tbuckley/cabot-search huggingface dataset:
Matrix-binding checkpoint immunotherapies enhance antitumor efficacy and reduce adverse events
Authors: Jun Ishihara, Kazuto Fukunaga, Ako Ishihara, Hans M. Larsson, Lambert Potin, Peyman Hosseinchi, Gabriele Galliverti, Melody A. Swartz, Jeffrey A. Hubbell
Journal: Science Translational Medicine (2017)

Immune checkpoint blockade exhibits considerable antitumor activity, but previous studies have reported instances of severe treatment-related adverse events. We sought to explore local immune checkpoint blockade, with an antibody (Ab) form that would be retained intra- or peritumorally, limiting systemic exposure. To accomplish this, we conjugated the checkpoint blockade Abs to an extracellular matrix (ECM)-super-affinity peptide derived from placenta growth factor-2 (PlGF-2123-144). We show enhanced tissue retention and lower Ab concentrations in blood plasma after PlGF-2123-144 conjugation, reducing systemic side effects such as the risk of autoimmune diabetes. Peritumoral injections of PlGF-2123-144-anti-CTLA4 (cytotoxic T lymphocyte antigen 4) and PlGF-2123-144-anti-PD-L1 (programmed death ligand 1) Abs delayed tumor growth and prolonged survival compared to the unmodified Abs in genetically engineered murine tumor models of melanoma and breast cancer. The PlGF-2123-144-Abs increased tumor-infiltrating activated CD8+ and CD4+ T cells, resulting in a delay of distant tumor growth as well. This simple and translatable approach of engineered ECM-binding Abs may present a viable and safer approach in checkpoint blockade.
NIMG-59. RADIOLOGIC SUBTYPES OF GLIOBLASTOMA CALCULATED VIA MULTI-PARAMETRIC IMAGING SIGNATURES REVEAL COMPLEMENTARY INFORMATION TO CURRENT WHO CLASSIFICATION
Authors: Saima Rathore, Hamed Akbari, Martin Rozycki, Kalil Abdullah, MacLean Nasrallah, Zev A Binder, Robert Lustig, Nadia Dahmane, Michel Bilello, Donald O’Rourke, Christos Davatzikos
Journal: Neuro-Oncology (2017)

The World Health Organization (WHO) has recently changed the classifications of glioblastoma based on molecular information. The aim of this study was to systematically find imaging signatures via quantitative multi-parametric MRI pattern analysis that can provide complementary information to the current WHO classifications for patients’ prognosis. We analyzed a discovery cohort of N=208 de novo glioblastoma patients with available preoperative multi-parametric MRI data (T1, T1-Gd, T2, FLAIR, DTI, DSC). We conducted a pattern analysis based on comprehensive features, which were extracted from multi-parametric MRI in various parts of the tumor. The features comprised shape measures of circularity and sphericity, Haralick texture measures, intensity statistical parameters, volumetric measures, and percentage in each bin of intensity distribution. Unsupervised clustering was used on imaging measures to find radiologic subtypes, which were initially cross-validated in the discovery cohort and subsequently evaluated in a replication cohort (N=53). Our results revealed three radiologic subtypes of glioblastoma with distinct overall survival rates (hazard ratio = 4.174 (2.463–7.072,P<0.001), CI 95%), spatial location, and radiological measures of cell-density, vascularization, infiltration, and size of peritumoral edema (ANOVA: P<0.01 for all). The combination of subtype with IDH1 mutation predicted better survival compared to either of these alone (Subtype=73.91%, IDH1=75.00%, Combined=80.02% classification accuracy). Further, our subtypes were not only consistent with WHO classifications by assigning 75% IDH1 mutants to the long survivor subtype, but were also an excellent predictor of survival within IDH1-wildtype patients (median survival: 7, 11.5, 19 months for IDH1-wildtype patients in three subtypes, ANOVA P<0.01), thereby highlighting the complementary value of imaging to the established WHO classifications for patient’s prognosis. Advanced pattern analysis of multi-parametric MRI reveals radiological subtypes of glioblastoma that are predictive of an individual patient’s prognosis, substantially beyond the current IDH1-based WHO classifications and which therefore might assist in personalized treatment.
CBIO-06. POTENTIAL ROLE OF RNU6 ISOLATED FROM CIRCULATING EXOSOMES AS A DIAGNOSTIC BIOMARKER FOR GLIOBLASTOMA
Authors: Montserrat Puigdelloses, Marisol González-Huarriz, Marc Garcia-Moure, Naiara Martínez-Vélez, Sarah Besora, Jordi Bruna Escuer, Beatriz Zandio, Teresa Ayuso, María Otano, Jaime Gallego Culleré, Eduardo Martínez-Vila, Ana Patiño-Garcia, Miguel Marigil Sanchez, Ricardo Diez Valle, Sonia Tejada, Marta M Alonso, Jaime Gallego Pérez-Larraya
Journal: Neuro-Oncology (2017)

Glioblastomas (GBM) are highly malignant brain tumors with a poor prognosis despite intensive research and clinical effort. Circulating biomarkers for the disease would be desirable in order to allow for non-invasive tumor detection and follow-up. Recent findings show that GBM cells release microvesicles that contain a select subset of cellular proteins and RNA. Previously, we observed that exosomes isolated from serum of GBM patients had an increased expression of RNU6 (a small non-coding RNA) compared to control samples, and hence could serve as a non-invasive diagnostic biomarker for GBM. In this study, we set to investigate whether this small non-coding RNA could serve as a differential diagnostic biomarker to distinguish GBM from other brain lesions resembling GBM in neuroimaging. We analyzed the expression of RNU6 in circulating exosomes of patients with six types of brain lesions that can mimic GBM on magnetic resonance imaging (i.e. subacute stroke, acute-subacute haemorrhage, acute demyelinating lesions, abscesses, brain metastases and primary CNS lymphomas). First, we isolated the exosomes from the serum of a subset of patients (20–30 patients) with these pathological conditions using an adsorption method (Exoquick). The same was done in a similar group of healthy controls and GBM patients. Then RNU6 levels were analyzed by digital droplet PCR (ddPCR). Corroborating our previous results, we found that the expression of RNU6 was significantly higher in GBM patients than in healthy controls. In addition, RNU6 levels were significantly higher in exosomes from GBM patients than in exosomes from patients with stroke, haemorrhage or acute multiple sclerosis lesions. We are currently analyzing the data regarding the expression of RNU6 in CNS metastasis and lymphomas. Our preliminary data suggest that RNU6 could serve as a differential diagnostic biomarker for GBM patients.
Modeling breast cancer tumor morphology to predict drug response
Authors: Hermann B. Frieboes, Ernest S. Han, Vittorio Cristini, John P. Fruehauf
Journal: Cancer Research (2005)

5961   Previous investigators demonstrated that acquired drug resistance could be detected only in three-dimensional spheroids, rather than in monolayer cultures (Kobayashi  et al. , 1993). Further, the resistant phenotype was associated with a distinct spheroid morphology. Treated spheroids were more compact than drug-naive spheroids. These data suggest that intercellular interactions among constituents of solid tumors may have a profound impact on drug response, leading to the hypothesis that treatment response may be related to tumor morphology. We therefore set out to determine if tumor morphology in three-dimensional culture versus monolayer affected MCF-7  in vitro  drug response. We compared the MDR-1 positive doxorubicin-resistant (DoxR) cell line with the Dox-sensitive wildtype strain. Our group has developed an  in silico  model of tumor growth, and a second objective of our study was to incorporate spheroid morphology into this model. We evaluated three-dimensional growth characteristics and P-glycoprotein expression in the DoxR and Dox-sensitive cell lines. P-Glycoprotein expression was assessed with immunohistochemistry using JSB-1 antibody. Morphology was evaluated with phase contrast microscopy.  In vitro  drug response to doxorubicin was determined by hemocytometer trypan blue cell counts. For  in silico  modeling we used a multi-scale and multi-dimensional tumor simulator to model tumor morphological characteristics that were predictive of drug response. Model parameters were extended to include  in vitro  tumor morphology and P-glycoprotein expression. Three-dimensional spheroids of MCF-7 DoxR cells were found to have a more compact morphology than MCF-7 Dox-sensitive cells. P-Glycoprotein staining was observed in DoxR spheroids and monolayers, while Dox-sensitive cells lacked P-glycoprotein expression. For both drug-resistant and drug-sensitive cell lines, viability was approximately two-fold greater in spheroids as compared to monolayer culture when treated with 4μM doxorubicin.  In silico  simulations of tumor growth were able to predict higher drug resistance in compact versus diffuse spheroids. Compactness was measured as the ratio of surface area to volume. We developed an iterative translational technique to model tumor growth and response to therapy to answer the question of how morphology and structure of tissue may affect drug response. The three-dimensional morphology of MCF-7  in vitro  culture may confer drug resistance properties related to tumor compactness and P-glycoprotein expression. The experimental data provide a means to measure parameters whose biological meaning enables model validation. The model may then provide a theoretical framework through which drug response  in vivo  can be studied and predicted.
TMIC-07. HIGH ALDEHYDE DEHYDROGENASE ACTIVITY IDENTIFIES BRAIN METASTASIS-INITIATING CELLS IN BREAST CANCER
Authors: Mutsuko Minata, Heba Allah Alsheikh, Shuko Harada, Deniz Peker, Yancey Gillespie, Richard Cerione, Bakhos Tannous, Ichiro Nakano, Rajeev Samant, Songijan Lu, Shinobu Yamaguchi
Journal: Neuro-Oncology (2017)

Brain metastases (BM) from breast cancer (BC) are associated with significant morbidity and mortality. However, the mechanism of how BC cells initiate and propagate BM tumors remains elusive. In this study, we established a set of patient-derived models of circulating tumor cells (CTCs) from either hormone receptor positive (HR+) or negative (HR-) cells, and subsequent BM cells in vivo. Our brain-primed BC derivative lines exhibited a trend to form metastatic tumors in the brain more frequently than in the bones or lungs. In contrast, the naïve BC cells rarely formed BM tumors. Micro-MRI of mouse brains after cardiac injection of brain-primed BC derivatives detected the persistent attachment and subsequent colonization of these circuiting cells, whereas naïve BC cells, when injected into arterial circulation, were quickly eradicated from the brain. Transcriptomic expression analysis showed that ALDH isoforms including ALDH1A3 are highly upregulated in BM cells in contrast to BC cells. Silencing of ALDH1A3 by lentiviral shRNA infection specifically attenuated in vivo BM formation from the BC derivatives through arterial circulation, while it did not affect formation of the metastases in the lungs and bones. RNA sequencing detected that the expression of tissue transglutaminase (TG2), constitutive activator of transcription factor-kB (NF-kB), is higher in BM but not in lung and bone metastasis and its expression was attenuated by reducing ALDH1A3. Clinically, matched pairs of human primary BC and BM tissue samples showed the elevation of ALDH1A3 expression in BM tumors. In addition, ALDH1A3 expression was significantly correlated with poor prognosis. To develop therapeutics for ALDH1A3, we designed and synthesized a small molecule ALDH1A3 inhibitor, termed GA11. Systemic treatment of the CTC-BM mouse models with GA11 yielded a prominent inhibitory effect on BM formation. Taken together, our results suggest that ALDH1A3 might be a promising therapeutic target for BM tumors.
P3.04-006 SYSTEMS-2: Randomized Phase II Trial of Standard Versus Dose Escalated Radiotherapy for Pain in Malignant Pleural Mesothelioma
Authors: M. Ashton, N. O'Rourke, N. Macleod, S. Smith, R. Valentine, B. Laird, S. Sheridan, L. Alexander, A. Chalmers
Journal: Journal of Thoracic Oncology (2017)
Stop rollout of online consultations until there is evidence of benefit to patients, say LMCs
Authors: Gareth Iacobucci
Journal: BMJ (2017)

The BMA’s GP committee should formally oppose the expansion of online consulting until there is evidence that it benefits patients, England’s local medical committees have urged.

A motion passed by the LMCs, which represent GPs at the local level, at their annual conference in London on Friday 10 November expressed concern at the pressure to introduce online consulting into general practice when there was “no evidence that it will save time.”

The motion called on the BMA’s General Practitioners Committee “to make it clear to government and NHS England that GPs will not formally agree to begin …
P3.13-019 Preoperative Needle Biopsy Does Not Increase the Risk of Pleural Recurrence in ≤3cm Lung Adenocarcinoma
Authors: K. Kameda, T. Eguchi, R. Gaber, N. Rekhtman, Z. Tano, S. Solomon, W. Travis, D. Jones, P. Adusumilli
Journal: Journal of Thoracic Oncology (2017)
Cadherin-related Family Member 3 Genetics and Rhinovirus C Respiratory Illnesses
Authors: Klaus Bønnelykke, Amaziah T. Coleman, Michael D. Evans, Jonathan Thorsen, Johannes Waage, Nadja H. Vissing, Christian J. Carlsson, Jakob Stokholm, Bo L. Chawes, Leon E. Jessen, Thea K. Fischer, Yury A. Bochkov, Carole Ober, Robert F. Lemanske, Daniel J. Jackson, James E. Gern, Hans Bisgaard
Journal: American Journal of Respiratory and Critical Care Medicine (2017)

Rationale: Experimental evidence suggests that CDHR3 (cadherin-related family member 3) is a receptor for rhinovirus (RV)-C, and a missense variant in this gene (rs6967330) is associated with childhood asthma with severe exacerbations.Objectives: To determine whether rs6967330 influences RV-C infections and illnesses in early childhood.Methods: We studied associations between rs6967330 and respiratory infections and illnesses in the COPSAC2010 (Copenhagen Prospective Studies on Asthma in Childhood 2010) and COAST (Childhood Origins of Asthma Birth Cohort Study) birth cohorts, where respiratory infections were monitored prospectively for the first 3 years of life. Nasal samples were collected during acute infections in both cohorts and during asymptomatic periods in COAST and analyzed for RV-A, RV-B, and RV-C, and other common respiratory viruses.Measurements and Main Results: The CDHR3 asthma risk allele (rs6967330-A) was associated with increased risk of respiratory tract illnesses (incidence risk ratio [IRR] = 1.14 [95% confidence interval, 1.05–1.23]; P = 0.003). In particular, this variant was associated with risk of respiratory episodes with detection of RV-C in COPSAC2010 (IRR = 1.89 [1.14–3.05]; P = 0.01) and in COAST (IRR = 1.37 [1.02–1.82]; P = 0.03) children, and in a combined meta-analysis (IRR = 1.51 [1.13–2.02]; P = 0.006). In contrast, the variant was not associated with illnesses related to other viruses (IRR = 1.07 [0.92–1.25]; P = 0.37). Consistent with these observations, the CDHR3 variant was associated with increased detection of RV-C, but not of other viruses during scheduled visits at specific ages.Conclusions: The CDHR3 asthma risk allele is associated specifically with RV-C illnesses in two birth cohorts. This clinical evidence supports earlier molecular evidence indicating that CDHR3 functions as an RV-C receptor, and raises the possibility of preventing RV-C infections by targeting CDHR3.
A vigilância da sífilis e a evolução da epidemia em Alemanha desde a metade dos anos 90
Authors: U Marcus, V Bremer, O Hamouda
Journal: Eurosurveillance (2004)

Segundo relatorios recentes de vigilancia na Europa e nos Estados Unidos, o numero de casos de sifilis esta aumentado. Para um funcionamento adequado dos programas de deteccao e de intervencao e necessario dispor de dados epidemiologicos precisos sobre a distribuicao da sifilis. O sistema alemao de declaracao da sifilis foi modificado em 2001, estando agora baseado na notificacao dos laboratorios em lugar dos medicos. Esta mudanca foi acompanhada por um novo sistema sentinela de vigilancia das infeccoes sexualmente transmissiveis (IST). Depois de ter atingido a taxa de notificacoes muito baixa nos anos 1990, as declaracoes de sifilis aumentaram de novo de maneira significativa desde 2001, data que coincide com a introduccao do novo sistema de notificacao. Este aumento da incidencia nao se deve unicamente ao sistema precedente, mas refleta um verdadeiro aumento no numero de casos. Ele esta relacionado com a aparicao de surtos de sifilis em homens que tem relacoes sexuais com outros homens (HRSH). O primeiro de eses surtos foi em Hamburgo em 1997. Em 2003, a incidencia era 10 vezes maior em homens que em mulheres. Estima-se que 75% dos casos de sifilis diagnosticados actualmente sao HRSH. 
Uma larga proporcao desses pacientes (ate 50% segundo os dados do sistema sentinela) sao positivos para o VIH. O numero crescente de casos de sifilis em heterosexuais em Alemanha nos ultimos anos, comparado com outros paises da Europa occidental, poderia ser devido a movimentos de populacao frequentes entre Alemanha e regioes do leste y sudeste da Europa com alta incidencia de sifilis.
Vigilancia de la resistencia de Helicobacter pylori a los principales agentes antimicrobianos efectuada en centros de Inglaterra y Gales durante un período de 6 años (2000-2005)
Authors: S A Chisholm, E L Teare, K Davies, R J Owen
Journal: Eurosurveillance (2007)

La resistencia a los antibioticos es un factor clave en la ineficacia del tratamiento para la erradicacion de Helicobacter pylori, sin embargo existen pocas redes centinela, tanto de ambito local como nacional e internacional, para el seguimiento de las tendencias en lo que a dicha resistencia se refiere.
ANGI-14. A GSK-3/b-CATENIN/ARHGAP AXIS REGULATES GLIOBLASTOMA INVASION
Authors: Anke Brüning-Richardson, Michel Mittelbronn, Matthew Humphries, Filomena Esteves, Marjorie Boissinot, Daniel Tams, Alastair Droop, Julia Cockle, Sophie Taylor, Ruth Morton, Azzam Ismail, Sean E Lawler, Georgia Mavria, Susan C Short
Journal: Neuro-Oncology (2017)

Glycogen synthase kinase-3 (GSK-3) has been implicated as a potential target in glioblastoma migration and invasion. Here we investigated the effects of GSK-3 inhibition on downstream effector genes and discovered a novel GSK-3 /b-catenin/ARHGAP migration axis that drives glioblastoma invasion. Expression arrays of glioblastoma cells treated with the GSK-3 inhibitor 6-bromoindirubin-3’-oxime (BIO) were performed. Functional validation was carried out using 2D and 3D migration assays, siRNA knockdown and orthotopic xenograft models. Protein expression was investigated in patient glioblastoma samples. Microarray data analysis identified deregulation of expression of members of the ARHGAP gene family of GTPase regulators after BIO treatment of U251 cells. This was confirmed at the protein level by Western blotting and immunostaining. siRNA treatment indicated a specific promigratory role for ARHGAP29. U251 cells exposed to BIO displayed a decrease in migration as evidenced by loss of polarity and reduction in cell velocity. This was associated with a rearrangement of actin filaments and b-catenin translocation from the cell surface to the nucleus, where it is known to act as a transcription factor downstream of GSK-3 inhibition. We then found that ICG001, an inhibitor of b-catenin-induced transcription, essentially mimicking GSK-3 activation, induced transcription of ARHGAP29 and led to a partial increase of ARHGAP29 protein expression, reduction of b-catenin target gene expression and the ability of cells to migrate. In vivo studies, as well as data from glioblastoma patients, confirmed a pro-migratory role for ARHGAP29 as evidenced by elevated protein levels in migratory cells at the invasive front in orthotopic xenograft models and its association with disease recurrence. We demonstrate for the first time signalling events downstream of GSK-3 activation and b-catenin nuclear translocation which reveal a new pathway regulating glioblastoma migration through the transcription of the GTPase regulator ARHGAP29.
Digital health to end tuberculosis in the Sustainable Development Goals era: achievements, evidence and future perspectives
Authors: Dennis Falzon, Giovanni Battista Migliori, Ernesto Jaramillo, Karin Weyer, Guy Joos, Mario Raviglione
Journal: European Respiratory Journal (2017)

Until 2015, the United Nations Millennium Development Goals provided a framework for countries to work towards targets aimed at improving health. Major progress was achieved globally as a result of this drive. Important challenges, however, persist for both communicable ( e.g. tuberculosis (TB) and HIV) and noncommunicable ( e.g. tobacco use) health problems. The Sustainable Development Goals (SDGs), which now guide the global development agenda until 2030, approach these health problems more holistically [1]. The "integrated and indivisible" nature of the SDGs requires action across all layers of society. To achieve the health-specific Goal 3 ("Ensure healthy lives and promote well-being for all at all ages"), countries also need to act on the other 16 SDGs, such as poverty (Goal 1), malnutrition (Goal 2), gender-associated inequalities (Goal 5), investment in information and communications technology and in research by the public and private sectors (Goal 9), transparency, accountability and nondiscriminatory laws (Goal 16), and cross-sectoral collaboration and partnerships (Goal 17). Use of digital technologies to support TB care and prevention can be a model for broader action to achieve the SDGs <http://ow.ly/QEcE30fKnAZ> The authors acknowledge the contribution to the arguments presented in this article of the Global Task Force on digital health for TB , chaired by Giovanni Battista Migliori (WHO Collaborating Centre for TB and Lung Diseases, Maugeri Care and Research Institute, Tradate, Italy), and composed of Andrei Dadu (WHO Regional Office for Europe, Copenhagen, Denmark), Claudia Denkinger (FIND, Geneva, Switzerland), Luis Gustavo do Valle Bastos (Global Drug Facility, Geneva, Switzerland), Richard Garfein (University of California San Diego, San Diego, CA, USA), Richard Lester (University of British Columbia, Vancouver, Canada), Kirankumar Rade (Revised National TB Control Programme, New Delhi, India), Lal Sadasivan (PATH, Washington, DC, USA), Kaiser Shen (USAID, Washington, DC, USA), Alena Skrahina (National TB Programme, Minsk, Belarus), Giovanni Sotgiu (University of Sassari, Sassari, Italy), Alistair Story (Find & Treat, London, UK), Khin Swe Win (Myanmar Medical Association, Yangon, Myanmar), Zelalem Temesgen (Mayo Clinic, Rochester, MN, USA), Bruce V. Thomas (The Arcady Group, Richmond, VA, USA), Kristian van Kalmthout (KNCV Tuberculosis Foundation, The Hague, The Netherlands), Arne von Delft (TB PROOF, Cape Town, South Africa) and Mohammed Yassin (Global Fund to Fight AIDS, TB and Malaria, Geneva, Switzerland). This editorial also draws on some of the discussions at a WHO/ERS consulation held in February 2017 \[18\] (figure 1).