bluuebunny/crossref_metadata_2025 huggingface dataset:
Expression and Pathogenic Analysis of Integrin Family Genes in Systemic Sclerosis
Authors: Xu Dan , Li Ting , Wang Ruikang , Mu Rong
Published: July 2021

Objectives: Emerging evidence shows that integrin members are involved in inflammation and fibrosis in systemic sclerosis (SSc). This study aimed at evaluating the expression of integrin family genes in the skin tissue from SSc patients and exploring the potential pathogenic mechanism.

Methods: We utilized the public datasets of SSc skin tissue from the Gene Expression Omnibus (GEO) database to analyze the expression and clinical significance of integrin family genes in SSc. The expression of integrin members in skin tissue was also assessed by immunohistochemistry. In addition, functional enrichment and pathway analysis were conducted.

Results: Compared with healthy controls, the mRNA and protein levels of ITGA5, ITGB2, and ITGB5 were upregulated in the skin of SSc patients. Further analysis indicated that the mRNA expression levels of ITGA5, ITGB2, and ITGB5 were positively correlated with modified Rodnan skin thickness score (mRSS). Functional enrichment and pathway analysis showed that integrin members may play multiple roles in the pathogenesis of SSc. Among them, ITGA5, ITGB2, and ITGB5 might synergistically promote SSc through affecting extracellular matrix (ECM) turnover, ECM–receptor interaction, focal adhesion, and leukocyte trans-endothelial migration, while ITGA5 and ITGB5 also might affect angiogenesis and endothelial cell function. In addition, ITGA5, ITGB2, and ITGA5 were associated with different pathways, respectively. ITGA5 was uniquely enriched for actin organization, while ITGB5 was for TGF-β signaling and ITGB2 for immune cell activation.

Conclusion: Our results implied that the abnormal expression of integrin family genes including ITGA5, ITGB2, and ITGB5 may participate in multiple pathological processes in SSc. Further investigations are required for confirming this speculation.
Evaluation and Verification of Fast Computational Simulations of Stent-Graft Deployment in Endovascular Aneurysmal Repair
Authors: Pionteck Aymeric , Pierrat Baptiste , Gorges Sébastien , Albertini Jean-Noël , Avril Stéphane
Published: July 2021

Fenestrated Endovascular Aortic Repair, also known as FEVAR, is a minimally invasive procedure that allows surgeons to repair the aorta while still preserving blood flow to kidneys and other critical organs. Given the high complexity of FEVAR, there is a pressing need to develop numerical tools that can assist practitioners at the preoperative planning stage and during the intervention. The aim of the present study is to introduce and to assess an assistance solution named Fast Method for Virtual Stent-graft Deployment for computer assisted FEVAR. This solution, which relies on virtual reality, is based on a single intraoperative X-ray image. It is a hybrid method that includes the use of intraoperative images and a simplified mechanical model based on corotational beam elements. The method was verified on a phantom and validated on three clinical cases, including a case with fenestrations. More specifically, we quantified the errors induced by the different simplifications of the mechanical model, related to fabric simulation and aortic wall mechanical properties. Overall, all errors for both stent and fenestration positioning were less than 5 mm, making this method compatible with clinical expectations. More specifically, the errors related to fenestration positioning were less than 3 mm. Although requiring further validation with a higher number of test cases, our method could achieve an accuracy compatible with clinical specifications within limited calculation time, which is promising for future implementation in a clinical context.
Causes and Consequences of COVID-19-Associated Bacterial Infections
Authors: Farrell Jennifer M. , Zhao Conan Y. , Tarquinio Keiko M. , Brown Sam P.
Published: July 2021

The COVID-19 literature highlights that bacterial infections are more common in fatal cases than recovered cases. If bacterial infections drive mortality in COVID-19, this has clear implications for patient management. However, it is possible that the enrichment of bacterial infections in COVID-19 fatalities is simply a by-product of late-stage pathology, leading to different advice for patient management. To address this question, we review current knowledge on bacterial infections in COVID-19, assess information from past viral respiratory pandemics, and simulate alternate causal models of interactions between virus, bacteria, and mortality in COVID-19. From these models, we conclude that currently available data are not sufficient to discriminate between these alternate causal pathways, and we highlight what data are required to determine the relative contribution of bacterial infection to COVID-19 morbidity and mortality. We further summarize the potential long-term consequences of SARS-CoV-2 infection.
Plant Growth-Promoting Rhizobacteria HN6 Induced the Change and Reorganization of Fusarium Microflora in the Rhizosphere of Banana Seedlings to Construct a Healthy Banana Microflora
Authors: Yang Deyou , Wang Lanying , Wang Tianhao , Zhang Yunfei , Zhang Shujing , Luo Yanping
Published: July 2021

Streptomyces aureoverticillatus HN6 was isolated in our previous study and effectively controlled banana Fusarium wilt. We explored the role of HN6 in constructing a healthy rhizosphere microflora of banana seedlings. The method of antibiotic resistance was used to determine the colonization ability of HN6. The effect of HN6 on the rhizosphere microbial communities was assessed using culture-dependent and high-throughput sequencing. The effect of HN6 on the infection process of the pathogen was evaluated using a pot experiment and confocal laser scanning microscopy. The results showed that HN6 could prevent pathogen infection; it increased the nutrient content and diversity of the bacterial community in the rhizosphere, promoted plant growth, and decreased the mycotoxin fusaric acid content and abundance of pathogens in the banana rhizosphere. Thus, HN6 decreased the relative abundance of Fusarium species, increased the diversity of fungi, and increased the relative abundance of bacteria in the rhizosphere. HN6 induced the change and reorganization of the microbial community dominated by Fusarium in the rhizosphere of banana seedlings, and it evolved into a community dominated that was not conducive to the occurrence of diseases, shaping the rhizosphere microflora and promoting the growth of banana.
Effect of Dietary Amylose/Amylopectin Ratio on Intestinal Health and Cecal Microbes’ Profiles of Weaned Pigs Undergoing Feed Transition or Challenged With Escherichia coli Lipopolysaccharide
Authors: Yang Can , Wang Min , Tang XiaoWu , Yang HuanSheng , Li FengNa , Wang YanCan , Li Jianzhong , Yin YuLong
Published: July 2021

Background

Dietary amylose/amylopectin ratio (DAR) plays an important role in piglets’ intestinal health. It is controversial whether diarrhea could be relieved by changing DAR in weaning piglets.

Methods

Sixty (Landrace × Yorkshire) castrated male pigs (initial body weight (BW) 6.51 ± 0.64 kg) were randomly allocated to five groups (one pig per cage and 12 replicates per group) according to their BW. Piglets received diets with different DARs (0.00, 0.20, 0.40, 0.60, and 0.80) for 29 days. Feed transition occurs at day 15. The piglets were challenged with lipopolysaccharides (Escherichia coliLPS, 100 μg/kg BW) on day 29 by intraperitoneal injection at 12 h before slaughter. Chyme was collected for pH value, short-chain fatty acid (SCFA), and cecal microbe analysis using 16S rRNA gene sequencing; mucosa was sampled for detecting gene expression.

Results

Rate and degree of diarrhea were higher when DAR was 0.40 than when it was 0.20 and 0.80 during the third week (P< 0.05). The chyme pH value in the cecum was higher (P< 0.05) in 0.20 DAR than in 0.00 and 0.80 DARs, but with no significant difference compared with 0.40 and 0.60 DARs (P> 0.05). Cecal isobutyric acid and isovaleric acid concentrations were higher in 0.20 than in other groups (P< 0.01). Cecal SCFAs such as acetic acid, propionic acid, and total SCFA, concentrations were higher in 0.40 DAR than in 0.00, 0.60, and 0.80 DARs (P< 0.05), but with no significant difference when compared with 0.20 (P> 0.05). Cecal crypt depth was lower (P< 0.05) in 0.80 than in other groups, but not 0.40. Claudin mRNA expression in the mucosa of the ileum was higher in 0.20 than in other groups (P< 0.01). The alpha diversity of cecal microbe representative by goods coverage was higher in group 0.40 when compared with group 0.20 (P< 0.05). At the genus level, the abundances of theRuminococcaceae_NK4A214_groupandAnaerotruncuswere higher but that ofCetobacteriumwas lower in the cecal chyme of group 0.20 than that of group 0.60 (P< 0.05), with no significant difference compared with other groups (P> 0.05). The diarrhea rate during the third week was negatively correlated with the abundances ofRikenellaceae_RC9_gut_groupandX.Eubacterium_coprostanoligenes_group(P< 0.05).

Conclusion

Compared with diet high in amylose or amylopectin, diet with DAR 0.40 showed a worse degree of diarrhea in weaned piglets during feed transition. But the intestinal health will be improved the week after the microbes and metabolites are regulated by DAR.
Feeding Systems and Host Breeds Influence Ruminal Fermentation, Methane Production, Microbial Diversity and Metagenomic Gene Abundance
Authors: Bharanidharan Rajaraman , Lee Chang Hyun , Thirugnanasambantham Krishnaraj , Ibidhi Ridha , Woo Yang Won , Lee Hong-Gu , Kim Jong Geun , Kim Kyoung Hoon
Published: July 2021

Our previous research revealed the advantages of separate feeding (SF) systems compared to total mixed ration (TMR) in terms of ruminal methane (CH4) production. The purpose of this experiment was to confirm the advantage of SF as a nutritional strategy for CH4 mitigation, and to determine the effects of different feeding systems (TMR and SF) on the rumen microbiome and associated metagenome of two different breeds and on CH4 emissions. We randomly allocated four Holstein (305 ± 29 kg) and four Hanwoo steers (292 ± 24 kg) to two groups; the steers were fed a commercial concentrate with tall fescue (75:25) as TMR or SF, in a crossover design (two successive 22-day periods). Neither feeding systems nor cattle breeds had an effect on the total tract digestibility of nutrients. The TMR feeding system and Hanwoo steers generated significantly more CH4 (P < 0.05) and had a higher yield [g/d and g/kg dry matter intake (DMI)] compared to the SF system and Holstein steers. A larger rumen acetate:propionate ratio was observed for the TMR than the SF diet (P < 0.05), and for Hanwoo than Holstein steers (P < 0.001), clearly reflecting a shift in the ruminal H2 sink toward CH4 production. The linear discriminant analysis (LDA) effect size (LEfSe) revealed a greater abundance (α < 0.05 and LDA > 2.0) of operational taxonomic units (OTUs) related to methanogenesis for Hanwoo steers compared to Holstein steers. Kendall’s correlation analysis revealed wide variation of microbial co-occurrence patterns between feeding systems, indicating differential H2 thermodynamics in the rumen. A metagenome analysis of rumen microbes revealed the presence of 430 differentially expressed genes, among which 17 and 27 genes exhibited positive and negative associations with CH4 production, respectively (P < 0.001). A strong interaction between feeding system and breed was observed for microbial and metagenomic abundance. Overall, these results suggest that the TMR feeding system produces more CH4, and that Hanwoo cattle are higher CH4 emitters than SF diet and Holstein cattle, respectively. Interestingly, host-associated microbial interactions differed within each breed depending on the feeding system, which indicated that breed-specific feeding systems should be taken into account for farm management.
Preserved Thermal Pain in 3xTg-AD Mice With Increased Sensory-Discriminative Pain Sensitivity in Females but Affective-Emotional Dimension in Males as Early Sex-Specific AD-Phenotype Biomarkers
Authors: Cañete Toni , Giménez-Llort Lydia
Published: July 2021

The increase of the aging population, where quite chronic comorbid conditions are associated with pain, draws growing interest across its investigation and the underlying nociceptive mechanisms. Burn injuries associated problems might be of relevance in the older adult’s daily life, but in people with dementia, exposure to high temperatures and heat sources poses a significantly increased risk of burns. In this brief report, the hind paws and tail pain withdrawal reflexes and the emotional responses to thermal nociception in 3xTg-AD mice were characterized for the first time in the plantar test and compared to their non-transgenic (NTg) counterparts. We studied a cohort of male and female 3xTg-AD mice at asymptomatic (2 months), early (6 months), middle (9 months), and advanced (12 and 15 months) stages of the disease and as compared to sex- and age-matched NTg control mice with normal aging. At 20 and 40W intensities, the sensorial-discriminative thresholds eliciting the withdrawal responses were preserved from asymptomatic to advanced stages of the disease compared to NTg counterparts. Moreover, 3xTg-AD females consistently showed a greater sensory-discriminative sensitivity already at premorbid ages, whereas increased emotionality was shown in males. False-negative results were found in “blind to sex and age” analysis, warning about the need to study sexes independently. The current results and previous report in cold thermal stimulation provide two paradigms unveiling sex-specific early AD-phenotype nociceptive biomarkers to study the mechanistic underpinnings of sex-, age- and AD-disease-dependent thermal pain sensitivity.
A Deep Non-negative Matrix Factorization Model for Big Data Representation Learning
Authors: Chen Zhikui , Jin Shan , Liu Runze , Zhang Jianing
Published: July 2021

Nowadays, deep representations have been attracting much attention owing to the great performance in various tasks. However, the interpretability of deep representations poses a vast challenge on real-world applications. To alleviate the challenge, a deep matrix factorization method with non-negative constraints is proposed to learn deep part-based representations of interpretability for big data in this paper. Specifically, a deep architecture with a supervisor network suppressing noise in data and a student network learning deep representations of interpretability is designed, which is an end-to-end framework for pattern mining. Furthermore, to train the deep matrix factorization architecture, an interpretability loss is defined, including a symmetric loss, an apposition loss, and a non-negative constraint loss, which can ensure the knowledge transfer from the supervisor network to the student network, enhancing the robustness of deep representations. Finally, extensive experimental results on two benchmark datasets demonstrate the superiority of the deep matrix factorization method.
A Primer on Hyperdimensional Computing for iEEG Seizure Detection
Authors: Schindler Kaspar A. , Rahimi Abbas
Published: July 2021

A central challenge in today's care of epilepsy patients is that the disease dynamics are severely under-sampled in the currently typical setting with appointment-based clinical and electroencephalographic examinations. Implantable devices to monitor electrical brain signals and to detect epileptic seizures may significantly improve this situation and may inform personalized treatment on an unprecedented scale. These implantable devices should be optimized for energy efficiency and compact design. Energy efficiency will ease their maintenance by reducing the time of recharging, or by increasing the lifetime of their batteries. Biological nervous systems use an extremely small amount of energy for information processing. In recent years, a number of methods, often collectively referred to as brain-inspired computing, have also been developed to improve computation in non-biological hardware. Here, we give an overview of one of these methods, which has in particular been inspired by the very size of brains' circuits and termed hyperdimensional computing. Using a tutorial style, we set out to explain the key concepts of hyperdimensional computing including very high-dimensional binary vectors, the operations used to combine and manipulate these vectors, and the crucial characteristics of the mathematical space they inhabit. We then demonstrate step-by-step how hyperdimensional computing can be used to detect epileptic seizures from intracranial electroencephalogram (EEG) recordings with high energy efficiency, high specificity, and high sensitivity. We conclude by describing potential future clinical applications of hyperdimensional computing for the analysis of EEG and non-EEG digital biomarkers.
The Role of Edema in Subacute Lesion Progression After Treatment of Acute Ischemic Stroke
Authors: Konduri Praneeta , van Kranendonk Katinka , Boers Anna , Treurniet Kilian , Berkhemer Olvert , Yoo Albert J. , van Zwam Wim , Oostenbrugge Robert van , van der Lugt Aad , Dippel Diederik , Roos Yvo , Bot Joost , Majoie Charles , Marquering Henk ,   the MR CLEAN Trial Investigators (Multicenter Randomized Clinical Trial of Endovascular Treatment for Acute Ischemic Stroke in the Netherlands)
Published: July 2021

Background:Ischemic lesions commonly continue to progress even days after treatment, and this lesion growth is associated with unfavorable functional outcome in acute ischemic stroke patients. The aim of this study is to elucidate the role of edema in subacute lesion progression and its influence on unfavorable functional outcome by quantifying net water uptake.

Methods:We included all 187 patients from the MR CLEAN trial who had high quality follow-up non-contrast CT at 24 h and 1 week. Using a CT densitometry-based method to calculate the net water uptake, we differentiated total ischemic lesion volume (TILV) into edema volume (EV) and edema-corrected infarct volume (ecIV). We calculated these volumes at 24 h and 1 week after stroke and determined their progression in the subacute period. We assessed the effect of 24-h lesion characteristics on EV and ecIV progression. We evaluated the influence of edema and edema-corrected infarct progression on favorable functional outcome after 90 days (modified Rankin Scale: 0–2) after correcting for potential confounders. Lastly, we compared these volumes between subgroups of patients with and without successful recanalization using the Mann–WhitneyU-test.

Results:Median TILV increased from 37 (IQR: 18–81) ml to 68 (IQR: 30–130) ml between 24 h and 1 week after stroke, while the net water uptake increased from 22 (IQR: 16–26)% to 27 (IQR: 22–32)%. The TILV progression of 20 (8.8–40) ml was mostly caused by ecIV with a median increase of 12 (2.4–21) ml vs. 6.5 (2.7–15) ml of EV progression. Larger TILV, EV, and ecIV volumes at 24 h were all associated with more edema and lesion progression. Edema progression was associated with unfavorable functional outcome [aOR: 0.53 (0.28–0.94) per 10 ml;p-value: 0.05], while edema-corrected infarct progression showed a similar, non-significant association [aOR: 0.80 (0.62–0.99);p-value: 0.06]. Lastly, edema progression was larger in patients without successful recanalization, whereas ecIV progression was comparable between the subgroups.

Conclusion:EV increases in evolving ischemic lesions in the period between 1 day and 1 week after acute ischemic stroke. This progression is larger in patients without successful recanalization and is associated with unfavorable functional outcome. However, the extent of edema cannot explain the total expansion of ischemic lesions since edema-corrected infarct progression is larger than the edema progression.
A Neural Network Reveals Motoric Effects of Maternal Preconception Exposure to Nicotine on Rat Pup Behavior: A New Approach for Movement Disorders Diagnosis
Authors: Torabi Reza , Jenkins Serena , Harker Allonna , Whishaw Ian Q. , Gibb Robbin , Luczak Artur
Published: July 2021

Neurodevelopmental disorders can stem from pharmacological, genetic, or environmental causes and early diagnosis is often a key to successful treatment. To improve early detection of neurological motor impairments, we developed a deep neural network for data-driven analyses. The network was applied to study the effect of maternal nicotine exposure prior to conception on 10-day-old rat pup motor behavior in an open field task. Female Long-Evans rats were administered nicotine (15 mg/L) in sweetened drinking water (1% sucralose) for seven consecutive weeks immediately prior to mating. The neural network outperformed human expert designed animal locomotion measures in distinguishing rat pups born to nicotine exposed dams vs. control dams (87 vs. 64% classification accuracy). Notably, the network discovered novel movement alterations in posture, movement initiation and a stereotypy in “warm-up” behavior (repeated movements along specific body dimensions) that were predictive of nicotine exposure. The results suggest novel findings that maternal preconception nicotine exposure delays and alters offspring motor development. Similar behavioral symptoms are associated with drug-related causes of disorders such as autism spectrum disorder and attention-deficit/hyperactivity disorder in human children. Thus, the identification of motor impairments in at-risk offspring here shows how neuronal networks can guide the development of more accurate behavioral tests to earlier diagnose symptoms of neurodevelopmental disorders in infants and children.
High Red Meat Intake Exacerbates Dextran Sulfate-Induced Colitis by Altering Gut Microbiota in Mice
Authors: Li Dan-ping , Cui Min , Tan Fang , Liu Xiao-yan , Yao Ping
Published: July 2021

Inflammatory bowel disease (IBD) is a serious hazard to public health, but the precise etiology of the disease is unclear. High intake of red meat diet is closely related to the occurrence of IBD. In this study, we investigated whether the high intake of red meat can increase the sensitivity of colitis and the underlying mechanism. Mice were fed with different levels of red meat for 8 weeks and then the colonic contents were analyzed by 16S rRNA sequencing. Then 3% dextran sulfate sodium was used to induce colitis in mice. We observed the severity of colitis and inflammatory cytokines. We found that high-dose red meat caused intestinal microbiota disorder, reduced the relative abundance of Lachnospiraceae_NK4A136_group, Faecalibaculum, Blautia and Dubosiella, and increased the relative abundance of Bacteroides and Alistipes. This in turn leads to an increase in colitis and inflammatory cytokine secretion. Moreover, we found that high red meat intake impaired the colon barrier integrity and decreased the expression of ZO-1, claudin, and occludin. We also found high red meat intake induced the production of more inflammatory cytokines such as IL-1β, TNF-α, IL-17, and IL-6 and inflammatory inducible enzymes such as COX-2 and iNOS in dextran sulfate sodium-induced colitis. These results suggest that we should optimize the diet and reduce the intake of red meat to prevent the occurrence of IBD.
Context-Dependent Roles of Claudins in Tumorigenesis
Authors: Li Jian
Published: July 2021

The barrier and fence functions of the claudin protein family are fundamental to tissue integrity and human health. Increasing evidence has linked claudins to signal transduction and tumorigenesis. The expression of claudins is frequently dysregulated in the context of neoplastic transformation. Studies have uncovered that claudins engage in nearly all aspects of tumor biology and steps of tumor development, suggesting their promise as targets for treatment or biomarkers for diagnosis and prognosis. However, claudins can be either tumor promoters or tumor suppressors depending on the context, which emphasizes the importance of taking various factors, including organ type, environmental context and genetic confounders, into account when studying the biological functions and targeting of claudins in cancer. This review discusses the complicated roles and intrinsic and extrinsic determinants of the context-specific effects of claudins in cancer.
Platelet-to-Lymphocyte Ratio Is Associated With Favorable Response to Neoadjuvant Chemotherapy in Triple Negative Breast Cancer: A Study on 120 Patients
Authors: Lusho Sejdi , Durando Xavier , Mouret-Reynier Marie-Ange , Kossai Myriam , Lacrampe Nathalie , Molnar Ioana , Penault-Llorca Frederique , Radosevic-Robin Nina , Abrial Catherine
Published: July 2021

Introduction

Triple negative breast cancer (TNBC) is highly heterogeneous, but still most of the patients are treated by the anthracycline/taxane-based neoadjuvant therapy (NACT). Tumor-infiltrating lymphocytes (TILs) are a strong predictive and prognostic biomarker in TNBC, however are not always available. Peripheral blood counts, which reflect the systemic inflammatory/immune status, are easier to obtain than TILs. We investigated whether baseline white cell or platelet counts, as well as, Neutrophil-to-Lymphocyte Ratio (NLR) or Platelet-to-Lymphocyte Ratio (PLR) could replace baseline TILs as predictive or prognostic biomarkers in a series of TNBC treated by standard NACT.

Patients and Methods

One hundred twenty patients uniformly treated by FEC/taxane NACT in a tertiary cancer care center were retrospectively analyzed. The presence of pathological complete response (pCR: ypT0/Tis, ypN0) or the presence of pCR and/small residual disease (ypT0/Tis/T1ab, ypN0) were considered as good responses in data analysis. Baseline/pre-NACT blood count, NLR, PLR and TILs were evaluated as predictors of response, distant recurrence rate and distant recurrence-free survival (DRFS).

Results

TILs ≥30% and ≥1.5% were best predictors of pCR and distant recurrence risk, respectively (p = 0.007, p = 0.012). However, in this cohort, pCR status was not significantly associated with recurrence. Only the ensemble of patients with pCR and small residual disease had lower recurrence risk and longer survival DRFS (p = 0.042, p = 0.024, respectively) than the rest of the cohort (larger residual disease). The only parameter which could predict the pCR/small residual disease status was PLR: patients with values lower than 133.25 had significantly higher chance of reaching that status after NACT (p = 0.045). However, no direct correlation could be established between baseline PLR and metastatic recurrence. No correlation either was found between TIL and individual blood counts, or between TILs and NLR or PLR.

Conclusion

In this cohort, TILs retained their pCR predictive value; however PLR was a better predictor of the ensemble of responses which had good outcome in terms of less distant recurrences or longer DRFS (pCR or small residual disease). Thus, baseline PLR is worth further, prospective investigation together with baseline TILs, as it might indicate a good TNBC response to NACT when TILs are unavailable.
Retrospective Study of the Safety and Efficacy of Anlotinib Combined With Dose-Dense Temozolomide in Patients With Recurrent Glioblastoma
Authors: She Lei , Su Lin , Shen Liangfang , Liu Chao
Published: July 2021

Purpose

The purpose of this study was to retrospectively analyze the safety and clinical efficacy of anlotinib combined with dose-dense temozolomide (TMZ) as the first-line therapy in the treatment of recurrent glioblastoma (rGBM).

Patients and Methods

We collected the clinical data of 20 patients with rGBM. All patients received anlotinib (12 mg daily, orally for 2 weeks, discontinued for 1 week, repeated every 3 weeks) combined with dose-dense TMZ (100 mg/m2, 7 days on with 7 days off) until the disease progressed (PD) or adverse effects (AEs) above grade 4 appeared. Grade 3 AEs need to be restored to grade 2 before continuing treatment, and the daily dose of anlotinib is reduced to 10 mg. The patients were reexamined by head magnetic resonance imaging (MRI) every 1 to 3 months. The therapeutic effect was evaluated according to Response Assessment in Neuro-Oncology (RANO) criteria. The survival rate was analyzed by Kaplan-Meier survival curve analysis. The baseline of all survival index statistics was the start of anlotinib combined with dose-dense of TMZ. National Cancer Institute-Common Terminology Criteria Adverse Events version 4.0 (NCI-CTCAE 4.0) was used to evaluate AEs.

Results

Twenty cases of rGBM were evaluated according to the RANO criteria after treatment with anlotinib and dose-dense TMZ, including five cases of stable disease (SD), thirteen cases of partial response (PR), one case of complete response (CR), and one case of PD. The median follow-up time was 13.4 (95% CI, 10.5–16.3) months. The 1-year overall survival (OS) rate was 47.7%. The 6-month progression-free survival (PFS) rate was 55%. In the IDH wild type group, the median PFS and median OS were 6.1 and 11.9 months, respectively. We observed that AEs associated with treatment were tolerable. One patient stopped taking the drug because of cerebral infarction. There were no treatment-related deaths.

Conclusion

Anlotinib combined with dose-dense TMZ for the first-line therapy showed good efficacy in OS, PFS, ORR, and DCR in the treatment of rGBM, and the AEs were tolerant. Randomized controlled clinical trials investigating the treatment of rGBM with anlotinib are necessary.
Early Cumulative Fluid Balance and Outcomes in Pediatric Allogeneic Hematopoietic Cell Transplant Recipients With Acute Respiratory Failure: A Multicenter Study
Authors: Sallee Colin J. , Smith Lincoln S. , Rowan Courtney M. , Heckbert Susan R. , Angelo Joseph R. , Daniel Megan C. , Gertz Shira J. , Hsing Deyin D. , Mahadeo Kris M. , McArthur Jennifer A. , Fitzgerald Julie C.
Published: July 2021

Objectives

To evaluate the associations between early cumulative fluid balance (CFB) and outcomes among critically ill pediatric allogeneic hematopoietic cell transplant (HCT) recipients with acute respiratory failure, and determine if these associations vary by treatment with renal replacement therapy (RRT).

Methods

We performed a secondary analysis of a multicenter retrospective cohort of patients (1mo - 21yrs) post-allogeneic HCT with acute respiratory failure treated with invasive mechanical ventilation (IMV) from 2009 to 2014. Fluid intake and output were measured daily for the first week of IMV (day 0 = day of intubation). The exposure, day 3 CFB (CFB from day 0 through day 3 of IMV), was calculated using the equation [Fluid in – Fluid out] (liters)/[PICU admission weight](kg)*100. We measured the association between day 3 CFB and PICU mortality with logistic regression, and the rate of extubation at 28 and 60 days with competing risk regression (PICU mortality = competing risk).

Results

198 patients were included in the study. Mean % CFB for the cohort was positive on day 0 of IMV, and increased further on days 1-7 of IMV. For each 1% increase in day 3 CFB, the odds of PICU mortality were 3% higher (adjusted odds ratio (aOR) 1.03, 95% CI 1.00-1.07), and the rate of extubation was 3% lower at 28 days (adjusted subdistribution hazard ratio (aSHR) 0.97, 95% CI 0.95-0.98) and 3% lower at 60 days (aSHR 0.97, 95% CI 0.95-0.98). When day 3 CFB was dichotomized, 161 (81%) had positive and 37 (19%) had negative day 3 CFB. Positive day 3 CFB was associated with higher PICU mortality (aOR 3.42, 95% CI 1.48-7.87) and a lower rate of extubation at 28 days (aSHR 0.30, 95% CI 0.18-0.48) and 60 days (aSHR 0.30, 95% 0.19-0.48). On stratified analysis, the association between positive day 3 CFB and PICU mortality was significantly stronger in those not treated with RRT (no RRT: aOR 9.11, 95% CI 2.29-36.22; RRT: aOR 1.40, 95% CI 0.42-4.74).

Conclusions

Among critically ill pediatric allogeneic HCT recipients with acute respiratory failure, positive and increasing early CFB were independently associated with adverse outcomes.
Case Report: Hyper IgE, but Not the Usual Suspects–Kimura Disease in an Adolescent Female
Authors: Ramachandran Prasanna Venkatesh , Healy C. Mary , Lambert Elton M. , Guerra Deyanara , Curry Choladda V. , Vogel Tiphanie P.
Published: July 2021

Elevated immunoglobulin E (IgE) levels can be associated with infectious, allergic and inflammatory disorders, and rarely as a manifestation of an inborn error of immunity. Here we report the case of an adolescent female who presented with a gradually enlarging neck mass, lymphadenopathy, eosinophilia and highly elevated IgE levels. Laboratory and histopathologic evaluation revealed an unlikely diagnosis of Kimura Disease. We discuss the differential diagnosis of a neck mass with prominent eosinophils on histology, and review support for T-helper type 2 (Th2) cell activation and hyper-IgE in Kimura Disease.
The First Case Report of X-Linked Sideroblastic Anemia With Ataxia of Chinese Origin and Literature Review
Authors: Xiong Shiqiu , Jia Yang , Li Shijun , Huang Peng , Xiong Jie , Mao Dingan , He Qingnan , Liu Liqun
Published: July 2021

X-linked sideroblastic anemia with ataxia (XLSA/A) is a rare X-liked inherited disease, which was linked to the ABCB7 gene mutations. So far, five families have been reported worldwide. We present the first Chinese family of XLSA/A with novel ABCB7 gene mutation (c.2024A > G) and make a retrospective literature review. All affected patients were male. Age of symptom onset was <2 years old. The main symptoms included ataxia, delay in motor development, and mild sideroblastic anemia with obviously increased erythrocyte protoporphyrin. In this case, he had new symptoms that had not been reported in other cases such as epilepsy and cryptorchidism. We also discuss the possible molecular mechanism linking ABCB7 gene mutations to sideroblastic anemia and ataxia.
Pharmacotherapy for Behçet’s Disease and the Risk of Malignancy
Authors: Huang Mao-Xin , Wang Cai-Yun , Guo Jin-Yan , Li Jian-Hao , Li Xiao-Hong , Zhang Jiang-An , Yu Jian-Bin
Published: July 2021

Background: Behçet’s disease (BD) is associated with an increased risk of cancer. Few reports have been published on the relationship between drug exposure and the risk of cancer in patients with BD. Herein, we explored the relationship between pharmacologic interventions for BD and the risk of cancer.

Methods: we carried out a retrospective nested case-control study in a cohort of BD patients from attending our institution. Among 1,148 patients, 22 cancer patients were individually 1:2 matched to 44 cancer-free controls. The following biochemical indicators were evaluated: routine blood analysis, liver and kidney function tests, inflammatory indexes, blood gas analysis, blood electrolyte and previous pharmacologic interventions to manage BD including systemic glucocorticoids, methotrexate, cyclosporine-A, azathioprine, cyclophosphamide (CYC), and thalidomide, which are considered the primary medicines used for the management of BD.

Results: Among the 22 BD patients with cancers, myelodysplastic syndrome (MDS) (22.72%) was the most common type. Furthermore, CYC administration was significantly higher in BD patients with cancer compared with the cancer-free matched control group. Further, we observed that complement 4 (C4) (odds ratio [OR] = 0.0001, 95% confidence interval [CI]: 0.001–0.065) and hemoglobin (Hb) (OR = 0.891, 95% CI: 0.795–0.998) levels were independent protective factors for predicting cancer risk in BD patients on multivariate analyses.

Conclusion: Our study revealed that CYC was associated with a high risk of cancer in BD patients. Furthermore, C4 and Hb are independent protective factors for oncogenesis in BD patients. These findings may provide references and suggestions for clinicians to select appropriate treatments and for the early recognition of high-risk patients to reduce cancer incidence in BD patients.
Patient Preferences for Attributes of Chemotherapy for Lung Cancer: Discrete Choice Experiment Study in Japan
Authors: Sugitani Yasuo , Ito Kyoko , Ono Shunsuke
Published: July 2021

Our study objective was to determine lung cancer chemotherapy attributes that are important to patients in Japan. A discrete choice experiment survey in an anonymous web-based questionnaire format with a reward was completed by 200 lung cancer patients in Japan from November 25, 2019, to November 27, 2019. The relative importance of patient preferences for each attribute was estimated using a conditional logit model. A hierarchical Bayesian logit model was also used to estimate the impact of each demographic characteristic on the relative importance of each attribute. Of the 200 respondents, 191 with consistent responses were included in the analysis. In their preference, overall survival was the most important, followed by diarrhea, nausea, rash, bone marrow suppression (BMS), progression-free survival, fatigue, interstitial lung disease, frequency of administration, and duration of administration. The preferences were influenced by demographic characteristics (e.g., gender and age) and disease background (e.g., cancer type and stage). Interestingly, the experience of cancer drug therapies and adverse events had a substantial impact on the hypothetical drug preferences. For the Japanese lung cancer patients, improved survival was the most important attribute that influenced their preference for chemotherapy, followed by adverse events, including diarrhea, nausea, rash, and BMS. The preferences varied depending on the patient’s demographic and experience. As drug attributes can affect patient preferences, pharmaceutical companies should be aware of the patient preferences and develop drugs that respond to segmented market needs.
Medicinal Plants Used for Treating Mild Covid-19 Symptoms Among Thai Karen and Hmong
Authors: Phumthum Methee , Nguanchoo Varangrat , Balslev Henrik
Published: July 2021

Background: The COVID-19 pandemic is causing many severe problems globally, and it is not known for how long it will last. The only hope we have for dealing with the problem is to produce sufficient vaccines and administer them efficiently. However, the current demand for vaccines greatly exceeds the supply, and many people will suffer from the disease for still some time. Moreover, the period for immunity obtained by the vaccines remains unknown, and we cannot predict how long the world will suffer the COVID-19 infections. Therefore, there will be a continued demand for treatments of its symptoms. An alternative solution for providing such treatment is the use of traditional medicinal plants.

Aims: To document medicinal plants used by Hmong and Karen in Thailand to treat mild symptoms of COVID-19.

Methods: Traditional knowledge about ethnomedicinal plants used by Hmong and Karen in Thailand for treating mild symptoms listed by WHO as associated with COVID 19, was collected in field interviews and extracted from the literature.

Results: We identified 491 plant species used medicinally by both ethnic groups to treat fever, cough, diarrhea, muscle pain and ache, rash, headache, sore throat, and conjunctivitis. Of the 491 species 60 were mentioned at least five times in the literature or in our field data. Of these 60 species, we propose the most commonly used ones for treatments of mild COVID-19 symptoms. Ten of these most commonly mentioned species were used for treatments of fever, nine for treatment of cough, four for treatment of diarrhea, two for treatment of rash, and a single species was used to treat muscle pain and headache.

Conclusion: This study suggests alternative treatments for mild symptoms of COVID-19 with medicinal plants that are traditionally used by the ethnic minority groups of the Hmong and Karen in Thailand. Although COVID-19 is a new disease, its mild symptoms are shared with many other diseases. Traditional knowledge on medicinal plants used by the Thai Karen and Hmong could help in the treatments of these symptoms associated with COVID-19. Many of the proposed plants were used abundantly by both ethnic groups, and other studies on biological activities support their efficacy in such treatments.
Diarylpentanoid (1,5-bis(4-hydroxy-3-methoxyphenyl)-1,4-pentadiene-3-one) (MS13) Exhibits Anti-proliferative, Apoptosis Induction and Anti-migration Properties on Androgen-independent Human Prostate Cancer by Targeting Cell Cycle–Apoptosis and PI3K Signalling Pathways
Authors: Abd. Wahab Nurul Azwa , Abas Faridah , Othman Iekhsan , Naidu Rakesh
Published: July 2021

Diarylpentanoids exhibit a high degree of anti-cancer activity and stability in vitro over curcumin in prostate cancer cells. Hence, this study aims to investigate the effects of a diarylpentanoid, 1,5-bis(4-hydroxy-3-methoxyphenyl)-1,4-pentadiene-3-one (MS13) on cytotoxicity, anti-proliferative, apoptosis-inducing, anti-migration properties, and the underlying molecular mechanisms on treated androgen-independent prostate cancer cells, DU 145 and PC-3. A cell viability assay has shown greater cytotoxicity effects of MS13-treated DU 145 cells (EC50 7.57 ± 0.2 µM) and PC-3 cells (EC50 7.80 ± 0.7 µM) compared to curcumin (EC50: DU 145; 34.25 ± 2.7 µM and PC-3; 27.77 ± 6.4 µM). In addition, MS13 exhibited significant anti-proliferative activity against AIPC cells compared to curcumin in a dose- and time-dependent manner. Morphological observation, increased caspase-3 activity, and reduced Bcl-2 protein levels in these cells indicated that MS13 induces apoptosis in a time- and dose-dependent. Moreover, MS13 effectively inhibited the migration of DU 145 and PC-3 cells. Our results suggest that cell cycle-apoptosis and PI3K pathways were the topmost significant pathways impacted by MS13 activity. Our findings suggest that MS13 may demonstrate the anti-cancer activity by modulating DEGs associated with the cell cycle-apoptosis and PI3K pathways, thus inhibiting cell proliferation and cell migration as well as inducing apoptosis in AIPC cells.
Branched-chain Amino Acids: Catabolism in Skeletal Muscle and Implications for Muscle and Whole-body Metabolism
Authors: Mann Gagandeep , Mora Stephen , Madu Glory , Adegoke Olasunkanmi A. J.
Published: July 2021

Branched-chain amino acids (BCAAs) are critical for skeletal muscle and whole-body anabolism and energy homeostasis. They also serve as signaling molecules, for example, being able to activate mammalian/mechanistic target of rapamycin complex 1 (mTORC1). This has implication for macronutrient metabolism. However, elevated circulating levels of BCAAs and of their ketoacids as well as impaired catabolism of these amino acids (AAs) are implicated in the development of insulin resistance and its sequelae, including type 2 diabetes, cardiovascular disease, and of some cancers, although other studies indicate supplements of these AAs may help in the management of some chronic diseases. Here, we first reviewed the catabolism of these AAs especially in skeletal muscle as this tissue contributes the most to whole body disposal of the BCAA. We then reviewed emerging mechanisms of control of enzymes involved in regulating BCAA catabolism. Such mechanisms include regulation of their abundance by microRNA and by post translational modifications such as phosphorylation, acetylation, and ubiquitination. We also reviewed implications of impaired metabolism of BCAA for muscle and whole-body metabolism. We comment on outstanding questions in the regulation of catabolism of these AAs, including regulation of the abundance and post-transcriptional/post-translational modification of enzymes that regulate BCAA catabolism, as well the impact of circadian rhythm, age and mTORC1 on these enzymes. Answers to such questions may facilitate emergence of treatment/management options that can help patients suffering from chronic diseases linked to impaired metabolism of the BCAAs.
Rapalink-1 Increased Infarct Size in Early Cerebral Ischemia–Reperfusion With Increased Blood–Brain Barrier Disruption
Authors: Chi Oak Z. , Liu Xia , Cofano Sean , Patel Nikhil , Jacinto Estela , Weiss Harvey R.
Published: July 2021

It has been reported that the mechanistic target of rapamycin (mTOR) pathway is involved in cerebral ischemia–reperfusion injury. One of the important pathological changes during reperfusion after cerebral ischemia is disruption of blood–brain barrier (BBB). Rapamycin, a first-generation mTOR inhibitor, produces divergent effects on neuronal survival and alteration in BBB disruption. In this study, we investigated how Rapalink-1, a third-generation mTOR inhibitor, would affect neuronal survival and BBB disruption in the very early stage of cerebral ischemia–reperfusion that is within the time window of thrombolysis therapy. The middle cerebral artery occlusion (MCAO) was performed in rats under isoflurane anesthesia with controlled ventilation. Of note, 2 mg/kg of Rapalink-1 or vehicle was administered intraperitoneally 10 min after MCAO. After 1 h of MCAO and 2 h of reperfusion, the transfer coefficient (Ki) of 14C-α-aminoisobutyric acid (104 Da) and the volume of 3H-dextran (70,000 Da) distribution were determined to assess the degree of BBB disruption. At the same time points, phosphorylated S6 (Ser240/244) and Akt (Ser473) as well as matrix metalloproteinase-2 (MMP2) protein level were determined by Western blot along with the infarct size using tetrazolium stain. Rapalink-1 increased the Ki in the ischemic-reperfused cortex (IR-C, +23%, p < 0.05) without a significant change in the volume of dextran distribution. Rapalink-1 increased the percentage of cortical infarct out of the total cortical area (+41%, p < 0.005). Rapalink-1 significantly decreased phosphorylated S6 and Akt to half the level of the control rats in the IR-C, which suggests that both of the mechanistic target of rapamycin complex 1 and 2 (mTORC1 and mTORC2) were inhibited. The MMP2 level was increased suggesting that BBB disruption could be aggravated by Rapalink-1. Taken together, our data suggest that inhibiting both mTORC1 and mTORC2 by Rapalink-1 could worsen the neuronal damage in the early stage of cerebral ischemia–reperfusion and that the aggravation of BBB disruption could be one of the contributing factors.
A Variational Approach to Scripts
Authors: Albarracin Mahault , Constant Axel , Friston Karl J. , Ramstead Maxwell James D.
Published: July 2021

This paper proposes a formal reconstruction of the script construct by leveraging the active inference framework, a behavioral modeling framework that casts action, perception, emotions, and attention as processes of (Bayesian or variational) inference. We propose a first principles account of the script construct that integrates its different uses in the behavioral and social sciences. We begin by reviewing the recent literature that uses the script construct. We then examine the main mathematical and computational features of active inference. Finally, we leverage the resources of active inference to offer a formal model of scripts. Our integrative model accounts for the dual nature of scripts (as internal, psychological schema used by agents to make sense of event types and as constitutive behavioral categories that make up the social order) and also for the stronger and weaker conceptions of the construct (which do and do not relate to explicit action sequences, respectively).