bluuebunny/crossref_metadata_2025 huggingface dataset:
Conformation and cooperative order‐disorder transition in aqueous solutions of β‐1,3‐d‐glucan with different degree of branching varied by the Smith degradation
Authors: Yoshiba Kazuto , Saheki Toshihiko , Christensen Bjørn E. , Dobashi Toshiaki
Published: June 2019

β‐1,3‐d‐glucan with different degrees of branching were obtained by selectively and gradually removing side chains from schizophyllan, a water‐soluble triple helical polysaccharide, using the Smith degradation. Size exclusion chromatography combined with a multi‐angle light scattering detection was performed in aqueous 0.1 M NaCl. The degree of branching decreased after the Smith degradation, while the molar mass distributions were almost unchanged. The molecular conformation of the Smith‐degraded β‐1,3‐d‐glucan was analyzed on the basis of the molar mass dependency of the radius gyration, and found to be comparable to the original triple helix of schizophyllan. Differential scanning calorimetry in deuterium oxide–hexadeuterodimethylsulfoxide mixtures was performed to investigate the effects of the degree of branching on the cooperative order‐disorder transition. Removal of side chains affects both the transition temperature and transition enthalpy. The ordered structure is formed by the residual side chains in the triplex unit, so that the linear cooperative system of the triplex is maintained after the Smith degradation.
Screwing assembly oriented interactive model segmentation in HMD VR environment
Authors: Zhu Xiaoqiang , Song Lei , Wang Nan , Zhang Ruiheng , Chen Shenshuai , Wang Xiangyang , Zhu Mengyao , You Lihua , Deng Zhigang , Jin Xiaogang
Published: June 2019

Although different approaches of segmenting and assembling geometric models for 3D printing have been proposed, it is difficult to find any research studies, which investigate model segmentation and assembly in head‐mounted display (HMD) virtual reality (VR) environments for 3D printing. In this work, we propose a novel and interactive segmentation method for screwing assembly in the environments to tackle this problem. Our approach divides a large model into semantic parts with a screwing interface for repeated tight assembly. Specifically, after a user places the cutting interface, our algorithm computes the bounding box of the current part automatically for subsequent multicomponent semantic Boolean segmentations. Afterwards, the bolt is positioned with an improved K3M image thinning algorithm and is used for merging paired components with union and subtraction Boolean operations respectively. Moreover, we introduce a swept Boolean‐based rotation collision detection and location method to guarantee a collision‐free screwing assembly. Experiments show that our approach provides a new interactive multicomponent semantic segmentation tool that supports not only repeated installation and disassembly but also tight and aligned assembly.
An optimal checkpointing model with online OCI adjustment for stream processing applications
Authors: Zhuang Yuan , Wei Xiaohui , Li Hongliang , Wang Yongfang , He Xubin
Published: June 2019

Checkpoint‐based fault‐tolerant (FT) methods have been widely used to enhance the reliability of stream processing systems, but a checkpointing process usually introduces considerable overhead. It is a critical issue to choose the optimal checkpoint interval (OCI) that maximizes the processing efficiency. Traditional OCI models consider the recovery time equals to the execution time from the last checkpoint to the failure moment. However, for stream processing jobs, the recovery time is related to reprocessing workloads, depending on the real‐time input data before a failure. A new model is needed to choose the OCI for stream processing applications. Moreover, the input data rate of a stream processing job fluctuates over time. To solve these problems, we present a novel DSPS OCI (DOCI) model in this paper. We prove that it maximizes the processing efficiency for a given time. We propose an approach to dynamically adjust the OCI for an application to accommodate the workload fluctuations. We conduct simulation experiments to verify the effectiveness of our DOCI model and the efficiency of the online OCI adjustment algorithm. Experimental results with a real‐world dataset show that DOCI achieves an improvement on system efficiency by up to 32%, compared with existing FT approaches.
Proteome Analysis Using Gel‐LC‐MS/MS
Authors: Goldman Aaron R. , Beer Lynn A. , Tang Hsin‐Yao , Hembach Peter , Zayas‐Bazan Delaine , Speicher David W.
Published: June 2019

This article describes processing of protein samples using 1D SDS gels prior to protease digestion for proteomics workflows that subsequently utilize reversed‐phase nanocapillary ultra‐high‐pressure liquid chromatography (LC) coupled to tandem mass spectrometry (MS/MS). The resulting LC‐MS/MS data are used to identify peptides and thereby infer proteins present in samples ranging from simple mixtures to very complex proteomes. Bottom‐up proteome studies usually involve quantitative comparisons across several or many samples. For either situation, 1D SDS gels represent a simple, widely available technique that can be used to either fractionate complex proteomes or rapidly clean up low microgram samples with minimal losses. After gel separation and staining/destaining, appropriate gel slices are excised, and in‐gel reduction, alkylation, and protease digestion are performed. Digests are then processed for LC‐MS/MS analysis. Protocols are described for either sample fractionation with high‐throughput processing of many samples or simple cleanup without fractionation. An optional strategy is to conduct in‐solution reduction and alkylation prior to running gels, which is advantageous when a large number of samples will be separated into large numbers of fractions. Optimization of trypsin digestion parameters and comparison to in‐solution protease digestion are also described. © 2019 by John Wiley & Sons, Inc.
Investigation on the Existence of Sex‐By‐Formulation Interaction in Bioequivalence Trials
Authors: González‐Rojano Esperanza , Marcotegui Julio , Ochoa Dolores , Román Manuel , Álvarez Covadonga , Gordon John , Abad‐Santos Francisco , García‐Arieta Alfredo
Published: June 2019

The US Food and Drug Administration recommends that if a drug product is intended for use in both sexes, similar proportions should be recruited for bioequivalence (BE) studies. In contrast, in Europe, subjects can belong to either sex. Literature suggesting the existence of sex‐by‐formulation interaction (S × F) is limited to few studies. To investigate if S × F is observed, this work includes 120 BE studies. Differences larger than 20% between the ratio test/reference of women and men or statistically significant S × F occurred in 25 of 120 studies (20.8%). The prevalence is higher in small studies (36.00% vs. 16.8%). Large differences between the ratios of the sex groups are the tails of the distribution. Two studies were repeated, and the differences between the ratios of the sex groups disappeared. The 90% confidence intervals of S × F did not confirm any relevant S × F. There is no evidence to require studies in both sex groups, combined or separately.
Interparental conflict and gender moderate the prospective link between parents' perceptions of adolescents' weight and weight concerns
Authors: Hochgraf Anna K. , McHale Susan M. , Fosco Gregory M.
Published: June 2019

Objective

Parents' comments about their adolescents' weight have been linked with adolescents' disordered eating, but we know little about the personal and contextual conditions that promote or mitigate the effects of parents' perceptions on adolescents' weight concerns. This study examined whether the prospective association between parents' perceptions of adolescents' weight and adolescents' weight concerns differed as a function of exposure to interparental conflict or adolescent gender.

Method

Participants were 386 adolescents (52% female; ages 11–18 years; predominately Caucasian/European American) from 197 families (i.e., up to two adolescents per family) and their parents. Two‐parent families with a firstborn child in 8th, 9th, or 10th grade and a secondborn child 1–4 years younger were recruited to participate in a short‐term longitudinal study of adolescent development and family relationships. Annual home interviews were conducted with adolescents and parents. Multilevel models tested whether parents' perceptions of adolescents' weight predicted adolescents' weight concerns one year later and whether interparental conflict and youth gender moderated this prospective association.

Results

A significant three‐way interaction revealed that when interparental conflict was low, increases in fathers' but not mothers' perceptions of daughters' overweight predicted increases in daughters' weight concerns the following year. In contrast, females exposed to high interparental conflict reported elevated weight concerns the following year regardless of parents' perceptions. Results for males were not significant.

Discussion

Findings highlight the role of personal and family context characteristics in the development of weight concerns and the value of addressing family processes within preventive interventions for adolescent females' weight concerns.
Assessment of Sublethal Effects of Neonicotinoid Insecticides on the Life-History Traits of 2 Frog Species
Authors: Robinson S.A. , Richardson S.D. , Dalton R.L. , Maisonneuve F. , Bartlett A.J. , de Solla S.R. , Trudeau V.L. , Waltho N.
Published: June 2019

Neonicotinoid insecticides are used extensively in agriculture and, as a consequence, are now detectable in nearby aquatic environments. Few studies have evaluated the effects of neonicotinoids on amphibians in these aquatic environments. In the present study, we examined the effects of 2 commercial formulations of neonicotinoids (active ingredients clothianidin and thiamethoxam) on survival and life-history traits of wood frogs (Lithobates sylvaticus) and northern leopard frogs (Lithobates pipiens). We used artificial pond mesocosms to assess the effects of these neonicotinoids, at nominal concentrations of 2.5 and 250 µg/L, on amphibian larval development through metamorphosis. We found no differences between controls and neonicotinoid exposure for any of the endpoints assessed for either wood frogs or leopard frogs. The present study suggests that concentrations meeting or exceeding observed levels of clothianidin and thiamethoxam in surface waters will not directly affect metamorphosis in 2 amphibians. Environ Toxicol Chem 2019;38:1967–1977. © 2019 Her Majesty the Queen in Right of Canada. Environmental Toxicology and Chemistry published by Wiley Periodicals LLC on behalf of SETAC.
GlialHMOX1expression promotes central and peripheral α‐synuclein dysregulation and pathogenicity in parkinsonian mice
Authors: Cressatti Marisa , Song Wei , Turk Ariana Z. , Garabed Laurianne R. , Benchaya Joshua A. , Galindez Carmela , Liberman Adrienne , Schipper Hyman M.
Published: June 2019

α‐Synuclein is a key player in the pathogenesis of Parkinson disease (PD). Expression of human heme oxygenase‐1 (HO‐1) in astrocytes of GFAP.HMOX1 transgenic (TG) mice between 8.5 and 19 months of age results in a parkinsonian phenotype characterized by neural oxidative stress, nigrostriatal hypodopaminergia associated with locomotor incoordination, and overproduction of α‐synuclein. We identified two microRNAs (miR‐), miR‐153 and miR‐223, that negatively regulate α‐synuclein in the basal ganglia of male and female GFAP.HMOX1 mice. Serum concentrations of both miRNAs progressively declined in the wild‐type (WT) and GFAP.HMOX1 mice between 11 and 19 months of age. Moreover, at each time point surveyed, circulating levels of miR‐153 were significantly lower in the TG animals compared to WT controls, while α‐synuclein protein concentrations were elevated in erythrocytes of the GFAP.HMOX1 mice at 19 months of age relative to WT values. Primary WT neurons co‐cultured with GFAP.HMOX1 astrocytes exhibited enhanced protein oxidation, mitophagy and apoptosis, aberrant expression of genes regulating the dopaminergic phenotype, and an imbalance in gene expression profiles governing mitochondrial fission and fusion. Many, but not all, of these neuronal abnormalities were abrogated by small interfering RNA (siRNA) knockdown of α‐synuclein, implicating α‐synuclein as a potent, albeit partial, mediator of HO‐1's neurodystrophic effects in these parkinsonian mice. Overexpression of HO‐1 in stressed astroglia has previously been documented in the substantia nigra of idiopathic PD and may promote α‐synuclein production and toxicity by downmodulating miR‐153 and/or miR‐223 both within the CNS and in peripheral tissues.
Factors for predicting reversion from mild cognitive impairment to normal cognition: A meta‐analysis
Authors: Xue HuiPing , Hou Ping , Li YongNan , Mao Xin'e , Wu LinFeng , Liu YongBing
Published: June 2019

Objective

Subjects with mild cognitive impairment (MCI) may revert to normal cognition (NC), but predictive factors are under study. We therefore sought to identify factors which could help in predicting reversion from MCI to NC.

Methods

Relevant studies were retrieved from PubMed, EMBASE, Cochrane Library, MEDLINE, Web of Science, EBSCO, and OVID. According to the inclusion and exclusion criteria, high‐quality assessments of relevant literatures were conducted, followed by data extraction and meta‐analysis with Stata 12.0 software.

Results

A total of 17 studies with 6829 participants were included in the meta‐analysis. The overall reversion rate is 27.57%. Positive predictive factors were found in younger age (SMD = −0.345, 95% CI, −0.501 to −0.189), higher education level (SMD = 0.337, 95% CI, 0.117‐0.558), no APOE ε4 allele (OR = 0.728, 95% CI, 0.575‐0.922), no hypertension (OR = 0.826, 95% CI, 0.692‐0.987), no stroke (OR = 0.696, 95% CI, 0.507‐0.953), and higher Mini‐Mental State Examination (MMSE) score (SMD = 0.707, 95% CI, 0.461‐0.953).

Conclusion

Individuals who are at young age, have higher education level and MMSE score, and have no APOEe4 allele, no hypertension, and no stroke had a high probability to revert from MCI to NC.
Stimuli, presentation modality, and load‐specific brain activity patterns during n‐back task
Authors: Mencarelli Lucia , Neri Francesco , Momi Davide , Menardi Arianna , Rossi Simone , Rossi Alessandro , Santarnecchi Emiliano
Published: June 2019

Working memory (WM) refers to a set of cognitive processes that allows for the temporary storage and manipulation of information, crucial for everyday life skills. WM deficits are present in several neurological, psychiatric, and neurodevelopmental disorders, thus making the full understanding of its neural correlates a key aspect for the implementation of cognitive training interventions. Here, we present a quantitative meta‐analysis focusing on the underlying neural substrates upon which the n‐back, one of the most commonly used tasks for WM assessment, is believed to rely on, as highlighted by functional magnetic resonance imaging and positron emission tomography findings. Relevant published work was scrutinized through the activation likelihood estimate (ALE) statistical framework in order to generate a set of task‐specific activation maps, according to n‐back difficulty. Our results confirm the known involvement of frontoparietal areas across different types of n‐back tasks, as well as the recruitment of subcortical structures, cerebellum and precuneus. Specific activations maps for four stimuli types, six presentation modalities, three WM loads and their combination are provided and discussed. Moreover, functional overlap with resting‐state networks highlighted a strong similarity between n‐back nodes and the Dorsal Attention Network, with less overlap with other networks like Salience, Language, and Sensorimotor ones. Additionally, neural deactivations during n‐back tasks and their functional connectivity profile were examined. Clinical and functional implications are discussed in the context of potential noninvasive brain stimulation and cognitive enhancement/rehabilitation programs.
Phosphorylation of STAT1 serine 727 enhances platinum resistance in uterine serous carcinoma
Authors: Zeng Xiang , Baba Tsukasa , Hamanishi Junzo , Matsumura Noriomi , Kharma Budiman , Mise Yuka , Abiko Kaoru , Yamaguchi Ken , Horikawa Naoki , Hunstman David G. , Mulati Kumuluzi , Kitamura Sachiko , Taki Mana , Murakami Ryusuke , Hosoe Yuko , Mandai Masaki
Published: June 2019

Uterine serous carcinoma (USC) is a highly aggressive histological subtype of endometrial cancers harboring highly metastatic and chemoresistant features. Our previous study showed that STAT1 is highly expressed in USC and acts as a key molecule that is positively correlated with tumor progression, but it remains unclear whether STAT1 is relevant to the malicious chemorefractory nature of USC. In the present study, we investigated the regulatory role of STAT1 toward platinum‐cytotoxicity in USC. STAT1 suppression sensitized USC cells to increase cisplatin‐mediated apoptosis (p < 0.001). Furthermore, phosphorylation of STAT1 was prominently observed on serine‐727 (pSTAT1‐Ser727), but not on tyrosine‐701, in the nucleus of USC cells treated with cisplatin. Mechanistically, the inhibition of pSTAT1‐Ser727 by dominant‐negative plasmid elevated cisplatin‐mediated apoptosis by increasing intracellular accumulation of cisplatin through upregulation of CTR1 expression. TBB has an inhibitory effect on casein kinase 2 (CK2), which phosphorylate STAT1 at serine residues. Sequential treatment with TBB and cisplatin on USC cells greatly reduced nuclear pSTAT1‐Ser727, enhanced intracellular accumulation of cisplatin, and subsequently increased apoptosis. Tumor load was significantly reduced by combination therapy of TBB and cisplatin in in vivo xenograft models (p < 0.001). Our results collectively suggest that pSTAT1‐Ser727 may play a key role in platinum resistance as well as tumor progression in USC. Thus, targeting the STAT1 pathway via CK2 inhibitor can be a novel method for attenuating the chemorefractory nature of USC.
Juvenile cystic adenomyoma mimicking a Mullerian uterine anomaly successfully treated by laparoscopic excision
Authors: Strelec Mihajlo , Banović Maja , Banović Vladimir , Sirovec Alenka
Published: June 2019

A 14‐year‐old patient diagnosed with a juvenile cystic adenomyoma mimicking a Mullerian uterine anomaly successfully treated by a laparoscopic excision.
Hemothorax during miniaturized endoscopic combined intrarenal surgery under ureteroscope‐assisted ultrasound‐guided access
Authors: Tanaka Yutaro , Taguchi Kazumi , Hamamoto Shuzo , Ota Yuya , Oda Risa , Yokota Keisuke , Ando Ryosuke , Okada Atsushi , Tozawa Keiichi , Nakanishi Ryoichi , Yasui Takahiro
Published: June 2019

Introduction

Hemothorax is a rare but life‐threatening complication following mini‐endoscopic combined intrarenal surgery. Herein, we describe a patient with left staghorn kidney stone who presented with hemothorax following mini‐endoscopic combined intrarenal surgery under ureteroscope‐assisted ultrasound‐guided access.

Case presentation

A 47‐year‐old woman with left staghorn kidney stone underwent mini‐endoscopic combined intrarenal surgery, after which she developed shortness of breath. Chest radiography and computed tomography confirmed left hemothorax. Conservative management and left intercostal chest drainage were performed without improvement. Subsequently, video‐assisted thoracoscopic debridement was performed.

Conclusion

Hemothorax is a severe complication of mini‐endoscopic combined intrarenal surgery, which, regardless of accurate access through an ideal renal calyx under ureteroscope‐assisted ultrasound‐guided access, may lead to pleural injury. Refinement of the surgical technique and management after percutaneous nephrolithotomy is the key to avoiding life‐threatening situations.
Classification of mammogram images using the energy probability in frequency domain and most discriminative power coefficients
Authors: Benhassine Nasser Edinne , Boukaache Abdelnour , Boudjehem Djalil
Published: June 2019

The purpose of this work is to develop a computer‐aided diagnosis (CAD) system to assist radiologists in the classification of mammogram images. The CAD system is composed of three main steps. The first step is image preprocessing and segmentation with the seeded region growing algorithm applied on a localized triangular region to remove only the muscle. In the second step of the CAD system, we proposed a novel features extraction method, which consists of three stages. In the first, the discrete cosine transform (DCT) is applied on all obtained regions of interest and then only the upper left corner (ULC) of DCT coefficients is retained. Second, we have applied the energy probability to the ULCs that is used as a criterion for selecting discriminant information. At the last stage, a new Most Discriminative power coefficient algorithm has been proposed to select the most significant features. In the final step of the CAD, the support vector machines, Naive Bayes, and artificial neural network (ANN) classifiers are used to make an effective classification. The evaluation of the proposed algorithm on the mini‐Mammographic Image Analysis Society database shows its efficiency over other recently proposed CAD systems in the literature, whereas an accuracy of 100% can be achieved using ANN with a small number of features.
Apatite minerals derived from collagen phosphorylation modification induce the hierarchical intrafibrillar mineralization of collagen fibers
Authors: Du Tianming , Niu Xufeng , Hou Sen , Li Zhengwei , Li Ping , Fan Yubo
Published: June 2019

Collagen is the critical organic component of bone matrix, which is the template for bone biomineralization. Phosphorylation modification of collagen plays an important role in the process of biomineralization in vivo, but its mechanism on in vitro biomimetic mineralization of bone matrix remains unclear at the molecular level. Sodium tripolyphosphate is used to phosphorylate collagen in this study and new phosphate groups appear on collagen fibrils after phosphorylation modification. The chelating amount of calcium is improved linearly with increasing the phosphorylation degree of collagen fibrils, which demonstrates that the introduced phosphate groups serve as new nucleation sites and participate in the formation of apatite minerals inside the collagen fibers. Stabilized nanosized amorphous calcium phosphate by polyacrylic acid can also permeate into collagen fibers and further transform into another layer of hydroxyapatite minerals. Both layers of apatite minerals eventually induce the formation of hierarchical intrafibrillar mineralization structure within the phosphorylated collagen fibers. The present research enriches the previous biomineralization mechanism of bone matrix, provides a facile strategy for biomimetic mineralization of collagen, and offers the basis for future investigation of the advanced bone substitute materials.
Guidelines on the Use of Therapeutic Apheresis in Clinical Practice – Evidence‐Based Approach from the Writing Committee of the American Society for Apheresis: The Eighth Special Issue
Authors: Padmanabhan Anand , Connelly‐Smith Laura , Aqui Nicole , Balogun Rasheed A. , Klingel Reinhard , Meyer Erin , Pham Huy P. , Schneiderman Jennifer , Witt Volker , Wu Yanyun , Zantek Nicole D. , Dunbar Nancy M. , Schwartz Guest Editor: Joseph
Published: June 2019

The American Society for Apheresis (ASFA) Journal of Clinical Apheresis (JCA) Special Issue Writing Committee is charged with reviewing, updating and categorizing indications for the evidence‐based use of therapeutic apheresis (TA) in human disease. Since the 2007 JCA Special Issue (Fourth Edition), the committee has incorporated systematic review and evidence‐based approaches in the grading and categorization of apheresis indications. This Eighth Edition of the JCA Special Issue continues to maintain this methodology and rigor in order to make recommendations on the use of apheresis in a wide variety of diseases/conditions. The JCA Eighth Edition, like its predecessor, continues to apply the category and grading system definitions in fact sheets. The general layout and concept of a fact sheet that was introduced in the Fourth Edition, has largely been maintained in this edition. Each fact sheet succinctly summarizes the evidence for the use of TA in a specific disease entity or medical condition. The Eighth Edition comprises 84 fact sheets for relevant diseases and medical conditions, with 157 graded and categorized indications and/or TA modalities. The Eighth Edition of the JCA Special Issue seeks to continue to serve as a key resource that guides the utilization of TA in the treatment of human disease.
Self‐assembly: An intriguing relationship between structures of metal complexes and shapes of ancient Chinese characters
Authors: Thanasekaran Pounraj , Luo Tzuoo‐Tsair , Kao Ya‐Chuan , Lin Chih‐Chien , Yang Chen‐I , Lu Kuang‐Lieh
Published: June 2019

Self‐assembly is a fundamental principle, which generates structural organization on all scales from molecules to galaxies. In the field of chemistry and materials science, the self‐assembly process driven by noncovalent interactions offers considerable advantages over the stepwise bond formation in the construction of large supramolecular assemblies with different sizes and shapes. The structures of metal clusters are mainly constructed from the assembly of mononuclear metal center to dinuclear, trinuclear species, and so on. It is of interest that Chinese ancient people also used this concept to create and encrypt characters. Herein, we report on an intriguing relationship between structures of metal complexes and the shapes of ancient Chinese characters, in which the self‐assembly principle is clearly demonstrated.
Proteomics analysis of human serum of patients with non‐small‐cell lung cancer reveals proteins as diagnostic biomarker candidates
Authors: Boccellino Mariarosaria , Pinto Federica , Ieluzzi Vincenzo , Giovane Alfonso , Quagliuolo Lucio , Fariello Chiara , Coppola Mario , Carlucci Annalisa , Santini Mario , Ferati Kenan , Bexheti‐Ferati Arbëresha , Giordano Antonio , Di Domenico Marina
Published: June 2019

Non‐small‐cell lung carcinomas (NSCLC) is the most common type of lung cancer and it has a poor prognosis, because overall survival after 5 years is 20–25% for all stages. Thus, it is extremely important to increase the survival rate in the early stages NSCLC by focusing on novel screening tests of cancer identifying specific biomarkers expression associated with a more accurate tumor staging and patient prognosis. In this study, we focused our attention on quantitative proteomics of three heavily glycosylated serum proteins: AMBP, α2 macroglobulin, and SERPINA1. In particular, we analyzed serum samples from 20 NSCLC lung adenocarcinoma cancer patients in early and advanced stages, and 10 healthy donors to obtain a relative quantification through the MRM analysis of these proteins that have shown to be markers of cancer development and progression. AMBP, α2 macroglobulin, and SERPINA1 were chosen because all of them possess endopeptidase inhibitor activity and play key roles in cancer. We observe a variation in the expression of these proteins linked to the stage of the disease. Therefore, we believe that proteins like α2 macroglobulin, αmicroglobulin/bikunin, and SERPINA1 could be useful biomarkers for early detection of lung cancer and in monitoring its evolution.
Early response and safety of lenvatinib for patients with advanced hepatocellular carcinoma in a real‐world setting
Authors: Sho Takuya , Suda Goki , Ogawa Koji , Kimura Megumi , Shimazaki Tomoe , Maehara Osamu , Shigesawa Taku , Suzuki Kazuharu , Nakamura Akihisa , Ohara Masatsugu , Umemura Machiko , Kawagishi Naoki , Natsuizaka Mitsuteru , Nakai Masato , Morikawa Kenichi , Furuya Ken , Baba Masaru , Yamamoto Yoshiya , Kobayashi Tomoe , Meguro Takashi , Saga Akiyoshi , Miyagishima Takuto , Yokoo Hideki , Kamiyama Toshiya , Taketomi Akinobu , Sakamoto Naoya
Published: June 2019

Background and Aim

Lenvatinib has been recently approved as a first‐line systematic therapy for patients with advanced hepatocellular carcinoma (HCC) based on the results of the phase 3 clinical trial REFLECT. This trial excluded patients with a history of systemic chemotherapy, bile duct invasion, and Child‐Pugh grade B. We aimed to investigate the efficacy and safety of lenvatinib for these patients and in the real‐world setting.

Methods

Among patients who were administered lenvatinib for advanced HCC between April and October 2018 in Hokkaido University Hospital and related hospitals, we evaluated those who were followed for more than 2 months and whose treatment response was evaluated via dynamic computed tomography at baseline and 2 months after treatment initiation. Meanwhile, patients were excluded if they had decompensated liver cirrhosis, were followed up less than 2 months, or were not evaluated at 2 months. Patients were also stratified according to compliance with the REFLECT inclusion criteria for further analysis.

Results

A total of 41 patients were included; more than 50% did not meet the REFLECT inclusion criteria. In total, 5 (12.2%), 20 (48.8%), 12 (29.3%), and 4 (9.3%) showed complete response, partial response, stable disease, and progressive disease, respectively. The objective response rate was 61.2%. The objective response rate and disease control rate were similar between patients who did and did not meet the REFLECT inclusion criteria. Moreover, the safety profile was also similar between the two patient groups.

Conclusion

Lenvatinib showed high early response rate and tolerability in patients with advanced HCC. Favorable outcomes were similarly observed in patients who did not meet the REFLECT inclusion criteria.
Impact of the frequency of plasma viral load monitoring on treatment outcomes among children with perinatally acquired HIV
Authors: Sudjaritruk Tavitiya , Boettiger David C , Nguyen Lam Van , Mohamed Thahira J , Wati Dewi K , Bunupuradah Torsak , Hansudewechakul Rawiwan , Ly Penh S , Lumbiganon Pagakrong , Nallusamy Revathy A , Fong Moy S , Chokephaibulkit Kulkanya , Nik Yusoff Nik K , Truong Khanh H , Do Viet C , Sohn Annette H , Sirisanthana Virat ,   the TREAT Asia Pediatric HIV Observational Database of IeDEA Asia‐Pacific
Published: June 2019

Introduction

Recommendations on the optimal frequency of plasma viral load (pVL) monitoring in children living with HIV (CLWH) who are stable on combination antiretroviral therapy (cART) are inconsistent. This study aimed to determine the impact of annual versus semi‐annual pVL monitoring on treatment outcomes in Asian CLWH.

Methods

Data on children with perinatally acquired HIV aged <18 years on first‐line, non‐nucleoside reverse transcriptase inhibitor‐based cART with viral suppression (two consecutive pVL <400 copies/mL over a six‐month period) were included from a regional cohort study; those exposed to prior mono‐ or dual antiretroviral treatment were excluded. Frequency of pVL monitoring was determined at the site‐level based on the median rate of pVL measurement: annual 0.75 to 1.5, and semi‐annual >1.5 tests/patient/year. Treatment failure was defined as virologic failure (two consecutive pVL >1000 copies/mL), change of antiretroviral drug class, or death. Baseline was the date of the second consecutive pVL <400 copies/mL. Competing risk regression models were used to identify predictors of treatment failure.

Results

During January 2008 to March 2015, there were 1220 eligible children from 10 sites that performed at least annual pVL monitoring, 1042 (85%) and 178 (15%) were from sites performing annual (n = 6) and semi‐annual pVL monitoring (n = 4) respectively. Pre‐cART, 675 children (55%) had World Health Organization clinical stage 3 or 4, the median nadir CD4 percentage was 9%, and the median pVL was 5.2 log10 copies/mL. At baseline, the median age was 9.2 years, 64% were on nevirapine‐based regimens, the median cART duration was 1.6 years, and the median CD4 percentage was 26%. Over the follow‐up period, 258 (25%) CLWH with annual and 40 (23%) with semi‐annual pVL monitoring developed treatment failure, corresponding to incidence rates of 5.4 (95% CI: 4.8 to 6.1) and 4.3 (95% CI: 3.1 to 5.8) per 100 patient‐years of follow‐up respectively (p = 0.27). In multivariable analyses, the frequency of pVL monitoring was not associated with treatment failure (adjusted hazard ratio: 1.12; 95% CI: 0.80 to 1.59).

Conclusions

Annual compared to semi‐annual pVL monitoring was not associated with an increased risk of treatment failure in our cohort of virally suppressed children with perinatally acquired HIV on first‐line NNRTI‐based cART.
Superficial, suprahyoid, and infrahyoid neck musculature in naked mole‐rats (Heterocephalus glaber): Relative size and potential contributions to independent movement of the lower incisors
Authors: Cain Blake W. , Reynolds Taylor , Sarko Diana K.
Published: June 2019

Naked mole‐rats (Heterocephalus glaber) are fossorial, eusocial rodents that exhibit the unusual capability of moving their lower incisors independently in lateral and rostroventral directions. The evolution of this trait would presumably also involve concurrent alterations in neck musculature to support and control movements of the lower incisors. In order to assess morphological adaptations that might facilitate these movements, we performed detailed dissections of the neck musculature of adult naked mole‐rats. In addition to characterizing attachment sites of superficial, suprahyoid, and infrahyoid musculature, we also quantified muscle mass and mandibular features thought to be associated with gape (condyle height, condyle length, and jaw length). Based on muscle attachment sites, the platysma myoides may contribute to lateral movement of the lower incisor and hemi‐mandible in naked mole‐rats. The large digastric muscle is likely to be a main contributor to rostroventral movement of each lower incisor. The geniohyoid and mylohyoid muscles also likely contribute to rostroventral movements of the lower incisors, and the mylohyoid may also produce lateral spreading of the hemi‐mandibles. The transverse mandibular (intermandibularis) muscle likely serves to reposition the lower incisors back to a midline orientation following a movement.
Spillover effects of supply chain news on consumers' perceptions of product quality: An examination within the triple bottom line
Authors: Nichols Bridget Satinover , Stolze Hannah , Kirchoff Jon F.
Published: June 2019

The purpose of this research is to examine the impact that news about supply chain operations related to the triple bottom line (TBL) has on consumers' perceptions. Specifically, it focuses on how sustainability successes and failures in a company's supply chain operations influence consumer perceptions of product quality. These perceptions are based on a spillover effect. The research study is set up across three experiments. Study one tests for the spillover effect in supply chain TBL‐related news and demonstrates that negative supply chain news across all three TBL dimensions reduces quality perceptions. Study two examines the effect across three levels of negative news intensity and finds that the spillover effect is consistent, even with stronger levels of negativity. Study three investigates whether a firm can improve damaged quality perceptions and purchase intentions through a recovery effort. The results of study three suggest that consumers' perceptions and purchase intentions are generally reparable. Collectively, the findings should encourage firms to more rigorously consider how news about their supply chain operations may impact consumers' perceptions and intentions toward the firm's products.
Increased miR‐323a induces bladder cancer cell apoptosis by suppressing c‐Met
Authors: Qiu Jun , Zeng Fu‐Ren , Fang Yi , Li Jian , Xiao Sheng‐Ying
Published: June 2019

The current study aimed to evaluate the expression and role of miR‐323a in the progression of bladder cancer (BC), thereby providing a theoretical basis and potential therapy methods for BC patients. Our data showed that miR‐323a levels were significantly reduced in BC tissues compared with those of non‐cancerous tissues. Meanwhile, miR‐323a was significantly decreased in human BC cell lines (T24, J82, TCCSUP, RT‐112) than that in human normal bladder epithelial cell line SV‐HUC‐1. Furthermore, inhibition of miR‐323a markedly enhanced the migration and invasive capacity of T24 and TCCSUP cells. Moreover, overexpression of miR‐323a significantly prompted the apoptosis of BC cells. Dual luciferase reporter assay and western blot analysis confirmed that c‐Met was a target gene of miR‐323a. More importantly, upregulation of c‐Met significantly prompted BC cell proliferation mainly as a result of the enhanced level of phosphorylation of AKT. This effect could be abolished when c‐Met was silenced in BC cells. In summary, reduced miR‐323a expression in BC contributed to enhanced BC cell proliferation and migration mainly by targeting c‐Met.
Activation of Wnt signaling promotes olaparib resistant ovarian cancer
Authors: Yamamoto Tomomi M. , McMellen Alexandra , Watson Zachary L. , Aguilera Jennifer , Ferguson Rebecca , Nurmemmedov Elmar , Thakar Tanay , Moldovan George‐Lucian , Kim Hyunmin , Cittelly Diana M. , Joglar Annette M. , Brennecke Elyse P. , Wilson Heidi , Behbakht Kian , Sikora Matthew J. , Bitler Benjamin G.
Published: June 2019

Epithelial ovarian cancer (EOC) has one of the highest death to incidence ratios among all cancers. High grade serous ovarian carcinoma (HGSOC) is the most common and deadliest EOC histotype due to the lack of therapeutic options following debulking surgery and platinum/taxane‐based chemotherapies. For recurrent chemosensitive HGSOC, poly(ADP)‐ribose polymerase inhibitors (PARPi; olaparib, rucaparib, or niraparib) represent an emerging treatment strategy. While PARPi are most effective in homologous recombination DNA repair‐deficient (HRD) HGSOCs, recent studies have observed a significant benefit in non‐HRD HGSOCs. However, all HGSOC patients are likely to acquire resistance. Therefore, there is an urgent clinical need to understand PARPi resistance and to introduce novel combinatorial therapies to manage PARPi resistance and extend HGSOC disease‐free intervals. In a panel of HGSOC cell lines, we established matched olaparib sensitive and resistant cells. Transcriptome analysis of the matched olaparib‐sensitive vs ‐resistant cells revealed activation of the Wnt signaling pathway and consequently increased TCF transcriptional activity in PARPi‐resistant cells. Forced activation of canonical Wnt signaling in several PARPi‐sensitive cells via WNT3A reduced olaparib and rucaparib sensitivity. PARPi resistant cells were sensitive to inhibition of Wnt signaling using the FDA‐approved compound, pyrvinium pamoate, which has been shown to promote downregulation of β‐catenin. In both an HGSOC cell line and a patient‐derived xenograft model, we observed that combining pyrvinium pamoate with olaparib resulted in a significant decrease in tumor burden. This study demonstrates that Wnt signaling can mediate PARPi resistance in HGSOC and provides a clinical rationale for combining PARP and Wnt inhibitors.
Macrophage migration inhibitory factor promotes the invasion and metastasis of oral squamous cell carcinoma through matrix metalloprotein‐2/9
Authors: Wang Sha‐Sha , Zheng Min , Pang Xin , Zhang Mei , Yu Xiang‐Hua , Wu Jing‐Biao , Gao Xiao‐Lei , Wu Jia‐Shun , Yang Xiao , Tang Ya‐Jie , Tang Ya‐Ling , Liang Xin‐Hua
Published: June 2019

Macrophage migration inhibitory factor (MIF) has been shown to closely associate with the malignant progression of a variety of human carcinomas. However, the role and its underlying molecular mechanisms of MIF in the invasion and metastasis of oral squamous cell carcinoma (OSCC) still remains unclear. Here, we found that MIF silencing reduced the cell proliferation, migration, and invasion, as well as matrix metalloprotein‐2 (MMP‐2) and MMP‐9 in OSCC cells. Overexpression of MMP‐2 or MMP‐9 restored the migration and invasion of MIF‐knockdown cells, indicating that MMP‐2 and MMP‐9 are downstream targets of MIF. In the xenograft model, MIF silencing inhibited tumor growth and in lymph metastasis model, MIF silencing reduced tumor metastasis. More importantly, immunohistochemistry staining in a tissue microarray (TMA) demonstrated that MIF expression was positively correlated with clinic stage, recurrence, metastasis, and poor prognosis of patients with OSCC as well as with the levels of MMP‐2 or MMP‐9 in TMA. Therefore, our findings suggest that MIF may promote the invasion and metastasis of OSCC through the activation of MMP‐2 and MMP‐9 and prompt further investigation into the therapeutic value of MIF for OSCC treatment.
Parkinsonism in essential tremor cases: A clinicopathological study
Authors: Rajput Ali H. , Rajput Emma F. , Bocking Sarah M. , Auer Roland N. , Rajput Alex
Published: June 2019

Background

Essential tremor and Parkinson's syndrome are two common movement disorders that may co‐occur in some individuals. There is no diagnostic neuropathology for essential tremor, but in PD and other Parkinson's syndrome variants, the neuropathology is well known. The spectrum of Parkinson's syndrome variants associated with essential tremor, their clinical features, and course have not been determined in autopsy‐confirmed cases.

Objectives

To identify: diagnostic features of essential tremor/Parkinson's syndrome, different Parkinson's syndrome variants, and long‐term clinical profile in such cases.

Methods

Patients that had an essential tremor diagnosis and a subsequent clinical or pathological diagnosis of Parkinson's syndrome seen in our clinic during 50 years were included. The diagnosis of parkinsonism was made when bradykinesia, rigidity, and resting tremor were all clinically evident.

Results

Twenty‐one cases were included. All the common variants of parkinsonism co‐occurred with essential tremor. The most common was PD (67%) followed by PSP. The pathological findings were not predicted clinically in 2 cases that had essential tremor/PD and in all 5 essential tremor/PSP cases.

Conclusion

In most essential tremor/Parkinson's syndrome patients, the main motor features of parkinsonism—bradykinesia, rigidity, and resting tremor—were identifiable. All known degenerative Parkinson's syndrome variants co‐occurred in essential tremor patients. © 2019 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.
The interindividual variability of transcranial magnetic stimulation effects: Implications for diagnostic use in movement disorders
Authors: Latorre Anna , Rocchi Lorenzo , Berardelli Alfredo , Bhatia Kailash P. , Rothwell John C.
Published: June 2019

Background

A large number of methods have been described that use transcranial magnetic stimulation to probe the physiology of the human motor cortex. Since the 1990s, hundreds of papers have used them to investigate neurophysiological signatures of different types of movement disorders. However, in recent years there has been increasing recognition of the interindividual variability of these measures and a focus on estimating their reliability and reproducibility. Although this work has been carried out in healthy individuals, it is highly relevant to movement disorders because it may impact the validity of some accepted (“canonical”) neurophysiological biomarkers. The aim of this review is to reexamine the diagnostic usefulness of transcranial magnetic stimulation methods in movement disorders in the context of present knowledge of methodological variability.

Methods

We conducted a search of the PubMed database for research and review articles on transcranial magnetic stimulation and its diagnostic utility in movement disorders (specifically Parkinson's disease and atypical parkinsonism, dystonia, Tourette syndrome and other chronic tic disorders, Huntington's disease, and essential tremor). We highlighted contradictions in the literature and common misconceptions with the aim of providing a clearer picture of the reliability of these measures in differential diagnosis of movement disorders.

Conclusion

Although there is no doubt that these studies have provided useful insight into the pathophysiology of movement disorders, there is a clear disagreement among many studies that questions the validity of some of the so called “canonical” findings as diagnostic markers. However, useful findings remain and even those with higher variability can be used to support clinical diagnosis in selected cases. © 2019 International Parkinson and Movement Disorder Society
Lingering patient concerns trigger Kaiser MH strike plans
Authors: Canady Valerie A.
Published: June 2019

A national union representing Kaiser Permanente's mental health clinicians continues to be engaged in a years‐long battle with the health care provider over timely access to care for patients with mental illness, many of whom have to wait up to four months for appointments. As a result, approximately 4,000 staff have called for an open‐ended strike scheduled for this week.
Effects of early intravesical administration of resiniferatoxin to spinal cord‐injured rats in neurogenic detrusor overactivity
Authors: Oliveira Raquel , Coelho Ana , Franquinho Filipa , Sousa Mónica M. , Cruz Francisco , D. Cruz Célia
Published: June 2019

Objectives

To investigate if intravesical administration during spinal shock of resiniferatoxin (RTX), an ultrapotent desensitizing agonist of transient receptor potential vanilloid‐1 (TRPV1), would silence TRPV1‐expressing bladder afferents at an early stage of disease progression and modulate neurogenic detrusor overactivity (NDO) emergence.

Materials and Methods

Rats submitted to largely incomplete spinal cord transection at T8/9 spinal segment were treated with intravesical RTX (50 nM) or its vehicle during spinal shock. Four weeks after spinal lesion, bladder‐reflex activity was evaluated by cystometry under urethane anesthesia, after which the bladder, spinal cord, and dorsal root ganglia were collected and processed.

Results

We found improvements on bladder function several weeks after early intravesical RTX administration, including a marked decrease of intravesical pressures and amplitude of bladder contractions. Such strong long‐lasting urodynamic effects resulted from the very potent desensitizing activity of RTX on peripheral terminals of sensory afferents, an effect restricted to the bladder.

Conclusion

Our results support that an early intervention with RTX could potentially attenuate NDO development and ensuing urinary incontinence, with a dramatic impact on the quality of life of spinal cord injury patients.
Backward error analysis for linearizations in heavily damped quadratic eigenvalue problem
Authors: Chen Hongjia , Meng Jie , Sakurai Tetsuya , Wang Xiang
Published: June 2019

Heavily damped quadratic eigenvalue problem (QEP) is a special type of QEPs. It has a large gap between small and large eigenvalues in absolute value. One common way for solving QEP is to linearize the original problem via linearizations. Previous work on the accuracy of eigenpairs of not heavily damped QEP focuses on analyzing the backward error of eigenpairs relative to linearizations. The objective of this paper is to explain why different linearizations lead to different errors when computing small and large eigenpairs. To obtain this goal, we bound the backward error of eigenpairs relative to the linearization methods. Using these bounds, we build upper bounds of growth factors for the backward error. We present results of numerical experiments that support the predictions of the proposed methods.