tbuckley/cabot-search huggingface dataset:
The Role of Adding Somatostatin Analogues to Peptide Receptor Radionuclide Therapy as a Combination and Maintenance Therapy
Authors: Anna Yordanova, Marcel M. Wicharz, Karin Mayer, Peter Brossart, Maria A. Gonzalez-Carmona, Christian P. Strassburg, Rolf Fimmers, Markus Essler, Hojjat Ahmadzadehfar
Journal: Clinical Cancer Research (2018)

Abstract Purpose: Although somatostatin analogues (SSA) and peptide receptor radionuclide therapy (PRRT) are validated therapies in patients with advanced gastroenteropancreatic neuroendocrine tumors (GEP-NET), it remains unclear whether SSA combined with PRRT or as maintenance therapy can provide prolonged survival compared with patients treated with PRRT alone. In this retrospective study, we aimed to investigate whether there is a survival benefit to adding SSA to PRRT as a combination therapy and/or maintenance therapy. Patients and Methods: The investigation included 168 patients with unresectable GEP-NETs treated at the University Hospital Bonn, Bonn, Germany. The patients were divided into two main groups: PRRT monotherapy (N = 81, group 1) and PRRT plus SSA (N = 87, group 2) as combined therapy with PRRT and/or as maintenance therapy after PRRT. Results: Data for overall survival (OS) were available from 168 patients, of whom 160 had data for progression-free survival (PFS). The median PFS was 27 months in group 1 versus 48 months in group 2 (P = 0.012). The median OS rates were 47 months in group 1 and 91 months in group 2 (P &amp;lt; 0.001). The death-event rates were lower in group 2 (26%) than in group 1 (63%). SSA as a combination therapy with PRRT and/or as a maintenance therapy showed a clinical benefit rate (objective response or stable disease) of 95%, which was significantly higher than group 1 (79%). Conclusions: SSA as a combination therapy and/or maintenance therapy may play a significant role in tumor control in patients with GEP-NET who underwent a PRRT. Clin Cancer Res; 24(19); 4672–9. ©2018 AACR.
Abstract 4644: Patient-derived 3D tumor cultures for clinical diagnostics and pre-clinical drug development
Authors: Thomas Dijkmans, Sander Basten, Bram Herpers, Kuan Yan, Torsten Giesemann, Julia Schueler, Willemijn Vader, Leo Price
Journal: Cancer Research (2018)

Abstract Ex vivo cultures of patient-derived tumor enable functional testing of treatment options and optimization of pre-clinical drug development. Patient biopsies or tumor from patient-derived xenografts (PDX) mouse models are a valuable source of human tumor material that can be cultured in 3D for screening of drug efficacy, drug resistance and cellular processes such as proliferation, survival and invasion. A high throughput approach using 384 well plates enables evaluation of multiple drug treatments and dose ranges in parallel. After compound exposure, cultures are fixed and stained with cellular markers. 3D image stack acquisition is followed by ultra-high content multiparametric analysis using the OMiner platform to profile drug responses and quantify tumor spheroid volume, apoptosis and tumor invasion. Dissected PDX material and tumor biopsy material, were used to establish 3D tumor cultures derived from various indications, including breast, ovarian, cervix, endometrium, stomach, pancreatic, colon, bladder and lung cancer. These were exposed to standard-of-care chemotherapeutics (e.g. 5-FU, taxanes, platinum compounds, anthracyclines, alkylating agents), small molecules (e.g. erlotinib, lapatinib, trametinib), targeted therapies (PARPi; niraparib, olaparib, rucaparib), antibodies (e.g. cetuximab, trastuzumab) and antibody-drug-conjugate (ADC, T-DM1) dose ranges. The tumor culture response was measured, generating dose-dependent profiles for relevant features. Patient-derived 3D tumor cultures were tested with standard-of-care and novel therapeutic agents and high content analysis was used to evaluate drug sensitivity. This method enables both the in vitro selection of drug candidates in a pre-clinical setting as well as efficient selection of PDX models for in vivo follow-up in the same tumor. This highly translational in vitro-in vivo PDX pipeline is expected to reduce attrition and increase efficiency in early drug-discovery. Correlation of drug sensitivity in 3D cultures from fresh patient tumor biopsies, on the other hand, can be used for development of predictive diagnostics and also provides a unique source of patient material for drug discovery and development. Citation Format: Thomas Dijkmans, Sander Basten, Bram Herpers, Kuan Yan, Torsten Giesemann, Julia Schueler, Willemijn Vader, Leo Price. Patient-derived 3D tumor cultures for clinical diagnostics and pre-clinical drug development [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 4644.
FRI0710-HPR Objective and subjective measures of physical functioning in women with fibromyalgia: what type of measure is associated most clearly with subjective well-being? the al-Ándalus project
Authors: F. Estevez-Lopez, F.M. Acosta, P. Acosta-Manzano, M. Rodriguez-Ayllon, B. Gavilán-Carrera, M. Herrador-Colmenero, A. Carbonell-Baeza, R. Geenen, B. Walitt, D. Munguía-Izquierdo, M. Pulido-Martos
Journal: Annals of the Rheumatic Diseases (2018)

<h3>Background:</h3> In fibromyalgia there is a discordance between performance-based (i.e., objective) and patient-reported (i.e., subjective) physical functioning (1,2). However, it is unknown whether the association of physical functioning with health outcomes is different between objective and subjective measures. <h3>Objectives:</h3> To analyse the associations of the objective and subjective dimensions of physical activity, sedentary behaviour, and physical fitness with subjective well-being in women with fibromyalgia. <h3>Methods:</h3> This population-based cross-sectional study included 375 women with fibromyalgia from southern Spain. Physical activity, sedentary behaviour, and physical fitness were measured by questionnaires, accelerometers, and performance testing. Participants self-reported their levels of positive affect, negative affect, and satisfaction with life. Conservative multivariate analyses were used to analyse the association between these physical functioning measures and the assessment of affect and life satisfaction. <h3>Results:</h3> We found independent associations of the objective measures but not the subjective assessments of physical activity with positive affect and satisfaction with life (both, <i>p</i>&lt;0.01 and adjusted <i>R<sup>2</sup></i>&gt;0.06) and of sedentary time with positive affect (<i>p</i>&lt;0.02 and adjusted <i>R<sup>2</sup></i>&gt;0.03). Moreover, we observed consistent and independent associations of both the objective and subjective dimensions of physical fitness with all the components of subjective well-being (all, <i>p</i>&lt;0.01 and adjusted <i>R<sup>2</sup></i> ranged from 0.02 to 0.05). <h3>Conclusions:</h3> Both objective and subjective measures of physical activity and sedentary behaviour independently impact affect and subjective well-being. Strategies to enhance both dimensions of physical fitness may be a promising approach for improving the subjective well-being in fibromyalgia. <h3>References</h3> 1. Estévez-López F, et al. Disabil Rehabil2018;40(3):329–337. 2. Estévez-López F, et al. Rheumatology (Oxford)2017;56(11):2015–2024. <h3>Acknowledgements:</h3> This study was funded by the Spanish Ministries of Economy and Competitiveness [I+D+I DEP2013–40908-R, I+D+I DEP2010–15639, BES-2014–067612] and Education [FPU15/00002]. <h3>Disclosure of Interest:</h3> None declared
Abstract 9860: Family Caregivers Have Greater Risk of Depression and Cardiovascular Disease than Non-caregivers in Rural Kentucky
Authors: Misook L Chung, Terry A Lennie, Gia Mudd-Martin, Susan K Frazier, Martha Biddle, Baretta Casey, Alison L Bailey, John Novak, Debra K Moser
Journal: Circulation (2012)

Introduction: Caregiving is known to be burdensome and to adversely affect physical health. It is not known whether caregiving contributes to increased depression and cardiovascular disease (CVD) risk among adults in rural Kentucky, an area notable for lack of social, economic, and health resources. Thus, the purpose of this study was to examine the association of caregiving with depression and CVD risk factors (i.e., lipids, body mass index (BMI), smoking, and hypertension) in this population. Method: Adults in rural Kentucky (n=640; age 50 ± 13.6 years, 75% female) participated in a physical assessment of CVD risk that included BMI, blood lipid profile, and blood pressure. Depression was assessed using the Patient Health Questionnaire-9 (PHQ). The sample was divided into caregivers (13%), family with chronic illness (adults who have a family member with chronic illness but are not caregivers, 18%), and non-caregivers (adults without a chronically ill family member, 69%). Logistic regressions determined the predictive power of caregiving status for depression and CVD risk factors after controlling for age and gender. Results: Nearly 20% of participants met criteria for depression; 30% were overweight and 58% obese. Compared to non-caregivers, caregivers were more likely to be depressed (OR = 2.1, 95% CI 1.2 - 3.6, p = .007), a smoker (OR = 2.3, 95% CI 1.2 - 4.4, p = .01), have hypertension (OR = 1.7, 95% CI 1.0 - 2.7, p = .037), lower HDL (OR = 2.0, 95% CI 1.2 - 3.5, p = .007), and higher triglycerides (OR = 1.96, 95% CI 1.2 - 3.2, p = .007). Family members with chronic illness were also more likely to be depressed (OR = 2.6, 95% CI 1.2 - 5.9, p =.021), obese (OR = 1.8, 95% CI 1.6 - 2.8, p = .009), and have hypertension (OR = 1.7, 95% CI 1.0 - 2.6, p = .018) compared with non-caregivers. Conclusion: Rural caregivers were at higher risk for depression and CVD. Rural adults with a chronically ill family member were at similar risk for depression but had fewer CVD risk factors than caregivers. Preventive interventions for CVD risk and mental health in rural adults should consider the burden of having a family member with a chronic illness, especially those requiring caregiving.
Multicombination Approach Suppresses <i>Listeria monocytogenes</i>‐Induced Septicemia‐Associated Acute Hepatic Failure: The Role of iRhom2 Signaling
Authors: Min‐Xuan Xu, Chen‐Xu Ge, Yu‐Ting Qin, Ting‐Ting Gu, De‐Shuai Lou, Qiang Li, Lin‐Feng Hu, Jun Tan
Journal: Advanced Healthcare Materials (2018)

Abstract The mortality rate of acute liver failure significantly increases due to fatal septicemia. Inactive rhomboid protein 2 (iRhom2) is an essential regulator of shedding TNF‐α by trafficking with TNF‐α converting enzyme (TACE). Fisetin, a flavonoid present in various fruits and plants, possesses anti‐oxidative stress and anti‐inflammatory activities. Here, multi‐combination nanoparticles Fe@Au conjugated with fisetin, iRhom2 small interfering RNA (siRNA), and TNF‐α inhibitor (FN) are prepared to examine their effects on fatal septicemia‐associated hepatic failure induced by Listeria monocytogenes (LM) in mice and to reveal the underlying mechanisms. After LM infection, upregulation of glutamic‐oxalacetic transaminease, glutamic‐pyruvic transaminase, alkaline phosphatase, TNF‐α, malondialdehyde, H 2 O 2 , and O 2 ‐ is observedcompared to FN‐treated mice. The iRhom2/TACE/TNF‐α signals are enhanced in vivo and in vitro, resulting in oxidative stress, which is especially associated with the activation of kupffer cells and other macrophages. Decrease in Nrf2 activation and increase of inflammation‐associated regulators are also noted in vivo and in vitro. Furthermore, overexpression of TNF‐α derived from macrophages aggravates hepatic failure. Inversely, the processes above are restored by FN nanoparticles through the regulation of the iRhom2/TACE/TNF‐α axis and Nrf2 activation. These findings suggest that FN may be a potential approach to protect against bacterial septicemia‐related diseases by targeting iRhom2.
Patients with Barcelona Clinic Liver Cancer Stages B and C Hepatocellular Carcinoma: Time for a Subclassification
Authors: Rita Golfieri, Irene Bargellini, Carlo Spreafico, Franco Trevisani
Journal: Liver Cancer (2018)

The Barcelona Clinic Liver Cancer (BCLC) intermediate and advanced stages (BCLC B and C) of hepatocellular carcinoma (HCC) both include heterogeneous populations. Patients classified as BCLC stage B present with different tumour burdens, and the recommended treatment is transarterial chemoembolization (TACE). A similar heterogeneity of tumour burden and liver function can be found among patients classified as BCLC stage C, which includes diverse clinical features (performance status [PS] 1-2), macrovascular invasion (MVI) including portal vein tumour (PVT) thrombosis, and/or extra-hepatic spread. Nonetheless, the anti-tumoural treatment formally recommended by Western guidelines is systemic therapy with sorafenib.
Epistatic Oncogenic Interactions Determine Cancer Susceptibility to Immunotherapy
Authors: Iñaki Etxeberria, Alvaro Teijeira, Luis M. Montuenga, Pedro Berraondo, Ignacio Melero
Journal: Cancer Discovery (2018)

Abstract Summary: Cancer genetic alterations and epigenetics control the malignant phenotype of tumor cells and the stroma. Synergistic oncogenic alterations may cooperatively dictate immunogenicity, level of infiltration by immune system cells, and response to immunotherapy in an epistatic fashion. The work of Skoulidis and colleagues shows that concomitant RAS and STK11/LKB1 mutations in non–small cell lung adenocarcinomas result in primary resistance to PD-1–based immunotherapy and poor T-cell infiltration. Cancer Discov; 8(7); 794–6. ©2018 AACR. See related article by Skoulidis et al., p. 822.
Developing Zika vaccines: the lessons for disease X
Authors: Alan D. T. Barrett
Journal: Genome Medicine (2018)

There is an urgent need to develop vaccines against emerging diseases, including those caused by pathogens that are currently unknown to cause human disease, termed 'disease X'. Here, Zika virus infection is considered as an example of disease X. The speed of Zika vaccine development provides optimism for our ability to prepare vaccines against unknown pathogens.
Abstract 1901: Structural basis for selective therapeutic targeting of BFL-1 in cancer by a covalent stapled peptide inhibitor
Authors: Edward P. Harvey, Hyuk-Soo Seo, Rachel M. Guerra, Gregory H. Bird, Sirano Dhe-Paganon, Loren D. Walensky
Journal: Cancer Research (2018)

Abstract BCL-2 family proteins are master regulators of the mitochondrial apoptotic pathway and dictate whether a cell will live or die in response to stress. Cancer cells hijack the anti-apoptotic arm of this signaling network, overexpressing BCL-2, MCL-1, and BFL-1, to enforce cellular immortality. Whereas BCL-2 has been drugged by the selective small-molecule inhibitor, venetoclax, and new MCL-1 inhibitor molecules have just entered phase I clinical testing, anti-apoptotic BFL-1 remains undrugged. Importantly, the expression of BFL-1 can cause resistance to these molecules and has been independently linked to the pathogenesis and chemoresistance of human cancers, including melanomas and hematologic malignancies. Given the emergence of BCL-2 family proteins as high-priority cancer targets, solving their structures, alone and in complex with their natural BH3 domain ligands, yields important blueprints for drug design. Whereas the structures of numerous “BH3-in-groove” complexes have been solved, the corresponding panel of apo structures remains incomplete. Here, we report the crystal structure of apo BFL-1 at 1.69 Å resolution, revealing similarities and key differences among unliganded anti-apoptotic targets. Unlike all other BCL-2 proteins, apo BFL-1 contains a surface-accessible cysteine within its BH3-binding groove, allowing for selective covalent targeting by BH3-based stapled peptide inhibitors. The crystal structure of a complex between BFL-1 and a cysteine-reactive and stapled NOXA BH3 α-helix demonstrated the sulfhydryl bond and fortuitous interactions between the acrylamide-bearing moiety and a newly formed hydrophobic cavity. Comparison of the apo and BH3-liganded structures further revealed an induced conformational change. The two BFL-1 structures expand our understanding of the surface landscapes available for selective targeting of BFL-1, and inform a new therapeutic strategy for overcoming BFL-1-dependent apoptotic blockades in human cancer. Citation Format: Edward P. Harvey, Hyuk-Soo Seo, Rachel M. Guerra, Gregory H. Bird, Sirano Dhe-Paganon, Loren D. Walensky. Structural basis for selective therapeutic targeting of BFL-1 in cancer by a covalent stapled peptide inhibitor [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 1901.
Abstract 2370: miR-19b enhances proliferation and apoptosis resistance via the epidermal growth factor receptor signalling pathway by targeting PP2A and BIM in non-small cell lung cancer
Authors: Erik Vassella
Journal: Cancer Research (2018)

Abstract Background: Epidermal growth factor receptor (EGFR) mutations enable constitutive active downstream signaling of PI3K/AKT, KRAS/ERK and JAK/STAT pathways, and promote tumor progression by inducing uncontrolled proliferation, evasion of apoptosis and migration of non-small cell lung cancer (NSCLC). In addition, EGFR mutations increase the susceptibility of patients with NSCLC to tyrosine kinase inhibitor (TKI) therapy, but treated patients will invariably relapse with resistant disease. A global understanding of underlying molecular mechanisms of EGFR signaling may improve the management of NSCLC patients. Results: Here, we defined 17 miRNAs that are regulated by the PI3K/AKT branch of the EGFR signaling pathway. Bioinformatics analysis revealed that miRNAs that are dysregulated following PI3K/AKT inhibition act in a concerted manner to enhance the activity of the EGFR signaling pathway. These findings were closely mirrored by attenuation of miR-19b expression in NSCLC cell lines, where cell cycle progression, clonogenic growth and migration were reduced and apoptosis was enhanced. Conversely, miR-19b overexpression resulted in enhanced phosphorylation of ERK, AKT and STAT in EGFR mutant NSCLC cells. Co-treatment of NSCLC cells with the tyrosine kinase inhibitor (TKI) gefitinib and anti-miR-19b construct reduced migration and clonogenic growth in a synergistic manner suggesting that EGFR and miR-19b act together to control oncogenic processes. Serine/threonine phosphatase PP2A subunit PPP2R5E and BCL2L11 encoding BIM were identified as major targets of miR-19b. Consistent with this finding, PP2A activity was strongly enhanced in NSCLC transduced with anti-miR-19b, but not in cells co-transduced with anti-miR-19b and shPPP2R5E, suggesting that PPP2R5E is a major constituent of the PP2A complex. Accordingly, proliferation enhancement by miR-19b was due to targeting PPP2R5E. In contrast, apoptosis resistance was mainly due to targeting BCL2L11. Conclusion: Our results provide insight into the importance of targeting PPP2R5E and BCL2L11 by miR-19b in oncogenic processes of NSCLC. Attenuation of miR-19b expression could potentially be exploited in adjuvant therapy of EGFR mutant NSCLC. Citation Format: Erik Vassella. miR-19b enhances proliferation and apoptosis resistance via the epidermal growth factor receptor signalling pathway by targeting PP2A and BIM in non-small cell 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 2370.
Abstract 8898: Oxygenation-induced Postnatal Remodeling of the Ductus Arteriosus
Authors: Jin MeiHua, Yokoyama Utako, Ishiwata Ryo, Minamisawa Susumu, Ishikawa Yoshihiro
Journal: Circulation (2012)

Introduction: Intimal thickening (IT) is an important remodeling for anatomical closure of the ductus arteirosus (DA). Although the immediate rise of oxygen tension at birth contracts DA smooth muscle, the role of oxygen in vascular remodeling remains unknown. Hypothesis: Raising oxygen tension promotes IT and anatomical DA closure. Methods: Tissues and vascular smooth muscle cells (SMCs) were obtained from the DA and aorta of rat fetuses on the 21st day of gestation. To examine the effect of raising oxygen tension, SMCs were cultured in a hypoxic chamber (1% O 2 , 5%CO 2 , pO 2 : 20 mmHg) for 3 days and then transferred to a normoxic chamber (21% O 2 , 5% CO 2 , pO 2 : 120 mmHg).Production of basic fibroblast growth factor (bFGF) and H 2 O 2 were measured by ELISA. The area of IT was evaluated by Elastica van Gieson stain. Immunohistochemical analysis was performed using human DA tissues from eight patients with various congenital heart diseases. Results: bFGF was highly expressed in the part of IT in human and rat neonatal DA. Oxygenation increased production of bFGF {1.6-fold (1h), 4.2-fold (6h), n=4-8, P &lt;0.001}, H 2 O 2 {1.8-fold (10 min), n=6, P &lt;0.01} and phosphorylation of ERK1/2 { 2.2-fold (15 min), n=5-9, P &lt;0.001} in rat DA SMCs, but not in aortic SMCs. Inhibition of reactive oxygen species (ROS) by apocinin or rotenone, or ERK inhibitor U0126 attenuated oxygen-induced bFGF production. Oxygenation and recombinant bFGF promoted DA SMC migration (1.8-fold, n=6, P &lt;0.001). Neutralizing antibody against bFGF, apocynin or rotenone attenuated oxygen-induced migration. In vivo study, intraperitoneal administration of anti-bFGF antibody, ROS inhibitor N -acetylcysteine or ERK1/2 inhibitor U0126 attenuated postnatal IT in full-term rat DA (0.8-fold, 0.8-fold, or 0.8-fold, respectively, n=4-10, P &lt;0.01). Furthermore, administration of bFGF promoted IT in preterm rat DA (1.4-fold n=4, P &lt;0.01). Co-administration of bFGF with a cyclooxygenase (COX) inhibitor, rather than a COX inhibitor alone, significantly enhanced IT and promoted closure of rat preterm DA. Conclusions: These results suggest that raising oxygen tension and subsequent induction of ROS induced bFGF secretion via ERK1/2, leading to postnatal anatomical losure of the DA.