tbuckley/cabot-search huggingface dataset:
CSIG-11. UNDERSTANDING THE MECHANISM OF RIOK2 FUNCTION IN GLIOBLASTOMA
Authors: Alexander Chen, Renee Read
Journal: Neuro-Oncology (2018)

Glioblastoma multiforme (GBM) is the most aggressive and prevalent form of primary brain cancer and is incurable. Amplification, mutation, and/or overexpression of the EGFR receptor tyrosine kinase and activating mutations in components of the PI3K pathway are common in GBM tumors, although the pathways that act downstream of EGFR and PI3K to drive tumorigenesis remain poorly understood. To better understand the underlying biology of tumorigenesis, we use a Drosophila melanogaster GBM model in which malignant neoplastic tumors arise from glial progenitor cells overexpressing activated oncogenic versions of EGFR and PI3K and identified Right-Open-Reading-Frame-2 (RIOK2), an atypical serine-threonine kinase, as a possible driver of EGFR-PI3K-dependent GBM. To elucidate downstream targets of RIOK2, we conducted preliminary immunoprecipitation experiments of RIOK2 from patient-derived GBM cell cultures coupled with proteomics and identified several novel RNA-binding proteins (RBPs) as binding partners and potential substrates of RIOK2. Subsequent experiments using our Drosophila GBM model show that RBP knock-down drastically reduced aberrant glial cell proliferation and invasion, similar to RIOK2 knock-down. Furthermore, co-immunoprecipitation experiments using patient derived primary GBM cells reveal that RIOK2 and novel RBPs are co-IPed and may operate in a complex. Moreover, RNA-binding protein immunoprecipitations (RIP) suggest that RIOK2 is associated with a number of oncogenic mRNAs. Based on our preliminary results, we hypothesize that RIOK2 drives tumorigenesis by modulating the activity of RBPs, and that this promotes the translation of RBP target mRNAs to drive tumor cell proliferation and survival.
The Dual PI3K/mTOR Pathway Inhibitor GDC-0084 Achieves Antitumor Activity in <i>PIK3CA</i>-Mutant Breast Cancer Brain Metastases
Authors: Franziska M. Ippen, Christopher A. Alvarez-Breckenridge, Benjamin M. Kuter, Alexandria L. Fink, Ivanna V. Bihun, Matthew Lastrapes, Tristan Penson, Stephen P. Schmidt, Gregory R. Wojtkiewicz, Jianfang Ning, Megha Subramanian, Anita Giobbie-Hurder, Maria Martinez-Lage, Scott L. Carter, Daniel P. Cahill, Hiroaki Wakimoto, Priscilla K. Brastianos
Journal: Clinical Cancer Research (2019)

Previous studies have shown that the PI3K/Akt/mTOR pathway is activated in up to 70% of breast cancer brain metastases, but there are no approved agents for affected patients. GDC-0084 is a brain penetrant, dual PI3K/mTOR inhibitor that has shown promising activity in a preclinical model of glioblastoma. The aim of this study was to analyze the efficacy of PI3K/mTOR blockade in breast cancer brain metastases models.
Characterization of Causal Variants at the GATA3 Loci Associated with Susceptibility to Ph-like Acute Lymphoblastic Leukemia
Authors: Hui Zhang, Hongbo Yang, Tingting Liu, Maoxiang Qian, Wenjian Yang, Kathryn G. Roberts, Virginia Perez-Andreu, Heng Xu, Julie M. Gastier-Foster, Colton Smith, Ching-Hon Pui, William E. Evans, Mary V. Relling, Stephen P. Hunger, Charles G. Mullighan, Mignon L. Loh, Feng Yue, Jun J. Yang
Journal: Blood (2017)
Association Between Long-term Opioid Use in Family Members and Persistent Opioid Use After Surgery Among Adolescents and Young Adults
Authors: Calista M. Harbaugh, Jay S. Lee, Kao-Ping Chua, Brooke Kenney, Theodore John Iwashyna, Michael J. Englesbe, Chad M. Brummett, Amy S. Bohnert, Jennifer F. Waljee
Journal: JAMA Surgery (2019)

Prior studies have found a substantial risk of persistent opioid use among adolescents and young adults undergoing surgical and dental procedures. It is unknown whether family-level factors, such as long-term opioid use in family members, is associated with persistent opioid use.To determine whether long-term opioid use in family members is associated with persistent opioid use among opioid-naive adolescents and young adults undergoing surgical and dental procedures.This retrospective cohort study used data from a commercial insurance claims database for January 1, 2010, to June 30, 2016, to study 346 251 opioid-naive patients aged 13 to 21 years who underwent 1 of 11 surgical and dental procedures and who were dependents on a family insurance plan.Long-term opioid use in family members, defined as having 1 or more family members who (1) filled opioid prescriptions totaling a 120 days' supply or more during the 12 months before the procedure date or (2) filled 3 or more opioid prescriptions in the 90 days before the procedure date.The main outcome measure was persistent opioid use, defined as 1 or more postoperative prescription opioid fills between 91 and 180 days among patients with an initial opioid prescription fill. Generalized estimating equations with robust SEs clustered at the family level were used to model persistent opioid use as a function of long-term opioid use among family members, controlling for procedure, total morphine milligram equivalents of the initial fill, and patient and family characteristics.A total of 346 251 patients (mean [SD] age, 17.0 [2.3] years; 175 541 [50.7%] female) were studied. Among these patients, 257 085 (74.3%) had an initial opioid fill. Among patients with an initial opioid fill, 11 016 (4.3%) had long-term opioid use in a family member. Persistent opioid use occurred in 453 patients (4.1%) with long-term opioid use in a family member compared with 5940 patients (2.4%) without long-term opioid use in a family member (adjusted odds ratio, 1.54; 95% CI, 1.39-1.71).The findings suggest that long-term opioid use among family members is associated with persistent opioid use among opioid-naive adolescents and young adults undergoing surgical and dental procedures. Physicians should screen young patients for long-term opioid use in their families and implement heightened efforts to prevent opioid dependence among patients with this important risk factor.
Effects of the LTD4 receptor antagonist montelukast sodium on a model of chronic airway inflammation in guinea pigs: comparison with corticosteroid treatment
Authors: E. A. Leick-Maldonado, M. C. Leonhardt, F. U. Kay, D. I. Kasahara, G. M. G. T. Spilborghs, Mílton de Arruda Martins, I. F. L. C. Tibério
Journal: European Respiratory Journal (2000)
MiR-644a Disrupts Oncogenic Transformation and Warburg Effect by Direct Modulation of Multiple Genes of Tumor-Promoting Pathways
Authors: Jey S. Ebron, Eswar Shankar, Jagjit Singh, Kavleen Sikand, Crystal M. Weyman, Sanjay Gupta, Daniel J. Lindner, Xiaoqi Liu, Moray J. Campbell, Girish C. Shukla
Journal: Cancer Research (2019)

Castration-resistant prostate cancer (CRPC) is defined by tumor microenvironment heterogeneity affecting intrinsic cellular mechanisms including dysregulated androgen signaling, aerobic glycolysis (Warburg effect), and aberrant activation of transcription factors including androgen receptor (AR) and c-Myc. Using in vitro, in vivo, and animal models, we find a direct correlation between miR-644a downregulation and dysregulation of essential cellular processes. MiR-644a downregulated expression of diverse tumor microenvironment drivers including c-Myc, AR coregulators, and antiapoptosis factors Bcl-xl and Bcl2. Moreover, miR-644a modulates epithelial-mesenchymal transition (EMT) by directly targeting EMT-promoting factors ZEB1, cdk6, and Snail. Finally, miR-644a expression suppresses the Warburg effect by direct targeting of c-Myc, Akt, IGF1R, and GAPDH expression. RNA sequencing analysis revealed an analogous downregulation of these factors in animal tumor xenografts. These data demonstrate miR-644a mediated fine-tuning of oncogenesis, stimulating pathways and resultant potentiation of enzalutamide therapy in CRPC patients. SIGNIFICANCE: This study demonstrates that miR-644a therapeutically influences the CRPC tumor microenvironment by suppressing androgen signaling and additional genes involved in metabolism, proliferation, Warburg effect, and EMT, to potentiate the enzalutamide therapy.Graphical Abstract: http://cancerres.aacrjournals.org/content/canres/79/8/1844/F1.large.jpg.
From Biology to Therapy: The CLL Success Story
Authors: Deyan Y. Yosifov, Christine Wolf, Stephan Stilgenbauer, Daniel Mertens
Journal: HemaSphere (2019)

Abstract Chemoimmunotherapy has been the standard of care for patients with chronic lymphocytic leukemia (CLL) over the last decade. Advances in monoclonal antibody technology have resulted in the development of newer generations of anti‐CD20 antibodies with improved therapeutic effectiveness. In parallel, our knowledge about the distinctive biological characteristics of CLL has progressively deepened and has revealed the importance of B‐cell receptor (BCR) signaling and upregulated antiapoptotic proteins for survival and expansion of malignant cell clones. This knowledge provided the basis for development of novel targeted agents that revolutionized treatment of CLL. Ibrutinib and idelalisib inhibit the Bruton tyrosine kinase (BTK) and phosphoinositide 3‐kinase (PI3K) delta, respectively, thus interfering with supportive signals coming from the microenvironment via the BCR. These drugs induce egress of CLL cells from secondary lymphoid organs and remarkably improve clinical outcomes, especially for patients with unmutated immunoglobulin heavy‐chain genes or with p53 abnormalities that do not benefit from classical treatment schemes. Latest clinical trial results have established ibrutinib with or without anti‐CD20 antibodies as the preferred first‐line treatment for most CLL patients, which will reduce the use of chemoimmunotherapy in the imminent future. Further advances are achieved with venetoclax, a BH3‐mimetic that specifically inhibits the antiapoptotic B‐cell lymphoma 2 protein and thus causes rapid apoptosis of CLL cells, which translates into deep and prolonged clinical responses including high rates of minimal residual disease negativity. This review summarizes recent advances in the development of targeted CLL therapies, including new combination schemes, novel BTK and PI3K inhibitors, spleen tyrosine kinase inhibitors, immunomodulatory drugs, and cellular immunotherapy.
Abstract 16911: Significant Reduction of Visceral Fat With Doctor-Supervised, Intense Weight Loss Program
Authors: Jessica Barnes, Gerald Dembrowski
Journal: Circulation (2018)

While effective therapies are available to treat cardiovascular disease (CVD) in the United States, few strategies exist targeting visceral fat (VF) as a means to reduce risk of CVD and other metabolic diseases. Commercial weight loss programs target body weight but provide minimal effect on validated surrogates of CVD risk. VF is a validated direct marker of cardiovascular and metabolic disease risk in both the young and old. The 20Lighter Program (T20LP), a doctor-supervised program combining patent-pending meal plans, nutritional supplementation, and daily oversight is designed to reduce VF, lower risk of disease, and improve health. T20LP employs VF reduction as a clinical indicator of cardiovascular and metabolic disease risk instead of a simple weight loss endpoint. For the first time, we present data collected over the past 3 years from the T20LP including 2200 men and women completing T20LP by Dec 31, 2017. Baseline age (54±9.5), BMI (34.1±6.1), comorbidities, medical history, and prescription medications were typical of metabolic syndrome. From initial baseline to 20 days, 40 days, and 60 days, T20LP participants showed statistically significant and clinically meaningful reductions in % body weight (6.7±0.64, 10.9±0.10, 13.1±0.15) and % visceral fat (14.0±0.24, 20.1±0.31, 25.1±0.43) (Figure 1). Unlike conventional weight loss programs, our results show a significant reduction in VF thereby lowering risk of cardiovascular and metabolic disease. T20LP is a comprehensive lifestyle program capable of complementing pharmacological CVD and metabolic syndrome treatments. Our data suggest a doctor-supervised, structured setting can provide safe and clinically relevant VF reduction in overweight adults and teens at risk of CVD and metabolic disease.
Oncogenic MSH6-CXCR4-TGFB1 Feedback Loop: A Novel Therapeutic Target of Photothermal Therapy in Glioblastoma Multiforme
Authors: Yaodong Chen, Pengfei Liu, Peng Sun, Jian Jiang, Yuanbo Zhu, Tianxiu Dong, Yingzhe Cui, Yuan Tian, Tingting An, Jiuwei Zhang, Zizhuo Li, Xiuhua Yang
Journal: Theranostics (2019)

Glioblastoma multiforme (GBM) has been considered the most aggressive glioma type.Temozolomide (TMZ) is the main first-line chemotherapeutic agent for GBM.Decreased mutS homolog 6 (MSH6) expression is clinically recognized as one of the principal reasons for GBM resistance to TMZ.However, the specific functions of MSH6 in GBM, in addition to its role in mismatch repair, remain unknown.Methods: Bioinformatics were employed to analyze MSH6 mRNA and protein levels in GBM clinical samples and to predict the potential cancer-promoting functions and mechanisms of MSH6.MSH6 levels were silenced or overexpressed in GBM cells to assess its functional effects in vitro and in vivo.Western blot, qRT-PCR, and immunofluorescence assays were used to explore the relevant molecular mechanisms.Cu2(OH)PO4@PAA nanoparticles were fabricated through a hydrothermal method.Their MRI and photothermal effects as well as their effect on restraining the MSH6-CXCR4-TGFB1 feedback loop were investigated in vitro and in vivo.Results: We demonstrated that MSH6 is an overexpressed oncogene in human GBM tissues.MSH6, CXCR4 and TGFB1 formed a triangular MSH6-CXCR4-TGFB1 feedback loop that accelerated gliomagenesis, proliferation (G1 phase), migration and invasion (epithelial-to-mesenchymal transition; EMT), stemness, angiogenesis and antiapoptotic effects by regulating the p-STAT3/Slug and p-Smad2/3/ZEB2 signaling pathways in GBM.In addition, the MSH6-CXCR4-TGFB1 feedback loop was a vital marker of GBM, making it a promising therapeutic target.Notably, photothermal therapy (PTT) mediated by Cu2(OH)PO4@PAA + near infrared (NIR) irradiation showed outstanding therapeutic effects, which might be associated with a repressed MSH6-CXCR4-TGFB1 feedback loop and its downstream factors in GBM.Simultaneously, the prominent MR imaging (T1WI) ability of Cu2(OH)PO4@PAA could provide visual guidance for PTT.Conclusions: Our findings indicate that the oncogenic MSH6-CXCR4-TGFB1 feedback loop is a novel therapeutic target for GBM and that PTT is associated with the inhibition of the MSH6-CXCR4-TGFB1 loop.
Melphalan-Based Autologous Transplantation in the Octogenarian Multiple Myeloma Patient Population
Authors: Neeraj Y Saini, Romil Patel, Ankur Varma, Qaiser Bashir, Ruby Delgado, Uday Popat, Chitra Hosing, Yago Nieto, Partow Kebriaei, Amin M. Alousi, Sairah Ahmed, Akash Mukherjee, Rohtesh S. Mehta, Issa F. Khouri, Stefan O. Ciurea, Elizabeth J. Shpall, Omar Hasan, Donna M. Weber, Sheeba K. Thomas, Hans C. Lee, Elisabet E. Manasanch, Krina K. Patel, Robert Z. Orlowski, Richard E Champlin, Muzaffar H. Qazilbash
Journal: Blood (2018)
P017 Non-antibody mediated pathogenic roles for synovial B cells in ACPA+ and ACPA- rheumatoid arthritis
Authors: A Floudas, C Low, M Biniecka, DJ Veale, U Fearon
Journal: Annals of the Rheumatic Diseases (2019)

<h3>Career situation of first and presenting author</h3> Post-doctoral fellow. <h3>Introduction</h3> RF and ACPA have been used extensively for the diagnosis of RA, however no clear mechanism of action towards disease pathogenesis and progression has been identified. Importantly, both seropositive and seronegative RA patients experience significant improvement in disease severity following B cell depletion. Therefore, we hypothesized that B cells have a central role in ACPA<sup>+</sup> and ACPA<sup>-</sup> RA irrespective of their capacity to produce auto-antibodies. <h3>Objectives</h3> To characterize B and T cell populations, their recruitment to the inflamed joint, B cell cytokine production and CD4<sup>+</sup> T cell polarization in RA synovial tissue biopsies and peripheral blood of ACPA<sup>+</sup>, ACPA<sup>-</sup> RA and arthralgia subjects. <h3>Methods</h3> Synovial tissue biopsies from ACPA<sup>+</sup> and ACPA<sup>-</sup> RA and ACPA<sup>+</sup> arthralgia subjects, with paired blood/synovial fluid, were obtained through key-hole arthroscopy and were enzymatically digested. B cell invasion assays and B and CD4<sup>+</sup> T cell <i>in vitro</i> stimulation were conducted under hypoxic conditions simulating the unique environment of the inflamed joint. Flow cytometric analysis was performed. <h3>Results</h3> Significant accumulation, compared to peripheral blood, of pro-inflammatory B cells and pro-inflammatory cytokine-producing CD4<sup>+</sup> T cells in the synovial tissue and fluid of RA patients, irrespective of ACPA status, as well as the synovial tissue of arthralgia subjects. SPICE analysis of peripheral blood B cells, for a panel of chemokine receptors, revealed a disease-specific expression pattern detected in RA and arthralgia subjects. Importantly, the tissue-invading B cells expressed CXCR3, with <i>in vitro</i> blockade of CXCR3 resulting in reduced B cell invasion in response to RA synovial tissue biopsy-conditioned media. Under the unique hypoxic conditions of the inflamed joint, RA patient but not healthy subject-derived B cells produce several pro-inflammatory cytokines including TNF-a and IL-6 and are capable of polarizing CD4<sup>+</sup> T cells towards a pro-inflammatory phenotype. <h3>Conclusions</h3> Accumulation of pro-inflammatory B cell subpopulations in the synovium of both ACPA<sup>+</sup> and ACPA<sup>-</sup> RA patients underlines a common, antibody-independent, contribution of B cells in synovial inflammation. Arthralgia early in disease, specific chemokine receptor expression and the accumulation of CXCR3<sup>+</sup> B cells in the inflamed joint offers an opportunity for therapeutic intervention. Once in the hypoxic environment of the inflamed RA joint, B cells show altered activation, cytokine production and T cell polarization capacity that could prove important for understanding the role of B cells in disease pathogenesis of RA. <h3>Disclosure of Interest</h3> None declared.
Identification of polo-like kinase 1 as a potential therapeutic target in squamous cell carcinoma
Authors: S. A. Watt, C. Pourreyron, J. Foerster, C. Hogan, K. Purdie, L. Bruckner-Tuderman, C. Proby, J. A. McGrath, I. M. Leigh, A. P. South
Journal: British Journal of Dermatology (2010)
Older Adults May Fuel an Upturn in Eczema Cases
Authors: Rebecca Voelker
Journal: JAMA (2019)

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Human colon organoids reveal distinct physiologic and oncogenic Wnt responses
Authors: Birgitta E. Michels, Mohammed H. Mosa, Britta M. Grebbin, Diego Yepes, Tahmineh Darvishi, Johannes Hausmann, Henning Urlaub, Stefan Zeuzem, Hans M. Kvasnicka, Thomas Oellerich, Henner F. Farin
Journal: The Journal of Experimental Medicine (2019)

Constitutive Wnt activation upon loss of Adenoma polyposis coli (APC) acts as main driver of colorectal cancer (CRC). Targeting Wnt signaling has proven difficult because the pathway is crucial for homeostasis and stem cell renewal. To distinguish oncogenic from physiological Wnt activity, we have performed transcriptome and proteome profiling in isogenic human colon organoids. Culture in the presence or absence of exogenous ligand allowed us to discriminate receptor-mediated signaling from the effects of CRISPR/Cas9-induced APC loss. We could catalog two nonoverlapping molecular signatures that were stable at distinct levels of stimulation. Newly identified markers for normal stem/progenitor cells and adenomas were validated by immunohistochemistry and flow cytometry. We found that oncogenic Wnt signals are associated with good prognosis in tumors of the consensus molecular subtype 2 (CMS2). In contrast, receptor-mediated signaling was linked to CMS4 tumors and poor prognosis. Together, our data represent a valuable resource for biomarkers that allow more precise stratification of Wnt responses in CRC.
The Mediterranean Diet and Cardiovascular Health
Authors: Miguel A. Martínez-González, Alfredo Gea, Miguel Ruiz-Canela
Journal: Circulation Research (2019)

The Mediterranean diet (MedDiet), abundant in minimally processed plant-based foods, rich in monounsaturated fat from olive oil, but lower in saturated fat, meats, and dairy products, seems an ideal nutritional model for cardiovascular health. Methodological aspects of Mediterranean intervention trials, limitations in the quality of some meta-analyses, and other issues may have raised recent controversies. It remains unclear whether such limitations are important enough as to attenuate the postulated cardiovascular benefits of the MedDiet. We aimed to critically review current evidence on the role of the MedDiet in cardiovascular health. We systematically searched observational prospective cohorts and randomized controlled trials which explicitly reported to assess the effect of the MedDiet on hard cardiovascular end points. We critically assessed all the original cohorts and randomized controlled trials included in the 5 most comprehensive meta-analyses published between 2014 and 2018 and additional prospective studies not included in these meta-analyses, totaling 45 reports of prospective studies (including 4 randomized controlled trials and 32 independent observational cohorts). We addressed the existing controversies on methodology and other issues. Some departures from individual randomization in a subsample of the landmark Spanish trial (PREDIMED [Prevención con Dieta Mediterránea]) did not represent any clinically meaningful attenuation in the strength of its findings and the results of PREDIMED were robust in a wide range of sensitivity analyses. The criteria for causality were met and potential sources of controversies did not represent any reason to compromise the main findings of the available observational studies and randomized controlled trials. The available evidence is large, strong, and consistent. Better conformity with the traditional MedDiet is associated with better cardiovascular health outcomes, including clinically meaningful reductions in rates of coronary heart disease, ischemic stroke, and total cardiovascular disease.