tbuckley/cabot-search huggingface dataset:
Abstract 4738: Cellular resistance screening with a novel selective c-Met inhibitor reveals a spectrum of missense mutations that partially overlap with activating mutations found in cancer patients
Authors: Ralph Tiedt, Elisa Degenkolbe, Pascal Furet, Brent A. Appleton, Joseph Schoepfer, David Ruddy, John Monahan, Michael D. Jones, Jutta Blank, Dorothea Haasen, Peter Drueckes, Markus Wartmann, Clive McCarthy, Francesco Hofmann
Journal: Cancer Research (2011)

Abstract Emergence of resistance is a major concern when treating cancer patients with targeted kinase inhibitors, as exemplified by the appearance of point mutations in Bcr-Abl in CML patients treated with imatinib or a secondary EGFR-T790M mutation in lung cancer patients treated with gefitinib or erlotinib. In vitro approaches to identify resistance mutations in Bcr-Abl have yielded mutation spectra that faithfully recapitulated clinical observations. In order to predict resistance mutations in the receptor tyrosine kinase c-Met that could emerge during inhibitor treatment in patients, we performed a resistance screen in BaF3 cells transformed with Tpr-Met using the novel selective c-Met inhibitor NVP-BVU972. The observed spectrum of mutations in resistant cells was dominated by substitutions of the residue Y1230 in the activation loop of the c-Met kinase domain, but also included other missense mutations. Intriguingly, some of the c-Met resistance mutations observed in this cellular screen were identical with previously described activating mutations in cancer patients that interfere with inhibitory interactions in the inactive conformation. Co-crystallization of the c-Met kinase domain in complex with NVP-BVU972 revealed a key role for Y1230 in binding of NVP-BVU972. This binding mode has also been reported for multiple other selective c-Met inhibitors, some of which have entered clinical trials, suggesting a broader relevance of the resistance profile obtained with NVP-BVU972. A second resistance screen in the same format with the c-Met inhibitor AMG 458 yielded a distinct spectrum of mutations that was rich in F1200 alterations. This is consistent with a different predicted binding mode. Again, the mutation profile observed with AMG 458 could be predictive for several other inhibitors that bind c-Met in a similar way. Collectively, our findings suggest that amino acid substitutions in the c-Met kinase domain of cancer patients need to be carefully monitored prior to and during treatment with c-Met inhibitors, as resistance may pre-exist or emerge. Compounds binding in the same manner as NVP-BVU972 might be particularly susceptible to the development of resistance through mutations in Y1230, a complication that could potentially be overcome by c-Met inhibitors with alternative binding modes. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4738. doi:10.1158/1538-7445.AM2011-4738
Red-Cell Lithium-Sodium Countertransport and Renal Lithium Clearance in Hypertension
Authors: Alan B. Weder
Journal: New England Journal of Medicine (1986)

Red-cell lithium–sodium countertransport is increased in patients with essential hypertension. It has been proposed that sodium–hydrogen ion exchange in the brush border of the renal proximal tubules is analogous to red-cell countertransport. To investigate the rate of sodium reabsorption by the proximal renal tubules in hypertension, we measured lithium clearance (a measure of proximal tubular reabsorption of sodium), as well as red-cell countertransport, in 14 patients with untreated essential hypertension and in 31 controls. As a group, the hypertensive patients had a higher average (±SEM) rate of red-cell countertransport (0.378±0.030 mmol of lithium per liter of cells per hour, P<0.01) and a lower renal fractional lithium clearance (13.96±0.69 percent, P<0.01) than normotensive subjects (0.317±0.015 mmol of lithium per liter of cells per hour and 17.75±0.81 percent, respectively). Within the normotensive group, subjects with hypertension in at least one first-degree relative had significantly lower fractional lithium clearances than subjects with no hypertensive relatives (15.37±0.84 percent vs. 19.06±1.07 percent, P<0.05). We conclude that hypertensive patients have heightened proximal tubular reabsorption of sodium and that red-cell countertransport is a marker of the renal abnormality. Enhanced proximal tubular sodium reabsorption may precede the development of essential hypertension. (N Engl J Med 1986; 314:198–201.)
511 HBSAG LEVELS DECLINE DURING PEGINTERFERON ALFA-2A [40KD] (PEGASYS) TREATMENT IN PATIENTS WITH HBEAG-NEGATIVE CHRONIC HEPATITIS B FAVORS 6 MONTHS POST-TREATMENT RESPONSE: PERSEAS COHORT INTERIM ANALYSIS
Authors: I. Goulis, E. Akriviadis, S. Karatapanis, M. Deutsch, G. Dalekos, M. Raptopoulou-Gigi, K. Mimidis, G. Germanidis, C. Triantos, C. Drakoulis, A. Chounta, F. Tsoplou, E. Zintzaras, G. Bakalos, G. Papatheodoridis
Journal: Journal of Hepatology (2012)
Abstract LB-416: Genetic analysis of pediatric brainstem glioma using protein analysis of cerebrospinal fluid
Authors: Amanda M. Saratsis, Javad Nazarian
Journal: Cancer Research (2012)

Abstract Abstract: Diffuse intrinsic pontine glioma (DIPG) is a leading cause of brain tumor death in children due to lack of effective therapy. Genetic analysis of DIPG has been limited due to the lack of readily available tumor tissue for molecular study. Molecular analysis of cerebrospinal fluid (CSF) could provide information on chromosomal abnormalities in DIPG. Methods: CSF samples from normal and brainstem glioma patients were analyzed by MS/MS label-free proteomic analysis using LTQ-Orbitrap-XL. Proteins were identified using the Sequest algorithm in the Bioworks browser against the Uniprot database and quantitated using ProteoIQ software. Relative protein expression was used to extrapolate potential regions of chromosomal amplification and deletion. Results: Quantitative proteomic analysis revealed 309 proteins detected in DIPG CSF specimens but absent in controls 76% of which correlated to regions of known genomic amplification in pediatric brainstem glioma. Specifically, 1q and 17q were chromosomal regions that showed the greatest amplification as judges by high expression in DIPGs CSF Specimens Moreover, 46 proteins were detected in all controls but absent in DIPG CSF specimens. Of these, 58% mapped to known genomic deletion sites, with X, 5p and 17p the most common abnormal regions. These findings correlate with existing data in the literature on genetic abnormalities of brainstem glioma. Conclusions: Cerebrospinal fluid from children with DIPG and other craniospinal tumors are more readily available than biopsies tumor specimen. Proteomic analysis can reveal potential regions of genomic change that correlates with existing data in the literature and can provide insight to pathways of brainstem gliomagenesis. Further analysis of CSF and validation of observed dysregulation is warranted. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr LB-416. doi:1538-7445.AM2012-LB-416
A transient dephosphorylation of JAK1 and JAK2 characterises the early-phase response of murine erythroleukemia cells to the differentiation inducer hexamethylenebisacetamide
Authors: A Arcangeli, L Fontana, O Crociani, A Cherubini, G Hofmann, E Piccini, S Polvani, M D'Amico, M Carlà, M Olivotto
Journal: Leukemia (2000)
NHS England will strengthen rules for managing conflicts of interest in CCGs
Authors: Gareth Iacobucci
Journal: BMJ (2016)

NHS England will introduce tougher rules for managing conflicts of interest in clinical commissioning groups (CCGs) as part of an NHS-wide overhaul of its policies.

In a strengthening of its statutory guidance to GP led bodies, NHS England will require all CCGs to nominate a conflicts of interest guardian to ensure “firmer and more consistent” decision making.

The changes, announced after a recent joint investigation by The BMJ and the Times newspaper,1 which found significant variation in the management of conflicts and the levels of transparency, will also advise CCGs to increase lay member numbers on their governing body from two to a minimum of three to provide extra scrutiny for …
AB0626 Non-invasive optical detection of cathepsin k-mediated fluorescence reveals osteoclast activity in mouse model of osteoporosis
Authors: S. Choi, A. Lee, Y. H. Seo, Y. H. Lee, J. D. Ji, G. G. Song
Journal: Annals of the Rheumatic Diseases (2013)

<h3>Background</h3> Osteoporosis is a skeletal disorder characterized by bone strength to an increased risk of fracture. It becomes an important public health issue, because of the ageing population. Osteoporosis imaging is important to identify individual at risk for fractures to reduce fracture and also monitoring response to treatment. <h3>Objectives</h3> Imaging modalities such as DXA, X-ray and pQCT report bone density. The development of image-based indicators of osteoclast activity will provide for early identification of changes in bone resorption. Individualized treatment was based on early detection of osteoclast activity. <h3>Methods</h3> Our team developed osteoclast specific smart nanoparticle (Cathepsin K target nanoprobe). Osteoclasts are one of the major source of cathepsin K. Cathepsins are a group of 11 enzymes belonging to the papain family of cysteine proteases. Especially, cathepsin K is known to play an important role in bone resorption in osteoporosis. Therefore, cathepsin K is an attractive target enzyme for both diagnosis and treatment of osteoporosis. Furthermore, in vivo imaging of cathepsin K could be used to detect biological activities related with progressive osteoporosis and to monitor therapeutic responses to drugs or inhibitors. <h3>Results</h3> We investigated a NIRF (near infrared fluorescent) smart nanoparticle which was activated by cathepsin K is shown in live osteoclast activity in mouse models of osteoporosis. In ovariectomized mice, cathepsin K probe intensity was detected very early time before any signs of structural or anatomic changes could be detected by the histologic and micro-CT analyses. <h3>Conclusions</h3> These results may provide valuable meanings for early diagnosis of upregulated resorption and rapid feedback on efficacy of treatment protocols prior to significant bone loss in the patients at risk. <h3>Disclosure of Interest</h3> None Declared
Abstract P6-07-38: The Value of Progesterone Receptor in Predicting the Recurrence Score for Hormone-Receptor–Positive Invasive Breast Cancer Patients
Authors: T Onoda, H Yamauchi, H Yagata, N Hayashi, A Yoshida, S Nakamura
Journal: Cancer Research (2012)

Abstract Background: Molecular genomic profiling currently plays a major role in treatment decisions for breast cancer patients. The 21-gene signature (Oncotype DX® [ODX]) is one of the most well-validated assays. Herein we evaluated the associations between high Recurrence Score (RS) measured by the ODX and pathological factors. Methods: From October 2007 to October 2010, the ODX assay was performed for 139 hormone-receptor–positive invasive breast cancer patients at single institution. Correlations between the RS and the following pathological factors were analyzed: tumor size (T), lymph node metastasis (N), nuclear atypia (NA), mitotic counts (MC), nuclear grade (NG), lymphatic and vascular invasion (LI and VI), estrogen receptor (ER), progesterone receptor (PgR), HER2, and Ki-67. Expression of ER, PgR, HER2, and Ki-67 was examined by immunohistochemistry. The Ki-67 labeling index was automatically counted with an Ariol-SL50 instrument (APPLIED IMAGING). The other pathological factors were estimated under the supervision of one experienced pathologist. Spearman rank correlation coefficients were calculated for the analyses. When the r was &amp;gt;0.4 or &amp;lt;–0.4 for two factors, they were determined to be well correlated. Results: Of 139 patients, the ODX assay revealed 68 (49%) low RS cases, 52 (37%) intermediate RS cases, and 19 (14%) high RS cases. Moderate positive or negative correlations were noted between the RS and PgR (r = −0.53), the RS and Ki-67 (r = 0.42), and the RS and NG (r = 0.41). No patients had high RS with PgR (3+) or NG1. The rate of high RS with Ki-67 (&amp;lt;20%) was one patient (2%). The number of cases who did not show PgR (3+) or NG1 or Ki-67 (&amp;lt;20%) was only 34 (25%). Among high RS cases, the correlation between PgR (0) and NG3 was 83%, the correlation between PgR (0) and NG2 was 75%, and the correlation between PgR (1+) and NG3 was 75%. The rate of high RS with PgR (0) and Ki-67 (≥20%) was 70%, that of PgR (1+) and Ki-67 (≥20%) was 58%, and that of PgR (2+) and Ki-67 (≥20%) was 21%. Correlations with T, N, NA, MC, LI, VI, ER, and HER2 were smaller (r ranging from −0.33 to 0.38). Conclusion: This study demonstrated that PgR, NG, and Ki-67 tend to be strongly correlated with the RS. Judging from PgR (3+), NG1, and Ki-67 (≥20%), we could select the patients who were proposed to perform the ODX. Among these factors, the correlation with PgR was particularly robust. PgR expression is a known marker of a functional ER and represents ER activity. In addition, the absence of PgR may reflect hyperactive cross-talk between ER and growth factor signaling pathways. We consider that these mechanisms could enhance the value of PgR in predicting the RS. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P6-07-38.
Lymphocyte Transformation Test in Fixed Drug Eruption
Authors: J.M. Gimenez-Camarasa, P. Garcia-Calderon, J.M. de Moragas
Journal: New England Journal of Medicine (1975)

Twenty-one patients with fixed drug eruption were studied with the lymphocyte transformation test. In no patient was there blast transformation when the responsible drug (1:10,000 dilution) was added to the lymphocyte culture. The addition to the lymphocyte culture of 0.4 ml of autologous serum, taken at the acme of the clinical reaction, produced blast transformation of the lymphocytes, and when the responsible drug (1:10,000 dilution) was added to this system, blast transformation increased by several times. The addition of the responsible drug to autologous serum obtained during clinical remission produced a minimal or negative response. These findings suggest that during fixed drug eruptions a blast transforming factor appears temporarily in the serum and increases its activity in the presence of the responsible drug. This factor spontaneously diminishes or disappears a few days after clinical exacerbation.
Adequacy of Antitetanus Prophylaxis in Six Hospital Emergency Rooms
Authors: Donald A. Brand, Denise Acampora, Louis D. Gottlieb, Kevin E. Glancy, William H. Frazier
Journal: New England Journal of Medicine (1983)

We studied the adequacy of antitetanus prophylaxis given to 620 patients with open soft-tissue injuries by 169 physicians in six hospital emergency rooms. Twenty-three per cent of the patients were treated incorrectly (6 per cent were undertreated and 17 per cent were overtreated) with tetanus toxoid or human tetanus immunoglobulin. Undertreatment ranged from 4 to 11 per cent, and overtreatment from 5 to 38 per cent at the different hospitals (P less than 0.01). Patients at highest risk for tetanus (those with tetanus-prone wounds who had never been given a complete initial course of immunizations) had the lowest likelihood (27 per cent) of receiving correct antitetanus treatment. By following an immunization protocol based on time since injury, mechanism of injury, estimated bacterial contamination, presence of devitalized tissue, wound depth, and past immunizations, physicians can better protect the population against tetanus while lowering the risk of adverse drug reactions and not increasing the cost of care.
Our Flawed but Beneficial Medicaid Program
Authors: Austin Frakt, Aaron E. Carroll, Harold A. Pollack, Uwe Reinhardt
Journal: New England Journal of Medicine (2011)

Many U.S. governors are proposing or implementing deep cuts to their states' Medicaid programs to address budget shortfalls, and some are calling for Medicaid to be converted to a block-grant program. Some commentators defend such policy retrenchment by claiming that Medicaid coverage fails to improve health outcomes — indeed, that its beneficiaries may have worse health outcomes than patients with no insurance at all.1 To make that case, these commentators have creatively interpreted observational studies that have examined clinical outcomes associated with particular medical interventions according to the patient's insurance type — Medicaid, Medicare, private coverage, or none — and . . .
COMPARISON BETWEEN FRACTIONAL FLOW RESERVE VERSUS MYOCARDIAL PERFUSION IMAGING USING AN ULTRAFAST CARDIAC GAMMA CAMERA FOR DIAGNOSIS OF CORONARY ARTERY DISEASE
Authors: Kenji Goto, Hiroki Yamane, Yoshimasa Morimoto, Arata Hagikura, Yuetsu Kikuta, Katsumasa Sato, Masahito Taniguchi, Shigeki Hiramatsu, Hideo Takebayashi, Seiichi Haruta
Journal: Journal of the American College of Cardiology (2015)
EXPERIENCIA EN NUESTRO CENTRO SOBRE LA INGESTA ACCIDENTAL DE PILA DE BOTÓN EN EDAD PEDIATRICA
Authors: M Muñoz Tornero, F Alberca De Las Parras, M Navalón Rubio, D Gil Ortega, A Garcia Lax, I Martinez Castaño, J Egea Valenzuela, J Alvarez Higueras Francisco, G Antón Ródenas, F Carballo Alvarez Luis
Journal: Endoscopy (2013)

Introducción: La ingesta accidental de pilas de botón puede tener consecuencias letales, máxime si quedan ubicadas en esófago, donde el daño se puede extender a tráquea o a aorta. Objetivo: Comunicar los casos de ingesta de pila de botón en los pacientes pediátricos de nuestra región en los últimos 5 años. Material y Método: Análisis retrospectivo de ingesta de pila de botón en pediatria los últimos 5 años. Se valoraron: sexo, edad, nivel socioeconómico, tiempo desde la ingesta hasta la consulta, sintomatología, ubicación de la pila, tiempo desde la consulta hasta la extracción endoscópica, hallazgos endoscópicos, y evolución. Resultados: Se recogieron 30 pacientes (19 varones y 11 mujeres). Edad media: 3,3 años (1 – 10 años). El nivel socioeconómico de los pacientes era bajo en un 70% de los casos. El tiempo medio desde la ingesta hasta la consulta fue de 18h (rango: 1h- 14 días). En el momento de la consulta, 11 tenían clínica y 19 no. La ubicación de la pila en la radiografía fue: estómago en 17, esófago en 10 e intestino en 3. El tiempo medio desde la consulta hasta la extracción endoscópica fue de 5,8 horas (0,5 – 72h). La endoscopia mostró lesiones en 13 casos,7 de los cuales consistían en úlceras profundas o zonas de necrosis. La evolución fue satisfactoria en la mayoría. Dos pacientes tuvieron complicaciones graves, uno desarrollo mediastinitis y otro paciente presentó una fístula aortoesofágica y falleció por shock hemorrágico tras sangrado centinela inicial. Conclusiones: Nuestros datos alertan de un aumento de los casos de ingesta de pila de botón en niños y gran parte de ellos no han sido presenciados, por lo necesita un alto índice de sospecha. Hay que diseñar una estrategia de monitorización de niños con lesiones esofágicas con el objetivo de detectar precozmente las complicaciones vasculares.
THU0225 Tofacitinib Monotherapy is Effective in Methotrexate-NaÏVe Patients with Disease Duration Less Than 6 Months: a Post-HOC Analysis of Early Rheumatoid Arthritis Subjects in a Phase 3 Trial
Authors: T. W. J. Huizinga, R. Fleischmann, R. van Vollenhoven, D. Gruben, B. Wilkinson, T. Koncz, J. Bradley, S. H. Zwillich, B. Benda
Journal: Annals of the Rheumatic Diseases (2013)

<h3>Background</h3> Tofacitinib is a novel oral Janus kinase (JAK) inhibitor for the treatment of rheumatoid arthritis (RA). <h3>Objectives</h3> To assess the efficacy of tofacitinib monotherapy in patients (pts) with early RA (eRA), as defined by disease duration (i.e., time since diagnosis) &lt;6 months, in a Phase 3, 24-month (Mo) study (ORAL Start, NCT01039688) of tofacitinib vs methotrexate (MTX) in MTX-naïve pts with active RA. Primary analyses have been reported.<sup>1</sup> <h3>Methods</h3> Pts were randomised 2:2:1 to tofacitinib 5 mg twice daily (BID), tofacitinib 10 mg BID, or MTX. Post-hoc subgroup analyses from the planned 12-Mo interim analyses of signs and symptoms (rates of ACR20, 50 and 70; DAS28-4[ESR] [DAS]-defined remission and low disease activity [LDA] [DAS &lt;2.6 and ≤3.2, respectively]), physical function (mean change from baseline [BL] in HAQ-DI) and structure preservation (mean change from BL in modified Total Sharp Score [mTSS] and rates of no radiographic progression [mTSS change ≤0.5]) in pts with eRA are presented. <h3>Results</h3> 409 of 952 pts receiving treatment had a disease duration &lt;6 Mo. In this eRA subpopulation, ACR (20/50/70) response rates, rates of DAS-defined remission and LDA and mean HAQ-DI improvement were significantly better with tofacitinib vs MTX at Mo 3 and inhibition of structural damage at Mo 6 and 12. Results by disease duration &lt;6 Mo or ≥6 Mo are summarised in Figure 1. <h3>Image/graph</h3> <h3>Conclusions</h3> Tofacitinib monotherapy significantly inhibited progression of structural damage and improved RA signs and symptoms and physical functioning vs MTX, in MTX-naïve pts with early as well as established disease. <h3>References</h3> Lee EB et al Arthritis Rheum 20;64(10[supplement]):S1049. <h3>Disclosure of Interest</h3> T. J. Huizinga Grant/research support from: Dutch Arthritis Foundation, The Dutch NIH en the EU, Consultant for: Merck, UCB, Bristol Myers Squibb, Biotest AG, Pfizer, Novartis, Roche, Sanofi-Aventis, Abbott, Crescendo Bioscience, Nycomed, Boeringher, Takeda, Eli Lilly, Employee of: LUMC, Paid instructor for: Roche, Pfizer, Speakers bureau: Roche, Pfizer, R. Fleischmann Grant/research support from: Pfizer Inc., Consultant for: Pfizer Inc., R. van Vollenhoven Grant/research support from: AbbVie, BMS, GSK, MSD, Pfizer, Roche, UCB, Consultant for: AbbVie, BMS, GSK, MSD, Pfizer, Roche, UCB, D. Gruben Shareholder of: Pfizer Inc., Employee of: Pfizer Inc., B. Wilkinson Shareholder of: Pfizer Inc., Employee of: Pfizer Inc., T. Koncz Shareholder of: Pfizer Inc., Employee of: Pfizer Inc., J. Bradley Shareholder of: Pfizer Inc., Employee of: Pfizer Inc., S. Zwillich Shareholder of: Pfizer Inc., Employee of: Pfizer Inc., B. Benda Shareholder of: Pfizer Inc., Employee of: Pfizer Inc.
Plasticity of cerebro-cerebellar interactions in patients with cerebellar dysfunction
Authors: Karl Wessel
Journal: Behavioral and Brain Sciences (1996)

Studies comparing movement-related cortical potentials, post-excitatory inhibition after transcranial magnetic brain stimulation, and PET findings in normal controls and patients with cerebellar degeneration demonstrate plasticity of cerebro-cerebellar interactions and hereby support Thach's theory that the cerebellum has the ability to play a role in building behavioral context-response linkages and to build up appropriate responses from simpler constitutive elements, [THACH]