tbuckley/cabot-search huggingface dataset:
EXTH-60. PLK1 INHIBITOR TARGETS MISMATCH REPAIR DEFICIENT TEMOZOLOMIDE RESISTANT GLIOMA
Authors: Fumi Higuchi, Daniel Cahill, Hiroaki Wakimoto
Journal: Neuro-Oncology (2017)

Mismatch repair (MMR) deficiency through MSH6 alteration has been identified in approximately 30% of recurrent high-grade gliomas, and represents a key molecular mechanism that underlies the development of acquired resistance to the alkylating agent temozolomide (TMZ). Additionally, glioma progression post-TMZ treatment is frequently accompanied by distinct genomic alterations such as amplification of the MYC locus and resulting signaling activation. There is an urgent need to establish new treatment strategies that do not rely upon MMR to target MMR deficient, TMZ resistant glioma. We first screened 14 compounds that modulate DNA damage response for their ability to suppress viability of an MSH6 knockdown, TMZ resistant glioma cell line. Efficacy of PLK1 inhibitors and combination with TMZ were assessed in glioblastoma cells lines and patient-derived glioblastoma neurosphere lines engineered with MSH6 silencing, MYC over-expression/silencing and controls. Impacts of PLK1 blockade on cell cycle distribution, apoptosis, and DNA damage effects were examined. The compound screening identified PLK1 selective inhibitor, volasertib, as the most potent inhibitor of proliferation of glioblastoma cells. PLK1 inhibition induced G2/M cell cycle arrest, DNA damage and caspase-mediated apoptosis in glioblastoma cells, but no toxicity in normal human astrocytes. Importantly, beneficial therapeutic effects of PLK1 inhibitors were not influenced by MMR deficiency due to MSH6 knockdown. Furthermore, we found that MYC overexpression sensitized while its silencing desensitized glioblastoma cells to PLK1 inhibitors. Selective PLK1 inhibitors are potently cytotoxic to glioblastoma and their action is independent of MMR status of the cells. Cells with deregulated MYC are vulnerable to PLK1 inhibition suggesting genomic MYC alteration as a biomarker for PLK inhibitor sensitivity. PLK inhibitor represents a novel therapeutic option for MMR deficient TMZ resistant recurrent gliomas, particularly those driven by MYC. In vivo testing of PLK1 inhibitor in an orthotopic setting of MMR defective glioblastoma is ongoing.
Does second-line therapy affect the outcome of the patients with cholangiocarcinoma? A single institution experience
Authors: L. Gurrieri, F. Giudici, D. Fedele, A.M. Dicorato, M. Malagoli, S. Moroso, G. Del Conte, F. Zanconati, A. Guglielmi
Journal: Annals of Oncology (2017)
Experimental asthma persists in IL-33 receptor knockout mice because of the emergence of thymic stromal lymphopoietin–driven IL-9+ and IL-13+ type 2 innate lymphoid cell subpopulations
Authors: Mukesh Verma, Sucai Liu, Lidia Michalec, Anand Sripada, Magdalena M. Gorska, Rafeul Alam
Journal: Journal of Allergy and Clinical Immunology (2017)
P1.09-008 A 4-microRNA Signature in Serum Can Discriminate Between Non-Small-Cell Lung Cancer and Malignant Pleural Mesothelioma
Authors: M. Kirschner, C. Leygo, S. Burgers, T. Korse, D. Van Den Broek, N. Van Zandwijk, G. Reid
Journal: Journal of Thoracic Oncology (2017)
P2.07-059 Phase I Trial of Gene Mediated Cytotoxic Immunotherapy (GMCI) for Malignant Pleural Effusion (MPE) and Malignant Pleural Mesothelioma (MPM)
Authors: D. Sterman, A. Haas, S. Metzger, L. Aguilar, E. Aguilar-Cordova, A. Manzanera, G. Gomez, S. Albelda, E. Alley, T. Evans, R. Cohen, J. Bauml, C. Langer, C. Aggarwal
Journal: Journal of Thoracic Oncology (2017)
QLIF-29. FUNCTIONAL AND EMPLOYMENT OUTCOMES IN IDH MUTANT GLIOBLASTOMA
Authors: Chelsea Demler, John Kelly
Journal: Neuro-Oncology (2017)

A diagnosis of Glioblastoma is associated with poor outcomes with respect to functional and employment status in the period following surgery, radiation and chemotherapy. Genomic characterization of glioblastoma has demonstrated that patients harboring an IDH mutation have longer survival. This study aims to determine if patients with IDH mutant glioblastoma have improved oncologic, functional, and employment outcomes. Patient data was obtained from a single surgeon series between the years 2013 and 2017. Of 230 patients diagnosed with WHO grade 4 glioblastoma 11 harbored mutation of IDH1. Records obtained included age at diagnosis, Karnofsky Performance Status (KPS), return to work date, stability of imaging at the 16 month interval, and overall length of survival. The median age for this cohort was 39.2 years. Average KPS following initial resection and diagnosis was 78.8. Return to work was seen in 64% of patients and the average return to work date was 17 months post diagnosis. Of the 11 patients, 2 were deceased from unrelated causes. After accounting for the two unrelated deaths, 77% of patients returned to work in some capacity. Average overall survival (OS) was difficult to determine as only one patient has died as a result of tumor progression (survival length for this patient was 52 months). Imaging stability was seen in 100% of patients at the 16 month interval. In comparison to historical data for glioblastoma, in our series, glioblastoma patients with IDH mutation have increased return to employment, higher functional status post treatment, and extended stability of disease. These results suggest that care management and rehabilitation goals for patients with IDH mutant glioblastoma should reflect their improved functional outcomes.
P3.02-011 A Prospective Study of Serial Circulating Tumor DNA Assessment in Detecting Recurrence of Resected Early-stage Lung Cancer
Authors: H.K. Kim, J.H. Cho, S. Lee, J. Lee, Y.S. Choi, J.I. Zo, Y.M. Shim, S. Mortimer, J. Odegaard, J. Kim
Journal: Journal of Thoracic Oncology (2017)
Annals Story Slam - Becoming Dr. Mom
Authors: Rebecca Masters
Journal: Annals of Internal Medicine (2017)

Web Exclusives7 November 2017Annals Story Slam - Becoming Dr. MomFREERebecca Masters, MDRebecca Masters, MDHershey Medical Center, Hershey, Pennsylvania (R.M.)Search for more papers by this authorAuthor, Article, and Disclosure Informationhttps://doi.org/10.7326/W17-0065 SectionsAboutVisual Abstract ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail Video. Annals Story Slam - Becoming Dr. Mom "Becoming Dr. Mom," by Dr. Rebecca Masters (Duration 8:35)Building on the popular Annals feature “On Being a Doctor,” storytellers share stories about the experience of doctoring on video. Here, Dr. Masters relays her story of balancing doctoring and parenting.For more videos from and information on Annals Story Slam, visit go.annals.org/StorySlam. Comments0 CommentsSign In to Submit A Comment Author, Article, and Disclosure InformationAffiliations: Hershey Medical Center, Hershey, Pennsylvania (R.M.)Current Author Address: Rebecca Masters, MD, Hershey Medical Center, Hershey, PA; e-mail, [email protected]net. PreviousarticleNextarticle Advertisement FiguresReferencesRelatedDetails Metrics 7 November 2017Volume 167, Issue 9Page: SS1 ePublished: 7 November 2017 Issue Published: 7 November 2017 Copyright & PermissionsCopyright © 2017 by American College of Physicians. All Rights Reserved.Loading ...
P3.01-005 ASTRIS: A Real World Study of Osimertinib Treatment in Patients with EGFR T790M Positive Advanced NSCLC; Interim Analysis
Authors: S. Kim, B.C. Cho, D. Kim, K. Park, M. Tiseo, M.R. Migliorino, A. Santo, J. Lee, D. Vicente, A. Paredes, E. O'Hanrahan, H. Freitas, M. Provencio, Y. Chen, P. Cheema, A. Milner, J. Rigas, Y. Wu, F. De Marinis
Journal: Journal of Thoracic Oncology (2017)
OA 16.08 A Modified Pathological N1 Classification Strategy Based on Systematic Dissection of N1 Nodes from Level 10 to 14 for Non-Small Cell Lung Cancer
Authors: S. Yan, X. Wang, Y. Wang, C. Lv, Y. Wang, S. Li, J. Wang, Y. Yang, W. Nan
Journal: Journal of Thoracic Oncology (2017)
CMET-41. OVERALL SURVIVAL OF MELANOMA BRAIN METASTASIS PATIENT COHORTS TREATED WITH STEREOTACTIC RADIOSURGERY WITH OR WITHOUT IMMUNOTHERAPY
Authors: Steven Nguyen, Luke Pearson, Andrew Keller, Sean All, Hanisha Patel, Naren Ramakrishna
Journal: Neuro-Oncology (2017)

We assessed the overall survival (OS) following stereotactic radiosurgery (SRS) among melanoma brain metastases (MBM) patient cohorts treated with or without immunotherapy. An IRB-approved retrospective analysis was performed on 69 MBM patients with 230 total lesions treated with SRS between November 2008 to February 2017. Actuarial survival outcomes were compared between patients receiving either sequential or concurrent immunotherapy (ipilimumab, nivolumab, and pembrolizumab) and those not treated with any immunotherapy. Survival analysis was performed using Kaplan-Meier estimates and Cox regression with SPSS. Median OS of the entire study population was 6.75 months (95% CI 2.92–10.59). Fifty of the 69 patients (73.9%) received either ipilimumab, nivolumab, or pembrolizumab treatments. This patient cohort had a median OS of 9.90 months (95% CI 2.34–17.45) versus 3.29 months (95% CI 2.55–4.02) for the cohort not treated with immunotherapy (HR 0.23, 95% CI 0.05–0.99, p = 0.049). Patient pre-treatment characteristics including GPA score, RPA score, KPS, age, history of WBRT, and number of brain metastases treated were not significantly different between the immunotherapy and non-immunotherapy patient cohorts. The median OS for subgroups receiving: (1) immunotherapy both before and after any SRS treatment (n = 19), (2) immunotherapy before SRS (n = 11), and (3) immunotherapy after SRS (n = 20) were 25.49 months (95% CI 18.53–32.45), 4.27 months (95% CI 1.15–7.40), and 7.61 months (95% CI 1.67–13.54), respectively (p = 0.004). In our patient group, overall survival following SRS for melanoma brain metastases is significantly longer among a cohort of patients who received immunotherapy, versus those who did not. Among patients receiving immunotherapy, those treated both before and after SRS had the longest median OS of 25.49 months. Further studies are underway to assess cause-specific mortality among these patient cohorts.
Perplexing Conclusions Concerning Heat-Not-Burn Tobacco Cigarettes
Authors: Massimo Caruso, Riccardo Polosa
Journal: JAMA Internal Medicine (2017)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA Internal Medicine HomeNew OnlineCurrent IssueFor Authors Podcast Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA Internal Medicine journal
Paludismo importado en Francia continental en 1996
Authors: F Legros, M Belkaid, M Danis
Journal: Eurosurveillance (1998)

El paludismo dejo de ser endemico en Francia en 1960, aunque en la provincia de Corse siguieron declarandose casos esporadicos hasta 1970. Desde entonces, no se han declarado mas casos autoctonos de paludismo en Francia. A continuacion ofrecemos datos epidemiologicos sobre el paludismo importado en 1996 (1).
DDIS-21. APPLICATION OF A FUNCTIONAL GENETICS APPROACH TO IDENTIFY PHARMACOLOGICAL INHIBITORS OF HIF-1α
Authors: Qichao Qi, Tor-Christian Aase Johannessen, Jian Wang, Xingang Li, Rolf Bjerkvig, Lars Prestegarden
Journal: Neuro-Oncology (2017)

Two phase III clinical trials with temozolomide (TMZ) in combination with bevacizumab for newly diagnosed glioblastoma multiforme (GBM) failed to demonstrate any survival benefit when compared to TMZ alone. Previous studies have shown that bevacizumab treatment increases intratumoral hypoxia followed by up-regulation of hypoxia-inducible factor 1 alpha (HIF-1α), a key mediator of tumor cell survival under hypoxic conditions. As such, inhibition of HIF-1α might be a promising therapeutic strategy in GBM. The aim of this study was to identify new pharmacological inhibitors of HIF-1α by combining functional genomics data with the Connectivity Map (cMap) database. First, a genome-wide lentiviral short hairpin RNA (shRNA) synthetic lethality screen was performed using a pool of 27,290 shRNAs targeting 5,046 known human genes to identify genes essential for GBM cell survival under hypoxia. The cMap database was subsequently interrogated using these results to identify drugs that would induce corresponding changes in gene expression. By applying this approach, we identified albendazole (ABZ), a widely used anti-helmintic drug, as a potent inhibitor of HIF-1α. ABZ treatment of GBM cells induced a broad-spectrum down-regulation of pro-angiogenic-factors, such as vascular endothelial growth factor (VEGF). Furthermore, ABZ induced a G2/M cell cycle arrest followed by apoptotic cell death. Mechanistically, we showed that ABZ disrupts microtubule polymerization leading to impaired translation of HIF-1α mRNA. The therapeutic potential of ABZ and concomitant bevacizumab is currently being assessed in vivo and the data will be presented. In conclusion, ABZ is a potent pharmacological inhibitor of HIF-1α. Considering that HIF-1α is a key mediator of resistance to anti-angiogenic therapy, a combined approach with ABZ and bevacizumab might be a promising treatment strategy for GBM patients.
OA 05.06 Phase 2 Study of Lorlatinib in Patients with Advanced ALK+/ROS1+ Non-Small-Cell Lung Cancer
Authors: B. Solomon, A. Shaw, S. Ou, B. Besse, E. Felip, T. Bauer, R. Soo, A. Bearz, C. Lin, J. Clancy, A. Abbattista, H. Thurm, G. Peltz, E. Masters, J. Martini, L. James, T. Seto
Journal: Journal of Thoracic Oncology (2017)
TMIC-02. GENETIC DRIVER-MUTATIONS DEFINE THE TUMORS ASSOCIATED MACROPHAGE COMPOSITION AND FUNCTION IN GLIOBLASTOMA
Authors: Zhihong Chen, Dolores Hambardzumyan
Journal: Neuro-Oncology (2017)

Glioblastoma (GBM) is the most aggressive and common type of brain tumor in adults. The GBM microenvironment is composed of numerous non-neoplastic cells, among which tumor-associated macrophages (TAMs) are the most abundant, accounting for up to 50% of total cells. TAMs are recruited to the GBM microenvironment are believed to be immunosuppressive and release growth factors and cytokines in response to neoplastic cells, thereby promoting tumor growth. TAMs comprise mixed populations of myeloid cells, including infiltrating macrophages from the blood circulation and resident brain microglia. By using a genetically-engineered mouse model of PDGF-driven GBM (an immunocompetent model of human Proneural GBM), in combination with double-transgenic reporter mice that express CX3CR1-GFP and CCR2-RFP, we have previously demonstrated that the infiltrating macrophages constitute ~80% of the total TAM population, with resident microglia accounting for the remaining ~20% of TAMs. Interestingly, in contrast to this previous finding, we show in this study that the composition of TAMs in NF1-silenced tumors (resembling human Mesenchymal GBM) are reversed, with the majority of TAMs derived from resident microglia. These observations inspired us to ask the question whether inhibiting TAM infiltration from the periphery can differentially improve the outcomes of PN and MES GBM subtypes in preclinical models. Macrophage chemoattractant proteins (MCPs) are CCL chemokines consisting 4 family members (-2, -7, -8, -12), which are crucial in mediating monocyte infiltration from the periphery. We tested our hypothesis by generating GBMs in mice deficient of individual MCP members. Notably, we found that limiting monocyte infiltration via Ccl2, Ccl7 or Ccl8/CcL12 genetic ablation prolonged the survival of PDGF-driven GBM-bearing mice. Our findings illuminate the unique composition and functions of infiltrating and resident myeloid cells in different subtypes of GBM, establishing a rationale to target infiltrating cells in this neoplasm.
Action levels for indoor radon: different risks for the same lung carcinogen?
Authors: Alberto Ruano-Ravina, Karl T. Kelsey, Alberto Fernández-Villar, Juan M. Barros-Dios
Journal: European Respiratory Journal (2017)

Assessment of the various risk factors for lung cancer has found that indoor radon exposure is the primary risk factor for lung cancer in never-smokers and the second ranked risk factor in ever-smokers [1, 2], following tobacco. Radon exposure is responsible for approximately half of the total ionising radiation that the average human being receives in a lifetime (followed in magnitude by medical radiation) and is the largest source of natural ionising radiation [3]. Radon is a colourless, odourless and tasteless gas that comes from the bedrock of the Earth's crust. Radon 222 is the most dangerous and the most common form of radon, from an epidemiological point of view, as 80% of all radon is radon 222. Indoor radon is usually measured in becquerels per cubic metre, and 1 becquerel per cubic metre is equivalent to one nuclear disintegration per second in such a volume. One nuclear disintegration releases one alpha particle. Radon is the second most important risk factor for lung cancer but recommended exposure differs in many countries <http://ow.ly/VZ8y30fDdYz>
Objectively Measured Physical Activity and Sedentary Time Are Associated With Cardiometabolic Risk Factors in Adults With Prediabetes: The PREVIEW Study
Authors: Nils Swindell, Kelly Mackintosh, Melitta McNarry, Jeffrey W. Stephens, Diewertje Sluik, Mikael Fogelholm, Mathijs Drummen, Ian MacDonald, J. Alfredo Martinez, Teodora Handjieva-Darlenska, Sally D. Poppitt, Jennie Brand-Miller, Thomas M. Larsen, Anne Raben, Gareth Stratton
Journal: Diabetes Care (2017)

OBJECTIVE The aim of the present cross-sectional study was to examine the association among physical activity (PA), sedentary time (ST), and cardiometabolic risk in adults with prediabetes. RESEARCH DESIGN AND METHODS Participants (n = 2,326; 25–70 years old, 67% female) from eight countries, with a BMI &amp;gt;25 kg ⋅ m−2 and impaired fasting glucose (5.6–6.9 mmol ⋅ L−1) or impaired glucose tolerance (7.8–11.0 mmol ⋅ L−1 at 2 h), participated. Seven-day accelerometry objectively assessed PA levels and ST. RESULTS Multiple linear regression revealed that moderate-to-vigorous PA (MVPA) was negatively associated with HOMA of insulin resistance (HOMA-IR) (standardized β = −0.078 [95% CI −0.128, −0.027]), waist circumference (WC) (β = −0.177 [−0.122, −0.134]), fasting insulin (β = −0.115 [−0.158, −0.072]), 2-h glucose (β = −0.069 [−0.112, −0.025]), triglycerides (β = −0.091 [−0.138, −0.044]), and CRP (β = −0.086 [−0.127, −0.045]). ST was positively associated with HOMA-IR (β = 0.175 [0.114, 0.236]), WC (β = 0.215 [0.026, 0.131]), fasting insulin (β = 0.155 [0.092, 0.219]), triglycerides (β = 0.106 [0.052, 0.16]), CRP (β = 0.106 [0.39, 0.172]), systolic blood pressure (BP) (β = 0.078 [0.026, 0.131]), and diastolic BP (β = 0.106 [0.39, −0.172]). Associations reported between total PA (counts ⋅ min−1), and all risk factors were comparable or stronger than for MVPA: HOMA-IR (β = −0.151 [−0.194, −0.107]), WC (β = −0.179 [−0.224, −0.134]), fasting insulin (β = −0.139 [−0.183, −0.096]), 2-h glucose (β = −0.088 [−0.131, −0.045]), triglycerides (β = −0.117 [−0.162, −0.071]), and CRP (β = −0.104 [−0.146, −0.062]). CONCLUSIONS In adults with prediabetes, objectively measured PA and ST were associated with cardiometabolic risk markers. Total PA was at least as strongly associated with cardiometabolic risk markers as MVPA, which may imply that the accumulation of total PA over the day is as important as achieving the intensity of MVPA.
SCDT-43. BLOCKING OF INTERACTING CK2 AND EGFR PATHWAYS BY TUMOR-TARGETING NANOCONJUGATES INCREASES THERAPEUTIC EFFICACY AGAINST GLIOBLASTOMA MULTIFORME
Authors: Keith Black, Rameshwar Patil, Hui Ding, Vladimir Ljubimov, Ekaterina Shatalova, Eggehard Holler, Julia Ljubimova
Journal: Neuro-Oncology (2017)

Glioblastoma multiforme (GBM) remains the deadliest brain tumor in adults. To inhibit GBMs more effectively, polymalic acid-based blood-brain barrier (BBB) crossing nanobioconjugates were synthesized that are delivered to the cytoplasm of cancer cells and specifically inhibit the master regulator serine/threonine protein kinase CK2 and/or the wild-type/mutated epidermal growth factor receptor (EGFR/EGFRvIII), which are overexpressed in gliomas according to The Cancer Genome Atlas (TCGA) GBM database. The used nanobioconjugates are novel nanotherapeutics where all moieties are covalently attached to poly(β-l-malic acid) (PMLA). Our biodegradable and non-toxic nanodrugs bind to the receptors enriched on tumor vasculature and cross BBB by transcytosis. They specifically bind to cancer cells and after internalization exit to the tumor cell cytoplasm using pH-sensitive endosomal disruption unit. Two xenogeneic mouse models bearing intracranial human GBMs from cell lines LN229 and U87MG that expressed both CK2 and EGFR/EGFRvIII were used. The knockdown of CK2α and EGFR/EGFRvIII suppressed their downstream prosurvival signaling. Treatment markedly reduced the expression of programmed death-ligand 1 (PD-L1), a negative regulator of cytotoxic lymphocytes. Downregulation of CK2 and EGFR also caused suppression of heat shock protein 90 (Hsp90) co-chaperone Cdc37, which inhibits the activity of key cellular kinases. The inhibition patterns of key molecular targets indicated cross talk between CK2 and EGFR pathways. Importantly, the dual nanodrug markedly suppressed the expression of cancer stem cell markers c-Myc, CD133, and nestin, which may contribute to the nanodrug efficacy and brain tumor local immunomodulation. In both tumor models, the dually targeted nanobioconjugate significantly increased (up to 2-fold) animal survival compared to PBS control. The versatile nanobioconjugates with anti-cancer drug delivery across biobarriers and inhibition of key tumor regulators offer a promising nanotherapeutic approach to treat GBMs and potentially retard brain tumor recurrence. Support: NIH grants U01 CA151815, R01 CA188743, R01 CA206220, R01 CA209921
Early loss of skeletal muscle mass (LSMM) as prognostic factor in metastatic pancreatic cancer (PC) patients
Authors: D. Basile, A. Parnofiello, M.G. Vitale, F. Cortiula, S.K. Garattini, L. Gerratana, V.J. Andreotti, E. Ongaro, C. Lisanti, M. Bartoletti, M. Bonotto, V. Fanotto, M. Cattaneo, D. Iacono, A. Bacco, P. Ermacora, F. Puglisi, G. Aprile, N. Pella, G.G. Cardellino, G. Fasola
Journal: Annals of Oncology (2017)