bluuebunny/crossref_metadata_2025_split huggingface dataset:
Phenotyping of Uracil and 5-Fluorouracil Metabolism Using LC-MS/MS for Prevention of Toxicity and Dose Adjustment of Fluoropyrimidines
Authors: Tafzi Naima , Woillard Jean-Baptiste , Fleytoux Aurélie , Picard Nicolas , Marquet Pierre 
Published: May 2020

Background:
Plasma concentrations of fluoropyrimidine exhibit a wide interindividual variability that depends mainly on the activity of dihydropyrimidine dehydrogenase, its major catabolic enzyme. Patients with low dihydropyrimidine dehydrogenase activity are at an increased risk of overexposure and often severe, sometimes lethal, toxicity. This study aimed to develop a quick and easy bioanalytical method for the simultaneous determination of endogenous uracil (U), exogenous 5-fluorouracil (5-FU), and their respective 5,6-dihydro-metabolite in human plasma using Liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS).

Methods:
After protein precipitation, the compounds were purified using liquid–liquid extraction. Chromatographic separation was conducted using a Cortecs T3 column and binary gradient elution. Detection and quantification were performed in the positive electrospray ionization and selected the reaction monitoring mode after 2 transitions per analyte and 1 per internal standard. The data obtained with this technique were retrospectively gathered for uracil metabolism phenotyping before fluoropyrimidine treatment (as enforced by national regulations) in a large group of 526 patients.

Results:
The analytical response was linear (r > 0.99 for all compounds), and it yielded a lower limit of quantification of 2 ng·mL−1 for U and UH2 as well as 4 ng·mL−1 for 5-FU and 5,6-dihydro-5-FUH2. The median uracil concentration in 526 patients was 10.6 mcg/L, with extreme values of 3.9 and 81.6 mcg/L; 78 patients (15%) had uracil concentration ≥16 mcg/L, that is, above the threshold of decreased enzyme activity and initial dose reduction.
Usage of Tacrolimus and Mycophenolic Acid During Conception, Pregnancy, and Lactation, and Its Implications for Therapeutic Drug Monitoring: A Systematic Critical Review
Authors: Le Hoang Lan , Francke Marith I. , Andrews Louise M. , de Winter Brenda C. M. , van Gelder Teun , Hesselink Dennis A. 
Published: May 2020

Background:Conception, pregnancy, and lactation following solid organ transplantation require appropriate management. The most frequently used immunosuppressive drug combination after solid organ transplantation consists of tacrolimus (Tac) plus mycophenolic acid (MPA). Here, the effects of Tac and MPA on fertility, pregnancy, and lactation are systematically reviewed, and their implications for therapeutic drug monitoring (TDM) are discussed.Methods:A systematic literature search was performed (August 19, 2019) using Ovid MEDLINE, EMBASE, the Cochrane Central Register of controlled trials, Google Scholar, and Web of Science, and 102 studies were included. Another 60 were included from the reference list of the published articles.Results:As MPA is teratogenic, women who are trying to conceive are strongly recommended to switch from MPA to azathioprine. MPA treatment in men during conception seems to have no adverse effect on pregnancy outcomes. Nevertheless, in 2015, the drug label was updated with additional risk minimization measures in a pregnancy prevention program. Data on MPA pharmacokinetics during pregnancy and lactation are limited. Tac treatment during conception, pregnancy, and lactation seems to be safe in terms of the health of the mother, (unborn) child, and allograft. However, Tac may increase the risk of hypertension, preeclampsia, preterm birth, and low birth weight. Infants will ingest very small amounts of Tac via breast milk from mothers treated with Tac. However, no adverse outcomes have been reported in children exposed to Tac during lactation. During pregnancy, changes in Tac pharmacokinetics result in increased unbound to whole-blood Tac concentration ratio. To maintain Tac concentrations within the target range, increased Tac dose and intensified TDM may be required. However, it is unclear if dose adjustments during pregnancy are necessary, considering the higher concentration of (active) unbound Tac.Conclusions:Tac treatment during conception, pregnancy and lactation seems to be relatively safe. Due to pharmacokinetic changes during pregnancy, a higher Tac dose might be indicated to maintain target concentrations. However, more evidence is needed to make recommendations on both Tac dose adjustments and alternative matrices than whole-blood for TDM of Tac during pregnancy. MPA treatment in men during conception seems to have no adverse effect on pregnancy outcomes, whereas MPA use in women during conception and pregnancy is strongly discouraged.
High-Performance Liquid Chromatography for Therapeutic Drug Monitoring of Serum Lenvatinib
Authors: Watanabe Yusuke , Doki Kosuke , Sekine Ikuo , Hara Hisato , Homma Masato 
Published: May 2020

Background:
Therapeutic drug monitoring (TDM) and dose adjustment of lenvatinib may be beneficial in the treatment of radioiodine-refractory thyroid cancer, by maximizing antitumor effects and minimizing adverse drug reactions. The aim of this study was, therefore, to develop and validate a high-performance liquid chromatography method using an ultraviolet detection system for routine serum lenvatinib detection in patients with thyroid cancer.

Methods:
Serum specimens, spiked with an internal standard, were treated by a solid-phase extraction through an octadecylsilyl silica cartridge. Lenvatinib and internal standard were concomitantly separated from serum using a conventional octadecylsilyl silica column through isocratic elution, using a mobile phase consisting of 0.02 mol/L sodium phosphate (pH 6.7) and acetonitrile (50/50, vol/vol) at a flow rate of 1.0 mL/min. The detection wavelength was set at 244 nm. Serum samples from 5 patients were used for clinical validation of the method.

Results:
The calibration curve for lenvatinib was linear (Pearson correlation coefficient, r = 0.9998) over the concentration range of 6.25–400 ng/mL, with a lower limit of quantification of 6.25 ng/mL. Extraction recoveries for lenvatinib were 97% or more, with coefficients of variation less than 2.2%. The coefficients of variation for intraday and interday assays were less than 4.7% and 6.0%, respectively.

Conclusions:
This sensitive high-performance liquid chromatography method can be used for lenvatinib therapeutic drug monitoring when liquid chromatography–tandem mass spectrometry facilities are unavailable.
Evaluation of Imatinib Concentrations in Samples Submitted for BCR-ABL1 or Imatinib Testing—Evidence to Support Therapeutic Drug Monitoring for Dose Optimization?
Authors: Smy Laura , Sadler Aaron J. , McMillin Gwendolyn A. 
Published: May 2020

Background:
Imatinib is one of the first-line therapies for chronic myeloid leukemia. Achieving a major molecular response early in treatment, as indicated by a BCR-ABL1 major international scale result of ≤0.1% within 6 months, is associated with better patient outcomes and is statistically associated with a trough imatinib concentration of approximately 1000 ng/mL. Adherence to therapy, drug resistance, drug–drug interactions, and pharmacokinetic/pharmacodynamic factors may hinder attaining this target. Therapeutic drug monitoring of imatinib is not currently standard-of-care, but may help to evaluate adherence and optimize treatment of patients with chronic myeloid leukemia. This study aimed to evaluate imatinib concentrations in real-world patient plasma samples to identify the proportion of imatinib-treated patients who achieved the therapeutic target of 1000 ng/mL.

Methods:
This was a retrospective, observational study that measured imatinib in residual plasma samples used for BCR-ABL1 tests (n = 1022) and analyzed clinician-ordered imatinib tests for therapeutic drug monitoring (n = 116). Imatinib was measured by competitive immunoassay. The frequency of imatinib concentrations achieving the therapeutic target was determined and correlated with BCR-ABL1 major international scale, age, and sex.

Results:
Seventy-two percent of patients tested for BCR-ABL1 may not have been prescribed or were not adherent to imatinib therapy. In the 29% of patients who did not achieve major molecular response, but had quantifiable imatinib concentrations, the therapeutic concentration was not met. For clinician-ordered imatinib tests, 45% of samples did not exceed the therapeutic target and 4% had potentially toxic plasma concentrations (>3000 ng/mL).

Conclusions:
Therapeutic drug monitoring for imatinib may assist clinicians in the identification of patients who may not be adherent to therapy, display variable pharmacokinetics or pharmacodynamics, or may be experiencing toxicity or treatment failure.
Chronic exercise mediates epigenetic suppression of L-type Ca2+ channel and BKCa channel in mesenteric arteries of hypertensive rats
Authors: Zhang Yanyan , Chen Yu , Xu Zhaoxia , Wu Ying , Zhang Yimin , Shi Lijun 
Published: May 2020

Background:
Regular exercise is a lifestyle intervention for controlling hypertension and has an improving effect on vascular function. Voltage-gated L-type Ca2+ (LTCC) and large-conductance Ca2+-activated K+ (BKCa) channels are two principal mediators of vascular smooth muscle cell contractility and arterial tone. The present study tested the hypothesis that DNA methylation dynamics plays a key role in exercise-induced reprogramming and downregulation of LTCC and BKCa channel in mesenteric arteries from spontaneously hypertensive rats (SHRs).

Methods:
SHRs and Wistar–Kyoto (WKY) rats were subjected to exercise training or kept sedentary, and vascular molecular and functional properties were evaluated.

Results:
Exercise inhibited hypertension-induced upregulation of LTCC and BKCa channel function in mesenteric arteries by repressing LTCC α1c and BKCa β1 subunit expression. In accordance, exercise triggered hypermethylation of α1c and β1 gene in SHR, with concomitant decreasing TET1, increasing DNMT1 and DNMT3b expression in mesenteric arteries, as well as altering peripheral α-KG and S-adenosylmethionine/ S-adenosylhomocysteine ratio. Acting synergistically, these exercise-induced functional and molecular amelioration could allow for attenuating hypertension-induced elevation in arterial blood pressure.

Conclusion:
Our results indicate that exercise suppresses LTCC and BKCa channel function via hypermethylation of α1c and β1 subunits, which contributes to the restoration of mesenteric arterial function and vasodilation during hypertension.
Effect of 3,3’-Diindolylmethane on Pulmonary Injury Following Thoracic Irradiation in CBA Mice
Authors: Laiakis Evagelia C. , McCart Elizabeth A. , Deziel Annabella , Rittase W. Bradley , Bouten Roxane M. , Jha Jyoti , Wilkins W. Louis , Day Regina M. , Fornace Albert J. 
Published: May 2020

Abstract
The molecule 3,3’-diindolylmethane (DIM) is small, a major bioactive metabolite of indole-3 carbinol (13C), and a phytochemical compound from cruciferous vegetables released upon exposure to the gut acid environment. DIM is a proposed anti-cancer agent and was previously demonstrated to prevent radiation damage in the bone marrow and the gastrointestinal tract. Here we investigated the effect of DIM on radiation-induced injury to the lung in a murine model through untargeted metabolomics and gene expression studies of select genes. CBA mice were exposed to thoracic irradiation (17.5 Gy). Mice were treated with vehicle or DIM (250 mg kg−1, subcutaneous injection) on days −1 pre-irradiation through +14 post-irradiation. DIM induced a significant improvement in survival by day 150 post-irradiation. Fibrosis-related gene expression and metabolomics were examined using lung tissue from days 15, 45, 60, 90, and 120 post-irradiation. Our qRT-PCR experiments showed that DIM treatment reduced radiation-induced late expression of collagen Iα and the cell cycle checkpoint proteins p21/waf1 (CDKN1A) and p16ink (CDKN2A). Metabolomic studies of lung tissue demonstrated a significant dampening of radiation-induced changes following DIM treatment. Metabolites associated with pro-inflammatory responses and increased oxidative stress, such as fatty acids, were suppressed by DIM treatment compared to irradiated samples. Together these data suggest that DIM reduces radiation-induced sequelae in the lung.
OPTICAL COHERENCE TOMOGRAPHY BIOMARKERS FOR REDUCTION OF DRUSENOID PIGMENT EPITHELIUM DETACHMENT
Authors: Kim Mirinae , Lee Yeo Jin , Park Wookyung , Park Young-Gun , Park Young-Hoon 
Published: May 2020

Purpose:
To identify the optical coherence tomography biomarkers that can collectively predict the probability of collapse or reduction of drusenoid pigment epithelium detachment (PED).

Methods:
This consecutive observational case series reviewed the clinical data of 24 eyes with non-neovascular drusenoid PED. Among the study population, 17 eyes showed collapse or reduction of drusenoid PED. The mean follow-up duration was 44.8 ± 24.6 months. Optical coherence tomography–derived parameters were analyzed at baseline, at the last available visit before reduction of PED, at the first available visit after reduction of PED, and at the final visit.

Results:
The mean subfoveal choroidal thickness showed a significant decrease after PED reduction and at the most recent visit (P = 0.015). Migration of retinal pigment epithelium cells was detected in 15 (88.2%) after PED reduction; however, there was no significance in the frequency of migration of retinal pigment epithelium cells at each time point (P = 0.392). Non-neovascular subretinal fluid was detected in 7 (41.2%) before PED reduction, 2 (11.8%) after PED reduction, and 2 (11.8%) at the final visit. Interestingly, subretinal fluid appeared more frequently just before reduction of PED (P = 0.029).

Conclusion:
We found evidence of non-neovascular subretinal fluid and choroidal thinning before reduction in PED. This finding might be useful for detection and prediction of the progression of drusenoid PED.
Intraocular lens formula comparison in axial hyperopia with a high-power intraocular lens of 30 or more diopters
Authors: Kane Jack X. , Melles Ronald B. 
Published: May 2020

Purpose:
To compare the accuracy of intraocular lens (IOL) power calculation formula predictions (Barrett Universal II, Emmetropia Verifying Optical [EVO] 2.0, Haigis, Hill-RBF 2.0, Holladay 1, Holladay 2, Hoffer Q, Kane, Olsen, and SRK/T) when using the Alcon SA60AT IOL of 30 or greater diopter (D) power.

Setting:
Kaiser Permanente, California, USA.

Design:
Multicenter retrospective consecutive case series.

Methods:
Data from patients having uneventful cataract surgery with insertion of a ≥30 D SA60AT IOL and preoperative LENSTAR 900 biometry were included. A single eye per qualifying patient was randomly selected for inclusion in the analysis. Lens constants were optimized using a large dataset of the same IOL model including the full range of axial lengths. The optimized lens constants were then used to calculate the predicted refraction for each formula, which was compared with the actual refractive outcome to give the prediction errors.

Results:
Included in the study were 182 eyes of 182 patients. From highest to lowest, the percentage of eyes with a prediction error within ±0.50 D was the Kane (58.8%), EVO 2.0 (57.7%), Haigis (55.5%), Holladay 2 (54.9%), Olsen (53.3%), Holladay 1 (50.5%), Hill-RBF 2.0 (43.9%), SRK/T (42.9%), Barrett Universal II (36.8%), and Hoffer Q (35.7%) formulas. The Kane formula had a statistically significant lower mean absolute prediction error compared with all formulas (P < .05) except the EVO 2.0 formula.

Conclusions:
The Kane formula had the lowest prediction error of the formulas studied, which was statistically significant compared with all formulas except the EVO 2.0 formula.
Prediction accuracy of IOL calculation formulas using the ASCRS online calculator for a diffractive extended depth-of-focus IOL after myopic laser in situ keratomileusis
Authors: Lwowski Christoph , Pawlowicz Katarzyna , Hinzelmann Lisa , Adas Mahmoud , Kohnen Thomas 
Published: May 2020

Background:
To evaluate IOL calculation formulas provided by an online calculation tool from the ASCRS for an extended depth-of-focus (EDOF) IOL after previous myopic laser in situ keratomileusis (LASIK).

Setting:
Department of Ophthalmology, Goethe University, Frankfurt, Germany.

Design:
Retrospective consecutive case series.

Methods:
Patients who underwent cataract surgery or refractive lens exchange with implantation of a diffractive EDOF IOL and who had a history of myopic LASIK were included. Biometry, refractive data regarding the LASIK procedure, target refraction, and postoperative refraction were collected. Mean prediction error, mean absolute error (MAE), and the number of eyes within ±0.5 diopters (D), ±1.0 D, ±1.5 D, and ±2.0 D were calculated with the following formulas from the ASCRS calculator: Shammas, Haigis-L, Barrett True-K, Barrett No History, Masket, modified Masket, and the average of all formulas (average).

Results:
Twenty-five eyes matched the inclusion criteria. Mean spherical equivalent (SE) was −0.81 ± 0.69 D; the mean pre-LASIK SE was −6.4 ± 3.63 D. The formulas ranked by MAE were Shammas (0.7 ± 0.75 D), Haigis-L (0.72 ± 0.57 D), average (0.79 ± 0.8 D), Barrett True-K (1.14 ± 0.89 D), modified Masket (1.4 ± 1.15 D), Barrett No History (1.45 ± 0.7D ), and Masket (1.64 ± 1.27 D). The formulas with the most eyes within ±0.5 D were average (52%), Shammas (48%), and Haigis-L (44%) formulas.

Conclusions:
Calculation of IOLs in eyes with a history of refractive surgery remains a challenge. In this study, the Shammas and Haigis-L formulas performed best regarding MAE and percentage of eyes within ±0.5 D; however, the average of all formulas delivered reasonable results.
Brain gray matter abnormalities in osteoarthritis pain: a cross-sectional evaluation
Authors: Barroso Joana , Vigotsky Andrew D. , Branco Paulo , Reis Ana Mafalda , Schnitzer Thomas J. , Galhardo Vasco , Apkarian A. Vania 
Published: May 2020

AbstractThe interaction between osteoarthritis (OA) pain and brain properties remains minimally understood, although anatomical and functional neuroimaging studies suggest that OA, similar to other chronic pain conditions, may impact as well as partly be determined by brain properties. Here, we studied brain gray matter (GM) properties in OA patients scheduled to undergo total joint replacement surgery. We tested the hypothesis that brain regional GM volume is distinct between hip OA (HOA) and knee OA (KOA) patients, relative to healthy controls and moreover, that these properties are related to OA pain. Voxel-based morphometry group contrasts showed lower anterior cingulate GM volume only in HOA. When we reoriented the brains (flipped) to examine the hemisphere contralateral to OA pain, precentral GM volume was lower in KOA and HOA, and 5 additional brain regions showed distortions between groups. These GM changes, however, did not reflect clinical parameters. Next, we subdivided the brain into larger regions, approximating Brodmann areas, and performed univariable and machine learning-based multivariable contrasts. The univariable analyses approximated voxel-based morphometry results. Our multivariable model distinguished between KOA and controls, was validated in a KOA hold-out sample, and generalized to HOA. The multivariable model in KOA, but not HOA, was related to neuropathic OA pain. These results were mapped into term space (using Neurosynth), providing a meta-analytic summary of brain anatomical distortions in OA. Our results indicate more subtle cortical anatomical differences in OA than previously reported and also emphasize the interaction between OA pain, namely its neuropathic component, and OA brain anatomy.
Neural correlates of conditioned pain responses in fibromyalgia subjects indicate preferential formation of new pain associations rather than extinction of irrelevant ones
Authors: Sandström Angelica , Ellerbrock Isabel , Tour Jeanette , Kadetoff Diana , Jensen Karin Birgitta , Kosek Eva 
Published: May 2020

Abstract
Behavioral studies have demonstrated aberrant safety processing in fibromyalgia subjects (FMSs) and suggested that patients accumulate new potential pain-related threats more effectively than extinguishing no longer relevant ones. The aim of the current study was to investigate the neural correlates of conditioned pain responses and their relationship with emotional distress in FMS (n = 67) and healthy controls (HCs, n = 34). Using functional magnetic resonance imaging, we traced conditioned pain responses to an identical moderately painful pressure (P30) depending on whether it was following a green (P30green) or a red (P30red) cue. The cues were previously associated with individually calibrated painful pressure stimuli of low and high intensity, corresponding to visual analogue scale 10 and 50 mm, respectively. Fibromyalgia subjects displayed increased P30green ratings over time, while P30red ratings remained elevated. Healthy controls adapted all pain ratings to resemble moderate pain. Fibromyalgia subjects exhibited increased activation for [P30green>P30red] in M1/anterior insula, whereas HC showed increased S2/mid-insula response to [P30red>P30green]. High pain catastrophizing scale (PCS) ratings in fibromyalgia (FM) covaried with heightened brain activation for [P30green] × PCS in left dorsolateral prefrontal cortex and medial prefrontal cortex/orbitofrontal cortex; and [P30green>P30red] × PCS in dorsal anterior cingulate cortex/mid-cingulate cortex; superior temporal pole, extending to anterior insula; bilateral thalamus; and posterior insula. Psychophysiological interaction analysis for FM [P30green>P30red] × PCS revealed a dissociation in functional connectivity between thalamus and bilateral inferior parietal lobe. In alignment with behavioral data, FMS displayed a cerebral response suggesting preferential formation of new pain-related associations while simultaneously maintaining no longer relevant ones. The opposite was observed in HC. Increased responses to pain-related threats in FM may contribute to dysfunctional pain-protective behaviors and disability.
Assigning transcriptomic class in the trigeminal ganglion using multiplex in situ hybridization and machine learning
Authors: von Buchholtz Lars J. , Lam Ruby M. , Emrick Joshua J. , Chesler Alexander T. , Ryba Nicholas J.P. 
Published: May 2020

Abstract
Single cell sequencing has provided unprecedented information about the transcriptomic diversity of somatosensory systems. Here, we describe a simple and versatile in situ hybridization (ISH)-based approach for mapping this information back to the tissue. We illustrate the power of this approach by demonstrating that ISH localization with just 8 probes is sufficient to distinguish all major classes of neurons in sections of the trigeminal ganglion. To further simplify the approach and make transcriptomic class assignment and cell segmentation automatic, we developed a machine learning approach for analyzing images from multiprobe ISH experiments. We demonstrate the power of in situ class assignment by examining the expression patterns of voltage-gated sodium channels that play roles in distinct somatosensory processes and pain. Specifically, this analysis resolves intrinsic problems with single cell sequencing related to the sparseness of data leading to ambiguity about gene expression patterns. We also used the multiplex in situ approach to study the projection fields of the different neuronal classes. Our results demonstrate that the surface of the eye and meninges are targeted by broad arrays of neural classes despite their very different sensory properties but exhibit idiotypic patterns of innervation at a quantitative level. Very surprisingly, itch-related neurons extensively innervated the meninges, indicating that these transcriptomic cell classes are not simply labeled lines for triggering itch. Together, these results substantiate the importance of a sensory neuron's peripheral and central connections as well as its transcriptomic class in determining its role in sensation.