tbuckley/cabot-search huggingface dataset:
A key role for Rac and Pak signaling in neutrophil extracellular traps (NETs) formation defines a new potential therapeutic target
Authors: Mathilde Gavillet, Kimberly Martinod, Raffaele Renella, Denisa D. Wagner, David A. Williams
Journal: American Journal of Hematology (2017)

NET formation in mice (NETosis) is supported by reactive oxygen species (ROS) production by NADPH oxidase and histone hypercitrullination by peptidylarginine deiminase 4 (PAD4). Rac1 and Rac2, expressed in polymorphonuclear neutrophils (PMNs), regulate the cytoskeleton, cell shape, adhesion, and migration and are also essential components of the NADPH oxidase complex. We aimed to explore the role of the Rac signaling pathway including the upstream guanosine exchange factor (GEF) activator, Vav, and a downstream effector, the p21-activated kinase, Pak, on NETosis in PMNs using a previously described flow-cytometry-based assay. Rac2-/- PMNs showed reduced levels of citrullinated histone H3 (H3Cit)-positive cells and defective NETosis. Rac1Δ/Δ ; Rac2-/- PMNs demonstrated a further reduction in PMA-induced H3Cit levels and a more profound impairment of NETosis than deletion of Rac2 alone, suggesting an overlapping role of these two highly related proteins. Genetic knockouts of Vav1, or Vav2, did not impair H3Cit response to phorbol myristate ester (PMA) or NETosis. Combined, Vav1 and Vav3 deletions decreased H3Cit response and caused a modest but significant impairment of NETosis. Pharmacologic inhibition of Pak by two inhibitors with distinct mechanisms of action, led to reduced H3Cit levels after PMA stimulation, as well as significant inhibition of NETosis. We validated the importance of Pak using Pak2Δ/Δ PMNs, which demonstrated significantly impaired histone H3 citrullination and NETosis. These data confirm and more comprehensively define the key role of the Rac signaling pathway in PMN NETosis. The Rac signaling cascade may represent a valuable target for inhibition of NETosis and related pathological processes.
P3.01-037 Understanding Mechanisms of Resistance to Osimertinib by Circulating Tumor DNA Genotyping in Advanced Non-Small-Cell Lung Cancer
Authors: Y. Du, W. Zang, G. Wang, Y. Sang, F. Gai, L. Li, Y. Yu, G. Cheng, P. Yu, G. Sun
Journal: Journal of Thoracic Oncology (2017)
Correlation of PD-L1 staining between primitive tumor and metastasis in advanced colorectal cancer patients
Authors: M. Tampellini, E. Falco, G. De Rosa, F. Montarolo, R. Dacomo, C. Baratelli, E. Sperti, M. Di Maio, G.V. Scagliotti, M. Volante
Journal: Annals of Oncology (2017)
SCDT-44. CLINICAL EVALUATION OF REGADENOSON AS A PHARMACOLOGIC AGENT TO TRANSIENTLY MODIFY BLOOD-BRAIN BARRIER INTEGRITY TO FACILITATE ENTRY OF CHEMOTHERAPY INTO BRAIN PARENCHYMA
Authors: Stuart Grossman, Michelle Rudek, Sadhana Jackson, Margaret Bynoe
Journal: Neuro-Oncology (2017)

Previous pre-clinical and rodent studies have demonstrated that adenosine A2A receptor activation can transiently modify: 1) blood-brain barrier (BBB) integrity thereby increasing entry of high molecular weight dextran and temozolomide to the central nervous system, 2) the actions of p-glycoprotein pumps, and 3) the ability of inflammatory cells to enter brain parenchyma. Studies in rodents have demonstrated a bell shaped dose/effect curve documenting that doses too high or too low result in minimal changes in BBB integrity. Regadenoson is an FDA approved and well tolerated adenosine A2A receptor agonist used in patients undergoing pharmacologic cardiac stress tests. Recent human studies exploring the ability of the FDA approved dose of regadenoson to transiently disrupt BBB integrity have shown no significant effect on: 1) the entry of 99mTc-sestamibi or visipaque into brain through an intact BBB as measured by SPECT or CT brain scans or 2) the entry of temozolomide into the brain using sensitive microdialysis techniques. It is very possible that the effect of adenosine A2A receptor activation in rodent and human brains is similar and that the FDA approved dose of regadenoson is either too high or too low for the desired pharmacologic outcome on BBB integrity. As a result, the 11 institution NCI funded Adult Brain Tumor Consortium has a protocol under development designed to describe the BBB integrity changes that occur after administration of a carefully considered range of regadenoson doses and schedules in patients with known brain tumors. These patients will have an MRI with contrast before and after regadenoson administration to follow changes in gadolinium entry to: 1) contralateral brain (normal blood brain barrier), 2) brain adjacent to tumor (T2 abnormal but without contrast enhancement) and 3) enhancing tumor. This study will provide valuable insight into regadenoson’s ability to transiently disrupt the BBB.
P3.16-032 Prediction of Postoperative Lung Function in Patients with Lung Cancer by Lung Lobe
Authors: K. Hara, N. Izumi, T. Tsukioka, K. Chung, H. Komatsu, M. Toda, H. Miyamoto, T. Kimura, S. Suzuki, A. Yoshida, S. Higashiyama, J. Kawabe, N. Nishiyama
Journal: Journal of Thoracic Oncology (2017)
P3.13-032 The Impact of Tobacco Exposure on Lung Nodules and Emphysema in a Pilot Silesian Study of Early Lung Cancer with LDCT
Authors: E. Wachuła, S. Szabłowska-Siwik, D. Czyżewski, S. Nawrocki, M. Adamek
Journal: Journal of Thoracic Oncology (2017)
CMET-16. THE ROLE OF SURGICAL RESECTION OF MELANOMA BRAIN METASTASES IN THE IMMUNOTHERAPY ERA
Authors: Christopher Alvarez-Breckenridge, Anita Giobbie-Hurder, Corey Gill, Mia Bertalan, Naema Nayyar, Donald Lawrence, Keith Flaherty, Helen Shih, Kevin Oh, Tracy Batchelor, Dan Cahill, Ryan Sullivan, Priscilla Brastianos
Journal: Neuro-Oncology (2017)

Immune checkpoint blockade is a treatment option for patients with melanoma brain metastases (MBM). This single institutional analysis investigated the optimal management for patients with MBM undergoing surgical resection and immunotherapy. An IRB-approved, retrospective study identified 142 MBM patients treated with immune checkpoint blockade between 2010 and 2015. Overall survival (OS) was calculated from the date of diagnosis of MBM until death from any cause. Model building included a prognostic model of OS and the effect of immunotherapy and surgical sequencing on OS. Parallel model-building techniques were used to address the potential for guarantee-time bias. The 2-year OS for patients treated with CTLA-4, PD-1 or combinatorial blockade were 19%, 54%, and 57%, respectively. Accounting for the time-dependent covariate of surgery, factors associated with increased hazard of death included abnormal LDH, presence of extracranial disease at time of brain metastasis diagnosis, and greater than 3 brain metastases. The sequence of therapy was associated with a 2.1-fold increase in the hazard of death amongst patients initially undergoing immunotherapy +/- subsequent surgery compared to surgical patients who went on to receive immunotherapy (HR: 2.1, 95% CI: 1.2 to 3.9, P=0.01). The observed increase in risk is primarily reflected in the subgroup of patients undergoing immunotherapy prior to brain metastases diagnosis +/- surgery, who had a statistically significant, 2.3-fold increase in the hazard of death (HR: 2.29, 95% CI: 1.2 to 4.4, P=0.04). In conclusion, the sequence of surgery and immunotherapy is associated with OS and surgical resection should be considered prior to commencing immunotherapy. A prospective, randomized trial comparing the sequence of surgery and immunotherapy for treatment-naïve MBM is warranted.
Sorveglianza della pertosse in Svizzera, dal 1992 al 1997: grande epidemia nel 1994. Cosa succederà in seguito?
Authors: H. C. Matter
Journal: Eurosurveillance (1999)

Dal Giugno 1991, i casi di tosse convulsa sono stati notificati dallo Swiss Sentinel Surveillance Network ‘Sentinella’ (SSSN) per monitorare l'andamento della pertosse in Svizzera e valutare l'attuale strategia di vaccinazione (1,2). La rete Sentinella comprende un campione di circa 200 medici di base, specialisti di medicina interna e pediatri con attivita privata che volontariamente, ogni settimana, notificano i dati sulla morbosita allo Swiss Federal Office of Public Health (SFOPH). I medici partecipanti costituiscono, in ognuno dei tre settori, circa il 3,5% di tutti i medici svizzeri sotto i 65 anni.
IMMU-22. COMBINATION IMMUNOTHERAPY WITH IDO1 INHIBITION ENHANCES TREATMENT EFFICACY IN MULTIPLE MODELS OF GLIOBLASTOMA MODEL
Authors: Erik Ladomersky, Lijie Zhai, Kristen Lauing, Meijing Wu, C David James, Roger Stupp, Derek Wainwright
Journal: Neuro-Oncology (2017)

Progress in improving outcomes for glioblastoma (GBM) patients has been modest at best. Despite maximum surgical resection, radiotherapy (RT), and chemotherapy, the combination of which is considered the best treatment for GBM, median overall survival (OS) is only approximately 15 months. Treatment approaches addressing the immunosuppressive microenvironment of GBM have the potential of contributing to improved outcomes. In this preclinical study, the efficacy of the novel, IDO1 inhibitor, BGB-5777, was investigated when used in combination with PD-1 blockade and/or whole brain radiation (WBRT) in an immunocompetent mouse model of GBM. Mice were intracranially-engrafted with 2x105 GL261 or CT-2A murine GBM cells, then treated, beginning day 14 post-tumor cell implantation, with 500µg loading dose IgG control mAb followed by three 200µg doses, administered every third day (n=7), or 2 Gy WBRT for 5 days, PD-1 mAb (J43) administered the same as IgG control mAb, and 100mg/kg BGB-5777 BID for 4 weeks (n=9). Mice engrafted with the GL261 tumors and treated with the combination therapy showed a significant increase in overall survival (53 days) compared to IgG treated mice (25 days). This therapy regimen also significantly increased durable survival (>120 days) (P<0.0001) in mice ic. unmodified GL261 or CT-2A cells. Paradoxically, mice with GBM cells overexpressing mouse IDO1 cDNA and treated with triple therapy showed a similar proportion of durable survivors (40%) vs. mice with similar tumors treated with IgG control (P<0.0001). This result suggests that the effectiveness of triple therapy is independent of tumor IDO1 expression level. Results from the analysis of WT and IDO1-/- mice with intracranial tumor indicate that in the presence of non-tumor IDO1, IDO1 inhibition is necessary to confer survival benefit (P<0.01). Ultimately, the data suggest that using radiation to induce potential immunogenicity and/or inflammation in GBM, while co-inhibiting immunosuppression, is a rational and potentially clinically-beneficial pursuit.
Abstract 20283: Two-Dimensional Echocardiography Incorrectly Identifies Tricuspid Regurgitation Jet Location Compared to Three-Dimensional Echocardiography in Pre-Operative Assessment of Tricuspid Valve Repair in Hypoplastic Left Heart Syndrome
Authors: Kandice Mah, Billie-Jean Martin, Silvia Alvarez, Nassiba Alami Laroussi, Ivan M Rebeyka, Jeffrey Smallhorn, Nee Khoo, Timothy Colen
Journal: Circulation (2016)

Background:  A recent study using two-dimensional echocardiogram (2DE) reported a predominance of antero-septal commissural regurgitation in patients (70%) undergoing tricuspid valve repair (TVR) in hypoplastic left heart syndrome (HLHS). Three-dimensional echocardiography (3DE) studies on assessment of TV morphology reports a high incidence of error in the identification of TV leaflets in conventional 2DE planes. This study aims to assess the pre-operative 2DE assessment of TR jet location compared to the reference standard of 3DE color datasets in HLHS.   Methods:  Twenty-five HLHS patients requiring TVR for TR between 2005 and 2015 were assessed using 2DE and 3DE to assess TR grade, 3DE vena contracta (VC) area, TV annulus diameter (indexed to body surface area, iTV) and primary TR jet location. The 2DE observer was blinded to the findings on 3DE. We compared the 2DE findings with 3DE using t-test and Pearson correlation. Surgical notes were reviewed for details of procedures performed.   Results:  Indexed 2DE iTV was no different to 3DE (61mm/m 2  ± 4 vs. 56mm/m 2  ± 4, p=0.34). 2DE qualitative TR grade correlated with 3DE VC area (r=0.69, p   Conclusions:  2DE was accurate in the assessment of the degree of TR and TV annular size, but in most patients incorrectly identified the primary regurgitation location in the antero-septal region instead of other location. This may have implications for planning of the primary surgical procedure in HLHS TV repair based on 2DE findings.
La mortalité au Portugal associée à la vague de chaleur d’août 2003 : évaluation rapide de l’impact, au moyen d’une méthode rapide
Authors: P J Nogueira, J M Falcão, M T Contreiras, E Paixão, J Brandão, I Batista
Journal: Eurosurveillance (2005)

Le Portugal a subi une vague de chaleur intense pendant les deux premieres semaines d’aout 2003. 
Suite a l’identification dans ce pays de l’influence des vagues de chaleur sur la mortalite en 1981 et 1991 (avec un exces estime d’environ 1900 et 1000 deces, respectivement), le Observatorio Nacional de Saude (ONSA) - Instituto Nacional de Saude Dr. Ricardo Jorge, en collaboration avec Vigilância Previsao e Informacao - Instituto de Meteorologia, a cree un systeme de surveillance appele ICARO, qui fonctionne depuis 1999. Le systeme identifie les vagues de chaleur ayant une influence potentielle sur la mortalite [1]. 
Avant la fin de la canicule de 2003, l’ONSA avait publie une evaluation provisoire de ses consequences sur la mortalite. Les resultats qui s’appuyaient sur le nombre de deces entre le 1er juin et le 12 aout 2003 ont ete presentes lors d’un seminaire de quatre jours. Les donnees ont ete recueillies aupres des 31 National Civil registrars, qui couvrent les capitales regionales des 18 regions du Portugal continental et representent environ 40% de la mortalite sur le continent. 
Le nombre de deces enregistre pendant la periode du 30 juillet au 12 aout a ete compare avec ceux enregistres lors de trois periodes de reference : 1-14 juillet, 1-28 juillet et 15-28 juillet). Pour la periode du 15 au 28 juillet, qui rappelait le plus la vague de chaleur par sa duree et ses caracteristiques, on a evalue un taux de mortalite superieur de 37,7% a la valeur attendue dans des conditions climatiques normales. Cette valeur a permis d’estimer un exces de 1316 deces pour le Portugal continental. 
Le principal objectif de cet article est de presenter la methode utilisee pour l’identification et l’evaluation de l’exces de mortalite pendant la vague de chaleur de l’ete 2003.
IRF3 and type I interferons fuel a fatal response to myocardial infarction
Authors: Kevin R King, Aaron D Aguirre, Yu-Xiang Ye, Yuan Sun, Jason D Roh, Richard P Ng, Rainer H Kohler, Sean P Arlauckas, Yoshiko Iwamoto, Andrej Savol, Ruslan I Sadreyev, Mark Kelly, Timothy P Fitzgibbons, Katherine A Fitzgerald, Timothy Mitchison, Peter Libby, Matthias Nahrendorf, Ralph Weissleder
Journal: Nature Medicine (2017)
The evolution of palliative care from the oncology patient to the chronic illness
Authors: G. Rampello, M. Zaiat, P. Leonardi, L. Guida, S. Benenati, R. Vitiello, S. Perticone, V. Titone, R. Possumato, V. Siddi, R. Grisetti
Journal: Annals of Oncology (2017)
Augmentation du nombre de gonococcies identifiées par le réseau RENAGO
Authors: V Goulet, P Sednaoui, A Laporte, C Billy, J C Desenclos
Journal: Eurosurveillance (2000)

En France, la surveillance des maladies sexuellement transmissibles (MST) est basee principalement sur les notifications de laboratoires car elles ne figurent pas sur la liste des maladies a declarer par les medecins (1). Le reseau RENAGO (Reseau National du Gonocoque) a pour but de suivre les tendances evolutives des gonococcies sur le plan national et d’etudier la sensibilite des souches de N gonorrhoeae aux antibiotiques. Il fonctionne depuis 1986 avec une centaine de correspondants jusqu’en 1992 et environ 200 correspondants depuis 1993, annee au cours de laquelle le reseau s’est elargi et a integre des laboratoires specialises (laboratoires collaborant avec des dispensaires anti-veneriens ou des consultations specialisees en MST).
Small interfering RNA targeting survivin specifically sensitizes non-small cell lung cancer cells to the HIV protease inhibitor ritonavir.
Authors: Anjaiah Srirangam, Ranjana Mitra, Seiji Fukuda, Louis M. Pelus, David A. Potter
Journal: Cancer Research (2006)

5503   Purpose: These studies were designed to determine whether ritonavir exhibits inhibitory activity against non-small cell lung cancer (NSCLC) lines in vitro and whether inhibition of receptor kinase pathways or promotion of apoptotic pathways can potentiate ritonavir activity. Reduction of survivin mRNA has been demonstrated to potentiate chemotherapy activity and therefore, its potential role in promoting ritonavir inhibition of NSCLC was examined. Experimental Design: Ritonavir was tested for inhibition of NSCLC growth and promotion of apoptosis in the NSCLC lines A549, H460, H522 and H23. Effects of siRNA targeting c-Src, STAT3 and survivin on ritonavir inhibition of NSCLC cell proliferation were studied. Results: Ritonavir inhibits growth of A549, H460, H522 and H23 lines, exhibiting IC 50  values of 35, 48, 42 and 44 microM, respectively. The lines A549 and H522 lines were studied in more detail for mechanism of ritonavir sensitivity. Ritonavir down-regulates CDK2, 4, and 6, and cyclin D 1  and dephosphorylates Rb, associated with G1 arrest. Ritonavir also induces apoptosis, but Akt and ERK phosphorylation may be increased or decreased depending upon the line, suggesting that this drug may inhibit other NSCLC survival pathways. Ritonavir reduced phospho-c-Src, phospho-STAT3 and survivin levels. siRNA species that target c-Src, STAT3 and survivin markedly reduce the proliferation of the A549 and H522 lines and induce apoptosis, confirming that all three lines are dependent upon these signaling proteins. To develop a therapeutic strategy to effectively use ritonavir for NSCLC inhibition, it was determined whether c-Src, STAT3 or survivin siRNA potentiates ritonavir inhibition. Survivin siRNA reduces the ritonavir IC 50  to 25 μM for both lines, while c-Src and STAT3 siRNA had no effect, indicating a specific role for survivin in resistance to ritonavir. Over-expression of survivin increases the ritonavir IC 50  in both lines further suggesting that ritonavir resistance may be mediated through the survivin. Conclusions: These results indicate that ritonavir inhibits NSCLC growth, in part, by inhibiting CDK regulation of cell cycle progression, in part, by inhibition of c-Src-, STAT3- and survivin-mediated proliferation and survival. Ritonavir may be of interest for clinical development for NSCLC therapeutics and its efficacy may be potentiated by strategies that target survivin.
Un brote de hepatitis A en hombres homosexuales, asociado a relaciones sexuales ocasionales y saunas gays en Copenhague, Dinamarca
Authors: A Mazick, M Howitz, S Rex, I P Jensen, N Weis, T L Katzenstein, J Haff, K Mølbak
Journal: Eurosurveillance (2005)

En 2004, en Copenhague, Dinamarca, durante un brote de hepatitis A que afecto especialmente a hombres que tenian relaciones sexuales con otros hombres (HRSH), se llevo a cabo un estudio de casos y controles para identificar los factores de riesgo de infeccion. Se consideraron casos a los HRSH de mas de 17 anos, que vivieran en Copenhague, infectados por el virus de la hepatitis A con IgM positiva diagnosticados entre Junio y Agosto de 2004 y que no hubieran tenido contacto con un caso de hepatitis A antes de la ocurrencia de la enfermedad. Los controles fueron seleccionados en el Festival del orgullo Gay de Copenhague. El estudio incluyo 18 casos y 64 controles. Dieciseis casos y 36 controles tenian parejas sexuales ocasionales (ORMH 5,6, IC 95% 1,2-26,9). Once casos y 14 controles habian tenido relaciones sexuales en saunas gays (ORMH 4,2, IC 95% 1,5-11,5). Parece que las relaciones en alojamientos privados fueron protectoras (ORMH 0,2, IC 95% 0,1-0,7). Las relaciones ocasionales incluyendo relaciones en saunas gays fueron un factor de riesgo importante para la distribucion del VHA en los HRSH en Copenhague. Los resultados concuerdan con los observados en otros brotes en Europa. Al disminuir la inmunidad general frente a la hepatitis A y aumentar el potencial epidemico, recomendamos una educacion sanitaria asi como la vacuna contra la hepatitis A para todos los hombres homosexuales que no tengan una pareja estable, particularmente si visitan saunas gays o algun otro sitio donde los cambios de pareja sean frecuentes. Para impedir la diseminacion de la hepatitis A en los varones homosexuales en Europa, seria necesario un consenso al nivel europeo sobre las medidas de prevencion y control.
HOUT-12. IMPROVED SURVIVAL OF GLIOBLASTOMA PATIENTS TREATED AT ACADEMIC CANCER PROGRAMS: A HOSPITAL-BASED STUDY FROM THE NATIONAL CANCER DATABASE
Authors: Ping Zhu, Xianglin Du, Jay-Jiguang Zhu, Yoshua Esquenazi
Journal: Neuro-Oncology (2017)

Multidisciplinary management, sub-specialization and treatment of patients in major teaching hospitals have revealed improved outcomes and lower mortality rates for medical and surgical conditions compared to patients treated by general practitioners/non-teaching hospitals. Prolonged survival in glioblastoma (GBM) has also been found when surgeries are performed by neurooncology neurosurgeons. We explored the association between the type of health care facility and outcomes in GBM derived from the National Cancer Database (NCDB). A retrospective cohort study was conducted in 39140 patients between 2004-2013. Patients were categorized to 4 groups of cancer programs according to facility type: Community (CCP); Comprehensive community (CCCP); Academic (ACP); and Integrated network (INCP). Primary outcome was overall survival (OS). Ninety-day mortality and length of stay (LOS) were secondary endpoints. Associations between health care facility and OS were analyzed using Kaplan-Meier and Cox proportional hazards models. Multivariate logistic regression was performed to analyze differences in treatment patterns and outcomes. A significant OS benefit was observed in patients treated at ACP (median OS: 12.6, 95% CI: 5.7-22.9, months), compared with CCP (10.2, 95% CI: 4.4-18.7), CCCP (10.1, 95% CI: 4.4-19.5) and INCP (11.1, 95% CI: 4.9-20.2). In multivariate Cox proportional hazards models, a 10% reduction in the risk of death (HR: 0.90, 95% CI: 0.86-0.95, P<0.001) was found in ACP. Multivariate logistic regression revealed that 90-day mortality was decreased by 17% (OR: 0.83, 95% CI: 0.69-1.00, P=0.049) in ACP. Tumor resections rather than biopsies were more common in ACP (OR: 1.19, 95% CI: 1.05-1.34, P=0.005) and the probability of prolonged LOS was reduced by 18% (OR: 0.82, 95% CI: 0.71-0.94, P=0.004). This study provides evidence of better outcomes when patients are treated in ACP. The benefit might be attributable to sub-specialization and an increased number of resections. These findings support the recommendations of treatment of GBM in large volume centers.