bluuebunny/crossref_metadata_2025_split huggingface dataset:
A Pharmacogenetic Predictive Model for Paclitaxel Clearance Based on the DMET Platform
Authors: de Graan Anne-Joy M. , Elens Laure , Smid Marcel , Martens John W. , Sparreboom Alex , Nieuweboer Annemieke J.M. , Friberg Lena E. , Elbouazzaoui Samira , Wiemer Erik A.C. , van der Holt Bronno , Verweij Jaap , van Schaik Ron H.N. , Mathijssen Ron H.J. 
Published: August 2013

Abstract
Purpose: Paclitaxel is used in the treatment of solid tumors and displays high interindividual variation in exposure. Low paclitaxel clearance could lead to increased toxicity during treatment. We present a genetic prediction model identifying patients with low paclitaxel clearance, based on the drug-metabolizing enzyme and transporter (DMET)-platform, capable of detecting 1,936 genetic variants in 225 metabolizing enzyme and drug transporter genes.
Experimental Design: In 270 paclitaxel-treated patients, unbound plasma concentrations were determined and pharmacokinetic parameters were estimated from a previously developed population pharmacokinetic model (NONMEM). Patients were divided into a training- and validation set. Genetic variants determined by the DMET platform were selected from the training set to be included in the prediction model when they were associated with low paclitaxel clearance (1 SD below mean clearance) and subsequently tested in the validation set.
Results: A genetic prediction model including 14 single-nucleotide polymorphisms (SNP) was developed on the training set. In the validation set, this model yielded a sensitivity of 95%, identifying most patients with low paclitaxel clearance correctly. The positive predictive value of the model was only 22%. The model remained associated with low clearance after multivariate analysis, correcting for age, gender, and hemoglobin levels at baseline (P = 0.02).
Conclusions: In this first large-sized application of the DMET-platform for paclitaxel, we identified a 14 SNP model with high sensitivity to identify patients with low paclitaxel clearance. However, due to the low positive predictive value we conclude that genetic variability encoded in the DMET-chip alone does not sufficiently explain paclitaxel clearance. Clin Cancer Res; 19(18); 5210–7. ©2013 AACR.
Prognostic Role of Lemur Tyrosine Kinase-3 Germline Polymorphisms in Adjuvant Gastric Cancer in Japan and the United States
Authors: Wakatsuki Takeru , LaBonte Melissa J. , Bohanes Pierre O. , Zhang Wu , Yang Dongyun , Azuma Mizutomo , Barzi Afsaneh , Ning Yan , Loupakis Fotios , Saadat Siamak , Volz Nico , Stintzing Sebastian , El-Khoueiry Rita , Koizumi Wasaburo , Watanabe Masahiko , Shah Manish , Stebbing Justin , Giamas Georgios , Lenz Heinz-Josef 
Published: August 2013

Abstract
Lemur tyrosine kinase-3 (LMTK3) was recently identified as an estrogen receptor (ER)-α modulator related to endocrine therapy resistance, and its polymorphisms rs9989661 (T&gt;C) T/T genotype and rs8108419 (G&gt;A) G/G or A/G genotype predicted improved outcomes in breast cancer. Because different predominant ER distributions link to breast and gastric cancer and little is known of the prognostic role of LMTK3 in gastric cancer, this study was carried out to clarify the prognostic role of these polymorphisms in gastric cancer. One-hundred and sixty-nine Japanese and 137 U.S. patients with localized gastric adenocarcinoma were enrolled. Genomic DNA was extracted from blood or tissue, and all samples were analyzed by PCR-based direct DNA sequencing. Overall, these polymorphisms were not associated with survival in both cohorts. When gender was considered, in multivariate analysis, harboring rs9989661 T/T genotype was associated with disease-free survival [HR, 4.37; 95% confidence interval (CI), 2.08–9.18; P &lt; 0.0001] and overall survival (OS; HR, 3.69; 95% CI, 1.65–8.24; P = 0.0014) in the Japanese males and time to recurrence (HR, 7.29; 95% CI, 1.07–49.80; P = 0.043) in the U.S. females. Meanwhile, harboring rs8108419 G/G genotype was associated with OS in the Japanese females (HR, 3.04; 95% CI, 1.08–8.56; P = 0.035) and the U.S. males (HR, 3.39; 95% CI, 1.31–8.80; P = 0.012). The prognostic role of these polymorphisms may be negative in gastric cancer. These findings suggest that the estrogen pathway may play a prognostic role in patients with gastric cancer but this may be dependent on the regional differences both in physiology and genetic alterations of gastric cancer. Mol Cancer Ther; 12(10); 2261–72. ©2013 AACR.
Chemotherapy Counteracts Metastatic Dissemination Induced by Antiangiogenic Treatment in Mice
Authors: Rovida Alessandra , Castiglioni Vittoria , Decio Alessandra , Scarlato Valentina , Scanziani Eugenio , Giavazzi Raffaella , Cesca Marta 
Published: August 2013

Abstract
The development of resistance and progressive disease after treatment with angiogenesis inhibitors is becoming a controversial issue. We investigated the experimental conditions that cause multireceptor tyrosine kinase inhibitors (RTKI) to augment metastasis and whether opportune combinations with chemotherapy could counteract this effect. The renal Renca-luc tumor was transplanted orthotopically in the kidney of Balb/c mice, which then were or were not nephrectomized. The Lewis Lung carcinoma (LLC) was transplanted in the tibial muscle of C57/Bl6 mice. Treatment with the RTKI sunitinib started at different stages of tumor progression, mimicking neoadjuvant or adjuvant settings. Combination studies with paclitaxel, doxorubicin, cisplatin, gemcitabine, and topotecan were done on the LLC model, using opportune regimens. In a neoadjuvant setting, sunitinib inhibited Renca-luc tumor growth, prolonging survival despite an increase in lung metastasis; treatment after primary tumor surgery (adjuvant setting) or on established metastasis prolonged survival and decreased metastasis. Sunitinib increased lung metastasis from mice bearing early-stage LLC, but did not affect established metastases (no acceleration) from advanced tumors. Combinations with doxorubicin, topotecan, gemcitabine, but not cisplatin and paclitaxel, counteracted the increase in metastasis from LLC, partly reflecting their antitumor activity. Histology analysis after sunitinib confirmed tumor vascular changes and increased hypoxia. Topotecan at suboptimal daily doses reduced sunitinib-related metastasis, reducing tumor hypoxia. Tyrosine kinase inhibitors, as sunitinib, can have adverse malignant effects mainly in the neoadjuvant setting. The addition of chemotherapy might influence metastasis, depending on each drug mechanism of action and its regimen of administration. Mol Cancer Ther; 12(10); 2237–47. ©2013 AACR.
NY-ESO-1 Expression in Meningioma Suggests a Rationale for New Immunotherapeutic Approaches
Authors: Baia Gilson S. , Caballero Otavia L. , Ho Janelle S.Y. , Zhao Qi , Cohen Tzeela , Binder Zev A. , Salmasi Vafi , Gallia Gary L. , Quinones-Hinojosa Alfredo , Olivi Alessandro , Brem Henry , Burger Peter , Strausberg Robert L. , Simpson Andrew J.G. , Eberhart Charles G. , Riggins Gregory J. 
Published: August 2013

Abstract
Meningiomas are the most common primary intracranial tumors. Surgical resection remains the treatment of choice for these tumors. However, a significant number of tumors are not surgically accessible, recur, or become malignant, necessitating the repetition of surgery and sometimes radiation. Chemotherapy is rarely used and is generally not recognized as an effective treatment. Cancer/testis (CT) genes represent a unique class of genes, which are expressed by germ cells, normally silenced in somatic cells, but activated in various cancers. CT proteins can elicit spontaneous immune responses in patients with cancer and this feature makes them attractive targets for immunotherapy-based approaches. We analyzed mRNA expression of 37 testis-restricted CT genes in a discovery set of 18 meningiomas by reverse transcription PCR. The overall frequency of expression of CT genes ranged from 5.6% to 27.8%. The most frequently expressed was NY-ESO-1, in 5 patients (27.8%). We subsequently analyzed NY-ESO-1 protein expression in a larger set of meningiomas by immunohistochemistry and found expression in 108 of 110 cases. In some cases, NY-ESO-1 expression was diffused and homogenous, but in most instances it was heterogeneous. Importantly, NY-ESO-1 expression was positively correlated with higher grade and patients presenting with higher levels of NY-ESO-1 staining had significantly worse disease-free and overall survival. We have also shown that NY-ESO-1 expression may lead to humoral immune response in patients with meningioma. Considering the limited treatment options for patients with meningioma, the potential of NY-ESO-1–based immunotherapy should be explored. Cancer Immunol Res; 1(5); 296–302. ©2013 AACR.
Chronic Lymphocytic Leukemia Monitoring with a Lamprey Idiotope-Specific Antibody
Authors: Nakahara Hirotomo , Herrin Brantley R. , Alder Matthew N. , Catera Rosa , Yan Xiao-Jie , Chiorazzi Nicholas , Cooper Max D. 
Published: August 2013

AbstractFor antigen recognition, lampreys use leucine-rich repeats (LRR) instead of immunoglobulin V-(D)-J domains to generate variable lymphocyte receptors (VLR) of three types: VLRA, VLRB, and VLRC. VLRB-bearing lymphocytes respond to immunization with proliferation and differentiation into plasmacytes that secrete multivalent VLRB antibodies. Here, we immunized lampreys with B cells from patients with chronic lymphocytic leukemia (CLL) to generate recombinant monoclonal VLRB antibodies, one of which, VLR39, was specific for the donor CLL cells. The target epitope of VLR39 was shown to be the complementarity determining region 3 (CDR3) of the heavy chain variable region (VH) of the B-cell receptor. Using this antibody to monitor the CLL donor after chemoimmunotherapy-induced remission, we detected VLR39+ B cells in the patient 51 months later, before significant increase in lymphocyte count or CD5+ B cells. This indication of reemergence of the leukemic clone was verified by VH sequencing. Lamprey antibodies can exhibit exquisite specificity for a protein epitope, a CLL signature VH CDR3 sequence in this case, and offer a rapid strategy for generating anti-idiotype antibodies for early detection of leukemia recurrence. Cancer Immunol Res; 1(4); 223–8. ©2013 AACR.
Age- and Sex-Based Reference Limits and Clinical Correlates of Myocardial Strain and Synchrony
Authors: Cheng Susan , Larson Martin G. , McCabe Elizabeth L. , Osypiuk Ewa , Lehman Birgitta T. , Stanchev Plamen , Aragam Jayashri , Benjamin Emelia J. , Solomon Scott D. , Vasan Ramachandran S. 
Published: August 2013

Background—
There is rapidly growing interest in applying measures of myocardial strain and synchrony in clinical investigations and in practice; data are limited regarding their reference ranges in healthy individuals.

Methods and Results—

We performed speckle-tracking–based echocardiographic measures of left ventricular myocardial strain and synchrony in healthy adults (n=739, mean age 63 years, 64% women) without cardiovascular disease. Reference values were estimated using quantile regression. Age- and sex-based upper (97.5th quantile) limits were: −14.4% to −17.1% (women) and −14.4 to −15.2% (men) for longitudinal strain; −22.3% to −24.7% (women) and −17.9% to −23.7% (men) for circumferential strain; 121 to 165 ms (women) and 143 to 230 ms (men) for longitudinal segmental synchrony (SD of regional time-to-peak strains); and 200 to 222 ms (women) and 216 to 303 ms (men) for transverse segmental synchrony. In multivariable analyses, women had ≈1.7% greater longitudinal strain, ≈2.2% greater transverse strain, and ≈3.2% greater circumferential strain (
P
<0.0001 for all) compared with men. Older age and higher diastolic blood pressure, even within the normal range, were associated with worse transverse segmental synchrony (
P
<0.001). Overall, covariates contributed to ≤12% of the variation in myocardial strain or synchrony in this healthy sample.

Conclusions—
We estimated age- and sex-specific reference limits for measures of left ventricular strain and synchrony in a healthy community-based sample, wherein clinical covariates contributed to only a modest proportion of the variation. These data may facilitate the interpretation of left ventricular strain-based measures obtained in future clinical research and practice.
Changes in Ambulance Calls After Implementation of a Smoke-Free Law and Its Extension to Casinos
Authors: Glantz Stanton A. , Gibbs Erin 
Published: August 2013

Background—
Casinos are often exempted from legislation mandating smoke-free environments, potentially putting employees and patrons at risk for adverse events triggered by secondhand smoke exposure.

Methods and Results—

We used an interrupted time series analysis of ambulance calls not originating and originating from casinos in Gilpin County, Colorado, a rural Colorado county with a large casino presence, from January 2000 through December 2012 to determine whether there was a change in ambulance calls originating from casinos when a state smoke-free law was extended to include them. Initial implementation of the smoke-free law (which exempted casinos) was followed by a significant 22.8% drop in ambulance calls (incidence rate ratio, 0.772; 95% confidence interval, 0.685–0.871;
P
<0.001) from locations other than casinos but no significant change in calls from casinos (
P
>0.9). The law requiring smoke-free casinos taking effect was followed by a 19.1% (incidence rate ratio, 0.809; 95% confidence interval, 0.724–0.905;
P
<0.001) drop in ambulance calls from casinos but no change in calls originating outside casinos (
P
>0.1).

Conclusions—
The observation that ambulance calls not coming from casinos dropped when the smoke-free law was initially implemented (excluding casinos) with no change in calls from casinos, followed by a comparable drop in calls originating from casinos (but not calls from elsewhere) when the law was extended to casinos, suggests that the important effects of secondhand smoke exposure occur acutely. These results also suggest that exempting casinos from smoke-free laws means that more people will suffer medical emergencies.
A Time-Series Method to Identify and Correct Range Sidelobes in Meteorological Radar Data
Authors: Westbrook C. D. , Nicol J. C. 
Published: August 2013

Abstract
The use of pulse compression techniques to improve the sensitivity of meteorological radars has become increasingly common in recent years. An unavoidable side effect of such techniques is the formation of “range sidelobes,” leading to the spreading of information across several range gates. These artifacts are particularly troublesome in regions where there is a sharp gradient in the power backscattered to the antenna as a function of range.
In this article a simple method for identifying and correcting range sidelobe artifacts is presented. The method makes use of the fact that meteorological targets produce an echo that fluctuates at random, and that this echo, like a fingerprint, is unique to each range gate. By cross correlating the echo time series from pairs of gates, therefore, information that has spread from one gate into another can be identified, and hence regions of contamination can be flagged. In addition it is shown that the correlation coefficients contain quantitative information about the fraction of power leaked from one range gate to another, and a simple algorithm to correct the corrupted reflectivity profile is proposed.
Development of a Nationwide, Low-Level Wind Shear Mosaic in France
Authors: Augros Clotilde , Tabary Pierre , Anquez Adrien , Moisselin Jean-Marc , Brovelli Pascal , Bousquet Olivier 
Published: August 2013

Abstract
An algorithm for the detection of horizontal wind shear at low levels was developed. The algorithm makes use of data collected by all radars from the Application Radar à la Météorologie Infra-Synoptique (ARAMIS) operational network, in order to build a complete mosaic of wind shear over metropolitan France. The product provides an estimation of the maximum horizontal wind shear detected in the low levels, between 0 and 2 km AGL. Examination of the wind shear mosaic for different cases shows that the product is able to retrieve small-scale wind shear signatures that can be linked to either convergence lines ahead of convective cells, which are indicative of gust fronts, or strong convergence areas inside intense cells. A statistical evaluation of the wind shear mosaic was performed, by comparing horizontal wind shear observed inside the area defined by convective objects with wind gusts recorded along their trajectory by weather stations. A link between those different observations was clearly established.
Therefore, the use of wind shear for wind gust prediction was tested in combination with other parameters: an estimation of the energetic potential of density currents, the cell surface with reflectivity over 51 dBZ, relative helicity, and cell propagation speed. Different wind gust warning rules were tested on 468 convection nowcasting objects (CONOs). The results clearly highlighted the benefits of using wind shear for wind gust estimation, and also demonstrated the improvement in forecasting skill when combining different parameters. The wind shear mosaic will be produced operationally before the end of 2013 and will be used to improve wind gust warnings provided to end users.
A novel ATP1A2 gene mutation in familial hemiplegic migraine and epilepsy
Authors: Costa Cinzia , Prontera Paolo , Sarchielli Paola , Tonelli Alessandra , Bassi Maria Teresa , Cupini Letizia Maria , Caproni Stefano , Siliquini Sabrina , Donti Emilio , Calabresi Paolo 
Published: August 2013

Background Familial hemiplegic migraine (FHM) is a rare autosomal dominant migraine subtype, characterized by fully reversible motor weakness as a specific symptom of aura. Mutations in the ion transportation coding genes CACNA1A, ATP1A2 and SCN1A are responsible for the FHM phenotype. Moreover, some mutations in ATP1A2 or SCN1A also may lead to epilepsy. Case Here we report on a three-generation family with five patients having a novel ATP1A2 mutation on exon 19, causing guanine-to-adenine substitution (c.2620G>A, p.Gly874Ser) that co-segregated in the five living relatives with migraine, four of whom had hemiplegic migraine. Moreover, three patients presented with epilepsy, one of whom had generalized epilepsy with febrile seizures plus (GEFS+). Conclusions The present study provides further evidence on the involvement of ATP1A2 mutations in both migraine and epilepsy, underlying the relevance of genetic analysis in families with a comorbidity of both disorders.
Lee John Cunliffe (on his own behalf, as administrator of the estate of his late wife and on behalf of his 3 children) – v- West Hertfordshire Hospitals NHS Trust
Authors: Rumley Paul 
Published: August 2013

The Claimant was widowed when his wife died, aged 33, as a result of an admitted negligent failure to treat her skin cancer. The Claimant was left to bring up three very young children on his own. The case was settled on the basis that but for the admitted negligence the Claimant's wife would have been cured of her cancer, and have had a near normal life-expectancy. The settlement included sums to compensate for the reduction in income which the Claimant's late wife would have brought into the family, and also the extra costs of employing childcare for the children, plus £70,000 for the Claimant's late wife's pain and suffering prior to her death as a result of the admitted negligence.
Sumatriptan/naproxen sodium combination versus its components administered concomitantly for the acute treatment of migraine: a pragmatic, crossover, open-label outcomes study
Authors: Landy Stephen , Hoagland Rebecca , Hoagland Dakota , Saiers Jane , Reuss Gena 
Published: August 2013

Objective: Efficacy and tolerability profiles of Treximet [sumatriptan/naproxen sodium combination tablet (SNC)] have been established in clinical trials but have to date been virtually unstudied in pragmatic research. The primary objective of this study was to compare the overall satisfaction of SNC to its monotherapy components, S/N [one 100 mg Imitrex tablet (S) and two Aleve (naproxen sodium) 220 mg tablets, total dose 440 mg (N)] administered concomitantly using the Patient Perception of Migraine Questionnaire –Revised (PPMQ-R). Methods: Adults with migraine ( n = 50) without ‘medication overuse headache’ were treated for up to 18 migraine attacks per 3-month study period with study medication; SNC during one study period and S/N during the other study period. For all endpoints, differences between treatments were compared with paired t tests. Results: The percentage of patients reporting satisfied/very satisfied for Overall Satisfaction of SNC versus S/N (primary endpoint) was 85% versus 72% respectively ( p = 0.054). For Overall Effectiveness, the results were 82% for SNC versus 73% for S/N ( p = 0.159); and for Overall Side Effects the results were 86% for SNC versus 69% for S/N ( p = 0.005). Mean PPMQ-R scores reflect greater satisfaction with SNC than S/N for Total score and for each of four subscales. The difference between SNC and S/N was significant for the Ease of Use subscale ( p = 0.004) and met the criterion of being clinically meaningful for both the Total score and Ease of Use. SNC did not differ from S/N with respect to pain-free response 2 h post dose, pain relief 2 h post dose, sustained 24 h pain-free response, or sustained 24 h pain relief. Conclusion: Although the primary endpoint only just failed, the results of this pragmatic outcomes study demonstrate SNC to have benefits over its concomitantly administered components in the acute treatment of migraine.
A reliable method for intracranial electrode implantation and chronic electrical stimulation in the mouse brain
Authors: Jeffrey Melanie , Lang Min , Gane Jonathan , Wu Chiping , Burnham W McIntyre , Zhang Liang 
Published: August 2013

Abstract

Background
Electrical stimulation of brain structures has been widely used in rodent models for kindling or modeling deep brain stimulation used clinically. This requires surgical implantation of intracranial electrodes and subsequent chronic stimulation in individual animals for several weeks. Anchoring screws and dental acrylic have long been used to secure implanted intracranial electrodes in rats. However, such an approach is limited when carried out in mouse models as the thin mouse skull may not be strong enough to accommodate the anchoring screws. We describe here a screw-free, glue-based method for implanting bipolar stimulating electrodes in the mouse brain and validate this method in a mouse model of hippocampal electrical kindling.

Methods
Male C57 black mice (initial ages of 6–8 months) were used in the present experiments. Bipolar electrodes were implanted bilaterally in the hippocampal CA3 area for electrical stimulation and electroencephalographic recordings. The electrodes were secured onto the skull via glue and dental acrylic but without anchoring screws. A daily stimulation protocol was used to induce electrographic discharges and motor seizures. The locations of implanted electrodes were verified by hippocampal electrographic activities and later histological assessments.

Results
Using the glue-based implantation method, we implanted bilateral bipolar electrodes in 25 mice. Electrographic discharges and motor seizures were successfully induced via hippocampal electrical kindling. Importantly, no animal encountered infection in the implanted area or a loss of implanted electrodes after 4–6 months of repetitive stimulation/recording.

Conclusion
We suggest that the glue-based, screw-free method is reliable for chronic brain stimulation and high-quality electroencephalographic recordings in mice. The technical aspects described this study may help future studies in mouse models.