bluuebunny/crossref_metadata_2025 huggingface dataset:
STAT3 and IL-6 Contribute to Corticosteroid Resistance in an OVA and Ozone-induced Asthma Model with Neutrophil Infiltration
Authors: Xue Yishu , Zhou Yan , Bao Wuping , Fu Qiang , Hao Huijuan , Han Lei , Zhang Xue , Tian Xue , Zhang Min
Published: October 2021

Exposure to high levels of ozone contributes to insensitivity to glucocorticoids in asthma treatment, but the underlying mechanisms are not known. We built two asthma models: a “T2-high” asthma model was established by ovalbumin (OVA) sensitization/challenge and OVA sensitization/challenge combined with ozone exposure (OVA + ozone) was used to induce airway inflammation with increased numbers of neutrophils to simulate “T2-low” asthma. The expression of T-helper (Th)1/2/17-related cytokines was measured by cytokine antibody arrays. Bronchial provocation tests were carried out to evaluate the lung resistance of mice. Hematoxylin and eosin staining, periodic acid-Schiff staining, and immunohistochemical (IHC) analyses of alpha-smooth muscle actin were undertaken to observe morphology changes in lungs. The expression of glucocorticoid receptors (GRs) and phosphorylated-GR (p-GR) was measured by western blotting. Nr3c1 mRNA was quantified by RT-qPCR. Protein expression of proinflammatory cytokines, signal transducer and activator of transcription 3 (STAT3), suppressor of cytokine signaling 3 (SOCS3), and CXCL1 was measured through ELISAs, western blotting, or IHC analyses. Resected lung tissue from seven asthma patients and 10 healthy controls undergoing thoracotomy for pulmonary nodules was evaluated by IHC analyses and ELISAs. In both asthma models, mucus hypersecretion, as well as inflammation, hyperresponsiveness, and remodeling of the airways, was present compared with the control group, whereas the OVA + ozone group showed severe neutrophil infiltration. The expression of Th17-related cytokines (interleukin (IL)-6, IL-17A, IL-21), GR protein, and CXCL1 increased in the OVA + ozone group, whereas the expression of p-GR decreased. Dexamethasone (Dex) could not totally reverse the expression of p-GR and histone deacetylase-2 in the OVA + ozone group. STAT3 expression increased in the OVA + ozone group and could not be completely reversed by Dex, and nor could IL-6 expression. A positive correlation between IL-6 or IL-17A and STAT3 and negative correlation between SOCS3 and STAT3 were shown, suggesting that the IL-6/STAT3 pathway may be involved in OVA + ozone–induced corticosteroid-resistant airway inflammation. In clinical samples, IL-17A expression in lung tissue was positively correlated with percent STAT3-positive area and negatively correlated with SOCS3 expression. The IL-6/STAT3 pathway may contribute to corticosteroid insensitivity in OVA + ozone–induced neutrophilic airway inflammation through regulation of Th17 cells and could provide new targets for individual treatment of corticosteroid resistance in asthma.
Progression of Fatigue in Early Parkinson’s Disease: A 3-Year Prospective Cohort Study
Authors: Ou Ruwei , Hou Yanbing , Liu Kuncheng , Lin Junyu , Jiang Zheng , Wei Qianqian , Zhang Lingyu , Cao Bei , Zhao Bi , Song Wei , Shang Huifang
Published: October 2021

Objective: To explore the frequency, evolution, associated factors, and risk factors of fatigue over 3-year of prospective follow-up in a cohort of patients with early Parkinson’s disease (PD).

Methods: A total of 174 PD patients in the early stage were enrolled and quantitively assessed motor and non-motor symptoms using comprehensive scales including the Fatigue Severity Scale (FSS) annually. Each subject was categorized as PD with and without fatigue based on a cut-off mean value of 4 using FSS. The generalized estimating equation (GEE) was utilized to investigate the associated factors, and the stepwise binary logistic regression model was performed to explore the predictors.

Results: The frequency of fatigue was slightly changed (ranging from 35.1 to 40.4%) during the 3-year follow-up. The changed pattern of the frequency of fatigue was similar to that of anxiety. Fatigue was significantly associated with nocturnal sleep disorders (B 2.446, P < 0.001), high Hamilton Anxiety Rating Scale (HAMA) score (B 1.072, P = 0.011), and high Unified PD Rating Scale (UPDRS) III score (B 1.029, P = 0.003) over time. High UPDRS III score [odds ratio (OR) 1.051, P = 0.015] at baseline increased the risk of developing fatigue after 1-year; high LEDD (OR 1.002, P = 0.037) increased the risk of developing fatigue after 2-year; and high LEDD (OR 1.003, P = 0.049) and high HAMA score (OR 1.077, P = 0.042) increased the risk of developing fatigue after 3-year.

Conclusion: Our present study provided evidence of the longitudinal evolution of fatigue in patients with early PD and help clinical management of fatigue.
Phyto-fabricated Nanoparticles and Their Anti-biofilm Activity: Progress and Current Status
Authors: Das Puja , Ghosh Sayantan , Nayak Bismita
Published: October 2021

Biofilm is the self-synthesized, mucus-like extracellular polymeric matrix that acts as a key virulence factor in various pathogenic microorganisms, thereby posing a serious threat to human health. It has been estimated that around 80% of hospital-acquired infections are associated with biofilms which are found to be present on both biotic and abiotic surfaces. Antibiotics, the current mainstream treatment strategy for biofilms are often found to be futile in the eradication of these complex structures, and to date, there is no effective therapeutic strategy established against biofilm infections. In this regard, nanotechnology can provide a potential platform for the alleviation of this problem owing to its unique size-dependent properties. Accordingly, various novel strategies are being developed for the synthesis of different types of nanoparticles. Bio-nanotechnology is a division of nanotechnology which is gaining significant attention due to its ability to synthesize nanoparticles of various compositions and sizes using biotic sources. It utilizes the rich biodiversity of various biological components which are biocompatible for the synthesis of nanoparticles. Additionally, the biogenic nanoparticles are eco-friendly, cost-effective, and relatively less toxic when compared to chemically or physically synthesized alternatives. Biogenic synthesis of nanoparticles is a bottom-top methodology in which the nanoparticles are formed due to the presence of biological components (plant extract and microbial enzymes) which act as stabilizing and reducing agents. These biosynthesized nanoparticles exhibit anti-biofilm activityviavarious mechanisms such as ROS production, inhibiting quorum sensing, inhibiting EPS production, etc. This review will provide an insight into the application of various biogenic sources for nanoparticle synthesis. Furthermore, we have highlighted the potential of phytosynthesized nanoparticles as a promising antibiofilm agent as well as elucidated their antibacterial and antibiofilm mechanism.
Dopaminergic and Cholinergic Modulation of Large Scale Networks in silico Using Snudda
Authors: Frost Nylen Johanna , Hjorth Jarl Jacob Johannes , Grillner Sten , Hellgren Kotaleski Jeanette
Published: October 2021

Neuromodulation is present throughout the nervous system and serves a critical role for circuit function and dynamics. The computational investigations of neuromodulation in large scale networks require supportive software platforms. Snudda is a software for the creation and simulation of large scale networks of detailed microcircuits consisting of multicompartmental neuron models. We have developed an extension to Snudda to incorporate neuromodulation in large scale simulations. The extended Snudda framework implements neuromodulation at the level of single cells incorporated into large-scale microcircuits. We also developed Neuromodcell, a software for optimizing neuromodulation in detailed multicompartmental neuron models. The software adds parameters within the models modulating the conductances of ion channels and ionotropic receptors. Bath application of neuromodulators is simulated and models which reproduce the experimentally measured effects are selected. In Snudda, we developed an extension to accommodate large scale simulations of neuromodulation. The simulator has two modes of simulation – denoted replay and adaptive. In the replay mode, transient levels of neuromodulators can be defined as a time-varying function which modulates the receptors and ion channels within the network in a cell-type specific manner. In the adaptive mode, spiking neuromodulatory neurons are connected via integrative modulating mechanisms to ion channels and receptors. Both modes of simulating neuromodulation allow for simultaneous modulation by several neuromodulators that can interact dynamically with each other. Here, we used the Neuromodcell software to simulate dopaminergic and muscarinic modulation of neurons from the striatum. We also demonstrate how to simulate different neuromodulatory states with dopamine and acetylcholine using Snudda. All software is freely available on Github, including tutorials on Neuromodcell and Snudda-neuromodulation.
Human Tau Isoforms and Proteolysis for Production of Toxic Tau Fragments in Neurodegeneration
Authors: Boyarko Ben , Hook Vivian
Published: October 2021

The human tau protein is implicated in a wide range of neurodegenerative “tauopathy” diseases, consisting of Alzheimer’s disease (AD) and frontotemporal lobar degeneration which includes progressive supranuclear palsy, corticobasal degeneration, Pick’s disease, and FTLD-tau (frontotemporal dementia with parkinsonism caused by MAPT mutations). Tau gene transcripts in the human brain undergo alternative splicing to yield 6 different tau protein isoforms that are expressed in different ratios in neurodegeneration which result in tau pathology of paired-helical filaments, neurofibrillary tangles, and tau fibrillar aggregates with detrimental microtubule destabilization. Protease-mediated tau truncation is an important post-translational modification (PTM) which drives neurodegeneration in a tau fragment-dependent manner. While numerous tau fragments have been identified, knowledge of the proteolytic steps that convert each parent tau isoform into specific truncated tau fragments has not yet been fully defined. An improved understanding of the relationships between tau isoforms and their proteolytic processing to generate neurotoxic tau fragments is important to the field. This review evaluates tau isoform expression patterns including PTMs and mutations that influence proteolysis of tau to generate toxic fragments that drive cognitive deficits in AD and other tauopathy models. This assessment identifies the gap in the field on understanding the details of proteolytic steps used to convert each tau isoform into fragments. Knowledge of the processing mechanisms of tau isoforms can lead to new protease targeted drug strategies to prevent the formation of toxic tau fragments in tauopathy neurodegenerative diseases.
Identification of Autism Spectrum Disorder With Functional Graph Discriminative Network
Authors: Li Jingcong , Wang Fei , Pan Jiahui , Wen Zhenfu
Published: October 2021

Autism spectrum disorder (ASD) is a specific brain disease that causes communication impairments and restricted interests. Functional connectivity analysis methodology is widely used in neuroscience research and shows much potential in discriminating ASD patients from healthy controls. However, due to heterogeneity of ASD patients, the performance of conventional functional connectivity classification methods is relatively poor. Graph neural network is an effective graph representation method to model structured data like functional connectivity. In this paper, we proposed a functional graph discriminative network (FGDN) for ASD classification. On the basis of pre-built graph templates, the proposed FGDN is able to effectively distinguish ASD patient from health controls. Moreover, we studied the size of training set for effective training, inter-site predictions, and discriminative brain regions. Discriminative brain regions were determined by the proposed model to investigate its applicability and biomarkers for ASD identification. For functional connectivity classification and analysis, FGDN is not only an effective tool for ASD identification but also a potential technique in neuroscience research.
The Role of Bacterial-Derived Aromatic Amino Acids Metabolites Relevant in Autism Spectrum Disorders: A Comprehensive Review
Authors: Zheng Yuanpeng , Bek Marie K. , Prince Naika Z. , Peralta Marzal Lucia N. , Garssen Johan , Perez Pardo Paula , Kraneveld Aletta D.
Published: October 2021

In recent years, the idea of the gut microbiota being involved in the pathogenesis of autism spectrum disorders (ASD) has attracted attention through numerous studies. Many of these studies report microbial dysregulation in the gut and feces of autistic patients and in ASD animal models. The host microbiota plays a large role in metabolism of ingested foods, and through the production of a range of metabolites it may be involved in neurodevelopmental disorders such as ASD. Two specific microbiota-derived host metabolites, p-cresol sulfate and 4-ethylphenyl sulfate, have been associated with ASD in both patients and animal models. These metabolites originate from bacterially produced p-cresol and 4-ethylphenol, respectively. p-Cresol and 4-ethylphenol are produced through aromatic amino acid fermentation by a range of commensal bacteria, most notably bacteria from the Clostridioides genus, which are among the dysregulated bacteria frequently detected in ASD patients. Once produced, these metabolites are suggested to enter the bloodstream, pass the blood–brain-barrier and affect microglial cells in the central nervous system, possibly affecting processes like neuroinflammation and microglial phagocytosis. This review describes the current knowledge of microbial dysbiosis in ASD and elaborates on the relevance and synthesis pathways of two specific ASD-associated metabolites that may form a link between the microbiota and the brain in autism. While the two discussed metabolites are promising candidates for biomarkers and (nutritional) intervention targets, more research into the role of these metabolites in ASD is required to causally connect these metabolites to ASD pathophysiology.
The Immediate and Short-Term Effects of Transcutaneous Spinal Cord Stimulation and Peripheral Nerve Stimulation on Corticospinal Excitability
Authors: Al’joboori Yazi , Hannah Ricci , Lenham Francesca , Borgas Pia , Kremers Charlotte J. P. , Bunday Karen L. , Rothwell John , Duffell Lynsey D.
Published: October 2021

Rehabilitative interventions involving electrical stimulation show promise for neuroplastic recovery in people living with Spinal Cord Injury (SCI). However, the understanding of how stimulation interacts with descending and spinal excitability remain unclear. In this study we compared the immediate and short-term (within a few minutes) effects of pairing Transcranial Magnetic Stimulation (TMS) with transcutaneous Spinal Cord stimulation (tSCS) and Peripheral Nerve Stimulation (PNS) on Corticospinal excitability in healthy subjects. Three separate experimental conditions were assessed. In Experiment I, paired associative stimulation (PAS) was applied, involving repeated pairing of single pulses of TMS and tSCS, either arriving simultaneously at the spinal motoneurones (PAS0ms) or slightly delayed (PAS5ms). Corticospinal and spinal excitability, and motor performance, were assessed before and after the PAS interventions in 24 subjects. Experiment II compared the immediate effects of tSCS and PNS on corticospinal excitability in 20 subjects. Experiment III compared the immediate effects of tSCS with tSCS delivered at the same stimulation amplitude but modulated with a carrier frequency (in the kHz range) on corticospinal excitability in 10 subjects. Electromyography (EMG) electrodes were placed over the Tibialis Anterior (TA) soleus (SOL) and vastus medialis (VM) muscles and stimulation electrodes (cathodes) were placed on the lumbar spine (tSCS) and lateral to the popliteal fossa (PNS). TMS over the primary motor cortex (M1) was paired with tSCS or PNS to produce Motor Evoked Potentials (MEPs) in the TA and SOL muscles. Simultaneous delivery of repetitive PAS (PAS0ms) increased corticospinal excitability and H-reflex amplitude at least 5 min after the intervention, and dorsiflexion force was increased in a force-matching task. When comparing effects on descending excitability between tSCS and PNS, a subsequent facilitation in MEPs was observed following tSCS at 30-50 ms which was not present following PNS. To a lesser extent this facilitatory effect was also observed with HF- tSCS at subthreshold currents. Here we have shown that repeated pairing of TMS and tSCS can increase corticospinal excitability when timed to arrive simultaneously at the alpha-motoneurone and can influence functional motor output. These results may be useful in optimizing stimulation parameters for neuroplasticity in people living with SCI.
Mitochondrial Extracellular Vesicles – Origins and Roles
Authors: Amari Lydia , Germain Marc
Published: October 2021

Extracellular vesicles (EVs) have emerged in the last decade as critical cell-to-cell communication devices used to carry nucleic acids and proteins between cells. EV cargo includes plasma membrane and endosomal proteins, but EVs also contain material from other cellular compartments, including mitochondria. Within cells, mitochondria are responsible for a large range of metabolic reactions, but they can also produce damaging levels of reactive oxygen species and induce inflammation when damaged. Consistent with this, recent evidence suggests that EV-mediated transfer of mitochondrial content alters metabolic and inflammatory responses of recipient cells. As EV mitochondrial content is also altered in some pathologies, this could have important implications for their diagnosis and treatment. In this review, we will discuss the nature and roles of mitochondrial EVs, with a special emphasis on the nervous system.
Joint Effects of Carbon Black Exposure and Dietary Antioxidant Vitamin Intake on Small Airway Dysfunction
Authors: Wang Tao , Li Jianyu , Liang Yi , Han Wei , Tang Jinglong , Cheng Guo , Zheng Yuxin
Published: October 2021

Objectives: Small airway dysfunction is considered as a precursor of chronic obstructive pulmonary disease and asthma. Our aim was to explore the joint effects of carbon black (CB) exposure and antioxidant vitamin intake on small airway dysfunction.

Methods: A total of 70 CB packers (CBPs) and 107 non-CBPs were enrolled from an established cohort of CBP. Carbon content in airway macrophage (CCAM) quantified in induced sputum was used as a bio-effective dosimetry for exposure to CB. Logistic regression models were used to examine the odds ratios (ORs) of CB and dietary intake of antioxidant vitamins on small airway dysfunction, and the dose–response association.

Results: The prevalence of small airway dysfunction was 32.9% (23 of 70) among CBPs, and 19.6% (21 of 107) among non-CBPs. For each 2.72-fold increase in CCAM, the OR of small airway dysfunction was 2.31 (95% CI = 1.20–4.44). For every 10 mg day−1 increase of the vitamin C intake, the risk of small airway dysfunction decreased by 6% (OR = 0.94, 95% CI = 0.88–0.99). Compared to non-CB exposure and higher vitamin C intake, CB exposure and lower vitamin C intake (OR = 7.56, 95% CI = 1.80 to 31.81) were associated with an increased risk of small airway dysfunction.

Conclusions: Chronic exposure to a high level of CB aerosol increased the risk of small airway dysfunction in CB baggers. Dietary intake of vitamin C might be a modifiable factor for preventing small airway dysfunction.
Impact of Sarcopenia on Survival and Clinical Outcomes in Patients With Liver Cirrhosis
Authors: Topan Mirabela-Madalina , Sporea Ioan , Dănilă Mirela , Popescu Alina , Ghiuchici Ana-Maria , Lupuşoru Raluca , Şirli Roxana
Published: October 2021

Background: Sarcopenia is now recognized more and more as a biomarker with poor outcomes in cirrhotic patients.

Aims: The purpose of this study was to investigate the prevalence of sarcopenia in patients with liver cirrhosis and prospectively investigate the association between sarcopenia and different complications and its impact on survival.

Material and Methods: This prospective study included patients with liver cirrhosis admitted to our department from 2018 to 2020. Sarcopenia was assessed according to EWGSOP2 criteria, incorporating low Handgrip strength (<27 kg for men and <16 kg for women) with low skeletal muscle index evaluated by CT (<50 for men and <39 for women). Associations between sarcopenia and portal hypertension-related complications, infectious complications, and risk of hepatocellular carcinoma, the number of in-hospital days, 30-day readmission, and survival over the next 6 and 12 months were analyzed.

Results: A total of 201 patients were enrolled in the study, 63.2% male, mean age 61.65 ± 9.49 years, 79.6% Child-Pugh class B and C. The primary etiology of liver cirrhosis was alcohol consumption (55.2%). The prevalence of sarcopenia was 57.2 %, with no significant differences between the male and female groups. Significant associations were found between sarcopenia and portal hypertension-related complications, infectious complications, and risk of hepatocellular carcinoma. In multivariate analysis, sarcopenia was assessed as a risk factor alone, increasing the risk for ascites 3.78 times, hepatocellular carcinoma by 9.23 times, urinary tract infection by 4.83 times, and spontaneous peritonitis 2.49 times. Sarcopenia was associated with more extended hospital stay and higher 30 days readmission. Six months and 1-year survival were reduced in the sarcopenia group than in the non-sarcopenia group (p < 0.0001).

Conclusion: Sarcopenia is a common complication of liver cirrhosis and associates with adverse health-related outcomes and poor survival rates.
The Significance of SIX1 as a Prognostic Biomarker for Survival Outcome in Various Cancer Patients: A Systematic Review and Meta-Analysis
Authors: Zhu Guang , Liu Ying , Zhao Lei , Lin Zhenhua , Piao Yingshi
Published: October 2021

Sine Oculis Homeobox Homolog 1 (SIX1) is reported to promote cancer initiation and progression in many preclinical models and is demonstrated in human cancer tissues. However, the correlation between SIX1 and cancer patients’ prognosis has not yet been systematically evaluated. Therefore, we performed a systematic review and meta-analysis in various human cancer types and extracted some data from TCGA datasets for further verification and perfection. We constructed 27 studies and estimated the association between SIX1 expression in various cancer patients’ overall survival and verified with TCGA datasets. Twenty-seven studies with 4899 patients are include in the analysis of overall, and disease-free survival, most of them were retrospective. The pooled hazard ratios (HRs) for overall and disease-free survival in high SIX1 expression patients were 1.54 (95% CI: 1.32-1.80, P<0.00001) and 1.83 (95% CI: 1.31-2.55, P=0.0004) respectively. On subgroup analysis classified in cancer type, high SIX1 expression was associated with poor overall survival in patients with hepatocellular carcinoma (HR 1.50; 95% CI: 1.17-1.93, P =0.001), breast cancer (HR 1.31; 95% CI: 1.10-1.55, P =0.002) and esophageal squamous cell carcinoma (HR 1.89; 95% CI: 1.42-2.52, P<0.0001). Next, we utilized TCGA online datasets, and the consistent results were verified in various cancer types. SIX1 expression indicated its potential to serve as a cancer biomarker and deliver prognostic information in various cancer patients. More works still need to improve the understandings of SIX1 expression and prognosis in different cancer types.
Prediction of Breast Cancer Recurrence Using a Deep Convolutional Neural Network Without Region-of-Interest Labeling
Authors: Phan Nam Nhut , Hsu Chih-Yi , Huang Chi-Cheng , Tseng Ling-Ming , Chuang Eric Y.
Published: October 2021

Purpose

The present study aimed to assign a risk score for breast cancer recurrence based on pathological whole slide images (WSIs) using a deep learning model.

Methods

A total of 233 WSIs from 138 breast cancer patients were assigned either a low-risk or a high-risk score based on a 70-gene signature. These images were processed into patches of 512x512 pixels by the PyHIST tool and underwent color normalization using the Macenko method. Afterward, out of focus and pixelated patches were removed using the Laplacian algorithm. Finally, the remaining patches (n=294,562) were split into 3 parts for model training (50%), validation (7%) and testing (43%). We used 6 pretrained models for transfer learning and evaluated their performance using accuracy, precision, recall, F1 score, confusion matrix, and AUC. Additionally, to demonstrate the robustness of the final model and its generalization capacity, the testing set was used for model evaluation. Finally, the GRAD-CAM algorithm was used for model visualization.

Results

Six models, namely VGG16, ResNet50, ResNet101, Inception_ResNet, EfficientB5, and Xception, achieved high performance in the validation set with an overall accuracy of 0.84, 0.85, 0.83, 0.84, 0.87, and 0.91, respectively. We selected Xception for assessment of the testing set, and this model achieved an overall accuracy of 0.87 with a patch-wise approach and 0.90 and 1.00 with a patient-wise approach for high-risk and low-risk groups, respectively.

Conclusions

Our study demonstrated the feasibility and high performance of artificial intelligence models trained without region-of-interest labeling for predicting cancer recurrence based on a 70-gene signature risk score.
Predictive Value of Multiparametric MRI for Response to Single-Cycle Induction Chemo-Immunotherapy in Locally Advanced Head and Neck Squamous Cell Carcinoma
Authors: Hellwig Konstantin , Ellmann Stephan , Eckstein Markus , Wiesmueller Marco , Rutzner Sandra , Semrau Sabine , Frey Benjamin , Gaipl Udo S. , Gostian Antoniu Oreste , Hartmann Arndt , Iro Heinrich , Fietkau Rainer , Uder Michael , Hecht Markus , Bäuerle Tobias
Published: October 2021

Objectives

To assess the predictive value of multiparametric MRI for treatment response evaluation of induction chemo-immunotherapy in locally advanced head and neck squamous cell carcinoma.

Methods

Twenty-two patients with locally advanced, histologically confirmed head and neck squamous cell carcinoma who were enrolled in the prospective multicenter phase II CheckRad-CD8 trial were included in the current analysis. In this unplanned secondary single-center analysis, all patients who received contrast-enhanced MRI at baseline and in week 4 after single-cycle induction therapy with cisplatin/docetaxel combined with the immune checkpoint inhibitors tremelimumab and durvalumab were included. In week 4, endoscopy with representative re-biopsy was performed to assess tumor response. All lesions were segmented in the baseline and restaging multiparametric MRI, including the primary tumor and lymph node metastases. The volume of interest of the respective lesions was volumetrically measured, and time-resolved mean intensities of the golden-angle radial sparse parallel-volume-interpolated gradient-echo perfusion (GRASP-VIBE) sequence were extracted. Additional quantitative parameters including the T1 ratio, short-TI inversion recovery ratio, apparent diffusion coefficient, and dynamic contrast-enhanced (DCE) values were measured. A model based on parallel random forests incorporating the MRI parameters from the baseline MRI was used to predict tumor response to therapy. Receiver operating characteristic (ROC) curves were used to evaluate the prognostic performance.

Results

Fifteen patients (68.2%) showed pathologic complete response in the re-biopsy, while seven patients had a residual tumor (31.8%). In all patients, the MRI-based primary tumor volume was significantly lower after treatment. The baseline DCE parameters of time to peak and wash-out were significantly different between the pathologic complete response group and the residual tumor group (p < 0.05). The developed model, based on parallel random forests and DCE parameters, was able to predict therapy response with a sensitivity of 78.7% (95% CI 71.24–84.93) and a specificity of 78.6% (95% CI 67.13–87.48). The model had an area under the ROC curve of 0.866 (95% CI 0.819–0.914).

Conclusions

DCE parameters indicated treatment response at follow-up, and a random forest machine learning algorithm based on DCE parameters was able to predict treatment response to induction chemo-immunotherapy.
Association of Myometrial Invasion With Lymphovascular Space Invasion, Lymph Node Metastasis, Recurrence, and Overall Survival in Endometrial Cancer: A Meta-Analysis of 79 Studies With 68,870 Patients
Authors: Wang Jianzhang , Xu Ping , Yang Xueying , Yu Qin , Xu Xinxin , Zou Gen , Zhang Xinmei
Published: October 2021

Background

Myometrial invasion has been demonstrated to correlate to clinicopathological characteristics and prognosis in endometrial cancer. However, not all the studies have the consistent results and no meta-analysis has investigated the association of myometrial invasion with lymphovascular space invasion (LVSI), lymph node metastasis (LNM), recurrence, and overall survival (OS). Therefore, a meta-analysis was performed to evaluate the relationship between myometrial invasion and clinicopathological characteristics or overall survival in endometrial cancer.

Materials and Methods

A search of Pubmed, Embase, and Web of Science was carried out to collect relevant studies from their inception until June 30, 2021. The quality of each included study was evaluated using Newcastle–Ottawa scale (NOS) scale. Review Manager version 5.4 was employed to conduct the meta-analysis.

Results

A total of 79 articles with 68,870 endometrial cancer patients were eligible including 9 articles for LVSI, 29 articles for LNM, 8 for recurrence, and 37 for OS in this meta-analysis. Myometrial invasion was associated with LVSI (RR 3.07; 95% CI 2.17–4.35; p < 0.00001), lymph node metastasis (LNM) (RR 4.45; 95% CI 3.29–6.01; p < 0.00001), and recurrence (RR 2.06; 95% CI 1.58–2.69; p < 0.00001). Deep myometrial invasion was also significantly related with poor OS via meta-synthesis of HRs in both univariate survival (HR 3.36, 95% CI 2.35–4.79, p < 0.00001) and multivariate survival (HR 2.00, 95% CI 1.59–2.53, p < 0.00001). Funnel plot suggested that there was no significant publication bias in this study.

Conclusion

Deep myometrial invasion correlated to positive LVSI, positive LNM, cancer recurrence, and poor OS for endometrial cancer patients, indicating that myometrial invasion was a useful evaluation criterion to associate with clinical outcomes and prognosis of endometrial cancer since depth of myometrial invasion can be assessed before surgery. The large scale and comprehensive meta-analysis suggested that we should pay more attention to myometrial invasion in clinical practice, and its underlying mechanism also deserves further investigation.
Multiparameter MRI Radiomics Model Predicts Preoperative Peritoneal Carcinomatosis in Ovarian Cancer
Authors: Yu Xiao Yu , Ren Jialiang , Jia Yushan , Wu Hui , Niu Guangming , Liu Aishi , Gao Yang , Hao Fene , Xie Lizhi
Published: October 2021

Objectives

To evaluate the predictive value of radiomics features based on multiparameter magnetic resonance imaging (MP-MRI) for peritoneal carcinomatosis (PC) in patients with ovarian cancer (OC).

Methods

A total of 86 patients with epithelial OC were included in this retrospective study. All patients underwent FS-T2WI, DWI, and DCE-MRI scans, followed by total hysterectomy plus omentectomy. Quantitative imaging features were extracted from preoperative FS-T2WI, DWI, and DCE-MRI images, and feature screening was performed using a minimum redundancy maximum correlation (mRMR) and least absolute shrinkage selection operator (LASSO) methods. Four radiomics models were constructed based on three MRI sequences. Then, combined with radiomics characteristics and clinicopathological risk factors, a multi-factor Logistic regression method was used to construct a radiomics nomogram, and the performance of the radiomics nomogram was evaluated by receiver operating characteristic curve (ROC) curve, calibration curve, and decision curve analysis.

Results

The radiomics model from the MP-MRI combined sequence showed a higher area under the curve (AUC) than the model from FS-T2WI, DWI, and DCE-MRI alone (0.846 vs. 0.762, 0.830, 0.807, respectively). The radiomics nomogram (AUC=0.902) constructed by combining radiomics characteristics and clinicopathological risk factors showed a better diagnostic effect than the clinical model (AUC=0.858) and the radiomics model (AUC=0.846). The decision curve analysis shows that the radiomics nomogram has good clinical application value, and the calibration curve also proves that it has good stability.

Conclusion

Radiomics nomogram based on MP-MRI combined sequence showed good predictive accuracy for PC in patients with OC. This tool can be used to identify peritoneal carcinomatosis in OC patients before surgery.
Breastfeeding Contributes to Physiological Immune Programming in the Newborn
Authors: Camacho-Morales Alberto , Caba Mario , García-Juárez Martín , Caba-Flores Mario Daniel , Viveros-Contreras Rubí , Martínez-Valenzuela Carmen
Published: October 2021

The first 1,000 days in the life of a human being are a vulnerable stage where early stimuli may program adverse health outcomes in future life. Proper maternal nutrition before and during pregnancy modulates the development of the fetus, a physiological process known as fetal programming. Defective programming promotes non-communicable chronic diseases in the newborn which might be prevented by postnatal interventions such as breastfeeding. Breast milk provides distinct bioactive molecules that contribute to immune maturation, organ development, and healthy microbial gut colonization, and also secures a proper immunological response that protects against infection and inflammation in the newborn. The gut microbiome provides the most critical immune microbial stimulation in the newborn in early life, allowing a well-trained immune system and efficient metabolic settings in healthy subjects. Conversely, negative fetal programming by exposing mothers to diets rich in fat and sugar has profound effects on breast milk composition and alters the immune profiles in the newborn. At this new stage, newborns become vulnerable to immune compromise, favoring susceptibility to defective microbial gut colonization and immune response. This review will focus on the importance of breastfeeding and its immunological biocomponents that allow physiological immune programming in the newborn. We will highlight the importance of immunological settings by breastfeeding, allowing proper microbial gut colonization in the newborn as a window of opportunity to secure effective immunological response.
Efficacy and Safety of Lipid-Lowering Drugs of Different Intensity on Clinical Outcomes: A Systematic Review and Network Meta-Analysis
Authors: Ma Wenrui , Pan Qinyuan , Pan Defeng , Xu Tongda , Zhu Hong , Li Dongye
Published: October 2021

There have been many meta-analyses for statins, ezetimibe and proprotein convertase subtilisin/kexin type 9 inhibitors (PCSK9i) to evaluate clinical outcomes, but the efficacy and safety of different intensity of these three drugs on clinical outcomes was absent. PCSK9i, ezetimibe, and statins were divided into seven interventions as follows: including PCSK9i + high-intensity statins (P9i+HT), PCSK9i + moderate-intensity statins (P9i+MT), ezetimibe + high-intensity statins (Eze+HT), ezetimibe + moderate-intensity statins (Eze+MT), high-intensity statins (HT), moderate-intensity statins (MT), and low-intensity statins (LT). The risk ratios (RR) and 95% confidence intervals (CI) were calculated to evaluate the clinical outcomes in all randomized controlled trials included. In traditional meta-analysis, the more intensive treatment had a lower risk of all-cause mortality (RR 0.91, 95% CI 0.88–0.95), cardiovascular mortality (RR 0.89, 95% CI 0.86–0.92), myocardial infarction (RR 0.79, 95% CI 0.77–0.81), coronary revascularization (RR 0.80, 95% CI 0.76-0.84), and cerebrovascular events (RR 0.84, 95% CI 0.80–0.88) compared with the less intensive treatment. However, the more intensive treatment had a higher risk of new-onset diabetes (RR 1.08, 95% CI 1.04-1.12). The network meta-analysis demonstrated that P9i+HT, P9i+MT, HT, and MT were significantly associated with a risk reduction in coronary revascularization and cerebrovascular events compared with PLBO. LT could effectively reduce the risk of cardiovascular mortality (RR 0.71, 95% CI 0.54–0.92), MI (RR 0.67, 95% CI 0.54-0.82), and coronary revascularization (RR 0.77, 95% CI 0.65–0.91) compared with PLBO. P9i+HT was superior to HT in reducing the risk of MI (RR 0.78, 95% CI 0.68–0.90), coronary revascularization (RR 0.84, 95% CI 0.73–0.96), and cerebrovascular events (RR 0.78, 95% CI 0.64–0.95). However, compared with PLBO, P9i+HT, HT, and MT could increase the risk of new-onset diabetes (RR 1.23, 95% CI 1.11–1.37; RR 1.23, 95% CI 1.14–1.33; RR 1.09, 95% CI 1.02–1.15, respectively). In conclusion, PCSK9i added to background statins may be recommended as preferred lipid-lowering therapy, and did not increase the additional risk of new-onset diabetes. The safety and efficacy of ezetimibe was not superior to that of statins. LT can be recommended as the initial therapy.
Block of Voltage-Gated Sodium Channels as a Potential Novel Anti-cancer Mechanism of TIC10
Authors: Fuchs Eva , Messerer David Alexander Christian , Karpel-Massler Georg , Fauler Michael , Zimmer Thomas , Jungwirth Bettina , Föhr Karl Josef
Published: October 2021

Background: Tumor therapeutics are aimed to affect tumor cells selectively while sparing healthy ones. For this purpose, a huge variety of different drugs are in use. Recently, also blockers of voltage-gated sodium channels (VGSCs) have been recognized to possess potentially beneficial effects in tumor therapy. As these channels are a frequent target of numerous drugs, we hypothesized that currently used tumor therapeutics might have the potential to block VGSCs in addition to their classical anti-cancer activity. In the present work, we have analyzed the imipridone TIC10, which belongs to a novel class of anti-cancer compounds, for its potency to interact with VGSCs.

Methods: Electrophysiological experiments were performed by means of the patch-clamp technique using heterologously expressed human heart muscle sodium channels (hNav1.5), which are among the most common subtypes of VGSCs occurring in tumor cells.

Results: TIC10 angular inhibited the hNav1.5 channel in a state- but not use-dependent manner. The affinity for the resting state was weak with an extrapolated Kr of about 600 μM. TIC10 most probably did not interact with fast inactivation. In protocols for slow inactivation, a half-maximal inhibition occurred around 2 µM. This observation was confirmed by kinetic studies indicating that the interaction occurred with a slow time constant. Furthermore, TIC10 also interacted with the open channel with an affinity of approximately 4 µM. The binding site for local anesthetics or a closely related site is suggested as a possible target as the affinity for the well-characterized F1760K mutant was reduced more than 20-fold compared to wild type. Among the analyzed derivatives, ONC212 was similarly effective as TIC10 angular, while TIC10 linear more selectively interacted with the different states.

Conclusion: The inhibition of VGSCs at low micromolar concentrations might add to the anti-tumor properties of TIC10.
Pharmacology of Natural Volatiles and Essential Oils in Food, Therapy, and Disease Prophylaxis
Authors: Sadgrove Nicholas John , Padilla-González Guillermo Federico , Leuner Olga , Melnikovova Ingrid , Fernandez-Cusimamani Eloy
Published: October 2021

This commentary critically examines the modern paradigm of natural volatiles in ‘medical aromatherapy’, first by explaining the semantics of natural volatiles in health, then by addressing chemophenetic challenges to authenticity or reproducibility, and finally by elaborating on pharmacokinetic and pharmacodynamic processes in food, therapy, and disease prophylaxis. Research over the last 50 years has generated substantial knowledge of the chemical diversity of volatiles, and their strengths and weaknesses as antimicrobial agents. However, due to modest in vitro outcomes, the emphasis has shifted toward the ability to synergise or potentiate non-volatile natural or pharmaceutical drugs, and to modulate gene expression by binding to the lipophilic domain of mammalian cell receptors. Because essential oils and natural volatiles are small and lipophilic, they demonstrate high skin penetrating abilities when suitably encapsulated, or if derived from a dietary item they bioaccumulate in fatty tissues in the body. In the skin or body, they may synergise or drive de novo therapeutic outcomes that range from anti-inflammatory effects through to insulin sensitisation, dermal rejuvenation, keratinocyte migration, upregulation of hair follicle bulb stem cells or complementation of anti-cancer therapies. Taking all this into consideration, volatile organic compounds should be examined as candidates for prophylaxis of cardiovascular disease. Considering the modern understanding of biology, the science of natural volatiles may need to be revisited in the context of health and nutrition.
Beyond the Chicken: Alternative Avian Models for Developmental Physiological Research
Authors: Flores-Santin Josele , Burggren Warren W.
Published: October 2021

Biomedical research focusing on physiological, morphological, behavioral, and other aspects of development has long depended upon the chicken (Gallus gallus domesticus) as a key animal model that is presumed to be typical of birds and generally applicable to mammals. Yet, the modern chicken in its many forms is the result of artificial selection more intense than almost any other domesticated animal. A consequence of great variation in genotype and phenotype is that some breeds have inherent aberrant physiological and morphological traits that may show up relatively early in development (e.g., hypertension, hyperglycemia, and limb defects in the broiler chickens). While such traits can be useful as models of specific diseases, this high degree of specialization can color general experimental results and affect their translational value. Against this background, in this review we first consider the characteristics that make an animal model attractive for developmental research (e.g., accessibility, ease of rearing, size, fecundity, development rates, genetic variation, etc.). We then explore opportunities presented by the embryo to adult continuum of alternative bird models, including quail, ratites, songbirds, birds of prey, and corvids. We conclude by indicating that expanding developmental studies beyond the chicken model to include additional avian groups will both validate the chicken model as well as potentially identify even more suitable avian models for answering questions applicable to both basic biology and the human condition.
Neuropeptide Bursicon Influences Reproductive Physiology in Tribolium Castaneum
Authors: Li Jingjing , Zhu Zidan , Bi Jingxiu , Feng Qili , Beerntsen Brenda T. , Song Qisheng
Published: October 2021

Bursicon is a neuropeptide belonging to the cystine knot family and is composed of burs and partner of burs (pburs) subunits. It can form heterodimers or homodimers to execute different biological functions. Bursicon heterodimers regulate cuticle sclerotization and wing maturation, whereas bursicon homodimers mediate innate immunity and midgut stem cell proliferation. A recent study has shown that bursicon potentially induces the expression of vitellogenin (Vg) in the black tiger shrimp Penaeus monodon; however, the underlying mechanism remains unknown. In this study, we investigated the role of bursicon in the reproductive physiology of the red flour beetle, Tribolium castaneum. The knockdown of burs, pburs, or its receptor T. castaneum rickets (Tcrk) in 2-day pupae significantly downregulated the expression levels of Vg1, Vg2, and Vg receptor (VgR) genes in females 3- and 5-day post-adult emergence, leading to abnormal oocytes with limited Vg content. The silencing of burs repressed the number of eggs laid and completely inhibited egg hatch, whereas the silencing of pburs dramatically decreased the number of eggs laid, hatch rate, and offspring larval size, and this RNA interference (RNAi) effects persisted to the next generation. Furthermore, the knockdown of burs or pburs downregulated the expression of the insulin/insulin-like signaling/target of rapamycin (TOR) signaling genes encoding insulin receptor (InR), protein kinase B (Akt), TOR, and ribosomal protein S6 kinase (S6K). Most importantly, the injection of recombinant pburs (r-pburs) protein was able to upregulate the expression of Vg, VgR, InR, Akt, TOR, S6K, JH synthesis (JHAMT), Methoprene-tolerant (Met), and Taiman (Tai) in normal females and rescue the expression of Vg and VgR in pburs RNAi females but failed to rescue Vg and VgR in Tcrk knockdown females. We infer that bursicon homodimers influence Vg expression via the receptor Tcrk, possibly by mediating the expression of the juvenile hormone (JH) and IIS/TOR pathway genes, thereby regulating reproduction in T. castaneum.
Coronary Large Conductance Ca2+-Activated K+ Channel Dysfunction in Diabetes Mellitus
Authors: Lu Tong , Lee Hon-Chi
Published: October 2021

Diabetes mellitus (DM) is an independent risk of macrovascular and microvascular complications, while cardiovascular diseases remain a leading cause of death in both men and women with diabetes. Large conductance Ca2+-activated K+ (BK) channels are abundantly expressed in arteries and are the key ionic determinant of vascular tone and organ perfusion. It is well established that the downregulation of vascular BK channel function with reduced BK channel protein expression and altered intrinsic BK channel biophysical properties is associated with diabetic vasculopathy. Recent efforts also showed that diabetes-associated changes in signaling pathways and transcriptional factors contribute to the downregulation of BK channel expression. This manuscript will review our current understandings on the molecular, physiological, and biophysical mechanisms that underlie coronary BK channelopathy in diabetes mellitus.
Human Sirtuin Regulators: The “Success” Stories
Authors: Curry Alyson M. , White Dawanna S. , Donu Dickson , Cen Yana
Published: October 2021

The human sirtuins are a group of NAD+-dependent protein deacylases. They “erase” acyl modifications from lysine residues in various cellular targets including histones, transcription factors, and metabolic enzymes. Through these far-reaching activities, sirtuins regulate a diverse array of biological processes ranging from gene transcription to energy metabolism. Human sirtuins have been intensely pursued by both academia and industry as therapeutic targets for a broad spectrum of diseases such as cancer, neurodegenerative diseases, and metabolic disorders. The last two decades have witnessed a flood of small molecule sirtuin regulators. However, there remain relatively few compounds targeting human sirtuins in clinical development. This reflects the inherent issues concerning the development of isoform-selective and potent molecules with good drug-like properties. In this article, small molecule sirtuin regulators that have advanced into clinical trials will be discussed in details as “successful” examples for future drug development. Special attention is given to the discovery of these compounds, the mechanism of action, pharmacokinetics analysis, formulation, as well as the clinical outcomes observed in the trials.