tbuckley/cabot-search huggingface dataset:
Interaction between sorafenib and erlotinib
Authors: J. G. Kuhn, M. Gilbert, P. Wen, T. Cloughesy, J. Cooper, V. Puduvalli, L. DeAngelis, F. Lieberman, K. Lamborn, M. Prados
Journal: Journal of Clinical Oncology (2009)

2500 Background: The combination of sorafenib plus erlotinib was evaluated in patients with recurrent glioblastoma (GBM). In addition to defining the maximum tolerated dose (MTD), pharmacokinetics (PKs) for single agent and combination were determined. Methods: Adults with recurrent GBM with the usual phase I inclusion/exclusion criteria were eligible. No enzyme inducing anti-epileptic agents were allowed. Starting doses for erlotinib and sorafenib were 100mg PO QD and 200 mg PO BID, respectively, for 28 days (a cycle). For cycle 1 PKs, erlotinib was started on day 1 followed on day 2 by sorafenib. Eight plasma samples were collected over 24hrs on days 1, 15 and 28. Sorafenib and its metabolite (N-oxide) were analyzed by HPLC and erlotinib and OSI-420 by LC/MS. PK parameters were characterized by standard non-compartmental methods. Results: The MTD was sorafenib 200 mg PO BID and erlotinib 100 mg PO QD. The PKs for erlotinib (OSI) are displayed below. Conclusions: The PKs for sorafenib are in agreement with previous reports and not affected by the co-administration of erlotinib. However, there is an apparent affect of sorafenib on the PKs of erlotinib. The expected accumulation of erlotinib's C max and AUC at steady-state was not observed. This interaction results in at least a 2+ fold decrease in exposure to erlotinib and its active metabolite. The interaction does not appear to be the classical enzyme induction due to the rapidity of the onset/offset. This same phenomenon has been reported with the co-administration of sorafenib with gefitinib (Clin Cancer Res 13:2684,2007). Increasing the maximal velocity (V max ) of CYP3A4, not the quantity of enzyme, is suggested as a testable hypothesis (J Pharmacol Exp Ther 290:1.1998). The clinical relevance of this interaction with regard to toxicity and efficacy warrants further evaluation. [Table: see text] No significant financial relationships to disclose.
£4bn of extra NHS funding should be allocated to patient centred reforms, IPPR think tank urges
Authors: Ingrid Torjesen
Journal: BMJ (2015)

Half of the additional £8bn (€11.4bn; $12.5bn) of NHS funding promised by the government over this parliament should go to a transformation fund to invest in new models of care in which citizens have more power, says a paper by the Institute for Public Policy Research (IPPR).1

Nick Pearce, IPPR director, said, “Empowerment in health and care has tended to focus on giving patients more rights, information and choices so that acute healthcare services are more responsive to them. There has been far less focus on the self management of chronic health conditions where 70% of the NHS’s resources are spent.”

He added, “Gaining more power and control over …
Acute Lymphoblastic Leukemia, Version 2.2015
Authors: Joseph C. Alvarnas, Patrick A. Brown, Patricia Aoun, Karen Kuhn Ballen, Stefan K. Barta, Uma Borate, Michael W. Boyer, Patrick W. Burke, Ryan Cassaday, Januario E. Castro, Peter F. Coccia, Steven E. Coutre, Lloyd E. Damon, Daniel J. DeAngelo, Dan Douer, Olga Frankfurt, John P. Greer, Robert A. Johnson, Hagop M. Kantarjian, Rebecca B. Klisovic, Gary Kupfer, Mark Litzow, Arthur Liu, Arati V. Rao, Bijal Shah, Geoffrey L. Uy, Eunice S. Wang, Andrew D. Zelenetz, Kristina Gregory, Courtney Smith
Journal: Journal of the National Comprehensive Cancer Network (2015)

Treatment of acute lymphoblastic leukemia (ALL) continues to advance, as evidenced by the improved risk stratification of patients and development of newer treatment options. Identification of ALL subtypes based on immunophenotyping and cytogenetic and molecular markers has resulted in the inclusion of Philadelphia-like ALL and early T-cell precursor ALL as subtypes that affect prognosis. Identification of Ikaros mutations has also emerged as a prognostic factor. In addition to improved prognostication, treatment options for patients with ALL have expanded, particularly with regard to relapsed/refractory ALL. Continued development of second-generation tyrosine kinase inhibitors and the emergence of immunotherapy, including blinatumomab and chimeric antigen receptor T-cell therapy, have improved survival. Furthermore, incorporation of minimal residual disease (MRD) monitoring has shown insight into patient outcomes and may lead to treatment modification or alternative treatment strategies in select populations. This excerpt focuses on the sections of the ALL guidelines specific to clinical presentation and diagnosis, treatment of relapsed/refractory ALL, and incorporation of MRD monitoring. To view the most recent complete version of these guidelines, visit NCCN.org.
Altered expression of glycosaminoglycans in the BAL of COPD patients with acute exacerbation
Authors: Eleni Papakonstantinou, Michael Roth, George Karakiulakis, Spasenija Savic, Michael Tamm, Daiana Stolz
Journal: European Respiratory Journal (2013)

BACKGROUND  Exacerbations of COPD (ECOPD) accelerate the deterioration of lung function, affecting the quality of life of COPD patients and moreover, remain a major cause of mortality and morbidity. Glycosaminoglycans (GAGs) are extracellular matrix molecules that regulate the viscoelastic and biomechanical properties of the lung.  AIM-HYPOTHESIS  We aimed to investigate the expression of various GAGs in the BAL of COPD patients with and without exacerbation. We hypothesize that the expression of specific GAGs is altered in BAL of patients with ECOPD.  METHODS  We included 70 patients with COPD diagnosed according to the GOLD guidelines with either stable disease (n=35) or ECOPD (n=35) undergoing diagnostic bronchoscopy. Mean age: 68.9±9.5 years, mean FEV1%pred: 49.9%±16.9 and mean DLCO%pred: 43.1%±18.8. Hyaluronic acid (HA), hyaluronidase, dermatan sulfate, chondroitin sulfate (CS) and heparan sulfate (HS) were measured in BAL by ELISA.  RESULTS  There were no significant differences in the amount of CS and HA in BAL samples from patients with COPD at stable state, and at ECOPD. However, we observed a significant decrease in HS and a significant increase in hyaluronidase in the BAL of ECOPD compared with BAL from patients with stable COPD.  CONCLUSIONS  Since: (a) HS exerts anti-inflammatory effects in the lung and (b) hyaluronidase results in the production of HA of low molecular weight, which is pro-inflammatory, our data suggest that the observed alterations in HS and hyaluronidase in ECOPD might contribute to increased inflammation. These molecules may be used as potential biomarkers for ECOPD and as alternative targets for pharmacological intervention for the prevention and/or treatment of ECOPD.
Patterns of<i>CTCF</i>and<i>ZFHX3</i>Mutation and Associated Outcomes in Endometrial Cancer
Authors: Christopher J. Walker, Mario A. Miranda, Matthew J. O’Hern, Joseph P. McElroy, Kevin R. Coombes, Ralf Bundschuh, David E. Cohn, David G. Mutch, Paul J. Goodfellow
Journal: JNCI Journal of the National Cancer Institute (2015)

The genetic events responsible for tumor aggressiveness in endometrioid endometrial cancer (EEC) remain poorly understood. The chromosome 16q22 tumor suppressor genes CTCF and ZFHX3 are both frequently mutated in EEC, but their respective roles in outcome have not been determined. Targeted deep sequencing of CTCF and ZFHX3 was performed for 542 EEC samples. Copy number loss (CNL) was determined using microsatellite typing of paired tumor and normal DNA and a novel Bayesian method based on variant allele frequencies of germline polymorphisms. All statistical tests were two-sided. Mutation rates for CTCF and ZFHX3 were 25.3% and 20.4%, respectively, and there was a statistically significant excess of tumors with mutation in both genes (P = .003). CNL rates were 17.4% for CTCF and 17.2% for ZFHX3, and the majority of CNLs included both CTCF and ZFHX3. Mutations were more frequent in tumors with microsatellite instability, and CNLs were more common in microsatellite-stable tumors (P < .001). Patients with ZFHX3 mutation and/or CNL had higher-grade tumors (P = .001), were older (P < .001), and tended to have more frequent lymphovascular space invasion (P = .07). These patients had reduced recurrence-free and overall survival (RFS: hazard ratio [HR] = 2.35, 95% confidence interval [CI] = 1.38 to 3.99, P = .007; OS: HR = 1.51, 95% CI = 1.11 to 2.07, P = .04). Our data demonstrate there is strong selection for inactivation of both CTCF and ZFHX3 in EEC. Mutation occurs at high frequency in microsatellite-unstable tumors, whereas CNLs are common in microsatellite-stable cancers. Loss of these two tumor suppressors is a frequent event in endometrial tumorigenesis, and ZFHX3 defects are associated with poor outcome.
Targeting <i>MYC</i> Translation in Colorectal Cancer
Authors: Alina Castell, Lars-Gunnar Larsson
Journal: Cancer Discovery (2015)

Abstract Summary: There is a great interest in finding ways to inhibit the expression or activity of the “undruggable” MYC, a master regulator of transcription and one of the most deadly oncoproteins in human cancer. In this issue of Cancer Discovery, Wiegering and colleagues find a way of inhibiting translation of MYC in colorectal cancer cells by directly targeting the translation initiation factor eIF4A, resulting in inhibition of MYC-dependent proliferation of colorectal tumor cells in vitro and in vivo. Cancer Discov; 5(7); 701–3. ©2015 AACR. See related article by Wiegering et al., p. 768.
THE PLASMA PROTEINS IN RELATION TO BLOOD HYDRATION
Authors: John P. Peters, Anna J. Eisenman, Harold A. Bulger
Journal: Journal of Clinical Investigation (1925)

Non-protein nitrogen was not determined on these samples, but the values for total nitrogen, in terms of per cent protein, were reduced by 0.19, corresponding to a blood non- protein nitrogen of 30 mg. per 100 cc.
Walking guide for COPD patients: Can be used as a promoter of physical activity?
Authors: María Hernandez, Fabricio Zambom, Jose Antonio Cascante, Javier Hueto, Milagros Antón, Pilar Cebollero
Journal: European Respiratory Journal (2013)

Introduction:   Reduced functional capacity has been associated with lower levels in physical activity in COPD patients. It is unknown which one is the best strategy to promote physical activity in then.   Objectives:   To examine the effects of the use a Walking Guide (WG) designed for COPD patients, as an unsupervised physical activity program, on pulmonary functional capacity, physical activity, and quality of life related to health compared with standard care.   Methods:   We recruited 25 men, mean age 70 years, moderate-severe COPD, dyspnea grade 2 (MMRC), randomized to 2 groups. Group WG(n=13): physical activity performed following the WG and group Control(n=12): standard recommended care. Assessment was performed at baseline and at 3 months: 6MWT, BODE, CAT, Baecke questionnaire, muscle strength, and physical activity by accelerometer as METS: sedentary 1-1.5, 1.5-3: Light, 3-6: moderate, 6-9 vigorous and> 9: very vigorous. Patients were followed monthly by telephone call.   Results:   There were no differences between groups at baseline in all parameters. Most patients have a degree of physical activity classified as sedentary (METS). Physical activity measuring by Baecke questionnaire was significantly higher (p = 0.0008) and so was the quality of life by using CAT score (p = 0.001) in the whole group before and after intervention. There were no statistical differences between groups. After intervention, there were no differences in 6MWT, BODE, and muscle strength.   Conclusions:   Encourage walking regularly in the standard care or using a WG for COPD patients, increased the physical activity and quality of life. No added benefit was found using a specifical tool as the walking guide in the first three months.
Abstract 3443: Wnt-beta-catenin-Rac1 signaling axis regulates metastasis-associated phenotypes in TNBC
Authors: Nandini Dey, Jennifer Carlson, Pradip De, Brian Leyland-Jones
Journal: Cancer Research (2014)

Abstract Background: RAC1-GTPase controls many cellular phenotypes including integrin-directed migration via its control over the actin-cytoskeleton. We and others have established the upregulation of Wnt-beta-catenin pathway (WP) in triple negative breast cancer (TNBC), the most aggressive subtype of breast cancer (Dey et al., 2013, BMC Cancer; Dey et al., 2013, PLOS ONE). Here we report for the first time that metastasis-associated phenotypes in TNBC are controlled by Wnt-beta-catenin-RAC1signaling axis. Methodology: The involvement of WP was tested using (1) WP modulators (CHIR99021, Wnt-C59, XAV939), (2) sulindac sulfide and (3) beta-catenin SiRNA. We studied metastasis-associated phenotypes including, (1) proliferation (CelltiterGLO) (2) clonogenic growth (3D On-TOP assay) (3) fibronectin-directed migration (4) matrigel invasion (5) vascular mimicry (6) actin dynamics (confocal-microscopy and podia-parameters) (7) protein expression (WB) (8) real-time imaging for migration and vascular mimicry and (9) adhesion in the context of RAC1 activation in a panel of 3-4 TNBC cell lines. Results: Sulindac sulfide as well as transient transfection of beta-catenin SiRNA (1) decreased cellular levels of beta-catenin, inhibited proliferation, attenuated metastasis-associated different phenotypes and blocked fibronectin-mediated RAC1 as well as Cdc42 activities and (2) altered actin dynamics and inhibited podia-parameters (lamellopodia and fillopodia). Both Wnt-antagonists and RAC1 inhibitor (NSC23766) blocked fibronectin-induced RAC1 activation and inhibited the metastasis-associated phenotypes, while Wnt-activator enhanced phenotypes like vascular mimicry. Conclusion: Results of our experiments show that upregulation of WP regulates metastasis-associated phenotypes in TNBC via activation of RAC1 GTP-ase. The functional link between WP, metastasis and the activation of RAC1 is being currently worked out using RAC1SiRNA and pharmacological inhibitor of RAC1 in brain metastasizing MDA-MB231BR cells to specifically address the role of Wnt-beta-catenin-RAC1 signaling axis in the context of distant metastasis, the results of which will be presented at the meeting. Citation Format: Nandini Dey, Jennifer Carlson, Pradip De, Brian Leyland-Jones. Wnt-beta-catenin-Rac1 signaling axis regulates metastasis-associated phenotypes in TNBC. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3443. doi:10.1158/1538-7445.AM2014-3443
The cytotoxicity of carbon black nanoparticles depends on their surface modification
Authors: Karina Weinhold, Peter König
Journal: European Respiratory Journal (2014)

Inhaled nanoparticles deposit on the airway epithelium. We are interested in how the effects of nanoparticles on the airway epithelium are changed after surface modification regarding impairment of mucociliary clearance and epithelial cytotoxicity.  We tested the following 14-nm Carbon Black nanoparticles (CBNP) with similar hydrodynamic diameter: unmodified CBNP (CBNP/-), surface-modified CBNP with 9-nitroanthracene (CBNP/Na) or benzo[a]pyrene (CBNP/BaP) and acetylene soot (A. soot). After incubation of mouse tracheae with 10 or 30 µg/ml CBNP for 24 h, their effect on cilia-driven particle transport, apoptosis and necrosis, epithelial integrity and the mRNA expression of cytokines, mucins and cytochrome oxidases ( Cyp ) were determined.  CBNP/- attached to cilia inducing an increase of ciliary beat frequency (CBF) and mucus release. In areas with mucus, particle transport speed (PTS) was decreased but in areas without mucus, PTS was increased. The epithelium remained intact and mRNA expression of cytokines, mucins or  Cyp  was not increased.  A. soot also led to an increase of CBF, whereas CBNP/Na and CBNP/BaP did not alter CBF. But all three modified particles caused a decrease of PTS based on induction of apoptosis and cell membrane perforation. Although epithelial cells were lost, the remaining epithelial cells preserved epithelial integrity. In addition, CBNP/Na, CBNP/BaP and A. soot induced mRNA expression of  Cyp1a1  and  Cyp1b1 , but A. soot alone increased mRNA expression of  MIP-2 ,  KC ,  IL-6  and  Muc5ac . None of the modified CBNP induced mucus release.  Our results indicate that the acute toxicity of CBNP is determined by their surface modification and modified CBNP can impair mucociliary clearance.
Mobile phone technology and hospitalized patients: a cross-sectional surveillance study of bacterial colonization, and patient opinions and behaviours
Authors: R.R. Brady, A.C. Hunt, A. Visvanathan, M.A. Rodrigues, C. Graham, C. Rae, P. Kalima, H.M. Paterson, A.P. Gibb
Journal: Clinical Microbiology and Infection (2011)
Altered expression of p53 and mdm-2 proteins at diagnosis is associated with early treatment failure in childhood acute lymphoblastic leukemia.
Authors: D I Marks, B W Kurz, M P Link, E Ng, J J Shuster, S J Lauer, D Carroll, I Brodsky, D S Haines
Journal: Journal of Clinical Oncology (1997)

To determine whether potential alteration in p53 function through p53 gene mutation or mdm-2 overexpression correlates with early treatment failure in childhood acute lymphoblastic leukemia (ALL).Diagnostic marrow samples from 34 children were analyzed for p53 gene alterations by western blot and SSCP/DNA sequence analysis and for mdm-2 overexpression by western blot analysis. These samples were derived from two groups of children with ALL: 17 good outcome patients who are in long-term continuous complete remission and 17 poor outcome patients who did not achieve a complete remission or relapsed within 6 months of achieving remission.Two children within the poor outcome group were found to have p53 gene mutations. Furthermore, five poor outcome patients were shown to have greater than 10-fold overexpression of mdm-2 protein compared with the mean level of mdm-2 protein measured in the good outcome group. Aberrant p53 protein expression was found in only one good outcome patient, whereas no good outcome children were found to have elevated levels (> 10-fold) of mdm-2 protein.We show for the first time that potential alteration in p53 function in childhood ALL is more common (P = .036) in cases of early treatment failure than in children who remain in long-term continuous remission.
Molecular epidemiology of enterovirus 71, coxsackievirus A16 and A6 associated with hand, foot and mouth disease in Spain
Authors: M. Cabrerizo, D. Tarragó, C. Muñoz-Almagro, E. del Amo, M. Domínguez-Gil, J. M Eiros, I. López-Miragaya, C. Pérez, J. Reina, A. Otero, I. González, J.E. Echevarría, G. Trallero
Journal: Clinical Microbiology and Infection (2013)
Delayed Development of Brain Connectivity in Adolescents With Schizophrenia and Their Unaffected Siblings
Authors: Andrew Zalesky, Christos Pantelis, Vanessa Cropley, Alex Fornito, Luca Cocchi, Harrison McAdams, Liv Clasen, Deanna Greenstein, Judith L. Rapoport, Nitin Gogtay
Journal: JAMA Psychiatry (2015)

Abnormalities in structural brain connectivity have been observed in patients with schizophrenia. Mapping these abnormalities longitudinally and understanding their genetic risk via sibship studies will provide crucial insight into progressive developmental changes associated with schizophrenia.To identify corticocortical connections exhibiting an altered developmental trajectory in adolescents with childhood-onset schizophrenia (COS) and to determine whether similar alterations are found in patients' unaffected siblings.Using prospective structural brain magnetic resonance imaging, large-scale corticocortical connectivity was mapped from ages 12 to 24 years in 109 patients with COS (272 images), 86 of their unaffected siblings (184 images), and 102 healthy controls (262 images) over a 20-year period beginning January 1, 1991, through April 30, 2011, as part of the ongoing COS study at the National Institute of Mental Health.Structural connectivity between pairs of cortical regions was estimated using a validated technique based on across-subject covariation in magnetic resonance imaging-derived cortical thickness measurements.Compared with normally developing controls, significant left-hemisphere occipitotemporal deficits in cortical thickness correlations were found in patients with COS as well as their healthy siblings (P < .05). Deficits in siblings normalized by mid-adolescence, whereas patients with COS showed significantly longer maturational delays, with cortical thickness correlations between the left temporal lobe and left occipital cortex not showing evidence of development until early adulthood. The normalization of deficits with age in patients with COS correlated with improvement in symptoms. Compared with controls, left-hemisphere occipitotemporal thickness correlations in a subgroup of patients with high positive symptoms were significantly reduced from age 14 to 18 years (P < .05); however, other patients with low positive symptoms showed no significant deficits.Delayed maturation of occipitotemporal connectivity appears to be a trait marker in patients with COS, with a milder endophenotype in unaffected siblings associated with resilience to developing schizophrenia. These findings indicate genetically influenced and connection-specific developmental abnormalities in the schizophrenia connectome, and lead to the hypothesis that visual hallucinations in patients with COS may be because of delayed development of the inferior longitudinal fasciculus, a prominent occipitotemporal fiber.
Systemic Juvenile Idiopathic Arthritis–like Syndrome in Mice Following Stimulation of the Immune System With Freund's Complete Adjuvant: Regulation by Interferon‐γ
Authors: Anneleen Avau, Tania Mitera, Stéphanie Put, Karen Put, Ellen Brisse, Jessica Filtjens, Catherine Uyttenhove, Jacques Van Snick, Adrian Liston, Georges Leclercq, An D. Billiau, Carine H. Wouters, Patrick Matthys
Journal: Arthritis & Rheumatology (2014)

Objective Systemic juvenile idiopathic arthritis (JIA) is unique among the rheumatic diseases of childhood, given its distinctive systemic inflammatory character. Inappropriate control of innate immune responses following an initially harmless trigger is thought to account for the excessive inflammatory reaction. The aim of this study was to generate a similar systemic inflammatory syndrome in mice by injecting a relatively innocuous, yet persistent, immune system trigger: Freund's complete adjuvant (CFA), containing heat‐killed mycobacteria. Methods Given the central role of interferon‐γ (IFNγ) in immune regulation, we challenged wild‐type (WT) and IFNγ‐knockout (KO) BALB/c mice with CFA, and analyzed their clinical symptoms and biologic characteristics. The production of cytokines and the effects of anticytokine antibodies were investigated. Results In WT mice, CFA injection resulted in splenomegaly, lymphadenopathy, neutrophilia, thrombocytosis, and increased cytokine expression. In the absence of IFNγ, these symptoms were more pronounced and were accompanied by weight loss, arthritis, anemia, hemophagocytosis, abundance of immature blood cells, and increased levels of interleukin‐6 (IL‐6), all of which are reminiscent of the symptoms of systemic JIA. CFA‐challenged IFNγ‐KO mice showed increased expression of IL‐17 by CD4+ T cells and by innate γ/δ T cells. Inflammatory and hematologic changes were prevented by treatment with anti–IL‐12/IL‐23p40 and anti–IL‐17 antibodies. Conclusion Immune stimulation of IFNγ‐KO mice with CFA produces a systemic inflammatory syndrome reflecting the clinical, biologic, and histopathologic picture of systemic JIA. The protective function of IFNγ in preventing anemia and overall systemic inflammation is a striking observation. The finding that both adaptive and innate T cells are important sources of IL‐17 may be of relevance in the pathogenesis of systemic JIA.