bluuebunny/crossref_metadata_2025 huggingface dataset:
Harmonization of the ICHOM Quality Measures to Enable Health Outcomes Measurement in Multimorbid Patients
Authors: Blom Mathias C. , Khalid Mona , Van-Lettow Britt , Hutink Henk , Larsson Stefan , Huff Stan , Ingvar Martin
Published: January 2021

Objectives:To update the sets of patient-centric outcomes measures (“standard-sets”) developed by the not-for-profit organization ICHOM to become more readily applicable in patients with multimorbidity and to facilitate their implementation in health information systems. To that end we set out to (i) harmonize measures previously defined separately for different conditions, (ii) create clinical information models from the measures, and (iii) restructure the annotation to make the sets machine-readable.

Materials and Methods:First, we harmonized the semantic meaning of individual measures across all the 28 standard-sets published to date, in a harmonized measure repository. Second, measures corresponding to four conditions (Breast cancer, Cataracts, Inflammatory bowel disease and Heart failure) were expressed as logical models and mapped to reference terminologies in a pilot study.

Results:The harmonization of semantic meaning resulted in a consolidation of measures used across the standard-sets by 15%, from 3,178 to 2,712. These were all converted into a machine-readable format. 61% of the measures in the 4 pilot sets were bound to existing concepts in either SNOMED CT or LOINC.

Discussion:The harmonization of ICHOM measures across conditions is expected to increase the applicability of ICHOM standard-sets to multi-morbid patients, as well as facilitate their implementation in health information systems.

Conclusion:Harmonizing the ICHOM measures and making them machine-readable is expected to expedite the global adoption of systematic and interoperable outcomes measurement. In turn, we hope that the improved transparency on health outcomes that follows will let health systems across the globe learn from each other to the ultimate benefit of patients.
Glucocorticoid-Induced Osteoporosis: Why Kids Are Different
Authors: Ward Leanne M.
Published: January 2021

Glucocorticoids (GC) are an important risk factor for bone fragility in children with serious illnesses, largely due to their direct adverse effects on skeletal metabolism. To better appreciate the natural history of fractures in this setting, over a decade ago the Canadian STeroid-associated Osteoporosis in the Pediatric Population (“STOPP”) Consortium launched a 6 year, multi-center observational cohort study in GC-treated children. This study unveiled numerous key clinical-biological principles about GC-induced osteoporosis (GIO), many of which are unique to the growing skeleton. This was important, because most GIO recommendations to date have been guided by adult studies, and therefore do not acknowledge the pediatric-specific principles that inform monitoring, diagnosis and treatment strategies in the young. Some of the most informative observations from the STOPP study were that vertebral fractures are the hallmark of pediatric GIO, they occur early in the GC treatment course, and they are frequently asymptomatic (thereby undetected in the absence of routine monitoring). At the same time, some children have the unique, growth-mediated ability to restore normal vertebral body dimensions following vertebral fractures. This is an important index of recovery, since spontaneous vertebral body reshaping may preclude the need for osteoporosis therapy. Furthermore, we now better understand that children with poor growth, older children with less residual growth potential, and children with ongoing bone health threats have less potential for vertebral body reshaping following spine fractures, which can result in permanent vertebral deformity if treatment is not initiated in a timely fashion. Therefore, pediatric GIO management is now predicated upon early identification of vertebral fractures in those at risk, and timely intervention when there is limited potential for spontaneous recovery. A single, low-trauma long bone fracture can also signal an osteoporotic event, and a need for treatment. Intravenous bisphosphonates are currently the recommended therapy for pediatric GC-induced bone fragility, typically prescribed to children with limited potential for medication-unassisted recovery. It is recognized, however, that even early identification of bone fragility, combined with timely introduction of intravenous bisphosphonate therapy, may not completely rescue the osteoporosis in those with the most aggressive forms, opening the door to novel strategies.
Acute Hyperglycemia May Induce Renal Tubular Injury Through Mitophagy Inhibition
Authors: Wang Jingyu , Yue Xiaodan , Meng Cheng , Wang Ziyan , Jin Xiaofang , Cui Xiao , Yang Juhong , Shan Chunyan , Gao Zhongai , Yang Yanhui , Li Jing , Chang Bai , Chang Baocheng
Published: January 2021

Aim

Acute hyperglycemia is closely related to kidney injury. Oxidative stress activation and notable mitochondria damages were found under acute hyperglycemia treatment in our previous work. In the present study, we explored the dose-effect relationship and the pivotal role of mitophagy in acute hyperglycemia induced tubular injuries.

Methods

Forty non-diabetic SD rats were randomly divided and treated with different concentrations of hyperglycemia respectively during the 6-h clamp experiment. Renal morphological and functional alterations were detected. Rat renal tubular epithelial cells were treated with different concentrations of glucose for 6 h. Markers and the regulation pathway of mitophagy were analyzed.

Results

Significant tubular injuries but not glomeruli were observed under both light and electron microscope after acute hyperglycemia treatment, which manifested as enlargement of tubular epithelial cells, disarrangement of epithelial cell labyrinths and swelling of mitochondria. Urinary microalbumin, β2-MG, CysC, NAG, GAL, and NGAL were increased significantly with the increase of blood glucose (P < 0.05). ROS was activated, mitochondrial membrane potential and LC3-II/LC3-I ratio were decreased but P62 and BNIP3L/Nix were increased in hyperglycemia groups (P < 0.05), which were reversed by AMPK activation or mTOR inhibition.

Conclusion

Acute hyperglycemia causes obvious tubular morphological and functional injuries in a dose-dependent manner. Acute hyperglycemia could inhibit mitophagy through AMPK/mTOR pathway, which would aggravate mitochondria damage and renal tubular impairment.
Idiopathic Hypoparathyroidism With Papillary Thyroid Carcinoma in a Young Male: A Rare Case Report
Authors: Chen Wenjie , Chen Liyun , Wei Tao , Li Zhihui , Lei Jianyong , Zhu Jingqiang
Published: January 2021

Background

Idiopathic hypoparathyroidism (IHP) is a rare disorder that is diagnosed by excluding other possible etiologies. Thyroid surgery causes approximately 14–60% of all cases of hypoparathyroidism; of these, surgery for papillary thyroid carcinoma (PTC) is the most common reason. Here, we report an extremely rare case of IHP combined with PTC.

Case presentation

A 22-year-old man presented with a history of uncontrollable extremity and facial numbness, spasm and twitch lasting for nine years. He had been misdiagnosed with epilepsy and gained no relief from antiepileptic therapy. The laboratory evaluation revealed reduced parathyroid hormone and serum calcium and elevated inorganic phosphorus. After considering IHP, ultrasound detected a solid hypoechoic and irregularly shaped nodule 13×8×9 mm in size in the upper pole of the right thyroid gland, and fine-needle aspiration biopsy indicated PTC. Then, the patient underwent surgical treatment and radioactive iodine ablation. The long-term treatment strategy consisted of oral levothyroxine for thyroid-stimulating hormone inhibition and oral calcium and vitamin D supplements for hypocalcemia control.

Conclusion

We report a rare case of IHP combined with PTC in a 22-year-old male. Some experiences and lessons from our treatment procedure merit discussion, and we hope that our report can serve as a reference for the diagnosis and treatment of similar patients in the future.
Face and Content Validity of an Automated Vehicle Road Course and a Corresponding Simulation Scenario
Authors: Classen Sherrilene , Wersal James , Mason Justin , Rogers Jason , Sisiopiku Virginia
Published: January 2021

Introduction: Automated vehicle use is rapidly expanding globally. Florida is one of the leading states for researching, testing, implementing, and operating automated vehicles. Although driving simulators may create an opportunity to assess user behaviors related to automated vehicles, their use in this context is not well-documented.

Objectives: This study examined face and content validity of an on-road automated shuttle route and its congruence to a driving simulator scenario representing the on-road route.

Methodology: Face validity (i.e., clarity, understandability, congruence) was examined directly by members of the Institute for Mobility, Activity, and Participation. Content validity was assessed via a content validity index (CVI) based on inputs from experts who represented a variety of disciplines. These included computer and information science, engineering, transportation engineering, rehabilitation science, industrial and systems engineering, experimental psychology, and driver rehabilitation science.

Findings: Face validity resulted in feedback pertaining to traffic, environment, hazards, fidelity, and “other” recommendations. Six of the recommendations were used to enhance the simulator scenario. For content validity, the CVI scale was equal to 0.83 and was above the acceptable threshold of 0.80. However, on the item level, two items, i.e., traffic flow (I-CVI = 0.57) and seat direction (I-CVI = 0.67), were rated lower than anticipated. The ratings resulted in implementing enhancements to the driving simulator scenario.

Conclusion: Automated vehicle on-road routes can be replicated in a driving simulator scenario but require a process of examining the face and content validity and refining the developed scenario as needed to ensure reasonable accuracy.
Metabolomic and Proteomic Profiles Associated With Ketosis in Dairy Cows
Authors: Wu Zhou-Lin , Chen Shi-Yi , Hu Shenqiang , Jia Xianbo , Wang Jie , Lai Song-Jia
Published: January 2021

Ketosis is a common metabolic disease in dairy cows during early lactation. However, information about the metabolomic and proteomic profiles associated with the incidence and progression of ketosis is still limited. In this study, an integrated metabolomics and proteomics approach was performed on blood serum sampled from cows diagnosed with clinical ketosis (case, ≥ 2.60 mmol/L plasma β-hydroxybutyrate; BHBA) and healthy controls (control, < 1.0 mmol/L BHBA). Samples were taken 2 weeks before parturition and 2 weeks after parturition from 19 animals (nine cases, 10 controls). All serum samples (n = 38) were subjected to Liquid Chromatography-Mass Spectrometry (LC-MS) based metabolomic analysis, and 20 samples underwent Data-Independent Acquisition (DIA) LC-MS based proteomic analysis. A total of 97 metabolites and 540 proteins were successfully identified, and multivariate analysis revealed significant differences in both metabolomic and proteomic profiles between cases and controls. We investigated clinical ketosis-associated metabolomic and proteomic changes using statistical analyses. Correlation analysis of statistically significant metabolites and proteins showed 78 strong correlations (correlation coefficient, R ≥ 0.7) between 38 metabolites and 25 proteins, which were then mapped to pathways using IMPaLA. Results showed that ketosis altered a wide range of metabolic pathways, such as metabolism, metabolism of proteins, gene expression and post-translational protein modification, vitamin metabolism, signaling, and disease related pathways. Findings presented here are relevant for identifying molecular targets for ketosis and biomarkers for ketosis detection during the transition period.
Development of an miRNA-Array-Based Diagnostic Signature for Periodontitis
Authors: Jin Su-Han , Zhou Jian-Guo , Guan Xiao-Yan , Bai Guo-Hui , Liu Jian-Guo , Chen Liang-Wen
Published: January 2021

Periodontitis progression is accompanied by irreversible alveolar bone absorption and leads to tooth loss. Early diagnosis is important for tooth stability and periodontal tissue preservation. However, there is no recognized miRNA diagnostic signature with convincing sensitivity and specificity for periodontitis. In this study, we obtained miRNA array expression profiles of periodontitis from the Gene Expression Omnibus (GEO) database. After screening for differentially expressed miRNAs, the least absolute shrinkage and selection operator (LASSO) method was performed to identify and construct a 17-miRNA-based diagnostic signature (hsa-miR-3917, hsa-mir-4271, hsa-miR-3156, hsa-miR-3141, hsa-miR-1246, hsa-miR-125a-5p, hsa-miR-671-5p, hcmv-mir-UL70, hsa-miR-650, hsa-miR-497-3p, hsa-miR-145-3p, hsa-miR-141-3p, hsa-miR-210-3p, hsa-miR-204-3p, hsa-miR-203a-5p, hsa-miR-99a-3p, and hsa-miR-30a-3p). Periodontal tissue samples with higher risk scores were more likely to show symptoms of periodontitis. Then, the receiver operating characteristic (ROC) curves were used to assess the diagnostic value of the miRNA signature, which indicated that the optimum cutoff value in periodontitis diagnosis was 0.5056 with an area under the ROC curve (AUC) of 0.996, a sensitivity of 97.3%, a specificity of 100.0% in the training cohort; in the testing cohort, the corresponding values were as follows: an AUC of 0.998, a sensitivity of 97.9%, and a specificity of 91.7%. We next evaluated the efficacy of the signature in differentiating disease subtype and affected range. Furthermore, we conducted functional enrichment analysis of the 17 miRNA-targeted mRNAs, including the regulation of mTOR activity and cell autophagy, Th1/Th2 cell balance and immunoregulation, cell apoptosis, and so on. In summary, our study identified and validated a 17-miRNA diagnostic signature with convincing AUC, sensitivity, and specificity for periodontitis.
Identification of Molecular Markers Associated With the Pathophysiology and Treatment of Lupus Nephritis Based on Integrated Transcriptome Analysis
Authors: Yao Menghui , Gao Congcong , Zhang Chunyi , Di Xueqi , Liang Wenfang , Sun Wenbo , Wang Qianqian , Zheng Zhaohui
Published: January 2021

Lupus nephritis (LN) is a well-known complication of systemic lupus erythematosus and is its leading cause of morbidity and mortality. Our study aimed to identify the molecular markers associated with the pathophysiology and treatment of LN. The renal tissue gene expression profiles of LN patients in the GSE32591 dataset were downloaded as a discovery cohort from the Gene Expression Omnibus. Differentially expressed genes (DEGs) were identified; weighted gene co-expression network analysis (WGCNA) was used to identify the co-expression modules of DEGs; and gene function enrichment analysis, molecular crosstalk analysis, and immune cell infiltration analysis were performed to explore the pathophysiological changes in glomeruli and tubulointerstitia of LN patients. The crosstalk genes were validated in another RNA-sequencing cohort. DEGs common in RNA-sequencing dataset and GSE32591 were uploaded to the Connectivity Map (CMap) database to find prospective LN-related drugs. Molecular docking was used to verify the targeting association between candidate small molecular compounds and the potential target. In all, 420 DEGs were identified; five modules and two modules associated with LN were extracted in glomeruli and tubulointerstitia, respectively. Functional enrichment analysis showed that type I interferon (IFN) response was highly active, and some biological processes such as metabolism, detoxification, and ion transport were impaired in LN. Gene transcription in glomeruli and tubulointerstitia might affect each other, and some crosstalk genes, such asIRF7,HLA-DRA,ISG15,PSMB8, andIFITM3, play important roles in this process. Immune cell infiltration analysis revealed that monocytes and macrophages were increased in glomeruli and tubulointerstitia, respectively. CMap analysis identified proscillaridin as a possible drug to treat LN. Molecular docking showed proscillaridin forms four hydrogen bonds with the SH2 domain of signal transducer and activator of transcription 1 (STAT1). The findings of our study may shed light on the pathophysiology of LN and provide potential therapeutic targets for LN.
Inference of Genetic Networks From Time-Series and Static Gene Expression Data: Combining a Random-Forest-Based Inference Method With Feature Selection Methods
Authors: Kimura Shuhei , Fukutomi Ryo , Tokuhisa Masato , Okada Mariko
Published: January 2021

Several researchers have focused on random-forest-based inference methods because of their excellent performance. Some of these inference methods also have a useful ability to analyze both time-series and static gene expression data. However, they are only of use in ranking all of the candidate regulations by assigning them confidence values. None have been capable of detecting the regulations that actually affect a gene of interest. In this study, we propose a method to remove unpromising candidate regulations by combining the random-forest-based inference method with a series of feature selection methods. In addition to detecting unpromising regulations, our proposed method uses outputs from the feature selection methods to adjust the confidence values of all of the candidate regulations that have been computed by the random-forest-based inference method. Numerical experiments showed that the combined application with the feature selection methods improved the performance of the random-forest-based inference method on 99 of the 100 trials performed on the artificial problems. However, the improvement tends to be small, since our combined method succeeded in removing only 19% of the candidate regulations at most. The combined application with the feature selection methods moreover makes the computational cost higher. While a bigger improvement at a lower computational cost would be ideal, we see no impediments to our investigation, given that our aim is to extract as much useful information as possible from a limited amount of gene expression data.
Sc-GPE: A Graph Partitioning-Based Cluster Ensemble Method for Single-Cell
Authors: Zhu Xiaoshu , Li Jian , Li Hong-Dong , Xie Miao , Wang Jianxin
Published: January 2021

Clustering is an efficient way to analyze single-cell RNA sequencing data. It is commonly used to identify cell types, which can help in understanding cell differentiation processes. However, different clustering results can be obtained from different single-cell clustering methods, sometimes including conflicting conclusions, and biologists will often fail to get the right clustering results and interpret the biological significance. The cluster ensemble strategy can be an effective solution for the problem. As the graph partitioning-based clustering methods are good at clustering single-cell, we developed Sc-GPE, a novel cluster ensemble method combining five single-cell graph partitioning-based clustering methods. The five methods are SNN-cliq, PhenoGraph, SC3, SSNN-Louvain, and MPGS-Louvain. In Sc-GPE, a consensus matrix is constructed based on the five clustering solutions by calculating the probability that the cell pairs are divided into the same cluster. It solved the problem in the hypergraph-based ensemble approach, including the different cluster labels that were assigned in the individual clustering method, and it was difficult to find the corresponding cluster labels across all methods. Then, to distinguish the different importance of each method in a clustering ensemble, a weighted consensus matrix was constructed by designing an importance score strategy. Finally, hierarchical clustering was performed on the weighted consensus matrix to cluster cells. To evaluate the performance, we compared Sc-GPE with the individual clustering methods and the state-of-the-art SAME-clustering on 12 single-cell RNA-seq datasets. The results show that Sc-GPE obtained the best average performance, and achieved the highest NMI and ARI value in five datasets.
Investigating Causal Relations Between Sleep-Related Traits and Risk of Type 2 Diabetes Mellitus: A Mendelian Randomization Study
Authors: Gao Xue , Sun Heli , Zhang Yu , Liu Long , Wang Juping , Wang Tong
Published: January 2021

Objective

Extensive literature put forward the link between sleep and type 2 diabetes mellitus (T2DM), however, little is known about the underlying causality of the associations. Here we aim to assess the causal relationships between five major sleep-related traits and T2DM.

Design, Setting, and Participants

Two-sample Mendelian randomization (MR) was utilized to investigate the potential causal relations. Independent genetic variants associated with five sleep-related phenotypes—insomnia, sleep duration, short sleep duration, long sleep duration, and morningness—were chosen as instrumental variables to estimate the causal associations with T2DM. Summary statistics were acquired from the genome-wide association studies of UK Biobank and 23andMe (for sleep-related measures), the DIAbetes Genetics Replication And Meta-analysis and the FinnGen (for T2DM).

Main Methods

Individual Cochran’s Q statistic was applied to remove the pleiotropic instruments, global Q statistics and MR-Egger regression were adopted to test for the global heterogeneity and horizontal pleiotropy of the screened instruments, respectively. Two T2DM cohorts were selected to analyze their associations with sleep traits. A modified inverse variance weighted (IVW) estimate was performed to combine the ratio estimators from each instrument and acquire the causal estimate, alternative methods including IVW with first-order weights, simple and weighted median estimations, and MR-Egger regression were conducted as sensitivity analyses, to ensure the robustness and solidity of the findings.

Results

Two-sample MR supported findings for an adverse effect of genetically predicted insomnia on T2DM risk (odds ratio [OR] = 1.14, 95% confidence interval [CI]: 1.09–1.19, p = 1.29E–08) at the Bonferroni-adjusted level of significance (p < 0.005). We further investigated the causal role of T2DM on insomnia but obtained a non-significant estimation. There was also little evidence for the causal effect of other sleep-related measures on T2DM. Results were largely consistent when leveraging two different T2DM cohorts, and were robust among various sensitivity analyses.

Conclusion

Findings provide significant evidence for an adverse effect of insomnia on T2DM risk. The study extends fundamental knowledge to further understanding of the pathophysiological mechanisms of T2DM, and points out the non-negligible role of insomnia on epidemiologic intervention and clinical therapeutics of T2DM.
Genetic Diversity, Inbreeding Level, and Genetic Load in Endangered Snub-Nosed Monkeys (Rhinopithecus)
Authors: Kuang Weimin , Hu Jingyang , Wu Hong , Fen Xiaotian , Dai Qingyan , Fu Qiaomei , Xiao Wen , Frantz Laurent , Roos Christian , Nadler Tilo , Irwin David M. , Zhou Linchun , Yang Xu , Yu Li
Published: January 2021

The snub-nosed monkey genus (Rhinopithecus) comprises five closely related species (R. avunculus, R. bieti, R. brelichi, R. roxellana, and R. strykeri). All are among the world's rarest and most endangered primates. However, the genomic impact associated with their population decline remains unknown. We analyzed population genomic data of all five snub-nosed monkey species to assess their genetic diversity, inbreeding level, and genetic load. For R. roxellana, R. bieti, and R. strykeri, population size is positively correlated with genetic diversity and negatively correlated with levels of inbreeding. Other species, however, which possess small population sizes, such as R. brelichi and R. avunculus, show high levels of genetic diversity and low levels of genomic inbreeding. Similarly, in the three populations of R. roxellana, the Shennongjia population, which possesses the lowest population size, displays a higher level of genetic diversity and lower level of genomic inbreeding. These findings suggest that although R. brelichi and R. avunculus and the Shennongjia population might be at risk, it possess significant genetic diversity and could thus help strengthen their long-term survival potential. Intriguingly, R. roxellana with large population size possess high genetic diversity and low level of genetic load, but they show the highest recent inbreeding level compared with the other snub-nosed monkeys. This suggests that, despite its large population size, R. roxellana has likely been experiencing recent inbreeding, which has not yet affected its mutational load and fitness. Analyses of homozygous-derived deleterious mutations identified in all snub-nosed monkey species indicate that these mutations are affecting immune, especially in smaller population sizes, indicating that the long-term consequences of inbreeding may be resulting in an overall reduction of immune capability in the snub-nosed monkeys, which could provide a dramatic effect on their long-term survival prospects. Altogether, our study provides valuable information concerning the genomic impact of population decline of the snub-nosed monkeys. We revealed multiple counterintuitive and unexpected patterns of genetic diversity in small and large population, which will be essential for conservation management of these endangered species.
Highly Sensitive Flow Cytometric Detection of Residual B-Cells After Rituximab in Anti-Neutrophil Cytoplasmic Antibodies-Associated Vasculitis Patients
Authors: van Dam Laura S. , Oskam Jelle M. , Kamerling Sylvia W. A. , Arends Eline J. , Bredewold O. W. , Berkowska Magdalena A. , van Dongen Jacques J. M. , Rabelink Ton J. , van Kooten Cees , Teng Y. K. Onno
Published: January 2021

Background

B-cell depletion with rituximab (RTX) is an effective treatment for anti-neutrophil cytoplasmic antibodies (ANCA)-associated vasculitis (AAV) patients. Nevertheless, relapses are frequent after RTX, often preceded by B-cell repopulation suggesting that residual autoreactive B-cells persist despite therapy. Therefore, this study aimed to identify minimal residual autoimmunity (MRA) in the B-cell compartment of AAV patients treated with RTX.

Methods

EuroFlow-based highly-sensitive flow cytometry (HSFC) was employed to study B-cell and plasma cell (PC) subsets in-depth in AAV patients before and after RTX treatment. Additionally, peripheral blood mononuclear cells (PBMCs) of these RTX-treated AAV patients were cultured and in vitro stimulated with CpG, IL-2, and IL-21 to induce antibody-secreting cells (ASC). (ANCA)-IgG was measured in these supernatants by ELISA.

Results

By employing EuroFlow-based HSFC, we detected circulating CD19+ B-cells at all timepoints after RTX treatment, in contrast to conventional low-sensitive flow cytometry. Pre-germinal center (Pre-GC) B-cells, memory B-cells and CD20+CD138− plasmablasts (PBs) were rapidly and strongly reduced, while CD20−CD138− PrePC and CD20-CD138+ mature (m)PCs were reduced slower and remained detectable. Both memory B-cells and CD20− PCs remained detectable after RTX. Serum ANCA-IgG decreased significantly upon RTX. Changes in ANCA levels strongly correlated with changes in naive, switched CD27+ and CD27− (double-negative) memory B-cells, but not with plasma cells. Lastly, we demonstrated in vitro ANCA production by AAV PBMCs, 24 and 48 weeks after RTX treatment reflecting MRA in the memory compartment of AAV patients.

Conclusion

We demonstrated that RTX induced strong reductions in circulating B-cells, but never resulted in complete B-cell depletion. Despite strongly reduced B-cell numbers after RTX, ANCA-specific memory B-cells were still detectable in AAV patients. Thus, MRA is identifiable in AAV and can provide a potential novel approach in personalizing RTX treatment in AAV patients.
Chimeric Antigen Receptor T Cells Targeting NKG2D-Ligands Show Robust Efficacy Against Acute Myeloid Leukemia and T-Cell Acute Lymphoblastic Leukemia
Authors: Driouk Lina , Gicobi Joanina K. , Kamihara Yusuke , Rutherford Kayleigh , Dranoff Glenn , Ritz Jerome , Baumeister Susanne H. C.
Published: January 2021

CAR T cell approaches to effectively target AML and T-ALL without off-tumor effects on healthy myeloid or T cell compartments respectively are an unmet medical need. NKG2D-ligands are a promising target given their absence on healthy cells and surface expression in a wide range of malignancies. NKG2D-ligand expression has been reported in a substantial group of patients with AML along with evidence for prognostic significance. However, reports regarding the prevalence and density of NKG2D-ligand expression in AML vary and detailed studies to define whether low level expression is sufficient to trigger NKG2D-ligand directed CART cell responses are lacking. NKG2D ligand expression in T-ALL has not previously been interrogated. Here we report that NKG2D-ligands are expressed in T-ALL cell lines and primary T-ALL. We confirm that NKG2D-ligands are frequently surface expressed in primary AML, albeit at relatively low levels. Utilizing CAR T cells incorporating the natural immune receptor NKG2D as the antigen binding domain, we demonstrate striking in vitro activity of CAR T cells targeting NKG2D-ligands against AML and T-ALL cell lines and show that even low-level ligand expression in primary AML targets results in robust NKG2D-CAR activity. We found that NKG2D-ligand expression can be selectively enhanced in low-expressing AML cell lines and primary AML blasts via pharmacologic HDAC inhibition. Such pharmacologic NKG2D-ligand induction results in enhanced NKG2D-CAR anti-leukemic activity without affecting healthy PBMC, thereby providing rationale for the combination of HDAC-inhibitors with NKG2D-CAR T cell therapy as a potential strategy to achieve clinical NKG2D-CAR T cell efficacy in AML.
Insight Into Inflammasome Signaling: Implications for Toxoplasma gondii Infection
Authors: Wang Yang , Zhu Jinjin , Cao Yuanyuan , Shen Jilong , Yu Li
Published: January 2021

Inflammasomes are multimeric protein complexes regulating the innate immune response to invading pathogens or stress stimuli. Recent studies have reported that nucleotide-binding leucine-rich repeat-containing (NLRs) proteins and DNA sensor absent in melanoma 2 (AIM2) serve as inflammasome sentinels, whose stimulation leads to the proteolytic activation of caspase-1, proinflammatory cytokine secretion, and pyroptotic cell death. Toxoplasma gondii, an obligate intracellular parasite of phylum Apicomplexans, is reportedly involved in NLRP1, NLRP3 and AIM2 inflammasomes activation; however, mechanistic evidence regarding the activation of these complexes is preliminary. This review describes the current understanding of inflammasome signaling in rodent and human models of T. gondii infection.
Tumor-Derived Extracellular Vesicles and the Immune System—Lessons From Immune-Competent Mouse-Tumor Models
Authors: Droste Marvin , Thakur Basant K. , Eliceiri Brian P.
Published: January 2021

Tumor-derived extracellular vesicles (TEVs) are important regulators of the immune response in cancer; however, most research so far has been carried out using cell culture systems. Immune-competent murine tumor models currently provide the best platform to assess proposed roles of TEVs usingin vivoanimal models and therefore are important for examining interactions between TEVs and the immune system. In this review, we present the current knowledge on TEVs usingin vivotumor-bearing animal models, with a focus on the role of TEVs in mediating crosstalk between tumor cells and both adaptive and innate immune cells. In particular, we address the question how animal models can clarify the reported heterogeneity of TEV effects in both anti-tumor responses and evasion of immune surveillance. The potential of TEVs in mediating direct antigen-presenting functions supports their potential as cancer vaccine therapeutics, therefore, we provide an overview of key findings of TEV trials that have the potential as novel immunotherapies, and shed light on challenges in the path toward the first in-human trials. We also highlight the important updates on the methods that continue to enhance the rigor and reproducibility of EV studies, particularly in functional animal models.
Genetic Engineering of Natural Killer Cells for Enhanced Antitumor Function
Authors: Mantesso Simone , Geerts Dirk , Spanholtz Jan , Kučerová Lucia
Published: January 2021

Natural Killer (NK) cells are unique immune cells capable of efficient killing of infected and transformed cells. Indeed, NK cell-based therapies induced response against hematological malignancies in the absence of adverse toxicity in clinical trials. Nevertheless, adoptive NK cell therapies are reported to have exhibited poor outcome against many solid tumors. This can be mainly attributed to limited infiltration of NK cells into solid tumors, downregulation of target antigens on the tumor cells, or suppression by the chemokines and secreted factors present within the tumor microenvironment. Several methods for genetic engineering of NK cells were established and consistently improved over the last decade, leading to the generation of novel NK cell products with enhanced anti-tumor activity and improved tumor homing. New generations of engineered NK cells are developed to better target refractory tumors and/or to overcome inhibitory tumor microenvironment. This review summarizes recent improvements in approaches to NK cell genetic engineering and strategies implemented to enhance NK cell effector functions.
Beyond T-Cells: Functional Characterization of CTLA-4 Expression in Immune and Non-Immune Cell Types
Authors: Oyewole-Said Damilola , Konduri Vanaja , Vazquez-Perez Jonathan , Weldon Scott A. , Levitt Jonathan M. , Decker William K.
Published: January 2021

The immune response consists of a finely-tuned program, the activation of which must be coupled with inhibitory mechanisms whenever initiated. This ensures tight control of beneficial anti-pathogen and anti-tumor responses while preserving tissue integrity, promoting tissue repair, and safeguarding against autoimmunity. A cogent example of this binary response is in the mobilization of co-stimulatory and co-inhibitory signaling in regulating the strength and type of a T-cell response. Of particular importance is the costimulatory molecule CD28 which is countered by CTLA-4. While the role of CD28 in the immune response has been thoroughly elucidated, many aspects of CTLA-4 biology remain controversial. The expression of CD28 is largely constrained to constitutive expression in T-cells and as such, teasing out its function has been somewhat simplified by a limited and specific expression profile. The expression of CTLA-4, on the other hand, while reported predominantly in T-cells, has also been described on a diverse repertoire of cells within both lymphoid and myeloid lineages as well as on the surface of tumors. Nonetheless, the function of CTLA-4 has been mostly described within the context of T-cell biology. The focus on T-cell biology may be a direct result of the high degree of amino acid sequence homology and the co-expression pattern of CD28 and CTLA-4, which initially led to the discovery of CTLA-4 as a counter receptor to CD28 (for which a T-cell-activating role had already been described). Furthermore, observations of the outsized role of CTLA-4 in Treg-mediated immune suppression and the striking phenotype of T-cell hyperproliferation and resultant disease in CTLA-4−/−mice contribute to an appropriate T-cell-centric focus in the study of CTLA-4. Complete elucidation of CTLA-4 biology, however, may require a more nuanced understanding of its role in a context other than that of T-cells. This makes particular sense in light of the remarkable, yet limited utility of anti-CTLA-4 antibodies in the treatment of cancers and of CTLA-4-Ig in autoimmune disorders like rheumatoid arthritis. By fully deducing the biology of CTLA-4-regulated immune homeostasis, bottlenecks that hinder the widespread applicability of CTLA-4-based immunotherapies can be resolved.
Gonadal Degeneration and Hepatopancreas Alteration in Orange Mud Crab Scylla olivacea Infected With Sacculina beauforti (Crustacea; Rhizocephala; Sacculinidae)
Authors: Fazhan Hanafiah , Waiho Khor , Glenner Henrik , Moh Julia Hwei Zhong , Hassan Marina , Ikhwanuddin Mhd
Published: January 2021

Infestation of Sacculina beauforti on an aquaculture species, mud crab Scylla olivacea is alarming due to its high prevalence and the extreme morphological changes in hosts. To further understand its pathological effect on growth and reproduction of S. olivacea, gonadal and hepatopancreatic histological changes of infected individuals were compared with healthy individuals. Also, the histological characteristics of S. beauforti's mature externa was described. Hepatopancreases of infected individuals were loosely packed and rootlets were observed in the intertubular spaces. Although hepatopancreatic tubule count was significantly lower, tubule diameters were unaffected. Gonads, however, were severely affected. No germ cells were found in the infected testes (except for remnants of spermatozoa), indicating the arrest of spermatogenesis. Rootlets were also present in testes of infected individuals. Ovarian tissues of infected females were severely damaged with no rigid cell structures. Gonadosomatic index (GSI) of infected males and females were lower, but the hepatosomatic index (HSI) were higher than their healthy counterparts. No significant differences in GSI and HSI values were observed among infected males and females. Multiple regression analysis revealed that carapace width, GSI and HSI are statistically important for the prediction of infection status. Given the high prevalence of S. beauforti infection and its disruptive effects on the morphology and internal physiology of S. olivacea, this study, albeit fundamental and incomprehensive, highlights to farmers and researchers the emergence of a castrating parasite and the urgency for the development of preventive measures and treatments for this disease in an economically important aquaculture species.
Probabilistic Application of an Integrated Catchment-Estuary-Coastal System Model to Assess the Evolution of Inlet-Interrupted Coasts Over the 21st Century
Authors: Bamunawala Janaka , Dastgheib Ali , Ranasinghe Roshanka , van der Spek Ad , Maskey Shreedhar , Murray A. Brad , Barnard Patrick L. , Duong Trang Minh , Sirisena T. A. J. G.
Published: January 2021

Inlet-interrupted sandy coasts are dynamic and complex coastal systems with continuously evolving geomorphological behaviors under the influences of both climate change and human activities. These coastal systems are of great importance to society (e.g., providing habitats, navigation, and recreational activities) and are affected by both oceanic and terrestrial processes. Therefore, the evolution of these inlet-interrupted coasts is better assessed by considering the entirety of the Catchment-Estuary-Coastal (CEC) systems, under plausible future scenarios for climate change and increasing pressures due to population growth and human activities. Such a holistic assessment of the long-term evolution of CEC systems can be achieved via reduced-complexity modeling techniques, which are also ably quantifying the uncertainties associated with the projections due to their lower simulation times. Here, we develop a novel probabilistic modeling framework to quantify the input-driven uncertainties associated with the evolution of CEC systems over the 21stcentury. In this new approach, probabilistic assessment of the evolution of inlet-interrupted coasts is achieved by (1) probabilistically computing the exchange sediment volume between the inlet-estuary system and its adjacent coast, and (2) distributing the computed sediment volumes along the inlet-interrupted coast. The model is applied at three case study sites: Alsea estuary (United States), Dyfi estuary (United Kingdom), and Kalutara inlet (Sri Lanka). Model results indicate that there are significant uncertainties in projected volume exchange at all the CEC systems (min-max range of 2.0 million cubic meters in 2100 for RCP 8.5), and the uncertainties in these projected volumes illustrate the need for probabilistic modeling approaches to evaluate the long-term evolution of CEC systems. A comparison of 50thpercentile probabilistic projections with deterministic estimates shows that the deterministic approach overestimates the sediment volume exchange in 2100 by 15–30% at Alsea and Kalutara estuary systems. Projections of coastline change obtained for the case study sites show that accounting for all key processes governing coastline change along inlet-interrupted coasts in computing coastline change results in projections that are between 20 and 134% greater than the projections that would be obtained if only the Bruun effect were taken into account, underlining the inaccuracies associated with using the Bruun rule at inlet-interrupted coasts.
Insights Into Insular Isolation of the Bull Shark, Carcharhinus leucas (Müller and Henle, 1839), in Fijian Waters
Authors: Glaus Kerstin B. J. , Appleyard Sharon A. , Stockwell Brian , Brunnschweiler Juerg M. , Shivji Mahmood , Clua Eric , Marie Amandine D. , Rico Ciro
Published: January 2021

The bull shark (Carcharhinus leucas) is a large, mobile, circumglobally distributed high trophic level predator that inhabits a variety of remote islands and continental coastal habitats, including freshwater environments. Here, we hypothesize that the barriers to dispersal created by large oceanic expanses and deep-water trenches result in a heterogeneous distribution of the neutral genetic diversity between island bull shark populations compared to populations sampled in continental locations connected through continuous coastlines of continental shelves. We analyzed 1,494 high-quality neutral single nucleotide polymorphism (SNP) markers in 215 individual bull sharks from widespread locations across the Indian and Pacific Oceans (South Africa, Indonesia, Western Australia, Papua New Guinea, eastern Australia, New Caledonia, and Fiji). Genomic analyses revealed partitioning between remote insular and continental populations, with the Fiji population being genetically different from all other locations sampled (FST = 0.034–0.044, P < 0.001), and New Caledonia showing marginal isolation (FST = 0.016–0.024, P < 0.001; albeit based on a small sample size) from most sampled sites. Discriminant analysis of principal components (DAPC) identified samples from Fiji as a distinct cluster with all other sites clustering together. Genetic structure analyses (Admixture, fastStructure and AssignPOP) further supported the genetic isolation of bull sharks from Fiji, with the analyses in agreement. The observed differentiation in bull sharks from Fiji makes this site of special interest, as it indicates a lack of migration through dispersal across deep-water trenches and large ocean expanses.
Marine Heatwaves, Sewage and Eutrophication Combine to Trigger Deoxygenation and Biodiversity Loss: A SW Atlantic Case Study
Authors: Brauko Kalina M. , Cabral Alex , Costa Natasha V. , Hayden Juliana , Dias Carlos E. P. , Leite Edilene S. , Westphal Renan D. , Mueller Carolina M. , Hall-Spencer Jason M. , Rodrigues Regina R. , Rörig Leonardo R. , Pagliosa Paulo R. , Fonseca Alessandra L. , Alarcon Orestes E. , Horta Paulo A.
Published: January 2021

Marine heatwaves (MHWs) are a major concern worldwide due to their increasing impacts in recent years, and these extreme events may trigger deoxygenation of coastal waters affected by sewage and eutrophication. Here we investigate the combined effects of MHWs and nutrient enrichment on the water quality and biodiversity of the Bay of Santa Catarina Island (Brazil). We used historical (1994–2020) sea surface temperature data from satellites andin situphysical, chemical and biological parameters to assess temporal trends. Oxygen levels have been decreasing whilst phosphorus levels have been increasing in the bay. During the austral summer of 2020 a regional sea surface heatwave was detected by satellite, lasting for 9 days and coinciding with our research cruise. During this period, seawater temperatures reached 29.8°C and anoxia was detected for the first time in the bay. A decrease in macrobenthic and phytoplankton community richness correlated with decreases in oxygen both through time and towards more urbanized areas. Overall, poor wastewater treatment is a key stressor that combined with MHWs to degrade coastal waters. Mitigation strategies are needed to minimize the impact of MHWs, including improved sewage treatment, restoration and conservation of wetlands and the use of nature-based technologies to promote coastal ecosystem recovery.
Ocean Acidification and Ocean Warming Effects on Pacific Herring (Clupea pallasi) Early Life Stages
Authors: Villalobos Cristina , Love Brooke A. , Olson M. Brady
Published: January 2021

Increasing green house gas emissions are expected to raise surface seawater temperatures and lead to locally intensified ocean acidity in the U.S. Pacific Northwest. Pacific herring (Clupea pallasi) are ecologically and economically important forage fish species native to this region. While the impacts of ocean acidification and ocean warming on organism physiology have been extensively studied, less is known on how concurrent climate change stressors will affect marine fish. Therefore, our study focused on the combined effects of ocean acidification and warming on Pacific herring early life history stages. Pacific herring embryos were incubated under a factorial design of two temperature (10°C or 16°C) and twopCO2(600 μatm or 1200 μatm) treatments from fertilization until hatch (6 to 15 days depending on temperature). ElevatedpCO2was associated with a small increase in embryo mortality. Elevated temperature, as a single stressor, generated greater embryo mortality and embryo heart rates, larger yolk areas upon hatch, lower hatching success, and shorter larval lengths; compared with the same parameters measured under ambient temperature. The interaction of elevated temperature andpCO2was associated with greater embryo heart rates and yolk areas compared to ambient conditions. This study suggests that while temperature is the primary global change stressor affecting Pacific herring embryology, interaction effects withpCO2could introduce additional physiological challenges.
Constitutive Modeling of the Flow Stress Behavior for the Hot Deformation of Cu-15Ni-8Sn Alloys
Authors: Niu Dongxin , Zhao Chao , Li Daoxi , Wang Zhi , Luo Zongqiang , Zhang Weiwen
Published: January 2021

Three constitutive models, strain-compensated Arrhenius model, modified Johnson–Cook (JC) model, and modified Zerilli–Armstrong (ZA) model, were established for the hot-deformed Cu-15Ni-8Sn alloy based on hot compression tests. By introducing average absolute relative error (AARE), correlation coefficient (R), and relative error, the prediction accuracy of these three models was assessed. The results indicate that strain-compensated Arrhenius model has the highest accuracy at describing the flow stress behavior of the studied alloy, followed by modified JC model and modified ZA model. Moreover, the strain-compensated Arrhenius model established in this work has a great practicability in the hot-extrusion simulation of Cu-15Ni-8Sn alloys. This article provides a theoretical basis for optimizing hot deformation parameters in industrial production of the Cu-15Ni-8Sn alloys.