bluuebunny/crossref_metadata_2025 huggingface dataset:
Safety and efficacy of trabectedin when administered in the inpatient versus outpatient setting: Clinical considerations for outpatient administration of trabectedin
Authors: Jones Robin L. , Maki Robert G. , Patel Shreyaskumar R. , Wang George , McGowan Tracy A. , Shalaby Waleed S. , Knoblauch Roland E. , von Mehren Margaret , Demetri George D.
Published: September 2019

Background

The results of the randomized, phase 3 ET743‐SAR‐3007 trial demonstrated that trabectedin had a significantly longer progression‐free survival (PFS) compared with dacarbazine in patients with advanced leiomyosarcoma/liposarcoma after the failure of prior chemotherapy. Patients randomized to trabectedin received a 24‐hour intravenous infusion either in an inpatient or outpatient setting. Herein, the authors reported the safety, efficacy, and patient‐reported outcomes based on first infusion site of care.

Methods

Patients were randomized 2:1 to trabectedin (at a dose of 1.5 mg/m2) or dacarbazine (1 g/m2 over 20‐120 minutes) with overall survival (OS) as the primary endpoint and PFS, time to disease progression, objective response rate, duration of response, safety, and patient‐reported symptom scoring as secondary endpoints. The setting of the trabectedin infusion was based on institutional preference and categorized based on the setting of the first infusion.

Results

Of the 378 patients who were treated with trabectedin, 100 (27%) and 277 (73%), respectively, first received trabectedin in the inpatient and outpatient setting. No differences were observed with regard to PFS or OS based on site of care. The median PFS was 4.1 months versus 4.2 months (hazard ratio, 0.90; P = .49) for inpatients versus outpatients, respectively, and the median OS was 14.3 months versus 13.7 months (hazard ratio, 0.89; P = .40), respectively. Grade 3/4 adverse events (classified according to the National Cancer Institute Common Terminology Criteria for Adverse Events [version 4.0]) were reported in 87 inpatients (87%) compared with 219 outpatients (79%); grade 3/4 serious adverse events were reported in 43 inpatients (43%) and 92 outpatients (33%). Extravasation occurred in 0 inpatients and 5 outpatients (2%), whereas the incidence of catheter‐related complications was similar between groups (16% vs 15%).

Conclusions

Although the majority of patients who were randomized to trabectedin received outpatient therapy, the outcomes of the current study suggested equivalent safety and efficacy in either setting.
Axonal localization of the fragile X family of RNA binding proteins is conserved across mammals
Authors: Shepard Katherine A. , Korsak Lulu I T. , DeBartolo Danielle , Akins Michael R.
Published: September 2019

Spatial segregation of proteins to neuronal axons arises in part from local translation of mRNAs that are first transported into axons in ribonucleoprotein particles (RNPs), complexes containing mRNAs and RNA binding proteins. Understanding the importance of local translation for a particular circuit requires not only identifying axonal RNPs and their mRNA cargoes, but also whether these RNPs are broadly conserved or restricted to only a few species. Fragile X granules (FXGs) are axonal RNPs containing the fragile X related family of RNA binding proteins along with ribosomes and specific mRNAs. FXGs were previously identified in mouse, rat, and human brains in a conserved subset of neuronal circuits but with species‐dependent developmental profiles. Here, we asked whether FXGs are a broadly conserved feature of the mammalian brain and sought to better understand the species‐dependent developmental expression pattern. We found FXGs in a conserved subset of neurons and circuits in the brains of every examined species that together include mammalian taxa separated by up to 160 million years of divergent evolution. A developmental analysis of rodents revealed that FXG expression in frontal cortex and olfactory bulb followed consistent patterns in all species examined. In contrast, FXGs in hippocampal mossy fibers increased in abundance across development for most species but decreased across development in guinea pigs and members of the Mus genus, animals that navigate particularly small home ranges in the wild. The widespread conservation of FXGs suggests that axonal translation is an ancient, conserved mechanism for regulating the proteome of mammalian axons.
Cooperatively Catalyzed Henry Reaction through Directed Metal‐Chitosan Interactions
Authors: Khoury Christine , Pappuru Sreenath , Gavriely Noa , Kleinerman Olga , Shpasser Dina , Segal‐Peretz Tamar , Gazit Oz M.
Published: September 2019

The main focus of the present work is on identifying the critical parameters involved in inducing acid‐base cooperative catalytic interaction in hybrid metal‐polymer materials. To makes these hybrid materials Ti or Sn acid sites are grafted to the hydroxy groups of chitosan (CS). The cooperative catalytic interactions between the Ti/Sn and the primary amine sites on CS are tested for the nitro‐aldol condensation of nitromethane with 4‐nitro‐benzaldehyde. The observed results show that the synthesis conditions have a pronounce effect on the 3D arrangement of the hybrid materials, which in turn affect the reaction activity and selectivity. The catalysts are characterized using N2‐pysisorption, XRD, FTIR, XPS and HRTEM in conjunctions with reaction kinetic analysis. Using the combined results, a reaction mechanism is proposed, which emphasizes the effect of proximity and orientation of the Lewis acid (Ti or Sn) and base (NH2) active sites on cooperative catalysis in the Henry reaction.
Drug‐Placebo Additivity in Randomized Clinical Trials
Authors: Hall Kathryn T. , Loscalzo Joseph
Published: September 2019

In randomized clinical trials (RCTs), it is assumed that nonspecific effects beyond action of pharmacological agents are roughly equivalent in drug and placebo treatment groups. Hence, since the inception of RCTs, drug efficacy is determined by comparing outcomes in active to those in placebo control arms. However, quantitation of efficacy is based on an unproven assumption, that drug and placebo responses are always additive. Response to treatment in RCTs can be differentially influenced by the perturbing effects of patient expectations, side effects, and pharmacogenomic interactions in both drug and placebo arms. Ability to control for these effects requires understanding of when and where they arise, how to mitigate, analyze, and even leverage their impact. Here, we examine three factors that influence additivity: expectation, side effects, and pharmacogenomics. Furthermore, to provide novel insights into nonadditivity and solutions for managing it, we introduce systems pharmacogenomics, a network approach to integrating and analyzing the effects of the numerous interacting perturbations to which a patient is exposed in RCTs.
A bias‐compensated proportionate NLMS algorithm with noisy input signals
Authors: Yoo JinWoo , Shin JaeWook , Park PooGyeon
Published: September 2019

This paper proposes a novel proportionate normalized least‐mean‐squares (PNLMS) algorithm that is robust to input noises. Through compensating for biases due to input noise added at the filter input, the proposed PNLMS algorithm avoids performance deterioration owing to the noisy input signals. Moreover, since the proposed PNLMS algorithm uses a new gain‐distribution matrix, it has a fast convergence rate compared with the existing PNLMS algorithms, even when there is no input noise. The experimental results verify that the proposed PNLMS algorithm enhances the filter performance for sparse system identification in the presence of input noises.
Comparative analysis on pore‐scale permeability prediction on micro‐CT images of rock using numerical and empirical approaches
Authors: Song Rui , Wang Yao , Liu Jianjun , Cui Mengmeng , Lei Yun
Published: September 2019

Varieties of pore‐scale numerical and empirical approaches have been proposed to predict the rock permeability when the pore structure is known, for example, microscopic computerized tomography (micro‐CT) technology. A comparative study on these approaches is conducted in this paper. A reference dataset of nine micro‐CT images of porous rocks is generated and processed including artificial sandpacks, tight sandstone, and carbonate. Multiple numerical and empirical approaches are used to compute the absolute permeability of micro‐CT images including the image voxel‐based solver (VBS), pore network model (PNM), Lattice Boltzmann method (LBM), Kozeny‐Carman (K‐C) equation, and Thomeer relation. Computational accuracy and efficiency of different numerical approaches are investigated. The results indicate that good agreements among numerical solvers are achieved for the sample with a homogeneous structure, while the disagreement increases with an increase in heterogeneity and complexity of pore structure. The LBM and VBS solver both have a relative higher computation accuracy, whereas the PNM solver is less accurate due to simplification on the topological structure. The computation efficiency of the different solver is generally computation resources dependent, and the PNM solver is the fastest, followed by VBS and LBM solver. As expected, empirical relation can over‐estimate permeability by a magnification of 50 or more, particularly for those strong heterogeneous structures reported in this study. Nevertheless, empirical relation is still applicable for artificial rocks.
Adjuvant therapies in the management of medication‐related osteonecrosis of the jaws: Systematic review
Authors: de Souza Tolentino Elen , de Castro Tamara F. , Michellon Felipe C. , Passoni Ana C. C. , Ortega Lorena J. A. , Iwaki Lilian C. V. , da Silva Mariliani C.
Published: September 2019

Background

We investigated the efficacy of hyperbaric oxygen (HBO), low‐intensity laser (LIL), and platelet‐rich plasma (PRP) in the management of medication‐related osteonecrosis of the jaws (MRONJ).

Methods

A literature search was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta‐Analyses statement. Two examiners independently assessed eligibility and risk of bias and extracted data.

Results

There was improvement in 75.6% of the 41 patients submitted to HBO, with positive effects on pain relief and decreased size and number of lesions at a faster rate, with better effects when the drug was discontinued. For LIL, 158 (64.2%) of the 246 patients/sites improved the symptoms and 98 (39.8%) healed completely. Fourteen (17.3%) of the 81 patients treated with PRP significantly improved the symptoms and 65 (80.2%) completely healed.

Conclusions

These therapies served as safe and effective adjuvant modalities for MRONJ treatment. The lack of randomized clinical trials evidences the need for more high‐quality investigations on the subject.
Effect on surgical decisions: Ulipristal acetate as key player in Belgian phase IV registration trial
Authors: Verguts Jasper , Godin Pierre Arnaud , De Vree Bart , Donnez Olivier , Cosyns Stefan , Luyckx Mathieu , Nisolle Michelle
Published: September 2019

Objective

To observe alterations in surgical planning that were due to the use of ulipristal acetate (UPA) 5 mg daily for symptomatic uterine fibroids.

Methods

A prospective cohort trial involving women with symptomatic fibroids was undertaken in 23 clinical practice sites within Belgium between October 1, 2014, and March 31, 2016, to compare initial surgical planning to performed surgical procedures following the use of UPA 5 mg daily for 3 months. Secondary outcomes were surgical complications, reduction in fibroids, bleeding control, and adverse effects.

Results

Two hundred and twenty‐two women were recruited for the trial. The requirement for surgery decreased with the use of UPA, with 54% of women undergoing surgery after treatment. The reduction in surgery performed was lower for women willing to conceive (40%) compared to women who were not (49%). The volume of the fibroids decreased significantly, with the largest measured fibroid decreasing by 50%. Bleeding and pain were significantly decreased with the use of UPA. No major complications were recorded, and no liver function abnormalities were reported during the treatment and in follow‐up.

Conclusion

By administering UPA, the required rate of surgery was significantly decreased. Also, the resulting reduction in size of the fibroids could have the potential benefit of reducing surgery‐related complications, and long‐term use may be warranted to avoid surgery completely.
The Importance of Biologically Active Vitamin D for Mineralization by Osteocytes After Parathyroidectomy for Renal Hyperparathyroidism
Authors: Yajima Aiji , Tsuchiya Ken , Burr David B , Wallace Joseph M , Damrath John D , Inaba Masaaki , Tominaga Yoshihiro , Satoh Shigeru , Nakayama Takashi , Tanizawa Tatsuhiko , Ogawa Hajime , Ito Akemi , Nitta Kosaku
Published: September 2019

Hypomineralized matrix is a factor determining bone mineral density. Increased perilacunar hypomineralized bone area is caused by reduced mineralization by osteocytes. The importance of vitamin D in the mineralization by osteocytes was investigated in hemodialysis patients who underwent total parathyroidectomy (PTX) with immediate autotransplantation of diffuse hyperplastic parathyroid tissue. No previous reports on this subject exist. The study was conducted in 19 patients with renal hyperparathyroidism treated with PTX. In 15 patients, the serum calcium levels were maintained by subsequent administration of alfacalcidol (2.0 μg/day), i.v. calcium gluconate, and oral calcium carbonate for 4 weeks after PTX (group I). This was followed in a subset of 4 patients in group I by a reduced dose of 0.5 μg/day until 1 year following PTX; this was defined as group II. In the remaining 4 patients, who were not in group I, the serum calcium (Ca) levels were maintained without subsequent administration of alfacalcidol (group III). Transiliac bone biopsy specimens were obtained in all groups before and 3 or 4 weeks after PTX to evaluate the change of the hypomineralized bone area. In addition, patients from group II underwent a third bone biopsy 1 year following PTX. A significant decrease of perilacunar hypomineralized bone area was observed 3 or 4 weeks after PTX in all group I and II patients. The area was increased again in the group II patients 1 year following PTX. In group III patients, an increase of the hypomineralized bone area was observed 4 weeks after PTX. The maintenance of a proper dose of vitamin D is necessary for mineralization by osteocytes, which is important to increase bone mineral density after PTX for renal hyperparathyroidism. © 2019 The Authors. JBMR Plus published by Wiley Periodicals, Inc. on behalf of American Society for Bone and Mineral Research.
A CTGF-RUNX2-RANKL Axis in Breast and Prostate Cancer Cells Promotes Tumor Progression in Bone
Authors: Kim Bongjun , Kim Haemin , Jung Suhan , Moon Aree , Noh Dong-Young , Lee Zang Hee , Kim Hyung Joon , Kim Hong-Hee
Published: September 2019

Metastasis to bone is a frequent occurrence in patients with breast and prostate cancers and inevitably threatens the patient's quality of life and survival. Identification of cancer-derived mediators of bone metastasis and osteolysis may lead to novel therapeutic strategies. In this study, we established highly bone-metastatic PC3 prostate and MDA-MB-231 (MDA) breast cancer cell sublines by in vivo selection in mice. In bone-metastatic cancer cells, the expression and secretion of connective tissue growth factor (CTGF) were highly upregulated. CTGF knockdown in bone-metastatic cells decreased invasion activity and MMP expression. RUNX2 overexpression in the CTGF knockdown cells restored the invasion activity and MMP expression. In addition, CTGF increased RUNX2 protein stability by inducing its acetylation via p300 acetyl transferase. The integrin αvβ3 receptor mediated these effects of CTGF. Furthermore, CTGF promoted RUNX2 recruitment to the RANKL promoter, resulting in increased RANKL production from the tumor cells and subsequent stimulation of osteoclastogenesis from precursor cells. In addition, animal model with injection of CTGF knocked-down prostate cancer cells into 6-week old BALB/c male mice showed reduced osteolytic lesions. More importantly, the expression levels of CTGF and RANKL showed a strong positive correlation in human primary breast tumor tissues and were higher in bone metastases than in other site metastases. These findings indicate that CTGF plays crucial roles for osteolytic bone metastasis both by enhancing invasiveness of tumor cells and by producing RANKL for osteoclastogenesis. Targeting CTGF may lead to the development of effective preventive and therapeutic strategies for osteolytic metastasis. © 2019 American Society for Bone and Mineral Research.
Secular Trends of Hip Fractures in Lebanon, 2006 to 2017: Implications for Clinical Practice and Public Health Policy in the Middle East Region
Authors: Saad Randa K , Harb Hilda , Bou-Orm Ibrahim R , Ammar Walid , El-Hajj Fuleihan Ghada
Published: September 2019

Country-specific hip fracture incidence rates (IRs) and longevity allow the Fracture Risk Assessment Tool (FRAX) to be adapted to individual countries. Secular trends can affect tool calibration. Data on hip fracture IRs in the Middle East is scarce, and long-term secular trend studies are nonexistent. Using the Ministry of Public Health hip fracture registry, we calculated age- and sex-specific hip fracture IRs in Lebanon, from 2006 to 2017, among individuals aged ≥50 years. We used Kendall's tau-b (τb) test to determine the correlation between time and hip fracture IRs, and calculated both the annual % change in IRs and the % change in IR compared to the baseline period (2006 to 2008). The registry recorded 6985 hip fractures, 74% at the femoral neck, 23% intertrochanteric, and 3% subtrochanteric. Men constituted 32% of the population, and were significantly younger than women (76.5 ± 11.0 years versus 77.7 ± 10.3 years; p < 0.001). Annual overall IRs, per 100,000, ranged from 126.6 in 2014 to 213.2 in 2017 in women, and 61.4 in 2015 to 111.7 in 2017 in men. The average women to men IR ratio was 1.8 (range, 1.5 to 2.1). IRs steadily increased with age, and IR ratios increased in parallel in both sexes, with a steeper and earlier rise (by 5 years) in women. Data showed a consistent decline in hip fracture IRs starting in 2006 in women, and in 2009 in men. There was a significant negative correlation between time (2006 to 2014) and hip fracture IRs in women (τb = −0.611, p = 0.022) but not in men (τb = −0.444, p = 0.095). The steady decrease in IRs reversed after 2015 in both sexes. This long-term data on secular trends in the Middle East is novel and consistent with worldwide changes in hip fracture rates. The impact of such changes on national FRAX-derived estimates is unclear, should be assessed, and may necessitate an update in the FRAX Lebanon calculator. © 2019 American Society for Bone and Mineral Research.
A six‐CpG‐based methylation markers for the diagnosis of ovarian cancer in blood
Authors: Wang Lei , Ni Sha , Du Zhenhua , Li Xiuqin
Published: September 2019

DNA methylation markers in the peripheral blood are able to be applied to treat epithelial cancer. Nevertheless, the diagnostic potential value of it for ovarian cancer (OV) has not been studied. The study aimed to explore the difference of DNA methylation in peripheral blood between OV patients and healthy women. Firstly, the whole blood of DNA methylation data was provided by the Gene Expression Omnibus (GEO) database. The linear model was applied to the identification of significantly differentially expressed methylated CpG sites (differentially methylation sites [DMP]), and the further screen of co‐expression CpG sites (Co‐DMP). A total of 2812 DMPs were identified, and weighted gene co‐expression network analysis helped to obtain seven co‐expression modules. Among them, the yellow module was the most related to OV. Co‐DMPs (167) in the yellow module were mainly distributed near the transcription start sites. However, most of them were not in the CpG island. Least absolute shrinkage and selection operator (LASSO) regression analysis was applied to the identification of stable OV‐related blood biomarkers that six Co‐DMPs (cg00134539, cg00226923, cg25268718, cg25697314, cg25839227, cg26574610) with the highest frequency were found as potential biomarkers. Finally, the diagnostic classifier was established using the support vector machine (SVM) with the accuracy rate of 87.1% and 74.5% in training data set and validation data set, respectively. To sum up, a new feature was provided here for the diagnosis of OV, which is helpful for the diagnosis and individualized treatments of early OV.
Working through shame with an intercultural couple in Japan: Transforming negative emotional interactions and expanding positive emotional resources
Authors: Iwakabe Shigeru
Published: September 2019

Japan is often described as an intricate yet contradictory society in which the elements of the most advanced technologies and ancient cultural traditions coexist. Social cohesion rooted in uniformity and ethnic purity has long been the implicit, normative ideal in Japan, while diversity as intrinsic value is still a relatively new concept. In this monocultural milieu, intercultural couples often encounter issues associated with culturally‐bound notions of gender roles and the societal pressure to conform to the implicit cultural ideal. The distress of unresolved past emotional injuries may also surface, which often results in the couple getting stuck in negative emotional cycles. This paper will discuss the case of Yoko and Frank, who were treated with an affect‐focused approach in which their emotional conflicts, particularly their feelings of shame, were worked through while each partner developed their self‐ and other‐emotion regulating capacity. The therapist also helped the couple develop new patterns of positive emotional interaction.
Age‐Dependent Changes of Kidney Injury Biomarkers in Pediatrics
Authors: van Donge Tamara , Welzel Tatjana , Atkinson Andrew , van den Anker John , Pfister Marc
Published: September 2019

Currently used creatinine‐based parameters for monitoring kidney function are not reliable for early detection of kidney injury (KI), particularly tubular damage. Several KI biomarkers allow for early detection of glomerular and tubular damage and may help to prevent drug‐related chronic kidney diseases in pediatrics. This literature review describes the state of current research and investigates reference values for these KI biomarkers in neonates, infants, and children to better understand age‐related changes. A total of 12 of 237 screened studies fulfilled predefined criteria, including 219 preterm neonates, 70 neonates, 596 infants, and 1726 children. KI biomarkers were analyzed in urine (6 studies), in serum/plasma (5 studies) and in serum and urine (1 study). Four studies (n = 555) measured urinary kidney injury molecule‐1, whereas urinary neutrophil gelatinase‐associated lipocalin was assessed in 5 studies (n = 888), and 2 studies (n = 203) investigated serum cystatin C. This review of KI biomarkers in different pediatric age groups indicates that (1) the majority of KI biomarkers are measured in urine; (2) the 3 most commonly analyzed KI biomarkers are urinary neutrophil gelatinase‐associated lipocalin, urinary kidney injury molecule‐1, and serum cystatin C; (3) values of KI biomarkers appear to decrease from prematurity to infancy; and (4) there is an unmet need to further enhance knowledge on age‐dependent changes of KI biomarkers in pediatrics. Studies are needed to better characterize reference values for these key KI biomarkers in healthy pediatric populations and to evaluate the value of these markers in the early detection of drug‐related KI in neonates, infants, and children.
Decarboxylation of stearic acid over Ni/MOR catalysts
Authors: Crawford James M , Zaccarine Sarah F , Kovach Nolan C , Smoljan Courtney S , Lucero Jolie , Trewyn Brian G , Pylypenko Svitlana , Carreon Moises A
Published: September 2019

BACKGROUND

Oils derived from plants, animal fats, and algae contain both saturated and unsaturated fatty acids. These fatty acids can be converted into liquid fuels and chemicals in the presence of active solid catalysts.

RESULTS

Nickel‐based catalysts were supported on mordenite via ion exchange synthesis and evaluated for the deoxygenation of stearic acid to diesel fuels. By tuning the synthesis pH, loadings of over 20 wt% Ni were obtained. Catalysts synthesized at pH 8.5 displayed the highest Ni loading and the highest activity for the decarboxylation/decarbonylation of stearic acid under inert nitrogen gas atmospheres, yielding 47% heptadecane. Characterization included scanning transmission electron microscopy‐energy‐dispersive spectroscopy (STEM‐EDS), X‐ray diffraction (XRD), field emission scanning electron microscopy (FE‐SEM), inductively coupled plasma atomic emission spectroscopy (ICP‐AES), N2 physisorption and thermogravimetric analysis (TGA), providing new insights into the recyclability of the catalyst. The observed loss of catalytic activity upon recycling was attributed to the agglomeration of Ni nanoparticles and the accumulation of carbonaceous coke.

CONCLUSION

This work demonstrates that Ni‐based catalysts supported on mordenite zeolite can effectively convert stearic acid into heptadecane. Yields to heptadecane were as high as 47%. Mechanistically, the reaction proceeds by decarboxylation and decarbonylation pathways. © 2019 Society of Chemical Industry
Efficacy and safety of chloroquine plus prednisone for the treatment of autoimmune hepatitis in a randomized trial
Authors: T de Moraes Falcão Lydia , Terrabuio Debora R B , Diniz Marcio A , da Silva Evangelista Andreia , Souza Fabricio G , R Cancado Eduardo L
Published: September 2019

Background and Aim

Standard treatment for autoimmune hepatitis (AIH) consists of predniso(lo)ne and azathioprine. However, alternative therapy is required for non‐ or partial responders and in cases of side effects. The aim of this study was to evaluate the treatment outcomes associated with chloroquine plus prednisone in AIH patients.

Methods

Fifty‐seven patients were recruited to receive either azathioprine or chloroquine, both with prednisone, in a randomized trial. The primary end‐point was complete remission, based on normalization of aminotransferase levels in the first 6 months of treatment plus maintenance for at least 18 months, with minimal or no inflammatory activity in the liver biopsy. Secondary end‐points were partial and nonresponse, severe side effects, and treatment withdrawal.

Results

There were no differences between groups regarding clinical, serological, histological, and treatment characteristics at baseline. There were no significant differences in the biochemical response rate (67.7 vs 53.8%, P = 0.41) or the complete remission rate (32.26 vs 15.38%, P = 0.217). However, despite the long study period, the sample size was smaller than that required for a noninferiority study. The mean prednisone dose was similar in both groups. There was a nonsignificantly higher rate of adverse effects and a tendency toward improvement in glycemic and cholesterol profiles in the chloroquine group (P = 0.09 and P = 0.07, respectively).

Conclusions

The combination of chloroquine and prednisone exhibited potentially beneficial effects in AIH patients (ClinicalTrials.gov: NCT02463331).
Synthesis of novel 2,3‐disubstituted quinazolin‐4(3H)‐one derivatives containing hydrazone skeleton as potent urease inhibitors and their antimicrobial activities
Authors: Akyüz Gülay , Beriş Fatih Şaban , Kahveci Bahittin , Menteşe Emre
Published: September 2019

A new series of quinazolinones containing hydrazone moiety were synthesized, and their inhibitory activities on urease were assessed in vitro. Most of the compounds exhibited potent urease inhibitory activity. Among the synthesized compounds, molecule 4a bearing furan ring has the best inhibitory effect against urease with IC50 = 2.90 ± 0.11 μg/mL. Compounds 4f, 4g, 4h, 4i, and 4j have hydroxy group on phenyl ring. Compound 4i is the most active inhibitor among these compounds with IC50 = 5.01 ± 0.10 μg/mL, which has 3‐Cl and 4‐Br on phenyl ring. Also, newly synthesized compounds had been tested for their antimicrobial effects against three of Gram‐positive bacteria (Bacillus cereus 702 Roma, Staphylococcus aureus ATCC 25923, and Streptococcus pyogenes ATCC 19615) and three of Gram‐negative bacteria (Escherichia coli ATCC 25922, Proteus vulgaris ATCC 13315, and Pseudomonas aeruginosa ATCC 27853). Antimicrobial activity results show that compounds 4a, 4h, 4j, 4f, and 4l have the lowest minimum inhibitory concentration (MIC) value of 1000 μg/mL to all tested bacteria. The other compounds have the MIC value of >1000 μg/mL to all tested bacteria.
The first European guidelines on phenylketonuria: Usefulness and implications for BH4 responsiveness testing
Authors: Evers Roeland A. F. , van Wegberg Annemiek M. J. , Anjema Karen , Lubout Charlotte M. A. , van Dam Esther , van Vliet Danique , Blau Nenad , van Spronsen Francjan J.
Published: September 2019

Objective

This study aimed to investigate and improve the usefulness of the 48‐hour BH4 loading test and to assess genotype for BH4 responsiveness prediction, using the new definition of BH4 responsiveness from the European guidelines, as well as an amended definition.

Method

Applying the definition of the European guidelines (≥100% increase in natural protein tolerance) and an amended definition (≥100% increase in natural protein tolerance or tolerating a safe natural protein intake) to a previous dataset, we first assessed the positive predictive value (PPV) of the 48‐hour BH4 loading test using a cutoff value of 30%. Then, we tried to improve this PPV by using different cutoff values and separate time points. Last, using the BIOPKU database, we compared predicted BH4 responsiveness (according to genotype) and genotypic phenotype values (GPVs) in BH4‐responsive and BH4‐unresponsive patients.

Results

The PPV of the 48‐hour loading test was 50.0% using the definition of the European guidelines, and 69.4% when applying the amended definition of BH4 responsiveness. Higher cutoff values led to a higher PPV, but resulted in an increase in false‐negative tests. Parameters for genotype overlapped between BH4‐responsive and BH4‐unresponsive patients, although BH4 responsiveness was not observed in patients with a GPV below 2.4.

Conclusion

The 48‐hour BH4 loading test is not as useful as previously considered and cannot be improved easily, whereas genotype seems mainly helpful in excluding BH4 responsiveness. Overall, the definition of BH4 responsiveness and BH4 responsiveness testing require further attention.
Variations of peel essential oils during fruit ripening in four lemon (Citrus limon (L.) Burm. F.) cultivars
Authors: Di Rauso Simeone Giuseppe , Di Matteo Antonio , Rao Maria Antonietta , Di Vaio Claudio
Published: September 2019

BACKGROUND

Lemon processing procedures yield a significant amount of waste as peels, which are 57% of processed lemons and represent a possible source of bioactive compounds (essential oils, EOs). EOs were extracted from lemon fruits belonging to four cultivars harvested at four different sampling times (25 October, 23 November, 20 December, 1 February), characterized, and quantified through gas chromatography–mass spectrometry.

RESULTS

The chemical composition of EOs highlighted that 26 compounds of the four lemon cultivars at the different ripening stages were clearly identified. The compounds analysed belonged to four chemical classes: monoterpene hydrocarbons, oxygenated monoterpenes, sesquiterpenes, and fatty alcohol esters. Among the monoterpene hydrocarbons, d‐limonene, β‐pinene, and γ‐terpinene were the most abundant; and among the oxygenated monoterpenes, α‐terpineol, nerol, and geraniol were the most abundant. Quantitative gas chromatography–mass spectrometry analysis of the most abundant monoterpene hydrocarbons (α‐pinene, β‐pinene, myrcene, d‐limonene, and γ‐terpinene) highlighted that the amount of EOs decreased during ripening stages. ‘Ovale di Sorrento’ and ‘Sfusato Amalfitano’ showed the highest level of EOs in December, whereas in ‘Femminello Cerza’ and ‘Femminello Adamo’ this occurred in November. EOs, as well as the phenolic compounds, were positively correlated with the antioxidant activity (2,2′‐azino‐bis(3‐ethylbenzothiazoline‐6‐sulphonic acid).

CONCLUSIONS

EOs reached the highest level in the four lemon cultivars at different ripening stages. Campanian cultivars (‘Ovale di Sorrento’ and ‘Sfusato Amalfitano’) showed the greatest EO content in November, whereas in Sicilian cultivars (‘Femminello Cerza’ and ‘Femminello Adamo’) this occurred in December. Besides phenolic compounds, measured in lemon peel extracts, EOs can contribute to antioxidant activity, as demonstrated by the positive correlation. © 2019 Society of Chemical Industry
Natural History of Ventriculomegaly in Fetal Agenesis of the Corpus Callosum
Authors: Masmejan Sophie , Blaser Susan , Keunen Johannes , Seaward Gareth , Windrim Rory , Kelly Edmond , Ryan Greg , Baud David , Van Mieghem Tim
Published: September 2019

Objectives

To assess the natural evolution of the size of the fetal lateral ventricles throughout pregnancy in fetuses with callosal anomalies.

Methods

Cases of fetal callosal anomalies were retrospectively classified as isolated or complex based on the presence of other structural or genetic anomalies. Longitudinal ultrasound studies were reviewed, and postnatal outcomes were retrieved for isolated cases.

Results

In 135 fetuses, those who first presented after 24 weeks’ gestation were more likely to have ventriculomegaly (n = 58 of 68 [85%]) than those who presented before 24 weeks (n = 39 of 67 [58%]; P < .001). In 79 cases that had longitudinal follow‐up, the mean increase in ventricular width was 0.6 mm/wk, without a significant difference between isolated and complex cases (mean ± SD, 0.6 ± 1.5 versus 0.6 ± 1.1 mm; P = .45).

Conclusions

Callosal anomalies are associated with progressive ventriculomegaly on prenatal ultrasound imaging, without a difference between isolated and complex anomalies. This feature should be considered part of the disease spectrum. The consequence of progressive ventriculomegaly on the long‐term neurodevelopmental outcome is still unknown, and further studies should be aimed at obtaining long‐term follow‐up of these cases.
Antiviral Therapy in Patients With Chronic Hepatitis C Is Associated With a Reduced Risk of Parkinsonism
Authors: Su Tung‐Hung , Yang Hung‐Chih , Tseng Tai‐Chung , Chou Shih‐Wan , Lin Chin‐Hsien , Liu Chen‐Hua , Liu Chun‐Jen , Chen Chi‐Ling , Kao Jia‐Horng
Published: September 2019

Background

The risk of parkinsonism after antiviral treatment against chronic hepatitis C (CHC) is unclear.

Objectives

To investigate the association between CHC and parkinsonism and the efficacy of antiviral therapy.

Methods

Using the National Health Insurance Research Database of Taiwan from 2004 to 2012, patients with and without CHC, patients receiving pegylated interferon‐based antiviral therapy, and those without such therapy were matched by age, gender, and comorbidities by propensity scores and followed for new diagnoses of parkinsonism and Parkinson's disease (PD). Multivariable Cox proportional hazards regression analyses were performed.

Results

Overall, 49,342 patients with CHC were matched with 49,342 non‐CHC patients. After adjustment for confounding factors, there was a significantly increased risk (31%) of parkinsonism (hazard ratio [HR] 1.306; 95% confidence interval [CI], 1.208–1.412) in those with CHC and the risk of parkinsonism requiring anti‐Parkinson medication (HR 1.323; 95% CI, 1.214–1.441). Furthermore, 23,647 untreated CHC patients were matched with 23,647 patients receiving antiviral therapy. Patients receiving antiviral therapy had a significantly lower risk of developing parkinsonism (38%; HR 0.618; 95% CI, 0.498–0.765) and a reduced risk of parkinsonism requiring anti‐Parkinson medication (HR 0.651; 95% CI, 0.515–0.823). In sensitivity analyses, antiviral therapy significantly reduced the risk of parkinsonism and PD after adjustment for detection, selection, disease latency biases, and competing mortality. Our results suggest successful antiviral therapy associates with a reduced risk of hepatitis C virus–related parkinsonism compared with those with treatment failure.

Conclusions

CHC infection is associated with an increased risk of parkinsonism or PD. Antiviral therapy against CHC is associated with a reduced risk of parkinsonism or PD. © 2019 International Parkinson and Movement Disorder Society
Energy decay to Timoshenko system with indefinite damping
Authors: Fatori Luci H. , Saito Tais O. , Sepúlveda Mauricio , Takahashi Renan
Published: September 2019

We consider the classical Timoshenko system for vibrations of thin rods. The system has an indefinite damping mechanism, ie, it has a damping function a=a(x) possibly changing sign, present only in the equation for the vertical displacement. We shall prove that exponential stability depends on conditions regarding of the indefinite damping function a and a nice relationship between the coefficient of the system. Finally, we give some numerical result to verify our analytical results.
An analytical model for the upper bound estimation of respiratory motion–induced dose uncertainty in spot‐scanning proton beam therapy
Authors: Li Heng , Zhang Xiaodong , Li Yupeng , Zhu Ronald X.
Published: September 2019

Purpose

We developed an analytical model of a spot‐scanning beam delivery system to estimate the upper bound of respiratory motion–induced dose uncertainty for a given treatment plan.

Methods

The effective delivery time for each spot position in the treatment plan was calculated on the basis of the parameters of the delivery system. The upper bound of the dose uncertainty was then calculated as a function of the effective delivery time. Two‐dimensional (2D) measurements with a detector array on a one‐dimensional moving platform were obtained to validate the model.

Results

We performed 351 two‐dimensional measurements on a moving platform for different delivery sequences of a single‐layer uniform pattern and patient treatment field. The measured dose uncertainty was a strong function of the effective delivery time: The shortest effective delivery time resulted in a maximum absolute dose error of >90%, while the longest ones resulted in a maximum absolute dose error of 4.9% for a single layer and 9.7% for a patient field with heterogeneity. The relationship of the effective delivery time and the measured dose uncertainty followed the analytical formula.

Conclusions

With our analytical model, the upper bound of the dose uncertainty due to motion can be estimated in spot‐scanning proton therapy without four‐dimensional dynamic dose calculation.
Extracting more for less: multi‐echo MP2RAGE for simultaneous T1‐weighted imaging, T1 mapping, mapping, SWI, and QSM from a single acquisition
Authors: Sun Hongfu , Cleary Jon O. , Glarin Rebecca , Kolbe Scott C. , Ordidge Roger J. , Moffat Bradford A. , Pike G. Bruce
Published: September 2019

Purpose

To demonstrate simultaneous T1‐weighted imaging, T1 mapping, mapping, SWI, and QSM from a single multi‐echo (ME) MP2RAGE acquisition.

Methods

A single‐echo (SE) MP2RAGE sequence at 7 tesla was extended to ME with 4 bipolar gradient echo readouts. T1‐weighted images and T1 maps calculated from individual echoes were combined using sum of squares and averaged, respectively. ME‐combined SWI and associated minimum intensity projection images were generated with TE‐adjusted homodyne filters. A QSM reconstruction pipeline was used, including a phase‐offsets correction and coil combination method to properly combine the phase images from the 32 receiver channels. Measurements of susceptibility, , and T1 of brain tissue from ME‐MP2RAGE were compared with those from standard ME‐gradient echo and SE‐MP2RAGE.

Results

The ME combined T1‐weighted, T1 map, SWI, and minimum intensity projection images showed increased SNRs compared to the SE results. The proposed coil combination method led to QSM results free of phase‐singularity artifacts, which were present in the standard adaptive combination method. T1‐weighted, T1, and susceptibility maps from ME‐MP2RAGE were comparable to those obtained from SE‐MP2RAGE and ME‐gradient echo, whereas maps showed increased blurring and reduced SNR. T1, , and susceptibility values of brain tissue from ME‐MP2RAGE were consistent with those from SE‐MP2RAGE and ME‐gradient echo.

Conclusion

High‐resolution structural T1 weighted imaging, T1 mapping, mapping, SWI, and QSM can be extracted from a single 8.5‐min ME‐MP2RAGE acquisition using a customized reconstruction pipeline. This method can be applied to replace separate SE‐MP2RAGE and ME‐gradient echo acquisitions to significantly shorten total scan time.
Identification and Validation of Stage‐Associated Serum Biomarkers in Colorectal Cancer Using MS‐Based Procedures
Authors: Marín‐Vicente Consuelo , Mendes Marta , de los Ríos Vivian , Fernández‐Aceñero Mª Jesús , Casal J. Ignacio
Published: September 2019

Purpose

Successful prevention of colorectal cancer (CRC) would benefit from a rapid serum screening for early detection. Here, a novel strategy for CRC biomarker discovery and validation exclusively based on MS procedures is reported.

Experimental design

Identification of CRC serum biomarkers is initially made using label‐free quantification on pooled serum samples from different CRC stages followed by two consecutive steps of targeted parallel reaction monitoring assays in different serum cohorts. Relevance of different protein depletion and peptide fractionation extent is investigated. Absolute quantification of a selected peptide is performed as a proof‐of‐concept.

Results

A total of 945 proteins showed differential abundance in the discovery phase. Based on their statistical significance and relative expression in disease stages, 123 potential biomarkers are selected for a training step. In the final validation step, five peptides belonging to four proteins are consistently quantified in individual CRC serum samples and controls. Different statistical analyses indicate that peptides GWVTDGFSSLK (APOC3) and LCNNPTPQFGGK (THBS1) are candidate biomarkers. Absolute quantification of LCNNPTPQFGGK shows statistical significance for the diagnosis of early respect to late CRC stages.

Conclusions and clinical relevance

Two peptides from APOC3 and THBS1 are validated by PRM as potential biomarkers for non‐invasive diagnosis of colorectal cancer.
Incidence of androgen receptor and androgen receptor variant 7 coexpression in prostate cancer
Authors: Vellky Jordan E. , Bauman Tyler M. , Ricke Emily A. , Huang Wei , Ricke William A.
Published: September 2019

Background

Prostate cancer (PRCA) is an androgen‐driven disease, where androgens act through the androgen receptor (AR) to induce proliferation and survival of tumor cells. Recently, AR splice variant 7 (ARv7) has been implicated in advanced stages of PRCA and clinical recurrence. With the widespread use of AR‐targeted therapies, there has been a rising interest in the expression of full‐length AR and ARv7 in PRCA progression and how these receptors, both independently and together, contribute to adverse clinicopathologic outcomes.

Methods

Despite a multitude of studies measuring the expression levels of AR and ARv7 in PRCA progression, the results have been inconsistent and sometimes contradictory due to technical and analytical discrepancies. To circumvent these inconsistencies, we used an automated multiplexed immunostaining platform for full‐length AR and ARv7 in human PRCA samples and objectively quantified expression changes with machine learning‐based software. With this technology, we can assess receptor prevalence both independently, and coexpressed, within specific tissue and cellular compartments.

Results

Full‐length AR and ARv7 expression increased in epithelial nuclei of metastatic samples compared to benign. Interestingly, a population of cells with undetectable AR persisted through all stages of PRCA progression. Coexpression analyses showed an increase of the double‐positive (AR+/ARv7+) population in metastases compared to benign, and an increase of the double‐negative population in PRCA samples compared to benign. Importantly, analysis of clinicopathologic outcomes associated with AR/ARv7 coexpression showed a significant decrease in the double‐positive population with higher Gleason score (GS), as well as in samples with recurrence in under 5 years. Conversely, the double‐negative population was significantly increased in samples with higher GS and in samples with recurrence in under 5 years.

Conclusions

Changes in AR and ARv7 coexpression may have prognostic value in PRCA progression and recurrence. A better understanding of the prevalence and clinicopathologic outcomes associated with changes in these receptors' coexpression may provide a foundation for improved diagnosis and therapy for men with PRCA.
Computationally efficient inference for center effects based on restricted mean survival time
Authors: Wang Xin , Zhong Yingchao , Mukhopadhyay Purna , Schaubel Douglas E.
Published: September 2019

Restricted mean survival time (RMST) has gained increased attention in biostatistical and clinical studies. Directly modeling RMST (as opposed to modeling then transforming the hazard function) is appealing computationally and in terms of interpreting covariate effects. We propose computationally convenient methods for evaluating center effects based on RMST. A multiplicative model for the RMST is assumed. Estimation proceeds through an algorithm analogous to stratification, which permits the evaluation of thousands of centers. We derive the asymptotic properties of the proposed estimators and evaluate finite sample performance through simulation. We demonstrate that considerable decreases in computational burden are achievable through the proposed methods, in terms of both storage requirements and run time. The methods are applied to evaluate more than 5000 US dialysis facilities using data from a national end‐stage renal disease registry.
Synthesis of Nickel Ferrite Nanoparticles Supported on Graphene Nanosheets as Composite Electrodes for High Performance Supercapacitor
Authors: Soam Ankur , Kumar Rahul , Sahoo Prasanta Kumar , Mahender C. , Kumar Balwant , Arya Nitin , Singh Mamraj , Parida Smrutiranjan , Dusane Rajiv O
Published: September 2019

This study presents a fabrication and electrochemical properties of nickel ferrite/graphene nanocomposite as electrodes material for supercapacitor application. The as‐prepared electrode was characterized using X‐ray diffraction, scanning electron microscopy, transmission electron microscopy and X‐ray photoelectron spectroscopy. The electrochemical properties were measured using cyclic voltammetry, galvanostatic charging/discharging methods and electrochemical impedance spectroscopy. Graphene nanosheets play an important role of governing the morphology of the electrode material and thereby enhancing the electrochemical performance of the composite electrode. The specific capacitance of 207 F/g is obtained for nickel ferrite/graphene nanocomposite, which is almost 4 times larger than pure nickel ferrite. The nanocomposite showed a stable capacitance of 95% after 1000 cycles in 1 M Na2SO4 electrolyte. Electrochemical impedance spectroscopy results indicate that graphene nanosheets reduced the charge transfer resistance on the composite electrode. The obtained results show that the nanocomposite has a great potential to be used in supercapacitor with good electrochemical performance and longer cycle stability.