bluuebunny/crossref_metadata_2025 huggingface dataset:
Effects of Baricitinib on Lipid, Apolipoprotein, and Lipoprotein Particle Profiles in a Phase IIb Study of Patients With Active Rheumatoid Arthritis
Authors: Kremer Joel M. , Genovese Mark C. , Keystone Edward , Taylor Peter C. , Zuckerman Steven H. , Ruotolo Giacomo , Schlichting Douglas E. , Crotzer Victoria L. , Nantz Eric , Beattie Scott D. , Macias William L.
Published: December 2016

Objective

To assess the effects of baricitinib on lipid profiles in patients with moderate‐to‐severe rheumatoid arthritis.

Methods

Treatment with once‐daily doses of baricitinib (1, 2, 4, or 8 mg) or placebo was studied in 301 randomized patients. Changes in lipid profile and lipoprotein particle size and particle number were assessed at weeks 12 and 24, and associations with clinical efficacy were evaluated. Apolipoproteins were assessed at weeks 4 and 12 in the placebo group and the 4‐mg and 8‐mg baricitinib groups.

Results

Treatment with baricitinib resulted in dose‐dependent increases in serum lipid levels from baseline to week 12 (low‐density lipoprotein [LDL] cholesterol increases of 3.4 mg/dl and 11.8 mg/dl in the 1 mg and 8 mg treatment groups, respectively; high‐density lipoprotein [HDL] cholesterol increases of 3.3 mg/dl and 8.1 mg/dl, respectively; triglycerides increases of 6.4 mg/dl and 15.4 mg/dl, respectively). Group‐wise mean increases in LDL cholesterol were coincident with mean increases in large LDL particles and mean reductions in small dense LDL particles. Increases from baseline to week 12 in apolipoprotein A‐I, apolipoprotein B, and apolipoprotein CIII were observed with 4‐mg doses of baricitinib (9.5%, 6.8%, and 23.0%, respectively) and with 8‐mg doses (12.2%, 7.1%, and 19.7%, respectively), with no increase in LDL‐associated apolipoprotein CIII (–4.5% with 4‐mg baricitinib; –9.0% with 8‐mg baricitinib). Baricitinib reduced HDL‐associated serum amyloid A when administered at 4 mg (−36.0%) and 8 mg (−32.0%); a significant reduction in lipoprotein (a) was observed only with 8‐mg doses (−16.6%). Increased HDL cholesterol at week 12 correlated with improved Disease Activity Scores and Simplified Disease Activity Index; changes in total cholesterol, LDL cholesterol, and triglycerides did not reveal a similar relationship.

Conclusion

Baricitinib‐associated increases in serum lipid levels were observed in this study. Increases in levels of HDL cholesterol correlated with improved clinical outcomes.
Carbonyl‐Grafted g‐C3N4 Porous Nanosheets for Efficient Photocatalytic Hydrogen Evolution
Authors: Su Feng‐Yun , Zhang Wei‐De
Published: December 2016

Carbonyl‐grafted g‐C3N4 porous nanosheets (COCNPNS) were fabricated by means of a two‐step thermal process using melamine and oxalic acid as starting reagents. The combination of melamine with oxalic acid to form a melamine–oxalic acid supramolecule as a precursor is key to synthesizing carbonyl‐grafted g‐C3N4. The bulk carbonyl‐grafted g‐C3N4 (COCN) was further thermally etched onto porous nanosheets by O2 under air. In such a process, the carbonyl groups were partly removed and the obtained sample showed remarkably enhanced visible‐light harvesting and promoted the separation and transfer of photogenerated electrons and holes. With its unique porous structure and enhanced light‐harvesting capability, under visible‐light illumination (λ>420 nm) the prepared COCNPNS exhibited a superior photocatalytic hydrogen evolution rate of 83.6 μmol h−1, which is 26 times that of the p‐CN obtained directly from thermal polycondensation of melamine.
Exome sequencing provides additional evidence for the involvement of ARHGAP29 in Mendelian orofacial clefting and extends the phenotypic spectrum to isolated cleft palate
Authors: Liu Huan , Busch Tamara , Eliason Steven , Anand Deepti , Bullard Steven , Gowans Lord J.J , Nidey Nichole , Petrin Aline , Augustine‐Akpan Eno‐Abasi , Saadi Irfan , Dunnwald Martine , Lachke Salil A. , Zhu Ying , Adeyemo Adebowale , Amendt Brad , Roscioli Tony , Cornell Robert , Murray Jeffrey , Butali Azeez
Published: December 2016

Background

Recent advances in genomics methodologies, in particular the availability of next‐generation sequencing approaches have made it possible to identify risk loci throughout the genome, in particular the exome. In the current study, we present findings from an exome study conducted in five affected individuals of a multiplex family with cleft palate only.

Methods

The GEnome MINIng (GEMINI) pipeline was used to functionally annotate the single nucleotide polymorphisms, insertions and deletions. Filtering methods were applied to identify variants that are clinically relevant and present in affected individuals at minor allele frequencies (≤1%) in the 1000 Genomes Project single nucleotide polymorphism database, Exome Aggregation Consortium, and Exome Variant Server databases. The bioinformatics tool Systems Tool for Craniofacial Expression‐Based Gene Discovery was used to prioritize cleft candidates in our list of variants, and Sanger sequencing was used to validate the presence of identified variants in affected and unaffected relatives.

Results

Our analyses approach narrowed the candidates down to the novel missense variant in ARHGAP29 (GenBank: NM_004815.3, NP_004806.3;c.1654T>C [p.Ser552Pro]. A functional assay in zebrafish embryos showed that the encoded protein lacks the activity possessed by its wild‐type counterpart, and migration assays revealed that keratinocytes transfected with wild‐type ARHGAP29 migrated faster than counterparts transfected with the p.Ser552Pro ARHGAP29 variant or empty vector (control).

Conclusion

These findings reveal ARHGAP29 to be a regulatory protein essential for proper development of the face, identifies an amino acid that is key for this, and provides a potential new diagnostic tool.Birth Defects Research 109:27–37, 2017. © 2016 Wiley Periodicals, Inc.
The effects of electromagnetic fields on B16‐BL6 cells are dependent on their spatial and temporal character
Authors: Buckner Carly A. , Buckner Alison L. , Koren Stan A. , Persinger Michael A. , Lafrenie Robert M.
Published: December 2016

Exposure to low intensity, low frequency electromagnetic fields (EMF) has effects on several biological systems. Spatiotemporal characteristics of these EMFs are critical. The effect of several complex EMF patterns on the proliferation of B16‐BL6 mouse melanoma cells was tested. Exposure to one of these patterns, the Thomas‐EMF, inhibited cell proliferation and promoted calcium uptake. The Thomas‐EMF is coded from a digital‐to‐analog file comprised of 849 points, which provides power to solenoids and can be set to alter timing, intensity, and duration of variable EMF. Setting the point duration to 3 ms generated a time‐varying EMF pattern which began at 25 Hz and slowed to 6 Hz over a 2.5 s repeat. Exposing B16‐BL6 cells to Thomas‐EMF set to 3 ms for 1 h/day inhibited cell proliferation by 40% after 5 days, while setting the point duration to 1, 2, 4, or 5 ms had no effect on cell proliferation. Similarly, exposing cells to Thomas‐EMF set to 3 ms promoted a three‐fold increase in calcium uptake after 1 h, while the other timings had no effect. Exposure to Thomas‐EMF for as short as 15 min/day slowed cell proliferation, but exposure for 1 h/day was optimal. This corresponded to the effect on calcium uptake where uptake was detected after 15 min exposure and was maximal by 1 h of treatment. Studies show that the specific spatiotemporal character of EMF is critical in mediating their biological activities. Bioelectromagnetics. 38:165–174, 2017. © 2016 Wiley Periodicals, Inc.
Enhancing the luminescence of Eu3+/Eu2+ ion‐doped hydroxyapatite by fluoridation and thermal annealing
Authors: Van Hoang Nhu , Tam Phuong Dinh , Kien Nguyen Duc Trung , Huy Pham Thanh , Pham Vuong‐Hung
Published: December 2016

This paper reports a novel way for the synthesis of a europium (Eu)‐doped fluor‐hydroxyapatite (FHA) nanostructure to control the luminescence of hydroxyapatite nanophosphor, particularly, by applying optimum fluorine concentrations, annealed temperatures and pH value. The Eu‐doped FHA was made using the co‐precipitation method followed by thermal annealing in air and reducing in a H2 atmosphere to control the visible light emission center of the nanophosphors. The intensities of the OH− group decreased with the increasing fluorine concentrations. For the specimens annealed in air, the light emission center of the nanophosphor was 615 nm, which was emission from the Eu3+ ion. However, when they were annealed in reduced gas (Ar + 5% H2), a 448 nm light emission center from the Eu2+ ion of FHA was observed. The presence of fluorine in Eu‐doped FHA resulted in a significant enhancement of nanophosphor luminescence, which has potential application in light emission and nanomedicine.
New phthalimide‐appended Schiff bases: Studies of DNA binding, molecular docking and antioxidant activities
Authors: Nayab Pattan Sirajuddin , Akrema  , Ansari Istikhar A. , Shahid Mohammad , Rahisuddin
Published: December 2016

Herein, we investigated new phthalimide‐based Schiff base molecules as promising DNA‐binding and free radical scavenging agents. Physicochemical properties of these molecules were demonstrated on the basis of elemental analysis, ultraviolet–visible (UV–Vis), infra‐red (IR), 1H and 13C nuclear magnetic resonance (NMR) spectroscopy. All spectral data are agreed well with the proposed Schiff base framework. The DNA‐binding potential of synthesized compounds were investigated by means of UV–visible, fluorescence, iodide quenching, circular dichroism, viscosity and thermal denaturation studies. The intrinsic binding constants (Kb) were calculated from absorption studies were found to be 1.1 × 104 and 1.0 × 104 M−1 for compounds 2a and 2b suggesting that compound 2a binding abilities with DNA were stronger than the compound 2b. Our studies showed that the presented compounds interact with DNA through groove binding. Molecular docking studies were carried out to predict the binding between Ct‐DNA and test compounds. Interestingly, in silico predictions were corroborated with in vitro DNA‐binding conclusions. Furthermore, the title compounds displayed remarkable antioxidant activity compared with reference standard.
FOXC1 is associated with estrogen receptor alpha and affects sensitivity of tamoxifen treatment in breast cancer
Authors: Wang Jinhua , Xu Yali , Li Li , Wang Lin , Yao Ru , Sun Qiang , Du Guanhua
Published: December 2016

FOXC1 is a member of Forkhead box transcription factors that participates in embryonic development and tumorigenesis. Our previous study demonstrated that FOXC1 was highly expressed in triple‐negative breast cancer. However, it remains unclear what is the relation between FOXC1 and ERα and if FOXC1 regulates expression of ERα. To explore relation between FOXC1 and ERα and discover regulation of ERα expression by FOXC1 in breast cancer, we analyzed data assembled in the Oncomine and TCGA, and found that there was significantly higher FOXC1 expression in estrogen receptor‐negative breast cancer than that in estrogen receptor‐positive breast cancer. Overexpression of FOXC1 reduced expression of ERα and cellular responses to estradiol (E2) and tamoxifen in the MCF‐7 FOXC1 and T47D FOXC1 cells, while knockdown of FOXC1 induced expression of ERα and improved responses to estradiol (E2) and tamoxifen in BT549 FOXC1 shRNA and HCC1806 FOXC1 shRNA cells. In addition, overexpression of FOXC1 reduced expression of progesterone receptor (PR), Insulin receptor substrate 1 (IRS1), and XBP1 (X‐Box Binding Protein 1) and significantly reduced luciferase activity caused by E2 using ERE luciferase reporter assay. These results suggested that FOXC1 regulated expression of ERα and affected sensitivity of tamoxifen treatment in breast cancer, and that FOXC1 may be used as a potential therapeutic target in ERα‐negative breast cancer.
Impact of genomic profiling on the treatment and outcomes of patients with advanced gastrointestinal malignancies
Authors: Dhir Mashaal , Choudry Haroon A. , Holtzman Matthew P. , Pingpank James F. , Ahrendt Steven A. , Zureikat Amer H. , Hogg Melissa E. , Bartlett David L. , Zeh Herbert J. , Singhi Aatur D. , Bahary Nathan
Published: December 2016

The impact of genomic profiling on the outcomes of patients with advanced gastrointestinal (GI) malignancies remains unknown. The primary objectives of the study were to investigate the clinical benefit of genomic‐guided therapy, defined as complete response (CR), partial response (PR), or stable disease (SD) at 3 months, and its impact on progression‐free survival (PFS) in patients with advanced GI malignancies. Clinical and genomic data of all consecutive GI tumor samples from April, 2013 to April, 2016 sequenced by FoundationOne were obtained and analyzed. A total of 101 samples from 97 patients were analyzed. Ninety‐eight samples from 95 patients could be amplified making this approach feasible in 97% of the samples. After removing duplicates, 95 samples from 95 patients were included in the further analysis. Median time from specimen collection to reporting was 11 days. Genomic alteration‐guided treatment recommendations were considered new and clinically relevant in 38% (36/95) of the patients. Rapid decline in functional status was noted in 25% (9/36) of these patients who could therefore not receive genomic‐guided therapy. Genomic‐guided therapy was utilized in 13 patients (13.7%) and 7 patients (7.4%) experienced clinical benefit (6 PR and 1 SD). Among these seven patients, median PFS was 10 months with some ongoing durable responses. Genomic profiling‐guided therapy can lead to clinical benefit in a subset of patients with advanced GI malignancies. Attempting genomic profiling earlier in the course of treatment prior to functional decline may allow more patients to benefit from these therapies.
Physicochemical, Antioxidant, and Cytotoxic Properties of Xao Tam Phan (Paramignya trimera) Root Extract and Its Fractions
Authors: Nguyen Van Tang , Sakoff Jennette A. , Scarlett Christopher J.
Published: December 2016

Xao tam phan (Paramignya trimera (Oliv.) Guillaum) has been used as a medicinal plant for cancer prevention and treatment in recent years. The objective of this study was to determine the physicochemical, antioxidant, and cytotoxic properties of crude P. trimera root (PTR) extract and its fractions using MeOH as a solvent and microwave‐assisted extraction as an advanced technique for preparation of the PTR extract. The results showed that the PTR extract had high contents of saponins, phenolics, flavonoids, and proanthocyanidins (7731.05 mg escin equiv. (EE), 238.13 mg gallic acid equiv. (GAE), 81.49 mg rutin equiv., and 58.08 mg catechin equiv. (CE)/g dried extract, resp.). Antioxidant activity of PTR extract was significantly higher (P < 0.05) than those of four its fractions and ostruthin, a key bioactive compound in the P. trimera, while potent cytotoxic capacity of PTR extract on various cancer cell lines in terms of MiaPaCa‐2 (pancreas), HT29 (colon), A2780 (ovarian), H460 (lung), A431 (skin), Du145 (prostate), BE2‐C (neuroblastoma), MCF‐7 (breast), MCF‐10A (normal breast), and U87, SJ‐G2, SMA (glioblastoma) was observed with GI50 values ranging from 15 to 32 μg/ml. Cytotoxic potential on pancreatic cancer cells of PTR extract (100 – 200 μg/ml) was significantly higher (P < 0.05) than those of its four fractions (50 μg/ml), ostruthin (20 μg/ml) and gemcitabine (50 nm), and being comparable to a saponin‐enriched extract from quillajia bark, a commercial product. Based on the results achieved, we can conclude that the PTR extract is a potential source for application of in the nutraceutical, medical, and pharmaceutical industries.
Yield, Composition and Antioxidant Capacity of the Essential Oil of Sweet Basil and Holy Basil as Influenced by Distillation Methods
Authors: Shiwakoti Santosh , Saleh Osama , Poudyal Shital , Barka Abdulssamad , Qian Yanping , Zheljazkov Valtcho D.
Published: December 2016

The profile and bioactivity of essential oil (EO) depends on genetic, environmental, and other factors. We hypothesized that the basil EO may be influenced by the distillation methods. Hence, a study was conducted to evaluate the effect of steam distillation (SD) and hydrodistillation (HD) extraction method on the yield, composition, and bioactivity of EO of sweet basil (Ocimum basilicum) and holy basil (Ocimum tenuiflorum). In both basil species, the EO yield (content) was significantly higher from SD than from HD. There were significant differences in the compounds’ concentrations of EO obtained from SD and HD as well, however, the same compounds were identified in the EO from HD and SD. In the EO of O. basilicum, the concentration of 74% of the identified compounds were higher in SD than HD, whereas in the EO of O. tenuiflorum, the concentration of 84% of identified compounds were higher in SD than in HD. However, the concentrations of two of the major compounds of O. basilicum EO (estragole and methyl cinnamate) and a major compound of O. tenuiflorum EO (methyl eugenol) were significantly higher in HD than in SD. The type of distillation did not affect the antioxidant capacity of basil EO within the species. This study demonstrated that the type of distillation may significantly affect oil yield and composition but not the antioxidant capacity of the EO from sweet and holy basil.
Biocatalytic α‐Oxidation of Cyclic Amines and N‐Methylanilines for the Synthesis of Lactams and Formamides
Authors: Zheng Daijun , Zhou Xiaojian , Cui Baodong , Han Wenyong , Wan Nanwei , Chen Yongzheng
Published: December 2016

An environmentally friendly method for the synthesis of lactams and formamides through the biocatalytic α‐oxidation of amines was developed by employing Pseudomonas plecoglossicida ZMU‐T04 as a biocatalyst. In this biocatalytic process, the α‐oxidation of cyclic amines and N‐methylanilines proceeded smoothly to give the corresponding amides in low to high yields. Furthermore, it was demonstrated that synthetic 3,4‐dihydroquinolin‐2(1H)‐one could be used as a key precursor of antidepressant bioactive molecules. The mechanism of this biocatalytic α‐oxidation process was investigated by isotope‐ labeling experiments.
Score‐based quantitative principal component analysis with application to the study of active pharmaceutical ingredients based on attenuated total reflection fourier‐transform‐infrared spectra
Authors: Balcerowska‐Czerniak Grażyna , Kupcewicz Bogumiła
Published: December 2016

This paper presents a novel algorithm, named Score‐based Quantitative Principal Component Analysis, for the quantification of different active ingredients in pharmaceutical tablets based on attenuated total reflection Fourier‐transform‐infrared spectra. The procedure is proposed for solving the problem of the simultaneous determination of the amount of several analytes in the presence of unknown interfering compounds. This is accomplished by incorporating into the analysis a Principal Component Analysis calibration data set model obtained for 2‐way mixture spectra which are deemed as a linear combination of all pure component spectral signals of known amount of the analyte of interest. A relatively simple model involving the relationship between principal component (PC)‐scores for mixture spectrum and PC‐scores for pure component spectra has been developed for predicting the amount of a compound in the presence of an unknown interference in a new sample. The performance of the proposed method has been evaluated using 2 commonly used measures of accuracy, and it was also compared with 3 classical methods, ordinary least squares, partial least squares regression and multivariate curve resolution‐alternating least squares. The results show that in multicomponent 2‐way system spectra in cases where classical methods are not able to predict the constituent concentration accurately the PC‐scores based approach, under some circumstances, can generate good predictive results. The power of the proposed method has been evaluated by applying it to the analysis of simulated and experimental data.
Novel recalibration methodologies for ion‐selective electrode arrays in the multi‐ion interference scenario
Authors: Wang Liang , Cheng Ying , Lamb Dane , Lesniewski Peter J. , Chen Zuliang , Megharaj Mallavarapu , Naidu Ravendra
Published: December 2016

Because of the deterioration of sensitivity and selectivity of ion‐selective electrode (ISE) arrays after a long period of storage or measurement, the recalibration of ISE arrays is a major challenge, which significantly affects the practical application of ISE arrays. Although approaches using artificial neural networks (ANN) to solve the problem have been widely studied, it is impractical for end‐users to frequently remeasure dozens of samples to rebuild an ANN model for measuring of ISE array. In this study, a system of equations was developed to simulate the ISE array response for the scenario of multiple interfering ions. By fitting the coefficients for the system of equations using optimization algorithms, such as genetic algorithms (GA), the ISE array can be recalibrated with only a couple of selected samples. As a case study, a solid‐state ISE array for the detection of 4 exchangeable cations was applied. The deterioration of sensitivity and selectivity of the ISE array over time was investigated. The simplified methodology for calibrating this ISE array was applied and demonstrated in this study.
Bulk separation of hydrogen and carbon monoxide by one‐column pressure swing adsorption: Experimental and statistical analysis
Authors: Saberimoghaddam Ali , Khebri Vahid
Published: December 2016

This work evaluates separation of CO/H2 mixture (50:50 vol%) on a commercial zeolite 5A by using 1‐column pressure swing adsorption process. Statistical analysis using response surface methodology was employed to evaluate the combined effect of 2 independent variables, namely, adsorption step time and purge‐to‐feed ratio (
ratio) on the hydrogen purity, recovery, and productivity as responses. These responses were efficiently modeled by 3 second‐order polynomial equations. Optimization of the response function was done based on the desirability. The optimum conditions were investigated at different values of responses. For instance, when hydrogen purity was set at maximum value, recovery and productivity were set at “in range” and the model predicted 99.85% hydrogen purity, 47.69%, and 1.26×

hydrogen recovery and productivity, respectively. In this condition, the optimum values of purge‐to‐feed ratio and adsorption time were 0.24 and 7.35 minutes. Validation of models was carried out by practical experiments in predicted optimum conditions, and the results confirmed the accuracy of models for predicted values.
Functional Pyrimidine‐Based Thermally Activated Delay Fluorescence Emitters: Photophysics, Mechanochromism, and Fabrication of Organic Light‐Emitting Diodes
Authors: Ganesan Paramaguru , Ranganathan Revathi , Chi Yun , Liu Xiao‐Ke , Lee Chun‐Sing , Liu Shih‐Hung , Lee Gene‐Hsiang , Lin Tzu‐Chieh , Chen Yi‐Ting , Chou Pi‐Tai
Published: December 2016

A new series of molecules, T1–T4, possessing thermally activated delayed fluorescence (TADF) have been strategically designed and synthesized. Molecules T1–T4 contain the dimethyl acridine as the electron donor, which is linked to either symmetrical or unsymmetrical diphenyl pyrimidine as an acceptor. In comparison to the ubiquitous triazine acceptor, the selection of pyrimidine as an acceptor has advantages of facile functionalization and less stabilized unoccupied π orbitals, so that the energy gap toward the blue region can be accessed. Together with acridine donors, the resulting donor–acceptor functional materials reveal remarkable TADF properties. In the solid state, molecules T1–T4 all exhibit intriguing mechanochromism. The crystal structures, together with spectroscopy and dynamics acquired upon application of stressing, lead us to propose two types of structural arrangement that give distinct emission properties, one with and the other without TADF. Upon fabricating organic light‐emitting diodes, the T1–T4 films prepared from sublimation all exhibit dominant TADF behavior; this accounts for their high performance: an electroluminescent emission at λ=490 nm, with an external quantum efficiency of 14.2 %, can be attained when T2 is used as an emitter.
Vulvar and vaginal melanoma: A unique subclass of mucosal melanoma based on a comprehensive molecular analysis of 51 cases compared with 2253 cases of nongynecologic melanoma
Authors: Hou June Y. , Baptiste Caitlin , Hombalegowda Radhika Bangalore , Tergas Ana I. , Feldman Rebecca , Jones Nathaniel L. , Chatterjee‐Paer Sudeshna , Bus‐Kwolfski Ama , Wright Jason D. , Burke William M.
Published: December 2016

BACKGROUND

Optimal treatments for vulvar and vaginal melanomas (VVMs) have not been identified. Herein, the authors compare molecular profiles between VVM and nongynecologic melanoma (NGM) subtypes with the objective of identifying novel, targetable biomarkers.

METHODS

In total, 2304 samples of malignant melanoma that were submitted to Caris Life Sciences between 2009 and 2015 were reviewed. In situ hybridization and immunohistochemistry were used to assess copy numbers and protein expression of selected genes. Sequenced variants were analyzed using a proprietary cancer panel.

RESULTS

In total, 51 VVMs (14 vaginal and 37 vulvar melanomas) were compared with 2253 malignant NGMs, including 2127 cutaneous, 105 mucosal, and 21 acral melanomas. In VVMs, B‐Raf proto‐oncogene serine/threonine kinase (BRAF) was the most frequently mutated gene (26%) compared with 8.3% of mucosal NGMs (P = .008). In BRAF‐mutated tumors, fewer VVMs (50%), compared with NGMs (82.1%), had a variant within the valine codon 600 (V600) domain. The KIT mutation rate was highest in VVMs (22%) compared with 3% in cutaneous (P < .001) and 8.8% in mucosal (P = .05) melanoma subtypes. NRAS mutations were rare in VVMs compared with cutaneous (25.9%; P = .009) and acral (40.6%; P = .002) melanoma subtypes. PD‐L1 (56%) and PD‐1 (75%) were frequently expressed in VVM, whereas PI3KCA pathway mutations and estrogen receptor/progesterone receptor expression were rare. Compared with VVMs that had KIT mutations, wild‐type KIT VVMs were more likely to express molecular markers suggestive of platinum resistance (ERCC1), alkylating sensitivity (MGMT), and anthracycline sensitivity (TOP2A).

CONCLUSIONS

The unique molecular features of VVM render this disease a distinct subtype of melanoma. Gene‐based molecular therapy and immunotherapies may be promising and should be evaluated in clinical trials. Cancer 2017;123:1333–1344. © 2016 American Cancer Society.
Complications, hospital length of stay, and readmission after total laryngectomy
Authors: Goepfert Ryan. P. , Hutcheson Katherine A. , Lewin Jan S. , Desai Neha G. , Zafereo Mark E. , Hessel Amy C. , Lewis Carol M. , Weber Randal S. , Gross Neil D.
Published: December 2016

BACKGROUND

The purpose of this study was to describe the 30‐day incidence of complications after total laryngectomy (TL) in a high‐volume institution and their impact on the hospital length of stay (LOS) and readmission rates.

METHODS

A retrospective cohort study of all patients who underwent TL at The University of Texas MD Anderson Cancer Center from January 1, 2010 through June 30, 2013 was conducted. The patient demographics, treatment history, LOS, and 30‐day post‐TL complications and readmissions were extracted from the medical record. Univariate associations were analyzed, and stepwise backward selection methods were used to fit multivariate models.

RESULTS

Two hundred forty‐five patients were included. Complications occurred in 83 patients (33.9%) and included 3 deaths (1.2%). Wound complications occurred in 53 patients (21.6%), and 34 were pharyngocutaneous fistulas (PCFs; 13.9% overall). Thirty‐four patients (13.9%) were readmitted within 30 days. A multivariate analysis revealed the following: wound complications were associated with former (odds ratio [OR], 5.1; P = .03) and current smokers (OR, 5.8; P = .02), PCFs were associated with prior wide‐field radiation (OR, 3.1; P = .01) but not prior narrow‐field (larynx‐only) radiation (OR, 1.4; P = .61), LOS was associated with the type of flap (P = .002) and postoperative hematomas (P = .05), and readmissions were associated with preoperative hypoalbuminemia (P = .003) and postoperative wound complications (P < .001).

CONCLUSIONS

Complications occurred in approximately one‐third of TL patients and particularly in patients with poor wound‐healing risk factors such as prior smoking and radiation. As expected, LOS was longer among reconstructed patients. Readmission was associated with hypoalbuminemia and postoperative wound complications. These data can inform quality improvement efforts and the counseling of high‐risk patients undergoing TL. Cancer 2017;123:1760–1767. © 2016 American Cancer Society.
Fluence Threshold Behaviour on Ablation and Bubble Formation in Pulsed Laser Ablation in Liquids
Authors: Reich Stefan , Schönfeld Patrick , Letzel Alexander , Kohsakowski Sebastian , Olbinado Margie , Gökce Bilal , Barcikowski Stephan , Plech Anton
Published: December 2016

The ablation yield and bubble‐formation process during nanosecond pulsed‐laser ablation of silver in water are analysed by stroboscopic videography, time‐resolved X‐ray radiography and in situ UV/Vis spectroscopy. This process is studied as function of lens–target distance and laser fluence. Both the ablation yield and the bubble‐cavitation process exhibit threshold behaviour as a function of fluence, which is linked to the efficiency of coupling of energy at the water/target interface. Although ablation happens below this threshold, quantitative material emission is linked to bubble formation. Above the threshold, both bubble size and ablation show linear behaviour.
Implementing Pharmacogenomics in Europe: Design and Implementation Strategy of the Ubiquitous Pharmacogenomics Consortium
Authors: van der Wouden CH , Cambon‐Thomsen A , Cecchin E , Cheung KC , Dávila‐Fajardo CL , Deneer VH , Dolžan V , Ingelman‐Sundberg M , Jönsson S , Karlsson MO , Kriek M , Mitropoulou C , Patrinos GP , Pirmohamed M , Samwald M , Schaeffeler E , Schwab M , Steinberger D , Stingl J , Sunder‐Plassmann G , Toffoli G , Turner RM , van Rhenen MH , Swen JJ , Guchelaar H‐J ,   on behalf of the Ubiquitous Pharmacogenomics Consortium
Published: December 2016

Despite scientific and clinical advances in the field of pharmacogenomics (PGx), application into routine care remains limited. Opportunely, several implementation studies and programs have been initiated over recent years. This article presents an overview of these studies and identifies current research gaps. Importantly, one such gap is the undetermined collective clinical utility of implementing a panel of PGx‐markers into routine care, because the evidence base is currently limited to specific, individual drug‐gene pairs. The Ubiquitous Pharmacogenomics (U‐PGx) Consortium, which has been funded by the European Commission's Horizon‐2020 program, aims to address this unmet need. In a prospective, block‐randomized, controlled clinical study (PREemptive Pharmacogenomic testing for prevention of Adverse drug REactions [PREPARE]), pre‐emptive genotyping of a panel of clinically relevant PGx‐markers, for which guidelines are available, will be implemented across healthcare institutions in seven European countries. The impact on patient outcomes and cost‐effectiveness will be investigated. The program is unique in its multicenter, multigene, multidrug, multi‐ethnic, and multihealthcare system approach.
Hox genes in the adult skeleton: Novel functions beyond embryonic development
Authors: Rux Danielle R. , Wellik Deneen M.
Published: December 2016

Hox genes encode evolutionarily conserved transcription factors that control skeletal patterning in the developing embryo. They are expressed in regionally restricted domains and function to regulate the morphology of specific vertebral and long bone elements. Recent work has provided evidence that Hox genes continue to be regionally expressed in adult tissues. Fibroblasts cultured from adult tissues show broadly maintained Hox gene expression patterns. In the adult skeleton, Hox genes are expressed in progenitor‐enriched populations of mesenchymal stem/stromal cells (MSCs), and genetic loss‐of‐function analyses have provided evidence that Hox genes function during the fracture healing process. This review will highlight our current understanding of Hox expression in the adult animal and its function in skeletal regeneration. Developmental Dynamics 246:310–317, 2017. © 2016 Wiley Periodicals, Inc.
Arctigenin protects against neuronal hearing loss by promoting neural stem cell survival and differentiation
Authors: Huang Xinghua , Chen Mo , Ding Yan , Wang Qin
Published: December 2016

Neuronal hearing loss has become a prevalent health problem. This study focused on the function of arctigenin (ARC) in promoting survival and neuronal differentiation of mouse cochlear neural stem cells (NSCs), and its protection against gentamicin (GMC) induced neuronal hearing loss. Mouse cochlea was used to isolate NSCs, which were subsequently cultured in vitro. The effects of ARC on NSC survival, neurosphere formation, differentiation of NSCs, neurite outgrowth, and neural excitability in neuronal network in vitro were examined. Mechanotransduction ability demonstrated by intact cochlea, auditory brainstem response (ABR), and distortion product optoacoustic emissions (DPOAE) amplitude in mice were measured to evaluate effects of ARC on GMC‐induced neuronal hearing loss. ARC increased survival, neurosphere formation, neuron differentiation of NSCs in mouse cochlear in vitro. ARC also promoted the outgrowth of neurites, as well as neural excitability of the NSC‐differentiated neuron culture. Additionally, ARC rescued mechanotransduction capacity, restored the threshold shifts of ABR and DPOAE in our GMC ototoxicity murine model.

This study supports the potential therapeutic role of ARC in promoting both NSCs proliferation and differentiation in vitro to functional neurons, thus supporting its protective function in the therapeutic treatment of neuropathic hearing loss in vivo.
Disturbance and productivity interactions mediate stability of forest composition and structure
Authors: O'Connor Christopher D. , Falk Donald A. , Lynch Ann M. , Swetnam Thomas W. , Wilcox Craig P.
Published: December 2016

Fire is returning to many conifer‐dominated forests where species composition and structure have been altered by fire exclusion. Ecological effects of these fires are influenced strongly by the degree of forest change during the fire‐free period. Response of fire‐adapted species assemblages to extended fire‐free intervals is highly variable, even in communities with similar historical fire regimes. This variability in plant community response to fire exclusion is not well understood; however, ecological mechanisms such as individual species’ adaptations to disturbance or competition and underlying site characteristics that facilitate or impede establishment and growth have been proposed as potential drivers of assemblage response. We used spatially explicit dendrochronological reconstruction of tree population dynamics and fire regimes to examine the influence of historical disturbance frequency (a proxy for adaptation to disturbance or competition), and potential site productivity (a proxy for underlying site characteristics) on the stability of forest composition and structure along a continuous ecological gradient of pine, dry mixed‐conifer, mesic mixed‐conifer, and spruce–fir forests following fire exclusion. While average structural density increased in all forests, species composition was relatively stable in the lowest productivity pine‐dominated and highest productivity spruce–fir‐dominated sites immediately following fire exclusion and for the next 100 years, suggesting site productivity as a primary control on species composition and structure in forests with very different historical fire regimes. Species composition was least stable on intermediate productivity sites dominated by mixed‐conifer forests, shifting from primarily fire‐adapted species to competition‐adapted, fire‐sensitive species within 20 years of fire exclusion. Rapid changes to species composition and stand densities have been interpreted by some as evidence of high‐severity fire. We demonstrate that the very different ecological process of fire exclusion can produce similar changes by shifting selective pressures from disturbance‐mediated to productivity‐mediated controls. Restoring disturbance‐adapted species composition and structure to intermediate productivity forests may help to buffer them against projected increasing temperatures, lengthening fire seasons, and more frequent and prolonged moisture stress. Fewer management options are available to promote adaptation in forest assemblages historically constrained by underlying site productivity.
Plant invasion and speciation along elevational gradients on the oceanic island La Palma, Canary Islands
Authors: Steinbauer Manuel J. , Irl Severin D. H. , González‐Mancebo Juana María , Breiner Frank T. , Hernández‐Hernández Raquel , Hopfenmüller Sebastian , Kidane Yohannes , Jentsch Anke , Beierkuhnlein Carl
Published: December 2016

Ecosystems that provide environmental opportunities but are poor in species and functional richness generally support speciation as well as invasion processes. These processes are expected not to be equally effective along elevational gradients due to specific ecological, spatial, and anthropogenic filters, thus controlling the dispersal and establishment of species. Here, we investigate speciation and invasion processes along elevational gradients. We assess the vascular plant species richness as well as the number and percentage of endemic species and non‐native species systematically along three elevational gradients covering large parts of the climatic range of La Palma, Canary Islands. Species richness was negatively correlated with elevation, while the percentage of Canary endemic species showed a positive relationship. However, the percentage of Canary–Madeira endemics did not show a relationship with elevation. Non‐native species richness (indicating invasion) peaked at 500 m elevation and showed a consistent decline until about 1,200 m elevation. Above that limit, no non‐native species were present in the studied elevational gradients. Ecological, anthropogenic, and spatial filters control richness, diversification, and invasion with elevation. With increase in elevation, richness decreases due to species–area relationships. Ecological limitations of native ruderal species related to anthropogenic pressure are in line with the absence of non‐native species from high elevations indicating directional ecological filtering. Increase in ecological isolation with elevation drives diversification and thus increased percentages of Canary endemics. The best preserved eastern transect, including mature laurel forests, is an exception. The high percentage of Canary–Madeira endemics indicates the cloud forest's environmental uniqueness—and thus ecological isolation—beyond the Macaronesian islands.
Climatic controls on the global distribution, abundance, and species richness of mangrove forests
Authors: Osland Michael J. , Feher Laura C. , Griffith Kereen T. , Cavanaugh Kyle C. , Enwright Nicholas M. , Day Richard H. , Stagg Camille L. , Krauss Ken W. , Howard Rebecca J. , Grace James B. , Rogers Kerrylee
Published: December 2016

Mangrove forests are highly productive tidal saline wetland ecosystems found along sheltered tropical and subtropical coasts. Ecologists have long assumed that climatic drivers (i.e., temperature and rainfall regimes) govern the global distribution, structure, and function of mangrove forests. However, data constraints have hindered the quantification of direct climate–mangrove linkages in many parts of the world. Recently, the quality and availability of global‐scale climate and mangrove data have been improving. Here, we used these data to better understand the influence of air temperature and rainfall regimes upon the distribution, abundance, and species richness of mangrove forests. Although our analyses identify global‐scale relationships and thresholds, we show that the influence of climatic drivers is best characterized via regional range‐limit‐specific analyses. We quantified climatic controls across targeted gradients in temperature and/or rainfall within 14 mangrove distributional range limits. Climatic thresholds for mangrove presence, abundance, and species richness differed among the 14 studied range limits. We identified minimum temperature‐based thresholds for range limits in eastern North America, eastern Australia, New Zealand, eastern Asia, eastern South America, and southeast Africa. We identified rainfall‐based thresholds for range limits in western North America, western Gulf of Mexico, western South America, western Australia, Middle East, northwest Africa, east central Africa, and west‐central Africa. Our results show that in certain range limits (e.g., eastern North America, western Gulf of Mexico, eastern Asia), winter air temperature extremes play an especially important role. We conclude that rainfall and temperature regimes are both important in western North America, western Gulf of Mexico, and western Australia. With climate change, alterations in temperature and rainfall regimes will affect the global distribution, abundance, and diversity of mangrove forests. In general, warmer winter temperatures are expected to allow mangroves to expand poleward at the expense of salt marshes. However, dispersal and habitat availability constraints may hinder expansion near certain range limits. Along arid and semiarid coasts, decreases or increases in rainfall are expected to lead to mangrove contraction or expansion, respectively. Collectively, our analyses quantify climate–mangrove linkages and improve our understanding of the expected global‐ and regional‐scale effects of climate change upon mangrove forests.
Outbreak of an undetected invasive species triggered by a climate anomaly
Authors: Walsh Jake R. , Munoz Samuel E. , Vander Zanden M. Jake
Published: December 2016

When an invasive species appears at a new location, we typically have no knowledge of the population dynamics leading up to that moment. Is the establishment of invasive propagules closely followed by the appearance of the population? Or alternatively, was there an established low‐density population that was released from a constraint and crossed the detection threshold? The early stages of the invasion process are a critical gap in our knowledge, yet vitally important for the detection and management of invasions. Here, we present multiple lines of evidence supporting the lag scenario for an invasive species outbreak. The invasive predatory zooplankton, spiny water flea (Bythotrephes longimanus), was detected in Lake Mendota, Wisconsin (USA), in summer of 2009 and rapidly reached and sustained exceptionally high densities. To evaluate whether Bythotrephes' outbreak immediately followed introduction or erupted from an established low‐density population, we constructed a population model of Bythotrephes in Lake Mendota. In the model, Bythotrephes persisted indefinitely at low levels until favorable thermal conditions in 2009, the coolest July since at least 1895, allowed it to erupt to high densities and establish a large egg bank in the lake sediments. The egg bank stabilized the population in the high‐density state despite a return to nonfavorable thermal conditions, which is further supported by demographic data suggesting a constant contribution from the egg bank during the year. The prolonged lag scenario is corroborated by the detection of two individual Bythotrephes in pre‐2009 archived samples, and the detection of Bythotrephes spines in lake sediment core layers dating back to 1994 (±5 yr). Together, our results suggest that Bythotrephes persisted for at least a decade below the detection limit, until optimal thermal conditions triggered a population outbreak. This work highlights the potential for environmental conditions to trigger invasive species outbreaks from low‐density populations.
Simulation of the effects of photodecay on long‐term litter decay using DayCent
Authors: Chen Maosi , Parton William J. , Adair E. Carol , Asao Shinichi , Hartman Melannie D. , Gao Wei
Published: December 2016

Recent studies have found that solar ultraviolet (UV) radiation significantly shifts the mass loss and nitrogen dynamics of plant litter decomposition in semi‐arid and arid ecosystems. In this study, we examined the role of photodegradation in litter decomposition by using the DayCent‐UV biogeochemical model. DayCent‐UV incorporated the following mechanisms related to UV radiation: (1) direct photolysis, (2) facilitation of microbial decomposition via production of labile materials, and (3) microbial inhibition effects. We also allowed maximum photodecay rate of the structural litter pool to vary with litter's initial lignin fraction in the model. We calibrated DayCent‐UV with observed ecosystem variables (e.g., volumetric soil water content, live biomass, actual evapotranspiration, and net ecosystem exchange), and validated the optimized model with Long‐Term Intersite Decomposition Experiment (LIDET) observations of remaining carbon and nitrogen at three semi‐arid sites in Western United States. DayCent‐UV better simulated the observed linear carbon loss patterns and the persistent net nitrogen mineralization in the 10‐year LIDET experiment at the three sites than the model without UV decomposition. In the DayCent‐UV equilibrium model runs, UV decomposition increased aboveground and belowground plant production, surface net nitrogen mineralization, and surface litter nitrogen pool, but decreased surface litter carbon, soil net nitrogen mineralization, and mineral soil carbon and nitrogen. In addition, UV decomposition had minimal impacts on trace gas emissions and biotic decomposition rates. The model results suggest that the most important ecological impact of photodecay of surface litter in dry grasslands is to increase N mineralization from the surface litter (25%), and decay rates of the surface litter (15%) and decrease the organic soil carbon and nitrogen (5%).
Palliative care in heart failure: facts and numbers
Authors: Riley Jillian P. , Beattie James M.
Published: December 2016

Millions of people worldwide have heart failure. Despite enormous advances in care that have improved outcome, heart failure remains associated with a poor prognosis. Worldwide, there is poor short‐term and long‐term survival. The 1 year survival following a heart failure admission is in the range of 20–40% with between‐country variation. For those living with heart failure, the symptom burden is high. Studies report that 55 to 95% of patients experience shortness of breath and 63 to 93% experience tiredness. These symptoms are associated with a high level of distress (43–89%). Fewer patients experience symptoms such as constipation (25–30%) or dry mouth (35–74%). However, when they do, such symptoms are associated with high levels of distress (constipation: 15–39%; dry mouth: 14–33%). Psychological symptoms also predominate with possibly as many as 50% experiencing depression. Palliative care services in heart failure are not widely available. Even in countries with well‐developed services, only around 4% of patients are referred for specialist palliative care. Many patients and their families would benefit from receiving specialist palliative care support.
EurJOC Keeps It Rolling
Authors: Ross Haymo
Published: December 2016

Editor‐in‐chief Haymo Ross looks at the past and highlights the exciting new features that readers can look forward to in EurJOC's 20th volume.