bluuebunny/crossref_metadata_2025_split huggingface dataset:
Dose Selection, Pharmacokinetics, and Pharmacodynamics of BRAF Inhibitor Dabrafenib (GSK2118436)
Authors: Falchook Gerald S. , Long Georgina V. , Kurzrock Razelle , Kim Kevin B. , Arkenau H.-Tobias , Brown Michael P. , Hamid Omid , Infante Jeffrey R. , Millward Michael , Pavlick Anna , Chin Melvin T. , O'Day Steven J. , Blackman Samuel C. , Curtis C. Martin , Lebowitz Peter , Ma Bo , Ouellet Daniele , Kefford Richard F. 
Published: June 2014

AbstractPurpose: Dabrafenib is a selective, potent ATP-competitive inhibitor of the BRAFV600-mutant kinase that has demonstrated efficacy in clinical trials. We report the rationale for dose selection in the first-in-human study of dabrafenib, including pharmacokinetics, tissue pharmacodynamics, 2[18F]fluoro-2-deoxy-D-glucose-positron emission tomography (FDG-PET) pharmacodynamics, and dose–response relationship.Experimental Design: Dabrafenib was administered orally once, twice (BID), or three times daily (TID). Selected dose cohorts were expanded to collect adequate data on safety, pharmacokinetics, or pharmacodynamics. A recommended phase II dose (RP2D) was chosen based on safety, pharmacokinetic, pharmacodynamic, and response data.Results: One hundred and eighty-four patients were enrolled and treated with doses ranging from 12 mg once daily to 300 mg BID in 10 cohorts. Pharmacokinetic assessment of dabrafenib demonstrated a less-than-dose-proportional increase in exposure after repeat dosing above 150 mg BID. Similar to parent drug concentrations, exposure for all metabolites demonstrated less-than-dose-proportional increases. Predicted target inhibition of pERK (&gt;80%) was achieved at 150 mg BID, with a similar magnitude of inhibition at higher doses in BRAFV600 mutation melanoma biopsy samples. Although there was large variability between patients, FDG uptake decreased with higher daily doses in patients with BRAFV600 mutation–positive melanoma. A favorable activity and tolerability profile was demonstrated at 150 mg BID. There was no improvement with TID dosing compared with BID dosing, based on FDG-PET and tumor response analyses in patients with melanoma.Conclusion: The RP2D of dabrafenib was determined to be 150 mg BID after considering multiple factors, including pharmacokinetics, tissue pharmacodynamics, FDG-PET pharmacodynamics, and the dose–response relationship. A maximum tolerated dose for dabrafenib was not determined. Clin Cancer Res; 20(17); 4449–58. ©2014 AACR.
CALGB 150905 (Alliance): Rituximab Broadens the Antilymphoma Response by Activating Unlicensed NK Cells
Authors: Du Juan , Lopez-Verges Sandra , Pitcher Brandelyn N. , Johnson Jeffrey , Jung Sin-Ho , Zhou Lili , Hsu Katharine , Czuczman Myron S. , Cheson Bruce , Kaplan Lawrence , Lanier Lewis L. , Venstrom Jeffrey M. 
Published: June 2014

Abstract
Natural killer (NK) cells contribute to clinical responses in patients treated with rituximab, but the rules determining NK-cell responsiveness to mAb therapies are poorly defined. A deeper understanding of the mechanisms responsible for antibody-dependent cellular cytotoxicity (ADCC) could yield useful biomarkers for predicting clinical responses in patients. Unlicensed NK cells, defined as NK cells lacking expression of an inhibitory KIR for self-HLA class I ligands, are hyporesponsive in steady state, but are potent effectors in inflammatory conditions. We hypothesized that antitumor antibodies such as rituximab can overcome NK-cell dependence on licensing, making unlicensed NK cells important for clinical responses. Here, we examined the influences of variations in KIR and HLA class I alleles on in vitro responses to rituximab. We tested the clinical significance in a cohort of patients with follicular lymphoma treated with rituximab-containing mAb combinations, and show that rituximab triggers responses from all NK-cell populations regardless of licensing. Neither IL2 nor accessory cells are required for activating unlicensed NK cells, but both can augment rituximab-mediated ADCC. Moreover, in 101 patients with follicular lymphoma treated with rituximab-containing mAb combinations, a “missing ligand” genotype (predictive of unlicensed NK cells) is associated with a higher rate of progression-free survival. Our data suggest that the clinical efficacy of rituximab may be driven, in part, by its ability to broaden the NK-cell repertoire to include previously hyporesponsive, unlicensed NK cells. A “missing ligand” KIR and HLA class I genotype may be predictive of this benefit and useful for personalizing treatment decisions in lymphomas and other tumors. Cancer Immunol Res; 2(9); 878–89. ©2014 AACR.
Plasma Levels of the Proinflammatory Chitin‐Binding Glycoprotein YKL‐40, Variation in the Chitinase 3‐Like 1 Gene (
CHI3L1
), and Incident Cardiovascular Events
Authors: Ridker Paul M , Chasman Daniel I. , Rose Lynda , Loscalzo Joseph , Elias Jack A. 
Published: June 2014

Background

YKL
‐40, encoded by the chitinase 3‐like 1 (

CHI
3L1

) gene, is a chitinase‐like protein involved in innate immune function hypothesized to play a role in the progression of atherosclerosis that may have differential roles in myocardial infarction (
MI
), as compared to stroke.

Methods and Results

In a nested case‐control study conducted within a prospective cohort of 23 294 initially healthy women of European ancestry, we (1) measured plasma concentration of
YKL
‐40 among 359 participants who subsequently developed cardiovascular events and among 359 age‐, smoking‐, and hormone replacement therapy–matched participants who remained free of disease during 17 years of follow‐up, (2) compared effects of
YKL
‐40 on vascular risk to that associated with 3 alternative inflammatory biomarkers (high‐sensitivity C‐reactive protein) ([hs
CRP
], soluble intracellular adhesion molecule 1, and fibrinogen), and (3) evaluated the role of 41 single‐nucleotide polymorphisms (
SNP
s) in the chitinase 3‐like 1 gene (

CHI
3L1

) as determinants of
YKL
‐40 levels and incident vascular events.
YKL
‐40 levels were higher in women with hypertension, diabetes, and obesity and correlated modestly with high‐density lipoprotein cholesterol, triglycerides, and hs
CRP
, but not with low‐density lipoprotein cholesterol. Baseline
YKL
‐40 level was significantly associated with incident thromboembolic stroke with a magnitude of effect (a 40% per quartile increase in odds ratio [
OR
],
P
=0.019) comparable to that of hs
CRP
(a 52% per quartile increase in
OR
,
P
=0.006). By contrast, no significant association was observed between
YKL
‐40 and incident
MI
. Genetic variation in

CHI
3L1

was strongly associated with
YKL
‐40 levels; however, in this sample set, we did not observe a statistically significant association between genotype and future vascular events.

Conclusions

Among initially healthy U.S. women, plasma levels of the proinflammatory chitenase‐like protein,
YKL
‐40, were influenced by environmental as well as genetic factors and predicted incident thromboembolic stroke, but not
MI
, a differential effect consistent with limited previous data.
Functional and Histological Assessment of an Experimental Model of Takotsubo's Cardiomyopathy
Authors: Sachdeva Jaspreet , Dai Wangde , Kloner Robert A. 
Published: June 2014

Background
Our objectives were to characterize functional and structural features of an experimental model of Takotsubo cardiomyopathy, and its response to beta‐blockers.

Methods and Results

In protocol 1, a dose‐finding study: 69 rats received various doses of isoproterenol (
ISO
) and echocardiographic and histologic parameters were measured on days 2 to 3 or day 8. There were no dose‐dependent effects and, out of 69
ISO
‐treated rats, 40 (58.0%) survived and 29 (42.0%) died within 24 hours. Of survivors, 30 had apical akinesis averaging 12.1±1.6% of the long axis
LV
circumference. Out of the 40 survivors, 32.5% showed apical akinesis ≥10%, 42.5% showed akinesis<10% and 25% showed no apical akinesis. The basal portion of the
LV
was always preserved. At 24 hours, histology and ultrastructure showed necrosis, vacuolization, lipid droplets, mononuclear cell infiltration, damaged mitochondria, and edema. On day 8, apical akinesis fully resolved but histologic abnormalities were still present. In protocol 2, rats were randomized to Control;
ISO
100 mg/kg; propranolol+
ISO
; and metoprolol+
ISO
groups. Pretreatment with propranolol and metoprolol improved survival to 90% and 100% respectively, compared with 60% in the
ISO
group, but did not reduce the incidence and extent of akinesis or the structural damage.

Conclusion

TC
can be mimicked in a rat model of
ISO
exposure that demonstrates apical akinesis on days 2 to 3 with full recovery of systolic regional wall motion abnormality despite the presence of persistent foci of necrosis and fibrosis on day 8. Pretreatment with beta‐blockers improved survival but did not affect structural and functional alterations.
Decreased Myocardial Injury and Improved Contractility After Administration of a Peptide Derived Against the Alpha‐Interacting Domain of the L‐Type Calcium Channel
Authors: Viola Helena M. , Jordan Maria C. , Roos Kenneth P. , Hool Livia C. 
Published: June 2014

Background

Myocardial infarction remains the leading cause of morbidity and mortality associated with coronary artery disease. The L‐type calcium channel (

I
C

a‐L
) is critical to excitation and contraction. Activation of the channel also alters mitochondrial function. Here, we investigated whether application of a alpha‐interacting domain/transactivator of transcription (
AID
‐
TAT)
peptide, which immobilizes the auxiliary β
2
subunit of the channel and decreases metabolic demand, could alter mitochondrial function and myocardial injury.

Methods and Results

Treatment with
AID
‐
TAT
peptide decreased ischemia‐reperfusion injury in guinea‐pig hearts ex vivo (n=11) and in rats in vivo (n=9) assessed with uptake of nitroblue tetrazolium, release of creatine kinase, and lactate dehydrogenase. Contractility (assessed with catheterization of the left ventricle) was improved after application of
AID
‐
TAT
peptide in hearts ex vivo (n=6) and in vivo (n=8) up to 12 weeks before sacrifice. In search of the mechanism for the effect, we found that intracellular calcium ([Ca
2+
]
i
, Fura‐2), superoxide production (dihydroethidium fluorescence), mitochondrial membrane potential (Ψ
m
,
JC
‐1 fluorescence), reduced nicotinamide adenine dinucleotide production, and flavoprotein oxidation (autofluorescence) are decreased after application of
AID
‐
TAT
peptide.

Conclusions

Application of
AID
‐
TAT
peptide significantly decreased infarct size and supported contractility up to 12 weeks postcoronary artery occlusion as a result of a decrease in metabolic demand during reperfusion.
The Neural Basis of Temporal Order Processing in Past and Future Thought
Authors: D'Argembeau Arnaud , Jeunehomme Olivier , Majerus Steve , Bastin Christine , Salmon Eric 
Published: June 2014

Abstract
Although growing evidence has shown that remembering the past and imagining the future recruit a common core network of frontal-parietal-temporal regions, the extent to which these regions contribute to the temporal dimension of autobiographical thought remains unclear. In this fMRI study, we focused on the event-sequencing aspect of time and examined whether ordering past and future events involve common neural substrates. Participants had to determine which of two past (or future) events occurred (or would occur) before the other, and these order judgments were compared with a task requiring to think about the content of the same past or future events. For both past and future events, we found that the left posterior hippocampus was more activated when establishing the order of events, whereas the anterior hippocampus was more activated when representing their content. Aside from the hippocampus, most of the brain regions that were activated when thinking about temporal order (notably the intraparietal sulcus, dorsolateral pFC, dorsal anterior cingulate, and visual cortex) lied outside the core network and may reflect the involvement of controlled processes and visuospatial imagery to locate events in time. Collectively, these findings suggest (a) that the same processing operations are engaged for ordering past events and planned future events in time, (b) that anterior and posterior portions of the hippocampus are involved in processing different aspects of autobiographical thought, and (c) that temporal order is not necessarily an intrinsic property of memory or future thought but instead requires additional, controlled processes.
Suggested avenues to reduce the stigma of mental illness in the Middle East
Authors: Sewilam Ahmed M , Watson Annie MM , Kassem Ahmed M , Clifton Sue , McDonald Margaret C , Lipski Rebecca , Deshpande Smita , Mansour Hader , Nimgaonkar Vishwajit L 
Published: June 2014

Background: Stigma toward mentally ill individuals acts as a barrier to accessing care and receiving treatment. Aim: To review current evidence pertaining to stigma toward mental illness in the Middle East in order to inform effective and sustainable interventions in this region. Methods: We conducted a systematic literature search using the PubMed database and evaluated all identified studies according to specific inclusion criteria. Results: Stigma toward individuals with mental illness does exist in the Middle East. Stigmatizing attitudes are particularly high toward culturally proscribed mental illnesses like alcohol abuse and lower for other disorders such as depression and psychosis. Conclusions: We propose the following initiatives to reduce stigma toward mental illness in the Middle East: (a) educate families to enable them to support their affected relatives, (b) increase cooperation between psychiatrists and faith healers and (c) educate young people in schools to increase their awareness and understanding of mental illnesses and to combat negative stereotypes.
Corticosteroids alter CGRP and melatonin release in cluster headache episodes
Authors: Neeb Lars , Anders Linn , Euskirchen Philipp , Hoffmann Jan , Israel Heike , Reuter Uwe 
Published: June 2014

Background Calcitonin gene-related peptide (CGRP) is a marker of trigeminal activation in acute cluster headache (CH). Melatonin production is altered in CH patients and may reflect hypothalamic dysfunction. We assessed the effects of short-term CH prevention with corticosteroids on CGRP and melatonin release in a prospective observational cohort study hypothesizing that corticosteroids influence the interictal activity of both systems indicated by the change of these biomarkers. Methods Episodic CH subjects ( n = 9) in the bout and controls with multiple sclerosis ( n = 6) received 1000 mg/d methylprednisolone (MPD) i.v. for three days followed by oral tapering with prednisone. We determined CGRP plasma levels in external jugular vein blood outside an attack and 6-sulfatoxymelatonin (aMT6s) – the stable metabolite of melatonin – in 12-hour day- and nighttime urine collection prior to and several times after MPD therapy and again when CH subjects were outside the bout in complete remission. CH patients recorded the frequency of attacks. Results In parallel to the reduction of headache frequency, administration of corticosteroids resulted in significantly decreased CGRP plasma levels and increased nocturnal aMT6s urine excretion in CH subjects. No significant changes were observed in controls. Conclusion Corticosteroids alter CGRP plasma and aMT6s urine levels in a cluster bout. These changes may indicate an effect of corticosteroids on trigeminal activation and hypothalamic dysfunction.
Turn-milling of blades in turning centres and multitasking machines controlling tool tilt angle
Authors: Calleja Amaia , Fernández Asier , Rodríguez Adrián , de Lacalle L Norberto López , Lamikiz Aitzol 
Published: June 2014

The machining of high–added value blades represents a challenge due to the parts’ complex geometry and tight tolerances. Blades are common in the aeronautic, energy or automotive sectors. Nowadays, there is a strong trend towards the integration of all machining operations in the same machine tool platform; this is the so-called multitasking machining. The main advantage is that the part reference system is maintained along all the operations, and it also achieves shorter production lead times. However, milling operations have to be programmed for being performed in machines with a general lathe structure, which must be solved. For this reason, in this work, advanced programming for the production of blades in turning centres and multitasking machines is developed. Blade machining is developed by successive techniques. This article mainly focuses on the study of the optimal machining strategy for blades turn-milling. For that purpose, different strategies and tilt angles have been tested and applied initially to a test part and finally to a real part. The proposed methodology has been applied to a blade case study in order to obtain the best parameters and toolpath strategies for blades machining. They represent the main novelty and article contribution.
Comparative Analysis of Gene Expression in Normal and Degenerative Human Tendon Cells
Authors: Choi Woo Jin , Park Min Sung , Park Kwang Hwan , Courneya Jean-Paul , Cho Jin Sun , Schon Lew C. , Lee Jin Woo 
Published: June 2014

Background: Tendinopathy is a clinical problem for which treatment shows mixed results and treatment options are limited. Gene expression signatures early in the mechanotransduction pathway can accurately predict risk and correlate with different clinical outcomes. Studies aimed at elucidating the molecular mechanisms of tendinopathy have focused on small cohorts of genes that show an incomplete picture of the degeneration process. This study compared the effect of cyclic strain on gene expression in tendon cells from normal tendon and chronically painful areas of tendinopathy in 3 patients. Methods: We measured a panel of mechanotransduction genes and cytoskeletal tensional balance with and without cyclic strain, which disrupts connective tissue synthetic-degradative equilibrium. Normal and degenerative tendons were obtained from patients undergoing surgery to treat chronic painful tendinopathy. A cyclic strain model was established to measure cytoskeletal tensional homeostasis. Results: Prior to cyclic strain, the normal tendon cells exhibited varying patterns of elevated expression of 7 genes compared with degenerative tendon cells. In response to cyclic strain, gene expression of COL1A1, ITGA6, CTNNA1, and CLEC3B was up-regulated in normal tendon cells. Cyclic strain had no effect on degenerative tendon cells. Cyclic strain exacerbated the inhibition of protein synthesis in both cell types, especially in the degenerative tendon cells. Conclusion: Alterations in the pattern of gene expression are suggestive of a dynamic equilibrium between synthesis and degradation, whereby cell adhesion molecules are predominantly up-regulated to facilitate cellular reorientation in response to their altered functional environment. Clinical Relevance: These data might have future applications, including the identification of markers for early diagnosis, targets for drug design, and indicators for treatment responsiveness and prognosis.
The autonomic balance predicts cardiac responses after the first dose of fingolimod
Authors: Rossi S , Rocchi C , Studer V , Motta C , Lauretti B , Germani G , Macchiarulo G , Marfia GA , Centonze D 
Published: June 2014

Background: Predictive markers of cardiac side effects would be helpful for the stratification and individualized monitoring of multiple sclerosis (MS) patients prescribed with fingolimod. Objective: To test whether the autonomic balance predicts a cardiac response after the first dose of fingolimod. Methods: A total of 55 consecutive relapsing–remitting MS (RRMS) patients underwent ‘head-up tilt’, Valsalva maneuver, deep breathing and handgrip tests before their first dose of fingolimod. The normalized unit of the high frequency (HF) component (HF normalized units; HFnu), reflecting mostly vagal activity; and the low frequency (LF) component (LF normalized units; LFnu) reflecting mostly sympathetic activity, were considered for the analysis of heart rate (HR) variability. The patients’ HR and electrocardiographic parameters ((the interval between P wave and ventricular depolarization (PR); the interval between Q and T waves (QT)) were recorded during 6-hour post-dose monitoring. Results: We found significant correlations between measures of parasympathetic function and fingolimod-induced bradycardia. Subjects with higher Valsalva ratio and HR variation during deep breathing had, in fact, nadir HR ≤ 50 beats/minute (bpm) after the first fingolimod dose. Conversely, significant negative correlations were found between measures of sympathetic function and fingolimod-induced PR interval increase. Subjects with lower LFnu at rest and less increase of blood pressure on the handgrip test showed a PR interval increase > 20 ms after fingolimod. Conclusions: Assessing autonomic control of cardiovascular functions can be useful to predict cardiac effects after the first fingolimod dose.
Checklists, global health and surgery: a five-year checkup of the WHO Surgical Safety checklist programme
Authors: Perry WRG , Kelley ET 
Published: June 2014

The WHO Surgical Safety Checklist has become a high-profile symbol for patient safety efforts in surgery. Since the landmark study by Haynes et al. 1 documenting its success at reducing peri-operative morbidity and mortality in a diversity of settings, others have gone on to show positive effects of the checklist on teamwork, communication, and patient outcomes. The widespread dissemination of the checklist has now allowed for a more global analysis of its role in surgery, and has highlighted two key points: first, the success of the checklist relies on effective and appropriate implementation; and second, the checklist needs to be introduced as part of a broader patient safety movement. Beyond universal challenges with implementation, some questions have been asked about its applicability to low- and middle-income countries. WHO acknowledges that checklist implementation in such settings needs to be well considered; limited availability of resources and less structure around patient safety provides a different context for effective use. Further research needs to be undertaken to better understand what if any modifications need to be made. WHO also hope to better coordinate patient safety efforts with the global surgery movement to maximize the effect of the checklist and improve surgical safety in low- and middle-income countries.
Viscosupplementation During Rehabilitation
Authors: Silvers Holly J. 
Published: June 2014

Context: Viscosupplementation (VS) and physical therapy are both used to treat pain associated with knee osteoarthritis (OA). Evidence Acquisition: PubMed and EMBASE searches were performed to July 2013. Search terms included hyaluronic acid OR hylan, physical therapy OR exercise, AND osteoarthritis. Study Design: Clinical review. Level of Evidence: Level 4. Results: The efficacy and safety of VS in painful knee OA is well documented, as are the appropriate candidates for this intervention. Studies suggest that adding VS to physical therapy and therapeutic exercise may lead to improved pain reduction and increased functionality compared with physical therapy alone. Conclusion: Appropriately selected patients undergoing physical therapy for knee OA may benefit from VS.