bluuebunny/crossref_metadata_2025 huggingface dataset:
Effect of Methionine Supplementation on Serum Metabolism and the Rumen Bacterial Community of Sika Deer (Cervus nippon)
Authors: Wu Yan , Guo Xiaolan , Zhao Dehui , Xu Chao , Sun Haoran , Yang Qianlong , Wei Qianqian , Si Huazhe , Wang Kaiying , Zhang Tietao
Published: August 2022

Methionine is the first or second limiting amino acid for ruminants, such as sika deer, and has a variety of biological functions such as antioxidant activity, immune response, and protein synthesis. This study aimed to investigate the effects of methionine supplementation on antler growth, serum biochemistry, rumen fermentation, and the bacterial community of sika deer during the antler-growing period. Twelve 4-year-old male sika deer were randomly assigned to three dietary groups supplemented with 0 g/day (n = 4, CON), 4.0 g/day (n = 4, LMet), and 6.0 g/day (n = 4, HMet) methionine. No significant difference (p > 0.05) was found in the production performance between the three groups, but antler weight was higher in both the LMet and HMet groups than in the CON group. Methionine supplementation significantly increased the serum glutathione peroxidase activity (p < 0.05). The serum immunoglobulin G level was significantly higher in the HMet group than in the other two groups (p < 0.05). No significant effect was found on the apparent amino acid digestibility of the three groups, but cysteine and methionine digestibility were higher in the LMet group. The serum hydroxylysine level was significantly lower in the LMet and HMet groups, whereas the serum lysine level was significantly lower in the HMet group compared with the CON group (p < 0.05). The LMet group had the highest but a nonsignificant total volatile fatty acid content and significantly higher microbial protein content in the rumen than the CON group (p < 0.05). The phyla Bacteroidetes, Firmicutes, and Proteobacteria were dominant in the rumen of the sika deer. The principal coordinate analysis (PCoA) and analysis of similarities (ANOSIM) results showed a significant change in the bacterial composition of the three groups (p < 0.05). The relative abundance of Prevotella and Rikenellaceae-RC9 was significantly higher in the LMet group compared with the CON group and CON and HMet groups, respectively. These results revealed that methionine supplementation improved the antioxidant activity and immune status, affecting amino acid metabolism and rumen microbial composition of the sika deer.
Special Issue on Functional Properties in Preharvest and Postharvest Fruit and Vegetables
Authors: Ma Gang , Kato Masaya , Jitareerat Pongphen
Published: August 2022

Fruit and vegetables, which represent an important part of our daily diet, are rich sources of bioactive compounds [...]
Inferential Statistics Is an Unfit Tool for Interpreting Data
Authors: Sand Anders
Published: August 2022

Null hypothesis significance testing is a commonly used tool for making statistical inferences in empirical studies, but its use has always been controversial. In this manuscript, I argue that even more problematic is that significance testing, and other abstract statistical benchmarks, often are used as tools for interpreting study data. This is problematic because interpreting data requires domain knowledge of the scientific topic and sensitivity to the study context, something that significance testing and other purely statistical approaches are not. By using simple examples, I demonstrate that researchers must first use their domain knowledge—professional expertise, clinical experience, practical insight—to interpret the data in their study and then use inferential statistics to provide some reasonable estimates about what can be generalized from the study data. Moving beyond the current focus on abstract statistical benchmarks will encourage researchers to measure their phenomena in more meaningful ways, transparently convey their data, and communicate their intellectual reasons for interpreting the data as they do, a shift that will better foster a scientific forum for cumulative science.
Joint Pattern Analysis of Forest Fire and Drought Indicators in Southeast Asia Associated with ENSO and IOD
Authors: Nurdiati Sri , Sopaheluwakan Ardhasena , Septiawan Pandu
Published: August 2022

Land and forest fires in Southeast Asia often coincide with severe dry seasons in the specific region caused by the warm phase of an El Niño Southern Oscillation (ENSO) and Indian Ocean Dipole (IOD). This research aims to identify and quantify the ENSO–IOD effect on a joint pattern between the dry season and land and forest fires in Southeast Asia. This research provides a quantitative result which represents the ENSO–IOD’s impact in Southeast Asia for hotspots, dry spells, and precipitation anomalies. The methods used in this research are singular value decomposition, probability density skill score, and coherence analysis. Cambodia, Myanmar, and Thailand gave a similar result with less than a 25% increasing severity in the hotspots from normal to either El Niño, positive IOD, or El Niño–positive IOD years. The maximum increase in hotspot severity in North Sumatra was 13.06% and happened during a weak El Niño and positive IOD. Meanwhile, South Sumatra had a maximum accumulation of more than 89% and Kalimantan had more than a 72% increase during the strong El Niño in 2015. Even though the relationship between the ENSO and IOD was inconsistent, the occurrence of both phenomena in the same year can lead to fires and need to be considered.
High Resolution Modelling of Traffic Emissions Using the Large Eddy Simulation Code Fluidity
Authors: Woodward Huw , Schroeder Anna K. , Le Cornec Clemence M. A. , Stettler Marc E. J. , ApSimon Helen , Robins Alan , Pain Christopher , Linden Paul F.
Published: August 2022

The large eddy simulation (LES) code Fluidity was used to simulate the dispersion of NOx traffic emissions along a road in London. The traffic emissions were represented by moving volume sources, one for each vehicle, with time-varying emission rates. Traffic modelling software was used to generate the vehicle movement, while an instantaneous emissions model was used to calculate the NOx emissions at 1 s intervals. The traffic emissions were also modelled as a constant volume source along the length of the road for comparison. A validation of Fluidity against wind tunnel measurements is presented before a qualitative comparison of the LES concentrations with measured roadside concentrations. Fluidity showed an acceptable comparison with the wind tunnel data for velocities and turbulence intensities. The in-canyon tracer concentrations were found to be significantly different between the wind tunnel and Fluidity. This difference was explained by the very high sensitivity of the in-canyon tracer concentrations to the precise release location. Despite this, the comparison showed that Fluidity was able to provide a realistic representation of roadside concentration variations at high temporal resolution, which is not achieved when traffic emissions are modelled as a constant volume source or by Gaussian plume models.
Data-Driven Prediction of COVID-19 Daily New Cases through a Hybrid Approach of Machine Learning Unsupervised and Deep Learning
Authors: Ramirez-Alcocer Ulises Manuel , Tello-Leal Edgar , Macías-Hernández Bárbara A. , Hernandez-Resendiz Jaciel David
Published: August 2022

Air pollution is associated with respiratory diseases and the transmission of infectious diseases. In this context, the association between meteorological factors and poor air quality possibly contributes to the transmission of COVID-19. Therefore, analyzing historical data of particulate matter (PM2.5 and PM10) and meteorological factors in indoor and outdoor environments to discover patterns that allow predicting future confirmed cases of COVID-19 is a challenge within a long pandemic. In this study, a hybrid approach based on machine learning and deep learning is proposed to predict confirmed cases of COVID-19. On the one hand, a clustering algorithm based on K-means allows the discovery of behavior patterns by forming groups with high cohesion. On the other hand, multivariate linear regression is implemented through a long short-term memory (LSTM) neural network, building a reliable predictive model in the training stage. The LSTM prediction model is evaluated through error metrics, achieving the highest performance and accuracy in predicting confirmed cases of COVID-19, using data of PM2.5 and PM10 concentrations and meteorological factors of the outdoor environment. The predictive model obtains a root-mean-square error (RMSE) of 0.0897, mean absolute error (MAE) of 0.0837, and mean absolute percentage error (MAPE) of 0.4229 in the testing stage. When using a dataset of PM2.5, PM10, and meteorological parameters collected inside 20 households from 27 May to 13 October 2021, the highest performance is obtained with an RMSE of 0.0892, MAE of 0.0592, and MAPE of 0.2061 in the testing stage. Moreover, in the validation stage, the predictive model obtains a very acceptable performance with values between 0.4152 and 3.9084 for RMSE, and a MAPE of less than 4.1%, using three different datasets with indoor environment values.
Daily Weather Forecasting Based on Deep Learning Model: A Case Study of Shenzhen City, China
Authors: Chen Guici , Liu Sijia , Jiang Feng
Published: August 2022

Daily weather conditions are closely related to every field of production and life, and the forecasting of weather conditions plays an important role in social development. Based on the data characteristics of urban weather conditions, a deep learning network was designed to forecast urban weather conditions, and its feasibility was proved by experiments. In view of the non-stationary and seasonal fluctuation of the time series of daily weather conditions in Shenzhen from 2015 to 2019, empirical mode decomposition (EMD) was used to carry out the stationary processing for the daily minimum humidity, minimum pressure, maximum temperature, maximum pressure, maximum wind speed and minimum temperature. The decomposed components, residual sequence and original sequence were reconstructed according to the degree of relevance. On this basis, a long short-term memory (LSTM) neural network for the Shenzhen daily weather forecast was used, using the advantages of the LSTM model in time-series data processing, using the grid search algorithm to find the optimal combination of the above parameters and combining with the gradient descent optimization algorithm to find optimal weights and bias, so as to improve the prediction accuracy of Shenzhen weather characteristics. The experimental results show that our design of the EMD-LSTM model has higher forecasting precision and efficiency than traditional models, which provides new ideas for the weather forecast.
Assessing Balance Loss and Stability Control in Older Adults Exposed to Gait Perturbations under Different Environmental Conditions: A Feasibility Study
Authors: Varas-Diaz Gonzalo , Jayakumar Udai , Taras Bradford , Wang Shuaijie , Bhatt Tanvi
Published: August 2022

This study investigated the feasibility of a perturbation-based balance protocol that incorporates a novel computer-controlled movable platform, the Surefooted Trainer, to induce losses of balance during overground walking under various environmental conditions. Twenty apparently healthy older adults (66.7 ± years old) participated in this study. The acceptability and safety of the perturbation-based balance protocol were assessed by tracking adherence, adverse events, and subjective physical and mental demands after the intervention. Additionally, biomechanical variables during perturbed and non-perturbed trials were analyzed and compared with behavioral outcomes. Overall, 95% of the participants completed the study. There were no serious or non-serious adverse events. The margin of stability and step length after perturbations were significantly lower during slip-perturbations in which the environmental conditions were more challenging. For trip-perturbation conditions, the maximum trunk angle was higher during the trials that resulted in losses of balance. We conclude that the Surefooted Trainer is an acceptable and valid device for an overground walking perturbation-based assessment and training protocol in older adults.
Development and Validation of a Novel Robot-Based Assessment of Upper Limb Sensory Processing in Chronic Stroke
Authors: Saenen Leen , Orban de Xivry Jean-Jacques , Verheyden Geert
Published: August 2022

Upper limb sensory processing deficits are common in the chronic phase after stroke and are associated with decreased functional performance. Yet, current clinical assessments show suboptimal psychometric properties. Our aim was to develop and validate a novel robot-based assessment of sensory processing. We assessed 60 healthy participants and 20 participants with chronic stroke using existing clinical and robot-based assessments of sensorimotor function. In addition, sensory processing was evaluated with a new evaluation protocol, using a bimanual planar robot, through passive or active exploration, reproduction and identification of 15 geometrical shapes. The discriminative validity of this novel assessment was evaluated by comparing the performance between healthy participants and participants with stroke, and the convergent validity was evaluated by calculating the correlation coefficients with existing assessments for people with stroke. The results showed that participants with stroke showed a significantly worse sensory processing ability than healthy participants (passive condition: p = 0.028, Hedges’ g = 0.58; active condition: p = 0.012, Hedges’ g = 0.73), as shown by the less accurate reproduction and identification of shapes. The novel assessment showed moderate to high correlations with the tactile discrimination test: a sensitive clinical assessment of sensory processing (r = 0.52–0.71). We conclude that the novel robot-based sensory processing assessment shows good discriminant and convergent validity for use in participants with chronic stroke.
Optimization of Synergetic Seismic and Energy Retrofitting Based on Timber Beams and Bio-Based Infill Panels: Application to an Existing Masonry Building in Switzerland
Authors: Zuluaga Simon Sanchez , Kallioras Stylianos , Tsiavos Anastasios
Published: August 2022

This paper presents an optimization process for the design of a novel synergetic seismic and energy retrofitting strategy that combines the favorable mechanical properties of timber and the attractive thermal insulation properties of bio-based materials. The novel method, defined as Strong Thermal and Seismic Backs (STSB), comprises the attachment of timber frames and bio-based thermal insulation panels on the vertical envelope and the facade walls of existing masonry buildings, thus improving both the seismic behavior and the energy performance of these buildings. This strategy is integrated and visualized in a novel synergetic framework for the holistic evaluation of the seismic behavior, the energy performance and the carbon footprint of existing buildings, defined as the Seismic and Energy Retrofitting Scoreboard (SERS). The benefit of the novel retrofitting strategy is quantified based on the numerical simulation of the seismic behavior of an unreinforced masonry building located in Switzerland, an assessment of the energy performance of the building and an evaluation of the carbon footprint of the proposed retrofit solution. Three retrofitting alternatives are investigated for the synergetic seismic and energy retrofitting of the building, comprising timber beams and two different bio-based materials for the thermal insulation of the vertical envelope of the building: cork and recycled natural grass. The optimal seismic and energy retrofitting strategy for the building among the alternatives assessed in this study is chosen based on a Multi-Criteria Decision Making (MCDM) procedure.
Immunology Meets Bioengineering: Improving the Effectiveness of Glioblastoma Immunotherapy
Authors: Fekrirad Zahra , Barzegar Behrooz Amir , Ghaemi Shokoofeh , Khosrojerdi Arezou , Zarepour Atefeh , Zarrabi Ali , Arefian Ehsan , Ghavami Saeid
Published: August 2022

Glioblastoma (GBM) therapy has seen little change over the past two decades. Surgical excision followed by radiation and chemotherapy is the current gold standard treatment. Immunotherapy techniques have recently transformed many cancer treatments, and GBM is now at the forefront of immunotherapy research. GBM immunotherapy prospects are reviewed here, with an emphasis on immune checkpoint inhibitors and oncolytic viruses. Various forms of nanomaterials to enhance immunotherapy effectiveness are also discussed. For GBM treatment and immunotherapy, we outline the specific properties of nanomaterials. In addition, we provide a short overview of several 3D (bio)printing techniques and their applications in stimulating the GBM microenvironment. Lastly, the susceptibility of GBM cancer cells to the various immunotherapy methods will be addressed.
Sarcopenia as a Predictor of Short- and Long-Term Outcomes in Patients Surgically Treated for Malignant Pleural Mesothelioma
Authors: Faccioli Eleonora , Terzi Stefano , Giraudo Chiara , Zuin Andrea , Modugno Antonella , Labella Francesco , Zambello Giovanni , Lorenzoni Giulia , Schiavon Marco , Gregori Dario , Pasello Giulia , Calabrese Fiorella , Dell’Amore Andrea , Rea Federico
Published: August 2022

Surgery for malignant pleural mesothelioma (MPM) should be reserved only for patients who have a good performance status. Sarcopenia, a well-known predictor of poor outcomes after surgery, is still underinvestigated in MPM. The aim of this study is to evaluate the role of sarcopenia as a predictor of short-and long-term outcomes in patients surgically treated for MPM. In our analysis, we included patients treated with a cytoreductive intent in a multimodality setting, with both pre- and post-operative CT scans without contrast available. We excluded those in whom a complete macroscopic resection was not achieved. Overall, 86 patients were enrolled. Sarcopenia was assessed by measuring the mean muscular density of the bilateral paravertebral muscles (T12 level) on pre-and post-operative CTs; a threshold value of 30 Hounsfield Units (HU) was identified. Sarcopenia was found pre-operatively in 57 (66%) patients and post-operatively in 61 (74%). Post-operative sarcopenic patients had a lower 3-year overall survival (OS) than those who were non-sarcopenic (34.9% vs. 57.6% p = 0.03). Pre-operative sarcopenia was significantly associated with a higher frequency of post-operative complications (65% vs. 41%, p = 0.04). The evaluation of sarcopenia, through a non-invasive method, would help to better select patients submitted to surgery for MPM in a multimodality setting.
Circulating miR-1246 and miR-485-3p as Promising Biomarkers of Clinical Response and Outcome in Melanoma Patients Treated with Targeted Therapy
Authors: Levati Lauretta , Bassi Cristian , Mastroeni Simona , Lupini Laura , Antonini Cappellini Gian Carlo , Bonmassar Laura , Alvino Ester , Caporali Simona , Lacal Pedro Miguel , Narducci Maria Grazia , Molineris Ivan , De Galitiis Federica , Negrini Massimo , Russo Giandomenico , D’Atri Stefania
Published: August 2022

Despite the significant improvements in advanced melanoma therapy, there is still a pressing need for biomarkers that can predict patient response and prognosis, and therefore support rational treatment decisions. Here, we investigated whether circulating miRNAs could be biomarkers of clinical outcomes in patients treated with targeted therapy. Using next-generation sequencing, we profiled plasma miRNAs at baseline and at progression in patients treated with BRAF inhibitors (BRAFi) or BRAFi + MEKi. Selected miRNAs associated with response to therapy were subjected to validation by real-time quantitative RT-PCR. Receiver Operating Characteristics (ROC), Kaplan–Meier and univariate and multivariate Cox regression analyses were performed on the validated miR-1246 and miR-485-3p baseline levels. The median baseline levels of miR-1246 and miR-485-3p were significantly higher and lower, respectively, in the group of patients not responding to therapy (NRs) as compared with the group of responding patients (Rs). In Rs, a trend toward an increase in miR-1246 and a decrease in miR-485-3p was observed at progression. Baseline miR-1246 level and the miR-1246/miR-485-3p ratio showed a good ability to discriminate between Rs and NRs. Poorer PFS and OS were observed in patients with unfavorable levels of at least one miRNA. In multivariate analysis, a low level of miR-485-3p and a high miR-1246/miR-485-3p ratio remained independent negative prognostic factors for PFS, while a high miR-1246/miR-485-3p ratio was associated with an increased risk of mortality, although statistical significance was not reached. Evaluation of miR-1246 and miR-485-3p baseline plasma levels might help clinicians to identify melanoma patients most likely to be unresponsive to targeted therapy or at higher risk for short-term PFS and mortality, thus improving their management.
Histone Deacetylase Inhibitors Restore Cancer Cell Sensitivity towards T Lymphocytes Mediated Cytotoxicity in Pancreatic Cancer
Authors: Looi Chin-King , Gan Li-Lian , Sim Wynne , Hii Ling-Wei , Chung Felicia Fei-Lei , Leong Chee-Onn , Lim Wei-Meng , Mai Chun-Wai
Published: August 2022

Despite medical advancements, the prognosis of pancreatic ductal adenocarcinoma (PDAC) has not improved significantly over the past 50 years. By utilising the large-scale genomic datasets available from the Australia Pancreatic Cancer Project (PACA-AU) and The Cancer Genomic Atlas Project (TCGA-PAAD), we studied the immunophenotype of PDAC in silico and identified that tumours with high cytotoxic T lymphocytes (CTL) killing activity were associated with favourable clinical outcomes. Using the STRING protein–protein interaction network analysis, the identified differentially expressed genes with low CTL killing activity were associated with TWIST/IL-6R, HDAC5, and EOMES signalling. Following Connectivity Map analysis, we identified 44 small molecules that could restore CTL sensitivity in the PDAC cells. Further high-throughput chemical library screening identified 133 inhibitors that effectively target both parental and CTL-resistant PDAC cells in vitro. Since CTL-resistant PDAC had a higher expression of histone proteins and its acetylated proteins compared to its parental cells, we further investigated the impact of histone deacetylase inhibitors (HDACi) on CTL-mediated cytotoxicity in PDAC cells in vitro, namely SW1990 and BxPC3. Further analyses revealed that givinostat and dacinostat were the two most potent HDAC inhibitors that restored CTL sensitivity in SW1990 and BxPC3 CTL-resistant cells. Through our in silico and in vitro studies, we demonstrate the novel role of HDAC inhibition in restoring CTL resistance and that combinations of HDACi with CTL may represent a promising therapeutic strategy, warranting its further detailed molecular mechanistic studies and animal studies before embarking on the clinical evaluation of these novel combined PDAC treatments.
Protein Panel of Serum-Derived Small Extracellular Vesicles for the Screening and Diagnosis of Epithelial Ovarian Cancer
Authors: Lai Huiling , Guo Yunyun , Tian Liming , Wu Linxiang , Li Xiaohui , Yang Zunxian , Chen Shuqin , Ren Yufeng , He Shasha , He Weipeng , Yang Guofen
Published: August 2022

Although ovarian cancer, a gynecological malignancy, has the highest fatality rate, it still lacks highly specific biomarkers, and the differential diagnosis of ovarian masses remains difficult to determine for gynecologists. Our study aimed to obtain ovarian cancer-specific protein candidates from the circulating small extracellular vesicles (sEVs) and develop a protein panel for ovarian cancer screening and differential diagnosis of ovarian masses. In our study, sEVs derived from the serum of healthy controls and patients with cystadenoma and ovarian cancer were investigated to obtain a cancer-specific proteomic profile. In a discovery cohort, 1119 proteins were identified, and significant differences in the protein profiles of EVs were observed among groups. Then, 23 differentially expressed proteins were assessed using the parallel reaction monitoring in a validation cohort. Through univariate and multivariate logistic regression analyses, a novel model comprising three proteins (fibrinogen gamma gene (FGG), mucin 16 (MUC16), and apolipoprotein (APOA4)) was established to screen patients with ovarian cancer. This model exhibited an area under the receiver operating characteristic curve (AUC) of 0.936 (95% CI, 0.888–0.984) with 92.0% sensitivity and 82.9% specificity. Another panel comprising serum CA125, sEV-APOA4, and sEV-CD5L showed excellent performance (AUC 0.945 (95% CI, 0.890–1.000), sensitivity of 88.0%, specificity of 93.3%, and accuracy of 89.2%) to distinguish malignancy from benign ovarian masses. Altogether, our study provided a proteomic signature of circulating sEVs in ovarian cancer. The diagnostic proteomic panel may complement current clinical diagnostic measures for screening ovarian cancer in the general population and the differential diagnosis of ovarian masses.
Cancer Associated Fibroblast (CAF) Regulation of PDAC Parenchymal (CPC) and CSC Phenotypes Is Modulated by ECM Composition
Authors: Cannone Stefania , Greco Maria Raffaella , Carvalho Tiago M. A. , Guizouarn Helene , Soriani Olivier , Di Molfetta Daria , Tomasini Richard , Zeeberg Katrine , Reshkin Stephan Joel , Cardone Rosa Angela
Published: August 2022

Background: Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest of all cancers, having one of the lowest five-year survival rates. One of its hallmarks is a dense desmoplastic stroma consisting in the abnormal accumulation of extracellular matrix (ECM) components, especially Collagen I. This highly fibrotic stroma embeds the bulk cancer (parenchymal) cells (CPCs), cancer stem cells (CSCs) and the main producers of the stromal reaction, the Cancer Associated Fibroblasts (CAFs). Little is known about the role of the acellular ECM in the interplay of the CAFs with the different tumor cell types in determining their phenotypic plasticity and eventual cell fate. Methods: Here, we analyzed the role of ECM collagen I in modulating the effect of CAF-derived signals by incubating PDAC CPCs and CSCs grown on ECM mimicking early (low collagen I levels) and late (high collagen I levels) stage PDAC stroma with conditioned medium from primary cultured CAFs derived from patients with PDAC in a previously described three-dimensional (3D) organotypic model of PDAC. Results: We found that CAFs (1) reduced CPC growth while favoring CSC growth independently of the ECM; (2) increased the invasive capacity of only CPCs on the ECM mimicking the early tumor; and (3) favored vasculogenic mimicry (VM) especially of the CSCs on the ECM mimicking an early tumor. Conclusions: We conclude that the CAFs and acellular stromal components interact to modulate the tumor behaviors of the PDAC CPC and CSC cell types and drive metastatic progression by stimulating the phenotypic characteristics of each tumor cell type that contribute to metastasis.
Consensus Molecular Subtypes Efficiently Classify Gastric Adenocarcinomas and Predict the Response to Anti-PD-1 Immunotherapy
Authors: Wu Xiangyan , Ye Yuhan , Vega Kenneth J. , Yao Jiannan
Published: August 2022

Background: Gastric adenocarcinoma (GAC) is highly heterogeneous and closely related to colorectal cancer (CRC) both molecularly and functionally. GAC is currently subtyped using a system developed by TCGA. However, with the emergence of immunotherapies, this system has failed to identify suitable treatment candidates. Methods: Consensus molecular subtypes (CMSs) developed for CRC were used for molecular subtyping in GAC based on public expression cohorts, including TCGA, ACRG, and a cohort of GAC patients treated with the programmed cell death 1 (PD-1) inhibitor pembrolizumab. All aspects of each subtype, including clinical outcome, molecular characteristics, oncogenic pathway activity, and the response to immunotherapy, were fully explored. Results: CMS classification was efficiently applied to GAC. CMS4, characterized by EMT activation, stromal invasion, angiogenesis, and the worst clinical outcomes (median OS 24.2 months), was the predominant subtype (38.8%~44.3%) and an independent prognostic indicator that outperformed classical TCGA subtyping. CMS1 (20.9%~21.5%) displayed hypermutation, low SCNV, immune activation, and best clinical outcomes (median OS > 120 months). CMS3 (17.95%~25.7%) was characterized by overactive metabolism, KRAS mutation, and intermediate outcomes (median OS 85.6 months). CMS2 (14.6%~16.3%) was enriched for WNT and MYC activation, differentiated epithelial characteristics, APC mutation, lack of ARID1A, and intermediate outcomes (median OS 48.7 months). Notably, CMS1 was strongly correlated with immunotherapy biomarkers and favorable for the anti-PD-1 drug pembrolizumab, whereas CMS4 was poorly responsive but became more sensitive after EMT-based stratification. Conclusions: Our study reveals the practical utility of CMS classification for GAC to improve clinical outcomes and identify candidates who will respond to immunotherapy.
Clinical Post-SARS-CoV-2 Infection Scenarios in Vaccinated and Non-Vaccinated Cancer Patients in Three German Cancer Centers: A Retrospective Analysis
Authors: Shumilov Evgenii , Aperdannier Lena , Schmidt Nicole , Szuszies Christoph , Neesse Albrecht , Hoffknecht Petra , Khandanpour Cyrus , Mikesch Jan-Henrik , Stelljes Matthias , Boeckel Göran Ramin , Tepasse Phil-Robin , Reitnauer Lea , Koch Raphael , Hasenkamp Justin , Bacher Ulrike , Scheithauer Simone , Trümper Lorenz , Schmitz Norbert , Wulf Gerald , Kerkhoff Andrea , Lenz Georg , Krekeler Carolin , Bleckmann Annalen
Published: August 2022

COVID-19 vaccines have become an integral element in the protection of cancer patients against SARS-CoV-2. To date, there are no direct comparisons of the course of COVID-19 infection in cancer patients between the pre- and post-vaccine era. We analyzed SARS-CoV-2 infections and their impact on cancer in COVID-19 vaccinated and non-vaccinated patients from three German cancer centers. Overall, 133 patients with SARS-CoV-2 were enrolled in pre- and post-vaccine eras: 84 non-vaccinated and 49 vaccinated, respectively. A mild course of COVID-19 was documented more frequently in vaccinated patients (49% vs. 29%), while the frequency of severe and critical courses occurred in approximately one-half of the non-vaccinated patients (22% vs. 42%, p = 0.023). Particularly, patients with hematologic neoplasms benefited from vaccination in this context (p = 0.031). Admissions to intermediate- and intensive-care units and the necessity of non-invasive and invasive respiratory support were reduced by 71% and 50% among vaccinated patients, respectively. The median length of admission was 11 days for non-vaccinated and 5 days for vaccinated patients (p = 0.002). COVID-19 mortality was reduced by 83% in vaccinated patients (p = 0.046). Finally, the median time from SARS-CoV-2 infection to restarting cancer therapy was 12 and 26 days among vaccinated and non-vaccinated groups, respectively (p = 0.002). Although this study does not have enough power to perform multivariate analyses to account for confounders, it provides data on COVID-19 in non-vaccinated and vaccinated cancer patients and illustrates the potential benefits of COVID-19 vaccines for these patients.
Uridine Diphosphate Glucuronosyl Transferase 2B28 (UGT2B28) Promotes Tumor Progression and Is Elevated in African American Prostate Cancer Patients
Authors: Ravindran Anindita , Krieger Kimiko L. , Kaushik Akash K. , Hovington Hélène , Mehdi Sadia , Piyarathna Danthasinghe Waduge Badrajee , Putluri Vasanta , Basil Paul , Rasaily Uttam , Gu Franklin , Dang Truong , Choi Jong Min , Sonavane Rajni , Jung Sung Yun , Wang Lisha , Mehra Rohit , Weigel Nancy L. , Putluri Nagireddy , Rowley David R. , Palapattu Ganesh S. , Guillemette Chantal , Lacombe Louis , Lévesque Éric , Sreekumar Arun
Published: August 2022

Prostate cancer (PCa) is the second most diagnosed cancer in the United States and is associated with metabolic reprogramming and significant disparities in clinical outcomes among African American (AA) men. While the cause is likely multi-factorial, the precise reasons for this are unknown. Here, we identified a higher expression of the metabolic enzyme UGT2B28 in localized PCa and metastatic disease compared to benign adjacent tissue, in AA PCa compared to benign adjacent tissue, and in AA PCa compared to European American (EA) PCa. UGT2B28 was found to be regulated by both full-length androgen receptor (AR) and its splice variant, AR-v7. Genetic knockdown of UGT2B28 across multiple PCa cell lines (LNCaP, LAPC-4, and VCaP), both in androgen-replete and androgen-depleted states resulted in impaired 3D organoid formation and a significant delay in tumor take and growth rate of xenograft tumors, all of which were rescued by re-expression of UGT2B28. Taken together, our findings demonstrate a key role for the UGT2B28 gene in promoting prostate tumor growth.
Pseudoislet Aggregation of Pancreatic β-Cells Improves Glucose Stimulated Insulin Secretion by Altering Glucose Metabolism and Increasing ATP Production
Authors: Cornell Deborah , Miwa Satomi , Georgiou Merilin , Anderson Scott James , Honkanen-Scott Minna , Shaw James A. M. , Arden Catherine
Published: August 2022

Appropriate glucose-stimulated insulin secretion (GSIS) by pancreatic β-cells is an essential component of blood glucose homeostasis. Configuration of β-cells as 3D pseudoislets (PI) improves the GSIS response compared to 2D monolayer (ML) culture. The aim of this study was to determine the underlying mechanisms. MIN6 β-cells were grown as ML or PI for 5 days. Human islets were isolated from patients without diabetes. Function was assessed by GSIS and metabolic capacity using the Seahorse bioanalyser. Connexin 36 was downregulated using inducible shRNA. Culturing MIN6 as PI improved GSIS. MIN6 PI showed higher glucose-stimulated oxygen consumption (OCR) and extracellular acidification (ECAR) rates. Further analysis showed the higher ECAR was, at least in part, a consequence of increased glycolysis. Intact human islets also showed glucose-stimulated increases in both OCR and ECAR rates, although the latter was smaller in magnitude compared to MIN6 PI. The higher rates of glucose-stimulated ATP production in MIN6 PI were consistent with increased enzyme activity of key glycolytic and TCA cycle enzymes. There was no impact of connexin 36 knockdown on GSIS or ATP production. Configuration of β-cells as PI improves GSIS by increasing the metabolic capacity of the cells, allowing higher ATP production in response to glucose.
MicroRNAs and Their Big Therapeutic Impacts: Delivery Strategies for Cancer Intervention
Authors: Holjencin Charles , Jakymiw Andrew
Published: August 2022

Three decades have passed from the initial discovery of a microRNA (miRNA) in Caenorhabditis elegans to our current understanding that miRNAs play essential roles in regulating fundamental physiological processes and that their dysregulation can lead to many human pathologies, including cancer. In effect, restoration of miRNA expression or downregulation of aberrantly expressed miRNAs using miRNA mimics or anti-miRNA inhibitors (anti-miRs/antimiRs), respectively, continues to show therapeutic potential for the treatment of cancer. Although the manipulation of miRNA expression presents a promising therapeutic strategy for cancer treatment, it is predominantly reliant on nucleic acid-based molecules for their application, which introduces an array of hurdles, with respect to in vivo delivery. Because naked nucleic acids are quickly degraded and/or removed from the body, they require delivery vectors that can help overcome the many barriers presented upon their administration into the bloodstream. As such, in this review, we discuss the strengths and weaknesses of the current state-of-the-art delivery systems, encompassing viral- and nonviral-based systems, with a specific focus on nonviral nanotechnology-based miRNA delivery platforms, including lipid-, polymer-, inorganic-, and extracellular vesicle-based delivery strategies. Moreover, we also shed light on peptide carriers as an emerging technology that shows great promise in being a highly efficacious delivery platform for miRNA-based cancer therapeutics.
Piezo1 Channel Activation Reverses Pulmonary Artery Vasoconstriction in an Early Rat Model of Pulmonary Hypertension: The Role of Ca2+ Influx and Akt-eNOS Pathway
Authors: Porto Ribeiro Thais , Barbeau Solène , Baudrimont Isabelle , Vacher Pierre , Freund-Michel Véronique , Cardouat Guillaume , Berger Patrick , Guibert Christelle , Ducret Thomas , Quignard Jean-François
Published: August 2022

In intrapulmonary arteries (IPAs), mechanical forces due to blood flow control vessel tone, and these forces change during pulmonary hypertension (PH). Piezo1, a stretch-activated calcium channel, is a sensor of mechanical stress present in both endothelial cells (ECs) and smooth muscle cells (SMCs). The present study investigated the role of Piezo1 on IPA in the chronic hypoxia model of PH. Rats were raised in chronically hypoxic conditions for 1 (1W-CH, early stage) or 3 weeks (3W-CH, late-stage) of PH or in normoxic conditions (Nx). Immunofluorescence labeling and patch-clamping revealed the presence of Piezo1 in both ECs and SMCs. The Piezo1 agonist, Yoda1, induced an IPA contraction in Nx and 3W-CH. Conversely, Yoda1 induced an endothelial nitric oxide (eNOS) dependent relaxation in 1W-CH. In ECs, the Yoda1-mediated intracellular calcium concentration ([Ca2+]i) increase was greater in 1W-CH as compared to Nx. Yoda1 induced an EC hyperpolarization in 1W-CH. The eNOS levels were increased in 1W-CH IPA compared to Nx or 3W-CH PH and Yoda1 activated phosphorylation of Akt (Ser473) and eNOS (Ser1177). Thus, we demonstrated that endothelial Piezo1 contributes to intrapulmonary vascular relaxation by controlling endothelial [Ca2+]i, endothelial-dependent hyperpolarization, and Akt-eNOS pathway activation in the early stage of PH.
Cutting-Edge: Preclinical and Clinical Development of the First Approved Lag-3 Inhibitor
Authors: Chocarro Luisa , Bocanegra Ana , Blanco Ester , Fernández-Rubio Leticia , Arasanz Hugo , Echaide Miriam , Garnica Maider , Ramos Pablo , Piñeiro-Hermida Sergio , Vera Ruth , Escors David , Kochan Grazyna
Published: August 2022

Immune checkpoint inhibitors (ICIs) have revolutionized medical practice in oncology since the FDA approval of the first ICI 11 years ago. In light of this, Lymphocyte-Activation Gene 3 (LAG-3) is one of the most important next-generation immune checkpoint molecules, playing a similar role as Programmed cell Death protein 1 (PD-1) and Cytotoxic T-Lymphocyte Antigen 4 (CTLA-4). 19 LAG-3 targeting molecules are being evaluated at 108 clinical trials which are demonstrating positive results, including promising bispecific molecules targeting LAG-3 simultaneously with other ICIs. Recently, a new dual anti-PD-1 (Nivolumab) and anti-LAG-3 (Relatimab) treatment developed by Bristol Myers Squibb (Opdualag), was approved by the Food and Drug Administration (FDA) as the first LAG-3 blocking antibody combination for unresectable or metastatic melanoma. This novel immunotherapy combination more than doubled median progression-free survival (PFS) when compared to nivolumab monotherapy (10.1 months versus 4.6 months). Here, we analyze the large clinical trial responsible for this historical approval (RELATIVITY-047), and discuss the preclinical and clinical developments that led to its jump into clinical practice. We will also summarize results achieved by other LAG-3 targeting molecules with promising anti-tumor activities currently under clinical development in phases I, I/II, II, and III. Opdualag will boost the entry of more LAG-3 targeting molecules into clinical practice, supporting the accumulating evidence highlighting the pivotal role of LAG-3 in cancer.
Mutated FANCA Gene Role in the Modulation of Energy Metabolism and Mitochondrial Dynamics in Head and Neck Squamous Cell Carcinoma
Authors: Bertola Nadia , Degan Paolo , Cappelli Enrico , Ravera Silvia
Published: August 2022

Fanconi Anaemia (FA) is a rare recessive genetic disorder characterized by a defective DNA repair mechanism. Although aplastic anaemia is the principal clinical sign in FA, patients develop a head and neck squamous cell carcinoma (HNSCC) with a frequency 500–700 folds higher than the general population, which appears more aggressive, with survival of under two years. Since FA gene mutations are also associated with a defect in the aerobic metabolism and an increased oxidative stress accumulation, this work aims to evaluate the effect of FANCA mutation on the energy metabolism and the relative mitochondrial quality control pathways in an HNSCC cellular model. Energy metabolism and cellular antioxidant capacities were evaluated by oximetric, luminometric, and spectrophotometric assays. The dynamics of the mitochondrial network, the quality of mitophagy and autophagy, and DNA double-strand damage were analysed by Western blot analysis. Data show that the HNSCC cellular model carrying the FANCA gene mutation displays an altered electron transport between respiratory Complexes I and III that does not depend on the OxPhos protein expression. Moreover, FANCA HNSCC cells show an imbalance between fusion and fission processes and alterations in autophagy and mitophagy pathways. Together, all these alterations associated with the FANCA gene mutation cause cellular energy depletion and a metabolic switch to glycolysis, exacerbating the Warburg effect in HNSCC cells and increasing the growth rate. In addition, the altered DNA repair due to the FANCA mutation causes a higher accumulation of DNA damage in the HNSCC cellular model. In conclusion, changes in energy metabolism and mitochondrial dynamics could explain the strict correlation between HNSCC and FA genes, helping to identify new therapeutic targets.
Effects of Dietary Inclusion of β-Hydroxy-β-Methylbutyrate on Growth Performance, Fat Deposition, Bile Acid Metabolism, and Gut Microbiota Function in High-Fat and High-Cholesterol Diet-Challenged Layer Chickens
Authors: Liao Qichao , Wu Tian , Fu Qinghua , Wang Peng , Zhao Yameng , Li Yan , Xiao Haihan , Zhou Lei , Song Ziyi
Published: August 2022

Excessive lipid deposition in layer chickens due to inappropriate feeding adversely affects egg production; however, nutritional manipulation methods to deal with this issue are still limited. β-hydroxy-β-methylbutyrate (HMB), a metabolite of L-leucine, was recently reported as a lipid-lowering nutrient in mice and pigs, although its role in layers had not been investigated. Here, we employed high-fat and high-cholesterol diet (HFHCD)−challenged growing layers as an obese model to explore HMB function in the regulation of lipid metabolism and the potential mechanisms involved. We found that dietary supplementation with (0.05% or 0.10%) HMB significantly reduced HFHCD−induced bodyweight growth in layers, mainly due to reduction in abdominal fat deposition. Mechanistically, HMB supplementation enhanced hepatic bile acid synthesis from cholesterol through elevating expression of Cyp7a1, a gene coding a key enzyme in bile acid synthesis. Furthermore, 16S rRNA gene sequencing revealed that HMB supplementation remodeled the diversity and composition of the layers’ cecal microbiota, and the abundance of Bacteroidetes at the phylum level were especially affected. Correlation analysis further indicated a strong negative association between Bacteroidetes abundance and lipid metabolism−related parameters. Taken together, these data suggest that dietary HMB supplementation could improve abdominal fat deposition in layers, probably through modulating hepatic bile acid synthesis and gut microbiota function.
Assessment of the Susceptibility of Aesthetic Orthodontic Brackets to Discoloration
Authors: Malkiewicz Konrad , Jastrzebska Aleksandra , Janas-Naze Anna , Boryczko Wojciech , Bartczak Jakub
Published: August 2022

The high aesthetic value of orthodontic appliance elements during treatment constitutes an important factor for an increasing number of adult patients. The aim of this study was to determine whether food dyes could significantly affect the color of both plastic and ceramic orthodontic brackets. Four brands of orthodontic brackets were investigated in the present study. Twenty-five samples of each kind were prepared. Five brackets of each series were stored in pure water, coffee, black tea and red wine for 1 h, 24 h, 7 days and 14 days. Total color change ΔE* of the samples was analyzed after storage with the use of the SpectroShade dental spectrophotometer (MHT, Verona, Italy) according to the CIE L*a*b* color scale. Correlations between bracket brand, kind of food dye and intensity of color change at the significance level p = 0.05 were investigated. After 1 and 24 h of incubation, water had the least influence on the color change of aesthetic orthodontic brackets, and tea had the greatest effect (p = 0.05). After 7 and 14 days of incubation of the samples, water still remained the environment influencing ΔE* change to the smallest extent, whereas storage in red wine changed the color of brackets to the significantly (p = 0.05) highest degree. The degree of discoloration of the assessed brackets depended on the type of material and the storage time in the environment of the individual food dyes (p = 0.05). The results of the present study show that, in the event of contact with food dyes, aesthetic orthodontic brackets discolor, the intensity of which can be influenced by the materials they are made of, the kind of food dye and the time of samples’ storage.
Preparation of Polyurethane/Acrylate Composite Emulsion for Inkjet Printing
Authors: Wang Xin , Wu Jimei , Chu Fuqiang , Feng Yao
Published: August 2022

Water-borne polyurethane/acrylate (WPUA) emulsion was prepared through emulsion polymerization between vinyl terminated waterborne polyurethane (WPU) and methyl methacrylate (MMA) in this research. Thermogravimetric Analysis (TGA), transmission electron microscopy (TEM), contact angle analysis, and particle size distribution analysis were employed to investigate the performance of the prepared emulsion and coatings with various content of MMA content. The results demonstrated that the thermal resistance, water resistance, and hardness of the prepared WPUA coatings were enhanced by the introduction of the MMA monomer. The contact angle (CA) and particle size of WPUA emulsion increased with the increase of MMA content. Meanwhile, the water-borne inkjet printing ink was prepared using WPUA emulsion as binder resin, and the printing test result showed that the prepared inkjet ink has good printability and color rendering, indicating that WPUA emulsion has great application prospects in the field of inkjet printing.