bluuebunny/crossref_metadata_2025 huggingface dataset:
Minimizing the monetary penalty and energy cost of server migration service
Authors: Fukushima Yukinobu , Suda Tatsuya , Murase Tutomu , Tarutani Yuya , Yokohira Tokumi
Published: April 2022

Current IaaS (infrastructure as a service) cloud service may not satisfy communication QoS (quality of service) requirements of delay‐sensitive network applications, if there is a significant physical distance between a server of the network application (NetApp server) at a data center and its network application clients (NetApp clients). In order to improve communication QoS of NetApp clients, we propose server migration service (SMS) in this article. SMS allows NetApp servers to migrate among different locations in the network (1) to optimally locate themselves in relation to NetApp clients and mitigate the QoS degradation caused by location‐related factors (ie, propagation delays on network links) and (2) to optimally distribute traffic load over routers and processing load over (physical) computers and decrease the energy consumption. We develop a mixed‐integer programming model that determines when and to which locations NetApp servers migrate to minimize the total operating cost of SMS, that is, the sum of the monetary penalty incurred due to QoS violation and energy cost incurred due to energy consumption, while preventing NetApp servers from excessively migrating and adversely impacting QoS of the non‐SMS service that share the resource of the substrate network with SMS. Simulation results show that the model developed in this article achieves up to 42% lower total operating cost of SMS compared to the model that only minimizes the monetary penalty of SMS without considering the energy cost of SMS.
Preparation of freeze‐dried bioluminescent bacteria and their application in the detection of acute toxicity of bisphenol A and heavy metals
Authors: Yang Jun , Hu Shulin , Liao Anqi , Weng Yetian , Liang Shuli , Lin Ying
Published: April 2022

Current chemical analysis approaches for contaminants have failed to reveal their biotoxicity. Moreover, conventional bioassays are time consuming and exhibit poor repeatability. In this study, we performed the acute toxicity detection of various contaminants (chromium (Cr), cadmium (Cd), lead (Pb), arsenic (As), mercury (Hg), tin (Sn), nickel (Ni), and bisphenol A (BPA)) with four bioluminescent bacteria (Vibrio qinghaiensis Q67, V. fischeri, Photobacterium phosphoreum T3, and P. phosphoreum 502) using a rapid, flexible, and low‐cost bioassay. We found that the temperature affected the bacterial luminescence, and freeze‐dried cells exhibited sensitive toxic responses to contaminants. Indeed, the optimized protectants containing 12% (w/v) trehalose, 4% sucrose, and 2% sorbitol displayed better luminescence and toxic sensitivity. Furthermore, freeze‐dried powders of these strains were prepared and subjected to acute toxicity detection. The results showed that all contaminants exhibited acute toxicity toward Q67, but the other strains did not show obvious response to nickel and tin. The relative half‐maximal effective concentration (EC50) values of BPA, Cr, Cd, Pb, As, Hg, Ni, and Sn to Q67 were 0.674, 1.313, 11.137, 5.921, 4.674, 0.911, 5.941, and 54.077 mg/L, respectively. In addition, the EC50 values of contaminants toward different strains were suggested to be statistically significant. Freeze‐dried Q67 exhibited toxic responses to more contaminants than the other bioluminescent strains; therefore, Q67 was selected to be more suitable than the other strains for single and mixture toxicity detection tests. Compared with other strains, Q67 was more appropriate for the rapid screening of the mixture toxicity of contaminants in samples as a nonspecific screening sensor before the use of standard analysis approaches.
New built and refurbished railway tunnels: Data delivery from BIM Models to OEBB's asset management
Authors: Großauer Karl , Huis Melanija , Jedlitschka Gernot , Matt Robert , Mulitzer Günther , Zwittnig Gerald
Published: April 2022

Digitalisation in the construction industry has been progressing continuously and bringing major changes for everyone involved in virtually all areas. Austrian Federal Railways ÖBB has been pushing BIM (Building Information Modelling) for the construction and rehabilitation of their infrastructure. By means of various pilot projects, the basics and the processes required for design and construction are developed and applied with a strong focus on system operation. For Granitztal tunnel and a total length of ≈6.1 km, the as‐built design of the civil structures is done with an element‐based, open BIM model. As part of the handover to the maintenance and operation division, the data of civil structures relevant for operation are derived from the BIM model, validated by means of automatic methods and transferred to the facility management system (AVS, Anlagen‐Verzeichnis‐System). In the absence of an IFC (Industry Foundation Class) structure tunnel, a semantic and spatial data structure is developed. Furthermore, the model will be enriched with components of railway equipment. On the other hand, there is the over‐100‐year‐old Karawanks tunnel as part of the railway section between Villach and Jesenice. The line has been in operation since 1906 and includes the ≈8 km‐long, single‐tube Karawanks tunnel. The current situation of the tunnel including the superstructure and technical equipment no longer meets performance, safety and durability requirements and is being rehabilitated within an international cooperation project between Austria and Slovenia. The focus in this BIM project is set on the as‐built design and merging data of the existing historic tunnel structure with information of new components implemented during refurbishment. A core task is the structured transfer of data contained in the BIM model to the facility/asset management system of ÖBB (AVS) and the Slovenian infrastructure operator. The case histories of Granitztal tunnel and Karawanks tunnel are used to describe the implementation of BIM, including the development of required data structures, validation mechanisms and data delivery to the asset management.
Demands on digital data capturing of TBM and conventional tunnel drives
Authors: Sabanovic Nedzad , Wannenmacher Helmut , Stauch Felix , Fentzloff Wolfgang
Published: April 2022

Tunnels are significant in shaping our future infrastructure. Increasing limitations of the available ground require underground solutions for future infrastructure projects. Due to various reasons, boundary conditions for project realization are becoming more and more substantial, and the parties involved have to tackle a wide range of stakeholders' interests. Digitization may be able to handle some of these challenges and is one of the most relevant topics in the near future of the construction industry. First approaches of digital data capturing in different activity fields of project execution, such as geological and geotechnical conditions, survey, and reporting, are launched within Implenia's initiative. This article discusses essential aspects of data capturing, particularly in the light of the vast data volumes generated throughout tunnel construction in Europe and gives an insight into the various activities of Implenia on how to tackle these problems. The various TBM and drill‐and‐blast excavated tunnel projects illustrate the variability of data management and implemented solutions to work with the tremendous amount of data. In each case, one can clearly state that construction teams involved in digital data management highly appreciated the merits for their daily business: saving time, gaining transparent information, controlling processes, and more. The beneficial capability of appropriate data management in project execution is evident and will be carried out within Implenia's projects.
Risk of cardiovascular disease and loss in life expectancy in NAFLD
Authors: Shang Ying , Nasr Patrik , Widman Linnea , Hagström Hannes
Published: April 2022

Background and Aims

Conflicting evidence exists on cardiovascular disease (CVD) risk in patients with NAFLD, and data are lacking on whether NAFLD increases mortality after a CVD event. Moreover, life expectancy in NAFLD has not been studied. We therefore examined CVD risk and life expectancy in patients with NAFLD compared with the general population.

Approach and Results

In this nationwide population‐based cohort, all patients with NAFLD diagnosis and without baseline CVD (ascertaining from the Swedish National Patient Register from 1987 to 2016, n = 10,023) were matched 10:1 on age, sex, and municipality to individuals from the general population (controls, n = 96,313). CVD diagnosis and mortality were derived from national registers. Multistate models and flexible parametric survival models were used to estimate adjusted hazard ratios (aHRs) for CVD risk and loss in life expectancy due to NAFLD. We identified 1037 (10.3%) CVD events in patients with NAFLD and 4041 (4.2%) in controls. CVD risk was 2.6‐fold higher in NAFLD compared with controls (aHR = 2.61, 95% CI = 2.36–2.88) and was strongest for nonfatal CVD (aHR = 3.71, 95% CI = 3.29–4.17). After a nonfatal CVD event, the risk for all‐cause mortality was similar between patients with NAFLD and controls (aHR = 0.89, 95% CI = 0.64–1.25). Life expectancy in patients with NAFLD was, on average, 2.8 years lower than controls, with the highest loss of life‐years when NAFLD was diagnosed in middle age (40–60 years).

Conclusions

NAFLD was associated with a higher risk of nonfatal CVD but did not affect post‐CVD mortality risk. Patients diagnosed with NAFLD have a lower life expectancy than the general population.
The superiority of Epstein‐Barr virus DNA in plasma over in peripheral blood mononuclear cells for monitoring EBV‐positive NK‐cell lymphoproliferative diseases
Authors: Zheng Miao , Bao Yuhan , Wang Jiachen , Ma Yaxian , Yang Yang , Zhang Peiling , Chen Liting , Zheng Kai , Zhou Jianfeng
Published: April 2022

Epstein‐Barr virus (EBV), characterized as an omnipresent virus, has been found able to infect NK cells and leads to NK‐cell type EBV‐positive lymphoproliferative diseases (EBV‐NK‐LPDs). We retrospective analyzed 202 EBV‐NK‐LPDs (including 64 CAEBV‐NK, 27 aggressive natural killer‐cell leukemia (ANKL), and 111 extranodal NK/T‐cell lymphoma (ENKTL)) patients' relationships between EBV DNA copies laboratory test results and clinical features. In CAEBV‐NK cohort, EBV DNA loads in either plasma or PBMCs had significant differences between the active state and the inactive state. Receiver operating characteristic curves were used to measure the diagnosis accuracy of EBV DNA copies. After comparing the area under the curve, EBV DNA loads in plasma had significantly higher accuracy in distinguishing disease activation than in PBMCs. Therefore, we propose redefining CAEBV‐NK diagnosis criteria as increased EBV DNA copies in plasma (over 7.1 × 102 copies/ml) instead of in peripheral blood. In ANKL and ENKTL cohorts, patients who received effective therapy had significantly lower EBV DNA copies in plasma & PBMCs than in those with ineffective therapy. The significant and consistent decline indicated EBV DNA loads in plasma being a more sensitive biomarker in monitoring EBV‐NK‐LPDs therapy responses. Hemophagocytic lymphohistiocytosis (HLH) can occur secondary to EBV‐NK‐LPDs, mostly associated with a poor prognosis, so we try to estimate the combination of HLH by monitoring EBV DNA copies. When comparing the Receiver operating characteristic curves of EBV DNA copies, EBV DNA loads in plasma had higher diagnosis accuracy. When the copies level over 4.16 × 103 copies/ml, it might indicate combining with HLH.
Risk factors, contemporary challenges and psychological well‐being of the Rohingya refugees in Bangladesh: Policy implications
Authors: Hossain Muhammad Anwar , Huda Md. Nazmul , Ullah A. K. M Ahsan , Renzaho Andre
Published: April 2022

Over the last few years, the number of Rohingya refugees in Bangladesh has increased exponentially. On arrival, they experience poor mental health and psychological well‐being. This commentary explores the risk factors and contemporary challenges that deteriorate Rohingyas' psychological well‐being in Bangladesh. The onslaught of Covid‐19 compounds the pre‐existing psychological health conditions of the Rohingyas living in cramped and flimsy camps. The recent relocation to Bhashan Char may likely trigger tensions and eventually exacerbates their existing psychological well‐being. The relocation to Bhashan Char has presumably happened against their volition. Meanwhile, the Myanmar military's coup has added additional fear about their bleak future of a safe and dignified return from Bangladesh to Myanmar. All these have contributed to the worsening of their existing psychological well‐being. In order to subside their psychological health challenges, this commentary suggests: (a) the immediate execution of ‘National Deployment and Vaccination Plan for Covid‐19 Vaccines and initiation of vaccine rollout among the refugees; and (b) involving Rohingyas in economic activities and making them a self‐reliant and economically empowered community. We suggest that safe and dignified repatriation is the only solution to the challenges they have been going through in Bangladesh and to preserve their psychological well‐being.
The effect of trastuzumab on cardiac function in patients with HER2‐positive metastatic breast cancer and reduced baseline left ventricular ejection fraction
Authors: Bouwer Nathalie I. , Steenbruggen Tessa G. , Rier Hánah N. , Kitzen Jos J. E. M. , Smorenburg Carolien H. , van Bekkum Marlies L. , de Jong Paul C. , Drooger Jan C. , Holterhues Cynthia , Kofflard Marcel J. M. , Boersma Eric , Sonke Gabe S. , Levin Mark‐David , Jager Agnes
Published: April 2022

We investigated the effect of trastuzumab on cardiac function in a real‐world historic cohort of patients with HER2‐positive metastatic breast cancer (MBC) with reduced baseline left ventricular ejection fraction (LVEF). Thirty‐seven patients with HER2‐positive MBC and baseline LVEF of 40% to 49% were included. Median LVEF was 46% (interquartile range [IQR] 44%‐48%) and median follow‐up was 18 months (IQR 9‐34 months). During this period, the LVEF did not worsen in 24/37 (65%) patients, while 13/37 (35%) patients developed severe cardiotoxicity defined as LVEF <40% with median time to severe cardiotoxicity of 7 months (IQR 4‐10 months) after beginning trastuzumab. Severe cardiotoxicity was reversible (defined as LVEF increase to a value <5%‐points below baseline value) in 7/13 (54%) patients, partly reversible (defined as absolute LVEF increase ≥10%‐points from nadir to a value >5%‐points below baseline) in 3/13 (23%) patients and irreversible (defined as absolute LVEF increase <10%‐points from nadir and to a value >5%‐points below baseline) in 3/13 (23%) patients. Likelihood of reversibility was numerically higher in patients who received cardio‐protective medications (CPM), including ACE‐inhibitors, beta‐blockers and angiotensine‐2 inhibitors, compared to those who did not receive any CPM (71% vs 13%, P = .091). Sixty‐five percent of patients who received trastuzumab for HER2‐positive MBC did not develop severe cardiotoxicity during a median follow‐up of 18 months, despite having a compromised baseline LVEF. If severe cardiotoxicity occurred, it was at least partly reversible in more than two‐thirds of the cases. Risks and benefits of trastuzumab use should be balanced carefully in this vulnerable population.
Castration‐resistant prostate cancer diagnosed during leuprorelin treatment for spinal and bulbar muscular atrophy
Authors: Yanase Atsuhi , Sugihara Toru , Akimoto Takahiro , Yokoyama Hirotaka , Kamei Jun , Fujisaki Akira , Ando Satoshi , Naoi Tameto , Morita Mitsuya , Fujimura Tetsuya
Published: April 2022

Introduction

We report a prostate cancer case diagnosed during leuprorelin treatment for spinal and bulbar muscular atrophy which is a X‐linked recessive, lower motor neuron disease.

Case presentation

A 64‐year‐old man who had received leuprorelin treatment over 3 years for his spinal and bulbar muscular atrophy presented with an enlarged prostate accompanied by abdominal pain and constipation. An abnormally high serum prostate‐specific antigen of 17.7 ng/mL and a low (castration level) serum testosterone level of 0.23 ng/mL were measured. Prostate needle biopsy revealed adenocarcinoma of the prostate. Orchiectomy, darolutamide, and radiation therapy for the prostate were initiated, resulting in a favorable response which was maintained at 12 months of treatment.

Conclusion

Prostate cancer can occur even when leuprorelin is used for spinal and bulbar muscular atrophy; therefore, checking serum prostate‐specific antigen to screen for prostate cancer before leuprorelin administration should be considered.
Loneliness and personal well‐being in young people: Moderating effects of individual, interpersonal, and community factors
Authors: Goodfellow Claire , Hardoon Deborah , Inchley Joanna , Leyland Alastair H. , Qualter Pamela , Simpson Sharon A. , Long Emily
Published: April 2022

Introduction

Loneliness is prevalent among young people. But, there is little work exploring the association between loneliness with well‐being among this age group. Framed by social‐ecological theory, we examined demographic, interpersonal, and community factors associated with personal wellbeing and, critically, identified malleable moderators of the relationship between loneliness and well‐being that could be targeted in intervention efforts.

Methods

We used cross‐sectional, secondary data from 965 young people (aged 16–24) from the Community Life Survey in England. Loneliness was measured using a single‐item direct measure; personal wellbeing was measured through a composite measure containing items assessing happiness, life satisfaction, and a sense that life is worthwhile (α = 0.88). Regression techniques were used to assess associations between individual, interpersonal, and community factors and well‐being, and to identify moderators of the relationship between loneliness and well‐being.

Results

Loneliness was negatively associated with well‐being. Chatting with neighbors and having people to provide help moderated the relationship between loneliness and well‐being. Full‐time students and those with good physical health had higher well‐being while being a carer was predictive of lower well‐being. All community variables were strongly associated with increased well‐being. Of all interpersonal variables investigated, only having people to count on was associated with increased well‐being.

Conclusions

Our results demonstrate that supportive relationships and close community ties are important for reducing the negative impact of loneliness on youth well‐being. Interventions to improve well‐being could benefit from targeting these aspects of young people's social and community lives, while acknowledging individual vulnerabilities, such as poor physical health.
Sports participation and alcohol use revisited: A longitudinal study of Norwegian postmillennial adolescents
Authors: Brunborg Geir Scott , Halkjelsvik Torleif Bjordal , Moan Inger Synnøve
Published: April 2022

Introduction

Recent developments in health behavior among adolescents may have been accompanied by changes in risk factors for alcohol use. Focusing on postmillennial cohorts of adolescents, we revisit the question of whether sports participation is a risk factor for alcohol use.

Method

This study analyses data from four waves (2017−2020) of the MyLife longitudinal study. Participants were 3425 (45% boys) Norwegian adolescents attending middle school in 2017 (age range: 12−15 years). Annual questionnaire assessments included questions about frequency of sports practice, frequency of alcohol use/heavy episodic drinking, parental cohabitation, unstructured leisure time, sensation‐seeking, and behavioral problems. We employed growth curve models (N = 2682) and fixed effects models (N = 3131).

Results

Overall, we did not find systematic differences in initial alcohol use or development over time according to sports practice frequency at the first assessment. However, adolescents with the highest initial sports frequency had slightly lower initial alcohol use and a steeper increase (initial use: b = −0.06, p = .351; linear slope: b = −0.12, p = .218; quadratic curvature: b = 0.09, p = .004). There was no, or only a weak negative, association between change in sports practice and change in alcohol use after adjusting for potential time‐varying confounders, b = −0.03, p = .065.

Conclusion

Contrary to most previous research, we found little evidence for an association between sports participation and alcohol use among Norwegian adolescents born after 2000. Sports activities might not require particular attention in the prevention of alcohol use.
Avoidance/emotion‐focused coping mediates the relationship between distress tolerance and problematic Internet use in a representative sample of adolescents in Taiwan: One‐year follow‐up
Authors: Lin Min‐Pei
Published: April 2022

Introduction

Based on the theoretical frameworks of the Theory of Triadic Influence (TTI), this longitudinal study was designed to examine the mediating role of avoidance/emotion‐focused coping in the relationship between distress tolerance and problematic Internet use (PIU) in a large representative sample of senior high school students in Taiwan.

Methods

Through a 1‐year follow‐up design, 2170 participants were recruited from high schools throughout Taiwan using both stratified and cluster sampling in time 1 (T1), and 1832 students were followed‐up 1 year later (T2).

Results

Structure equation modeling and bootstrap analyses results showed that after controlling for PIU measured at T1, PIU (T2) was significantly predicted by distress tolerance (T1) and fully mediated through avoidance/emotion‐focused coping (T2).

Conclusions

The results not only support the TTI framework, but can also serve as a reference to help educational agencies and mental health organizations create policies and design programs that will help in the prevention of PIU among adolescents. The mediating role of avoidance/emotion‐focused coping in the relationship between distress tolerance and PIU was discussed.
The protective effect of resveratrol on diazinon‐induced oxidative stress and glucose hemostasis disorder in rats' liver
Authors: Mehri Fereshteh , Ranjbar Akram , Shirafkan Naghmeh , Asl Sara S. , Esfahani Maryam
Published: April 2022

This study was intended to assess the possible protective effect of resveratrol (Res) against oxidative stress and glucose hemostasis disorder in rats exposed to diazinon (DZN) for 4 weeks. Totally 25 Sprague‐Dawley rats were divided randomly into five groups: Control (orally received corn oil), DZN group (orally received 70 mg/kg/day), and Res groups (received DZN 70 mg/kg/day plus Res doses of 5, 10, and 20 mg/kg bodyweight/‐day), respectively. DZN significantly inhibited serum acetylcholinesterase enzyme (Ach E), serum and liver catalase, glutathione peroxidase activities, also total antioxidant capacities. On the other hand, DZN increased serum and liver malondialdehyde. DZN significantly increased Forkhead box protein O1 (Foxo1) expression and decreased phosphatase and tensin homolog (PTEN) and sirtuin 1 (Sirt‐1) expression. DZN impaired glucose hemostasis. Instead, Res treatment significantly reversed status of oxidative stress and antioxidant enzymes activities induced by DZN. Also, Res improved glucose hemostasis. Res increased PTEN and Sirt‐1 expression and reduced Foxo1 expression. Res administration ameliorated liver histopathological changes induced by DZN. These data confirmed that DZN significantly enhances oxidative stress and impairs glucose hemostasis. While Res showed a protective effect against the toxicity induced by DZN in rats.
Silencing ATF4 inhibits JMJD3‐dependent JUNB/ETS1 axis and mitigates cerebral ischemic injury
Authors: Wu Gang , Zhang Xi'an , Li Shijun , Wang Lina , Bai Jie , Wang Hanxiang , Shu Qing
Published: April 2022

Activating transcription factor 4 (ATF4) is known to play an important role in cerebral ischemia through apoptosis and neuron regulation. Histone demethylase JMJD3, specifically removing the methylation of H3K27me3, is highlighted to attenuate cerebral ischemic injury. However, few studies have explored the interaction between ATF4 and JMJD3 in this disease. Thus, we intended to explore the effect of ATF4 on cerebral ischemia. We first constructed a mouse model of middle cerebral artery occlusion (MCAO) and cultured PC12 cells. Specifically, the regulatory function of ATF4 and demethylase JMJD3 on the ischemic injury was explored via using ectopic expression and depletion by determination of modified neurologic severity score, blood–brain barrier, brain water content, apoptosis, infarct size, oxidative stress, and inflammation. Moreover, the interaction among ATF4, JUNB, JMJD3, and ETS1 was assessed by western blot analysis, immunofluorescence, immunoprecipitation, and dual‐luciferase reporter gene assay. These data showed that ATF4 and JMJD3 were upregulated in the MCAO model and PC12 cells. In addition, ectopic expression of ATF4 aggravated the ischemic injury through demethylation of JMJD3. Meanwhile, JMJD3 upregulated JUNB expression by inhibiting H3K21me2/3 enrichment and promoted ETS1 expression as well. Altogether, ATF4 could exacerbate cerebral ischemic injury through JMJD3‐dependent upregulation of JUNB/ETS1 expression, suggesting a potential theoretical basis of treatment for cerebral ischemic injury.
Overreact, an in silico lab: Automative quantum chemical microkinetic simulations for complex chemical reactions
Authors: Schneider Felipe S. S. , Caramori Giovanni F.
Published: April 2022

Today's demand for precisely predicting chemical reactions from first principles requires research to go beyond Gibbs' free energy diagrams and consider other effects such as concentrations and quantum tunneling. The present work introduces overreact, a novel Python package for propagating chemical reactions over time using data from computational chemistry only. The overreact code infers all differential equations and parameters from a simple input that consists of a set of chemical equations and quantum chemistry package outputs for each chemical species. We evaluate some applications from the literature: gas‐phase eclipsed‐staggered isomerization of ethane, gas‐phase umbrella inversion of ammonia, gas‐phase degradation of methane by chlorine radical, and three solvation‐phase reactions. Furthermore, we comment on a simple solvation‐phase acid–base equilibrium. We show how it is possible to achieve reaction profiles and information matching experiments.
Subversion of the immune response of human pathogenic spirochetes
Authors: Huang Jielite , Chen Jinlin , Xie Yafeng , Liu Zhuoran
Published: April 2022

Spirochetes are a large group of prokaryotes that originated from Gram‐negative bacteria and are capable of causing a variety of human and animal infections. However, the pathogenesis of spirochetes remains unclear, as different types of spirochetes play pathogenic roles through different pathogenic substances and mechanisms. To survive and spread in the host, spirochetes have evolved complicated strategies to evade host immune responses. In this review, we aimed to provide a comprehensive overview of immune evasion strategies in spirochetes infection. These strategies can be explained from the following points: (i) Antigenic variation: random, unidirectional, and segmental conversion of the gene to evade immune surveillance; (ii) Overcoming the attack of the complement system: recruitment of host complement regulators, cleavage of complement components and inhibition of complement activation to evade immune defenses; (iii) Interfering with immune cells to regulating the immune system; (iv) Persistent infection: invading and colonizing the host cell to escape immune damage.
Inosine monophosphate dehydrogenase type1 sustains tumor growth in hepatocellular carcinoma
Authors: Jia Xiaoyuan , Liu Yao , Cheng Yan , Wang Yin , Kang Hui , Ma Zhongren , Chen Kan
Published: April 2022

Background

Inosine monophosphate dehydrogenase (IMPDH) is the key enzyme in the biosynthesis of purine nucleotides. IMPDH1 and IMPDH2 are the two isoforms of IMPDH and they share 84% amino acid similarity and virtually indistinguishable catalytic activity. Although high expression of IMPDH2 has been reported in various cancers, the roles of IMPDH1 in hepatocellular carcinoma (HCC) are largely unknown.

Methods

The expression and the clinical relevance of IMPDH1 in 154 HCC patients were detected by immunohistochemistry analysis. The stable IMPDH1 knockdown HuH7 cells were established by lentiviral RNAi approach. The single cell proliferation was detected by colony‐forming unit assay. The tumor initiation and growth ability were measured by using xenograft tumor model in immunodeficient mice. The effect of IMPDH1 on cellular signaling pathways was analyzed by genome‐wide transcriptomic profiling.

Results

The expression of IMPDH1 is upregulated in tumor tissue compared with adjacent liver tissue, and higher expression of IMPDH1 is associated with better patient cumulative survival. In experimental models, loss of IMPDH1 in HCC cells inhibits the ability of single cell colony formation in vitro, and reduces the efficiency of tumor initiation and growth in immunodeficient mice. Consistently, loss of IMPDH1 results in distinct alterations of signaling pathways revealed by genome‐wide transcriptomic profiling.

Conclusion

IMPDH1 sustains HCC growth and progression.
The investigation of in vitro effects of farnesol at different cancer cell lines
Authors: Yilmaz Öztürk Betül , Feyzullazade Narmın , Dağ İlknur , Şengel Tayfun
Published: April 2022

Farnesol (trans, trans‐3,7,11‐trimethyl‐2,6,10‐dodecatriene‐1‐ol) is an essential oil component that can be found in a variety of plants. In this study, in vitro effects of farnesol on human lung cancer A549 cell line, colon adenocarcinoma (Caco‐2) cell line and healthy human lung epithelial BEAS‐2B cell lines, WST‐1 cytotoxicity test, dual staining of cell survival (DAPI‐PI) analysis, micronucleus test, and transmission electron microscopy (TEM). Farnesol acted in a concentration‐dependent manner at the dose ranges studied for cancer cell lines, and while at certain doses it reduced proliferation, interestingly at higher concentrations it induced growth more than the control. In the healthy BEAS‐2B cell line, it was tested over a wide range of doses and at all studied concentrations, it did not suppress cellular growth, but rather increased. This seems promising in that farnesol harms cancer cell lines but does not cause significant damage to healthy cells. Obtained TEM data after treatment with farnesol at IC50 dose showed both autophagic and apoptotic findings in cancer cell lines compared to control, and normal findings exhibited in BEAS‐2B cell line, cell survival, and micronucleus analyzes showed the presence of apoptotic findings and chromosomal damage as a result of farnesol application in cancer cell lines.

Research Highlights

Farnesol has dose‐dependent effects on human lung cancer and colon adenocarcinoma cell lines, with no significant damaging effects on healthy human lung epithelial cell lines.

TEM, cell survival, and micronucleus findings support the findings of autophagic, apoptotic, and chromosomal damage on cancer cell lines.
Use of SMOF lipid emulsion in very preterm infants does not affect the incidence of bronchopulmonary dysplasia–free survival
Authors: Ndiaye Aissatou B.K.T. , Mohamed Ibrahim , Pronovost Etienne , Angoa Georgina , Piedboeuf Bruno , Lemyre Brigitte , Afifi Jehier , Qureshi Mosarrat , Sériès Thibaut , Guillot Mireille , Simonyan David , Yusuf Kamran , Lavoie Pascal M. , Fraser William D. , Mâsse Benoît , Nuyt Anne Monique , Lacaze‐Masmonteil Thierry , Marc Isabelle
Published: April 2022

Background

We aim to assess whether the docosahexaenoic acid (DHA)–containing lipid emulsion (LE) SMOFlipid 20% (Fresenius Kabi Canada Ltd) is associated with bronchopulmonary dysplasia (BPD)–free survival at 36 weeks' postmenstrual age in very preterm infants.

Methods

This cohort study is nested in the MOBYDIck randomized clinical trial (NCT02371460), which investigated the effect of maternal DHA supplementation on BPD‐free survival in breastfed very preterm infants born between 23 0/7 and 28 6/7 weeks' gestation in 16 Canadian neonatal intensive care units (2015–2018). Parenteral SMOF‐LE was given to the infants according to the sites' routine care protocols. Relative risks (RRs) were estimated using a modified Poisson regression model with generalized estimating equations taking into account recruitment site, multiple birth, DHA supplementation, birth weight, sex, and gestational age.

Results

Among 528 infants (mean gestational age, 26.5 weeks [SD, 1.6]), 272 received SMOF‐LE. Overall, 56.7% of the infants in the SMOF‐LE group and 59.7% infants in the non–SMOF‐LE group survived without BPD (adjusted RR, 0.94 [95% CI, 0.77–1.14]; P = 0.51). BPD rates were 39.3% in the SMOF‐LE group vs 34.1% in the non–SMOF‐LE group (adjusted RR, 1.10 [95% CI, 0.82–1.47]; P = 0.53). Severe BPD rates were 31.8% in the SMOF‐LE group vs 28.8% in the non–SMOF‐LE group (adjusted P = 0.59). Mortality was not significantly different between the SMOF‐LE (6.7%) and non–SMOF‐LE groups (9.5%; adjusted P = 0.40).

Conclusion

In very preterm infants, intravenous DHA‐containing SMOF‐LE during the neonatal period was not associated with BPD‐free survival.
Interferon activated gene 204 protects against bone loss in experimental periodontitis
Authors: Swanson Karen V. , Girnary Mustafa , Alves Tomaz , Ting Jenny PY , Divaris Kimon , Beck Jim , Pucinelli Carolina Maschietto , da Silva Raquel Assed Bezerra , Uyan Dilek , Wilson Justin E. , Seaman William T. , Webster‐Cyriaque Jennifer , Vias Nishma , Jiao Yizu , Cantley Lloyd , Marlier Arnaud , Arnold Roland R. , Marchesan Julie T.
Published: April 2022

Background

Periodontal destruction can be the result of different known and yet‐to‐be‐discovered biological pathways. Recent human genetic association studies have implicated interferon‐gamma inducible protein 16 (IFI16) and absent in melanoma 2 (AIM2) with high periodontal interleukin (IL)‐1β levels and more destructive disease, but mechanistic evidence is lacking. Here, we sought to experimentally validate these observational associations and better understand IFI16 and AIM2's roles in periodontitis.

Methods

Periodontitis was induced in Ifi204–/– (IFI16 murine homolog) and Aim2–/– mice using the ligature model. Chimeric mice were created to identify the main source cells of Ifi204 in the periodontium. IFI16‐silenced human endothelial cells were treated with periodontal pathogens in vitro. Periodontal tissues from Ifi204–/– mice were evaluated for alveolar bone (micro‐CT), cell inflammatory infiltration (MPO+ staining), Il1b (qRT‐PCR), and osteoclast numbers (cathepsin K+ staining).

Results

Ifi204‐deficient mice> exhibited >20% higher alveolar bone loss than wild‐type (WT) (P < 0.05), while no significant difference was found in Aim2–/– mice. Ifi204's effect on bone loss was primarily mediated by a nonbone marrow source and was independent of Aim2. Ifi204‐deficient mice had greater neutrophil/macrophage trafficking into gingival tissues regardless of periodontitis development compared to WT. In human endothelial cells, IFI16 decreased the chemokine response to periodontal pathogens. In murine periodontitis, Ifi204 depletion elevated gingival Il1b and increased osteoclast numbers at diseased sites (P < 0.05).

Conclusions

These findings support IFI16's role as a novel regulator of inflammatory cell trafficking to the periodontium that protects against bone loss and offers potential targets for the development of new periodontal disease biomarkers and therapeutics.
Characterization of chemical composition variations in raw and processed Codonopsis Radix by integrating metabolomics and glycomics based on multiple chromatography‐mass spectrometry technology
Authors: Wang Yan , Zhang Jing‐jing , Wang Zi‐xia , Cui Fang , Zhang Qian‐Nian , Song Ping‐ping , Li Bing , Tang Zhuo‐shi , Hu Fang‐di , Shi Xiao‐feng
Published: April 2022

Codonopsis Radix, a popular food homology medicine, is widely used in clinical traditional Chinese medicine and food supplement, raw products and three types of processed products are the main forms of decoction pieces in China. However, there is no scientific basis for comprehensive chemical characterization of raw and three types of processed products. Herein, we investigated qualitatively and quantificationally secondary and primary metabolites in raw Codonopsis Radix and three types of processed products by metabolomics and glycomics employing multiple chromatography‐mass spectrometry technology combined with chemometric analysis further to look for differential compounds and propose the processing‐induced chemical mechanisms. The results indicated that Codonopsis Radix became dark‐colored and the smell of burnt incense odor was observed after processing. The principal component analysis demonstrated that secondary metabolome and glycome were significantly altered between raw and processed products, and 36 differential secondary metabolites and 11 differential primary metabolites were finally screened through orthogonal partial least‐squares‐discriminant analysis. The main types of compounds are alkaloids, terpenoids, glycosides, amino acids, monosaccharides, oligosaccharides, and furfural derivatives. Meanwhile, Chemical mechanisms could be involved, including oxidation, glycosidic hydrolysis, esterification, dehydration, and Maillard reaction. This work supplies a chemical basis for the application of various types of Codonopsis Radix decoction pieces.
Development and Validation of Automated Magnetic Resonance Parkinsonism Index 2.0 to Distinguish Progressive Supranuclear Palsy‐Parkinsonism From Parkinson's Disease
Authors: Quattrone Andrea , Bianco Maria G. , Antonini Angelo , Vaillancourt David E. , Seppi Klaus , Ceravolo Roberto , Strafella Antonio P. , Tedeschi Gioacchino , Tessitore Alessandro , Cilia Roberto , Morelli Maurizio , Nigro Salvatore , Vescio Basilio , Arcuri Pier Paolo , De Micco Rosa , Cirillo Mario , Weis Luca , Fiorenzato Eleonora , Biundo Roberta , Burciu Roxana G. , Krismer Florian , McFarland Nikolaus R. , Mueller Christoph , Gizewski Elke R. , Cosottini Mirco , Del Prete Eleonora , Mazzucchi Sonia , Quattrone Aldo
Published: April 2022

Background

Differentiating progressive supranuclear palsy‐parkinsonism (PSP‐P) from Parkinson's disease (PD) is clinically challenging.

Objective

This study aimed to develop an automated Magnetic Resonance Parkinsonism Index 2.0 (MRPI 2.0) algorithm to distinguish PSP‐P from PD and to validate its diagnostic performance in two large independent cohorts.

Methods

We enrolled 676 participants: a training cohort (n = 346; 43 PSP‐P, 194 PD, and 109 control subjects) from our center and an independent testing cohort (n = 330; 62 PSP‐P, 171 PD, and 97 control subjects) from an international research group. We developed a new in‐house algorithm for MRPI 2.0 calculation and assessed its performance in distinguishing PSP‐P from PD and control subjects in both cohorts using receiver operating characteristic curves.

Results

The automated MRPI 2.0 showed excellent performance in differentiating patients with PSP‐P from patients with PD and control subjects both in the training cohort (area under the receiver operating characteristic curve [AUC] = 0.93 [95% confidence interval, 0.89–0.98] and AUC = 0.97 [0.93–1.00], respectively) and in the international testing cohort (PSP‐P versus PD, AUC = 0.92 [0.87–0.97]; PSP‐P versus controls, AUC = 0.94 [0.90–0.98]), suggesting the generalizability of the results. The automated MRPI 2.0 also accurately distinguished between PSP‐P and PD in the early stage of the diseases (AUC = 0.91 [0.84–0.97]). A strong correlation (r = 0.91, P < 0.001) was found between automated and manual MRPI 2.0 values.

Conclusions

Our study provides an automated, validated, and generalizable magnetic resonance biomarker to distinguish PSP‐P from PD. The use of the automated MRPI 2.0 algorithm rather than manual measurements could be important to standardize measures in patients with PSP‐P across centers, with a positive impact on multicenter studies and clinical trials involving patients from different geographic regions. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society
The design of a novel direction modulated brachytherapy vaginal cylinder applicator for optimizing coverage of the apex
Authors: Meftahi Moeen , Fields Emma , Guy Christopher , Song William Y.
Published: April 2022

Purpose

High‐dose‐rate (HDR) vaginal cuff brachytherapy is an effective adjuvant therapy for women with stage I endometrial cancer. Although infrequent, failures do occur, most frequently at the vaginal vault. A potential cause of failure is insufficient dosimetric coverage at the vaginal apex due to cold spots from the anisotropic dose distribution of the source. Here, we propose a novel direction modulated brachytherapy (DMBT)‐concept vaginal cylinder (VC) applicator that resolves this dosimetric issue.

Methods and materials

The novel DMBT‐VC applicator was designed and simulated with the GEANT4 Monte Carlo code. The outer cylinder material chosen was polyphenylsulfone (PPSU) plastic, and the central part was a detachable rod, housing a single lumen made of either polyether ether ketone (PEEK) plastic or an MR‐compatible tungsten alloy. The PPSU‐based outer cylinder, together with the inner PEEK rod provides the dose distribution of a conventional VC applicator. The PEEK rod is then replaced with an MR‐compatible tungsten alloy rod of the same dimensions to generate directional “pencil‐like” beams to compensate for the anisotropic cold spots. Two widely used192Ir HDR sources, VS2000 and GammaMedPlus, were also simulated.

Results

The novel DMBT‐VC applicator was able to remove the underdosage at the apex due to the anisotropy effect regardless of the HDR sources without unnecessarily increasing the dose to the periphery of the applicator. Also, further directional modulation to reach deeper in the apex by up to 14 mm beyond the VC surface was achievable, again without increasing the peripheral doses. Total treatment dwell times increased only by 7–13%.

Conclusions

The novel DMBT‐VC applicator provides improved dose coverage at the vaginal apex by overcoming the classical anisotropy issue ubiquitous to all HDR brachytherapy sources. The next step in development of the device is manufacturing a prototype for clinical testing.
Neurocognitive outcomes in survivors of childhood acute lymphoblastic leukemia: Experience from a tertiary care center in India
Authors: CR Vishwa , Das Gargi , Seth Rachna , Sapra Savita , Sri Prasanth , Meena Jagdish Prasad , Gupta Aditya Kumar , Sreenivas Vishnu
Published: April 2022

Background

Data of neurocognitive deficits in survivors of acute lymphoblastic leukemia (ALL) is scarce from low middle‐income countries (LMICs), and is influenced by biological and cultural variations. The objective of this study was to assess the prevalence and spectrum of neurocognitive deficits in a cohort of survivors from India.

Procedure

Seventy survivors of childhood ALL were evaluated for neurocognitive deficits by the Indian adaptation of Wechsler Intelligence Scale for Children ‐ Fourth Edition (WISC‐IVINDIA). The prevalence of neurocognitive deficits was calculated based on the full‐scale intelligence quotient (FSIQ), and scores in discrete domains like verbal comprehension, perceptual reasoning, working memory, and processing speed were calculated and compared to demographics, treatment, and sociocultural factors.

Results

The mean (SD) current age and time since diagnosis was 10.5 (±3.2) years and 5 (±2.8) years, respectively. The mean FSIQ was 86.1 ± 20.5, with significant neurocognitive deficit (FSIQ <90) being prevalent in 50% (95% CI: 38%–62%) of the cohort. The proportion of survivors with deficits in individual domains of verbal comprehension, perceptual reasoning, working memory, and processing speed were 49%, 50%, 47%, and 44%, respectively. The odds of having neurocognitive deficits were higher when a child belonged to lower socioeconomic strata (OR 5.7, p = .004), parents with lower education attainment (OR 4.3, p = .041), and whose birth order was higher (OR 20.1, p = .005). Age at diagnosis/assessment, chemotherapy received, or dose of radiotherapy did not have a direct impact on neurocognition.

Conclusions and relevance

Rates of neurocognitive deficits are higher in survivors in LMICs, with socioeconomic variables contributing more than the direct neurotoxic effects of treatment.
How essential are in‐person clinic visits during maintenance treatment of children with acute lymphoblastic leukemia?
Authors: Rabinowicz Ron , Maguire Bryan , Hitzler Johann , Punnett Angela
Published: April 2022

Background

Acute lymphoblastic leukemia (ALL) is the most common cancer in children. Treatment consists of an initial intensive phase of chemotherapy, followed by a prolonged period of maintenance chemotherapy intended to reduce the risk of relapse. During the COVID‐19 pandemic, the need arose to identify and reduce non‐essential hospital visits.

Objective

We aimed to determine which proportion of in‐person clinic visits during ALL maintenance therapy was associated with a change of management based on the results of the physical examination.

Patients and methods

Medical records of children receiving maintenance chemotherapy for B‐precursor ALL between September 2019 and February 2020 were reviewed. Visits with a new finding on physical examination were divided into those where an in‐person assessment was deemed essential versus not essential. Finally, we determined the proportion of essential in‐person visits that resulted in a change of management.

Results

A total of 240 maintenance visits by 75 children were analyzed. An abnormal finding on physical examination was noted during 20 visits (8.3%). Of those, 14 (5.8%) uncovered a new finding, six (2.5%) were classified as “in‐person visit essential,” and among those six visits, three (1.2%) resulted in a change of patient management (one for acute otitis media, one for wheezing, and one for limp).

Conclusion

Our findings support the evaluation of care delivery models other than in‐person visits during ALL maintenance therapy. A prospective study is required to delineate criteria, benefits/risks, and families’ perspectives associated with virtual care delivery and the optimal frequency of in‐person visits.