bluuebunny/crossref_metadata_2025 huggingface dataset:
Trust as Extended Control: Human-Machine Interactions as Active Inference
Authors: Schoeller Felix , Miller Mark , Salomon Roy , Friston Karl J.
Published: October 2021

In order to interact seamlessly with robots, users must infer the causes of a robot’s behavior–and be confident about that inference (and its predictions). Hence, trust is a necessary condition for human-robot collaboration (HRC). However, and despite its crucial role, it is still largely unknown how trust emerges, develops, and supports human relationship to technological systems. In the following paper we review the literature on trust, human-robot interaction, HRC, and human interaction at large. Early models of trust suggest that it is a trade-off between benevolence and competence; while studies of human to human interaction emphasize the role of shared behavior and mutual knowledge in the gradual building of trust. We go on to introduce a model of trust as an agent’ best explanation for reliable sensory exchange with an extended motor plant or partner. This model is based on the cognitive neuroscience of active inference and suggests that, in the context of HRC, trust can be casted in terms of virtual control over an artificial agent. Interactive feedback is a necessary condition to the extension of the trustor’s perception-action cycle. This model has important implications for understanding human-robot interaction and collaboration–as it allows the traditional determinants of human trust, such as the benevolence and competence attributed to the trustee, to be defined in terms of hierarchical active inference, while vulnerability can be described in terms of information exchange and empowerment. Furthermore, this model emphasizes the role of user feedback during HRC and suggests that boredom and surprise may be used in personalized interactions as markers for under and over-reliance on the system. The description of trust as a sense of virtual control offers a crucial step toward grounding human factors in cognitive neuroscience and improving the design of human-centered technology. Furthermore, we examine the role of shared behavior in the genesis of trust, especially in the context of dyadic collaboration, suggesting important consequences for the acceptability and design of human-robot collaborative systems.
Maternal Neu5Ac Supplementation During Pregnancy Improves Offspring Learning and Memory Ability in Rats
Authors: Bian DongSheng , Wang Xinyue , Huang Jiale , Chen Xiaoxuan , Li Hongwei
Published: October 2021

Sialic acids are postulated to improve cognitive abilities. This study aimed to evaluate the effects of sialic acid on behavior when administered in a free form as N-acetylneuraminic acid (Neu5Ac) to pregnant mothers or rat pups. The experiment involved 40 male 21-day-old rat pups and 20 15-day-pregnant rats that were randomized into four Neu5Ac treated groups: 0 (control), or 10, 20, and 40 mg/kg. Morris water maze test and shuttle box test were performed on the rat pups and maternal Neu5Ac-supplemented offspring on day 100 to evaluate their cognitive performance. The Neu5Ac levels in the cerebral cortex and hippocampus were tested with high-performance liquid chromatography-fluorescence detection (HPLC-FLD). We found that the maternal Neu5Ac-supplemented offspring showed better cognitive performance, less escape latency in the Morris water maze test, and less electric shock time shuttle box test, compared with the untreated control. In the meantime, the Neu5Ac level in the cerebral cortex and hippocampus of the offspring was higher in the Neu5Ac treatment group than that in the untreated control group. However, no significant differences were observed between rat pups in the treated and the untreated control groups in terms of cognitive performance and Neu5Ac content in the cerebral cortex and hippocampus. Maternal Neu5Ac supplementation during pregnancy could effectively promote the brain Neu5Ac content of the offspring and enhance their cognitive performance, but Neu5Ac had no such effect on rat pups while directly supplemented with Neu5Ac.
Surface-Displayed Amuc_1100 From Akkermansia muciniphila on Lactococcus lactis ZHY1 Improves Hepatic Steatosis and Intestinal Health in High-Fat-Fed Zebrafish
Authors: Zhang Feng-Li , Yang Ya-Lin , Zhang Zhen , Yao Yuan-Yuan , Xia Rui , Gao Chen-Chen , Du Dong-Dong , Hu Juan , Ran Chao , Liu Zhen , Zhou Zhi-Gang
Published: October 2021

Fatty liver and intestinal barrier damage were widespread in most farmed fish, which severely restrict the development of aquaculture. Therefore, there was an urgent need to develop green feed additives to maintain host liver and intestinal health. In this study, a probiotic pili-like protein, Amuc_1100 (AM protein), was anchored to the surface of Lactococcus lactis ZHY1, and the effects of the recombinant bacteria AM-ZHY1 on liver fat accumulation and intestinal health were evaluated. Zebrafish were fed a basal diet, high-fat diet, and high-fat diet with AM-ZHY1 (108 cfu/g) or control bacteria ZHY1 for 4 weeks. Treatment with AM-ZHY1 significantly reduced hepatic steatosis in zebrafish. Quantitative PCR (qPCR) detection showed that the expression of the lipogenesis [peroxisome-proliferator-activated receptors (PPARγ), sterol regulatory element-binding proteins-1c (SREBP-1c), fatty acid synthase (FAS), and acetyl-CoA carboxylase 1 (ACC1)] and lipid transport genes (CD36 and FABP6) in the liver were significantly downregulated (p < 0.05), indicating that AM-ZHY1 could reduce liver fat accumulation by inhibiting lipid synthesis and absorption. Moreover, supplementing AM-ZHY1 to a high-fat diet could significantly reduce serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels, indicating that liver injury caused by high-fat diets was improved. The expression of tumor necrosis factor (TNF)-a and interleukin (IL)-6 in the liver decreased significantly (p < 0.05), while IL-1β and IL-10 did not change significantly in the AM-ZHY1 group. Compared to the high-fat diet-fed group, the AM-ZHY1 group, but not the ZHY1 group, significantly increased the expression of intestinal tight junction (TJ) proteins (TJP1a, claudina, claudin7, claudin7b, claudin11a, claudin12, and claudin15a; p < 0.05). Compared to the high-fat diet group, the Proteobacteria and Fusobacteria were significantly reduced and increased in the AM-ZHY1 group, respectively. In conclusion, the recombinant bacteria AM-ZHY1 has the capacity to maintain intestinal health by protecting intestinal integrity and improving intestinal flora structure and improving fatty liver disease by inhibiting lipid synthesis and absorption. This study will lay a foundation for the application of AM protein in improving abnormal fat deposition and restoring the intestinal barrier in fish.
Role of the Aryl Hydrocarbon Receptor and Gut Microbiota-Derived Metabolites Indole-3-Acetic Acid in Sulforaphane Alleviates Hepatic Steatosis in Mice
Authors: Xu Xiuxiu , Sun Siyuan , Liang Ling , Lou Chenxi , He Qijin , Ran Maojuan , Zhang Lu , Zhang Jingyue , Yan Chen , Yuan Hengjie , Zhou Lu , Chen Xin , Dai Xin , Wang Bangmao , Zhang Jie , Zhao Jingwen
Published: October 2021

Scope: Gut microbiome-derived metabolites are the major mediators of diet-induced host-microbial interactions. Aryl hydrocarbon receptor (AHR) plays a crucial role in glucose, lipid, and cholesterol metabolism in the liver. In this study, we aimed to investigate the role of indole-3-acetic acid (IAA) and AHR in sulforaphane (SFN) alleviates hepatic steatosis in mice fed on a high-fat diet (HFD).

Methods and Results: The HFD-fed male C57BL/6 mice were intervened with SFN for 6 weeks. HFD-mice showed classical pathophysiological characteristics of hepatic steatosis. The results showed that SFN significantly reduced body weight, liver inflammation and hepatic steatosis in HFD-fed mice. SFN reduced hepatic lipogenesis by activating AHR/SREBP-1C pathway, which was confirmed in HepG2 cell experiments. Moreover, SFN increased hepatic antioxidant activity by modulating Nrf-2/NQO1 expression. SFN increased serum and liver IAA level in HFD mice. Notably, SFN manipulated the gut microbiota, resulting in reducing Deferribacteres and proportions of the phylum Firmicutes/Bacteroidetes and increasing the abundance of specific bacteria that produce IAA. Furthermore, SFN upregulated Ahr expression and decreased the expression of inflammatory cytokines in Raw264.7 cells.

Conclusions: SFN ameliorated hepatic steatosis not only by modulating lipid metabolism via AHR/SREBP-1C pathway but regulating IAA and gut microbiota in HFD-induced NAFLD mice.
Risk Factors of Lymph Node Metastasis and Its Prognostic Significance in Early Gastric Cancer: A Multicenter Study
Authors: Wang Jinfeng , Wang Liang , Li Sha , Bai Fei , Xie Hailong , Shan Hanguo , Liu Zhuo , Ma Tiexiang , Tang Xiayu , Tang Haibing , Qin Ang , Lei Sanlin , Zuo Chaohui
Published: October 2021

Background

Early gastric cancer (EGC) is invasive gastric cancer that invades no deeper than the submucosa, regardless of lymph node metastasis (LNM). It is mainly treated by surgery. Recently, the resection range of EGC has been minimized, but cancer recurrence and overall survival in some patients should be given high status. LNM is an important indicator of prognosis and treatment in gastric cancer. The law of the number and location of metastatic lymph nodes in EGC is not yet clear. Therefore, we aimed to identify the risk factors of LNM in radically resected EGC and guide treatment.

Methods

The clinicopathological factors of 611 patients with EGC were retrospectively analyzed in six hospitals between January 2010 and December 2016. The relationship between clinicopathological factors and LNM, as well as their prognostic significance, were analyzed by univariate and multivariate analyses.

Results

The rate of LNM was 20.0% in the 611 EGC patients. The depth of invasion, differentiation type, tumor diameter, morphological ulceration, and lymphovascular invasion were independent risk factors for LNM (P<0.05) by logistic regression analysis. Tumor location in the proximal third of the stomach and morphological ulceration were significant factors for group 2 LNM. Moreover, the 5-year survival rate was 94.9% for patients with no positive nodes, 88.5% for patients with 1-2 positive nodes, 64.3% for patients with 3-6 positive nodes, and 41.8% for patients with >6 metastatic nodes. Interestingly, the 7-year risk of relapse diminished for patients with no LNM or retrieved no less than 15 lymph nodes.

Conclusions

Fifteen lymph node dissection and D2 radical operation are the surgical options in case of high risk factors for LNM. Extended lymph node dissection (D2+) is recommended for morphological ulceration or disease located in the proximal third of the stomach due to their high rate of group 2 LNM. Furthermore, LNM is a significant prognostic factor of EGC. Moreover, lymph nodes can also play a significant role in the chemotherapeutic and radiotherapy approach for non-surgical patients with EGC.
The Genomic Landscape of Serrated Lesion of the Colorectum: Similarities and Differences With Tubular and Tubulovillous Adenomas
Authors: Tornillo Luigi , Lehmann Frank Serge , Garofoli Andrea , Paradiso Viola , Ng Charlotte K. Y. , Piscuoglio Salvatore
Published: October 2021

Serrated lesions of the colorectum are the precursors of 15–30% of colorectal cancers (CRCs). These lesions have a peculiar morphological appearance, and they are more difficult to detect than conventional adenomatous polyps. In this study, we sought to define the genomic landscape of these lesions using high-depth targeted sequencing. Eight sessile serrated lesions without dysplasia (SSL), three sessile serrated lesions with dysplasia (SSL/D), two traditional serrated adenomas (TSA), and three tubular adenomas (TA) were retrieved from the files of the Institute of Pathology of the University Hospital Basel and from the GILAB AG, Allschwil, Switzerland. Samples were microdissected together with the matched normal counterpart, and DNA was extracted for library preparation. Library preparation was performed using the Oncomine Comprehensive Assay targeting 161 common cancer driver genes. Somatic genetic alterations were defined using state-of-the-art bioinformatic analysis. Most SSLs, as well as all SSL/Ds and TSAs, showed the classical BRAF p.V600E mutation. The BRAF-mutant TSAs showed additional alterations in CTNNB1, NF1, TP53, NRAS, PIK3CA, while TA showed a consistently different profile, with mutations in ARID1A (two cases), SMAD4, CDK12, ERBB3, and KRAS. In conclusion, our results provide evidence that SSL/D and TSA are similar in somatic mutations with the BRAF hotspot somatic mutation as a major driver of the disease. On the other hand, TAs show a different constellation of somatic mutations such as ARID1A loss of function.
Controlling Nutritional Status Score Before Receiving Treatment as a Prognostic Indicator for Patients With Urothelial Cancer: An Exploration Evaluation Methods
Authors: Peng Lei , Du Chunxiao , Meng Chunyang , Li Jinze , You Chengyu , Li Xianhui , Zhao Pan , Cao Dehong , Li Yunxiang
Published: October 2021

Introduction

This meta-analysis aims to assess whether the Controlling nutritional status (CONUT) score before treatment can be an independent predictor of the prognosis of patients with urothelial cancer (UC).

Methods

The system searches Web of Science, PubMed, MEDLINE, China National Knowledge Infrastructure (CNKI), and Cochrane Library, and the search time is up to April 2021. Use STATA 16.0 and Engauge Digitizer 4.1 software for data processing and statistical analysis.

Results

A total of 8 studies were included in this meta-analysis. The meta-analysis results show that compared with the low CONUT group, the high CONUT group has worse over survival (OS) [HR=1.58, 95%CI (1.34, 1.86), P=0.001], cancer-specific survival (CSS) [HR=2.03, 95%CI (1.25-3.29), P=0.04] and recurrence-free survival (RFS) [HR=1.97, 95%CI (1.15, 3.40), P=0.014]; for progression-free survival (PFS), or disease-free survival (DFS), the difference between the two groups was not statistically significant [HR=2.30, 95%CI (0.72, 7.32), P=0.158]. According to different carcinoma types, cut-off value, and region, subgroup analysis of OS was performed, and similar results were obtained.

Conclusions

Based on current evidence, this meta-analysis proves that the CONUT score of UC patients before treatment is an independent prognostic predictor. It performs well on OS, CSS, and RFS, but the conclusions on DFS/PFS need to be treated with caution.

Systematic Review Registration

https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42021251890, identifier CRD42021251890.
SARS-CoV-2 Infection in Cancer Patients: A Population-Based Study
Authors: Zorzi Manuel , Guzzinati Stefano , Avossa Francesco , Fedeli Ugo , Calcinotto Arianna , Rugge Massimo
Published: October 2021

Aim

In a consecutive series of cancer patients tested for SARS-CoV-2 infection, this retrospective population-based study investigates the risks of viral infection and death.

Methods

Malignancies were distinguished as incident or prevalent (active or inactive). Cancer management and vital status were retrieved from institutional regional databases. Comorbidities were recorded, based on Adjusted Clinical Groups (ACG). Six Resource Utilization Bands (RUBs) were also considered. Independent risk factors for SARS-CoV-2 infection and death were identified using multivariable logistic regression, considering sex, age, comorbidities and RUBs, cancer status (active versus prevalent), primary cancer site, and treatments (chemotherapy and/or radiotherapy).

Results

Among 34,929 cancer patients, 1,090 (3.1%) tested positive for SARS-CoV-2 infection (CoV2+ve). The risk of infection was associated with age (OR per 1-year increase=1.012; 95%CI=1.007-1.017), prevalent-inactive disease, hematologic malignancies (OR=1.33; 95%CI=1.03-1.72) and RUB (OR per 1-level increase=1.14; 95%CI=1.05-1.24). Among CoV2+ve cancer patients, the risk of death was doubled for males, and increased with age (OR per 1-year increase=1.07; 95%CI=1.06-1.09) and comorbidities (renal [OR=3.18; 95%CI=1.58-6.49], hematological [OR=3.08; 95%CI=1.49-6.50], respiratory [OR=2.87; 95%CI=1.61-5.14], endocrine [OR=2.09; 95%CI=1.25-3.51]). Lung and blood malignancies raised the mortality risk (OR=3.55; 95%CI=1.56-8.33, and OR=1.81; 95%CI=1.01-3.25 respectively). Incident or prevalent-active disease and recent chemotherapy and radiotherapy (OR=4.34; 95%CI=1.85-10.50) increased the risk of death.

Conclusion

In a large cohort of cancer patients, the risk of SARS-CoV-2 infection was higher for those with inactive disease than in incident or prevalent-active cases. Among CoV2+ve cancer patients, active malignancies and recent multimodal therapy both significantly raised the risk of death, which increased particularly for lung cancer.
Nomogram Combining Radiomics With the American College of Radiology Thyroid Imaging Reporting and Data System Can Improve Predictive Performance for Malignant Thyroid Nodules
Authors: Huang Xingzhi , Wu Zhenghua , Zhou Aiyun , Min Xiang , Qi Qi , Zhang Cheng , Chen Songli , Xu Pan
Published: October 2021

Purpose

To develop and validate a nomogram combining radiomics of B-mode ultrasound (BMUS) images and the American College of Radiology (ACR) Thyroid Imaging Reporting and Data System (TI-RADS) for predicting malignant thyroid nodules and improving the performance of the guideline.

Method

A total of 451 thyroid nodules referred for surgery and proven pathologically at an academic referral center from January 2019 to September 2020 were retrospectively collected and randomly assigned to training and validation cohorts (7:3 ratio). A nomogram was developed through combining the BMUS radiomics score (Rad-Score) with ACR TI-RADS score (ACR-Score) in the training cohort; the performance of the nomogram was assessed with respect to discrimination, calibration, and clinical application in the validation and entire cohorts.

Results

The ACR-Rad nomogram showed good calibration and yielded an AUC of 0.877 (95% CI 0.836–0.919) in the training cohort and 0.864 (95% CI 0.799–0.931) in the validation cohort, which were significantly better than the ACR-Score model (p < 0.001 and 0.031, respectively). The significantly improved AUC, net reclassification index (NRI), and integrated discriminatory improvement (IDI) of the nomogram were found for both senior and junior radiologists (all p < 0.001). Decision curve analysis indicated that the nomogram was clinically useful. When cutoff values for 50% predicted malignancy risk (ACR-Rad_50%) were applied, the nomogram showed increased specificity, accuracy and positive predictive value (PPV), and decreased unnecessary fine-needle aspiration (FNA) rates in comparison to ACR TI-RADS.

Conclusion

The ACR-Rad nomogram has favorable value in predicting malignant thyroid nodules and improving performance of the ACR TI-RADS for senior and junior radiologists.
Tumor-Derived Exosomal Non-Coding RNAs: The Emerging Mechanisms and Potential Clinical Applications in Breast Cancer
Authors: Yi Yi , Wu Min , Zeng Hong , Hu Weijie , Zhao Chongru , Xiong Mingchen , Lv Wenchang , Deng Pei , Zhang Qi , Wu Yiping
Published: October 2021

Breast cancer (BC) is the most frequent malignancy and is ranking the leading cause of cancer-related death among women worldwide. At present, BC is still an intricate challenge confronted with high invasion, metastasis, drug resistance, and recurrence rate. Exosomes are membrane-enclosed extracellular vesicles with the lipid bilayer and recently have been confirmed as significant mediators of tumor cells to communicate with surrounding cells in the tumor microenvironment. As very important orchestrators, non-coding RNAs (ncRNAs) are aberrantly expressed and participate in regulating gene expression in multiple human cancers, while the most reported ncRNAs within exosomes in BC are microRNAs (miRNAs), long-noncoding RNAs (lncRNAs), and circular RNAs (circRNAs). Notably, ncRNAs containing exosomes are novel frontiers to shape malignant behaviors in recipient BC cells such as angiogenesis, immunoregulation, proliferation, and migration. It means that tumor-derived ncRNAs-containing exosomes are pluripotent carriers with intriguing and elaborate roles in BC progression via complex mechanisms. The ncRNAs in exosomes are usually excavated based on specific de-regulated expression verified by RNA sequencing, bioinformatic analyses, and PCR experiments. Here, this article will elucidate the recent existing research on the functions and mechanisms of tumor-derived exosomal miRNA, lncRNA, circRNA in BC, especially in BC cell proliferation, metastasis, immunoregulation, and drug resistance. Moreover, these tumor-derived exosomal ncRNAs that existed in blood samples are proved to be excellent diagnostic biomarkers for improving diagnosis and prognosis. The in-depth understanding of tumor-derived exosomal ncRNAs in BC will provide further insights for elucidating the BC oncogenesis and progress and exploring novel therapeutic strategies for combating BC.
A Novel Ferroptosis-Related 4-Gene Prognostic Signature for Cholangiocarcinoma and Photodynamic Therapy
Authors: Zhang Zi-jian , Huang Yun-peng , Li Xiao-xue , Liu Zhong-tao , Liu Kai , Deng Xiao-feng , Xiong Li , Zou Heng , Wen Yu
Published: October 2021

Cholangiocarcinoma is the second most common malignant tumor in the hepatobiliary system. Compared with data on hepatocellular carcinoma, fewer public data and prognostic-related studies on cholangiocarcinoma are available, and effective prognostic prediction methods for cholangiocarcinoma are lacking. In recent years, ferroptosis has become an important subject of tumor research. Some studies have indicated that ferroptosis plays an important role in hepatobiliary cancers. However, the prediction of the prognostic effect of ferroptosis in patients with cholangiocarcinoma has not been reported. In addition, many reports have described the ability of photodynamic therapy (PDT), a potential therapy for cholangiocarcinoma, to regulate ferroptosis by generating reactive oxygen species (ROS). By constructing ferroptosis scores, the prognoses of patients with cholangiocarcinoma can be effectively predicted, and potential gene targets can be discovered to further enhance the efficacy of PDT. In this study, gene expression profiles and clinical information (TCGA, E-MTAB-6389, and GSE107943) of patients with cholangiocarcinoma were collected and divided into training sets and validation sets. Then, a model of the ferroptosis gene signature was constructed using least absolute shrinkage and selection operator (LASSO)-penalized Cox regression analysis. Furthermore, through the analysis of RNA-seq data after PDT treatment of cholangiocarcinoma, PDT-sensitive genes were obtained and verified by immunohistochemistry staining and Western blot. The results of this study provide new insight for predicting the prognosis of cholangiocarcinoma and screening target genes that enhance the efficacy of PDT.
Adipocytic Glutamine Synthetase Upregulation via Altered Histone Methylation Promotes 5FU Chemoresistance in Peritoneal Carcinomatosis of Colorectal Cancer
Authors: Zhang Xuan , Li Qing , Du Aibei , Li Yifei , Shi Qing , Chen Yanrong , Zhao Yang , Wang Bin , Pan Feng
Published: October 2021

The development of resistance to 5-fluorouracil (5FU) chemotherapy is a major handicap for sustained effective treatment in peritoneal carcinomatosis (PC) of colorectal cancer (CRC). Metabolic reprogramming of adipocytes, a component of the tumor microenvironment and the main composition of peritoneum, plays a significant role in drug resistance of PC, with the mechanisms being not fully understood. By performing metabolomics analysis, we identified glutamine (Gln), an important amino acid, inducing resistance to 5FU-triggered tumor suppression of CRC-PC through activating mTOR pathway. Noteworthily, genetic overexpression of glutamine synthetase (GS) in adipocytes increased chemoresistance to 5FU in vitro and in vivo while this effect was reversed by pharmacological blockage of GS. Next, we showed that methionine metabolism were enhanced in amino acid omitted from CRC-PC of GS transgenic (TgGS) mice, increasing intracellular levels of S-carboxymethy-L-cys. Moreover, loss of dimethylation at lysine 4 of histone H3 (H3k4me2) was found in adipocytes in vitro, which may lead to increased expression of GS. Furthermore, biochemical inhibition of lysine specific demethylase 1 (LSD1) restored H3k4me2, thereby reducing GS-induced chemoresistance to 5FU. Our findings indicate that GS upregulation-induced excessive of Gln in adipocytes via altered histone methylation is potential mediator of resistance to 5FU chemotherapy in patients with CRC-PC.
Stenotrophomonas maltophilia Infections in Pediatric Patients – Experience at a European Center for Pediatric Hematology and Oncology
Authors: Zöllner Stefan K. , Kampmeier Stefanie , Froböse Neele J. , Herbrüggen Heidrun , Masjosthusmann Katja , van den Heuvel Alijda , Reicherts Christian , Ranft Andreas , Groll Andreas H.
Published: October 2021

Stenotrophomonas maltophiliais an important nosocomial pathogen in immunocom-promised individuals and characterized by intrinsic resistance to broad-spectrum antibacterial agents. Limited data exists on its clinical relevance in immunocompromised pediatric patients, particularly those with hematological or oncological disorders. In a retrospective single center cohort study in pediatric patients receiving care at a large european pediatric hematology and oncology department, ten cases of invasiveS.maltophiliainfections (blood stream infections (BSI), 4; BSI and pneumonia, 3, or soft tissue infection, 2; and pneumonia, 1) were identified between 2010 and 2020. Seven patients had lymphoblastic leukemia and/or were post allogeneic hematopoietic cell transplantation. InvasiveS.maltophiliainfections occurred in a setting of indwelling central venous catheters, granulocytopenia, defective mucocutaneous barriers, treatment with broad-spectrum antibacterial agents, and admission to the intensive care unit. Whole genome sequencing based typing revealed no genetic relationship among four individualS.maltophiliaisolates. The case fatality rate and mortality at 100 days post diagnosis were 40 and 50%, respectively, and three patients died from pulmonary hemorrhage. InvasiveS.maltophiliainfections are an emerging cause of infectious morbidity in patients receiving care at departments of pediatric hematology and oncology and carry a high case fatality rate.
Improving Outcomes of Tyrosine Kinase Inhibitors in Hepatocellular Carcinoma: New Data and Ongoing Trials
Authors: Mou Lisha , Tian Xiaohe , Zhou Bo , Zhan Yongqiang , Chen Jiao , Lu Ying , Deng Jing , Deng Ying , Wu Zijing , Li Qi , Song Yi’an , Zhang Hongyuan , Chen Jinjun , Tian Kuifeng , Ni Yong , Pu Zuhui
Published: October 2021

Targeted therapies such as oral tyrosine kinase inhibitors (TKIs) are the main therapeutic strategy effective for advanced hepatocellular carcinoma (HCC). Currently six tyrosine kinase inhibitors for HCC therapy have been approved. The newly approved first-line drug donafenib represent the major milestones in HCC therapeutics in recent years. However, drug resistance in HCC remains challenging due to random mutations in target receptors as well as downstream pathways. TKIs-based combinatorial therapies with immune checkpoint inhibitors such as PD-1/PD-L1 antibodies afford a promising strategy to further clinical application. Recent developments of nanoparticle-based TKI delivery techniques improve drug absorption and bioavailability, enhance efficient targeting delivery, prolonged circulation time, and reduce harmful side effects on normal tissues, which may improve the therapeutic efficacy of the TKIs. In this review, we summarize the milestones and recent progress in clinical trials of TKIs for HCC therapy. We also provide an overview of the novel nanoparticle-based TKI delivery techniques that enable efficient therapy.
Gene-Guided Treatment Decision-Making in Non-Small Cell Lung Cancer – A Systematic Review
Authors: Saarenheimo Jatta , Andersen Heidi , Eigeliene Natalja , Jekunen Antti
Published: October 2021

Decision-making in cancer treatment is part of clinicians’ everyday work, and it is especially challenging in non-small cell lung cancer (NSCLC) patients, for whom decisions are clearly dependent on gene alterations or the lack of them. The multimodality of treatments, involvement of gene alterations in defining systemic cancer therapies, and heterogeneous nature of tumors and their responsiveness provide extra challenges. This article reviews the existing literature to 2021 with extra effort to explore the role of genes and gene-driven therapies as part of decision-making. The process and elements in this decision-making participation are recognized and discussed comprehensively. Genetic health literacy aids are provided as a part of the review. Our systematic review, data extraction and analysis found that with current methods and broad gene panels, patients benefit from early molecular testing of liquid biopsy samples. An estimated 79% of liquid biopsy samples showed somatic mutations based on 8 original studies included in the systematic review. When both liquid biopsy samples and tissue samples are evaluated, the sensitivity to detect targetable mutations in NSCLC increases. We recommend early testing with liquid biopsy. Additional effort is needed for the logistics of obtaining and evaluating samples, and tissue samples should be saved and stored for tests that are not possible from liquid biopsy.
Prognostic Factors and Surgery for Breast Cancer Patients With Locoregional Recurrence: An Analysis of 5,202 Consecutive Patients
Authors: Huang Jiahui , Tong Yiwei , Chen Xiaosong , Shen Kunwei
Published: October 2021

Purpose

With the application of “less extensive surgery” in breast cancer treatment, the pattern of locoregional recurrence (LRR) has significantly changed. This study aims to evaluate the risk and prognostic factors of LRR in a recent large breast cancer cohort.

Methods

Consecutive early breast cancer patients who received surgery from January 2009 to March 2018 in Shanghai Ruijin Hospital were retrospectively analyzed. LRR was defined as recurrence at the ipsilateral breast (IBTR), chest wall, or regional lymph nodes and without concurrent distant metastasis (DM). Patients’ characteristics and survival were compared among these groups.

Results

Among 5,202 patients included, 87 (1.7%) and 265 (5.1%) experienced LRR and DM as first event after a median 47.0 (3.0–122.5) months’ follow-up. LRR was significantly associated with large tumor size and positive lymph node status (p < 0.05). Forty (46.0%) patients received further salvage surgery after LRR and had a significantly better 3-year post-recurrence overall survival than those who did not (94.7% vs. 60.7%, p = 0.012). Multivariate analysis showed that salvage surgery for LRR was independently associated with better survival (HR = 0.12, 95% CI 0.02–0.93, p = 0.043) along with estrogen receptor (ER) positivity (HR = 0.33, 95% CI 0.12–0.91, p = 0.033).

Conclusion

LRR rate was relatively low in recent era of breast cancer treatment. Tumor size and lymph node status were associated with risk of LRR, and salvage surgery for selected LRR patients achieved an excellent outcome.
A Systematic Review and Meta-Analysis of Moderate-to-Vigorous Physical Activity Levels in Children and Adolescents With and Without ASD in Inclusive Schools
Authors: Li Ru , Liang Xiao , Zhou Yujuan , Ren Zhanbing
Published: October 2021

Background: The health benefits of physical activity (PA) participation are well-documented. Little was known about the PA levels of students with autism spectrum disorder (ASD) and their typically developing (TD) peers in inclusive schools. This study aimed to synthesize available studies examining PA levels of children and adolescents with and without ASD and its associated factors that affected their PA participation during inclusive schools applying the social–relational model of disability (SRMD).

Methods: Eight databases were searched including CINAHL Complete, SPORTDiscus with Full Text, PubMed, Embase, Web of Science, Eric, APA PsycINFO, and Scopus from inception through May 2021 to identify related studies. Two researchers independently screened studies, assessed methodological quality, and summarized relevant data. The McMaster Critical Reviewer Form for quantitative studies was used to evaluate the methodological quality of the included articles.

Results: A total of seven articles were included in this systematic review. Overall, meta-analysis results indicated that children and adolescents with ASD had a moderately decreased PA levels compared with their TD peers [SMD = −0.585, 95% CI (−0.774, −0.425), p < 0.01]. Individual-, social-, and environmental-level factors that influence PA levels in children and adolescents with ASD were identified from the perspective of SRMD.

Conclusion: This review indicates that children and adolescents with ASD have lower PA levels than their TD peers in inclusive schools and multilevel factors affect their PA.
Dapagliflozin Ameliorates Diabetic Kidney Disease via Upregulating Crry and Alleviating Complement Over-activation in db/db Mice
Authors: Chang Dong-Yuan , Li Xiao-Qian , Chen Min , Zhao Ming-Hui
Published: October 2021

Sodium-glucose cotransporter 2(SGLT2) inhibitors show prominent renal protective effect in diabetic kidney disease (DKD), anti-inflammatory effect being one of its key mechanisms. Over-activation of the complement system, a crucial part of innate immunity, plays an important role in DKD. We aimed to investigate the effect of SGLT2 inhibitors on alleviating complement over-activation in DKD. Db/db mice were randomly divided into two groups, with 7 mice in each group treated with dapagliflozin and vehicle respectively, and 7 mice in m/m mice group. Laboratory and renal pathological parameters were evaluated. Mouse proximal tubular epithelial cells (MPTECs) were cultured and treated with high glucose. Dapagliflozin and dimethyloxallyl glycine (DMOG) were added as conditional treatment. Dapagliflozin-treated db/db mice showed significantly lower urinary albumin than vehicle-treated ones. Besides typical glomerular and tubulointerstitial injury, both C3b and membrane attack complex (MAC) depositions were significantly attenuated in dapagliflozin-treated db/db mice. The expression of complement receptor type 1-related protein y (Crry), a key complement regulator which inhibits complement over-activation, was significantly upregulated by dapagliflozin. Dapagliflozin-mediated Crry upregulation was associated with inhibition of HIF-1α accumulation under high glucose. When HIF-1α expression was stabilized by DMOG, the protective effect of dapagliflozin via upregulating Crry was blocked. In conclusion, dapagliflozin could attenuate complement over-activation in diabetic mice via upregulating Crry, which is associated with the suppression of HIF-1α accumulation in MPTECs.
Based on Activation of p62-Keap1-Nrf2 Pathway, Hesperidin Protects Arsenic-Trioxide-Induced Cardiotoxicity in Mice
Authors: Jia Yuxin , Li Jing , Liu Panpan , Si Mingdong , Jin Yanyu , Wang Hongfang , Ma Donglai , Chu Li
Published: October 2021

Background: Hesperidin (HES) is a flavonoid glycoside found in the tangerine peel and has antioxidant properties. Arsenic trioxide (ATO) is an anti-tumour drug; however, its serious cardiotoxicity limits its clinical application. In addition, the protection of HES against ATO-induced cardiotoxicity has not been explored.

Objective: The study aims to investigate and identify the underlying effect and mechanism of HES on ATO-induced cardiotoxicity.

Methods: Fifty mice were randomly assigned to five groups. Mice were orally given HES:100 or 300 mg/kg/day concurrently and given ATO intraperitoneal injections: 7.5 mg/kg/day for 1 week. Blood and heart tissues were collected for examination. Evaluated in serum was the levels of creatine kinase (CK), lactate dehydrogenase (LDH) and cardiac troponin I (cTnI). In addition, evaluated in heart tissues were the levels of reactive oxygen species (ROS), superoxide dismutase (SOD), malondialdehyde (MDA), glutathione (GSH), catalase (CAT), tumour necrosis factor-α (TNF-α), interleukin-6 (IL-6), B-cell lymphoma-2 (Bcl-2), Bcl-2-associated X protein (Bax), Caspase-3, cleaved-Caspase-3, p62, Kelch-like ECH-associated protein 1 (Keap1), and nuclear factor erythroid 2-related factor 2 (Nrf2). The heart tissues were also examined for histopathology and mitochondrial ultrastructure.

Results: Compared with the ATO group, the HES treatment groups reduced the levels of CK, LDH, cTnI, ROS, MDA, TNF-α, IL-6, Bax, Caspase-3, cleaved-Caspase-3 and Keap1 and enhanced the levels of SOD, GSH, CAT, Bcl-2, p62 and Nrf2.

Conclusions: The results demonstrate that HES protects against ATO-induced cardiotoxicity, through inhibiting oxidative stress, and subsequent inflammation and apoptosis. The underlying results are closely related to the regulation of the p62-Keap1-Nrf2 signalling pathway.
Development of a Mosquito Repellent Formulation Based on Nanostructured Lipid Carriers
Authors: Abrantes Daniele Carvalho , Rogerio Carolina Barbara , de Oliveira Jhones L. , Campos Estefânia V. R. , de Araújo Daniele Ribeiro , Pampana Laurindo Cesar , Duarte Marcelo José , Valadares Geórgio Freesz , Fraceto Leonardo Fernandes
Published: October 2021

Arboviral diseases are a threat to global public health systems, with recent data suggesting that around 40% of the world’s population is at risk of contracting arboviruses. The use of mosquito repellents is an appropriate strategy to avoid humans coming into contact with vectors transmitting these viruses. However, the cost associated with daily applications of repellents can make their use unfeasible for the low-income populations that most need protection. Therefore, the development of effective formulations offers a way to expand access to this means of individual protection. Consequently, research efforts have focused on formulations with smaller quantities of active agents and sustained release technology, aiming to reduce re-applications, toxicity, and cost. The present study investigates the development of nanostructured lipid carriers (NLCs) loaded with a mixture of the compounds icaridin (synthetic) and geraniol (natural), incorporated in cellulose hydrogel. The NLCs were prepared by the emulsion/solvent evaporation method and were submitted to physicochemical characterization as a function of time (at 0, 15, 30, and 60 days). The prepared system presented an average particle size of 252 ± 5 nm, with encapsulation efficiency of 99% for both of the active compounds. The stability profile revealed that the change of particle size was not significant (p > 0.05), indicating high stability of the system. Rheological characterization of the gels containing NLCs showed that all formulations presented pseudoplastic and thixotropic behavior, providing satisfactory spreadability and long shelf life. Morphological analysis using atomic force microscopy (AFM) revealed the presence of spherical nanoparticles (252 ± 5 nm) in the cellulose gel matrix. Permeation assays showed low fluxes of the active agents through a Strat-M® membrane, with low permeability coefficients, indicating that the repellents would be retained on the surface to which they are applied, rather than permeating the tissue. These findings open perspectives for the use of hybrid formulations consisting of gels containing nanoparticles that incorporate repellents effective against arthropod-borne virus. These systems could potentially provide improvements considering the issues of effectiveness, toxicity, and safety.
Tongluo Yishen Decoction Ameliorates Renal Fibrosis via Regulating Mitochondrial Dysfunction Induced by Oxidative Stress in Unilateral Ureteral Obstruction Rats
Authors: Jia Qi , Han Lin , Zhang Xiaoyu , Yang Wenning , Gao Yushan , Shen Yifan , Li Bing , Wang Shuyan , Qin Mingzhen , Lowe Scott , Qin Jianguo , Hao Gaimei
Published: October 2021

Tongluo Yishen (TLYS) decoction is an herb that is extensively applied for the treatment of chronic kidney disease (CKD) in traditional Chinese medicine. In this study, 37 different dominant chemical constituents of TLYS were identified. Rats with unilateral ureteral obstruction (UUO) were used as animal models, and TLYS decoction was administered orally for 14 days. TLYS decoction reduced the levels of renal function indicators, serum creatinine levels and blood urea nitrogen levels and alleviated renal pathological changes. Gene Ontology (GO) and KEGG pathway analyses of RNA sequencing data showed that TLYS decoction had significant effects on biological processes, cellular components and molecular functions in UUO rats and that the phagosome (a membrane source in the early stages of autophagy), lysosome (an important component of autolysosome), and oxidation pathways (which contribute to mitochondrial function) might be related to the antifibrotic effects of TLYS decoction. Moreover, we found significant mitochondrial function impairment, including a decreased mitochondrial membrane potential (MMP) and an imbalance in mitochondrial dynamics, excessive oxidative stress, and activation of Pink1/Parkin-mediated mitophagy in UUO rats. Treatment with TLYS decoction significantly increased the MMP, normalized mitochondrial dynamics and ameliorated renal injury. Moreover, TLYS alleviated the mitophagy clearance deficiency. In conclusion, our study showed that TLYS decoction can ameliorate mitochondrial dynamics by reducing oxidative stress and regulating mitophagy, thereby relieving renal injury, protecting renal function, and reducing renal fibrosis. This study provides support for the application of and further research on TLYS decoction.
Ecological Stoichiometry of Bumblebee Castes, Sexes, and Age Groups
Authors: Krams Ronalds , Munkevics Māris , Popovs Sergejs , Dobkeviča Linda , Willow Jonathan , Contreras Garduño Jorge , Krama Tatjana , Krams Indrikis A.
Published: October 2021

Ecological stoichiometry is important for revealing how the composition of chemical elements of organisms is influenced by their physiological functions and ecology. In this study, we investigated the elemental body composition of queens, workers, and males of the bumblebee Bombus terrestris, an important pollinator throughout Eurasia, North America, and northern Africa. Our results showed that body elemental content differs among B. terrestris castes. Young queens and workers had higher body nitrogen concentration than ovipositing queens and males, while castes did not differ significantly in their body carbon concentration. Furthermore, the carbon-to-nitrogen ratio was higher in ovipositing queens and males. We suggest that high body nitrogen concentration and low carbon-to-nitrogen ratio in young queens and workers may be related to their greater amount of flight muscles and flight activities than to their lower stress levels. To disentangle possible effects of stress in the agricultural landscape, further studies are needed to compare the elemental content of bumblebee bodies between natural habitats and areas of high-intensity agriculture.
The Chloride Conductance Inhibitor NS3623 Enhances the Activity of a Non-selective Cation Channel in Hyperpolarizing Conditions
Authors: Monedero Alonso David , Pérès Laurent , Hatem Aline , Bouyer Guillaume , Egée Stéphane
Published: October 2021

Handbooks of physiology state that the strategy adopted by red blood cells (RBCs) to preserve cell volume is to maintain membrane permeability for cations at its minimum. However, enhanced cation permeability can be measured and observed in specific physiological and pathophysiological situations such as in vivo senescence, storage at low temperature, sickle cell anemia and many other genetic defects affecting transporters, membrane or cytoskeletal proteins. Among cation pathways, cation channels are able to dissipate rapidly the gradients that are built and maintained by the sodium and calcium pumps. These situations are very well-documented but a mechanistic understanding of complex electrophysiological events underlying ion transports is still lacking. In addition, non-selective cation (NSC) channels present in the RBC membrane have proven difficult to molecular identification and functional characterization. For instance, NSC channel activity can be elicited by Low Ionic Strength conditions (LIS): the associated change in membrane potential triggers its opening in a voltage dependent manner. But, whereas this depolarizing media produces a spectacular activation of NSC channel, Gárdos channel-evoked hyperpolarization's have been shown to induce sodium entry through a pathway thought to be conductive and termed Pcat. Using the CCCP method, which allows to follow fast changes in membrane potential, we show here (i) that hyperpolarization elicited by Gárdos channel activation triggers sodium entry through a conductive pathway, (ii) that chloride conductance inhibition unveils such conductive cationic conductance, (iii) that the use of the specific chloride conductance inhibitor NS3623 (a derivative of Neurosearch compound NS1652), at concentrations above what is needed for full anion channel block, potentiates the non-selective cation conductance. These results indicate that a non-selective cation channel is likely activated by the changes in the driving force for cations rather than a voltage dependence mechanism per se.
Sarcoplasmic Reticulum Calcium Release Is Required for Arrhythmogenesis in the Mouse
Authors: Edwards Andrew G. , Mørk Halvor , Stokke Mathis K. , Lipsett David B. , Sjaastad Ivar , Richard Sylvain , Sejersted Ole M. , Louch William E.
Published: October 2021

Dysfunctional sarcoplasmic reticulum Ca2+ handling is commonly observed in heart failure, and thought to contribute to arrhythmogenesis through several mechanisms. Some time ago we developed a cardiomyocyte-specific inducible SERCA2 knockout mouse, which is remarkable in the degree to which major adaptations to sarcolemmal Ca2+ entry and efflux overcome the deficit in SR reuptake to permit relatively normal contractile function. Conventionally, those adaptations would also be expected to dramatically increase arrhythmia susceptibility. However, that susceptibility has never been tested, and it is possible that the very rapid repolarization of the murine action potential (AP) allows for large changes in sarcolemmal Ca2+ transport without substantially disrupting electrophysiologic stability. We investigated this hypothesis through telemetric ECG recording in the SERCA2-KO mouse, and patch-clamp electrophysiology, Ca2+ imaging, and mathematical modeling of isolated SERCA2-KO myocytes. While the SERCA2-KO animals exhibit major (and unique) electrophysiologic adaptations at both the organ and cell levels, they remain resistant to arrhythmia. A marked increase in peak L-type calcium (ICaL) current and slowed ICaL decay elicited pronounced prolongation of initial repolarization, but faster late repolarization normalizes overall AP duration. Early afterdepolarizations were seldom observed in KO animals, and those that were observed exhibited a mechanism intermediate between murine and large mammal dynamical properties. As expected, spontaneous SR Ca2+ sparks and waves were virtually absent. Together these findings suggest that intact SR Ca2+ handling is an absolute requirement for triggered arrhythmia in the mouse, and that in its absence, dramatic changes to the major inward currents can be resisted by the substantial K+ current reserve, even at end-stage disease.