tbuckley/cabot-search huggingface dataset:
Abstract 1531: A bispecific chimeric-antigen receptor T-cell factory for triple-negative breast cancer
Authors: Emily G. Kuiper, Leo L. Chan, Matthew R. Chang, Quan K. Zhu, Wayne A. Marasco
Journal: Cancer Research (2018)

Abstract Triple-negative breast cancer (TNBC) is a highly aggressive subtype of breast cancer with poor clinical prognosis. While treated with chemotherapies, the high incidence of relapse signifies the need for novel, targeted therapies. Immune therapies offer an exciting therapeutic option for TNBC. Our goal is to engineer a chimeric-antigen receptor (CAR) T-cell factory, a CAR T-cell that secretes immune-modulating antibodies, for TNBC. Chimeric-antigen receptor (CAR) T-cell therapies redirect a patient's T-cells to kill tumor cells by the exogenous expression of a CAR. A CAR is a membrane spanning fusion protein that links the antigen recognition domain of an antibody to the intracellular signaling domains of the T-cell receptor and co-receptor. Solid tumors offer unique challenges for CAR-T therapies. Unlike blood cancers, tumor-associated target proteins are overexpressed between the tumor and healthy tissue resulting in on-target/off-tumor T-cell killing of healthy tissues. Furthermore, immune repression in the tumor microenvironment (TME) limits the activation of CAR-T cells towards killing the tumor. We hypothesize that a bispecific CAR targeting two antigens on TNBC will mitigate on-target/off-tumor T-cell killing and that the secretion of a checkpoint blockade antibody will remove repression in the tumor microenvironment. Following local immune restoration, the CAR-T cells and other cells in the TME will work synergistically to shrink and clear tumors. Our current work evaluates human single-chain variable fragments (scFvs) to serve as CAR-targeting moieties. We are evaluating the efficacy of scFvs to specifically kill target cells in vitro. This work will define lead scFvs used for engineering of our bispecific CAR. Future work will evaluate this therapy in humanized mouse models of TNBC. Citation Format: Emily G. Kuiper, Leo L. Chan, Matthew R. Chang, Quan K. Zhu, Wayne A. Marasco. A bispecific chimeric-antigen receptor T-cell factory for triple-negative breast 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 1531.
Abstract 20254: Left Atrial Dimensions Can Help in Predicting Thromboembolic Risk in Non Valvular Atrial Fibrillation Patients Treated With Direct Oral Anticoagulants
Authors: Francesco Adamo, Antonio Fusto, Riccardo Di Pietro, Nicolò Salvi, Paola Scarparo, Alessandra Cinque, Ilaria Mancini, Gennaro Alfano, Massimo Mancone, Fabio Ferrante, Francesco Fedele
Journal: Circulation (2016)

Introduction: The discriminative ability of the widely used CHA2DS2-VASc score for thromboembolic risk stratification in non valvular atrial fibrillation (NVAF) is known as modest, thus, it would b...
Autoantibody to transcriptional intermediary factor‐1β as a myositis‐specific antibody: clinical correlation with clinically amyopathic dermatomyositis or dermatomyositis with mild myopathy
Authors: I. Ueda‐Hayakawa, Y. Hamaguchi, N. Okiyama, S. Motegi, T. Yamaoka, S. Miyake, A. Higashi, H. Okamoto, K. Takehara, M. Fujimoto
Journal: British Journal of Dermatology (2018)

Myositis‐specific autoantibodies (MSAs) are associated with unique clinical subsets in polymyositis/dermatomyositis (PM/DM). Autoantibodies against transcriptional intermediary factor (TIF)‐1γ and TIF‐1α are known to be MSAs. Previously, we reported that TIF‐1β is also targeted in patients with DM with or without concomitant anti‐TIF‐1α/γ antibodies. To evaluate the clinical features of seven cases with anti‐TIF‐1β antibodies alone. Serum autoantibody profiles were determined, and protein and RNA immunoprecipitation studies were conducted. Western blotting was performed to confirm autoantibody reactivity against TIF‐1β. Anti‐TIF‐1β antibody was identified by immunoprecipitation assay in 24 cases. Among them, seven patients were positive for anti‐TIF‐1β antibody alone. Six of the seven patients were classified as having DM. Among the six cases of DM, two patients had no muscle weakness and normal creatine kinase (CK) levels, and were classified as having clinically amyopathic DM. Four patients had muscle weakness, but three of them had normal serum CK levels that responded well to systemic steroids. Characteristic features of DM included skin rashes, such as Gottron sign, periungual erythema, punctate haemorrhage on the perionychium and facial erythema including heliotrope, which were observed in 86%, 57%, 86% and 71% of our cases, respectively. One of the seven patients had appendiceal cancer. None of the patients had interstitial lung disease. Seven patients were confirmed to have anti‐TIF‐1β antibody without any other MSAs, including TIF‐1α/γ antibodies, and six of them were diagnosed with DM. We suggest that anti‐TIF‐1β antibody is an MSA, and that it is associated with clinically amyopathic DM or DM with mild myopathy.
Preconditioning by Mitochondrial ATP-Sensitive Potassium Channel Openers
Authors: Egidijus Kevelaitis, Abdeslam Oubénaïssa, Jacqueline Peynet, Christian Mouas, Philippe Menasché
Journal: Circulation (1999)

Background —Recent studies have implicated mitochondrial ATP-sensitive potassium (K ATP ) channels in the cardioprotective effects of ischemic preconditioning. The present study used a model of prolonged cold heart storage to assess whether the mitochondrial K ATP opener diazoxide could reproduce the protection conferred by ischemic preconditioning. Methods and Results —Fifty-four isolated rat hearts were arrested with and stored in Celsior at 4°C for 10 hours before a 2-hour reperfusion. They were divided into 5 groups. Group 1 hearts served as controls. In group 2, hearts were preconditioned by two 5-minute episodes of global ischemia, each separated by 5 minutes of reperfusion before arrest. In group 3, hearts received a 15-minute infusion of the mitochondrial K ATP opener diazoxide (30 μmol/L) followed by 5 minutes of washout before arrest. In groups 4 and 5, hearts underwent a protocol similar to that used in groups 2 and 3, respectively, except that the preconditioning was preceded by a 10-minute infusion of the mitochondrial K ATP blocker 5-hydroxydecanoate (5-HD, 100 μmol/L). Both ischemic and diazoxide preconditioning provided a similar degree of cardioprotection demonstrated by a significantly better preservation of left ventricular compliance, reduced leakage of creatine kinase, and smaller degree of myocardial edema compared with control hearts. These beneficial effects were abolished by 5-HD pretreatment. Postischemic left ventricular contractility and endothelium-dependent coronary response to 5-hydroxytryptamine and acetylcholine were not different among groups. However, the endothelium-independent vasodilatory postischemic response to papaverine was better preserved after ischemic and diazoxide preconditioning than in the other groups. Conclusions —These data support the concept that the cardioprotective effects of ischemic preconditioning can be duplicated by a mitochondrial K ATP opener and suggest that activation of these channels could be an effective means of improving the preservation of globally ischemic cold-stored hearts, as occurs during cardiac transplantation.
Abstract 16842: A Time-dependent Risk Prediction Score of Life-threatening Cardiac Events in Patients With Long QT Syndrome
Authors: Meng Wang, Scott McNitt, Derick Peterson, David Q Rich, Christopher L Seplaki, Ilan Goldenberg, Valentina Kutyifa, Alon Barsheshet, Arthur J Moss, Wojciech Zareba
Journal: Circulation (2017)

Introduction: Currently there is no integrated risk stratification algorithm to predict life-threatening cardiac events in ICD treatment-naive long QT syndrome (LQTS) patients. We aim to develop a ...
Acceleration of the Healing Process and Myocardial Regeneration May Be Important as a Mechanism of Improvement of Cardiac Function and Remodeling by Postinfarction Granulocyte Colony–Stimulating Factor Treatment
Authors: ShinyaMinatoguchi, GenzouTakemura, Xue-HaiChen, NingyuanWang, YoshihiroUno, MasahikoKoda, MasazumiArai, YuMisao, ChuanjiangLu, KojiSuzuki, KazukoGoto, AiKomada, TomoyukiTakahashi, KenichiroKosai, TakakoFujiwara, HisayoshiFujiwara
Journal: Circulation (2004)

Background— We investigated whether the improvement of cardiac function and remodeling after myocardial infarction (MI) by granulocyte colony–stimulating factor (G-CSF) relates to acceleration of the healing process, in addition to myocardial regeneration. Methods and Results— In a 30-minute coronary occlusion and reperfusion rabbit model, saline (S) or 10 μg · kg−1 · d−1 of human recombinant G-CSF (G) was injected subcutaneously from 1 to 5 days after MI. Smaller left ventricular (LV) dimension, increased LV ejection fraction, and thicker infarct-LV wall were seen in G at 3 months after MI. At 2, 7, and 14 days and 3 months after MI, necrotic tissue areas were 14.2±1.5/13.4±1.1, 0.4±0.1/1.8±0.5*, 0/0, and 0/0 mm2 · slice−1 · kg−1, granulation areas 0/0, 4.0±0.7/8.5±1.0*, 3.9±0.8/5.7±0.7,* and 0/0 mm2 · slice−1 · kg−1, and scar areas 0/0, 0/0, 0/0, and 4.2±0.5/7.9±0.9* mm2 · slice−1 · kg−1 in G and S, respectively (*P<0.05, G versus S). Clear increases of macrophages and of matrix metalloproteinases (MMP)...
Abstract 1414: Germline cancer predisposition gene mutations among patients with early onset rectal cancer
Authors: Caroline Beltrami, Luisa Matos Alvim, Bruna Elisa Kupper, Annabeth Petersen, Mads Jørgensen, Samuel Aguiar Junior, Silvia Regina Rogatto
Journal: Cancer Research (2018)

Abstract Background: Although the incidence rates of rectal cancer (ReCa) have been increasing, the mechanisms or mutations involved in the development of the disease are poorly explored, especially in younger patients. To date, rectal tumors from young patients show molecular, clinical and pathological differences compared with colorectal cancer from older patients. Few studies have reported the presence of a hereditary factor involved in the risk of developing ReCa in a set of patients even in the absence of family history of cancer. Patients and Method: Twenty-seven ReCa younger patients (&amp;lt;40 years old) were screened for germline alterations in DNA from blood samples. The family history and clinical-pathological findings were assessed from the medical records from all subjects. DNA library was performed from SureSelectQXT Library Prep kit (Agilent, Santa Clara, CA) and next-generation sequencing was applied using a multigenic panel with 105 cancer-related genes (SureSelectXT Custom Panel; Agilent, Santa Clara). The generated sequences were aligned to human genome (hg19) and reported as pathogenic, likely pathogenic, variant of uncertain significance (VUS), benign and likely benign according to the American College of Medical Genetics and Genomics guidelines. Sanger sequencing was used to confirm the pathogenic variants. Results: Two patients carried out high penetrance genes associated with colorectal cancer, MUTYH biallelic and BMPR1A. MTHFR and MUTYH variants were found in two patients. POT1 (melanoma predisposition), MEN1 (high penetrance) and ATM (moderate penetrance) variants were found in three additional ReCa patients. Three patients carried out likely pathogenic varaints (BMPR1A, CHEK2 and RAD51D genes). Four of ten patients with pathogenic variants had no family history of cancer. Conclusion: Pathogenic (7/27) and likely pathogenic (3/27) variants were found in 37% of ReCa patients younger than 40 years old affecting genes with high or moderate penetrance. Our data suggest that genetic testing using a multigene panel and genetic counseling should be offered for younger patients with rectal cancer. Citation Format: Caroline Beltrami, Luisa Matos Alvim, Bruna Elisa Kupper, Annabeth Petersen, Mads Jørgensen, Samuel Aguiar Junior, Silvia Regina Rogatto. Germline cancer predisposition gene mutations among patients with early onset rectal 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 1414.
Angiotensin II Type 1 Receptor–Induced Extracellular Signal–Regulated Protein Kinase Activation Is Mediated by Ca2+/Calmodulin-Dependent Transactivation of Epidermal Growth Factor Receptor
Authors: SatoshiMurasawa, YasukiyoMori, YoshihisaNozawa, NorikoGotoh, MasabumiShibuya, HiroyaMasaki, KatsuyaMaruyama, YoshiakiTsutsumi, YasutakaMoriguchi, YasunobuShibazaki, YohkoTanaka, ToshijiIwasaka, MitsuoInada, HiroakiMatsubara
Journal: Circulation Research (1998)

Abstract—The signaling cascade elicited by angiotensin II (Ang II) resembles that characteristic of growth factor stimulation, and recent evidence suggests that G protein–coupled receptors transactivate growth factor receptors to transmit mitogenic effects. In the present study, we report the involvement of epidermal growth factor receptor (EGF-R) in Ang II–induced extracellular signal–regulated kinase (ERK) activation, c-fos gene expression, and DNA synthesis in cardiac fibroblasts. Ang II induced a rapid tyrosine phosphorylation of EGF-R in association with phosphorylation of Shc protein and ERK activation. Specific inhibition of EGF-R function by either a dominant-negative EGF-R mutant or selective tyrphostin AG1478 completely abolished Ang II–induced ERK activation. Induction of c-fos gene expression and DNA synthesis were also abolished by the inhibition of EGF-R function. Calmodulin or tyrosine kinase inhibitors, but not protein kinase C (PKC) inhibitors or downregulation of PKC, completely abolishe...
Associations between maternal socioeconomic position and psoriasis: a cohort study among the offspring of the Danish National Birth Cohort
Authors: J. Groot, A.M. Nybo Andersen, A. Adam, T.E. Tind Nielsen, C. Blegvad, L. Skov
Journal: British Journal of Dermatology (2018)

The socioeconomic determinants of paediatric‐onset psoriasis have not been previously investigated. To identify whether a social gradient exists for paediatric‐onset psoriasis, using measures of maternal socioeconomic position. Data on paediatric‐onset psoriasis from 36 003 Danish National Birth Cohort offspring were cross‐linked with nationwide registry data on maternal age and three measures of maternal socioeconomic position: maternal educational attainment, maternal labour market attachment and equivalized household income. Univariable and multivariable logistic regression analyses were conducted to estimate the odds ratios (ORs) of psoriasis in the offspring, in cohort analyses for data from the year of enrolment and cross‐sectional analyses from the year of the 11‐year follow‐up. Maternal age at birth, maternal educational attainment and equivalized household income were inversely associated with psoriasis in the offspring. Low maternal educational attainment was associated with offspring psoriasis [adjusted OR 1·62, 95% confidence interval (CI) 1·20–2·18] after adjusting for maternal psoriasis and age in the cohort analysis. The crude OR of psoriasis in offspring of mothers in the highest quartile compared with mothers in the lowest quartile of equivalized household income was 0·57 (95% CI 0·43–0·76), and the adjusted OR was 0·59 (95% CI 0·44–0·80) after adjusting for maternal psoriasis and age. Similar results were observed for data on maternal socioeconomic position at enrolment and at follow‐up. A steep social gradient in paediatric‐onset psoriasis was observed. Maternal socioeconomic position may play a role in early‐life exposure to modifiable risk factors for psoriasis. Future studies may help to elucidate which biological factors mediate the social gradient observed in our study.
Abstract 680: FLLL12 is a small molecule JAK2 inhibitor that inhibits JAK-STAT3 pathway in head and neck cancer
Authors: ARM Ruhul Amin, ASM Anisuzzaman, Abu B. Siddique, James R. Fuchs
Journal: Cancer Research (2018)

Abstract Purpose: We have recently reported that FLLL12, a synthetic curcumin analog, induces apoptosis of lung cancer cells through a death receptor (DR) 5-dependent pathway and in squamous cell carcinoma of head and neck (SCCHN) by modifying multiple Bcl-2 proteins. However, the direct molecular target (receptor) of FLLL12 is unknown. The purpose of the current study is to identify the receptor of FLLL12. Methods: Computer-aided molecular docking was used to predict molecular interaction. Isothermal titration calorimetry and thermal shift assays were used to confirm molecular interactions in a cell free system. SCCHN cell lines were used to study the effect of this interaction on JAK-STAT3 pathway. Protein expression levels were measured by Western blotting. Results: Computer-aided molecular docking modeling of FLLL12 and JAK2 (PDB code: 5CF5) predicted that FLLL12 fit well into the JAK2 catalytic pocket. Although curcumin also fit into the JAK2 catalytic pocket, the binding sites were different for FLLL12 and curcumin. Docking score for FLLL12, natural ligand and curcumin were -7.2, -12.1 and -6.9, respectively. FLLL12 also docked into the STAT3 catalytic pocket (PDB code: 5AX3). However, the docking score was worse than those for natural ligand and curcumin (-5.1, -7.3 and -7.4 respectively). We confirmed that FLLL12 interacted with JAK2 in a cell free system using recombinant JAK2. Isothermal titration calorimetry assay revealed one binding site for both FLLL12 and the FDA-approved JAK inhibitor ruxolitinib. The Ka values were 3.84E6±1.03E5 and 2.31E7±6.78E6 M-1, respectively. FLLL12 and JAK2 interactions were further confirmed by thermal shift assay. Kd values were 1.12±0.14 μM and 2.24 ±0.18 μM for ruxolitinib and FLLL12, respectively. Two hour pretreatment with FLLL12 also inhibited IL-6 induced phosphorylation of JAK2 and STAT3. Finally, FLLL12 strongly inhibited constitutively active STAT3 phosphorylation in SCCHN cell lines, a downstream effector of JAK. Conclusions: Our results strongly suggest that FLLL12 is a novel small molecule inhibitor for JAK2 and FLLL12-JAK2 interaction inhibits IL-6-induced as well as constitutively active STAT3 phosphorylation, thus has great promise for cancer prevention and therapy. Grant Support: Start-up fund from Department of Hematology and Medical Oncology, Winship Cancer Institute of Emory University and from Department of Pharmaceutical Sciences and Research, Marshall University. Citation Format: ARM Ruhul Amin, ASM Anisuzzaman, Abu B. Siddique, James R. Fuchs. FLLL12 is a small molecule JAK2 inhibitor that inhibits JAK-STAT3 pathway in head and neck 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 680.
Heterogeneity of Kv2.1 mRNA Expression and Delayed Rectifier Current in Single Isolated Myocytes From Rat Left Ventricle
Authors: Jobst-HendrikSchultz, TilmannVolk, HeimoEhmke
Journal: Circulation Research (2001)

Abstract—Expression of the voltage-gated K+ channel Kv2.1, a possible molecular correlate for the cardiac delayed rectifier current (IK), has recently been shown to vary between individual ventricular myocytes. The functional consequences of this cell-to-cell heterogeneity in Kv2.1 expression are not known. Using multiplex single-cell reverse transcriptase–polymerase chain reaction (RT-PCR), we detected Kv2.1 mRNA in 47% of isolated midmyocardial myocytes from the rat left ventricular free wall that were positive for α-myosin heavy chain mRNA (n=74). Whole-cell patch-clamp recordings demonstrated marked differences in the magnitude of IK (200 to 1450 pA at VPip=40 mV) between individual myocytes of the same origin. Furthermore, the tetraethylammonium (TEA)–sensitive outward current (ITEA), known to be partly encoded by Kv2.1 in mice, revealed a wide range of current magnitudes between single cells (150 to 1130 pA at VPip=40 mV). Combined patch-clamp recordings and multiplex single-cell RT-PCR analysis of ...
Abstract 3593: Noncoding RNAs in early detection of radiation-induced late pulmonary effects
Authors: Marshleen Yadav, Feifei Song, Zahida Qamri, Arnab Chakravarti, Naduparambil K. Jacob
Journal: Cancer Research (2018)

Abstract Normal tissue toxicity is an undesired outcome in patients receiving radiation therapy, manifested as acute radiation syndromes (ARS) and as late effects in survivors. The purpose of the study is to develop biomarkers for assessing the extent of lung inflammation and early detection of delayed and late radiation toxicities such as pneumonitis and pulmonary fibrosis. Circulating miRNAs offer great promise as diagnostic predictive biomarkers due to their high abundance, high stability and sensitivity. A longitudinal analysis of evolutionarily conserved noncoding RNAs was done using NanoString platform in serum samples from leukemia patients and pneumonitis-prone BALB/c mice exposed to clinically relevant doses of whole-body, organ-targeted/protected irradiation to compare the treatment-induced alterations. The associated immune response was evaluated by cytokine multiplexing and gene expression analysis and imaging with micro-CT. Bleomycin and targeted miRNA knockout mice models were used to evaluate functional significance of the identified biomarkers. Quantification of time-dependent alterations in serum and plasma miRNAs from rodents samples collected after thoracic, gut versus whole-body exposure have identified a panel of five miRNAs that are capable of providing an early readout of delayed lung toxicities. The specificity of the candidate miRNAs as potential early indicators of lung injury was confirmed in a bleomycin model of acute lung injury where an overlapping miRNA signature was observed in serum. Among these conserved miRNAs, serum miR-21 and miR-29a were found significantly elevated in two weeks in lung irradiated animals with concomitant increase in proinflammatory cytokines. The significance of the markers was further validated in serum miRNA profile of leukemia patients who exhibited pneumonitis symptoms post radiation therapy. The functional role of miR-21 in promoting radiation-induced inflammation was evident from compromised response of genes associated with inflammation in irradiated miR-21-/- mice. Our study has identified a panel of evolutionarily and functionally conserved sensitive miRNA biomarkers that facilitate rapid and early detection of late pulmonary toxicities in leukemia and lung cancer patients who receive therapeutic radiation. Analysis of circulating biomarkers will potentially assist in making therapeutic and follow-up decision based on individual's own physiologic response and developing strategies for timely mitigation and treatment. Citation Format: Marshleen Yadav, Feifei Song, Zahida Qamri, Arnab Chakravarti, Naduparambil K. Jacob. Noncoding RNAs in early detection of radiation-induced late pulmonary effects [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 3593.