bluuebunny/crossref_metadata_2025_split huggingface dataset:
Releasing the restraints of Vγ9Vδ2 T-cells in cancer immunotherapy
Authors: Ridgley Laura A. , Caron Jonathan , Dalgleish Angus , Bodman-Smith Mark 
Published: January 2023

ObjectivesVγ9Vδ2 T-cells are a subset of T-cells with a crucial role in immunosurveillance which can be activated and expanded by multiple means to stimulate effector responses. Little is known about the expression of checkpoint molecules on this cell population and whether the ligation of these molecules can regulate their activity. The aim of this study was to assess the expression of both activatory and inhibitory receptors on Vγ9Vδ2 T-cells to assess potential avenues of regulation to target with immunotherapy.MethodsExpression of various activatory and inhibitory receptors was assessed on Vγ9Vδ2 T-cells by flow cytometry following activation and expansion using zoledronic acid (ZA) and Bacillus Calmette-Guérin (BCG). Expression of these markers and production of effector molecules was also examined following co-culture with various tumour cell targets. The effect of immune checkpoint blockade on Vγ9Vδ2 T-cells was also explored.ResultsVγ9Vδ2 T-cells expressed high levels of activatory markers both at baseline and following stimulation. Vγ9Vδ2 T-cells expressed variable levels of inhibitory checkpoint receptors with many being upregulated following stimulation. Expression of these markers is further modulated upon co-culture with tumour cells with changes reflecting activation and effector functions. Despite their high expression of inhibitory receptors when cultured with tumour cells expressing cognate ligands there was no effect on Vδ2+ T-cell cytotoxic capacity or cytokine production with immune checkpoint blockade.ConclusionsOur work suggests the expression of checkpoint receptors present on Vγ9Vδ2 T-cells which may provide a mechanism with the potential to be utilised by tumour cells to subvert Vγ9Vδ2 T-cell cytotoxicity. This work suggests important candidates for blockade by ICI therapy in order to increase the successful use of Vγ9Vδ2 T-cells in immunotherapy.
Distinct SARS-CoV-2 RNA fragments activate Toll-like receptors 7 and 8 and induce cytokine release from human macrophages and microglia
Authors: Wallach Thomas , Raden Martin , Hinkelmann Lukas , Brehm Mariam , Rabsch Dominik , Weidling Hannah , Krüger Christina , Kettenmann Helmut , Backofen Rolf , Lehnardt Seija 
Published: January 2023

IntroductionThe pandemic coronavirus disease 19 (COVID-19) is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and is marked by thromboembolic events and an inflammatory response throughout the body, including the brainMethodsEmploying the machine learning approach BrainDead we systematically screened for SARS-CoV-2 genome-derived single-stranded (ss) RNA fragments with high potential to activate the viral RNA-sensing innate immune receptors Toll-like receptor (TLR)7 and/or TLR8. Analyzing HEK TLR7/8 reporter cells we tested such RNA fragments with respect to their potential to induce activation of human TLR7 and TLR8 and to activate human macrophages, as well as iPSC-derived human microglia, the resident immune cells in the brain.ResultsWe experimentally validated several sequence-specific RNA fragment candidates out of the SARS-CoV-2 RNA fragments predicted in silico as activators of human TLR7 and TLR8. Moreover, these SARS-CoV-2 ssRNAs induced cytokine release from human macrophages and iPSC-derived human microglia in a sequence- and species-specific fashion.DiscussionOur findings determine TLR7 and TLR8 as key sensors of SARS-CoV-2-derived ssRNAs and may deepen our understanding of the mechanisms how this virus triggers, but also modulates an inflammatory response through innate immune signaling.
The association between sedentary behavior, exercise, and sleep disturbance: A mediation analysis of inflammatory biomarkers
Authors: You Yanwei , Chen Yuquan , Fang Wen , Li Xingtian , Wang Rui , Liu Jianxiu , Ma Xindong 
Published: January 2023

BackgroundTwo related lifestyle behaviors associated with sleep disturbance are sedentary behavior and physical exercise participation. We aimed to use a population-based study to disentangle the relationships between sedentary behavior, exercise, and sleep disturbance based on blood-cell-based inflammatory biomarkers.MethodsA total of 22,599 participants from the National Health and Nutrition Examination Survey (NHANES) were included in the analyses. Sleep disturbance was assessed according to the NHANES questionnaire. Exercise participation ansd sedentary behavior were evaluated by the global physical activity questionnaire. The inflammatory biomarkers in the examination were white blood cell (WBC) count, neutrophil count (NEU), neutrophil-to-lymphocyte ratio (NLR), and systemic immune inflammation index (SII). A complex multistage sampling design and weighted multivariable logistic regression were applied for further analysis. Mediation models were constructed to figure out the mediating role of inflammatory biomarkers.ResultsThe weighted prevalence of sleep disturbance was 24.17%. Sedentary behavior and exercise were associated with sleep disturbance after full adjustment [for sedentary behavior, OR (95% CI): 1.261 (1.154, 1.377); for exercise, OR (95% CI): 0.849 (0.757, 0.953)]. In severe sedentary behavior groups, the mitigation effect of exercise on sleep disturbance was observed [OR (95% CI): 0.687 (0.551, 0.857)]. For the mechanism, strong associations were detected between inflammatory biomarkers and sleep disturbance. Mediation analysis showed that WBC, NEU, NLR, and SII mediated the statistical association between sedentary behavior and sleep disturbance with proportions (%) of 2.09, 2.27, 1.76, and 0.82, respectively.ConclusionsOur data suggested that sedentary behavior was a risk factor for sleep disturbance. Blood-cell-based inflammatory biomarkers were an easily accessible and cost-effective strategy for identifying sleep disturbance and also significantly mediated the association between sedentary behavior and sleep disturbance. Exercise was proved to be effective in severe sedentary behavior groups to improve sleep disturbance symptoms, while the internal mechanism needed further exploration.
Surgical treatment of locally advanced right colon cancer invading neighboring organs
Authors: Ri HyokJu , Kang HaoNan , Xu ZhaoHui , Gong ZeZhong , Jo HyonSu , Amadou Boureima Hamidou , Xu Yang , Ren YanYing , Zhu WanJi , Chen Xin 
Published: January 2023

PurposeInvasion of the pancreas and/or duodenum with/without neighboring organs by locally advanced right colon cancer (LARCC) is a very rare clinical phenomenon that is difficult to manage. The purpose of this review is to suggest the most reasonable surgical approach for primary right colon cancer invading neighboring organs such as the pancreas and/or duodenum.MethodsAn extensive systematic research was conducted in PubMed, Medline, Embase, Scopus, and the Cochrane Central Register of Controlled Trials (CENTRAL) using the MeSH terms and keywords. Data were extracted from the patients who underwent en bloc resection and local resection with right hemicolectomy (RHC), the analysis was performed with the survival rate as the outcome parameters.ResultsAs a result of the analysis of 117 patient data with locally advanced colon cancer (LACC) (73 for males, 39 for females) aged 25–85 years old from 11 articles between 2008 and 2021, the survival rate of en bloc resection was 72% with invasion of the duodenum, 71.43% with invasion of the pancreas, 55.56% with simultaneous invasion of the duodenum and pancreas, and 57.9% with invasion of neighboring organs with/without invasion of duodenum and/or pancreas. These survival results were higher than with local resection of the affected organ plus RHC.ConclusionWhen the LARCC has invaded neighboring organs, particularly when duodenum or pancreas are invaded simultaneously or individually, en bloc resection is a reasonable option to increase patient survival after surgery.
Longitudinal observation of viral load in patients infected with Omicron variant and its relationship with clinical symptoms
Authors: Zhou Kai , Hu Bingjie , Zhao Xinzhuan , Chi Hongbo , Pan Juan , Zheng Yufen , Bi Xiaojie , Chen Mengyuan , Xie Jicheng , Xu Jiaqin , Tung Tao-Hsin , Shen Bo , Zhu Hongguo 
Published: January 2023

ObjectiveIn 2022, a new coronavirus variant (Omicron) infection epidemic broke out in Shanghai, China. However, it is unclear whether the duration of this omicron variant is different from that of the prototype strain.MethodsWe retrospectively analyzed 157 cases of Omicron variant infection in Taizhou Public Health Center from March 29, 2022, to April 18, 2022, and observed the dynamics of nucleic acid Ct values during the admission and discharge of patients. Clinical and laboratory indicators of these patients were also obtained.ResultsCompared to the prototype strain, the Omicron variant showed a broad population susceptibility in infected individuals (regardless of age and presence of underlying disease) and had slight damage to the immune system and renal function; the viral loads peaked was 2-3 days from disease onset; the median duration of omicron variant was 15-18 days; the nucleic acid Ct value of nasopharyngeal swabs of infected patients is lower than that of throat swabs, and the Ct value of oropharyngeal swabs is unstable during the recovery period.ConclusionTherefore, we found that the time to peak viral load of this Omicron variant was 2-3 days after the onset of the disease, and the duration was 15-18 days; symptomatic patients had higher viral load and longer hospitalization time. This finding will provide a basis for understanding omicron variants and formulating the national prevention and control strategy.
Host-microbiota interactions and responses of Metapenaeus ensis infected with decapod iridescent virus 1
Authors: Liao Minze , Liao Xuzheng , Long Xinxin , Zhao Jichen , He Zihao , Zhang Jingyue , Wu Tingfen , Sun Chengbo 
Published: January 2023

IntroductionDecapod iridescent virus 1 (DIV1) has caused severe economic losses in shrimp aquaculture. So far, Researchs on DIV1-infected shrimp have mainly focused on the hemocytes immune response, while studies on the host-intestine microbiota interactions during DIV1 infection have been scarce.MethodsThis study determined the lethal concentration 50 (LC50) of DIV1 to Metapenaeus ensis, preliminarily determining that M. ensis could serve as a susceptible object for DIV1. The interactions and responses between the immune and intestine microbiota of shrimp under DIV1 infection were also investigated.Results and DiscussionDIV1 infection decreases intestine bacterial diversity and alters the composition of intestine microbiota. Specifically, DIV1 infection decreases the abundance of potentially beneficial bacteria (Bacteroidetes, Firmicutes, and Actinobacteria), and significantly increases the abundance of pathogenic bacteria such as Vibrio and Photobacterium, thereby increasing the risk of secondary bacterial infections. The results of PICRUSt functional prediction showed that altered intestine microbiota induces host metabolism disorders, which could be attributed to the bioenergetic and biosynthetic requirements for DIV1 replication in shrimp. The comparative transcriptomic analysis showed that some metabolic pathways related to host immunity were significantly activated following DIV1 infection, including ncRNA processing and metabolic process, Ascorbate and aldarate metabolism, and Arachidonic acid metabolism. M. ensis may against DIV1 infection by enhancing the expression of some immune-related genes, such as Wnt16, heat shock protein 90 (Hsp90) and C-type lectin 3 (Ctl3). Notably, correlation analysis of intestinal microbial variation with host immunity showed that expansion of pathogenic bacteria (Vibrio and Photobacterium) in DIV1 infection could increased the expression of NF-κB inhibitors cactus-like and Toll interacting protein (Tollip), which may limit the TLR-mediated immune response and ultimately lead to further DIV1 infection.Significance and Impact of the StudyThis study enhances our understanding of the interactions between shrimp immunity and intestinal microbiota. The ultimate goal is to develop novel immune enhancers for shrimp and formulate a safe and effective DIV1 defense strategy.
AlphaFold predicted structure of the Hsp90-like domains of the neurodegeneration linked protein sacsin reveals key residues for ATPase activity
Authors: Perna Laura , Castelli Matteo , Frasnetti Elena , Romano Lisa E. L. , Colombo Giorgio , Prodromou Chrisostomos , Chapple J. Paul 
Published: January 2023

The ataxia-linked protein sacsin has three regions of partial homology to Hsp90’s N-terminal ATP binding domain. Although a crystal structure for this Hsp90-like domain has been reported the precise molecular interactions required for ATP-binding and hydrolysis are unclear and it is debatable whether ATP biding is compatible with these domains. Furthermore, the Identification of a sacsin domain(s) equivalent to the middle domain of Hsp90 has been elusive. Here we present the superimposition of an AlphaFold structure of sacsin with yeast Hsp90, which provides novel insights into sacsin’s structure. We identify residues within the sacsin Hsp90-like domains that are required for ATP binding and hydrolysis, including the putative catalytic arginine residues equivalent to that of the Hsp90 middle domain. Importantly, our analysis allows comparison of the Hsp90 middle domain with corresponding sacsin regions and identifies a shorter lid segment, in the sacsin ATP-binding domains, than the one found in the N-terminal domain of Hsp90. Our results show how a realignment of residues in the lid segment of sacsin that are involved in ATP binding can better match equivalent residues seen in Hsp90, which we then corroborated using molecular dynamic simulations. We speculate, from a structural viewpoint, why some ATP competitive inhibitors of Hsp90 may not bind sacsin, while others would. Together our analysis supports the hypothesis that sacsin’s function is ATP-driven and would be consistent with it having a role as a super molecular chaperone. We propose that the SR1 regions of sacsin be renamed as HSP-NRD (Hsp90 N-Terminal Repeat Domain; residues 84-324) and the fragment immediately after as HSP-MRD (Hsp90 Middle Repeat Domain; residues 325-518).
Case report: Identification of acute promyelocytic leukemia during osimertinib resistance followed by granulocyte colony-stimulating factor and pembrolizumab
Authors: Tian Huohuan , Yang Linhui , Hou Wang , Wu Yu , Dai Yang , Yu Jiang , Liu Dan 
Published: January 2023

BackgroundThe occurrence of acute promyelocytic leukemia (APL) during the management of lung cancer is rare and life-threatening. It was mainly reported to be secondary to chemoradiotherapy. A few studies reported an increased incidence of therapy-related acute promyelocytic leukemia (t-APL) after gefitinib became available.Case presentationWe reported a patient who developed thrombocytopenia after receiving oral osimertinib in combination with intensity-modulated radiotherapy (IMRT). For half a year, she had an unrecoverable low platelet count, which progressed to concomitant leukopenia and the transient appearance of orthochromatic normoblasts in the peripheral blood test, indicating a dormant myeloid disorder. Due to simultaneous resistance to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKI), pembrolizumab and granulocyte colony-stimulating factor (G-CSF) were administered, revealing prominent signs of hematological malignancy in a peripheral blood test that was later identified as t-APL.ConclusionIn general, patients undergoing EGFR-TKI combined with local radiotherapy should be concerned about their hematological assessment. If patients exhibit unrecoverable abnormalities in routine blood tests, a secondary nonsolid malignancy other than myelosuppression should be considered, and further lung cancer treatment should be discontinued.
Study on differentially expressed genes between stage M and stage MS neuroblastoma
Authors: Wu Yuying , Zhang Jun 
Published: January 2023

ObjectiveTo search for the DEGs between stage MS NB and stage M NB and speculate the possible mechanism of spontaneous regression of stage MS NB.Materials and methodsThe NB datasets GSE49710 and GSE45547 in the GEO database were selected to screen the DEGs between children with NB stage MS vs. stage M, &lt; 18 months. GO enrichment and KEGG pathway analysis of DEGs was performed using DAVID. The intersecting genes among DEGs and RCD-related genes were selected, and their survival roles and functions were assessed. We then used the collected clinical samples to validate the expression of these genes at the protein level using IHC methods and further analysis to explore their role.ResultsBIRC5, SLCO4A1, POPDC3, and HK2 were found to be downregulated in stage MS NB and related to apoptosis. BIRC5 and HK2 also participate in autophagy. The TF gene is upregulated in stage MS NB and related to ferroptosis. The above five genes are closely related to the survival of children with NB. And the expression levels of all five genes at the protein level were verified by IHC to be consistent with the results of the preliminary screening described above.ConclusionBIRC5, SLCO4A1, POPDC3, HK2 and TF are expected to become new important indicators to predict the prognosis of NB and can be used as the basis for further explored the benign prognosis and spontaneous regression mechanism of stage MS NB.
The apolipoprotein B and apolipoprotein A-I Ratio serves as a strong prognostic factor for the overall survival of patients with colorectal cancer
Authors: Pan Yangxun , Ye Zhiwei , Ling Yihong , Kong Lingheng , Wang Chenwei , Chen Gong , Wan Desen , Chen Minshan , Hu Dandan 
Published: January 2023

BackgroundThe lipid metabolism status of patients with colorectal cancer (CRC) has not been understood comprehensively. The present study investigated the characteristics of lipid metabolism parameters in CRC patients with or without metastases and identified the independent prognostic factors of long-term prognosis.MethodsThe clinicopathological data of 231 CRC patients along with 259 formalin-fixed paraffin-embedded samples with or without liver or lung metastasis were retrieved and stained for apolipoprotein B (apoB) via immunohistochemistry (IHC) in our center. The correlation and multivariable analysis between blood circulating apolipoprotein A-I (apoA1), apoB and overall survival (OS) were analyzed.ResultsIn the multivariable analysis, apoA1, apoB and apolipoprotein B and apolipoprotein A-I (apoB/A) ratio, were identified as independent prognostic factors for OS. Moreover, the apoB/A ratio showed a significantly negative association with OS time (R=-0.187, P=0.004). CRC patients with low apoB/A ratio had better 1-, 3- and 5-year OS rates than those who had high apoB/A ratio (87.1%, 54.3%, and 37.1% vs. 92.5%, 72.0%, and 59.5%, respectively, P=0.001). On histological level, similar expression intensity of apoB between primary CRC and liver metastases indicated better prognostic outcomes than those with different expression levels (100%, 83.3%, and 77.8% vs. 100%, 66.7%, and 33.3%, respectively; P=0.033). Higher level of apoB in the primary CRC interprets into increased incidence of liver metastases. However, the apoB expression levels in the CRC tumor were not parallel to the circulating lipid metabolism parameters.ConclusionsThe apoB/A ratio was a reliable independent prognostic factor for predicting the long-term OS of CRC patients. Moreover, the IHC of the primary CRC and metastatic lesions verified the metastatic potential of apoB through a different aspect. Lipid metabolism status for cancer progression reported in the present study possessed potentially prognostic value, but bench-scale studies are needed for their future clinical applications.
Prediction of portal dosimetry quality assurance results using log files-derived errors and machine learning techniques
Authors: Lew Kah Seng , Chua Clifford Ghee Ann , Koh Calvin Wei Yang , Lee James Cheow Lei , Park Sung Yong , Tan Hong Qi 
Published: January 2023

ObjectiveThis work aims to use machine learning models to predict gamma passing rate of portal dosimetry quality assurance with log file derived features. This allows daily treatment monitoring for patients and reduce wear and tear on EPID detectors to save cost and prevent downtime.Methods578 VMAT trajectory log files selected from prostate, lung and spine SBRT were used in this work. Four machine learning models were explored to identify the best performing regression model for predicting gamma passing rate within each sub-site and the entire unstratified data. Predictors used in these models comprised of hand-crafted log file-derived features as well as modulation complexity score. Cross validation was used to evaluate the model performance in terms of R2 and RMSE.ResultUsing gamma passing rate of 1%/1mm criteria and entire dataset, LASSO regression has a R2 of 0.121 ± 0.005 and RMSE of 4.794 ± 0.013%, SVM regression has a R2 of 0.605 ± 0.036 and RMSE of 3.210 ± 0.145%, Random Forest regression has a R2 of 0.940 ± 0.019 and RMSE of 1.233 ± 0.197%. XGBoost regression has the best performance with a R2 and RMSE value of 0.981 ± 0.015 and 0.652 ± 0.276%, respectively.ConclusionLog file-derived features can predict gamma passing rate of portal dosimetry with an average error of less than 2% using the 1%/1mm criteria. This model can potentially be applied to predict the patient specific QA results for every treatment fraction.
Distinct cholangiocarcinoma cell migration in 2D monolayer and 3D spheroid culture based on galectin-3 expression and localization
Authors: Sukphokkit Siriwat , Kiatwuthinon Pichamon , Kumkate Supeecha , Janvilisri Tavan 
Published: January 2023

IntroductionCholangiocarcinoma (CCA) is difficult to cure due to its ineffective treatment and advanced stage diagnosis. Thoroughly mechanistic understandings of CCA pathogenesis crucially help improving the treatment success rates. Using three-dimensional (3D) cell culture platform offers several advantages over a traditional two-dimensional (2D) culture as it resembles more closely to in vivo tumor. MethodsHere, we aimed to establish the 3D CCA spheroids with lowly (KKU-100) and highly (KKU-213A) metastatic potentials to investigate the CCA migratory process and its EMT-associated galectin-3 in the 3D setting. Results and discussionFirstly, the growth of lowly metastatic KKU-100 cells was slower than highly metastatic KKU-213A cells in both 2D and 3D systems. Hollow formation was observed exclusively inside the KKU-213A spheroids, not in KKU-100. Additionally, the migration activity of KKU-213A cells was higher than that of KKU-100 cells in both 2D and 3D systems. Besides, altered expression of galectin-3 were observed across all CCA culture conditions with substantial relocalization from inside the 2D cells to the border of spheroids in the 3D system. Notably, the CCA migration was inversely proportional to the galectin-3 expression in the 3D culture, but not in the 2D setting. This suggests the contribution of culture platforms to the alternation of the CCA cell migration process. ConclusionsThus, our data revealed that 3D culture of CCA cells was phenotypically distinct from 2D culture and pointed to the superiority of using the 3D culture model for examining the CCA cellular mechanisms, providing knowledges that are better correlated with CCA phenotypes in vivo.