bluuebunny/crossref_metadata_2025 huggingface dataset:
The Relationships Between Lipid Accumulation Product Levels and Cognitive Decline Over 4 Years in a Rural Area of Xi’an, China
Authors: Wang Yanyu , Wei Shan , Zhou Rong , Shang Suhang , Dang Liangjun , Gao Ling , Chen Chen , Huo Kang , Wang Jingyi , Wang Jin , Qu Qiumin
Published: November 2021

Background and Aims: The relationships between blood lipid levels and obesity and cognitive impairment have not been fully determined. Considering that the lipid accumulation product (LAP) is a composite index of blood lipid levels and obesity, we investigated the relationships between LAP levels at baseline and cognitive decline over 4 years.

Methods: A total of 983 subjects (≥40 years) from a longitudinal cohort in a village of Xi’an, China, who completed the baseline survey were followed-up for 4 years. All participants underwent face-to-face interviews and cognitive assessments at baseline and at the 4-year follow-up. The Mini-Mental State Examination (MMSE) was used to assess cognitive function, and an MMSE score dropping ≥ 2 points from baseline was defined as cognitive decline. The relationships between LAP and cognitive decline were analyzed by linear regression models.

Results: During the 4-year follow-up, 172 patients exhibited cognitive decline (17.5%). Univariate analysis showed that the rate of change in MMSE score was significantly different between the low-LAP group and the high-LAP group (t = −2.26, p = 0.024). Multiple linear regression indicated that a high LAP was positively associated with cognitive decline (β = 0.564, p = 0.012). Stratified multivariate analysis showed that LAP was positively associated with cognitive decline in the normal blood pressure female subgroup (β = 1.29, p = 0.002) but not in the high blood pressure group or the male group.

Conclusions: High LAP is associated with cognitive decline in females with normal blood pressure but not in those with high blood pressure or males. This indicates that the relationships between blood lipid levels and obesity and cognitive impairment may be affected by blood pressure and sex.
Dendritic Architecture Predicts in vivo Firing Pattern in Mouse Ventral Tegmental Area and Substantia Nigra Dopaminergic Neurons
Authors: Montero Trinidad , Gatica Rafael Ignacio , Farassat Navid , Meza Rodrigo , González-Cabrera Cristian , Roeper Jochen , Henny Pablo
Published: November 2021

The firing activity of ventral tegmental area (VTA) and substantia nigra pars compacta (SNc) dopaminergic (DA) neurons is an important factor in shaping DA release and its role in motivated behavior. Dendrites in DA neurons are the main postsynaptic compartment and, along with cell body and axon initial segment, contribute to action potential generation and firing pattern. In this study, the organization of the dendritic domain in individual VTA and SNc DA neurons of adult male mice, and their relationship to in vivo spontaneous firing, are described. In comparison with dorsal VTA DA neurons, ventrally located VTA neurons (as measured by cell body location) possess a shorter total dendritic length and simpler dendritic architecture, and exhibit the most irregular in vivo firing patterns among DA neurons. In contrast, for DA neurons in the SNc, the higher irregularity of firing was related to a smaller dendritic domain, as measured by convex hull volumes. However, firing properties were also related to the specific regional distribution of the dendritic tree. Thus, VTA DA neurons with a larger extension of their dendritic tree within the parabrachial pigmented (PBP) nucleus fired more regularly compared with those with relatively more dendrites extending outside the PBP. For DA neurons in the SNc, enhanced firing irregularity was associated with a smaller proportion of dendrites penetrating the substantia nigra pars reticulata. These results suggest that differences in dendritic morphology contribute to the in vivo firing properties of individual DA neurons, and that the existence of region-specific synaptic connectivity rules that shape firing diversity.
Dual-Task Training Program for Older Adults: Blending Gait, Visuomotor and Cognitive Training
Authors: Nayak Akshata , Alhasani Rehab , Kanitkar Anuprita , Szturm Tony
Published: November 2021

Objective: Physical and cognitive impairments are common with aging and often coexist. Changes in the level of physical and mental activity are prognostic for adverse health events and falls. Dual-task (DT) training programs that can improve mobility and cognition simultaneously can bring significant improvements in rehabilitation. The objective of this mixed methods exploratory RCT was to provide evidence for the feasibility and therapeutic value of a novel game-assisted DT exercise program in older adults.

Methods: Twenty-two community dwelling participants, between the ages of 70–85 were randomized to either dual-task treadmill walking (DT-TR) or dual-task recumbent bicycle (DT-RC). Both groups viewed a standard LED computer monitor and performed a range of cognitive game tasks while walking or cycling; made possible with the use of a “hands-free”, miniature, inertial-based computer mouse. Participants performed their respective 1-h DT exercise program twice a week, for 12 weeks at a community fitness centre. Semi-structured interviews and qualitative analysis was conducted to evaluate the participant’s experiences with the exercise program. Quantitative analysis included measures of standing balance, gait function (spatiotemporal gait variable), visuomotor and executive cognitive function, tested under single and DT walking conditions.

Results: Compliance was 100% for all 22 participants. Four themes captured the range of participant’s experiences and opinions: 1) reasons for participation, 2) difficulties with using the technologies, 3) engagement with the computer games, and 4) positive effects of the program. Both groups showed significant improvements in standing balance performance, visuomotor and visuospatial executive function. However, significant improvement in dual task gait function was observed only in the DT-TR group. Medium to large effect sizes were observed for most balance, spatiotemporal gait variables, and cognitive performance measure.

Conclusion: With only minor difficulties with the technology being reported, the findings demonstrate feasible trial procedures and acceptable DT oriented training with a high compliance rate and positive outcomes. These findings support further research and development, and will direct the next phase of a full-scale RCT.
Lipid Metabolism in the Development and Progression of Vascular Cognitive Impairment: A Systematic Review
Authors: Qin Qi , Yin Yunsi , Xing Yi , Wang Xuan , Wang Yan , Wang Fan , Tang Yi
Published: November 2021

Background: Vascular cognitive impairment (VCI) is a major public health problem. The current diagnosis of VCI is made based on the assessment of clinical symptoms and neuropsychological measurements, and is supported by neuroimaging. These methods are both time-consuming and expensive, which leads to needs for alternative biomarkers for VCI. Metabolomics is an emerging and powerful tool to discover of new biomarkers of disease, which can investigate variations in different metabolic processes such as lipid, since the brain is highly enriched in lipids and that lipid changes may lead to pathology in the brain. Vascular cognitive impairment is vulnerable to the disturbance of lipid metabolism. Furthermore, blood samples, which could be identified as reliable clinical biomarkers are relatively convenient to obtain and provide a non-invasive assessment. Therefore, our study aims to understand whether peripheral lipid biomarkers can be used as diagnostic biomarkers and monitor the progression of VCI.

Methods: We systematically searched the PubMed, Embase, CNKI, and VIP databases to find VCI and lipid metabolism in reports from inception through February 2021. Studies meeting the following criteria were eligible: (1) original studies in humans; (2) lipid metabolites in blood; (3) reports of VCI.

Results: Through our review, nine original articles were eligible. Blood-based metabolites that might be potential biomarkers were identified. Most of them including PC, PE, Cers, and ChEs were significantly lower, while elevation of FAs and DGs were associated with VCI. Most importantly, these blood-based metabolites might be proposed as potential biomarkers for VCI, which provides direction for further validation.

Discussion and Conclusion: To the best of our knowledge, this is the first systemic review concerning the relationship of lipid metabolism and VCI. It identifies potential biomarkers and provides insights into the disease pathobiology. However, more advanced studies and researches on a lipidomic platform must be done to understand the exact pathology behind and identify potential lipid biomarkers, which might help achieve the goal of discovering novel therapeutics.
The Effects of Continuous vs. Intermittent Prism Adaptation Protocols for Treating Visuospatial Neglect: A Randomized Controlled Trial
Authors: Scheffels Jannik Florian , Korabova Sona , Eling Paul , Kastrup Andreas , Hildebrandt Helmut
Published: November 2021

Visuospatial neglect may interfere with activities of daily living (ADL). Prism adaptation (PA) is one treatment option and may involve two components: recalibration (more strategic) and realignment (more implicit). We examined whether recalibration or realignment is the driving force in neglect rehabilitation using PA. In a randomized controlled trial with two recruitment series and a cross-over design, 24 neglect patients were allocated to a continuous (PA-c) or intermittent (PA-i) PA procedure. During the PA-c condition, goggles were worn without doffing. In the PA-i condition, patients donned goggles twice (first series of patients) or three times (second series) during training to induce more recalibrations. Primary outcome parameters were performance (omissions) on the Apples Cancellation Test and ADL scores. To assess the efficacy of the PA treatment, we compared effect sizes of the current study with those from three groups from previous studies at the same rehabilitation unit: (1) a passive treatment with a similar intensity, (2) a placebo treatment with a similar intensity, and (3) a PA treatment with fewer therapy sessions. Treatment conditions did not significantly predict scores on primary and most secondary outcome parameters. However, the spontaneous ipsilesional body orientation improved only in patients receiving the PA-i condition and this improvement also appeared in patients showing a strong after-effect (irrespective of condition). Effect sizes for the Apples Cancellation Test and the Functional Independence Measure were larger for both PA treatment protocols than the historical control groups. We conclude that more recalibrations during an intermittent PA treatment may have a beneficial effect on spontaneous body orientation but not on other aspects of neglect or on ADL performance.

Clinical Trial Registration:German Clinical Trials Register, identifier: DRKS00018813, DRKS00021539.
Evaluation of Blood Glial Fibrillary Acidic Protein as a Potential Marker in Huntington's Disease
Authors: You Huajing , Wu Tengteng , Du Gang , Huang Yue , Zeng Yixuan , Lin Lishan , Chen Dingbang , Wu Chao , Li Xunhua , Burgunder Jean-marc , Pei Zhong
Published: November 2021

Objective: Huntington's disease (HD) is an autosomal dominant neurodegenerative disorder. Neurofilament light protein (NfL) is correlated with clinical severity of HD but relative data are the lack in the Chinese population. Reactive astrocytes are related to HD pathology, which predicts their potential to be a biomarker in HD progression. Our aim was to discuss the role of blood glial fibrillary acidic protein (GFAP) to evaluate clinical severity in patients with HD.

Methods: Fifty-seven HD mutation carriers (15 premanifest HD, preHD, and 42 manifest HD) and 26 healthy controls were recruited. Demographic data and clinical severity assessed with the internationally Unified Huntington's Disease Rating Scale (UHDRS) were retrospectively analyzed. Plasma NfL and GFAP were quantified with an ultra-sensitive single-molecule (Simoa, Norcross, GA, USA) technology. We explored their consistency and their correlation with clinical severity.

Results: Compared with healthy controls, plasma NfL (p < 0.0001) and GFAP (p < 0.001) were increased in Chinese HD mutation carriers, and they were linearly correlated with each other (r = 0.612, p < 0.001). They were also significantly correlated with disease burden, Total Motor Score (TMS) and Total Functional Capacity (TFC). The scores of Stroop word reading, symbol digit modalities tests, and short version of the Problem Behaviors Assessments (PBAs) for HD were correlated with plasma NfL but not GFAP. Compared with healthy controls, plasma NfL has been increased since stage 1 but plasma GFAP began to increase statistically in stage 2.

Conclusions: Plasma GFAP was correlated with plasma NfL, disease burden, TMS, and TFC in HD mutation carriers. Plasma GFAP may have potential to be a sensitive biomarker for evaluating HD progression.
Dietary Regulation of Gut-Brain Axis in Alzheimer’s Disease: Importance of Microbiota Metabolites
Authors: Frausto Dulce M. , Forsyth Christopher B. , Keshavarzian Ali , Voigt Robin M.
Published: November 2021

Alzheimer’s disease (AD) is a neurodegenerative disease that impacts 45 million people worldwide and is ranked as the 6th top cause of death among all adults by the Centers for Disease Control and Prevention. While genetics is an important risk factor for the development of AD, environment and lifestyle are also contributing risk factors. One such environmental factor is diet, which has emerged as a key influencer of AD development/progression as well as cognition. Diets containing large quantities of saturated/trans-fats, refined carbohydrates, limited intake of fiber, and alcohol are associated with cognitive dysfunction while conversely diets low in saturated/trans-fats (i.e., bad fats), high mono/polyunsaturated fats (i.e., good fats), high in fiber and polyphenols are associated with better cognitive function and memory in both humans and animal models. Mechanistically, this could be the direct consequence of dietary components (lipids, vitamins, polyphenols) on the brain, but other mechanisms are also likely to be important. Diet is considered to be the single greatest factor influencing the intestinal microbiome. Diet robustly influences the types and function of micro-organisms (called microbiota) that reside in the gastrointestinal tract. Availability of different types of nutrients (from the diet) will favor or disfavor the abundance and function of certain groups of microbiota. Microbiota are highly metabolically active and produce many metabolites and other factors that can affect the brain including cognition and the development and clinical progression of AD. This review summarizes data to support a model in which microbiota metabolites influence brain function and AD.
Role of the Stria Vascularis in the Pathogenesis of Sensorineural Hearing Loss: A Narrative Review
Authors: Yu Wenting , Zong Shimin , Du Peiyu , Zhou Peng , Li Hejie , Wang Enhao , Xiao Hongjun
Published: November 2021

Sensorineural hearing loss is a common sensory impairment in humans caused by abnormalities in the inner ear. The stria vascularis is regarded as a major cochlear structure that can independently degenerate and influence the degree of hearing loss. This review summarizes the current literature on the role of the stria vascularis in the pathogenesis of sensorineural hearing loss resulting from different etiologies, focusing on both molecular events and signaling pathways, and further attempts to explore the underlying mechanisms at the cellular and molecular biological levels. In addition, the deficiencies and limitations of this field are discussed. With the rapid progress in scientific technology, new opportunities are arising to fully understand the role of the stria vascularis in the pathogenesis of sensorineural hearing loss, which, in the future, will hopefully lead to the prevention, early diagnosis, and improved treatment of sensorineural hearing loss.
Mimetic Self-Reflexivity and Intersubjectivity in Complementary and Alternative Medicine Practices: The Mirror Neuron System in Breast Cancer Survivorship
Authors: Agarwal Vinita
Published: November 2021

This study examines complementary and alternative medicine (CAM) providers’ practices in the treatment of their breast cancer survivor (BCS) clients and interprets these practices within the context of existing neuroscientific research on the mirror neuron system (MNS). Purposive and snowball sampling was conducted to recruit CAM providers (N= 15) treating BCSs from integrative medicine centers, educational institutions, private practices, and professional medical associations across the United States. In-depth semi-structured interviewing (N= 252 single-spaced pages) and inductive qualitative content analysis reveal CAM therapeutic practices emphasize a diachronic form of mimetic self-reflexivity and a serendipitous form of mimetic intersubjectivity in BCS pain management to allow the providers to tune-in to their clients’ internal states over time and experience themselves as an embodied subject in an imaginative, shared space. By employing imagination and an intentional vulnerability in their embodied simulation of the others’ internal states, CAM providers co-create experiences of pain while recognizing what about the other remains an unknown. Although MNs provide the mechanism for imitation and simulation underlying empathy through a neuronally wired grasp of the other’s intentionality, the study suggests that examining mimetic self-reflexivity and intersubjectivity in the therapeutic space may allow for a shared simulation of participants’ subjective experiences of pain and potentially inform research on self-recognition and self-other discrimination as an index of self-awareness which implicates the MNS in embodied social cognition in imaginative ways.
European NCAP Program Developments to Address Driver Distraction, Drowsiness and Sudden Sickness
Authors: Fredriksson Rikard , Lenné Michael G. , van Montfort Sjef , Grover Colin
Published: November 2021

Driver distraction and drowsiness remain significant contributors to death and serious injury on our roads and are long standing issues in road safety strategies around the world. With developments in automotive technology, including driver monitoring, there are now more options available for automotive manufactures to mitigate risks associated with driver state. Such developments in Occupant Status Monitoring (OSM) are being incorporated into the European New Car Assessment Programme (Euro NCAP) Safety Assist protocols. The requirements for OSM technologies are discussed along two dimensions: detection difficulty and behavioral complexity. More capable solutions will be able to provide higher levels of system availability, being the proportion of time a system could provide protection to the driver, and will be able to capture a greater proportion of complex real-word driver behavior. The testing approach could initially propose testing using both a dossier of evidence provided by the Original Equipment Manufacturer (OEM) alongside selected use of track testing. More capable systems will not rely only on warning strategies but will also include intervention strategies when a driver is not attentive. The roadmap for future OSM protocol development could consider a range of known and emerging safety risks including driving while intoxicated by alcohol or drugs, cognitive distraction, and the driver engagement requirements for supervision and take-over performance with assisted and automated driving features.
Chemical Compounds, Antioxidant Activities, and Inhibitory Activities Against Xanthine Oxidase of the Essential Oils From the Three Varieties of Sunflower (Helianthus annuus L.) Receptacles
Authors: Liu Xin-Sheng , Gao Bo , Dong Zhan-De , Qiao Zi-An , Yan Min , Han Wei-Wei , Li Wan-Nan , Han Lu
Published: November 2021

Background/Aim: Essential oils of sunflower receptacles (SEOs) have antibacterial and antioxidant potential. However, the differences of biological activities from the different varieties of sunflowers have not been studied till now. The purpose of this study was to compare the differences of chemical compounds, antioxidant activities, and inhibitory activities against xanthine oxidase (XO) of SEOs from the three varieties of sunflowers including LD5009, SH363, and S606.

Methods: SEOs were extracted by using the optimal extraction conditions selected by response surface methodology (RSM). Chemical compounds of SEOs were identified from the three varieties of sunflowers by gas chromatography-mass spectrometry (GC-MS). Antioxidant activities of SEOs were detected by 2,2′-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) (ABTS), 2,2-diphenyl-1-picrylhydrazyl (DPPH), and iron ion reduction ability. Inhibitory activities of SEOs against XO were measured by using UV spectrophotometer. XO inhibitors were selected from the main chemical compounds of SEOs by the high-throughput selections and molecular simulation docking.

Results: The extraction yields of SEOs from LD5009, SH363, and S606 were 0.176, 0.319, and 0.580%, respectively. A total of 101 chemical compounds of SEOs were identified from the three varieties of sunflowers. In addition, the results of inhibitory activities against XO showed that SEOs can reduce uric acid significantly. Eupatoriochromene may be the most important chemical compounds of SEOs for reducing uric acid. The results of antioxidant activities and inhibitory activities against XO showed that SEOs of LD5009 had the strongest antioxidant and XO inhibitory activities. The Pearson correlation coefficient (r > 0.95) showed that γ-terpinene, (E)-citral, and L-Bornyl acetate were highly correlated with the antioxidant activities and XO inhibitory ability.

Conclusion: SEOs had antioxidant activities and XO inhibitory ability. It would provide more scientific information for utilization and selection of varieties of sunflowers, which would increase the food quality of sunflowers and incomes of farmers.
The Sharp Rise in the Use of Low- and No-Calorie Sweeteners in Non-Alcoholic Beverages in Slovenia: An Update Based on 2020 Data
Authors: Hafner Edvina , Pravst Igor
Published: November 2021

Reducing added sugars in non-alcoholic beverages is an important public health goal, which can result in increased use of low- and no-calorie sweeteners (LNCS). The aim of this study was to investigate recent changes in the use of LNCS in non-alcoholic beverages in the Slovenian food supply. The national branded foods dataset was updated with beverages available in 2020, and compared with previous datasets. The data were extracted from food labels. In 2020, N = 1,650 unique beverages were found in shops from five different retailers, covering the majority of the national market. The use of LNCS increased from 13.2% in 2017 and 15.5% in 2019 to 20.2% in 2020, with a major growth in soft drinks (16.8, 19.6, and 26.7%, respectively). We observed a significant growth of beverages containing both LNCS and added sugar. Results were also consistent with sales data, which showed that increased offer of beverages with LNCS also resulted in similarly increased sales of such beverages. The average energy and total sugar content in non-alcoholic beverages decreased, which reflects both the higher percentage of beverages with LNCS, and also the reduction of the sugar content in beverages with only added sugar. Analyses of product-specific reformulation practices highlighted reduced sugar content in 16.8% of products, and in 3.6% with the use of LNCS. The most commonly used LNCS are acesulfame K, sucralose, and aspartame. Typically, combinations are used, however steviol glycosides, sucralose and saccharin are also used alone, in most cases combined with added sugar. The results indicated rapid changes in the use of LNCS in non-alcoholic beverages in the Slovenian food supply, making further monitoring of this area highly relevant.
A Novel Clinical-Radiomics Model Based on Sarcopenia and Radiomics for Predicting the Prognosis of Intrahepatic Cholangiocarcinoma After Radical Hepatectomy
Authors: Deng Liming , Chen Bo , Zhan Chenyi , Yu Haitao , Zheng Jiuyi , Bao Wenming , Deng Tuo , Zheng Chongming , Wu Lijun , Yang Yunjun , Yu Zhengping , Wang Yi , Chen Gang
Published: November 2021

Background

Intrahepatic cholangiocarcinoma (ICC) is a highly aggressive malignant tumor with a poor prognosis. This study aimed to establish a novel clinical-radiomics model for predicting the prognosis of ICC after radical hepatectomy.

Methods

A clinical-radiomics model was established for 82 cases of ICC treated with radical hepatectomy in our hospital from May 2011 to December 2020. Radiomics features were extracted from venous-phase and arterial-phase images of computed tomography. Kaplan-Meier survival analysis was generated to compare overall survival (OS) between different groups. The independent factors were identified by univariate and multivariate Cox regression analyses. Nomogram performance was evaluated regarding discrimination, calibration, and clinical utility. C-index and area under the curve (AUC) were utilized to compare the predictive performance between the clinical-radiomics model and conventional staging systems.

Results

The radiomics model included five features. The AUC of the radiomics model was 0.817 in the training cohort, and 0.684 in the validation cohort. The clinical-radiomics model included psoas muscle index, radiomics score, hepatolithiasis, carcinoembryonic antigen, and neutrophil/lymphocyte ratio. The reliable C-index of the model was 0.768, which was higher than that of other models. The AUC of the model for predicting OS at 1, and 3 years was 0.809 and 0.886, which was significantly higher than that of the American Joint Committee on Cancer 8th staging system (0.594 and 0.619), radiomics model (0.743 and 0.770), and tumor differentiation (0.645 and 0.628). After stratification according to the constructed model, the median OS was 59.8 months for low-risk ICC patients and 10.1 months for high-risk patients (p < 0.0001).

Conclusion

The clinical-radiomics model integrating sarcopenia, clinical features, and radiomics score was accurate for prognostic prediction for mass-forming ICC patients. It provided an individualized prognostic evaluation in patients with mass-forming ICC and could helped surgeons with clinical decision-making.
Identification of Hub Genes Correlated With Poor Prognosis for Patients With Uterine Corpus Endometrial Carcinoma by Integrated Bioinformatics Analysis and Experimental Validation
Authors: Yuan Yi , Chen Zhengzheng , Cai Xushan , He Shengxiang , Li Dong , Zhao Weidong
Published: November 2021

Uterine Corpus Endometrial Carcinoma (UCEC) is one of the most common malignancies of the female genital tract and there remains a major public health problem. Although significant progress has been made in explaining the progression of UCEC, it is still warranted that molecular mechanisms underlying the tumorigenesis of UCEC are to be elucidated. The aim of the current study was to investigate key modules and hub genes related to UCEC pathogenesis, and to explore potential biomarkers and therapeutic targets for UCEC. The RNA-seq dataset and corresponding clinical information for UCEC patients were obtained from the Cancer Genome Atlas (TCGA) database. Differentially expressed genes (DEGs) were screened between 23 paired UCEC tissues and adjacent non-cancerous tissues. Subsequently, the co-expression network of DEGs was determined via weighted gene co-expression network analysis (WGCNA). The Blue and Brown modules were identified to be significantly positively associated with neoplasm histologic grade. The highly connected genes of the two modules were then investigated as potential key factors related to tumor differentiation. Additionally, a protein-protein interaction (PPI) network for all genes in the two modules was constructed to obtain key modules and nodes. 10 genes were identified by both WGCNA and PPI analyses, and it was shown by Kaplan-Meier curve analysis that 6 out of the 10 genes were significantly negatively related to the 5-year overall survival (OS) in patients (AURKA, BUB1, CDCA8, DLGAP5, KIF2C, TPX2). Besides, according to the DEGs from the two modules, lncRNA-miRNA-mRNA and lncRNA-TF-mRNA networks were constructed to explore the molecular mechanism of UCEC-related lncRNAs. 3 lncRNAs were identified as being significantly negatively related to the 5-year OS (AC015849.16, DUXAP8 and DGCR5), with higher expression in UCEC tissues compared to non-tumor tissues. Finally, quantitative Real-time PCR was applied to validate the expression patterns of hub genes. Cell proliferation and colony formation assays, as well as cell cycle distribution and apoptosis analysis, were performed to test the effects of representative hub genes. Altogether, this study not only promotes our understanding of the molecular mechanisms for the pathogenesis of UCEC but also identifies several promising biomarkers in UCEC development, providing potential therapeutic targets for UCEC.
Integrated CT Radiomics Features Could Enhance the Efficacy of 18F-FET PET for Non-Invasive Isocitrate Dehydrogenase Genotype Prediction in Adult Untreated Gliomas: A Retrospective Cohort Study
Authors: Zhou Weiyan , Huang Qi , Wen Jianbo , Li Ming , Zhu Yuhua , Liu Yan , Dai Yakang , Guan Yihui , Zhou Zhirui , Hua Tao
Published: November 2021

Purpose

We aimed to investigate the predictive models based on O-[2-(18F)fluoroethyl]-l-tyrosine positron emission tomography/computed tomography (18F-FET PET/CT) radiomics features for the isocitrate dehydrogenase (IDH) genotype identification in adult gliomas.

Methods

Fifty-eight consecutive pathologically confirmed adult glioma patients with pretreatment 18F-FET PET/CT were retrospectively enrolled. One hundred and five radiomics features were extracted for analysis in each modality. Three independent radiomics models (PET-Rad Model, CT-Rad Model and PET/CT-Rad Model) predicting IDH mutation status were generated using the least absolute shrinkage and selection operator (LASSO) regression analysis based on machine learning algorithms. All-subsets regression and cross validation were applied for the filter and calibration of the predictive radiomics models. Besides, semi-quantitative parameters including maximum, peak and mean tumor to background ratio (TBRmax, TBRpeak, TBRmean), standard deviation of glioma lesion standardized uptake value (SUVSD), metabolic tumor volume (MTV) and total lesion tracer uptake (TLU) were obtained and filtered for the simple model construction with clinical feature of brain midline involvement status. The area under the receiver operating characteristic curve (AUC) was applied for the evaluation of the predictive models.

Results

The AUC of the simple predictive model consists of semi-quantitative parameter SUVSD and dichotomized brain midline involvement status was 0.786 (95% CI 0.659-0.883). The AUC of PET-Rad Model building with three 18F-FET PET radiomics parameters was 0.812 (95% CI 0.688-0.902). The AUC of CT-Rad Model building with three co-registered CT radiomics parameters was 0.883 (95% CI 0.771-0.952). While the AUC of the combined 18F-FET PET/CT-Rad Model building with three CT and one PET radiomics features was 0.912 (95% CI 0.808-0.970). DeLong test results indicated the PET/CT-Rad Model outperformed the PET-Rad Model (p = 0.048) and simple predictive model (p = 0.034). Further combination of the PET/CT-Rad Model with the clinical feature of dichotomized tumor location status could slightly enhance the AUC to 0.917 (95% CI 0.814-0.973).

Conclusion

The predictive model combining 18F-FET PET and integrated CT radiomics features could significantly enhance and well balance the non-invasive IDH genotype prediction in untreated gliomas, which is important in clinical decision making for personalized treatment.
Immunotherapy and Radioimmunotherapy for Desmoplastic Small Round Cell Tumor
Authors: Espinosa-Cotton Madelyn , Cheung Nai-Kong V.
Published: November 2021

Desmoplastic small round cell tumor (DRSCT) is a highly aggressive primitive sarcoma that primarily affects adolescent and young adult males. The 5-year survival rate is 15-30% and few curative treatment options exist. Although there is no standard treatment for DSRCT, patients are most often treated with a combination of aggressive chemotherapy, radiation, and surgery. Targeted therapy inhibitors of PDGFA and IGF-1R, which are almost uniformly overexpressed in DSRCT, have largely failed in clinical trials. As in cancer in general, interest in immunotherapy to treat DSRCT has increased in recent years. To that end, several types of immunotherapy are now being tested clinically, including monoclonal antibodies, radionuclide-conjugated antibodies, chimeric antigen receptor T cells, checkpoint inhibitors, and bispecific antibodies (BsAbs). These types of therapies may be particularly useful in DSRCT, which is frequently characterized by widespread intraperitoneal implants, which are difficult to completely remove surgically and are the frequent cause of relapse. Successful treatment with immunotherapy or radioimmunotherapy following debulking surgery could eradiate these micrometasteses and prevent relapse. Although there has been limited success to date for immunotherapy in pediatric solid tumors, the significant improvements in survival seen in the treatment of other pediatric solid tumors, such as metastatic neuroblastoma and its CNS spread, suggest a potential of immunotherapy and specifically compartmental immunotherapy in DSRCT.
Early Drug Discovery and Development of Novel Cancer Therapeutics Targeting DNA Polymerase Eta (POLH)
Authors: Wilson David M. , Duncton Matthew A. J. , Chang Caleb , Lee Luo Christie , Georgiadis Taxiarchis M. , Pellicena Patricia , Deacon Ashley M. , Gao Yang , Das Debanu
Published: November 2021

Polymerase eta (or Pol η or POLH) is a specialized DNA polymerase that is able to bypass certain blocking lesions, such as those generated by ultraviolet radiation (UVR) or cisplatin, and is deployed to replication foci for translesion synthesis as part of the DNA damage response (DDR). Inherited defects in the gene encoding POLH (a.k.a., XPV) are associated with the rare, sun-sensitive, cancer-prone disorder, xeroderma pigmentosum, owing to the enzyme’s ability to accurately bypass UVR-induced thymine dimers. In standard-of-care cancer therapies involving platinum-based clinical agents, e.g., cisplatin or oxaliplatin, POLH can bypass platinum-DNA adducts, negating benefits of the treatment and enabling drug resistance. POLH inhibition can sensitize cells to platinum-based chemotherapies, and the polymerase has also been implicated in resistance to nucleoside analogs, such as gemcitabine. POLH overexpression has been linked to the development of chemoresistance in several cancers, including lung, ovarian, and bladder. Co-inhibition of POLH and the ATR serine/threonine kinase, another DDR protein, causes synthetic lethality in a range of cancers, reinforcing that POLH is an emerging target for the development of novel oncology therapeutics. Using a fragment-based drug discovery approach in combination with an optimized crystallization screen, we have solved the first X-ray crystal structures of small novel drug-like compounds, i.e., fragments, bound to POLH, as starting points for the design of POLH inhibitors. The intrinsic molecular resolution afforded by the method can be quickly exploited in fragment growth and elaboration as well as analog scoping and scaffold hopping using medicinal and computational chemistry to advance hits to lead. An initial small round of medicinal chemistry has resulted in inhibitors with a range of functional activity in an in vitro biochemical assay, leading to the rapid identification of an inhibitor to advance to subsequent rounds of chemistry to generate a lead compound. Importantly, our chemical matter is different from the traditional nucleoside analog-based approaches for targeting DNA polymerases.
Second-Generation Dual Scan Mammoscope With Photoacoustic, Ultrasound, and Elastographic Imaging Capabilities
Authors: Zheng Emily , Zhang Huijuan , Goswami Soumya , Kabir Irteza Enan , Doyley Marvin M. , Xia Jun
Published: November 2021

We recently developed the photoacoustic dual-scan mammoscope (DSM), a system that images the patient in standing pose analog to X-ray mammography. The system simultaneously acquires three-dimensional photoacoustic and ultrasound (US) images of the mildly compressed breast. Here, we describe a second-generation DSM (DSM-2) system that offers a larger field of view, better system stability, higher ultrasound imaging quality, and the ability to quantify tissue mechanical properties. In the new system, we doubled the field of view through laterally shifted round-trip scanning. This new design allows coverage of the entire breast tissue. We also adapted precisely machined holders for the transducer-fiber bundle sets. The new holder increased the mechanical stability and facilitated image registration from the top and bottom scanners. The quality of the US image is improved by increasing the firing voltage and the number of firing angles. Finally, we incorporated quasi-static ultrasound elastography to allow comprehensive characterization of breast tissue. The performance of the new system was demonstrated through in vivo human imaging experiments. The experimental results confirmed the capability of the DSM-2 system as a powerful tool for breast imaging.
Ubiquitin-Specific Peptidase 7: A Novel Deubiquitinase That Regulates Protein Homeostasis and Cancers
Authors: Zhou Lin , Ouyang Taohui , Li Meihua , Hong Tao , MHS Alriashy , Meng Wei , Zhang Na
Published: November 2021

Ubiquitin-Specific Peptidase 7 (USP7), or herpes virus-associated protease (HAUSP), is the largest family of the deubiquitinating enzymes (DUBs). Recent studies have shown that USP7 plays a vital role in regulating various physiological and pathological processes. Dysregulation of these processes mediated by USP7 may contribute to many diseases, such as cancers. Moreover, USP7 with aberrant expression levels and abnormal activity are found in cancers. Therefore, given the association between USP7 and cancers, targeting USP7 could be considered as an attractive and potential therapeutic approach in cancer treatment. This review describes the functions of USP7 and the regulatory mechanisms of its expression and activity, aiming to emphasize the necessity of research on USP7, and provide a better understanding of USP7-related biological processes and cancer.
Case Report: Fatal Neurotoxicity Following Resmethrin Poisoning in a Child
Authors: Huang Lilin , Peng Shumei , Li Ronghan , Huang Dongping , Xie Danyu
Published: November 2021

Resmethrin, a type I pyrethroid insecticide, can activate sodium channels, causing neurotoxicity in both mammals and insects. Possible routes of poisoning include inhalation, dermal contact and ingestion. There are no specific symptoms for resmethrin poisoning. Until now, no antidote has been available for resmethrin. Resmethrin poisoning is rarely reported in children. Here, we report a fatal case of resmethrin poisoning that might have been caused by accidental ingestion by a 26-month-old child. He presented with neurotoxic symptoms that included vomiting, recurrent seizures, and coma. The cranial CT showed extensive lesions of low intensity in the bilateral white matter, thalamus, brainstem, and cerebellum. Lumbar punctures showed increased intracranial pressure (ICP > 25 mmHg). Cerebrospinal fluid (CSF) tests revealed that protein was elevated to 289.2 mg/dL without pleocytosis. Resmethrin was detected in his blood by liquid chromatography-mass spectrometry, which confirmed the diagnosis of resmethrin poisoning. The child developed brain stem herniation and then was declared brain dead at the 77th h after admission. Resmethrin poisoning can be fatal, and it requires immediate diagnosis and treatment. Previous studies reported that cranial CT and CSF analyses were all normal in patients with pyrethroid poisoning. This case might extend the knowledge of neuroimaging and CSF analysis in children with resmethrin poisoning.
Effect of Angiotensin–Neprilysin Versus Renin–Angiotensin System Inhibition on Renal Outcomes: A Systematic Review and Meta-Analysis
Authors: Xu Ying , Chen Yang , Zhao Jia Wei , Li Chao , Wang Amanda Y
Published: November 2021

Aims: We aim to perform a systematic review and meta-analysis examining randomized controlled trials assessing the efficacy and safety of sacubitril/valsartan in patients on renal outcomes, in comparison with the renin–angiotensin–aldosterone system inhibitor (RAASi).

Methods: Eligible studies were retrieved on MEDLINE, EMBASE, and Cochrane until September 2021. The primary outcome was the incidence of renal impairment, which was defined as the composite of increases in serum creatinine by >0.3 mg/dl and/or a reduction in eGFR ≥25%, development of ESRD, or renal death. We pooled relative risks (RRs) with 95% confidence intervals (CIs) or the mean difference with 95% CIs for the variables.

Results: Our search yielded 10 randomized controlled trials with a total of 18,362 patients. Compared with RAASi treatment, patients treated with sacubitril/valsartan had lower incidence of composite renal impairment (10 studies, 18,362 patients, RR 0.84; 95% CI 0.72–0.96, p = 0.01; I2 = 22%), ESRD development (3 studies, 13,609 patients, RR 0.53; 95% CI 0.30–0.96, p = 0.03; I2 = 0%), drug discontinuation due to renal events (4 studies, 9,995 patients, RR 0.58; 95% CI 0.40–0.83, p = 0.003; I2 = 47%), severe hyperkalemia (6 studies, 16,653 patients, RR 0.80; 95% CI 0.68–0.93, p = 0.01; I2 = 25%) and a slower eGFR decline (4 studies, 13,608 patients, WMD 0.56; 95% CI 0.36–0.76, p < 0.00001; I2 = 65%). Subgroup analysis demonstrated that sacubitril/valsartan was associated with a lower incidence of renal impairment in patients with heart failure and preserved ejection fraction (HFpEF), but not in those with heart failure and reduced ejection fraction (HFrEF). The superior renal function preservation of sacubitril/valsartan treatment was not associated with different baseline eGFR levels and follow-up duration. There was a smaller increase in the change in the urine albumin-to-creatinine ratio (UACR) (3 studies, 9,114 patients, SMD 0.06; 95% CI 0.02–0.10, p = 0.003; I2 = 14%) with sacubitril/valsartan treatment. However, patients with heart failure appeared to have increased microalbuminuria, not patients without HF (p = 0.80 for interaction).

Conclusion: Sacubitril/valsartan was associated with a lower incidence of composite renal impairment especially in patients with HFpEF, but higher microalbuminuria in patients with heart failure (both HFrEF and HFpEF) compared with RAASi. The lower incidence of severe hyperkalemia and drug discontinuation due to renal events in patients with sacubitril/valsartan treatment demonstrated its superior safety compared with RAASi.
A Novel ELISA-Based Peptide Biosensor Assay for Screening ABL1 Activity in vitro: A Challenge for Precision Therapy in BCR-ABL1 and BCR-ABL1 Like Leukemias
Authors: Montecchini Oksana , Braidotti Stefania , Franca Raffaella , Zudeh Giulia , Boni Christian , Sorio Claudio , Toffoletti Eleonora , Rabusin Marco , Tommasini Alberto , Decorti Giuliana , Stocco Gabriele
Published: November 2021

The pathogenic role of the overactivated ABL1 tyrosine kinase (TK) pathway is well recognized in some forms of BCR-ABL1 like acute lymphoblastic leukemia (ALL); TK inhibitors represent a useful therapeutic choice in these patients who respond poorly to conventional chemotherapy. Here we report a novel peptide biosensor (PABL)-ELISA assay to investigate ABL1 activity in four immortalized leukemic cell lines with different genetic background. The PABL sequence comprises an ABL1 tyrosine (Y) phosphorylation site and a targeting sequence that increases the specificity for ABL1; additional peptides (Y-site-mutated (PABL-F) and fully-phosphorylated (PPHOSPHO-ABL) biosensors) were included in the assay. After incubation with whole cell lysates, average PABL phosphorylation was significantly increased (basal vs. PABL phosphorylation: 6.84 ± 1.46% vs. 32.44 ± 3.25%, p-value < 0.0001, two-way ANOVA, Bonferroni post-test, percentages relative to PPHOSPHO-ABL in each cell line). Cell lines expressing ABL1-chimeric proteins (K562, ALL-SIL) presented the higher TK activity on PABL; a lower signal was instead observed for NALM6 and REH (p < 0.001 and p < 0.05 vs. K562, respectively). Phosphorylation was ABL1-mediated, as demonstrated by the specific inhibition of imatinib (p < 0.001 for K562, NALM6, ALL-SIL and p < 0.01 for REH) in contrast to ruxolitinib (JAK2-inhibitor), and occurred on the ABL1 Y-site, as demonstrated by PABL-F whose phosphorylation was comparable to basal levels. In order to validate this novel PABL-ELISA assay on leukemic cells isolated from patient’s bone marrow aspirates, preliminary analysis on blasts derived from an adult affected by chronic myeloid leukaemia (BCR-ABL1 positive) and a child affected by ALL (BCR-ABL1 negative) were performed. Phosphorylation of PABL was specifically inhibited after the incubation of BCR-ABL1 positive cell lysates with imatinib, but not with ruxolitinib. While requiring further optimization and validation in leukemic blasts to be of clinical interest, the PABL-based ELISA assay provides a novel in vitro tool for screening both the aberrant ABL1 activity in BCR-ABL1 like ALL leukemic cells and their potential response to TK inhibitors.
Network Pharmacology and Molecular Docking–Based Investigation: Prunus mume Against Colorectal Cancer via Silencing RelA Expression
Authors: Zhou Minfeng , Li Jinxiao , Luo Dan , Zhang Haiming , Yu Zhaomin , Chen Youlin , Li Qiumeng , Liang Fengxia , Chen Rui
Published: November 2021

Colorectal cancer (CRC) is one of the most pervasive cancers in the human disease spectrum worldwide, ranked the second most common cause of cancer death by the end of 2020. Prunus mume (PM) is an essential traditional Chinese medicine for the adjuvant treatment of solid tumors, including CRC. In the current study, we utilize means of network pharmacology, molecular docking, and multilayer experimental verification to research mechanism. The five bioactive compounds and a total of eight critical differentially expressed genes are screened out using the bioinformatics approaches of Cytoscape software, String database, Gene Ontology analysis, Kyoto Encyclopedia of Genes and Genomes pathways, and molecular docking. RelA has been proven to be highly expressed in CRC. Experiments in vitro have shown that kaempferol, the main active component of PM, dramatically inhibited the growth, migration, and invasion of CRC cells, and experiments in vivo have shown that PM effectively delays CRC formation and improves the survival cycle of mice. Further analysis shows that PM inhibits the CRC progression by down-regulating the expression level of RelA, Bax, caspase 3, caspase 9, and EGFR in CRC. PM and its extract are potentially effective therapeutics for the treatment of CRC via the RelA/nuclear factor κB signaling pathway.