tbuckley/cabot-search huggingface dataset:
STEM-25. QUAKING (QKI) LOSS ENHANCES GSC STEMNESS AND PROMOTES GLIOMAGENESIS THROUGH REGULATING INTRACELLULAR VESICLE TRAFFICKING
Authors: Takashi Shingu, Jian Hu
Journal: Neuro-Oncology (2017)

Glioma stem cells (GSCs) have higher self-renewal capacity than neural stem cells (NSCs), yet the underlying molecular mechanism is less clear. Here we report the generation of a novel conditional KO allele of Quaking (Qki), a tumor suppressor in glioblastoma with RNA binding activity. When Qki was deleted in Nestin-CreERT2;QkiL/L mice, the NSC population, which is characterized by long-term BrdU retention and GFAP+/Nestin+ double positive staining, was greatly increased, indicating that Qki deletion enhances NSC self-renewal. To determine whether Qki deletion promotes gliomagenesis, we generated a Nestin-CreERT2;QkiL/L;PtenL/L;p53L/L cohort, in which 92% of the mice developed glioblastoma with a median survival of 105 days. However, the Nestin-CreERT2;PtenL/L;p53L/L cohort did not develop any glioma up to a year; therefore Qki deletion greatly promotes gliomagenesis. Transcriptomic and proteomic profiling coupled with PAR-CLIP (Photoactivatable-Ribonucleoside-Enhanced Crosslinking and Immunoprecipitation) analyses revealed that genes involved in intracellular vesicle trafficking were greatly enriched by Qki deletion. Specifically, 34% of the genes up-regulated by Qki deletion are involved in receptor delivery, and 39% of the genes down-regulated by Qki deletion are subunits of receptor degradation machineries such as endosomes and lysosomes. High level of receptor delivery and low level of receptor degradation concomitantly enrich receptors on the membrane and enhance the activity of the receptors that are involved in maintaining stemness, including RTK, Notch1 and Frizzled. Lower lysosomal activity induced by Qki deletion also leads to defective mitophagy, which consequently leads to accumulation of damaged mitochondria, high level of ROS, and genomic instability in Qki-deficient NSCs. We identified that genomic instability induced by Qki deletion led to accumulation of classical glioblastoma-associated mutations such as copy number gains of PDGFRa, Cyclin D1 and Cyclin D3. Taken together, our data suggest that Qki loss-induced endolysosomal defects promotes gliomagenesis through both reducing receptor degradation and inducing genomic instability.
La legionelosis asociada a los viajes en Europa : 2003
Authors: K D Ricketts, C Joseph
Journal: Eurosurveillance (2004)

Veinte paises notificaron 676 casos de legionelosis asociada a viajes al sistema de vigilancia EWGLINET y se detectaron 94 agrupaciones. El test de antigeno en orina permitio diagnosticar el 80,5% de todos los casos. 
El periodo medio entre el inicio de sintomas y la notificacion de los casos fue de 20,5 dias, frente a 51,5 en 1993. 
Desde la introduccion de las recomendaciones del EWGLI (1 Julio 2002) hasta el final del ano 2002, fueron aceptados por el centro coordinador 37 informes de vigilancia, todos ellos de seis semanas de duracion, enviados a tiempo y considerados satisfactorios. En 2002 fueron investigados 274 lugares de alojamiento. 
Los patrones turisticos de los principales declarantes a EWGLINET influyeron en los periodos de actividad maxima y ayudaron a determinar que paises tenian mayor carga en terminos de investigacion.
DDIS-17. POLYNITROXYL ALBUMIN INHIBITS BRAIN TUMORIGENIC CASCADE THROUGH A REACTIVE OXYGEN SPECIES MECHANISM ACROSS THE BLOOD BRAIN BARRIER
Authors: Katie Grausam, Ross Lanier, Amanda Schaefer, Li Ma, Bohdan Soltys, Carleton Hsia, Keith Miskimins, Haotian Zhao
Journal: Neuro-Oncology (2017)

This study seeks to develop a safe therapy with potential for a broad spectrum of brain tumors. For this pilot study, we have selected medulloblastoma (MB), the most common malignant pediatric brain cancer that arises from the cerebellum. MB can disseminate through the cerebrospinal fluid to the leptomeninges covering the brain and spinal cord. Leptomeningeal metastasis, a frequent finding at diagnosis and recurrence, is a serious complication for which innovative therapies are urgently needed to improve patient survival while reducing treatment-related toxicity. Polynitroxyl albumin (PNA) has been tested at Sanford Research and shown to reduce intracellular levels of reactive oxygen species (ROS) and inhibition of the tumorigenic cascade: proliferation, progression, and metastasis. This ROS inhibition appears to be responsive in multiple cancers, including triple negative breast cancer and two chemoradiation-resistant head & neck squamous cell carcinoma cell lines. Because intracellular ROS are readily membrane permeable, we have tested efficacy of PNA across the blood brain barrier (BBB) in treating MB. For this we used a metastatic mouse model of the Sonic Hedgehog (SHH) subgroup. PNA was administered i.p. on a thrice weekly schedule; an albumin-only control group was also treated. Survival analysis was obtained, along with histopathology of both brain and spinal cord; primary tumor, leptomeningeal dissemination, and secondary tumor growth were examined. In our preclinical model, a significant decrease in disseminated MB within the brain was detected (P < 0.05), along with secondary tumor growth along the spinal cord (P < 0.05), compared to the control group. Our results compliment PNA studies in other cancer models; PNA works across the BBB to decrease proliferation of tumor cells and inhibit metastatic growth. Follow up studies are warranted to compare the therapeutic index of intra- vs extra-cerebral PNA delivery to generate preclinical efficacy data in support of conjunctive MB clinical therapy.
Primary antibiotic resistance of Helicobacter pylori in Chinese patients: a multiregion prospective 7-year study
Authors: D.-S. Liu, Y.-H. Wang, Z.-R. Zeng, Z.-Y. Zhang, H. Lu, J.-M. Xu, Y.-Q. Du, Y. Li, J.-B. Wang, S.-P. Xu, Y. Chen, C.-H. Lan, H. Cheng, M.-D. Jiang, L.-X. Zhang, L.-J. Huo, S.-Y. Chen, G.-X. Zhang, K.-C. Wu, X. Zhu, Y.-X. Chen, Y. Zhu, X. Shu, Y. Xie, N.-H. Lu
Journal: Clinical Microbiology and Infection (2017)

To explore the characteristics of Helicobacter pylori resistance in China and the association between antibiotic resistance and several clinical factors.H. pylori strains were collected from patients in 13 provinces or cities in China between 2010 and 2016. Demographic data including type of disease, geographic area, age, gender and isolation year were collected to analyse their association with antibiotic resistance. Antibiotic resistance was detected using the Etest test and the Kirby-Bauer disc diffusion method.H. pylori were successfully cultured from 1117 patients. The prevalence of metronidazole, clarithromycin (CLA), azithromycin, levofloxacin (LEV), moxifloxacin, amoxicillin (AMO), tetracycline and rifampicin resistance was 78.2, 22.1, 23.3, 19.2, 17.2, 3.4, 1.9 and 1.5%, respectively. No resistance to furazolidone was observed. The resistance rates to LEV and moxifloxacin were higher in strains isolated from patients with gastritis compared to those with duodenal ulcer and among women. Compared to patients ≥40 years old, younger patients exhibited lower resistance rates to CLA, azithromycin, LEV and moxifloxacin. The resistance rates to CLA and AMO were higher in strains isolated more recently, and we also found that the prevalence of resistance to metronidazole, CLA, azithromycin and AMO were significantly different among different regions of China.The resistance rates to metronidazole, CLA and LEV were high in China. Patient age, gender, disease and location were associated with the resistance of H. pylori to some antibiotics. Furazolidone, AMO and tetracycline are better choices for H. pylori treatment in China.
YKL-40 in the brain and cerebrospinal fluid of neurodegenerative dementias
Authors: Franc Llorens, Katrin Thüne, Waqas Tahir, Eirini Kanata, Daniela Diaz-Lucena, Konstantinos Xanthopoulos, Eleni Kovatsi, Catharina Pleschka, Paula Garcia-Esparcia, Matthias Schmitz, Duru Ozbay, Susana Correia, Ângela Correia, Ira Milosevic, Olivier Andréoletti, Natalia Fernández-Borges, Ina M. Vorberg, Markus Glatzel, Theodoros Sklaviadis, Juan Maria Torres, Susanne Krasemann, Raquel Sánchez-Valle, Isidro Ferrer, Inga Zerr
Journal: Molecular Neurodegeneration (2017)

YKL-40 (also known as Chitinase 3-like 1) is a glycoprotein produced by inflammatory, cancer and stem cells. Its physiological role is not completely understood but YKL-40 is elevated in the brain and cerebrospinal fluid (CSF) in several neurological and neurodegenerative diseases associated with inflammatory processes. Yet the precise characterization of YKL-40 in dementia cases is missing. In the present study, we comparatively analysed YKL-40 levels in the brain and CSF samples from neurodegenerative dementias of different aetiologies characterized by the presence of cortical pathology and disease-specific neuroinflammatory signatures. YKL-40 was normally expressed in fibrillar astrocytes in the white matter. Additionally YKL-40 was highly and widely expressed in reactive protoplasmic cortical and perivascular astrocytes, and fibrillar astrocytes in sporadic Creutzfeldt-Jakob disease (sCJD). Elevated YKL-40 levels were also detected in Alzheimer's disease (AD) but not in dementia with Lewy bodies (DLB). In AD, YKL-40-positive astrocytes were commonly found in clusters, often around β-amyloid plaques, and surrounding vessels with β-amyloid angiopathy; they were also distributed randomly in the cerebral cortex and white matter. YKL-40 overexpression appeared as a pre-clinical event as demonstrated in experimental models of prion diseases and AD pathology. CSF YKL-40 levels were measured in a cohort of 288 individuals, including neurological controls (NC) and patients diagnosed with different types of dementia. Compared to NC, increased YKL-40 levels were detected in sCJD (p < 0.001, AUC = 0.92) and AD (p < 0.001, AUC = 0.77) but not in vascular dementia (VaD) (p > 0.05, AUC = 0.71) or in DLB/Parkinson's disease dementia (PDD) (p > 0.05, AUC = 0.70). Further, two independent patient cohorts were used to validate the increased CSF YKL-40 levels in sCJD. Additionally, increased YKL-40 levels were found in genetic prion diseases associated with the PRNP-D178N (Fatal Familial Insomnia) and PRNP-E200K mutations. Our results unequivocally demonstrate that in neurodegenerative dementias, YKL-40 is a disease-specific marker of neuroinflammation showing its highest levels in prion diseases. Therefore, YKL-40 quantification might have a potential for application in the evaluation of therapeutic intervention in dementias with a neuroinflammatory component.
Actualización de la OMS sobre la gripe A(H5N1) en Hong Kong
Authors: D Lavanchy
Journal: Eurosurveillance (1998)

Los virus de la gripe se dividen en los tipos A, B y C y, a su vez, el tipo A se clasifica en subtipos. Los tipos A y B circulan en poblaciones humanas y mutan constantemente, dando lugar a la necesidad de modificar las vacunas cada ano. En ocasiones, aparece un nuevo virus de la gripe al cual nadie es inmune porque nadie habia sido previamente expuesto al mismo.
JCES 01.27 Patients with ALK IHC-Positive/FISH-Negative NSCLC Benefit from ALK TKI Treatment: Response Data from the Global ALEX Trial
Authors: T. Mok, S. Peters, D. Ross Camidge, S. Gadgeel, S.I. Ou, D. Kim, R. Dziadziuszko, F. De Marinis, R. Sangha, A. Zeaiter, J. Noe, E. Nueesch, T. Liu, I. Loftin, C. Williams, A. Shaw
Journal: Journal of Thoracic Oncology (2017)
PATH-56. OPTIMIZED ISOLATION OF PLASMA EXTRACELLULAR VESICLES FOR USE AS POTENTIAL BIOMARKERS IN PATIENTS WITH GLIOBLASTOMA
Authors: Luz Milbeth Cumba Garcia, Timothy Peterson, Aaron J Johnson, Ian F Parney
Journal: Neuro-Oncology (2017)

Glioblastoma (GBM) is the most common brain tumor and is nearly universally fatal within five years despite aggressive treatment. Tissue histopathology is required for definitive diagnosis. Imaging alone is inadequate to distinguish tumor progression from treatment-related inflammatory pseudoprogression, particularly following immunotherapy. Therefore, there is a need for non-invasive diagnostic alternatives. GBM’s release extracellular vesicles (EV’s) including exosomes (<100nm) and microvesicles (100nm–1000nm). GBM EV’s in plasma may have biological effects including mediating immunosuppression and could serve as liquid biopsies as they contain signature tumor-associated antigen immunosuppressive protein profiles. However, plasma EV isolation techniques have not been optimized. Here, we present a simple technique to isolate plasma EV’s from grade 3 and 4 GBM patients (n=15) and normal donors (n=14) using a two-step ultracentrifugation protocol. After ultracentrifugation using a sucrose gradient (90 minutes at 100,000 x g), nanotracker (NanoSight) analysis revealed that GBM patients have similar plasma EV concentration, but decreased EV size (69.9 ± 3.9nm) compared to normal donors (80.6 ± 7.1nm) (P≤0.01). Further ultracentrifugation (16 hours at 100,000 x g) concentrated EV’s efficiently for additional analysis, but resulted in EV aggregation that skewed nanotracker results. Western blot analysis of isolated plasma EVs confirmed exosome markers CD63 and HSP70 in both GBM patients and healthy donors. Interestingly, a higher expression of the immunosuppressive molecule programmed death-ligand 1 (PD-L1) was observed in GBM patients in comparison to healthy donors. Preliminary microarray analysis showed higher production of the Th2 cytokine IL-13 in plasma EV’s from GBM patients. These findings suggest that a simple two-step ultracentrifugation protocol efficiently isolates plasma EVs with distinct differences between GBM patients and normal donors that could be used as a non-invasive biomarker.
EXTH-16. RATIONAL DESIGN OF COMBINATION THERAPY AGAINST HER2+ BRAIN METASTASES OF BREAST CANCER USING JQ-1 AND VINORELBINE
Authors: Wojciech K Panek, Deepak Kanojia, Annie Xiao, Maciej S Lesniak
Journal: Neuro-Oncology (2017)

Brain metastasis is a late complication of breast cancer progression and portends poor survival, in part due to an absence of targeted therapies. Our previous work established βIII-tubulin as a novel therapeutic target for brain metastases of breast cancer. Beta III-tubulin is a protein expressed primarily in the brain, however, the amplified expression of βIII-tubulin in cancer cells leads to therapy resistance to taxanes, a class of widely used chemotherapy drugs for breast cancer. We propose to explore the potential therapeutic benefits of βIII-tubulin inhibitors, such as Vinorelbine, via inhibition of cellular division of cancer cells with amplified βIII-tubulin. Known for its cytostatic and pro-regeneration effects on the central nervous system, Vinorelbine selectively impacts βIII-tubulin-dependent cancer cells. Furthermore, given that βIII-tubulin amplification occurs in tumor cells resistant to chemotherapy, we hypothesize that combining Vinorelbine with chemotherapy drugs that upregulate βIII-tubulin expression offers enhanced therapeutic benefits compared with chemotherapy alone. Through systematic analysis of various breast cancer chemotherapeutics, including Stattic, Lapatinib, Apigenenin, Wortmanin, BKM-120, JQ-1, Decitabine, Trastuzumab, etc. in 4 HER2+ breast cancer cell lines (HCC1954, HCC1569, BT474, BT474-Br), we observed robust increases in βIII-tubulin RNA levels after treatment with JQ-1, as well as increases at the protein level in a dose-dependent manner, which was further confirmed by immunofluorescence. JQ-1 is a BET (Bromodomain and extraterminal domain) family inhibitor and tumor suppressant that decreases the expression of oncogenes, such as c-myc, a crucial transcription factor involved in breast cancer oncogenesis. This pilot study establishes the rationale of combined therapy against HER2+ metastatic breast cancer cells, and paves the way for combination therapy validation using JQ-1 and Vinorelbine in xenograft models of HER2+ breast cancer brain metastases.
Circulating programmed death ligand-1 (PD-L1) in non-small cell lung cancer (NSCLC)
Authors: S. Vecchiarelli, A. D'Incecco, M. Gallo, A. De Luca, G. Minuti, L. Landi, C. Bennati, M. Spreafico, M. D'Arcangelo, L. Attilia, V. Mazza, N. Normanno, F. Cappuzzo
Journal: Annals of Oncology (2017)
RTHP-33. PIK3 MUTATIONS ARE ASSOCIATED WITH DECREASED LOCAL CONTROL IN BRAIN METASTASES TREATED WITH RADIATION
Authors: Natalie Lockney, Diana Wang, Andrew Lin, Xin Pei, Timothy Chan, Yoshiya Yamada, Kathryn Beal, T Jonathan Yang
Journal: Neuro-Oncology (2017)

Hyperactivation of the phosphatidylinositol-3-kinases (PI3K) pathway has been reported to be associated with radioresistance in preclinical models. We examined whether PIK3 mutations are associated with poor radiation (RT) response in brain metastases (BM). We retrospectively reviewed 259 patients with BM treated with RT from 2004-2017 for whom MSK-IMPACT testing data was available for primary or metastatic lesions. MSK-IMPACT analyzes 341 genes, including PIK3C2G, PIK3C3, PIK3CA, PIK3CB, PIK3CD, PIK3CG, PIK3R1, PIK3R2 and PIK3R3. Association between clinical factors, mutation status, and local control (LC) was evaluated with Cox regression multivariate analysis. The Kaplan-Meier method was used to assess differences in LC rates and overall survival (OS). 147 patients received stereotactic radiation (SRS) and 112 patients received whole brain radiation (WBRT). The most common histologies were lung (48%) and breast (20%). Eighty-three (32%) patients had PIK3 mutations, and 36 (14%) patients specifically had PIK3CA mutations. Median follow-up was 10.8 months. LC was 82% at 12 months. The presence of any PIK3 mutation (HR=0.4, p<0.001), PIK3CA mutation (HR=0.7, p=0.006), and receipt of WBRT (HR=0.1, p<0.001) were associated with decreased LC, while age and histology were not. For patients who received WBRT, mutation status resulted in worse LC at 12-months: 42% for PIK3 mutation positive vs. 65% for mutation negative, p<0.001; 50% for PIK3CA mutation positive vs. 60% for mutation negative, p=0.002. Interestingly, for SRS treatments, PIK3 mutation positivity did not result in worse LC at 12 months (90% vs. 93% mutation negative, p=0.17), while PIK3CA mutation positivity did (76% vs. 92% mutation negative, p=0.05). There was no difference in OS based on PIK3 mutation status. Patients with PIK3 mutations are at significantly higher risk for decreased LC after RT for BM. Specifically, patients with PIK3CA mutations are more likely to developed local recurrence that is not abrogated by SRS.
P2.07-061 Nivolumab for Patients with Non-Small Cell Lung Carcinoma in Patients with Progression to One or More Lines of Chemotherapy in Mexican Population
Authors: J. Rodriguez-Cid, D. Bonilla-Molina, L. Martínez-Barreda, J. Díaz-Rico, P. Arellanes-Herrera, E. Del Olmo Gil, J.C. Chagoya-Bello, J.A. Alatorre Alexander
Journal: Journal of Thoracic Oncology (2017)
PUB062 Sarcopenia Is a Novel Predictor of Poor Prognosis in Male Patients with Pathological Stage I Non-Small Cell Lung Cancer
Authors: T. Tsukioka, N. Izumi, K. Chung, H. Komatsu, M. Toda, K. Hara, H. Miyamoto, N. Nishiyama
Journal: Journal of Thoracic Oncology (2017)
EXTH-44. ADDITION OF THE CARBONIC ANHYDRASE IX INHIBITOR SLC-0111 TO TEMOZOLOMIDE EXTENDS SURVIVAL OF MICE BEARING ORTHOTOPIC GLIOBLASTOMAS
Authors: Nathaniel Boyd, Kiera Walker, Anh Tran, James Hackney, Paul McDonald, Gloria Benavides, Mark Bevensee, Yancey Gillespie, Burt Nabors, Victor Darley-Usmar, Shoukat Dedhar, Anita Hjelmeland
Journal: Neuro-Oncology (2017)

Brain tumor microenvironments characterized by hypoxia, restricted glucose, and acidic stress contain a subset of neoplastic cells that thrive in these environments, identified as brain tumor initiating cells (BTICs). BTICs are resistant to chemo- and radiotherapy, providing a reservoir for tumor recurrence and a desirable target for glioma treatments. Standard of care for glioblastoma (GBM) includes surgical resection, radiation therapy, and the chemotherapeutic agent temozolomide, which prolongs life expectancy by months and is not curative. Prior studies suggested the efficacy of chemotherapies including temozolomide was increased by reducing expression of carbonic anhydrase 9 (CA9). CA9 is a hypoxia responsive gene elevated in tumors that is important for regulating intracellular pH and contributing to the acidic extracellular microenvironment. After confirming basal and hypoxia-induced expression of CA9 in GBM BTICs, we targeted CA9 activity with the small molecule inhibitor SLC-0111 alone or in combination with temozolomide. In multiple GBM BTIC lines, SLC-0111 reduced cell growth in vitro and showed additional benefit when used concurrently with temozolomide. Mechanistically, SLC-0111 treatment increased temozolomide DNA damage and resulted in changes to cellular metabolism and pH. SLC-0111 decreased the enrichment of BTICs after temozolomide treatment as determined via BTIC marker expression and functionally with neurosphere formation. SLC-0111 was detected in the brain after oral gavage administration of a formulation in Phase I clinical trials for breast cancer patients. SLC-0111 and temozolomide also significantly reduced the growth of subcutaneous and orthotopic models of a recurrent GBM greater than either drug alone. Together, our data suggest that SLC-0111 can sensitize GBM BTICs to the chemotherapy temozolomide and extend animal survival.
The role of clinical and molecular characteristics in low grade gliomas
Authors: A. Mura, E. Franceschi, S. Minichillo, A. Tosoni, A. Fioravanti, A. Talacchi, L. Volpin, G. Tallini, D. De Biase, M. Visani, R. Degli Esposti, G. Genestreti, S. Pizzolitto, R. Agati, C. Bortolotti, S. Bartolini, A. Paccapelo, A.A. Brandes
Journal: Annals of Oncology (2017)
P2.01-043 PD-L1 Expression, EGFR and KRAS Mutations in First-Line Therapy (1L) for Non-Small Cell Lung Cancer (NSCLC) Patients
Authors: D. Cronin-Fenton, T. Dalvi, E. Hedgeman, M. Norgaard, L. Petersen, H. Hansen, J. Fryzek, D. Lawrence, J. Walker, A. Mellemgaard, T. Rasmussen, N. Shire, J. Rigas, D. Potter, S. Hamilton-Dutoit, H. Sorensen
Journal: Journal of Thoracic Oncology (2017)