bluuebunny/crossref_metadata_2025 huggingface dataset:
Insulinoma‐associated protein 1 immunostaining for various types of neuroendocrine tumors on FNA smears
Authors: Hou Tieying , Gan Qiong , Joseph Cicily T. , Sun Xiaoping , Gong Yun
Published: June 2020

Background

Insulinoma‐associated protein 1 (INSM1) has recently emerged as a reliable nuclear immunostaining marker for detecting neuroendocrine tumors (NETs) in paraffin‐embedded surgical samples and cytologic cell blocks, but the reliability of INSM1 staining on cytologic smears is understudied. This study investigated the performance of INSM1 staining on cytologic smears for the detection of various NETs in comparison with chromogranin (CG) and synaptophysin (SYN).

Methods

INSM1, CG, and SYN were stained on cytologic smears of 70 NETs, including 20 pancreatic NETs, 10 lung carcinoid tumors, 11 small cell lung carcinomas (SCLCs), 10 medullary thyroid carcinomas, 10 Merkel cell carcinomas, 4 thymic atypical carcinoid tumors, and 5 olfactory neuroblastomas. The detection rate, the percentage of positive cells, and the staining intensity were recorded.

Results

The overall detection rate of INSM1 (94%) was higher than the rates of CG (79%) and SYN (89%). The detection rate of INSM1 was higher than the rates of CG and SYN in SCLC, Merkel cell carcinoma, and olfactory neuroblastoma; higher than the rate of CG and equal to the rate of SYN in pancreatic NETs and medullary thyroid carcinoma; equal to the rate of CG and higher than the rate of SYN in thymic atypical carcinoid tumors; and equal to the rate of CG and lower than the rate of SYN in lung carcinoid tumors. INSM1 staining was easier to interpret than CG and SYN staining, especially in high‐grade NETs.

Conclusions

INSM1 can be reliably stained on cytologic smears and outperforms CG and SYN in the verification of clinically or radiologically suspected NETs.
Two Dimensional Oblique Molecular Packing within a Model Peptide Ribbon Aggregate
Authors: Kuczera Stefan , Rüter Axel , Roger Kevin , Olsson Ulf
Published: June 2020

A10K (A=alanine, K=lysine) model peptides self‐assemble into ribbon‐like β‐sheet aggregates. Here, we report an X‐ray diffraction investigation on a flow‐aligned dispersion of these self‐assembly structures. The two‐dimensional wide‐angle X‐ray scattering pattern suggests that peptide pack in a two‐dimensional oblique lattice, essentially identical to the crystalline packing of polyalanine, An (for n>4). One side of the oblique unit cell, corresponding to the anti‐parallel β‐sheet, is oriented along the ribbon's axis. Together with recently published small angle X‐ray scattering data of the same system, this work thus yields a detailed description of the self‐assembled ribbon aggregates, down to the molecular length scale. Notably, our results highlight the importance of the crystalline peptide packing within its self‐assembly aggregates, which is often neglected.
An Electronic Health Record Text Mining Tool to Collect Real‐World Drug Treatment Outcomes: A Validation Study in Patients With Metastatic Renal Cell Carcinoma
Authors: van Laar Sylvia A. , Gombert‐Handoko Kim B. , Guchelaar Henk‐Jan , Zwaveling Juliëtte
Published: June 2020

Real‐world evidence can close the inferential gap between marketing authorization studies and clinical practice. However, the current standard for real‐world data extraction from electronic health records (EHRs) for treatment evaluation is manual review (MR), which is time‐consuming and laborious. Clinical Data Collector (CDC) is a novel natural language processing and text mining software tool for both structured and unstructured EHR data and only shows relevant EHR sections improving efficiency. We investigated CDC as a real‐world data (RWD) collection method, through application of CDC queries for patient inclusion and information extraction on a cohort of patients with metastatic renal cell carcinoma (RCC) receiving systemic drug treatment. Baseline patient characteristics, disease characteristics, and treatment outcomes were extracted and these were compared with MR for validation. One hundred patients receiving 175 treatments were included using CDC, which corresponded to 99% with MR. Calculated median overall survival was 21.7 months (95% confidence interval (CI) 18.7–24.8) vs. 21.7 months (95% CI 18.6–24.8) and progression‐free survival 8.9 months (95% CI 5.4–12.4) vs. 7.6 months (95% CI 5.7–9.4) for CDC vs. MR, respectively. Highest F1‐score was found for cancer‐related variables (88.1–100), followed by comorbidities (71.5–90.4) and adverse drug events (53.3–74.5), with most diverse scores on international metastatic RCC database criteria (51.4–100). Mean data collection time was 12 minutes (CDC) vs. 86 minutes (MR). In conclusion, CDC is a promising tool for retrieving RWD from EHRs because the correct patient population can be identified as well as relevant outcome data, such as overall survival and progression‐free survival.
Monitoring CAR‐T cell kinetics in clinical trials by multiparametric flow cytometry: Benefits and challenges
Authors: Sarikonda Ghanashyam , Pahuja Anil , Kalfoglou Creton , Burns Kerri , Nguyen Kevin , Ch'en Irene L. , Pollner Reinhold , Tangri Shabnam , Dakappagari Naveen
Published: June 2020

Exceptional clinical responses produced by the first chimeric antigen receptor T [CAR‐T] cell therapies, and their entry into commercial markets prompted a logarithmic increase in the number of next generation CAR‐T clinical trials. As a result, there is a growing interest in understanding the analytical approaches utilized for reliable monitoring of these “living” drugs, and the challenges encountered during their clinical development. Multiparametric flow cytometry (MFC) assays have played a crucial role in understanding the phenotype and function of first approved CAR‐T therapies. Herein, three main areas for monitoring CAR‐T therapies in clinical trials are discussed: (1) analytical considerations critical for development of MFC assays for the reliable enumeration of CAR‐T levels, (2) operational challenges associated with clinical trial sampling and transportation, and (3) differential cellular kinetics observed by MFC and qPCR analyses and their relationship with efficacy (measurable residual disease levels). Initial experiences described here may enable design of fit‐for‐purpose tools and help to more rapidly advance the development of next generation CAR‐T therapies.
An improved distance‐based ant colony optimization routing for vehicular ad hoc networks
Authors: Ramamoorthy Raghu , Thangavelu Menakadevi
Published: June 2020

Vehicular ad hoc network (VANET) has earned tremendous attraction in the recent period due to its usage in a wireless intelligent transportation system. VANET is a unique form of mobile ad hoc network (MANET). Routing issues such as high mobility of nodes, frequent path breaks, the blind broadcasting of messages, and bandwidth constraints in VANET increase communication cost, frequent path failure, and overhead and decrease efficiency in routing, and shortest path in routing provides solutions to overcome all these problems. Finding the shortest path between source and destination in the VANET road scenario is a challenging task. Long path increases network overhead, communication cost, and frequent path failure and decreases routing efficiency. To increase efficiency in routing a novel, improved distance‐based ant colony optimization routing (IDBACOR) is proposed. The proposed IDBACOR determines intervehicular distance, and it is triggered by modified ant colony optimization (modified ACO). The modified ACO method is a metaheuristic approach, motivated by the natural behavior of ants. The simulation result indicates that the overall performance of our proposed scheme is better than ant colony optimization (ACO), opposition‐based ant colony optimization (OACO), and greedy routing with ant colony optimization (GRACO) in terms of throughput, average communication cost, average propagation delay, average routing overhead, and average packet delivery ratio.
Predicting child effortful control: An integrative analysis of child physiological, familial, and community factors
Authors: Sun Xiaoning , Measelle Jeffrey , Ablow Jennifer C.
Published: June 2020

Effortful control (EC) is a regulatory capacity that refers to children's ability to inhibit a dominant response to perform a subdominant response. Although attempts have been made to identify early predictors of children's EC, the confluence and interaction of child‐, familial‐, and community factors has not been pursued adequately. This study investigated how predictors from different aspects of children's rearing environment interacted to predict later EC. In a sample of 88 primiparous women with elevated depressive symptomotology and low household income, we examined how children's own psychobiology (baseline cortisol), familial relationship (mother–child attachment), and community resources (social support) at 17 months independently and jointly predicted EC at age 5. Our results showed that, controlling for maternal depressive symptomotology and household income, predictors from child‐, familial‐, and community‐aspect function integratively, rather than independently, in predicting later EC. Specifically, within the context of a secure attachment relationship, baseline cortisol positively predicts later EC only for children of mothers who reported low social support. Whereas within the context of an insecure attachment relationship, baseline cortisol negatively predicts later EC, regardless of the perceived social support levels. Our results highlighted the importance of taking into consideration predictors from multiple aspects for intervention designs.
Maternal approach behaviors toward neonatal calls are impaired by mother's experiences of raising pups with a risk gene variant for autism
Authors: Kato Risa , Machida Akihiro , Nomoto Kensaku , Kang Gina , Hiramoto Takeshi , Tanigaki Kenji , Mogi Kazutaka , Hiroi Noboru , Kikusui Takefumi
Published: June 2020

How the intrinsic sequence structure of neonatal mouse pup ultrasonic vocalization (USV) and maternal experiences determine maternal behaviors in mice is poorly understood. Our previous work showed that pups with a Tbx1 heterozygous (HT) mutation, a genetic risk for autism spectrum disorder (ASD), emit altered call sequences that do not induce maternal approach behaviors in C57BL6/J mothers. Here, we tested how maternal approach behaviors induced by wild‐type and HT USVs are influenced by the mother's experience in raising pups of these two genotypes. The results showed that wild‐type USVs were effective in inducing maternal approach behaviors when mothers raised wild‐type but not HT pups. The USVs of HT pups were ineffective regardless of whether mothers raised HT or wild‐type pups. However, the sequence structure of pup USVs had no effect on the general, non‐directional incentive motivation of maternal behaviors. Our data show how the mother's experience with a pup with a genetic risk for ASD alters the intrinsic incentive values of USV sequences in maternal approach behaviors.
Recent Advances in Photocatalytic Functionalization of Quinoxalin‐2‐ones
Authors: Rostoll‐Berenguer Jaume , Blay Gonzalo , Pedro José R. , Vila Carlos
Published: June 2020

Visible‐light‐mediated chemical reactions have become highly popular in the last ten years. This review covers the recent developments in visible‐light photofunctionalization of quinoxalin‐2‐one derivatives. Reaction types have been categorized depending on the kind of bond formed: C–C, C–O, C–N, C–S, C–P, and C–X, with representative examples and discussion on the catalyst used providing insightful mechanistic details. Moreover, their applications to the synthesis of biologically active compounds has also been discussed.
Determination of Chlorpromazine Hydrochloride with a Layered Double Hydroxide Modified Glassy Carbon Electrode as a Nanocatalyst
Authors: Jaberi Seyedeh Yasaman Shajaripour , Ghaffarinejad Ali , Kamalifar Mohsen , Heidari Mozhgan
Published: June 2020

We report a simple and sensitive voltammetric sensor for the determination of chlorpromazine (CPZ) based on Ni−Al layered double hydroxide (NiAlLDH) modified glassy carbon electrode (GCE). NiAlLDH was simply electrodeposited on GCE surface in a very short time. The response linear range was 1×10−3–1×10−9 mol L−1, with a detection limit of 1×10−9 mol L−1. The NiAlLDH film showed well defined and well separate peaks for dopamine, ascorbic acid, uric acid and CPZ in the same solution. The proposed electrode was used to measure the active pharmaceutical ingredient of CPZ tablet as a real sample.
Explaining the causal effect of adherence to medication on cholesterol through the marginal patient
Authors: Depalo Domenico
Published: June 2020

This paper investigates the relation between adherence to prescribed medication and reduction of cholesterol in Italy, taking into account the possible sorting of patients into treatment and the heterogeneity of the effect. As predicted by a theoretical model, I find that patients who benefit most from medication are more likely to adhere to prescribed regime than those who benefit least. These results are used to study the effects of three hypothetical policies that aim at increasing the share of patients adherent to prescribed medication: one policy is directed toward patients, one toward physicians, and one toward both patients and physicians. For each policy, I describe the observable characteristics of patients induced into treatment. Although the policy with the highest return is directed toward patients, the policies differ substantially with respect to the population affected. Therefore, a policy with lower return that targets better the desired population may be preferred to the policy with the highest return.
Jurisdiction concerning annex actions in the context of the insolvency and Brussels Ibis regulations
Authors: Fabok Zoltan
Published: June 2020

The legislation of the European Union has addressed the private international law aspects of civil and commercial matters and those of insolvency cases separately. While the Brussels Ibis Regulation (and its predecessors) focuses on “classic” civil of commercial cases, insolvency proceedings are subject to the (recast) Insolvency Regulation. However, the close interference between the two related areas of law—commercial and insolvency—results in a category of cases that are commercial and contentious in nature, and so they would tend to gravitate towards the Brussels regime, but yet they are so closely connected to the insolvency proceedings that justifies a special approach. This article focuses on the question of international jurisdiction regarding these “annex actions” in the context of the EU law. It will attempt to explore the historical roots of the current provisions and the evolution of both the European legislation and the relevant case law. The examination of this progression provides a better understanding of the current legislation and answers some questions apparently left open in the recast Insolvency Regulation.
Six autoantibodies as potential serum biomarkers of hepatocellular carcinoma: A prospective multicenter study
Authors: Okada Rei , Otsuka Yuichiro , Wakabayashi Taiga , Shinoda Masahiro , Aoki Takeshi , Murakami Masahiko , Arizumi Shunichi , Yamamoto Masakazu , Aramaki Osamu , Takayama Tadatoshi , Wakiyama Shigeki , Yanaga Katsuhiko , Amikura Katsumi , Kaneko Hironori , Shimada Hideaki
Published: June 2020

Serum autoantibodies have been reported to react with tumor‐associated antigen (TAA) in various cancers. This multicenter study evaluated the diagnostic and prognostic value of six autoantibodies against a panel of six hepatocellular carcinoma (HCC)‐associated antigens, including Sui1, p62, RalA, p53, NY‐ESO‐1 and c‐myc. A total of 160 patients with HCC and 74 healthy controls were prospectively enrolled from six institutions. Serum antibody titers were determined by enzyme‐linked immunosorbent assays. The sensitivities were 19% for Sui1, 18% for p62, 17% for RalA, 11% for p53, 10% for NY‐ESO‐1 and 9% for c‐myc. Overall sensitivity of the TAA panel (56%) was higher than that of α‐fetoprotein (41%, P < .05). The combined sensitivity of the TAA panel and α‐fetoprotein was significantly higher than that of α‐fetoprotein alone (P < .001). The difference in overall survival of TAA panel‐positive and panel‐negative patients was significant when the Stage I/II patients were combined (P = .023). Overall survival was worse in NY‐ESO‐1 antibody‐positive than in NY‐ESO‐1 antibody‐negative patients (P = .002). Multivariate analysis found that positivity for the TAA panel was independently associated with poor prognosis (P = .030). This TAA panel may have diagnostic and prognostic value in the patients with HCC.
Segmentation of tumor using PCA based modified fuzzy C means algorithms on MR brain images
Authors: Yepuganti Karuna , Saladi Saritha , Narasimhulu C. V.
Published: June 2020

In the field of medical sciences, automatic detection of tumor using magnetic resonance (MR) brain images is a major research area. The goal of the proposed work is to identify the tumors in MR images using segmentation methods and to locate the affected regions of the brain more accurately. Medical images have vast information but they are difficult to examine with lesser computational time. An innovative process is proposed to extract tumor cells using the discrete wavelet transform (DWT). After extracting features with DWT feature reduction is carried out with the principal component analysis (PCA). Modified fuzzy C means (MFCM) technique is used for segmenting the tumor cells. The efficiency of the proposed method to identify different abnormalities in real MR images for intracranial neoplasm detection, tuberculoma, and bilateral thalamic fungal granulomas identification is tested. The results obtained are shown in‐terms of Accuracy, Dice Similarity Index (DSI), and Jaccard Index (JI) measures. The performance of the proposed method is tested in terms of performance measures like Accuracy, DSI, and JI. These results are compared with the conventional fuzzy C means (FCM) method.
Mothers’ self‐reported emotion dysregulation: A potentially valid method in the field of infant mental health
Authors: Leerkes Esther M. , Su Jinni , Sommers Savannah A.
Published: June 2020

In the current study, we evaluated the extent to which mothers reported emotion dysregulation on the Difficulties with Emotion Regulation Questionnaire (DERS) (a) converged with physiological indices of emotion dysregulation while parenting, (b) correlated with maternal sensitivity, and (c) predicted infant attachment disorganization and behavior problems in a sample of 259 mothers and their infants. When infants were 6 months old, mothers’ physiological arousal and regulation were measured during parenting tasks and mothers completed the DERS. Maternal sensitivity was observed during distress‐eliciting tasks when infants were 6 and 14 months old. Infant attachment disorganization was assessed during the Strange Situation when infants were 14 months old and mothers reported on infants’ behavior problems when infants were 27 months old. Mothers who reported greater emotion regulation difficulties were more physiologically dysregulated during stressful parenting tasks and also showed lower levels of maternal sensitivity at 6 months. Mother‐reported dysregulation predicted higher likelihood of infant attachment disorganization and more behavior problems. Results suggest that the DERS is a valid measure of maternal emotional dysregulation and may be a useful tool for future research and intervention efforts aimed toward promoting positive parenting and early child adjustment.
What makes leader cells arise: Intrinsic properties and support from neighboring cells
Authors: Chen Bing‐Jun , Wu Jia‐Shun , Tang Ya‐Jie , Tang Ya‐Ling , Liang Xin‐Hua
Published: June 2020

Cancer cells collectively invading as a cohesive and polarized group is termed collective invasion, which is a fundamental property of many types of cancers. In this multicellular unit, cancer cells are heterogeneous, consisting of two morphologically and functionally distinct subpopulations, leader cells and follower cells. Leader cells at the invasive front are responsible for exploring the microenvironment, paving the way, and transmitting information to follower cells. Here, in this review, we will describe the important role of leader cells in collective invasion and the emerging underlying mechanisms of leader cell formation including intrinsic properties and the support from neighboring cells. It will help us to elucidate the essence of collective invasion and provide new anticancer therapeutic clues.
Systematic identification, development, and validation of prognostic biomarkers involving the tumor‐immune microenvironment for glioblastoma
Authors: Zhao Binghao , Wang Yuekun , Wang Yaning , Chen Wenlin , Liu Peng Hao , Kong Ziren , Dai Congxin , Wang Yu , Ma Wenbin
Published: June 2020

Gliomas are infiltrative neoplasms with a highly invasive nature. Due to its distinct genomic, genetic and epigenetic features, the immune prognostic signature (IPS) and immune microenvironment of glioblastoma (GBM) merit further research. We aimed to explore prognosis‐related immune genes and develop an IPS model for predicting prognosis in GBM. RNA‐sequencing data, as well as clinical information, from The Cancer Genome Atlas (TCGA) and Chinese Glioma Genome Atlas (CGGA) public cohorts were analyzed. To develop the IPS, least absolute shrinkage and selection operator (LASSO) Cox analysis was performed for immune‐related genes that were differentially expressed between GBM and normal tissues. Then, interaction effects of the IPS on the immune microenvironment were systematically analyzed; the precise prognostic model was developed based on the IPS and clinical data and was then further validated. A total of 21 immune prognostic genes were identified based on GBM microenvironment status. An 8‐gene IPS was established, and the GBM patients were effectively stratified into low‐ and high‐risk groups in the TCGA cohort as a training set. Univariate and multivariate Cox analyses revealed that IPS was an independent prognostic factor, and the prognostic performance of individual IPS genes was systematically illustrated. In addition, a comprehensive and novel nomogram model was initially established to estimate overall survival in TCGA‐GBM patients, and high‐risk patients had higher levels of dendritic cell and neutrophil infiltration. Furthermore, the nomogram model was developed and validated in the CGGA validation set. The low‐risk IPS was linked to a stronger response to anti‐PD‐L1 immunotherapy and clinical advantages in the IMvigor210 cohort. This novel IPS with promising biomarkers classifies GBM patients into subgroups with distinct clinical outcomes and immunophenotypes. Our findings and this resource may help to characterize the immune microenvironment, inform cancer immunotherapy and facilitate the development of precision immuno‐oncology.
GSK3β suppression inhibits MCL1 protein synthesis in human acute myeloid leukemia cells
Authors: Lee Yuan‐Chin , Shi Yi‐Jun , Wang Liang‐Jun , Chiou Jing‐Ting , Huang Chia‐Hui , Chang Long‐Sen
Published: June 2020

Previous studies have shown that glycogen synthase kinase 3β (GSK3β) suppression is a potential strategy for human acute myeloid leukemia (AML) therapy. However, the cytotoxic mechanism associated with GSK3β suppression remains unresolved. Thus, the underlying mechanism of N‐(4‐methoxybenzyl)‐N′‐(5‐nitro‐1,3‐thiazol‐2‐yl)urea (AR‐A014418)‐elicited GSK3β suppression in the induction of AML U937 and HL‐60 cell death was investigated in this study. Our study revealed that AR‐A014418‐induced MCL1 downregulation remarkably elicited apoptosis of U937 cells. Furthermore, the AR‐A014418 treatment increased p38 MAPK phosphorylation and decreased the phosphorylated Akt and ERK levels. Activation of p38 MAPK subsequently evoked autophagic degradation of 4EBP1, while Akt inactivation suppressed mTOR‐mediated 4EBP1 phosphorylation. Furthermore, AR‐A014418‐elicited ERK inactivation inhibited Mnk1‐mediated eIF4E phosphorylation, which inhibited MCL1 mRNA translation in U937 cells. In contrast to GSK3α, GSK3β downregulation recapitulated the effect of AR‐A014418 in U937 cells. Transfection of constitutively active GSK3β or cotransfection of constitutively activated MEK1 and Akt suppressed AR‐A014418‐induced MCL1 downregulation. Moreover, AR‐A014418 sensitized U937 cells to ABT‐263 (BCL2/BCL2L1 inhibitor) cytotoxicity owing to MCL1 suppression. Collectively, these results indicate that AR‐A014418‐induced GSK3β suppression inhibits ERK–Mnk1–eIF4E axis‐modulated de novo MCL1 protein synthesis and thereby results in U937 cell apoptosis. Our findings also indicate a similar pathway underlying AR‐A014418‐induced death in human AML HL‐60 cells.
Molecular structure and function of microfibrillar‐associated proteins in skeletal and metabolic disorders and cancers
Authors: Zhu Sipin , Ye Lin , Bennett Samuel , Xu Huazi , He Dengwei , Xu Jiake
Published: June 2020

Microfibrillar‐associated proteins (MFAPs) are extracellular matrix glycoproteins, which play a role in microfibril assembly, elastinogenesis, and tissue homeostasis. MFAPs consist of five subfamily members, including MFAP1, MFAP2, MFAP3, MFAP4, and MFAP5. Among these, MFAP2 and MFAP5 are most closely related, and exhibit very limited amino acid sequence homology with MFAP1, MFAP3, and MFAP4. Gene expression profiling analysis reveals that MFAP2, MFAP5, and MFAP4 are specifically expressed in osteoblastic like cells, whereas MFAP1 and MFAP3 are more ubiquitously expressed, indicative of their diverse role in the tropism of tissues. Molecular structural analysis shows that each MFAP family member has distinct features, and functional evidence reveals discrete purposes of individual MFAPs. Animal studies indicate that MFAP2‐deficient mice exhibit progressive osteopenia with elevated receptor activator of NF‐κB ligand (RANKL) expression, whereas MFAP5‐deficient mice are neutropenic, and MFAP4‐deficient mice displayed emphysema‐like pathology and the impaired formation of neointimal hyperplasia. Emerging data also suggest that MFAPs are involved in cancer progression and fat metabolism. Further understanding of tissue‐specific pathophysiology of MFAPs might offer potential novel therapeutic targets for related diseases, such as skeletal and metabolic disorders, and cancers.
Irisin deficiency disturbs bone metabolism
Authors: Zhu Xiaofang , Li Xiangfen , Wang Xiaoxuan , Chen Ting , Tao Fengjuan , Liu Chuanju , Tu Qisheng , Shen Guofang , Chen Jake J.
Published: June 2020

Balancing the process of bone formation and resorption is important in the maintenance of healthy bone. Therefore, the discovery of novel factors that can regulate bone metabolism remains needed. Irisin is a newly identified hormone‐like peptide. Recent studies have reported the involvement of irisin in many physiological and pathological conditions with bone mineral density changes, including osteopenia and osteoporotic fractures. In this study, we generated the first line of Osx‐Cre:FNDC5/irisin KO mice, in which FNDC5/irisin was specifically deleted in the osteoblast lineage. Gene and protein expressions of irisin were remarkably decreased in bones but no significant differences in other tissues were observed in knockout mice. FNDC5/irisin deficient mice showed a lower bone density and significantly delayed bone development and mineralization from early‐stage to adulthood. Our phenotypical analysis exhibited decreased osteoblast‐related gene expression and increased osteoclast‐related gene expression in bone tissues, and reduced adipose tissue browning due to bone‐born irisin deletion. By harvesting and culturing MSCs from the knockout mice, we found that osteoblastogenesis was inhibited and osteoclastogenesis was increased. By using irisin stimulated wildtype primary cells as a gain‐of‐function model, we further revealed the effects and mechanisms of irisin on promoting osteogenesis and inhibiting osteoclastogenesis in vitro. In addition, positive effects of exercise, including bone strength enhancement and body weight loss were remarkably weakened due to irisin deficiency. Interestingly, these changes can be rescued by supplemental administration of recombinant irisin during exercise. Our study indicates that irisin plays an important role in bone metabolism and the crosstalk between bone and adipose tissue. Irisin represents a potential molecule for the prevention and treatment of bone metabolic diseases.
Efficacy of daratumumab combination regimen in patients with multiple myeloma: A combined analysis of phase III randomized controlled trials
Authors: Htut Thura W. , Thein Kyaw Z. , Lawrie Alastair , Tighe Jane , Preston Gavin
Published: June 2020

The use of the CD38 monoclonal antibody daratumumab in combination with standard myeloma chemotherapy regimens has been studied extensively in recent years. We undertook an updated meta‐analysis of phase III randomized controlled trials (RCT) to determine the efficacy of daratumumab combination regimens. The relative risk for progression was significantly lower in daratumumab‐treated cohorts (HR 0.46, 95% CI 0.38‐0.55) and this was consistent across newly diagnosed and relapsed cases. No statistically significant improvement was identified in newly diagnosed patients with high‐risk cytogenetics and this group remains a therapeutic challenge.
An efficient synthesis of designed 4‐thiazolidinone fused pyrimidine derivatives as potent antimicrobial agents
Authors: Patel Janki J. , Morja Mayur I. , Chikhalia Kishor H.
Published: June 2020

A novel series of hybrid 2‐substituted ((pyrimidin‐2‐yl)hydrazinyl)thiazolidin‐4‐one derivatives were synthesized by means of aromatic nucleophilic displacement of chlorine atoms of 2,4,6‐trichloro pyrimidine. Synthesis of some novel 2‐(2‐(6‐morpholino‐4‐substituted(phenyl amino)pyrimidin‐2‐yl)hydrazinyl)thiazol‐4(5H)‐one derivatives have been carried out by the displacement of chlorine atoms on the basis of functionality concept on varying conditions. The synthesized hydrazinyl thiazolidin‐4‐one pyrimidine derivatives were evaluated for their expected antimicrobialactivity; where, the majority of these compounds showed potent antibacterial and antifungal activities against the tested strains of bacteria and fungi. Afforded title analogs were subsequently characterized by elemental analysis, IR, 1H NMR, 13C NMR, Mass spectroscopy. SAR and HOMO‐LUMO studies were also carried out for confirming the structure biological activity. Thus, these studies suggested that hydrazinyl pyrimidine derivatives bearing thiazolidinone moiety are interesting scaffolds for the development of novel antimicrobial agents.
LPS-mediated neutrophil VEGF-A release is modulated by cannabinoid receptor activation
Authors: Braile Mariantonia , Cristinziano Leonardo , Marcella Simone , Varricchi Gilda , Marone Giancarlo , Modestino Luca , Ferrara Anne Lise , De Ciuceis Agnese , Scala Sara , Galdiero Maria Rosaria , Loffredo Stefania
Published: June 2020

Neutrophils (PMNs) are innate immune cells with primary roles in inflammation and in host defense against infections. Both inflammatory and tumor angiogenesis are modulated by a sequential, coordinated production of angiogenic factors such as vascular endothelial growth factors (VEGFs), angiopoietins, hepatocyte growth factor (HGF), and chemokines. These factors are produced by several immune cells, including PMNs. Activation of cannabinoid receptor type-1 (CB1) and -2 (CB2) has been suggested as a new strategy to modulate in vitro and in vivo angiogenesis. We sought to investigate whether activation of CB1 and CB2 by CB agonists modulate LPS-mediated angiogenic activity of human PMNs. Highly purified PMNs were isolated from buffy coats of healthy donors. Cells were stimulated with CB1 and CB2 agonists/antagonists alone and/or in combination with LPS. Angiogenic factors in cell-free supernatants were measured by ELISA. The modulation of activation markers of PMNs by CB agonists was evaluated by flow cytometry. Angiogenesis in vitro was measured as tube formation by optical microscopy. Endothelial cell permeability was assessed by an in vitro vascular permeability assay. LPS-activated PMNs released VEGF-A, CXCL8, and HGF. Preincubation of PMNs with low concentrations of CB1 and CB2 agonists inhibited VEGF-A release induced by LPS, but did not affect CXCL8 and HGF production. The effects of CB agonists on VEGF-A release induced by LPS were reversed by preincubation with CB antagonists. CB agonists modulated in vitro angiogenesis and endothelial permeability induced by supernatants of LPS-activated PMNs through the reduction of VEGF-A. Neutrophils play a central role in the control of bacterial infections and in the outcome of sepsis. The latter condition is associated with an increase in circulating levels of VEGF-A. We demonstrated that low concentrations of CB agonists inhibit VEGF-A release from LPS-activated PMNs. These results suggest that CB agonists might represent a novel therapeutic strategy in patients with sepsis.
TLR3 expression by maternal and fetal cells at the maternal-fetal interface in normal and preeclamptic pregnancies
Authors: Gierman Lobke M , Silva Gabriela B , Pervaiz Zahra , Rakner Johanne J , Mundal Siv B , Thaning Astrid J , Nervik Ingunn , Elschot Mattijs , Mathew Seema , Thomsen Liv Cecilie V , Bjørge Line , Iversen Ann-Charlotte
Published: June 2020

Inflammation and oxidative stress at the maternal-fetal interface characterize the placental dysfunction that underlies the pregnancy disorder preeclampsia. Specialized fetal trophoblasts directly interact with leukocytes at both sites of the maternal-fetal interface; the uterine wall decidua; and the placenta. TLR3 has been implicated in the harmful inflammation at the maternal-fetal interface in preeclampsia, but the cellular involvement in the decidua and placenta has not been determined. This study aimed to characterize and quantify cell-specific TLR3 expression and function at the maternal-fetal interface in normal and preeclamptic pregnancies. TLR3 expression was assessed by immunohistochemistry and quantified by a novel image-based and cell-specific quantitation method. TLR3 was expressed at the maternal-fetal interface by all decidual and placental trophoblast types and by maternal and fetal leukocytes. Placental, but not decidual, TLR3 expression was significantly higher in preeclampsia compared to normal pregnancies. This increase was attributed to placental intravillous tissue and associated with both moderate and severe placental dysfunction. TLR3 pathway functionality in the decidua and placenta was confirmed by TLR3 ligand-induced cytokine response, but the TLR3 expression levels did not correlate between the two sites. In conclusion, functional TLR3 was broadly expressed by maternal and fetal cells at both sites of the maternal-fetal interface and the placental intravillous expression was increased in preeclampsia. This suggests TLR3-mediated inflammatory involvement with local regulation at both sites of the maternal-fetal interface in normal and preeclamptic pregnancies.
Spinal microglia-neuron interactions in chronic pain
Authors: Ho Idy H T , Chan Matthew T V , Wu William K K , Liu Xiaodong
Published: June 2020

Current deficiency in our understanding of acute-to-chronic pain transition remains a hurdle for developing effective treatments against chronic pain. Whereas neurocentric mechanisms alone are insufficient to provide satisfactory explanation for such transition, neuro-immune crosstalk has attracted attention in recent pain research. In contrast to brain microglia, spinal microglia are activated immediately in various pain states. The fast-responsive enrichment and activation of spinal microglia among different pain conditions have highlighted the crucial role of neuroinflammation caused by microglia-neuron crosstalk in pain initiation. Recent studies have revealed spinal microglia-neuron interactions are also involved in chronic pain maintenance, albeit, with different anatomic distribution, cellular and molecular mechanisms, and biologic functions. Delineating the exact temporal discrepancies of spinal microglia distribution and functions along acute-to-chronic pain transition may provide additional mechanistic insights for drug development to prevent deterioration of acute pain into the chronic state. This narrative review summerizes the longitudinal alterations of spinal microglia-neuron interactions in the initiation of pain hypersensitivity, acute-to-chronic pain progression, and chronic pain maintenance, followed by an overview of current clinical translation of preclinical studies on spinal microglia. This review highlights the crucial role of the interaction between spinal microglia and neighboring neurons in the initiation and maintenance of pain hypersensitivity, in relation to the release of cytokines, chemokines, and neuroactive substances, as well as the modulation of synaptic plasticity. Further exploration of the uncharted functions of spinal microglia-neuron crosstalk may lead to the design of novel drugs for preventing acute-to-chronic pain transition.
The Controversial Effect of Age on Divergent Thinking Abilities: A Systematic Review
Authors: Fusi Giulia , Lavolpe Sara , Crepaldi Maura , Rusconi Maria Luisa
Published: June 2020

Divergent thinking (DT) is considered as an indicator of creative potential and a predictor of creative achievement. Furthermore, it is also conceptualized as an indicator of cognitive reserve (CR) in healthy elderly. CR refers to a functional benefit that can potentially offer protection against brain pathologies and is thereby considered a protective factor against cognitive decline. Creativity researchers have therefore attempted to understand the impact of the aging processes on DT abilities; however, it is difficult to draw a coherent picture from these studies. The aim of our systematic review was to more consistently summarize and interpret evidence about this topic. We selected 16 studies using the Preferred Reporting Items for Systematic reviews and Meta‐Analyses (PRISMA) guidelines. Our findings highlight a complex and multidimensional, rather than a simple linear relationship between the aging processes and DT performances, especially if the different DT indexes are considered separately. We also found that findings from more recent studies suggest that older subjects are able to think as divergently as younger people, particularly in the verbal domain, if no time constraints are imposed and if the workload is not too high. We conclude by discussing theoretical and methodological issues and implications for future research.
Pharmacists subject to complaints: a national study of pharmacists reported to health regulators in Australia
Authors: Taouk Yamna , Bismark Marie , Hattingh Hendrika Laetitia
Published: June 2020

Background

Complaints against pharmacists provide an opportunity for learning and improvement within the profession. The aim of the present study was to describe the nature and prevalence of complaints about pharmacists in Australia and to identify factors associated with an increased risk of complaints.

Method

De‐identified data on all pharmacists registered to practise in Australia between 1 January 2011 and 31 December 2016 was linked with complaints about pharmacists lodged with health regulators during the same period. Descriptive statistics describe the source, nature, outcome, and clustering of complaints. Regression analyses identify factors associated with complaints.

Results

Around 6% of pharmacists who were registered over the six‐year study period were subject to at least one complaint to a regulator. Over half of these complaints resulted in regulatory action. Four‐fifths of complaints related to five issues: accuracy and appropriateness of dispensing, lawfulness of supply, communication and interpersonal behaviour, records and information, and the health of the pharmacist. Fewer than 1% of pharmacists were the subject of two or more complaints: this group accounted for nearly a third of all complaints. Male pharmacists and those aged 36 to 44 years were at increased risk of complaints compared with their peers.

Conclusion

A small group of pharmacists in Australia receive a disproportionate share of complaints. Complaints against pharmacists provide an opportunity for learning and improvement within the profession. Improved understanding of complaint patterns may assist in the development of programs to reduce risk to patients and support safe practice by pharmacists.
Recent advances of ambient ionization mass spectrometry imaging in clinical research
Authors: Li Na , Nie Honggang , Jiang Liping , Ruan Guihua , Du Fuyou , Liu Huwei
Published: June 2020

The structural information and spatial distribution of molecules in biological tissues are closely related to the potential molecular mechanisms of disease origin, transfer, and classification. Ambient ionization mass spectrometry imaging is an effective tool that provides molecular images while describing in situ information of biomolecules in complex samples, in which ionization occurs at atmospheric pressure with the samples being analyzed in the native state. Ambient ionization mass spectrometry imaging can directly analyze tissue samples at a fairly high resolution to obtain molecules in situ information on the tissue surface to identify pathological features associated with a disease, resulting in the wide applications in pharmacy, food science, botanical research, and especially clinical research. Herein, novel ambient ionization techniques, such as techniques based on spray and solid‐liquid extraction, techniques based on plasma desorption, techniques based on laser desorption ablation, and techniques based on acoustic desorption were introduced, and the data processing of ambient ionization mass spectrometry imaging was briefly reviewed. Besides, we also highlight recent applications of this imaging technology in clinical researches and discuss the challenges in this imaging technology and the perspectives on the future of the clinical research.
Longterm Outcomes of Patients Undergoing Liver Transplantation for Acute‐on‐Chronic Liver Failure
Authors: Sundaram Vinay , Mahmud Nadim , Perricone Giovanni , Katarey Dev , Wong Robert J. , Karvellas Constantine J. , Fortune Brett E. , Rahimi Robert S. , Maddur Harapriya , Jou Janice H. , Kriss Michael , Stein Lance L. , Lee Moses , Jalan Rajiv ,   for the Multi‐Organ Dysfunction, Evaluation for Liver Transplantation (MODEL) Consortium
Published: June 2020

Recent data have demonstrated >80% 1‐year survival probability after liver transplantation (LT) for patients with severe acute‐on‐chronic liver failure (ACLF). However, longterm outcomes and complications are still unknown for this population. Our aim was to compare longterm patient and graft survival among patients transplanted across all grades of ACLF. We analyzed the United Network for Organ Sharing database for the years 2004‐2017. Patients with ACLF were identified using the European Association for the Study of the Liver–Chronic Liver Failure criteria. Kaplan‐Meier and Cox regression methods were used to determine patient and graft survival and associated predictors of mortality in adjusted models. A total of 56,801 patients underwent transplantation of which 31,024 (54.6%) had no ACLF, 8757 (15.4%) had ACLF grade 1, 9039 (15.9%) had ACLF grade 2, and 7891 (14.1%) had ACLF grade 3. The 5‐year patient survival after LT was lower in the ACLF grade 3 patients compared with the other groups (67.7%; P < 0.001), although after year 1, the percentage decrease in survival was similar among all groups. Infection was the primary cause of death among all patient groups in the first year. Infection was the primary cause of death among all patient groups in the first year. After the first year, infection was the main cause of death in patients transplanted with ACLF grade 1 (32.1%), ACLF grade 2 (33.9%), and ACLF grade 3 (37.6%), whereas malignancy was the predominant cause of death in those transplanted with no ACLF (28.5%). In conclusion, patients transplanted with ACLF grade 3 had lower 5‐year survival as compared with patients with ACLF grades 0‐2, but mortality rates were not significantly different after the first year following LT. Graft survival was excellent across all ACLF groups.
Role of Terlipressin and Albumin for Hepatorenal Syndrome in Liver Transplantation
Authors: Sharma Pratima , Moore Kevin , Ganger Daniel , Grewal Priya , Brown Robert S.
Published: June 2020

Hepatorenal syndrome (HRS) is one of the most ominous complications of portal hypertension in patients with decompensated cirrhosis and ascites. It is associated with very high mortality on the wait list. Liver transplantation (LT) is the most successful therapeutic option for patients with HRS. However, not all the LT candidates with HRS are able to receive a deceased donor allograft in a timely manner because it is a scarce resource and patients may need alternative best supportive treatment with systemic splanchnic vasoconstrictors and albumin as a bridge to transplant. The combination of terlipressin and albumin is efficacious in the reversal of HRS and is used worldwide. More recently, the multicenter, randomized, placebo‐controlled double‐blind study to confirm efficacy and safety of terlipressin in subjects with hepatorenal syndrome type 1 (the CONFIRM study) trial demonstrated the efficacy of terlipressin and albumin in the reversal of HRS in a North American cohort. The aim of this article is to review the role of terlipressin and albumin in LT candidates with HRS in the United States.
Axiomatizing first order consequences in inclusion logic
Authors: Yang Fan
Published: June 2020

Inclusion logic is a variant of dependence logic that was shown to have the same expressive power as positive greatest fixed‐point logic. Inclusion logic is not axiomatisable in full, but its first order consequences can be axiomatized. In this paper, we provide such an explicit partial axiomatization by introducing a system of natural deduction for inclusion logic that is sound and complete for first order consequences in inclusion logic.
The choice property in tame expansions of o‐minimal structures
Authors: Eleftheriou Pantelis E. , Günaydın Ayhan , Hieronymi Philipp
Published: June 2020

We establish the choice property, a weak analogue of definable choice, for certain tame expansions of o‐minimal structures. Most noteworthily, this property holds for dense pairs of real closed fields, as well as for expansions of o‐minimal structures by a dense independent set.
The Cichoń diagram for degrees of relative constructibility
Authors: Switzer Corey Bacal
Published: June 2020

Following a line of research initiated in [4], we describe a general framework for turning reduction concepts of relative computability into diagrams forming an analogy with the Cichoń diagram for cardinal characteristics of the continuum. We show that working from relatively modest assumptions about a notion of reduction, one can construct a robust version of such a diagram. As an application, we define and investigate the Cichoń diagram for degrees of constructibility relative to a fixed inner model W. Many analogies hold with the classical theory as well as some surprising differences. Along the way, we introduce a new axiom stating, roughly, that the constructibility diagram is as complex as possible.