format: Entkhab M. Alanisi, Jiuhui Wang, Yande Guo, Daotai Nie. Long noncoding RNAs in tumor responses toward lovastatin [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 2463.
Abstract 852: Specificity of PSMA-617 radiotherapy for prostate cancer
Authors: Joseph A. Reddy, Melissa Nelson, LeCun Xu, Elaine Westrick, Marilynn Vetzel, Leroy Wheeler, Albert Felten, Hari Santhapuram, Iontcho Vlahov, Christopher P. Leamon
Journal: Cancer Research (2018)

Abstract Prostate-specific membrane antigen (PSMA) is a biomarker that is overexpressed on prostate cancer as well as on the neovasculature of many non-prostate solid tumors. Lately, several small molecular PSMA binding ligands chelated to various radionuclides have been studied for imaging and treatment of prostate cancer lesions. One such clinically tested agent is PSMA-617, a DOTA derivative of a PSMA-specific targeting ligand. In our hands, radiochemical yields of PSMA-617 labeled with either 177Lu (β emitter) or 225Ac (α emitter) were greater than 97%. Binding experiments with 177Lu and 225Ac chelates of PSMA-617 and D-Glu PSMA-617 (a predicted non-PSMA binding, D-glutamic acid isomer of PSMA-617) were performed using the PSMA-positive, 22RV1 cell line. PSMA-617, was found to bind in a concentration dependent manner with very high affinity, whereas the cellular association of D-Glu PSMA-617 was found to be &amp;gt; 60-fold lower. The in vivo biodistribution of these two agents were investigated in BALB/c nu/nu mice bearing subcutaneous 22RV1 xenografts. Organ distribution revealed specific PSMA-617 uptake in the 22RV1 tumors and the PSMA+ kidneys, while the uptake of D-Glu PSMA-617 remained near background in both of these tissues. Different from tumor, PSMA-617 exhibited a rapid clearance from the kidneys to yield a high tumor-to-background contrast (tumor:blood = 300; tumor:muscle = 290; and tumor:kidney = 15) at 24 h post dose. Complementary antitumor activity studies were performed with 225Ac-labeled PSMA-617. Here, significant tumor growth inhibition was observed without detectable hematologic or renal toxicity to the mice. These data provide additional support for a phase 3 prospective trial currently being planned to evaluate 177Lu-PSMA-617 in patients with metastatic PSMA+ prostate cancers, along with the continued clinical investigation of 225Ac-PSMA-617 in a similar patient population. Citation Format: Joseph A. Reddy, Melissa Nelson, LeCun Xu, Elaine Westrick, Marilynn Vetzel, Leroy Wheeler, Albert Felten, Hari Santhapuram, Iontcho Vlahov, Christopher P. Leamon. Specificity of PSMA-617 radiotherapy for prostate cancer [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 852.